Processes And Compositions For Methylation-based Enrichment Of Fetal Nucleic Acid From A Maternal Sample Useful For Non-invasive Prenatal Diagnoses

Abstract

Provided are compositions and processes that utilize genomic regions that are differentially methylated between a mother and her fetus to separate, isolate or enrich fetal nucleic acid from a maternal sample. The compositions and processes described herein are particularly useful for non-invasive prenatal diagnostics, including the detection of chromosomal aneuploidies.

Description

RELATED APPLICATIONS

[0001] This patent application claims the benefit of U.S. Provisional Patent Application No. 61/671,628 filed on Jul. 13, 2012, entitled PROCESSES AND COMPOSITIONS FOR METHYLATION-BASED ENRICHMENT OF FETAL NUCLEIC ACID FROM A MATERNAL SAMPLE USEFUL FOR NON-INVASIVE PRENATAL DIAGNOSES, naming John Allen TYNAN and Mengjia TANG as inventors, and designated by Attorney Docket No. SEQ-6022-PV2, and claims the benefit of U.S. Provisional Patent Application No. 61/721,929, filed on Nov. 2, 2012, entitled PROCESSES AND COMPOSITIONS FOR METHYLATION-BASED ENRICHMENT OF FETAL NUCLEIC ACID FROM A MATERNAL SAMPLE USEFUL FOR NON-INVASIVE PRENATAL DIAGNOSES, naming John Allen TYNAN and Grant HOGG as inventors, and designated by Attorney Docket No. SEQ-6022-PV3. The entire content of the foregoing applications are incorporated herein by reference, including all text, tables and drawings.

SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Sep. 3, 2013, is named SEQ-6022-UT2_SL.txt and is 437,311 bytes in size.

FIELD

[0003] The technology in part relates to prenatal diagnostics and enrichment methods.

BACKGROUND

[0004] Non-invasive prenatal testing is becoming a field of rapidly growing interest. Early detection of pregnancy-related conditions, including complications during pregnancy and genetic defects of the fetus is of crucial importance, as it allows early medical intervention necessary for the safety of both the mother and the fetus. Prenatal diagnosis has been conducted using cells isolated from the fetus through procedures such as chorionic villus sampling (CVS) or amniocentesis. However, these conventional methods are invasive and present an appreciable risk to both the mother and the fetus. The National Health Service currently cites a miscarriage rate of between 1 and 2 percent following the invasive amniocentesis and chorionic villus sampling (CVS) tests.

[0005] An alternative to these invasive approaches has been developed for prenatal screening, e.g., to detecting fetal abnormalities, following the discovery that circulating cell-free fetal nucleic acid can be detected in maternal plasma and serum (Lo et al., Lancet 350:485-487, 1997; and U.S. Pat. No. 6,258,540). Circulating cell free fetal nucleic acid (cffNA) has several advantages making it more applicable for non-invasive prenatal testing. For example, cell free nucleic acid is present at higher levels than fetal cells and at concentrations sufficient for genetic analysis. Also, cffNA is cleared from the maternal bloodstream within hours after delivery, preventing contamination from previous pregnancies.

[0006] Examples of prenatal tests performed by detecting fetal DNA in maternal plasma or serum include fetal rhesus D (RhD) genotyping (Lo et al., N. Engl. J. Med. 339:1734-1738, 1998), fetal sex determination (Costa et al., N. Engl. J. Med. 346:1502, 2002), and diagnosis of several fetal disorders (Amicucci et al., Clin. Chem. 46:301-302, 2000; Saito et al., Lancet 356:1170, 2000; and Chiu et al., Lancet 360:998-1000, 2002). In addition, quantitative abnormalities of fetal DNA in maternal plasma/serum have been reported in preeclampsia (Lo et al., Clin. Chem. 45:184-188, 1999 and Zhong et al., Am. J. Obstet. Gynecol. 184:414-419, 2001), fetal trisomy 21 (Lo et al., Clin. Chem. 45:1747-1751, 1999 and Zhong et al., Prenat. Diagn. 20:795-798, 2000) and hyperemesis gravidarum (Sekizawa et al., Clin. Chem. 47:2164-2165, 2001).

SUMMARY

[0007] The technology herein provides inter alia human epigenetic biomarkers that are useful for the noninvasive detection of fetal genetic traits, including, but not limited to, the presence or absence of fetal nucleic acid, the absolute or relative amount of fetal nucleic acid, fetal sex, and fetal chromosomal abnormalities such as aneuploidy. The human epigenetic biomarkers of the technology herein represent genomic DNA that display differential CpG methylation patterns between the fetus and mother. The compositions and processes of the technology herein allow for the detection and quantification of fetal nucleic acid in a maternal sample based on the methylation status of the nucleic acid in said sample. More specifically, the amount of fetal nucleic acid from a maternal sample can be determined relative to the total amount of nucleic acid present, thereby providing the percentage of fetal nucleic acid in the sample. Further, the amount of fetal nucleic acid can be determined in a sequence-specific (or locus-specific) manner and with sufficient sensitivity to allow for accurate chromosomal dosage analysis (for example, to detect the presence or absence of a fetal aneuploidy).

[0008] In the first aspect of the technology herein, a method is provided for enriching fetal nucleic acids from a maternal biological sample, based on differential methylation between fetal and maternal nucleic acid comprising the steps of: (a) binding a target nucleic acid, from a sample, and a control nucleic acid, from the sample, to a methylation-specific binding protein; and (b) eluting the bound nucleic acid based on methylation status, where differentially methylated nucleic acids elute at least partly into separate fractions. In an embodiment, the nucleic acid sequence includes one or more of the polynucleotide sequences of SEQ ID NOs: 1-261. SEQ ID NOs: 1-261 are provided in Tables 4A-4C. The technology herein includes the sequences of SEQ ID NOs: 1-261, and variations thereto. In an embodiment, a control nucleic acid is not included in step (a).

[0009] In a related embodiment, a method is provided for enriching fetal nucleic acid from a maternal sample, which comprises the following steps: (a) obtaining a biological sample from a woman; (b) separating fetal and maternal nucleic acid based on the methylation status of a CpG-containing genomic sequence in the sample, where the genomic sequence from the fetus and the genomic sequence from the woman are differentially methylated, thereby distinguishing the genomic sequence from the woman and the genomic sequence from the fetus in the sample. In an embodiment, the genomic sequence is at least 15 nucleotides in length, comprising at least one cytosine, further where the region consists of (1) a genomic locus selected from Tables 1A-1C; and (2) a DNA sequence of no more than 10 kb upstream and/or downstream from the locus. For this aspect and all aspects of the technology herein, obtaining a biological sample from a woman is not meant to limit the scope of the technology herein. Said obtaining can refer to actually drawing a sample from a woman (e.g., a blood draw) or to receiving a sample from elsewhere (e.g., from a clinic or hospital) and performing the remaining steps of the method.

[0010] In a related embodiment, a method is provided for enriching fetal nucleic acid from a maternal sample, which comprises the following steps: (a) obtaining a biological sample from the woman; (b) digesting or removing maternal nucleic acid based on the methylation status of a CpG-containing genomic sequence in the sample, where the genomic sequence from the fetus and the genomic sequence from the woman are differentially methylated, thereby enriching for the genomic sequence from the fetus in the sample. Maternal nucleic acid may be digested using one or more methylation sensitive restriction enzymes that selectively digest or cleave maternal nucleic acid based on its methylation status. In an embodiment, the genomic sequence is at least 15 nucleotides in length, comprising at least one cytosine, further where the region consists of (1) a genomic locus selected from Tables 1A-1C; and (2) a DNA sequence of no more than 10 kb upstream and/or downstream from the locus.

[0011] In a second aspect of the technology herein, a method is provided for preparing nucleic acid having a nucleotide sequence of a fetal nucleic acid, which comprises the following steps: (a) providing a sample from a pregnant female; (b) separating fetal nucleic acid from maternal nucleic acid from the sample of the pregnant female according to a different methylation state between the fetal nucleic acid and the maternal nucleic acid counterpart, where the nucleotide sequence of the fetal nucleic acid comprises one or more CpG sites from one or more of the polynucleotide sequences of SEQ ID NOs: 1-261 within a polynucleotide sequence from a gene or locus that contains one of the polynucleotide sequences of SEQ ID NOs: 1-261; and (c) preparing nucleic acid comprising a nucleotide sequence of the fetal nucleic acid by an amplification process in which fetal nucleic acid separated in part (b) is utilized as a template. In an embodiment, a method is provided for preparing nucleic acid having a nucleotide sequence of a fetal nucleic acid, which comprises the following steps: (a) providing a sample from a pregnant female; (b) digesting or removing maternal nucleic acid from the sample of the pregnant female according to a different methylation state between the fetal nucleic acid and the maternal nucleic acid counterpart, where the nucleotide sequence of the fetal nucleic acid comprises one or more CpG sites from one or more of the polynucleotide sequences of SEQ ID NOs: 1-261 within a polynucleotide sequence from a gene that contains one of the polynucleotide sequences of SEQ ID NOs: 1-261; and (c) preparing nucleic acid comprising a nucleotide sequence of the fetal nucleic acid. The preparing process of step (c) may be a hybridization process, a capture process, or an amplification process in which fetal nucleic acid separated in part (b) is utilized as a template. Also, in the above embodiment where maternal nucleic acid is digested, the maternal nucleic acid may be digested using one or more methylation sensitive restriction enzymes that selectively digest or cleave maternal nucleic acid based on its methylation status. In either embodiment, the polynucleotide sequences of SEQ ID NOs: 1-261 may be within a polynucleotide sequence from a CpG island that contains one of the polynucleotide sequences of SEQ ID NOs: 1-261. The polynucleotide sequences of SEQ ID NOs: 1-261 are further characterized in Tables 1-3 herein, including the identification of CpG islands that overlap with the polynucleotide sequences provided in SEQ ID NOs: 1-261. In an embodiment, the nucleic acid prepared by part (c) is in solution. In yet an embodiment, the method further comprises quantifying the fetal nucleic acid from the amplification process of step (c).

[0012] In a third aspect of the technology herein, a method is provided for enriching fetal nucleic acid from a sample from a pregnant female with respect to maternal nucleic acid, which comprises the following steps: (a) providing a sample from a pregnant female; and (b) separating or capturing fetal nucleic acid from maternal nucleic acid from the sample of the pregnant female according to a different methylation state between the fetal nucleic acid and the maternal nucleic acid, where the nucleotide sequence of the fetal nucleic acid comprises one or more CpG sites from one or more of the polynucleotide sequences of SEQ ID NOs: 1-261 within a polynucleotide sequence from a gene that contains one of the polynucleotide sequences of SEQ ID NOs: 1-261. In an embodiment, the polynucleotide sequences of SEQ ID NOs: 1-261 may be within a polynucleotide sequence from a CpG island that contains one of the polynucleotide sequences of SEQ ID NOs: 1-261. The polynucleotide sequences of SEQ ID NOs: 1-261 are characterized in Tables 1A-1C herein. In an embodiment, the nucleic acid separated by part (b) is in solution. In yet an embodiment, the method further comprises amplifying and/or quantifying the fetal nucleic acid from the separation process of step (b).

[0013] In a fourth aspect of the technology herein, a composition is provided comprising an isolated nucleic acid from a fetus of a pregnant female, where the nucleotide sequence of the nucleic acid comprises one or more of the polynucleotide sequences of SEQ ID NOs: 1-261. In one embodiment, the nucleotide sequence consists essentially of a nucleotide sequence of a gene, or portion thereof. In an embodiment, the nucleotide sequence consists essentially of a nucleotide sequence of a CpG island, or portion thereof. The polynucleotide sequences of SEQ ID NOs: 1-261 are further characterized in Tables 1A-1C. In an embodiment, the nucleic acid is in solution. In an embodiment, the nucleic acid from the fetus is enriched relative to maternal nucleic acid. In an embodiment, the composition further comprises an agent that binds to methylated nucleotides. For example, the agent may be a methyl-CpG binding protein (MBD) or fragment thereof.

[0014] In a fifth aspect of the technology herein, a composition is provided comprising an isolated nucleic acid from a fetus of a pregnant female, where the nucleotide sequence of the nucleic acid comprises one or more CpG sites from one or more of the polynucleotide sequences of SEQ ID NOs: 1-261 within a polynucleotide sequence from a gene, or portion thereof, that contains one of the polynucleotide sequences of SEQ ID NOs: 1-261. In an embodiment, the nucleotide sequence of the nucleic acid comprises one or more CpG sites from one or more of the polynucleotide sequences of SEQ ID NOs: 1-261 within a polynucleotide sequence from a CpG island, or portion thereof, that contains one of the polynucleotide sequences of SEQ ID NOs: 1-261. The polynucleotide sequences of SEQ ID NOs: 1-261 are further characterized in Tables 1A-1C. In an embodiment, the nucleic acid is in solution. In an embodiment, the nucleic acid from the fetus is enriched relative to maternal nucleic acid. Hyper- and hypomethylated nucleic acid sequences of the technology herein are identified in Tables 1A-1C. In an embodiment, the composition further comprises an agent that binds to methylated nucleotides. For example, the agent may be a methyl-CpG binding protein (MBD) or fragment thereof.

[0015] In some embodiments, a nucleotide sequence of the technology herein includes three or more of the CpG sites. In an embodiment, the nucleotide sequence includes five or more of the CpG sites. In an embodiment, the nucleotide sequence is from a gene region that comprises a PRC2 domain (see Table 3). In an embodiment, the nucleotide sequence is from a gene region involved with development. For example, SOX14--which is an epigenetic marker of the present technology (See Table 1A)--is a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of cell fate.

[0016] In some embodiments, the genomic sequence from the woman is methylated and the genomic sequence from the fetus is unmethylated. In other embodiments, the genomic sequence from the woman is unmethylated and the genomic sequence from the fetus is methylated. In an embodiment, the genomic sequence from the fetus is hypermethylated relative to the genomic sequence from the mother. Fetal genomic sequences found to be hypermethylated relative to maternal genomic sequence are provided in SEQ ID NOs: 1-59, 90-163, 176, 179, 180, 184, 188, 189, 190, 191, 193, 195, 198, 199, 200, 201, 202, 203, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 221, 223, 225, 226, 231, 232, 233, 235, 239, 241, 257, 258, 259, and 261. Alternatively, the genomic sequence from the fetus is hypomethylated relative to the genomic sequence from the mother. Fetal genomic sequences found to be hypomethylated relative to maternal genomic sequence are provided in SEQ ID NOs: 60-85, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 177, 178, 181, 182, 183, 185, 186, 187, 192, 194, 196, 197, 204, 215, 216, 217, 218, 219, 220, 222, 224, 227, 228, 229, 230, 234, 236, 237, 238, 240, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, and 260. Methylation sensitive restriction enzymes of the technology herein may be sensitive to hypo- or hyper-methylated nucleic acid.

[0017] In an embodiment, the fetal nucleic acid is extracellular nucleic acid. Generally the extracellular fetal nucleic acid is about 500, 400, 300, 250, 200 or 150 (or any number there between) nucleotide bases or less. In an embodiment, the digested maternal nucleic acid is less than about 90, 100, 110, 120, 130, 140 or 150 base pairs. In a related embodiment, the fetal nucleic acid is selectively amplified, captured or separated from or relative to the digested maternal nucleic acid based on size. For example, PCR primers may be designed to amplify nucleic acid greater than about 75, 80, 85, 90, 95, 100, 105, 110, 115 or 120 (or any number there between) base pairs thereby amplifying fetal nucleic acid and not digested maternal nucleic acid. In an embodiment, the nucleic acid is subjected to fragmentation prior to the methods of the technology herein. Examples of methods of fragmenting nucleic acid, include but are not limited to sonication and restriction enzyme digestion. In some embodiments the fetal nucleic acid is derived from the placenta. In other embodiments the fetal nucleic acid is apoptotic.

[0018] In some embodiments, the present technology provides a method in which the sample is a member selected from the following: maternal whole blood, maternal plasma or serum, amniotic fluid, a chorionic villus sample, biopsy material from a pre-implantation embryo, fetal nucleated cells or fetal cellular remnants isolated from maternal blood, maternal urine, maternal saliva, washings of the female reproductive tract and a sample obtained by celocentesis or lung lavage. In certain embodiments, the biological sample is maternal blood. In some embodiments, the biological sample is a chorionic villus sample. In certain embodiments, the maternal sample is enriched for fetal nucleic acid prior to the methods of the present technology. Examples of fetal enrichment methods are provided in PCT Publication Nos. WO/2007140417A2, WO2009/032781A2 and US Publication No. 20050164241.

[0019] In some embodiments, all nucleated and anucleated cell populations are removed from the sample prior to practicing the methods of the technology herein. In some embodiments, the sample is collected, stored or transported in a manner known to the person of ordinary skill in the art to minimize degradation or the quality of fetal nucleic acid present in the sample.

[0020] The sample can be from any animal, including but not limited, human, non-human, mammal, reptile, cattle, cat, dog, goat, swine, pig, monkey, ape, gorilla, bull, cow, bear, horse, sheep, poultry, mouse, rat, fish, dolphin, whale, and shark, or any animal or organism that may have a detectable pregnancy-associated disorder or chromosomal abnormality.

[0021] In some embodiments, the sample is treated with a reagent that differentially modifies methylated and unmethylated DNA. For example, the reagent may comprise bisulfite; or the reagent may comprise one or more enzymes that preferentially cleave methylated DNA; or the reagent may comprise one or more enzymes that preferentially cleave unmethylated DNA. Examples of methylation sensitive restriction enzymes include, but are not limited to, HhaI and HpaII.

[0022] In one embodiment, the fetal nucleic acid is separated from the maternal nucleic acid by an agent that specifically binds to methylated nucleotides in the fetal nucleic acid. In an embodiment, the fetal nucleic acid is separated or removed from the maternal nucleic acid by an agent that specifically binds to methylated nucleotides in the maternal nucleic acid counterpart. In an embodiment, the agent that binds to methylated nucleotides is a methyl-CpG binding protein (MBD) or fragment thereof.

[0023] In a sixth aspect of the technology herein, a method is provided for determining the amount or copy number of fetal DNA in a maternal sample that comprises differentially methylated maternal and fetal DNA. The method is performed by a) distinguishing between the maternal and fetal DNA based on differential methylation status; and b) quantifying the fetal DNA of step a). In a specific embodiment, the method comprises a) digesting the maternal DNA in a maternal sample using one or more methylation sensitive restriction enzymes thereby enriching the fetal DNA; and b) determining the amount of fetal DNA from step a). The amount of fetal DNA can be used inter alia to confirm the presence or absence of fetal nucleic acid, determine fetal sex, diagnose fetal disease or a pregnancy-associated disorder, or be used in conjunction with other fetal diagnostic methods to improve sensitivity or specificity. In one embodiment, the method for determining the amount of fetal DNA does not require the use of a polymorphic sequence. For example, an allelic ratio is not used to quantify the fetal DNA in step b). In an embodiment, the method for determining the amount of fetal DNA does not require the treatment of DNA with bisulfite to convert cytosine residues to uracil. Bisulfite is known to degrade DNA, thereby, further reducing the already limited fetal nucleic acid present in maternal samples. In one embodiment, determining the amount of fetal DNA in step b) is done by introducing one or more competitors at known concentrations. In an embodiment, determining the amount of fetal DNA in step b) is done by RT-PCR, primer extension, sequencing or counting. In a related embodiment, the amount of nucleic acid is determined using BEAMing technology as described in US Patent Publication No. US20070065823. In another related embodiment, the amount of nucleic acid is determined using the shotgun sequencing technology described in US Patent Publication No. US20090029377 (U.S. application Ser. No. 12/178,181), or variations thereof. In an embodiment, the restriction efficiency is determined and the efficiency rate is used to further determine the amount of fetal DNA. Exemplary differentially methylated nucleic acids are provided in SEQ ID NOs: 1-261.

[0024] In a seventh aspect of the technology herein, a method is provided for determining the concentration of fetal DNA in a maternal sample, where the maternal sample comprises differentially methylated maternal and fetal DNA, comprising a) determining the total amount of DNA present in the maternal sample; b) selectively digesting the maternal DNA in a maternal sample using one or more methylation sensitive restriction enzymes thereby enriching the fetal DNA; c) determining the amount of fetal DNA from step b); and d) comparing the amount of fetal DNA from step c) to the total amount of DNA from step a), thereby determining the concentration of fetal DNA in the maternal sample. The concentration of fetal DNA can be used inter alia in conjunction with other fetal diagnostic methods to improve sensitivity or specificity. In one embodiment, the method for determining the amount of fetal DNA does not require the use of a polymorphic sequence. For example, an allelic ratio is not used to quantify the fetal DNA in step b). In an embodiment, the method for determining the amount of fetal DNA does not require the treatment of DNA with bisulfite to convert cytosine residues to uracil. In one embodiment, determining the amount of fetal DNA in step b) is done by introducing one or more competitors at known concentrations. In an embodiment, determining the amount of fetal DNA in step b) is done by RT-PCR, sequencing or counting. In an embodiment, the restriction efficiency is determined and used to further determine the amount of total DNA and fetal DNA. Exemplary differentially methylated nucleic acids are provided in SEQ ID NOs: 1-261.

[0025] In an eighth aspect of the technology herein, a method is provided for determining the presence or absence of a fetal aneuploidy using fetal DNA from a maternal sample, where the maternal sample comprises differentially methylated maternal and fetal DNA, comprising a) selectively digesting the maternal DNA in a maternal sample using one or more methylation sensitive restriction enzymes thereby enriching the fetal DNA; b) determining the amount of fetal DNA from a target chromosome; c) determining the amount of fetal DNA from a reference chromosome; and d) comparing the amount of fetal DNA from step b) to step c), where a biologically or statistically significant difference between the amount of target and reference fetal DNA is indicative of the presence of a fetal aneuploidy. In one embodiment, the method for determining the amount of fetal DNA does not require the use of a polymorphic sequence. For example, an allelic ratio is not used to quantify the fetal DNA in step b). In an embodiment, the method for determining the amount of fetal DNA does not require the treatment of DNA with bisulfite to convert cytosine residues to uracil. In one embodiment, determining the amount of fetal DNA in steps b) and c) is done by introducing one or more competitors at known concentrations. In an embodiment, determining the amount of fetal DNA in steps b) and c) is done by RT-PCR, sequencing or counting. In an embodiment, the amount of fetal DNA from a target chromosome determined in step b) is compared to a standard control, for example, the amount of fetal DNA from a target chromosome from euploid pregnancies. In an embodiment, the restriction efficiency is determined and used to further determine the amount of fetal DNA from a target chromosome and from a reference chromosome. Exemplary differentially methylated nucleic acids are provided in SEQ ID NOs: 1-261.

[0026] In a ninth aspect of the technology herein, a method is provided for detecting the presence or absence of a chromosomal abnormality by analyzing the amount or copy number of target nucleic acid and control nucleic acid from a sample of differentially methylated nucleic acids comprising the steps of: (a) enriching a target nucleic acid, from a sample, and a control nucleic acid, from the sample, based on its methylation state; (b) performing a copy number analysis of the enriched target nucleic acid in at least one of the fractions; (c) performing a copy number analysis of the enriched control nucleic acid in at least one of the fractions; (d) comparing the copy number from step (b) with the copy number from step (c); and (e) determining if a chromosomal abnormality exists based on the comparison in step (d), where the target nucleic acid and control nucleic acid have the same or substantially the same methylation status. In a related embodiment, a method is provided for detecting the presence or absence of a chromosomal abnormality by analyzing the amount or copy number of target nucleic acid and control nucleic acid from a sample of differentially methylated nucleic acids comprising the steps of: (a) binding a target nucleic acid, from a sample, and a control nucleic acid, from the sample, to a binding agent; (b) eluting the bound nucleic acid based on methylation status, where differentially methylated nucleic acids elute at least partly into separate fractions; (c) performing a copy number analysis of the eluted target nucleic acid in at least one of the fractions; (d) performing a copy number analysis of the eluted control nucleic acid in at least one of the fractions; (e) comparing the copy number from step (c) with the copy number from step (d); and (f) determining if a chromosomal abnormality exists based on the comparison in step (e), where the target nucleic acid and control nucleic acid have the same or substantially the same methylation status. Differentially methylated nucleic acids are provided in SEQ ID NOs: 1-261.

[0027] In a tenth aspect of the technology herein, a method is provided for detecting the presence or absence of a chromosomal abnormality by analyzing the allelic ratio of target nucleic acid and control nucleic acid from a sample of differentially methylated nucleic acids comprising the steps of: (a) binding a target nucleic acid, from a sample, and a control nucleic acid, from the sample, to a binding agent; (b) eluting the bound nucleic acid based on methylation status, where differentially methylated nucleic acids elute at least partly into separate fractions; (c) performing an allelic ratio analysis of the eluted target nucleic acid in at least one of the fractions; (d) performing an allelic ratio analysis of the eluted control nucleic acid in at least one of the fractions; (e) comparing the allelic ratio from step c with the all from step d; and (f) determining if a chromosomal abnormality exists based on the comparison in step (e), where the target nucleic acid and control nucleic acid have the same or substantially the same methylation status. Differentially methylated nucleic acids are provided in SEQ ID NOs: 1-261, and SNPs within the differentially methylated nucleic acids are provided in Table 2. The methods may also be useful for detecting a pregnancy-associated disorder.

[0028] In an eleventh aspect of the technology herein, the amount of maternal nucleic acid is determined using the methylation-based methods of the technology herein. For example, fetal nucleic acid can be separated (for example, digested using a methylation-sensitive enzyme) from the maternal nucleic acid in a sample, and the maternal nucleic acid can be quantified using the methods of the technology herein. Once the amount of maternal nucleic acid is determined, that amount can subtracted from the total amount of nucleic acid in a sample to determine the amount of fetal nucleic acid. The amount of fetal nucleic acid can be used to detect fetal traits, including fetal aneuploidy, as described herein.

[0029] For all aspects and embodiments of the technology described herein, the methods may also be useful for detecting a pregnancy-associated disorder. In some embodiments, the sample comprises fetal nucleic acid, or fetal nucleic acid and maternal nucleic acid. In the case when the sample comprises fetal and maternal nucleic acid, the fetal nucleic acid and the maternal nucleic acid may have a different methylation status. Nucleic acid species with a different methylation status can be differentiated by any method known in the art. In an embodiment, the fetal nucleic acid is enriched by the selective digestion of maternal nucleic acid by a methylation sensitive restriction enzyme. In an embodiment, the fetal nucleic acid is enriched by the selective digestion of maternal nucleic acid using two or more methylation sensitive restriction enzymes in the same assay. In an embodiment, the target nucleic acid and control nucleic acid are both from the fetus. In an embodiment, the average size of the fetal nucleic acid is about 100 bases to about 500 bases in length. In an embodiment the chromosomal abnormality is an aneuploidy, such as trisomy 21. In some embodiments, the target nucleic acid is at least a portion of a chromosome which may be abnormal and the control nucleic acid is at least a portion of a chromosome which is very rarely abnormal. For example, when the target nucleic acid is from chromosome 21, the control nucleic acid is from a chromosome other than chromosome 21--preferably another autosome. In an embodiment, the binding agent is a methylation-specific binding protein such as MBD-Fc. Also, the enriched or eluted nucleic acid is amplified and/or quantified by any method known in the art. In an embodiment, the fetal DNA is quantified using a method that does not require the use of a polymorphic sequence. For example, an allelic ratio is not used to quantify the fetal DNA. In an embodiment, the method for quantifying the amount of fetal DNA does not require the treatment of DNA with bisulfite to convert cytosine residues to uracil.

[0030] In some embodiments, the methods of the technology herein include the additional step of determining the amount of one or more Y-chromosome-specific sequences in a sample. In a related embodiment, the amount of fetal nucleic acid in a sample as determined by using the methylation-based methods of the technology herein is compared to the amount of Y-chromosome nucleic acid present.

[0031] Methods for differentiating nucleic acid based on methylation status include, but are not limited to, methylation sensitive capture, for example using, MBD2-Fc fragment; bisulfite conversion methods, for example, MSP (methylation-sensitive PCR), COBRA, methylation-sensitive single nucleotide primer extension (Ms-SNuPE) or Sequenom MassCLEAVE.TM. technology; and the use of methylation sensitive restriction enzymes. Except where explicitly stated, any method for differentiating nucleic acid based on methylation status can be used with the compositions and methods of the technology herein.

[0032] In some embodiments, methods of the technology herein may further comprise an amplification step. The amplification step can be performed by PCR, such as methylation-specific PCR. In an embodiment, the amplification reaction is performed on single molecules, for example, by digital PCR, which is further described in U.S. Pat. Nos. 6,143,496 and 6,440,706, both of which are hereby incorporated by reference. In other embodiments, the method does not require amplification. For example, the amount of enriched fetal DNA may be determined by counting the fetal DNA (or sequence tags attached thereto) with a flow cytometer or by sequencing means that do not require amplification. In an embodiment, the amount of fetal DNA is determined by an amplification reaction that generates amplicons larger than the digested maternal nucleic acid, thereby further enriching the fetal nucleic acid.

[0033] In some embodiments, the fetal nucleic acid (alone or in combination with the maternal nucleic acid) comprises one or more detection moieties. In one embodiment, the detection moiety may be any one or more of a compomer, sugar, peptide, protein, antibody, chemical compound (e.g., biotin), mass tag (e.g., metal ions or chemical groups), fluorescent tag, charge tag (e.g., such as polyamines or charged dyes) and hydrophobic tag. In a related embodiment, the detection moiety is a mass-distinguishable product (MDP) or part of an MDP detected by mass spectrometry. In a specific embodiment, the detection moiety is a fluorescent tag or label that is detected by mass spectrometry. In some embodiments, the detection moiety is at the 5' end of a detector oligonucleotide, the detection moiety is attached to a non-complementary region of a detector oligonucleotide, or the detection moiety is at the 5' terminus of a non-complementary sequence. In certain embodiments, the detection moiety is incorporated into or linked to an internal nucleotide or to a nucleotide at the 3' end of a detector oligonucleotide. In some embodiments, one or more detection moieties are used either alone or in combination. See for example US Patent Applications US20080305479 and US20090111712. In certain embodiments, a detection moiety is cleaved by a restriction endonuclease, for example, as described in U.S. application Ser. No. 12/726,246. In some embodiments, a specific target chromosome is labeled with a specific detection moiety and one or more non-target chromosomes are labeled with a different detection moiety, whereby the amount target chromsome can be compared to the amount of non-target chromosome.

[0034] For embodiments that require sequence analysis, any one of the following sequencing technologies may be used: a primer extension method (e.g., iPLEX.RTM.; Sequenom, Inc.), direct DNA sequencing, restriction fragment length polymorphism (RFLP analysis), real-time PCR, for example using "STAR" (Scalable Transcription Analysis Routine) technology (see U.S. Pat. No. 7,081,339), or variations thereof, allele specific oligonucleotide (ASO) analysis, methylation-specific PCR (MSPCR), pyrosequencing analysis, acycloprime analysis, Reverse dot blot, GeneChip microarrays, Dynamic allele-specific hybridization (DASH), Peptide nucleic acid (PNA) and locked nucleic acids (LNA) probes, TaqMan, Molecular Beacons, Intercalating dye, FRET primers, fluorescence tagged dNTP/ddNTPs, AlphaScreen, SNPstream, genetic bit analysis (GBA), Multiplex minisequencing, SNaPshot, GOOD assay, Microarray miniseq, arrayed primer extension (APEX), Microarray primer extension, Tag arrays, Coded microspheres, Template-directed incorporation (TDI), fluorescence polarization, Colorimetric oligonucleotide ligation assay (OLA), Sequence-coded OLA, Microarray ligation, Ligase chain reaction, Padlock probes, Invader.TM. assay, hybridization using at least one probe, hybridization using at least one fluorescently labeled probe, electrophoresis, cloning and sequencing, for example as performed on the 454 platform (Roche) (Margulies, M. et al. 2005 Nature 437, 376-380), IIlumina Genome Analyzer (or Solexa platform) or SOLiD System (Applied Biosystems) or the Helicos True Single Molecule DNA sequencing technology (Harris T D et al. 2008 Science, 320, 106-109), the single molecule, real-time (SMRT.TM.) technology of Pacific Biosciences, or nanopore-based sequencing (Soni G V and Meller A. 2007 Clin Chem 53: 1996-2001), for example, using an Ion Torrent ion sensor that measures an electrical charge associated with each individual base of DNA as each base passes through a tiny pore at the bottom of a sample well, or Oxford Nanopore device that uses a nanopore to measure the electrical charge associated with each individual unit of DNA, and combinations thereof. Nanopore-based methods may include sequencing nucleic acid using a nanopore, or counting nucleic acid molecules using a nanopore, for example, based on size where sequence information is not determined.

[0035] The absolute copy number of one or more nucleic acids can be determined, for example, using mass spectrometry, a system that uses a competitive PCR approach for absolute copy number measurements. See for example, Ding C, Cantor CR (2003) A high-throughput gene expression analysis technique using competitive PCR and matrix-assisted laser desorption ionization time-of-flight MS. Proc Natl Acad Sci USA 100:3059-3064, and U.S. patent application Ser. No. 10/655,762, which published as US Patent Publication No. 20040081993, both of which are hereby incorporated by reference.

[0036] In some embodiments, the amount of the genomic sequence is compared with a standard control, where an increase or decrease from the standard control indicates the presence or progression of a pregnancy-associated disorder. For example, the amount of fetal nucleic acid may be compared to the total amount of DNA present in the sample. Or when detecting the presence or absence of fetal aneuploidy, the amount of fetal nucleic acid from target chromosome may be compared to the amount of fetal nucleic acid from a reference chromosome. Preferably the reference chromosome is another autosome that has a low rate of aneuploidy. The ratio of target fetal nucleic acid to reference fetal nucleic acid may be compared to the same ratio from a normal, euploid pregnancy. For example, a control ratio may be determined from a DNA sample obtained from a female carrying a healthy fetus who does not have a chromosomal abnormality. Preferably, one uses a panel of control samples. Where certain chromosome anomalies are known, one can also have standards that are indicative of a specific disease or condition. Thus, for example, to screen for three different chromosomal aneuploidies in a maternal plasma of a pregnant female, one preferably uses a panel of control DNAs that have been isolated from mothers who are known to carry a fetus with, for example, chromosome 13, 18, or 21 trisomy, and a mother who is pregnant with a fetus who does not have a chromosomal abnormality.

[0037] In some embodiments, the present technology provides a method in which the alleles from the target nucleic acid and control nucleic acid are differentiated by sequence variation. The sequence variation may be a single nucleotide polymorphism (SNP) or an insertion/deletion polymorphism. In some embodiments, the fetal nucleic acid should comprise at least one high frequency heterozygous polymorphism (e.g., about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 35%, 40%, 45%, 50%, 55%, 60% or more frequency rate), which allows the determination of the allelic-ratio of the nucleic acid in order to assess the presence or absence of the chromosomal abnormality. Lists of example SNPs are provided in Table 2, Table 9 and Table 10, however, these do not represent a complete list of polymorphic alleles that can be used as part of the technology herein. In some embodiments, any SNP meeting the following criteria, for example, may also be considered: (a) the SNP has a heterozygosity frequency greater than about 2% (preferably across a range of different populations), (b) the SNP is a heterozygous locus; and (c)(i) the SNP is within a nucleic acid sequence described herein, or (c)(iii) the SNP is within about 5 to about 2000 base pairs of a SNP described herein (e.g., within about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1250, 1500, 1750 or 2000 base pairs of a SNP described herein). In some cases, SNPs are selected by other criteria described in further detail herein.

[0038] In other embodiments, the sequence variation is a short tandem repeat (STR) polymorphism. In some embodiments, the sequence variation falls in a restriction site, whereby one allele is susceptible to digestion by a restriction enzyme and the one or more other alleles are not. In some embodiments, the sequence variation is a methylation site.

[0039] In some embodiments, performing an allelic ratio analysis comprises determining the ratio of alleles of the target nucleic acid and control nucleic acid from the fetus of a pregnant woman by obtaining an nucleic acid-containing biological sample from the pregnant woman, where the biological sample contains fetal nucleic acid, partially or wholly separating the fetal nucleic acid from the maternal nucleic acid based on differential methylation, discriminating the alleles from the target nucleic acid and the control nucleic acid, followed by determination of the ratio of the alleles, and detecting the presence or absence of a chromosomal disorder in the fetus based on the ratio of alleles, where a ratio above or below a normal, euploid ratio is indicative of a chromosomal disorder. In one embodiment, the target nucleic acid is from a suspected aneuploid chromosome (e.g., chromosome 21) and the control nucleic acid is from a euploid chromosome from the same fetus.

[0040] In some embodiments, the present technology is combined with other fetal markers to detect the presence or absence of multiple chromosomal abnormalities, where the chromosomal abnormalities are selected from the following: trisomy 21, trisomy 18 and trisomy 13, or combinations thereof. In some embodiments, the chromosomal disorder involves the X chromosome or the Y chromosome.

[0041] In some embodiments, the compositions or processes may be multiplexed in a single reaction. For example, the amount of fetal nucleic acid may be determined at multiple loci across the genome. Or when detecting the presence or absence of fetal aneuploidy, the amount of fetal nucleic acid may be determined at multiple loci on one or more target chromosomes (e.g., chromosomes 13, 18 or 21) and on one or more reference chromosomes. If an allelic ratio is being used, one or more alleles from Table 2, Table 9, and/or Table 10 can be detected and discriminated simultaneously. When determining allelic ratios, multiplexing embodiments are particularly important when the genotype at a polymorphic locus is not known. In some instances, for example when the mother and child are homozygous at the polymorphic locus, the assay may not be informative. In one embodiment, greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 100, 200, 300 or 500, and any intermediate levels, polynucleotide sequences of the technology herein are enriched, separated and/or examined according the methods of the technology. When detecting a chromosomal abnormality by analyzing the copy number of target nucleic acid and control nucleic acid, less than 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 polynucleotide sequences may need to be analyzed to accurately detect the presence or absence of a chromosomal abnormality. In an embodiment, the compositions or processes of the technology herein may be used to assay samples that have been divided into 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 100 or more replicates, or into single molecule equivalents. Methods for analyzing fetal nucleic acids from a maternal sample in replicates, including single molecule analyses, are provided in U.S. application Ser. No. 11/364,294, which published as US Patent Publication No. US 2007-0207466 A1, which is hereby incorporated by reference.

[0042] In a further embodiment, the present technology provides a method where a comparison step shows an increased risk of a fetus having a chromosomal disorder if the ratio of the alleles or absolute copy number of the target nucleic acid is higher or lower by 1 standard deviation from the standard control sequence. In some embodiments, the comparison step shows an increased risk of a fetus having a chromosomal disorder if the ratio of the alleles or absolute copy number of the target nucleic acid is higher or lower by 2 standard deviations from the standard control sequence. In some other embodiments, the comparison step shows an increased risk of a fetus having a chromosomal disorder if the ratio of the alleles or absolute copy number of the target nucleic acid is higher or lower by 3 standard deviations from the standard control sequence. In some embodiments, the comparison step shows an increased risk of a fetus having a chromosomal disorder if the ratio of the alleles or absolute copy number of the target nucleic acid is higher or lower than a statistically significant standard deviation from the control. In one embodiment, the standard control is a maternal reference, and in an embodiment the standard control is a fetal reference chromosome (e.g., non-trisomic autosome).

[0043] In some embodiments, the methods of the technology herein may be combined with other methods for diagnosing a chromosomal abnormality. For example, a noninvasive diagnostic method may require confirmation of the presence or absence of fetal nucleic acid, such as a sex test for a female fetus or to confirm an RhD negative female fetus in an RhD negative mother. In an embodiment, the compositions and methods of the technology herein may be used to determine the percentage of fetal nucleic acid in a maternal sample in order to enable another diagnostic method that requires the percentage of fetal nucleic acid be known. For example, does a sample meet certain threshold concentration requirements? When determining an allelic ratio to diagnose a fetal aneuploidy from a maternal sample, the amount or concentration of fetal nucleic acid may be required to make a diagnose with a given sensitivity and specificity. In other embodiments, the compositions and methods of the technology herein for detecting a chromosomal abnormality can be combined with other known methods thereby improving the overall sensitivity and specificity of the detection method. For example, mathematical models have suggested that a combined first-trimester screening program utilizing maternal age (MA), nuchal translucency (NT) thickness, serum-free beta-hCG, and serum PAPP-A will detect more than 80% of fetuses with Down's syndrome for a 5% invasive testing rate (Wald and Hackshaw, Prenat Diagn 17(9):921-9 (1997)). However, the combination of commonly used aneuploidy detection methods combined with the non-invasive free fetal nucleic acid-based methods described herein may offer improved accuracy with a lower false positive rate. Examples of combined diagnostic methods are provided in PCT Publication Number WO2008157264A2 (assigned to the Applicant), which is hereby incorporated by reference. In some embodiments, the methods of the technology herein may be combined with cell-based methods, where fetal cells are procured invasively or non-invasively.

[0044] In certain embodiments, an increased risk for a chromosomal abnormality is based on the outcome or result(s) produced from the compositions or methods provided herein. An example of an outcome is a deviation from the euploid absolute copy number or allelic ratio, which indicates the presence of chromosomal aneuploidy. This increase or decrease in the absolute copy number or ratio from the standard control indicates an increased risk of having a fetus with a chromosomal abnormality (e.g., trisomy 21). Information pertaining to a method described herein, such as an outcome, result, or risk of trisomy or aneuploidy, for example, may be transfixed, renditioned, recorded and/or displayed in any suitable medium. For example, an outcome may be transfixed in a medium to save, store, share, communicate or otherwise analyze the outcome. A medium can be tangible (e.g., paper) or intangible (e.g., electronic medium), and examples of media include, but are not limited to, computer media, databases, charts, patient charts, records, patient records, graphs and tables, and any other medium of expression. The information sometimes is stored and/or renditioned in computer readable form and sometimes is stored and organized in a database. In certain embodiments, the information may be transferred from one location to another using a physical medium (e.g., paper) or a computer readable medium (e.g., optical and/or magnetic storage or transmission medium, floppy disk, hard disk, random access memory, computer processing unit, facsimile signal, satellite signal, transmission over an internet or transmission over the world-wide web).

[0045] In practicing the present technology within all aspects mentioned above, a CpG island may be used as the CpG-containing genomic sequence in some cases, whereas in other cases the CpG-containing genomic sequence may not be a CpG island.

[0046] In some embodiments, the present technology provides a kit for performing the methods of the technology. One component of the kit is a methylation-sensitive binding agent.

[0047] Also provided, in some aspects, are methods for determining the amount of fetal nucleic acid in a sample comprising (a) contacting a sample nucleic acid with one or more agents that differentially modify methylated nucleic acid and unmethylated nucleic acid, which sample nucleic acid comprises differentially methylated fetal nucleic acid and maternal nucleic acid, the combination of the fetal nucleic acid and the maternal nucleic acid comprising total nucleic acid in the sample, thereby generating differentially modified sample nucleic acid; (b) contacting under amplification conditions the differentially modified sample nucleic acid with: (i) a first set of amplification primers that specifically amplify a first region in sample nucleic acid comprising one or more loci that are differentially methylated between the fetal nucleic acid and maternal nucleic acid, and (ii) a second set of amplification primers that amplify a second region in the sample nucleic acid allowing for a determination of total nucleic acid in the sample, where the first region and the second region are different, thereby generating fetal nucleic acid amplification products and total nucleic acid amplification products; (c) incorporating adaptor oligonucleotides into the amplification products in (b); thereby generating adaptor-modified amplification products; (d) obtaining nucleotide sequences of the adaptor-modified amplification products in (c) by a sequencing process, thereby generating sequence reads; (e) quantifying the sequence reads; and (f) determining the amount of fetal nucleic acid in the sample based on a quantification of the sequence reads in (e).

[0048] Also provided, in some aspects, are methods for determining the amount of fetal nucleic acid in a sample comprising (a) contacting a sample nucleic acid with one or more methylation sensitive restriction enzymes, which sample nucleic acid comprises differentially methylated fetal nucleic acid and maternal nucleic acid, the combination of the fetal nucleic acid and the maternal nucleic acid comprising total nucleic acid in the sample, thereby generating differentially digested sample nucleic acid; (b) contacting under amplification conditions the digested sample nucleic acid with (i) a first set of amplification primers that specifically amplify a first region in sample nucleic acid comprising one or more loci that are differentially methylated between the fetal nucleic acid and maternal nucleic acid, and (ii) a second set of amplification primers that amplify a second region in the sample nucleic acid allowing for a determination of total nucleic acid in the sample, where the first region and the second region are different, thereby generating fetal nucleic acid amplification products and total nucleic acid amplification products; (c) incorporating adaptor oligonucleotides into the amplification products in (b); thereby generating adaptor-modified amplification products; (d) obtaining nucleotide sequences of the adaptor-modified amplification products in (c) by a sequencing process, thereby generating sequence reads; (e) quantifying the sequence reads; and (f) determining the amount of fetal nucleic acid in the sample based on a quantification of the sequence reads in (e).

[0049] Also provided, in some aspects, are methods for determining the copy number of fetal nucleic acid in a sample comprising (a) contacting a sample nucleic acid with one or more agents that differentially modify methylated nucleic acid and unmethylated nucleic acid, which sample nucleic acid comprises differentially methylated fetal nucleic acid and maternal nucleic acid, the combination of the fetal nucleic acid and the maternal nucleic acid comprising total nucleic acid in the sample, thereby generating differentially modified sample nucleic acid; (b) contacting under amplification conditions the differentially modified sample nucleic acid with (i) a first set of amplification primers that specifically amplify a first region in sample nucleic acid comprising one or more loci that are differentially methylated between the fetal nucleic acid and maternal nucleic acid, and (ii) a predetermined copy number of one or more first competitor oligonucleotides that compete with the first region for hybridization of primers of the first amplification primer set, thereby generating fetal nucleic acid amplification products and competitor amplification products; (c) incorporating adaptor oligonucleotides into the amplification products in (b); thereby generating adaptor-modified amplification products; (d) obtaining nucleotide sequences of the adaptor-modified amplification products in (c) by a sequencing process, thereby generating sequence reads; (e) quantifying the sequence reads; and (f) determining the copy number of fetal nucleic acid in the sample based on a quantification of the sequence reads in (e) and the amount of competitor oligonucleotide used.

[0050] Also provided, in some aspects, are methods for detecting the presence or absence of a fetal aneuploidy in a sample comprising (a) contacting a sample nucleic acid with one or more agents that differentially modify methylated nucleic acid and unmethylated nucleic acid, which sample nucleic acid comprises differentially methylated fetal nucleic acid and maternal nucleic acid, the combination of the fetal nucleic acid and the maternal nucleic acid comprising total nucleic acid in the sample, thereby generating differentially modified sample nucleic acid; (b) contacting under amplification conditions the differentially modified sample nucleic acid with (i) a first set of amplification primers that specifically amplify one or more loci in a target chromosome that are differentially methylated between the fetal nucleic acid and maternal nucleic acid, and (ii) a second set of amplification primers that specifically amplify one or more loci in a reference chromosome that are differentially methylated between the fetal nucleic acid and maternal nucleic acid, thereby generating target chromosome amplification products and reference chromosome amplification products; (c) incorporating adaptor oligonucleotides into the amplification products in (b); thereby generating adaptor-modified amplification products; (d) obtaining nucleotide sequences of the adaptor-modified amplification products in (c) by a sequencing process, thereby generating sequence reads; (e) quantifying the sequence reads; and (f) detecting the presence or absence of a fetal aneuploidy in the sample based on a quantification of the sequence reads in (e).

[0051] In some embodiments, the first region comprises one or more loci which each contain a restriction site for a methylation-sensitive restriction enzyme. In some embodiments, the one or more agents that differentially modify methylated nucleic acid and unmethylated nucleic acid comprise one or more methylation sensitive restriction enzymes. In some embodiments, the second region comprises one or more loci which do not contain a restriction site for a methylation-sensitive restriction enzyme. In some embodiments, the one or more agents that differentially modify methylated nucleic acid and unmethylated nucleic acid comprise bisulfite. In some embodiments, the target chromosome comprises one or more loci which each contain a restriction site for a methylation-sensitive restriction enzyme. In some embodiments, the reference chromosome comprises one or more loci which each contain a restriction site for a methylation-sensitive restriction enzyme.

[0052] In some embodiments, the adaptor oligonucleotides are incorporated into the amplification products by ligation. In some cases, the ligation is unidirectional ligation. In some embodiments, the adaptor oligonucleotides are incorporated into the amplification products using amplification primers comprising the adaptor oligonucleotide sequences. In some embodiments, the adaptor oligonucleotides comprise one or more index sequences. In some cases, the one or more index sequences comprise a sample-specific index. In some cases, the one or more index sequences comprise an aliquot-specific index.

[0053] In some embodiments, at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NOs:1-261, or a fragment thereof. In some cases, at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NOs:1-89, or a fragment thereof. In some cases, at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NOs:90-261, or a fragment thereof. In some cases, at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NOs:1-59 and SEQ ID NOs:86-89, or a fragment thereof. In some cases, at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NOs:1-59, or a fragment thereof. In some cases, at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:154, SEQ ID NO:158 and SEQ ID NO:163.

[0054] In some embodiments, at least one of the one or more loci in the target chromosome comprises a nucleotide sequence selected from among SEQ ID NOs:1-261, or a fragment thereof. In some cases, at least one of the one or more loci in the target chromosome comprises a nucleotide sequence selected from among SEQ ID NOs:1-89, or a fragment thereof. In some cases, at least one of the one or more loci in the target chromosome comprises a nucleotide sequence selected from among SEQ ID NOs:90-261, or a fragment thereof. In some cases, at least one of the one or more loci in target chromosome comprises a nucleotide sequence selected from among SEQ ID NOs:1-59 and SEQ ID NOs:86-89, or a fragment thereof. In some cases, at least one of the one or more loci in the target chromosome comprises a nucleotide sequence selected from among SEQ ID NOs:1-59, or a fragment thereof. In some cases, at least one of the one or more loci in the target chromosome comprises a nucleotide sequence selected from among SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:154, SEQ ID NO:158 and SEQ ID NO:163.

[0055] In some embodiments, at least one of the one or more loci in the reference chromosome comprises a nucleotide sequence selected from among SEQ ID NOs:1-261, or a fragment thereof. In some cases, at least one of the one or more loci in the reference chromosome comprises a nucleotide sequence selected from among SEQ ID NOs:1-89, or a fragment thereof. In some cases, at least one of the one or more loci in the reference chromosome comprises a nucleotide sequence selected from among SEQ ID NOs:90-261, or a fragment thereof. In some cases, at least one of the one or more loci in reference chromosome comprises a nucleotide sequence selected from among SEQ ID NOs:1-59 and SEQ ID NOs:86-89, or a fragment thereof. In some cases, at least one of the one or more loci in the reference chromosome comprises a nucleotide sequence selected from among SEQ ID NOs:1-59, or a fragment thereof. In some cases, at least one of the one or more loci in the reference chromosome comprises a nucleotide sequence selected from among SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:154, SEQ ID NO:158 and SEQ ID NO:163.

[0056] In some embodiments, the sequencing process is a sequencing by synthesis method. In some embodiments, the sequencing process is a reversible terminator-based sequencing method.

[0057] In some embodiments, the amount of fetal nucleic acid determined is the fraction of fetal nucleic acid in the sample based on the amount of each of the fetal nucleic acid amplification products and total nucleic acid amplification products. In some cases, the fraction of fetal nucleic acid is a ratio of fetal nucleic acid amplification product amount to total nucleic acid amplification product amount.

[0058] In some embodiments, a method further comprises contacting under amplification conditions the nucleic acid sample with a second set of amplification primers that amplify a second region in the sample nucleic acid allowing for a determination of total nucleic acid in the sample, where the first region and the second region are different. In some cases, the second region comprises one or more loci which do not contain a restriction site for a methylation-sensitive restriction enzyme.

[0059] In some embodiments, a method further comprises contacting under amplification conditions the nucleic acid sample with a third set of amplification primers that amplify a third region in the sample nucleic acid allowing for a determination of the presence or absence of fetal specific nucleic acid. In some cases, the fetal specific nucleic acid is Y chromosome nucleic acid. In some cases, the third region comprises one or more loci within chromosome Y.

[0060] In some embodiments, a method further comprises contacting under amplification conditions the nucleic acid sample with a fourth set of amplification primers that amplify a fourth region in the sample nucleic acid allowing for a determination of the amount of digested or undigested nucleic acid, as an indicator of digestion efficiency. In some cases, the fourth region comprises one or more loci present in both fetal nucleic acid and maternal nucleic acid and unmethylated in both fetal nucleic acid and maternal nucleic acid.

[0061] In some embodiments, a method further comprises contacting under amplification conditions the nucleic acid sample with a predetermined copy number of one or more first competitor oligonucleotides that compete with the first region for hybridization of primers of the first amplification primer set. In some embodiments, a method further comprises contacting under amplification conditions the nucleic acid sample with a predetermined copy number of one or more first competitor oligonucleotides that compete with the target chromosome for hybridization of primers of the first amplification primer set.

[0062] In some embodiments, a method further comprises contacting under amplification conditions the nucleic acid sample with a predetermined copy number of one or more second competitor oligonucleotides that compete with the second region for hybridization of primers of the second amplification primer set. In some embodiments, a method further comprises contacting under amplification conditions the nucleic acid sample with a predetermined copy number of one or more second competitor oligonucleotides that compete with the reference chromosome for hybridization of primers of the second amplification primer set.

[0063] In some embodiments, a method further comprises contacting under amplification conditions the nucleic acid sample with a predetermined copy number of one or more third competitor oligonucleotides that compete with the third region for hybridization of primers of the third amplification primer set.

[0064] In some embodiments, a method further comprises contacting under amplification conditions the nucleic acid sample with a predetermined copy number of one or more fourth competitor oligonucleotides that compete with the fourth region for hybridization of primers of the fourth amplification primer set.

[0065] In some embodiments, the amount of fetal nucleic acid determined is the copy number of fetal nucleic acid based on the amount of competitor oligonucleotide used. In some embodiments, the amount of fetal nucleic acid determined is the copy number of fetal nucleic acid based on a quantification of sequence reads.

[0066] In some embodiments, the sample nucleic acid is extracellular nucleic acid. In some cases, the nucleic acid sample is obtained from a pregnant female subject. In some cases, the subject is human. In some embodiments, the sample nucleic acid is from plasma or serum.

[0067] In some embodiments, two or more independent loci in the first region are assayed. In some embodiments, two or more independent loci in the target chromosome are assayed. In some embodiments, two or more independent loci in the reference chromosome are assayed. In some embodiments, the target chromosome is chromosome 13. In some embodiments, the target chromosome is chromosome 18. In some embodiments, the target chromosome is chromosome 21.

[0068] In some embodiments, the amount of fetal nucleic acid is substantially equal to the amount of fetal nucleic acid determined using a mass spectrometry method. In some embodiments, the amount of fetal nucleic acid is determined with an R.sup.2 value of 0.97 or greater when compared to an amount of fetal nucleic acid determined using a mass spectrometry method. In some embodiments, the copy number of fetal nucleic acid is substantially equal to the copy number of fetal nucleic acid determined using a mass spectrometry method. In some embodiments, the copy number of fetal nucleic acid is determined with an R.sup.2 value of 0.97 or greater when compared to a copy number of fetal nucleic acid determined using a mass spectrometry method.

[0069] Also provided, in some aspects, are methods for determining fetal fraction in a sample comprising (a) enriching a sample nucleic acid for a plurality of polymorphic nucleic acid targets, which sample nucleic acid comprises fetal nucleic acid and maternal nucleic acid; (b) obtaining nucleotide sequences for some or all of the nucleic acid targets by a sequencing process; (c) analyzing the nucleotide sequences of (b); and (d) determining fetal fraction based on the analysis of (c), where the polymorphic nucleic acid targets and number thereof result in at least five polymorphic nucleic acid targets being informative for determining the fetal fraction for at least 90% of samples.

[0070] In some embodiments, the enriching comprises amplifying the plurality of polymorphic nucleic acid targets. In some cases, the enriching comprises generating amplification products in an amplification reaction, and sometimes the amplification reaction is performed in a single vessel.

[0071] In some embodiments, the maternal genotype and the paternal genotype at each of the polymorphic nucleic acid targets are not known prior to (a). In some embodiments, polymorphic nucleic acid targets having a minor allele population frequency of about 40% or more are selected.

[0072] In some embodiments, a method comprises determining an allele frequency in the sample for each of the polymorphic nucleic acid targets. In some embodiments, determining which polymorphic nucleic acid targets are informative comprises identifying informative genotypes by comparing each allele frequency to one or more fixed cutoff frequencies. In some cases, the fixed cutoff for identifying informative genotypes from non-informative homozygotes is about a 2% or greater shift in allele frequency and sometimes is a 1% or greater shift in allele frequency. In some cases, the fixed cutoff for identifying informative genotypes from non-informative heterozygotes is about a 50% or greater shift in allele frequency and sometimes is a 25% or greater shift in allele frequency. In some embodiments, determining which polymorphic nucleic acid targets are informative comprises identifying informative genotypes by comparing each allele frequency to one or more target-specific cutoff frequencies. In some cases, the one or more target-specific cutoff frequencies are determined for each polymorphic nucleic acid target. In some cases, each target-specific cutoff frequency is determined based on the allele frequency variance for the corresponding polymorphic nucleic acid target.

[0073] In some embodiments, a method comprises determining an allele frequency mean. In some cases, fetal fraction is determined based, in part, on the allele frequency mean. In some embodiments, the fetal genotype at one or more informative polymorphic nucleic acid targets is heterozygous. In some embodiments, the fetal genotype at one or more informative polymorphic nucleic acid targets is homozygous. In some embodiments, fetal fraction is determined with a coefficient of variance (CV) of 0.20 or less. In some cases, fetal fraction is determined with a coefficient of variance (CV) of 0.10 or less, and sometimes fetal fraction is determined with a coefficient of variance (CV) of 0.05 or less.

[0074] In some embodiments, the polymorphic nucleic acid targets each comprise at least one single nucleotide polymorphism (SNP). In some cases, the SNPs are selected from: rs10413687, rs10949838, rs1115649, rs11207002, rs11632601, rs11971741, rs12660563, rs13155942, rs1444647, rs1572801, rs17773922, rs1797700, rs1921681, rs1958312, rs196008, rs2001778, rs2323659, rs2427099, rs243992, rs251344, rs254264, rs2827530, rs290387, rs321949, rs348971, rs390316, rs3944117, rs425002, rs432586, rs444016, rs4453265, rs447247, rs4745577, rs484312, rs499946, rs500090, rs500399, rs505349, rs505662, rs516084, rs517316, rs517914, rs522810, rs531423, rs537330, rs539344, rs551372, rs567681, rs585487, rs600933, rs619208, rs622994, rs639298, rs642449, rs6700732, rs677866, rs683922, rs686851, rs6941942, rs7045684, rs7176924, rs7525374, rs870429, rs949312, rs9563831, rs970022, rs985462, rs1005241, rs1006101, rs10745725, rs10776856, rs10790342, rs11076499, rs11103233, rs11133637, rs11974817, rs12102203, rs12261, rs12460763, rs12543040, rs12695642, rs13137088, rs13139573, rs1327501, rs13438255, rs1360258, rs1421062, rs1432515, rs1452396, rs1518040, rs16853186, rs1712497, rs1792205, rs1863452, rs1991899, rs2022958, rs2099875, rs2108825, rs2132237, rs2195979, rs2248173, rs2250246, rs2268697, rs2270893, rs244887, rs2736966, rs2851428, rs2906237, rs2929724, rs3742257, rs3764584, rs3814332, rs4131376, rs4363444, rs4461567, rs4467511, rs4559013, rs4714802, rs4775899, rs4817609, rs488446, rs4950877, rs530913, rs6020434, rs6442703, rs6487229, rs6537064, rs654065, rs6576533, rs6661105, rs669161, rs6703320, rs675828, rs6814242, rs6989344, rs7120590, rs7131676, rs7214164, rs747583, rs768255, rs768708, rs7828904, rs7899772, rs7900911, rs7925270, rs7975781, rs8111589, rs849084, rs873870, rs9386151, rs9504197, rs9690525, and rs9909561.

[0075] In some cases, the SNPs are selected from: rs10413687, rs10949838, rs1115649, rs11207002, rs11632601, rs11971741, rs12660563, rs13155942, rs1444647, rs1572801, rs17773922, rs1797700, rs1921681, rs1958312, rs196008, rs2001778, rs2323659, rs2427099, rs243992, rs251344, rs254264, rs2827530, rs290387, rs321949, rs348971, rs390316, rs3944117, rs425002, rs432586, rs444016, rs4453265, rs447247, rs4745577, rs484312, rs499946, rs500090, rs500399, rs505349, rs505662, rs516084, rs517316, rs517914, rs522810, rs531423, rs537330, rs539344, rs551372, rs567681, rs585487, rs600933, rs619208, rs622994, rs639298, rs642449, rs6700732, rs677866, rs683922, rs686851, rs6941942, rs7045684, rs7176924, rs7525374, rs870429, rs949312, rs9563831, rs970022, and rs985462.

[0076] In some cases, the SNPs are selected from: rs1005241, rs1006101, rs10745725, rs10776856, rs10790342, rs11076499, rs11103233, rs11133637, rs11974817, rs12102203, rs12261, rs12460763, rs12543040, rs12695642, rs13137088, rs13139573, rs1327501, rs13438255, rs1360258, rs1421062, rs1432515, rs1452396, rs1518040, rs16853186, rs1712497, rs1792205, rs1863452, rs1991899, rs2022958, rs2099875, rs2108825, rs2132237, rs2195979, rs2248173, rs2250246, rs2268697, rs2270893, rs244887, rs2736966, rs2851428, rs2906237, rs2929724, rs3742257, rs3764584, rs3814332, rs4131376, rs4363444, rs4461567, rs4467511, rs4559013, rs4714802, rs4775899, rs4817609, rs488446, rs4950877, rs530913, rs6020434, rs6442703, rs6487229, rs6537064, rs654065, rs6576533, rs6661105, rs669161, rs6703320, rs675828, rs6814242, rs6989344, rs7120590, rs7131676, rs7214164, rs747583, rs768255, rs768708, rs7828904, rs7899772, rs7900911, rs7925270, rs7975781, rs8111589, rs849084, rs873870, rs9386151, rs9504197, rs9690525, and rs9909561.

[0077] The polymorphic targets can comprise one or more of any of the single nucleotide polymorphisms (SNPs) listed above and any combination thereof.

[0078] In some embodiments, the polymorphic nucleic acid targets and number thereof result in at least five polymorphic nucleic acid targets being informative for determining the fetal fraction for at least 95% of samples. In some cases, the polymorphic nucleic acid targets and number thereof result in at least five polymorphic nucleic acid targets being informative for determining the fetal fraction for at least 99% of samples. In some cases, the polymorphic nucleic acid targets and number thereof result in at least ten polymorphic nucleic acid targets being informative for determining the fetal fraction for at least 90% of samples. In some cases, the polymorphic nucleic acid targets and number thereof result in at least ten polymorphic nucleic acid targets being informative for determining the fetal fraction for at least 95% of samples. In some cases, the polymorphic nucleic acid targets and number thereof result in at least ten polymorphic nucleic acid targets being informative for determining the fetal fraction for at least 99% of samples. Sometimes, 10 or more polymorphic nucleic acid targets are enriched, sometimes 50 or more polymorphic nucleic acid targets are enriched, sometimes 100 or more polymorphic nucleic acid targets are enriched, and sometimes 500 or more polymorphic nucleic acid targets are enriched. Sometimes, about 40 to about 100 polymorphic nucleic acid targets are enriched.

[0079] In some embodiments, the sequencing process comprises a sequencing by synthesis method. In some cases, the sequencing by synthesis method comprises a plurality of synthesis cycles. Sometimes, the sequencing by synthesis method comprises about 36 cycles and sometimes the sequencing by synthesis method comprises about 27 cycles. In some embodiments, the sequencing process comprises a sequencing by ligation method. In some embodiments, the sequencing process comprises a single molecule sequencing method.

[0080] In some embodiments, the sequencing process comprises sequencing a plurality of samples in a single compartment. In some cases, the fetal fraction is determined for 10 or more samples. In some cases, the fetal fraction is determined for 100 or more samples. In some cases, the fetal fraction is determined for 1000 or more samples.

[0081] In some embodiments, the sample nucleic acid is cell-free DNA. In some embodiments, the sample nucleic acid is obtained from a pregnant female subject. In some cases, the subject is human. In some cases, the sample nucleic acid is from plasma or serum.

[0082] Certain embodiments are described further in the following description, examples, claims and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0083] The drawings illustrate embodiments of the technology herein and are not limiting. For clarity and ease of illustration, the drawings are not made to scale and, in some instances, various aspects may be shown exaggerated or enlarged to facilitate an understanding of particular embodiments.

[0084] FIG. 1 shows the design of the recombinant MBD-Fc protein used to separate differentially methylated DNA.

[0085] FIG. 2 shows the methyl-CpG-binding, antibody-like protein has a high affinity and high avidity to its "antigen", which is preferably DNA that is methylated at CpG di-nucleotides.

[0086] FIG. 3 shows the methyl binding domain of MBD-FC binds all DNA molecules regardless of their methylation status. The strength of this protein/DNA interaction is defined by the level of DNA methylation. After binding genomic DNA, eluate solutions of increasing salt concentrations can be used to fractionate non-methylated and methylated DNA allowing for a controlled separation.

[0087] FIG. 4 shows the experiment used to identify differentially methylated DNA from a fetus and mother using the recombinant MBD-Fc protein and a microarray.

[0088] FIG. 5 shows typical results generated by Sequenom.RTM. EpiTYPER.TM. method, which was used to validate the results generated from the experiment illustrated in FIG. 4.

[0089] FIG. 6 shows the correlation between the log ratios derived from microarray analysis (x axis) and methylation differences obtained by EpiTYPER.TM. analysis (y axis). Each data point represents the average for one region across all measured samples. The microarray analysis is comparative in nature because the highly methylated fraction of the maternal DNA is hybridized together with the highly methylated fraction of placenta DNA. Positive values indicate higher methylation of the placenta samples. In mass spectrometry each samples is measured individually. The difference in methylation was calculated by subtracting the maternal methylation values from the placenta methylation value. To compare the results with the microarray data the average of the differences for all maternal/placenta DNA pairs was calculated. Figure discloses SEQ ID NOS 387 and 388, respectively, in order of appearance.

[0090] FIG. 7 shows a correlation between microarray and EpiTYPER.TM. results.

[0091] FIG. 8 shows the correlation between the number of gDNA molecules that were expected and the number of molecules measured by competitive PCR in combination with mass spectrometry analysis. In this experiment, DNA derived from whole blood (black plus signs) was used and commercially available fully methylated DNA (red crosses) was used in a 90 to 10 ratio. The MBD-FC fusion protein was used to separate the non-methylated and the methylated fraction of DNA. Each fraction was subject to competitive PCR analysis with mass spectrometry readout. The method has been described earlier for the analysis of copy number variations and is commercially available for gene expression analysis. The approach allows absolute quantification of DNA molecules with the help of a synthetic oligonucleotides of know concentration. In this experiment the MGMT locus was targeted, which was not methylated in the whole blood sample used here. Using an input of 300 total gDNA copies, 270 copies of non-methylated DNA and 30 copies of methylated DNA was expected. The measured copy numbers are largely in agreement with the expected values. The data point at 600 copies of input DNA indicates a bias in the reaction and shows that this initial proof of concept experiment needs to be followed up with more development work, before the assay can be used. However, this initial data indicates the feasibility of the approach for capturing and quantifying of a few copies of methylated DNA in the presence of an excess of unmethylated DNA species.

[0092] FIG. 9A-9L show bar graph plots of the methylation differences obtained from the microarray analysis (dark bars) and the mass spectrometry analysis (light grey bars) with respect to their genomic location. For each of the 85 regions that were identified to be differentially methylated by microarray an individual plot is provided. The x axis for each plot shows the chromosomal position of the region. The y axis depicts the log ration (in case of the microarrays) and the methylation differences (in case of the mass spectrometry results). For the microarrays each hybridization probe in the area is shown as a single black (or dark grey) bar. For the mass spectrometry results each CpG site, is shown as a light grey bar. Bars showing values greater than zero indicate higher DNA methylation in the placenta samples compared to the maternal DNA. For some genes the differences are small (i.e. RB1 or DSCR6) but still statistically significant. Those regions would be less suitable for a fetal DNA enrichment strategy.

[0093] FIG. 10 shows one embodiment of the Fetal Quantifier Method. Maternal nucleic acid is selectively digested and the remaining fetal nucleic acid is quantified using a competitor of known concentration. In this schema, the analyte is separated and quantified by a mass spectrometer.

[0094] FIG. 11 shows one embodiment of the Methylation-Based Fetal Diagnostic Method. Maternal nucleic acid is selectively digested and the remaining fetal nucleic acid is quantified for three different chromosomes (13, 18 and 21). Parts 2 and 3 of the Figure illustrate the size distribution of the nucleic acid in the sample before and after digestion. The amplification reactions can be size-specific (e.g., greater than 100 base pair amplicons) such that they favor the longer, non-digested fetal nucleic acid over the digested maternal nucleic acid, thereby further enriching the fetal nucleic acid. The spectra at the bottom of the Figure show an increased amount of chromosome 21 fetal nucleic acid indicative of trisomy 21.

[0095] FIG. 12 shows the total number of amplifiable genomic copies from four different DNA samples isolated from the blood of non-pregnant women. Each sample was diluted to contain approximately 2500, 1250, 625 or 313 copies per reaction. Each measurement was obtained by taking the mean DNA/competitor ratio obtained from two total copy number assays (ALB and RNAseP in Table X). As FIG. 12 shows, the total copy number is accurate and stable across the different samples, thus validating the usefulness of the competitor-based approach.

[0096] FIGS. 13A and 13B show a model system that was created that contained a constant number of maternal non-methylated DNA with varying amounts of male placental methylated DNA spiked-in. The samples were spiked with male placental amounts ranging from approximately 0 to 25% relative to the maternal non-methylated DNA. The fraction of placental DNA was calculated using the ratios obtained from the methylation assays (FIG. 13A) and the Y-chromosome marker (FIG. 13B) as compared to the total copy number assay. The methylation and Y-chromosome markers are provided in Table X.

[0097] FIGS. 14A and 14B show the results of the total copy number assay from plasma samples. In FIG. 14A, the copy number for each sample is shown. Two samples (no 25 and 26) have a significantly higher total copy number than all the other samples. A mean of approximately 1300 amplifiable copies/ml plasma was obtained (range 766-2055). FIG. 14B shows a box-and-whisker plot of the given values, summarizing the results.

[0098] FIGS. 15A and 15B show the amount (or copy numbers) of fetal nucleic acid from 33 different plasma samples taken from pregnant women with male fetuses plotted. The copy numbers obtained were calculated using the methylation markers and the Y-chromosome-specific markers using the assays provided in Table X. As can be seen in FIG. 15B, the box-and-whisker plot of the given values indicated minimal difference between the two different measurements, thus validating the accuracy and stability of the method.

[0099] FIG. 16 shows a paired correlation between the results obtained using the methylation markers versus the Y-chromosome marker from FIG. 15A.

[0100] FIG. 17 shows the digestion efficiency of the restriction enzymes using the ratio of digestion for the control versus the competitor and comparing this value to the mean total copy number assays. Apart from sample 26 all reactions indicate the efficiency to be above about 99%.

[0101] FIG. 18 provides a specific method for calculating fetal DNA fraction (or concentration) in a sample using the Y-chromosome-specific markers for male pregnancies and the mean of the methylated fraction for all pregnancies (regardless of fetal sex).

[0102] FIG. 19 provides a specific method for calculating fetal DNA fraction (or concentration) in a sample without the Y-chromosome-specific markers. Instead, only the Assays for Methylation Quantification were used to determine the concentration of fetal DNA.

[0103] FIG. 20 shows a power calculation t-test for a simulated trisomy 21 diagnosis using the methods of the technology herein. The Figure shows the relationship between the coefficient of variation (CV) on the x-axis and the power to discriminate the assay populations using a simple t-test (y-axis). The data indicates that in 99% of all cases, one can discriminate the two population (euploid vs. aneuploid) on a significance level of 0.001 provided a CV of 5% or less.

[0104] FIG. 21 shows a scheme for ligating a PCR amplicon with Illumina sequencing adaptors.

[0105] FIG. 22 shows a modified ligation scheme.

[0106] FIG. 23 shows a comparison of copy numbers of individual markers determined by a fetal quantification assay using MPSS (FQA Sequencing; x-axis) with those obtained by a fetal quantification assay using MASSARRAY (FQA MA; y-axis). The results from both methods were highly correlated (R.sup.2>0.97). In some cases, platform-specific allele bias resulted in slight copy number differences and slopes of the linear fit which deviated from 1.

[0107] FIG. 24 shows a comparison of mean copy numbers for each of the marker groups determined by a fetal quantification assay using MPSS (FQA Sequencing; x-axis) with those obtained by a fetal quantification assay using MASSARRAY (FQA MA; y-axis).

[0108] FIG. 25 shows a comparison of fetal fractions derived from either methylation (left) or Y-chromosome markers determined by a fetal quantification assay using MPSS (FQA Sequencing; x-axis) with those obtained by a fetal quantification assay using MASSARRAY (FQA MA; y-axis).

[0109] FIG. 26 shows an example of a likelihood chart for an informative fetal/maternal genotype combination.

[0110] FIG. 27 illustrates a possible distribution of maternal and paternal alleles.

[0111] FIG. 28 illustrates a method for calculating fetal fraction by MPSS.

[0112] FIG. 29 illustrates a scheme for multiplexed amplicon library generation and sequencing.

[0113] FIG. 30 shows allele frequencies per SNP for a particular sample.

[0114] FIG. 31 shows allele frequencies per SNP for a particular sample.

[0115] FIG. 32 shows allele frequencies per sample for a collection of 46 samples.

[0116] FIG. 33 shows allele frequencies per sample (folded on 0.5) for a collection of 46 samples.

[0117] FIG. 34 shows fetal fraction values calculated from informative genotypes for each sample.

[0118] FIG. 35 shows a correlation plot for SNP-based fetal fraction estimates versus methylation-based fetal fraction estimates.

[0119] FIG. 36 shows a comparison of informative genotype measurements at varying sequencing coverage.

[0120] FIG. 37 shows probabilities of the number of informative SNPs for each of the selected thresholds (1-6 informative SNPs) at increasing numbers of total SNPs assayed.

DEFINITIONS

[0121] The term "pregnancy-associated disorder," as used in this application, refers to any condition or disease that may affect a pregnant woman, the fetus, or both the woman and the fetus. Such a condition or disease may manifest its symptoms during a limited time period, e.g., during pregnancy or delivery, or may last the entire life span of the fetus following its birth. Some examples of a pregnancy-associated disorder include ectopic pregnancy, preeclampsia, preterm labor, RhD incompatibility, fetal chromosomal abnormalities such as trisomy 21, and genetically inherited fetal disorders such as cystic fibrosis, beta-thalassemia or other monogenic disorders. The compositions and processes described herein are particularly useful for diagnosis, prognosis and monitoring of pregnancy-associated disorders associated with quantitative abnormalities of fetal DNA in maternal plasma/serum, including but not limited to, preeclampsia (Lo et al., Clin. Chem. 45:184-188, 1999 and Zhong et al., Am. J. Obstet. Gynecol. 184:414-419, 2001), fetal trisomy (Lo et al., Clin. Chem. 45:1747-1751, 1999 and Zhong et al., Prenat. Diagn. 20:795-798, 2000) and hyperemesis gravidarum (Sekizawa et al., Clin. Chem. 47:2164-2165, 2001). For example, an elevated level of fetal nucleic acid in maternal blood (as compared to a normal pregnancy or pregnancies) may be indicative of a preeclamptic pregnancy. Further, the ability to enrich fetal nucleic from a maternal sample may prove particularly useful for the noninvasive prenatal diagnosis of autosomal recessive diseases such as the case when a mother and father share an identical disease causing mutation, an occurrence previously perceived as a challenge for maternal plasma-based non-trisomy prenatal diagnosis.

[0122] The term "chromosomal abnormality" or "aneuploidy" as used herein refers to a deviation between the structure of the subject chromosome and a normal homologous chromosome. The term "normal" refers to the predominate karyotype or banding pattern found in healthy individuals of a particular species, for example, a euploid genome (in humans, 46XX or 46XY). A chromosomal abnormality can be numerical or structural, and includes but is not limited to aneuploidy, polyploidy, inversion, a trisomy, a monosomy, duplication, deletion, deletion of a part of a chromosome, addition, addition of a part of chromosome, insertion, a fragment of a chromosome, a region of a chromosome, chromosomal rearrangement, and translocation. Chromosomal abnormality may also refer to a state of chromosomal abnormality where a portion of one or more chromosomes is not an exact multiple of the usual haploid number due to, for example, chromosome translocation. Chromosomal translocation (e.g. translocation between chromosome 21 and 14 where some of the 14th chromosome is replaced by extra 21st chromosome) may cause partial trisomy 21. A chromosomal abnormality can be correlated with presence of a pathological condition or with a predisposition to develop a pathological condition. A chromosomal abnormality may be detected by quantitative analysis of nucleic acid.

[0123] The terms "nucleic acid" and "nucleic acid molecule" may be used interchangeably throughout the disclosure. The terms refer to nucleic acids of any composition from, such as DNA (e.g., complementary DNA (cDNA), genomic DNA (gDNA) and the like), RNA (e.g., message RNA (mRNA), short inhibitory RNA (siRNA), ribosomal RNA (rRNA), tRNA, microRNA, RNA highly expressed by the fetus or placenta, and the like), and/or DNA or RNA analogs (e.g., containing base analogs, sugar analogs and/or a non-native backbone and the like), RNA/DNA hybrids and polyamide nucleic acids (PNAs), all of which can be in single- or double-stranded form, and unless otherwise limited, can encompass known analogs of natural nucleotides that can function in a similar manner as naturally occurring nucleotides. For example, the nucleic acids provided in SEQ ID NOs: 1-261 (see Tables 4A-4C) can be in any form useful for conducting processes herein (e.g., linear, circular, supercoiled, single-stranded, double-stranded and the like) or may include variations (e.g., insertions, deletions or substitutions) that do not alter their utility as part of the present technology. A nucleic acid may be, or may be from, a plasmid, phage, autonomously replicating sequence (ARS), centromere, artificial chromosome, chromosome, or other nucleic acid able to replicate or be replicated in vitro or in a host cell, a cell, a cell nucleus or cytoplasm of a cell in certain embodiments. A template nucleic acid in some embodiments can be from a single chromosome (e.g., a nucleic acid sample may be from one chromosome of a sample obtained from a diploid organism). Unless specifically limited, the term encompasses nucleic acids containing known analogs of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, single nucleotide polymorphisms (SNPs), and complementary sequences as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues (Batzer et al., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chem. 260:2605-2608 (1985); and Rossolini et al., Mol. Cell. Probes 8:91-98 (1994)). The term nucleic acid is used interchangeably with locus, gene, cDNA, and mRNA encoded by a gene. The term also may include, as equivalents, derivatives, variants and analogs of RNA or DNA synthesized from nucleotide analogs, single-stranded ("sense" or "antisense", "plus" strand or "minus" strand, "forward" reading frame or "reverse" reading frame) and double-stranded polynucleotides. Deoxyribonucleotides include deoxyadenosine, deoxycytidine, deoxyguanosine and deoxythymidine. For RNA, the base cytosine is replaced with uracil. A template nucleic acid may be prepared using a nucleic acid obtained from a subject as a template.

[0124] A "nucleic acid comprising one or more CpG sites" or a "CpG-containing genomic sequence" as used herein refers to a segment of DNA sequence at a defined location in the genome of an individual such as a human fetus or a pregnant woman. Typically, a "CpG-containing genomic sequence" is at least 15 nucleotides in length and contains at least one cytosine. Preferably, it can be at least 30, 50, 80, 100, 150, 200, 250, or 300 nucleotides in length and contains at least 2, 5, 10, 15, 20, 25, or 30 cytosines. For anyone "CpG-containing genomic sequence" at a given location, e.g., within a region centering around a given genetic locus (see Tables 1A-1C), nucleotide sequence variations may exist from individual to individual and from allele to allele even for the same individual. Typically, such a region centering around a defined genetic locus (e.g., a CpG island) contains the locus as well as upstream and/or downstream sequences. Each of the upstream or downstream sequence (counting from the 5' or 3' boundary of the genetic locus, respectively) can be as long as 10 kb, in other cases may be as long as 5 kb, 2 kb, 1 kb, 500 bp, 200 bp, or 100 bp. Furthermore, a "CpG-containing genomic sequence" may encompass a nucleotide sequence transcribed or not transcribed for protein production, and the nucleotide sequence can be an inter-gene sequence, intra-gene sequence, protein-coding sequence, a non protein-coding sequence (such as a transcription promoter), or a combination thereof.

[0125] As used herein, a "methylated nucleotide" or a "methylated nucleotide base" refers to the presence of a methyl moiety on a nucleotide base, where the methyl moiety is not present in a recognized typical nucleotide base. For example, cytosine does not contain a methyl moiety on its pyrimidine ring, but 5-methylcytosine contains a methyl moiety at position 5 of its pyrimidine ring. Therefore, cytosine is not a methylated nucleotide and 5-methylcytosine is a methylated nucleotide. In another example, thymine contains a methyl moiety at position 5 of its pyrimidine ring, however, for purposes herein, thymine is not considered a methylated nucleotide when present in DNA since thymine is a typical nucleotide base of DNA. Typical nucleoside bases for DNA are thymine, adenine, cytosine and guanine. Typical bases for RNA are uracil, adenine, cytosine and guanine. Correspondingly a "methylation site" is the location in the target gene nucleic acid region where methylation has, or has the possibility of occurring. For example a location containing CpG is a methylation site where the cytosine may or may not be methylated.

[0126] As used herein, a "CpG site" or "methylation site" is a nucleotide within a nucleic acid that is susceptible to methylation either by natural occurring events in vivo or by an event instituted to chemically methylate the nucleotide in vitro.

[0127] As used herein, a "methylated nucleic acid molecule" refers to a nucleic acid molecule that contains one or more methylated nucleotides that is/are methylated.

[0128] A "CpG island" as used herein describes a segment of DNA sequence that comprises a functionally or structurally deviated CpG density. For example, Yamada et al. (Genome Research 14:247-266, 2004) have described a set of standards for determining a CpG island: it must be at least 400 nucleotides in length, has a greater than 50% GC content, and an OCF/ECF ratio greater than 0.6. Others (Takai et al., Proc. Natl. Acad. Sci. U.S.A. 99:3740-3745, 2002) have defined a CpG island less stringently as a sequence at least 200 nucleotides in length, having a greater than 50% GC content, and an OCF/ECF ratio greater than 0.6.

[0129] The term "epigenetic state" or "epigenetic status" as used herein refers to any structural feature at a molecular level of a nucleic acid (e.g., DNA or RNA) other than the primary nucleotide sequence. For instance, the epigenetic state of a genomic DNA may include its secondary or tertiary structure determined or influenced by, e.g., its methylation pattern or its association with cellular proteins.

[0130] The term "methylation profile" "methylation state" or "methylation status," as used herein to describe the state of methylation of a genomic sequence, refers to the characteristics of a DNA segment at a particular genomic locus relevant to methylation. Such characteristics include, but are not limited to, whether any of the cytosine (C) residues within this DNA sequence are methylated, location of methylated C residue(s), percentage of methylated C at any particular stretch of residues, and allelic differences in methylation due to, e.g., difference in the origin of the alleles. The term "methylation" profile" or "methylation status" also refers to the relative or absolute concentration of methylated C or unmethylated C at any particular stretch of residues in a biological sample. For example, if the cytosine (C) residue(s) within a DNA sequence are methylated it may be referred to as "hypermethylated"; whereas if the cytosine (C) residue(s) within a DNA sequence are not methylated it may be referred to as "hypomethylated". Likewise, if the cytosine (C) residue(s) within a DNA sequence (e.g., fetal nucleic acid) are methylated as compared to another sequence from a different region or from a different individual (e.g., relative to maternal nucleic acid), that sequence is considered hypermethylated compared to the other sequence. Alternatively, if the cytosine (C) residue(s) within a DNA sequence are not methylated as compared to another sequence from a different region or from a different individual (e.g., the mother), that sequence is considered hypomethylated compared to the other sequence. These sequences are said to be "differentially methylated", and more specifically, when the methylation status differs between mother and fetus, the sequences are considered "differentially methylated maternal and fetal nucleic acid".

[0131] The term "agent that binds to methylated nucleotides" as used herein refers to a substance that is capable of binding to methylated nucleic acid. The agent may be naturally-occurring or synthetic, and may be modified or unmodified. In one embodiment, the agent allows for the separation of different nucleic acid species according to their respective methylation states. An example of an agent that binds to methylated nucleotides is described in PCT Patent Application No. PCT/EP2005/012707, which published as WO06056480A2 and is hereby incorporated by reference. The described agent is a bifunctional polypeptide comprising the DNA-binding domain of a protein belonging to the family of Methyl-CpG binding proteins (MBDs) and an Fc portion of an antibody (see FIG. 1). The recombinant methyl-CpG-binding, antibody-like protein can preferably bind CpG methylated DNA in an antibody-like manner. That means, the methyl-CpG-binding, antibody-like protein has a high affinity and high avidity to its "antigen", which is preferably DNA that is methylated at CpG dinucleotides. The agent may also be a multivalent MBD (see FIG. 2).

[0132] The term "polymorphism" or "polymorphic nucleic acid target" as used herein refers to a sequence variation within different alleles of the same genomic sequence. A sequence that contains a polymorphism is considered a "polymorphic sequence". Detection of one or more polymorphisms allows differentiation of different alleles of a single genomic sequence or between two or more individuals. As used herein, the term "polymorphic marker" or "polymorphic sequence" refers to segments of genomic DNA that exhibit heritable variation in a DNA sequence between individuals.

[0133] Such markers include, but are not limited to, single nucleotide polymorphisms (SNPs), restriction fragment length polymorphisms (RFLPs), short tandem repeats, such as di-, tri- or tetra-nucleotide repeats (STRs), deletions, duplications, and the like. Polymorphic markers according to the present technology can be used to specifically differentiate between a maternal and paternal allele in the enriched fetal nucleic acid sample.

[0134] The terms "single nucleotide polymorphism" or "SNP" as used herein refer to the polynucleotide sequence variation present at a single nucleotide residue within different alleles of the same genomic sequence. This variation may occur within the coding region or non-coding region (i.e., in the promoter or intronic region) of a genomic sequence, if the genomic sequence is transcribed during protein production. Detection of one or more SNP allows differentiation of different alleles of a single genomic sequence or between two or more individuals.

[0135] The term "allele" as used herein is one of several alternate forms of a gene or non-coding regions of DNA that occupy the same position on a chromosome. The term allele can be used to describe DNA from any organism including but not limited to bacteria, viruses, fungi, protozoa, molds, yeasts, plants, humans, non-humans, animals, and archeabacteria.

[0136] The terms "ratio of the alleles" or "allelic ratio" as used herein refer to the ratio of the population of one allele and the population of the other allele in a sample. In some trisomic cases, it is possible that a fetus may be tri-allelic for a particular locus. In such cases, the term "ratio of the alleles" refers to the ratio of the population of any one allele against one of the other alleles, or any one allele against the other two alleles.

[0137] The term "non-polymorphism-based quantitative method" as used herein refers to a method for determining the amount of an analyte (e.g., total nucleic acid, Y-chromosome nucleic acid, or fetal nucleic acid) that does not require the use of a polymorphic marker or sequence. Although a polymorphism may be present in the sequence, said polymorphism is not required to quantify the sequence. Examples of non-polymorphism-based quantitative methods include, but are not limited to, RT-PCR, digital PCR, array-based methods, sequencing methods, nanopore-based methods, nucleic acid-bound bead-based counting methods and competitor-based methods where one or more competitors are introduced at a known concentration(s) to determine the amount of one or more analytes. In some embodiments, some of the above exemplary methods (for example, sequencing) may need to be actively modified or designed such that one or more polymorphisms are not interrogated.

[0138] As used herein, a "competitor oligonucleotide" or "competitive oligonucleotide" or "competitor" is a nucleic acid polymer that competes with a target nucleotide sequence for hybridization of amplification primers. Often, a competitor has a similar nucleotide sequence as a corresponding target nucleotide sequence. In some cases, a competitor sequence and a corresponding target nucleotide sequence differ by one or more nucleotides. In some cases, a competitor sequence and a corresponding target nucleotide sequence are the same length. In some cases, the competitor optionally has an additional length of nucleotide sequence that is different from the target nucleotide sequence. In some embodiments, a known amount, or copy number, of competitor is used. In some embodiments, two or more competitors are used. In some cases, the two or more competitors possess similar characteristics (e.g. sequence, length, detectable label). In some cases, the two or more competitors possess different characteristics (e.g. sequence, length, detectable label). In some embodiments, one or more competitors are used for a particular region. In some cases, the competitor possesses a characteristic that is unique for each set of competitors for a given region. Often, competitors for different regions possess different characteristics.

[0139] A competitor oligonucleotide may be composed of naturally occurring and/or non-naturally occurring nucleotides (e.g., labeled nucleotides), or a mixture thereof. Competitor oligonucleotides suitable for use with embodiments described herein, may be synthesized and labeled using known techniques. Competitor oligonucleotides may be chemically synthesized according to any suitable method known, for example, the solid phase phosphoramidite triester method first described by Beaucage and Caruthers, Tetrahedron Letts., 22:1859-1862, 1981, using an automated synthesizer, as described in Needham-VanDevanter et al., Nucleic Acids Res. 12:6159-6168, 1984. Purification of competitor oligonucleotides can be effected by any suitable method known, for example, native acrylamide gel electrophoresis or by anion-exchange high-performance liquid chromatography (HPLC), for example, as described in Pearson and Regnier, J. Chrom., 255:137-149, 1983.

[0140] The terms "absolute amount" or "copy number" as used herein refers to the amount or quantity of an analyte (e.g., total nucleic acid or fetal nucleic acid). The present technology provides compositions and processes for determining the absolute amount of fetal nucleic acid in a mixed maternal sample. Absolute amount or copy number represents the number of molecules available for detection, and may be expressed as the genomic equivalents per unit. The term "concentration" refers to the amount or proportion of a substance in a mixture or solution (e.g., the amount of fetal nucleic acid in a maternal sample that comprises a mixture of maternal and fetal nucleic acid). The concentration may be expressed as a percentage, which is used to express how large/small one quantity is, relative to another quantity as a fraction of 100. Platforms for determining the quantity or amount of an analyte (e.g., target nucleic acid) include, but are not limited to, mass spectrometery, digital PCR, sequencing by synthesis platforms (e.g., pyrosequencing), fluorescence spectroscopy and flow cytometry.

[0141] The term "sample" as used herein refers to a specimen containing nucleic acid. Examples of samples include, but are not limited to, tissue, bodily fluid (for example, blood, serum, plasma, saliva, urine, tears, peritoneal fluid, ascitic fluid, vaginal secretion, breast fluid, breast milk, lymph fluid, cerebrospinal fluid or mucosa secretion), umbilical cord blood, chorionic villi, amniotic fluid, an embryo, a two-celled embryo, a four-celled embryo, an eight-celled embryo, a 16-celled embryo, a 32-celled embryo, a 64-celled embryo, a 128-celled embryo, a 256-celled embryo, a 512-celled embryo, a 1024-celled embryo, embryonic tissues, lymph fluid, cerebrospinal fluid, mucosa secretion, or other body exudate, fecal matter, an individual cell or extract of the such sources that contain the nucleic acid of the same, and subcellular structures such as mitochondria, using protocols well established within the art.

[0142] Fetal DNA can be obtained from sources including but not limited to maternal blood, maternal serum, maternal plasma, fetal cells, umbilical cord blood, chorionic villi, amniotic fluid, urine, saliva, lung lavage, cells or tissues.

[0143] The term "blood" as used herein refers to a blood sample or preparation from a pregnant woman or a woman being tested for possible pregnancy. The term encompasses whole blood or any fractions of blood, such as serum and plasma as conventionally defined.

[0144] The term "bisulfite" as used herein encompasses all types of bisulfites, such as sodium bisulfite, that are capable of chemically converting a cytosine (C) to a uracil (U) without chemically modifying a methylated cytosine and therefore can be used to differentially modify a DNA sequence based on the methylation status of the DNA.

[0145] As used herein, a reagent or agent that "differentially modifies" methylated or non-methylated DNA encompasses any reagent that modifies methylated and/or unmethylated DNA in a process through which distinguishable products result from methylated and non-methylated DNA, thereby allowing the identification of the DNA methylation status. Such processes may include, but are not limited to, chemical reactions (such as a C.fwdarw.U conversion by bisulfite) and enzymatic treatment (such as cleavage by a methylation-dependent endonuclease). Thus, an enzyme that preferentially cleaves or digests methylated DNA is one capable of cleaving or digesting a DNA molecule at a much higher efficiency when the DNA is methylated, whereas an enzyme that preferentially cleaves or digests unmethylated DNA exhibits a significantly higher efficiency when the DNA is not methylated.

[0146] The terms "non-bisulfite-based method" and "non-bisulfite-based quantitative method" as used herein refer to any method for quantifying methylated or non-methylated nucleic acid that does not require the use of bisulfite. The terms also refer to methods for preparing a nucleic acid to be quantified that do not require bisulfite treatment. Examples of non-bisulfite-based methods include, but are not limited to, methods for digesting nucleic acid using one or more methylation sensitive enzymes and methods for separating nucleic acid using agents that bind nucleic acid based on methylation status.

[0147] The terms "methyl-sensitive enzymes" and "methylation sensitive restriction enzymes" are DNA restriction endonucleases that are dependent on the methylation state of their DNA recognition site for activity. For example, there are methyl-sensitive enzymes that cleave or digest at their DNA recognition sequence only if it is not methylated. Thus, an unmethylated DNA sample will be cut into smaller fragments than a methylated DNA sample. Similarly, a hypermethylated DNA sample will not be cleaved. In contrast, there are methyl-sensitive enzymes that cleave at their DNA recognition sequence only if it is methylated. As used herein, the terms "cleave", "cut" and "digest" are used interchangeably.

[0148] The term "target nucleic acid" as used herein refers to a nucleic acid examined using the methods disclosed herein to determine if the nucleic acid is part of a pregnancy-related disorder or chromosomal abnormality. For example, a target nucleic acid from chromosome 21 could be examined using the methods of the technology herein to detect Down's Syndrome.

[0149] The term "control nucleic acid" as used herein refers to a nucleic acid used as a reference nucleic acid according to the methods disclosed herein to determine if the nucleic acid is part of a chromosomal abnormality. For example, a control nucleic acid from a chromosome other than chromosome 21 (herein referred to as a "reference chromosome") could be as a reference sequence to detect Down's Syndrome. In some embodiments, the control sequence has a known or predetermined quantity.

[0150] The term "sequence-specific" or "locus-specific method" as used herein refers to a method that interrogates (for example, quantifies) nucleic acid at a specific location (or locus) in the genome based on the sequence composition. Sequence-specific or locus-specific methods allow for the quantification of specific regions or chromosomes.

[0151] The term "gene" means the segment of DNA involved in producing a polypeptide chain; it includes regions preceding and following the coding region (leader and trailer) involved in the transcription/translation of the gene product and the regulation of the transcription/translation, as well as intervening sequences (introns) between individual coding segments (exons).

[0152] In this application, the terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to a polymer of amino acid residues. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. As used herein, the terms encompass amino acid chains of any length, including full-length proteins (i.e., antigens), where the amino acid residues are linked by covalent peptide bonds.

[0153] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, .gamma.-carboxyglutamate, and O-phosphoserine.

[0154] Amino acids may be referred to herein by either the commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[0155] "Primers" as used herein refer to oligonucleotides that can be used in an amplification method, such as a polymerase chain reaction (PCR), to amplify a nucleotide sequence based on the polynucleotide sequence corresponding to a particular genomic sequence, e.g., one located within the CpG island CG1137, PDE9A, or CGI009 on chromosome 21, in various methylation status. At least one of the PCR primers for amplification of a polynucleotide sequence is sequence-specific for the sequence.

[0156] The term "template" refers to any nucleic acid molecule that can be used for amplification in the technology herein. RNA or DNA that is not naturally double stranded can be made into double stranded DNA so as to be used as template DNA. Any double stranded DNA or preparation containing multiple, different double stranded DNA molecules can be used as template DNA to amplify a locus or loci of interest contained in the template DNA.

[0157] The term "amplification reaction" as used herein refers to a process for copying nucleic acid one or more times. In embodiments, the method of amplification includes but is not limited to polymerase chain reaction, self-sustained sequence reaction, ligase chain reaction, rapid amplification of cDNA ends, polymerase chain reaction and ligase chain reaction, Q-beta phage amplification, strand displacement amplification, or splice overlap extension polymerase chain reaction. In some embodiments, a single molecule of nucleic acid is amplified, for example, by digital PCR.

[0158] The term "sensitivity" as used herein refers to the number of true positives divided by the number of true positives plus the number of false negatives, where sensitivity (sens) may be within the range of 0.ltoreq.sens.ltoreq.1. Ideally, method embodiments herein have the number of false negatives equaling zero or close to equaling zero, so that no subject is wrongly identified as not having at least one chromosome abnormality or other genetic disorder when they indeed have at least one chromosome abnormality or other genetic disorder. Conversely, an assessment often is made of the ability of a prediction algorithm to classify negatives correctly, a complementary measurement to sensitivity. The term "specificity" as used herein refers to the number of true negatives divided by the number of true negatives plus the number of false positives, where sensitivity (spec) may be within the range of 0 spec 1. Ideally, methods embodiments herein have the number of false positives equaling zero or close to equaling zero, so that no subject wrongly identified as having at least one chromosome abnormality other genetic disorder when they do not have the chromosome abnormality other genetic disorder being assessed. Hence, a method that has sensitivity and specificity equaling one, or 100%, sometimes is selected.

[0159] One or more prediction algorithms may be used to determine significance or give meaning to the detection data collected under variable conditions that may be weighed independently of or dependently on each other. The term "variable" as used herein refers to a factor, quantity, or function of an algorithm that has a value or set of values. For example, a variable may be the design of a set of amplified nucleic acid species, the number of sets of amplified nucleic acid species, percent fetal genetic contribution tested, percent maternal genetic contribution tested, type of chromosome abnormality assayed, type of genetic disorder assayed, type of sex-linked abnormalities assayed, the age of the mother and the like. The term "independent" as used herein refers to not being influenced or not being controlled by another. The term "dependent" as used herein refers to being influenced or controlled by another. For example, a particular chromosome and a trisomy event occurring for that particular chromosome that results in a viable being are variables that are dependent upon each other.

[0160] One of skill in the art may use any type of method or prediction algorithm to give significance to the data of the present technology within an acceptable sensitivity and/or specificity. For example, prediction algorithms such as Chi-squared test, z-test, t-test, ANOVA (analysis of variance), regression analysis, neural nets, fuzzy logic, Hidden Markov Models, multiple model state estimation, and the like may be used. One or more methods or prediction algorithms may be determined to give significance to the data having different independent and/or dependent variables of the present technology. And one or more methods or prediction algorithms may be determined not to give significance to the data having different independent and/or dependent variables of the present technology. One may design or change parameters of the different variables of methods described herein based on results of one or more prediction algorithms (e.g., number of sets analyzed, types of nucleotide species in each set). For example, applying the Chi-squared test to detection data may suggest that specific ranges of maternal age are correlated to a higher likelihood of having an offspring with a specific chromosome abnormality, hence the variable of maternal age may be weighed differently verses being weighed the same as other variables.

[0161] In certain embodiments, several algorithms may be chosen to be tested. These algorithms can be trained with raw data. For each new raw data sample, the trained algorithms will assign a classification to that sample (i.e. trisomy or normal). Based on the classifications of the new raw data samples, the trained algorithms' performance may be assessed based on sensitivity and specificity. Finally, an algorithm with the highest sensitivity and/or specificity or combination thereof may be identified.

DETAILED DESCRIPTION

[0162] The presence of fetal nucleic acid in maternal plasma was first reported in 1997 and offers the possibility for non-invasive prenatal diagnosis simply through the analysis of a maternal blood sample (Lo et al., Lancet 350:485-487, 1997). To date, numerous potential clinical applications have been developed. In particular, quantitative abnormalities of fetal nucleic acid, for example DNA, concentrations in maternal plasma have been found to be associated with a number of pregnancy-associated disorders, including preeclampsia, preterm labor, antepartum hemorrhage, invasive placentation, fetal Down syndrome, and other fetal chromosomal aneuploidies. Hence, fetal nucleic acid analysis in maternal plasma represents a powerful mechanism for the monitoring of fetomaternal well-being.

[0163] However, fetal DNA co-exists with background maternal DNA in maternal plasma. Hence, most reported applications have relied on the detection of Y-chromosome sequences as these are most conveniently distinguishable from maternal DNA. Such an approach limits the applicability of the existing assays to only 50% of all pregnancies, namely those with male fetuses. Thus, there is much need for the development of sex-independent compositions and methods for enriching and analyzing fetal nucleic acid from a maternal sample. Also, methods that rely on polymorphic markers to quantify fetal nucleic acid may be susceptible to varying heterozygosity rates across different ethnicities thereby limiting their applicability (e.g., by increasing the number of markers that are needed).

[0164] It was previously demonstrated that fetal and maternal DNA can be distinguished by their differences in methylation status (U.S. Pat. No. 6,927,028, which is hereby incorporated by reference). Methylation is an epigenetic phenomenon, which refers to processes that alter a phenotype without involving changes in the DNA sequence. By exploiting the difference in the DNA methylation status between mother and fetus, one can successfully detect and analyze fetal nucleic acid in a background of maternal nucleic acid.

[0165] The present inventors provides novel genomic polynucleotides that are differentially methylated between the fetal DNA from the fetus (e.g., from the placenta) and the maternal DNA from the mother, for example from peripheral blood cells. This discovery thus provides a new approach for distinguishing fetal and maternal genomic DNA and new methods for accurately quantifying fetal nucleic which may be used for non-invasive prenatal diagnosis.

Methodology

[0166] Practicing the technology herein utilizes routine techniques in the field of molecular biology. Basic texts disclosing the general methods of use in the technology herein include Sambrook and Russell, Molecular Cloning, A Laboratory Manual (3rd ed. 2001); Kriegler, Gene Transfer and Expression: A Laboratory Manual (1990); and Current Protocols in Molecular Biology (Ausubel et al., eds., 1994)).

[0167] For nucleic acids, sizes are given in either kilobases (kb) or base pairs (bp). These are estimates derived from agarose or acrylamide gel electrophoresis, from sequenced nucleic acids, or from published DNA sequences. For proteins, sizes are given in kilodaltons (kDa) or amino acid residue numbers. Protein sizes are estimated from gel electrophoresis, from sequenced proteins, from derived amino acid sequences, or from published protein sequences.

[0168] Oligonucleotides that are not commercially available can be chemically synthesized, e.g., according to the solid phase phosphoramidite triester method first described by Beaucage & Caruthers, Tetrahedron Lett. 22: 1859-1862 (1981), using an automated synthesizer, as described in Van Devanter et. al., Nucleic Acids Res. 12: 6159-6168 (1984). Purification of oligonucleotides is performed using any art-recognized strategy, e.g., native acrylamide gel electrophoresis or anion-exchange high performance liquid chromatography (HPLC) as described in Pearson & Reanier, J. Chrom. 255: 137-149 (1983).

Samples

[0169] Provided herein are methods and compositions for analyzing nucleic acid. In some embodiments, nucleic acid fragments in a mixture of nucleic acid fragments are analyzed. A mixture of nucleic acids can comprise two or more nucleic acid fragment species having different nucleotide sequences, different fragment lengths, different origins (e.g., genomic origins, fetal vs. maternal origins, cell or tissue origins, sample origins, subject origins, and the like), or combinations thereof.

[0170] Nucleic acid or a nucleic acid mixture utilized in methods and apparatuses described herein often is isolated from a sample obtained from a subject. A subject can be any living or non-living organism, including but not limited to a human, a non-human animal, a plant, a bacterium, a fungus or a protist. Any human or non-human animal can be selected, including but not limited to mammal, reptile, avian, amphibian, fish, ungulate, ruminant, bovine (e.g., cattle), equine (e.g., horse), caprine and ovine (e.g., sheep, goat), swine (e.g., pig), camelid (e.g., camel, llama, alpaca), monkey, ape (e.g., gorilla, chimpanzee), ursid (e.g., bear), poultry, dog, cat, mouse, rat, fish, dolphin, whale and shark. A subject may be a male or female (e.g., woman).

[0171] Nucleic acid may be isolated from any type of suitable biological specimen or sample. Non-limiting examples of specimens include fluid or tissue from a subject, including, without limitation, umbilical cord blood, chorionic villi, amniotic fluid, cerbrospinal fluid, spinal fluid, lavage fluid (e.g., bronchoalveolar, gastric, peritoneal, ductal, ear, athroscopic), biopsy sample (e.g., from pre-implantation embryo), celocentesis sample, fetal nucleated cells or fetal cellular remnants, washings of female reproductive tract, urine, feces, sputum, saliva, nasal mucous, prostate fluid, lavage, semen, lymphatic fluid, bile, tears, sweat, breast milk, breast fluid, embryonic cells and fetal cells (e.g. placental cells). In some embodiments, a biological sample is a cervical swab from a subject. In some embodiments, a biological sample may be blood and sometimes plasma or serum. As used herein, the term "blood" encompasses whole blood or any fractions of blood, such as serum and plasma as conventionally defined, for example. Blood plasma refers to the fraction of whole blood resulting from centrifugation of blood treated with anticoagulants. Blood serum refers to the watery portion of fluid remaining after a blood sample has coagulated. Fluid or tissue samples often are collected in accordance with standard protocols hospitals or clinics generally follow. For blood, an appropriate amount of peripheral blood (e.g., between 3-40 milliliters) often is collected and can be stored according to standard procedures prior to further preparation. A fluid or tissue sample from which nucleic acid is extracted may be acellular. In some embodiments, a fluid or tissue sample may contain cellular elements or cellular remnants. In some embodiments fetal cells or cancer cells may be included in the sample.

[0172] A sample often is heterogeneous, by which is meant that more than one type of nucleic acid species is present in the sample. For example, heterogeneous nucleic acid can include, but is not limited to, (i) fetally derived and maternally derived nucleic acid, (ii) cancer and non-cancer nucleic acid, (iii) pathogen and host nucleic acid, and more generally, (iv) mutated and wild-type nucleic acid. A sample may be heterogeneous because more than one cell type is present, such as a fetal cell and a maternal cell, a cancer and non-cancer cell, or a pathogenic and host cell. In some embodiments, a minority nucleic acid species and a majority nucleic acid species is present.

[0173] For prenatal applications of technology described herein, fluid or tissue sample may be collected from a female at a gestational age suitable for testing, or from a female who is being tested for possible pregnancy. Suitable gestational age may vary depending on the prenatal test being performed. In certain embodiments, a pregnant female subject sometimes is in the first trimester of pregnancy, at times in the second trimester of pregnancy, or sometimes in the third trimester of pregnancy. In certain embodiments, a fluid or tissue is collected from a pregnant female between about 1 to about 45 weeks of fetal gestation (e.g., at 1-4, 4-8, 8-12, 12-16, 16-20, 20-24, 24-28, 28-32, 32-36, 36-40 or 40-44 weeks of fetal gestation), and sometimes between about 5 to about 28 weeks of fetal gestation (e.g., at 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or 27 weeks of fetal gestation).

Acquisition of Blood Samples and Extraction of DNA

[0174] The present technology relates to separating, enriching and analyzing fetal DNA found in maternal blood as a non-invasive means to detect the presence and/or to monitor the progress of a pregnancy-associated condition or disorder. Thus, the first steps of practicing the technology herein are to obtain a blood sample from a pregnant woman and extract DNA from the sample.

[0175] Acquisition of Blood Samples

[0176] A blood sample is obtained from a pregnant woman at a gestational age suitable for testing using a method of the present technology. The suitable gestational age may vary depending on the disorder tested, as discussed below. Collection of blood from a woman is performed in accordance with the standard protocol hospitals or clinics generally follow. An appropriate amount of peripheral blood, e.g., typically between 5-50 ml, is collected and may be stored according to standard procedure prior to further preparation. Blood samples may be collected, stored or transported in a manner known to the person of ordinary skill in the art to minimize degradation or the quality of nucleic acid present in the sample.

[0177] Preparation of Blood Samples

[0178] The analysis of fetal DNA found in maternal blood according to the present technology may be performed using, e.g., the whole blood, serum, or plasma. The methods for preparing serum or plasma from maternal blood are well known among those of skill in the art. For example, a pregnant woman's blood can be placed in a tube containing EDTA or a specialized commercial product such as Vacutainer SST (Becton Dickinson, Franklin Lakes, N.J.) to prevent blood clotting, and plasma can then be obtained from whole blood through centrifugation. On the other hand, serum may be obtained with or without centrifugation-following blood clotting. If centrifugation is used then it is typically, though not exclusively, conducted at an appropriate speed, e.g., 1,500-3,000 times g. Plasma or serum may be subjected to additional centrifugation steps before being transferred to a fresh tube for DNA extraction.

[0179] In addition to the acellular portion of the whole blood, DNA may also be recovered from the cellular fraction, enriched in the buffy coat portion, which can be obtained following centrifugation of a whole blood sample from the woman and removal of the plasma.

[0180] Extraction of DNA

[0181] There are numerous known methods for extracting DNA from a biological sample including blood. The general methods of DNA preparation (e.g., described by Sambrook and Russell, Molecular Cloning: A Laboratory Manual 3d ed., 2001) can be followed; various commercially available reagents or kits, such as Qiagen's QIAamp Circulating Nucleic Acid Kit, QiaAmp DNA Mini Kit or QiaAmp DNA Blood Mini Kit (Qiagen, Hilden, Germany), GenomicPrep.TM. Blood DNA Isolation Kit (Promega, Madison, Wis.), and GFX.TM. Genomic Blood DNA Purification Kit (Amersham, Piscataway, N.J.), may also be used to obtain DNA from a blood sample from a pregnant woman. Combinations of more than one of these methods may also be used.

[0182] In some embodiments, the sample may first be enriched or relatively enriched for fetal nucleic acid by one or more methods. For example, the discrimination of fetal and maternal DNA can be performed using the compositions and processes of the present technology alone or in combination with other discriminating factors. Examples of these factors include, but are not limited to, single nucleotide differences between chromosome X and Y, chromosome Y-specific sequences, polymorphisms located elsewhere in the genome, size differences between fetal and maternal DNA and differences in methylation pattern between maternal and fetal tissues.

[0183] Other methods for enriching a sample for a particular species of nucleic acid are described in PCT Patent Application Number PCT/US07/69991, filed May 30, 2007, PCT Patent Application Number PCT/US2007/071232, filed Jun. 15, 2007, U.S. Provisional Application Nos. 60/968,876 and 60/968,878 (assigned to the Applicant), (PCT Patent Application Number PCT/EP05/012707, filed Nov. 28, 2005) which are all hereby incorporated by reference. In certain embodiments, maternal nucleic acid is selectively removed (either partially, substantially, almost completely or completely) from the sample.

Nucleic Acid Isolation and Processing

[0184] Nucleic acid may be derived from one or more sources (e.g., cells, soil, etc.) by methods known in the art. Cell lysis procedures and reagents are known in the art and may generally be performed by chemical, physical, or electrolytic lysis methods. For example, chemical methods generally employ lysing agents to disrupt cells and extract the nucleic acids from the cells, followed by treatment with chaotropic salts. Physical methods such as freeze/thaw followed by grinding, the use of cell presses and the like also are useful. High salt lysis procedures also are commonly used. For example, an alkaline lysis procedure may be utilized. The latter procedure traditionally incorporates the use of phenol-chloroform solutions, and an alternative phenol-chloroform-free procedure involving three solutions can be utilized. In the latter procedures, one solution can contain 15 mM Tris, pH 8.0; 10 mM EDTA and 100 ug/ml Rnase A; a second solution can contain 0.2N NaOH and 1% SDS; and a third solution can contain 3M KOAc, pH 5.5. These procedures can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y., 6.3.1-6.3.6 (1989), incorporated herein in its entirety.

[0185] The terms "nucleic acid" and "nucleic acid molecule" are used interchangeably. The terms refer to nucleic acids of any composition form, such as deoxyribonucleic acid (DNA, e.g., complementary DNA (cDNA), genomic DNA (gDNA) and the like), ribonucleic acid (RNA, e.g., message RNA (mRNA), short inhibitory RNA (siRNA), ribosomal RNA (rRNA), transfer RNA (tRNA), microRNA, RNA highly expressed by the fetus or placenta, and the like), and/or DNA or RNA analogs (e.g., containing base analogs, sugar analogs and/or a non-native backbone and the like), RNA/DNA hybrids and polyamide nucleic acids (PNAs), all of which can be in single- or double-stranded form.

[0186] Unless otherwise limited, a nucleic acid can comprise known analogs of natural nucleotides, some of which can function in a similar manner as naturally occurring nucleotides. A nucleic acid can be in any form useful for conducting processes herein (e.g., linear, circular, supercoiled, single-stranded, double-stranded and the like). A nucleic acid may be, or may be from, a plasmid, phage, autonomously replicating sequence (ARS), centromere, artificial chromosome, chromosome, or other nucleic acid able to replicate or be replicated in vitro or in a host cell, a cell, a cell nucleus or cytoplasm of a cell in certain embodiments. A nucleic acid in some embodiments can be from a single chromosome (e.g., a nucleic acid sample may be from one chromosome of a sample obtained from a diploid organism). Nucleic acids also include derivatives, variants and analogs of RNA or DNA synthesized, replicated or amplified from single-stranded ("sense" or "antisense", "plus" strand or "minus" strand, "forward" reading frame or "reverse" reading frame) and double-stranded polynucleotides. Deoxyribonucleotides include deoxyadenosine, deoxycytidine, deoxyguanosine and deoxythymidine. For RNA, the base cytosine is replaced with uracil and the sugar 2' position includes a hydroxyl moiety. A nucleic acid may be prepared using a nucleic acid obtained from a subject as a template.

[0187] Nucleic acid may be isolated at a different time point as compared to another nucleic acid, where each of the samples is from the same or a different source. A nucleic acid may be from a nucleic acid library, such as a cDNA or RNA library, for example. A nucleic acid may be a result of nucleic acid purification or isolation and/or amplification of nucleic acid molecules from the sample.

[0188] Nucleic acid provided for processes described herein may contain nucleic acid from one sample or from two or more samples (e.g., from 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, or 20 or more samples).

[0189] Nucleic acid can include extracellular nucleic acid in certain embodiments. The term "extracellular nucleic acid" as used herein refers to nucleic acid isolated from a source having substantially no cells and also is referred to as "cell-free" nucleic acid and/or "cell-free circulating" nucleic acid. Extracellular nucleic acid often includes no detectable cells and may contain cellular elements or cellular remnants. Non-limiting examples of acellular sources for extracellular nucleic acid are blood plasma, blood serum and urine. As used herein, the term "obtain cell-free circulating sample nucleic acid" includes obtaining a sample directly (e.g., collecting a sample) or obtaining a sample from another who has collected a sample. Without being limited by theory, extracellular nucleic acid may be a product of cell apoptosis and cell breakdown, which provides basis for extracellular nucleic acid often having a series of lengths across a spectrum (e.g., a "ladder").

[0190] Extracellular nucleic acid can include different nucleic acid species, and therefore is referred to herein as "heterogeneous" in certain embodiments. For example, blood serum or plasma from a person having cancer can include nucleic acid from cancer cells and nucleic acid from non-cancer cells. In another example, blood serum or plasma from a pregnant female can include maternal nucleic acid and fetal nucleic acid. In some instances, fetal nucleic acid sometimes is about 5% to about 50% of the overall nucleic acid (e.g., about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49% of the total nucleic acid is fetal nucleic acid). In some embodiments, the majority of fetal nucleic acid in nucleic acid is of a length of about 500 base pairs or less (e.g., about 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% of fetal nucleic acid is of a length of about 500 base pairs or less). In some embodiments, the majority of fetal nucleic acid in nucleic acid is of a length of about 250 base pairs or less (e.g., about 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% of fetal nucleic acid is of a length of about 250 base pairs or less). In some embodiments, the majority of fetal nucleic acid in nucleic acid is of a length of about 200 base pairs or less (e.g., about 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% of fetal nucleic acid is of a length of about 200 base pairs or less). In some embodiments, the majority of fetal nucleic acid in nucleic acid is of a length of about 150 base pairs or less (e.g., about 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% of fetal nucleic acid is of a length of about 150 base pairs or less). In some embodiments, the majority of fetal nucleic acid in nucleic acid is of a length of about 100 base pairs or less (e.g., about 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% of fetal nucleic acid is of a length of about 100 base pairs or less).

[0191] Nucleic acid may be provided for conducting methods described herein without processing of the sample(s) containing the nucleic acid, in certain embodiments. In some embodiments, nucleic acid is provided for conducting methods described herein after processing of the sample(s) containing the nucleic acid. For example, a nucleic acid may be extracted, isolated, purified or amplified from the sample(s). The term "isolated" as used herein refers to nucleic acid removed from its original environment (e.g., the natural environment if it is naturally occurring, or a host cell if expressed exogenously), and thus is altered by human intervention (e.g., "by the hand of man") from its original environment. An isolated nucleic acid is provided with fewer non-nucleic acid components (e.g., protein, lipid) than the amount of components present in a source sample. A composition comprising isolated nucleic acid can be about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater than 99% free of non-nucleic acid components. The term "purified" as used herein refers to nucleic acid provided that contains fewer nucleic acid species than in the sample source from which the nucleic acid is derived. A composition comprising nucleic acid may be about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater than 99% free of other nucleic acid species. The term "amplified" as used herein refers to subjecting nucleic acid of a sample to a process that linearly or exponentially generates amplicon nucleic acids having the same or substantially the same nucleotide sequence as the nucleotide sequence of the nucleic acid in the sample, or portion thereof.

[0192] Nucleic acid also may be processed by subjecting nucleic acid to a method that generates nucleic acid fragments, in certain embodiments, before providing nucleic acid for a process described herein. In some embodiments, nucleic acid subjected to fragmentation or cleavage may have a nominal, average or mean length of about 5 to about 10,000 base pairs, about 100 to about 1,000 base pairs, about 100 to about 500 base pairs, or about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000 or 9000 base pairs. Fragments can be generated by any suitable method known in the art, and the average, mean or nominal length of nucleic acid fragments can be controlled by selecting an appropriate fragment-generating procedure. In certain embodiments, nucleic acid of a relatively shorter length can be utilized to analyze sequences that contain little sequence variation and/or contain relatively large amounts of known nucleotide sequence information. In some embodiments, nucleic acid of a relatively longer length can be utilized to analyze sequences that contain greater sequence variation and/or contain relatively small amounts of nucleotide sequence information.

[0193] Nucleic acid fragments may contain overlapping nucleotide sequences, and such overlapping sequences can facilitate construction of a nucleotide sequence of the non-fragmented counterpart nucleic acid, or a portion thereof. For example, one fragment may have subsequences x and y and another fragment may have subsequences y and z, where x, y and z are nucleotide sequences that can be 5 nucleotides in length or greater. Overlap sequence y can be utilized to facilitate construction of the x-y-z nucleotide sequence in nucleic acid from a sample in certain embodiments. Nucleic acid may be partially fragmented (e.g., from an incomplete or terminated specific cleavage reaction) or fully fragmented in certain embodiments.

[0194] Nucleic acid can be fragmented by various methods known in the art, which include without limitation, physical, chemical and enzymatic processes. Non-limiting examples of such processes are described in U.S. Patent Application Publication No. 20050112590 (published on May 26, 2005, entitled "Fragmentation-based methods and systems for sequence variation detection and discovery," naming Van Den Boom et al.). Certain processes can be selected to generate non-specifically cleaved fragments or specifically cleaved fragments. Non-limiting examples of processes that can generate non-specifically cleaved fragment nucleic acid include, without limitation, contacting nucleic acid with apparatus that expose nucleic acid to shearing force (e.g., passing nucleic acid through a syringe needle; use of a French press); exposing nucleic acid to irradiation (e.g., gamma, x-ray, UV irradiation; fragment sizes can be controlled by irradiation intensity); boiling nucleic acid in water (e.g., yields about 500 base pair fragments) and exposing nucleic acid to an acid and base hydrolysis process.

[0195] As used herein, "fragmentation" or "cleavage" refers to a procedure or conditions in which a nucleic acid molecule, such as a nucleic acid template gene molecule or amplified product thereof, may be severed into two or more smaller nucleic acid molecules. Such fragmentation or cleavage can be sequence specific, base specific, or nonspecific, and can be accomplished by any of a variety of methods, reagents or conditions, including, for example, chemical, enzymatic, physical fragmentation.

[0196] As used herein, "fragments", "cleavage products", "cleaved products" or grammatical variants thereof, refers to nucleic acid molecules resultant from a fragmentation or cleavage of a nucleic acid template gene molecule or amplified product thereof. While such fragments or cleaved products can refer to all nucleic acid molecules resultant from a cleavage reaction, typically such fragments or cleaved products refer only to nucleic acid molecules resultant from a fragmentation or cleavage of a nucleic acid template gene molecule or the portion of an amplified product thereof containing the corresponding nucleotide sequence of a nucleic acid template gene molecule. For example, an amplified product can contain one or more nucleotides more than the amplified nucleotide region of a nucleic acid template sequence (e.g., a primer can contain "extra" nucleotides such as a transcriptional initiation sequence, in addition to nucleotides complementary to a nucleic acid template gene molecule, resulting in an amplified product containing "extra" nucleotides or nucleotides not corresponding to the amplified nucleotide region of the nucleic acid template gene molecule). Accordingly, fragments can include fragments arising from portions of amplified nucleic acid molecules containing, at least in part, nucleotide sequence information from or based on the representative nucleic acid template molecule.

[0197] As used herein, the term "complementary cleavage reactions" refers to cleavage reactions that are carried out on the same nucleic acid using different cleavage reagents or by altering the cleavage specificity of the same cleavage reagent such that alternate cleavage patterns of the same target or reference nucleic acid or protein are generated. In certain embodiments, nucleic acid may be treated with one or more specific cleavage agents (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more specific cleavage agents) in one or more reaction vessels (e.g., nucleic acid is treated with each specific cleavage agent in a separate vessel).

[0198] Nucleic acid may be specifically cleaved by contacting the nucleic acid with one or more specific cleavage agents. The term "specific cleavage agent" as used herein refers to an agent, sometimes a chemical or an enzyme that can cleave a nucleic acid at one or more specific sites. Specific cleavage agents often cleave specifically according to a particular nucleotide sequence at a particular site.

[0199] Examples of enzymatic specific cleavage agents include without limitation endonucleases (e.g., DNase (e.g., DNase I, II); RNase (e.g., RNase E, F, H, P); Cleavase.TM. enzyme; Taq DNA polymerase; E. coli DNA polymerase I and eukaryotic structure-specific endonucleases; murine FEN-1 endonucleases; type I, II or III restriction endonucleases such as Acc I, Afl III, Alu I, Alw44 I, Apa I, Asn I, Ava I, Ava II, BamH I, Ban II, Bcl I, Bgl I. Bgl II, Bln I, Bsm I, BssH II, BstE II, Cfo I, Cla I, Dde I, Dpn I, Dra I, EclX I, EcoR I, EcoR I, EcoR II, EcoR V, Hae II, Hae II, Hind III, Hind III, Hpa I, Hpa II, Kpn I, Ksp I, Mlu I, MluN I, Msp I, Nci I, Nco I, Nde I, Nde II, Nhe I, Not I, Nru I, Nsi I, Pst I, Pvu I, Pvu II, Rsa I, Sac I, Sal I, Sau3A I, Sca I, ScrF I, Sfi I, Sma I, Spe I, Sph I, Ssp I, Stu I, Sty I, Swa I, Taq I, Xba I, Xho I; glycosylases (e.g., uracil-DNA glycolsylase (UDG), 3-methyladenine DNA glycosylase, 3-methyladenine DNA glycosylase II, pyrimidine hydrate-DNA glycosylase, FaPy-DNA glycosylase, thymine mismatch-DNA glycosylase, hypoxanthine-DNA glycosylase, 5-Hydroxymethyluracil DNA glycosylase (HmUDG), 5-Hydroxymethylcytosine DNA glycosylase, or 1,N6-etheno-adenine DNA glycosylase); exonucleases (e.g., exonuclease III); ribozymes, and DNAzymes. Nucleic acid may be treated with a chemical agent, and the modified nucleic acid may be cleaved. In non-limiting examples, nucleic acid may be treated with (i) alkylating agents such as methylnitrosourea that generate several alkylated bases, including N3-methyladenine and N3-methylguanine, which are recognized and cleaved by alkyl purine DNA-glycosylase; (ii) sodium bisulfite, which causes deamination of cytosine residues in DNA to form uracil residues that can be cleaved by uracil N-glycosylase; and (iii) a chemical agent that converts guanine to its oxidized form, 8-hydroxyguanine, which can be cleaved by formamidopyrimidine DNA N-glycosylase. Examples of chemical cleavage processes include without limitation alkylation, (e.g., alkylation of phosphorothioate-modified nucleic acid); cleavage of acid lability of P3'-N5'-phosphoroamidate-containing nucleic acid; and osmium tetroxide and piperidine treatment of nucleic acid.

[0200] Nucleic acid also may be exposed to a process that modifies certain nucleotides in the nucleic acid before providing nucleic acid for a method described herein. A process that selectively modifies nucleic acid based upon the methylation state of nucleotides therein can be applied to nucleic acid, for example. In addition, conditions such as high temperature, ultraviolet radiation, x-radiation, can induce changes in the sequence of a nucleic acid molecule. Nucleic acid may be provided in any form useful for conducting a sequence analysis or manufacture process described herein, such as solid or liquid form, for example. In certain embodiments, nucleic acid may be provided in a liquid form optionally comprising one or more other components, including without limitation one or more buffers or salts.

[0201] Nucleic acid may be single or double stranded. Single stranded DNA, for example, can be generated by denaturing double stranded DNA by heating or by treatment with alkali, for example. In some cases, nucleic acid is in a D-loop structure, formed by strand invasion of a duplex DNA molecule by an oligonucleotide or a DNA-like molecule such as peptide nucleic acid (PNA). D loop formation can be facilitated by addition of E. Coli RecA protein and/or by alteration of salt concentration, for example, using methods known in the art.

Genomic DNA Target Sequences

[0202] In some embodiments of the methods provided herein, one or more nucleic acid species, and sometimes one or more nucleotide sequence species, are targeted for amplification and quantification. In some embodiments, the targeted nucleic acids are genomic DNA sequences. Certain genomic DNA target sequences are used, for example, because they can allow for the determination of a particular feature for a given assay. Genomic DNA target sequences can be referred to herein as markers for a given assay. In some cases, genomic target sequences are polymorphic, as described herein. In some embodiments, more than one genomic DNA target sequence or marker can allow for the determination of a particular feature for a given assay. Such genomic DNA target sequences are considered to be of a particular "region". As used herein, a "region" is not intended to be limited to a description of a genomic location, such as a particular chromosome, stretch of chromosomal DNA or genetic locus. Rather, the term "region" is used herein to identify a collection of one or more genomic DNA target sequences or markers that can be indicative of a particular assay. Such assays can include, but are not limited to, assays for the detection and quantification of fetal nucleic acid, assays for the detection and quantification of maternal nucleic acid, assays for the detection and quantification of total DNA, assays for the detection and quantification of methylated DNA, assays for the detection and quantification of fetal specific nucleic acid (e.g. chromosome Y DNA), and assays for the detection and quantification of digested and/or undigested DNA, as an indicator of digestion efficiency. In some embodiments, the genomic DNA target sequence is described as being within a particular genomic locus. As used herein, a genomic locus can include any or a combination of open reading frame DNA, non-transcribed DNA, intronic sequences, extronic sequences, promoter sequences, enhancer sequences, flanking sequences, or any sequences considered by one of skill in the art to be associated with a given genomic locus.

[0203] Assays for the Determination of Methylated DNA

[0204] In some embodiments of the methods provided herein, one or more genomic DNA target sequences are used that can allow for the determination of methylated DNA. Generally, genomic DNA target sequences used for the determination of methylated DNA are differentially methylated in fetal and maternal nucleic acid, and thus, differentially digested according to the methods provided herein for methylation-sensitive restriction enzymes. In some cases, a genomic DNA target sequence is a single copy gene. In some cases, a genomic DNA target sequence is located on chromosome 13, chromosome 18, chromosome 21, chromosome X, or chromosome Y. In some cases, a genomic DNA target sequence is not located on chromosome 13. In some cases, a genomic DNA target sequence is not located on chromosome 18. In some cases, a genomic DNA target sequence is not located on chromosome 21. In some cases, a genomic DNA target sequence is not located on chromosome X. In some cases, a genomic DNA target sequence is not located on chromosome Y. In some cases, a genomic DNA target sequence is typically methylated in one DNA species such as, for example, placental DNA (i.e. at least about 50% or greater methylation). In some cases, the genomic DNA target sequence is minimally methylated in another DNA species such as, for example, maternal DNA (i.e. less than about 1% methylation). In some cases, the genomic DNA target sequence does not contain any known single nucleotide polymorphisms (SNPs) within the PCR primer hybridization sequences. In some cases, the genomic DNA target sequence does not contain any known mutations within the PCR primer hybridization sequences. In some cases, the genomic DNA target sequence does not contain any known insertion or deletions within the PCR primer hybridization sequences. In some cases, the melting temperature of the PCR primers that can hybridize to a genomic DNA target sequence is not below 65.degree. C. In some cases, the melting temperature of the PCR primers that can hybridize to a genomic DNA target sequence is not above 75.degree. C. In some cases, the genomic DNA target sequence contains at least two restriction sites within the amplified region. In some embodiments, the genomic DNA target sequence length is about 50 base pairs to about 200 base pairs. In some cases, the genomic DNA target sequence length is 70 base pairs. In some cases, the genomic DNA target sequence does not possess any negative .DELTA.G values for secondary structure of the complete amplicon prediction using mfold (M. Zuker, Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res. 31 (13), 3406-15, (2003)). In some embodiments, the genomic DNA target sequence used for the determination of methylated DNA is within the TBX3 locus. In some embodiments, the genomic DNA target sequence used for the determination of methylated DNA is within the SOX14 locus. Additional genomic targets that can be used for the determination of methylated DNA in conjunction with the methods provided herein are presented in Example 3.

[0205] Assays for the Determination of Total DNA

[0206] In some embodiments of the methods provided herein, one or more genomic DNA target sequences are used that can allow for the determination of total DNA. Generally, genomic DNA target sequences used for the determination of total DNA are present in every genome copy (e.g. is present in fetal DNA and maternal DNA, cancer DNA and normal DNA, pathogen DNA and host DNA). In some cases, a genomic DNA target sequence is a single copy gene. In some cases, a genomic DNA target sequence is located on chromosome 13, chromosome 18, chromosome 21, chromosome X, or chromosome Y. In some cases, a genomic DNA target sequence is not located on chromosome 13. In some cases, a genomic DNA target sequence is not located on chromosome 18. In some cases, a genomic DNA target sequence is not located on chromosome 21. In some cases, a genomic DNA target sequence is not located on chromosome X. In some cases, a genomic DNA target sequence is not located on chromosome Y. In some cases, a genomic DNA target sequence does not contain any known single nucleotide polymorphisms (SNPs) within the PCR primer hybridization sequences. In some cases, a genomic DNA target sequence does not contain any known mutations within the PCR primer hybridization sequences. In some cases, a genomic DNA target sequence does not contain any known insertion or deletions within the PCR primer hybridization sequences. In some cases, the melting temperature of the PCR primers that can hybridize to a genomic DNA target sequence is not below 65.degree. C. In some cases, the melting temperature of the PCR primers that can hybridize to a genomic DNA target sequence is not above 75.degree. C. In some embodiments, the genomic DNA target sequence length is about 50 base pairs to about 200 base pairs. In some cases, the genomic DNA target sequence length is 70 base pairs. In some cases, the genomic DNA target sequence does not possess any negative .DELTA.G values for secondary structure of the complete amplicon prediction using mfold (M. Zuker, Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res. 31 (13), 3406-15, (2003)). In some embodiments, the genomic DNA target sequence used for the determination of total DNA is within the ALB locus. In some embodiments, the genomic DNA target sequence used for the determination of total DNA is within the APOE or RNAseP locus.

[0207] Assays for the Determination of Fetal DNA

[0208] In some embodiments of the methods provided herein, one or more genomic DNA target sequences are used that can allow for the determination of fetal DNA. In some embodiments, genomic DNA target sequences used for the determination of fetal DNA are specific to the Y chromosome. In some cases, the genomic DNA target sequence is a single copy gene. In some cases, the genomic DNA target sequence does not contain any known single nucleotide polymorphisms (SNPs) within the PCR primer hybridization sequences. In some cases, the genomic DNA target sequence does not contain any known mutations within the PCR primer hybridization sequences. In some cases, the genomic DNA target sequence does not contain any known insertion or deletions within the PCR primer hybridization sequences. In some cases, the melting temperature of the PCR primers that can hybridize to a genomic DNA target sequence is not below 65.degree. C. In some cases, the melting temperature of the PCR primers that can hybridize to a genomic DNA target sequence is not above 75.degree. C. In some cases, the genomic DNA target sequence does not contain the restriction site GCGC within the amplified region. In some embodiments, the genomic DNA target sequence length is about 50 base pairs to about 200 base pairs. In some cases, the genomic DNA target sequence length is 70 base pairs. In some cases, the genomic DNA target sequence does not possess any negative .DELTA.G values for secondary structure of the complete amplicon prediction using mfold (M. Zuker, Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res. 31 (13), 3406-15, (2003)). In some embodiments, the genomic DNA target sequence used for the determination of fetal DNA is within the UTY locus. In some embodiments, the genomic DNA target sequence used for the determination of fetal DNA is within the SRY1 or SRY2 locus.

[0209] Assays for the Determination of Digested and/or Undigested DNA

[0210] In some embodiments of the methods provided herein, one or more genomic DNA target sequences are used that can allow for the determination of the amount of digested or undigested nucleic acid, as an indicator of digestion efficiency. Such genomic DNA target sequences are present in every genome in the sample (e.g. maternal and fetal species genomes). Generally, genomic DNA target sequences used for the determination of digested or undigested DNA contain at least one restriction site present in a genomic DNA target sequence used in another assay. Thus, the genomic DNA target sequences used for the determination of digested or undigested DNA serve as controls for assays that include differential digestion. Generally, the genomic DNA target sequence is unmethylated in all nucleic acid species tested (e.g. unmethylated in both maternal and fetal species genomes). In some cases, the genomic DNA target sequence is a single copy gene. In some cases, the genomic DNA target sequence is not located on chromosome 13. In some cases, the genomic DNA target sequence is not located on chromosome 18. In some cases, the genomic DNA target sequence is not located on chromosome 21. In some cases, the genomic DNA target sequence is not located on chromosome X. In some cases, the genomic DNA target sequence is not located on chromosome Y. In some cases, the genomic DNA target sequence does not contain any known single nucleotide polymorphisms (SNPs) within the PCR primer hybridization sequences. In some cases, the genomic DNA target sequence does not contain any known mutations within the PCR primer hybridization sequences. In some cases, the genomic DNA target sequence does not contain any known insertion or deletions within the PCR primer hybridization sequences. In some cases, the melting temperature of the PCR primers that can hybridize to a genomic DNA target sequence is not below 65.degree. C. In some cases, the melting temperature of the PCR primers that can hybridize to a genomic DNA target sequence is not above 75.degree. C. In some embodiments, the genomic DNA target sequence length is about 50 base pairs to about 200 base pairs. In some cases, the genomic DNA target sequence length is 70 base pairs. In some cases, the genomic DNA target sequence does not possess any negative .DELTA.G values for secondary structure of the complete amplicon prediction using mfold (M. Zuker, Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res. 31 (13), 3406-15, (2003)). In some embodiments, the genomic DNA target sequence used for the determination of digested or undigested DNA is within the POP5 locus. In some embodiments, the genomic DNA target sequence used for the determination of digested or undigested DNA is within the LDHA locus.

Methylation Specific Separation of Nucleic Acid

[0211] The methods provided herein offer an alternative approach for the enrichment of fetal DNA based on the methylation-specific separation of differentially methylated DNA. It has recently been discovered that many genes involved in developmental regulation are controlled through epigenetics in embryonic stem cells. Consequently, multiple genes can be expected to show differential DNA methylation between nucleic acid of fetal origin and maternal origin. Once these regions are identified, a technique to capture methylated DNA can be used to specifically enrich fetal DNA. For identification of differentially methylated regions, a novel approach was used to capture methylated DNA. This approach uses a protein, in which the methyl binding domain of MBD2 is fused to the Fc fragment of an antibody (MBD-FC) (Gebhard C, Schwarzfischer L, Pham T H, Schilling E, Klug M, Andreesen R, Rehli M (2006) Genome wide profiling of CpG methylation identifies novel targets of aberrant hypermethylation in myeloid leukemia. Cancer Res 66:6118-6128). This fusion protein has several advantages over conventional methylation specific antibodies. The MBD-FC has a higher affinity to methylated DNA and it binds double stranded DNA. Most importantly the two proteins differ in the way they bind DNA. Methylation specific antibodies bind DNA stochastically, which means that only a binary answer can be obtained. The methyl binding domain of MBD-FC on the other hand binds all DNA molecules regardless of their methylation status. The strength of this protein--DNA interaction is defined by the level of DNA methylation. After binding genomic DNA, eluate solutions of increasing salt concentrations can be used to fractionate non-methylated and methylated DNA allowing for a more controlled separation (Gebhard C, Schwarzfischer L, Pham T H, Andreesen R, Mackensen A, Rehli M (2006) Rapid and sensitive detection of CpG-methylation using methyl-binding (MB)-PCR. Nucleic Acids Res 34:e82). Consequently this method, called Methyl-CpG immunoprecipitation (MCIP), cannot only enrich, but also fractionate genomic DNA according to methylation level, which is particularly helpful when the unmethylated DNA fraction should be investigated as well.

Methylation Sensitive Restriction Enzyme Digestion

[0212] The technology herein also provides compositions and processes for determining the amount of fetal nucleic acid from a maternal sample. The technology herein allows for the enrichment of fetal nucleic acid regions in a maternal sample by selectively digesting nucleic acid from said maternal sample with an enzyme that selectively and completely or substantially digests the maternal nucleic acid to enrich the sample for at least one fetal nucleic acid region. Preferably, the digestion efficiency is greater than about 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. Following enrichment, the amount of fetal nucleic acid can be determined by quantitative methods that do not require polymorphic sequences or bisulfite treatment, thereby, offering a solution that works equally well for female fetuses and across different ethnicities and preserves the low copy number fetal nucleic acid present in the sample.

[0213] For example, there are methyl-sensitive enzymes that preferentially or substantially cleave or digest at their DNA recognition sequence if it is non-methylated. Thus, an unmethylated DNA sample will be cut into smaller fragments than a methylated DNA sample. Similarly, a hypermethylated DNA sample will not be cleaved. In contrast, there are methyl-sensitive enzymes that cleave at their DNA recognition sequence only if it is methylated.

[0214] Methyl-sensitive enzymes that digest unmethylated DNA suitable for use in methods of the technology herein include, but are not limited to, HpaII, HhaI, MaeII, BstUI and AciI. An enzyme that can be used is HpaII that cuts only the unmethylated sequence CCGG. Another enzyme that can be used is HhaI that cuts only the unmethylated sequence GCGC. Both enzymes are available from New England BioLabs.RTM., Inc. Combinations of two or more methyl-sensitive enzymes that digest only unmethylated DNA can also be used. Suitable enzymes that digest only methylated DNA include, but are not limited to, Dpn I, which cuts at a recognition sequence GATC, and McrBC, which belongs to the family of AAA.sup.+ proteins and cuts DNA containing modified cytosines and cuts at recognition site 5' . . . Pu.sup.mC (N.sub.40-3000) Pu.sup.mC . . . 3' (New England BioLabs, Inc., Beverly, Mass.).

[0215] Cleavage methods and procedures for selected restriction enzymes for cutting DNA at specific sites are well known to the skilled artisan. For example, many suppliers of restriction enzymes provide information on conditions and types of DNA sequences cut by specific restriction enzymes, including New England BioLabs, Pro-Mega Biochems, Boehringer-Mannheim, and the like. Sambrook et al. (See Sambrook et al., Molecular Biology: A laboratory Approach, Cold Spring Harbor, N.Y. 1989) provide a general description of methods for using restriction enzymes and other enzymes. Enzymes often are used under conditions that will enable cleavage of the maternal DNA with about 95%-100% efficiency, preferably with about 98%-100% efficiency.

Other Methods for Methylation Analysis

[0216] Various methylation analysis procedures are known in the art, and can be used in conjunction with the present technology. These assays allow for determination of the methylation state of one or a plurality of CpG islands within a DNA sequence. In addition, the methods maybe used to quantify methylated nucleic acid. Such assays involve, among other techniques, DNA sequencing of bisulfite-treated DNA, PCR (for sequence-specific amplification), Southern blot analysis, and use of methylation-sensitive restriction enzymes.

[0217] Genomic sequencing is a technique that has been simplified for analysis of DNA methylation patterns and 5-methylcytosine distribution by using bisulfite treatment (Frommer et al., Proc. Natl. Acad. Sci. USA 89:1827-1831, 1992). Additionally, restriction enzyme digestion of PCR products amplified from bisulfite-converted DNA may be used, e.g., the method described by Sadri & Hornsby (Nucl. Acids Res. 24:5058-5059, 1996), or COBRA (Combined Bisulfite Restriction Analysis) (Xiong & Laird, Nucleic Acids Res. 25:2532-2534, 1997).

[0218] COBRA analysis is a quantitative methylation assay useful for determining DNA methylation levels at specific gene loci in small amounts of genomic DNA (Xiong & Laird, Nucleic Acids Res. 25:2532-2534, 1997). Briefly, restriction enzyme digestion is used to reveal methylation-dependent sequence differences in PCR products of sodium bisulfite-treated DNA. Methylation-dependent sequence differences are first introduced into the genomic DNA by standard bisulfite treatment according to the procedure described by Frommer et al. (Proc. Natl. Acad. Sci. USA 89:1827-1831, 1992). PCR amplification of the bisulfite converted DNA is then performed using primers specific for the interested CpG islands, followed by restriction endonuclease digestion, gel electrophoresis, and detection using specific, labeled hybridization probes. Methylation levels in the original DNA sample are represented by the relative amounts of digested and undigested PCR product in a linearly quantitative fashion across a wide spectrum of DNA methylation levels. In addition, this technique can be reliably applied to DNA obtained from microdissected paraffin-embedded tissue samples. Typical reagents (e.g., as might be found in a typical COBRA-based kit) for COBRA analysis may include, but are not limited to: PCR primers for specific gene (or methylation-altered DNA sequence or CpG island); restriction enzyme and appropriate buffer; gene-hybridization oligo; control hybridization oligo; kinase labeling kit for oligo probe; and radioactive nucleotides. Additionally, bisulfite conversion reagents may include: DNA denaturation buffer; sulfonation buffer; DNA recovery reagents or kits (e.g., precipitation, ultrafiltration, affinity column); desulfonation buffer; and DNA recovery components.

[0219] The MethyLight.TM. assay is a high-throughput quantitative methylation assay that utilizes fluorescence-based real-time PCR (TaqMan.RTM.) technology that requires no further manipulations after the PCR step (Eads et al., Cancer Res. 59:2302-2306, 1999). Briefly, the MethyLight.TM. process begins with a mixed sample of genomic DNA that is converted, in a sodium bisulfite reaction, to a mixed pool of methylation-dependent sequence differences according to standard procedures (the bisulfite process converts unmethylated cytosine residues to uracil). Fluorescence-based PCR is then performed either in an "unbiased" (with primers that do not overlap known CpG methylation sites) PCR reaction, or in a "biased" (with PCR primers that overlap known CpG dinucleotides) reaction. Sequence discrimination can occur either at the level of the amplification process or at the level of the fluorescence detection process, or both.

[0220] The MethyLight assay may be used as a quantitative test for methylation patterns in the genomic DNA sample, where sequence discrimination occurs at the level of probe hybridization. In this quantitative version, the PCR reaction provides for unbiased amplification in the presence of a fluorescent probe that overlaps a particular putative methylation site. An unbiased control for the amount of input DNA is provided by a reaction in which neither the primers, nor the probe overlie any CpG dinucleotides. Alternatively, a qualitative test for genomic methylation is achieved by probing of the biased PCR pool with either control oligonucleotides that do not "cover" known methylation sites (a fluorescence-based version of the "MSP" technique), or with oligonucleotides covering potential methylation sites.

[0221] The MethyLight process can by used with a "TaqMan" probe in the amplification process. For example, double-stranded genomic DNA is treated with sodium bisulfite and subjected to one of two sets of PCR reactions using TaqMan.RTM. probes; e.g., with either biased primers and TaqMan.RTM. probe, or unbiased primers and TaqMan.RTM. probe. The TaqMan.RTM. probe is dual-labeled with fluorescent "reporter" and "quencher" molecules, and is designed to be specific for a relatively high GC content region so that it melts out at about 10.degree. C. higher temperature in the PCR cycle than the forward or reverse primers. This allows the TaqMan.RTM. probe to remain fully hybridized during the PCR annealing/extension step. As the Taq polymerase enzymatically synthesizes a new strand during PCR, it will eventually reach the annealed TaqMan.RTM. probe. The Taq polymerase 5' to 3' endonuclease activity will then displace the TaqMan.RTM. probe by digesting it to release the fluorescent reporter molecule for quantitative detection of its now unquenched signal using a real-time fluorescent detection system.

[0222] Typical reagents (e.g., as might be found in a typical MethyLight.TM.-based kit) for MethyLight.TM. analysis may include, but are not limited to: PCR primers for specific gene (or methylation-altered DNA sequence or CpG island); TaqMan.RTM. probes; optimized PCR buffers and deoxynucleotides; and Taq polymerase.

[0223] The Ms-SNuPE technique is a quantitative method for assessing methylation differences at specific CpG sites based on bisulfite treatment of DNA, followed by single-nucleotide primer extension (Gonzalgo & Jones, Nucleic Acids Res. 25:2529-2531, 1997). Briefly, genomic DNA is reacted with sodium bisulfite to convert unmethylated cytosine to uracil while leaving 5-methylcytosine unchanged. Amplification of the desired target sequence is then performed using PCR primers specific for bisulfite-converted DNA, and the resulting product is isolated and used as a template for methylation analysis at the CpG site(s) of interest. Small amounts of DNA can be analyzed (e.g., microdissected pathology sections), and it avoids utilization of restriction enzymes for determining the methylation status at CpG sites.

[0224] Typical reagents (e.g., as might be found in a typical Ms-SNuPE-based kit) for Ms-SNuPE analysis may include, but are not limited to: PCR primers for specific gene (or methylation-altered DNA sequence or CpG island); optimized PCR buffers and deoxynucleotides; gel extraction kit; positive control primers; Ms-SNuPE primers for specific gene; reaction buffer (for the Ms-SNuPE reaction); and radioactive nucleotides. Additionally, bisulfite conversion reagents may include: DNA denaturation buffer; sulfonation buffer; DNA recovery regents or kit (e.g., precipitation, ultrafiltration, affinity column); desulfonation buffer; and DNA recovery components.

[0225] MSP (methylation-specific PCR) allows for assessing the methylation status of virtually any group of CpG sites within a CpG island, independent of the use of methylation-sensitive restriction enzymes (Herman et al. Proc. Nat. Acad. Sci. USA 93:9821-9826, 1996; U.S. Pat. No. 5,786,146).

[0226] Briefly, DNA is modified by sodium bisulfite converting all unmethylated, but not methylated cytosines to uracil, and subsequently amplified with primers specific for methylated versus unmethylated DNA. MSP requires only small quantities of DNA, is sensitive to 0.1% methylated alleles of a given CpG island locus, and can be performed on DNA extracted from paraffin-embedded samples. Typical reagents (e.g., as might be found in a typical MSP-based kit) for MSP analysis may include, but are not limited to: methylated and unmethylated PCR primers for specific gene (or methylation-altered DNA sequence or CpG island), optimized PCR buffers and deoxynucleotides, and specific probes.

[0227] The MCA technique is a method that can be used to screen for altered methylation patterns in genomic DNA, and to isolate specific sequences associated with these changes (Toyota et al., Cancer Res. 59:2307-12, 1999). Briefly, restriction enzymes with different sensitivities to cytosine methylation in their recognition sites are used to digest genomic DNAs from primary tumors, cell lines, and normal tissues prior to arbitrarily primed PCR amplification. Fragments that show differential methylation are cloned and sequenced after resolving the PCR products on high-resolution polyacrylamide gels. The cloned fragments are then used as probes for Southern analysis to confirm differential methylation of these regions. Typical reagents (e.g., as might be found in a typical MCA-based kit) for MCA analysis may include, but are not limited to: PCR primers for arbitrary priming Genomic DNA; PCR buffers and nucleotides, restriction enzymes and appropriate buffers; gene-hybridization oligos or probes; control hybridization oligos or probes.

[0228] Another method for analyzing methylation sites is a primer extension assay, including an optimized PCR amplification reaction that produces amplified targets for subsequent primer extension genotyping analysis using mass spectrometry. The assay can also be done in multiplex. This method (particularly as it relates to genotyping single nucleotide polymorphisms) is described in detail in PCT publication WO05012578A1 and US publication US20050079521A1. For methylation analysis, the assay can be adopted to detect bisulfite introduced methylation dependent C to T sequence changes. These methods are particularly useful for performing multiplexed amplification reactions and multiplexed primer extension reactions (e.g., multiplexed homogeneous primer mass extension (hME) assays) in a single well to further increase the throughput and reduce the cost per reaction for primer extension reactions.

[0229] Four additional methods for DNA methylation analysis include restriction landmark genomic scanning (RLGS, Costello et al., 2000), methylation-sensitive-representational difference analysis (MS-RDA), methylation-specific AP-PCR (MS-AP-PCR) and methyl-CpG binding domain column/segregation of partly melted molecules (MBD/SPM).

[0230] Additional methylation analysis methods that may be used in conjunction with the present technology are described in the following papers: Laird, P. W. Nature Reviews Cancer 3, 253-266 (2003); Biotechniques; Uhlmann, K. et al. Electrophoresis 23:4072-4079 (2002)--PyroMeth; Colella et al. Biotechniques. 2003 July; 35(1):146-50; Dupont J M, Tost J, Jammes H, and Gut I G. Anal Biochem, October 2004; 333(1): 119-27; and Tooke N and Pettersson M. IVDT. November 2004; 41.

Nucleic Acid Quantification

[0231] In some embodiments, the amount of fetal nucleic acid in a sample is determined. In some cases, the amount of fetal nucleic acid is determined based on a quantification of sequence read counts described herein. Quantification may be achieved by direct counting of sequence reads covering particular methylation sites and/or target sites, or by competitive PCR (i.e., co-amplification of competitor oligonucleotides of known quantity, as described herein). The term "amount" as used herein with respect to nucleic acids refers to any suitable measurement, including, but not limited to, absolute amount (e.g. copy number), relative amount (e.g. fraction or ratio), weight (e.g., grams), and concentration (e.g., grams per unit volume (e.g., milliliter); molar units).

[0232] Fraction Determination

[0233] In some embodiments, a fraction or ratio can be determined for the amount of one nucleic acid relative to the amount of another nucleic acid. In some embodiments, the fraction of fetal nucleic acid in a sample relative to the total amount of nucleic acid in the sample is determined. To calculate the fraction of fetal nucleic acid in a sample relative to the total amount of the nucleic acid in the sample, the following equation can be applied:

The fraction of fetal nucleic acid=(amount of fetal nucleic acid)/[(amount of total nucleic acid)].

[0234] Copy Number Determination Using Competitors

[0235] In some embodiments, the absolute amount (e.g. copy number) of fetal nucleic acid is determined. Often, the copy number of fetal nucleic acid is determined based on the amount of a competitor oligonucleotide used. In some embodiments, the copy number of maternal nucleic acid is determined. To calculate the copy number of fetal nucleic acid in a sample, the following equation can be applied:

Copy number(fetal nucleic acid)=[(amount of the fetal nucleic acid)/(amount of the fetal competitor)].times.C

where C is the number of competitor oligonucleotides added into the reaction. In some cases, the amounts of the fetal nucleic acid and fetal competitor are obtained in a readout generated by a sequencing reaction (e.g. sequence read counts).

Additional Methods for Determining Fetal Nucleic Acid Content

[0236] The amount of fetal nucleic acid (e.g., concentration, relative amount, absolute amount, copy number, and the like) in nucleic acid is determined in some embodiments. In some cases, the amount of fetal nucleic acid in a sample is referred to as "fetal fraction". In certain embodiments, the amount of fetal nucleic acid is determined according to markers specific to a male fetus (e.g., Y-chromosome STR markers (e.g., DYS 19, DYS 385, DYS 392 markers); RhD marker in RhD-negative females), allelic ratios of polymorphic sequences, or according to one or more markers specific to fetal nucleic acid and not maternal nucleic acid (e.g., differential epigenetic biomarkers (e.g., methylation; described in further detail below) between mother and fetus, or fetal RNA markers in maternal blood plasma (see e.g., Lo, 2005, Journal of Histochemistry and Cytochemistry 53 (3): 293-296)).

[0237] Polymorphism-Based Fetal Quantifier Assay

[0238] Determination of fetal nucleic acid content (e.g., fetal fraction) sometimes is performed using a polymorphism-based fetal quantifier assay (FQA), as described herein. This type of assay allows for the detection and quantification of fetal nucleic acid in a maternal sample based on allelic ratios of polymorphic sequences (e.g., single nucleotide polymorphisms (SNPs)). In some cases, nucleotide sequence reads are obtained for a maternal sample and fetal fraction is determined by comparing the total number of nucleotide sequence reads that map to a first allele and the total number of nucleotide sequence reads that map to a second allele at an informative polymorphic site (e.g., SNP) in a reference genome. In some cases, fetal alleles are identified, for example, by their relative minor contribution to the mixture of fetal and maternal nucleic acids in the sample when compared to the major contribution to the mixture by the maternal nucleic acids. In some cases, fetal alleles are identified by a deviation of allele frequency from an expected allele frequency, as described below. In some cases, the relative abundance of fetal nucleic acid in a maternal sample can be determined as a parameter of the total number of unique sequence reads mapped to a target nucleic acid sequence on a reference genome for each of the two alleles of a polymorphic site. In some cases, the relative abundance of fetal nucleic acid in a maternal sample can be determined as a parameter of the relative number of sequence reads for each allele from an enriched sample.

[0239] In some embodiments, determining fetal fraction comprises enriching a sample nucleic acid for one or more polymorphic nucleic acid targets. In some cases, a plurality of polymorphic targets is enriched. A plurality of polymorphic nucleic acid targets is sometimes referred to as a collection or a panel (e.g., target panel, SNP panel, SNP collection). A plurality of polymorphic targets can comprise two or more targets. For example, a plurality of polymorphic targets can comprise 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or more targets. In some cases, 10 or more polymorphic nucleic acid targets are enriched. In some cases, 50 or more polymorphic nucleic acid targets are enriched. In some cases, 100 or more polymorphic nucleic acid targets are enriched. In some cases, 500 or more polymorphic nucleic acid targets are enriched. In some cases, about 10 to about 500 polymorphic nucleic acid targets are enriched. In some cases, about 20 to about 400 polymorphic nucleic acid targets are enriched. In some cases, about 30 to about 200 polymorphic nucleic acid targets are enriched. In some cases, about 40 to about 100 polymorphic nucleic acid targets are enriched. In some cases, about 60 to about 90 polymorphic nucleic acid targets are enriched. For example, in certain embodiments, about 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or 90 polymorphic nucleic acid targets are enriched.

[0240] In some embodiments, at least one polymorphic nucleic acid target of the plurality of polymorphic nucleic acid targets is informative for determining fetal fraction in a given sample. A polymorphic nucleic acid target that is informative for determining fetal fraction, sometimes referred to as an informative target, informative polymorphism, or informative SNP, typically differs in some aspect between the fetus and the mother. For example, an informative target may have one allele for the fetus and a different allele for the mother (e.g., the mother has allele A at the polymorphic target and the fetus has allele B at the polymorphic target site). Typically, a fetal allele that differs from either of the maternal alleles is paternally inherited (i.e., is from the father). Thus, paternally inherited alleles that differ from maternal alleles can be useful for identifying and/or quantifying fetal nucleic acid (e.g., determining fetal fraction).

[0241] In some cases, polymorphic nucleic acid targets are informative in the context of certain maternal/fetal genotype combinations. For a biallelic polymorphic target (i.e., two possible alleles (e.g., A and B)), possible maternal/fetal genotype combinations include: 1) maternal AA, fetal AA; 2) maternal AA, fetal AB; 3) maternal AB, fetal AA; 4) maternal AB, fetal AB; 5) maternal AB; fetal BB; 6) maternal BB, fetal AB; and 7) maternal BB, fetal BB. Genotypes AA and BB are considered homozygous genotypes and genotype AB is considered a heterozygous genotype. In some cases, informative genotype combinations (i.e., genotype combinations for a polymorphic nucleic acid target that may be informative for determining fetal fraction) include combinations where the mother is homozygous and the fetus is heterozygous (e.g., maternal AA, fetal AB; or maternal BB, fetal AB). Such genotype combinations may be referred to as Type 1 informative genotypes or informative heterozygotes. In some cases, informative genotype combinations (i.e., genotype combinations for a polymorphic nucleic acid target that may be informative for determining fetal fraction) include combinations where the mother is heterozygous and the fetus is homozygous (e.g., maternal AB, fetal AA; or maternal AB, fetal BB). Such genotype combinations may be referred to as Type 2 informative genotypes or informative homozygotes. In some cases, non-informative genotype combinations (i.e., genotype combinations for a polymorphic nucleic acid target that may not be informative for determining fetal fraction) include combinations where the mother is heterozygous and the fetus is heterozygous (e.g., maternal AB, fetal AB). Such genotype combinations may be referred to as non-informative genotypes or non-informative heterozygotes. In some cases, non-informative genotype combinations (i.e., genotype combinations for a polymorphic nucleic acid target that may not be informative for determining fetal fraction) include combinations where the mother is homozygous and the fetus is homozygous (e.g., maternal AA, fetal AA; or maternal BB, fetal BB). Such genotype combinations may be referred to as non-informative genotypes or non-informative homozygotes.

[0242] In some embodiments, individual polymorphic nucleic acid targets and/or panels of polymorphic nucleic acid targets are selected based on certain criteria, such as, for example, minor allele population frequency, variance, coefficient of variance, MAD value, and the like. In some cases, polymorphic nucleic acid targets are selected so that at least one polymorphic nucleic acid target within a panel of polymorphic targets has a high probability of being informative for a majority of samples tested. Additionally, in some cases, the number of polymorphic nucleic acid targets (i.e., number of targets in a panel) is selected so that least one polymorphic nucleic acid target has a high probability of being informative for a majority of samples tested. For example, selection of a larger number of polymorphic targets generally increases the probability that least one polymorphic nucleic acid target will be informative for a majority of samples tested (see, FIG. 37, for example). In some cases, the polymorphic nucleic acid targets and number thereof (e.g., number of polymorphic targets selected for enrichment) result in at least about 2 to about 50 or more polymorphic nucleic acid targets being informative for determining the fetal fraction for at least about 80% to about 100% of samples. For example, the polymorphic nucleic acid targets and number thereof result in at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 or more polymorphic nucleic acid targets being informative for determining the fetal fraction for at least about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of samples. In some cases, the polymorphic nucleic acid targets and number thereof result in at least five polymorphic nucleic acid targets being informative for determining the fetal fraction for at least 90% of samples. In some cases, the polymorphic nucleic acid targets and number thereof result in at least five polymorphic nucleic acid targets being informative for determining the fetal fraction for at least 95% of samples. In some cases, the polymorphic nucleic acid targets and number thereof result in at least five polymorphic nucleic acid targets being informative for determining the fetal fraction for at least 99% of samples. In some cases, the polymorphic nucleic acid targets and number thereof result in at least ten polymorphic nucleic acid targets being informative for determining the fetal fraction for at least 90% of samples. In some cases, the polymorphic nucleic acid targets and number thereof result in at least ten polymorphic nucleic acid targets being informative for determining the fetal fraction for at least 95% of samples. In some cases, the polymorphic nucleic acid targets and number thereof result in at least ten polymorphic nucleic acid targets being informative for determining the fetal fraction for at least 99% of samples.

[0243] In some embodiments, individual polymorphic nucleic acid targets are selected based, in part, on minor allele population frequency. In some cases, polymorphic nucleic acid targets having minor allele population frequencies of about 10% to about 50% are selected. For example, polymorphic nucleic acid targets having minor allele population frequencies of about 15%, 20%, 25%, 30%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, or 49% are selected. In some embodiments, polymorphic nucleic acid targets having a minor allele population frequency of about 40% or more are selected.

[0244] In some embodiments, individual polymorphic nucleic acid targets and/or panels of polymorphic nucleic acid targets are selected based, in part, on degree of variance for an individual polymorphic target or a panel of polymorphic targets. Variance, in come cases, can be specific for certain polymorphic targets or panels of polymorphic targets and can be from systematic, experimental, procedural, and or inherent errors or biases (e.g., sampling errors, sequencing errors, PCR bias, and the like). Variance of an individual polymorphic target or a panel of polymorphic targets can be determined by any method known in the art for assessing variance and may be expressed, for example, in terms of a calculated variance, an error, standard deviation, p-value, mean absolute deviation, median absolute deviation, median adjusted deviation (MAD score), coefficient of variance (CV), and the like. In some embodiments, measured allele frequency variance (i.e., background allele frequency) for certain SNPs (when homozygous, for example) can be from about 0.001 to about 0.01 (i.e., 0.1% to about 1.0%). For example, measured allele frequency variance can be about 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, or 0.009. In some cases, measured allele frequency variance is about 0.007.

[0245] In some cases, noisy polymorphic targets are excluded from a panel of polymorphic nucleic acid targets selected for determining fetal fraction. The term "noisy polymorphic targets" or "noisy SNPs" refers to (a) targets or SNPs that have significant variance between data points (e.g., measured fetal fraction, measured allele frequency) when analyzed or plotted, (b) targets or SNPs that have significant standard deviation (e.g., greater than 1, 2, or 3 standard deviations), (c) targets or SNPs that have a significant standard error of the mean, the like, and combinations of the foregoing. Noise for certain polymorphic targets or SNPs sometimes occurs due to the quantity and/or quality of starting material (e.g., nucleic acid sample), sometimes occurs as part of processes for preparing or replicating DNA used to generate sequence reads, and sometimes occurs as part of a sequencing process. In certain embodiments, noise for some polymorphic targets or SNPs results from certain sequences being over represented when prepared using PCR-based methods. In some cases, noise for some polymorphic targets or SNPs results from one or more inherent characteristics of the site such as, for example, certain nucleotide sequences and/or base compositions surrounding, or being adjacent to, a polymorphic target or SNP. A SNP having a measured allele frequency variance (when homozygous, for example) of about 0.005 or more may be considered noisy. For example, a SNP having a measured allele frequency variance of about 0.006, 0.007, 0.008, 0.009, 0.01 or more may be considered noisy.

[0246] In some embodiments, variance of an individual polymorphic target or a panel of polymorphic targets can be represented using coefficient of variance (CV). Coefficient of variance (i.e., standard deviation divided by the mean) can be determined, for example, by determining fetal fraction for several aliquots of a single maternal sample comprising maternal and fetal nucleic acid, and calculating the mean fetal fraction and standard deviation. In some cases, individual polymorphic nucleic acid targets and/or panels of polymorphic nucleic acid targets are selected so that fetal fraction is determined with a coefficient of variance (CV) of 0.30 or less. For example, fetal fraction may determined with a coefficient of variance (CV) of 0.25, 0.20, 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13, 0.12, 0.11, 0.10, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01 or less, in some embodiments. In some cases, fetal fraction is determined with a coefficient of variance (CV) of 0.20 or less. In some cases, fetal fraction is determined with a coefficient of variance (CV) of 0.10 or less. In some cases, fetal fraction is determined with a coefficient of variance (CV) of 0.05 or less.

[0247] In some embodiments, an allele frequency is determined for each of the polymorphic nucleic acid targets in a sample. This sometimes is referred to as measured allele frequency. Allele frequency can be determined, for example, by counting the number of sequence reads for an allele (e.g., allele B) and dividing by the total number of sequence reads for that locus (e.g., allele B+allele A). In some cases, an allele frequency average, mean or median is determined. Fetal fraction can be determined based on the allele frequency mean (e.g., allele frequency mean multiplied by two), in some cases.

[0248] In some embodiments, determining whether a polymorphic nucleic acid target is informative comprises comparing its measured allele frequency to a fixed cutoff frequency. In some cases, determining which polymorphic nucleic acid targets are informative comprises identifying informative genotypes by comparing each allele frequency to one or more fixed cutoff frequencies. Fixed cutoff frequencies may be predetermined threshold values based on one or more qualifying data sets, for example. In some cases, the fixed cutoff for identifying informative genotypes from non-informative genotypes is expressed as a percent (%) shift in allele frequency from an expected allele frequency. Generally, expected allele frequencies for a given allele (e.g., allele A) are 0 (for a BB genotype), 0.5 (for an AB genotype) and 1.0 (for an AA genotype), or equivalent values on any numerical scale. A deviation from an expected allele frequency that is beyond one or more fixed cutoff frequencies may be considered informative. The degree of deviation generally is proportional to fetal fraction (i.e., large deviations from expected allele frequency may be observed in samples having high fetal fraction).

[0249] In some cases, the fixed cutoff for identifying informative genotypes from non-informative homozygotes is about a 0.5% or greater shift in allele frequency. For example, a fixed cutoff may be about a 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 3%, 4%, 5%, 10% or greater shift in allele frequency. In some cases, the fixed cutoff for identifying informative genotypes from non-informative homozygotes is about a 1% or greater shift in allele frequency. In some cases, the fixed cutoff for identifying informative genotypes from non-informative homozygotes is about a 2% or greater shift in allele frequency. In some embodiments, the fixed cutoff for identifying informative genotypes from non-informative heterozygotes is about a 10% or greater shift in allele frequency. For example, a fixed cutoff may be about a 10%, 15%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 80% or greater shift in allele frequency. In some cases, the fixed cutoff for identifying informative genotypes from non-informative heterozygotes is about a 25% or greater shift in allele frequency. In some cases, the fixed cutoff for identifying informative genotypes from non-informative heterozygotes is about a 50% or greater shift in allele frequency.

[0250] In some embodiments, determining whether a polymorphic nucleic acid target is informative comprises comparing its measured allele frequency to a target-specific cutoff value. In some embodiments, target-specific cutoff frequencies are determined for each polymorphic nucleic acid target. Typically, target-specific cutoff frequency is determined based on the allele frequency variance for the corresponding polymorphic nucleic acid target. In some embodiments, variance of individual polymorphic targets can be represented by a median absolute deviation (MAD), for example. In some cases, determining a MAD value for each polymorphic nucleic acid target can generate unique (i.e., target-specific) cutoff values. To determine median absolute deviation, measured allele frequency can be determined, for example, for multiple replicates (e.g., 5, 6, 7, 8, 9, 10, 15, 20 or more replicates) of a maternal only nucleic acid sample (e.g., buffy coat sample). Each polymorphic target in each replicate will typically have a slightly different measured allele frequency due to PCR and/or sequencing errors, for example. A median allele frequency value can be identified for each polymorphic target. A deviation from the median for the remaining replicates can be calculated (i.e., the difference between the observed allele frequency and the median allele frequency). The absolute value of the deviations (i.e., negative values become positive) is taken and the median value of the absolute deviations is calculated to provide a median absolute deviation (MAD) for each polymorphic nucleic acid target. A target-specific cutoff can be assigned, for example, as a multiple of the MAD (e.g., 1.times.MAD, 2.times.MAD, 3.times.MAD, 4.times.MAD or 5.times.MAD). Typically, polymorphic targets having less variance have a lower MAD and therefore a lower cutoff value than more variable targets.

[0251] In some embodiments, enriching comprises amplifying the plurality of polymorphic nucleic acid targets. In some cases, the enriching comprises generating amplification products in an amplification reaction. Amplification of polymorphic targets may be achieved by any method described herein or known in the art for amplifying nucleic acid (e.g., PCR). In some cases, the amplification reaction is performed in a single vessel (e.g., tube, container, well on a plate) which sometimes is referred to herein as multiplexed amplification.

[0252] In some embodiments, certain parental genotypes are known prior to the enriching of polymorphic nucleic acid targets. In some cases, the maternal genotype for one or more polymorphic targets is known prior to enriching. In some cases, the paternal genotype for one or more polymorphic targets is known prior to enriching. In some cases, the maternal genotype and the paternal genotype for one or more polymorphic targets are known prior to enriching. In some embodiments, certain parental genotypes are not known prior to the enriching of polymorphic nucleic acid targets. In some cases, the maternal genotype for one or more polymorphic targets is not known prior to enriching. In some cases, the paternal genotype for one or more polymorphic targets is not known prior to enriching. In some cases, the maternal genotype and the paternal genotype for one or more polymorphic targets are not known prior to enriching. In some embodiments, parental genotypes are not known for any of the polymorphic nucleic acid targets prior to enriching. In some cases, the maternal genotype for each of the polymorphic targets is not known prior to enriching. In some cases, the paternal genotype for each of the polymorphic targets is not known prior to enriching. In some cases, the maternal genotype and the paternal genotype for each of the polymorphic targets are not known prior to enriching.

[0253] In some embodiments, the polymorphic nucleic acid targets each comprise at least one single nucleotide polymorphism (SNP). In some embodiments, the SNPs are selected from: rs10413687, rs10949838, rs1115649, rs11207002, rs11632601, rs11971741, rs12660563, rs13155942, rs1444647, rs1572801, rs17773922, rs1797700, rs1921681, rs1958312, rs196008, rs2001778, rs2323659, rs2427099, rs243992, rs251344, rs254264, rs2827530, rs290387, rs321949, rs348971, rs390316, rs3944117, rs425002, rs432586, rs444016, rs4453265, rs447247, rs4745577, rs484312, rs499946, rs500090, rs500399, rs505349, rs505662, rs516084, rs517316, rs517914, rs522810, rs531423, rs537330, rs539344, rs551372, rs567681, rs585487, rs600933, rs619208, rs622994, rs639298, rs642449, rs6700732, rs677866, rs683922, rs686851, rs6941942, rs7045684, rs7176924, rs7525374, rs870429, rs949312, rs9563831, rs970022, rs985462, rs1005241, rs1006101, rs10745725, rs10776856, rs10790342, rs11076499, rs11103233, rs11133637, rs11974817, rs12102203, rs12261, rs12460763, rs12543040, rs12695642, rs13137088, rs13139573, rs1327501, rs13438255, rs1360258, rs1421062, rs1432515, rs1452396, rs1518040, rs16853186, rs1712497, rs1792205, rs1863452, rs1991899, rs2022958, rs2099875, rs2108825, rs2132237, rs2195979, rs2248173, rs2250246, rs2268697, rs2270893, rs244887, rs2736966, rs2851428, rs2906237, rs2929724, rs3742257, rs3764584, rs3814332, rs4131376, rs4363444, rs4461567, rs4467511, rs4559013, rs4714802, rs4775899, rs4817609, rs488446, rs4950877, rs530913, rs6020434, rs6442703, rs6487229, rs6537064, rs654065, rs6576533, rs6661105, rs669161, rs6703320, rs675828, rs6814242, rs6989344, rs7120590, rs7131676, rs7214164, rs747583, rs768255, rs768708, rs7828904, rs7899772, rs7900911, rs7925270, rs7975781, rs8111589, rs849084, rs873870, rs9386151, rs9504197, rs9690525, and rs9909561.

[0254] In some embodiments, the SNPs are selected from: rs10413687, rs10949838, rs1115649, rs11207002, rs11632601, rs11971741, rs12660563, rs13155942, rs1444647, rs1572801, rs17773922, rs1797700, rs1921681, rs1958312, rs196008, rs2001778, rs2323659, rs2427099, rs243992, rs251344, rs254264, rs2827530, rs290387, rs321949, rs348971, rs390316, rs3944117, rs425002, rs432586, rs444016, rs4453265, rs447247, rs4745577, rs484312, rs499946, rs500090, rs500399, rs505349, rs505662, rs516084, rs517316, rs517914, rs522810, rs531423, rs537330, rs539344, rs551372, rs567681, rs585487, rs600933, rs619208, rs622994, rs639298, rs642449, rs6700732, rs677866, rs683922, rs686851, rs6941942, rs7045684, rs7176924, rs7525374, rs870429, rs949312, rs9563831, rs970022, and rs985462.

[0255] In some embodiments, SNPs are selected from: rs1005241, rs1006101, rs10745725, rs10776856, rs10790342, rs11076499, rs11103233, rs11133637, rs11974817, rs12102203, rs12261, rs12460763, rs12543040, rs12695642, rs13137088, rs13139573, rs1327501, rs13438255, rs1360258, rs1421062, rs1432515, rs1452396, rs1518040, rs16853186, rs1712497, rs1792205, rs1863452, rs1991899, rs2022958, rs2099875, rs2108825, rs2132237, rs2195979, rs2248173, rs2250246, rs2268697, rs2270893, rs244887, rs2736966, rs2851428, rs2906237, rs2929724, rs3742257, rs3764584, rs3814332, rs4131376, rs4363444, rs4461567, rs4467511, rs4559013, rs4714802, rs4775899, rs4817609, rs488446, rs4950877, rs530913, rs6020434, rs6442703, rs6487229, rs6537064, rs654065, rs6576533, rs6661105, rs669161, rs6703320, rs675828, rs6814242, rs6989344, rs7120590, rs7131676, rs7214164, rs747583, rs768255, rs768708, rs7828904, rs7899772, rs7900911, rs7925270, rs7975781, rs8111589, rs849084, rs873870, rs9386151, rs9504197, rs9690525, and rs9909561.

[0256] The polymorphic targets can comprise one or more of any of the single nucleotide polymorphisms (SNPs) listed above and any combination thereof.

[0257] SNPs may be selected from any SNP provided herein or known in the art that meets any one or all of the criteria described herein for SNP selection. In some cases, SNPs can be located on any chromosome (e.g., chromosome 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, X and/or Y). In some cases, SNPs can be located on autosomes (e.g., chromosome 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22), and not on chromosome X or chromosome Y. In some cases, SNPs can be located on certain autosomes (e.g., chromosome 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 19, 20, 22 and not chromosome 13, 18 or 22). In some cases, SNPs can be located on certain chromosomes suspected of having a genetic variation (e.g., aneuploidy), such as, for example, chromosome 13, 18, 21, X and/or Y (i.e., test chromosome(s)). In some cases, SNPs are located on a reference chromosome. In some cases, fetal fraction and the presence or absence of a genetic variation (e.g., aneuploidy) are determined simultaneously using a method provided herein.

[0258] In some embodiments, enriched (e.g., amplified) polymorphic nucleic acid targets are sequenced by a sequencing process. In some cases, the sequencing process is a sequencing by synthesis method, as described herein. Typically, sequencing by synthesis methods comprise a plurality of synthesis cycles, whereby a complementary nucleotide is added to a single stranded template and identified during each cycle. The number of cycles generally corresponds to read length. In some cases, polymorphic targets are selected such that a minimal read length (i.e., minimal number of cycles) is required to include amplification primer sequence and the polymorphic target site (e.g., SNP) in the read. In some cases, amplification primer sequence includes about 10 to about 30 nucleotides. For example, amplification primer sequence may include about 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 nucleotides, in some embodiments. In some cases, amplification primer sequence includes about 20 nucleotides. In some embodiments, a SNP site is located within 1 nucleotide base position (i.e., adjacent to) to about 30 base positions from the 3' terminus of an amplification primer. For example, a SNP site may be within 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 nucleotides of an amplification primer terminus. Read lengths can be any length that is inclusive of an amplification primer sequence and a polymorphic sequence or position. In some embodiments, read lengths can be about 10 nucleotides in length to about 50 nucleotides in length. For example, read lengths can be about 15, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or 45 nucleotides in length. In some cases, read length is about 36 nucleotides. In some cases, read length is about 27 nucleotides. Thus, in some cases, the sequencing by synthesis method comprises about 36 cycles and sometimes comprises about 27 cycles.

[0259] In some embodiments, a plurality of samples is sequenced in a single compartment (e.g., flow cell), which sometimes is referred to herein as sample multiplexing. Thus, in some embodiments, fetal fraction is determined for a plurality of samples in a multiplexed assay. For example, fetal fraction may be determined for about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000 or more samples. In some cases, fetal fraction is determined for about 10 or more samples. In some cases, fetal fraction is determined for about 100 or more samples. In some cases, fetal fraction is determined for about 1000 or more samples.

[0260] Methylation-Based Fetal Quantifier Assay

[0261] Determination of fetal nucleic acid content (e.g., fetal fraction) sometimes is performed using a methylation-based fetal quantifier assay (FQA) as described herein and, for example, in U.S. Patent Application Publication No. 2010/0105049, which is hereby incorporated by reference. This type of assay allows for the detection and quantification of fetal nucleic acid in a maternal sample based on the methylation status of the nucleic acid in the sample. In some cases, the amount of fetal nucleic acid from a maternal sample can be determined relative to the total amount of nucleic acid present, thereby providing the percentage of fetal nucleic acid in the sample. In some cases, the copy number of fetal nucleic acid can be determined in a maternal sample. In some cases, the amount of fetal nucleic acid can be determined in a sequence-specific (or locus-specific) manner and sometimes with sufficient sensitivity to allow for accurate chromosomal dosage analysis (for example, to detect the presence or absence of a fetal aneuploidy).

[0262] A fetal quantifier assay (FQA) can be performed in conjunction with any of the methods described herein. Such an assay can be performed by any method known in the art and/or described herein and in U.S. Patent Application Publication No. 2010/0105049, such as, for example, by a method that can distinguish between maternal and fetal DNA based on differential methylation status, and quantify (i.e. determine the amount of) the fetal DNA. Methods for differentiating nucleic acid based on methylation status include, but are not limited to, methylation sensitive capture, for example, using a MBD2-Fc fragment in which the methyl binding domain of MBD2 is fused to the Fc fragment of an antibody (MBD-FC) (Gebhard et al. (2006) Cancer Res. 66(12):6118-28); methylation specific antibodies; bisulfite conversion methods, for example, MSP (methylation-sensitive PCR), COBRA, methylation-sensitive single nucleotide primer extension (Ms-SNuPE) or Sequenom MassCLEAVE.TM. technology; and the use of methylation sensitive restriction enzymes (e.g., digestion of maternal DNA in a maternal sample using one or more methylation sensitive restriction enzymes thereby enriching the fetal DNA). Methyl-sensitive enzymes also can be used to differentiate nucleic acid based on methylation status, which, for example, can preferentially or substantially cleave or digest at their DNA recognition sequence if the latter is non-methylated. Thus, an unmethylated DNA sample will be cut into smaller fragments than a methylated DNA sample and a hypermethylated DNA sample will not be cleaved. Except where explicitly stated, any method for differentiating nucleic acid based on methylation status can be used with the compositions and methods of the technology herein. The amount of fetal DNA can be determined, for example, by introducing one or more competitors at known concentrations during an amplification reaction. Determining the amount of fetal DNA also can be done, for example, by RT-PCR, primer extension, sequencing and/or counting. In certain instances, the amount of nucleic acid can be determined using BEAMing technology as described in U.S. Patent Application Publication No. 2007/0065823. In some cases, the restriction efficiency can be determined and the efficiency rate is used to further determine the amount of fetal DNA.

[0263] In some cases, a fetal quantifier assay (FQA) can be used to determine the concentration of fetal DNA in a maternal sample, for example, by the following method: a) determine the total amount of DNA present in a maternal sample; b) selectively digest the maternal DNA in a maternal sample using one or more methylation sensitive restriction enzymes thereby enriching the fetal DNA; c) determine the amount of fetal DNA from step b); and d) compare the amount of fetal DNA from step c) to the total amount of DNA from step a), thereby determining the concentration of fetal DNA in the maternal sample. In some cases, the absolute copy number of fetal nucleic acid in a maternal sample can be determined, for example, using mass spectrometry and/or a system that uses a competitive PCR approach for absolute copy number measurements. See for example, Ding and Cantor (2003) Proc Natl Acad Sci USA 100:3059-3064, and U.S. Patent Application Publication No. 2004/0081993, both of which are hereby incorporated by reference.

[0264] Determining Fetal Nucleic Acid Content in Conjunction with Other Methods

[0265] The amount of fetal nucleic acid in extracellular nucleic acid (e.g., fetal fraction) can be quantified and used in conjunction with other methods for assessing a genetic variation (e.g., fetal aneuploidy, fetal gender). Thus, in certain embodiments, methods for determining the presence or absence of a genetic variation, for example, comprise an additional step of determining the amount of fetal nucleic acid. The amount of fetal nucleic acid can be determined in a nucleic acid sample from a subject before or after processing to prepare sample nucleic acid. In certain embodiments, the amount of fetal nucleic acid is determined in a sample after sample nucleic acid is processed and prepared, which amount is utilized for further assessment. In some embodiments, an outcome comprises factoring the fraction of fetal nucleic acid in the sample nucleic acid (e.g., adjusting counts, removing samples, making a call or not making a call).

[0266] The determination of fetal nucleic acid content (e.g., fetal fraction) can be performed before, during, at any one point in a method for assessing a genetic variation (e.g., aneuploidy detection, fetal gender determination), or after such methods. For example, to achieve a fetal gender or aneuploidy determination method with a given sensitivity or specificity, a fetal nucleic acid quantification method may be implemented prior to, during or after fetal gender or aneuploidy determination to identify those samples with greater than about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25% or more fetal nucleic acid. In some embodiments, samples determined as having a certain threshold amount of fetal nucleic acid (e.g., about 15% or more fetal nucleic acid; about 4% or more fetal nucleic acid) are further analyzed for fetal gender or aneuploidy determination, or the presence or absence of aneuploidy or genetic variation, for example. In certain embodiments, determinations of, for example, fetal gender or the presence or absence of aneuploidy are selected (e.g., selected and communicated to a patient) only for samples having a certain threshold amount of fetal nucleic acid (e.g., about 15% or more fetal nucleic acid; about 4% or more fetal nucleic acid).

Additional Methods for Enriching for a Subpopulation of Nucleic Acid

[0267] In some embodiments, nucleic acid (e.g., extracellular nucleic acid) is enriched or relatively enriched for a subpopulation or species of nucleic acid. Nucleic acid subpopulations can include, for example, fetal nucleic acid, maternal nucleic acid, nucleic acid comprising fragments of a particular length or range of lengths, or nucleic acid from a particular genome region (e.g., single chromosome, set of chromosomes, and/or certain chromosome regions). Such enriched samples can be used in conjunction with the methods provided herein. Thus, in certain embodiments, methods of the technology herein comprise an additional step of enriching for a subpopulation of nucleic acid in a sample, such as, for example, fetal nucleic acid. In some cases, a method for determining fetal fraction described above also can be used to enrich for fetal nucleic acid. In certain embodiments, maternal nucleic acid is selectively removed (partially, substantially, almost completely or completely) from the sample. In some cases, enriching for a particular low copy number species nucleic acid (e.g., fetal nucleic acid) may improve quantitative sensitivity. Methods for enriching a sample for a particular species of nucleic acid are described herein and, for example, in U.S. Pat. No. 6,927,028, International Patent Application Publication No. WO2007/140417, International Patent Application Publication No. WO2007/147063, International Patent Application Publication No. WO2009/032779, International Patent Application Publication No. WO2009/032781, International Patent Application Publication No. WO2010/033639, International Patent Application Publication No. WO2011/034631, International Patent Application Publication No. WO2006/056480, and International Patent Application Publication No. WO2011/143659, all of which are incorporated by reference herein.

[0268] In some embodiments, nucleic acid is enriched for certain target fragment species and/or reference fragment species. In some cases, nucleic acid is enriched for a specific nucleic acid fragment length or range of fragment lengths using one or more length-based separation methods described below. In some cases, nucleic acid is enriched for fragments from a select genomic region (e.g., chromosome) using one or more sequence-based separation methods described herein and/or known in the art. Certain methods for enriching for a nucleic acid subpopulation (e.g., fetal nucleic acid) in a sample are described in detail below.

[0269] Some methods for enriching for a nucleic acid subpopulation (e.g., fetal nucleic acid) that can be used with the methods described herein include methods that exploit epigenetic differences between maternal and fetal nucleic acid. For example, fetal nucleic acid can be differentiated and separated from maternal nucleic acid based on methylation differences. Methylation-based fetal nucleic acid enrichment methods are described herein and, for example, in U.S. Patent Application Publication No. 2010/0105049, which is incorporated by reference herein. Such methods sometimes involve binding a sample nucleic acid to a methylation-specific binding agent (methyl-CpG binding protein (MBD), methylation specific antibodies, and the like) and separating bound nucleic acid from unbound nucleic acid based on differential methylation status. Such methods also can include the use of methylation-sensitive restriction enzymes (as described above; e.g., HhaI and HpaII), which allow for the enrichment of fetal nucleic acid regions in a maternal sample by selectively digesting nucleic acid from the maternal sample with an enzyme that selectively and completely or substantially digests the maternal nucleic acid to enrich the sample for at least one fetal nucleic acid region.

[0270] Another method for enriching for a nucleic acid subpopulation (e.g., fetal nucleic acid) that can be used with the methods described herein is a restriction endonuclease enhanced polymorphic sequence approach, such as a method described in U.S. Patent Application Publication No. 2009/0317818, which is incorporated by reference herein. Such methods include cleavage of nucleic acid comprising a non-target allele with a restriction endonuclease that recognizes the nucleic acid comprising the non-target allele but not the target allele; and amplification of uncleaved nucleic acid but not cleaved nucleic acid, where the uncleaved, amplified nucleic acid represents enriched target nucleic acid (e.g., fetal nucleic acid) relative to non-target nucleic acid (e.g., maternal nucleic acid). In some cases, nucleic acid may be selected such that it comprises an allele having a polymorphic site that is susceptible to selective digestion by a cleavage agent, for example.

[0271] Some methods for enriching for a nucleic acid subpopulation (e.g., fetal nucleic acid) that can be used with the methods described herein include selective enzymatic degradation approaches. Such methods involve protecting target sequences from exonuclease digestion thereby facilitating the elimination in a sample of undesired sequences (e.g., maternal DNA). For example, in one approach, sample nucleic acid is denatured to generate single stranded nucleic acid, single stranded nucleic acid is contacted with at least one target-specific primer pair under suitable annealing conditions, annealed primers are extended by nucleotide polymerization generating double stranded target sequences, and digesting single stranded nucleic acid using a nuclease that digests single stranded (i.e. non-target) nucleic acid. In some cases, the method can be repeated for at least one additional cycle. In some cases, the same target-specific primer pair is used to prime each of the first and second cycles of extension, and in some cases, different target-specific primer pairs are used for the first and second cycles.

[0272] Some methods for enriching for a nucleic acid subpopulation (e.g., fetal nucleic acid) that can be used with the methods described herein include massively parallel signature sequencing (MPSS) approaches. MPSS typically is a solid phase method that uses adapter (i.e. tag) ligation, followed by adapter decoding, and reading of the nucleic acid sequence in small increments. Tagged PCR products are typically amplified such that each nucleic acid generates a PCR product with a unique tag. Tags are often used to attach the PCR products to microbeads. After several rounds of ligation-based sequence determination, for example, a sequence signature can be identified from each bead. Each signature sequence (MPSS tag) in a MPSS dataset is analyzed, compared with all other signatures, and all identical signatures are counted.

[0273] In some cases, certain MPSS-based enrichment methods can include amplification (e.g., PCR)-based approaches. In some cases, loci-specific amplification methods can be used (e.g., using loci-specific amplification primers). In some cases, a multiplex SNP allele PCR approach can be used. In some cases, a multiplex SNP allele PCR approach can be used in combination with uniplex sequencing. For example, such an approach can involve the use of multiplex PCR (e.g., MASSARRAY system) and incorporation of capture probe sequences into the amplicons followed by sequencing using, for example, the Illumina MPSS system. In some cases, a multiplex SNP allele PCR approach can be used in combination with a three-primer system and indexed sequencing. For example, such an approach can involve the use of multiplex PCR (e.g., MASSARRAY system) with primers having a first capture probe incorporated into certain loci-specific forward PCR primers and adapter sequences incorporated into loci-specific reverse PCR primers, to thereby generate amplicons, followed by a secondary PCR to incorporate reverse capture sequences and molecular index barcodes for sequencing using, for example, the Illumina MPSS system. In some cases, a multiplex SNP allele PCR approach can be used in combination with a four-primer system and indexed sequencing. For example, such an approach can involve the use of multiplex PCR (e.g., MASSARRAY system) with primers having adaptor sequences incorporated into both loci-specific forward and loci-specific reverse PCR primers, followed by a secondary PCR to incorporate both forward and reverse capture sequences and molecular index barcodes for sequencing using, for example, the Illumina MPSS system. In some cases, a microfluidics approach can be used. In some cases, an array-based microfluidics approach can be used. For example, such an approach can involve the use of a microfluidics array (e.g., Fluidigm) for amplification at low plex and incorporation of index and capture probes, followed by sequencing. In some cases, an emulsion microfluidics approach can be used, such as, for example, digital droplet PCR.

[0274] In some cases, universal amplification methods can be used (e.g., using universal or non-loci-specific amplification primers). In some cases, universal amplification methods can be used in combination with pull-down approaches. In some cases, the method can include biotinylated ultramer pull-down (e.g., biotinylated pull-down assays from Agilent or IDT) from a universally amplified sequencing library. For example, such an approach can involve preparation of a standard library, enrichment for selected regions by a pull-down assay, and a secondary universal amplification step. In some cases, pull-down approaches can be used in combination with ligation-based methods. In some cases, the method can include biotinylated ultramer pull down with sequence specific adapter ligation (e.g., HALOPLEX PCR, Halo Genomics). For example, such an approach can involve the use of selector probes to capture restriction enzyme-digested fragments, followed by ligation of captured products to an adaptor, and universal amplification followed by sequencing. In some cases, pull-down approaches can be used in combination with extension and ligation-based methods. In some cases, the method can include molecular inversion probe (MIP) extension and ligation. For example, such an approach can involve the use of molecular inversion probes in combination with sequence adapters followed by universal amplification and sequencing. In some cases, complementary DNA can be synthesized and sequenced without amplification.

[0275] In some cases, extension and ligation approaches can be performed without a pull-down component. In some cases, the method can include loci-specific forward and reverse primer hybridization, extension and ligation. Such methods can further include universal amplification or complementary DNA synthesis without amplification, followed by sequencing. Such methods can reduce or exclude background sequences during analysis, in some cases.

[0276] In some cases, pull-down approaches can be used with an optional amplification component or with no amplification component. In some cases, the method can include a modified pull-down assay and ligation with full incorporation of capture probes without universal amplification. For example, such an approach can involve the use of modified selector probes to capture restriction enzyme-digested fragments, followed by ligation of captured products to an adaptor, optional amplification, and sequencing. In some cases, the method can include a biotinylated pull-down assay with extension and ligation of adaptor sequence in combination with circular single stranded ligation. For example, such an approach can involve the use of selector probes to capture regions of interest (i.e. target sequences), extension of the probes, adaptor ligation, single stranded circular ligation, optional amplification, and sequencing. In some cases, the analysis of the sequencing result can separate target sequences form background.

[0277] In some embodiments, nucleic acid is enriched for fragments from a select genomic region (e.g., chromosome) using one or more sequence-based separation methods described herein. Sequence-based separation generally is based on nucleotide sequences present in the fragments of interest (e.g., target and/or reference fragments) and substantially not present in other fragments of the sample or present in an insubstantial amount of the other fragments (e.g., 5% or less). In some embodiments, sequence-based separation can generate separated target fragments and/or separated reference fragments. Separated target fragments and/or separated reference fragments typically are isolated away from the remaining fragments in the nucleic acid sample. In some cases, the separated target fragments and the separated reference fragments also are isolated away from each other (e.g., isolated in separate assay compartments). In some cases, the separated target fragments and the separated reference fragments are isolated together (e.g., isolated in the same assay compartment). In some embodiments, unbound fragments can be differentially removed or degraded or digested.

[0278] In some embodiments, a selective nucleic acid capture process is used to separate target and/or reference fragments away from the nucleic acid sample. Commercially available nucleic acid capture systems include, for example, Nimblegen sequence capture system (Roche NimbleGen, Madison, Wis.); Illumina BEADARRAY platform (Illumina, San Diego, Calif.); Affymetrix GENECHIP platform (Affymetrix, Santa Clara, Calif.); Agilent SureSelect Target Enrichment System (Agilent Technologies, Santa Clara, Calif.); and related platforms. Such methods typically involve hybridization of a capture oligonucleotide to a portion or all of the nucleotide sequence of a target or reference fragment and can include use of a solid phase (e.g., solid phase array) and/or a solution based platform. Capture oligonucleotides (sometimes referred to as "bait") can be selected or designed such that they preferentially hybridize to nucleic acid fragments from selected genomic regions or loci (e.g., one of chromosomes 21, 18, 13, X or Y, or a reference chromosome).

[0279] In some embodiments, nucleic acid is enriched for a particular nucleic acid fragment length, range of lengths, or lengths under or over a particular threshold or cutoff using one or more length-based separation methods. Nucleic acid fragment length typically refers to the number of nucleotides in the fragment. Nucleic acid fragment length also is sometimes referred to as nucleic acid fragment size. In some embodiments, a length-based separation method is performed without measuring lengths of individual fragments. In some embodiments, a length based separation method is performed in conjunction with a method for determining length of individual fragments. In some embodiments, length-based separation refers to a size fractionation procedure where all or part of the fractionated pool can be isolated (e.g., retained) and/or analyzed. Size fractionation procedures are known in the art (e.g., separation on an array, separation by a molecular sieve, separation by gel electrophoresis, separation by column chromatography (e.g., size-exclusion columns), and microfluidics-based approaches). In some cases, length-based separation approaches can include fragment circularization, chemical treatment (e.g., formaldehyde, polyethylene glycol (PEG)), mass spectrometry and/or size-specific nucleic acid amplification, for example.

[0280] Certain length-based separation methods that can be used with methods described herein employ a selective sequence tagging approach, for example. In such methods, a fragment size species (e.g., short fragments) nucleic acids are selectively tagged in a sample that includes long and short nucleic acids. Such methods typically involve performing a nucleic acid amplification reaction using a set of nested primers which include inner primers and outer primers. In some cases, one or both of the inner can be tagged to thereby introduce a tag onto the target amplification product. The outer primers generally do not anneal to the short fragments that carry the (inner) target sequence. The inner primers can anneal to the short fragments and generate an amplification product that carries a tag and the target sequence. Typically, tagging of the long fragments is inhibited through a combination of mechanisms which include, for example, blocked extension of the inner primers by the prior annealing and extension of the outer primers. Enrichment for tagged fragments can be accomplished by any of a variety of methods, including for example, exonuclease digestion of single stranded nucleic acid and amplification of the tagged fragments using amplification primers specific for at least one tag.

[0281] Another length-based separation method that can be used with methods described herein involves subjecting a nucleic acid sample to polyethylene glycol (PEG) precipitation. Examples of methods include those described in International Patent Application Publication Nos. WO2007/140417 and WO2010/115016. This method in general entails contacting a nucleic acid sample with PEG in the presence of one or more monovalent salts under conditions sufficient to substantially precipitate large nucleic acids without substantially precipitating small (e.g., less than 300 nucleotides) nucleic acids.

[0282] Another size-based enrichment method that can be used with methods described herein involves circularization by ligation, for example, using circligase. Short nucleic acid fragments typically can be circularized with higher efficiency than long fragments. Non-circularized sequences can be separated from circularized sequences, and the enriched short fragments can be used for further analysis.

Nucleic Acid Amplification and Detection

[0283] Following separation of nucleic acid in a methylation-differential manner, nucleic acid may be amplified and/or subjected to a detection process (e.g., sequence-based analysis, mass spectrometry). Furthermore, once it is determined that one particular genomic sequence of fetal origin is hypermethylated or hypomethylated compared to the maternal counterpart, the amount of this fetal genomic sequence can be determined. Subsequently, this amount can be compared to a standard control value and serve as an indication for the potential of certain pregnancy-associated disorder.

[0284] Nucleotide sequences, or amplified nucleic acid sequences, or detectable products prepared from the foregoing, can be detected by a suitable detection process. Non-limiting examples of methods of detection, quantification, sequencing and the like include mass detection of mass modified amplicons (e.g., matrix-assisted laser desorption ionization (MALDI) mass spectrometry and electrospray (ES) mass spectrometry), a primer extension method (e.g., iPLEX.TM.; Sequenom, Inc.), direct DNA sequencing, Molecular Inversion Probe (MIP) technology from Affymetrix, restriction fragment length polymorphism (RFLP analysis), allele specific oligonucleotide (ASO) analysis, methylation-specific PCR (MSPCR), pyrosequencing analysis, acycloprime analysis, Reverse dot blot, GeneChip microarrays, Dynamic allele-specific hybridization (DASH), Peptide nucleic acid (PNA) and locked nucleic acids (LNA) probes, TaqMan, Molecular Beacons, Intercalating dye, FRET primers, AlphaScreen, SNPstream, genetic bit analysis (GBA), Multiplex minisequencing, SNaPshot, GOOD assay, Microarray miniseq, arrayed primer extension (APEX), Microarray primer extension, Tag arrays, Coded microspheres, Template-directed incorporation (TDI), fluorescence polarization, Colorimetric oligonucleotide ligation assay (OLA), Sequence-coded OLA, Microarray ligation, Ligase chain reaction, Padlock probes, Invader assay, hybridization using at least one probe, hybridization using at least one fluorescently labeled probe, cloning and sequencing, electrophoresis, the use of hybridization probes and quantitative real time polymerase chain reaction (QRT-PCR), digital PCR, nanopore sequencing, chips and combinations thereof. In some embodiments the amount of each amplified nucleic acid species is determined by mass spectrometry, primer extension, sequencing (e.g., any suitable method, for example nanopore or pyrosequencing), Quantitative PCR (Q-PCR or QRT-PCR), digital PCR, combinations thereof, and the like.

[0285] Nucleic acid detection and/or quantification also may include, for example, solid support array based detection of fluorescently labeled nucleic acid with fluorescent labels incorporated during or after PCR, single molecule detection of fluorescently labeled molecules in solution or captured on a solid phase, or other sequencing technologies such as, for example, sequencing using ION TORRENT or MISEQ platforms or single molecule sequencing technologies using instrumentation such as, for example, PACBIO sequencers, HELICOS sequencer, or nanopore sequencing technologies.

[0286] In some cases, nucleotide sequences, or amplified nucleic acid sequences, or detectable products prepared from the foregoing, are detected using a sequencing process (e.g., such as a sequencing process described herein). Nucleic acid quantifications generated by a method comprising a sequencing detection process may be compared to nucleic acid quantifications generated by a method comprising a different detection process (e.g., mass spectrometry). Such comparisons may be expressed using an R.sup.2 value, which is a measure of correlation between two outcomes (e.g., nucleic acid quantifications). In some cases, nucleic acid quantifications (e.g., fetal copy number quantifications) are highly correlated (i.e., have high R.sup.2 values) for quantifications generated using different detection processes (e.g., sequencing and mass spectrometry). In some cases, R.sup.2 values for nucleic acid quantifications generated using different detection processes may be between about 0.90 and about 1.0. For example, R.sup.2 values may be about 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, or 0.99.

[0287] Amplification of Nucleotide Sequences

[0288] In many instances, it is desirable to amplify a nucleic acid sequence of the technology herein using any of several nucleic acid amplification procedures which are well known in the art (listed above and described in greater detail below). Specifically, nucleic acid amplification is the enzymatic synthesis of nucleic acid amplicons (copies) which contain a sequence that is complementary to a nucleic acid sequence being amplified. Nucleic acid amplification is especially beneficial when the amount of target sequence present in a sample is very low. By amplifying the target sequences and detecting the amplicon synthesized, the sensitivity of an assay can be vastly improved, since fewer target sequences are needed at the beginning of the assay to better ensure detection of nucleic acid in the sample belonging to the organism or virus of interest.

[0289] A variety of polynucleotide amplification methods are well established and frequently used in research. For instance, the general methods of polymerase chain reaction (PCR) for polynucleotide sequence amplification are well known in the art and are thus not described in detail herein. For a review of PCR methods, protocols, and principles in designing primers, see, e.g., Innis, et al., PCR Protocols: A Guide to Methods and Applications, Academic Press, Inc. N.Y., 1990. PCR reagents and protocols are also available from commercial vendors, such as Roche Molecular Systems.

[0290] PCR is most usually carried out as an automated process with a thermostable enzyme. In this process, the temperature of the reaction mixture is cycled through a denaturing region, a primer annealing region, and an extension reaction region automatically. Machines specifically adapted for this purpose are commercially available.

[0291] Although PCR amplification of a polynucleotide sequence is typically used in practicing the present technology, one of skill in the art will recognize that the amplification of a genomic sequence found in a maternal blood sample may be accomplished by any known method, such as ligase chain reaction (LCR), transcription-mediated amplification, and self-sustained sequence replication or nucleic acid sequence-based amplification (NASBA), each of which provides sufficient amplification. More recently developed branched-DNA technology may also be used to qualitatively demonstrate the presence of a particular genomic sequence of the technology herein, which represents a particular methylation pattern, or to quantitatively determine the amount of this particular genomic sequence in the maternal blood. For a review of branched-DNA signal amplification for direct quantitation of nucleic acid sequences in clinical samples, see Nolte, Adv. Clin. Chem. 33:201-235, 1998.

[0292] The compositions and processes of the technology herein are also particularly useful when practiced with digital PCR. Digital PCR was first developed by Kalinina and colleagues (Kalinina et al., "Nanoliter scale PCR with TaqMan detection." Nucleic Acids Research. 25; 1999-2004, (1997)) and further developed by Vogelstein and Kinzler (Digital PCR. Proc Natl Acad Sci USA. 96; 9236-41, (1999)). The application of digital PCR for use with fetal diagnostics was first described by Cantor et al. (PCT Patent Publication No. WO05023091A2) and subsequently described by Quake et al. (US Patent Publication No. US 20070202525), which are both hereby incorporated by reference. Digital PCR takes advantage of nucleic acid (DNA, cDNA or RNA) amplification on a single molecule level, and offers a highly sensitive method for quantifying low copy number nucleic acid. Fluidigm.RTM. Corporation offers systems for the digital analysis of nucleic acids.

[0293] The terms "amplify", "amplification", "amplification reaction", or "amplifying" refer to any in vitro process for multiplying the copies of a nucleic acid. Amplification sometimes refers to an "exponential" increase in nucleic acid. However, "amplifying" as used herein can also refer to linear increases in the numbers of a select nucleic acid, but is different than a one-time, single primer extension step. In some embodiments a limited amplification reaction, also known as pre-amplification, can be performed. Pre-amplification is a method in which a limited amount of amplification occurs due to a small number of cycles, for example 10 cycles, being performed. Pre-amplification can allow some amplification, but stops amplification prior to the exponential phase, and typically produces about 500 copies of the desired nucleotide sequence(s). Use of pre-amplification may also limit inaccuracies associated with depleted reactants in standard PCR reactions, for example, and also may reduce amplification biases due to nucleotide sequence or abundance of the nucleic acid. In some embodiments a one-time primer extension may be performed as a prelude to linear or exponential amplification.

[0294] Any suitable amplification technique can be utilized. Amplification of polynucleotides include, but are not limited to, polymerase chain reaction (PCR); ligation amplification (or ligase chain reaction (LCR)); amplification methods based on the use of Q-beta replicase or template-dependent polymerase (see US Patent Publication Number US20050287592); helicase-dependant isothermal amplification (Vincent et al., "Helicase-dependent isothermal DNA amplification". EMBO reports 5 (8): 795-800 (2004)); strand displacement amplification (SDA); thermophilic SDA nucleic acid sequence based amplification (3SR or NASBA) and transcription-associated amplification (TAA). Non-limiting examples of PCR amplification methods include standard PCR, AFLP-PCR, Allele-specific PCR, Alu-PCR, Asymmetric PCR, Colony PCR, Hot start PCR, Inverse PCR (IPCR), In situ PCR (ISH), Intersequence-specific PCR (ISSR-PCR), Long PCR, Multiplex PCR, Nested PCR, Quantitative PCR, Reverse Transcriptase PCR(RT-PCR), Real Time PCR, Single cell PCR, Solid phase PCR, digital PCR, combinations thereof, and the like. For example, amplification can be accomplished using digital PCR, in certain embodiments (see e.g. Kalinina et al., "Nanoliter scale PCR with TaqMan detection." Nucleic Acids Research. 25; 1999-2004, (1997); Vogelstein and Kinzler (Digital PCR. Proc Natl Acad Sci USA. 96; 9236-41, (1999); PCT Patent Publication No. WO05023091A2; US Patent Publication No. US 20070202525). Digital PCR takes advantage of nucleic acid (DNA, cDNA or RNA) amplification on a single molecule level, and offers a highly sensitive method for quantifying low copy number nucleic acid. Systems for digital amplification and analysis of nucleic acids are available (e.g., Fluidigm.RTM. Corporation). Reagents and hardware for conducting PCR are commercially available.

[0295] A generalized description of an amplification process is presented herein. Primers and nucleic acid are contacted, and complementary sequences anneal to one another, for example. Primers can anneal to a nucleic acid, at or near (e.g., adjacent to, abutting, and the like) a sequence of interest. In some embodiments, the primers in a set hybridize within about 10 to 30 nucleotides from a nucleic acid sequence of interest and produce amplified products. In some embodiments, the primers hybridize within the nucleic acid sequence of interest.

[0296] A reaction mixture, containing components necessary for enzymatic functionality, is added to the primer-nucleic acid hybrid, and amplification can occur under suitable conditions. Components of an amplification reaction may include, but are not limited to, e.g., primers (e.g., individual primers, primer pairs, primer sets and the like) a polynucleotide template, polymerase, nucleotides, dNTPs and the like. In some embodiments, non-naturally occurring nucleotides or nucleotide analogs, such as analogs containing a detectable label (e.g., fluorescent or colorimetric label), may be used for example. Polymerases can be selected by a person of ordinary skill and include polymerases for thermocycle amplification (e.g., Taq DNA Polymerase; Q-Bio.TM. Taq DNA Polymerase (recombinant truncated form of Taq DNA Polymerase lacking 5'-3' exo activity); SurePrime.TM. Polymerase (chemically modified Taq DNA polymerase for "hot start" PCR); Arrow.TM. Taq DNA Polymerase (high sensitivity and long template amplification)) and polymerases for thermostable amplification (e.g., RNA polymerase for transcription-mediated amplification (TMA) described at World Wide Web URL "gen-probe.com/pdfs/tma_whiteppr.pdf"). Other enzyme components can be added, such as reverse transcriptase for transcription mediated amplification (TMA) reactions, for example.

[0297] PCR conditions can be dependent upon primer sequences, abundance of nucleic acid, and the desired amount of amplification, and therefore, one of skill in the art may choose from a number of PCR protocols available (see, e.g., U.S. Pat. Nos. 4,683,195 and 4,683,202; and PCR Protocols: A Guide to Methods and Applications, Innis et al., eds, 1990. Digital PCR is also known in the art; see, e.g., United States Patent Application Publication no. 20070202525, filed Feb. 2, 2007, which is hereby incorporated by reference). PCR is typically carried out as an automated process with a thermostable enzyme. In this process, the temperature of the reaction mixture is cycled through a denaturing step, a primer-annealing step, and an extension reaction step automatically. Some PCR protocols also include an activation step and a final extension step. Machines specifically adapted for this purpose are commercially available. A non-limiting example of a PCR protocol that may be suitable for embodiments described herein is, treating the sample at 95.degree. C. for 5 minutes; repeating thirty-five cycles of 95.degree. C. for 45 seconds and 68.degree. C. for 30 seconds; and then treating the sample at 72.degree. C. for 3 minutes. A completed PCR reaction can optionally be kept at 4.degree. C. until further action is desired. Multiple cycles frequently are performed using a commercially available thermal cycler. Suitable isothermal amplification processes known and selected by the person of ordinary skill in the art also may be applied, in certain embodiments.

[0298] In some embodiments, an amplification product may include naturally occurring nucleotides, non-naturally occurring nucleotides, nucleotide analogs and the like and combinations of the foregoing. An amplification product often has a nucleotide sequence that is identical to or substantially identical to a nucleic acid sequence herein, or complement thereof. A "substantially identical" nucleotide sequence in an amplification product will generally have a high degree of sequence identity to the nucleotide sequence species being amplified or complement thereof (e.g., about 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater than 99% sequence identity), and variations sometimes are a result of infidelity of the polymerase used for extension and/or amplification, or additional nucleotide sequence(s) added to the primers used for amplification.

[0299] Primers

[0300] Primers useful for detection, amplification, quantification, sequencing and analysis of nucleic acid are provided. The term "primer" as used herein refers to a nucleic acid that includes a nucleotide sequence capable of hybridizing or annealing to a target nucleic acid, at or near (e.g., adjacent to) a specific region of interest. Primers can allow for specific determination of a target nucleic acid nucleotide sequence or detection of the target nucleic acid (e.g., presence or absence of a sequence or copy number of a sequence), or feature thereof, for example. A primer may be naturally occurring or synthetic. The term "specific" or "specificity", as used herein, refers to the binding or hybridization of one molecule to another molecule, such as a primer for a target polynucleotide. That is, "specific" or "specificity" refers to the recognition, contact, and formation of a stable complex between two molecules, as compared to substantially less recognition, contact, or complex formation of either of those two molecules with other molecules. As used herein, the term "anneal" refers to the formation of a stable complex between two molecules. The terms "primer", "oligo", or "oligonucleotide" may be used interchangeably throughout the document, when referring to primers.

[0301] A primer nucleic acid can be designed and synthesized using suitable processes, and may be of any length suitable for hybridizing to a nucleotide sequence of interest (e.g., where the nucleic acid is in liquid phase or bound to a solid support) and performing analysis processes described herein. Primers may be designed based upon a target nucleotide sequence. A primer in some embodiments may be about 10 to about 100 nucleotides, about 10 to about 70 nucleotides, about 10 to about 50 nucleotides, about 15 to about 30 nucleotides, or about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 nucleotides in length. A primer may be composed of naturally occurring and/or non-naturally occurring nucleotides (e.g., labeled nucleotides), or a mixture thereof. Primers suitable for use with embodiments described herein, may be synthesized and labeled using known techniques. Primers may be chemically synthesized according to the solid phase phosphoramidite triester method first described by Beaucage and Caruthers, Tetrahedron Letts., 22:1859-1862, 1981, using an automated synthesizer, as described in Needham-VanDevanter et al., Nucleic Acids Res. 12:6159-6168, 1984. Purification of primers can be effected by native acrylamide gel electrophoresis or by anion-exchange high-performance liquid chromatography (HPLC), for example, as described in Pearson and Regnier, J. Chrom., 255:137-149, 1983.

[0302] All or a portion of a primer nucleic acid sequence (naturally occurring or synthetic) may be substantially complementary to a target nucleic acid, in some embodiments. As referred to herein, "substantially complementary" with respect to sequences refers to nucleotide sequences that will hybridize with each other. The stringency of the hybridization conditions can be altered to tolerate varying amounts of sequence mismatch. Included are target and primer sequences that are 55% or more, 56% or more, 57% or more, 58% or more, 59% or more, 60% or more, 61% or more, 62% or more, 63% or more, 64% or more, 65% or more, 66% or more, 67% or more, 68% or more, 69% or more, 70% or more, 71% or more, 72% or more, 73% or more, 74% or more, 75% or more, 76% or more, 77% or more, 78% or more, 79% or more, 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more or 99% or more complementary to each other.

[0303] Primers that are substantially complimentary to a target nucleic acid sequence are also substantially identical to the compliment of the target nucleic acid sequence. That is, primers are substantially identical to the anti-sense strand of the nucleic acid. As referred to herein, "substantially identical" with respect to sequences refers to nucleotide sequences that are 55% or more, 56% or more, 57% or more, 58% or more, 59% or more, 60% or more, 61% or more, 62% or more, 63% or more, 64% or more, 65% or more, 66% or more, 67% or more, 68% or more, 69% or more, 70% or more, 71% or more, 72% or more, 73% or more, 74% or more, 75% or more, 76% or more, 77% or more, 78% or more, 79% or more, 80% or more, 81% or more, 82% or more, 83% or more, 84% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more or 99% or more identical to each other. One test for determining whether two nucleotide sequences are substantially identical is to determine the percent of identical nucleotide sequences shared.

[0304] Primer sequences and length may affect hybridization to target nucleic acid sequences. Depending on the degree of mismatch between the primer and target nucleic acid, low, medium or high stringency conditions may be used to effect primer/target annealing. As used herein, the term "stringent conditions" refers to conditions for hybridization and washing. Methods for hybridization reaction temperature condition optimization are known to those of skill in the art, and may be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y., 6.3.1-6.3.6 (1989). Aqueous and non-aqueous methods are described in that reference and either can be used. Non-limiting examples of stringent hybridization conditions are hybridization in 6.times. sodium chloride/sodium citrate (SSC) at about 45.degree. C., followed by one or more washes in 0.2.times.SSC, 0.1% SDS at 50.degree. C. Another example of stringent hybridization conditions are hybridization in 6.times. sodium chloride/sodium citrate (SSC) at about 45.degree. C., followed by one or more washes in 0.2.times.SSC, 0.1% SDS at 55.degree. C. A further example of stringent hybridization conditions is hybridization in 6.times. sodium chloride/sodium citrate (SSC) at about 45.degree. C., followed by one or more washes in 0.2.times.SSC, 0.1% SDS at 60.degree. C. Often, stringent hybridization conditions are hybridization in 6.times. sodium chloride/sodium citrate (SSC) at about 45.degree. C., followed by one or more washes in 0.2.times.SSC, 0.1% SDS at 65.degree. C. More often, stringency conditions are 0.5M sodium phosphate, 7% SDS at 65.degree. C., followed by one or more washes at 0.2.times.SSC, 1% SDS at 65.degree. C. Stringent hybridization temperatures can also be altered (i.e. lowered) with the addition of certain organic solvents, formamide for example. Organic solvents, like formamide, reduce the thermal stability of double-stranded polynucleotides, so that hybridization can be performed at lower temperatures, while still maintaining stringent conditions and extending the useful life of nucleic acids that may be heat labile. Features of primers can be applied to probes and oligonucleotides, such as, for example, the competitive and inhibitory oligonucleotides provided herein.

[0305] As used herein, the phrase "hybridizing" or grammatical variations thereof, refers to binding of a first nucleic acid molecule to a second nucleic acid molecule under low, medium or high stringency conditions, or under nucleic acid synthesis conditions. Hybridizing can include instances where a first nucleic acid molecule binds to a second nucleic acid molecule, where the first and second nucleic acid molecules are complementary. As used herein, "specifically hybridizes" refers to preferential hybridization under nucleic acid synthesis conditions of a primer, to a nucleic acid molecule having a sequence complementary to the primer compared to hybridization to a nucleic acid molecule not having a complementary sequence. For example, specific hybridization includes the hybridization of a primer to a target nucleic acid sequence that is complementary to the primer.

[0306] In some embodiments primers can include a nucleotide subsequence that may be complementary to a solid phase nucleic acid primer hybridization sequence or substantially complementary to a solid phase nucleic acid primer hybridization sequence (e.g., about 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater than 99% identical to the primer hybridization sequence complement when aligned). A primer may contain a nucleotide subsequence not complementary to or not substantially complementary to a solid phase nucleic acid primer hybridization sequence (e.g., at the 3' or 5' end of the nucleotide subsequence in the primer complementary to or substantially complementary to the solid phase primer hybridization sequence).

[0307] A primer, in certain embodiments, may contain a modification such as one or more inosines, abasic sites, locked nucleic acids, minor groove binders, duplex stabilizers (e.g., acridine, spermidine), Tm modifiers or any modifier that changes the binding properties of the primers or probes. A primer, in certain embodiments, may contain a detectable molecule or entity (e.g., a fluorophore, radioisotope, colorimetric agent, particle, enzyme and the like, as described above for labeled competitor oligonucleotides).

[0308] A primer also may refer to a polynucleotide sequence that hybridizes to a subsequence of a target nucleic acid or another primer and facilitates the detection of a primer, a target nucleic acid or both, as with molecular beacons, for example. The term "molecular beacon" as used herein refers to detectable molecule, where the detectable property of the molecule is detectable only under certain specific conditions, thereby enabling it to function as a specific and informative signal. Non-limiting examples of detectable properties are, optical properties, electrical properties, magnetic properties, chemical properties and time or speed through an opening of known size.

[0309] In some embodiments, the primers are complementary to genomic DNA target sequences. In some cases, the forward and reverse primers hybridize to the 5' and 3' ends of the genomic DNA target sequences. In some embodiments, primers that hybridize to the genomic DNA target sequences also hybridize to competitor oligonucleotides that were designed to compete with corresponding genomic DNA target sequences for binding of the primers. In some cases, the primers hybridize or anneal to the genomic DNA target sequences and the corresponding competitor oligonucleotides with the same or similar hybridization efficiencies. In some cases the hybridization efficiencies are different. The ratio between genomic DNA target amplicons and competitor amplicons can be measured during the reaction. For example if the ratio is 1:1 at 28 cycles but 2:1 at 35, this could indicate that during the end of the amplification reaction the primers for one target (i.e. genomic DNA target or competitor) are either reannealing faster than the other, or the denaturation is less effective than the other.

[0310] In some embodiments primers are used in sets. As used herein, an amplification primer set is one or more pairs of forward and reverse primers for a given region. Thus, for example, primers that amplify genomic targets for region 1 (i.e. targets 1a and 1b) are considered a primer set. Primers that amplify genomic targets for region 2 (i.e. targets 2a and 2b) are considered a different primer set. In some embodiments, the primer sets that amplify targets within a particular region also amplify the corresponding competitor oligonucleotide(s). A plurality of primer pairs may constitute a primer set in certain embodiments (e.g., about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 pairs). In some embodiments a plurality of primer sets, each set comprising pair(s) of primers, may be used.

[0311] Determination of Polynucleotide Sequences

[0312] Techniques for polynucleotide sequence determination are also well established and widely practiced in the relevant research field. For instance, the basic principles and general techniques for polynucleotide sequencing are described in various research reports and treatises on molecular biology and recombinant genetics, such as Wallace et al., supra; Sambrook and Russell, supra, and Ausubel et al., supra. DNA sequencing methods routinely practiced in research laboratories, either manual or automated, can be used for practicing the present technology. Additional means suitable for detecting changes in a polynucleotide sequence for practicing the methods of the present technology include but are not limited to mass spectrometry, primer extension, polynucleotide hybridization, real-time PCR, and electrophoresis.

[0313] Use of a primer extension reaction also can be applied in methods of the technology herein. A primer extension reaction operates, for example, by discriminating the SNP alleles by the incorporation of deoxynucleotides and/or dideoxynucleotides to a primer extension primer which hybridizes to a region adjacent to the SNP site. The primer is extended with a polymerase. The primer extended SNP can be detected physically by mass spectrometry or by a tagging moiety such as biotin. As the SNP site is only extended by a complementary deoxynucleotide or dideoxynucleotide that is either tagged by a specific label or generates a primer extension product with a specific mass, the SNP alleles can be discriminated and quantified.

[0314] Reverse transcribed and amplified nucleic acids may be modified nucleic acids. Modified nucleic acids can include nucleotide analogs, and in certain embodiments include a detectable label and/or a capture agent. Examples of detectable labels include without limitation fluorophores, radioisotopes, colormetric agents, light emitting agents, chemiluminescent agents, light scattering agents, enzymes and the like. Examples of capture agents include without limitation an agent from a binding pair selected from antibody/antigen, antibody/antibody, antibody/antibody fragment, antibody/antibody receptor, antibody/protein A or protein G, hapten/anti-hapten, biotin/avidin, biotin/streptavidin, folic acid/folate binding protein, vitamin B12/intrinsic factor, chemical reactive group/complementary chemical reactive group (e.g., sulfhydryl/maleimide, sulfhydryl/haloacetyl derivative, amine/isotriocyanate, amine/succinimidyl ester, and amine/sulfonyl halides) pairs, and the like. Modified nucleic acids having a capture agent can be immobilized to a solid support in certain embodiments

[0315] Mass spectrometry is a particularly effective method for the detection of a polynucleotide of the technology herein, for example a PCR amplicon, a primer extension product or a detector probe that is cleaved from a target nucleic acid. The presence of the polynucleotide sequence is verified by comparing the mass of the detected signal with the expected mass of the polynucleotide of interest. The relative signal strength, e.g., mass peak on a spectra, for a particular polynucleotide sequence indicates the relative population of a specific allele, thus enabling calculation of the allele ratio directly from the data. For a review of genotyping methods using Sequenom.RTM. standard iPLEX.TM. assay and MassARRAY.RTM. technology, see Jurinke, C., Oeth, P., van den Boom, D., "MALDI-TOF mass spectrometry: a versatile tool for high-performance DNA analysis." Mol. Biotechnol. 26, 147-164 (2004); and Oeth, P. et al., "iPLEX.TM. Assay: Increased Plexing Efficiency and Flexibility for MassARRAY.RTM. System through single base primer extension with mass-modified Terminators." SEQUENOM Application Note (2005), both of which are hereby incorporated by reference. For a review of detecting and quantifying target nucleic using cleavable detector probes that are cleaved during the amplification process and detected by mass spectrometry, see U.S. patent application Ser. No. 11/950,395, which was filed Dec. 4, 2007, and is hereby incorporated by reference.

[0316] Sequencing technologies are improving in terms of throughput and cost. Sequencing technologies, such as that achievable on the 454 platform (Roche) (Margulies, M. et al. 2005 Nature 437, 376-380), Illumina Genome Analyzer (or Solexa platform) or SOLiD System (Applied Biosystems) or the Helicos True Single Molecule DNA sequencing technology (Harris T D et al. 2008 Science, 320, 106-109), the single molecule, real-time (SMRT.TM.) technology of Pacific Biosciences, and nanopore sequencing (Soni G V and Meller A. 2007 Clin Chem 53: 1996-2001), allow the sequencing of many nucleic acid molecules isolated from a specimen at high orders of multiplexing in a parallel fashion (Dear Brief Funct Genomic Proteomic 2003; 1: 397-416).

[0317] Each of these platforms allow sequencing of clonally expanded or non-amplified single molecules of nucleic acid fragments. Certain platforms involve, for example, (i) sequencing by ligation of dye-modified probes (including cyclic ligation and cleavage), (ii) pyrosequencing, and (iii) single-molecule sequencing. Nucleotide sequence species, amplification nucleic acid species and detectable products generated there from can be considered a "study nucleic acid" for purposes of analyzing a nucleotide sequence by such sequence analysis platforms.

[0318] Sequencing by ligation is a nucleic acid sequencing method that relies on the sensitivity of DNA ligase to base-pairing mismatch. DNA ligase joins together ends of DNA that are correctly base paired. Combining the ability of DNA ligase to join together only correctly base paired DNA ends, with mixed pools of fluorescently labeled oligonucleotides or primers, enables sequence determination by fluorescence detection. Longer sequence reads may be obtained by including primers containing cleavable linkages that can be cleaved after label identification. Cleavage at the linker removes the label and regenerates the 5' phosphate on the end of the ligated primer, preparing the primer for another round of ligation. In some embodiments primers may be labeled with more than one fluorescent label (e.g., 1 fluorescent label, 2, 3, or 4 fluorescent labels). An example of a system that can be used by a person of ordinary skill based on sequencing by ligation generally involves the following steps. Clonal bead populations can be prepared in emulsion microreactors containing study nucleic acid ("template"), amplification reaction components, beads and primers. After amplification, templates are denatured and bead enrichment is performed to separate beads with extended templates from undesired beads (e.g., beads with no extended templates). The template on the selected beads undergoes a 3' modification to allow covalent bonding to the slide, and modified beads can be deposited onto a glass slide. Deposition chambers offer the ability to segment a slide into one, four or eight chambers during the bead loading process. For sequence analysis, primers hybridize to the adapter sequence. A set of four color dye-labeled probes competes for ligation to the sequencing primer. Specificity of probe ligation is achieved by interrogating every 4th and 5th base during the ligation series. Five to seven rounds of ligation, detection and cleavage record the color at every 5th position with the number of rounds determined by the type of library used. Following each round of ligation, a new complimentary primer offset by one base in the 5' direction is laid down for another series of ligations. Primer reset and ligation rounds (5-7 ligation cycles per round) are repeated sequentially five times to generate 25-35 base pairs of sequence for a single tag. With mate-paired sequencing, this process is repeated for a second tag. Such a system can be used to exponentially amplify amplification products generated by a process described herein, e.g., by ligating a heterologous nucleic acid to the first amplification product generated by a process described herein and performing emulsion amplification using the same or a different solid support originally used to generate the first amplification product. Such a system also may be used to analyze amplification products directly generated by a process described herein by bypassing an exponential amplification process and directly sorting the solid supports described herein on the glass slide.

[0319] Pyrosequencing is a nucleic acid sequencing method based on sequencing by synthesis, which relies on detection of a pyrophosphate released on nucleotide incorporation. Generally, sequencing by synthesis involves synthesizing, one nucleotide at a time, a DNA strand complimentary to the strand whose sequence is being sought. Study nucleic acids may be immobilized to a solid support, hybridized with a sequencing primer, incubated with DNA polymerase, ATP sulfurylase, luciferase, apyrase, adenosine 5' phosphsulfate and luciferin. Nucleotide solutions are sequentially added and removed. Correct incorporation of a nucleotide releases a pyrophosphate, which interacts with ATP sulfurylase and produces ATP in the presence of adenosine 5' phosphsulfate, fueling the luciferin reaction, which produces a chemiluminescent signal allowing sequence determination.

[0320] An example of a system that can be used by a person of ordinary skill based on pyrosequencing generally involves the following steps: ligating an adaptor nucleic acid to a study nucleic acid and hybridizing the study nucleic acid to a bead; amplifying a nucleotide sequence in the study nucleic acid in an emulsion; sorting beads using a picoliter multiwell solid support; and sequencing amplified nucleotide sequences by pyrosequencing methodology (e.g., Nakano et al., "Single-molecule PCR using water-in-oil emulsion;" Journal of Biotechnology 102: 117-124 (2003)). Such a system can be used to exponentially amplify amplification products generated by a process described herein, e.g., by ligating a heterologous nucleic acid to the first amplification product generated by a process described herein.

[0321] Certain single-molecule sequencing embodiments are based on the principal of sequencing by synthesis, and utilize single-pair Fluorescence Resonance Energy Transfer (single pair FRET) as a mechanism by which photons are emitted as a result of successful nucleotide incorporation. The emitted photons often are detected using intensified or high sensitivity cooled charge-couple-devices in conjunction with total internal reflection microscopy (TIRM). Photons are only emitted when the introduced reaction solution contains the correct nucleotide for incorporation into the growing nucleic acid chain that is synthesized as a result of the sequencing process. In FRET based single-molecule sequencing, energy is transferred between two fluorescent dyes, sometimes polymethine cyanine dyes Cy3 and Cy5, through long-range dipole interactions. The donor is excited at its specific excitation wavelength and the excited state energy is transferred, non-radiatively to the acceptor dye, which in turn becomes excited. The acceptor dye eventually returns to the ground state by radiative emission of a photon. The two dyes used in the energy transfer process represent the "single pair", in single pair FRET. Cy3 often is used as the donor fluorophore and often is incorporated as the first labeled nucleotide. Cy5 often is used as the acceptor fluorophore and is used as the nucleotide label for successive nucleotide additions after incorporation of a first Cy3 labeled nucleotide. The fluorophores generally are within 10 nanometers of each for energy transfer to occur successfully.

[0322] An example of a system that can be used based on single-molecule sequencing generally involves hybridizing a primer to a study nucleic acid to generate a complex; associating the complex with a solid phase; iteratively extending the primer by a nucleotide tagged with a fluorescent molecule; and capturing an image of fluorescence resonance energy transfer signals after each iteration (e.g., U.S. Pat. No. 7,169,314; Braslavsky et al., PNAS 100(7): 3960-3964 (2003)). Such a system can be used to directly sequence amplification products generated by processes described herein. In some embodiments the released linear amplification product can be hybridized to a primer that contains sequences complementary to immobilized capture sequences present on a solid support, a bead or glass slide for example. Hybridization of the primer--released linear amplification product complexes with the immobilized capture sequences, immobilizes released linear amplification products to solid supports for single pair FRET based sequencing by synthesis. The primer often is fluorescent, so that an initial reference image of the surface of the slide with immobilized nucleic acids can be generated. The initial reference image is useful for determining locations at which true nucleotide incorporation is occurring. Fluorescence signals detected in array locations not initially identified in the "primer only" reference image are discarded as non-specific fluorescence. Following immobilization of the primer--released linear amplification product complexes, the bound nucleic acids often are sequenced in parallel by the iterative steps of, a) polymerase extension in the presence of one fluorescently labeled nucleotide, b) detection of fluorescence using appropriate microscopy, TIRM for example, c) removal of fluorescent nucleotide, and d) return to step a with a different fluorescently labeled nucleotide.

[0323] In some embodiments, nucleotide sequencing may be by solid phase single nucleotide sequencing methods and processes. Solid phase single nucleotide sequencing methods involve contacting sample nucleic acid and solid support under conditions in which a single molecule of sample nucleic acid hybridizes to a single molecule of a solid support. Such conditions can include providing the solid support molecules and a single molecule of sample nucleic acid in a "microreactor." Such conditions also can include providing a mixture in which the sample nucleic acid molecule can hybridize to solid phase nucleic acid on the solid support. Single nucleotide sequencing methods useful in the embodiments described herein are described in U.S. Provisional Patent Application Ser. No. 61/021,871 filed Jan. 17, 2008.

[0324] In certain embodiments, nanopore sequencing detection methods include (a) contacting a nucleic acid for sequencing ("base nucleic acid," e.g., linked probe molecule) with sequence-specific detectors, under conditions in which the detectors specifically hybridize to substantially complementary subsequences of the base nucleic acid; (b) detecting signals from the detectors and (c) determining the sequence of the base nucleic acid according to the signals detected. In certain embodiments, the detectors hybridized to the base nucleic acid are disassociated from the base nucleic acid (e.g., sequentially dissociated) when the detectors interfere with a nanopore structure as the base nucleic acid passes through a pore, and the detectors disassociated from the base sequence are detected. In some embodiments, a detector disassociated from a base nucleic acid emits a detectable signal, and the detector hybridized to the base nucleic acid emits a different detectable signal or no detectable signal. In certain embodiments, nucleotides in a nucleic acid (e.g., linked probe molecule) are substituted with specific nucleotide sequences corresponding to specific nucleotides ("nucleotide representatives"), thereby giving rise to an expanded nucleic acid (e.g., U.S. Pat. No. 6,723,513), and the detectors hybridize to the nucleotide representatives in the expanded nucleic acid, which serves as a base nucleic acid. In such embodiments, nucleotide representatives may be arranged in a binary or higher order arrangement (e.g., Soni and Meller, Clinical Chemistry 53(11): 1996-2001 (2007)). In some embodiments, a nucleic acid is not expanded, does not give rise to an expanded nucleic acid, and directly serves a base nucleic acid (e.g., a linked probe molecule serves as a non-expanded base nucleic acid), and detectors are directly contacted with the base nucleic acid. For example, a first detector may hybridize to a first subsequence and a second detector may hybridize to a second subsequence, where the first detector and second detector each have detectable labels that can be distinguished from one another, and where the signals from the first detector and second detector can be distinguished from one another when the detectors are disassociated from the base nucleic acid. In certain embodiments, detectors include a region that hybridizes to the base nucleic acid (e.g., two regions), which can be about 3 to about 100 nucleotides in length (e.g., about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 nucleotides in length). A detector also may include one or more regions of nucleotides that do not hybridize to the base nucleic acid. In some embodiments, a detector is a molecular beacon. A detector often comprises one or more detectable labels independently selected from those described herein. Each detectable label can be detected by any convenient detection process capable of detecting a signal generated by each label (e.g., magnetic, electric, chemical, optical and the like). For example, a CD camera can be used to detect signals from one or more distinguishable quantum dots linked to a detector.

[0325] In certain sequence analysis embodiments, reads may be used to construct a larger nucleotide sequence, which can be facilitated by identifying overlapping sequences in different reads and by using identification sequences in the reads. Such sequence analysis methods and software for constructing larger sequences from reads are known to the person of ordinary skill (e.g., Venter et al., Science 291: 1304-1351 (2001)). Specific reads, partial nucleotide sequence constructs, and full nucleotide sequence constructs may be compared between nucleotide sequences within a sample nucleic acid (i.e., internal comparison) or may be compared with a reference sequence (i.e., reference comparison) in certain sequence analysis embodiments. Internal comparisons sometimes are performed in situations where a sample nucleic acid is prepared from multiple samples or from a single sample source that contains sequence variations. Reference comparisons sometimes are performed when a reference nucleotide sequence is known and an objective is to determine whether a sample nucleic acid contains a nucleotide sequence that is substantially similar or the same, or different, than a reference nucleotide sequence. Sequence analysis is facilitated by sequence analysis apparatus and components known to the person of ordinary skill in the art.

[0326] Methods provided herein allow for high-throughput detection of nucleic acid species in a plurality of nucleic acids (e.g., nucleotide sequence species, amplified nucleic acid species and detectable products generated from the foregoing). Multiplexing refers to the simultaneous detection of more than one nucleic acid species. General methods for performing multiplexed reactions in conjunction with mass spectrometry, are known (see, e.g., U.S. Pat. Nos. 6,043,031, 5,547,835 and International PCT application No. WO 97/37041). Multiplexing provides an advantage that a plurality of nucleic acid species (e.g., some having different sequence variations) can be identified in as few as a single mass spectrum, as compared to having to perform a separate mass spectrometry analysis for each individual target nucleic acid species. Methods provided herein lend themselves to high-throughput, highly-automated processes for analyzing sequence variations with high speed and accuracy, in some embodiments. In some embodiments, methods herein may be multiplexed at high levels in a single reaction.

[0327] In certain embodiments, the number of nucleic acid species multiplexed include, without limitation, about 1 to about 500 (e.g., about 1-3, 3-5, 5-7, 7-9, 9-11, 11-13, 13-15, 15-17, 17-19, 19-21, 21-23, 23-25, 25-27, 27-29, 29-31, 31-33, 33-35, 35-37, 37-39, 39-41, 41-43, 43-45, 45-47, 47-49, 49-51, 51-53, 53-55, 55-57, 57-59, 59-61, 61-63, 63-65, 65-67, 67-69, 69-71, 71-73, 73-75, 75-77, 77-79, 79-81, 81-83, 83-85, 85-87, 87-89, 89-91, 91-93, 93-95, 95-97, 97-101, 101-103, 103-105, 105-107, 107-109, 109-111, 111-113, 113-115, 115-117, 117-119, 121-123, 123-125, 125-127, 127-129, 129-131, 131-133, 133-135, 135-137, 137-139, 139-141, 141-143, 143-145, 145-147, 147-149, 149-151, 151-153, 153-155, 155-157, 157-159, 159-161, 161-163, 163-165, 165-167, 167-169, 169-171, 171-173, 173-175, 175-177, 177-179, 179-181, 181-183, 183-185, 185-187, 187-189, 189-191, 191-193, 193-195, 195-197, 197-199, 199-201, 201-203, 203-205, 205-207, 207-209, 209-211, 211-213, 213-215, 215-217, 217-219, 219-221, 221-223, 223-225, 225-227, 227-229, 229-231, 231-233, 233-235, 235-237, 237-239, 239-241, 241-243, 243-245, 245-247, 247-249, 249-251, 251-253, 253-255, 255-257, 257-259, 259-261, 261-263, 263-265, 265-267, 267-269, 269-271, 271-273, 273-275, 275-277, 277-279, 279-281, 281-283, 283-285, 285-287, 287-289, 289-291, 291-293, 293-295, 295-297, 297-299, 299-301, 301-303, 303-305, 305-307, 307-309, 309-311, 311-313, 313-315, 315-317, 317-319, 319-321, 321-323, 323-325, 325-327, 327-329, 329-331, 331-333, 333-335, 335-337, 337-339, 339-341, 341-343, 343-345, 345-347, 347-349, 349-351, 351-353, 353-355, 355-357, 357-359, 359-361, 361-363, 363-365, 365-367, 367-369, 369-371, 371-373, 373-375, 375-377, 377-379, 379-381, 381-383, 383-385, 385-387, 387-389, 389-391, 391-393, 393-395, 395-397, 397-401, 401-403, 403-405, 405-407, 407-409, 409-411, 411-413, 413-415, 415-417, 417-419, 419-421, 421-423, 423-425, 425-427, 427-429, 429-431, 431-433, 433-435, 435-437, 437-439, 439-441, 441-443, 443-445, 445-447, 447-449, 449-451, 451-453, 453-455, 455-457, 457-459, 459-461, 461-463, 463-465, 465-467, 467-469, 469-471, 471-473, 473-475, 475-477, 477-479, 479-481, 481-483, 483-485, 485-487, 487-489, 489-491, 491-493, 493-495, 495-497, 497-501).

[0328] Design methods for achieving resolved mass spectra with multiplexed assays can include primer and oligonucleotide design methods and reaction design methods. See, for example, the multiplex schemes provided in Tables X and Y. For primer and oligonucleotide design in multiplexed assays, the same general guidelines for primer design applies for uniplexed reactions, such as avoiding false priming and primer dimers, only more primers are involved for multiplex reactions. For mass spectrometry applications, analyte peaks in the mass spectra for one assay are sufficiently resolved from a product of any assay with which that assay is multiplexed, including pausing peaks and any other by-product peaks. Also, analyte peaks optimally fall within a user-specified mass window, for example, within a range of 5,000-8,500 Da. In some embodiments multiplex analysis may be adapted to mass spectrometric detection of chromosome abnormalities, for example. In certain embodiments multiplex analysis may be adapted to various single nucleotide or nanopore based sequencing methods described herein. Commercially produced micro-reaction chambers or devices or arrays or chips may be used to facilitate multiplex analysis, and are commercially available.

[0329] Additional Methods for Obtaining Nucleotide Sequence Reads

[0330] In some embodiments, nucleic acids (e.g., nucleic acid fragments, sample nucleic acid, cell-free nucleic acid) may be sequenced. In some cases, a full or substantially full sequence is obtained and sometimes a partial sequence is obtained. Sequencing, mapping and related analytical methods are known in the art (e.g., United States Patent Application Publication US2009/0029377, incorporated by reference). Certain aspects of such processes are described hereafter.

[0331] As used herein, "reads" are short nucleotide sequences produced by any sequencing process described herein or known in the art. Reads can be generated from one end of nucleic acid fragments ("single-end reads"), and sometimes are generated from both ends of nucleic acids ("double-end reads"). In certain embodiments, "obtaining" nucleic acid sequence reads of a sample from a subject and/or "obtaining" nucleic acid sequence reads of a biological specimen from one or more reference persons can involve directly sequencing nucleic acid to obtain the sequence information. In some embodiments, "obtaining" can involve receiving sequence information obtained directly from a nucleic acid by another.

[0332] In some embodiments, one nucleic acid sample from one individual is sequenced. In certain embodiments, nucleic acid samples from two or more biological samples, where each biological sample is from one individual or two or more individuals, are pooled and the pool is sequenced. In the latter embodiments, a nucleic acid sample from each biological sample often is identified by one or more unique identification tags.

[0333] In some embodiments, a fraction of the genome is sequenced, which sometimes is expressed in the amount of the genome covered by the determined nucleotide sequences (e.g., "fold" coverage less than 1). When a genome is sequenced with about 1-fold coverage, roughly 100% of the nucleotide sequence of the genome is represented by reads. A genome also can be sequenced with redundancy, where a given region of the genome can be covered by two or more reads or overlapping reads (e.g., "fold" coverage greater than 1). In some embodiments, a genome is sequenced with about 0.1-fold to about 100-fold coverage, about 0.2-fold to 20-fold coverage, or about 0.2-fold to about 1-fold coverage (e.g., about 0.2-, 0.3-, 0.4-, 0.5-, 0.6-, 0.7-, 0.8-, 0.9-, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 30-, 40-, 50-, 60-, 70-, 80-, 90-fold coverage).

[0334] In certain embodiments, a fraction of a nucleic acid pool that is sequenced in a run is further sub-selected prior to sequencing. In certain embodiments, hybridization-based techniques (e.g., using oligonucleotide arrays) can be used to first sub-select for nucleic acid sequences from certain chromosomes (e.g., a potentially aneuploid chromosome and other chromosome(s) not involved in the aneuploidy tested). In some embodiments, nucleic acid can be fractionated by size (e.g., by gel electrophoresis, size exclusion chromatography or by microfluidics-based approach) and in certain instances, fetal nucleic acid can be enriched by selecting for nucleic acid having a lower molecular weight (e.g., less than 300 base pairs, less than 200 base pairs, less than 150 base pairs, less than 100 base pairs). In some embodiments, fetal nucleic acid can be enriched by suppressing maternal background nucleic acid, such as by the addition of formaldehyde. In some embodiments, a portion or subset of a pre-selected pool of nucleic acids is sequenced randomly. In some embodiments, the nucleic acid is amplified prior to sequencing. In some embodiments, a portion or subset of the nucleic acid is amplified prior to sequencing.

[0335] In some cases, a sequencing library is prepared prior to or during a sequencing process. Methods for preparing a sequencing library are known in the art and commercially available platforms may be used for certain applications. Certain commercially available library platforms may be compatible with certain nucleotide sequencing processes described herein. For example, one or more commercially available library platforms may be compatible with a sequencing by synthesis process. In some cases, a ligation-based library preparation method is used (e.g., ILLUMINA TRUSEQ, Illumina, San Diego Calif.). Ligation-based library preparation methods typically use a methylated adaptor design which can incorporate an index sequence at the initial ligation step and often can be used to prepare samples for single-read sequencing, paired-end sequencing and multiplexed sequencing. In some cases, a transposon-based library preparation method is used (e.g., EPICENTRE NEXTERA, Epicentre, Madison Wis.). Transposon-based methods typically use in vitro transposition to simultaneously fragment and tag DNA in a single-tube reaction (often allowing incorporation of platform-specific tags and optional barcodes), and prepare sequencer-ready libraries.

[0336] Any sequencing method suitable for conducting methods described herein can be utilized. In some embodiments, a high-throughput sequencing method is used. High-throughput sequencing methods generally involve clonally amplified DNA templates or single DNA molecules that are sequenced in a massively parallel fashion within a flow cell (e.g. as described in Metzker M Nature Rev 11:31-46 (2010); Volkerding et al. Clin Chem 55:641-658 (2009)). Such sequencing methods also can provide digital quantitative information, where each sequence read is a countable "sequence tag" or "count" representing an individual clonal DNA template or a single DNA molecule. High-throughput sequencing technologies include, for example, sequencing-by-synthesis with reversible dye terminators, sequencing by oligonucleotide probe ligation, pyrosequencing and real time sequencing.

[0337] Systems utilized for high-throughput sequencing methods are commercially available and include, for example, the Roche 454 platform, the Applied Biosystems SOLID platform, the Helicos True Single Molecule DNA sequencing technology, the sequencing-by-hybridization platform from Affymetrix Inc., the single molecule, real-time (SMRT) technology of Pacific Biosciences, the sequencing-by-synthesis platforms from 454 Life Sciences, Illumina/Solexa and Helicos Biosciences, and the sequencing-by-ligation platform from Applied Biosystems. The ION TORRENT technology from Life technologies and nanopore sequencing also can be used in high-throughput sequencing approaches.

[0338] In some embodiments, first generation technology, such as, for example, Sanger sequencing including the automated Sanger sequencing, can be used in the methods provided herein. Additional sequencing technologies that include the use of developing nucleic acid imaging technologies (e.g. transmission electron microscopy (TEM) and atomic force microscopy (AFM)), also are contemplated herein. Examples of various sequencing technologies are described below.

[0339] A nucleic acid sequencing technology that may be used in the methods described herein is sequencing-by-synthesis and reversible terminator-based sequencing (e.g. Illumina's Genome Analyzer; Genome Analyzer II; HISEQ 2000; HISEQ 2500 (Illumina, San Diego Calif.)). With this technology, millions of nucleic acid (e.g. DNA) fragments can be sequenced in parallel. In one example of this type of sequencing technology, a flow cell is used which contains an optically transparent slide with 8 individual lanes on the surfaces of which are bound oligonucleotide anchors (e.g., adaptor primers). A flow cell often is a solid support that can be configured to retain and/or allow the orderly passage of reagent solutions over bound analytes. Flow cells frequently are planar in shape, optically transparent, generally in the millimeter or sub-millimeter scale, and often have channels or lanes in which the analyte/reagent interaction occurs.

[0340] In certain sequencing by synthesis procedures, for example, template DNA (e.g., circulating cell-free DNA (ccfDNA)) sometimes is fragmented into lengths of several hundred base pairs in preparation for library generation. In some embodiments, library preparation can be performed without further fragmentation or size selection of the template DNA (e.g., ccfDNA). Sample isolation and library generation may be performed using automated methods and apparatus, in certain embodiments. Briefly, template DNA is end repaired by a fill-in reaction, exonuclease reaction or a combination of a fill-in reaction and exonuclease reaction. The resulting blunt-end repaired template DNA is extended by a single nucleotide, which is complementary to a single nucleotide overhang on the 3' end of an adapter primer, and often increases ligation efficiency. Any complementary nucleotides can be used for the extension/overhang nucleotides (e.g., A/T, C/G), however adenine frequently is used to extend the end-repaired DNA, and thymine often is used as the 3' end overhang nucleotide.

[0341] In certain sequencing by synthesis procedures, for example, adapter oligonucleotides are complementary to the flow-cell anchors, and sometimes are utilized to associate the modified template DNA (e.g., end-repaired and single nucleotide extended) with a solid support, such as the inside surface of a flow cell, for example. In some embodiments, the adapter also includes identifiers (i.e., indexing nucleotides, or "barcode" nucleotides (e.g., a unique sequence of nucleotides usable as an identifier to allow unambiguous identification of a sample and/or chromosome)), one or more sequencing primer hybridization sites (e.g., sequences complementary to universal sequencing primers, single end sequencing primers, paired end sequencing primers, multiplexed sequencing primers, and the like), or combinations thereof (e.g., adapter/sequencing, adapter/identifier, adapter/identifier/sequencing). Identifiers or nucleotides contained in an adapter often are six or more nucleotides in length, and frequently are positioned in the adaptor such that the identifier nucleotides are the first nucleotides sequenced during the sequencing reaction. In certain embodiments, identifier nucleotides are associated with a sample but are sequenced in a separate sequencing reaction to avoid compromising the quality of sequence reads. Subsequently, the reads from the identifier sequencing and the DNA template sequencing are linked together and the reads de-multiplexed. After linking and de-multiplexing the sequence reads and/or identifiers can be further adjusted or processed as described herein.

[0342] In certain sequencing by synthesis procedures, utilization of identifiers allows multiplexing of sequence reactions in a flow cell lane, thereby allowing analysis of multiple samples per flow cell lane. The number of samples that can be analyzed in a given flow cell lane often is dependent on the number of unique identifiers utilized during library preparation and/or probe design. Non limiting examples of commercially available multiplex sequencing kits include Illumina's multiplexing sample preparation oligonucleotide kit and multiplexing sequencing primers and PhiX control kit (e.g., Illumina's catalog numbers PE-400-1001 and PE-400-1002, respectively). The methods described herein can be performed using any number of unique identifiers (e.g., 4, 8, 12, 24, 48, 96, or more). The greater the number of unique identifiers, the greater the number of samples and/or chromosomes, for example, that can be multiplexed in a single flow cell lane. Multiplexing using 12 identifiers, for example, allows simultaneous analysis of 96 samples (e.g., equal to the number of wells in a 96 well microwell plate) in an 8 lane flow cell. Similarly, multiplexing using 48 identifiers, for example, allows simultaneous analysis of 384 samples (e.g., equal to the number of wells in a 384 well microwell plate) in an 8 lane flow cell.

[0343] In certain sequencing by synthesis procedures, adapter-modified, single-stranded template DNA is added to the flow cell and immobilized by hybridization to the anchors under limiting-dilution conditions. In contrast to emulsion PCR, DNA templates are amplified in the flow cell by "bridge" amplification, which relies on captured DNA strands "arching" over and hybridizing to an adjacent anchor oligonucleotide. Multiple amplification cycles convert the single-molecule DNA template to a clonally amplified arching "cluster," with each cluster containing approximately 1000 clonal molecules. Approximately 50.times.10.sup.6 separate clusters can be generated per flow cell. For sequencing, the clusters are denatured, and a subsequent chemical cleavage reaction and wash leave only forward strands for single-end sequencing. Sequencing of the forward strands is initiated by hybridizing a primer complementary to the adapter sequences, which is followed by addition of polymerase and a mixture of four differently colored fluorescent reversible dye terminators. The terminators are incorporated according to sequence complementarity in each strand in a clonal cluster. After incorporation, excess reagents are washed away, the clusters are optically interrogated, and the fluorescence is recorded. With successive chemical steps, the reversible dye terminators are unblocked, the fluorescent labels are cleaved and washed away, and the next sequencing cycle is performed. This iterative, sequencing-by-synthesis process sometimes requires approximately 2.5 days to generate read lengths of 36 bases. With 50.times.10.sup.6 clusters per flow cell, the overall sequence output can be greater than 1 billion base pairs (Gb) per analytical run.

[0344] Another nucleic acid sequencing technology that may be used with the methods described herein is 454 sequencing (Roche). 454 sequencing uses a large-scale parallel pyrosequencing system capable of sequencing about 400-600 megabases of DNA per run. The process typically involves two steps. In the first step, sample nucleic acid (e.g. DNA) is sometimes fractionated into smaller fragments (300-800 base pairs) and polished (made blunt at each end). Short adaptors are then ligated onto the ends of the fragments. These adaptors provide priming sequences for both amplification and sequencing of the sample-library fragments. One adaptor (Adaptor B) contains a 5'-biotin tag for immobilization of the DNA library onto streptavidin-coated beads. After nick repair, the non-biotinylated strand is released and used as a single-stranded template DNA (sstDNA) library. The sstDNA library is assessed for its quality and the optimal amount (DNA copies per bead) needed for emPCR is determined by titration. The sstDNA library is immobilized onto beads. The beads containing a library fragment carry a single sstDNA molecule. The bead-bound library is emulsified with the amplification reagents in a water-in-oil mixture. Each bead is captured within its own microreactor where PCR amplification occurs. This results in bead-immobilized, clonally amplified DNA fragments.

[0345] In the second step of 454 sequencing, single-stranded template DNA library beads are added to an incubation mix containing DNA polymerase and are layered with beads containing sulfurylase and luciferase onto a device containing pico-liter sized wells. Pyrosequencing is performed on each DNA fragment in parallel. Addition of one or more nucleotides generates a light signal that is recorded by a CCD camera in a sequencing instrument. The signal strength is proportional to the number of nucleotides incorporated. Pyrosequencing exploits the release of pyrophosphate (PPi) upon nucleotide addition. PPi is converted to ATP by ATP sulfurylase in the presence of adenosine 5' phosphosulfate. Luciferase uses ATP to convert luciferin to oxyluciferin, and this reaction generates light that is discerned and analyzed (see, for example, Margulies, M. et al. Nature 437:376-380 (2005)).

[0346] Another nucleic acid sequencing technology that may be used in the methods provided herein is Applied Biosystems' SOLiD.TM. technology. In SOLiD.TM. sequencing-by-ligation, a library of nucleic acid fragments is prepared from the sample and is used to prepare clonal bead populations. With this method, one species of nucleic acid fragment will be present on the surface of each bead (e.g. magnetic bead). Sample nucleic acid (e.g. genomic DNA) is sheared into fragments, and adaptors are subsequently attached to the 5' and 3' ends of the fragments to generate a fragment library.

[0347] The adapters are typically universal adapter sequences so that the starting sequence of every fragment is both known and identical. Emulsion PCR takes place in microreactors containing all the necessary reagents for PCR. The resulting PCR products attached to the beads are then covalently bound to a glass slide. Primers then hybridize to the adapter sequence within the library template. A set of four fluorescently labeled di-base probes compete for ligation to the sequencing primer. Specificity of the di-base probe is achieved by interrogating every 1st and 2nd base in each ligation reaction. Multiple cycles of ligation, detection and cleavage are performed with the number of cycles determining the eventual read length. Following a series of ligation cycles, the extension product is removed and the template is reset with a primer complementary to the n-1 position for a second round of ligation cycles. Often, five rounds of primer reset are completed for each sequence tag. Through the primer reset process, each base is interrogated in two independent ligation reactions by two different primers. For example, the base at read position 5 is assayed by primer number 2 in ligation cycle 2 and by primer number 3 in ligation cycle 1.

[0348] Another nucleic acid sequencing technology that may be used in the methods described herein is the Helicos True Single Molecule Sequencing (tSMS). In the tSMS technique, a polyA sequence is added to the 3' end of each nucleic acid (e.g. DNA) strand from the sample. Each strand is labeled by the addition of a fluorescently labeled adenosine nucleotide. The DNA strands are then hybridized to a flow cell, which contains millions of oligo-T capture sites that are immobilized to the flow cell surface. The templates can be at a density of about 100 million templates/cm.sup.2. The flow cell is then loaded into a sequencing apparatus and a laser illuminates the surface of the flow cell, revealing the position of each template. A CCD camera can map the position of the templates on the flow cell surface. The template fluorescent label is then cleaved and washed away. The sequencing reaction begins by introducing a DNA polymerase and a fluorescently labeled nucleotide. The oligo-T nucleic acid serves as a primer. The polymerase incorporates the labeled nucleotides to the primer in a template directed manner. The polymerase and unincorporated nucleotides are removed. The templates that have directed incorporation of the fluorescently labeled nucleotide are detected by imaging the flow cell surface. After imaging, a cleavage step removes the fluorescent label, and the process is repeated with other fluorescently labeled nucleotides until the desired read length is achieved. Sequence information is collected with each nucleotide addition step (see, for example, Harris T. D. et al., Science 320:106-109 (2008)).

[0349] Another nucleic acid sequencing technology that may be used in the methods provided herein is the single molecule, real-time (SMRT.TM.) sequencing technology of Pacific Biosciences. With this method, each of the four DNA bases is attached to one of four different fluorescent dyes. These dyes are phospholinked. A single DNA polymerase is immobilized with a single molecule of template single stranded DNA at the bottom of a zero-mode waveguide (ZMW). A ZMW is a confinement structure which enables observation of incorporation of a single nucleotide by DNA polymerase against the background of fluorescent nucleotides that rapidly diffuse in an out of the ZMW (in microseconds). It takes several milliseconds to incorporate a nucleotide into a growing strand. During this time, the fluorescent label is excited and produces a fluorescent signal, and the fluorescent tag is cleaved off. Detection of the corresponding fluorescence of the dye indicates which base was incorporated. The process is then repeated.

[0350] Another nucleic acid sequencing technology that may be used in the methods described herein is ION TORRENT (Life Technologies) single molecule sequencing which pairs semiconductor technology with a simple sequencing chemistry to directly translate chemically encoded information (A, C, G, T) into digital information (0, 1) on a semiconductor chip. ION TORRENT uses a high-density array of micro-machined wells to perform nucleic acid sequencing in a massively parallel way. Each well holds a different DNA molecule. Beneath the wells is an ion-sensitive layer and beneath that an ion sensor. Typically, when a nucleotide is incorporated into a strand of DNA by a polymerase, a hydrogen ion is released as a byproduct. If a nucleotide, for example a C, is added to a DNA template and is then incorporated into a strand of DNA, a hydrogen ion will be released. The charge from that ion will change the pH of the solution, which can be detected by an ion sensor. A sequencer can call the base, going directly from chemical information to digital information. The sequencer then sequentially floods the chip with one nucleotide after another. If the next nucleotide that floods the chip is not a match, no voltage change will be recorded and no base will be called. If there are two identical bases on the DNA strand, the voltage will be double, and the chip will record two identical bases called. Because this is direct detection (i.e. detection without scanning, cameras or light), each nucleotide incorporation is recorded in seconds.

[0351] Another nucleic acid sequencing technology that may be used in the methods described herein is the chemical-sensitive field effect transistor (CHEMFET) array. In one example of this sequencing technique, DNA molecules are placed into reaction chambers, and the template molecules can be hybridized to a sequencing primer bound to a polymerase. Incorporation of one or more triphosphates into a new nucleic acid strand at the 3' end of the sequencing primer can be detected by a change in current by a CHEMFET sensor. An array can have multiple CHEMFET sensors. In another example, single nucleic acids are attached to beads, and the nucleic acids can be amplified on the bead, and the individual beads can be transferred to individual reaction chambers on a CHEMFET array, with each chamber having a CHEMFET sensor, and the nucleic acids can be sequenced (see, for example, U.S. Patent Application Publication No. 2009/0026082).

[0352] Another nucleic acid sequencing technology that may be used in the methods described herein is electron microscopy. In one example of this sequencing technique, individual nucleic acid (e.g. DNA) molecules are labeled using metallic labels that are distinguishable using an electron microscope. These molecules are then stretched on a flat surface and imaged using an electron microscope to measure sequences (see, for example, Moudrianakis E. N. and Beer M. Proc Natl Acad Sci USA. 1965 March; 53:564-71). In some cases, transmission electron microscopy (TEM) is used (e.g. Halcyon Molecular's TEM method). This method, termed Individual Molecule Placement Rapid Nano Transfer (IMPRNT), includes utilizing single atom resolution transmission electron microscope imaging of high-molecular weight (e.g. about 150 kb or greater) DNA selectively labeled with heavy atom markers and arranging these molecules on ultra-thin films in ultra-dense (3 nm strand-to-strand) parallel arrays with consistent base-to-base spacing. The electron microscope is used to image the molecules on the films to determine the position of the heavy atom markers and to extract base sequence information from the DNA (see, for example, International Patent Application No. WO 2009/046445).

[0353] Other sequencing methods that may be used to conduct methods herein include digital PCR and sequencing by hybridization. Digital polymerase chain reaction (digital PCR or dPCR) can be used to directly identify and quantify nucleic acids in a sample. Digital PCR can be performed in an emulsion, in some embodiments. For example, individual nucleic acids are separated, e.g., in a microfluidic chamber device, and each nucleic acid is individually amplified by PCR. Nucleic acids can be separated such that there is no more than one nucleic acid per well. In some embodiments, different probes can be used to distinguish various alleles (e.g. fetal alleles and maternal alleles). Alleles can be enumerated to determine copy number. In sequencing by hybridization, the method involves contacting a plurality of polynucleotide sequences with a plurality of polynucleotide probes, where each of the plurality of polynucleotide probes can be optionally tethered to a substrate. The substrate can be a flat surface with an array of known nucleotide sequences, in some embodiments. The pattern of hybridization to the array can be used to determine the polynucleotide sequences present in the sample. In some embodiments, each probe is tethered to a bead, e.g., a magnetic bead or the like. Hybridization to the beads can be identified and used to identify the plurality of polynucleotide sequences within the sample.

[0354] In some embodiments, nanopore sequencing can be used in the methods described herein. Nanopore sequencing is a single-molecule sequencing technology whereby a single nucleic acid molecule (e.g. DNA) is sequenced directly as it passes through a nanopore. A nanopore is a small hole or channel, of the order of 1 nanometer in diameter. Certain transmembrane cellular proteins can act as nanopores (e.g. alpha-hemolysin). In some cases, nanopores can be synthesized (e.g. using a silicon platform). Immersion of a nanopore in a conducting fluid and application of a potential across it results in a slight electrical current due to conduction of ions through the nanopore. The amount of current which flows is sensitive to the size of the nanopore. As a DNA molecule passes through a nanopore, each nucleotide on the DNA molecule obstructs the nanopore to a different degree and generates characteristic changes to the current. The amount of current which can pass through the nanopore at any given moment therefore varies depending on whether the nanopore is blocked by an A, a C, a G, a T, or in some cases, methyl-C. The change in the current through the nanopore as the DNA molecule passes through the nanopore represents a direct reading of the DNA sequence. In some cases a nanopore can be used to identify individual DNA bases as they pass through the nanopore in the correct order (see, for example, Soni GV and Meller A. Clin Chem 53: 1996-2001 (2007); International Patent Application No. WO2010/004265).

[0355] There are a number of ways that nanopores can be used to sequence nucleic acid molecules. In some embodiments, an exonuclease enzyme, such as a deoxyribonuclease, is used. In this case, the exonuclease enzyme is used to sequentially detach nucleotides from a nucleic acid (e.g. DNA) molecule. The nucleotides are then detected and discriminated by the nanopore in order of their release, thus reading the sequence of the original strand. For such an embodiment, the exonuclease enzyme can be attached to the nanopore such that a proportion of the nucleotides released from the DNA molecule is capable of entering and interacting with the channel of the nanopore. The exonuclease can be attached to the nanopore structure at a site in close proximity to the part of the nanopore that forms the opening of the channel. In some cases, the exonuclease enzyme can be attached to the nanopore structure such that its nucleotide exit trajectory site is orientated towards the part of the nanopore that forms part of the opening.

[0356] In some embodiments, nanopore sequencing of nucleic acids involves the use of an enzyme that pushes or pulls the nucleic acid (e.g. DNA) molecule through the pore. In this case, the ionic current fluctuates as a nucleotide in the DNA molecule passes through the pore. The fluctuations in the current are indicative of the DNA sequence. For such an embodiment, the enzyme can be attached to the nanopore structure such that it is capable of pushing or pulling the target nucleic acid through the channel of a nanopore without interfering with the flow of ionic current through the pore. The enzyme can be attached to the nanopore structure at a site in close proximity to the part of the structure that forms part of the opening. The enzyme can be attached to the subunit, for example, such that its active site is orientated towards the part of the structure that forms part of the opening.

[0357] In some embodiments, nanopore sequencing of nucleic acids involves detection of polymerase bi-products in close proximity to a nanopore detector. In this case, nucleoside phosphates (nucleotides) are labeled so that a phosphate labeled species is released upon the addition of a polymerase to the nucleotide strand and the phosphate labeled species is detected by the pore. Typically, the phosphate species contains a specific label for each nucleotide. As nucleotides are sequentially added to the nucleic acid strand, the bi-products of the base addition are detected. The order that the phosphate labeled species are detected can be used to determine the sequence of the nucleic acid strand.

[0358] The length of the sequence read is often associated with the particular sequencing technology. High-throughput methods, for example, provide sequence reads that can vary in size from tens to hundreds of base pairs (bp). Nanopore sequencing, for example, can provide sequence reads that can vary in size from tens to hundreds to thousands of base pairs. In some embodiments, the sequence reads are of a mean, median or average length of about 15 bp to 900 bp long (e.g. about 20 bp, about 25 bp, about 30 bp, about 35 bp, about 40 bp, about 45 bp, about 50 bp, about 55 bp, about 60 bp, about 65 bp, about 70 bp, about 75 bp, about 80 bp, about 85 bp, about 90 bp, about 95 bp, about 100 bp, about 110 bp, about 120 bp, about 130, about 140 bp, about 150 bp, about 200 bp, about 250 bp, about 300 bp, about 350 bp, about 400 bp, about 450 bp, or about 500 bp. In some embodiments, the sequence reads are of a mean, median or average length of about 1000 bp or more.

[0359] In some embodiments, nucleic acids may include a fluorescent signal or sequence tag information. Quantification of the signal or tag may be used in a variety of techniques such as, for example, flow cytometry, quantitative polymerase chain reaction (qPCR), gel electrophoresis, gene-chip analysis, microarray, mass spectrometry, cytofluorimetric analysis, fluorescence microscopy, confocal laser scanning microscopy, laser scanning cytometry, affinity chromatography, manual batch mode separation, electric field suspension, sequencing, and combination thereof.

[0360] Adaptors

[0361] In some embodiments, nucleic acids (e.g., PCR primers, PCR amplicons, sample nucleic acid) may include an adaptor sequence and/or complement thereof. Adaptor sequences often are useful for certain sequencing methods such as, for example, a sequencing-by-synthesis process described herein. Adaptors sometimes are referred to as sequencing adaptors or adaptor oligonucleotides. Adaptor sequences typically include one or more sites useful for attachment to a solid support (e.g., flow cell). Adaptors also may include sequencing primer hybridization sites (i.e. sequences complementary to primers used in a sequencing reaction) and identifiers (e.g., indices) as described below. Adaptor sequences can be located at the 5' and/or 3' end of a nucleic acid and sometimes can be located within a larger nucleic acid sequence. Adaptors can be any length and any sequence, and may be selected based on standard methods in the art for adaptor design.

[0362] One or more adaptor oligonucleotides may be incorporated into a nucleic acid (e.g., PCR amplicon) by any method suitable for incorporating adaptor sequences into a nucleic acid. For example, PCR primers used for generating PCR amplicons (i.e., amplification products) may comprise adaptor sequences or complements thereof. Thus, PCR amplicons that comprise one or more adaptor sequences can be generated during an amplification process. In some cases, one or more adaptor sequences can be ligated to a nucleic acid (e.g., PCR amplicon) by any ligation method suitable for attaching adaptor sequences to a nucleic acid. Ligation processes may include, for example, blunt-end ligations, ligations that exploit 3' adenine (A) overhangs generated by Taq polymerase during an amplification process and ligate adaptors having 3' thymine (T) overhangs, and other "sticky-end" ligations. Ligation processes can be optimized such that adaptor sequences hybridize to each end of a nucleic acid and not to each other.

[0363] In some cases, adaptor ligation is bidirectional, which means that adaptor sequences are attached to a nucleic acid such that both ends of the nucleic acid are sequenced in a subsequent sequencing process. In some cases, adaptor ligation is unidirectional, which means that adaptor sequences are attached to a nucleic acid such that one end of the nucleic acid is sequenced in a subsequent sequencing process. Examples of unidirectional and bidirectional ligation schemes are discussed in Example 4 and shown in FIGS. 21 and 22.

[0364] Identifiers

[0365] In some embodiments, nucleic acids (e.g., PCR primers, PCR amplicons, sample nucleic acid, sequencing adaptors) may include an identifier. In some cases, an identifier is located within or adjacent to an adaptor sequence. An identifier can be any feature that can identify a particular origin or aspect of a genomic target sequence. For example, an identifier (e.g., a sample identifier) can identify the sample from which a particular genomic target sequence originated. In another example, an identifier (e.g., a sample aliquot identifier) can identify the sample aliquot from which a particular genomic target sequence originated. In another example, an identifier (e.g., chromosome identifier) can identify the chromosome from which a particular genomic target sequence originated. An identifier may be referred to herein as a tag, index, barcode, identification tag, index primer, and the like. An identifier may be a unique sequence of nucleotides (e.g., sequence-based identifiers), a detectable label such as the labels described below (e.g., identifier labels), and/or a particular length of polynucleotide (e.g., length-based identifiers; size-based identifiers) such as a stuffer sequence. Identifiers for a collection of samples or plurality of chromosomes, for example, may each comprise a unique sequence of nucleotides. Identifiers (e.g., sequence-based identifiers, length-based identifiers) may be of any length suitable to distinguish certain target genomic sequences from other target genomic sequences. In some embodiments, identifiers may be from about one to about 100 nucleotides in length. For example, identifiers independently may be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 nucleotides in length. In some embodiments, an identifier contains a sequence of six nucleotides. In some cases, an identifier is part of an adaptor sequence for a sequencing process, such as, for example, a sequencing-by-synthesis process described in further detail herein. In some cases, an identifier may be a repeated sequence of a single nucleotide (e.g., poly-A, poly-T, poly-G, poly-C). Such identifiers may be detected and distinguished from each other, for example, using nanopore technology, as described herein.

[0366] In some embodiments, the analysis includes analyzing (e.g., detecting, counting, processing counts for, and the like) the identifier. In some embodiments, the detection process includes detecting the identifier and sometimes not detecting other features (e.g., sequences) of a nucleic acid. In some embodiments, the counting process includes counting each identifier. In some embodiments, the identifier is the only feature of a nucleic acid that is detected, analyzed and/or counted.

Detection of Fetal Aneuploidy

[0367] For the detection of fetal aneuploidies, some methods rely on measuring the ratio between maternally and paternally inherited alleles. However, the ability to quantify chromosomal changes is impaired by the maternal contribution of cell free nucleic acids, which makes it necessary to deplete the sample from maternal DNA prior to measurement. Promising approaches take advantage of the different size distribution of fetal and maternal DNA or measure RNA that is exclusively expressed by the fetus (see for example, U.S. patent application Ser. No. 11/384,128, which published as US20060252071 and is hereby incorporated by reference). Assuming fetal DNA makes up only about 5% of all cell free DNA in the maternal plasma, there is a decrease of the ratio difference from 1.6% to only about 1.2% between a trisomy sample and a healthy control. Consequently, reliable detection of allele ratio changes requires enriching the fetal fraction of cell free DNA, for example, using the compositions and methods of the present technology.

[0368] Some methods rely on measuring the ratio of maternal to paternally inherited alleles to detect fetal chromosomal aneuploidies from maternal plasma. A diploid set yields a 1:1 ratio while trisomies can be detected as a 2:1 ratio. Detection of this difference is impaired by statistical sampling due to the low abundance of fetal DNA, presence of excess maternal DNA in the plasma sample and variability of the measurement technique. The latter is addressed by using methods with high measurement precision, like digital PCR or mass spectrometry. Enriching the fetal fraction of cell free DNA in a sample is currently achieved by either depleting maternal DNA through size exclusion or focusing on fetal-specific nucleic acids, like fetal-expressed RNA. Another differentiating feature of fetal DNA is its DNA methylation pattern. Thus, provided herein are novel compositions and methods for accurately quantifying fetal nucleic acid based on differential methylation between a fetus and mother. The methods rely on sensitive absolute copy number analysis to quantify the fetal nucleic acid portion of a maternal sample, thereby allowing for the prenatal detection of fetal traits. The methods of the technology herein have identified approximately 3000 CpG rich regions in the genome that are differentially methylated between maternal and fetal DNA. The selected regions showed highly conserved differential methylation across all measured samples. In addition the set of regions is enriched for genes important in developmental regulation, indicating that epigenetic regulation of these areas is a biologically relevant and consistent process (see Table 3). Enrichment of fetal DNA can now be achieved by using the MBD-FC protein to capture all cell free DNA and then elute the highly methylated DNA fraction with high salt concentrations. Using the low salt eluate fractions, the MBD-FC is equally capable of enriching non-methylated fetal DNA.

[0369] The present technology provides 63 confirmed genomic regions on chromosomes 13, 18 and 21 with low maternal and high fetal methylation levels. After capturing these regions, SNPs can be used to determine the aforementioned allele ratios. When high frequency SNPs are used around 10 markers have to be measured to achieve a high confidence of finding at least one SNP where the parents have opposite homozygote genotypes and the child has a heterozygote genotype.

[0370] In an embodiment, a method for chromosomal abnormality detection is provided that utilizes absolute copy number quantification. A diploid chromosome set will show the same number of copies for differentially methylated regions across all chromosomes, but, for example, a trisomy 21 sample would show 1.5 times more copies for differentially methylated regions on chromosome 21. Normalization of the genomic DNA amounts for a diploid chromosome set can be achieved by using unaltered autosomes as reference (also provided herein--see Table 1B). Comparable to other approaches, a single marker is less likely to be sufficient for detection of this difference, because the overall copy numbers are low. Typically there are approximately 100 to 200 copies of fetal DNA from 1 ml of maternal plasma at 10 to 12 weeks of gestation. However, the methods of the present technology offer a redundancy of detectable markers that enables highly reliable discrimination of diploid versus aneuploid chromosome sets.

Data Processing and Identifying Presence or Absence of a Chromosome Abnormality

[0371] The term "detection" of a chromosome abnormality as used herein refers to identification of an imbalance of chromosomes by processing data arising from detecting sets of amplified nucleic acid species, nucleotide sequence species, or a detectable product generated from the foregoing (collectively "detectable product"). Any suitable detection device and method can be used to distinguish one or more sets of detectable products, as addressed herein. An outcome pertaining to the presence or absence of a chromosome abnormality can be expressed in any suitable form, including, without limitation, probability (e.g., odds ratio, p-value), likelihood, percentage, value over a threshold, or risk factor, associated with the presence of a chromosome abnormality for a subject or sample. An outcome may be provided with one or more of sensitivity, specificity, standard deviation, coefficient of variation (CV) and/or confidence level, or combinations of the foregoing, in certain embodiments.

[0372] Detection of a chromosome abnormality based on one or more sets of detectable products may be identified based on one or more calculated variables, including, but not limited to, sensitivity, specificity, standard deviation, coefficient of variation (CV), a threshold, confidence level, score, probability and/or a combination thereof. In some embodiments, (i) the number of sets selected for a diagnostic method, and/or (ii) the particular nucleotide sequence species of each set selected for a diagnostic method, is determined in part or in full according to one or more of such calculated variables.

[0373] In certain embodiments, one or more of sensitivity, specificity and/or confidence level are expressed as a percentage. In some embodiments, the percentage, independently for each variable, is greater than about 90% (e.g., about 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99%, or greater than 99% (e.g., about 99.5%, or greater, about 99.9% or greater, about 99.95% or greater, about 99.99% or greater)). Coefficient of variation (CV) in some embodiments is expressed as a percentage, and sometimes the percentage is about 10% or less (e.g., about 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1%, or less than 1% (e.g., about 0.5% or less, about 0.1% or less, about 0.05% or less, about 0.01% or less)). A probability (e.g., that a particular outcome determined by an algorithm is not due to chance) in certain embodiments is expressed as a p-value, and sometimes the p-value is about 0.05 or less (e.g., about 0.05, 0.04, 0.03, 0.02 or 0.01, or less than 0.01 (e.g., about 0.001 or less, about 0.0001 or less, about 0.00001 or less, about 0.000001 or less)).

[0374] For example, scoring or a score may refer to calculating the probability that a particular chromosome abnormality is actually present or absent in a subject/sample. The value of a score may be used to determine for example the variation, difference, or ratio of amplified nucleic detectable product that may correspond to the actual chromosome abnormality. For example, calculating a positive score from detectable products can lead to an identification of a chromosome abnormality, which is particularly relevant to analysis of single samples.

[0375] In certain embodiments, simulated (or simulation) data can aid data processing for example by training an algorithm or testing an algorithm. Simulated data may for instance involve hypothetical various samples of different concentrations of fetal and maternal nucleic acid in serum, plasma and the like. Simulated data may be based on what might be expected from a real population or may be skewed to test an algorithm and/or to assign a correct classification based on a simulated data set. Simulated data also is referred to herein as "virtual" data. Fetal/maternal contributions within a sample can be simulated as a table or array of numbers (for example, as a list of peaks corresponding to the mass signals of cleavage products of a reference biomolecule or amplified nucleic acid sequence), as a mass spectrum, as a pattern of bands on a gel, or as a representation of any technique that measures mass distribution. Simulations can be performed in most instances by a computer program. One possible step in using a simulated data set is to evaluate the confidence of the identified results, i.e. how well the selected positives/negatives match the sample and whether there are additional variations. A common approach is to calculate the probability value (p-value) which estimates the probability of a random sample having better score than the selected one. As p-value calculations can be prohibitive in certain circumstances, an empirical model may be assessed, in which it is assumed that at least one sample matches a reference sample (with or without resolved variations). Alternatively other distributions such as Poisson distribution can be used to describe the probability distribution.

[0376] In certain embodiments, an algorithm can assign a confidence value to the true positives, true negatives, false positives and false negatives calculated. The assignment of a likelihood of the occurrence of a chromosome abnormality can also be based on a certain probability model.

[0377] Simulated data often is generated in an in silico process. As used herein, the term "in silico" refers to research and experiments performed using a computer. In silico methods include, but are not limited to, molecular modeling studies, karyotyping, genetic calculations, biomolecular docking experiments, and virtual representations of molecular structures and/or processes, such as molecular interactions.

[0378] As used herein, a "data processing routine" refers to a process, that can be embodied in software, that determines the biological significance of acquired data (i.e., the ultimate results of an assay). For example, a data processing routine can determine the amount of each nucleotide sequence species based upon the data collected. A data processing routine also may control an instrument and/or a data collection routine based upon results determined. A data processing routine and a data collection routine often are integrated and provide feedback to operate data acquisition by the instrument, and hence provide assay-based judging methods provided herein.

[0379] As used herein, software refers to computer readable program instructions that, when executed by a computer, perform computer operations. Typically, software is provided on a program product containing program instructions recorded on a computer readable medium, including, but not limited to, magnetic media including floppy disks, hard disks, and magnetic tape; and optical media including CD-ROM discs, DVD discs, magneto-optical discs, and other such media on which the program instructions can be recorded.

[0380] Different methods of predicting abnormality or normality can produce different types of results. For any given prediction, there are four possible types of outcomes: true positive, true negative, false positive, or false negative. The term "true positive" as used herein refers to a subject correctly diagnosed as having a chromosome abnormality. The term "false positive" as used herein refers to a subject wrongly identified as having a chromosome abnormality. The term "true negative" as used herein refers to a subject correctly identified as not having a chromosome abnormality. The term "false negative" as used herein refers to a subject wrongly identified as not having a chromosome abnormality. Two measures of performance for any given method can be calculated based on the ratios of these occurrences: (i) a sensitivity value, the fraction of predicted positives that are correctly identified as being positives (e.g., the fraction of nucleotide sequence sets correctly identified by level comparison detection/determination as indicative of chromosome abnormality, relative to all nucleotide sequence sets identified as such, correctly or incorrectly), thereby reflecting the accuracy of the results in detecting the chromosome abnormality; and (ii) a specificity value, the fraction of predicted negatives correctly identified as being negative (the fraction of nucleotide sequence sets correctly identified by level comparison detection/determination as indicative of chromosomal normality, relative to all nucleotide sequence sets identified as such, correctly or incorrectly), thereby reflecting accuracy of the results in detecting the chromosome abnormality.

EXAMPLES

[0381] The following examples are provided by way of illustration only and not by way of limitation. Thus, the examples set forth below illustrate certain embodiments and do not limit the technology. Those of skill in the art will readily recognize a variety of non-critical parameters that could be changed or modified to yield essentially the same or similar results.

[0382] In Example 1 below, the Applicants used a new fusion protein that captures methylated DNA in combination with CpG Island array to identify genomic regions that are differentially methylated between fetal placenta tissue and maternal blood. A stringent statistical approach was used to only select regions which show little variation between the samples, and hence suggest an underlying biological mechanism. Eighty-five differentially methylated genomic regions predominantly located on chromosomes 13, 18 and 21 were validated. For this validation, a quantitative mass spectrometry based approach was used that interrogated 261 PCR amplicons covering these 85 regions. The results are in very good concordance (95% confirmation), proving the feasibility of the approach.

[0383] Next, the Applicants provide an innovative approach for aneuploidy testing, which relies on the measurement of absolute copy numbers rather than allele ratios.

Example 1

[0384] In the below Example, ten paired maternal and placental DNA samples were used to identify differentially methylated regions. These results were validated using a mass spectrometry-based quantitative methylation assay. First, genomic DNA from maternal buffy coat and corresponding placental tissue was first extracted. Next the MBD-FC was used to capture the methylated fraction of each DNA sample. See FIGS. 1-3. The two tissue fractions were labeled with different fluorescent dyes and hybridized to an Agilent.RTM. CpG Island microarray. See FIG. 4. This was done to identify differentially methylated regions that could be utilized for prenatal diagnoses. Therefore, two criteria were employed to select genomic regions as potential enrichment markers: the observed methylation difference had to be present in all tested sample pairs, and the region had to be more than 200 bp in length.

DNA Preparation and Fragmentation

[0385] Genomic DNA (gDNA) from maternal buffy coat and placental tissue was prepared using the QIAamp DNA Mini Kit.TM. and QIAamp DNA Blood Mini Kit.TM., respectively, from Qiagen.RTM. (Hilden, Germany). For MCIp, gDNA was quantified using the NanoDrop ND 1000.TM. spectrophotometer (Thermo Fisher.RTM., Waltham, Mass., USA). Ultrasonication of 2.5 .mu.g DNA in 500 .mu.l TE buffer to a mean fragment size of 300-500 bp was carried out with the Branson Digital Sonifier 450.TM. (Danbury, Conn., USA) using the following settings: amplitude 20%, sonication time 110 seconds, pulse on/pulse off time 1.4/0.6 seconds. Fragment range was monitored using gel electrophoresis.

Methyl-CpG Immunoprecipitation

[0386] Per sample, 56 .mu.g purified MBD-Fc protein and 150 .mu.l of Protein A Sepharose 4 Fast Flow beads (Amersham Biosciences.RTM., Piscataway, N.J., USA) were rotated in 15 ml TBS overnight at 4.degree. C. Then, the MBD-Fc beads (150 .mu.l/assay) were transferred and dispersed in to 2 ml Ultrafree-CL centrifugal filter devices (Millipore.RTM., Billerica, Mass., USA) and spin-washed three times with Buffer A (20 mM Tris-HCl, pH8.0, 2 mM MgCl2, 0.5 mM EDTA 300 mM NaCl, 0.1% NP-40). Sonicated DNA (2 .mu.g) was added to the washed MBD-Fc beads in 2 ml Buffer A and rotated for 3 hours at 4.degree. C. Beads were centrifuged to recover unbound DNA fragments (300 mM fraction) and subsequently washed twice with 600 .mu.l of buffers containing increasing NaCl concentrations (400, 500, 550, 600, and 1000 mM). The flow through of each wash step was collected in separate tubes and desalted using a MinElute PCR Purification Kit.TM. (Qiagen.RTM.). In parallel, 200 ng sonicated input DNA was processed as a control using the MinElute PCR Purification Kit.TM. (Qiagen.RTM.).

Microarray Handling and Analysis

[0387] To generate fluorescently labeled DNA for microarray hybridization, the 600 mM and 1M NaCl fractions (enriched methylated DNA) for each sample were combined and labeled with either Alexa Fluor 555-aha-dCTP (maternal) or Alexa Fluor 647-aha-dCTP (placental) using the BioPrime Total Genomic Labeling System.TM. (Invitrogen.RTM., Carlsbad, Calif., USA). The labeling reaction was carried out according to the manufacturer's manual. The differently labeled genomic DNA fragments of matched maternal/placental pairs were combined to a final volume of 80 .mu.l, supplemented with 50 .mu.g Cot-1 DNA (Invitrogen.RTM.), 52 .mu.l of Agilent 10.times. blocking reagent (Agilent Technologies.RTM., Santa Clara, Calif., USA), 78 .mu.l of deionized formamide, and 260 .mu.l Agilent 2.times. hybridization buffer. The samples were heated to 95.degree. C. for 3 min, mixed, and subsequently incubated at 37.degree. C. for 30 min. Hybridization on Agilent CpG Island Microarray Kit.TM. was then carried out at 67.degree. C. for 40 hours using an Agilent SureHyb.TM. chamber and an Agilent hybridization oven. Slides were washed in Wash I (6.times.SSPE, 0.005% N-lauroylsarcosine) at room temperature for 5 min and in Wash II (0.06.times.SSPE) at 37.degree. C. for an additional 5 min. Next, the slides were submerged in acetonitrile and Agilent Ozone Protection Solution.TM., respectively, for 30 seconds. Images were scanned immediately and analyzed using an Agilent DNA Microarray Scanner.TM. Microarray images were processed using Feature Extraction Software v9.5 and the standard CGH protocol.

Bisulfite Treatment

[0388] Genomic DNA sodium bisulfite conversion was performed using EZ-96 DNA Methylation Kit.TM. (ZymoResearch, Orange County, Calif.). The manufacturer's protocol was followed using 1 ug of genomic DNA and the alternative conversion protocol (a two temperature DNA denaturation).

Quantitative Methylation Analysis

[0389] Sequenom's MassARRAY.RTM. System was used to perform quantitative methylation analysis. This system utilizes matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry in combination with RNA base specific cleavage (Sequenom.RTM. MassCLEAVE.TM.). A detectable pattern is then analyzed for methylation status. PCR primers were designed using Sequenom.RTM. EpiDESIGNER.TM. (www.epidesigner.com). A total of 261 amplicons, covering 85 target regions, were used for validation (median amplification length=367 bp, min=108, max=500; median number of CpG's per amplicon=23, min=4, max=65). For each reverse primer, an additional T7 promoter tag for in-vivo transcription was added, as well as a 10mer tag on the forward primer to adjust for melting temperature differences. The MassCLEAVE.TM. biochemistry was performed as previously described (Ehrich M, et al. (2005) Quantitative high-throughput analysis of DNA methylation patterns by base specific cleavage and mass spectrometry. Proc Natl Acad Sci USA 102:15785-15790). Mass spectra were acquired using a MassARRAY.TM. Compact MALDI-TOF (Sequenom.RTM., San Diego) and methylation ratios were generated by the EpiTYPER.TM. software v1.0 (Sequenom.RTM., San Diego).

Statistical Analysis

[0390] All statistical calculations were performed using the R statistical software package (www.r-project.org). First, the array probes were grouped based on their genomic location. Subsequent probes that were less than 1000 bp apart were grouped together. To identify differentially methylated regions, a control sample was used as reference. In the control sample, the methylated fraction of a blood derived control DNA was hybridized against itself. Ideally this sample should show log ratios of the two color channels around 0. However because of the variability in hybridization behavior, the probes show a mean log ratio of 0.02 and a standard deviation of 0.18. Next the log ratios observed in the samples were compared to the control sample. A two way, paired t-test was used to test the NULL hypothesis that the groups are identical. Groups that contained less than 4 probes were excluded from the analysis. For groups including four or five probes, all probes were used in a paired t-test. For Groups with six or more probes, a sliding window test consisting of five probes at a time was used, whereby the window was moved by one probe increments. Each test sample was compared to the control sample and the p-values were recorded. Genomic regions were selected as being differentially methylated if eight out of ten samples showed a p value <0.01, or if six out of ten samples showed a p value <0.001. The genomic regions were classified as being not differentially methylated when the group showed less than eight samples with a p value <0.01 and less than six samples with a p value <0.001. Samples that didn't fall in either category were excluded from the analysis. For a subset of genomic regions that have been identified as differentially methylated, the results were confirmed using quantitative methylation analysis.

[0391] The Go analysis was performed using the online GOstat tool (http://gostat.wehi.edu.au/cgibin/-goStat.pl). P values were calculated using Fisher's exact test.

Microarray-Based Marker Discovery Results

[0392] To identify differentially methylated regions a standard sample was used, in which the methylated DNA fraction of monocytes was hybridized against itself. This standard provided a reference for the variability of fluorescent measurements in a genomic region. Differentially methylated regions were then identified by comparing the log ratios of each of the ten placental/maternal samples against this standard. Because the goal of this study was to identify markers that allow the reliable separation of maternal and fetal DNA, the target selection was limited to genes that showed a stable, consistent methylation difference over a contiguous stretch of genomic DNA. This focused the analysis on genomic regions where multiple probes indicated differential methylation. The selection was also limited to target regions where all samples showed differential methylation, excluding those with strong inter-individual differences. Two of the samples showed generally lower log ratios in the microarray analysis. Because a paired test was used for target selection, this did not negatively impact the results.

[0393] Based on these selection criteria, 3043 genomic regions were identified that were differentially methylated between maternal and fetal DNA. 21778 regions did not show a methylation difference. No inter-chromosomal bias in the distribution of differentially methylated regions was observed. The differentially methylated regions were located next to or within 2159 known genes.

[0394] The majority of differentially methylated regions are located in the promoter area (18%) and inside the coding region (68%), while only few regions are located downstream of the gene (7%) or at the transition from promoter to coding region (7%). Regions that showed no differential methylation showed a similar distribution for promoter (13%) and downstream (5%) locations, but the fraction of regions located in the transition of promoter to coding region was higher (39%) and the fraction inside the coding region was lower (43%).

[0395] It has been shown in embryonic stem cells (ES) that genes targeted by the polycomb repressive complex2 (PRC2) are enriched for genes regulating development (Lee T I, et al. (2006) Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 125:301-313). It has also been shown that differentially methylated genes are enriched for genes targeted by PRC2 in many cancer types (Ehrich M, et al. (2008) Cytosine methylation profiling of cancer cell lines. Proc Natl Acad Sci USA 105:4844-48). The set of genes identified as differentially methylated in this study is also enriched for genes targeted by PRC2 (p-value <0.001, odds ratio=3.6, 95% CI for odds ratio=3.1-4.2). A GO analysis of the set of differentially methylated genes reveals that this set is significantly enriched for functions important during development. Six out of the ten most enriched functions include developmental or morphogenic processes [anatomical structure morphogenesis (GO:0009653, p value=0), developmental process (GO:0032502, p value=0), multicellular organismal development (GO:0007275, p value=0), developmental of an organ (GO:0048513, p value=0), system development (GO:0048731, p value=0) and development of an anatomical structure (GO:0048856, p value=0)].

Validation Using Sequenom.RTM. EpiTYPER.TM.

[0396] To validate the microarray findings, 63 regions from chromosomes 13, 18 and 21 and an additional 26 regions from other autosomes were selected for confirmation by a different technology. Sequenom EpiTYPER.TM. technology was used to quantitatively measure DNA methylation in maternal and placental samples. For an explanation of the EpiTYPER.TM. methods, see Ehrich M, Nelson M R, Stanssens P, Zabeau M, Liloglou T, Xinarianos G, Cantor C R, Field J K, van den Boom D (2005) Quantitative high-throughput analysis of DNA methylation patterns by base specific cleavage and mass spectrometry. Proc Natl Acad Sci USA 102:15785-15790). For each individual CpG site in a target region the average methylation value across all maternal DNA samples and across all placenta samples was calculated. The difference between average maternal and placenta methylation was then compared to the microarray results. The results from the two technologies were in good concordance (see FIG. 7). For 85 target regions the quantitative results confirm the microarray results (95% confirmation rate). For 4 target regions, all located on chromosome 18, the results could not be confirmed. The reason for this discrepancy is currently unclear.

[0397] In contrast to microarrays, which focus on identification of methylation differences, the quantitative measurement of DNA methylation allowed analysis of absolute methylation values. In the validation set of 85 confirmed differentially methylated regions, a subset of 26 regions is more methylated in the maternal DNA sample and 59 regions are more methylated in the placental sample (see Table 1A). Interestingly, genes that are hypomethylated in the placental samples tend to show larger methylation differences than genes that are hypermethylated in the placental sample (median methylation difference for hypomethylated genes=39%, for hypermethylated genes=20%).

Example 2

[0398] Example 2 describes a non-invasive approach for detecting the amount of fetal nucleic acid present in a maternal sample (herein referred to as the "Fetal Quantifier Method"), which may be used to detect or confirm fetal traits (e.g., fetal sex of RhD compatibility), or diagnose chromosomal abnormalities such as Trisomy 21 (both of which are herein referred to as the "Methylation-Based Fetal Diagnostic Method"). FIG. 10 shows one embodiment of the Fetal Quantifier Method, and FIG. 11 shows one embodiment of the Methylation-Based Fetal Diagnostic Method. Both processes use fetal DNA obtained from a maternal sample. The sample comprises maternal and fetal nucleic acid that is differentially methylated. For example, the sample may be maternal plasma or serum. Fetal DNA comprises approximately 2-30% of the total DNA in maternal plasma. The actual amount of fetal contribution to the total nucleic acid present in a sample varies from pregnancy to pregnancy and can change based on a number of factors, including, but not limited to, gestational age, the mother's health and the fetus' health.

[0399] As described herein, the technical challenge posed by analysis of fetal DNA in maternal plasma lies in the need to be able to discriminate the fetal DNA from the co-existing background maternal DNA. The methods of the present technology exploit such differences, for example, the differential methylation that is observed between fetal and maternal DNA, as a means to enrich for the relatively small percentage of fetal DNA present in a sample from the mother. The non-invasive nature of the approach provides a major advantage over conventional methods of prenatal diagnosis such as, amniocentesis, chronic villus sampling and cordocentesis, which are associated with a small but finite risk of fetal loss. Also, because the method is not dependent on fetal cells being in any particular cell phase, the method provides a rapid detection means to determine the presence and also the nature of the chromosomal abnormality. Further, the approach is sex-independent (i.e., does not require the presence of a Y-chromosome) and polymorphic-independent (i.e., an allelic ratio is not determined). Thus, the compositions and methods of the technology herein represent improved universal, noninvasive approaches for accurately determining the amount of fetal nucleic acid present in a maternal sample.

Assay Design and Advantages

[0400] There is a need for accurate detection and quantification of fetal DNA isolated noninvasively from a maternal sample. The present technology takes advantage of the presence of circulating, cell free fetal nucleic acid (ccfDNA) in maternal plasma or serum. In order to be commercially and clinically practical, the methods of the technology herein should only consume a small portion of the limited available fetal DNA. For example, less than 50%, 40%, 30%, 25%, 20%, 15%, 10%, 5% or less of the sample. Further, the approach should preferably be developed in a multiplex assay format in which one or more (preferably all) of the following assays are included: [0401] Assays for the detection of total amount of genomic equivalents present in the sample, i.e., assays recognizing both maternal and fetal DNA species; [0402] Assays for the detection of fetal DNA isolated from a male pregnancy, i.e., sequences specific for chromosome Y; [0403] Assays specific for regions identified as differentially methylated between the fetus and mother; or [0404] Assays specific for regions known to be hypomethylated in all tissues to be investigated, which can serve as a control for restriction efficiency.

[0405] Other features of the assay may include one or more of the following: [0406] For each assay, a target-specific, competitor oligonucleotide that is identical, or substantially identical, to the target sequence apart from a distinguishable feature of the competitor, such as a difference in one or more nucleotides relative to the target sequence. This oligonucleotide when added into the PCR reaction will be co-amplified with the target and a ratio obtained between these two PCR amplicons will indicate the number of target specific DNA sequences (e.g., fetal DNA from a specific locus) present in the maternal sample. [0407] The amplicon lengths should preferably be of similar length in order not to skew the amplification towards the shorter fragments. However, as long as the amplification efficiency is about equal, different lengths may be used. [0408] Differentially methylated targets can be selected from Tables 1A-1C or from any other targets known to be differentially methylated between mother and fetus. These targets can be hypomethylated in DNA isolated from non-pregnant women and hypermethylated in samples obtained from fetal samples. These assays will serve as controls for the restriction efficiency. [0409] The results obtained from the different assays can be used to quantify one or more of the following: [0410] Total number of amplifiable genomes present in the sample (total amount of genomic equivalents); [0411] The fetal fraction of the amplifiable genomes (fetal concentration or percentage); or [0412] Differences in copy number between fetally-derived DNA sequences (for example, between fetal chromosome 21 and a reference chromosome such as chromosome 3).

Examples of Assays Used in the Test

[0413] Below is an outline of the reaction steps used to perform a method of the technology herein, for example, as provided in FIG. 10. This outline is not intended to limit the scope of the technology herein. Rather it provides one embodiment of the technology herein using the Sequenom.RTM. MassARRAY.RTM. technology. [0414] 1) DNA isolation from plasma samples. [0415] 2) Digestion of the DNA targets using methylation sensitive restriction enzymes (for example, HhaI and HpaII).

[0416] For each reaction the available DNA was mixed with water to a final volume of 25 ul.

[0417] 10 ul of a reaction mix consisting of 10 units Hhal, 10 units HpaII and a reaction buffer were added. The sample was incubated at an optimal temperature for the restriction enzymes. HhaI and HpaII digest non-methylated DNA (and will not digest hemi- or completely methylated DNA). Following digestion, the enzymes were denatured using a heating step. [0418] 3) Genomic Amplification--PCR was performed in a total volume of 50 ul by adding PCR reagents (Buffer, dNTPs, primers and polymerase). Exemplary PCR and extend primers are provided below. In addition, synthetic competitor oligonucleotide was added at known concentrations. [0419] 4) Replicates (optional)--Following PCR the 50 ul reaction was split into 5 ul parallel reactions (replicates) in order to minimize variation introduced during the post PCR steps of the test. Post PCR steps include SAP, primer extension (MassEXTEND.RTM. technology), resin treatment, dispensing of spectrochip and MassARRAY. [0420] 5) Quantification of the Amplifiable Genomes--Sequenom MassARRAY.RTM. technology was used to determine the amount of amplification product for each assay. Following PCR, a single base extension assay was used to interrogate the amplified regions (including the competitor oligonucleotides introduced in step 3). Specific extend primers designed to hybridize directly adjacent to the site of interest were introduced. See extend primers provided below. These DNA oligonucleotides are referred to as iPLEX.RTM. MassEXTEND.RTM. primers. In the extension reaction, the iPLEX primers were hybridized to the complementary DNA templates and extended with a DNA polymerase. Special termination mixtures that contain different combinations of deoxy- and dideoxynucleotide triphosphates along with enzyme and buffer, directed limited extension of the iPLEX primers. Primer extension occurs until a complementary dideoxynucleotide is incorporated.

[0421] The extension reaction generated primer products of varying length, each with a unique molecular weight. As a result, the primer extension products can be simultaneously separated and detected using Matrix Assisted Laser Desorption/Ionization, Time-Of-Flight (MALDI-TOF) mass spectrometry on the MassARRAY.RTM. Analyzer Compact. Following this separation and detection, SEQUENOM's proprietary software automatically analyzes the data. [0422] 6) Calculating the amount and concentration of fetal nucleic acid--Methods for calculating the total amount of genomic equivalents present in the sample, the amount (and concentration) of fetal nucleic acid isolated from a male pregnancy, and the amount (and concentration) of fetal nucleic based on differentially methylated targets are provided below and in FIGS. 18 and 19.

[0423] The above protocol can be used to perform one or more of the assays described below. In addition to the sequences provided immediately below, a multiplex scheme that interrogates multiple targets is provided in Table X below.

1) Assay for the Quantification of the Total Number of Amplifiable Genomic Equivalents in the Sample.

[0424] Targets were selected in housekeeping genes not located on the chromosomes 13, 18, 21, X or Y. The targets should be in a single copy gene and not contain any recognition sites for the methylation sensitive restriction enzymes.

[0425] Underlined sequences are PCR primer sites, italic is the site for the single base extend primer and bold letter (C) is the nucleotide extended on human DNA [0426] ApoE Chromosome 19:45409835-45409922 DNA target sequence with interrogated nucleotide C in bold. All of the chromosome positions provided in this section are from the February 2009 UCSC Genome Build.

TABLE-US-00001 [0426] (SEQ ID NO: 262) GATTGACAGTTTCTCCTTCCCCAGACTGGCCAATCACAGGCAGGAAGATG AAGGTTCTGTGGGCTGCGTTGCTGGTCACATTCCTGGC ApoE Forward Primer: (SEQ ID NO: 263) 5'-ACGTTGGATG-TTGACAGTTTCTCCTTCCCC (Primer contains a 5' 10 bp MassTag separated by a dash) ApoE Reverse Primer: (SEQ ID NO: 264) 5'-ACGTTGGATG-GAATGTGACCAGCAACGCAG (Primer contains a 5' 10 bp MassTag separated by a dash) ApoE Extension Primer: (SEQ ID NO: 265) 5'-GCAGGAAGATGAAGGTT [C/T] Primer extends C on human DNA targets and T on synthetic DNA targets ApoE synthetic competitor oligonucleotide: (SEQ ID NO: 266) 5'-GATTGACAGTTTCTCCTTCCCCAGACTGGCCAATCACAGGCAGGAAG ATGAAGGTTTTGTGGGCTGCGTTGCTGGTCACATTCCTGGC (Bold T at position 57 is different from human DNA)

2) Assay for the Quantification of the Total Number of Chromosome Y Sequences in the Sample.

[0427] Targets specific for the Y-chromosome were selected, with no similar or paralog sequences elsewhere in the genome. The targets should preferably be in a single copy gene and not contain any recognition sites for the methylation sensitive restriction enzyme(s).

[0428] Underlined sequences are PCR primer sites, and italic nucleotide(s) is the site for the single-base extend primer and bold letter (C) is the nucleotide extended on human DNA.

TABLE-US-00002 SRY on chrY: 2655628-2655717 (reverse complement) (SEQ ID NO: 267) GAGTTTTGGATAGTAAAATAAGTTTCGAACTCTGGCACCTTTCAATTTT GTCGCACTCTCCTTGTTTTTGACAATGCAATCATATGCTTC SRY Forward Primer: (SEQ ID NO: 268) 5'-ACG-TGGATAGTAAAATAAGTTTCGAACTCTG (Primer contains a 5' 3 bp MassTag separated by a dash) SRY Reverse Primer: (SEQ ID NO: 269) 5'-GAAGCATATGATTGCATTGTCAAAAAC SRY Extension Primer: (SEQ ID NO: 270) 5'-aTTTCAATTTTGTCGCACT [C/T] Primer extends C on human DNA targets and T on synthetic DNA targets. 5' Lower case "a" is a non-complementary nucleotide SRY synthetic competitor oligonucleotide: (SEQ ID NO: 271) 5'-GAGTTTTGGATAGTAAAATAAGTTTCGAACTCTGGCACCTTTCAATT TTGTCGCACTTTCCTTGTTTTTGACAATGCAATCATATGCTTC

3) Assay for the Quantification of Fetal Methylated DNA Sequences Present in the Sample.

[0429] Targets were selected in regions known to be differentially methylated between maternal and fetal DNA. Sequences were selected to contain several restriction sites for methylation sensitive enzymes. For this study the HhaI (GCGC) and HpaII (CCGG) enzymes were used.

[0430] Underlined sequences are PCR primer sites, italic is the site for the single base extend primer and bold letter (C) is the nucleotide extended on human DNA, lower case letter are recognition sites for the methylation sensitive restriction enzymes.

TABLE-US-00003 TBX3 on chr12: 115124905-115125001 (SEQ ID NO: 272) GAACTCCTCTTTGTCTCTGCGTGCccggcgcgcCCCCCTCccggTGGGT GATAAACCCACTCTGgcgccggCCATgcgcTGGGTGATTAATTTGCGA TBX3 Forward Primer: (SEQ ID NO: 273) 5'-ACGTTGGATG-TCTTTGTCTCTGCGTGCCC (Primer contains a 5' 10 bp MassTag separated by a dash) TBX3 Reverse Primer: (SEQ ID NO: 274) 5'-ACGTTGGATG-TTAATCACCCAGCGCATGGC (Primer contains a 5' 10 bp MassTag separated by a dash) TBX3 Extension Primer: (SEQ ID NO: 275) 5'-CCCCTCCCGGTGGGTGATAAA [C/T] Primer extends C on human DNA targets and T on synthetic DNA targets. 5' Lower case "a" is a non-complementary nucleotide TBX3 synthetic competitor oligonucleotide: (SEQ ID NO: 276) 5'-GAACTCCTCTTTGTCTCTGCGTGCCCGGCGCGCCCCCCTCCCGGTGG GTGATAAATCCACTCTGGCGCCGGCCATGCGCTGGGTGATTAATTTGCGA

4) Control Assay for the Enzyme Restriction Efficiency.

[0431] Targets were selected in regions known not to be methylated in any tissue to be investigated. Sequences were selected to contain no more than one site for each restriction enzyme to be used.

[0432] Underlined sequences are PCR primer sites, italic nucleotide(s) represent the site for the single-base extend primer and bold letter (G) is the reverse nucleotide extended on human DNA, lower case letter are recognition sites for the methylation sensitive restriction enzymes.

TABLE-US-00004 CACNA1G chr17: 48637892-48637977 (reverse complement) (SEQ ID NO: 277) CCATTGGCCGTCCGCCGTGGCAGTGCGGGCGGGAgcgcAGGGAGAGAACC ACAGCTGGAATCCGATTCCCACCCCAAAACCCAGGA Hhal Forward Primer: (SEQ ID NO: 278) 5'-ACGTTGGATG-CCATTGGCCGTCCGCCGTG (Primer contains a 5' 10 bp MassTag separated by a dash) Hhal Reverse Primer: (SEQ ID NO: 279) 5'-ACGTTGGATG-TCCTGGGTTTTGGGGTGGGAA (Primer contains a 5' 10 bp MassTag separated by a dash) Hhal Extension Primer: (SEQ ID NO: 280) 5'-TTCCAGCTGTGGTTCTCTC Hhal synthetic competitor oligonucleotide: (SEQ ID NO: 281) 5'-CCATTGGCCGTCCGCCGTGGCAGTGCGGGCGGGAGCGCAGAGAGAGA ACCACAGCTGGAATCCGATTCCCACCCCAAAACCCAGGA

Validation Experiments

[0433] The sensitivity and accuracy of the present technology was measured using both a model system and clinical samples. In the different samples, a multiplex assay was run that contains 2 assays for total copy number quantification, 3 assays for methylation quantification, 1 assay specific for chromosome Y and 1 digestion control assay. See Table X. Another multiplex scheme with additional assays is provided in Table Y.

TABLE-US-00005 TABLE X PCR Primers and Extend Primers Gene First Primer Second Primer Extend Primer ID * (SEQ ID NOS 282-288) (SEQ ID NOS 289-295) (SEQ ID NOS 296-302) SOX14 M ACGTTGGATGACATGGTCGGCCCCACGGAAT ACGTTGGATGCTCCTTCCTAGTGTGAGAACCG CAGGTTCCGGGGCTTGGG Hhal_ D ACGTTGGATGACCCATTGGCCGTCCGCCGT ACGTTGGATGTTTTGGGGTGGGAATCGGATT CGCAGGGAGAGAACCACAG CTRL TBX3 M ACGTTGGATGGAACTCCTCTTTGTCTCTGCG ACGTTGGATGTGGCATGGCCGGCGCCAGA CCCCTCCCGGTGGGTGATAAA SRY Y ACGTTGGATGCGCAGCAACGGGACCGCTACA ACGTTGGCATCTAGGTAGGTCTTTGTAGCCAA AAAGCTGTAGGACAATCGGGT ALB T ACGTTGCGTAGCAACCTGTTACATATTAA ACGTTGGATCTGAGCAAAGGCAATCAACACCC CATTTTTCTACATCCTTTGTTT EDG6 M ACGTTGGATGCATAGAGGCCCATGATGGTGG ACGTTGGATGACCTTCTGCCCCTCTACTCCAA agAAGATCACCAGGCAGAAGAGG RNaseP T ACGTTGGATGGTGTGGTCAGCTCTTCCCTTCAT ACGTTGGCCCACATGTAATGTGTTGAAAAAGCA ACTTGGAGAACAAAGGACACCGTTA

TABLE-US-00006 TABLE X Competitor Oligonucleotide Sequence Gene ID * Competitor Oligonucleotide Sequence (SEQ ID NOS 303-309) SOX14 M GGTCGGCCCCACGGAATCCCGGCTCTGTGTGCGCCCAGGTTCCGGGGCTTGGGTGTTGCCGGTTCT- CACACTAGGAAGGAG Hhal_ D CCATTGGCCGTCCGCCGTGGCAGTGCGGGCGGGAGCGCAGAGAGAGAACCACAGCTGGAATCCGAT- TCCCACCCCAAAA CTRL TBX3 M GAACTCCTCTTTGTCTCTGCGTGCCCGGCGCGCCCCCCTCCCGGTGGGTGATAAATCCACTCTGGCG- CCGGCCATGC SRY Y GCAGCAACGGGACCGCTACAGCCACTGGACAAAGCCGTAGGACAATCGGGTAACATTGGCTACAAAGA- CCTACCTAGATGC ALB T GCGTAGCAACCTGTTACATATTAAAGTTTTATTATACTACATTTTTCTACATCCTTTGTTTCAGAGTG- TTGATTGCCTTTGCTCAGTATCTTCAG EDG6 M CCTTCTGCCCCTCTACTCCAAGCGCTACACCCTCTTCTGCCTGGTGATCTTTGCCGGCGTCCTGGCC- ACCATCATGGGCCTCTATG RNaseP T GTGTGGTCAGCTCTTCCCTTCATCACATACTTGGAGAACAAAGGACACCGTTATCCATGCTTTTT- CAACACATTACATGTGGG

TABLE-US-00007 TABLE Y PCR Primers and Extend Primers Gene First Primer Second Primer Extend Primer ID * (SEQ ID NOS 310-319) (SEQ ID NOS 320-329) (SEQ ID NOS 330-339) EDG6 M ACGTTGGATGTTCTGCCCCTCTACTCCAAG ACGTTGGATGCATAGAGGCCCATGATGGTG TTCTGCCTGGTGATCTT RNAseP T ACGTTGGATGTCAGCTCTTCCCTTCATCAC ACGTTGGATGCCTACCTCCCACATGTAATGT AACAAAGGACACCGTTA ApoE T ACGTTGGATGTTGACAGTTTCTCCTTCCCC ACGTTGGATGGAATGTGACCAGCAACGCAG GCAGGAAGATGAAGGTT SOX14 M ACGTTGGATGCGGTCGGCCCCACGGAAT ACGTTGGATGCTCCTTCCTAGTGTGAGAACCG aAGGTTCCGGGGCTTGGG SRY no2 Y ACGTGGATAGTAAAATAAGTTTCGAACTCTG GAAGCATATGATTGCATTGTCAAAAAC aTTTCAATTTTGTCGCACT SRY no1 Y ACGTTGGATGCACAGCTCACCGCAGCAACG ACGTTGGATGCTAGGTAGGTCTTTGTAGCCAA AGCTGTAGGACAATCGGGT TBX3 M ACGTTGGATGTCTTTGTCTCTGCGTGCCC ACGTTGGATGTTAATCACCCAGCGCATGGC CCCTCCCGGTGGGTGATAAA CACNA1G D ACGTTGGATGGACTGAGCCCCAGAACTCG ACGTTGGATGGTGGGTTTGTGCTTTCCACG AGGGCCGGGGTCTGCGCGTG dig CTRL 1 DAPK1 dig D ACGTTGGATGAAGCCAAGTTTCCCTCCGC ACGTTGGATGCTTTTGCTTTCCCAGCCAGG GAGGCACTGCCCGGACAAACC CTRL 2 ALB T ACGTTAGCGTAGCAACCTGTTACATATTAA ACGTTGGATGCTGAGCAAAGGCAATCAACA CATTTTTCTACATCCTTTGTTT

TABLE-US-00008 TABLE Y Competitor Oligonucleotide Sequence Gene ID * Competitor (SEQ ID NOS 340-343) EDG6 M CCTTCTGCCCCTCTACTCCAAGCGCTACACCCTCTTCTGCCTGGTGATCTTTGCCGGCGTCCTGGCC- ACCATCATGGGCCTCTATG RNAseP T GTGTGGTCAGCTCTTCCCTTCATCACATACTTGGAGAACAAAGGACACCGTTATCCATGCTTTTT- CAACACATTACATGTGGGAGGTAGG Apo E T GATTGACAGTTTCTCCTTCCCCAGACTGGCCAATCACAGGCAGGAAGATGAAGGTTTTGTGGGCTG- CGTTGCTGGTCACATTCCTGGC SOX14 M AAAACCAGAGATTCGCGGTCGGCCCCACGGAATCCCGGCTCTGTGTGCGCCCAGGTTCCGGGGCTT- GGGTGTTGCCGGTTCTCACACTAGG AAGGAGC Competitor (SEQ ID NOS 344-349) SRY no2 Y GAGTTTTGGATAGTAAAATAAGTTTCGAACTCTGGCACCTTTCAATTTTGTCGCACTTTCCTTG- TTTTTGACAATGCAATCATATGCTTC SRY no1 Y GCAGCCAGCTCACCGCAGCAACGGGACCGCTACAGCCACTGGACAAAGCTGTAGGACAATCGGG- TGACATTGGCTACAAAGACCTACCTAG ATGC TBX3 M GAACTCCTCTTTGTCTCTGCGTGCCCGGCGCGCCCCCCTCCCGGTGGGTGATAAATCCACTCTGGCG- CCGGCCATGCGCTGGGTGATTAAT TTGCGA CACNA1G D GTGGGTTTGTGCTTTCCACGCGTGCACACACACGCGCAGACCCCGGCCCTTGCCCCGCCTACCT- CCCCGAGTTCTGGGGCTCAGTC dig CTRL 1 DAPK1 D GCGCCAGCTTTTGCTTTCCCAGCCAGGGCGCGGTGAGGTTTGTCCGGGCAGTGCCTCGAGCAACTG- GGAAGGCCAAGGCGGAGGGAAAC dig CTRL 2 ALB T GCGTAGCAACCTGTTACATATTAAAGTTTTATTATACTACATTTTTCTACATCCTTTGTTTTAGGGTG- TTGATTGCCTTTGCTCAGTATCT TCAGC T = Assay for Total Amount M = Assay for Methylation quantification Y = Y-Chromosome Specific Assay D = Digestion control

Model System Using Genomic DNA

[0434] In order to determine the sensitivity and accuracy of the method when determining the total number of amplifiable genomic copies in a sample, a subset of different DNA samples isolated from the blood of non-pregnant women was tested. Each sample was diluted to contain approximately 2500, 1250, 625 or 313 copies per reaction. The total number of amplifiable genomic copies was obtained by taking the mean DNA/competitor ratio obtained from the three total copy number assays. The results from the four different samples are shown in FIG. 12.

[0435] To optimize the reaction, a model system was developed to simulate DNA samples isolated from plasma. These samples contained a constant number of maternal non-methylated DNA and were spiked with different amounts of male placental methylated DNA. The samples were spiked with amounts ranging from approximately 0 to 25% relative to the maternal non-methylated DNA. The results are shown in FIGS. 13A and B. The fraction of placental DNA was calculated using the ratios obtained from the methylation assays (FIG. 13A), the SRY markers (FIG. 13B) and the total copy number assays. The primer sequences for the methylation assays (TBX), Y-chromosome assays (SRY) and total copy number (APOE) are provided above. The model system demonstrated that the methylation-based method performed equal to the Y-chromosome method (SRY markers), thus validating the methylation-based method as a sex-independent fetal quantifier.

Plasma Samples

[0436] To investigate the sensitivity and accuracy of the methods in clinical samples, 33 plasma samples obtained from women pregnant with a male fetus were investigated using the multiplex scheme from Table X. For each reaction, a quarter of the DNA obtained from a 4 ml extraction was used in order to meet the important requirement that only a portion of the total sample is used.

[0437] Total Copy Number Quantification

[0438] The results from the total copy number quantification can be seen in FIGS. 14A and B. In FIG. 14A, the copy number for each sample is shown. Two samples (nos. 25 and 26) have a significantly higher total copy number than all the other samples. In general, a mean of approximately 1300 amplifiable copies/ml plasma was obtained (range 766-2055). FIG. 14B shows a box-and-whisker plot of the given values, summarizing the results.

[0439] Correlation Between Results Obtained from the Methylation Markers and the Y-Chromosome Marker

[0440] In FIGS. 15A and B, the numbers of fetal copies for each sample are plotted. As all samples were from male pregnancies. The copy numbers obtained can be calculated using either the methylation or the Y-chromosome-specific markers. As can be seen in FIG. 15B, the box-and-whisker plot of the given values indicated minimal difference between the two different measurements.

[0441] The results showing the correlation between results obtained from the methylation markers and the Y-chromosome marker (SRY) is shown in FIG. 16. Again, the methylation-based method performed equal to the Y-chromosome method (SRY markers), further validating the methylation-based method as a sex-independent and polymorphism-independent fetal quantifier. The multiplexed assays disclosed in Table X were used to determine the amount fetal nucleic.

[0442] Finally, the digestion efficiency was determined by using the ratio of digestion for the control versus the competitor and comparing this value to the mean total copy number assays. See FIG. 17. Apart from sample 26 all reactions indicate the efficiency to be above 99%.

Data Analysis

[0443] Mass spectra analysis was done using Typer 4 (a Sequenom software product). The peak height (signal over noise) for each individual DNA analyte and competitor assay was determined and exported for further analysis.

[0444] The total number of molecules present for each amplicon was calculated by dividing the DNA specific peak by the competitor specific peak to give a ratio. (The "DNA" Peak in FIGS. 18 and 19 can be thought of as the analyte peak for a given assay). Since the number of competitor molecules added into the reaction is known, the total number of DNA molecules can be determined by multiplying the ratio by the number of added competitor molecules.

[0445] The fetal DNA fraction (or concentration) in each sample was calculated using the Y-chromosome-specific markers for male pregnancies and the mean of the methylated fraction for all pregnancies. In brief, for chromosome Y, the ratio was obtained by dividing the analyte (DNA) peak by the competitor peak and multiplying this ratio by the number of competitor molecules added into the reaction. This value was divided by a similar ratio obtained from the total number of amplifiable genome equivalents determination (using the Assay(s) for Total Amount). See FIG. 18. Since the total amount of nucleic acid present in a sample is a sum of maternal and fetal nucleic acid, the fetal contribution can be considered to be a fraction of the larger, background maternal contribution. Therefore, translating this into the equation shown in FIG. 18, the fetal fraction (k) of the total nucleic acid present in the sample is equal to the equation: k=2.times.R/(1-2R), where R is the ratio between the Y-chromosome amount and the total amount. Since the Y-chromosome is haploid and Assays for the Total Amount are determined using diploid targets, this calculation is limited to a fetal fraction smaller than 50% of the maternal fraction.

[0446] In FIG. 19, a similar calculation for the fetal concentration is shown by using the methylation specific markers (see Assays for Methylation Quantification). In contrast to Y-chromosome specific markers, these markers are from diploid targets, therefore, the limitations stated for the Y-Chromosome Specific Assay can be omitted. Thus, the fetal fraction (k) can be determined using the equation: k=R(1-R), where R is the ratio between the methylation assay and the total assay.

Simulation

[0447] A first simple power calculation was performed that assumes a measurement system that uses 20 markers from chromosome 21, and 20 markers from one or more other autosomes. Starting with 100 copies of fetal DNA, a measurement standard deviation of 25 copies and the probability for a type I error to be lower than 0.001, it was found that the methods of the technology herein will be able to differentiate a diploid from a triploid chromosome set in 99.5% of all cases. The practical implementation of such an approach could for example be achieved using mass spectrometry, a system that uses a competitive PCR approach for absolute copy number measurements. The method can run 20 assays in a single reaction and has been shown to have a standard deviation in repeated measurements of around 3 to 5%. This method was used in combination with known methods for differentiating methylated and non-methylated nucleic acid, for example, using methyl-binding agents to separate nucleic acid or using methylation-sensitive enzymes to digest maternal nucleic acid. FIG. 8 shows the effectiveness of MBD-FC protein (a methyl-binding agent) for capturing and thereby separating methylated DNA in the presence of an excess of unmethylated DNA (see FIG. 8).

[0448] A second statistical power analysis was performed to assess the predictive power of an embodiment of the Methylation-Based Fetal Diagnostic Method described herein. The simulation was designed to demonstrate the likelihood of differentiating a group of trisomic chromosome 21 specific markers from a group of reference markers (for example, autosomes excluding chromosome 21). Many parameters influence the ability to discriminate the two populations of markers reliably. For the present simulation, values were chosen for each parameter that have been shown to be the most likely to occur based on experimentation. The following parameters and respective values were used:

Copy Numbers

[0449] Maternal copy numbers=2000 [0450] Fetal copy numbers for chromosomes other than 21, X and Y=200 [0451] Fetal copy numbers for chromosome 21 in case of euploid fetus=200 [0452] Fetal copy numbers for chromosome 21 in case of aneuploid T21 fetus=300 Percent fetal DNA (before methylation-based enrichment)=10% (see above)

Methylation Frequency

[0452] [0453] Average methylation percentage in a target region for maternal DNA=10% [0454] Average methylation percentage in a target region for fetal DNA=80% Average percentage of non-methylated and non-digested maternal DNA (i.e., a function of restriction efficiency (among other things)=5% Number of assays targeting chromosome 21=10 Number of assays targeting chromosomes other than 21, X and Y=10

[0455] The results are displayed in FIG. 20. Shown is the relationship between the coefficient of variation (CV) on the x-axis and the power to discriminate the assay populations using a simple t-test (y-axis). The data indicates that in 99% of all cases, one can discriminate the two population (euploid vs. aneuploid) on a significance level of 0.001 provided a CV of 5% or less. Based on this simulation, the method represents a powerful noninvasive diagnostic method for the prenatal detection of fetal aneuploidy that is sex-independent and will work in all ethnicities (i.e., no allelic bias).

Example 3

Additional Differentially-Methylated Targets

Differentially-Methylated Targets not Located on Chromosome 21

[0456] Additional differentially-methylated targets were selected for further analysis based upon previous microarray analysis. See Example 1 for a description of the microarray analysis. During the microarray screen, differentially methylated regions (DMRs) were defined between placenta tissue and PBMC. Regions were selected for EpiTYPER confirmation based upon being hypermethylated in placenta relative to PBMC. After directionality of the change was selected for, regions were chosen based upon statistical significance with regions designed beginning with the most significant and working downward in terms of significance. These studies were performed in eight paired samples of PBMC and placenta. Additional non-chromosome 21 targets are provided in Table 1B, along with a representative genomic sequence from each target in Table 4B.

Differentially-Methylated Targets Located on Chromosome 21

[0457] The microarray screen uncovered only a subset of DMRs located on chromosome 21. The coverage of chromosome 21 by the microarray, however, was insufficient. Therefore a further analysis was completed to examine all 356 CpG islands on chromosome 21 using the standard settings of the UCSC genome browser. As shown in Table 1C below, some of these targets overlapped with those already examined in Table 1A. More specifically, CpG sites located on chromosome 21 including .about.1000 bp upstream and downstream of each CpG was investigated using Sequenom's EpiTYPER.RTM. technology. See Example 1, "Validation using Sequenom.RTM. EpiTYPER.TM." for a description of Sequenom's EpiTYPER.RTM. technology. These studies were performed in eight paired samples of PBMC and placenta. In addition, since DMRs may also be located outside of defined CpG islands, data mining was performed on publicly available microarray data to identify potential candidate regions with the following characteristics: hypermethylated in placenta relative to maternal blood, not located in a defined CpG island, contained greater than 4 CpG dinucleotides, and contained a recognition sequence for methylation sensitive restriction enzymes. Regions that met these criteria were then examined using Sequenom's EpiTYPER.RTM. technology on eight paired PBMC and placenta samples. Additional chromosome 21 targets are provided in Table 10, along with a representative genomic sequence from each target in Table 4C.

[0458] Tables 1B and 10 provide a description of the different targets, including their location and whether they were analyzed during the different phases of analysis, namely microarray analysis, EpiTYPER 8 analysis and EpiTYPER 73 analysis. A "YES" indicates it was analyzed and a "NO" indicates it was not analyzed. The definition of each column in Table 1B and 10 is listed below. [0459] Region Name: Each region is named by the gene(s) residing within the area defined or nearby. Regions where no gene name is listed but rather only contain a locus have no refseq genes in near proximity. [0460] Gene Region: For those regions contained either in close proximity to or within a gene, the gene region further explains the relationship of this region to the nearby gene. [0461] Chrom: The chromosome on which the DMR is located using the hg18 build of the UCSC genome browser. [0462] Start: The starting position of the DMR as designated by the hg18 build of the UCSC genome browser. [0463] End: The ending position of the DMR as designated by the hg18 build of the UCSC genome browser. [0464] Microarray Analysis: Describes whether this region was also/initially determined to be differentially methylated by microarray analysis. The methylated fraction of ten paired placenta and PBMC samples was isolated using the MBD-Fc protein. The two tissue fractions were then labeled with either Alexa Fluor 555-aha-dCTP (PBMC) or Alexa Fluor 647-aha-dCTP (placental) using the BioPrime Total Genomic Labeling System.TM. and hybridized to Agilent.RTM. CpG Island microarrays. Many regions examined in these studies were not contained on the initial microarray. [0465] EpiTYPER 8 Samples: Describes whether this region was analyzed and determined to be differentially methylated in eight paired samples of placenta and peripheral blood mononuclear cells (PBMC) using EpiTYPER technology. Regions that were chosen for examination were based on multiple criteria. First, regions were selected based on data from the Microarray Analysis. Secondly, a comprehensive examination of all CpG islands located on chromosome 21 was undertaken. Finally, selected regions on chromosome 21 which had lower CpG frequency than those located in CpG islands were examined. [0466] EpiTYPER 73 Samples: Describes whether this region was subsequently analyzed using EpiTYPER technology in a sample cohort consisting of 73 paired samples of placenta and PBMC. All regions selected for analysis in this second sample cohort were selected based on the results from the experimentation described in the EpiTYPER 8 column. More specifically, the regions in this additional cohort exhibited a methylation profile similar to that determined in the EpiTYPER 8 Samples analysis. For example, all of the regions listed in Tables 1B-1C exhibit different levels of DNA methylation in a significant portion of the examined CpG dinucleotides within the defined region. Differential DNA methylation of CpG sites was determined using a paired T Test with those sites considered differentially methylated if the p-value (when comparing placental tissue to PBMC) is p<0.05. [0467] Previously Validated EpiTYPER: Describes whether this region or a portion of this region was validated using EpiTYPER during previous experimentation. (See Examples 1 and 2). [0468] Relative Methylation Placenta to Maternal: Describes the direction of differential methylation. Regions labeled as "hypermethylation" are more methylated within the designated region in placenta samples relative to PBMC and "hypomethylation" are more methylated within the designated region in PBMC samples.

TABLE-US-00009 [0468] TABLE 1A MEAN LOG METHYLATION RELATIVE RATIO MEAN MATERNAL MEAN PLACENTA DIFFERENCE METHYLATION MICRO- METHYLATION METHYLATION PLACENTA- PLACENTA TO GENE NAME CHROM START END CpG ISLAND ARRAY EPITYPER EPITYPER MATERNAL MATERNAL chr13 group00016 chr13 19773745 19774050 chr13: 19773518-19774214 0.19 0.22 0.32 0.1 HYPERMETHYLATION chr13 group00005 chr13 19290394 19290768 : -- -0.89 0.94 0.35 -0.59 HYPOMETHYLATION CRYL1 chr13 19887090 19887336 chr13: 19887007-19887836 -0.63 0.74 0.21 -0.53 HYPOMETHYLATION IL17D chr13 20193675 20193897 chr13: 20193611-20194438 -1.01 0.53 0.13 -0.39 HYPOMETHYLATION CENPJ chr13 24404023 24404359 : -- 0.57 0.17 0.49 0.32 HYPERMETHYLATION ATP8A2 chr13 25484475 25484614 chr13: 25484287-25484761 0.81 0.16 0.43 0.27 HYPERMETHYLATION GSH1 chr13 27265542 27265834 chr13: 27264549-27266505 0.57 0.13 0.19 0.05 HYPERMETHYLATION PDX1 chr13 27393789 27393979 chr13: 27392001-27394099 0.55 0.06 0.2 0.14 HYPERMETHYLATION PDX1 chr13 27400459 27401165 chr13: 27400362-27400744; 0.73 0.12 0.26 0.14 HYPERMETHYLATION chr13: 27401057-27401374 MAB21L1 chr13 34947737 34948062 chr13: 34947570-34948159 0.66 0.11 0.17 0.06 HYPERMETHYLATION RB1 chr13 47790983 47791646 chr13: 47790636-47791858 0.18 0.45 0.48 0.03 HYPERMETHYLATION PCDH17 chr13 57104856 57106841 chr13: 57104527-57106931 0.46 0.15 0.21 0.06 HYPERMETHYLATION KLHL1 chr13 69579933 69580146 chr13: 69579733-69580220 0.79 0.09 0.28 0.2 HYPERMETHYLATION POU4F1 chr13 78079515 78081073 chr13: 78079328-78079615; 0.66 0.12 0.23 0.11 HYPERMETHYLATION chr13: 78080860-78081881 GPC6 chr13 92677402 92678666 chr13: 92677246-92678878 0.66 0.06 0.19 0.13 HYPERMETHYLATION SOX21 chr13 94152286 94153047 chr13: 94152190-94153185 0.94 0.16 0.4 0.25 HYPERMETHYLATION ZIC2 chr13 99439660 99440858 chr13: 99439335-99440189; 0.89 0.13 0.35 0.22 HYPERMETHYLATION chr13: 99440775-99441095 IRS2 chr13 109232856 109235065 chr13: 109232467-109238181 -0.17 0.73 0.38 -0.35 HYPOMETHYLATION chr13 group00350 chr13 109716455 109716604 chr13: 109716325-109716726 -0.37 0.77 0.41 -0.36 HYPOMETHYLATION chr13 group00385 chr13 111595578 111595955 chr13: 111595459-111596131 0.87 0.06 0.2 0.14 HYPERMETHYLATION chr13 group00390 chr13 111756337 111756593 chr13: 111755805-111756697 0.71 0.12 0.34 0.22 HYPERMETHYLATION chr13 group00391 chr13 111759856 111760045 chr13: 111757885-111760666 0.86 0.11 0.36 0.25 HYPERMETHYLATION chr13 group00395 chr13 111808255 111808962 chr13: 111806599-111808492; 0.96 0.13 0.35 0.22 HYPERMETHYLATION chr13: 111808866-111809114 chr13 group00399 chr13 112033503 112033685 chr13: 112032967-112033734 0.38 0.26 0.43 0.18 HYPERMETHYLATION MCF2L chr13 112724910 112725742 chr13: 112724782-112725121; -0.47 0.91 0.33 -0.58 HYPOMETHYLATION chr13: 112725628-112725837 F7 chr13 112799123 112799379 chr13: 112798487-112799566 -0.05 0.97 0.55 -0.41 HYPOMETHYLATION PROZ chr13 112855566 112855745 chr13: 112855289-112855866 0.29 0.15 0.3 0.16 HYPERMETHYLATION chr18 group00039 chr18 6919797 6919981 chr18: 6919450-6920088 -0.38 0.88 0.39 -0.49 HYPOMETHYLATION CIDEA chr18 12244327 12244696 chr18: 12244147-12245089 0.23 0.14 0.23 0.1 HYPERMETHYLATION chr18 group00091 chr18 12901467 12901643 chr18: 12901024-12902704 0.16 0.15 0.43 0.29 HYPERMETHYLATION chr18 group00094 chr18 13126819 13126986 chr18: 13126596-13127564 0.41 0.07 0.34 0.27 HYPERMETHYLATION C18orf1 chr18 13377536 13377654 chr18: 13377385-13377686 -0.12 0.95 0.69 -0.26 HYPOMETHYLATION KLHL14 chr18 28603978 28605183 chr18: 28603688-28606300 0.83 0.07 0.19 0.12 HYPERMETHYLATION CD33L3 chr18 41671477 41673011 chr18: 41671386-41673101 -0.34 0.49 0.44 -0.05 HYPOMETHYLATION ST8SIA3 chr18 53171265 53171309 chr18: 53170705-53172603 1.02 0.09 0.25 0.16 HYPERMETHYLATION ONECUT2 chr18 53254808 53259810 chr18: 53254152-53259851 0.74 0.09 0.23 0.14 HYPERMETHYLATION RAX chr18 55086286 55086436 chr18: 55085813-55087807 0.88 0.11 0.26 0.16 HYPERMETHYLATION chr18 group00277 chr18 57151972 57152311 chr18: 57151663-57152672 0.58 0.08 0.21 0.13 HYPERMETHYLATION TNFRSF11A chr18 58203013 58203282 chr18: 58202849-58203367 -0.33 0.88 0.28 -0.6 HYPOMETHYLATION NETO1 chr18 68685099 68687060 chr18: 68684945-68687851 0.65 0.09 0.22 0.13 HYPERMETHYLATION chr18 group00304 chr18 70133945 70134397 chr18: 70133732-70134724 0.12 0.93 0.92 -0.01 NOT CONFIRMED TSHZ1 chr18 71128742 71128974 chr18: 71128638-71129076 0.23 0.95 0.92 -0.03 NOT CONFIRMED ZNF236 chr18 72664454 72664736 chr18: 72662797-72664893 -0.62 0.17 0.1 -0.07 HYPOMETHYLATION MBP chr18 72953150 72953464 chr18: 72953137-72953402 0.6 0.44 0.72 0.28 HYPERMETHYLATION chr18 group00342 chr18 74170347 74170489 chr18: 74170210-74170687 -0.2 0.78 0.48 -0.3 HYPOMETHYLATION NFATC1 chr18 75385424 75386008 chr18: 75385279-75386532 0.23 0.14 0.84 0.7 HYPERMETHYLATION CTDP1 chr18 75596358 75596579 chr18: 75596009-75596899 0.07 0.97 0.96 -0.01 NOT CONFIRMED chr18 group00430 chr18 75653272 75653621 : -- 0.52 0.24 0.62 0.39 HYPERMETHYLATION KCNG2 chr18 75760343 75760820 chr18: 75759900-75760988 0.01 0.84 0.75 -0.09 NOT CONFIRMED OLIG2 chr21 33317673 33321183 chr21: 33316998-33322115 0.66 0.11 0.2 0.09 HYPERMETHYLATION OLIG2 chr21 33327593 33328334 chr21: 33327447-33328408 -0.75 0.77 0.28 -0.49 HYPOMETHYLATION RUNX1 chr21 35180938 35185436 chr21: 35180822-35181342; -0.68 0.14 0.07 -0.07 HYPOMETHYLATION chr21: 35182320-35185557 SIM2 chr21 36994965 36995298 chr21: 36990063-36995761 0.83 0.08 0.26 0.18 HYPERMETHYLATION SIM2 chr21 36999025 36999410 chr21: 36998632-36999555 0.87 0.06 0.24 0.18 HYPERMETHYLATION DSCR6 chr21 37300407 37300512 chr21: 37299807-37301307 0.22 0.04 0.14 0.11 HYPERMETHYLATION DSCAM chr21 41135559 41135706 chr21: 41135380-41135816 1.03 0.06 0.29 0.23 HYPERMETHYLATION chr21 group00165 chr21 43643421 43643786 chr21: 43643322-43643874 1.14 0.16 0.81 0.65 HYPERMETHYLATION AIRE chr21 44529935 44530388 chr21: 44529856-44530472 -0.55 0.62 0.27 -0.35 HYPOMETHYLATION SUMO3 chr21 45061293 45061853 chr21: 45061154-45063386 -0.41 0.55 0.46 -0.09 HYPOMETHYLATION C21orf70 chr21 45202815 45202972 chr21: 45202706-45203073 -0.46 0.96 0.51 -0.46 HYPOMETHYLATION C21orf123 chr21 45671984 45672098 chr21: 45671933-45672201 -0.63 0.92 0.43 -0.49 HYPOMETHYLATION COL18A1 chr21 45754383 45754487 chr21: 45753653-45754639 -0.18 0.97 0.72 -0.25 HYPOMETHYLATION PRMT2 chr21 46911967 46912385 chr21: 46911628-46912534 1.08 0.04 0.25 0.21 HYPERMETHYLATION SIX2 chr2 45081223 45082129 chr2: 45081148-45082287 1.15 0.08 0.36 0.28 HYPERMETHYLATION SIX2 chr2 45084851 45085711 chr2: 45084715-45084986; 1.21 0.07 0.35 0.28 HYPERMETHYLATION chr2: 45085285-45086054 SOX14 chr3 138971870 138972322 chr3: 138971738-138972096; 1.35 0.08 0.33 0.25 HYPERMETHYLATION chr3: 138972281-138973691 TLX3 chr5 170674439 170676431 chr5: 170674208-170675356; 0.91 0.11 0.35 0.24 HYPERMETHYLATION chr5: 170675783-170676712 FOXP4 chr6 41623666 41624114 chr6: 41621630-41624167 1.1 0.07 0.27 0.2 HYPERMETHYLATION FOXP4 chr6 41636384 41636779 chr6: 41636244-41636878 1.32 0.04 0.33 0.29 HYPERMETHYLATION chr7 group00267 chr7 12576755 12577246 chr7: 12576690-12577359 0.94 0.08 0.26 0.17 HYPERMETHYLATION NPY chr7 24290224 24291508 chr7: 24290083-24291605 0.93 0.09 0.3 0.21 HYPERMETHYLATION SHH chr7 155291537 155292091 chr7: 155288453-155292175 0.98 0.19 0.52 0.33 HYPERMETHYLATION OSR2 chr8 100029764 100030536 chr8: 100029673-100030614 1.21 0.08 0.43 0.35 HYPERMETHYLATION GLIS3 chr9 4288283 4289645 chr9: 4287817-4290182 1.24 0.06 0.24 0.18 HYPERMETHYLATION PRMT8 chr12 3472714 3473190 chr12: 3470227-3473269 0.86 0.07 0.23 0.16 HYPERMETHYLATION TBX3 chr12 113609153 113609453 chr12: 113609112-113609535 1.45 0.09 0.56 0.48 HYPERMETHYLATION chr12 group00801 chr12 118516189 118517435 chr12: 118515877-118517595 1.1 0.06 0.25 0.19 HYPERMETHYLATION PAX9 chr14 36201402 36202386 chr14: 36200932-36202536 0.89 0.11 0.32 0.21 HYPERMETHYLATION SIX1 chr14 60178801 60179346 chr14: 60178707-60179539 0.95 0.1 0.33 0.22 HYPERMETHYLATION ISL2 chr15 74420013 74421546 chr15: 74419317-74422570 1.08 0.08 0.27 0.19 HYPERMETHYLATION DLX4 chr17 45397228 45397930 chr17: 45396281-45398063 1.25 0.1 0.32 0.22 HYPERMETHYLATION CBX4 chr17 75428613 75431793 chr17: 75427586-75433676 1 0.07 0.27 0.21 HYPERMETHYLATION EDG6 chr19 3129836 3130874 chr19: 3129741-3130986 1.35 0.04 0.87 0.83 HYPERMETHYLATION PRRT3 chr3 9963364 9964023 chr3: 9962895-9964619 -0.85 0.9 0.09 -0.81 HYPOMETHYLATION MGC29506 chr5 138757911 138758724 chr5: 138755609-138758810 -0.63 0.93 0.17 -0.76 HYPOMETHYLATION TEAD3 chr6 35561812 35562252 chr6: 35561754-35562413 -1.17 0.92 0.13 -0.8 HYPOMETHYLATION chr12 group00022 chr12 1642456 1642708 chr12: 1642195-1642774 -1.33 0.66 0.09 -0.57 HYPOMETHYLATION CENTG1 chr12 56406249 56407788 chr12: 56406176-56407818 -1.07 0.95 0.19 -0.77 HYPOMETHYLATION CENTG1 chr12 56416146 56418794 chr12: 56416095-56416628; -0.94 0.85 0.16 -0.69 HYPOMETHYLATION chr12: 56418745-56419001

Information in Table 1A based on the March 2006 human reference sequence (NCBI Build 36.1), which was produced by the International Human Genome Sequencing Consortium.

TABLE-US-00010 TABLE 1B Non-Chromosome 21 differentially methylated regions Micro- Relative array Previously Methylation Analy- EpiTYPER EpiTYPER Validated Placenta to Region Name Gene Region Chrom Start End sis 8 Samples 73 Samples EpiTYPER Maternal TFAP2E Intron chr1 35815000 35816200 YES YES NO NO Hypermethylation LRRC8D Intron/Exon chr1 90081350 90082250 YES YES NO NO Hypermethylation TBX15 Promoter chr1 119333500 119333700 YES YES NO NO Hypermethylation C1orf51 Upstream chr1 148520900 148521300 YES YES NO NO Hypermethylation chr1: Intergenic chr1 179553900 179554600 YES YES NO NO Hypermethylation 179553900-179554600 ZFP36L2 Exon chr2 43304900 43305100 YES YES NO NO Hypermethylation SIX2 Downstream chr2 45081000 45086000 YES YES NO YES Hypermethylation chr2: Intergenic chr2 137238500 137240000 YES YES NO NO Hypermethylation 137238500-137240000 MAP1D Intron/Exon chr2 172652800 172653600 YES YES NO NO Hypermethylation WNT6 Intron chr2 219444250 219444290 YES YES NO NO Hypermethylation INPP5D Promoter chr2 233633200 233633700 YES YES YES NO Hypermethylation chr2: Intergenic chr2 241211100 241211600 YES YES YES NO Hypermethylation 241211100-241211600 WNT5A Intron chr3 55492550 55492850 YES YES NO NO Hypermethylation chr3: Intergenic chr3 138971600 138972200 YES YES YES YES Hypermethylation 138971600-138972200 ZIC4 Intron chr3 148598200 148599000 YES YES NO NO Hypermethylation FGF12 Intron/Exon chr3 193608500 193610500 YES YES NO NO Hypermethylation GP5 Exon chr3 195598400 195599200 YES YES NO NO Hypermethylation MSX1 Upstream chr4 4910550 4911100 YES YES NO NO Hypermethylation NKX3-2 Intron/Exon chr4 13152500 13154500 YES YES NO NO Hypermethylation chr4: Intergenic chr4 111752000 111753000 YES YES YES NO Hypermethylation 111752000-111753000 SFRP2 Promoter chr4 154928800 154930100 YES YES NO NO Hypermethylation chr4: Intergenic chr4 174664300 174664800 YES YES NO NO Hypermethylation 174664300-174664800 chr4: Intergenic chr4 174676300 174676800 YES YES NO NO Hypermethylation 174676300-174676800 SORBS2 Intron chr4 186796900 186797500 YES YES NO NO Hypermethylation chr5: Intergenic chr5 42986900 42988200 YES YES NO NO Hypermethylation 42986900-42988200 chr5: Intergenic chr5 72712000 72714100 YES YES NO NO Hypermethylation 72712000-72714100 chr5: Intergenic chr5 72767550 72767800 YES YES NO NO Hypermethylation 72767550-72767800 NR2F1 Intron/Exon chr5 92955000 92955250 YES YES NO NO Hypermethylation PCDHGA1 Intron chr5 140850500 140852500 YES YES YES NO Hypermethylation chr6: Intergenic chr6 10489100 10490200 YES YES YES NO Hypermethylation 10489100-10490200 FOXP4 Intron chr6 41636200 41637000 YES YES NO YES Hypermethylation chr7: Intergenic chr7 19118400 19118700 YES YES NO NO Hypermethylation 19118400-19118700 chr7: Intergenic chr7 27258000 27258400 YES YES NO NO Hypermethylation 27258000-27258400 TBX20 Upstream chr7 35267500 35268300 YES YES NO NO Hypermethylation AGBL3 Promoter chr7 134321300 134322300 YES YES NO NO Hypermethylation XPO7 Downstream chr8 21924000 21924300 YES YES NO NO Hypermethylation chr8: Intergenic chr8 41543400 41544000 YES YES NO NO Hypermethylation 41543400-41544000 GDF6 Exon chr8 97225400 97227100 YES YES NO NO Hypermethylation OSR2 Intron/Exon chr8 100029000 100031000 YES YES YES YES Hypermethylation GLIS3 Intron/Exon chr9 4288000 4290000 YES YES NO YES Hypermethylation NOTCH1 Intron chr9 138547600 138548400 YES YES YES NO Hypermethylation EGFL7 Upstream chr9 138672350 138672850 YES YES NO NO Hypermethylation CELF2 Intron/Exon chr10 11246700 11247900 YES YES NO NO Hypermethylation HHEX Intron chr10 94441000 94441800 YES YES NO NO Hypermethylation DOCK1/FAM196A Intron/Exon chr10 128883000 128883500 YES YES NO NO Hypermethylation PAX6 Intron chr11 31782400 31783500 YES YES NO NO Hypermethylation FERMT3 Intron/Exon chr11 63731200 63731700 YES YES YES NO Hypermethylation PKNOX2 Intron chr11 124541200 124541800 YES YES NO NO Hypermethylation KIRREL3 Intron chr11 126375150 126375300 YES YES NO NO Hypermethylation BCAT1 Intron chr12 24946700 24947600 YES YES NO NO Hypermethylation HOXC13 Intron/Exon chr12 52625000 52625600 YES YES NO NO Hypermethylation TBX5 Promoter chr12 113330500 113332000 YES YES NO NO Hypermethylation TBX3 Upstream chr12 113609000 113609500 YES YES NO YES Hypermethylation chr12: Intergenic chr12 113622100 113623000 YES YES YES NO Hypermethylation 113622100-113623000 chr12: Intergenic chr12 113657800 113658300 YES YES NO NO Hypermethylation 113657800-113658300 THEM233 Promoter chr12 118515500 118517500 YES YES NO YES Hypermethylation NCOR2 Intron/Exon chr12 123516200 123516800 YES YES YES NO Hypermethylation THEM132C Intron chr12 127416300 127416700 YES YES NO NO Hypermethylation PTGDR Promoter chr14 51804000 51805200 YES YES NO NO Hypermethylation ISL2 Intron/Exon chr15 74420000 74422000 YES YES NO YES Hypermethylation chr15: Intergenic chr15 87750000 87751000 YES YES NO NO Hypermethylation 87750000-87751000 chr15: Intergenic chr15 87753000 87754100 YES YES NO NO Hypermethylation 87753000-87754100 NR2F2 Upstream chr15 94666000 94667500 YES YES YES NO Hypermethylation chr16: Intergenic chr16 11234300 11234900 YES YES NO NO Hypermethylation 11234300-11234900 SPN Exon chr16 29582800 29583500 YES YES YES NO Hypermethylation chr16: Intergenic chr16 85469900 85470200 YES YES NO NO Hypermethylation 85469900-85470200 SLFN11 Promoter chr17 30725100 30725600 YES YES NO NO Hypermethylation DLX4 Upstream chr17 45396800 45397800 YES YES NO YES Hypermethylation SLC38A10 (MGC15523) Intron chr17 76873800 76874300 YES YES YES NO Hypermethylation S1PR4 Exon chr19 3129900 3131100 YES YES YES YES Hypermethylation MAP2K2 Intron chr19 4059700 4060300 YES YES YES NO Hypermethylation UHRF1 Intron chr19 4867300 4867800 YES YES YES NO Hypermethylation DEDD2 Exon chr19 47395300 47395900 YES YES YES NO Hypermethylation CDC42EP1 Exon chr22 36292300 36292800 YES YES YES NO Hypermethylation

TABLE-US-00011 TABLE 1C Chromosome 21 differentially methylated regions Previously Micro- Epi Epi TYPER Validated array TYPER 8 73 Epi Relative Methylation Region Name Gene Region Chrom Start End Analysis Samples Samples TYPER Placenta to Maternal chr21: 9906600-9906800 Intergenic chr21 9906600 9906800 NO YES NO NO Hypomethylation chr21: 9907000-9907400 Intergenic chr21 9907000 9907400 NO YES NO NO Hypomethylation chr21: 9917800-9918450 Intergenic chr21 9917800 9918450 NO YES NO NO Hypomethylation TPTE Promoter chr21 10010000 10015000 NO YES NO NO Hypomethylation chr21: 13974500-13976000 Intergenic chr21 13974500 13976000 NO YES NO NO Hypomethylation chr21: 13989500-13992000 Intergenic chr21 13989500 13992000 NO YES NO NO Hypomethylation chr21: 13998500-14000100 Intergenic chr21 13998500 14000100 NO YES NO NO Hypomethylation chr21: 14017000-14018500 Intergenic chr21 14017000 14018500 NO YES NO NO Hypomethylation chr21: 14056400-14058100 Intergenic chr21 14056400 14058100 NO YES NO NO Hypomethylation chr21: 14070250-14070550 Intergenic chr21 14070250 14070550 NO YES NO NO Hypomethylation chr21: 14119800-14120400 Intergenic chr21 14119800 14120400 NO YES NO NO Hypomethylation chr21: 14304800-14306100 Intergenic chr21 14304800 14306100 NO YES NO NO Hypomethylation chr21: 15649340-15649450 Intergenic chr21 15649340 15649450 NO YES YES NO Hypermethylation C21orf34 Intron chr21 16881500 16883000 NO YES NO NO Hypomethylation BTG3 Intron chr21 17905300 17905500 NO YES NO NO Hypomethylation CHODL Promoter chr21 18539000 18539800 NO YES YES NO Hypermethylation NCAM2 Upstream chr21 21291500 21292100 NO YES NO NO Hypermethylation chr21: 23574000-23574600 Intergenic chr21 23574000 23574600 NO YES NO NO Hypomethylation chr21: 24366920-24367060 Intergenic chr21 24366920 24367060 NO YES NO NO Hypomethylation chr21: 25656000-25656900 Intergenic chr21 25656000 25656900 NO YES NO NO Hypomethylation MIR155HG Promoter chr21 25855800 25857200 NO YES YES NO Hypermethylation CYYR1 Intron chr21 26830750 26830950 NO YES NO NO Hypomethylation chr21: 26938800-26939200 Intergenic chr21 26938800 26939200 NO YES NO NO Hypomethylation GRIK1 Intron chr21 30176500 30176750 NO YES NO NO Hypomethylation chr21: 30741350-30741600 Intergenic chr21 30741350 30741600 NO YES NO NO Hypermethylation TIAM1 Intron chr21 31426800 31427300 NO YES YES NO Hypermethylation TIAM1 Intron chr21 31475300 31475450 NO YES NO NO Hypermethylation TIAM1 Intron chr21 31621050 31621350 NO YES YES NO Hypermethylation SOD1 Intron chr21 31955000 31955300 NO YES NO NO Hypomethylation HUNK Intron/Exon chr21 32268700 32269100 NO YES YES NO Hypermethylation chr21: 33272200-33273300 Intergenic chr21 33272200 33273300 NO YES NO NO Hypomethylation OLIG2 Promoter chr21 33314000 33324000 YES YES NO YES Hypermethylation OLIG2 Downstream chr21 33328000 33328500 YES YES NO NO Hypomethylation RUNX1 Intron chr21 35185000 35186000 NO YES NO NO Hypomethylation RUNX1 Intron chr21 35320300 35320400 NO YES NO NO Hypermethylation RUNX1 Intron chr21 35321200 35321600 NO YES NO NO Hypermethylation RUNX1 Intron/Exon chr21 35340000 35345000 NO YES YES NO Hypermethylation chr21: 35499200-35499700 Intergenic chr21 35499200 35499700 NO YES YES NO Hypermethylation chr21: 35822800-35823500 Intergenic chr21 35822800 35823500 NO YES YES NO Hypermethylation CBR1 Promoter chr21 36364000 36364500 NO YES NO NO Hypermethylation DOPEY2 Downstream chr21 36589000 36590500 NO YES NO NO Hypomethylation SIM2 Promoter chr21 36988000 37005000 YES YES YES YES Hypermethylation HLCS Intron chr21 37274000 37275500 YES YES YES NO Hypermethylation DSCR6 Upstream chr21 37300200 37300400 YES YES NO YES Hypermethylation DSCR3 Intron chr21 37551000 37553000 YES YES YES NO Hypermethylation chr21: 37841100-37841800 Intergenic chr21 37841100 37841800 NO YES YES NO Hypermethylation ERG Intron chr21 38791400 38792000 NO YES YES NO Hypermethylation chr21: 39278700-39279800 Intergenic chr21 39278700 39279800 NO YES YES NO Hypermethylation C21orf129 Exon chr21 42006000 42006250 NO YES YES NO Hypermethylation C2CD2 Intron chr21 42188900 42189500 NO YES YES NO Hypermethylation UMODL1 Upstream chr21 42355500 42357500 NO YES YES NO Hypermethylation UMODL1/C21orf128 Intron chr21 42399200 42399900 NO YES NO NO Hypomethylation ABCG1 Intron chr21 42528400 42528600 YES YES NO NO Hypomethylation chr21: 42598300-42599600 Intergenic chr21 42598300 42599600 YES YES NO NO Hypomethylation chr21: 42910000-42911000 Intergenic chr21 42910000 42911000 NO YES NO NO Hypomethylation PDE9A Upstream chr21 42945500 42946000 NO YES NO NO Hypomethylation PDE9A Intron chr21 42961400 42962700 NO YES NO NO Hypomethylation PDE9A Intron chr21 42977400 42977600 NO YES NO NO Hypermethylation PDE9A Intron/Exon chr21 42978200 42979800 YES YES NO NO Hypomethylation PDE9A Intron chr21 43039800 43040200 NO YES YES NO Hypermethylation chr21: 43130800-43131500 Intergenic chr21 43130800 43131500 NO YES NO NO Hypomethylation U2AF1 Intron chr21 43395500 43395800 NO YES NO NO Hypermethylation U2AF1 Intron chr21 43398000 43398450 NO YES YES NO Hypermethylation chr21: 43446600-43447600 Intergenic chr21 43446600 43447600 NO YES NO NO Hypomethylation CRYAA Intron/Exon chr21 43463000 43466100 NO YES NO NO Hypomethylation chr21: 43545000-43546000 Intergenic chr21 43545000 43546000 YES YES NO NO Hypomethylation chr21: 43606000-43606500 Intergenic chr21 43606000 43606500 NO YES NO NO Hypomethylation chr21: 43643000-43644300 Intergenic chr21 43643000 43644300 YES YES YES YES Hypermethylation C21orf125 Upstream chr21 43689100 43689300 NO YES NO NO Hypermethylation C21orf125 Downstream chr21 43700700 43701700 NO YES NO NO Hypermethylation HSF2BP Intron/Exon chr21 43902500 43903800 YES YES NO NO Hypomethylation AGPAT3 Intron chr21 44161100 44161400 NO YES YES NO Hypermethylation chr21: 44446500-44447500 Intergenic chr21 44446500 44447500 NO YES NO NO Hypomethylation TRPM2 Intron chr21 44614500 44615000 NO YES NO NO Hypomethylation C21orf29 Intron chr21 44750400 44751000 NO YES NO NO Hypomethylation C21orf29 Intron chr21 44950000 44955000 NO YES YES NO Hypermethylation ITGB2 Intron/Exon chr21 45145500 45146100 NO YES NO NO Hypomethylation POFUT2 Downstream chr21 45501000 45503000 NO YES NO NO Hypomethylation chr21: 45571500-45573700 Intergenic chr21 45571500 45573700 NO YES NO NO Hypomethylation chr21: 45609000-45610600 Intergenic chr21 45609000 45610600 NO YES NO NO Hypomethylation COL18A1 Intron chr21 45670000 45677000 YES YES NO YES Hypomethylation COL18A1 Intron/Exon chr21 45700500 45702000 NO YES NO NO Hypomethylation COL18A1 Intron/Exon chr21 45753000 45755000 YES YES NO YES Hypomethylation chr21: 45885000-45887000 Intergenic chr21 45885000 45887000 NO YES NO NO Hypomethylation PCBP3 Intron chr21 46111000 46114000 NO YES NO NO Hypomethylation PCBP3 Intron/Exon chr21 46142000 46144500 NO YES NO NO Hypomethylation COL6A1 Intron/Exon chr21 46227000 46233000 NO YES NO NO Hypomethylation COL6A1 Intron/Exon chr21 46245000 46252000 NO YES NO NO Hypomethylation chr21: 46280500-46283000 Intergenic chr21 46280500 46283000 NO YES NO NO Hypomethylation COL6A2 Intron chr21 46343500 46344200 NO YES NO NO Hypomethylation COL6A2 Intron/Exon chr21 46368000 46378000 NO YES NO NO Hypomethylation C21orf56 Intron/Exon chr21 46426700 46427500 NO YES NO NO Hypomethylation C21orf57 Intron chr21 46541568 46541861 NO YES NO NO Hypermethylation C21orf57 Exon chr21 46541872 46542346 NO YES NO NO Hypermethylation C21orf57 Downstream chr21 46542319 46542665 NO YES NO NO Hypermethylation C21orf58 Intron chr21 46546914 46547404 NO YES NO NO Hypomethylation PRMT2 Downstream chr21 46911000 46913000 YES YES NO YES Hypermethylation ITGB2 Intron chr21 45170700 45171100 NO YES YES NO Hypermethylation

TABLE-US-00012 TABLE 2 GENE NAME CHROM START END SNPs chr13 chr13 19773745 19774050 rs7996310; rs12870878 group00016 chr13 chr13 19290394 19290768 rs11304938 group00005 CENPJ chr13 24404023 24404359 rs7326661 ATP8A2 chr13 25484475 25484614 rs61947088 PDX1 chr13 27400459 27401165 rs58173592; rs55836809; rs61944011 RBI chr13 47790983 47791646 rs2804094; rs4151432; rs4151433; rs4151434; rs4151435 PCDH17 chr13 57104856 57106841 rs35287822; rs34642962; rs41292834; rs45500496; rs45571031; rs41292836; rs28374395; rs41292838 KLHL1 chr13 69579933 69580146 rs3751429 POU4F1 chr13 78079515 78081073 rs11620410; rs35794447; rs2765065 GPC6 chr13 92677402 92678666 rs35689696; rs11839555; rs55695812; rs35259892 SOX21 chr13 94152286 94153047 rs41277652; rs41277654; rs35276096; rs5805873; rs35109406 ZIC2 chr13 99439660 99440858 rs9585309; rs35501321; rs9585310; rs7991728; rs1368511 IRS2 chr13 109232856 109235065 rs61747993; rs1805097; rs9583424; rs35927012; rs1056077; rs1056078; rs34889228; rs1056080; rs1056081; rs12853546; rs4773092; rs35223808; rs35894564; rs3742210; rs34412495; rs61962699; rs45545638; rs61743905 chr13 chr13 111808255 111808962 rs930346 group00395 MCF2L chr13 112724910 112725742 rs35661110; rs2993304; rs1320519; rs7320418; rs58416100 F7 chr13 112799123 112799379 rs2480951; rs2476320 CIDEA chr18 12244327 12244696 rs60132277 chr18 chr18 12901467 12901643 rs34568924; rs8094284; rs8094285 group00091 C18orf1 chr18 13377536 13377654 rs9957861 KLHL14 chr18 28603978 28605183 rs61737323; rs61737324; rs12960414 CD33L3 chr18 41671477 41673011 rs62095363; rs2919643 ONECUT2 chr18 53254808 53259810 rs35685953; rs61735644; rs8084084; rs35937482; rs35427632; rs7232930; rs3786486; rs34286480; rs3786485; rs28655657; rs4940717; rs4940719; rs3786484; rs34040569; rs35542747; rs33946478; rs35848049; rs7231349; rs7231354; rs34481218; rs12962172; rs3911641 RAX chr18 55086286 55086436 rs58797899; rs45501496 chr18 chr18 57151972 57152311 rs17062547 group00277 TNFRSF11A chr18 58203013 58203282 rs35114461 NETO1 chr18 68685099 68687060 rs4433898; rs34497518; rs35135773; rs6566677; rs57425572; rs36026929; rs34666288; rs10627137; rs35943684; rs9964226; rs4892054; rs9964397; rs4606820; rs12966677; rs8095606 chr18 chr18 70133945 70134397 rs8086706; rs8086587; rs8090367; rs999332; rs17806420; rs58811193 group00304 TSHZ1 chr18 71128742 71128974 rs61732783; rs3744910; rs1802180 chr18 chr18 74170347 74170489 rs7226678 group00342 NFATC1 chr18 75385424 75386008 rs28446281; rs56384153; rs4531815; rs3894049 chr18 chr18 75653272 75653621 rs34967079; rs35465647 group00430 KCNG2 chr18 75760343 75760820 rs3744887; rs3744886 OLIG2 chr21 33317673 33321183 rs2236618; rs11908971; rs9975039; rs6517135; rs2009130; rs1005573; rs1122807; rs10653491; rs10653077; rs35086972; rs28588289; rs7509766; rs62216114; rs35561747; rs7509885; rs11547332 OLIG2 chr21 33327593 33328334 rs7276788; rs7275842; rs7275962; rs7276232; rs16990069; rs13051692; rs56231743; rs35931056 RUNX1 chr21 35180938 35185436 rs2843956; rs55941652; rs56020428; rs56251824; rs13051109; rs13051111; rs3833348; rs7510136; rs743289; rs5843690; rs33915227; rs11402829; rs2843723; rs8128138; rs8131386; rs2843957; rs57537540; rs13048584; rs7281361; rs2843965; rs2843958 SIM2 chr21 36994965 36995298 rs2252821 SIM2 chr21 36999025 36999410 rs58347144; rs737380 DSCAM chr21 41135559 41135706 rs35298822 AIRE chr21 44529935 44530388 rs35110251; rs751032; rs9978641 SUMO3 chr21 45061293 45061853 rs9979741; rs235337; rs7282882 C21orf70 chr21 45202815 45202972 rs61103857; rs9979028; rs881318; rs881317 COL18A1 chr21 45754383 45754487 rs35102708; rs9980939 PRMT2 chr21 46911967 46912385 rs35481242; rs61743122; rs8131044; rs2839379 SIX2 chr2 45081223 45082129 rs62130902 SIX2 chr2 45084851 45085711 rs35417092; rs57340219 SOX14 chr3 138971870 138972322 rs57343003 TLX3 chr5 170674439 170676431 rs11134682; rs35704956; rs2964533; rs35601828 FOXP4 chr6 41623666 41624114 rs12203107; rs1325690 FOXP4 chr6 41636384 41636779 rs56835416 chr7 chr7 12576755 12577246 rs56752985; rs17149965; rs6948573; rs2240572 group00267 NPY chr7 24290224 24291508 rs2390965; rs2390966; rs2390967; rs2390968; rs3025123; rs16146; rs16145; rs16144; rs13235842; rs13235935; rs13235938; rs13235940; rs13235944; rs36083509; rs3025122; rs16143; rs16478; rs16142; rs16141; rs16140; rs16139; rs2229966; rs1042552; rs5571; rs5572 SHH chr7 155291537 155292091 rs9333622; rs1233554; rs9333620; rs1233555 GLIS3 chr9 4288283 4289645 rs56728573; rs12340657; rs12350099; rs35338539; rs10974444; rs7852293 PRMT8 chr12 3472714 3473190 rs12172776 TBX3 chr12 113609153 113609453 rs60114979 chr12 chr12 118516189 118517435 rs966246; rs17407022; rs970095; rs2711748 group00801 PAX9 chr14 36201402 36202386 rs17104893; rs12883298; rs17104895; rs35510737; rs12882923; rs12883049; rs28933970; rs28933972; rs28933971; rs28933373; rs61734510 SIX1 chr14 60178801 60179346 rs761555 ISL2 chr15 74420013 74421546 rs34173230; rs11854453 DLX4 chr17 45397228 45397930 rs62059964; rs57481357; rs56888011; rs17638215; rs59056690; rs34601685; rs17551082 CBX4 chr17 75428613 75431793 rs1285243; rs35035500; rs12949177; rs3764374; rs62075212; rs62075213; rs3764373; rs3764372; rs55973291 EDG6 chr19 3129836 3130874 rs34728133; rs34573539; rs3826936; rs34914134; rs61731111; rs34205484 MGC29506 chr5 138757911 138758724 rs11748963; rs7447765; rs35262202 CENTG1 chr12 56406249 56407788 rs61935742; rs12318065; rs238519; rs238520; rs238521; rs808930; rs2640595; rs2640596; rs2640597; rs2640598; rs34772922 CENTG1 chr12 56416146 56418794 rs11830475; rs34482618; rs2650057; rs2518686; rs12829991

TABLE-US-00013 TABLE 3 RELATIVE METHYLATION GENE NAME PLACENTA TO MATERNAL PRC2 TARGET CRYL1 HYPOMETHYLATION TRUE IL17D HYPOMETHYLATION TRUE GSH1 HYPERMETHYLATION TRUE MAB21L1 HYPERMETHYLATION TRUE PCDH17 HYPERMETHYLATION TRUE KLHL1 HYPERMETHYLATION TRUE POU4F1 HYPERMETHYLATION TRUE SOX21 HYPERMETHYLATION TRUE ZIC2 HYPERMETHYLATION TRUE CIDEA HYPERMETHYLATION TRUE KLHL14 HYPERMETHYLATION TRUE ONECUT2 HYPERMETHYLATION TRUE RAX HYPERMETHYLATION TRUE TNFRSF11A HYPOMETHYLATION TRUE OLIG2 HYPERMETHYLATION TRUE OLIG2 HYPOMETHYLATION TRUE SIM2 HYPERMETHYLATION TRUE SIM2 HYPERMETHYLATION TRUE SIX2 HYPERMETHYLATION TRUE SIX2 HYPERMETHYLATION TRUE SOX14 HYPERMETHYLATION TRUE TLX3 HYPERMETHYLATION TRUE SHH HYPERMETHYLATION TRUE OSR2 HYPERMETHYLATION TRUE TBX3 HYPERMETHYLATION TRUE PAX9 HYPERMETHYLATION TRUE SIX1 HYPERMETHYLATION TRUE ISL2 HYPERMETHYLATION TRUE DLX4 HYPERMETHYLATION TRUE CBX4 HYPERMETHYLATION TRUE CENTG1 HYPOMETHYLATION TRUE CENTG1 HYPOMETHYLATION TRUE

TABLE-US-00014 TABLE 4A SEQ ID GENE NO NAME SEQUENCE 1 chr13 CAGCAGGCGCGCTCCCGGCGAATCTGCCTGAATCGCCGTGAATGCGGTGGGGTGCAGGGCAGGGG- CTGGTTTTCTCAGCCGGTCTTGG group- CTTTTCTCTTTCTCTCCTGCTCCACCAGCAGCCCCTCCGCGGGTCCCATGGGCTCCGCGCTCAGAA- CAGCCCGGAACCAGGCGCCGCTC 00016 GCCGCTCGCTGGGGGCCACCCGCCTCTCCCCGGAACAGCCTCCCGCGGGCCTCTTGGCCTCGCACTG- GCGCCCTCACCCACACATCGT CCCTTTATCCGCTCAGACGCTGCAAAGGGCCTTCTGTCTC 2 CENPJ GCTTTGGATTTATCCTCATTGGCTAAATCCCTCCTGAAACATGAAACTGAAACAAAGCCCTGAAC- CCCCTCAGGCTGAAAAGACAAACCCC GCCTGAGGCCGGGTCCCGCTCCCCACCTGGAGGGACCCAATTCTGGGCGCCTTCTGGCGACGGTCCCTGCTA- GGGACGCTGCGCTCTC CGAGTGCGAGTTTTCGCCAAACTGATAAAGCACGCAGAACCGCAATCCCCAAACTAACACTGAACCCGGACC- CGCGATCCCCAAACTGAC AAGGGACCCGGAACAGCGACCCCCAAACCGACACGGGACTCGGGAACCGCTATCTCCAAAGGGCAGC 3 ATP8A TTTCCACAACAGGGAGCCAGCATTGAGGCGCCCAGATGGCATCTGCTGGAAATCACGGGCCGCTG- GTGAAGCACCACGCCTTACCCGAC 2 GTGGGGAGGTGATCCCCCACCTCATCCCACCCCCTTCTGTCTGTCTCCTT 4 GSH1 GCTGGACAAGGAGCGCTCACTGTAGCTCTGCTGTGGATTGTGTTGGGGCGAAGAGATGGGTAAGAG- GTCAAAGTCGTAGGATTCTGGCG ACCGCCTACCAAGGGATTGGGTCCACAGCACAGAGGTCTGATCGCTTCCTTCTCTGCTCTGCCACCTCCAGA- CAGCAGCTCTAACCAGCT GCCCAGCAGCAAGAGGATGCGCACGGCTTTCACCAGCACGCAGCTGCTAGAGCTGGAGCGCGAGTTCGCTTC- TAATATGTACCTGTCCC GCCTACGTCGCATCGAGATCGCGA 5 PDX1 TGCCTGACACTGACCCCAGGCGCAGCCAGGAGGGGCTTTGTGCGGGAGAGGGAGGGGGACCCCAGC- TTGCCTGGGGTCCACGGGACT CTCTTCTTCCTAGTTCACTTTCTTGCTAAGGCGAAGGTCCTGAGGCAGGACGAGGGCTGAACTGCGCTGCAA- TCGTCCCCACCTCCAGCG AAACCCAGTTGAC 6 PDX1 TCGGCGGAGAGACCTCGAGGAGAGTATGGGGAAAGGAATGAATGCTGCGGAGCGCCCCTCTGGGCT- CCACCCAAGCCTCGGAGGCGG GACGGTGGGCTCCGTCCCGACCCCTTAGGCAGCTGGACCGATACCTCCTGGATCAGACCCCACAGGAAGACT- CGCGTGGGGCCCGATA TGTGTACTTCAAACTCTGAGCGGCCACCCTCAGCCAACTGGCCAGTGGATGCGAATCGTGGGCCCTGAGGGG- CGAGGGCGCTCGGAAC TGCATGCCTGTGCACGGTGCCGGGCTCTCCAGAGTGAGGGGGCCGTAAGGAGATCTCCAAGGAAGCCGAAAA- AAGCAGCCAGTTGGGC TTCGGGAAAGACTTTTCTGCAAAGGAAGTGATCTGGTCCCAGAACTCCAGGGTTGACCCCAGTACCTGACTT- CTCCGGGAGCTGTCAGCT CTCCTCTGTTCTTCGGGCTTGGCGCGCTCCTTTCATAATGGACAGACACCAGTGGCCTTCAAAAGGTCTGGG- GTGGGGGAACGGAGGAA GTGGCCTTGGGTGCAGAGGAAGAGCAGAGCTCCTGCCAAAGCTGAACGCAGTTAGCCCTACCCAAGTGCGCG- CTGGCTCGGCATATGC GCTCCAGAGCCGGCAGGACAGCCCGGCCCTGCTCACCCCGAGGAGAAATCCAACAGCGCAGCCTCCTGCACC- TCCTTGCCCCAGAGAC 7 MAB21 AGATCCCGGTGCATTTAAAGGCCGGCGTGATCTGCACCACGTACCTATCTCGGATTCTCAGTTTC- ACTTCGCTGGTGTCTGCCACCATCTT L1 TACCACATCCCGGTAGCTACATTTGTCTACCGCTTGAGCCACCAGCGTCTGAAACCTGGACCGGATTTTG- CGCGCCGAGAGGTAGCCGG AGGCGGTAATGAATTCCACCCAGAGGGACATGCTCCTCTTGCGCCCGTCGCTCAACTTCAGCACCGCGCAGC- CGGGCAGTGAGCCATCG TCCACGAAGTTGAACACCCCCATTTGGTTGAGATAAAGCACCACTTCAAATTCGGT 8 RB1 ACTATGCCTTGAGGGTCAAAACGTCTGGATTTCCTGATCGATGCTGTCGTCGCTGTCCACGGAGCTA- CTGTCGCCGTCAGAGCGGGAAG GCACGTTCAGGGAGTAGAAGCGTGGGCTTGCAGAAAGGGACCTGTTGCTGCCTTACATGGGGGCCGGCAGGG- TAGTCTTGGAAATGCC CAAGATTGCTTCCGCGCGCGTCAGTTCAGCGGACGTGTCTGCCTGGCACGAGGACCGTTCTACAAACTCGTT- CCTGGAAGCCGGGCTCG CTGGAGGCGGAGCTTTGGTTTCCTTCGGGAGCTTGTGGGGAATGGTCAGCGTCTAGGCACCCCGGGCAAGGG- TCTGTGGCCTTGGTGG CCACTGGCTTCCTCTAGCTGGGTGTTTTCCTGTGGGTCTCGCGCAAGGCACTTTTTTGTGGCGCTGCTTGTG- CTGTGTGCGGGGTCAGGC GTCCTCTCTCCTCCCGGCGCTGGGCCCTCTGGGGCAGGTCCCCGTTGGCCTCCTTGCGTGTTTGCCGCAGCT- AGTACACCTGGATGGCC TCCTCAGTGCCGTCGTTGCTGCTGGAGTCTGACGCCTCGGGCGCCTGCGCCGCACTTGTGACTTGCTTTCCC- CTTCTCAGGGCGCCAGC GCTCCTCTTGACCCCGCTTTTATTCTGTGGTGCTTCTGAAG 9 PCDH1 GCAAGTCGGGTAGCTACCGGGTGCTGGAGAACTCCGCACCGCACCTGCTGGACGTGGACGCAGAC- AGCGGGCTCCTCTACACCAAGCA 7 GCGCATCGACCGCGAGTCCCTGTGCCGCCACAATGCCAAGTGCCAGCTGTCCCTCGAGGTGTTCGCCAACG- ACAAGGAGATCTGCATGA TCAAGGTAGAGATCCAGGACATCAACGACAACGCGCCCTCCTTCTCCTCGGACCAGATCGAAATGGACATCT- CGGAGAACGCTGCTCCG GGCACCCGCTTCCCCCTCACCAGCGCACATGACCCCGACGCCGGCGAGAATGGGCTCCGCACCTACCTGCTC- ACGCGCGACGATCACG GCCTCTTTGGACTGGACGTTAAGTCCCGCGGCGACGGCACCAAGTTCCCAGAACTGGTCATCCAGAAGGCTC- TGGACCGCGAGCAACAG AATCACCATACGCTCGTGCTGACTGCCCTGGACGGTGGCGAGCCTCCACGTTCCGCCACCGTACAGATCAAC- GTGAAGGTGATTGACTC CAACGACAACAGCCCGGTCTTCGAGGCGCCATCCTACTTGGTGGAACTGCCCGAGAACGCTCCGCTGGGTAC- AGTGGTCATCGATCTGA ACGCCACCGACGCCGATGAAGGTCCCAATGGTGAAGTGCTCTACTCTTTCAGCAGCTACGTGCCTGACCGCG- TGCGGGAGCTCTTCTCC ATCGACCCCAAGACCGGCCTAATCCGTGTGAAGGGCAATCTGGACTATGAGGAAAACGGGATGCTGGAGATT- GACGTGCAGGCCCGAGA CCTGGGGCCTAACCCTATCCCAGCCCACTGCAAAGTCACGGTCAAGCTCATCGACCGCAACGACAATGCGCC- GTCCATCGGTTTCGTCTC CGTGCGCCAGGGGGCGCTGAGCGAGGCCGCCCCTCCCGGCACCGTCATCGCCCTGGTGCGGGTCACTGACCG- GGACTCTGGCAAGAA CGGACAGCTGCAGTGTCGGGTCCTAGGCGGAGGAGGGACGGGCGGCGGCGGGGGCCTGGGCGGGCCCGGGGG- TTCCGTCCCCTTCA AGCTTGAGGAGAACTACGACAACTTCTACACGGTGGTGACTGACCGCCCGCTGGACCGCGAGACACAAGACG- AGTACAACGTGACCATC GTGGCGCGGGACGGGGGCTCTCCTCCCCTCAACTCCACCAAGTCGTTCGCGATCAAGATTCTAGACGAGAAC- GACAACCCGCCTCGGTT CACCAAAGGGCTCTACGTGCTTCAGGTGCACGAGAACAACATCCCGGGAGAGTACCTGGGCTCTGTGCTCGC- CCAGGATCCCGACCTGG GCCAGAACGGCACCGTATCCTACTCTATCCTGCCCTCGCACATCGGCGACGTGTCTATCTACACCTATGTGT- CTGTGAATCCCACGAACG GGGCCATCTACGCCCTGCGCTCCTTTAACTTCGAGCAGACCAAGGCTTTTGAGTTCAAGGTGCTTGCTAAGG- ACTCGGGGGCGCCCGCG CACTTGGAGAGCAACGCCACGGTGAGGGTGACAGTGCTAGACGTGAATGACAACGCGCCAGTGATCGTGCTC- CCCACGCTGCAGAACGA CACCGCGGAGCTGCAGGTGCCGCGCAACGCTGGCCTGGGCTATCTGGTGAGCACTGTGCGCGCCCTAGACAG- CGACTTCGGCGAGAGC GGGCGTCTCACCTACGAGATCGTGGACGGCAACGACGACCACCTGTTTGAGATCGACCCGTCCAGCGGCGAG- ATCCGCACGCTGCACC CTTTCTGGGAGGACGTGACGCCCGTGGTGGAGCTGGTGGTGAAGGTGACCGACCACGGCAAGCCTACCCTGT- CCGCAGTGGCCAAGCT CATCATCCGCTCGGTGAGCGGATCCCTTCCCGAGGGGGTACCACGGGTGAATGGCGAGCAGCACCACTGGGA- CATGTCGCTGCCGCTC ATCGTGACTCTGAGCACTATCTCCATCATCCTCCTA 10 KLHL1 ATGCGCCCTCTGCACCCCTAGAGCCAGAAGACGCTAGGTGGGCTGCGCGCTCTGCCAGGCGAAGG- CTGGAGCGCAGACGGCAAAGCC GCGCGTTTCAGCCGTGGTCGGGTCCGCAGGACCTGGGCGTGGGGACACCACCAGGCAGGAGCAGAGGCAGGA- CTGGGACGCCAAAAG CTGAGAATCCTCGATGCCCGCGCGAGAGCCCCGTGTTAT 11 POU4F TTCTGGAAACCGGGCCCCACTTGCAGGCCCGGCCACCTTGGGTTCTGGTGGCCGAAGCCGGAGCT- GTGTTTCTCGCAGACTCGGGGAG 1 CTACATTGTGCGTAGGCAATTGTTTAGTTTGAAAGGAGGCACATTTCACCACGCAGCCAGCGCCCTGCATG- CAGGAGAAGCCCCCAGGG CCCAGGGTCGGCTGGCTTTAGAGGCCACTTAGGTTGTTTTAAGCACATGTGAAAGGGCAGACAGCAGGGGAG- CAGGATATGGGTAAGAT CTTCGGGTCTCAGAACAGGGGCTGCCCTTGGGCTGTCCCGGCGCCCTGGGCTCTGACACTGAAGGGTGGAAT- GGAGGAAGGAATGGAG AAAGGACGGTGGAACTTTCGCTTCCCCTCTGGGCCGCCTTCCCAGGGTCATGCCTGAGCTGCTTTGATCCCA- GTGTCGCGCATCTTGGTC CGCTACCTCCCAGGCGATAGCTACTGGGCTCCTCGCTGGCCTCACTGGGGGCCATCCCGGGCAGTGGCCTGC- CCTCCGAGGCCCGCGG GACCCAGCCCAGAGCTGAGGTTGGAGTTCTCCGGGCCACGTTCCGGGTCGCTTAGGCTCGGAGATTTCCCGG- AGACCGTCGTCCTCCCT TTCTGCTTGGCACTGCGGAGCTCCCTCGGCCTCTCTCCTCCTCTGGTCCCTAAGGCCCGGAGTGGTTGGCGG- TACTGGGGCCCGTCGTC ATCTCTGCTTCTAAGGCATTCAGACTGGGCTCCAGCTGGGACCGGCAGAGGAGGTTCTCAAGGAAACTGGTG- GGAAATATAGTTTTCTTT CGTCTGGTCGTTTAATTTAAATGCAACTTCCCTTGGGGACATTTTCCTGGACGTTAACCAGACCACCTTGAG- ATGTCGTTGATGACCTAGA GACCCAGATGATGCGTCCCAGGAAAGTTCACTGCTGACTATTGTCACTCTTGGCGTTATATCTATAGATATA- GACCTATGTACATATCTCCA CCCTGATCTCTCCGTGGACATGAAACCCACCTACCTTGTGAAAGCCCTACGGGTGACACATGACTACTACGT- CTCTGTCCCAACAGGGGC TGGGCCTCCCCTGCCTAATAGTTGCCAGGAGTTTCGCAGCCCAAGTGAATAATGTCTTATGGCTGAACGTGG- CCAAGGACTCCTGTGATT TAGGTCCCAGGAGGAGCAGAGACGTCCCCGCCCCGCCTGGGCCCTGCCGCATTCAAAGCTGGAAGAAGGCGC- TGATCAGAGAAGGGGC TTCCAGGTCCTGGGTTAGAACAACAACAAACAAACGAAACTCCACAACAGACACGCCTGCCCATGACCCCAC- GCAAGGACATAGGAAGTT CTGTCGCCTTCCTGCTCCGCGGATAGCCGCCTGCCGTCTGCTGCCACCAGAACGCACGGACGCTCGGGGTGG- AGGTAGTCAATGGGCA GCAGGGGACCCCCAGCCCCCACAAGCGCGGCTCCGAGGACCTGGAAGCGGGTGCCTGTCGCTCTCCGCAGGC- TCCGCTCTGCCTCCA GGAGCAAGATCCCCAAAAGGGTCTGGAAGCTGTGGAGAAAAC 12 GPC6 TTTTTTAAACACTTCTTTTCCTTCTCTTCCTCGTTTTGATTGCACCGTTTCCATCTGGGGGCTAGA- GGAGCAAGGCAGCAGCCTTCCCAGCC AGCCCTTGTTGGCTTGCCATCGTCCATCTGGCTTATAAAAGTTTGCTGAGCGCAGTCCAGAGGGCTGCGCTG- CTCGTCCCCTCGGCTGGC AGAAGGGGGTGACGCTGGGCAGCGGCGAGGAGCGCGCCGCTGCCTCTGGCGGGCTTTCGGCTTGAGGGGCAA- GGTGAAGAGCGCACC GGCCGTGGGGTTTACCGAGCTGGATTTGTATGTTGCACCATGCCTTCTTGGATCGGGGCTGTGATTCTTCCC- CTCTTGGGGCTGCTGCTC TCCCTCCCCGCCGGGGCGGATGTGAAGGCTCGGAGCTGCGGAGAGGTCCGCCAGGCGTACGGTGCCAAGGGA- TTCAGCCTGGCGGAC ATCCCCTACCAGGAGATCGCAGGTAAGCGCGGGCGCGCTGCAGGGGCAGGCTGCAGCCCTCGGCTGCCGCAC- GTCCCACTGGCCGCC CGGCGTCCCCTTCCTTCCCCCTGTTGCTGAGTTGGTGCTCACTTTCTGCCACCGCTATGGGACTCCGCGTCT- CCGTGTTGGGCGGCGGA TGCTCCTGCGGCTTCTTCGGCGGGGGAAGGTGTGCGTCTCCGCCGCCTCATTGTGTGCACACGCGGGAGCAC- CCTGGCTCCCGCCTCC CGCTGCTCTCGCGCCCTTCTACCCCTTAGTTGATGGCTCAGGCCCGGCTGGCCAGGGAGCCCGGGTCACTCC- GGGGCGGCTGCAAGGC GCAGACGGAGAGCCGAGCCGGGCGCTCACTCCGCGTTCTGGTTCGGGCAAACTTGGAAGAACTGCGACCGCA- GTTTGCCCAGCGCCAC AGTCTGAGTGGCGCCTTCTCCACTCCCGCCCTTGCGCCGGCAGGGGCGGTGGAGAGACGCGGAGGGCTCCCC- CAGCCCCTCTCTCCCC TATCCGTCCTTCGGGCGACAGAGCGCCCGGCGCTCGGGCCGGGGGCGGGCAAGGCTGGGAGGGACCCTCGCC- GGGGACCTGGCCTC TGGACGCCGGCGTTTCAAGGCTGGTTTGGGGACTTCACGGGCTGCCTGTTTCAGATGTGGGGCGGGCTTTCC- CGTTAGGGTTCCTCAGT GCTTCCCCAGTTGCTGTTGGCCACTCAGGGCCCGGGGACACCCTGCCACCCGGTCTGGAGCCGGCCTCGTCT- GCCAGCGAACAGCCAA CTTTAGCGGGTGGCTCAGCTGGGGATT 13 SOX21 CACTCAGTGTGTGCATATGAGAGCGGAGAGACAGCGACCTGGAGGCCATGGGTGGGGGCGGGTGG- TGAAGCTGCCGAAGCCTACACAT ACACTTAGCTTTGACACTTCTCGTAGGTTCCAAAGACGAAGACACGGTGGCTTCAGGGAGACAAGTCGCAAG- GGCGACTTTTCCAAGCGG GAGATGGTGAAGTCTTTGGACGTGTAGTGGGTAGGTGATGATCCCCGCAGCCGCCTGTAGGCCCGCAGACTT- CAGAAAACAAGGGCCTT CTGTGAGCGCTGTGTCCTCCCCGGAATCCGCGGCTTAACACATTCTTTCCAGCTGCGGGGCCAGGATCTCCA- CCCCGCGCATCCGTGGA CACACTTAGGGTCGCCTTTGTTTTGCGCAGTGATTCAAGTTGGGTAACCCTTGCTCAACACTTGGGAAATGG- GGAGAATCTCCCCCACCC GCAACCTCCCGCACCCCAGGTTCCCAAAATCTGAATCTGTATCCTAGAGTGGAGGCAGCGTCTAGAAAGCAA- AGAAACGGTGTCCAAAGA CCCCGGAGAGTTGAGTGAGCGCAGATCCGTGACGCCTGCGGTACGCTAGGGCATCCAGGCTAGGGTGTGTGT- GTGCGGGTCGGGGGG CGCACAGAGACCGCGCTGGTTTAGGTGGACCCGCAGTCCCGCCCGCATCTGGAACGAGCTGCTTCGCAGTTC- CGGCTCCCGGCGCCCC AGAGAAGTTCGGGGAGCGGTGAGCCTAGCCGCCGCGCGCTCATGTTTATT 14 ZIC2 AGTCACTCCAGGATCAGAGGCCGCGTCGGTTCTGCTTGGGGCATGGGCAGAGGGAGGCTGCTGGGG- CCAAGCCCCGGCTGGACGCGA GGGAAGAAACTCGTCCCAGGACCCGCACGCCCATACCTGGCTGTCCCAGAGCTCTTCCCTAGGCCGGCACCT- TCGCTCTTCCTCTTCCC CACCCCCTAGCCCTTTTGTCTCTTTTTCAGACGGATGTTTTCAGTCTCAAGTGGTTTTATTTTCCGCACAAA- ACCCTGAGATCAAGGGCAGA TCACAGACTGTACCGGAGGCTCGGGTTTCCCTGGACTCTGTGCTGTTCTGCGTCCCAGGGTTGGCTAGGAAG- GAAGGCCTGGGCCGGC GAGGTGACGGGTCTCCCGCCCAGGTCGGCAGGACGGGGGGAGGTGTGTCCCGGTAGGTCCCTGGTGAGCTCA- CCCGTGGCATCGGGG ACCCGCGGGAACCCACCGGGCGCCCACTAGAGACTCGGGTCCTACCCTCCCCCACACTACTCCACCGAAATG- ATCGGAAGGGCGCGCT AGGCCTGCTTCCAAGGGCTCAGTGATAAAGGCCTCAAAATCACACTCCATCAAGACTTGGTTGAAGCTTTGG- GTAGGTTTGTTGTTGTTGT TGTTGTTGTTTGTTTGTTTGTTTTAGCAGACACGTCCTGGAAAGAGGTCCTCAGAACCCAAAGGTTCAATAA- TGATTTGTGGATGGATTGAT TATAGTCTGATATCGCTCTGGTTCCACAGAAACCCGGAGCTCCTTGGCCCACTGTTACCCCAGCAGACCTAA- ATGGACGGTTTCTGTTTTT CACTGGCAGCTCAGAACTGGACCGGAAGAAGTTCCCCTCCACTTCCCCCCTCCCGACACCAGATCATTGCTG- GGTTTTTATTTTCGGGGG AAAAACAACAACAACAACAACAAAAAAAACACTAGGTCCTTCCAGACTGGATCAGGTGATCGGGCAAAAACC- CTCAGGCTAGTCCGGCTG GGTGCCCGAGCATGAAAAGGCCTCCGTGGCCGTTTGAACAGGGTGTTGCAAATGAGAACTTTTGTAAGCCAT- AACCAGGGCATCCTGAG GGTCTGAGTTCACGGTCAAGGCTGTGGGCTACTAGGTCCAGCGAGTCCAGGCCTCGCCCCGCCCCCGAGCTG- CCACAGCCAAGATCTTC GGCAGGGAATTCGAGACCAGGGTCCTCCCACTCCT 15 chr13 TTTCGTGCCGCTGTTTTCAATGCGCTAACGAGGCACGTTATTCTTAGCCGCGTCCGGGAGGGGAT- CACATTCCTGCGCAGTTGCGCTGCT group- GGCGGAAGTGACTTGTTTTCTAACGACCCTCGTGACAGCCAGAGAATGTCCGTTTCTCGGAGCGCA- GCACAGCCTGTCCCATCGAGAAG 00385 CCTCGGGTGAGGGGCCCGGTGGGCGCCCGGAGGCCGCTGGAGGGCTGTGGGAGGGACGGTGGCTCCC-

CACTCCCGTGGCGAAGGGC AGGCAAACCAGAAGCCTCTTTTGAGAGCCGTTTGGGATTGAGACGAGTAAGCCACAGCGAGTGGTTAGAAGT- AGGTTAGGAAGAAGGGG AGGTAAGAAAGCCGAGTAGGGTT 16 chr13 GTTCGGTGGACAAGGGGGCAGCGCCCACAGCAAGCCGGAAAGAGGGAGGCGCGGGGCCGCGCTTG- GGGCCTGCCGCTGCACGCCAG group- CCTGGGCAAAGAGCTGCCACCTTCTGCGGGCGAAGCGGGTCGGGACGCAGGACGGCAGCGGGGCTG- GAGGCAGCTACGTGGGTCCAC 00390 ACCCCCATGCCCTGCAAGGCTCCTTGGCCCTGCTTCTCCTCTGTCTCGGCGGGAGAGGAGCAGCCTC- GGTTTTACAGAATTTC 17 chr13 TGTGCCATTTAGTGAGAGGTGTTTTGGGCAAAGAATCAATTTAACTGTGACTGACCGACGGGCTT- GACTGTATTAATTCTGCTACCGAAAA group- AAAAAAAAAAAAAAAAGCAATGAGCCGCAAGCCTTGGACTCGCAGAGCTGCCGGTGCCCGTCCGAG- AGCCCCACCAGCGCGGCTCACGC 00391 CTCAGTCTC 18 chr13 AGAGTCCCAGTTCTGCAGGCCGCTCCAGGGCTAGGGGTAGAGATGGTGGCAGGTGGTGCGTCAAC- TCTCTAGGGAAGAGGAACTTGCAT group- TACAAAGACTTGTCTTTCTGAGCTGAAGTCAAAACGGGGGCGTCAAGCGCGCTCCGTTTGGCGGCG- GTGGAGGGGCCGCGCGCCCGCG 00395 CTGTCCCAGCCGGAGCTGCCCTGGCTGGTGATTGGAGGTTTAACGTCCGGAATTCAGGCGCTTCTGC- AGCTCAGATTTGCCGGCCAAGG GGCCTCAGTTGCAACTTTTCAAAATGGTGTTTCTGGAAAATAACAAATTCAGACTCAACTGGTGACAGCTTT- TGGCTATAGAGAATGAAACT GCTTCCCTTTGGCGGTGGAACTCTTAAACTTCGAAGAGTGAAAGAATACAATGAAATAAAATGCCATAAGAT- CACTGGATTTTTCAGAAAAA GGAAGACCCCAAATTACTCCCAAAATGAGGCTTTGTAAATTCTTGTTAAAAATCTTTAAATCTCGAATTTCC- CCCTACAACATCTGATGAGTG CTTTAAGAGCAAACGAGCAAATCCCACCTCGAGAATCAACAAACCCAAGCTCTGGCCAAGGCTCTCCCCGCG- TTTTCTTCTCGTGACCTG GGGAATGTCCCGCCCCATCGCTCACCTGGCTCTTGTCATCTCGCTCATCTTGAAGTGACCCGTGGACAATGC- TG 19 chr13 AGCTGCCCTCTGTGGCCATGAGCGGGTGTCCAGCCCCTTCCAAGGCTGCACCGGGGAGACGCTGG- TTTTCTGCTCGCTGTGACCGAACA group- AAGCCCCTAAGAGTCAGTGCGCGGAACAGAAGAGCCGGACCCCGACGGGCCGAGTCCCAACGTGAG- GCACCCGGCAGAGAAAACACGT 00399 TCACG 20 PROZ CCTCGGCAGCACCGGCATGGCTGGAGGCCAGTACGGCCAGGTGTGGCGGGAGGGAGCGCCGTCTGG- CTTGGGTCGTCCATCCTGACA GGACGCTGCAAGGGCAGGAGCCCCGCGCCCCGTGTCCTGCGCCCCCGCTCGAGGACAAGCCCCAGCCGCCGG- TCTCCGCTGGGTTCC GACAG 21 CIDEA CTTTAAGAGGCTGTGCAGGCAGACAGACCTCCAGGCCCGCTAGGGGATCCGCGCCATGGAGGCCG- CCCGGGACTATGCAGGAGCCCTC ATCAGGCGAGTGCCCCGCGTCCCCCTGATTGCCGTGCGCTTCCAATCGCCTTGCGTTCGGTGGCCTCATATT- CCCCTGTGCGCCTCTAGT ACCGTACCCCGCTCCCTTCAGCCCCCTGCTCCCCGCATTCTCTTGCGCTCCGCGACCCCGCGCACACACCCA- TCCGCCCCACTGGTGCC CAAGCCGTCCAGCCGCGCCCGCGGGCAGAGCCCAATCCCGTCCCGCGCCTCCTCACCCTCTTGCAGCTGGGC- ACAGGTACCAGGTGTG GCTCTTGCGAGGTG 22 chr18 AGACTTGCAGAACTCGGGCCCCCTGGAGGAGACCTAACCGCCACGGTCTTGGGGAGGTTCCGGAG- GGCCTCGGTTGTCTGCACTCCCA group- ACACCAAGAAACCCCTGAGACGCGAAGCTGCCAGCGTGCTGCCCTCAGAGCAGGGCGACGCAAAGC- CAGCGGACCCCGGGGTGGCGG 00091 G 23 chr18 TGCTCGGCTGGGGGGCTCGCTCCGCACTTTCGGTGCCAGAAAATGCCCAGAGGAGCGGGGCGGCC- CCAGAGCCTCCTTTCGGGGCGC group- GAGGCCCGGCGCGTGTGTACGGAGTCCAGTCCCCCCAGGGAGTGGGGTGCCCGCACCTTCCCCTCC- GCGCTCGGAGCCAC 00094 24 KLHL14 TCTTGCACACCTGCTTGTAGTTCTGCACCGAGATCTGGTCGTTGAGGAACTGCACGCAGAGCTT- GGTGACCTGGGGGATGTGCAGGATCT TGCTGACCGACAGCACCTCCTCCACCGTGTCCAGGGACAGGGTCACGTTGGCCGTGTAGAGGTACTCGAGCA- CCAGGCGCAGCCCGAT GGACGAGCAGCCCTGCAGCACCAGGTTGTTGATGGCCCGGGGGCTGGTCAGCAGCTTGTCGTCGGGGGAGGA- AGAAGGAGTCCCGGG CTCCTCCTGCGGCGGCGGCTGCTGCTGCTGTGACGGCTGCTGCTGCGGCGGCTGCTGCTGGTCCTTGGGGGC- CCCCAGGCCGTCCTG GCCGCCGACCCCTCCCCCGAGAGGGGGGTGGCTGGAGAAGAGCGATCGGAAGTACTGCGAGCAGGAGGCCAG- CACGGCCTTGTGGCA ATGGAACTGCTGGCCCTGGGCCGTCAGGGTCACGTCGCAAAACAGCTGCTTCCTCCACAGCAGGTTGAGGCC- GTGCAGCAGGTTGTCGC TGTGGCTGGGGTCGAAGGTGGAGGTCCTGTCCCCGGATCTGGACATGGCGAGCTGACTCGGTGCACCTGGCT- TTAAACCCTCCTCCAAC CTGGCAGACAGGGGTGGGGGATGGGAGGGAGGGGAGCAGGGTGGTGGAGCGGGTGGGGTGTGGTCGGGGTGG- GGAAGGGTGTGGA GGGGAGGGGAGGGCGAAGAACAAGAATCAAGGCTCAGCTTGACTCCCTCCTGGCGCGCTCCGGACCCCGACC- CTAGGAGGAAAGTCCG AAGACGCTGGATCCGTGAGCGCCACCAGAAGGGCCCTGTCTGGGGTCCCGGCGCCGGTTCTGCGCCCTGCGG- CTCCTCTCGCCACCTC CCACACACTTCGTCCCTCACTTTCCTAAAACCAACCACCTCAGCTCGGCTGTTGGCAGCAACAGCAGTGGCA- GCAGCGACGGCAAAGTG GCGGCTGAGGCCGAGGCACCTCGTGGGCTCGTGTCCATGCCGGGCCAGATGAAGGGAAAGGCCGGGAAGTGG- GGAGCCGGGGGTGC CCTGAAAGCTCAGAGGCGACCGACGGCGAAGGTTCCAGGTCAACTTGTGCCCGAAGCTTTGCTTTTCGCAGT- TGGCCCAGTTTGGGGGA GGGGGTAGGAACAGGGGCCCGACCAGCGTGCGGGGTGTGCGAATCTTAGCTCTCCAAAAGCTG 25 ST8SIA CCTCTGTGTTAGTGCCCTCGGGAATTTGGTTGATGGGGTGTTTG 3 26 ONECU TGATGTCGCACCTGAACGGCCTGCACCACCCGGGCCACACTCAGTCTCACGGGCCGGTGCTGGCA- CCCAGTCGCGAGCGGCCACCCTC T2 GTCCTCATCGGGCTCGCAGGTGGCCACGTCGGGCCAGCTGGAAGAAATCAACACCAAAGAGGTGGCCCAG- CGCATCACAGCGGAGCTG AAGCGCTACAGTATCCCCCAGGCGATCTTTGCGCAGAGGGTGCTGTGCCGGTCTCAGGGGACTCTCTCCGAC- CTGCTCCGGAATCCAAA ACCGTGGAGTAAACTCAAATCTGGCAGGGAGACCTTCCGCAGGATGTGGAAGTGGCTTCAGGAGCCCGAGTT- CCAGCGCATGTCCGCCT TACGCCTGGCAGGTAAGGCCGGGGCTAGCCAGGGGCCAGGCTGCTGGGAAGAGGGCTCCGGGTCCGGTGCTT- GTGGCCCAAGTCTGCGC GCCGAGTCACTTCTCTTGATTCTTTCCTTCTCTTTCCTATACACGTCCTCTTTCTTCTCGTTTTTATTTCTT- CTTCCATTTTCTCTTTCTCTT CCGCTCTTCCCCTACTTTCCCTTCTCCCTTTTCTTTTTCTTTCTTACTCTCTCCTTGTCCCTGAGCTTTCAT- TGACCGACCCCCCCCCATTTC ATTCGCCCTCCCCTCAATGTGCCAACCTTTGCCCTATTTCCGATCTTCCCAGGTACTGGGAGGCGGGATGGG- GGTGTGCGTTTTCCTCTA GGAGCCCTGTCTTTCCAAGACCCACAGAAACCAGGACCTGCCCTTATTCAAAACCCCATGCACTTCAAGTCT- CTTTTAGACAACACATTTC AATTTTCCGGGCTGACTAGTCTCCCTGTGCAGAGGCAGTTGAGAGGCTTTGCTCTGCAGAGGGAAAAGAGCT- CTCTACTCTCCCACCCAC CATATAGGCAAACTTATTTGGTCATTGGCTGAAGGCACAGCCTTGCCCCCGCGGGGAACCGGCGGCCAGGAT- ACAACAGCGCTCCTGGA GCCCATCTCTGGCCTTGGCGTTGGCGCAGGGACTTTCTGACCGGGCTTGAGGGGCTCGGGCCAGCTCCAATG- TCACTACCTACAGCGAG GGCAGGGTGTAAGGTTGAGAAGGTCACATTCACCGCTTTGGGAGGACGTGGGAGAAGAGACTGAGGTGGAAA- GCGCTTTGCCTTGCTCA CCGGCCGTCCTTGCCCCGGTCCCAGCGTTTGCTGGGATTTGCCAGGATTTGCCGGGGCTCCGGGAGACCCTG- AGCACTCGCAGGAAGA GGTGCTGAGAAATTAAAAATTCAGGTTAGTTAATGCATCCCTGCCGCCGGCTGCAGGCTCCGCCTTTGCATT- AAGCGGGCGCTGATTGTG CGCGCCTGGCGACCGCGGGGAGGACTGGCGGCCCGCGGGAGGGGACGGGTAGAGGCGCGGGTTACATTGTTC- TGGAGCCGGCTCGG CTCTTTGTGCCTCCTCTAGCGGCCAAGCTGCGAGGTACAGCCCTCTATTGTTCTAGGAGCACAGAAACCTCC- TGTGTGGGCGGCGGGTG CGCGAGCTAGAGGGAAAGATGCAGTAGTTACTGCGACTGGCACGCAGTTGCGCGCTTTTGTGCGCACGGACC- CCGCGCGGTGTGCGTG GCGACTGCGCTGCCCCTAGGAGCAAGCCACGGGCCCAGAGGGGCAAAATGTCCAGGTCCCCCGCTGGGAAGG- ACACACTATACCCTAT GGCAAGCCAGGGTGGGCGACTTCCCATGGATCGGGTGGAGGGGGGTATCTTTCAGGATCGGCGGGCGGTCTA- GGGGAACAATTCGTGG TGGCGATGATTTGCATAGCGCGGGTCTTGGGATGCGCGCGGTTCCGAGCCAGCCTCGCACAGCTCGCTTCCG- GAGCTGCGAGCTCAGG TTTCCACCCCCGATCCCCCGGGCTTTCCTCGCACCGCTGAGCCCAGCTTGTGGGGTGCACTCGACCAACGCC- CGACAGGGCTGGGGAA TGTGACAGGCAGCAGGTTCACCCGGGCTTGGGGAGGGGGAGTTTCCGCTTTGACAGCATTTTCCTTTGCCGT- CTGCTGGTGGATTCCTAT TCCCAGTCGGTAATCGCCCCGCAGTGTTGATCTAAGAAGGTAAAGAAAACTAGGTTTCCCTGCAAAGAGCCT- CCCCCAAATCGGCGGACTCC GGATACTTTGAGTGGATTTAGAAATTTATGTAATCTTTCTCCTTTAGTTTATTTTTCATCCTCTCCTACAGT- TTTCTCTGATTTGCTGTTGG TTCGGGGCAAGATAAAGCAGCCAGTAGAGAGCGATAATAATAGCGGCGGGAAATGAACTGGAGACTGGCTGA- CAGTTCTTAACATTTTGT CATAGATCCCCCCGAATGTCCCAGGCTGTCTCTGGTGGGTTTTAGTACCCGCCGGCTTCTTGGGCACCGGGG- ACCAGAAGGAACTTGGC AGCTGGTCTTAGGGGTACAGTTAAAGGCAGGATGACAGCTATTCTCCTGCTCATCTCAGAGCGCTGCCGCCC- CCTCATGCCGGTCGCGC AAAGAACACAGCTTTTAAAAAACACGTGCCTTCTGCCCATATAGGTCTGAAAGTGATGAGGAAAGTAATGCT- TCGCCTATTAGCGAGTTTCA GCTTTTAAAATGATCCCAAGCGTTGCTGAGATGAGAAAGCGTGGCATCCCGGGGGTCCTCAGCCCCACCCGC- GCCCATGGTGCAAGTCT GCAGGGACAGGCCCGGGACAGCACTGCCCACGCTGCTAGATTTTCCGCAGAGGATCGCTGAAGCTGCCTTCG- TGGGAGACAGAATGCC TCCTCCAGCGAGTGGAAAAGGCCTGCTGAGGACCCCGCTTTGCTCGAGCATTCAAATGTGTGTCTGTTTTAT- TACCCTGGGTTGAAAAGG GACAAGAGCTTTAGCCTTTTTATCTGGCCATTTTATCAGCAACTACAAGTGTGTTGAGTGGTTATTATTACA- TAGGAGGCTTTTCAGTTTGG GGTCAGTAGATCAGTCTCTTCAGACACTGATGCAGAAGCTGGGACTGGTAAGTAGGTATTATGTGCTCGGAG- CGCTAGGGGACAGGAGC AAATGGAGAAGAAAAGCGGAGGCTTTCTCCGCCCGGAGTATCGATCGGAATCCCCGCCGGTACGCCGCAGAG- GGCCCTCGCCGTTGGG CCCCGGGGGTTTAACAAGCCCAGCCGCTCCGCAGGCGGCTCGGCCGGACTCTCAGACCGGTGCCTGGAAGAC- ACCGTCCCTGCCCCCC TCCCGCCAAACCTGCCTCTTCTCTTTCTCTCATAGGTTATAGGTTCCCTTTCTCTCTCATTTTGGCCCCGCC- CCCGGGTCCTGCCAAACAG CCAAGCAGGCCGGGGTTTAGGGGGCTCAGAATGAAGAGGTCTGATTTGGCCAGCGCCGGCAAAGCTCACCCT- TAGGCGAGGTCACAAC AGAGGCAGGTCCTTCCTGCCCAGCCTGCCGGTGTAGTCACAGCCAAGGGTGGCACTTGAAAGGAAAAGGGAG- AAAACTTCGGAGAAATT TAGATTGCCCCAACGTTAGATTTCAGAGAAATTGACTCCAAATGCACGGATTCGTTCGGAAAGGGCGGCTAA- GTGGCAGGTGGTTGCAAC CCCGCCCGGTCGGGCCTTCGCAGAGGTTCCCCAAGACCAGCCCTTGCAGGGCGGTTTTCAGCAACCTGACAA- GAGGCGGCCAAGACAA ATTTCTGCGGGTTCGAGCACACACTCTCGGGCGTTGGGCCCCAGAGACCTCTAAACCAAGCACAAACAAGAA- GGGAGTGAGAGAACCCA GGCTAGAACTTGCACGGGCATCCCACTGAGGAAAAGCGAGGCCTCGGTGGCAGGCATGTTTTCTTCCGACGC- CCGAAAATCGAGCCGAG CGCCCGACTACATTTACTGCAGAGGTTTCCGCCTCCAGTGAGCCCGGATCCCCCAGCGGCCTGCCCGGAGCT- GGTCTCCAGTCCCCGCC GTAGTCCGACGCACGGCCCTCTCCTGGCAGCAAGCTCCCAGCGGCCAGTCTGAAGCCAATTCTGTTCAGGCG- GCCGAGGGCCCTTAGC CAACCCACCATGATGTCGCCTGGGCCACCTGATGCCCGCAGCGGCGGGACACGGCCCGGGCAGTGCGCAGTG- GCTCCTGCTAGGGGC ACCGCGTGCGTGCTTGTCTCCCGCTGCGCCGGGGACGTCCTTGGGTGACACGGGCCGCTGGGCACCTCCCAA- GCCGAGGAAACGGAC CCCCTTCGCAGAGTCTCGCGCCCACCCCCCAACCTCCCACCTCGTTTCTCGCTGCTAGGGCTCCCGACTCAG- CCCACCTCTCCTGGCGG TTTAGTTAGGGATCAGAGCTGGAGAGGCTGAACGCAACCCGTGCCAGTACGGAACAGACGATATGTTTGCCT- GCTAGCTGCTTGGATGAA TAATTGAAAAGTTCGCTGCAGTCTGTGCTTCGTCAAGTCCCGGGTGCCGGGAGAACACCTTCCCAACACGCA- TCAGGGTGGGCGGGAGC GGGCAGAGGAGGCGGGACCCGAGGGAGGAGAGTGAACCCGAGCAGGAGAAGCAGCCCAGGCAGCCAGGCGCC- CTCGATGCGAGAGG CTGGGCATTTATTTTTATTCCAGGCTTTCCACTGTGTGGTTATGTCACTTTCTCAAACAAATGTGTATATGG- AGGGAGATCGATGCTGATAA TGTTTAGAAGATTAAAAGAGCATTAATGCTGGCAACAATAACGTAAACGTGTGGACCCAGATTTCATTGATC- TGGAACTTGATCCGGCGCG TTTCCAGTAAGCCCGACGGCGCGCTCTTCCCAGCAGAGCGCTCACCAGCGCCACGGCCCCGCGGTTTTCCAG- CGGTGCCGCTTCGCCA GCTCTGCGCGGGTTCTCCCGTCTGACCGCAGCTCCTCCCCCGCGAGGCCCCAGCCCGCCTTACTTCCCCGAG- GTTTTCTCCTCCTCTCG CGGGGCTCTCTGCCCTCTGCACCCCCTCCCCCGACCTCTGCACCACCCGCCCCTGTGCGCACACACCGCTAC- TTGCGCTTCCGGCGATC CGCCTG 27 RAX AACCGGAGATCTGCTTGGTGAACTGAGAGGAGTCCTTAGGAGAGCGGGGACGCCAGGGGCCGGGGGA- CACTTCGCTCTCGCCCTAGGG AAGGTGGTCTTGACGCTTTCTATTGAAGTCAAACTTGAAAATATCAGCTGCCGCTGGACTAT 28 chr18 CGTGAGCAGAACGCCCGCCCTGGAGCAGTTAGGACCGAAGGTCTCCGGAGAGTCGCCGGCGGTGC- CAGGTAACGCAGAGGGCTCGGG group- TCGGGCCCCGCTTCTGGGGCTTGGGACTCCGGGCGCGCGGAGCCAGCCCTCTGGGGCGAAATCCCC- GGGCGGCGTGCGCGGTCCCTC 00277 TCCGCGCTGTGCTCTCCCAGCAACTCCCTGCCACCTCGACGAGCCTACCGGCCGCTCCGAGTTCGAC- TTCCTCGGACTTAGTGGGAGAA GGGGTTGGAAATGGGCTGCCGGGACTGGGGGAGCTGCTCTCTGGAAGCAGGGAAGCTGGGGCGCACCGGGGC- AGGT 29 NETO1 TAGAAGAGGAAGACTCCTCTGGCCCCACTAGGTATCATCCGCGCTCTCCCGCTTTCCACCTGCGC- CCTCGCTTGGGCCAATCTCTGCCGC ACGTGTCCATCCCTGAACTGCACGCTATCCTCCACCCCCGGGGGGTTCCTGCGCACTGAAAGACCGTTCTCC- GGCAGGTTTTGGGATCC GGCGACGGCTGACCGCGCGCCGCCCCCACGCCCGGTTCCACGATGCTGCAATACAGAAAGTTTACGTCGGCC- CCGACCCGCGCGGGAC TGCAGGGTCCGCCGGAGCGCGGCGCAGAGGCTTTTCCTGCGCGTTCGGCCCCGGGAAAGGGGCGGGAGGGCT- GGCTCCGGGAGCGC ACGGGCGCGGCGGGGAGGGTACTCACTGTGAAGCACGCTGCGCCCATGGATCATGTCTGTGCGTTACACCAG- AGGCTCCGGGCTCCAC TAATTCCATTTAGAGACGGGAAGACTTCCAGTGGCGGGGGGAGGACAGGGTCGAGAGGTGTTAAAGACGCAA- AGCAAGAAGGAAATAAA GGGGGGCCGAGAGGGAGACCGAGAGGAAGGGGGAGCTCCGAGCCCACGCTGCAGCCAGATCCGGATGAGTCC- GTCCTCCGCCCCGG GCGGGCTCTCGCTCTCGCTGGCCCTCAGCGCCGCGCAGCCAGCAGCATCCCCACCGTGACGCTCGCATCACA- CCCGGGCGCCGGCCG CCACCATCCGCGCCGCCGCCGTCAGGACCCTCCTCCCGGGCATCGTCGCCGCCGCGGGGTCGGGAGGACGCG- GCGCGCGGGAGGCG GCGGTCGCAGGGCGAGCCCCGGGACGCCCCGAGCCGGGGCCGGGGCCGGGGAGAGGGCGCAGCGAGGTGGGG- GCCAGTCCAGACC GACGGCAGCGACGGAGCGGGCGGCGGCGGCGGCGCCGGCGGCGGCGGGGTGGCTCAGTCCCCAGTCTCAGAC- GCGCCGCGCAGCA GGTCGGAGCAGCCTCCCCGGGAGGATGTCCAGCGGCAGCGCTCCTCGCTCCAGCCCTTGGGGATCTTCCGCT- GAGGCATTGAAGGCAG

GAAGAAGGGGTCCGTCATCGGCTCGCCGGGCTGCGCGCCACCTCTGCTATCTTGCGGAAAGAGGAGCGGGTG- GGTGGGCGTCTGGGA GGCGGGCTGGAGGGCGGTGCAGGGGAGCGGGGCGGCCGGGGGGGGGGCCGGGGGGCGGGGAAGGGAGGGAGG- AGAAAGGAGCCG GAAGAGGGCAGAGTTACCAAATGGGCTCCTTAGTCATGGCTTGGGGCTCCACGACCCTCCTGGAAGCCCGGA- GCCTGGGTGGGATAGC GAGGCTGCGCGCGGCCGGCGCCCCGGGGCTGGTGCGCGGCAGAATGGGGCCGCGGCGGCGGCAGCAAGGACA- TCCCAGCCGCGCG GATCTGGGGGAGGGGCGGGGAGGGGGTGAGGACCCGGCTGGGATCCGCGGCTCGGCCCGCCAGGGCGCAGAG- AGAGGATGCAGCCG CAAATCCCGAGCCGGATCCTCGTGCCGGACGGAAGGCGTGGAAGCGGGAGGGGCCTTCGTGTGAAAATCCCT- TGTGGGGTTTGGTGTTT CACTTTTTAAAGGTTAGACCTTGCGGGCTCTCTGCCTCCCACCCCTTCTTTTCCATCCGCGTAAAGGAACTG- GGCGCCCCCTCTCCCTCCC TCCCTGGGGCGCAGGTTTCGCCGCGGACTCCGCGCTCAGCTTGGGAGACACGGCAGGGGCGCGCCCCAGGGA- AAGGCGGCCGTAAAA GTTTCGCGGTTGAGCACTGGGCCTGATGTCCAGTCCCCCCACCAAATTACTCCTGCAAAGACGCGGGCTTCT- TGCAATTGAGCCCCCCAC CTCGAGGTATTTAAAACCACCCCAAGGCACACACGGACCCCCGTTCCCCCGCGCCACTTCCTCCTACAGGCT- CGCGCGGCGCGTTAAAG TCTGGGAGACACGAGTTGCGGGGAAACAGCACCGGAAG 30 MBP AAGAAACAGCTCATTTCGGAGCTGAGGACAAGGCGTGGGAAGAAGACGCGTTTGGTTTCACCCAGGC- GGGTGGCGGCAAAGCTGTGGG ATGCGCGCTGCACACTCCTTCCGTCATCCCGTTCCCACCTTCCACACACACCTGCGGGAGGTCGGACATGTC- CTGATTGCGTGTTCATCA CGATGGCAAACCGAACATGAGGAGAACGCCACTGACGCTGGGTGCGCCGGCTTTCCCAGCCCTCGTGCATAA- CGGGGAGGGAGATGCA GAAGTTTTTTCCAACATCGGTGCAAAGGGGAAGCTGAGGTTTTCCTAT 31 NFATC TCTGTCAGCTGCTGCCATGGGGCAGCGGGAAGGCCCTGGAGGGTGCCTGGGCTGTGTCTGGTCCC- GGCCACGCGTCCCTGCAGCGTCT 1 GAGACCTTGTGGAACACACTTGACCCGGCGCTGGGACGGGGTCGGCCCACACGCACCGCCAGCCCGCAGGA- GTGAGGTGCAGGCTGC CGCTGGCTCCTTAGGCCTCGACAGCTCTCTTGAGGTCGGCCCTCCTCCCCTCCCGAGAGCTCAGCAGCCGCA- GACCCAGGCAGAGAGA GCAAAGGAGGCTGTGGTGGCCCCCGACGGGAACCTGGGTGGCCGGGGGACACACCGAGGAACTTTCCGCCCC- CCGACGGGCTCTCCC ACCGAGGCTCAGGTGCTCGTGGGCAGCAAGGGGAAGCCCCATGGCCATGCCGCTTCCCTTTCACCCTCAGCG- ACGCGCCCTCCTGTGC CCGCGGGGAACAAGACGGCTCTCGGCGGCCATGCAGGCGGCCTGTCCCACGAACACGATGGAGACCTCAGAC- GCCGTCCCCACCCTGT CACTGTCACCATCACCCATCCTGTCCCCTCACGCCTCCCCACATCCCATCATTACTAC 32 chr18 GAAGTAGAATCACAGTAAATGAGGAGTTAGGGAATTTAGGGTAGAGATTAAAGTAATGAACAGAG- GAGGAGGCCTGAGACAGCTGCAGAG group- AGACCCTGTGTTCCCTGTGAGGTGAAGCGTCTGCTGTCAAAGCCGGTTGGCGCTGAGAAGAGGTAC- CGGGGGCAGCACCCGCCTCCTG 00430 GGAGAGGGATGGGCCTGCGGGCACCTGGGGGAACCGCACGGACACAGACGACACTATAAACGCGGGC- GAGACATCAGGGACCGGGAA ACAGAAGGACGCGCGTTTCGAGCAGCTGCCCAGTGGGCCACAAGCCCCGCCACGCCACAGCCTCTTCCCCTC- AGCACGCAGAGA 33 OLIG2 TACTCCGGCGACGGGAGGATGTTGAGGGAAGCCTGCCAGGTGAAGAAGGGGCCAGCAGCAGCACA- GAGCTTCCGACTTTGCCTTCCAG GCTCTAGACTCGCGCCATGCCAAGACGGGCCCCTCGACTTTCACCCCTGACTCCCAACTCCAGCCACTGGAC- CGAGCGCGCAAAGAACC TGAGACCGCTTGCTCTCACCGCCGCAAGTCGGTCGCAGGACAGACACCAGTGGGCAGCAACAAAAAAAGAAA- CCGGGTTCCGGGACAC GTGCCGGCGGCTGGACTAACCTCAGCGGCTGCAACCAAGGAGCGCGCACGTTGCGCCTGCTGGTGTTTATTA- GCTACACTGGCAGGCG CACAACTCCGCGCCCCGACTGGTGGCCCCACAGCGCGCACCACACATGGCCTCGCTGCTGTTGGCGGGGTAG- GCCCGAAGGAGGCATC TACAAATGCCCGAGCCCTTTCTGATCCCCACCCCCCCGCTCCCTGCGTCGTCCGAGTGACAGATTCTACTAA- TTGAACGGTTATGGGTCA TCCTTGTAACCGTTGGACGACATAACACCACGCTTCAGTTCTTCATGTTTTAAATACATATTTAACGGATGG- CTGCAGAGCCAGCTGGGAA ACACGCGGATTGAAAAATAATGCTCCAGAAGGCACGAGACTGGGGCGAAGGCGAGAGCGGGCTGGGCTTCTA- GCGGAGACCGCAGAGG GAGACATATCTCAGAACTAGGGGCAATAACGTGGGTTTCTCTTTGTATTTGTTTATTTTGTAACTTTGCTAC- TTGAAGACCAATTATTTACTA TGCTAATTTGTTTGCTTGTTTTTAAAACCGTACTTGCACAGTAAAAGTTCCCCAACAACGGAAGTAACCCGA- CGTTCCTCACACTCCCTAGG AGACTGTGTGCGTGTGTGCCCGCGCGTGCGCTCACAGTGTCAAGTGCTAGCATCCGAGATCTGCAGAAACAA- ATGTCTGAATTCGAAATG TATGGGTGTGAGAAATTCAGCTCGGGGAAGAGATTAGGGACTGGGGGAGACAGGTGGCTGCCTGTACTATAA- GGAACCGCCAACGCCAG CATCTGTAGTCCAAGCAGGGCTGCTCTGTAAAGGCTTAGCAATTTTTTCTGTAGGCTTGCTGCACACGGTCT- CTGGCTTTTCCCATCTGTA AAATGGGTGAATGCATCCGTACCTCAGCTACCTCCGTGAGGTGCTTCTCCAGTTCGGGCTTAATTCCTCATC- GTCAAGAGTTTTCAGGTTT CAGAGCCAGCCTGCAATCGGTAAAACATGTCCCAACGCGGTCGCGAGTGGTTCCATCTCGCTGTCTGGCCCA- CAGCGTGGAGAAGCCTT GCCCAGGCCTGAAACTTCTCTTTGCAGTTCCAGAAAGCAGGCGACTGGGACGGAAGGCTCTTTGCTAACCTT- TTACAGCGGAGCCCTGCT TGGACTACAGATGCCAGCGTTGCCCCTGCCCCAAGGCGTGTGGTGATCACAAAGACGACACTGAAAATACTT- ACTATCATCCGGCTCCCC TGCTAATAAATGGAGGGGTGTTTAACTACAGGCACGACCCTGCCCTTGTGCTAGCGCGGTTACCGTGCGGAA- ATAACTCGTCCCTGTACC CACACCATCCTCAACCTAAAGGAGAGTTGTGAATTCTTTCAAAACACTCTTCTGGAGTCCGTCCCCTCCCTC- CTTGCCCGCCCTCTACCCC TCAAGTCCCTGCCCCCAGCTGGGGGCGCTACCGGCTGCCGTCGGAGCTGCAGCCACGGCCATCTCCTAGACG- CGCGAGTAGAGCACCA AGATAGTGGGGACTTTGTGCCTGGGCATCGTTTACATTTGGGGCGCCAAATGCCCACGTGTTGATGAAACCA- GTGAGATGGGAACAGGC GGCGGGAAACCAGACAGAGGAAGAGCTAGGGAGGAGACCCCAGCCCCGGATCCTGGGTCGCCAGGGTTTTCC- GCGCGCATCCCAAAAG GTGCGGCTGCGTGGGGCATCAGGTTAGTTTGTTAGACTCTGCAGAGTCTCCAAACCATCCCATCCCCCAACC- TGACTCTGTGGTGGCCGT ATTTTTTACAGAAATTTGACCACGTTCCCTTTCTCCCTTGGTCCCAAGCGCGCTCAGCCCTCCCTCCATCCC- CCTTGAGCCGCCCTTCTCC TCCCCCTCGCCTCCTCGGGTCCCTCCTCCAGTCCCTCCCCAAGAATCTCCCGGCCACGGGCGCCCATTGGTT- GTGCGCAGGGAGGAGG CGTGTGCCCGGCCTGGCGAGTTTCATTGAGCGGAATTAGCCCGGATGACATCAGCTTCCCAGCCCCCCGGCG- GGCCCAGCTCATTGGC GAGGCAGCCCCTCCAGGACACGCACATTGTTCCCCGCCCCCGCCCCCGCCACCGCTGCCGCCGTCGCCGCTG- CCACCGGGCTATAAAA ACCGGCCGAGCCCCTAAAGGTGCGGATGCTTATTATAGATCGACGCGACACCAGCGCCCGGTGCCAGGTTCT- CCCCTGAGGCTTTTCGG AGCGAGCTCCTCAAATCGCATCCAGAGTAAGTGTCCCCGCCCCACAGCAGCCGCAGCCTAGATCCCAGGGAC- AGACTCTCCTCAACTCG GCTGTGACCCAGAATGCTCCGATACAGGGGGTCTGGATCCCTACTCTGCGGGCCATTTCTCCAGAGCGACTT- TGCTCTTCTGTCCTCCCC ACACTCACCGCTGCATCTCCCTCACCAAAAGCGAGAAGTCGGAGCGACAACAGCTCTTTCTGCCCAAGCCCC- AGTCAGCTGGTGAGCTC CCCGTGGTCTCCAGATGCAGCACATGGACTCTGGGCCCCGCGCCGGCTCTGGGTGCATGTGCGTGTGCGTGT- GTTTGCTGCGTGGTGT CGATGGAGATAAGGTGGATCCGTTTGAGGAACCAAATCATTAGTTCTCTATCTAGATCTCCATTCTCCCCAA- AGAAAGGCCCTCACTTCCC ACTCGTTTATTCCAGCCCGGGGGCTCAGTTTTCCCACACCTAACTGAAAGCCCGAAGCCTCTAGAATGCCAC- CCGCACCCCGAGGGTCAC CAACGCTCCCTGAAATAACCTGTTGCATGAGAGCAGAGGGGAGATAGAGAGAGCTTAATTATAGGTACCCGC- GTGCAGCTAAAAGGAGG GCCAGAGATAGTAGCGAGGGGGACGAGGAGCCACGGGCCACCTGTGCCGGGACCCCGCGCTGTGGTACTGCG- GTGCAGGCGGGAGCAGC TTTTCTGTCTCTCACTGACTCACTCTCTCTCTCTCTCCCTCTCTCTCTCTCTCATTCTCTCTCTTTTCTCCT- CCTCTCCTGGAAGTTTTCG GGTCCGAGGGAAGGAGGACCCTGCGAAAGCTGCGACGACTATCTTCCCCTGGGGCCATGGACTCGGACGCCA- GCCTGGTGTCCAGCCG CCCGTCGTCGCCAGAGCCCGATGACCTTTTTCTGCCGGCCCGGAGTAAGGGCAGCAGCGGCAGCGCCTTCAC- TGGGGGCACCGTGTCC TCGTCCACCCCGAGTGACTGCCC 34 SIM2 TTAATTCGAAAATGGCAGACAGAGCTGAGCGCTGCCGTTCTTTTCAGGATTGAAAATGTGCCAGTG- GGCCAGGGGCGCTGGGACCCGCG GTGCGGAAGACTCGGAACAGGAAGAAATAGTGGCGCGCTGGGTGGGCTGCCCCGCCGCCCACGCCGGTTGCC- GCTGGTGACAGTGGC TGCCCGGCCAGGCACCTCCGAGCAGCAGGTCTGAGCGTTTTTGGCGTCCCAAGCGTTCCGGGCCGCGTCTTC- CAGAGCCTCTGCTCCCA GCGGGGTCGCTGCGGCCTGGCCCGAAGGATTTGACTCTTTGCTGGGAGGCGCGCTGCTCAGGGTTCTG 35 SIM2 CCGGTCCCCAGTTTGGAAAAAGGCGCAAGAAGCGGGCTTTTCAGGGACCCCGGGGAGAACACGAGG- GCTCCGACGCGGGAGAAGGATT GAAGCGTGCAGAGGCGCCCCAAATTGCGACAATTTACTGGGATCCTTTTGTGGGGAAAGGAGGCTTAGAGGC- TCAAGCTATAGGCTGTC CTAGAGCAACTAGGCGAGAACCTGGCCCCAAACTCCCTCCTTACGCCCTGGCACAGGTTCCCGGCGACTGGT- GTTCCCAAGGGAGCCCC CTGAGCCTACCGCCCTTGCAGGGGGTCGTGCTGCGGCTTCTGGGTCATAAACGCCGAGGTCGGGGGTGGCGG- AGCTGTAGAGGCTGCC CGCGCAGAAAGCTCCAGGATCCCAATATGTG 36 DSCR6 GCGCAGGTCCCCCCAGTCCCCGAGGGAGTGCGCCCGACGGAAACGCCCCTAGCCCGCGGGCCTCG- CTTTCCTCTCCCGGGTTCCTGG GTCACTTCCCGCTGTCTC 37 DSCAM TTCCCTCGCGGCTTTGGAAAGGGGGTGCAAATGCACCCTTCTGCGGGCCCGCTACCCGCTGCAAC- ACCTGTGTTTCCTTTCTGGGCACCT TCTAGGTTTCTAGATATTGCTGTGAATACGGTCCTCCGCTGTACAGTTGAAAACAAA 38 chr21 TGGGAATTTAGGTCGGGCACTGCCGATATGTCGCCTTCCACAAGGCGGGCCCGGGCCTCTGCTGA- CCGTGCACCGGTCCTGGGGCTGG group- GTAATTCTGCAGCAGCAGCGCAGCCCATGCCGGGGAATTTGCGGGCAGAGGAGACAGTGAGGCCCG- CGTTCTGTGCGGGAACTCCCGA 00165 GCTCACAGAGCCCAAGACCACACGGCTGCATCTGCTTGGCTGACTGGGCCAGGCCCACGCGTAGTAA- CCCGGACGTCTCTCTCTCACAG TCCCCTTGCGTCTGGCCAGGGAGCTGCCAGGCTGCACCCCGCGGTGGGGATCGGGAGAGGGGCAGTGTCGCC- CATCCCCGGAAGGCT GAGCCTGGTGCAG 39 PRMT2 CGGTTTTCTCCTGGAGGACTGTGTTCAGACAGATACTGGTTTCCTTATCCGCAGGTGTGCGCGGC- GCTCGCAAGTGGTCAGCATAACGCC GGGCGAATTCGGAAAGCCCGTGCGTCCGTGGACGACCCACTTGGAAGGAGTTGGGAGAAGTCCTTGTTCCCA- CGCGCGGACGCTTCCC TCCGTGTGTCCTTCGAGCCACAAAAAGCCCAGACCCTAACCCGCTCCTTTCTCCCGCCGCGTCCATGCAGAA- CTCCGCCGTTCCTGGGA GGGGAAGCCCGCGAGGCGTCGGGAGAGGCACGTCCTCCGTGAGCAAAGAGCTCCTCCGAGCGCGCGGCGGGG- ACGCTGGGCCGACA GGGGACCGCGGGGGCAGGGCGGAGAGGACCCGCCCTCGAGTCGGCCCAGCCCTAACACTCAGGAC 40 SIX2 AGGGAATCGGGCTGACCAGTCCTAAGGTCCCACGCTCCCCTGACCTCAGGGCCCAGAGCCTCGCAT- TACCCCGAGCAGTGCGTTGGTTA CTCTCCCTGGAAAGCCGCCCCCGCCGGGGCAAGTGGGAGTTGCTGCACTGCGGTCTTTGGAGGCCTAGGTCG- CCCAGAGTAGGCGGAG CCCTGTATCCCTCCTGGAGCCGGCCTGCGGTGAGGTCGGTACCCAGTACTTAGGGAGGGAGGACGCGCTTGG- TGCTCAGGGTAGGCTG GGCCGCTGCTAGCTCTTGATTTAGTCTCATGTCCGCCTTTGTGCCGGCCTCTCCGATTTGTGGGTCCTTCCA- AGAAAGAGTCCTCTAGGG CAGCTAGGGTCGTCTCTTGGGTCTGGCGAGGCGGCAGGCCTTCTTCGGACCTATCCCCAGAGGTGTAACGGA- GACTTTCTCCACTGCAG GGCGGCCTGGGGCGGGCATCTGCCAGGCGAGGGAGCTGCCCTGCCGCCGAGATTGTGGGGAAACGGCGTGGA- AGACACCCCATCGGA GGGCACCCAATCTGCCTCTGCACTCGATTCCATCCTGCAACCCAGGAGAAACCATTTCCGAGTTCCAGCCGC- AGAGGCACCCGCGGAGT TGCCAAAAGAGACTCCCGCGAGGTCGCTCGGAACCTTGACCCTGACACCTGGACGCGAGGTCTTTCAGGACC- AGTCTCGGCTCGGTAGC CTGGTCCCCGACCACCGCGACCAGGAGTTCCTTCTTCCCTTCCTGCTCACCAGCCGGCCGCCGGCAGCGGCT- CCAGGAAGGAGCACCA ACCCGCGCTGGGGGCGGAGGTTCAGGCGGCAGGAATGGAGAGGCTGATCCTCCTCTAGCCCCGGCGCATTCA- CTTAGGTGCGGGAGCC CTGAGGTTCAGCCTGACTTTC 41 SIX2 CACTACGGATCTGCCTGGACTGGTTCAGATGCGTCGTTTAAAGGGGGGGGCTGGCACTCCAGAGAG- GAGGGGGCGCTGCAGGTTAATT GATAGCCACGGAAGCACCTAGGCGCCCCATGCGCGGAGCCGGAGCCGCCAGCTCAGTCTGACCCCTGTCTTT- TCTCTCCTCTTCCCTCT CCCACCCCTCACTCCGGGAAAGCGAGGGCCGAGGTAGGGGCAGATAGATCACCAGACAGGCGGAGAAGGACA- GGAGTACAGATGGAG GGACCAGGACACAGAATGCAAAAGACTGGCAGGTGAGAAGAAGGGAGAAACAGAGGGAGAGAGAAAGGGAGA- AACAGAGCAGAGGCGG CCGCCGGCCCGGCCGCCCTGAGTCCGATTTCCCTCCTTCCCTGACCCTTCAGTTTCACTGCAAATCCACAGA- AGCAGGTTTGCGAGCTCG AATACCTTTGCTCCACTGCCACACGCAGCACCGGGACTGGGCGTCTGGAGCTTAAGTCTGGGGGTCTGAGCC- TGGGACCGGCAAATCCG CGCAGCGCATCGCGCCCAGTCTCGGAGACTGCAACCACCGCCAAGGAGTACGCGCGGCAGGAAACTTCTGCG- GCCCAATTTCTTCCCCA GCTTTGGCATCTCCGAAGGCACGTACCCGCCCTCGGCACAAGCTCTCTCGTCTTCCACTTCGACCTCGAGGT- GGAGAAAGAGGCTGGCA AGGGCTGTGCGCGTCGCTGGTGTGGGGAGGGCAGCAGGCTGCCCCTCCCCGCTTCTGCAGCGAGTTTTCCCA- GCCAGGAAAAGGGAGG GAGCTGTTTCAGGAATTTCAGTGCCTTCACCTAGCGACTGACACAAGTCGTGTGTATAGGAAG 42 SOX14 GGAGCCTGAAGTCAGAAAAGATGGGGCCTCGTTACTCACTTTCTAGCCCAGCCCCTGGCCCTGGG- TCCCGCAGAGCCGTCATCGCAGGC TCCTGCCCAGCCTCTGGGGTCGGGTGAGCAAGGTGTTCTCTTCGGAAGCGGGAAGGGCTGCGGGTCGGGGAC- GTCCCTTGGCTGCCAC CCCTGATTCTGCATCCTTTTCGCTCGAATCCCTGCGCTAGGCATCCTCCCCGATCCCCCAAAAGCCCAAGCA- CTGGGTCTGGGTTGAGGA AGGGAACGGGTGCCCAGGCCGGACAGAGGCTGAAAGGAGGCCTCAAGGTTCCTCTTTGCTACAAAGTGGAGA- AGTTGCTCTACTCTGGA GGGCAGTGGCCTTTTCCAAACTTTTCCACTTAGGTCCGTAAGAAAAGCAATTCATACACGATCAGCGCTTTC- GGTGCGAGGATGGAAAGAA ACTTC 43 TLX3 TTTTCCTGTTACAGAGCTGAGCCCACTCATGTGGTGCCAAGTAGCGACTATCTCTCGGCCACCTCC- ACCCAGAGCAATGTGGGCGCCCCC AGCGGGTGGGAGCGATTGCCGAGCGGCGCAAGGGCGTTTAACGCCTAACCCCCTCCTCCTGGGTTGCCAAGC- CGCTAGGTCGCCGTTT CCAACGTGGCTGCGCGGGACTGAAGTCCGACGACTCCTCGTCCTCAGTAGGAGACACACCTCCCACTGCCCC- CAGCCACGCGAGCTATG GGCAGAATCGGGGCAACGGTAATATCTGGATGGGGCAGGCTCCCCTGAGGCTGTGCTTAAGAAAAAAGGAAT- CTGGAGTAGCCTGAGGG GCCCCACGAGGGGGCCTCCTTTGCGATCGTCTCCCAGCCTTAGGCCAAGGCTACGGAGGCAGGCGGCCGAGT- GTTGGCGCCCAGCCC GGCCGAGGACTGGATGGAGGACGAGAAGCAGCCTGCCTCTGGGCGACAGCTGCGGACGCAGCCTCGCCGCCT- CGCCGCCTCAGCCTC GGTCCCAGCGTCTCTAAAGCCGCGCCCATTTTACAGATGCAGGGCAGGGAGACAAGAGGCATCTCCGGGGGC- CGAGTAGAATGATGGC GCGGGTTCTCCCGGCGCCCTGATTTCGAGGCTGCGCCCGGGGCCCTACATGCAGGCGGGGAGGCCTGGGCCG- AAGGCGTCTGCAAGG AGGGGCGAGTCTGCCCGGTCCGGGCAGGGAGTGAGGCCACAGTCAGTTCTCCCTAGGAGGCCGCGCAGCGGG- TAGGGTATGGGACTG

GGGGACGCAACGGGGACCTGGCCGAATCAGAGCCCTCAGCAGAGAACGCCGAAAACTCTGGGGCCGGCCGCT- CGCTTCCCGCTAGTG GGAATGGTTTCCGGTCATCCGTTCCCAGTCCAGCCCCGGGTAGGGAGCTCTGATTTGCAATGCACAGCACTT- GCGAGGTTCGAATGCCC CCGCAATTTGCAGATGGAAATACTAAGCCTAGGCCGGGCGTGGTGGCTCAAGCCTATCATCTCAGCCCTTTG- GGAGGCCAAGCCGGGAG GATTGTTTGAGCCCAAGAATTCAAAACCAGCCTGAGCAACATAGCGACCCCGTCTCTACAAAATAAAATAAA- ATAAATTATCCGGGCGTGG TGGCACGCGCCTGTGGTTCCAGCTACTCCGGAGGCTGAGGTGGGAGGATCGCTTGAGTCCGGGAGGTCGAGG- CTACAGTGAGCCGTGA TCGCACCACTGCACTCCAGCCTGGGCGACAGAGTGAGACCTTGTCTCAAAAAAGGAAAAAAAGAAAAAGAAA- GTAAGCTTCAAAGAAGCT CTGATAATAGTTCTGGGTCGTGCAGCGGTGGCGGCCCCGCGCTCTCGCCCCTAAAGCAAGCGCTCTTTGTAC- TGGGTGGAGGAGCTTTG AGTAGTGAGGGTGGAGATGCAGCTTCGGGGTGGCGCAGCCACCCTGACACTAGGCCCGGGGTCGCAGTGGGA- CAGAAGAGTCTGCCG CTCTGACTTGGGCTCTGAGTTCCAAGGGCGCCCGGCACTTCTAGCCTCCCAGGCTTGCGCGCTGGCGCCTTT- GCCATCCGTGCCGAAGT GGGGAGACCTAGCCGCGACCACCACGAGCGCAGCGGTGACACCCAGAGGTCCCACCGGGCCCCTGGGCAGGG- TAACCTTAGCCTGTC CGCTTCGGCAGCTTTGCGAAGAGTGGCGCGCAGCTAGGGCTGAGGCTCTTGCGGACCTGCGGTCGAAGCAGG- CGGCTGAGCCAGTTCG ATCGCCAAGGCCTGGGCTGCCGACAGTGGTGCGCGCTCTGTTCCGCCGCGGCCGGGCCAGGCGCTCTGGAAT- AGCGATGGGGGGACA CGGCCTCCAACTTTCTGCAGAGACCATCGGGCAGCTCCGGGCCTAAGCAGCGACCTCACCGAAGGTTCCTGG- GAACCTTTGCCAAAATC CCAGCCTCTGCCTCGGTCCAGCTAAACCGTGTGTAAACAAGTGCACCAAG 44 FOXP4 ATAAAGGACCGGGTAATTTCGCGGAATGCGGATTTTGAGACAGGCCCAGACGGCGGCGGATTCCC- TGTGTCCCCCAACTGGGGCGATCT CGTGAACACACCTGCGTCCCACCCCGATCCTAGGTTGGGGGGAAAGGGTATGGGAACCCTGAGCCCAGAGCG- CGCCCCGCTCTTTCCTT TGCTCCCCGGCTTCCCTGGCCAGCCCCCTCCCGGCTGGTTTCCTCGCTCACTCGGCGCCTGGCGTTTCGGGC- GTCTGGAGATCACCGC GTGTCTGGCACCCCAACGTCTAGTCTCCCCGCAGGTTGACCGCGGCGCCTGGAGCCGGGAATAGGGGTGGGG- AGTCCGGAGAACCAAA CCCGAGCCTGAAGTTGCCATTCGGGTGACTCCCGAGAAAGCCCGGGAGCATTTTGGCCAATGCGGGTTTTTA- CCTGAACTTCAGCATCTT CACC 45 FOXP4 AATTGGAAAACCCTGGTATTGTGCCTGTTTGGGGGAAGAAAACGTCAATAAAAATTAATTGATGA- GTTGGCAGGGCGGGCGGTGCGGGTT CGCGGCGAGGCGCAGGGTGTCATGGCAAATGTTACGGCTCAGATTAAGCGATTGTTAATTAAAAAGCGACGG- TAATTAATACTCGCTACG CCATATGGGCCCGTGAAAAGGCACAAAAGGTTTCTCCGCATGTGGGGTTCCCCTTCTCTTTTCTCCTTCCAC- AAAAGCACCCCAGCCCGT GGGTCCCCCCTTTGGCCCCAAGGTAGGTGGAACTCGTCACTTCCGGCCAGGGAGGGGATGGGGCGGTCTCCG- GCGAGTTCCAAGGGC GTCCCTCGTTGCGCACTCGCCCGCCCAGGTTCTTTGAA 46 chr7 GGGAAGCGATCGTCTCCTCTGTCAACTCGCGCCTGGGCACTTAGCCCCTCCCGTTTCAGGGCGCCG- CCTCCCCGGATGGCAAACACTAT group- AAAGTGGCGGCGAATAAGGTTCCTCCTGCTGCTCTCGGTTTAGTCCAAGATCAGCGATATCACGCG- TCCCCCGGAGCATCGCGTGCAGG 00267 AGCCATGGCGCGGGAGCTATACCACGAAGAGTTCGCCCGGGCGGGCAAGCAGGCGGGGCTGCAGGTC- TGGAGGATTGAGAAGCTGGA GCTGGTGCCCGTGCCCCAGAGCGCTCACGGCGACTTCTACGTCGGGGATGCCTACCTGGTGCTGCACACGGC- CAAGACGAGCCGAGGC TTCACCTACCACCTGCACTTCTGGCTCGGTAAGGGACGGCGGGCGGCGGGACCCCGACGCACCAAGGCCGGC- GAGGGGAGGGCGTAG GGGTCTGAGATTTGCAGGCGTGGGAGTAAAGGGGACCGCAAACTGAGCTAG 47 NPY CTCAGGGGCGGGAAGTGGCGGGTGGGAGTCACCCAAGCGTGACTGCCCGAGGCCCCTCCTGCCGCGG- CGAGGAAGCTCCATAAAAGC CCTGTCGCGACCCGCTCTCTGCACCCCATCCGCTGGCTCTCACCCCTCGGAGACGCTCGCCCGACAGCATAG- TACTTGCCGCCCAGCCA CGCCCGCGCGCCAGCCACCGTGAGTGCTACGACCCGTCTGTCTAGGGGTGGGAGCGAACGGGGCGCCCGCGA- ACTTGCTAGAGACGC AGCCTCCCGCTCTGTGGAGCCCTGGGGCCCTGGGATGATCGCGCTCCACTCCCCAGCGGACTATGCCGGCTC- CGCGCCCCGACGCGGA CCAGCCCTCTTGGCGGCTAAATTCCACTTGTTCCTCTGCTCCCCTCTGATTGTCCACGGCCCTTCTCCCGGG- CCCTTCCCGCTGGGCGGT TCTTCTGAGTTACCTTTTAGCAGATATGGAGGGAGAACCCGGGACCGCTATCCCAAGGCAGCTGGCGGTCTC- CCTGCGGGTCGCCGCCT TGAGGCCCAGGAAGCGGTGCGCGGTAGGAAGGTTTCCCCGGCAGCGCCATCGAGTGAGGAATCCCTGGAGCT- CTAGAGCCCCGCGCCC TGCCACCTCCCTGGATTCTTGGGCTCCAAATCTCTTTGGAGCAATTCTGGCCCAGGGAGCAATTCTCTTTCC- CCTTCCCCACCGCAGTCGT CACCCCGAGGTGATCTCTGCTGTCAGCGTTGATCCCCTGAAGCTAGGCAGACCAGAAGTAACAGAGAAGAAA- CTTTTCTTCCCAGACAAG AGTTTGGGCAAGAAGGGAGAAAAGTGACCCAGCAGGAAGAACTTCCAATTCGGTTTTGAATGCTAAACTGGC- GGGGCCCCCACCTTGCAC TCTCGCCGCGCGCTTCTTGGTCCCTGAGACTTCGAACGAAGTTGCGCGAAGTTTTCAGGTGGAGCAGAGGGG- CAGGTCCCGACCGGAC GGCGCCCGGAGCCCGCAAGGTGGTGCTAGCCACTCCTGGGTTCTCTCTGCGGGACTGGGACGAGAGCGGATT- GGGGGTCGCGTGTGG TAGCAGGAGGAGGAGCGCGGGGGGCAGAGGAGGGAGGTGCTGCGCGTGGGTGCTCTGAATCCCCAAGCCCGT- CCGTTGAGCCTTCTG TGCCTGCAGATGCTAGGTAACAAGCGACTGGGGCTGTCCGGACTGACCCTCGCCCTGTCCCTGCTCGTGTGC- CTGGGTGCGCTGGCCG AGGCGTACCCCTCCAAGCCGGACAACCCGGGCGAGGACGCACCAG 48 SHH TGGAGAACCTTGGGCTCTGTGGCCTCAAAGGTAGGGGTGATTTCGAGGGGCCGGCACCTCACAGGGC- AGGTTCCACCGCGGAAACGCA GTCATCGCCCAGCGACCCTGCTCCTGGCCCTCAGCCTCCCCCCAGGTTTCTTTTTCTCTTGAATCAAGCCGA- GGTGCGCCAATGGCCTTC CTTGGGTCGGATCCGGGGGGCCAGGGCCAGCTTACCTGCTTTCACCGAGCAGTGGATATGTGCCTTGGACTC- GTAGTACACCCAGTCGA AGCCGGCCTCCACCGCCAGGCGGGCCAGCATGCCGTACTTGCTGCGGTCGCGGTCAGACGTGGTGATGTCCA- CTGCGCGGCCCTCGTA GTGCAGAGACTCCTCTGAGTGGTGGCCATCTTCGTCCCAGCCCTCGGTCACCCGCAGTTTCACTCCTGGCCA- CTGGTTCATCACCGAGAT GGCCAAAGCGTTCAACTTGTCCTTACACCTCTGCGAAGACAAGGGGACCCCCACCGACGGACACGTTAGCCT- GGGCAACCGCCACCCCT CCCGGCCCCTCCATCAGCCT 49 OSR2 TCTCACGACCCATCCGTTAACCCACCGTTCCCAGGAGCTCCGAGGCGCAGCGGCGACAGAGGTTCG- CCCCGGCCTGCTAGCATTGGCAT TGCGGTTGACTGAGCTTCGCCTAACAGGCTTGGGGAGGGTGGGCTGGGCTGGGCTGGGCTGGGCTGGGTGCT- GCCCGGCTGTCCGCC TTTCGTTTTCCTGGGACCGAGGAGTCTTCCGCTCCGTATCTGCCTAGAGTCTGAATCCGACTTTCTTTCCTT- TGGGCACGCGCTCGCCAGT GGAGCACTTCTTGTTCTGGCCCCGGGCTGATCTGCACGCGGACTTGAGCAGGTGCCAAGGTGCCACGCAGTC- CCCTCACGGCTTTCGGG GGGTCTTGGAGTCGGGTGGGGAGGGAGACTTAGGTGTGGTAACCTGCGCAGGTGCCAAAGGGCAGAAGGAGC- AGCCTTGGATTATAGT CACGGTCTCTCCCTCTCTTCCCTGCCATTTTTAGGGCTTTCTCTACGTGCTGTTGTCTCACTGGGTTTTTGT- CGGAGCCCCACGCCCTCCG GCCTCTGATTCCTGGAAGAAAGGGTTGGTCCCCTCAGCACCCCCAGCATCCCGGAAAATGGGGAGCAAGGCT- CTGCCAGCGCCCATCCC GCTCCACCCGTCGCTGCAGCTCACCAATTACTCCTTCCTGCAGGCCGTGAACACCTTCCCGGCCACGGTGGA- CCACCTGCAGGGCCTGT ACGGTCTCAGCGCGGTACAGACCATGCACATGAACCACTGGACGCTGGGGTATCCCAAT 50 GLIS3 TGGTTTCCTTTCGCTTCTCGCCTCCCAAACACCTCCAGCAAGTCGGAGGGCGCGAACGCGGAGCC- AGAAACCCTTCCCCAAAGTTTCTCC CGCCAGGTACCTAATTGAATCATCCATAGGATGACAAATCAGCCAGGGCCAAGATTTCCAGACACTTGAGTG- ACTTCCCGGTCCCCGAGG TGACTTGTCAGCTCCAGTGAGTAACTTGGAACTGTCGCTCGGGGCAAGGTGTGTGTCTAGGAGAGAGCCGGC- GGCTCACTCACGCTTTC CAGAGAGCGACCCGGGCCGACTTCAAAATACACACAGGGTCATTTATAGGGACTGGAGCCGCGCGCAGGACA- ACGTCTCCGAGACTGAG ACATTTTCCAAACAGTGCTGACATTTTGTCGGGCCCCATAAAAAATGTAAACGCGAGGTGACGAACCCGGCG- GGGAGGGTTCGTGTCTGG CTGTGTCTGCGTCCTGGCGGCGTGGGAGGTTATAGTTCCAGACCTGGCGGCTGCGGATCGCCGGGCCGGTAC- CCGCGAGGAGTGTAGG TACCCTCAGCCCGACCACCTCCCGCAATCATGGGGACACCGGCTTGGATGAGACACAGGCGTGGAAAACAGC- CTTCGTGAAACTCCACA AACACGTGGAACTTGAAAAGACAACTACAGCCCCGCGTGTGCGCGAGAGACCTCACGTCACCCCATCAGTTC- CCACTTCGCCAAAGTTTC CCTTCAGTGGGGACTCCAGAGTGGTGCGCCCCATGCCCGTGCGTCCTGTAACGTGCCCTGATTGTGTACCCC- TCTGCCCGCTCTACTTG AAATGAAAACACAAAAACTGTTCCGAATTAGCGCAACTTTAAAGCCCCGTTATCTGTCTTCTACACTGGGCG- CTCTTAGGCCACTGACAGA AACATGGTTTGAACCCTAATTGTTGCTATCAGTCTCAGTCAGCGCAGGTCTCTCAGTGACCTGTGACGCCGG- GAGTTGAGGTGCGCGTAT CCTTAAACCCGCGCGAACGCCACCGGCTCAGCGTAGAAAACTATTTGTAATCCCTAGTTTGCGTCTCTGAGC- TTTAACTCCCCCACACTCT CAAGCGCCCGGTTTCTCCTCGTCTCTCGCCTGCGAGCAAAGTTCCTATGGCATCCACTTACCAGGTAACCGG- GATTTCCACAACAAAGCC CGGCGTGCGGGTCCCTTCCCCCGGCCGGCCAGCGCGAGTGACAGCGGGCGGCCGGCGCTGGCGAGGAGTAAC- TTGGGGCTCCAGCC CTTCAGAGCGCTCCGCGGGCTGTGCCTCCTTCGGAAATGAAAACCCCCATCCAAACGGGGGGACGGAGCGCG- GAAACCCGGCCCAAGT GCCGTGTGTGCGCGCGCGTCTG 51 PRMT8 GAAAGCCATCCTTACCATTCCCCTCACCCTCCGCCCTCTGATCGCCCACCCGCCGAAAGGGTTTC- TAAAAATAGCCCAGGGCTTCAAGGC CGCGCTTCTGTGAAGTGTGGAGCGAGCGGGCACGTAGCGGTCTCTGCCAGGTGGCTGGAGCCCTGGAAGCGA- GAAGGCGCTTCCTCCC TGCATTTCCACCTCACCCCACCCCCGGCTCATTTTTCTAAGAAAAAGTTTTTGCGGTTCCCTTTGCCTCCTA- CCCCCGCTGCCGCGCGGG GTCTGGGTGCAGACCCCTGCCAGGTTCCGCAGTGTGCAGCGGCGGCTGCTGCGCTCTCCCAGCCTCGGCGAG- GGTTAAAGGCGTCCGG AGCAGGCAGAGCGCCGCGCGCCAGTCTATTTTTACTTGCTTCCCCCGCCGCTCCGCGCTCCCCCTTCTCAGC- AGTTGCACATGCCAGCT CTGCTGAAGGCATCAATGAAAACAGCAGTAG 52 TBX3 ATCGAAAATGTCGACATCTTGCTAATGGTCTGCAAACTTCCGCCAATTATGACTGACCTCCCAGAC- TCGGCCCCAGGAGGCTCGTATTAGG CAGGGAGGCCGCCGTAATTCTGGGATCAAAAGCGGGAAGGTGCGAACTCCTCTTTGTCTCTGCGTGCCCGGC- GCGCCCCCCTCCCGGT GGGTGATAAACCCACTCTGGCGCCGGCCATGCGCTGGGTGATTAATTTGCGAACAAACAAAAGCGGCCTGGT- GGCCACTGCATTCGGGT TAAACATTGGCCAGCGTGTTCCGAAGGCTTGT 53 chr12 ATCAACATCGTGGCTTTGGTCTTTTCCATCATGGTGAGTGAATCACGGCCAGAGGCAGCCTGGGA- GGAGAGACCCGGGCGGCTTTGAGC group- CCCTGCAGGGGAGTCCGCGCGCTCTCTGCGGCTCCCTTCCTCACGGCCCGGCCCGCGCTAGGTGTT- CTTTGTCCTCGCACCTCCTCCTC 00801 ACCTTTCTCGGGCTCTCAGAGCTCTCCCCGCAATCATCAGCACCTCCTCTGCACTCCTCGTGGTACT- CAGAGCCCTGATCAAGCTTCCCC CAGGCTAGCTTTCCTCTTCTTTCCAGCTCCCAGGGTGCGTTTCCTCTCCAACCCGGGGAAGTTCTTCCGTGG- ACTTTGCTGACTCCTCTGA CCTTCCTAGGCACTTGCCCGGGGCTTCTCAACCCTCTTTTCTAGAGCCCCAGTGCGCGCCACCCTAGCGAGC- GCAGTAAGCTCATACCCC GAGCATGCAGGCTCTACGTTCCTTTCCCTGCCGCTCCGGGGGCTCCTGCTCTCCAGCGCCCAGGACTGTCTC- TATCTCAGCCTGTGCTC CCTTCTCTCTTTGCTGCGCCCAAGGGCACCGCTTCCGCCACTCTCCGGGGGGTCCCCAGGCGATTCCTGATG- CCCCCTCCTTGATCCCG TTTCCGCGCTTTGGCACGGCACGCTCTGTCCAGGCAACAGTTTCCTCTCGCTTCTTCCTACACCCAACTTCC- TCTCCTTGCCTCCCTCCGG CGCCCCCTTTTTAACGCGCCCGAGGCTGGCTCACACCCACTACCTCTTTAGGCCTTTCTTAGGCTCCCCGTG- TGCCCCCCTCACCAGCAA AGTGGGTGCGCCTCTCTTACTCTTTCTACCCAGCGCGTCGTAGTTCCTCCCCGTTTGCTGCGCACTGGCCCT- AACCTCTCTTCTCTTGGTG TCCCCCAGAGCTCCCAGGCGCCCCTCCACCGCTCTGTCCTGCGCCCGGGGCTCTCCCGGGAATGAACTAGGG- GATTCCACGCAACGTG CGGCTCCGCCCGCCCTCTGCGCTCAGACCTCCCGAGCTGCCCGCCTCTCTAGGAGTGGCCGCTGGGGCCTCT- AGTCCGCCCTTCCGGA GCTCAGCTCCCTAGCCCTCTTCAACCCTGGTAGGAACACCCGAGCGAACCCCACCAGGAGGGCGACGAGCGC- CTGCTAGGCCCTCGCC TTATTGACTGCAGCAGCTGGCCCGGGGGTGGCGGCGGGGTGAGGTTCGTACCGGCACTGTCCCGGGACAACC- CTTGCAGTTGC 54 PAX9 ACAAATAAAACACCCTCTAGCTTCCCCTAGACTTTGTTTAACTGGCCGGGTCTCCAGAAGGAACGC- TGGGGATGGGATGGGTGGAGAGAG GGAGCGGCTCAAGGACTTTAGTGAGGAGCAGGCGAGAAGGAGCACGTTCAGGCGTCAAGACCGATTTCTCCC- CCTGCTTCGGGAGACTT TTGAACGCTCGGAGAGGCCCGGCATCTCACCACTTTACTTGGCCGTAGGGGCCTCCGGCACGGCAGGAATGA- GGGAGGGGGTCCGATT GGACAGTGACGGTTTGGGGCCGTTCGGCTATGTTCAGGGACCATATGGTTTGGGGACAGCCCCAGTAGTTAG- TAGGGGACGGGTGCGTT CGCCCAGTCCCCGGATGCGTAGGGAGGCCCAGTGGCAGGCAGCTGTCCCAAGCAGCGGGTGCGCGTCCCTGC- GCGCTGTGTGTTCATT TTGCAGAGCCAGCCTTCGGGGAGGTGAACCAGCTGGGAGGAGTGTTCGTGAACGGGAGGCCGCTGCCCAACG- CCATCCGGCTTCGCAT CGTGGAACTGGCCCAACTGGGCATCCGACCGTGTGACATCAGCCGCCAGCTACGGGTCTCGCACGGCTGCGT- CAGCAAGATCCTGGCG CGATACAACGAGACGGGCTCGATCTTGCCAGGAGCCATCGGGGGCAGCAAGCCCCGGGTCACTACCCCCACC- GTGGTGAAACACATCC GGACCTACAAGCAGAGAGACCCCGGCATCTTCGCCTGGGAGATCCGGGACCGCCTGCTGGCGGACGGCGTGT- GCGACAAGTACAATGT GCCCTCCGTGAGCTCCATCAGCCGCATTCTGCGCAACAAGATCGGCAACTTGGCCCAGCAGGGTCATTACGA- CTCATACAAGCAGCACC AGCCGACGCCGCAGCCAGCGCTGCCCTACAACCACATCTACTCGTACCCCAGCCCTATCACGGCGGCGGCCG- CCAAGGTGCCCACGCC ACCCGGGGTGC 55 SIX1 AGGAGGCGCAACGCGCTGCCAGGGCGGCTTTATCCTGCCGCCACAGGGCGGGGACCAGCCCGGCAG- CCGGGTGTCCAGCGCCGCTCA CGTGCCTCGCCTGGAGCTTAGCTCTCAGACTCCGAAGAGGGCGACTGAGACTTGGGCCTGGGAGTTGGCTTC- GGGGTACCCAAGGCGA CGACAGCTGAGTTGTACCACGAAGCTCAGGCCGAGGCCTCCTCCCTTGTCTGGCCTTCGAATCCATACTGGC- AGCCTCTCCTCTCAGGCA CTCCGCGGGCCGGGCCACTAGGCCCCCTGCTCCTGGAGCTGCGCTATGATCCGGGTCTTGAGATGCGCGCGA- TTCTCTCTGAACCGGT GGAGAGGAGGCTCTGCCCCGCGCGGAGCGAGGACAGCGGCGCCCGAGCTTCCCGCGCCTCTCCAGGGCCCAA- TGGCAAGAACAGCCT CCGAAGTGCGCGGATGACAGGAAAAGATCTTCAGTTCTTCTGCCGCTAGAGAAGTGCGGGATACAAGCCTCT- ATTGGATCCACAACCTGG AGTCCTGCCTTCGGA 56 ISL2 ATCTGCGTGCCCTTTTCTGGGCGAGCCCTGGGAGATCCAGGGAGAACTGGGCGCTCCAGATGGTGT- ATGTCTGTACCTTCACAGCAAGG CTTCCCTTGGATTTGAGGCTTCCTATTTTGTCTGGGATCGGGGTTTCTCCTTGTCCCAGTGGCAGCCCCGCG- TTGCGGGTTCCGGGCGCT GCGCGGAGCCCAAGGCTGCATGGCAGTGTGCAGCGCCCGCCAGTCGGGCTGGTGGGTTGTGCACTCCGTCGG- CAGCTGCAGAAAGGT GGGAGTGCAGGTCTTGCCTTTCCTCACCGGGCGGTTGGCTTCCAGCACCGAGGCTGACCTATCGTGGCAAGT- TTGCGGCCCCCGCAGAT

CCCCAGTGGAGAAAGAGGGCTCTTCCGATGCGATCGAGTGTGCGCCTCCCCGCAAAGCAATGCAGACCCTAA- ATCACTCAAGGCCTGGA GCTCCAGTCTCAAAGGTGGCAGAAAAGGCCAGACCTAACTCGAGCACCTACTGCCTTCTGCTTGCCCCGCAG- AGCCTTCAGGGACTGAC TGGGACGCCCCTGGTGGCGGGCAGTCCCATCCGCCATGAGAACGCCGTGCAGGGCAGCGCAGTGGAGGTGCA- GACGTACCAGCCGCC GTGGAAGGCGCTCAGCGAGTTTGCCCTCCAGAGCGACCTGGACCAACCCGCCTTCCAACAGCTGGTGAGGCC- CTGCCCTACCCGCCCC GACCTCGGGACTCTGCGGGTTGGGGATTTAGCCACTTAGCCTGGCAGAGAGGGGAGGGGGTGGCCTTGGGCT- GAGGGGCTGGGTACA GCCCTAGGCGGTGGGGGAGGGGGAACAGTGGCGGGCTCTGAAACCTCACCTCGGCCCATTACGCGCCCTAAA- CCAGGTCTCCCTGGAT TAAAGTGCTCACAAGAGAGGTCGCAGGATTAACCAACCCGCTCCCCCGCCCTAATCCCCCCCTCGTGCGCCT- GGGGACCTGGCCTCCTT CTCCGCAGGGCTTGCTCTCAGCTGGCGGCCGGTCCCCAAGGGACACTTTCCGACTCGGAGCACGCGGCCCTG- GAGCACCAGCTCGCGT GCCTCTTCACCTGCCTCTTCCCGGTGTTTCCGCCGCCCCAGGTCTCCTTCTCCGAGTCCGGCTCCCTAGGCA- ACTCCTCCGGCAGCGAC GTGACCTCCCTGTCCTCGCAGCTCCCGGACACCCCCAACAGTATGGTGCCGAGTCCCGTGGAGACGTGAGGG- GGACCCCTCCCTGCCA GCCCGCGGACCTCGCATGCTCCCTGCATGAGACTCACCCATGCTCAGGCCATTCCAGTTCCGAAAGCTCTCT- CGCCTTCGTAATTATTCT ATTGTTATTTATGAGAGAGTACCGAGAGACACGGTCTGGACAGCCCAAGGCGCCAGGATGCAACCTGCTTTC- ACCAGACTGCAGACCCCT GCTCCGAGGACTCTTAGTTTTTCAAAACCAGAATCTGGGACTTACCAGGGTTAGCTCTGCCCTCTCCTCTCC- TCTCTACGTGGCCGCCGCT CTGTCTCTCCACGCCCCACCTGTGT 57 DLX4 AGGTCTCTTCAGACTGCCCATTCTCCGGGCCTCGCTGAATGCGGGGGCTCTATCCACAGCGCGCGG- GGCCGAGCTCAGGCAGGCTGGG GCGAAGATCTGATTCTTTCCTTCCCGCCGCCAAACCGAATTAATCAGTTTCTTCAACCTGAGTTACTAAGAA- AGAAAGGTCCTTCCAAATAA AACTGAAAATCACTGCGAATGACAATACTATACTACAAGTTCGTTTTGGGGCCGGTGGGTGGGATGGAGGAG- AAAGGGCACGGATAATCC CGGAGGGCCGCGGAGTGAGGAGGACTATGGTCGCGGTGGAATCTCTGTTCCGCTGGCACATCCGCGCAGGTG- CGGCTCTGAGTGCTGG CTCGGGGTTACAGACCTCGGCATCCGGCTGCAGGGGCAGACAGAGACCTCCTCTGCTAGGGCGTGCGGTAGG- CATCGTATGGAGCCCA GAGACTGCCGAGAGCACTGCGCACTCACCAAGTGTTAGGGGTGCCCGTGATAGACCGCCAGGGAAGGGGCTG- GTTCGGAGGGAATTCC CGCTACCGGGAAGGTCGGAACTCGGGGTGATCAAACAAGGAATGCATCTCACCTCCGTGGGTGCTTGTGCTG- CGCAAGGAATTATTACC GGAGCGGTTGCGATGGCCTTTGCCCGGCGACCCAAGAAGAGTAAGCAAACTACCGTCCACCCAGCGGATCAG- GTCCAAT 58 CBX4 GATGTCCTGTTTCTAGCAGCCTCCAGAGCCAAGCTAGGCGAGAGGCGTAGGAGGCAGAGAGAGCGG- GCGCGGGAGGCCAGGGTCCGC CTGGGGGCCTGAGGGGACTTCGTGGGGTCCCGGGAGTGGCCTAGAAACAGGGAGCTGGGAGGGCCGGGAAGA- GCTTGAGGCTGAGCG GGGGACGAACGGGCAGCGCAAAGGGGAGATGAACGGAATGGCCGAGGAGCCACGCATTCGCCTTGTGTCCGC- GGACCCTTGTTCCCGA CAGGCGACCAAGCCAAGGCCCTCCGGACTGACGCGGCCTGAGCAGCAGCGAGTGTGAAGTTTGGCACCTCCG- GCGGCGAGACGGCGC GTTCTGGCGCGCGGCTCCTGCGTCCGGCTGGTGGAGCTGCTGCGCCCTATGCGGCCTGCCGAGGGCGCCGCC- GAGGGCCCGCGAGCT CCGTGGGGTCGGGGTGGGGGGACCCGGGAGCGGACAGCGCGGCCCGAGGGGCAGGGGCAGGGGCGCGCCTGG- CCTGGGGTGTGTC TGGGCCCCGGCTCCGGGCTCTTGAAGGACCGCGAGCAGGAGGCTTGCGCAATCCCTTGGCTGAGCGTCCACG- GAGAAAGAAAAAGAGC AAAAGCAGAGCGAGAGTGGAGCGAGGGATGGGGGCGGGCAAAGAGCCATCCGGGTCTCCACCACCGCCCTGA- CACGCGACCCGGCTG TCTGTTGGGGACCGCACGGGGGCTCGGGCGAGCAGGGGAGGGAGGAGCCTGCGCGGGGCTCGTGTTCGCCCA- GGAATCCCGGAGAA GCTCGAAGACGGTCTGGTGTTGAACGCACACGTGGACTCCATTTCATTACCACCTTGCAGCTCTTGCGCCAC- GGAGGCTGCTGCTGCCC GGCGGCTGCTACCCACCGAGACCCACGTGGCCCCTCCCCAGGGGTGTAGGGGTGACGGTTGTCTTCTGGTGA- CAGCAGAGGTGTTGGG TTTGCGACTGATCTCTAACGAGCTTGAGGCGCAAACCTAGGATTCCCTGAGTGTTGGGGTGCGGCGGGGGGG- CAAGCAAGGTGGGACG ACGCCTGCCTGGTTTCCCTGACTAGTTGCGGGGGGTGGGGGCCGGCTCTCAGGGGCCACCAGAAGCTGGGTG- GGTGTACAGGAAAATA TTTTTCTCCTGCCGTGTTTGGCTTTTTCCTGGCATTTTTGCCCAGGGCGAAGAACTGTCGCGCGGGGCAGCT- CCACCGCGGAGGGAGAG GGGTCGCGAGGCTGGCGCGGGAAGCGCTGTAGGTGGCAGTCATCCGTCCACGCCGCACAGGCCGTCTGCGCC- GTCGGACCATCGGGA GGTCTGCAGCAACTTTGTCCCGGCCAGTCCCCTTGTCCGGGAAGGGGCTGAGCTTCCCGACACTCTACCCTC- CCCCTCTTGAAAATCCCC TGGAAAATCTGTTTGCAATGGGTGTTTCCGCGGCGTCCAGGTCTGGGCTGCCGGGGGAGGCCGAGCGGCTGC- TGCAGCCTCCCTGCTG CCAGGGGCGTCGGACTCCGCTTCGCTCACTACGCCCAGGCCCCTCAGGGGCCCACGCTCAGGACTTCGGGGC- CACACAGCAGGACCC GGTGCCCCGACGACGAGTTTGCGCAGGACCCGGGCTGGGCCAGCCGCGGAGCTGGGGAGGAAGGGGCGGGGG- TCGGTGCAGCGGAT CTTTTCTGTTGCTGCCTGTGCGGCGGCAGGAAGCGTCTTGAGGCTCCCCAAGACTACCTGAGGGGCCGCCCA- AGCACTTCAGAAGCCCA AGGAGCCCCCGGCCACCCCCGCTCCTGGCCTTTTTGCCAACGACTTTGAAAGTGAAATGCACAAGCACCAGC- AATTGACTTCCCTTCCGT GGTTATTTATTTTGTCTTTGTGGATGGTGGGCAGATGGGGAGAGAGGCCCCTACCTAACCTCGGTGGCTGGT- CCCTAGACCACCCCTGCC AGCCGGTGTGGGGAGGAGCTCAGGTCCGCGGGAGAGCGAATGGGCGCCAGGAGGTGGGACAGAATCCTGGGA- AGGTACAGCGGACGC CCTGGAAGCTCCCCTGATGCCCCAGAGGGCCCTTCCTGGGAAACCTCCCGGGGGGGTGCCCCATACCATCCC- ACCCGGCTGTCTTGGC CCCTCCCAGGGAGCCGCAGGAGAAACTAGCCCTACACCTGGGATTCCCAGAGCCTTCTGCTGGGGCTCCTGC- CCCCGACTTCGGATAAC CAGCTCCGCACAGGTCCCCGAGAAGGGCCGCTGGCCTGCTTATTTGATACTGCCCCCTCCCAGACAGGGGCT- GGTCGAGCCCCTGGTTC TGCTGCCAGACTGAAGCCTTCCAGACGCCACCTCGGTTTGGGCCCCCAGGGCCCTCAGGGGCCCCAGGAGAG- GAGAGCTGCTATCTAG CTCAGCCACAGGCTCGCTCCTGGTGGGGGCCAGGCTGAAGGAGTGGACCCTGGAGAGGTCGGGAACCTTTTA- ACAGCCGTGGGCTGGA GGGTGGCTACTAAGTGTTCGGTCTGGGAAGAGGCATGACCCGCACCATCCCGGGGAAATAAACGACTTCTTA- AGGGAATCTTCTCGCTGA GCGGGTGCTCTGGGCCAGGAGATTGCCACCGCCAGCCCACGGAACCCAGATTTGGGCTCTGCCTTGAGCGGG- CCGCCTGTGGCTTCCC GGGTCGCTCCCCCGACTCAGAAAGCTCTCAAGTTGGTATCGTTTTCCCGGCCCTCGGAGGTGGATTGCAGAT- CACCGAGAGGGGATTTA CCAGTAACCACTACAGAATCTACCCGGGCTTTAACAAGCGCTCATTTCTCTCCCTTGTCCTTAGAAAAACTT- CGCGCTGGCGTTGATCATAT CGTACTTGTAGCGGCAGCTTAGGGGCAGCGGAACTGGTGGGGTTGTGCGTGCAGGGGGAGGCTGTGAGGGAG- CCCTGCACTCCGCCC CTCCACCCTTCTGGAGGAGTGGCTTTGTTTCTAAGGGTGCCCCCCCAACCCCCGGGTCCCCACTTCAATGTT- TCTGCTCTTTGTCCCACC GCCCGTGAAAGCTCGGCTTTCATTTGGTCGGCGAAGCCTCCGACGCCCCCGAGTCCCACCCTAGCGGGCCGC- GCGGCACTGCAGCCGG GGGTTCCTGCGGACTGGCCCGACAGGGTGCGCGGACGGGGACGCGGGCCCCGAGCACCGCGACGCCAGGGTC- CTTTGGCAGGGCCC AAGCACCCCT 59 EDG6 TGGCGGCCGGCGGGCACAGCCGGCTCATTGTTCTGCACTACAACCACTCGGGCCGGCTGGCCGGGC- GCGGGGGGCCGGAGGATGGC GGCCTGGGGGCCCTGCGGGGGCTGTCGGTGGCCGCCAGCTGCCTGGTGGTGCTGGAGAACTTGCTGGTGCTG- GCGGCCATCACCAGC CACATGCGGTCGCGACGCTGGGTCTACTATTGCCTGGTGAACATCACGCTGAGTGACCTGCTCACGGGCGCG- GCCTACCTGGCCAACGT GCTGCTGTCGGGGGCCCGCACCTTCCGTCTGGCGCCCGCCCAGTGGTTCCTACGGGAGGGCCTGCTCTTCAC- CGCCCTGGCCGCCTCC ACCTTCAGCCTGCTCTTCACTGCAGGGGAGCGCTTTGCCACCATGGTGCGGCCGGTGGCCGAGAGCGGGGCC- ACCAAGACCAGCCGCG TCTACGGCTTCATCGGCCTCTGCTGGCTGCTGGCCGCGCTGCTGGGGATGCTGCCTTTGCTGGGCTGGAACT- GCCTGTGCGCCTTTGAC CGCTGCTCCAGCCTTCTGCCCCTCTACTCCAAGCGCTACATCCTCTTCTGCCTGGTGATCTTCGCCGGCGTC- CTGGCCACCATCATGGGC CTCTATGGGGCCATCTTCCGCCTGGTGCAGGCCAGCGGGCAGAAGGCCCCACGCCCAGCGGCCCGCCGCAAG- GCCCGCCGCCTGCTG AAGACGGTGCTGATGATCCTGCTGGCCTTCCTGGTGTGCTGGGGCCCACTCTTCGGGCTGCTGCTGGCCGAC- GTCTTTGGCTCCAACCT CTGGGCCCAGGAGTACCTGCGGGGCATGGACTGGATCCTGGCCCTGGCCGTCCTCAACTCGGCGGTCAACCC- CATCATCTACTCCTTCC GCAGCAGGGAGGTGTGCAGAGCCGTGCTCAGCTTCCTCTGCTGCGGGTGTCTCCGGCTGGGCATGCGAGGGC- CCGGGGACTGCCTGG CCCGGGCCGTCGAGGCTCACTCCGGAGCTTCCACCACCGACAGCTCTCTGAGGCCAAGGGACAGCTTTC 60 chr13 TAGTAAGGCACCGAGGGGTGGCTCCTCTCCCTGCAGCGGCTGTCGCTTACCATCCTGTAGACCGT- GACCTCCTCACACAGCGCCAGGAC group- GAGGATCGCGGTGAGCCAGCAGGTGACTGCGATCCTGGAGCTGGTCGCAGCAGGCCATCCTGCACG- CGGTGGAGGCGCCCCCTGCAG 00005 GCCGCAGCGCATCCCCAGCTTCTGGACGCACTGTGAGCGGTTATGCAGCAGCACGCTCATATGAGAT- GCCCCGCAGGGTGCTATGCAGG CCCACGTCCCCACAAAGCCCATGGCAGGCGCCCGGGTGCCGGAGCACGCACTTGGCCCCATGGATCTCTGTG- CCCAGGGCTCAGCCAG GCATCTGGCCGCTAAAGGTTT 61 CRYL1 TCTCATCTGAGCGCTGTCTTTCACCAGAGCTCTGTAGGACTGAGGCAGTAGCGCTGGCCCGCCTG- CGAGAGCCCGACCGTGGACGATGC GTCGCGCCCTTCCCATCGCGGCCTGGGCGGGCCCGCCTGCCCTCGGCTGAGCCCGGTTTCCCTACCCCGGGG- CACCTCCCCTCGCCC GCACCCGGCCCCAGTCCCTCCCAGGCTTGCGGGTAGAGCCTGTCTTTGCCCAGAAGGCCGTCTCCAAGCT 62 IL17D CAGTCCCCGAGGCCCTCCCCGGTGACTCTAACCAGGGATTTCAGCGCGCGGCGCGGGGCTGCCCC- CAGGCGTGACCTCACCCGTGCTC TCTCCCTGCAGAATCTCCTACGACCCGGCGAGGTACCCCAGGTACCTGCCTGAAGCCTACTGCCTGTGCCGG- GGCTGCCTGACCGGGCT GTTCGGCGAGGAGGACGTGCGCTTCCGCAGCGCCCCTGTCTACAT 63 IRS2 AGAGAGACATTTTCCACGGAGGCCGAGTTGTGGCGCTTGGGGTTGTGGGCGAAGGACGGGGACACG- GGGGTGACCGTCGTGGTGGAG GAGAAGGTCTCGGAACTGTGGCGGCGGCGGCCCCCCTGCGGGTCTGCGCGGATGACCTTGGCGCCGCGGTGG- GGGTCCGGGGGCTG GCTGGCCTGCAGGAAGGCCTCGACTCCCGACACCTGCTCCATGAGGCTCAGCCTCTTCACGCCCGACGTCGG- GCTGGCCACGCGGGCA GCTTCTGGCTTCGGGGGGGCCGCGATAGGTTGCGGCGGGGTGGCGGCCACACCAAAAGCCATCTCGGTGTAG- TCACCATTGTCCCCGG TGTCCGAGGACAACGATGAGGCGGCGCCCGGGCCCTGGGCGGTGGCAACGGCCGAGGCGGGGGGCAGGCGGT- ACAGCTCCCCCGGG GCCGGCGGCGGTGGCGGCGGCTGCAGAGACGACGACGGGGACGCGGACGGACGCGGGGGCAACGGCGGATAC- GGGGAGGAGGCCT CGGGGGACAGGAGGCCGTCCAAGGAGCCCACGGGGTGGCCGCTCGGGGCGCCCGGCTTAGGAGACTTGGGGG- AGCTGAAGTCGAGG TTCATGTAGTCGGAGAGCGGAGACCGCTGCCGGCTGTCGCTGCTGGTGCCCGGGGTGCCTGAGCCCAGCGAC- GAGGCCGGGCTGCTG GCGGACAAGAGCGAGGAGGACGAGGCCGCCGACGCCAGCAGGGGAGGCGCGGGCGGCGACAGGCGGGCCCCG- GGCTCGCCAAAGT CGATGTTGATGTACTCGCCGGGGCTCTTGGGCTCCGGTGGCAGTGGGTACTCGTGCATGCTGGGCAGGCTGG- GCAGCCCCTCCAGGGA CAGGCGCGTGGGCCTCACCGCCCGGCCGCGCTGGCCCAAGAAGCCCTCCGGGCGGCCGCCGCTAGGCCGCAC- GGGCGAAGGCACTA CAGGGTGAGGGGGCTGCGTGGGGCCGGCCCCGAAGGCGCTGGCCGCCTGGCTGGGCCCTGGCGTGGCCTGAG- GCTCCAGACGCTCC TCCTCCAGGATGCGCCCCACGGGGGAGCTCATGAGCACGTACTGGTCGCTGTCCCCGCCACAGGTGTAGGGG- GCCTTGTAGGAGCGGG GCAAGGAGCTGTAGCAGCAGCCGGGAACGCCCCTGAGCGGCTCCCCGCCGGGGTGCAGGGCTGCGGAGAAGA- AGTCGGGCGGGGTG CCCGTGGTGACCGCGTCGCTGGGGGACACGTTGAGGTAGTCCCCGTTGGGCAGCAGCTTGCCATCTGCATGC- TCCATGGACAGCTTGG AACCGCACCACATGCGCATGTACCCACTGTCCTCGGGGGAGCTCTCGGCGGGCGAGCTGGCCTTGTAGCCGC- CCCCGCTCGCCGGGAA TGTCCTGCCCGCCGCAGAGGTGGGTGCTGGCCCCGCAGGCCCCGCAGAAGGCACGGCGGCGGCGGCGGCGGC- GGCGGCCCTGGGCT GCAAGATCTGCTTGGGGGCGGACACGCTGGCGGGGCTCATGGGCATGTAGTCGTCGCTCCTGCAGCTGCCGC- TCCCACTGCCCGCGAG GGCCGCGCCGGGCGTCATGGGCATGTAGCCGTCGTCTGCCCCCAGGTTGCTGCTGGAGCTCCTGTGGGAGCC- GATCTCGATGTCTCCG TAGTCCTCTGGGTAGGGGTGGTAGGCCACCTTGGGAGAGGACGCGGGGCAGGACGGGCAGAGGCGGCCCGCG- CTGCCCGAGAAGGTG GCCCGCATCAGGGTGTATTCATCCAGCGAGGCAGAGGAGGGCTGGGGCACCGGCCGCTGCCGGGCTGGCGTG- GTCAGGGAGTAGGTC CTCTTGCGCAGCCCTCGGTCCAGGTCCTGGGCCGCGTCCCCCGAGACCCGGCGGTAGGAGCGGCCACAGTGG- CTCAGGGGCCTGTCC ATGGTCATGTACCCGTAGAACTCACCGCCGCCGCCGCCGTCTCGGGCCGGGGGCGTCTCCGCGATGGACTCG- GGCGTGTTGCTTCGGT GGCTGCAGAAGGCGCGCAGGTCGCCTGGGCTGGAGCCGTACTCGTCCAGGGACATGAAGCCGGGGTCGCTGG- GGGAGCCCGAGGCG GAGGCGCTGCCGCTGGAGGGCCGCTGGCCGGGGCCGTGGTGCAGCGGATGCGGCAGAGGCGGGTGCGGGCCG- GGCGGCGGCGGGT AGGAGCCCGAGCCGTGGCCGCTGCTGGACGACAGGGAGC 64 chr13 TAACCTAAAGAATGAAGTCATGCCCCGGCCTGCACCCGGGAAACTGCACACAGCGAAAGATCGCC- ACTGAGATAAAGAGCTGAAAGCTAT group- TCCCCAATTCAGCTGTTTCAGCCGTGCGGTCTCACAATGGGCTCACAGACGGCAGCATC 00350 65 MCF2L GTTTCCACAATCCACCTCGTAGCTGGGGCGTGCCGCTTGCCTCGGCTTGTCCCGGCAGAACACTC- TTACCTTTAATGGCGACTGAAAAGT TGCCACGAGTTCCTGATCATTGTGGTAGGTGCTGCGTGAAGCTGAGACGTGCGTGAGCCACATCCCAGGGGG- CTTTGAGCCCCCACCGC GGCGGCGGCTGAGGGGAGGCTTGTCGTACTCGCACAGGAGGACACAGGGCTGCAGTGTTCACTCCAGGGCCT- CTTATCATTGGGATCT GAGGAATTTTCCGAGAGGAAGTGCGAATTAACAATGATGAAAGGTTTGTGAGTGAGTGACAGGCACGTTCTA- TTGAGCACTGCATGGGGC ATTATGTGCCACCAGAGACGGGGGCAGAGGTCAAGAGCCCTCGAGGGCTGGGAGAGTTCGGAGGATAGAAGT- CATCAGAGCACAATGAA GCCAGACCCTGCAGCCGCCTTCCCCTTCGGGGGCTTCCTTAGAATGCAGCATTGCGGGGACTGAGCTGTCCC- AGGTGAAGGGGGGCCG TCACGGTGTGTGGACGCCCCTCGGCTCAGCCCTCTAAGAGACTCGGCAGCCAGGATGGGCTCAAGGCATGAG- CCCTCAAAGGAGGTTA GGAAGGAGCGAGGGAGAAAAGATATGCTTGTGTGACGTCCTGGCCGAAGTGAGAACAATTGTATCAGATAAT- GAGTCATGTCCCATTGAG GGGTGCCGACAAGGACTCGGGAGGAGGCCACGGAGCCCTGTACTGAGGAGACGCCCACAGGGAGCCTCGGGG- GCCCAGCGTCCCGG GATCACTGGATGGTAAAGCCGCCCTGCCTGGCGT 66 F7 TCCAGCTGCAGCGAGGGCGGCCAGGCCCCCTTCTCCGACCTGCAGGGGTAGCGCGGCCTCGGCGCCGG- AGACCCGCGCGCTGTCTGG GGCTGCGGTGGCGTGGGGAGGGCGCGGCCCCCGGACGCCCCGAGGAAGGGGCACCTCACCGCCCCCACCCAG- AGCGCCTGGCCGTG CGGGCTGCAGAGGACCCCTCCGGGGCAGAGGCAGGTTCCACGGAAGACCCCGGCCCGCTGGGGCTTCCCCGG- AGACTCCAGAG 67 chr18 ACTTACTGCTTCCAAAAGCGCTGGGCACAGCCTTATATGACTGACCCCGCCCCCGAGTCCCAGGC- CGCCCCATGCAACCGCCCAACCGC

group- CCAACCGCCACTCCAAAGGTCACCAACCACTGCTCCAGGCCACGGGCTGCCTCTCCCCACGGCTCT- AGGGCCCTTCCCCTCCACCGCAG 00039 GCTGAC 68 C18orf1 TGCCACACCCAGGTACCGCCCGCCCGCGCGAGAGCCGGGCAGGTGGGCCGCGGATGCTCCCAG- AGGCCGGCCCAGCAGAGCGATGG ACTTGGACAGGCTAAGATGGAAGTGACCTGAG 69 CD33L3 TCGCCAGCGCAGCGCTGGTCCATGCAGGTGCCACCCGAGGTGAGCGCGGAGGCAGGCGACGCGG- CAGTGCTGCCCTGCACCTTCACG CACCCGCACCGCCACTACGACGGGCCGCTGACGGCCATCTGGCGCGCGGGCGAGCCCTATGCGGGCCCGCAG- GTGTTCCGCTGCGCT GCGGCGCGGGGCAGCGAGCTCTGCCAGACGGCGCTGAGCCTGCACGGCCGCTTCCGGCTGCTGGGCAACCCG- CGCCGCAACGACCTC TCGCTGCGCGTCGAGCGCCTCGCCCTGGCTGACGACCGCCGCTACTTCTGCCGCGTCGAGTTCGCCGGCGAC- GTCCATGACCGCTACG AGAGCCGCCACGGCGTCCGGCTGCACGTGACAGGCGAGGCGGCGTGGGAGCGGGTCCCCGGCCTCCCTTCCC- GCCCTCCCGCCTGCC CCGCCCCAAGGGCTACGTGGGTGCCAGGCGCTGTGCTGAGCCAGGAAGGGCAACGAGACCCAGCCCTCTCCT- CTACCCCAGGGATCTC ACACCTGGGGGTAGTTTAGGACCACCTGGGAGCTTGACACAAATGCAGAATCCAGGTCCCAGGAAGGGCTGA- GGTGGGCCCGGGAATA GGCATTGCCGTGACTCTCGTAGAGTGACTGTCCCCAGTGGCTCTCAGACGAAGAGGCGAGAAAGACAAGTGA- ATGGCAATCCTAAATATG CCAAGAGGTGCAATGTGGTGTGTGCTACCAGCCCGGAAAGACACTCGCAGCCCCTCTACCCAGGGGTGCACA- GACAGCCCACCAAGTAG TGCCTAGCACTTTGCCAGACCCTGATATACAAAGATGCCTGAACCAGGGTCCCGTCCCTAGAGCAGTGGCTC- TCCACTCTAGCCCCCACC CTGCTCTGCGACAATAATGGCCACTTAGCATTTGCTAGGGAGCCGGGACCTAGTCCAAGCACCCACAAGCAT- GAATTTGCCAAATCTTTTC AGCAACCTCTTAAGGCAACTGCTATCATGATCCTCACTTTACACATGGAGAAGCAGAAGCAGAGATGATAGA- ATCTTTCGCCCAAGGCCAC ATCTGTATTGGGACGGGGGCAGCCTGGCACCCAAGTGCCCATTCCTCCCTTCTGACCAGCCCCCACCCCTCC- GGCTCTGGCGTCCAAAG GGCTAAGGGGAGGGGTGCCCTTGTGACAGTCACCCGCCTTCTCCCCTGCAGCCGCGCCGCGGATCGTCAACA- TCTCGGTGCTGCCCAG TCCGGCTCACGCCTTCCGCGCGCTCTGCACTGCCGAAGGGGAGCCGCCGCCCGCCCTCGCCTGGTCCGGCCC- GGCCCTGGGCAACAG CTTGGCAGCCGTGCGGAGCCCGCGTGAGGGTCACGGCCACCTAGTGACCGCCGAACTGCCCGCACTGACCCA- TGACGGCCGCTACACG TGTACGGCCGCCAACAGCCTGGGCCGCTCCGAGGCCAGCGTCTACCTGTTCCGCTTCCATGGCGCCAGCGGG- GCCTCGACGGTCGCCC TCCTGCTCGGCGCTCTCGGCTTCAAGGCGCT 70 TNFRS ATGAACTTCAAGGGCGACATCATCGTGGTCTACGTCAGCCAGACCTCGCAGGAGGGCGCGGCGGC- GGCTGCGGAGCCCATGGGCCGCC F11A CGGTGCAGGAGGAGACCCTGGCGCGCCGAGACTCCTTCGCGGGGAACGGCCCGCGCTTCCCGGACCCG- TGCGGCGGCCCCGAGGGG CTGCGGGAGCCGGAGAAGGCCTCGAGGCCGGTGCAGGAGCAAGGCGGGGCCAAGGCTTGAGCGCCCCCCATG- GCTGGGAGCCCGAA GCTCGGAGC 71 ZNF236 TCAGTGTTATGTGGGGAGCGCTAGATCGTGCACACAGTAGGCGTCAGGAAGTGTTTTCCCCAGT- AATTTATTCTCCATGGTACTTTGCTAA AGTCATGAAATAACTCAGATTTTGTTTTCCAAGGAAGGAGAAAGGCCCAGAATTTAAGAGCAGGCAGACACA- CAACCGGGCACCCCCAGA CCCTGGCCCTTCCAGCAGTCAGGAATTGACTTGCCTTCCAAAGCCCCAGCCCGGAGCTTGAGGAACGGACTT- TCCTGCGCAGGGGGATC GGGGCGCACTCG 72 chr18 GTGGAAACACAACCTGCCTTCCATTGTCTGCGCCTCCAAAACACACCCCCCGCGCATCCGTGAAG- CTGTGTGTTTCTGTGTTACTACAGG group- GGCCGGCTGTGGAAATCCCACGCTCCAGACCGCGTGCCGGGCAGGCCCAGCC 00342 73 OLIG2 TCCACACCTCGGGCAGTCACTAGGAAAAGGGTCGCCAACTGAAAGGCCTGCAGGAACCAGGATGA- TACCTGCGTCAGTCCCGCGGCTGC TGCGAGTGCGCGCTCTCCTGCCAGGGGGACCTCAGACCCTCCTTTACAGCACACCGAGGGCCCTGCAGACAC- GCGAGCGGGCCTTCAG TTTGCAAACCCTGAAAGCGGGCGCGGTCCACCAGGACGATCTGGCAGGGCTCTGGGTGAGGAGGCCGCGTCT- TTATTTGGGGTCCTCG GGCAGCCACGTTGCAGCTCTGGGGGAAGACTGCTTAAGGAACCCGCTCTGAACTGCGCGCTGGTGTCCTCTC- CGGCCCTCGCTTCCCCG ACCCCGCACAGGCTAACGGGAGACGCGCAGGCCCACCCCACCGGCTGGAGACCCCGGCACGGCCCGCATCCG- CCAGGATTGAAGCAG CTGGCTTGGACGCGCGCAGTTTTCCTTTGGCGACATTGCAGCGTCGGTGCGGCCACAATCCGTCCACTGGTT- GTGGGAACGGTTGGAGG TCCCCCAAGAAGGAGACACGCAGAGCTCTCCAGAACCGCCTACATGCGCATGGGGCCCAAACAGCCTCCCAA- GGAGCACCCAGGTCCAT GCACCCGAGCCCAAAATCACAGACCCGCTACGGGCTTTTGCACATCAGCTCCAAACACCTGAGTCCACGTGC- ACAGGCTCTCGCACAGG GGACTCACGCACCTGAGTTCGCGCTCACAGATC 74 RUNX1 CTGCCCTCGCGGATCTCCCCCGGCCTCGCCGGCCTCCGCCTGTCCTCCCACCACCCTCTCCGGGC- CAGTACCTTGAAAGCGATGGGCA GGGTCTTGTTGCAGCGCCAGTGCGTAGGCAGCACGGAGCAGAGGAAGTTGGGGCTGTCGGTGCGCACCAGCT- CGCCCGGGTGGTCGG CCAGCACCTCCACCATGCTGCGGTCGCCGCTCCTCAGCTTGCCGGCCAGGGCAGCGCCGGCGTCCGGGGCGC- CCAGCGGCAACGCCT CGCTCATCTTGCCTGGGCTCAGCGCGGTGGAAGGCGGCGTGAAGCGGCGGCTCGTGCTGGCATCTACGGGGA- TACGCATCACAACAAG CCGATTGAGTTAGGACCCTGCAAACAGCTCCTACCAGACGGCGACAGGGGCGCGGATCTTCAGCAAGCAGCT- CCCGGGAGACCAACATA CACGTTCAGGGGCCTTTATTACTGCGGGGGGTGGGGGGGGGCGGGGGTGGTTAGGGGAGGAGGGAGACTAAG- TTACTAACAGTCCAGG AGGGGAAAACGTTCTGGTTCTGCGGATCGGCCTCTGACCCAGGATGGGCTCCTAGCAACCGATTGCTTAGTG- CATTAAAAAGTGGAGACT ATCTTCCACGAATCTTGCTTGCAGAGGTTAAGTTCTGTCTTTGGCTGTTAGAAAAGTTCCTGAAGGCAAAAT- TCTCATACACTTCCTAAAATA TTTATGCGAAGAGTAAAACGATCAGCAAACACATTATTTGGAAGTTCCAGTAGTTAATGCCTGTCAGTTTTT- TGCAGGTGAGTTTTGTCTAA AGTCCCAACAGAACACAATTATCTCCCGTAACAAGGCCACTTTTATCATGCAAAACTGGCTTCAGTCCCGAA- AAGCAAGAGCTGAGACTTCCA AAGGTAGTGCTACTAATGTATGTGCACGTATATATAAATATATACATATGCTCTACTTCATAAAATATTTAC- AATACAATCTGTGGAGAATT TAAACACAACAGAAATCCATTAATGTACGCTGCAGATTTTTTTAAGTAGCCTTGAAAATCAGCTTCAGTAGT- TGGAGCAGTGCTGAGCTAGA AGTACTTGTCATGTTCTCTGTTCTCTCAATGAATTCTGTCAAAACGCTCAGTGCAGAAAATTCAGCGTTTCA- GAGATCTTCAGCTAATCTTAA AACAACAATCATAAGAAGGCCCAGTCGATGACACTCAGGGTTCTACAGCTCTCCCACATCTGTGAACTCGGG- TTTGGGGATGTTGGTTAA GTTTGTGGCTGGTCCTCTGGTTTGTTGGGAGTTGAGCAGCCGCAGAGTCACACACATGCAAACACGCACTCT- TCGGAAGGCAGCCACTGT CTACATCAGCTGGGTGACTCAGCCCTGACTCGGGCAGCAGCGAGACGATACTCCTCCACCGTCGCCCAGCAC- CCGCCGGTTAGCTGCTC CGAGGCACGAACACCCACGAGCGCCGCGTAACCGCAGCAGGTGGAGCGGGCCTTGAGGGAGGGCTCCGCGGC- GCAGATCGAAACAGA TCGGGCGGCTCGGGTTACACACGCACGCACATCCTGCCACGCACACTGCCACGCACACGCAACTTCACGGCT- CGCCTCGGACCACAGA GCACTTTCTCCCCCTGTTGTAAAAGGAAAACAATTGGGGAAAAGTTCGCAGCCAGGAAAGAAGTTGAAAACA- TCCAGCCAAGAAGCCAGT TAATTCAAAAGGAAGAAAGGGGAAAAACAAAAAAAAACAACAAAAAAAGGAAGGTCCAACGCAGGCCAAGGA- GAAGCAGCAGAGGTTGAC TTCCTTCTGGCGTCCCTAGGAGCCCCGGAAAGAAGTGCCTGGCGGCGCAGGGCCGGGCAGCGTGGTGCCCTG- GCTGGGTCCGGCCGC GGGGCGCCCGTCCCGCCCGCGCCCGCTGGCTCTATGAATGAGAGTGCCTGGAAATGAACGTGCTTTTACTGT- AAGCCCGGCCGGAGGA ATTCCATTCCCTCAGCTCGTTTGCATAGGGGCGGCCGGCGGCCAATCACAGGCCTTTCCGGTATCAGCCAGG- GCGCGGCTCGCCGCCG CCGGCTCCTGGAATTGGCCCGCGCGCCCCCGCCGCCGCGCCGCGCGCTACTGTACGCAGCCCGGGCGGGGAG- TCGGAGGCCACCCC CGCGCCCCGCATCCAAGCCTGCATGCTGGCCCGGGGCCCCGCCCGCGTGCGGACCCCTTTCCGCAGCCACAC- GCAGGCTTGTGCGGC TCCGCGAGTGGCCACGGTCCGGAGACCTGGAAAAAGAAAGCAGGCCCCGCCGGCCCGAGGAGGACCCGGCCG- GCGCGCCGCACCCG GAGAGGCCCGGCCCCGCGAGCCGCTGCAGGCAGGCGCAGTGGCCGCCACGAGGCTCCCGAACCGGGCTGCAG- CCCGCGGACGGCCC CAGATCCTGCGCGGCCGCCCAGGGCCAGGCCTCCGCTTCCAGGGCGGGGGTGCGATTTGGCCGCGGGGCCCG- GGGGAGCCACTCCG CGCTCCTGCACCGTCCGGCTGGCAGCTGCGGCGAAGCGGCGCTGATTCCTTGCATGAGGCCGGACGGCGTCC- GCGCGTGCCGTTTGCT CTCAGCGTCTTCCCTTGGGTCGGTTTCTGTAATGGGTGTTTTTTACCGCTGCGCCCGGGCCGCGGCTCGATC- CCTCCGCGCGTCTCACTT GCTGCGTGCGTCAGCGGCCAGCGAAGAGTTTCCTAGTCAGGAAAGACCCCAAGAACGCGCGGCTGGAAGGAA- AGTTGAAAGCAGCCAC GCGGCTTGCTCCCGGGCCTTGTAGCGCCGGCACCCGCAGCAGCCGGACAGCCTGCCCGGGCCCCGCGTCTCC- CCTCCGGCTCCCCGG AAGCGGCCCCCGCTCCTCTCCCCGCCCCCGTGCGCTCGAGCGGCCCCAGGTGCGGAACCCACCCCGGCTTCG- CGTGCGGGCGGCCGC TTCCCCCTGCGCCGGTCCCCGCGGTGCTGCGGGCATTTTCGCGGAGCTCGGAGGGCCCCGCCCCCGGTCCGG- CGTGCGCTGCCAACT CCGACCCCGCCCGGCGGGGCTCCCTCCCAGCGGAGGCTGCTCCCGTCACCATGAGTCCCTCCACGCCCTCCC- TGCCGGGCCCTGCAC CTCCCGGGGCCTCTCATCCACCCCGGGGCTGCAACCCAGTCCCCGGATCCCGGCCCCGTTCCACCGCGGGCT- GCTTTGTGGTCCCCGC GGAGCCCCTCAATTAAGCTCCCCGGCGCGGGGGTCCCTCGCCGACCTCACGGGGCCCCTGACGCCCGCTCCT- CCCTCCCCCAGGGCTA GGGTGCTGTGGCCGCTGCCGCGCAGGGACTGTCCCCGGGCGTTGCCGCGGGCCCGGACGCAGGAGGGGGCCG- GGGTTGACTGGCGT GGAGGCCTTTCCCGGGCGGGCCCGGACTGCGCGGAGCTGTCGGGACGCGCCGCGGGCTCTGGCGGACGCCAG- GGGGCAGCAGCCGC CCTCCCTGGACGCCGCGCGCAGTCCCCGGAGCTCCCGGAACGCCCCCGACGGCGCGGGGCTGTGCGGCCCGC- CTCGTGGCCTTCGG GTCGCCCGGGAAGAACTAGCGTTCGAGGATAAAAGACAGGAAGCCGCCCCAGAGCCCACTTGAGCTGGAACG- GCCAAGGCGCGTTTCC GAGGTTCCAATATAGAGTCGCAGCCGGCCAGGTGGGGACTCTCGGACCAGGCCTCCCCGCTGTGCGGCCCGG- TCGGGGTCTCTTCCCG AAGCCCCTGTTCCTGGGGCTTGACTCGGGCCGCTCTTGGCTATCTGTGCTTCAGGAGCCCGGGCTTCCGGGG- GGCTAAGGCGGGCGGC CCGCGGCCTCAACCCTCTCCGCCTCCGCTCCCCCTGGGCACTGCCAGCACCCGAGTTCAGTTTTGTTTTAAT- GGACCTGGGGTCTCGGAAA GAAAACTTACTACATTTTTCTTTTAAAATGATTTTTTTAAGCCTAATTCCAGTTGTAAATCCCCCCCTCCCC- CCGCCCAAACGTCCACTTT CTAACTCTGTCCCTGAGAAGAGTGCATCGCGCGCGCCCGCCCGCCCGCAGGGGCCGCAGCGCCTTTGCCTGC- GGGTTCGGACGCGGC CCGCTCTAGAGGCAAGTTCTGGGCAAGGGAAACCTTTTCGCCTGGTCTCCAATGCATTTCCCCGAGATCCCA- CCCAGGGCTCCTGGGGC CACCCCCACGTGCATCCCCCGGAACCCCCGAGATGCGGGAGGGAGCACGAGGGTGTGGCGGCTCCAAAAGTA- GGCTTTTGACTCCAGG GGAAATAGCAGACTCGGGTGATTTGCCCCTCGGAAAGGTCCAGGGAGGCTCCTCTGGGTCTCGGGCCGCTTG- CCTAAAACCCTAAACCC CGCGACGGGGGCTGCGAGTCGGACTCGGGCTGCGGTCTCCCAGGAGGGAGTCAAGTTCCTTTATCGAGTAAG- GAAAGTTGGTCCCAGC CTTGCATGCACCGAGTTTAGCCGTCAGAGGCAGCGTCGTGGGAGCTGCTCAGCTAGGAGTTTCAACCGATAA- A 75 AIRE TTCGGAAGTGAGAGTTCTCTGAGTCCCGCACAGAGCGAGTCTCTGTCCCCAGCCCCCAAGGCAGCT- GCCCTGGTGGGTGAGTCAGGCCA GGCCCGGAGACTTCCCGAGAGCGAGGGAGGGACAGCAGCGCCTCCATCACAGGGAAGTGTCCCTGCGGGAGG- CCCTGGCCCTGATTG GGCGCCGGGGCGGAGCGGCCTTTGCTCTTTGCGTGGTCGCGGGGGTATAACAGCGGCGCGCGTGGCTCGCAG- ACCGGGGAGACGGG CGGGCGCACAGCCGGCGCGGAGGCCCCACAGCCCCGCCGGGACCCGAGGCCAAGCGAGGGGCTGCCAGTGTC- CCGGGACCCACCGC GTCCGCCCCAGCCCCGGGTCCCCGCGCCCACCCCATGGCGACGGACGCGGCGCTACGCCGGCTTCTGAGGCT- GCACCGCACGGAGAT CGCGGTGGCCGTGGACAG 76 SUMO3 ACGCACACTGGGGGTGTGATGGAAAGGGGGACGCGATGGATAGGGGTGGGCGCACACTGGGGGAC- GCGACGGGGAGGGGTGAGCAC ACACTGGGGGTGTGATGGAGAGGGCGACGCAATAGGGAGGGGTGGGCGCACACCAGGGACGCGATGATGGGG- ACGGGTGGGCGCAC ACCAGGTGGCATGATGGGGAGGAGTGGGTACACACCATGGGGGGCGTGATGGGGAGGCGTGGGCGTACACCG- GGGGGCGCGATGGG GAGGGGTGGGCGCACACCGGGGGACGCGATGGAGGCGGTGGGTGCACACGGGGCGCGATGGGTGGGAGTAGG- TGCACACTGAGGGC ACGATTGGGGAGACACGAAGGAGAGGGGTGGGCGCACACTGGGGGACGCGATGGCCGGGACACGATGCGGAG- AAGTGGGTGAATACC GGGGTCGCGATGGGCGCCCTGGAAGGACGGCAGTGCTGCTCACAGGGGCCAGGCCCCTCAGAGCGCGCCCCT- TGGGGGTAACCCCAG ACGCTTGTTCCCGAGCCGACTCCGTGCACTCGACACAGGATC 77 C21orf7 CCACAGGGTGGGGTGCGCCCACCTGCCCTGTCCATGTGGCCTTGGGCCTGCGGGGGAGAGGGA- ATCAGGACCCACAGGGCGAGCCCC 0 CTCCGTAGCCCGCGGCACCGACTGGATCTCAGTGAACACCCGTCAGCCCATCCAGAGGCTAGAAGGGGGA 78 C21orf1 TTGAGGTCTCTGTGCATGCTTGTGCGTACCCTGGACTTTGCCGTGAGGGGTGGCCAGTGCTCT- GGGTGCCTTTGCCAGACAACTGGTCT 23 GCCGGGCCGAGCATTCATGCTGGTC 79 COL18 TGACGCGCCCCTCTCCCCGCAGCTCCACCTGGTTGCGCTCAACAGCCCCCTGTCAGGCGGCATGC- GGGGCATCCGCGGGGCCGACTTC A1 CAGTGCTTCCAGCAGG 80 PRRT3 AACACACTGTCTCGCACTAGGTGCTCGCGGAAGAGCGCGGCGTCGATGCTGCGGCTCAGGTTGAT- GGGCGATGGCGGCCGCAGATCCA GCTCGCTCAGCGATGGCGCCGGTCCCACACCGTTGCGGGACAGTCCCGGGCCACCCTGGGGTCCGCGACCCA- ACGACGCAGCCGAGC CCCAGGCGCCTGAACTGGGCGTGGCCAGCTGCCCACTCTCCGCCGGGTTGCGGATGAGGCTCTTGCTGATGT- CCAAGCTGCCTGCACC AACGTTGCTGGGCCCTGCATAGCAGTTATTGGGTCGCTCCGGCACCTCGCTCTTTCCTGACGGCGCCGGGCA- CGCCAGACGCATCAGCT TAGCCCAGCAAGCGTGCTCCGTGGGCGGCCTGGGTCTCGCGGCAGCCACCGCGGCCAACGCCAGGGCGAGCG- CCCATGTCAGCTCCA GGAGGCGCAGCCAGAAGTGGACACCCCACCAGGCCCACGAGAAGCGGCCCACGCGGCCTGGGCCCGGGTACA- GCCAGAGCGCAGCC GCCAGCTGCAAGCCGCTAGCCAGCAGCCCCAGCGCGCCCGCCACAGCCAACAGCCGAGGGCCCGGGCTGGCA- TCCCAGCCCCGTGGG CCGTCCAGCAGGCGGCGACGGCACAGGCAGAGCGTGCCCAGAGCCAC 81 MGC29 GTCTGCACGAAGCCCGCGGCGGCCTGCAGGGGGCCCAGCGACTCGTCCAGGGAACCGGTGCGCAG- GAGCAGCCGGGGGCGCGGCGC 506 GCCGGCCGCCCTTGGGGGACTCTGGGGCCGGGGGCGCAGCTCGATCTGACGCTTGGGCACTGTCCGGGG- CCTGGCGGGCGCGGCGC CCTCCTCCAGAGCCACCTCCACACACTCGAACTGCGCTGGGGCGGCAGGACTTGGCCCACGGGGCCGCAGCT- CTAGGTAGGTGGCCCA GCGGGAGCCACCATCGGGGACCTGGGACTGGCGTGGGACCGCGGCGGGAGACGCTGGCCCCGGCGGCAAGGG- GCTGATGAAGGCCG GCTCCGTGAACTGTTGTTGCGCCTCGCGATCGTCTGCGCCGGAGCAGCCGAACAGGGGTCCGACGCCGAAGA- TGACTTCCATCTCCCCC GACGGCAGCGTGCGCAGCTGGGGCTGGGGTGGCCGTGGGCCGGAACCTGGGCCTCGCGGGAAACCCGAGCCG-

GGCCCGTGCCGCTG GCGGCTATTCTGGGCGCTGACGGACAGGCGAGGCTGCGCGCCCGCCCCCCGCCCAGGAGCCACCCAGGGCCA- ATTCGCTGGGCCTTT CGCGTCCGGCCCAACGTCCGGGGGCTCCGGAGAACCTGGAGCCGTGTAGTAGGAGCCTGACGAACCGGAGGA- GTCCTGGCGCCGCGC GGGGGCCGTGGGCAGCTGCCTCGGGATCCCAGGCAGGGCTGGCGGGGCGAGCGCGGTCAGCATGGTGGGGCC- GGACGCCGTGCACT ATCTCCCTCGCATTCGCCTCCGCTGGTGGCGC 82 TEAD3 CTGGAGAGAACTATACGGGCTGTGGGAGTCACCGGGCGACTATCACCGGGCCTCCTTTCCACATC- CTCCTCCGGGAAGGGACCCCGTTC CGGGCCTCGACCGGCGCAGACTGGGCTGACCCACTTTCTTGGGCCCACTGAGTCACCTCGAAACCTCCAGGC- CGGTAGCGGGGAGGAG AGGAGGAGCAGGCGGGGGTGCCAAGGTGTGGGCTGCGCCCTGGTTAGGGGGCGAGCCCGGCTTGTTTATGAG- GAGGAGCGCGGAGGA GGATCCAGACACACAGGCTTGCGCGCCCAGACTCGCCCGGCCAGCGGCTGGCGGCCTCCGACGTCACCAAAC- CGGTTGGGTGAGAGG GCAGAGAGCAGGGGGAAGGGCCGCAGTCCCGCCCGCGCCCCCCGGCACGCACCGTACATCTTGCCCTCGTCT- GACAGGATGATCTTCC G 83 chr12 GAGTGCGGAGTGAAGGGGTGCACTGGGCACTCAGCGCGGCCCTTGGGAGGCAGGGCCGCCCCAGC- CTGCCCTCCTGTCTGGGAAGGC group- CGTCCAGAAGCAGGAGCCCCGGGGAAAACAACTGGCTGGACGGGGCGGCCTTCAGTGTCTCTCCCA- GCCTGAGAGTCGCTTCCCACCA 00022 CCTGGGCACGAACCTGCTCTGCGATCTCCGGCAAGTTCCTGCGCCTCCTGTCGGTAAAATGCAGATC- GTGGCGTCTT 84 CENTG TCTTCTTTCCGCCCCTAGGGGGCACAAGCGGGCATGTCCAAGCGCCTAGGAGCCCGTACCGCTGG- GGACCTCCCCTTCCGCGAACCCC 1 GAGCGGGTAGACCCAGAGCAATCCGAGTGTGGAAACAATGGAGAGGGGGCGTGTTGAGCTGGGGTCTCCAT- GCCTCGTTGGGGAGAGG GAGGTGAGTTTGTGTCTTCTGGAAGGCGTGGGGGCTGTGCCCTCGTGGGGGTAGGAAGTGCTCCCGTGGGGC- GGGGTGCGGATCGGA GAGGTGAGTGGGTGCGTCTGTCCAGCGGTCCGCCCGGTGTGGTCGTGCCCGGCCCGCGTGGGGATGGGGGTG- TCTCTCCCGCTGGGC AACTATACCAGCGCAACCGGGGCGTCGGCGCGGCCCACGCTAGCGGCGCTGCTCCGGCGGCGGGGGCTGGGC- GTGGCGGTGATGCT GGGCGTGGTGGCCGCGCTGGGCGTGGTGGCCGCGCTGCCGCCCTCACCCGGGCAGCCGTGCTGGAGAAGGAT- GTCGGCGCACAGCT GGCTTCCAGCCTGGCGGGCGTAGAACAGCGCCGTGCGGCCCTGGGCGTCACGGGCCGCCACGTCCGCGCCGT- ACTAGAGGGCGGAAA CGGCCGCGTGACCGCGCGTCCCCAGGGCGCCCACACCCGGCGCCGCCTCCCCCACATGGCCAAGCCTACTTC- CGGGGTCCCTCTGGG AATTTCGGGCTTTCCCGCGCCAGGCGTTTTCCGAGATGAAGCCTCAAAGACCCCCTTTCCTCCCCCCAGCTC- ACGTACCCACAGCAGCAG TTGCGTGATGACGACGTGGGCGAGCTCGGCCGCCAGGTGGAGTGGGGAGCGCAGCTGTGGGTCCTCTACGCT- GGTGTCGAGCGGCCC GTGTCGCGCATGGGCCAAAAGCAGGAGAACGGTAGCCACGTCCTGGGCCTGCACGGCGGCCCACAGCTGGCG- GCCCAGCGGCTCCTC CGAGGTGCTCAGCGGCGCCAGGAACAGTAGCTGCTCGTACTTGGCGCGAATCCACGACTCGCGCTCCTCCCT- GCAAGACCAGGGATCAA CGGAAAAGGCTCTAGGGACCCCCAGCCAGGACTTCTGCCCCTACCCACGGGACCGTCTCAGGTTCGCACACC- CTCAGCAACCCTCCCCC CGCTCTGTTCCCTCACGCTTACCGCGAAGAGTCCCGCGAGGGCTTGGCACGGCCTCGCGTGTCGCTTTCCCA- CACGCGGTTGGCCGTGT CGTTGCCAATAGCCGTCAGCACCAGGGTCAGCTCCCGTGGCCAGTCGTCCAAGTCCAGCGAGCGAACGCGGG- ACAGGTGTGTGCCCAG GTTGCGGTGGATGCCAGAACACTCGATGCAGATGAGGGCGCCCAGGTTCAAGCTGGCCCACGTGGGGTCTGC- GGAAGGAGCGTAGAGG TCGGCTCCCAGCCGGGCAGCACAGGCACCCCGGCATTCACTACACTCCCTAGCCCCTCCGCTGCCTCCTGGC- ACTCACTGGGGGCCCC GCAGTCCACGCAGATTGAATTCCCCTTGGCGTTCCGGATCGCCTGGAT 85 CENTG AGCCAGGTCCAGCCCCCGCGCCTGACACCGGCCGGACGTTCCCGGGGCGCCGCAGCTGCGGCGGG- AACTCTGGGATCCGGAGCCATC 1 TGCTCCCACCCGCTCCGGAGCCAAACCCCGGGGGCCGCCTCCGCTCCCGGACCCGCCTCCTCTCCCGGGAG- TGTGAGCCGAACCAAGA GTCTCCTGCCTATCTCCTCCAGTAGGAAAATAGTAATAATAATAGACACCCTGCCCCCGTAAAAAACACTAC- CTTCCCCGTACCGCCTCCC AAGTCTCCCGGGGTACGGATTGCCTTTGCAGCAGTTCCGCCCCACCTGACTCACTCCAGGGTCAGCCCCGGG- TGGGTTTCAATGCGGCT CTGGGGAGGGGGTGGGCAGTGGGGGAAGTGAGGCTTCCTATCCGCCCCCTCTCACTTCACATTTAAATATTC- TGCACGTTCCAGCCCCC GCGGACTCGCGTACCGCCCAATCCGCCTTCACCGCACGAAAAACATCACTAGCCTGCTCTCAGCCCAGGGGA- CGACTAGTCCCTGGCGA GAAGCTGCCTGCAAGGTCACTGTCATGCCACCTGCCCCAAGTGCTCAGGGGAAACTGAGGCTTCCTCATCCC- CTTCACCTTCAACGTCGC TCTAAACACGGCAAAGCCCCGTTTCCATGCTCCCAGAGTTCAGCTGAGGCTGGAAGTGGGGTCCTGGGCTTC- TCTGGGAGCAATTTTCTA GTCACTCTGATCAAGGACGTTACTTTCCCAGAAAGCTCTGAGGCTGAGTCCCTCTGAAATCAAGTCCTTTCT- CCTGTCGCACAATGTAGCT ACTCGCCCCGCTTCAGGACTCCTATTCTTTGCCCCAATCCTTGACAGAGGGGTGAGCTTGGTTCATCCGCCC- ACCCCAGAGAAAAGCTTC CCTAGTTTCCTGGACCTCGCTCCTCCACCCCAAGCTGAGCATTCCAGGTACCCTTCCCTCCCTGTTCTCAAG- CCCTGACTCAACTCACTAG GGGAAGCGCGGAGCTCGGCGCCCAGCAGCTCCCTGGACCCGCTGCCAGAAGACAGGCTGGGGGGTCCGGGAA- GGGGCCCGGAGCCA GGAGGCCCTCCTGTGCTCTTGGTGAAGATGCCGCTGATAAACTTGAGCATCTTGCGGTCACGAGTGGATGCT- CGGCCCCCCTCCCGGCC CCGTTTCAGCCCCGGAGCTGGAGGCTCCAGAGTGATTGGAGGTGCAGGCCCGGGGGGCTGCGCGGAAGCAGC- GGTGACAGCAGTGGC TGGACTCGGAGTTGGTGGGAGGGTTAGCGGAGGAGGAGAGCCGGCAGGCGGTCCCGGATGCAAGTCACTGTT- GTCCAAGGTCTTACTC TTGCCTTTCCGAGGGGACAACTTCCCTCGGGCTCCAGCCCCAGCCCCGACCCCACCAGAGGTCGAAGCTGTA- GAGCCCCCTCCCCCGG CGGCGGCGGCGGTGGCGGCGGCAGAGACCGAAGCTCCAGTCCCGGCGCTGCTCTTTGACCCCTTGACCCTGG- GCTTGCCCTCGCTTTC GGGCCATGACAGGCGGCTACCCGCGCCCTTGCCCCCGCCGGCTTTGGCTCCACTCGTGGTCACGGTCTTGCA- AGGCTTGGGAGCCGGC GGAGGAGGCGCCACCTTGAGCCTCCGGCTGCCGGTGCCAGGGTGCGGAGAGGATGAGCCAGGGATGCCGCCG- CCCGCCCGGCCTTCG GGCTCCGGGCCGCCCCAGCTCGGGCTGCTGAGCAGGGGGCGCCGGGAGGAGGTGGGGGCGCCCCCAGGCTTG- GGGTCGGGGCTCAG TCCCCCGGAGAGCGGGGGTCCCGGAGGGACGGCCCAGAGGGAGAGGCGGCGGCCGGGAGCGGGGGAGACTGG- GCGGGCCGGACTG GCCGGAGCCGGGGACAGGGCTGGGGGCTCCGCGCCCCCGGTGCCCGCGCTGCTCGTGCTGATCCACAGCGCA- TCCTGCCGGTGGAAG AGACGTTCGTGCCGCTTCTTGCCCGGCTCCTCCGCGCCTCGGGGGCTGCCAGGATCCCCAGTCTCGGAGCCT- CTGGCACCGGCGGCGC CGGCCGCGGCCGCAGACGGAGAAGGCGGCGGCGGAGGCACCGACTCGAGCTTAACCAGGGTCAGCGAGATGA- GGTAGGTCGTTGTCC GGCGCTGAAGCGCGCCCGCGCCCCGGCTCATGGGGCCCGGAGACCCCCGAGCTGGGGAGGGGAGGGGACTCC- CCCGGACTGCCTCA GGGGGGCCCGGCCATGGGGCCGCCCTGCTCGCTGCCCCCAGCCCCCGGACCCCGCTGAGCCCCCGGCCCGGC- TCCGCTGTCGCCGC CGCCTCCGCCGCCTCCGCTTGCGCCCCCCTCCCATCACATGGGGCGCCCCCTCCCCATGCTCCCCGCCCTGC- GCCCCCACCCTCTTGG AGCCCCGGGACCTTGGTGCTGCTCCAGGGAGGCGCGCCGGACCGTCCACCCCGGCCTGGGTGGGGGCGCTGA- GATGGGTGGGGGAG GGCGGGGAGGACAGTAGTGGGGGCAAATGGGGGAGAGAGAGGAAAAGGGAGCAGAAAAGGGGACCGGAGGCT- AGGGGAAACGAACCT GTGCGGGGGAGGCAGGGGCGGGGAATTGGGACTCAAGGGACAGGGGCCGCGGATGCGGTCGGAAAGAGGGTC- TAGAGGAGGGTGGG AAGCTAGTGG 86 chr18 AGGAGCGCAAGGCTTGCAGGGCATGCTGGGAGAGCGCAGGGAACGCTGGGAGAGCGCGGGAAATA- CTGGGATTGGCTCCCGAGGGCT group- GTGAGGAGGGCACGAGGGGACACTCCGATGAAGGCAGGGCACGCGGGGCGAGCCGGGAGCGTCTCC- TGAGGGCAGCGAGGAGGGAG 00304 CTGAGGCACGCGGGCTCTCAATCGACGCCCCACAGAGACCAAGAGGCCTGGCCTTGGGGGGCAGCTG- CTTGAAGGAGGCAGAGCGGA AGCGAGGGAGACTGCTGGAGGCCCTGCCGCCCACCCGCCCTTTCCTCCCCCTGAGGAGACGCCTGACGCATC- TGCAGTGCAGGAGGCC GTGGGCGTTAGAAGTGTTGCTTTTCCAGTTTGTAAGACCATTTTCCTGATTCTCTTCCCCACGGTTGCGGAG- GAGCAGGTCAGGGCCGCC ATGAGGGCAGGATC 87 TSHZ1 TCGACCGCTACTATTATGAAAACAGCGACCAGCCCATTGACTTAACCAAGTCCAAGAACAAGCCG- CTGGTGTCCAGCGTGGCTGATTCGG TGGCATCACCTCTGCGGGAGAGCGCACTCATGGACATCTCCGACATGGTGAAAAACCTCACAGGCCGCCTGA- CGCCCAAGTCCTCCACG CCCTCCACAGTTTCAGAGAAGTCCGATGCTGATGGCAGCAGCTTTGAGGAGGC 88 CTDP1 TGTGCCGTCGCACACAGACGCCCTCAACGTCGGAGAGCTGTGAGCGGGGCCGTGCTCTTGGGATG- GGAGCCCCCGGGAGAGCTGCCC GCCAACACCACTCCGACGTGATCCATGCTGGACATAAAGTGCTCTTCCCTCCGCTAGTCATCGGCCGAGCGG- GCCCCTCGCTCCTGGGT GTAAGTTCTTTCTGTGCGTCCTTCTCCCATCTCCGTGCAGTTCAG 89 KCNG2 CCATGCGCCGCTGCGCGCGCGAGTTCGGGCTGCTGCTGCTGTTCCTCTGCGTGGCCATGGCGCTC- TTCGCGCCACTGGTGCACCTGGC CGAGCGCGAGCTGGGCGCGCGCCGCGACTTCTCCAGCGTGCCCGCCAGCTATTGGTGGGCCGTCATCTCCAT- GACCACCGTGGGCTAC GGCGACATGGTCCCGCGCAGCCTGCCCGGGCAGGTGGTGGCGCTCAGCAGCATCCTCAGCGGCATCCTGCTC- ATGGCCTTCCCGGTCA CCTCCATCTTCCACACCTTTTCGCGCTCCTACTCCGAGCTCAAGGAGCAGCAGCAGCGCGCGGCCAGCCCCG- AGCCGGCCCTGCAGGA GGACAGCACGCACTCGGCCACAGCCACCGAGGACAGCTCGCAGGGCCCCGACAGCGCGGGCCTGGCCGACGA- CTCCGCGGATGCGCT GTGGGTGCGGGCAGGGCGCTGACGCCTGCGCCGCCCAC

TABLE-US-00015 TABLE 4B SEQ ID NO GENE NAME SEQUENCE 90 TFAP2E GTCCTAACATCCCAGGTGGCGGCGCGCTGGCTCCCTGGAGCGGGGCGGGACGCGGCCGCGCGGA- CTCACGTGCACAACCGCGCGGGA CGGGGCCACGCGGACTCACGTGCACAACCGCGGGACCCCAGCGCCAGCGGGACCCCAGCGCCAGCGGGACCC- CAGCGCCAGCGGGAC CCCAGCGCCAGCGGGACCCCAGCGCCAGCGGGACCCCAGCGCCAGCGGGACCCCAGCGCCAGCGGGTCTGTG- GCCCAGTGGAGCGAG TGGAGCGCTGGCGACCTGAGCGGAGACTGCGCCCTGGACGCCCCAGCCTAGACGTCAAGTTACAGCCCGCGC- AGCAGCAGCAAAGGGG AAGGGGCAGGAGCCGGGCACAGTTGGATCCGGAGGTCGTGACCCAGGGGAAAGCGTGGGCGGTCGACCCAGG- GCAGCTGCGGCGGCG AGGCAGGTGGGCTCCTTGCTCCCTGGAGCCGCCCCTCCCCACACCTGCCCTCGGCGCCCCCAGCAGTTTTCA- CCTTGGCCCTCCGCGGT CACTGCGGGATTCGGCGTTGCCGCCAGCCCAGTGGGGAGTGAATTAGCGCCCTCCTTCGTCCTCGGCCCTTC- CGACGGCACGAGGAACT CCTGTCCTGCCCCACAGACCTTCGGCCTCCGCCGAGTGCGGTACTGGAGCCTGCCCCGCCAGGGCCCTGGAA- TCAGAGAAAGTCGCTCT TTGGCCACCTGAAGCGTCGGATCCCTACAGTGCCTCCCAGCCTGGGCGGGAGCGGCGGCTGCGTCGCTGAAG- GTTGGGGTCCTTGGTGC GAAAGGGAGGCAGCTGCAGCCTCAGCCCCACCCCAGAAGCGGCCTTCGCATCGCTGCGGTGGGCGTTCTCGG- GCTTCGACTTCGCCAGC GCCGCGGGGCAGAGGCACCTGGAGCTCGCAGGGCCCAGACCTGGGTTGGAAAAGCTTCGCTGACTGCAGGCA- AGCGTCCGGGAGGGGC GGCCAGGCGAAGCCCCGGCGCTTTACCACACACTTCCGGGTCCCATGCCAGTTGCATCCGCGGTATTGGGCA- GGAAATGGCAGGGCTGA GGCCGACCCTAGGAGTATAAGGGAGCCCTCCATTTCCTGCCCACATTTGTCACCTCCAGTTTTGCAACCTAT- CCCAGACACACAGAAAGCA AGCAGGACTGGTGGGGAGACGGAGCTTAACAGGAATATTTTCCAGCAGTGA 91 LRRC8D CACCTTCCCCGAGGTAATTATTTTCTGGGGGGTAGGGGTGGGGGTTGGGAGGGTGAAGAAAGGA- AGAAAAAGAAGGCCGATCACACTGG GCACCGGCGGAGGAAGCGTGGAGTCCATTGATCTAGGTACTTGTGGGGAGGGGAGAACCCGAGCAGCAGCTG- CAAACGGAAGGGCTGTG AGCGAGCGGGCGGGCGGGTGGCTGGCAGCGAGGCCACCAGCAGGGGGGGCCCGGGCCGAGGCCGCGCCACCT- CGGCACCACGCGGG CAGCCGGTGCGGCGGGGTCGCCACGGCCAGGGGAGCGCTGGGTGCCCACCATGGCAGTTATGCAAGCGGTGA- CCCCCTGGTCTTGCCT CCCCGCCGCCCTGCACTCCTTCCTCCCCGCTGCCGACACTTGGATCTCTCTAGCTCTTTCTCTCCCCTGTGT- TTTCAAACAGGAAGTGCAC GGCTGTCTATAACGTGCTGCCGGGTCTCAGGATGGAGGAGTGAAGTCTCCTGTCGCCGTGGTTCCAGCCTCC- GGAGCTCGCCCAAGCCG CGTCCCCAGAGAGCGCCCTGAGAGAACAGGGTGGCCGCTTGGTCCAGGTGCGCGGGGTCGGGTCTGGGTCCA- GGGAGCGGGTCGGGAA GTCTGCGGCACGGAGCACTGCTAGTGTCGGATCTGCATCTCCAGCTCTGTGCTGCAGCTTCACTTGCCCGCC- CCCCACCACTGGCTTCTC ACCCGGGGTCTCTGCCAAACTCTGGCTGCTGCCGCCCTGGGTTCGGGCCGGCGGAAGGCCCTGGGCGTGCGC- TGCGGAGCCGCCTGCG AGGACTCCACTAGGGCGCTTTCCAGGCTGGACTGCCCCGGGCTGCGCTGGAGCTGCCAGTGCTCGGGGAGTC- TTCCTGGAGTCCCCAGC TGCCCTCTCCACC 92 TBX15 CTCTTCCCAAGTTACGCCACCGGTCGAGGACGGCAGGAGACCCCCGAGTGCAGAGAAAGCTCAAA- CCGGCAGCGAAGTCGGTCCTAGCC AAGCTGAAAAAACGTCTCGGATTTCGCGGACAGCGGCCTAGACACAGCCCGATCTTCCAGTCCTAGTGCCCT- GGTCGAGACGGTTCTATCCTTTTGCAAAG AAGCCGGAAA 93 C1orf51 TCTCGGTTGCAATCCCCACCCTCCTCACCCAGCAGGGCAGGAGGCACCCAACTTGGAGGAGAA- AGGGGTGGGGGAGGTGAAACAGAGAC CGGAGAGTCACGAGGGCTGGGCCGCCGAGAGCAGGAGAATATACCGTGTCACACACCTCCATTCTCTCACAC- ACGTTGCAGACACAAATC ACTGACGGTTTCCACGTGCTGCGCTCGTGAGCGGAGGTGTTCAAAGAGGGGGCAGATGAGTTACTTCCCGAG- ACGGAACCGGGGGTCCC ACGTCCGCCGCCTTCAGTAGCACAACCAATCTCTGAACACTCAAACCGCGCATCTCTGGCGCATCACCATCC- TATTTAAGGCCACGGGCTC CGCCCTTTTCCTCCCCTCCCTTCTTTTCCACTCTTTTTCCA 94 chr1: 179553900-179554600 CTGCCAGAGATGTGTCTGTCTTGCGCCCCGCATGCACTGCCTGCGGGGCTGCGCTGCACTCCCCGGCGGCGCC- ACGGGTCTGGCCCCC GCGCTTCTACGTGTTGGGGGGATGCATGGACCTTGGAGATCCGTAGTTGGCCCTAACCTTCTCGGAATCTCC- TCTGCACGCGCTGCCTGTT CCTCCTCTGCACGCTCTGTCCGTTCCTTTGCAACTTCTGTGGGAATTGTCCTGGCGTGGGAAACGCCCCCGC- GCTCTTTGGCACTTAGGGT GTGAGTGTTGCGCCCCTTGCCGCAGCGCTCAGGGCAGCATCCCGCTCGAGGATGCAGGGTTCTCACCAAGCA- GTGAGGGGGACTCACGC GCCGCCGGGGAGCGGAGCCAGGCTCCGAGAAGGGAGCAGGCTCGAGCCGCTGGGTTTTCGCAAGCCTTGGGG- CCTCTGGCCGCCCTTC CATGCCTCCGGGCGCGGGCGGCTCAGCAGGTCCCCGGCTTCGGGAAGTTTTGTGCGCGGATCGCTGGTGGGG- AGGGCGCGCGGGCCA GTGGCTGAGCTTGCAGCGAAGTTTCCGTGAAGGAAACTGCATGTGCCTTTGGAGGCGACTCGGGACTGCTGT- AGGGTGGACTGGGTGTCT ATGGAGTTGCGGGTCAGAGCGAGTAGGGTGGGTCCTTTCCTGGGACAGGACTGGGAATTGGGGCTCGAAGTA- GGGG 95 ZFP36L2 AGGGGTGTCCTCCAACATCTCTGAACCGCCTTCCCTTCCTCCTCACTGGCGCCCTCTTGCCTC- AGTCGTCGGAGATGGAGAGGCGGCTGA AGATTGGCAGGCGGCGGCCAGGGTCGAGGCTGGGAGACTCAGAGCCGCTGAGGCTGCCGGAGCTCAGGGAGC- CGCTTAGGTAGCTGTC GCGGTCCGACAGCGAGTCCGGG 96 SIX2 TCTGACTCTCGGGCTGGAGCAGCCGAGACAGCGCTCCCCAGCGGGACTACAGAATCCCGGGTGTCG- GCCTGGGGGCCCTGGATTGGCA GTGGTGGAGTCTTCTGAGCCTAACAGCTACTAGGAATGACAGAGTTGCAGATGGCTTTGTCGCCCGCGGGGC- GGCTCAAGCGTCCTGGGT CCCAGGCCTCTGTCCTACGGCCAGGCCGCCGGCTCAACGGGCCGAAGGGAATCGGGCTGACCAGTCCTAAGG- TCCCACGCTCCCCTGAC CTCAGGGCCCAGAGCCTCGCATTACCCCGAGCAGTGCGTTGGTTACTCTCCCTGGAAAGCCGCCCCCGCCGG- GGCAAGTGGGAGTTGCT GCACTGCGGTCTTTGGAGGCCTAGGTCGCCCAGAGTAGGCGGAGCCCTGTATCCCTCCTGGAGCCGGCCTGC- GGTGAGGTCGGTACCCA GTACTTAGGGAGGGAGGACGCGCTTGGTGCTCAGGGTAGGCTGGGCCGCTGCTAGCTCTTGATTTAGTCTCA- TGTCCGCCTTTGTGCCGG CCTCTCCGATTTGTGGGTCCTTCCAAGAAAGAGTCCTCTAGGGCAGCTAGGGTCGTCTCTTGGGTCTGGCGA- GGCGGCAGGCCTTCTTCG GACCTATCCCCAGAGGTGTAACGGAGACTTTCTCCACTGCAGGGCGGCCTGGGGCGGGCATCTGCCAGGCGA- GGGAGCTGCCCTGCCGC CGAGATTGTGGGGAAACGGCGTGGAAGACACCCCATCGGAGGGCACCCAATCTGCCTCTGCACTCGATTCCA- TCCTGCAACCCAGGAGAA ACCATTTCCGAGTTCCAGCCGCAGAGGCACCCGCGGAGTTGCCAAAAGAGACTCCCGCGAGGTCGCTCGGAA- CCTTGACCCTGACACCTG GACGCGAGGTCTTTCAGGACCAGTCTCGGCTCGGTAGCCTGGTCCCCGACCACCGCGACCAGGAGTTCCTTC- TTCCCTTCCTGCTCACCA GCCGGCCGCCGGCAGCGGCTCCAGGAAGGAGCACCAACCCGCGCTGGGGGCGGAGGTTCAGGCGGCAGGAAT- GGAGAGGCTGATCCT CCTCTAGCCCCGGCGCATTCACTTAGGTGCGGGAGCCCTGAGGTTCAGCCTGACTTTCCCGACTCCGCCGGG- CGCTTGGTGGGCTCCTG GGCTTCTGGGCTCACCCTTACACCTGTGTACTAAAGGGCTGCTACCCTCCCGAGGTGTACGTCCGCCGCCTC- GGCGCTCATCGGGGTGTT TTTTCACCCTCTCGCGGTGCACGCTTTTTCTCTCACGTCAGCTCACATCTTTCAGTACACAGCCACTGGGTC- TCCCTGCCCCTCCAGCCTTT CCTAGGCAGCTTTGAGGGCCCAGACGACTGAAGTCTTACTGCTAGGATGGGAACACGATGAAAAAGGAAGGG- GCCCAGTCAAAAGTCCTC TCCTCTTCGGTTTTTCTTCAACTGTCCTTCACAAAAACATTTATTTCTGTCCCAGCGCCCTGGCGGATTTCG- GCAGATGGGCCCTAGGGGGT TGTGGAGGCCAAATTCCCAGGATGCTGGTCCTGCCTTTTTCATTGGCCAAAACTGTATTTCCTACAACGACT- AAAGATAACCAAGAACTGAG TAGACCCTGTTCTCTCACCAGATCTCCCTGGCTCTGTTTAACTTTTCCTGGTGCAATGCGATGGCACCACCA- GCTCCCCAGGCAGGCACCA CTCCCTCAAGATACCATTTGGGGTAGGGATTTGAGTCCTGGAGAGGGTCAGCGGGGCGCCGGGGTGGGGGTG- GGAAGGAGACTGACAG GGACACACCGCGAGCTCCGCATACTCTCCTCTGCCCCCTGTAGCCCGGGGCTTTAATGACCCCAAGCAGATT- TCCTGTCTCTGGTCTAGCC AGCTGCCCCTAGGGCTGGATTTTATTTCTTCATGGGGTTTCACCCTAAAGGGCCCCCTGGTCATGGGACCTG- GTTGGGAACAAATGAAAGA TGTCTTGTAGCAAATGCTTTCAGGGGAGCAGAAAAGAAGATTGGGCACTTCCAGTCACTTGGTCACTTTAGG- TGGCTGGAACAAAACTGGT GACTTTCACGACTGCTACAGGGTGAGGGGGTGAAGGGTGGCAGAGAGGTGACAAGCCACTGGGAATCCTATT- CAGTGGGGATGCCGACA GGGAGTGGCTGTAATCAACTGAGCAACATCTGTGTGAATGTTATTCACAGGTCAGGACAGCAGCTTGGTCTT- CCCAGGTGAGGAACTGAGG ACTGGCCTGCATAGATTTGTGCAGTAGGTGAGTAGCTTCCAAATTTATTTTCAGAACTTCCATGTAGTACCT- GCCTCTCCATTTAAATATTTTT TAAAATTTTATTTATTTAAATATTTTCTTGGTTAGCTTTCCAAGAGGGAGGAAAAGAGGGGAGTTGCAACAA- GTAGTGCCCCTATGCTGGGAT TCATTTTCCAGAGTAAAGCCTGGGACTGGCACCCTGACCCCTACCGGCAGGTGAAAACTCCAGGCAAACTGC- TGAGATCCCACCTGGGCT GGCTGAGATAGTGCCTGGGGTGCATCCCTCAGCAGCTGCCACCTGGGCCCTGGGGCCATCTCTTTCTCTGGC- ATCAAGCAGCCAGGTGTC AAGGCCTTCCCAGCAATCCATGCTGCATGGCTGGGTCTTGTTCTAGCAGGTCGATGGGCAGGGACTGGTAGC- TTAGCCAGGGCACCAGTG CGTGGCTGTGGGTTTGTGTGCTTCTGTGGAGAAGCATGATGTGTATGTGTGTGTGTGGGCACAGGCATGAGG- AAGGGTTCATTTGTGCAG GTATCTCCCATGTATATCAGTGTGGGAGAGTGCCTGAGGATGTGTTTGTGTGTCTGAAAATGGGCGGAGGGT- CTGTTGTGCTAATGTGTGC AGGGGTGAACATGTGTGTGACAGTCTGTGTGTTTCCCTGAGTGGTGGCTGCGTGAGAGGGTGAGGGGATTTG- GTGTTGTCTACCATGCCC GGCACATAGCAGGCTCTTAATAATCTTGAATTTAATTAATGTTAAATGTGTATGTTCCCATCCTTGTGGAAG- TTGGTATAGAGCCTGTTTTCCT GTGATTGTGAGACTGGAAAATGGGGGACGGGCAGGGGCGAGACAGGATACAGAGGCTACTGTTTTCTTCCTC- CCTAGAAGTAAGTACATA GAAGAGTGGGCTCTGGCACCTCACGGGACATCACCAAGTCCTGTGTGGCTGGCTAGGCTGTCCCAAGGTGGC- TTCAGGCATCACTTGAAT CTTTTGAGACCTTCAGGCAGTAGCCTGCCATTCACCCTGTCAGTCAGCAGAAGTTGGGCCCACACAGGCCAT- AGAAACACAGAGCAGTTCC CGGGAGGACCTGAGCTGTCCCTGAGAGCAGAGCTTCCAGGAGAGGCCGCAGGAACTGCCTTGACCGGAATTC- CTCTTGGGGTGCAAAGG TGGAGGGACACATGGTGCGACCCCAGGCAGAGGACTGCAGCCACTCCGTGCAGTCCCAGCCTCTGGGGTAGC- CCCTTGACCTCCAGGCC TGCACAGATCCAAGGCCGAGGTCCAGGCTCCAGCGCCAAATTAGCTGGCCTAGCAGCCTGCAGCCGCTCTAA- TCTCAACTAGGAAGGAAT CCTTGCGCTTAGAAAGTCCAAGCGAAAGGGTATTCTGATTTTATCCCGGTTTTACCAGAAAATGCTGAAAGG- AAAAGCCCCGAGAGGACAC AGTGCTCTAGGAACTCGGGGCGCCACGAGCGCCTCATCCCCTCCCTTCCGCCCGGCCGCGGTGCCCTGGTCG- CTGAGGGACGCGGTCA GTACCTACCGCCACTGCGACCCGAGAAGGGAAAGCCTCAACTTCTTCCTCTCGGAGTCCTGCCCACTACGGA- TCTGCCTGGACTGGTTCA GATGCGTCGTTTAAAGGGGGGGGCTGGCACTCCAGAGAGGAGGGGGCGCTGCAGGTTAATTGATAGCCACGG- AAGCACCTAGGCGCCCC ATGCGCGGAGCCGGAGCCGCCAGCTCAGTCTGACCCCTGTCTTTTCTCTCCTCTTCCCTCTCCCACCCCTCA- CTCCGGGAAAGCGAGGGC CGAGGTAGGGGCAGATAGATCACCAGACAGGCGGAGAAGGACAGGAGTACAGATGGAGGGACCAGGACACAG- AATGCAAAAGACTGGCA GGTGAGAAGAAGGGAGAAACAGAGGGAGAGAGAAAGGGAGAAACAGAGCAGAGGCGGCCGCCGGCCCGGCCG- CCCTGAGTCCGATTTC CCTCCTTCCCTGACCCTTCAGTTTCACTGCAAATCCACAGAAGCAGGTTTGCGAGCTCGAATACCTTTGCTC- CACTGCCACACGCAGCACC GGGACTGGGCGTCTGGAGCTTAAGTCTGGGGGTCTGAGCCTGGGACCGGCAAATCCGCGCAGCGCATCGCGC- CCAGTCTCGGAGACTGC AACCACCGCCAAGGAGTACGCGCGGCAGGAAACTTCTGCGGCCCAATTTCTTCCCCAGCTTTGGCATCTCCG- AAGGCACGTACCCGCCCT CGGCACAAGCTCTCTCGTCTTCCACTTCGACCTCGAGGTGGAGAAAGAGGCTGGCAAGGGCTGTGCGCGTCG- CTGGTGTGGGGAGGGCA GCAGGCTGCCCCTCCCCGCTTCTGCAGCGAGTTTTCCCAGCCAGGAAAAGGGAGGGAGCTGTTTCAGGAATT- TCAGTGCCTTCACCTAGC GACTGACACAAGTCGTGTGTATAGGAAGGCGTCTGGCTGTTTCGGGACTCACCAGAGAGCATCGCCAACCAG- AACGGCCCACCCGGGGT GTCGAGTCTTGGTAGGGAAATCAGACACAGCTGCACTCCCGGCCCGCGGGCCTTGTGGCATATAACCATTTA- TATATTTATGATTTCTAATT TTATTATAAAATAAAAGCAGAAATATTTCCCGAAGAACATTCACATGAGGGCATTACGGGGAGACGGCAAGT- CGGCGGCTCGGGGGGCGC GCTCAGCCGGGAGCGCTGTAGTCACAGTCCCGGGAGGAAGAGCGCG 97 chr2: 137238500-137240000 TGGAACAAGTGTCAGAGAGTAAGCAAACGACTTTCTGAGCTGTGACTCTGCTCCTCGACTGCCCACGTGCTCT- CCGCTGTCTGCACTCCTG CCTCACCTGGGCTGACTCGGACTCTCCACCTCCTTTGCTGCTTCCGGCATGAGCTACCCAGGAGCCTAAGGC- GCTCCTTCCCGCAACTCC GGTCCCCGCGCCCCGGGACTGCAAATCCTTTAAACAGAGGCCCCAGAGCTAGGGGTTTTCCCAGGCTCTGGT- GGGCGTGGGCTGACAGT CGCTGGGAGCCCCGCAACAGGGGGGATGTCCAGGCAGGTATGCACCCAGCTCCCGGCGTTTCCCGGAGTCAC- CACAATGTTTCCCTTTCT CTCTCCCCCACGTATGCTGCTAGGGGTACTCCCCAGATAGGATTTTCTTTGTCTTTTCTCCTAGTAACACCG- AAGCCCTCTCGTGCCCGGG GACTGCAGAGGAACGCCAGACCATCCGGACCTTGCGGGATGGCTCGGTGTGTGTGTTTTACTGTGTGTCGGA- GTGTCGCGCATGTGTGCG TGTTGGGGCGCGTTATCAACAGGGGCCTAGGGCACCCCCACTCTTTCTTGCTCTCTTCCCCCATCACTTCAT- GGACCTCCGAGGCGCAAAG CGCTCGACCCTCTCCTGGGCTCAGTGGCTTGGGTACTCCGGGCTGAGCTCAGCTGGGGAGTCCCCTTACCCA- GCCCGCACCGGCACCCC GAAGCTTCAAAGTTGCGGCAAACAGTTGCGGGGAGCAGAGGAACTGAGGTCCAGGCCAGCGCGCCCGCGGTC- GCTCGCCTTGGGGAGC AGGCTGAGCCGAGGGTCGTGCGGGTGCGCGGCAGAGGCGGTAGGAGGCGGAGGAGAGGGGGGAGAAAGAGGG- GGCGGTGGGGAACA GCTGCCGGGGTAGGCGAGGCGCAAGGTGGCTCCCCGCGGCCCCGCGCCCCGCGGCTCTCGGACGCACCAGGC- AGCCAATGGCTGCGC AGAGGTGTACAGCAGATGGCGTCTGACTGCGCCGTTCCTTCCTCCTCCTCCTCCTCCTCCTTCTCTTCCTCC- TCCTCCTTCTCTTCCTCCTC CTCCTCCTTCAGTGCTGAGGAGCCAGAGTCGCCGCCGGGTTGCCAGACGCTGGAATGGGTGGTCTTCCGACA- CACACCACCATCTTTCTT GCGCTCGGGAAGCTCGGGGCTCAGCGGCTCCCAGAGGTTACGGCGGCGGCTCTGGCGAGACGGGTGAGTGCA- AGCACGCGGAGCCCC GAGTCGGGGATGCCGGGCCCCCTGGCCGGCCGACTGGGGCGCGGGGTGGCAGCGCCGGGGAAGGGGGCGCGC- TGCCGGCGCAGACT TTGCTCTTTCCTCGCCGGACAGCCATCGTCGCCCCTTCTCCCAGCCAGACGCGGGAACTTGGAAGCGGATCT- TCTCGGACGCCTCTGGCT TGGGGCTGCGGGAAGCGTGGGCTGCCCGGGGCGCAGTGTGCGGAGACCCTCTAGGCGGGCGGGGACGCCCCA- C 98 MAP1D GTTATTATCCACGGGGTCCTAATTAAAGCTTGATTAAAATGCCCTTCTTTCTCTAAAAAATTACG- AACTAGGCAACTTCATACATTTTGAATGG CGCAGTGTTTCCTCTTCCAACTGTTTAGTTTGTAGTATACTATGTAAGCAACATCAATTATCAACCCTTGCA- AGATGACAACATGAGCCTGTG GGGGAAGCACTTGAGGGGAGGGAGGAGAAACTTCTCTTTTTTAATAATCAGCCGGAAACAATGTTTAACAAG- AATCTGATGAGGTCACTGC AGTAAATATTTTTCCTCTTACAGAGCCAATCATCACGGAGGGATCCCCTGAATTTAAAGTCCTGGAGGATGC-

ATGGACTGTGGTCTCCCTAG ACAATCAAAGGTGTTTGCTTTCTGCTCTGTTGCTTTTAAATTGTATGGGAAAGGAAGATTGGTCCGACGGCG- CGCTTGTGGCCCGGCCGGA GCTTGCGTGCGCGTTCTGACGGCTGGGTGCTGTGTTACAGGTCGGCGCAGTTCGAGCACACGGTTCTGATCA- CGTCGAGGGGCGCGCAG ATCCTGACCAAACTACCCCATGAGGCCTGAGGAGCCGCCCGAAGGTCGCGGTGACCTGGTGCCTTTTTAAAT- AAATTGCTGAAATTTGGCT GGAGAACTTTTAGAAGAAACAGGGAAATGACCGGTGGTGCGGTAACCTGCGTGGCTCCTGATAGCGTTTGGA- AGAACGCGGGGGAGACTG AAGAGCAACTGGGAACTCGGATCTGAAGCCCTGCTGGGGTCGCGCGGCTTTGGAAAAACAAATCCTGGC 99 WNT6 TCCCTGCTGTGGGACCCGAGGAGAGGAGAACTGGTTCGCT 100 INPP5D TCTCTCTCTCTCTCTTGCTTGGTTTCTGTAATGAGGAAGTTCTCCGCAGCTCAGTTTCCTTTC- CCTCACTGAGCGCCTGAAACAGGAAGTCA GTCAGTTAAGCTGGTGGCAGCAGCCGAGGCCACCAAGAGGCAACGGGCGGCAGGTTGCAGTGGAGGGGCCTC- CGCTCCCCTCGGTGGT GTGTGGGTCCTGGGGGTGCCTGCCGGCCCGGCCGAGGAGGCCCACGCCCACCATGGTCCCCTGCTGGAACCA- TGGCAACATCACCCGC TCCAAGGCGGAGGAGCTGCTTTCCAGGACAGGCAAGGACGGGAGCTTCCTCGTGCGTGCCAGCGAGTCCATC- TCCCGGGCATACGCGCT CTGCGTGCTGTGAGTACAACCTGCTCCCTCCCCGGGCACAGATATGACAGAGGGGCTTAGAGGGGGCCCAGC- TTTGAGATGGGTTGTTCT TATGTCACAGGACAGAGTGATCTGACATGCACACTTCCCCGCCACCCTGTCAT 101 chr2: 241211100-241211600 TGTCCTCGAAGAAGGGCCTGAGCAGCAGCAGAGGACCCCAGGCGACCGTGCCTGAGCCGGGCGCCGACGACGA- CTGAGCACCTGATAT GTCCCCGGCACTCGCAGCCCCGCGGCCGGAGTCGCTGTGGGTGAGCGGTCGTCGAGCTTCACAGAGGCCGGG- CTCTGTGCCAGGGCCC CGACAGGGCAGGAAGCAGATAGAGTCCCACAAGCACAAGCCCAGTGCGCAGAAAGGGTTACTTAAAAAATAA- GTTCTGTGATAAAATCAAA CAGGGTGAAGGGCTGGAAACAGGTCATGAGGGCGCAAACAGGTCGTGAGGGCGCAAACAGGTCGTGAGGGCG- CAAACAGGTCGTGAGG GCGCAAACAGGTCGTGAGGGCGCAAACAGGTCGTGAGGGCGCAAACAGATCGTGAGGGCGCAAACAGGTCGT- GAGGGCGCAAACAGGT CGTGAGGGTGCAAACAGGTCGTGAGGGCGCAAACAGGTCGTGAGGGTGCAAACAGGT 102 WNT5A AAATGAGACCTCTGGGGAGACTGTCAACCCCAGGGGTAAAACAAAAATTCTGATCAGAAACTGA- GTTTCCCAAAGAAGGGGCTAAATGTTTTCCAACACTTTCG GGGCTCAGGGAAGATGACTCTGTAAGGACACTGAGAATCTTCCTCGCGTGCCACGGGGAGGAGGACTGGGGG- CGTTTGAGGGGCTCAGCGCA CCAGAGGAGTGAGGTGGAGGAGGGCGTTCCCGCGTCCTCCTCTTCAATCCAGAGCAGCTCAACGACGTGGCT- CCCAGGGGCTCATTTCTATG TATCCCTCAAAGCCTTCGCGT 103 chr3: 138971600-138972200 TAGGCTCTAGTGGACCTAGCAGTGGGAGAGCTACTTGGGCTGGTTTCTTTCCTGACGCTGCAGGGATGGGCAT- CGGCCTGGAACCAGAAG CGCAGGAGCTGGGCCACGGCAGAGTAATTAAGAAAATAATGAAATTGATGGCGGATGGGGGCGCTAGAAATC- CTGGGGCGTCTACTTAAA ACCAGAGATTCGCGGTCGGCCCCACGGAATCCCGGCTCTGTGTGCGCCCAGGTTCCGGGGCTTGGGCGTTGC- CGGTTCTCACACTAGGA AGGAGCCTGAAGTCAGAAAAGATGGGGCCTCGTTACTCACTTTCTAGCCCAGCCCCTGGCCCTGGGTCCCGC- AGAGCCGTCATCGCAGGC TCCTGCCCAGCCTCTGGGGTCGGGTGAGCAAGGTGTTCTCTTCGGAAGCGGGAAGGGCTGCGGGTCGGGGAC- GTCCCTTGGCTGCCACC CCTGATTCTGCATCCTTTTCGCTCGAATCCCTGCGCTAGGCATCCTCCCCGATCCCCCAAAAGCCCAAGCAC- TGGGTCTGGGTTGAGGAAG GGAACGGGTGCCCAGGCCGGACAGAGGCTGAAAGGAGGCCTCAAGGTTCCTCTTTGCTACA 104 ZIC4 GAGGTTGCTGACTCAGGAGCCAGGAGCTGAGAAACTCCTAGGCTAGCAGCCGTTGAGCCTAATTT- TATTTTCTGGCTTTCTCCGAAATGTCT CGTTTCCCTCATCTTTCTGGTCCTTTTCGTCTCTCTTATTTTCCCCAAAACGTCTACCTCACTTCGTCTTCC- TTTCTCCTCCCCTCCCCCTCTC TTTCCTCTATACTCTCTTCCCATTTAGCCTTGCAGGCCCCTCCTCCCCGGTGTTGGAGAGCTCAAAGACGCG- CGAAACTCAAGGATCTGGC CCTGACCAGGGACGGGATTAGGCGGGAAGTGGTGACGGCCTGAAAAGGCTGGGCTCGAACCCGTGCCTTCCT- GAAAGGACTCTCCCCGC CACAAGTCACACCCACCCGCAGGCCTGCTGGCCAAAGAAACAAAGGAGTCGGGCGTGGATCCAGGAGAAACA- GGTTTTCGCTCTCGGATC TCCCTGGGCAAATCAGGGATCCTGAGCGCTATACCCCGCAGTCGTACGGAGCCTCTGGGAAAGGGGATTTAA- GGGTGACTTCCACTTTCA GCTTCGGCTACTTGTTGCCTGCGGTCCAAGCCTTCTCTGCTTCCTCCTACCTCGTCTTAGGCCTCTGTAGAA- AGTGCACGCCGCGTTTCCC CTTCCAGGCTCTGAGAGGGCCTGCAGGCCCGTGGCCGCCTCCGACAAGATGCCTTCCAGTGCTAGGGGGGCC- ACTTTGGCGGGATGGGG GTCGGTTGGTTAAAAAAAACTTAAGTTCTGGCTCAGTCGAGTGTGGCAAAAGCCGAGGGTCGGGGGTTGGGG- GG 105 FGF12 TACTGACCTGGTCTCCGCCTCACCGGCCTCTTGCGGCCGCTGCAGAAGCGCACTTTGCTGAACA- CCCCGAGGACGTGCCTCTCGCACAGG GAGCGCCCGTCTTTGCTGGGGCTGGAGCGGCGCTTGGAGGCCGACACTCGGTCGCTGTTGGACTCCCTCGCC- TGCCGCTTCTGCCGGAT CAAGGAGCTGGCTATCGCCGCAGCCATAGCTGCTCAGCGAGGGCCTCAGGCCCCAGCCTCTACTGCGCCCTC- CGGCTTGCGCTCCGCCG GGGCGAGGGCAGGACCTGGGCGGCCAGGGAAAGGGCAGTCGCGGGGAGGCAGTGCTAAAATTTGAGGAGGCT- GCAGTATCGAAAACCC GGCGCTCACAAGGTTAGTCAAAGTCTGGGCAGTGGCGACAAAATGTGTGAAAATCCAGATGTAAACTTCCCC- AACCTCTGGCGGCCGGGG GGCGGGGCGGGGCGGTCCCAGGCCCTCTTGCGAAGTAGACGTTTGCACCCCAAACTTGCACCCCAAGGCGAT- CGGCGTCCAAGGGGCA GTGGGGAGTTTAGTCACACTGCGTTCGGGGTACCAAGTGGAAGGGGAAGAACGATGCCCAAAATAACAAGAC- GTGCCTCTGTTGGAGAGG CGCAAGCGTTGTAAGGTGTCCAAAGTATACCTACACATACATACATAGAAAACCCGTTTACAAAGCAGAGTC- TGGACCCAGGCGGGTAGCG CGCCCCCGGTAGAAAATACTAAAAAGTGAATAAAACGTTCCTTTAGAAAACAAGCCACCAACCGCACGAGAG- AAGGAGAGGAAGGCAGCAA TTTAACTCCCTGCGGCCCGCGGTTCTGAAGATTAGGAGGTCCGTCCCAGCAGGGTGAGGTCTACAGAATGCA- TCGCGCCGGCTGCGGCTT TCCAGGGGCCGGCCACCCGAGTTCTGGAATTCCGAGAGGCGCGAAGTGGGAGCGGTTACCCGGAGTCTGGGT- AGGGGCGCGGGGCGG GGGCAGCTGTTTCCAGCTGCGGTGAGAGCAACTCCCGGCCAGCAGCACTGCAAAGAGAGCGGGAGGCGAGGG- AGGGGGGAGGGCGCG AGGGAGGGAGGGAGATCCTCGAGGGCCAAGCACCCCTCGGGGAGAAACCAGCGAGAGGCGATCTGCGGGGTC- CCAAGAGTGGGCGCTC TTTCTCTTTCCGCTTGCTTTCCGGCACGAGACGGGCACAGTTGGTGATTATTTAGGGAATCCTAAATCTGGA- ATGACTCAGTAGTTTAAATAA GCCCCCTCAAAAGGCAGCGATGCCGAAGGTGTCCTCTCCAGCTCGGCGCCCACACGCCTTTAACTGGAGCTC- CCCGCCATGGTCCACCC GGGGCCGCCGCACCGAGCTGGTCTCCGCACAGGCTCAGAGGGAGCGAGGGAAGGGAGGGAAGGAAGGGGCGC- CCTGGCGGGCTCGGG ATCAGGTCATCGCCGCGCTGCTGCCCGTGCCCCCTAGGCTCGCGCGCCCCGGCAGTCAGCAGCTCACAGGCA- GCAGATCAGATGGGGAT TACCCGCCGGACGCAAGGCCGATCACTCAGTCCCGCGCCGCCCATCCCGGCCGAGGAAGGAAGTGACCCGCG- CGCTGCGAATACCCGC GCGTCCGCTCGGGTGGGGCGGGGGCTGGCTGCAGGCGATGTTGGCTCGCGGCGGCTGAGGCTCCTGGCCGGA- GCTGCCCACCATGGT CTGGCGCCAGGGGCGCAGGCGGGGCCCCTAGGCCTCCTGGGGCTACCTCGCGAGGCAGCCGAGGGCGCAACC- CGGGCGCTTGGGGCC GGAGGCGGAATCAGGGGCCGGGGCCAGGAGGCAGGTGCAGGCGGCTGCCAACTCGCCCAACTTGCTGCGCGG- GTGGCCGCTCAGAGC CGCGGGCTTGCGGGGCGCCCCCCGCCGCCGCGCCGCCGCCTCCCCAGGCCCGGGAGGGGGCGCTCAGGGTGG- AGTCCCATTCATGGG CTGAGGCTCTGGGCGCGCGGAGCCGCCGCCGCCCCTCCGGCTGGCTCA 106 GP5 GGGGGACACAGAGAGGAGGGGTTGCGGGCCTGTGAGAATGAAGAGCACAGAGCGGAGAGGGGGAGG- AGGAGGGAAAGGAAGGCGTGG CAGTGAGAGAGAAGAGGAAGAAGAGAGGAGGAGTGGGGAGGGGAGGGAGAGCAAGACAGCAGCGGGTCTGGA- TTCCCCTCCGAGCCAC ATCTGGTCAGGTTCTAAGTAATTAGAAGATTTTCCCATTGGTTTACCCAAGGGCTCTCTCTCTGATTAATTT- TCGAAAGAGTTGGCCAATTTTA ATCATAGCAAACACGATGATCACGGTGATCATGGCCTGAACAGCTAAAAGCAGAAAATAAAACCCCCAGAAC- GGACTATGATCTTGACCTTT GCCCGTGGTCACCGGCTGGGCCCACACCCAGGGTTCTGAGCTGTTGGGAGCCAAGGCTGGGTGGACAGGGGC- TTCCGAGGAGCTGTCC GCAGCGGGGCGGGGAGGCGGGCCCCGGGGGCCCGGGCACTCCGCGTCACCCCCCGGCAGGGCCCAGAGCGGC- AGGCCGGCGTGCGC CCCAGGGCCTGCGCACCGTGGGGGCTCTTCCCCGCCCACGAGGCCTAGGTGCTGCCGCAGCCACCCCAGGAA- GGGCCCCAGGCCACAG TCGCAGCGCCAGGAGTTGTGCCCCAACAGGACCTCCGTCAGCCGGGGCAGAGCCCCAAACACGTCGCCAGGC- AGGGTCTCCAGCTGGTT GTGGTCGAGCTGGACGCTCTCCAGGCTGCTGAGATTGCGGAAGAGGGCACGGGGCAGGGCGCGCAGCCTGTT- GCGGCGCAGGGACACC 107 MSX1 GCCCCGGTGCACCGCGCGTCCAGCCGGCCCAACTCGAGCTAGAAGCCCCAACCACTGCCCAGTGC- CTGAGTTGCAGTCTTGGGTCCTTTA GAAACCTGGAGATGTGCGTAAAATTCAGATGCCGGTATTCCCGAACTTCCCCAGGCCTCAGCATATCTCGGC- GGCCTGTGGACAGATGGG AGGCTACCAATCGCTCCGGCGTCCGCAGCCCGACCCCTGCCGCCAGACCCCGGACGTCTTCCGGATAATAAA- GTTCCCGCTCTAATTCAT TTTCCCTAATCTGGACGCCCCTAATCTACAGCTTTTATTGCGCCCAGTTAAAAGTCGAGGGAATTCGCTGTC- CCTCCGCGCTCGGATAATTA CCCCTAAATGGCCACGGCAGCCCCTTGTGTTTCCTGGAGATTAGAACCCCGCAGTCATCAATGGCAGGGCCG- AGTGAGCCGCCAATCACC TCCGCTCACTCCCTGAGAGCCGCTGGCCTGGGCCGCAGGAGGAGAGGCCATAAAGCGACAGGCGCAGAAAAT- GGCCAAGCCCCGACCC CGCTTCAGGC 108 NKX3-2 AGGGTGCCTCTGTTCAAATTAGAAAAAGGCGCCCCCTCAGGGCAGACTCAGCCCAGCTGCCAG- GGGACAAGTCCTGGCTAACGGGAGCT GGAGCTGGGTTTCACCTCCAGGTGCCTCCTTGGCGGGGCGCCCCGTGCAGGCTACAGCCTACAGCTGTCAGC- GCCGGTCCGGAGCCGG AGCGCGGGAATCACTCGCTGCCTCAGCCCAAGCGGGTTCACTGGGTGCCTGCGGCAGCTGCGCAGGTGGAGA- GCGCCCAGCCTGGGAG GCAGTAGTACGGGTAATAGTAGGAGGGCTGCAGTGGCAGAAGCGAGGGTGGCCGCAGCACTTCGCCGGGCAG- GTATTGTCTCTGGTCGT CGCGCACCAGCACCTTTACGGCCACCTTCTTGGCGGCGGGCGCCGAGGCCAGCAGGTCGGCTGCCATCTGCC- GGCGCTTTGTCTTGTAG CGACGGTTCTGGAACCAGATTTTCACCTGCGTCTCGGTGAGCTTCAGCGACGCGGCCAGGTCTGCGCGCTCG- GGCCCGGACAGGTAGCG CTGGTGGTTAAAGCGGCGCTCCAGCTCGAAGACCTGCGCGTGGGAGAAAGCGGCCCGCGAGCGCTTCTTGCG- TGGCTTGGGCGCCGCC GGCTCCTCCTCCTCCTCCGCGACGCCTGCCGGCCCGCTGCCGCCCCCGCCGCCGGCCCCGCTGCACAGCGCG- GACACGTGTGCACCTC TGGGGCCAACACCGTCGTCCTCGGTCCTTGGGCTGCGGTCGCCTGCGGACCCCGGTGGGAACAGAAACAAGA- GACTGTCAGCGCCACAG ACGAGGTGAGGCCGGGCCTCAACTGCAGGGGTCACGGGAGTGGGGCGGAAATACACTTTGATCCCACTCAAG- CGGAGCGGAGGTCTGG GAGGCCCTGGGCCCGGGAGACCAGTCTTAGACTCTTGCCCCACTGGGTATCCCATCTAGGCCTCTTCTGGGG- AGGGCGGCAGACTCAGC CGCTGTGTCAACGCTGTGTTGTCGAGACCAGCTCCCCACCCTCTCTGGGCCCCAGGCTCCCCTCAGTAACTT- GGGGCACTCGACCCGAGC ATCCGCGAAAGCCCTCCCGGCTCTCAGCGTTGAGCATTGGGATTCTAGACTGCATTTCCGTCTCTCTGCTTG- GGTTCACGCGCCTCTCCAC ACTTAGTTCACACGCACACACGCGCGCGTCCTCGCAGCACACACTTGTCTGGTGCAGGTAAGGGAAGGTGGA- GGCGGATCCTGGGGCCA AAGGTATTTAGAATCTTTCACCCTCAGCCGCCTGGGATTGCTGTGAGAGACATGGAAACAGGCTGAGCCGAG- GCCTTAGATGAGAGGATG GACTGGAGAGTAAAGAGGGAGGGTTGCCCCTGCATCGAGTTTTTGGACCCTGATCCCACACCAGCTTCTCGG- TCTCGTACCCGCCCTTCC GAAGAACTCCAGCAGAAAGGTCCAGCGGTCCCCTGTGCTTGAGGCCTACAGAAGCTTGTACCCAACTAGGGC- AGGCACCCGGGTCTTCCA GACCACAGGACAGGACAGGCCACGGCTGAGGAGGCCTCTCTCCTGCCTCCAGGATGAACTAAAGACCCAATC- CGGGATCTTCGGCCTAG GGCTGCTCTCCCAGACCTGGGGTCTGAGAAAGCCAAACCAGCCCTTTCCCCAAAGCTCTAGTTCTGCAGATT- CTCAGCTCTGGCCCACTCG GAGGTGTTCTTCACCACCTATCCACCTACTGTGGGGCCCGGCCCTGGGACCTTGAACTGGCAGGTCTCTGGT- CCAGAGCTAGGTCACTGG CTACCTGAGGTCTCTGAACCCCTCACTTTTCCGCTTCCCTGATTTTGGGGATTTGGGGACAGACACGGCAGA- AAGCACTGGCGACGAACTC AAAAACTCCCGAACGCAAGGGGCAGCGGTTCTCCCAACCCAGTCTAATGCACATTGGCCCAGGATGTCTCAG- GCCTCACCCCAGGACGTA GGGCTCTGAGGAGCTACTCCGGTCTCTCGCGGGCT 109 chr4: 111752000-111753000 GAGAAGGGATGTGGCGGGGGGCTCCTCCGGCCCTGGACTCCCTGGGTGGACTAGAAAAGGGCAAAGAAGTGGT- CACATCTGTGGGCCAG ACTGGTGCGCGATCTTTGGAGGCGCAGCAGCAAGGCCGCGCCAGGGCTGAGCCCAGACCGCCCACGAGGAGG- CCCGCCAGGCCCGGA GCAGCGGCGCGTGCGGGGGCGTGCCGAGCGCAGGCTCTAGGGCCCCTGCTTCGCCCCAGCTGGACCCCGCGG- GCGGTCGGTGCAGCT CGAGCGTGTGGGCTGCGATGCCCTGCCTGAGACTTCGGGCTAGGGATGCGGGCGGGAAGTGGGGGTGCGGCG- GCAGCTGCAGATTAGA TTCCTTTTTTTTTTGGCCGGAGGGACGTGCAAACTTCTAGTGCCCGGGCCAAGAGGGCGACCCCGGAGGTGC- GTAGGTGGCCCTCCGGGT TCCCGCTTCTCCTAGTGCCTCTGAAAATACCGTCAGGGTAAAGGGAGACAGGCAGTAAGTCTTACCACCACC- GCCCTTTCCCCATGTCATT GGCCAAAAACTGAACATTAAGATAAAGCAGCTGTTTCAGTCAATGGAAAGCGGTAGGGCGAGGTTGTACCCA- AAACCCGGTTTAGACGGCC AATGAAGTCCTAGGAAAAGCCGCCCCGGGGGCACGTTCAGGTGGAGCGGCTGCACCTCGGGTCGTTCTAAGG- GATGGGCTGCGTGGTAC CCACGGAATTCATGGGTCCAAAAGGTCCTGGTCACCTGTCCAAACATCCATCCCCTGGCGCATGGCGGTTGA- CAAGATGGCCCGGCCACC CAGAGGAAGGAGGATCCGGGACGGGGAACTTCGCGCCGGGAAGCTGTAGCCCAGAGCTGCAGCTCAGCATTC- GCAAGAGATTCATCTTTT TTTTCTCTCGTGTTCGGAGAAACAGATAAACAAGACACCGCCTCATCAGATAAGAACGTCTCCTTCGATGTC- ACGGATTTCAAGAGGTAGCTGGAGAAACTG ACGTCA 110 SFRP2 CAGGTCAGGCAGAACTTCTGCCCTTCCCGCTACTGGCACCCCAAGCAGGGATGCACTGGGATGC- GTGGCAGGGGCGGGATCTCCTGGGA GCGTCTCAGCCCAGCAGGGAGTGGGGAAGCAAGAGGGAAGGCTTACCTTCCTCGGTGGCTGGCAGGAGGTGG- TCGCTGCTAGCGAGGG GGATGCAAAGGTCGTTGTCCTGGGGGAAACGGTCGCACTCAAGCATGTCGGGCCAGGGGAAGCCGAAGGCGG- ACATGACCGGGGCGCA GCGGTCCTTCACCTGCACGCAGAGCGAGTGGCATGGCTGGATGGTCTCGTCTAGGTCATCGAGGCAGACGGG- GGCGAAGAGCGAGCACA GGAACTTCTTGGTGTCCGGGTGGCACTGCTTCATGACCAGCGGGATCCAAGCGCCGGCCTGCTCCAGCACCT- CCTTCATGGTCTCGTGGC CCAGCAGGTTGGGCAGCCGCATGTTCTGGTATTCGATGCCGTGGCACAGCTGCAGGTTGGCAGGGATGGGCT- TGCAATTGCTGCGCTTGT AGGAGAAGTCGGGCTGGCCAAAGAGGAAGAGCCCGCGCGCCGAGCCCAGGCAGCAGTGCGAGGCGAGGAAGA- GCAGCAGCAGCGAGC CAGGGCCCTGCAGCATCGTGGGCGCGCGACCCCGAGGGGGCAGAGGGAGCGGAGCCGGGGAAGGGCGAGGCG- GCCGGAGTTCGAGC TTGTCCCGGGCCCGCTCTCTTCGCTGGGTGCGACTCGGGGCCCCGAAAAGCTGGCAGCCGGCGGCTGGGGCG- CGGAGAAGCGGGACAC CGGGAGGACAGCGCGGGCGAGGCGCTGCAAGCCCGCGCGCAGCTCCGGGGGGCTCCGACCCGGGGGAGCAGA- ATGAGCCGTTGCTGG GGCACAGCCAGAGTTTTCTTGGCCTTTTTTATGCAAATCTGGAGGGTGGGGGGAGCAAGGGAGGAGCCAATG-

AAGGGTAATCCGAGGAGG GCTGGTCACTACTTTCTGGGTCTGGTTTTGCGTTGAGAATGCCCCTCACGCGCTTGCTGGAAGGGAATTCTG- GCTGCGCCCCCTCCCCTAG ATGCCGCCGCTCGCCCGCCCTAGGATTTCTTTAAACAACAAACAGAGAAGCCTGGCCGCTGCGCCCCCACAG- TGAGCGAGCAGGGCGCG GGCTGCGGGAGTGGGGGGCACGCAGGGCACCCCGCGAGCGGCCTCGCGACCAGGTACTGGCGGGAACGCGCC- TAGCCCCGCGTGCCG CCGGGGCCCGGGCTTGTTTTGCCCCAGTCCGAAGTTTCTGCTGGGTTGCCAGGCATGAGTG 111 chr4: 174664300-174664800 TGCGATCATTAAAATCAGTTCCTTCCCTCCTGTCCTGAGGGTAGGGGCGGGCAGATTTTATTACTTCTCTTTT- CCTGATAGCAGAACTGAGG CGGGGTTGTGGAGGAGCGACGGAGGACCACCTCTAACTTCCCTTCACTTCCTGGATTTGAAGCCTCAGGGCC- ACCGGCCTCAGTCCTGTT ACGGTGGCGGACTCGCGAGGTTTTCCAGCAGCTCATTCCGGGACGGCGGTGTCTAGTCCAGTCCAGGGTAAC- TGGGCTCTCTGAGAGTCC GACCTCCATCGGTCTGGGAGCGAGTGGTTCGAGTTCAGATGCTGGGAACCGTCGCTTCTCCCCGGCCGGGCT- CGCTGTTTTCTCCTCCGC TCGCCGTCATCAAGCCCGGCTATGAGCAGGGCTTTAAATCCTCCCTCCCTCACCCGCAGGTTTACCGAGCAG- CCCCGGAGCTCTCAGACA TGCTGCGCTGCGGCGGCCAGAGGAGGGGTGGGGGCATTGCCCTCTGCA 112 chr4: 174676300-174676800 GGGCTTGGGCCGCAGGCTTCCCTGGACTTCCGCAGTCCCCCTTCTCCCCATTCCAGAACCTGCCGAGCCCCTG- CTGCATCTGGGACCCGC CTTCACCGTTTCCCAATCCCAGCGGTTAGCCCCTGCGCCCCCTTTTTGGTCTCCACTTTGCCGTTCGAAAAT- GCCTAGGTTGGTGGATCGA CCCTCCGCGGAGCAAAGACGGATGGCTGGCAGGAGCAGGTTCAGGAGCTGGGCCAAGGTATTCTCTGCTTCC- GCCTTTGTGTCCGCCCC CCCGCCCCCTGCTCCCCGCTTCCCGCCAGCATCTCTCCTTTTCTGCTCAGGAGTGTTTGGCCCGGCGGTCCA- CCCCGGCTTCCCGAGATA CGCTAGAGTTGCCCCCACGTCCTGTCCGCCGCGCCCCTACCCACCGGGTTGCCTTCGGGGCCCTTCGGTGCT- GTGTAGTCGGCGTGGCG CTGTGAGCTAGGCGAACAGGAACCCCCAGGCCCGCCACGTCTACGCTATTA 113 SORBS2 TTCTGGGGCCTGGATGGGTGCGAGCGGGACCCGGGGGAGTGGGAGTCGCCAGGCTCTGAGCAA- GCAAGGGCTGCACCTGCACCTCTGC CGGGCATGAAGAAAGGTAAGGAAGGAAGGAGCTCACCCGGGTGGGAGACAGAGCCGGGGCGCGCGAGCTTGG- TGTGGGGGCGCCACTC CGGGGCGGAGGGGAGGGGCTACCAGTGACTTCTCCGAGTCGGGAGCTAGAAAGAGGCTTCCGGCCAGGTTCC- CTTGGAACAGGTGTCG GAGTTGTTGGGAGAGGGGGCTGCAAGAAAGAGGGGTGCAGAAACTGGTTCATTAGATGGAGGCTCTGGGCGG- AACCGCGAGGACACCCT GGCAGCGCGCTGTGCCTGCGTTAGGCCGGGAGGGGAGAGGCCTCCGGACGGCGAAGTGTCCCTAGGGACCCA- GACGCCTCGGGAGCG ATCCGGGCCGCTGCGAAGCCCTGCCCACCAGGAGTGGATCCCCAGGATTCACCTCCCGGCTGCCTGCTCTGA- GCTGAGAAGGGGATCTG GTTCTTCACAATACCGTGGATGGCGGGGAAGGGGAGGGAGCCTGGGGTAAAATCCCATCTTGGTTTCCTCG 114 chr5: 42986900-42988200 TGTCACAGAAACCCCAGCAGCGCAGCCACCGGACTGGGTTCTGGAGGCCGAGCCGCAGTCCGTGCGGCGGCGC- TGGGAAGAGAAGGCG CCCCGGCAGCTCCCCTGCCACCGGCCCCGAGGAGCGGCTGGCTCCCCCAGCCCAGCGCCGCCGCCGCCCGGT- AACTCCAGGCGCAACT GGGCGCAACTGGGGCAGCTGCGACACCGAATCCCTCACATCTGCAACCTGGGTGCTGCGGCCACTGAGAAAA- TGGAGGCGCAGACCAAC GAGCGGTGCCGCGACCGAGAGACCTCGGCTGGCGAAATGGTGGTGCCGGGAGCCTGCGAGTGACGCCAGCCG- GCGGGGTTGTCAAGGA CAACATTCGTTTTGACGCAGCCAATGGCGCCGTCACCAAGAAACCATCGACTCTGAGAAAAAAGAGAGGTTC- GGCCACCGAGAAACTCCGT ACGACAAGTGCTGTGGCAGAAAAACCGCCTACTCCGCGCCACAGGCAAAACAGCCAATGGAAACCCCAGGTG- CTGCGACCGTGACACCG GCACTAGAGGGTCTCGGATGGAGAAAGCGGCGCACGGAGACCAGGAAACTATGTGTAGCACAACTAGCAGAA- AACCGTCTGGTCGGCCAT CCGGGAGAAAGCGCGGATCAGAAACAAGCGACTTCGATGCAGGGAACCGCGCAGCCACTGAAGAAAGTGACC- CACGTGGCAGTGGTGCC AGCGAAACACTGCAGTTTGGACGGCAGCTGTGGGGATGCCACAGAGAAACATGCACTGCCACTGAAGTACAT- CCAGCTCCGCGGAGCTAG TGTTCATATGATCAAGAAACCGCCAGTTGGGCTCTGCTAGAAACTTTTAGTCCTCCCTTAACGGCTATCCTA- CCCACAACAGACAATGCCTTT ACCCAGCACCTAGCGGTGCTGAGACCCGCCTGGGCCAGCACAGAGCGCAGAGCAGTACGGGTACGGAGAAAC- GCCGGACTCAGTGAAAC CAGCCTTGCCTCCAGCGGATTCCCCGGCTTCGCCGGACGCCACAGGCAGAGTGCCGCGGGGAAACCTCTGGC- TCCCTAAACCGATTAGA TTGTGGGAGTGGGGGGGACACTCACAAGTTGTGTGGAAGGGAACCAGCGGCAATGGGACCCGGCGAGCACTT- GCCCGCAGCAAATGCCT GCGCTGCTGCAAAAAAAACAACTTTTGGCGCAAAGAATGTTGCGGCCAGAGAGCATCCGCTGTCGCTGACAA- AGGAGTAGCAATGGCAAT GAGAAACCGCCGGCGCCACGGCCGACCGCGGCGGCTCACGCCTATGAT 115 chr5: 72712000-72714100 CAAACGCTGAGAGACAAAAAGACACCAACACCCACCAGGACTGCGTCCTGCCAGCTCTTCACTCCGCTGACCT- GACCTTCCACGCCCCTA GTCCTCGAGCGGACTTGACCTGTGGGGGAGTACCGAACCGTCCCCATGAGGCCCTCCAAGCGGCCAGGTGGC- CTCCGCCACTCTCTCCA CCCCCACCTCCTCCACCCCCCAGCCCATCGGTCCATCTTCGATCTGCAAAACACGCCGGGTCAGCGACGCAT- CGGTCCCAGGCTTGTGAC CACCTCTTTCTCTGTTACTTGGGGAGCCAGGCCCACCGCTCAGGATCACAGTGAGGAGAAAAAAGACACAAA- CGCCAGGACAGGGCGGCT GGGGAAGGAAACTGCTAGGGACCGCTCATTGTCAGCCTGGCGTGTCCCACGGATCGCAGGACCCGTCGAGGC- TTTGCTCTCTGCGACCC GAATACTCCTGGGCCTCTCGACCTCCTCCTCGGACTCAGGCGTCCGCGTCTCCGGTCATCACGGGAGACCAA- TTGGTTTACAAATAGTGAT GATAAACCTGGGACCGACCTTGGGGCTGTGTAAAAGTCTACTGACAGATGTAATGGAGGGTTGTTAGCAGTC- ACAAAGCCTGTCGGACCCG TAGCATTAGTTCAAGAGACTATTTTCGTGTCGCACCAAAATTACTGCGCGTGTAAACCAATTTCCCCGACGG- AAGAATAAACAGAGATTCGTT TGAAGCGCGAGATGAAAACAGATGGGGTATCGCAAACAGTTCCCCAAAATACAACAGACTTCTGGGCCAATT- ACACGTGGTTAGCTCTGAA TGGCAGAGGAAATAGTTTTCTTTGCTGCTAAATGTCACAAAAGTCACCTAAAGGCACAGAGGAGGCCGCTCT- GTTTTTGCGAAACTTGCTAA AATTAATCTGCGCTGGGCCACTTGCAGAAAGCAGAACCACCTCCCGCCCCCACCTCGCCTCCAGCCGCCGGG- GTTCAGGCGTTTGTGAAA GACAGAACCTTTGGGCTAGGGACCCGGGCACTGGTGCTTCGAAGTCCGAATCCGCCGGCCGAGAAAACGACA- AGAGAAAGAAAATCCAGC GGGCGCTCTCTCCAGCGCCAGGCCGGTGTAGGAGGGCGCTGGGGCTCGGCCTGCCACCCCTACCCGACATTG- GGAAGCAGCCCCTGCG CTCCCGCGGCGCCTCAGCCTCCGGTCCCCGCCCCGAGGTGCGCGTTCCTCCTCCCGCATGCCCGTCTCGGGC- CCCACGGAGCAAGAAG ATAGACGATGACGAGGCGCGCCCATCCATCCGGGCCGACGAGGTCAGGCCCGCGCCACAGGCAAAAATTGCG- CAAGCCCGGCCGCAGG GATTTCGCGGGCGCCTGGGTCCCAGGTGCGCGGCCGAAATCCTCAGGGAAAATCCCGAGGGGCCAACGGTCT- AGGCCACAGGGCTGCT GGGCCCGGGCCTGGCTCAGAGCGCATTCGGGCGGGGAGGCCGCACGCCGCACCCGGGCCTCTCCTCCGAGCC- CGAGGCAGGCACTGA GCTCCGGGCCAGCCAGGTGCCTCCCGGCTGGTGCGAGACCCCGGGCCTGCTGGGAGGCGTGGGCAGGGCAGG- GCAGGGCTGAACCCC AGCGACTGAATCTCGAAGGCAGGAGGCCTCGGAGGTCATCGGCCCAGCTCGCCTGAAACTGTCCCTGCTCGT- GCCAGGGCGCGGGCAGA GGAGAAAGGACAGGGCGGAGCAAGCCCACTGCAGAACTGCGGTCGGTGGCTGCGAAGGGTCCGGGTCACCGC- GCTCCCGGACGCCGGA AGCCGCGCTGGCGGGGCCGCGGGGAGGGAGGCTGGGTACCGGGGCCGTCCGGCCGGAGGAAGCGGCTCCGGC- CGCGCTGTCCGCGC TTGGGAGCCGCGTGCAGGGTTCAGCCGTGTTTCAGTTGCCCTCTGACCTGACCCCGGGCGCACAAAGGCCTC- CCGGGTGCGCCGCCATG GCCCAGTCTTCCAGTCGCTGCCAAATTAATGAGCCCACGTCAGGTTGGGTTTACAGCTCGGCCGGGAAGCAG- CCGAGTGGAAAATGAGCT CGGGGCCGCTCCAGAGGCTCCCGCACAACTGCAGAGGCTGCCCGCG 116 chr5: 72767550-72767800 TTTCCAAGACAGAAGGAGGGAACTAGGCGCCTTTTTTCCACTCCGCTGACCCCAACGTCTGGGCTGTGCGTTG- TAACGCAGTTGGCGGGG CCTTCAGCTTGGGATGAGGGCGAAGGGGCTCGGGATGGGTGGGAAAGCAAGGACCGGGCAACAGGTGGGGAG- GTGGCGGACTTTTGTC TCGGGGAAGGAAATCGGCTGTGCTGAAAGGGCGGAAAGCAGTAGCGCACAGAACTAGTGTCTGCGGGGTCCC 117 NR2F1 CCCTCCTGTGGCTGCTTGGGCAGACGCCTGTGGCCTGTCGGATGCGGCCCACATCGAGAGCCTG- CAGGAGAAGTCGCAGTGCGCACTGG AGGAGTACGTGAGGAGCCAGTACCCCAACCAGCCCAGCCGTTTTGGCAAACTGCTGCTGCGACTGCCCTCGC- TGCGCACCGTGTCCTCCT CCGTCATCGAGCAGCTCTTCTTCGTCCGTTTGGTAGGTAAAACCCCCATCGAAACTCTCATCCGCGATATG 118 PCDHGA1 TCCTCCTTTGTGTATGTCAACCCAGAGGATGGACGGATCTTTGCCCAGCGTACCTTTGACTATGAATTGCTGC- AGATGCTGCAGATTGTGGT GGGGGTTCGAGACTCCGGCTCTCCCCCATTGCATGCCAACACATCTCTGCATGTGTTTGTCCTAGACGAGAA- TGATAATGCCCCAGCTGTG CTGCACCCACGGCCAGACTGGGAACACTCAGCCCCCCAGCGTCTCCCTCGCTCTGCTCCTCCTGGCTCCTTG- GTCACCAAGGTGACAGCC GTGGATGCTGATGCAGGCCACAATGCGTGGCTCTCCTACTCACTGTTGCCACAGTCCACAGCCCCAGGACTG- TTCCTCGTGTCTACACACA CTGGTGAGGTGCGCACAGCCCGGGCCTTACTGGAGGATGACTCTGACACCCAGCAGGTGGTGGTCCTGGTGA- GGGACAATGGTGACCCT TCACTCTCCTCCACAGCCACAGTGCTGCTGGTTCTGGAGGATGAGGACCCTGAGGAAATGCCCAAATCCAGT- GACTTCCTCATACACCCTC CTGAGCGTTCAGACCTTACCCTTTACCTCATTGTGGCTCTAGCGACCGTCAGTCTCTTATCCCTAGTCACCT- TCACCTTTCTGTCAGCGAAG TGCCTTCAGGGAAACGCAGACGGGGACGGGGGTGGAGGGCAGTGCTGCAGGCGCCAGGACTCACCCTCCCCG- GACTTCTATAAGCAGTC CAGCCCCAACCTGCAGGTGAGCTCGGACGGCACGCTCAAGTACATGGAGGTGACGCTGCGGCCCACAGACTC- GCAGAGCCACTGCTACA GGACGTGCTTTTCACCGGCCTCGGACGGCAGTGACTTCACTTTTCTAAGACCCCTCAGCGTTCAGCAGCCCA- CAGCTCTGGCGCTGGAGC CTGACGCCATCCGGTCCCGCTCTAATACGCTGCGGGAGCGGAGCCAGGTGAGGGGCTCGGCGCCGCCCCGGG- CGACCCCTGGGGGCG GCACTGGAGAAGCCGCCCGTCCTCATAAGGGATTGAACTTGCATCCACTCCTCTCCGGCCGGCTTGGTCGCT- GGCTGCGCTCCACCCGAT TCTCGGGATCATTGGACCGTTTGCGCGAAACCAGAGTGGCCGATTAAGGGATGGGGCTCCGAGCACCGGGGG- TGGTGGCGACTGTGGGC GAGGGGAGGTGGGACCGACCCCCACCCCTACACTCAAAAAAGGCCGGGGCCTCCTTCGAGCTTCCGGTGAAT- TTCGGGCGATTTCCGCG GGTGTCGGGGGTCCCGGGAGGAGGCAGTCACAGATCCACCCCTGCAGCCAGCCTCCTAGGCGCCGGCTCCGG- CACGCTTCGCCGGTCT GTAGATTTCCTCTTCGATTTCTCCCCAGCTCCCAGCATCTGTGACTTCACTGTTACCCTCCCTATCCCCGCA- TCACCCAACCGCACCTGTCT GCGGGACTTAGGTGTGCGCGCGGGGCTCATGCGTGTCCTCCCTGCTGGCCACCCCCACGGCCCACACAAGTT- GCACGGGCTCGCCACGC CCCGCCAACACGTGCGCGGACGCACGCACGCACTCCTCGCACGTGGGCTTACGCGAATACCAGCTTTCACTG- CCACTCGCTCGCGGCCA GATTCACAGGCCTGTTCCGGTCCACTCGCAGCTCCCCTCTGCCGCTCCCTCCGCCGGGCTCAGGAGTACTCG- TAGCTGATTGTGCGCGCC TGAGGGTCCCAGATCGCGGCCGCCCAGGACCAGGCGAGGACTCCGGAGCCTCCTCTCACCTCTCCCACCTGC- GCCCCGGGCTGGGCCG GGTCGCCTGGGGGGCGGCCTGAGCGAGGCGCGGGGCCAGGAGCGCTGGAGCGACTGCCGCTCTAAGTGCCGG- GCGGGCAGGACTCTA CGATCCTTGGGCCAGAGGTCCGGATGGTCCCGGGACTCCGTCTCAAGGGTCGGCGACCCCTCAACCCAGAAG- CCTCGAGCAGGCGGACA GGCAGAGCTGCCCAGTGGCCGAGGCGCGG 119 chr6: 10489100-10490200 ATTTGTCGTTGTGCCATTGCTGCCACTGTTGTTCTTGTCCAGGGAAACACCGGTGGCCAACCCAGATCGGATA- CAATGGTGCGGCTCTGGA CTGAGCCTCCAACCACATTAGCCATGGGCAGCATTGTTGCTGCCGCTGCTGTTATTTTAATTATGATTGTAC- GTTAACCACCACCTTCCTTCC TCTGCCTCCCTTCAGCTGCAATGATGTATGTTACTTTTTGGTAACTGGATTTCATTAACATTTATGAACTCT- CATAAAGTAGTAGAAAAAGCAA TTTGTGTGGAAGAATTTTCCACCTCATTAAACAGTGTTCTTTTGGGGGTCAAGCTGATATTTTTTTTGTTGT- TAGATTTTTTTTATAGGTCCTTT GTCCTTCCCTAAGCCCTGGGGGATGAAAGGAGAGCCGTCCACCCAGCGAGGGGCTTGTGTGCCCTAGAGGGC- GCTGGGCCCCGCGCGC TTTCCTGGCTGTCCCCGCCGGCTTTCCACCCTCCCCAAAGCCCAGGTGCCCACCGTGGGTCGCTGCGGCCTT- TCCCCTTCTTGGCCAAAT CCGATTACTTCGCAGCCTGCAGATGGCATCGCCGGCTAAGGGCAGCCTGCGGCAGGTCCCCGAGCCTGAGCA- CTCCTCCTATCTGGGGC CTGAGAGGACGCTCTGGGCTTTTTCCCAGGCCCAGGGTGCGCGGCCTGCTAGCGCCTTTCGAGGCACAGTCC- CAAGATAGGCTCTTGTCC TTCGACGCCCCCTTGGCACAAGCGCACTGGCGCCCTCCGCTCAACCCACCTTGCCTTTGGGGCGGGCTTCAA- CCCTGGGAAGACAGGCC TGGGGGAAGCGAGAGGAGAGGCCCGAATAGAGGTTCCGGCTCAATCTTTCCCAGACGGAGGCCTGGTGTTTC- CAGCTCAGTTGCATCTTC CAGCCGCGGGCTCCTGGCCCAAACAGAATGTGTTTGCTTTCACACCGGGACGGCAAGCGGAGTCCGCCTCAG- TGAGCAGCGAGCTGCGC AGTCCGGACGGGTGTCGCCCCCAGAGACTCGCCAGCCGCCCCCAGACACTCGCCAGCCGTCCCCATCTCTAA- TCCACCGTCCAGGCCCG GGCCCTGGGAAGA 120 FOXP4 CCGTGTCTCCCTTAAGAACTGGGGCCTCATCTCCACTCCAGCTGCGCGTGCACGTGTGCTCCCG- GCAGGACGCGCGCCCAGGAGCGCGC TGGGGGCTGCCCCGCCCCTCTCTCCCTCCCCCGCGGGTAAACTCCGGGCATCCATCAGTCTGTTAATTGCAC- TAATTAGAGATCGCAGAG GTGTTAATTGGAAAACCCTGGTATTGTGCCTGTTTGGGGGAAGAAAACGTCAATAAAAATTAATTGATGAGT- TGGCAGGGCGGGCGGTGCG GGTTCGCGGCGAGGCGCAGGGTGTCATGGCAAATGTTACGGCTCAGATTAAGCGATTGTTAATTAAAAAGCG- ACGGTAATTAATACTCGCT ACGCCATATGGGCCCGTGAAAAGGCACAAAAGGTTTCTCCGCATGTGGGGTTCCCCTTCTCTTTTCTCCTTC- CACAAAAGCACCCCAGCCC GTGGGTCCCCCCTTTGGCCCCAAGGTAGGTGGAACTCGTCACTTCCGGCCAGGGAGGGGATGGGGCGGTCTC- CGGCGAGTTCCAAGGG CGTCCCTCGTTGCGCACTCGCCCGCCCAGGTTCTTTGAAGAGCCAGGAGCCTCCGGGGAAGTGGGAGCCCCC- AGCGGCCCGCAGACTGC CTCAGAGCGGAAGAGGCAGCCGCGGCTTTGACCCAGCTTCCTTCCGACGGCATCTGCAGGAGCCTCTAGGCC- TGACATAGGCTCCGAGG TGCCCTGGCTCCCCCACGGGGAATGCTGAGGGTTGGGCCACTAGGTCCTGCCTAAGTGCAGGACCTGAGCCT- CAGACAAATC 121 chr7: 19118400-19118700 GGGATTGCCGGCTTTGAGAAAATATGAAGAAACCGATTTCTCCTTCCACTTTGCCAGTGCACTTTCCTTCCAC- TTTCACTGGTGCTGGGGGCGGCGCACTCTT TACGACATATAAGCGGAAAATTCTGCAAAAGTGGCCCCCGGGGATCCCCGCCCGACCCCTGTCTGTCGCTAA- TGTGGGCCTGTCTCCGGAAA TTCGAGGTTGGGCCTTTGCCTGAATCTGTTGCTATTGCTCCCCTTGCTACCGCTGACACTTGGCACCGCCGC- CTCCTAGCAGCGGCCAG ACGCGGGGCTGGGGGC 122 chr7: 27258000-27258400 GTTGCGAGCGCGGCACAGGTTGCTGGTAGCTTCTGGACTCTGGAGGCTTGGCCTTCCTTCTAAGCCGATGGCG- GGGAAAGAACCTCGTTT CCACAGCTTCCCCGACCCCCGCCGCTTGCCATTTGGGGACGGGAAGCGCGCCCGGGTCGCTTCACGTCCCTC- TGGGCCGGAGCCCTTTC CATGGCTGGCTCCTCTGGGGGCCCTTGGGCCTGTGAGCAGCGTCTACTTCCCTCAGAGAAGAATCCTTTCCT-

TCCCCCATCGAAGTGTCCC TTTCTGTATCCTGAAATAACCCCTCCTGGGTGAGGCCAGTTCCCCTCTGTCGCCCTCCTCCCGCAGGCGTCC- GGGAGCCTCGTGAGGACC CCGTGCAGTTGAGTCCAGGCGACAGGTGCCTCCCCAGGTG 123 TBX20 CAGTGCGCCCCTTACCGGAGCACCCATGGCCTCCCGCGTTACCCCAAATTTTGTAGGCAGACTG- TCAGAGTTCGAAGCCAGCTGTGTCCT CTGCGGGCCGTGTGACCCTAGGCTATCTGGGCTGCTCGGAGCCTTAGTTTCCCTAGTTGTGAAGAGGGAGGG- TGTGACCATGGCCCGGA GCTCTCCGAAAGGCTGTGCGGATTGCTCGGTGGCGGGATGTGGAGCGCGTCTTCTATGATGCCAGGTGCTGG- CCAAGCGCTCGATGCAG GCTGCTCCAGTTAGGTCGATGCGATGGCGGGAAGCACTTTCCTCTGCAATGGAGAGACGCCGACACCCCGAG- CCCGAAGGCTTGCAAGG CGCGCTCTCGCCACTGGGGTCGGGGATCCGTGGGTTCTCTATCCCGCTTACCCACTCCATCCTTAGCAGCTG- TCGTCGGTCCCAGACCTC TACCTTGGAGAGACCAAGGCGGCCCAGAGCCCAGGAGACTACTGCGCGGTACGCCAGGATCCAGAAGTGGAT- TCTGACTTCTAAAGACCC CTCCCAAGCCAACGCTATCAGGGTCCCTGCAAGCGGTTGACTGTGGCGGAGGCAGAACCAAAACCTTTGCTC- TGCCCGCGGCGCTCCAGC CTCTCACCCAGGACAGTGCTCTGGGCTCCAGCCGCTGCAGTGGGGTCGGGACACAGACGCCGAGTTAGAAGC- CCCGCCGCTGCAGGTCC CTGCTTGGTCGGCGCGGTGACGGTGTCGCTGGCGGCGGCGGGGGCCTTCCTTTGGCTGCCCGGCCATTTAAT- CAGAGCTATTAT 124 AGBL3 TTTAGTATTTAAGGAGAAAAGCCTCATTTTCCAGAATCGAATAAGCGAATTAATCGCACAATTG- TGTAGAATGGAACTCAGTCTGTAAAAAAT CAAGACCAACGTACTTTTTAATATTCTAACATCTCCAAGTAGTAGTTACAAGTATTGTACCCATGAAGTCCA- GGTAATTAATTTGTTCAATGTC ACACTGTTAAAAGTCAGGTGGGCTCCAAAGCACAGTCCTAACCAGCATGCTCTACTGCCTCCTCTGAGGCAA- CAGCCGAAGTGCAGACCAC TGGGAATAAATAGCTGCCCGGTCTTCCCCACTCCTAAATTCTCCCGACAGACCCCAAAGCCTCTCTGAGAGC- CTCTCTGACCGCCCTGCGG CCCACCCCGAGTTCCCGGCATCCTCTGGGATCCCTCTTCCTGGAGCCAAAACCTACGCAGGCTCCTTTCCTC- CGAGCTGGTTGCTAGGTG ATCTCCGAAGGCTGTCCGAAGTCTCGCGAGGGCGGACCCGTTGCCTGATGACGAGAGTTGGGAGTGTGGCTG- GGGCTGCGGATCTCCAG CAGTGGCGTTACTTCTAGCGGCTGGATACCGGGTTCTCCGCGAGATCGCGAGATCCCGAGATATTCTCCCCG- CACGGAAGCGACGACTGG CCTGGCCAGAGGACTCGCGTGGGAGCGAGGTGCCGGCCCCGACAGGACGGTGAGGTATGCAGAAGTAAGGCG- GGGCGCCCCCTGCGG GAAGCGAGCGCGCCCCGGAAAATGAGCGCCTCCCCACACCAAGGTGTCCAGGAGTGAGTGCGGGAAGGAACT- CGGCCGCCCGGAGTTG TGGCCTCATCGTGCTTCCCGCCAAAAACGCCTTGGTACTGTCGGGACGCGGCTAAGCGTGGACGCGCCCGCA- TCTGCCCCTCCTCCGCA GTGGTGGAAGACACCCGCGGAGCGCCGGTGGATAAGGGCCGTTTCCTGAGACCAGAGCTGTATCCGCAGCAG- GTCAGCACTTCGTGCGC CCTGTGTGC 125 XPO7 AGCGGCGCTGTTCCCGGGCTGGGTGCAGCTGCTAAGGACAAGGCCCCTGCTCCGAAGAACGCGGT- GGCTCGGGGATACCCTGAAAGGG ACGGCCATGGCGCACATGGGATGCCCTAGGGTTCGTGGGAGGGCATGCAGGCGCAGCCCCCGCAGGGGTTGG- CCTGCCAGAGAAGGCA GGGGAGAGCACTCGGGGCTGCACAAATGGTGTGGCCGGAGGGAAGGTGCAGCCTTGTGTGTGTCTGGATGAG- GGCTGGGCATAGGAGC TTGGTATTTGATCCTGAAAGCTCTGCGTTTCCAAAG 126 chr8: 41543400-41544000 GAGTCATACTTGTAGTCACATCCTTTTCCTTTCTCCAACCCACTGGTTAATCATGAAAGGCTCTTCTGATTGG- CTGCCTCCTGGCAGTAGTGC CTCAGCGCGACGGTTCGGGAGCAAATAAATAATTCCCGCTGGGAAGCTGTTTCTCAGACAGGAGCAGCGACA- CCCCTGCCACGCCTGCCG CCTGGAGTTGAGTGGGGTAAGCACGCCGGCCTCCAGGAATCGACGGTGCCACGTGGTTCTTCTTGCACTTCT- CTTCTTCTCCAGTTTCAGG GGACACCGTGGGGTGTGCGAGCCCGGGGGAGCGCAGGGAAGGGCGGGTTGGGCTGCAGGTGGGAATGTGCGG- TCCTTCTGCGCCCTCA ACAGAGCTTCCTTCCTTTTTGCCAAGGTCCCCGTGCCGCCTTCAGCGCGCCTCCTTATGCACCTCTACCTCT- GCTGCAGCGTACCTCTTCC GCAGCCCTAGCGGCCTCCCCGAGGGGCGCCGCGGCCTCGGCTGTCCCTCCCCTGCCTGGCACGACCACCTGA- CCCCCAGCGACCCAAG AAGCAAGTTGTGTTTGCAGACGCAAAGGGGCTGTCGTTGGTATCGGTGCACTGGTTTGA 127 GDF6 ACACTTTCTGTGTGGGAGGGCACAAGACATGGGCTATGACATGGCCAGAGACCCCACCTTCTTTA- CACATGTAAAAACCAACCAAATCAAG ATGCGTCAACGGTGATTCTTCCTCCCACATTGTTTCCCTTTTTAAACTGTTATTTTTTCAATCCATGGAGCA- GTTGAGAAACGGGTATGCATC TCTCCTCCCCTCCCCTTCTATCAAAGCCTGTAAGACACATAAGGAAATCCAAAGCCACAGTAATAGAGAGAG- AGAGAGAGAGAGAGAGAGA GAGAGAGAGAGAGAGAGAGAAAACAGAACAAAAGAAATCCTCCTTGGCTTGTTTTTCCAGGGTGGCCAGGCA- AGGTGTGAAAATCCATATT TCCCTCTGGGCTGGCAGGTAGAAGTTACTGGGAAGGCTGCGCTCCCTTCTCTCCCACCGGCTCTCACATCCA- GGCTGTTCCCTCACCCTCA GCCTCCCCCAGCGCCAGCTTCCTCCTCCGCCTCTCTGCAGCCAGGCCTCCCCTGCAAGGCGGACCTTGGCCC- ACCTTGGTTCCGGGCCA AGGCGGCGGGAAAGGCACCGCTACCTGCAGCCGCACGACTCCACCACCATGTCCTCGTACTGCTTGTAGACC- ACATTATTGCCCGCGTCG ATGTATAGAATGCTGATGGGAGTCAATTTGGTGGGCACGCAGCAGCTGGGCGGGGTGGAGCCGGGGTCCATG- GAGTTCATCAGCGTCTG GATGATGGCGTGGTTGGTGGGCTCCAGGTGCGAGCGCAGCGGGAAGTCGCATACACCCTCGCAGTGATAGGC- CTCGTACTCCAGGGGCG CGATAATCCAGTCGTCCCAGCCCAGCTCCTTGAAGTTCACGTGCAGGGGCTTCTTGCTGCAGCGTAGCCTGG- ACTTCTTGCCGTGCCGCTT GCCATGGCGACTGGCGAAGGCCGTGCGCCGCCGCCGGCGGCCGGGCGAGGGCAGCCAAGGCCTGGCATCCGG- GGCGCCCGACGGCG GCGGCCACGACCCCTCGGCGCCCGCGCCCGGGCCCGCAGCCTCGGCCGAGCCCAGCTGCTCGCGCATCTCTG- CGAACAGGTTCTTGCG CTGGGATCTGGTGAATACCACCAGCAGGGCCCGCTCCTGGGGAGGCCGCACCCTCCGGCCGAAGCCCAGACT- CCGCAGGTCCGGGGGC GGCGGTTGCTGGGGTCCCCGCGCGCGCGCCTCGGCCTCCCCGGCGTCCAGCTCGCCCCATGCGGCCCGCAGC- TCCAAGCACAGCTGCT TCCAGGGCTGGTGGCGCAGGCCCTGCCACACGTCGAAGACTTCCCAGCCGGCCGGCGGCGCCCCCTGCGGGT- CCAGGGTCCGCGCGTC CAGCAGTAGGGGCGAAAGGCAAGGGAAGAGCTGCACGTGGAGCGGCCCGGCTGGTGGCCCCCAGGGCGCTGA- GGGCGCCTGGCGAAA GAGCCGCAGCTCCGCGCCCACCAGCTCTTCTTTGTCTGAGAGCATGGACACATCAAACAAATACTTCTGTCT- CCGGAGAGGAGTGTGCGA GAGATCGTCTGCGAGATAAAAAATAATTACAGTCAGTTTCACTTAAGGGGGAGATCAGCCCGGTGCTCTTCG- GCCGCCCCGGGAGGAAAA GGGCGGGGAGTGGGGGCAGGTCGGCCGGGCAGTCCAGCTTGCCCGGCCCAGGGCCTGACCACCCCGGCTCCC- CATCTGGCTGGTGCAT GG 128 OSR2 GCCCGCTGTGAATGTAGGTGAGGTGATCCCGGGAACCTGGGTCTGAAATCAGACCTGTGTTGCCA- TTGGGAGCACGGAGAGAGGGGAAG CGCCCTGCTTAGGCCCAGGCCGGGCGTCCTGGTGGTGGGACCGCAGCCGCACTCACCTCCAGGCCAACGGAC- AAGGTTCCTGCAAGCCA GCAGGGCCACTCTGTGCTTGGCCTACTGCAGCTCCCCTGCAGCTCCTTTCCTCTCCCTCCCCGGAGCGCTCT- CCTCTCTCCTCTCCCCTCT CTTCTCTCTCCTCTCTCGTCTCCTGGGGCATCCCGGGTGGAGGGATGTAGGGGTCGCTCCTCGGTGCCAGGC- CGGGAAGCAGCTCAGGC CTCCCAAGAGCTTGGCGCTCAGTCTGGGAAAAGGGGTTCCTCTGGCCTCAGGGACGTTCTCCGCCCCCACCC- CACCCCCTGGGAGCCTG AACCATCTGGAAGGGATCTTAGTCGGGGGTTGGGAGGAGAGCCCGTGGATAGGAGGAGGGGGCGATTCTAGG- CCGAATCCAGCCCCTGA GGTGTCACTTTTCTTTCCTGCGGCCCGTCACCGCTGATAGATGGGGCTGAGGGCAGAGGAAGGAAAAAGAAA- ACCTCCGAGGTCAGTGCG GGGCGAGGTGAGCCCCTCCCAGGGCCCTCTGGCCCAGGAGGATGAAGCGCGCCGGCTTCGCTCTTGCACGCC- GGCTTGCCATCCGGGT AAGCGCGGGAAAGGCGGCCACAGGGCGCGGCGGCAGCGCAGCGCGTGGGATCTCACGACCCATCCGTTAACC- CACCGTTCCCAGGAGC TCCGAGGCGCAGCGGCGACAGAGGTTCGCCCCGGCCTGCTAGCATTGGCATTGCGGTTGACTGAGCTTCGCC- TAACAGGCTTGGGGAGG GTGGGCTGGGCTGGGCTGGGCTGGGCTGGGTGCTGCCCGGCTGTCCGCCTTTCGTTTTCCTGGGACCGAGGA- GTCTTCCGCTCCGTATC TGCCTAGAGTCTGAATCCGACTTTCTTTCCTTTGGGCACGCGCTCGCCAGTGGAGCACTTCTTGTTCTGGCC- CCGGGCTGATCTGCACGCG GACTTGAGCAGGTGCCAAGGTGCCACGCAGTCCCCTCACGGCTTTCGGGGGGTCTTGGAGTCGGGTGGGGAG- GGAGACTTAGGTGTGGT AACCTGCGCAGGTGCCAAAGGGCAGAAGGAGCAGCCTTGGATTATAGTCACGGTCTCTCCCTCTCTTCCCTG- CCATTTTTAGGGCTTTCTC TACGTGCTGTTGTCTCACTGGGTTTTTGTCGGAGCCCCACGCCCTCCGGCCTCTGATTCCTGGAAGAAAGGG- TTGGTCCCCTCAGCACCCC CAGCATCCCGGAAAATGGGGAGCAAGGCTCTGCCAGCGCCCATCCCGCTCCACCCGTCGCTGCAGCTCACCA- ATTACTCCTTCCTGCAGG CCGTGAACACCTTCCCGGCCACGGTGGACCACCTGCAGGGCCTGTACGGTCTCAGCGCGGTACAGACCATGC- ACATGAACCACTGGACG CTGGGGTATCCCAATGTGCACGAGATCACCCGCTCCACCATCACGGAGATGGCGGCGGCGCAGGGCCTCGTG- GACGCGCGCTTCCCCTT CCCGGCCCTGCCTTTTACCACCCACCTATTCCACCCCAAGCAGGGGGCCATTGCCCACGTCCTCCCAGCCCT- GCACAAGGACCGGCCCCG TTTTGACTTTGCCAATTTGGCGGTGGCTGCCACGCAAGAGGATCCGCCTAAGATGGGAGACCTGAGCAAGCT- GAGCCCAGGACTGGGTAG CCCCATCTCGGGCCTCAGTAAATTGACTCCGGACAGAAAGCCCTCTCGAGGAAGGTTGCCCTCCAAAACGAA- AAAAGAGTTTATCTGCAAG TTTTGCGGCAGACACTTTACCAAATCCTACAATTTGCTCATCCATGAGAGGACCCACACGGACGAGAGGCCG- TACACGTGTGACATCTGCCACAAGGCCTT CCGGAGGCAAGATCACCT 129 GLIS3 CACTCCCCCGCCGCCTCCGCCCCTAACCCTCGGCCCCGTGCGCGAGCGAGCGAGGGAGCGAACG- CAGCGCAACAAAACAAACTAGTGCC GGCTTCCTGTTGTGCAACTCGCTCCTGAGTGAGTCGGGGGCCGAAAGGGTGCTGCGGCTGGGAAGCCCGGGC- GCCGGGGACCTGCGCG CGCTGCCCGGCCTGGCCGGAGCCTGTAGCCCGGGGGCGCCACGGCCGGGCTCGCAGTCCCCCCACGCCGGCC- CCCCGGTCCCCGCCG AGCCAGTGTCCTCACCCTGTGGTTTCCTTTCGCTTCTCGCCTCCCAAACACCTCCAGCAAGTCGGAGGGCGC- GAACGCGGAGCCAGAAAC CCTTCCCCAAAGTTTCTCCCGCCAGGTACCTAATTGAATCATCCATAGGATGACAAATCAGCCAGGGCCAAG- ATTTCCAGACACTTGAGTGA CTTCCCGGTCCCCGAGGTGACTTGTCAGCTCCAGTGAGTAACTTGGAACTGTCGCTCGGGGCAAGGTGTGTG- TCTAGGAGAGAGCCGGCG GCTCACTCACGCTTTCCAGAGAGCGACCCGGGCCGACTTCAAAATACACACAGGGTCATTTATAGGGACTGG- AGCCGCGCGCAGGACAAC GTCTCCGAGACTGAGACATTTTCCAAACAGTGCTGACATTTTGTCGGGCCCCATAAAAAATGTAAACGCGAG- GTGACGAACCCGGCGGGGA GGGTTCGTGTCTGGCTGTGTCTGCGTCCTGGCGGCGTGGGAGGTTATAGTTCCAGACCTGGCGGCTGCGGAT- CGCCGGGCCGGTACCCG CGAGGAGTGTAGGTACCCTCAGCCCGACCACCTCCCGCAATCATGGGGACACCGGCTTGGATGAGACACAGG- CGTGGAAAACAGCCTTC GTGAAACTCCACAAACACGTGGAACTTGAAAAGACAACTACAGCCCCGCGTGTGCGCGAGAGACCTCACGTC- ACCCCATCAGTTCCCACTT CGCCAAAGTTTCCCTTCAGTGGGGACTCCAGAGTGGTGCGCCCCATGCCCGTGCGTCCTGTAACGTGCCCTG- ATTGTGTACCCCTCTGCC CGCTCTACTTGAAATGAAAACACAAAAACTGTTCCGAATTAGCGCAACTTTAAAGCCCCGTTATCTGTCTTC- TACACTGGGCGCTCTTAGGC CACTGACAGAAACATGGTTTGAACCCTAATTGTTGCTATCAGTCTCAGTCAGCGCAGGTCTCTCAGTGACCT- GTGACGCCGGGAGTTGAGG TGCGCGTATCCTTAAACCCGCGCGAACGCCACCGGCTCAGCGTAGAAAACTATTTGTAATCCCTAGTTTGCG- TCTCTGAGCTTTAACTCCCC CACACTCTCAAGCGCCCGGTTTCTCCTCGTCTCTCGCCTGCGAGCAAAGTTCCTATGGCATCCACTTACCAG- GTAACCGGGATTTCCACAA CAAAGCCCGGCGTGCGGGTCCCTTCCCCCGGCCGGCCAGCGCGAGTGACAGCGGGCGGCCGGCGCTGGCGAG- GAGTAACTTGGGGCT CCAGCCCTTCAGAGCGCTCCGCGGGCTGTGCCTCCTTCGGAAATGAAAACCCCCATCCAAACGGGGGGACGG- AGCGCGGAAACCCGGCC CAAGTGCCGTGTGTGCGCGCGCGTCTGCGAGGGCAGCGGCGGCAGGGGGAGGAGGAGGCAGAGGCGGGGTGG- CTGGACCCTCGGCAT CAGCTCATTCTCCCCTGCTACACACATACACACACAAATAATGTTTCTAAAAAGTTCAGTTGCGACTTTGTG- CCTCGCCTGTCCTGTTCATCC TCGTCCTGGGCCGGGGAATGCTTCTGGGGGCCGACCCCGGGATGCTGGCTAATTGCTGCCGGCGGGTTCCGT- CGCCGGTGTGACCCTG GACGGCGCGGACGGCGTACAGGGGGTCCCGGGAGGGGCAGTGGCCGCGGCACTCGCCGCCGGTGCCCGTGCG- CGCCGCGCTCTGGG CTGCCCGGGCGGCGCAGTGTGGACGCGG 130 NOTCH1 CTGAAAAGCCGTCAGGGAAACCACACATGTTCAACCCCTGGCGGCTCCCCCAAACCTCTCATT- TCCAGTAACTGTGTGTTTCCGCTCGTCA ACAGCTGAAACCGAGCGGAACTTGGGGGGCCCCACCACGCGGCCCTGCTGTGCGGCACGGGGCTCATCTGTC- CCCCGGCTGCGGGGAG TCAGCTCTCACCGCCCACCTCCTTCCCAGATAGTCTCTGTGCCCACTCGACGGCCCGGCAAGCCCAGCCCCT- GCCTGCCACGGCCACAGC AGCCTCAGAGAGCTGCCCTCTCTGGCCAGGGTCAGGGCCTGAGCTGCTGCCTCCCGCAGGGTCGAGGGCAGG- ACACTTGTCTGAGGCTT GGGTGGGGCAATGGCACCTCCTCAGGGCCTCAGCCCCCGGGCAGGCTCGGTGACCATGGGCCTACAGCAGGG- AAAATTCTGGGCCAAAA GCTCCAGCCTCCTACTAGGGCATCTGTCTGCAAATGCACCTTAACCTGACCGCTTGGGCTGTGGGGGAGCCT- GTTTCAGGGAAAGTGAGG GACGCGCCAGTTTCCTCCTTTGGACTTGATGAGGCACGAACGCATCTCTAATAAAGCCAGGTCTCCCCGCCG- TGGCTCCCTGGGCGGGTG CCTGTGGCTCGGGCCATGAGTCACGCTGGGTAACCCCACTACGGGGAAGAGGGCAGGAAGCTGGGAGCCACC- GCCTCTGTGCCCGGTTG TCATCTCGGCACGAGGGCGACCGTCGGCTTCGTCCTGCCCTCATGGCTGAGGGCTTTTGGGATGTGGCGGGA- GACGGGGGAGTC 131 EGFL7 AAATCATCAGAATGGCTAAAATGAAAAAGACAGACAACAGCAAGTGCTGACAAGGGTGTGGGGC- GGCCAAATGCTCCTGCACTGCTGGCA GGGGACCTGAGAACTGCAGGGCATTCCCTGGCTTCCTGCCCCTCCTGGGACTGGGGACCCCCCAGGGACAGC- CTAAGGGAACTGCATTT ATCTTCACGTCTGCCAAAAGATAACACGAAGATGTTCAAAGCTAAGCCCCCAGGCTGGTAAGAGCTCCAAGG- CACCAGCAGTGTGTGCAGA ACTGGGGGGAGTCTGTTCTCCCAGGGATGCTCCCATCACCTGCTGCCAGCAGTGGGGCATGCCGGTCCCCTG- GGGTGTGGCCAAGGGGC TGTGTCTCCTGCCCGGGCTGCCGGCCCCTCTCAGGTTCACTTTCCCATCTCTAAGCCCACGTCTCGCTGCAG- TTCAAGTTTGCCAGGCCAC CAACGGGTGACACGCCCGGCGCAGTGGGGGACTCCGCACTTTCTGCGCAC 132 CELF2 ACCCTTTGTGCCTGGGTCCCATAAACAATGTGCTTTTTAAAGGGGAGCCCCCTCCCAGCTCCGG- CCTTTTTCTCCAGCGTGGGCAGCCAAT CAGCTGCGCAGAGCTGCATAGCTGGACCGCTTTCCATTCTGAGTAGCAACAACGTACTAATTTGATGCACAC- ATGGATGCCTCGCGCACTC TGCAAATTCATCACCCGCATCTTGCATTAGTCATCTGACGGACTGCCAAGTGTTTCATTTTCTTTCCATGTG- ACTTTATTATTACCACCTCTCT CCTCTCTTCCAAAAACCTCCCAAAAAGGGCGGTGGGGCGGGGGGCGGGGCAGGGAGAGGGAGAGAAATCCAG- CAGACATCTAGCTCTGC CTTTCTTTCCCAGCCACAGCCAGGGTAGGGCTGATAAGGCGCTGATGCGTTGATGGCAGCCTTGCAGAGCTA- GACCTGCACTTAACTTGCA GCTGCCTCCCGAGCCTCCAAGATGTCCACGCCCTGGGTGACAGGCGGCAGGGCGCTGCCCCGTGCTCCCCCG- GCTCTGCTCGACAGCA GCACGCAGTGAGAGCCTCGCCGCCGCCGAGGAGCAACTCATGGTGCCTCCGCTTTGTTTTAGTTCATCAAAT- TTCTACGACTCATTAGGCA CTTTGCCACTGCTCTTCTTCCTCCTCCTTCCGCCTCCCCGCTCCCCCACCCCCACTATTTTTTCTTCCTGTC- CCTCATCGTGCCGCCCTAAC TCTGGCTCCCGGTTCCGTTTTTGACAGTAACGGCACAGCCAACAAGATGAACGGAGCTTTGGATCACTCAGA-

CCAACCAGACCCAGATGCC ATTAAGATGTTTGTCGGACAGATCCCCCGGTCATGGTCGGAAAAGGAGCTGAAAGAACTTTTTGAGCCTTAC- GGAGCCGTCTACCAGATCA ACGTCCTCCGGGACCGGAGTCAGAACCCTCCGCAGAGTAAAGGTACAGAGCGCGGGGCGGGGGTCGCCAGGC- GTCCAGGTGGGCGTCG CGGGGCACTGGGGCTGTCCGAGCCCCCAGCCTGCAGGAGGAAGGGCGGGTAGGCAGGAGGGCTGGAAGCAGC- CGGTGCTGGCGGCCC CTGTGCTCCAGGGGCTGCTCCCGACTCCTCCCCGCACCCCCGCCCGCCTGCCCGCCGGGACAGGTTGGAGGC- GGGAGAGAGGGACCGA GGCAGGGCGGGAGCGCAGAGGCTCGGTC 133 HHEX TAACAAATAAGCCGCCCGTGGTCCGCGCTGTGGGTGACCCTTGGCGCCTTCGAGGTCTGGAGCCC- TAGGGTAAATAAGGAAACGGGGCG CCTCTAGAGTTTTAAATGAACTCTGTTATTGGAAGCTTCAGTAGGGACCCTGAAAACAATTAACGTCTTAAT- TAGCATTTTAATGTCTCCATTA TTACGGCGCGGGCTCTAGCTCAGCCCTTTACCTTACCTTCTCACCGTTAACAGGGGAGGGGGATTGTATTTT- TAGTTCATCTTTTTATGTTTT TGAGTTGTTATCCTGTCTGTCTGATTCCAGCCTCGAGGGTTTGATGATGCGGCCCGAGCCTGGCTGTGGTCG- CCTGTCGGGGCTGGAGCG GGACCCTCAGCCGGGCCGGGCCTGGGGGCTAACGTTTTCACAGTGCGCCCTGAGTTTCCTTGGGTTACTGCT- GGGACCGCGCAGGAGGA AGCAAAGAGTTTTTCGAGCTAGACCAACAGGAAACACATTGACGGAAATGTTGCCATAGCCCATGGGGTGGC- TTTAACTGGCCGCCCCCGC GGGCTGGGTGTGAAATCAGAGGAGGCCGCGGCTCCCCCGGCCAGGATTGGAGGCTCCTCGCGCAACCTAATG- CGGGTGTCCGGGCCCG AGCGCTTCCCGCGCAGCCAGGCCTTGTCGGTGCAGCAGCCCCGCTCCTCCCCAACACGCACACACCCGGTGT- TCGCAAGTGCGGCTCAC CAAGGGAGATCCAAGGGGGCAAAAAGTTATGTATAAATCCGAGAGCCACTGGGGAAAGAGGGTCGTGGTATT- GTAAG 134 DOCK1/ CTACCCTGTGCTATCCTGAGCTGTAGTCTTCTGAAATGATCGTTTGGCTTCCCAGCCAAGGCA- GGGCTCCCCCAAAGTTCATTCCCACTCTT FAM196A GCAGTTTCACCTCGGGATGCTTCCGCAGAATTTCAGCGCCTAAGCAGACAAGGTCAAAGTAAACC- GCTTCACCGCTGCTTCTGGCGCAGG GGCCCAGAGCGCGTGCAGCTCCCCAGCACAGACCAACAGCAGGAGAGGGGTCCGGGCGGGAGCCCTGGGCTG- TAGATAAGCAAAACGC ACCCATTTTCTCTCCTATTTACTCCAGAGGCACCTCTCCTCCCCCACTCCTGGCATCTCTTTATCACTGGCT- CCCTCTCCCTGTGGCATATTT TTGGGTAGTAGAATGCTGAGGTCACAGGGAGCGGCTCTTTATCCAAGCAGTGGGGACATCAGCCTGGAGCCC- TGAGCATGAACCAGCAAG ATGCAGACTCTCGCTCTTGACTTTGGGCTCCAGGAGCTGCCCCGACC 135 PAX6 CAGTGCTCCGCTCCGGGAAATTGCATCGTCACGACAAACGGGACCGTGATAAAACGACCCTTTCC- GTCCTTATTTGTAGATCACTCAGACG AGATTGAACTGCACTTGTTTCCCCTTCGAGGGGAGCCGCGTTTTCAGGGTAGCCGAAGGCTTGGGGCTGAGG- GGGGGCCCTCACCAAGG CGCGGGTGGGGGCCGGAGCCTCAACTCGATGAGAAGTGACAGGCGTTTGGGGGATCTGGGCTCCGGCCGGGA- CCAGCGCAAGCAGGGA CTTTGCGGGGACACCGCTTCTCCAACAGAGCAAGGCCTGGCCCACGTTTCCGGTTTCTCCTAACTTCCTTTT- ATTGCCTTCCTTTGCTTCGC AAGTTCCATCTACCCCTCCAGCTACAGAGCCCCACCTCTAGGCACAGGAAGCTTCCCGGAAAAAGAAAGGCT- GTCCCAGAAAGAGACCGA GAGAGACTTTCCAAACTTCGGGCATAGCCACGGCAATTCCCAGTCTGCTAATGCCAAGGCGGGCGCGTAAGG- CCGCCTAAATCTAGACCT CCCTCCTCACTCATTTCAAAAAATAACAACGTGCCAGCCACCTCCGCAGATACCGCCGGCTGGTGCTTGCCC- AGGAGACGCCAGGGCCAG AGCGCCACTCCCAGCATCGAAATGGCAGAGAGAAAGCGCAGCTCCAAATTCCCCTTCAGAGGTTAAGCCTCA- ATCATTGTGTCCCTTCCCT AGGGACTGCTGGCGCTCTCGCCCACTGGCGATGATTATGCGCCTAGAACTCGACCGCGAAGCAACTAATAGG- AAAACATATGGTGTCAATT TGGATGCTCCGCGCCTCGCGCACACCCGGGAACGAGCGGCACAAAGCCCTGCCGGCCGGCCCGCGACCCCGC- GCCCCTCGGGGCCTG CCAGCCGGGCCGCAGCGACAAACGCTCAGGGCTGCGCGCCCTGGCTGGGGCCCGCCCGAGAGACAGCCTGCG- GCTGGGGAGTCTGAG CTCCAAGGGGAGAGCCCAGCCGCCGAAGGCGAGCCTACCGGCCAAGCCCTGGGGTCCGGCAGGTTCTGCACA- ACTACTCCCGCAAAGCT CGCCACCTTTGTGCCCTTTCCTCAG 136 FERMT3 GGGCCCTCGCGGCTCAAGCGCCAGCGCTGGAGAGAGAGTCTGAGGGTACCACGGGCGTGCTGG- CCTGGGTGCTCACTCCCGCCCTCCT TCATGAGCGGCTTTCCTCTGGGTGTGTCCAGGGCATCACAGAGCTCTTCTGCCCAAACCCGGAGGCCTACCA- GGGCCTGCCCACCTTGCC TCCTTCCACACTCTCTGTAGCAGCAGCCGCAGCCATGGCGGGGATGAAGACAGCCTCCGGGGACTACATCGA- CTCGTCATGGGAGCTGCG GGTGTTTGTGGGAGAGGAGGACCCAGAGGCCGAGTCGGTCACCCTGCGGGTCACTGGGGAGTCGCACATCGG- CGGGGTGCTCCTGAAG ATTGTGGAGCAGATCAGTGAGTGTCCGCTGCCCGCTTGCTGAACTCGGCACCATGGGCGGCCGCCACGGGTG- TCTCTGGGCACTTCCGG GCCATCCCTGCTGCTCAGCTCCCGATAATGGTGTCACGGTGACTCAGGCATTAGC 137 PKNOX2 TGTTTACGGAATCGGGATCGAGGGGCCGATAAGTAGTTTACACGCCGGCCAGAGCAGAGGGCT- GGAGGTCGGAGTTGGGGGCTGGAGGA ACGGGTGGCGTTTTTAGGATTCAGTAACAGGATCACAGCTTTTTCTTGTGGTGGAAGCTATTGGAATTTGGG- GAGGGTAGCACGAGGGGTC CTGCAGCTCCGCGTGTGAAAAAGCGTTTAGGTAGGCGATGAAAGTAGTTGATCTGAGCCATGGCAGGCGAGC- CCCGAATTTTTGCTGCTTC CCCCTGAAAGTGTTTCTTTAGGAGGAGAGGACTTGGGCCACACAGGACCCGGTCCTAAGAGAGCGATTCCGG- GAAGCGGACAGATCGAAG AGACCTTCTGGGCGAAGCGGCAGGGCAGCCTCGCGGGGCTGGGAGTGGATCTGAGGTCCCGACCCAGGCGGC- TCGGAGTGCTCCAGGA GCCACCTGGGTCTGCGGGCGCAGCGCGGCGGGGCGGGAGCGGTGGCCCGCAGGGGCCGCGGCCTGCGATGAA- GGCCGGGGGGCAGC GCTAGCAGCGAGGTGCCACAGTGGGCCGAGGAGTCTGGGCTGTGGCCCAGGGTAGGACCGGCTCA 138 KIRREL3 ACCTAAACCAAGCTCTCCCTCCCTGCCGTCTCCTTCCCTGGCCTGGGTCTGAAGGAGAGGAGGTGCCCAGAAG- TTCAGAGCGGCATAACCACAGAGA TACTACCTAATTAACATACCAGAAGCATAAAGAACTCATTTGCATTGGAGAGT 139 BCAT1 ATAACTACGGGGGTGGGGGTGGGGAAGGAAGAGATCCAAGGAGGCAGAAGGCTGCGGTCAAAAT- ATTTTGGGGTGGCAGAGTCACGTAG GATGTGGCTGTGGGTTCTGGCAGCCCAGAGATTCAGCTCCCGCCTCCTCCCTCAGAGCGAGTCCATAGCTAC- CCTCACGTCCCCCGTGGC GGTCCTCGCCACGCTCCGGAGCGGGTTACCCATGAGGGTGCTAGACCTGGGCAGCGGGAACCTCGAAGAGGT- GGAGATTGCAGGCTGG GACTCCAGATTTCGGGCAGGGATGCGGGGAAGGGAAGACGCCTCGCTGGAGGCGGAATGGAGGGCAAGGCGA- AGGAGGATGGTGCAGG AAACGGCGACAAGGCGCCCGGCCAGGCCCGCGAGCTACCGAGACCCGGGTTCCAATCCTCCCCCCTTCCGCA- AACGCCCGGGTTCGAG GTACCTGGCGGGCAAGGGCCGCAGCGGAGCGAAGCGGGCTGGCCATGGGGAGGCTGCGGGGACGCGGGGCTG- CAGAGAGCGGCAGT GGCACGGAGCGCGCGGCTGGAAGCGAAAGCAGGCGGTGTGGCCAAGCCCCGGCGCACGGCCCATAGGGCGCT- GGGTACCACGACCTG GGGCCGCGCGCCAGGGCCAGGCGCAGGGTACGACGCAACCCCTCCAGCATCCCTTGGGGAGGAGCCTCCAAC- CGTCTCGTCCCAGTCT GTCTGCAGTCGCTAAAACCGAAGCGGTTGTCCCTGTCACCGGGGTCGCTTGCGGAGGCCCGAGAATGCGCGC- CACGAACGAGCGCCTTT CCAAGCGCAGATATTTCGCGAGCATCCTTGTTTATTAAACAACCTCTAGGTGAATGGCCGGGAAGCGCCCCT- CGGTCAAGGCTAAGGAAAC CTCGGAGAAACTACAT 140 HOXC13 CAGTCCAGCCGCTTGCCTCACTTCTTCCCGCTTGCCTTATCTCCCCGCAGACGTGGTTCCCCT- GCAGCCCGAGGTGAGCAGCTACCGGCG CGGGCGCAAGAAACGCGTGCCCTACACTAAGGTGCAGCTGAAGGAGCTAGAGAAGGAATACGCGGCTAGCAA- GTTCATCACCAAAGAGAA GCGCCGGCGCATCTCCGCCACCACGAACCTCTCTGAGCGCCAGGTAACCATCTGGTTCCAGAACCGGCGGGT- CAAAGAGAAGAAGGTGG TCAGCAAATCGAAAGCGCCTCATCTCCACTCCACCTGACCACCCACCCGCTGCTTGCCCCATCTATTTATGT- CTCCGCTTTGTACCATAACC GAACCCACGGAAAGACGCTGCGCGGGTGCAGAAGAGTATTTAATGTTAAGGAAAGAGAAGAACCGCGCCGCC- CGGAGGCAGAGAGGCTC CATGGCCGTGCTGCTGGGCCATCCCCAACTCCCTATCCCATCCCCAGCCTCCACCCCCATCCAGATGGGACT- CACGTGGCTTCAACAGCT TTGGAAATGGGTCCCGAGTGGGCCGTGCGAGGAAGGCTGTCGACCTCTACTCCTCCTTGC 141 TBX5 CAAGATCGACTTTCTTAGGAAGGGGGAGAGGAGGGAACTCTTCACGAAGGGAGGTGGGAGTCCAC- CTCAGACCTCTATTGGAAGGAAATC GAGTTGTTCCGGGGGACTGAGGTCTCTTGCATAAGGCATGGGATCCTTATTATTATTATTATTATTTTTAAA- TCCCCCGCGGAGGAGCTCTG GGCAAATGAATACCGAGGCGCCGCTCTAGCTGGTTAGGCTTGGGATGCGATAACTCAGTGCCCTCTTGCAGA- CTTGCATAGAAATAATTAC TGGGTTGTCGTGGAGGGGACACGAGACAGAGGGAGTTCTCCGTAATGTGCCTTGCGGAGAGAAAGGTCCAAG- AATGCAATTCGTCCCAGA GTGGCCCGGCAGGGGCGGGGTGCGAGTGGGTGGTGGAGTAGGGGTGGGAGTGGAGAGAGGTGGTTTCTGTAG- AGAATAATTATTGTACC AGGGCCCGCCGAGGCACGAGGCACTCTATTTTGTTTTGTAATCACGACGACTATTATTTTTAGTCTGATCAA- TGGGCACAATTTCTAAGCAG CGCAGTGGTGGATGCTCGCAAACTTTTGCGCACCGCTGGAAACCCACTAGGTTGAGTTGCAAAACGTACCGC- GTAGACGCCCCTGGTGGC GCCGAGAGAAGAGCTAGGCCTGCCCAGCACAGAGCCGGAGAGCGTCGGGCCTTCCGGAAGGGTAAGTTCTCC- GCCAAGGGGTCCCGAG GGAGCTGGACGTCTGAATCTGGACTTGCCCCCAGCTTCGGGGTTCGATTCTGGGTTTTGCGCGTCCCCAACC- CCCAGGGCTTTCCGAAGC ATGGCCTGGCTCCAGGCCCGGTCCTGTAAGGACTGGAACGGCAGCAAAATGTGCAGGGAGGCAGTCGGCCGG- CAGAGCTGCGGCGGGA GCCAAGGTCAGGCCCGCGGGGAGAGCGGGCAGCTTCCAGCGCCGGCCACAAGCTCCCAGGCCAGCTGGGCCG- CAGACCCCTTTGCTTC CAGAGAGCACAACCCGCGTCCTTTCTCTCAGCCAGGCTGCAGTGGCTGCCCCGAGCTTCGCTTTCGTTTCCC- AAGCTGTTAATAACGATAT GTCCCCAAATCCGAGGCTCGTGTTTGCTCCCAGATGCCAAGAACGCAACCCGAAATCCTTCTCCCAAACCCT- AGGTCGACGAGATGAGTTC CTACTTGACCTCTGAGCCGAGGTGGGCCGGAAACCGAGGCCTAGGCCCCGCCGGGGCTGCAAGGAAAAGGGG- AAACTCCGAGCGTAGC GTCTTTTCCTTGTGGTTCCTTTCTCCGGCATCCCGGACTGCGGGCCCTGCAGCCACCTGGACCGGCATTCAA- AGGATTCTGCAAGTCCAGC TTCACAGACTGGCTTTCCCAGACGCTCCGAAGCCCGCACCACGAACAGAATAAAGGAGAGACGAGAGATCGC- AACTAGATTTGAGAATCCTCGTTCTTTTCC CCAATCGTTCGGGCAGTAAACTCCGGAGCCGGCTACAGCGCGCATCCTC 142 TBX3 ACTGTCCTCCTCCCTCAATTGCCTATTTTTTGCCCATAGCTCTAACTTAACCCTGTGATCACCCC- AGATCGCTACTTCTGACCCCCATCTCCT CTCCCACACCAACCTCCAGCGCGCGAAGCAGAGAACGAGAGGAAAGTTTGCGGGGTTCGAATCGAAAATGTC- GACATCTTGCTAATGGTCT GCAAACTTCCGCCAATTATGACTGACCTCCCAGACTCGGCCCCAGGAGGCTCGTATTAGGCAGGGAGGCCGC- CGTAATTCTGGGATCAAA AGCGGGAAGGTGCGAACTCCTCTTTGTCTCTGCGTGCCCGGCGCGCCCCCCTCCCGGTGGGTGATAAACCCA- CTCTGGCGCCGGCCATG CGCTGGGTGATTAATTTGCGAACAAACAAAAGCGGCCTGGTGGCCACTGCATTCGGGTTAAACATTGGCCAG- CGTGTTCCGAAGGCTTGTG CTGGGCCTGGCCTCCAGGAGAACCCACGAGGCCAGCGCTCCCCGGA 143 chr12: 113622100-113623000 CTCAGGGAATCACATGTCCGCCTGGCCTGGCCTGGTACCAAATGTTTATAGACAGGACGAGGGTCGCTGGAAT- CGCCTCGCTCCTTTCAG CTTGGCGCTAAGGCGCGAATCTCGATCCTCCTAGTATTTCTCTGGCGTCTGTCTCTATCTCAGTCTCTGCTT- TTGTCTCTTTCTCCCTCCCTC CGCCCCAGTCTTTCCGTCTCTTTTTCCTCGAATGCACGTGGAATTCGGAATTGAAAATTGAGGTCAGAATCT- CCCTTTTTCTTCCAGTTATCC GCGCCGCTGCCCCACGCCTAGCGGCTTGGATCTGCATAGACATCTATCTACCCGCAACAAGATCCGAGCTGC- AGAAGCAAACCTAATCTGT CTCCGCACCATCCCCTGCTCTGTAGACCCACTGCCCCATCCCACGCCACATCCTTGAGGTTCAAGTAGCGAC- TCCAGCGGATGATTCGGA GAATGCCCTGCTTTCCAAAGGCCCCAACCCGTGTTTTTATTTTCTTTTTCCTTTGCCCGCTTGACCAACTTT- GGTTTCTTTCAGGGCCCGGAG GTGCCTGCGCCGCGCTTGGCTTTGCTTTCCGCCGCCCCAGGAGACCCGGGACTGTGGTTTCCGCTCGCCACA- TCCCAGCCTGGTGCGCA CACAAGAGCCTGGCGAGCTTCCCTCGCGCGCTTACAGTCAACTACTTTGGGCCTCGGTTTCCCTGCTCCTTG- TAGATCAGAGAAGGGACG GGCGAAATGCCTGCGAGGGAGGGTTGGCGAATGGGTTGGTTGGTGGCAAGACTGCAGTTCTTGTACATGGAC- GGGGGTTGGGGGGTCAA CACTGGAAGAACTCCTGCCTGACGCCAAGAGCCACCCGCTTTCCAGCTCGTCCCACTCCGCGGATGTTTACC- CACCTTCATG 144 chr12: 113657800-113658300 TTTGGGGCACCCAACCCTTCCCAAGCCTCGGTTTTCCCGATCTTGTGGGATCCTTGCGGCGCGAATGGGGTTG- GAAGCACCTTGGAAGCT ACAGAGTACCGGGTCGGGACAATTTCCGGCACTGCCCCAGTTCAGTGGTTTATAGAAAATTTCTTTCTCTCT- CTCAGGTCCACTAAGACCGA GAGAGAGAGAGAAGTCGACTCTGGCACACCCGGGCGAGGGGCTGCCGGGATTCGGGAGCTGGCGCGGTTGAT- TTTTTCCGAGAATCCTC CACTTGGGGTGACGTCGGGCAGCGCGCGCGGGCCGTGAGGTTAATGCCCAGGCTTTTCTCTAAAGCGTCCGG- GAATGATCCGGCGAATA AAACGGGTGTCTGCAAAGTTAATGAATTGTACAAGGAGGCTGAGGGTGGGGACTTCGACCCGGGGAGCCAGA- GGCGGTTCTGGTGGACG CTTCCCCGTGCGCCTAGGGGTGCGCTGGGCTTTCCCAGCCGAGGTCTGCAG 145 THEM233 CCAGACAGTTAAGGTAAAACGTTGAAGTCAAGAGGAAGTAGTGAGTCTGTTGCCAACTGGATAGGGTTGGTCC- TGTCCCATCTAAATGTATT AGAATTAAGTGGCTTTTAAAAATGAGCTGGTCATCTTCAGCCCACGGGCTGGCCAATTTGGAACTTAATGGG- CCTTTGCGTCCTCCTTCCCT GAGCCTCCTTTTATTCCAGACTTCTCAGTGTGAGTCTGTGCGTCCCTCCGACGATCTCAGGGAGTGGGGTGC- CTTCATCTGCCTGTTCCCT GTTCCTCAGGCTGACGCTCCCGCTGTCCTCCCCGCCTCCCCTCACTCCTTTTCTCCCTCCCTTCCTCCTTGT- GGGGAGGCTCTTGGCCAGG GTCCCTGAGCCCGGGCGGGTGCTGGCAGAGGACGCAGAAGGGGTGAGGTCACGTCTCCCTTGAGCCCCGAGC- CGCTGGCTTTTCAGAG CCTCGCCACAAGCCGGCGGCCAGAGCCCCAGACCACACAGACCGTGCGCTCCTCCGCCCTCCCGGCGCCGCC- GGCCTCGCCCATGTCT CAGTACGCCCCTAGCCCGGACTTCAAGAGGGCTTTGGACAGCAGTCCCGAGGCCAACACTGAAGATGACAAG- ACCGAGGAGGACGTGCC CATGCCCAAGAACTACCTGTGGCTCACCATCGTCTCGTGTTTTTGCCCTGCGTACCCCATCAACATCGTGGC- TTTGGTCTTTTCCATCATGG TGAGTGAATCACGGCCAGAGGCAGCCTGGGAGGAGAGACCCGGGCGGCTTTGAGCCCCTGCAGGGGAGTCCG- CGCGCTCTCTGCGGCT CCCTTCCTCACGGCCCGGCCCGCGCTAGGTGTTCTTTGTCCTCGCACCTCCTCCTCACCTTTCTCGGGCTCT- CAGAGCTCTCCCCGCAATC ATCAGCACCTCCTCTGCACTCCTCGTGGTACTCAGAGCCCTGATCAAGCTTCCCCCAGGCTAGCTTTCCTCT- TCTTTCCAGCTCCCAGGGT GCGTTTCCTCTCCAACCCGGGGAAGTTCTTCCGTGGACTTTGCTGACTCCTCTGACCTTCCTAGGCACTTGC- CCGGGGCTTCTCAACCCTC TTTTCTAGAGCCCCAGTGCGCGCCACCCTAGCGAGCGCAGTAAGCTCATACCCCGAGCATGCAGGCTCTACG- TTCCTTTCCCTGCCGCTC CGGGGGCTCCTGCTCTCCAGCGCCCAGGACTGTCTCTATCTCAGCCTGTGCTCCCTTCTCTCTTTGCTGCGC- CCAAGGGCACCGCTTCCG CCACTCTCCGGGGGGTCCCCAGGCGATTCCTGATGCCCCCTCCTTGATCCCGTTTCCGCGCTTTGGCACGGC- ACGCTCTGTCCAGGCAAC AGTTTCCTCTCGCTTCTTCCTACACCCAACTTCCTCTCCTTGCCTCCCTCCGGCGCCCCCTTTTTAACGCGC- CCGAGGCTGGCTCACACCC ACTACCTCTTTAGGCCTTTCTTAGGCTCCCCGTGTGCCCCCCTCACCAGCAAAGTGGGTGCGCCTCTCTTAC- TCTTTCTACCCAGCGCGTC

GTAGTTCCTCCCCGTTTGCTGCGCACTGGCCCTAACCTCTCTTCTCTTGGTGTCCCCCAGAGCTCCCAGGCG- CCCCTCCACCGCTCTGTCC TGCGCCCGGGGCTCTCCCGGGAATGAACTAGGGGATTCCACGCAACGTGCGGCTCCGCCCGCCCTCTGCGCT- CAGACCTCCCGAGCTGC CCGCCTCTCTAGGAGTGGCCGCTGGGGCCTCTAGTCCGCCCTTCCGGAGCTCAGCTCCCTAGCCCTCTTCAA- CCCTGGTAGGAACACCCG AGCGAACCCCACCAGGAGGGCGACGAGCGCCTGCTAGGCCCTCGCCTTATTGACTGCAGCAGCTGGCCCGGG- GGTGGCGGCGGGGTGA GGTTCGTACCGGCACTGTCCCGGGACAACCCTTGCAGTTGCGCTCCCTCCCCCACCGGCTCACCTCGCCTGC- AGCTGGGCCACGGAACT CCCCGGCCACAGACGCA 146 NCOR2 CTCTCTGGGCCTTAGGAAAATGGAAATGACACCTGTACCTGCCCTTCCAGGACTGACAGGAGGG- GCTGCTCCATGAAACCTCACTGCTGC GGTCATAATGTCATTATCTTTTGCCTTAAAGGGATTTCTTCTGCACCAGCACCTAAAGTGGCAGCCCCTTAC- CCTTGGCCATCAGCTGGACC CTGGTGCTCTCCTGGAGCCCAAAACCTCTGTTTTGTGTTGCATCCTGCTGACCAGCCACAGTCCACACCCAT- CTGAGTGTCTGAGCAGAAC AGCCCAGAGGCCACACCAGGATGGCTTTCCACCGGTCACCTTCCCCCACCCACTCATAAACCCTGCGTCTCT- GGGGGAGAGGGTGGCGA GGTCCCCTCCCCACATAGATGGAAACACTGAGGCCTGATTCATGGTGCCCCCTGTGAAGCGCCTCATGGCCA- GCACCGGGGGGCAGCAG GCCAGGGCGGGGACACATACCCGGTTCTCGTCGTAGATGATCTGCACCAGGCTGCGGTGCTTCGACTCGATG- GGCGGCGGTGACACGGG CTTCTCAGGCTCGGGCGGCTTGGCAGCCTCCTCCTCCAGCTGTTGCTGTGGGGAGAGGCA 147 THEM132C CTTGAAAACTCCCAGCCCCCTTTGTCCAGATGGGGATGGAGGTGGCCAGGCTGCCCCGTTGATTGTGTGCCGA- GGAGCCCTCCCCGGGA AGGCTGTGATTTATACGCGCAGGCTTGTCACGGGGTGAAAGGAAGGGCCACTTTTTCATTTTGATCCAATGT- TAGGTTTGAAAGCCACCCAC TGCTGTAAACTCAGCTGGATCCGCGGGCCGTGATTAAACACATTGCCCGCTTTGTTGCCGAGATGGTGTTTC- GGAAGGCGCTGTGAATGCA CTTCCCTTTGCGGGGCTCACACAGACAAGATGTGTGTTGCAAGGATGAGGCGCCTGCTCGGCCTCCAGCCCA- GGGCCGGGAAGGGAGAA GGTGCTGTGCGTCGCTGCCTGTGTCGCCCGCGGCTCTCC 148 PTGDR CGCGTCAGGGCCGAGCTCTTCACTGGCCTGCTCCGCGCTCTTCAATGCCAGCGCCAGGCGCTCA- CCCTGCAGAGCGTCCCGCCTCTCAA AGAGGGGTGTGACCCGCGAGTTTAGATAGGAGGTTCCTGCCGTGGGGAACACCCCGCCGCCCTCGGAGCTTT- TTCTGTGGCGCAGCTTCT CCGCCCGAGCCGCGCGCGGAGCTGCCGGGGGCTCCTTAGCACCCGGGCGCCGGGGCCCTCGCCCTTCCGCAG- CCTTCACTCCAGCCCT CTGCTCCCGCACGCCATGAAGTCGCCGTTCTACCGCTGCCAGAACACCACCTCTGTGGAAAAAGGCAACTCG- GCGGTGATGGGCGGGGT GCTCTTCAGCACCGGCCTCCTGGGCAACCTGCTGGCCCTGGGGCTGCTGGCGCGCTCGGGGCTGGGGTGGTG- CTCGCGGCGTCCACTG CGCCCGCTGCCCTCGGTCTTCTACATGCTGGTGTGTGGCCTGACGGTCACCGACTTGCTGGGCAAGTGCCTC- CTAAGCCCGGTGGTGCTG GCTGCCTACGCTCAGAACCGGAGTCTGCGGGTGCTTGCGCCCGCATTGGACAACTCGTTGTGCCAAGCCTTC- GCCTTCTTCATGTCCTTCT TTGGGCTCTCCTCGACACTGCAACTCCTGGCCATGGCACTGGAGTGCTGGCTCTCCCTAGGGCACCCTTTCT- TCTACCGACGGCACATCAC CCTGCGCCTGGGCGCACTGGTGGCCCCGGTGGTGAGCGCCTTCTCCCTGGCTTTCTGCGCGCTACCTTTCAT- GGGCTTCGGGAAGTTCGT GCAGTACTGCCCCGGCACCTGGTGCTTTATCCAGATGGTCCACGAGGAGGGCTCGCTGTCGGTGCTGGGGTA- CTCTGTGCTCTACTCCAG CCTCATGGCGCTGCTGGTCCTCGCCACCGTGCTGTGCAACCTCGGCGCCATGCGCAACCTCTATGCGATGCA- CCGGCGGCTGCAGCGGC ACCCGCGCTCCTGCACCAGGGACTGTGCCGAGCCGCGCGCGGACGGGAGGGAAGCGTCCCCTCAGCCCCTGG- AGGAGCTGGATCACCT CCTGCTGCTGGCGCTGATGACCGTGCTCTTCACTATGTGTTCTCTGCCCGTAATTGTGAGTCCCCGGGCCCC- GAGGCAGCAGGGCACTGA GACTGTCCGGCCGCGGATGCGGGGCGGGAAGGGTGGA 149 ISL2 CTTCCGCCGCGGTATCTGCGTGCCCTTTTCTGGGCGAGCCCTGGGAGATCCAGGGAGAACTGGGC- GCTCCAGATGGTGTATGTCTGTACC TTCACAGCAAGGCTTCCCTTGGATTTGAGGCTTCCTATTTTGTCTGGGATCGGGGTTTCTCCTTGTCCCAGT- GGCAGCCCCGCGTTGCGGG TTCCGGGCGCTGCGCGGAGCCCAAGGCTGCATGGCAGTGTGCAGCGCCCGCCAGTCGGGCTGGTGGGTTGTG- CACTCCGTCGGCAGCT GCAGAAAGGTGGGAGTGCAGGTCTTGCCTTTCCTCACCGGGCGGTTGGCTTCCAGCACCGAGGCTGACCTAT- CGTGGCAAGTTTGCGGCC CCCGCAGATCCCCAGTGGAGAAAGAGGGCTCTTCCGATGCGATCGAGTGTGCGCCTCCCCGCAAAGCAATGC- AGACCCTAAATCACTCAA GGCCTGGAGCTCCAGTCTCAAAGGTGGCAGAAAAGGCCAGACCTAACTCGAGCACCTACTGCCTTCTGCTTG- CCCCGCAGAGCCTTCAGG GACTGACTGGGACGCCCCTGGTGGCGGGCAGTCCCATCCGCCATGAGAACGCCGTGCAGGGCAGCGCAGTGG- AGGTGCAGACGTACCA GCCGCCGTGGAAGGCGCTCAGCGAGTTTGCCCTCCAGAGCGACCTGGACCAACCCGCCTTCCAACAGCTGGT- GAGGCCCTGCCCTACCC GCCCCGACCTCGGGACTCTGCGGGTTGGGGATTTAGCCACTTAGCCTGGCAGAGAGGGGAGGGGGTGGCCTT- GGGCTGAGGGGCTGGG TACAGCCCTAGGCGGTGGGGGAGGGGGAACAGTGGCGGGCTCTGAAACCTCACCTCGGCCCATTACGCGCCC- TAAACCAGGTCTCCCTG GATTAAAGTGCTCACAAGAGAGGTCGCAGGATTAACCAACCCGCTCCCCCGCCCTAATCCCCCCCTCGTGCG- CCTGGGGACCTGGCCTCC TTCTCCGCAGGGCTTGCTCTCAGCTGGCGGCCGGTCCCCAAGGGACACTTTCCGACTCGGAGCACGCGGCCC- TGGAGCACCAGCTCGCG TGCCTCTTCACCTGCCTCTTCCCGGTGTTTCCGCCGCCCCAGGTCTCCTTCTCCGAGTCCGGCTCCCTAGGC- AACTCCTCCGGCAGCGAC GTGACCTCCCTGTCCTCGCAGCTCCCGGACACCCCCAACAGTATGGTGCCGAGTCCCGTGGAGACGTGAGGG- GGACCCCTCCCTGCCAG CCCGCGGACCTCGCATGCTCCCTGCATGAGACTCACCCATGCTCAGGCCATTCCAGTTCCGAAAGCTCTCTC- GCCTTCGTAATTATTCTATT GTTATTTATGAGAGAGTACCGAGAGACACGGTCTGGACAGCCCAAGGCGCCAGGATGCAACCTGCTTTCACC- AGACTGCAGACCCCTGCT CCGAGGACTCTTAGTTTTTCAAAACCAGAATCTGGGACTTACCAGGGTTAGCTCTGCCCTCTCCTCTCCTCT- CTACGTGGCCGCCGCTCTGT CTCTCCACGCCCCACCTGTGTCCCCATCTCGGCCGGCCCGGAGCTCGCCCACGCGGACCCCCGCCCTGCCCC- AGCTCAGCGCTCCCTGG CGGCTTCGCCCGGGCTCCTAGCGGGGAAAAGGAAGGGGATAACTCAGAGGAACAGACACTCAAACTCCCAAA- GCGCATGATTGCTGGGAA ACAGTAGAAACCAGACTTGCCTTGAAAGTGTTTAAGTTATTCGACGGAGGACAGAGTATGTGAGCCTTTGCC- GAACAAACAAACGTAAGTTA TTGTTATTTATTGTGAGAACAGCCAGTTCATAGTGGGACTTGTATTTTGATCTTAATAAAAAATAATAACCC- GGGGCGACGCCACTCCTCTGT GCTGTTGGCGCGGCGGGAGGGCCGGCGGAGGCCAGTTCAGGGGTCAGGCTGGCGTCGGCTGCCGGGGCTCCG- CGTGCTGCGGGCGG GGCGGGCCCGGTGGGGATTGGGCGC 150 chr15: 87750000-87751000 AGTTTGGGGAGCCTTTTCTCCATTTGAGAAAAAACAAACTTACAGCGAGGGGTGAGGGGTTAGGGTTTGGGAT- TGGGGAAAATGTGGGTGG GGAGCCCCCCCAAGGAAGTGAGGAGGGGGCTGCAAGGATTACACCTGGGCATACGTTTCCCTAGAAATCACA- TTCATTGTATTTTTATAATT TATTCTAAATCTTTCATGCGAAGAAAGTCAGTAGTGAGTGTTAGTACTGGTGGCCCTCCTGATCACACTTGC- ATCTCTTGAGTGTGCCTTAAA GGTCTTGGGAATGGAAAATATAAAAACTGCTTCGTGATGCGTCATCTTTATCCCCCACTCCCCCACCCATTC- CAATATATTTTCTACTTCCAG CCTAAATTCGGGGCCCCCTACCGAGGCCGGCCATGATCTTGAGGGCGGCATAGGGGAGGCCGCGCTCTGTCC- ACCCCAGCCTGGTGATG CCGTTCGCTTCTTGTGCCCGGTATTGTGGGCTACATGCCTTTCCGGCGTACGGAGCTGAGCGTCCAGGCCAG- TGCCCCTCAACCTCTCAG TAATGTTTACCCGAGGCCGTCGTGCAATGAGACTATTCGCATGGCATTGTCAACGCGGCGGCGCGCGCGTCT- CGGCCCTCCGCGGCTTGC CAGACTGTCCTGCAAACCACCTCACCCGTCTCTTTGGCGCAGGAGACTCAGGCTGTAACCGGAGAAAACACT- TCACCCTGGAACCCTAACT CAGGTCCTGGCAAAAGATGCGAGAGGAAGACTTGCTCTCTTAATAAATCTCGGCCGCCCGCACATCTGGCCC- CTAGACCTGCTCGGTAGA GGACTGGCTGGTGGATGCGCGGTCCAGGCCGTGGGCACTCGACCCACCTCTATTTTCCTTCCCGAGGCGCCC- CTGGATTACCACTTTCGGTTTGCGCTTACA TCCGGGATGTCGAATTTCCCAGGGAATCATAATTATTTTATCTATAATTTATTCTAACCCCAAGGTTCCAAG- AAAATCT 151 chr15: 87753000-87754100 ACATTCCTTCTAAAATGTGGGCTTTCTGTGTACATGGGCGCGCATTCCCAGGACTCGGTTCCCTGGGTGGAAT- TCACCCAGGAATACAATC GATTTTCTGAACCTGCGTAAGGCCACAGGCAGCTCTGAAAATGAAAGCGTTTGCTAAGTGGGGGAGATCTCA- CCGATCGAACGTTTAAAAA TGGCTTTGTCTTCATTCAGCTCTCCCGATTTATTCTGTGTTTTACAAATAGAAGCTCAGAGCTTCTGTCGCC- CAGTCCTTGCATGACTCATGG CGGTGGCCACACGGGTTTCAGGGATAACGGGATGTTTAGAAAATCGCTGCATATCGGAGTTTCCTAGCACGT- TCCATTTATACTGAACGCA GGCGGCCGCTGAAAATCCAGCCTCGACTCTTGCTAATGACTGGGTAGGACCCTCGGGGTCCTGCGACGGTGC- TGGAGGGTGTTCCCGGC TCCGATGTGGGGAGGCCTGCGCGGGGACTAGGTTCTCGAGAGGCGAGCGGGCGCGCCAGAGAACCCGAGACT- GCTGCGGGGCCGGAT GCGGGATCCCTGGGCTGCGGTTCTACGCAGAAACGCCAATGGCCATGCCTCCCCAGCTCCTCCCAGCCCCAG- TCACTAGGCCGGCGCCT GGCCCGGAGATCCTCCCAGAGCCCTGGCGGTGCCATCATGCCGGAGAAGACAAGCTCGGCCCCGCTGGAATT- CGCTCCAAACACAGATG CTCATTTTTGGAATATTCTAGAAAAATAACAAGATCTTGTTTGTCGTTATGATTCACGGGAGGTAACTGATG- GGAGGGCCATTTACATGAGGG CAGACACTGTGGGGCGAAGGTGACTTCTGGACGTAGGCTTTAAAGTAGGAACGGCTCCAAATTCCCAATATC- TCCGGCCTTACCGGTTGCA AATCGGACCCCTGCGGGAAAACCAGACACTTCTGTTTCGTGGCTTTCGGGCTGCCTCCAGCCCACGCAGGCT- CGTTTAGTCCCCGTGGAG TCAGCCCCGAGCCTTCCTAGTCCTGGAACAAGGGCTCCAGGTCGCGGCCGCGGGAAGCCGCCAAGAGGGCGG- GGAGTAGGGATTCCCT CCAGCTCCGCAGGGCATC 152 NR2F2 TCCTCCTCGGCCTCAGATGTCGTCCCACCTGCCCACGAGCAGGGAACCTGGAACCCACTCTCCC- GGCAGTCCCCAGCGGGTTCCGCCAC CCGGCGGCCGCCCCTGACACCGAGTGGGTGGGAGGAAGAGGCAGCTGGCGGGGATGGGCCATTGAGACCTCT- TGAAAAATATTAAAAGA CAGGATGGGTAGAGATTTCTCCGGGAGAAAGTTCGAGGGTGCATCGGGTCGCGGCTGGGAGGAGTACCCGAA- ATGCCAGCAGGAGAAAT GCAACCTGTTTAGGCCACACCTTCAATCCCCGAGGCTGTCTGGAGAGACTGCGTGCGGGGGACTTGCCGGCG- TTCCCACACCGCGCCTG CAATCCACTCCCGCGGCTGCCTGGCCTCTGCCACTCGCGGCTTGAAGCCAGTGGCTCTCAAGCCCTCGGCCC- CGCGGCGGCCCGCGCAG CCTTCACCCGGCGCCGGCACCACGAAGCCTGGCCGCAGTGGACTCCCCGCAGCTCGCTGCGCCCTGGCGTCT- CCCGTCGAGGAGGGAG GGACGGAGGCCTGAGCCGGGAGCTCCCTGGCGGTGGTCGGGCCGCCCCCCTTGAGGCCTGCTCCCCCCTCTC- GGCCTCGCCAAATCCC TGAAAGCCCAGTCCCCCTTCGTCACCCCGGGGGCTTCTAATCACTCGGTATCGATTTCCCTAACTCTTTTCA- TCCTGTTGAAGACACATCTT AAAACACTCCAGCCCGGAGTGTGCTCTGGGCTTTATCCACACTAATAAAATGATTTACCCTTCTCTCCGCGC- TCTCCTCACAGAGGAAAATC GTTCGAGCCCCGGCTATTTGTGTGTGATCAGTAAATATTTAGTGCGCTGACATCCTTAGCTGGGCTTCGGAT- CGATTCGGGGCCCACCGGG AGGTGCGCACGGTCCGGGCGGGGCCGCGCCGAGCTCGCCGAGGGGGCTCCTCCCGCCCTCGCCGCCGGCCGC- TGATTTACGGCCCCT GCAACCAGCTAAGGGGGGCGAAAGCGCGCCTGGAAAATTGGCTTTTCAACCTTTTACTTTTGACATTCAGCC- ACTTCCCCAGGCTCTAATTC TCGCCCGCACTCCTCCCTCCCGCCCTACTAAGGGTTGCCCTGTGCGCCCTGCGAGCCCTTCCAGCAGCAACG- CGCGGCGCTCGCGCCCC CTCGGCCCGGGGACCACCTATCACAGCCCTGAGCCGCGACGCGGGGAGGCCCCGGCCCCTGCTATGGGGGTC- GCCTCCTTCGAGGAGA GATGCTCTCCGCCCGCCCACACCTCTGAGGGAGGAGAGGGGGTGGAGAAGCCCAGAGCTGCATCTGCTGGAT- GACGAGCCGCTCTCCCT GCTACCCTTTCTCCGACCCGTCGGCCTTTCTCCTACTCTGGAGACTGATCCTCGACGTCCATCGGGCCGGAT- GGCGTCGGGTGGAAGCGT TACTTTCCTCGCAGAAAAACTCCTCCTCTTTCCTAAGATCAGAAAAAGCGCTTAGCTTGGAATTGTTAG 153 chr16: 11234300-11234900 CCTAGGCATTCTCAGCCCGTTTTGCTGGAGGGGGCATTTGAGGCCTGGCCAGCTTAGCCAGCCTACAAGGAGT- GTTACTGGGGTGAAAAC AGCCAGCGGGGACCAGTCTGCTTGTGGCCCGCCAGGTGCCTGGGATGGGGAAGCAGCAAATGCCCACCTTCC- TGCCCAACCCCCTCCTC CCTCTTCATGGGGGGAACTGGGGGTGGCAGCGGCTGCCGGGTGCGAGCGGGCTCAGGCCTGTGGCCCTGCCT- GACGTTGGTCCCCATC AAGCCATGTGACGAGACCAGGCCACAAGAAAGAGGTTTCAACAAGCGTTATCGTTTCCTGGAACTCCAACTC- GGCGACTTCCCCGAAGACC GGCTGTGCCTGGCGGGCGGGCTGCGCACAGCGGGGACAAGGCTGCCCCCTTCCTCCTCCGCTGCCTCCGCGG- CCGCGTCTATCTCAGT CTGACTACCTGGAAGCAGCACTCCACCCTCCAGCCCAGCGGCCCTCGGCTCAGCTGCCAGGTCACCGGCAAC- CCCGGGAGCGGTGGGG CAGGGGCTGCTCCGCCAGCCTCTGTGATGTTCAGGCCGGGCTGCACCAGCCCGGGACCCCTAGGTG 154 SPN GCACTGGTTCCCCTTTACCTGAGCCAACAACCTACCAGGAAGTTTCCATCAAGATGTCATCAGTGC- CCCAGGAAACCCCTCATGCAACCAG TCATCCTGCTGTTCCCATAACAGCAAACTCTCTAGGATCCCACACCGTGACAGGTGGAACCATAACAACGAA- CTCTCCAGAAACCTCCAGTA GGACCAGTGGAGCCCCTGTTACCACGGCAGCTAGCTCTCTGGAGACCTCCAGAGGCACCTCTGGACCCCCTC- TTACCATGGCAACTGTCT CTCTGGAGACTTCCAAAGGCACCTCTGGACCCCCTGTTACCATGGCAACTGACTCTCTGGAGACCTCCACTG- GGACCACTGGACCCCCTGT TACCATGACAACTGGCTCTCTGGAGCCCTCCAGCGGGGCCAGTGGACCCCAGGTCTCTAGCGTAAAACTATC- TACAATGATGTCTCCAACG ACCTCCACCAACGCAAGCACTGTGCCCTTCCGGAACCCAGATGAGAACTCACGAGGCATGCTGCCAGTGGCT- GTGCTTGTGGCCCTGCTG GCGGTCATAGTCCTCGTGGCTCTGCTCCTGCTGTGGCGCCGGCGGCAGAAGCGGCGGACTGGGGCCCTCGTG- CTGAGCAGAGGCGGCA AGCGTAACGGGGTGGTGGACGCCTGGGCTGGGCCAGCCCAGGTCCCTGAGGAGGGGGCCGTGACAGT 155 chr16: 85469900-85470200 TGTCCGACAGGCACACAGAGCGCCGCCAGGCACGGCCCTCATTCTTCACCCCGAGCTCCCGCAAGGTCGGCGA- GGAGGCTGGAGCAGC GGGTAGGAAGCGGGCCGAGGCTCCCCCGACGCTGGGCCGCAACTGTCATCGCAGATCCCTGAAAAACGAGCT- CTGTAATCGTTGCCGTC AGCGGGTGTACAATTGCAGCCTTATGTTTCCTGCCGCTGTTTACCTTCCTGAGCGGCGCCCAGAGATGCACA- CACGCTGCCCTGAAGCGG GACGTGACCTCTGGGCACCTGTGAGGTCCTGGG 156 SLFN11 GTCGGCTCCTGCGCTCCCAACGGGGTGGCCGTTTCCTTCCTCGCACCCTCTTCTCTCCCGGTG- CCTGCGGTCCCACCTTCCAGATACCCC TCGGAGAGTCCAGCTGAGCTCTCGCCAGAGCTTTCCCCTTCCAACCCGCTCGACTTGCCCAGATCCCAAGCT- GGGCTTCTCTCTCCATCGC CCCAGAAAGTGGGTCTTGGAGACCGAGGCAAGAATTTGGGCCTCCGCTTCTGTTCCAGACCCCGGACCCCTT- GCCAAAATGCGGCAGATG TGCAGATTGGGCCGCGCTTGGTTCCTGGCTGGGTTTATGGAGCCTGCGGCTGAGGCAGGCTCCGCAGACCCC- GAGCCAGAGTGGGATTT AACGGCGGCCGGTGCGCTGTGCTTGGTCAACCCCGGTAACCGTCACGCTGCTAGTGATATGAAAAAAACCTG- CCAGCGTTCTGCTTTTCTGCCCCGCTGCAGT CTTTAGCACCCGCCAGGATTCTGTCCGAGTGTTTGGA 157 DLX4 TTTAGTGTGTGCATAAAACATCCCAGCTAATCTCAAATAGACTTTTCCTGAGCAGAGGCTGAAAT- TTGCAAGTAATGCAAAGAAGACTCCGG GAGAGCGTCGCCGATGGTGGAGCGGGAGACGGGCGTGGGGAGCCCCACTGCAGTGCTGGGATCGAAGTGGTG-

CTGACCCCAAGACCTC TCCCCTCCTCCTCCCCCGGGAGCTTCTCCAGGGTTATTTGGGAAATGAGGGGGAACTCCAATCCCTGAGAAA- GCGCTCAGGGGCTTGCTG AGGTGAGCGCAAATGGAAGCACAAGGCCGGGCTGGCCGTGGGCTCAGTAACCAGTCGGCTGCCCGGCTTGCG- CCAGCACTAAATGCTCG ATCAGAAAGAGAAAAAGAGGCGCAATAATTCCAAATTTCAGGAAAAGTCAAATCGGAGAGGGGGGACGCAGG- TCTCTTCAGACTGCCCATT CTCCGGGCCTCGCTGAATGCGGGGGCTCTATCCACAGCGCGCGGGGCCGAGCTCAGGCAGGCTGGGGCGAAG- ATCTGATTCTTTCCTTC CCGCCGCCAAACCGAATTAATCAGTTTCTTCAACCTGAGTTACTAAGAAAGAAAGGTCCTTCCAAATAAAAC- TGAAAATCACTGCGAATGACA ATACTATACTACAAGTTCGTTTTGGGGCCGGTGGGTGGGATGGAGGAGAAAGGGCACGGATAATCCCGGAGG- GCCGCGGAGTGAGGAGG ACTATGGTCGCGGTGGAATCTCTGTTCCGCTGGCACATCCGCGCAGGTGCGGCTCTGAGTGCTGGCTCGGGG- TTACAGACCTCGGCATCC GGCTGCAGGGGCAGACAGAGACCTCCTCTGCTAGGGCGTGCGGTAGGCATCGTATGGAGCCCAGAGACTGCC- GAGAGCACTGCGCACTC ACCAAGTGTTAGGGGTGCCCGTGATAGACCGCCAGGGAAGGGGCTGGTTCGGAGGGAATTCCCGCTACCGGG- AAGGTCGGAACTCGGG GTGATCAAACAA 158 SLC38A10 CATGGTGCTTCAGGAAGGGAGGGGACGAGAGCCCTGGGCTTGTGGTGTCCACGTGGACAGCTAATGAGGAGCC- TTGCCGATGAGGAGCA TGCGTTCCCGACGGGGCGGCCGAATGCGGAAGGAGCCGCCATTCTCTCCGCCCTGACCGCGGGATTCTCTGC- AGCAGATGAGAAACGGC GCTGACTCAGCAGGGTCCCTCCCAGGCCCCGAGCGGTCATCTGGTGACCCCCGCGCTTCCCCCACGGCCCAG- CCGGAGAAGGGCAAAG GGAAGTCCCGGCTCCAAGGCGCACCCAGAGATGCGGTGCATGTGGCAGGATGGCCCAGCCCCGTCGGCAGCC- CCAGCTTCCTGCCCCT GGTTTCCTTCCTCCCACGGGCTACAGGCCTCTGATGAGCTTTGGAAAGCAGGAAACACACAGGCTAGTAACT- ATGAATGGGTCCAAAAAAC ACTCCTTATTACTTTAAACTACTTAGGAAGAAGCACAGCGTTGCCAAACGCCAGA 159 S1PR4 GCGCGGGGGGCCGGAGGATGGCGGCCTGGGGGCCCTGCGGGGGCTGTCGGTGGCCGCCAGCTGC- CTGGTGGTGCTGGAGAACTTGCT GGTGCTGGCGGCCATCACCAGCCACATGCGGTCGCGACGCTGGGTCTACTATTGCCTGGTGAACATCACGCT- GAGTGACCTGCTCACGG GCGCGGCCTACCTGGCCAACGTGCTGCTGTCGGGGGCCCGCACCTTCCGTCTGGCGCCCGCCCAGTGGTTCC- TACGGGAGGGCCTGCT CTTCACCGCCCTGGCCGCCTCCACCTTCAGCCTGCTCTTCACTGCAGGGGAGCGCTTTGCCACCATGGTGCG- GCCGGTGGCCGAGAGCG GGGCCACCAAGACCAGCCGCGTCTACGGCTTCATCGGCCTCTGCTGGCTGCTGGCCGCGCTGCTGGGGATGC- TGCCTTTGCTGGGCTGG AACTGCCTGTGCGCCTTTGACCGCTGCTCCAGCCTTCTGCCCCTCTACTCCAAGCGCTACATCCTCTTCTGC- CTGGTGATCTTCGCCGGCG TCCTGGCCACCATCATGGGCCTCTATGGGGCCATCTTCCGCCTGGTGCAGGCCAGCGGGCAGAAGGCCCCAC- GCCCAGCGGCCCGCCG CAAGGCCCGCCGCCTGCTGAAGACGGTGCTGATGATCCTGCTGGCCTTCCTGGTGTGCTGGGGCCCACTCTT- CGGGCTGCTGCTGGCCG ACGTCTTTGGCTCCAACCTCTGGGCCCAGGAGTACCTGCGGGGCATGGACTGGATCCTGGCCCTGGCCGTCC- TCAACTCGGCGGTCAAC CCCATCATCTACTCCTTCCGCAGCAGGGAGGTGTGCAGAGCCGTGCTCAGCTTCCTCTGCTGCGGGTGTCTC- CGGCTGGGCATGCGAGG GCCCGGGGACTGCCTGGCCCGGGCCGTCGAGGCTCACTCCGGAGCTTCCACCACCGACAGCTCTCTGAGGCC- AAGGGACAGCTTTCGCG GCTCCCGCTCGCTCAGCTTTCGGATGCGGGAGCCCCTGTCCAGCATCTCCAGCGTGCGGAGCATCTGAAGTT- GCAGTCTTGCGTGTGGAT GGTGCAGCCACCGGGTGCGTGCCAGGCAGGCCCTCCTGGGGTACAGGAAGCTGTGTGCACGCAGCCTCGCCT- GTATGGGGAGCAGGGA ACGGGACAGGCCCCCATGGTCTTCCCGGTGGCCTCTCGGGGCTTC 160 MAP2K2 GGGCGGGTTGCCACACTGTCCCCTTTCTGCATGGGAGGAAGGGGGCTCGAGAACTGAGTCAGC- CACACAAAACGAGGATGGACAGAACT CCTGAGTAGCGAGGGTGCCTGCCGGGCGCGAGGAGGAGGGGGAAGACGAGGAAGACGAGGAGGAGGAATAGG- GAGCACCACATGACA GAGGGGCTGCCTCAGACCACAAAGCGCTTCCTCATCCTTTCCTCGCCCTTTGATGCCGCCGGCAACGTGACT- CTGCGAGCAGCGGGGCAG ACGCCAGGTCTCCCTCGCAGGCGGGAAAGGGGCTCCAAGGCGGGTGCTGCCTTGCTCGGGTCACATGGCTAC- GTGGGGGCCTTGCTCAA ATTCACTTCCTGCCTTCATTACAAAACTGTCAAAGGGGATCGCACGTTTGCAGGGTGTCACCCAAGCATTCT- GGTTTTGCAAACGACGCTGT GCGGCAGGCGGTCTGATACCTGATGAGCTCGGTGTGGCGGGGTCGGCAGCATTTCCTCCGGGGTTTTGAGCT- CTGGCCACTTCTCCTTTT GTTCCACCCAATCTCACCCACTTCTGGGCTTCGAGGCCAGAGTGTCTTAACAAGGGGGCACGT 161 UHRF1 GAGCGAGACTTTGTCTCAAAAAAAAAAAAAACCAAATAAATTGAAAGCTGAGAAATTCAGAGCA- CAAGAAGACAAGCGCGCCCCCTCTTTTA GCTGTCAACATGGCGGAGCCGTCCCTGGTGACGCAGCCTCCAAAGGCCTCCCTGTGCCCTCCTGAGACCGCA- AGAGGGAAAGTGGCAGC GACAGTGATCGTGGTGTCTTTGTGGCGGTTGTGTTGACCTCACTGACCCCCGAAGTGCCGCTCTAGGGTCTG- TCCTCAGCGGTGACCCGG CCGGGTCGAAGGGCAGAGTTCCGCTGTCACTAGCCCTCCACCCGTCCTGTGTGCTGGGATGCCCTCGCGGCG- CCGTCCACGCCACCGCC GCCCCCTCTTGTGGGTTCTGTCTCCTCCGTGTCTAGGATCCTCCTGCATCCGTTTTTCCTTCCTCCCTTCTC- TCCCTCCGTCTGTCTTGCCCGCACCTGAGG TTGTCGCAGAGGCGCTGAGACGGGCCAGCAGGAGCTGT 162 DEDD2 TGCTGTCCCGGTCCTGTCGCAGTCCTCAAAGATGCTAGAGTGACAGTCCTCTAGGGGTAGAGAT- GGTCGTCCTCCCAGGAGAAGGTGGCC CGGAGACTTGGAGGTGGGATCAATCCTGCCAGTCCTGGATCAGGAGGCCTCTGTCGGGCGCCGCCCCCCTTC- CTCCTCCATCAGCAACAG GCGGCGCCGGCCAGCCTCATAGTCAGCCTCATCCACACTGACCAGCAGGCGAACAGCCTCCCGGCCCACAGC- CTCTCGCAGGGCCTCAG TCAGGAACACGCCCCGCAGGGCCTGCAGCAGGGCGCCACTCAGGTAGTCGCCCCAGAAGGCGTCCAGATAGG- AGAGCTCTGAGAACTTG ATGTCACAAACCACAGAGCCCAGGTCCCTTGAGCGCAGCACTGCGGTGGCCTGCCCAAACACGTCCAGCTGC- CGCGCCAGCGCCTGGGG CCGCCGGGATGCCACGCCCTGCTCCAAGGCTGGCCCATGCTCGCAGTACTCTGCTCGAACCCGGAGCCGGAT- GTCTGCAGGGGAAGGAG GGATTTGTCAGGGAGGGGGCCAACACTAGACACACTTATGGGGAACGCCACCCTTCCTCCCTCC 163 CDC42EP1 TGATGCCCGGCCCCCAGGGGGGCAGAGGCGCCGCCACCATGAGCCTGGGCAAGCTCTCGCCTGTGGGCTGGGT- GTCCAGTTCACAGGG AAAGAGGCGGCTGACTGCAGACATGATCAGCCACCCACTCGGGGACTTCCGCCACACCATGCATGTGGGCCG- TGGCGGGGATGTCTTCG GGGACACGTCCTTCCTCAGCAACCACGGTGGCAGCTCCGGGAGCACCCATCGCTCACCCCGCAGCTTCCTGG- CCAAGAAGCTGCAGCTG GTGCGGAGGGTGGGGGCGCCCCCCCGGAGGATGGCATCTCCCCCTGCACCCTCCCCGGCTCCACCGGCCATC- TCCCCCATCATCAAGAA CGCCATCTCCCTGCCCCAGCTCAACCAGGCCGCCTACGACAGCCTCGTGGTTGGCAAGCTCAGCTTCGACAG- CAGCCCCACCAGCTCCAC GGACGGCCACTCCAGCTACGGTGAGGGCCTGGGCCATCTTGGCCCACTTTTCAGA

TABLE-US-00016 TABLE 4C SEQ ID NO GENE NAME SEQUENCE 164 chr21: 9906600-9906800 GGCCGGGCAAAAAGCCGCCGCAACAAAAAGCTGCGCTGACGGGCGGAAAAAGCCGCGGCGGCGGAGCCAAAAA- GCCGGGGCGGCAAAAAGCCACGGTGGCGG GCGCAAACAGCCGCAAAAAGCCGCGGTGGTGGGGGCAAAATCAGTGGGAGCAGGGGCAAAAAAACACAAAAA- GCCGCGGCGGCGGGGGCAAAAAGCCA 165 chr21: 9907000-9907400 TGGCTTTGCTGGAGTGTGATGTGATAGGAAATGTGCAGCCAAAGACAAAAGAAGATGTAAGTAGGCTTGACTC- ATTGCAGCTAAGAACCCA GATGTTACCTTGAGGGTATTAACTAATAAGCAGTTTAAATCAGAATGGCACATTCTGATTTGTTTTTTGTAT- GTTCACATTTGGCAGGCATAGA TACTGTTTGAAAAGAGAAAAGTCAGTACATAGAGGTAACAAGCTTAAATATGTGCCAAGTCTAGAAACAAGA- GACTAGGGGGATAAGGACCT TTCGAAATTAAATGCAAGATTTGAAAACTGATTGGCTGGGGGATGAGGCAAAGGCAGGTCTTTAAGGTCAAT- CCCTGTTTTGCTTTAAGTTG TTAGCGGGTGGTTTTATCATATATTGTAGAA 166 chr21: 9917800-9918450 TTCCTGGGAATGTCAGCTAACCTGAGCCTAGGGGCCTGAGCCCAAGGGCAGACTGAGGCTCCCCCAGCACAGG- GAGGTGCTGCCTGTGA CAAGGGGTAGTGCTGGCACAGTGCAGGCTACTCCCTAGAAAGATCAGCTTGAATATGCAGGAAGAGCAGGAC- CCTCGGGCTGAGGCAGA GGTGGAATGGGAAGTGCATGGTGGTAATTTAGTTCTCCAGAGGCCAGAAGTAGGAGGAGCGGTTGGAATGCT- GATGGCCCAAAGGGAAAC CCTGGACTACCCTGGCCTCCCACAGGACTCTCATAGTAATTGCGGCTCCCTGCAGTGGTGAGGCCAGAAGGA- GTGTTGCCCAATGCTGTC ATCATCCAGTCCACCCCCCACCCACCATCAACAGATGAGTATGGTCATGAGTGTGGTCACCTCATCAGTCAT- TTGCTCAGTTGTGAAAAAGA AATTGTTCAGAGAAGAGCAAAGTGTTTTTCCATGAGCCAAAGGTCAGCCAAGTTATGCTAATGAGGAGGACT- GGAGACAGCGTGTCACAGA CACCGAGAAGGAGCACTGGGCAAGGGCACTTCTCCCAGGGCAGAGCCCACAAGAAGCGTCCTGGCACCAGAC- ACTCAGGGAACTGAAGG CTGGCAGGGGCCCGCCCAGT 167 TPTE TCCCCCCAGCTGGGTATAAGCAAACTTTCCTGTCTATGGGCCGCAGAGACCACCATCTAGTTCCC- CCGCCAAAACTTTACATGATTTTAATT CTCCTGATGAAGATGAGAGGATAACAGCCAACAGAGAGGGCAGAGGATGGGATGGGACTCCCTTGCTCAGAG- ACCTCACCTCTAGGTCTT TACCTCCTATTGAGAATAAGTCAGTTCTGTAGTAAGAACTCTGTGTCCACGGCAACCCCAAACAGAATCCTA- GCGCTCTTGTGATTCTTGTA GAATGGGGAATAGAACGAGCTTGGCCCAAGACTGCACAGACTTAAAAACATACTATTCTTTGAAAATGGCAA- TCATTAAAAAGTCAGGAAAC AACAGGTGCTGGAGAGGATGTGGAGAAATAGGAACACTTTTACACTGTTGGTGGGACTGTAAACTAGTTCAA- CCATGGTGGAAGTCAGTGT GGCGATTCCTCAGGGATCTAGAACTAGAAATACCATTTGACCCAGCCATCCCATTACTGGGTATATACCCAA- AGGACTATAAATCATGCTGC TATACAGACACATGCACACGTATGTTTACTGCAGCACTATTCACAATAGCAAAGACTTGGAACCAACCCAAA- TGTCCAACAATGATAGACTG GATTAAGAAAATGTGGCACATATACACCATGGAATACTATGCAGCCATAAAAAATGATGAGTTCATGTCCTT- TGTAGGGACATGGATGAAATT GGAAATCATTCTCAGTAAACTATCGCAAGAACAAAAAACCAAACACTGCATATTCTCACTCATAGGTGGGAA- CTGAACAATGAGAACACGTG GACCCAGGAAGGGGAACATCACACTCTGGGGACTGTTGTGGGGTGGGGGGAGGGGGGAGGGATAGCATTGGG- AGATATACCAAATGCTA GATGAGGAGTTTGTGGGTGCAGCGCACCAGCATGTCACACGTTTACATATGTAACTAACCTGCACATTGTGC- ACATGTACCCTAAAACTTAA AGTATAATAAAAAAAATACTGTTCTGCCATACATACAGATACTCATTAAAGATGAGGGAGAAGGGCATGGGG- TGGGGGAGAATGTACCAAAA CCAAAGACCACAGGATAATAACCTCAGAGCAGAGACTATCTCTCTAGTTATTTTTTCTTTTGTATGTAATGG- AGAGGATTATTATTTACTCTGA TGAAGAAGTTTACATCAAGTGTTCAGCTTCCTTTGTGGGTTACAGAGAATAACCAGAGGGCTCAGTTATGCT- CTCTGAATAACTATGTTTGCT TAGTGTTTTCTAAACAATATTAAATTTCACTAAAATAGACAAGGTTGATAGGACTTGGGGGCATAACTCATT- GACTCAAGCTATCATTTTATAG GATTGTGAGAAAACAAATAGATGAACATTTAAAATACACTCATATTCTCGCTAGAAAAGAGGATTTTGAATA- TTCTTACATCAAAGACATGGTA AATGTTTAAGGCAATGAATATGCTAATTACCATGATTTGATCATTATGCAATGTAAAATGTACTGAAACATC- ACATTGTACCTCATAAATATGTA CAATTTATTATGTGCGAATTAAAATTTTGAGTATAAGAAAAAATAAACTTCAATTGTAAGAAAACAACCCAA- CTTTTAAAAAACGGGCAAAATA CGTGAACAGATACTTCACTAATAGAGATTTGCAACTGGCAAATAAGCAAATGAAAAACTGGTCATCATCACT- ATCTATTAGAGAAATGCAGAT TAAAACTACAATAAGAAACAATGCTGCCCGTCCAGACGCATTGTTTTGACCGTTTCCAACTTGTCCCAGCCC- TTCCCGGGGCATCGCTGGG GACCCTACGCCGACGTCCCCCCTCCGCCCGCGCCCCAAGGGCCGACTGGGCAAATTGGGAGACCCGCCCCGC- GGGGCGACCCAACTTT TCGGAACAGCACCCCACCGCCCACCCCCGCAGACCCCCGGACCCCCGCTCCCGGCGGAGACTCAGGGAACCC- CGCACCCCAAGCCCTT CTAAATCGTGCAGCGTGAGTGTGACGGCCAAGAGCGGATGCAGCCCGGGATCGCCCGCACCTTCCCGTGGGC- GGAAGCGCAGGAGCCA GCTGGGGAGGGGGCGCCCTAGAGGAGCGGCTAGAAAGCAGACACGGGGAACTCAGGTCATCCTGGGGGGGGA- CAAGACAACGAGAGCC GGGCGCCTCGGGGGCGGCGCGGGAGCCTCCGCAGGACCGGGCGGGCGCCCCGGCTGGCGCGGGCGGGGGGCG- CGCCCCCTTTACCT GCGGCTCCGGCTCCTAGGCCATTTCCTCACGCGGCGGCGGCCGGGACTGAGCTAACACCACTCAGGCCGGCC- GGGTTTGAATGAGGAGG AGCGGGCGCGGAGAGGAGGGGACGGGGAGGGCGGAGGGAGGGAGGGAGGCGTCGCGGAGTTTTTCTCGGCCT- TTTGTGCGGACACCT CCCGGATTCCGCGCCCGCACCCGGCCCCCCAAAAGACACGGGGAGCCGCGGGCGAGGGGTTCAGCCATCCGC- CGAGGCGCCTAGTGCC TTCGCGCCTCCAAGACCCCCCCCCAACAAAAAGGAGCGTCCCCCACCCCTACCCCCGCCCGGAGGACTTAGG- GCCTGGGCTCACCTCGG GCGCGGAGCTAAGTGTAGGCGCCGGGGGTCCCTAGAGCCGCCGGGGCGCAGCGAGTCCGGCGCTGGGTAACT- GTTGGGTCAGAAACTG TTCAGGTAGCAGCTGTTGTGCCCTCCCTTGGCCCCGCCGCTCGGAGACGCCCCGCCCCCTGCCTTGAACGGC- CGCCCGGCCCCGCCCCA GCGCCCACGTGACTAGCATAGGCGCGCCCCCGTTCCGCCCGCCGCCGCAGACTCCGCCTCCGGGACGCGAGC- GAGCGGCGAGCGCGC GCACTACCAGTTCTTGCTCGGCGACTCCCGCGCACGCGCGCGCCGTGCCACCCTCCCCGCACCCCTCCTCCC- GCCATCCGGCTTAACGT GGCGGGCGCGCGCCGCGGCAGTAGCCGTGACAGGTACCCGGCGGGGCGGGGGGGGAGGGGGTTGGCCCGCGA- GGGTGTGCGCAGGC ACAGACCCGGGTCCTGTCCCCGCCGCCCCCTCCTCTGCAAGGTGTGCCTGGGCGAGGGGAGGGGCCCGCGGC- CCGAACCCCTGGGTCA CCCCCGAATTACAAACAAAAACCTTAACGCCATTGCTCGCGGGTTAGAAGGCAGCTGTGCGTGCTCAGGAAA- AGAAGCCACGCACAAGAG ACCGCACGCGGCGTGGATACAGTGACACGAAACACCCAAAATCTCTTTTGAAAGGGAAACCAGGCACAGTGG- CTCATGCCTATAATCCCAG CACTTTCGGGGGCCAAGGCGCTCACCTAAACCCGAGAGTTCAAGACCAGCCTGGGCAATACAGCGAAACCCT- GTCTCTACGAAAAATATAA AAATTAGCTGGGCATAGGGCTGGGCACGGTGGCTCACGCCTGTAATCCCAGCATTTTGGAGGCCGAGGCGGG- CGGATCACGAGGTCAGG AGTTCCAGACCATCCTGGCTAACACAGTGAAACCTTCTCTCTACTAAAAATACAAAAAAAATTAGCCGGGCG- TGGTGGCAGGTGCCTGTAGT CCTAGCTACTTGGGAGGTTGAGGCAGGAGAATGGCATGAATCAGGGAGCGGAGGCTGCAGTGAGCTGAGATT- GCGCCACTGCACTCCAG CCTGGGGGACAGAGTGAGACTCCGTCTCAAAAAAAAAAATAATAATTAGCTGGGCATGGTGGCTGGCACACA- TGGTCCCAGCTACTCAGGA GGCTGAGGTGGAAGGATCTCTTGATCCCGGGGAGGTCAAGGCTGCAGTGAGCCAAGATGGCATCACCGCACT- CCAGCCTGGGCCACAGA CCCTGTCTCAAAAAAAAAAGAGAAAGTGGGGAAGAAAATGTAATACAAATTAATATACCAACAGCAATTAGT- GAGTACTTTTTCCATGGAGCT GGGAGAGGGAATAAATGTTTGTAAAATTAAAATGTTCTACGCTAGAAATCAACTTTCCTTCTATGCTTTCTT- TACTTCACCCCTTATAGCTACT TAGTAAATCTCACAAATCCTATCCTTCTGATCTCTCTGAAATGTATGTACCCTTTCCCTTCTATTCTCACCA- CCCATGTTTCTTTGTTTCCTTCT AGCCTGTGTAATAATCTCATAATCGCACCTCCTGTACCTGCCTTCTTTCTAGTCCAGAATACGTTTTCCTAA- ATTCCACCAATAACCATCCTG CTACTGCTTTGTGTGAAATTCTCCAAAAAAAATTTTACTTTTCCAAAATAAGTCAGGCTCCCTCTCTTAGGA- TACAAAACCACACCATGGTCCC AGCCAATCTTTCAGCCTGATTCACTCAGTATATATTTATTGACCTCTCCTTTCTCCCAAGCACTTGGCTAGA- TAATAATTAAAGAGTGCGGCA CAAAACAAATTGGATTCCTCCCCTCATGGAGCTTGTATTTTCACAGGAAGCACAGACATTAAATAAATTAAA- ACACAAAAAAATAGACAAGCA TATAATTACAGTATGTATCCTAGAGAAATATCACTCATGCAGAAAGCATACACAAGGATGCAGCACTGTTTC- CAATAGCGAAAAGCTAGAAAC AACCTACATGTTCACCAAAAGAAAATGGCCACATAAACTATACCATATCCAAATTATCCAAATTTTAGAATA- TAGACAACAGGTTGGGCGCGG TGGCTCACACCTGTAATCCCAGCACTTTGGGAAGCCGAGGCGGGTGGATCACAAGGTCAGGAGTTCAAGACC- AGCCTGGCCAACATGGTG AAACCCCGTCTCCTCTAAAAAAACAAAAAAATCAGCTGGGCACTGTGGCAGGAGCCTGTAATCCCAGCTACT- GAGGAGACTGAGGCAGGAG AATCGCTTGAACCCTGGAGGCAGAGGTTGCAGTGAGCCAAGATCGCGCCACTGCACTCTAGCCTGGGTGACA- GAGCAAGACTCCATCTCAG 168 chr21: 13974500-13976000 TGTAGGAGTCCTCCGGTGCTGGAGTCCAGAGCACAGTGAGGCTGGGTCCTCCCGTGCCATAGTGTAGGGCATG- GCGGGACAGGGATCCT GCCCTGCGATAGTCCAGTGCTTGAGTCCGCAGTAAGGCAATGGTCCTCCAATGCTGGAGTTCACGGCGTTGT- GGGGTCGGGGTCCTTTGG TGACTTAGTCCAGGGCGTACCAGGGCGGGGGTCCACAGTTGCCATAGTGAGGATCTTGGAGGAAGGTGGTTC- CTGCCTTGCTGTAGTCCG GGGAGCAGGGGGCAGGGGTCCTCTCTTGTCAGAGTCTCTGGCGCGGGGTGGGGGTGGAGGTGGGGGTTTTCC- TATGCGATAGCCCACG GGTCGGTGAAGCCGGGTCCTCCCGTGCCTTTGTCCAGGGCGCAGGGGGGCGAGGGTCTTCGGTGGTGGAGTC- CGCGGAGCGGCAGGAC GGGGGTCCTCCAGTGCCATATTCCAGGGCGCGGCGGAGTGGGGGACCTGTCCTGCAGTGGTCCAGGGCATGT- GGGAGTGGTGGTCCTG CTGTGCCTCAGTCCAGTGCGCGGTGGGACGGCGGTCCTGCTGTGCTGTAGTGCAGGACGCGGTGGCGCAGGG- GTAGTCCAGAGAGCGC CGTGGCAGGGGGTCCTCCAGTGCTGGAATCCAGTGCAAGGCGGGTCAGGGGTCTTACCGTGCCGAAGTCGGT- GGCAAGGGTCCTCCCGT GCCATAGTCTAGGGGGCGACGGGGCAGGGTTCTCTAGTGCAGGTGTCCAGGGTGTGGCAGGGCAGGAGTCCT- CTTGTGCAGGAGTCCAG GACGTAGCCGAGGAGTCCTCCAATGTCAGAGTCCAGGGCTCTGCGGGGCCGGGTTCCCCCATGCCAGAGTGT- AGGGCGCGTTCAGGTGA GGGTCTTGGCGTGCAGTAATCCAGGGTGCGGTGGGGCAGGGGTAGTCCAGACCTCCATGGCGGGCGTCCCTC- TGTGCAGGAGCCCAGT GCCTGGCGGATCGGGGGTCCTTCTGTGCTGTAGTCCAGGGCACCGCAAGGTGTGGGTCCTCTGGTGCCCTAG- TCCAGGGGGCGGCGAGT CAGAGGTTCTCCCGTGTCTCAGTCTAGGGCCTGGTAGGACTGGGGTCCTGGAGTCCACGTGGTAGCCCAAGT- TGCCGCAGGACCAGGTA CTCTGGAACCACAGTCCAGGGCGCTGAGGGGCAGGAGTAGTTCAGGGCGAGCCGGGGCCCAGGTCCTCGGGA- GCCAGAGTCCAGGGTG TGGAGGGGTGGGGGTTCTGCAGTGGCACAGTCCAGGACACCGCGGGGCGGGACAGGGCGGGGATCCTCCCGT- GCCTTAGTCCAGGGCT GAGCCGCGGGAGAGGTCCTTCAGTAGCACAGTCTAGCGCACGGCGTTGCAGGTGTCCTCCAGTGCCTGAGGC- CACGGCAGGTCGCGGGT CCCACTGTGCTCTAGTTCAGGGCGGAGTGGGTCTGAGGTCTTCTCCTGCCTCAGTCTAGGGCGCTGGAGAGC- GGGGATCCT 169 chr21: 13989500-13992000 GGGTTGGTCCTAGAAAGCGTGAGGATCGCCGAGTGCACTGCCCTCCCAGCCTAGGGTCCACTCTTCCTTGGCC- CGAGCCCAGAGCTCGG GGTTTCAGGCGCTGGGCCCTGTGCAGCTGCCCAGAATAGGCTGAGCGGCAGGTTCCCGCCCTGGCAAGGGAT- CCAGCAGTGGAATCCTC ACTGCTGTTGGCTGCGGGCAAGGTCAGCGGGGTTTCCATCGCTGCTGGTGGGAGCCACCTGGCGGTGGTAGC- TGCAAGTGAGCGCGTGG CAGAGACTGGCAGGGCTGGTCCCAGACACCCTGAGGGTCTCTGGGTGCATCGCCCTACCACCCTAGGGTCTG- CTCTTCCTTAGCCTGCTC CCAGGACGCGGTGTACGAGGGCTAGACTCTGAGCAGCCTCCAGGATGGGGCTGAGCAGCGGATTCCTGCCCT- GCTGCAGCTACAGTCTG AATTAGGCGCCACCGCAGTATCTGGCCCTGGGGTACGTGCTACTGGGTGGCATGGACAGAGATGGGGGCTGC- CACAGCTGCTATGGGGC TGAGCAGCCGATTCTCGCCCTGCTGCAGCGGGCGACCGCTGCAATCCCCAGCGCTATGGGACCGACCACCTG- ACTTAGATGCCTTGGAG GCATCCGGTCCTGGGGTCTTGCTGCTGGTGTCTGCGGGCAGGGTCACGGCTGCCACTACTACTGCTGTGCGC- CATGGGCAGGTGCCAGC TGCAGCTGAGTCCGAGGCAGATGCTGTCAGGGCTGGTCTGAGGTTGCCTAAGGGTGGCTGAGTGCACCACGC- TTCCACCCCAGGGTCCG TTATTCCTAGGCCGGCTCCCAGATTGCAGGGTTGTGGGCGTTGGACACTGTGCAGCCATGAGGATCTGGTTG- GGTGCAGATTCCCGCCCT CCTGCAGCTGAGAAGCCAATCTCATAACAGGCGCTGCAGTGACCTCTGGCTCTGCGGTCCGCGCTGCTGCTG- GAGCTGGCAGAGAACAGA GCTGCCACCGCTGCTGCTTCCAGGAGTGTGCAGCTGGCAGCTGCAGCTGAGCCCGTGGCGGAGGCTGGAAGG- CCTTATTCCAGAAGCCT TGAGGGTCCCCGAATGCACCGCCCTCCCACCCTAAGGTCCAGTCTTCCTTGCCCGCGCCCAGAGAGTTGGAT- TGCAGGCGCTGAGCACAG TGCAGGTGCTGGGATGGGGCTAAGCTGAAAGTTTCCGCCCTCTGGCTGCTGCGGGGCCGACAGCCTGAGTTA- TGCGCCGCGGCGGCTTT TGGTCATGGGATCCGCACTGCCGGTGGCTTGCACAGGGTCGGGGGCTGCCACAGCTGCTATAGTTCACCGTG- TGCACGTGGCAGCCGCC CCTGAGCCCACCGCTGAGGCTGCAGGGCTGGTCCGGTCCCAGACGGCCTGAGGGCCATTTGCCCGCGCCCAG- ATCCGGGTGGCTGCGC TGGGCACTGTGCAGCCTCCCGGAATCCGCTGAAGGGCACGTTCCCGCTCTCCTACAGCTGTGGGCCGACTGC- CTGATTTTGGCCACTAGG TGGAGTCTGGCTCTAGGGTTTCGAGGCCGCTGGTGTTGGTGGGCGGAGTCCGGGTTTGCCACCGCTGCGCTC- CATGAGCAGGTAGCAGC TGCAGCGGAGCTTTAGACCGAGGCTGGCAGGGCTGGCCCCAGACGGCCTGAGGGTCAGGGAGTGCAGGGTCC- TCCCACCCTAGGTCCG CTCTTCCTTTCCCCTTACCCAGAGCGGGTTGTGCGGGCTCTGGGCTCTGTGCCGGCGCTGGGCTCTGTGCAG- CCGCCGAGATGGGGCTG AGCAGCGGATTTCCTCCCTGCTGCAGCTGGAGGACGATTACCTGCACTAGCCGCTGAGGCGGCATCTGGCCC- TGGGTTACTGCAGCTGGT GACGCGGGCAGGGTCAGGGTTGGTTGCAGGTGGCAGCTGCTGCTAAACCCATTGCGAGCCTCAGGGTCACCA- AGTTCACCGTCCTTTCAT CATAGTATCTGATCTTTGGCCCGCGCCCAGAGTGCGGACTGGCCTGCGCTGGGGACTGCATAGCTTCTGGGG- GCCGGTCAGCGCCAGTTT CACGTCCTCCTGCAGCTGCGTGGCCTAAGGTCTTAGGCGCCGCGGCGCTATCTGGCCCTGCTGTCGACGCTG- CTGGTGGTGGGGACAGG GTCAAGGGTTGCCACTGCTGCTCCCGTGCGCCATCGGCAGGTGGCAGTTGCAGATGAGCCCACAATTGAGGC- TGTTGGGGCTGCTCCCA GGTTGTTAGAGGGTCGCCGAGTTCACCGACATGCCACCCTAGGTTACGCTCTTGGCCCGCACCCAGAGCGCC- GGGTTACGGGTCCTGGG CCCTGTGCAGCCACGGGGATGGTGCTGAGTGCAGGTTCCCGTCTTCCTGAGATGCGGGGCGACCACTGGAAT- TAGCCTCTGTGGTGGTAT CTGACCCTAGGGTCCGAGCTGCTGGTGGCGTGGGCGGGGTCGAAGTCGCCTCTGTTGCTGCGGCGTGCCATT- TGCACCGTCCTCTGGTAC 170 chr21: 13998500-14000100 AAATACTCTACTGAAAAAACAGAAATAGTAAATGAATACAGTAAAGTTTTAGAATACAAAATCAGCATAGAAA- AATCAGTCGCATTTCTATACC CAACAGCATACCATCTGAAAAAGGAATCAAGAAACCAATCCCATTTAAAATAGCTATAAAAAAATGCCTGGG- AATAAACTAAGCCAAATAAAT ATGTCTAAAATGAAAACTATAAAACATTGATAAAAATCAATTGAAAAAGATACAAATAAAGGGAAAGTTATC- CCATTTTTATGAATTAGAAGTAT

TAATACTGTTAAAATGACCATCATACTCAAATCAGTCTATAGGTCCAATACAATCTCTAACAAATTTCCAAT- GTAATTCTTCAGAGATGTTAAAA AAGGTTTTAAAAATCGTTCTGCGGATGTTAAAAGGATTTTTAAAACGCTTTTTTCGTTCTGCAGGCGAAGGC- TGTGGCCGTGCTCCCGCCGG CCAGTTCCCAGCAGCAGCGCATTGCCCCTGCTCCACGCCTTCGCTCCAGGCCCGCAGGGGCGCAGCCCCGCG- GGAATCAGCACTGAGCC GGTCCCGCCGCCGCCCCAGTGTCCGGGCTGCGACTGCGGGGAGCCGATCGCCCAGCGATTGGAGGAGGGCGA- CGAGGCCTTCCGCCA GAGCGAGTACCAGAAAGCAGCCGGGCTCTTCCGCTCCACGCTGGCCCGGCTGGCGCAGCCCGACCGCGGTCA- GTGCCTGAGGCTGGGG AACGCGCTGGCCCGCGCCGACCGCCTCCCGGTGGCCCTGGGCGCGTTCTGTGTCGCCCTGCGGCTCGAGGCG- CTGCGGCCGGAGGAG CTGGGAGAGCTGGCAGAGCTGGCGGGCGGCCTGGTGTGCCCCGGCCTGCGCGAACGGCCACTGTTCACGGGG- AAGCCGGGCGGCGAG CTTGAGGCGCCAGGCTAGGGAGGGCCGGCCCTGGAGCCCGGCGCGCCCCGCGACCTGCTCGGCTGCCCGCGG- CTGCTGCACAAGCCG GTGACACTGCCCTGCGGGCTCACGGTCTGCAAGCGCTGCGTGGAGCCGGGGCCGAGCGGCCACAGGCGCTGC- GCGTGAACGTGGTGCT GAGCCGCAAGCTGGAGAGGTGCTTCCCGGCCAAGTGCCCGCTGCTCAGGCTGGAGGGTCAGGCGCGGAGCCT- GCAGCGCCAGCAGCAG CCCGAGGCCGCGCTGCTCAGGTGCGACCAGGCCCTGTAGCTGTGACTTGGCTGTGGGGCTGGCCCGCCTCCC- TGACCCCTGTCAGGCG GAGCAGCTGGAGCTGACCCACGGGCCTGGGCTTTCGAGCGCTTTGTCCAGGCGCTAATGATGGGAAGGTGAA- AGGTGGGGGTGGCCACA CCCTGCAGTCAGGGTGGCAGGTGTCAGAGGCCACATGCAACCCACTGGTTTTGTCTTTTCCAGGATGCTGAT- AAGTTTCCCGCGGCCCCC GGAGCAGCTCTGTAAGGCCCTGTAATTGCCTTTCGTTCCCTTCTGCTCTATTGAGGAGTGGGAAGATGACAA- AGTGTTTTTGCTCAACCCGA AGGAAAATGCACATGGGAGGACACACCGGGTTACTATTTGAGTAGCCCAGACAGGAGAGCAGCGGTCTGCT 171 chr21: 14017000-14018500 TGGGTGGATTGCTTGAGCCCAGGAGTTCGAGACCAGCCTGGACAAAATGGCAGAAACTCCATGTCTACAAAAA- ATACAAAAATTAGCCGGG CATGATGTTCTGCGCCTGTAGTCCCAGCTACTCAGGAGGCTGAGGTGGGAGGATCGCTTGAGCCCAGGAGGC- GGAGTTTGCAGTGAGCT GAGATGTCACTGCATTCCAGCCTGGGAGACAGAGCCAGACTCTGTCTCAAAAGAAAAAAAGAAAAAAAAAAA- AGAAAAGAAAAAACGAAATT GTATTCTGAATACATCTTCTAAAACACTACATTTACTTGCACTATATTAAACTGGTTTTATCCTGACCACAA- TTGCAGGTGAAAGATACCACTG TTGTTCTATTTTTCTGGTAAGTAGAGTGAGCCATGTCTTCCCCAGGGAAAGACGCCTCCTAAAAATTTGTAG- GACCACCTTTGGTTTTCTTCC AGATATTTTTTTTGTCATCGCTTTTCCTGCGCCCAATTCCCATCTGTCTAGCCCTTCTGCCTCCGCTGGTCT- TTTTCGCGAGCCTCTCCCCAG CCGCAGGTATTCGTCTGGGCTGCAGCCCCTCCCATCTCCTGGGGCGTGACCACCTGTCCAGGCCCCGCCCCC- GTCCAACCCGCGGAGAC CCGCCCCCTTCCCCGGACACCGGGTTCAGCGCCCGAGCGTGCGAGCGCGTCCCCGCTCGTCGCCCGGCTCGG- CGTCGGGAGCGCGCTC TGTGTGGTCGCTGCTGCAGTGTTGTTGTGGCTGTGAGAAGGCGGCGGCGGCGGCGGAGCAGCAGCCGGACCA- GACTCCCTAGTAGCTCA GGCGCTGCCCTGCGCCGGCCCTGGCAGGGAGCCTGGTGAGATGGTGGAGGAGGAGGCTGTGCCGTGGCTGGC- CTTGCTGTGTCCTGCT GCCTGGTTAGAACCCCATCCCCGTCCCCCGTCTCCTCCGGGGGGTGAGGAGGAGCTGGAAGAGGGGCCGGCC- TCTGTCCGGCCCGGCC AGGCGGCAGTCACCCTCTGAGGAGGCAGCGCCCGGGGAGGGGCCTCCCAGGCGGCCGCCGCCGCCAGGGGGA- GGCGCTGGGAGTGG GAGTGGGAGCGGGACCTCAGCTGCCAAGCTCGGCCCGGACCCTAGGTGCGGGGGAGGCGGGGTCCCGGGCTC- GGGCTGCCTGCCCGG ACCTGGCGGGGATGGGCCCGTGCGGCTCCGGGTGTGGGACGTACCCTCAGAGCGCCCGGGGTTATTCCCACT- GACTCCAGGGAGGTGA GTGTGCGCCCTTCGCTCCCTGCCGTGTCTGTGAGGGTCCATCGTTGCCGGAGACTGGAGGTCGGGGGCCATG- GGAGCCCCGGGGCGAA CGGTGCGGACATGGGCCTTGTGGAAAGGAGGAGTGACCGCCTGAGCGTGCAGCAGGACATCTTCCTGACCTG- GTAATAATTAGGTGAGAA GGATGGTTGGGGGCGGTCGGCGTAACTCAGGGAACACTGGTCAGGCTGCTCCCCAAACGATTACGGT 172 chr21: 14056400-14058100 GTCTCTAGGACACCCTAAGATGGCGGCGAGGGAGACGGTGAAGGTTGGCTCCCGCCTGTCTGGGCTCTGATCC- TCTGTCTCCCCCTCCCC CTGCGGCCGGCTCATGGCCTGGCGGAGGCCCGAACCAAAGACCTCCGCACCGCCGTGTACAACGCCGCCCGT- GACGGCAAGGGGGCAG CTGCTCCAGAAGCTGCTCAGCAGCCGGAGCCGGGAGGAACTGGACGAGCTGACTGGCTAGGTGGCCGGCGGG- GGGACGCCGCTGCTCA TCGCCGCCTGCTACGGCCACCTGGACGTGGTGGAGTACCTGGTGGACCCGTGCGGCGCGAGCGTGGAGGCCG- GTGGCTCGGTGCACTT CGATGGCGAGACCATGGAGGGTGCGCCGCCGCTGTGGGCGCGGACCACCTGGACGTGGTGCGGAGCCTGCTG- CGCCGCGGGGCCTCG GTGAACTGCACCACGCGCACCAACTCCACGCCCCTCCGCGCCGCCTGCTTCGAGGGCCTCCTGGAGGTGGTG- CGCTACCTGGTCGGCGA GCACCAGGCCAACCTGGAGGTGGCCAACCGGCACGGCCACATGTGCCTCATGATCTCGTGCTACAAGGGCCA- CCGTGAGATCGCCCGCT ACCTGCTGGAGCAGGGCGCCCAGGTGAACTGGCGCAGCGCCAAGGGCAACACGGCCCTGCACAACTGTGCCG- AGACCAGCAGCCTGGA GATCCTGCAGCTGCTGCTGGGGTGCAAGGCCAGCATGGAACGTGATAGCTACGGCATGACCCCGTTGCTCCC- GGCCAGCGTGACGGGCC ACACCAACATCGTGGAGTACCTCATCCAGGAGCAGCCCGGCCAGGAGCAGCTCATAGGGGTAGAGGCTCAGC- TTAGGCTGCCCCAAGAA GGCTCCTCCACCAGCCAGGGGTGTGCGCAGCCTCAGGGGGCTCCGTGCTGCATCTTCTCCCCTGAGGTACTG- AACGGGGAATCTTACCAA AGCTGCTGTCCCACCAGCCGGGAAGCTGCCATGGAAGCCTTGGAATTGCTGGGATCTACCTATGTGGATAAG- AAACGAGATCTGCTTGGG GCCCTTAAACACTGGAGGCGGGCCATGGAGCTGCGTCACCAGGGGGGTGAGTACCTGCCCAAACTGGAGCCC- CCACAGCTGGTCCTGGC CTATGACTATTCCAGGGAGGTCAACACCACCGAGGAGCTGGAGGCGCTGATCACCGACGCCGATGAGATGCG- TATGCAGGCCTTGTTGAT CCGGGAGCGCATCCTCAGTCCCTCGCACCCCGACACTTCCTATTGTATCCGTTACAGGGGCGCAGTGTACGC- CGACTCGGGGAATATCGA GTGCTACATCCGCTTGTGGAAGTACGCCCTGGACATGCAACAGAGCAACCTGGAGCCTCTGAGCCCCATGAG- CGCCAGCAGCTTCCTCTC CTTCGCCGAACTCTTCTCCTACGTGCTGCAGGACCCGGCTGCCAAAGGCAGCCTGGGCACCCAGATCGGCTT- TGCAGACCTCATGGGGGTCCT CACCAAAGGGGTCCGGGAAGTGGAATGGGCCCTGCAGCTGCTCAGGGAGCCTAGAGACTCGGCCCAGTTCAA- CAAGGCGCTGGCCATCATCCTC CACCTGCTCTACCTGCTGGAGAAAGTGGAGTGCACCCCCAGCCAGGAGCACCTGAAGCACCAGACCATCTAT- CGCCTGCTCAAGTGCGC 173 chr21: 14070250-14070550 TAAAAATAAATTGTAATAAATATGCCGGCGGATGGTAGAGATGCCGACCCTACCGAGGAGCAGATGGCAGAAA- CAGAGAGAAACGACGAG GAGCAGTTCGAATGCCAGGAACGGCTCAAGTGCCAGGTGCAGGTGGGGGCCCCCGAGGAGGAGGAGGAGGAC- GCGGGCCTGGTGGCC AAGGCCGAGGCCGTGGCTGCAGGCTGGATGCTCGATTTCCTCCGCTTCTCTCTTTGCCGAGCTTTCCGCGAC- GGCCGCTCGGAGGACTTC TGCAGGATCCGCAACAGGGCAGAGGCTATTATT 174 chr21: 14119800-14120400 CGCCACCACGTGCGGGTAGCGCCGCATCGCCCCAGCCGTGTTCCTTGGTCTCCGTCTCCGCCGCGCCCGCCTG- GTGAACTGGAGCACAG GGACCATAGTTCTGGAAATTTATCCTTTTTCTCTCCATGGATTCAGCAGCAGTGTCTAAAAGAAAAAAATTC- ATCAATCATTTATGTATATTTTA ATATAAAGGTAAAACACTGCGAACCAGTGGAACCGGATAGAAAGTAATTCAGTTTTACAGAACACAACTGTT- TTTCAGGCTCTTTTATTAAAT ATAAAAGAGCCATATATATTTCTGTGGAATTCCCCTTTTACTTAAGAATTCATTATCAGCGAATTAGTTTAA- GGAGGCTGTTTTGTTAGAGGCT GTGGTTGCATTCAAAAATTGGAATAGGAACAATGACTTGTAAAAATTCAACATTTTATTTTATTTTTGAGAT- GGAGTCTCGCTCTGTCGCCCAG GCTGTAGTGCAGTGGCGCGATCTCGGCTCACTGCAACCTCAGCCTCCCGGGTTTAAGGAATTCTCTGCTTCA- GCCTCCTGAATAGCTGGGA TTACAGGCGCATGCCACCAAGCCCAGCTAATTTTTTTTGTATTT 175 chr21: 14304800-14306100 CCCTGAACAGTCAGAGTTTACTGCCCACTTTTGCTGGAGGAGAAGCTCCTGAACAACTAGAGAGACTGTGGTT- CCCAAAGAGCAGCCTGTA GGCCTGAGGACTGCTCTATGACCGGCGTCAGTCCCTGCCTCCCTCCCTCCGTCCCTCCTTCCCTCCTTCCTT- CCCAGGCCTTCTCTGACTA CCAGATCCAGCAGATGACGGCCAACTTTGTGGATCAGTTTGGCTTCAATGATGAGGAGTTTGCAGACCATGA- CAACAACATCAAGTGAGTC CACTTGGATGCCCCCTGCACGAGGCACGACTCCCCCTCCTCGCTGCTGAAGTCCCATGGGGGCAGCTCCCTT- AGTCCTTGCCGGGAGATA ACAGGTGTTTCCAGTTGCATGAGGGTGCTGAGGCCCCCAGTGAGAACCAGGGGAGGAGCACTGAGGCCTCAG- ATGAGCACCGGGGGAGG AGCCCTGAGGCCCCAGATGAGCACCAGGGGAGGAGCACTGAGGCCCCAGATGAGCACCGGGGGAGGAGCGTT- GAAGCCCCAGATGAGC ACCAGAGGAGGAGAGCTGAGGCCCCAGATGAGCCCCGGGGGAGGAGCTCTGAGGCCCCAGACGAGCACCGGG- GGAGGAGCGCCGAGG CCCCAGATGAGCACCGGGGGAGGAGCGCCGAGGCCCCAGATGAGCAGTGGGGGAGGAGCCCCGAGGCCCCCA- GATGAGCAGTGGGCG GGGCAGGGAGCGCCGAGGCCATCCCCCTTGCTCTTGCAGCGCCCCATTTGACAGGATCGCGGAGATCAACTT- CAACATCGACACTGACGA GGACAGTGTGAGCGAGCGGGGCTGTGCGGGGTCATGCAGGCACCCTGTTCCCAGGCAGCTCAGGCCGCGCCC- ATGGCTCGGTCTGTGG TGGGCCTGTGCGGTGGGGCTGGGAGAGGCCCCTCTGTGGAGCTAGGAACAGTCGCTTTTCTTGACCCTCCCC- ATCATGCCCTCCAGCCCA TGGCGCCCACATCCTGAACTAAGCCCCTCTGGGAGCCCTGTGGGGAGAGCGCCTCCTGTCTCCCCCAGACCC- TCTGGAAACTGACCTTGG CGTTTTACTCTGCAGCCCAGCGCGGCTCTGAGGCCTGCTGCAGCGACCGCATCCAGCACTTTGATGAGAACG- AGGACATCTCGGAGGACA GCGACACTTGCTGTGCTGCCCAGGTGAAGGCCAGAGCCAGGTGCGGGGCCTGCCCATCCCCCCAAAGCCTCT- GCCGAGGAGGTGCAGC CCCCAGAACACCCGTCAGATGCCCAGACGCCCTGCTGTTTGTTATGCCGG 176 chr21: 15649340-15649450 TTTGGGCCACGAGGCAAGTTCAAAGCGGGAGACTTTTGTTTTATAAAATGATGGTGAGCAGCTCCGGTTTTAT- GTCAAACATCAGGGTTTCG TGCAGGATATAAACATTT 177 C21orf34 ATTGCCGTACTTTGCTTCCCTTTGTATGTATTTCTTGTATGCTGCCGAGTCACTGATGGCTAGCTCTGTCTGG- CAAGTAATTCAAAAATGCTG TTTATGTAGAAAGGAAAGGTAGGGACTTTACCACACTCTGTCATTAAAGGGAGCAATTGAAGAACAAAGGAA- CTGAGTAAATACCTATATATT GCCTTTTGTGTTGCGAAACACTGTAGCACAAACACATTTGTGTTCAGCCAAATGTTTTACTTCCTTTTGTAA- TAACGCATATAGTAGGTTGTCT CCACATATGTACAAGAATCCATATTTTATTTAAACGTATATAGTCAATTGTTCATATTTATAGGCTGCAAAC- ATTTCTCAATCTCAAAGACTTTT ACATATCCACTCCCACACAGCTATTTGTTATTATTTTAAAAGTTCTTAAATTAAAAAAAAAAATAAAATATA- CTAATATCTCTGTTGGTTGATTTT ATTAAGCAACTTAGGATTTCAACACAGTTTAAATCATATTGATGACTCAGATCCTGGCAGGTCTTACAATTC- CTGTGAAATGAGAGCACAGCT AATAAAAATATTAAGCAATTACTTTTATTAAAATCATAGGGTTTTTTTCATTATCACATAGAAATGATTGAT- CTATACAGATTGGTCTCACTCAT GTGTCTTTTGGGCTGCTTGGGAGCTTCATGTAGAAGTGGAAAGTCCCCTTTGCTCTTCCTTCGACCAAGGTG- GGGAAAATGAAGGCATAGA ATACAATCTAGGGCTATTAAAGAATTGCTGGCATTACTTCTCTCTATCACGTGTGAGCCTGGCTGCCTGCTT- CCTGAGGTAGGGGATCCAGG ATGAGACTGTGCCGGAGCCTGTTTCCACAACTGCATTTGGAGATCCGTCTTATTGATTAGCGGGGGAAAGGG- GTGGGGATCAGGAGTGTG AGGTGAGGGGAGGACCAACTGACGACTGGCTCAATGAAGCACAAGACATTTTCTTCCGGAAAGATGTCAAAC- AACTGAGAAACAGCCAGAG AGGAAGTAGAAAGGTGGAAAAATGAGGAGACCCTGGAAGAAATGAAGGCATTTCCTATGAGACAGCCTTGGG- GCTTTTTTCTTTTCTTTCTT TTTTTTTGCTTCCATCATCTGACCTGCAAAGGCTAGAGTGACAGCGTCATGCAAATGCTGCAGTCCAGCAGG- TCTGGGAGAGGGTGGATGC TAGACTGTGAGTTAATGTTAATGATGAGCGCAGTGAAAATACCAGCCGCTGCCACCCCCTGCTCACAGAAGC- GCTCTGAGTCAGCATCAGA TGCTTTGCCTCGCCTCTCGCTGTGTATCTGTATGCCTGTGTGCGCGCGCGTGCTCGCTCGGGCATCCGTGTC- TAGCCGAGGGGAGGGGGT GGCGTGTGAGTGCGTGGAGGGTAAAAGCCAGTCAGTCAGTGAGAAGCAAAGGTACGTTGGAGAGCAACTAAA- ATCTGACTGATTTCCATCT TTGGAGCATCAGATGTATTCCC 178 BTG3 GCAGCCTCCTCCTGAAAAATGTAAGCCATTTCCACTTTGTAAAGCTACGTTTATATTCCACCACG- ATACGATGGAAAAGAAAACCCAAGGCAATTTAATATACG GGTTGGGAAGAAAGTTTTGCTGATGGAACTACATTAGCCTCCACTCCAGCAAAGCAAACAAGGAACCACACT- AAAGAAATGTACTGAATCTTTTAA 179 CHODL TGCCTGAGCGCAGAGCGGCTGCTGCTGCTGTGATCCAGGACCAGGGCGCACCGGCTCAGCCTCT- CACTTGTCAGAGGCCGGGGAAGAGA AGCAAAGCGCAACGGTGTGGTCCAAGCCGGGGCTTCTGCTTCGCCTCTAGGACATACACGGGACCCCCTAAC- TTCAGTCCCCCAAACGCG CACCCTCGAAGTCTTGAACTCCAGCCCCGCACATCCACGCGCGGCACAGGCGCGGCAGGCGGCAGGTCCCGG- CCGAAGGCGATGCGCG CAGGGGGTCGGGCAGCTGGGCTCGGGCGGCGGGAGTAGGGCCCGGCAGGGAGGCAGGGAGGCTGCAGAGTCA- GAGTCGCGGGCTGC GCCCTGGGCAGAGGCCGCCCTCGCTCCACGCAACACCTGCTGCTGCCACCGCGCCGCGATGAGCCGCGTGGT- CTCGCTGCTGCTGGGC GCCGCGCTGCTCTGCGGCCACGGAGCCTTCTGCCGCCGCGTGGTCAGCGGTGAGTCAGGGGCCGTCTCCCCG- AAGAACGAGCGGGGAG AGGGGACCACGGGGCGCGGCGGGCAGCCTGTTCTCGGGCGGAGGCTCTCCGGGGCGTTGGAAACCTGCATGG- TGTAAGGACCCGGGAG GAGGCGGGGAGAAATTGATTGTGCTGTTCTCCTCCCTCTCTTCTCTAACACACACGCAGAAAAGTTTAAATT- TTTGTGAAGCGCTTGCTTAC GTAGCTGCGGAGCGAGCCTCTGCTTCATTACGAGCGGCATAGCCTTTTTCAGGAGTGATTTCCACTTTCTTT- GTGAGAGAGTTGACCACAC 180 NCAM2 TTCAATTTACACTCGCACACGCGGGTACGTGGGTGTTCGGGGTAGGGCACTGATCTGGGGAAGG- TCTCCCCCCCGCGACCCAACTCATCT TTGCACATTTGCAGTCCTCCCTCGGTGCACTCCTGGCGGGGATCTGGCCAGTGCAGCGCACTGGGACCGAGG- GCAGAGCCCGCGGAGTG AGGCCAGGAGAGACTTCAGGCCTCTAAGGACACAGCTGAGGCTAAGGCTGAGTTGAACGCAGCCCCTCCCGC- GGCTCGTCCCCTCTCCA GTGTCTCTCCCGTAAGGTGCCGCTCCCAACAGCAATGGGTCGAGATGTAGAGGAAACACTCTGTACGTTATT- TTTCCGCCCACCCTTTAGC GCCTGAGGAGACAGACAGTGTAGACTTTAGGGTACAATTGCTTCCCCTCTGTCGCGGCGGGGTGGGGAGCGT- GGGAAGGGGACAGCCGC GCAAGGGGCCAGCCTGCTCCAGGTTTGAGCGAGAGAGGGAGAAGGAGGTCCACGGAGAGACAAGAATCTCCC- TCCTCCCACGCCCAAAA GGAATAAGCTGCGGGGCACACCGCCCGCCTCCAGATCCCCCATTCACGTTGAGCCGGGGCGCG 181 chr21: 23574000-23574600 TCATTATCCGATTGATTTTCCTGGTATCACATCACTTAAGTTTAAGTAGCTCTTATGTTACTTAGTAATGACT- GCAAAACACGAGTTGTGATGC GGGCAATTTGGATACAACAAAAAGAAGCCATTAAGTTTGTTCGTTAGTTAACAGGTGAAAGCTCTCAAGTTA- TTAAGGATAAAAATGCTAGTA TATATATATATGGTTTGGAACTATACTGCGGATTTTGGATCATATCCGCCATGGATAAGGGAGGAATACTAT- AATCAGGTTTGTTTTAAATTCC ATGTCTAATGACTTCGTTATCTAGATCACCTGTAGAGCTGTTTTTATTGTAGGAGTTTTCCTTGGTTTTAAT- CTTTTGATTTGTTTTTCATGTTA ATACTGAAATTTTTAAAAATTGCATATTGTACTTCCTATATGAAAATTTTACTATGTATTTTTATTTTTATT- TTCCTTTTCCTTTAGGAAGAATTAG TTTGTTCCCTGACAGAGTTAGAGTAAGGGCAAATTACTTGTCTCTATAAACAACTCAGATGTTTTGAGCCGG- TGTTGTAGGGGTTATCTTTTT

CTGGTTTTGCATTTTATTATAGGACATAGTGCTT 182 chr21: 24366920-24367060 AGAAAGAAGAAATCCGGTAAAAGGATGTGTTATTGAGTTTGCAGTTGGTGTTTGATCTTGCACAGATTTTCTC- AGGGGCCTTAAGACCGGTG CCTTGGAACTGCCATCTGGGCATAGACAGAAGGGAGCATTTATACGCC 183 chr21: 25656000-25656900 CGAAGATGGCGGAGGTGCAGGTCCTGGTGCTCGATGGTCGAGGCCATCTCCTGGTCCGCCTGGCGGCCATCGT- GGCTAAACAGGTACTG CTGGGCCGGAAAGTGGTGGTCGTACGCTGCGAAGGCATCAACATTTCTGGCAATTTCTACAGAAACAAGTTG- AAGTACCTGGGTTTCCTCC GCAAGCGGATGAACACCCACCTTTCCCGAGGTCCCTACCACTTCCGGGCCCCCCAGCCGCATCTTCTGGCGG- ACCGTGCGAGGTATGCC GCCCCACAAGACCAAGCGAGGCCAGGCTTCTCTGGACCGCCTCAAGGTGTTTGACCGCATCCCACCGCCCTA- CGACAAGAAAAAGCGGAT GGTGTTCCTGCTCCCTCAAGGTTGTGCGTCTGAAGCCTACAAGAAAGTTTGCCTATCTGGGGCGCCTGGCTC- ACGAGGTTGGCTGGAAGT ACCAGGCAGTGACAGCCACCCTGGAGGAGAAGAGGAAAGAGAAAGCCAAGATCCACTACCGGAAGAAGAAAC- AGCTCATGAGGCTACGG AAACAGGCCGAGAAGAACATGGAGAAGAAAATTGACAAATACACAGAGGTCCTCAAGACCCACAGACTCCTG- GTCTGAGCCCAATAAAGAC TGTTAATTCCTCATGCGTGGCCTGCCCTTCCTCCATCGTCGCCCTGGAATGTACGGGACCCAGGGGCAGCAG- CAGTCCAGGCGCCACAGG CAGCCTCGGACACAGGAAGCTGGGAGCAAGGAAAGGGTCTTAGTCACTGCCTCCCGAAGTTGCTTGAAAGCA- CTCGGAGAACTGTGCAGG TGTCATTTATCTATGACCAATAGGAAGAGCAACCAGTTACTATTAGTGAAAGGGAGCCAGAAGACTGATTGG- AGGGCCCTATCTTGTGAGC 184 MIR155HG GCCTGAAGACCATTTCTTCCTCTCTTAGGGACCTGCTGGTCTCCAGCTGATTCGGTCCAGGAGGAAAAACCTC- CCACTTGCTCCTCTCGGG CTCCCTGCAAGGAGAGAGTAGAGACACTCCTGCCACCCAGTTGCAAGAAGTCGCCACTTCCCCCTCCAGCCG- ACTGAAAGTTCGGGCGAC GTCTGGGCCGTCATTTGAAGGCGTTTCCTTTTCTTTAAGAACAAAGGTTGGAGCCCAAGCCTTGCGGCGCGG- TGCAGGAAAGTACACGGC GTGTGTTGAGAGAAAAAAAATACACACACGCAATGACCCACGAGAAAGGGAAAGGGGAAAACACCAACTACC- CGGGCGCTGGGCTTTTTC GACTTTTCCTTTAAAAAGAAAAAAGTTTTTCAAGCTGTAGGTTCCAAGAACAGGCAGGAGGGGGGAGAAGGG- GGGGGGGGTTGCAGAAAA GGCGCCTGGTCGGTTATGAGTCACAAGTGAGTTATAAAAGGGTCGCACGTTCGCAGGCGCGGGCTTCCTGTG- CGCGGCCGAGCCCGGGC CCAGCGCCGCCTGCAGCCTCGGGAAGGGAGCGGATAGCGGAGCCCCGAGCCGCCCGCAGAGCAAGCGCGGGG- AACCAAGGAGACGCT CCTGGCACTGCAGGTACGCCGACTTCAGTCTCGCGCTCCCGCCCGCCTTTCCTCTCTTGAACGTGGCAGGGA- CGCCGGGGGACTTCGGT GCGAGGGTCACCGCCGGGTTAACTGGCGAGGCAAGGCGGGGGCAGCGCGCACGTGGCCGTGGAGCCCGGCCT- GGTCCCGCGCGCGCC TGCGGGTGCCCCCTGGGGACTCAGTGGTGTCGCCTCGCCCGGGACCAGAGATTGCGCTGGATGGATTCCCGC- GGGCAGAGGCAGGGGG AAGGAGGGGTGTTCGAAACCTAATACTTGAGCTTCTTTGCAAAGTTTCCTTGGATGGTTGGGGACGTACCTG- TATAATGGCCCTGGACCAG CTTCCCTGTTGGAGTGGCCAGAGAAGTGTGTAAAACACACTAGAGGGGCAGGGTGGAAAAAGAGACTGCCTT- CAAAACTTGTATCTTTTCG ATTTCATTTTGAAAAATAACTACAAATCTATTTTAATTTTACAAAGTTAGACTCATAGCATTTTAGATATCA- ATGTCTTCATTTAACAGAAGTGAA GATGGAGCAAACGCTCAATCAGCGTCTGTATTTATTCGCTCCTGTTGTGCCAGGGTGCGTTTTTGCCGAGCG- GTTGCCTTTCTTTACTCACA AAACCCCCTTGATGTCTGTCCTCCACGTTTTACGAGGGAGAGCCGGATCTTTTGAAGTTTGTATCATCTAAA- GCAGGTATATTGGGATGACT ATGGATAGAATTTAACCTGAAAACACTGAAGTTGACAGCTGACAAAG 185 CYYR1 CATAACAAGAGTCATTCTAATGTGATTATAAAGGACCCGAAGCTTTGCTTTTAAAATTCAATAC- TTAGGTAGAAAGAAAATGATAACTTTTTCCCTTTG ATTTTTATTCACTATTTTTATAACACTAGCAGCCCTGAGACACCGGATTGGAAATATCTATGCCTCTTGATG- TTACCTGGGCACCACTGCATCACAGTCCT 186 chr21: 26938800-26939200 AATAGTAATTGCCAACAGTCAAGATATGTACTACCACCAAATTCCGTGTTATTTGTGATCAAAAGATATACAC- AGATACTTGAAAACTGATTTC TACGTTGCATATGGGAAAAATACCTCATTTTTCTCAGCTGTCCATTATTTTTGAGATATTATGTGCAGTGAT- AGTAAGAACAAGCAGATTTGGA ACACATCAGCAATAATTTTTTCAATCAGAGTCCTGCCAAAATGAAAGAATTTGACAGTATCCGGCACCCTGT- ACTCATGCTTGGCTTCTGTAG AAACTGTGGCTTGCAAAAGGGCAGCTGGGTACTGTGTTTTGGTACCTCATTCTTTAAACGTATAATGGGAAT- CTGGTTGGTTCAGGAAAACC CTTGCCTACTTATTATTACTCTGTTTT 187 GRIK1 GGCCCATACTTAATGTATTTTTAAACGTTTTAACATTTACTAATATAGAACCTTCTATTGCCTA- TTTCCTTCTGGTTTATTCCCTTTCCTTCTGT CATTGAAGAAATGGTTCTAGTGGTAGAAATACTCCACGATTGAGAAGAATGTGGGAAGAAAGGAGGGCTGGT- GGGTAAGAATTGCTCATGA TGTCTCCCTCTGAATTCTGTGCTCTCACAATGACACTCCAATGTGTGGTTTGACGCCTGGAAGA 188 chr21: 30741350-30741600 TGCTTCAACCGGAAATGTGGTTGAATTACCCTTACAGTGAACCTGATCAGTGGTAACAGGAGATGCTAGAACA- GGAAAAGACAAGTTTCCCC TTTCCTCCCTATCCCATCAATTACTTTGAGGTGTATTTTTTCTTTGCAACCCCTCCAGAGAAGTCGGCAATG- TTTAACGAGCATGCCTGCCAA GTGGCTTGCCTTATACCTCATTATGAAGTGATACTCAGGGCCACTAACACATCGCACAGCATTGC 189 TIAM1 TATGATTCCCTCGATTTCCCTCAATCTTAACCATTGTGGATCACAGCAGGAGGGCCAGAAAGTG- AGCTTCAGCCTGGCACCGGGACCTCAG CCTCTCCCTTAAACTTTCCCTAATCCTCGGAGCTAGTGTTACTCAAGTGACTCCACAGTGTTGCCCGATCCC- TTCAGACATGGCCTTGATGA TCTCCAAAACTCATGCTACCTTTGCCAGCCTAAAGCATCCACTCTGTGCCCCAAAACGTGAATGTCAAATAC- CCTTCAAGGCAGAAGGCTAT TTCTATTTTTGTTTGTTTCTGTTTAAGGCAACAATCACCAACATTTGGTACACATGAGCCATCCTGTGAAAC- ATCAAGGCGCTTCGTTGGCAG CAAGTCAACTTCGGTTTCAGAAGAAAGCTGCACTATTTCCTGAGGTTAGAGGTTTAAACCAAAACAAGACAA- CCACATTTTAACCCCAAATCT GCCGACTGAGGGTAACCATGATCCTTCCTTCACAGCACC 190 TIAM1 TACTAAATCAACCCAAACCCGAGAACCCGGTCATGGAGAAATAAATGATAGTAATCTATGCTGT- TCATCTGTTCCATCACTCACTCACTCTCT TGCTGAACAAGAAAGGGCCACCCATGTAGCAAACCACATGTAAAGAGCCGGGAAGAC 191 TIAM1 TATTATTTTGTTCAAAGTAGACGGGTATACTAACATCTGTGGGCAAGTTTACCACACGCCACTT- AAAACAGGCTAACAGGGTCATATGCCAAA ACGTTCAGGTTTGCATTTTTGAAAAGCTCAGAGATCTGACAGATGTGTTCCGGCCGCGATTTAACATGCGGC- TCCAGTGAGAAGGAAGCAG ATATGACAAATGGTTCACTTATTTCAGAACTAAAACCCCAGAGGAGCAGCCTGAGCCAAAAAGGGAAGTGAT- CAATGGAAAAGACGGTCGA ATCTGCTCACAGGCAAGGCAAGGGG 192 SOD1 AAGACCTGGAGTTTCCATTACACCGAATTGGCACTTAATAACTGTTGTCGGAGCATTTCTTAAGC- CACATTTTCGTAAAGTGGCTTTAAAATT GCTCTGCCAGTAGGCAGGTTGCTAAGATGGTCAGAGACAAACTTCTGAACGACTCTTGTAAAATATACAGAA- ATATTTTCAGAACTTTTATCA GTAAAATTACAAAACGTGTTGCAAGGAAGGTGCTTGTGATAACACTGTCCCCAGAACCTTAGTGAAGTTACC- AACTGGTGGAAAATTTTCTCT TGCACTCGGCTTAAAAATCAT 193 HUNK GCAGGGGTGACTGGTCCTCTCTCTCTGCACCTCGCAGGATTTCTCTGGAAGATCTGAGCCCGAGC- GTCGTGCTGCACATGACCGAGAAGC TGGGTTACAAGAACAGCGACGTGATCAACACTGTGCTCTCCAACCGCGCCTGCCACATCCTGGCCATCTACT- TCCTCTTAAACAAGAAACT GGAGCGCTATTTGTCAGGGGTAAGTGCGACCCTAGAGGCGATCGTCTCTGCTGTCTGTGGAAAAAAGAGCTC- CTACACCCAAAGTGCTTCT CAGTTGCTGACACTTGATCCAAGCTGCTAATTTAATCTAATGTGAGGCTGAGTTTTCTGAATGTGGGATAAA- GTCGTAGCTAAACCTGCTTCT CAGGGAGTGCCTTTTATCTGCAATGTTTTTCAAAT 194 chr21: 33272200-33273300 AAGTAACGGGATCAAATTAATTATTATTTTGGTGGCCGCCTCTCTTCTCCACCCCAAGCCAGGCAAGACTCAC- CCTCGGCCCTGCCCGCCC CAGCATTTCAAATGGAATACCTAGGTGGCCCAGGGGGACCCCTGACCCCTATATCCTGTTTCTTTCTGCCTG- CTTTGCTACTTTTCTCCTTG ATAAAAGGAGAGAGTGAGAGATAATTAACAAAAAACATGGCCCCAGGACAATGAAACAACTGGCCTTGGCCG- GCCAGAAATGTATCCTGGT TTTCTAGGTGAACTTTCTCCCATCAATCTTTCCTTTAACCTCTCTGTTAGTGGAAGCAATAGGAACACCCCT- CCCCTCCCCTGAGCAAATGCT TTCTTTTGACTGGAAACAAAACAGGGGCTCGGCGAAGGCTGAGGTGAAATCTGGGTGGCATGGGCGCCGCAC- AATGGGGCCGCTGTTCCC CGGCCCGGGCTTGTGTTTTACAACAGGGGAGGGGCGGGCGTGAATGGTCTGATGATTGGAACAATCCCCCCG- ATTCAGGCCTACAAACGC ATCTTCTGTTCCACACCGAGGGGACAGAAAGGAGAAAAGTGACAAAGAACGCGGGGCGGGGGGAATTAAAAC- AAAATGCGCTCGACTAAA AAATCTCTCATATCCTGCATATTCCAGAAAGCGGCTCTATGGAGAGAGCCTTCAGGAGGCCTCAGCCATATC- TGAATGGCTTTCTCTGGCCT CTGATTTATTGATGAAGCTGAAGCGACTTGCTGGAGAAAGGCCTGGAGCCTTCTTTGTCTCCGAGATGAAGT- ACAATAGGCCACAGGGCGG AGATCTCTTGTGATGCTCTCGGGTCCTGCCTTTCTCTTGCCCTCTCCTCCCTGCAAATACCAGCAGCGGTGA- CAAACGATTGGTGGTGTGCCT GGGAGAGCCGGTGACAAGACTGGGCCACTTGAGGTCTCCTTAAGAGGGTATTATGGCCAGGGCGACGTTTGT- GCTGTGAAGATGGCACACTCCA TTTTGTCAATGGCTCTCATCGGCCCAGATAATCGCCCCCTGCCTGCCTGTCAGGGGCGCAGCCGGCCGATTC- ATGGCGCCCTCGGAGAAAGTA 195 OLIG2 GTCTTTCCCGCCCCCTTGTCTAAACTCAAAACCGAGTCCGGGCGCGCCTTGCAGGGCGCCCGAG- CTCTGCAGCGGCGTTGCGGGCTGAA CCCATCCGGCACAAACTGCGGGCCACTGGCCCCTCACACCTGGGAGTTTGCGGCGCTGGCCTGCAGCCCGGG- GCCCACGTGGCGGAAG CTTTCCCGGGCGCGCGCTGCGCAGCCCCGCGGGGCCGGGGAGACACCGCTCGGGAGTCCTCCGCTCGGCTGC- AGAATCTTTATCAGCT GCACTTTACCGCAGCCCTGGCTAGGACGCTAGGCGGTGGAGCGCCCTATCCAGGTGCGCCGCCGCACCATGG- ATCACCGCGCCCGGTCC CGCAGTCCCGCCATGGCCTGGGGAGGCCCGAAGCCCGGGGACAGTGGCCGGCCCATCTCCGGCTCCGCGGAC- CCCCGGCTCAGGCGG GAGGGCAGGCGGGTCCCTGCAGGCCCCCAGGGAGCCCGGGAGCCTCTCTCTGGCGTCATTCAGTCCCGGGGC- AACCTGAAGCGCGGTA GATATTGGAGAGGGGGCGTCTGTTGGGGGGACCTGGCGTCATTACTGATGGCTAGCAGGGAGGAGGGAACGG- GTTGTCACCTCGGCCTC ATAAGGCCGTGAGTGAGTAGTCCAGGGCCTCTTCAGGCATTTTTGAAACTGGATTAACTAGGGGGGAAATTG- TAGCACTGAAGCCACCGTG ACTGTCTTTTGCGCTGTGTGGAAACTCCGGTAAAACTCTTTGGGCAACAGTCTTATCACCAGCTCTTCAACG- TGTGCAGCCCTTCTGGTCCT GTCCCTGTTCTGGGCCCCAGGAATGCAAAGCAGGTCCAGGCACTGTGAAGACCCTGGCGGTGGAGGAAGAGG- CTTCCCGGCTGTGGAGG AAGCCAGACCCTTACAACACAAGACGAGAACCAGACCTGCGTGGGGGAGCTCTGGATGCTACAGGGGCTCAA- GGAGGGGTGGAGGGGCC TTCCCAGGCCAACCCCTGAACGGCTTGGACAAGATGCTCAGATGGACGGGAGGAACGGCGTGTGGGATGGGG- GAGCTGGAGGCGGGTG GGTGGGGGGGGGAGGATGGGGAAAGCGCTGGCCCACCCAGTGTGGGAGGGGTAGAGGAAAAGCCCGCAGGGG- CCAGGTTGGGACCCC GTAGGCCGGGTTAGAGGGCTTGGACTTGATCCTGACAGGCGACAGGGAGACATATTGCTACTTATTATGTGC- ACAGTGGCCAGATCTCTAA AGAAAACACCATCCCCCACCCCCACCCCCCATATAGTAAACCAGGTGGTCCGCCCAGTGCTCCCAGGGAGGT- GATGGGAAATCCCACTCC ATACCCTGCGGTGAGGGGTTCCATGCCCTCCACGTGTGCAACTACTCCGGGCCCAGGGAAACACTGGGCCCC- ATCCGGTAACCCCCGGC CCAGTCGGGTTTCCCAGTTCACATTATAACCAAACGGTCTTGCCAGCTAGACAGACAGACACCCCTGACCTG- TTTACCCTGATCCTCTGCTC TCAGGATTAATCACAACTTGTCGAAGGGGGTGGCTTCCAGTGGGGTGGACCGCTCTGTCAATGCCAGCGTGT- GTCTAGCATCTCCTGGGG TGGGGGTGTGGGGAAGGGAGGTGTAGGATGAAGCCCTAGAAGCCTCAGGCAATTGTGATCCGGTGGGCTGGA- TACTGAAGCCCACCCCT GCCTTGACCTCAATTTTCAGTATCTTCATCTGTAAAATGGGAACAACCTGCCTTCCTCCTAGCCCTAAAGGG- GCTGCTGTCAAGATTGGCTG AGATAGCTGTTTGCAAGCTGAGCTCAATGAAAGTTCATTGTGTCCCCCTCAGTCCTATCCCAATATCGTCTC- ACTGCAAAGGTGGGGGGCA GCTTAACTTCAAGGGCACTTCAAGGATAGCCAGGTGGCTGTCAGCCCAGCTTTCCAGGATGGGAGCAGGATC- TTGACAGAAGGGTTGACT GGGAGGGGCAGTTGCTGGTTTGGGCTTCGTTAGGTTGCATTTTTGTTTGTTGTCCTTTCATTTCCCTGGGGC- AGCACCCCTTCCTGCAAGCT CCAGGCCTTCCTCTGGAATGCTCCTAGAGCCCAACCTCTGCTGGTGCCTGAGCTTAAGCCAGGCCAGCTAAG- GGGATCCTGGATTCACAC GGCCTCACAGTCACTCAGATTGTTAGCAGAAGACAAAAATTACAAGGGGAGGGCGTCATGTGATTCTTACAC- ACCCTCCAAATCCAGCAGA CACCTTGGAAGCCACAGGTAGCTTCAAGAAACCCATTTTACGGATGAGAACCTGAGATGGAGAAAGGACAAC- TGGAGATCTCTGAGTCTCT GAGCCCACACTCCCTACCTCCCTGCACCTCCAGGCACTCTGCTGGCAGGATCTTGGGCAAATGCCCACAGCT- CTCTGAGAGTCAGTTTTCC TGTCTGTAAAATGGGAGTCATACCTTCCTCCTATGGCCGGTGAGAGACTAAATTAAACTATGTCTGTCAAGA- CACCTGAAACTCCTGGCACA ATTTAGGTTGCCTTCAAGTGGTCACAGTTGTCATTAGGTGGAAGTCAACACCCCAATCATTGTAAAGGTGCC- CATATACCCCAAGATCCAGA TTACAGCTCTCACAGTTTATTATATACAGCGAAAAAACACATAACACACCTTTGCCCACATTTACATGTATT- TTACGGACCATGTTTCACATCA GTCCGCATGCACATCTGCACGTGTGTGCATTCGGCAGTATTTACCAAGCACCTGCCAAGTGCCAGGGCCTGT- CCTCCGCACCCGGCGTGA ACTGTCCTGGACCAGTCCCGGGAGCCGCGGTTCTGACCAGCCGTGCTGACCCTGGACGACTCCATGAGCTGT- TTTGTGAGAAAGACACGC CATTTGTTTGCAGAGTTCTGACTTCTGAGGGGTCATGTAGCACATGTTTGGTAGCCAAACGCTGTCATTCAC- GACCAGGAGCGATGGCTGC AATGCCTTTTTCTTTGCTTTGCTTTCCGGTGCCGGGAGCCTTGCCTCCCGCCGCCACCCCTGGTCAGCTCTG- CGCAAGAACGTCGTTCTGT TTGGCAGCCAGGCCGAGACGCAGCCTGAATGTGAGCAGGAACTCGGAGAAGGGAAGGGAGAGAATCAGAAAG- AAGGCCCGGGAGGGAC CCGGGAAGCAGTGGGAGGTCTGCGCCCTGGAGCCCCGCGAGAGCCCGCCGGTTTGGCACGGGCTCCTCCCGG- GCCGCCCGGCGGTCC AACAAAGGCCGGCCCCGACACGCACCCGGTCTTTTGTGGGAGAGAAACACAAAGAAGAGGGAAAAACACGGA- GGAGGCCAACAGCACCA GGACGCGGGGGCCAACCAGGAACTCCCGGAGCCGGGGCCCATTAGCCTCTGCAAATGAGCACTCCATTCCCC- AGGAAGGGGCCCCAGCT GCGCGCGCTGGTGGGAACCGCAGTGCCTGGGACCCGCCCAGGTCGCCCACCCCGGGCGCCGGGCGCAGGACC- CGGACAAGTCCTGGG GACGCCTCCAGGACGCACCAGGGCAAGCTTGGGCACCGGGATCTAATTTCTAGTTATTCCTGGGACGGGGTG- GGGAGGCATAGGAGACA CACCGAGAGGTACTCAGCATCCGATTGGCACCAGGGCCAAGGGAGCCCAGGGGCGACACAGACCTCCCCGAC- CTCCCAAGCTACTCCGG CGACGGGAGGATGTTGAGGGAAGCCTGCCAGGTGAAGAAGGGGCCAGCAGCAGCACAGAGCTTCCGACTTTG- CCTTCCAGGCTCTAGAC TCGCGCCATGCCAAGACGGGCCCCTCGACTTTCACCCCTGACTCCCAACTCCAGCCACTGGACCGAGCGCGC- AAAGAACCTGAGACCGCT TGCTCTCACCGCCGCAAGTCGGTCGCAGGACAGACACCAGTGGGCAGCAACAAAAAAAGAAACCGGGTTCCG- GGACACGTGCCGGCGGC TGGACTAACCTCAGCGGCTGCAACCAAGGAGCGCGCACGTTGCGCCTGCTGGTGTTTATTAGCTACACTGGC- AGGCGCACAACTCCGCGC CCCGACTGGTGGCCCCACAGCGCGCACCACACATGGCCTCGCTGCTGTTGGCGGGGTAGGCCCGAAGGAGGC- ATCTACAAATGCCCGAG

CCCTTTCTGATCCCCACCCCCCCGCTCCCTGCGTCGTCCGAGTGACAGATTCTACTAATTGAACGGTTATGG- GTCATCCTTGTAACCGTTG GACGACATAACACCACGCTTCAGTTCTTCATGTTTTAAATACATATTTAACGGATGGCTGCAGAGCCAGCTG- GGAAACACGCGGATTGAAAA ATAATGCTCCAGAAGGCACGAGACTGGGGCGAAGGCGAGAGCGGGCTGGGCTTCTAGCGGAGACCGCAGAGG- GAGACATATCTCAGAAC TAGGGGCAATAACGTGGGTTTCTCTTTGTATTTGTTTATTTTGTAACTTTGCTACTTGAAGACCAATTATTT- ACTATGCTAATTTGTTTGCTTGT TTTTAAAACCGTACTTGCACAGTAAAAGTTCCCCAACAACGGAAGTAACCCGACGTTCCTCACACTCCCTAG- GAGACTGTGTGCGTGTGTGC CCGCGCGTGCGCTCACAGTGTCAAGTGCTAGCATCCGAGATCTGCAGAAACAAATGTCTGAATTCGAAATGT- ATGGGTGTGAGAAATTCAG CTCGGGGAAGAGATTAGGGACTGGGGGAGACAGGTGGCTGCCTGTACTATAAGGAACCGCCAACGCCAGCAT- CTGTAGTCCAAGCAGGG CTGCTCTGTAAAGGCTTAGCAATTTTTTCTGTAGGCTTGCTGCACACGGTCTCTGGCTTTTCCCATCTGTAA- AATGGGTGAATGCATCCGTA CCTCAGCTACCTCCGTGAGGTGCTTCTCCAGTTCGGGCTTAATTCCTCATCGTCAAGAGTTTTCAGGTTTCA- GAGCCAGCCTGCAATCGGTA AAACATGTCCCAACGCGGTCGCGAGTGGTTCCATCTCGCTGTCTGGCCCACAGCGTGGAGAAGCCTTGCCCA- GGCCTGAAACTTCTCTTT GCAGTTCCAGAAAGCAGGCGACTGGGACGGAAGGCTCTTTGCTAACCTTTTACAGCGGAGCCCTGCTTGGAC- TACAGATGCCAGCGTTGC CCCTGCCCCAAGGCGTGTGGTGATCACAAAGACGACACTGAAAATACTTACTATCATCCGGCTCCCCTGCTA- ATAAATGGAGGGGTGTTTA ACTACAGGCACGACCCTGCCCTTGTGCTAGCGCGGTTACCGTGCGGAAATAACTCGTCCCTGTACCCACACC- ATCCTCAACCTAAAGGAGA GTTGTGAATTCTTTCAAAACACTCTTCTGGAGTCCGTCCCCTCCCTCCTTGCCCGCCCTCTACCCCTCAAGT- CCCTGCCCCCAGCTGGGGG CGCTACCGGCTGCCGTCGGAGCTGCAGCCACGGCCATCTCCTAGACGCGCGAGTAGAGCACCAAGATAGTGG- GGACTTTGTGCCTGGGC ATCGTTTACATTTGGGGCGCCAAATGCCCACGTGTTGATGAAACCAGTGAGATGGGAACAGGCGGCGGGAAA- CCAGACAGAGGAAGAGCT AGGGAGGAGACCCCAGCCCCGGATCCTGGGTCGCCAGGGTTTTCCGCGCGCATCCCAAAAGGTGCGGCTGCG- TGGGGCATCAGGTTAGT TTGTTAGACTCTGCAGAGTCTCCAAACCATCCCATCCCCCAACCTGACTCTGTGGTGGCCGTATTTTTTACA- GAAATTTGACCACGTTCCCTT TCTCCCTTGGTCCCAAGCGCGCTCAGCCCTCCCTCCATCCCCCTTGAGCCGCCCTTCTCCTCCCCCTCGCCT- CCTCGGGTCCCTCCTCCA GTCCCTCCCCAAGAATCTCCCGGCCACGGGCGCCCATTGGTTGTGCGCAGGGAGGAGGCGTGTGCCCGGCCT- GGCGAGTTTCATTGAGC GGAATTAGCCCGGATGACATCAGCTTCCCAGCCCCCCGGCGGGCCCAGCTCATTGGCGAGGCAGCCCCTCCA- GGACACGCACATTGTTC CCCGCCCCCGCCCCCGCCACCGCTGCCGCCGTCGCCGCTGCCACCGGGCTATAAAAACCGGCCGAGCCCCTA- AAGGTGCGGATGCTTAT TATAGATCGACGCGACACCAGCGCCCGGTGCCAGGTTCTCCCCTGAGGCTTTTCGGAGCGAGCTCCTCAAAT- CGCATCCAGAGTAAGTGT CCCCGCCCCACAGCAGCCGCAGCCTAGATCCCAGGGACAGACTCTCCTCAACTCGGCTGTGACCCAGAATGC- TCCGATACAGGGGGTCT GGATCCCTACTCTGCGGGCCATTTCTCCAGAGCGACTTTGCTCTTCTGTCCTCCCCACACTCACCGCTGCAT- CTCCCTCACCAAAAGCGAG AAGTCGGAGCGACAACAGCTCTTTCTGCCCAAGCCCCAGTCAGCTGGTGAGCTCCCCGTGGTCTCCAGATGC- AGCACATGGACTCTGGGC CCCGCGCCGGCTCTGGGTGCATGTGCGTGTGCGTGTGTTTGCTGCGTGGTGTCGATGGAGATAAGGTGGATC- CGTTTGAGGAACCAAATC ATTAGTTCTCTATCTAGATCTCCATTCTCCCCAAAGAAAGGCCCTCACTTCCCACTCGTTTATTCCAGCCCG- GGGGCTCAGTTTTCCCACAC CTAACTGAAAGCCCGAAGCCTCTAGAATGCCACCCGCACCCCGAGGGTCACCAACGCTCCCTGAAATAACCT- GTTGCATGAGAGCAGAGG GGAGATAGAGAGAGCTTAATTATAGGTACCCGCGTGCAGCTAAAAGGAGGGCCAGAGATAGTAGCGAGGGGG- ACGAGGAGCCACGGGCC ACCTGTGCCGGGACCCCGCGCTGTGGTACTGCGGTGCAGGCGGGAGCAGCTTTTCTGTCTCTCACTGACTCA- CTCTCTCTCTCTCTCCCTC TCTCTCTCTCTCATTCTCTCTCTTTTCTCCTCCTCTCCTGGAAGTTTTCGGGTCCGAGGGAAGGAGGACCCT- GCGAAAGCTGCGACGACTAT CTTCCCCTGGGGCCATGGACTCGGACGCCAGCCTGGTGTCCAGCCGCCCGTCGTCGCCAGAGCCCGATGACC- TTTTTCTGCCGGCCCGG AGTAAGGGCAGCAGCGGCAGCGCCTTCACTGGGGGCACCGTGTCCTCGTCCACCCCGAGTGACTGCCCGCCG- GAGCTGAGCGCCGAGC TGCGCGGCGCTATGGGCTCTGCGGGCGCGCATCCTGGGGACAAGCTAGGAGGCAGTGGCTTCAAGTCATCCT- CGTCCAGCACCTCGTCG TCTACGTCGTCGGCGGCTGCGTCGTCCACCAAGAAGGACAAGAAGCAAATGACAGAGCCGGAGCTGCAGCAG- CTGCGTCTCAAGATCAAC AGCCGCGAGCGCAAGCGCATGCACGACCTCAACATCGCCATGGATGGCCTCCGCGAGGTCATGCCGTACGCA- CACGGCCCTTCGGTGCG CAAGCTTTCCAAGATCGCCACGCTGCTGCTGGCGCGCAACTACATCCTCATGCTCACCAACTCGCTGGAGGA- GATGAAGCGACTGGTGAG CGAGATCTACGGGGGCCACCACGCTGGCTTCCACCCGTCGGCCTGCGGCGGCCTGGCGCACTCCGCGCCCCT- GCCCGCCGCCACCGCG CACCCGGCAGCAGCAGCGCACGCCGCACATCACCCCGCGGTGCACCACCCCATCCTGCCGCCCGCCGCCGCA- GCGGCTGCTGCCGCCG CTGCAGCCGCGGCTGTGTCCAGCGCCTCTCTGCCCGGATCCGGGCTGCCGTCGGTCGGCTCCATCCGTCCAC- CGCACGGCCTACTCAAG TCTCCGTCTGCTGCCGCGGCCGCCCCGCTGGGGGGCGGGGGCGGCGGCAGTGGGGCGAGCGGGGGCTTCCAG- CACTGGGGCGGCATG CCCTGCCCCTGCAGCATGTGCCAGGTGCCGCCGCCGCACCACCACGTGTCGGCTATGGGCGCCGGCAGCCTG- CCGCGCCTCACCTCCG ACGCCAAGTGAGCCGACTGGCGCCGGCGCGTTCTGGCGACAGGGGAGCCAGGGGCCGCGGGGAAGCGAGGAC- TGGCCTGCGCTGGGC TCGGGAGCTCTGTCGCGAGGAGGGGCGCAGGACCATGGACTGGGGGTGGGGCATGGTGGGGATTCCAGCATC- TGCGAACCCAAGCAAT GGGGGCGCCCACAGAGCAGTGGGGAGTGAGGGGATGTTCTCTCCGGGACCTGATCGAGCGCTGTCTGGCTTT- AACCTGAGCTGGTCCAG TAGACATCGTTTTATGAAAAGGTACCGCTGTGTGCATTCCTCACTAGAACTCATCCGACCCCCGACCCCCAC- CTCCGGGAAAAGATTCTAAA AACTTCTTTCCCTGAGAGCGTGGCCTGACTTGCAGACTCGGCTTGGGCAGCACTTCGGGGGGGGAGGGGGTG- TTATGGGAGGGGGACAC ATTGGGGCCTTGCTCCTCTTCCTCCTTTCTTGGCGGGTGGGAGACTCCGGGTAGCCGCACTGCAGAAGCAAC- AGCCCGACCGCGCCCTCC AGGGTCGTCCCTGGCCCAAGGCCAGGGGCCACAAGTTAGTTGGAAGCCGGCGTTCGGTATCAGAAGCGCTGA- TGGTCATATCCAATCTCA ATATCTGGGTCAATCCACACCCTCTTAGAACTGTGGCCGTTCCTCCCTGTCTCTCGTTGATTTGGGAGAATA- TGGTTTTCTAATAAATCTGTG GATGTTCCTTCTTCAACAGTATGAGCAAGTTTATAGACATTCAGAGTAGAACCACTTGTGGATTGGAATAAC- CCAAAACTGCCGATTTCAGG GGCGGGTGCATTGTAGTTATTATTTTAAAATAGAAACTACCCCACCGACTCATCTTTCCTTCTCTAAGCACA- AAGTGATTTGGTTATTTTGGTA CCTGAGAACGTAACAGAATTAAAAGGCAGTTGCTGTGGAAACAGTTTGGGTTATTTGGGGGTTCTGTTGGCT- TTTTAAAATTTTCTTTTTTGG ATGTGTAAATTTATCAATGATGAGGTAAGTGCGCAATGCTAAGCTGTTTGCTCACGTGACTGCCAGCCCCAT- CGGAGTCTAAGCCGGCTTTC CTCTATTTTGGTTTATTTTTGCCACGTTTAACACAAATGGTAAACTCCTCCACGTGCTTCCTGCGTTCCGTG- CAAGCCGCCTCGGCGCTGCC TGCGTTGCAAACTGGGCTTTGTAGCGTCTGCCGTGTAACACCCTTCCTCTGATCGCACCGCCCCTCGCAGAG- AGTGTATCATCTGTTTTATT TTTGTAAAAACAAAGTGCTAAATAATATTTATTACTTGTTTGGTTGCAAAAACGGAATAAATGACTGAGTGT- TGAGATTTTAAATAAAATTTAAA GTAAAGTCGGGGGATTTCCATCCGTGTGCCACCCCGAAAAGGGGTTCAGGACGCGATACCTTGGGACCGGAT- TTGGGGATCGTTCCCCCA GTTTGGCACTAGAGACACACATGCATTATCTTTCAAACATGTTCCGGGCAAATCCTCCGGGTCTTTTTCACA- ACTTGCTTGTCCTTATTTTTAT TTTCTGACGCCTAACCCGGAACTGCCTTTCTCTTCAGTTGAGTATTGAGCTCCTTTATAAGCAGACATTTCC- TTCCCGGAGCATCGGACTTTG GGACTTGCAGGGTGAGGGCTGCGCCTTTGGCTGGGGGTCTGGGCTCTCAGGAGTCCTCTACTGCTCGATTTT- TAGATTTTTATTTCCTTTCT GCTCAGAGGCGGTCTCCCGTCACCACCTTCCCCCTGCGGGTTTCCTTGGCTTCAGCTGCGGACCTGGATTCT- GCGGAGCCGTAGCGTTCC CAGCAAAGCGCTTGGGGAGTGCTTGGTGCAGAATCTACTAACCCTTCCATTCCTTTTCAGCCATCTCCACTA- CCCTCCCCCAGCGGCCACC CCCGCCTTGAGCTGCAAAGGATCAGGTGCTCCGCACCTCTGGAGGAGCACTGGCAGCGCTTTGGCCTCTGTG- CTCTTTCCT 196 OLIG2 CCGGCACGGCCCGCATCCGCCAGGATTGAAGCAGCTGGCTTGGACGCGCGCAGTTTTCCTTTGG- CGACATTGCAGCGTCGGTGCGGCCA CAATCCGTCCACTGGTTGTGGGAACGGTTGGAGGTCCCCCAAGAAGGAGACACGCAGAGCTCTCCAGAACCG- CCTACATGCGCATGGGG CCCAAACAGCCTCCCAAGGAGCACCCAGGTCCATGCACCCGAGCCCAAAATCACAGACCCGCTACGGGCTTT- TGCACATCAGCTCCAAAC ACCTGAGTCCACGTGCACAGGCTCTCGCACAGGGGACTCACGCACCTGAGTTCGCGCTCACAGATCCACGCA- CACCGGTGCTTGCACACG CAAGGGCCTAGAACTGCAAAGCAGCGGCCTCTCTGGACCGCCTCCCTCCGGCCCTCCTGAGCCCTACTGAGC- CCTGCTGAGTCCTGGAG GCCCTGTGACCCGGTGTCCTTGGACCGCAAGCATCCTGGTTTACCATCCCTAC 197 RUNX1 GGACGCGGCCCGCTCTAGAGGCAAGTTCTGGGCAAGGGAAACCTTTTCGCCTGGTCTCCAATGC- ATTTCCCCGAGATCCCACCCAGGGCT CCTGGGGCCACCCCCACGTGCATCCCCCGGAACCCCCGAGATGCGGGAGGGAGCACGAGGGTGTGGCGGCTC- CAAAAGTAGGCTTTTGA CTCCAGGGGAAATAGCAGACTCGGGTGATTTGCCCCTCGGAAAGGTCCAGGGAGGCTCCTCTGGGTCTCGGG- CCGCTTGCCTAAAACCCT AAACCCCGCGACGGGGGCTGCGAGTCGGACTCGGGCTGCGGTCTCCCAGGAGGGAGTCAAGTTCCTTTATCG- AGTAAGGAAAGTTGGTC CCAGCCTTGCATGCACCGAGTTTAGCCGTCAGAGGCAGCGTCGTGGGAGCTGCTCAGCTAGGAGTTTCAACC- GATAAACCCCGAGTTTGA AGCCCGACAAAAAGCTGATAGCAATCACAGCTTTTGCTCCTTGACTCGATGGGATCGCGGGACATTTGGGTT- TCCCCGGAGCGGCGCAGG CTGTTAACTGCGCAGCGCGGTGCCCTCTTGAAAAGAAGAAACAGACCAACCTCTGCCCTTCCTTACTGAGGA- TCTAAAATGAATGGAAAGA GGCAGGGGCTCCGGGGAAAGGGAACCCCTTAGTCGGCCGGGCATTTTACGGAGCCTGCACTTTCAAGGACAG- CCACAGCGTGTACGAAG TGAGGAATTCCTTTCCACCAAGAGCGCTCATTTTAGCGACAATACAGAATTCCCCTTCCTTTGCCTAAGGGA- GAAAGGAAAGGAAACATTAC CAGGTTCATTCCCAGTGTTTCCCTGGAGTAATGCTAGAATTTACTTTTGTCATAATGCAAAATTAAAAAAAA- AAAAAATACAACGAAGCGATAC GTTGGGCGGATGCTACGTGACAGATTTTTCCAAATTTTGTTGCGGGGAGAGGGAGGGAGGAGAATTGAAAAC- GGCTCACAACAGGAATGA AATGTA 198 RUNX1 TTTTTAATGCTCAGAGAAGTTCGTATTACTGATTCGGGAACACTGAGTTTTTCAGCTCCTGTAA- AACTATTTTCAGGTTTATTTTCAAGTACATTCTTTA 199 RUNX1 CACCCTAGAGGCAAGGACGGGGTCTGTGTCAAGAGGCTTCCCAGAGAAGTGAAAACTCTGCAGG- TGCAGCCGCTGGGAGAGCATCAAGA AGGGCAGGGTGGAGGGGCAGGGGGCGAAGGGAGGGGGTGAAGCCCGCACCCTACCCCCACATGAAACTGATT- CCACTACCCCATCTCTG CAAGCGTCCAGAGGCAGAGAGGCCAACATTTCGGGGACAGCTTGGAGGCGGGAGATTTAGGCAGGGCTCCTT- AAACTTTTATGTGCATGA AAATCAGGCCAATCACGGGGCTCTTGAGCAAATGGGGACGATGATTCAGCAGGTCTGGGCTGAGGCCTCAGA- TTCTGCACTTCTAACAAGT TCCCAGGTGGTAGTGATGCTGCCAGTCCAAAGACCACACTG 200 RUNX1 TGCTTCAGTGGGGTAAACTTGAACCGCTGAGAAGACAAGCAGGGAGTCGGTCTCGCTGAGATTT- TTACCTGTGGTTCTAGGAACGCAGAGG CATGTGAGTGTTCAGGCTTTGCATAGACCACTAAGCCACTTCTAAGAACAAGGCTACCTGAGCCATTTTGCA- AAAATATGTACGTGCCGAGG CTTTTCCTCCCCACACCTACCTCAACTCTTTCTGCCGACACACTGCACTTTTCAAGGGAACCCAAGTTTGGG- TTCGGCAAGAATTGTACGTT GCACACCGTGTGTGATAATTCCAGGGAATTTCAATCGCATCTTGTCTTCCTTCCTAAGCAAATTCGGTGGGA- ACCTGGTGTGGTGTGATAGA AAAAGCCCCGAGTTCTCTGTGGTAGACCACATCAATTTCATGTGCCAGTCTCTCAGACTCCGGCTTGCCTCT- CTCAAGGAAGGGAACAATG GTTTGCTTGGCTTCACTCCTCTCTTTCCCCCCAATTTCCACATGGGTATCTGGCTAAAAATGAGTTACAGGT- TTCCTTCTGTGAGAATTGCAT GGACTGATAAAGTACCATCCCAGGAAGAAAACAAAGATGCTGTCTTCCCTTTCGGCTCACAGTTGCCGTTGG- GGAGGGAACACACGCTGTA AATTATAGGCAGCCAGAAGTGACCGCATTGACCACTGCGAGTGGCCCAGCTATGGCAACAGGCTGAGAACTC- TGGGGGAGAGCCATTTGT TGGCAGGGATGGTGATTCTTCTAGCATCAAGCTCTAAGATGATGACCAAACGGTATCAAAAGAAATGATATT- TTGCTACCTCTCCGGCTTGG GTGAATGATGTGGACAGTTAACCTGGACAATTTAAACCTTTATGTTGATGGATCACTTGGATGAAATTAACC- AGGAAATTGCCAAGATTTCAC TTGGCCCTCTGACATCAAATCTCAATATTATATTACCAAATTAGAGATTCTAAAGAACCCTGAGTTCCTTTC- ACTGAAAGGAAGGAGTGGAAA AACCTTTCCAGATGATCCCTTTTGAGTCTTGGTGCGAGCTCAGGCCCTCCCTACACTGCCTCCGTGAAAGCT- AACCGACCCTTGTTCCTAAC CTAGCGCAGGTCAGCTGAGTGTCCATCGGGCACAGGAGCCCTGGGCTTGTCCGGGAGATAGCCAGACTCCTG- CTATTTCCTGATGTCTGC ATAGCTCAGCGTGTCCCTCACCATCTTTGCCGTTGGCCAGTAAGGAGAGCCCCAGGGGCCAGCACTGCACAC- TGAAACCCAACCTATTGCT CAATGGAATGCTTAAAAATTTCCTGAATCTGCCTTCCTGAGTTGATAAAATAGGAAACAATACACGTTCTGA- GGGGGTACTGAAAGCAGAGT AAAGCCAGGAAGATCTTTTTTTTCTGTTATTCTATACAAATATTGCTTCCTCTGCTTGTTAGCAGCCCAGAG- GAAATGCAGCCAGGGAGCCGT TTGCAGCTTTTCACCAGTGGCCGGTGTCTCTGTGTTACCAACCAAACGACGCTGCAAGACTAGTGACTAACG- CACGTCTGCATGATTCAACT TCACTAAAATTCCCTCTGCTGCCAGTAAAGAAGCACTTGAAAACTCTTTAATTTGAAACTTGAGCTTGGTTA- ATGACTTGTTTTCTTCTCTTTC TCTTTAACTTCTCTCTTGCCATCTCCAACACACACACACACACACACACACACACACACACACACACACACA- CACTCTCTCTCTCTCTCTCTC TCTCTCTCTCTCTCTCTCATCAAGTTTTTTAATTTCAGGGACCCGGAAACATACAGCCCCGTGCATTCACAA- TAGCATTTGCTGTGATAAAGT GGCCGGCAAGCCCTCTGCATTCCCCTGCTCACTTAGCTGTATGAATAAATAATGAGTCACAGATACAATTTG- GGTGCTCAAGAGAGTTTGTA GCCAGAAAATTAATTATTCTCCCATCCCAGCCCACTCCATCTCAGCTTTGCCAAACCATCAAGATACACTTT- GCAGGCACTGGTCAGAGTGC GTGCCCCGACGCACACGGCAATGCCTTTGAGACATTTTATGTTATTATTTTTGTTTGTTTAAGCACAGCCCT- CTTTTACCACGAAAGATACAC AAGACGCACATGCACACACATACTCACACACTCACAGCTCAACCACAGCTTTGTCCATTTCAAGAGGCTGGT- TTCAAAAATGGAGACAGGTT TTCCACCCTGGCTGTTCCTATTCATAAGCCTGTAATCTAACGACTTAAGCTGCGAGAATGCTTAACTCGGGA- AACTTCTCTATTGCCCTTTTC CAGAGAGACCTCGGTATGCCACAATTTGCTTCCTTTCTCTCTTGAAAGATGCTGGTTGTCTCTTTGCATTGA- GGCTACAAGGAAAAACACAG CACAGCCCCATGCTGATGATTTTAACCTAACCAAGTCTGTCAGTCTCCTGTACTCTCTGCCTTATAGAGACA- GCTGCCTTGCCACTTTGGCC CTGAAGTCCCCAGGCTGGTGCAAGGCTATCTGAGAGCCTCCGCCTCCTGCCCCACACTGGCACCAGCCCTCC- TGGCTGGCTCTGTGCATG TGCCTGCTAAGCCCCAGGGCAGGCTGCATTCTGGGCCACACAGCATGCCGAGTTAAGGATAACTCAGACACA- GGCATTCCGGGCAAGGGA CAGCAAAATAAAACCCAGGGAGCTTCGTGCAAGCTTCATAATCTCTAAGCCTTTAAACAAGACCAGCACAAC- TTACTCGCACTTGACAAAGT TCTCACGCACCGACTGAACACTCCAACAGCATAACTAAGTATTTATTAAAACATTTCTGAAGAGCTTCCATC- TGATTAGTAAGTAATCCAATA GACTTGTAATCATATGCCTCAGTTTGAATTCCTCTCACAAACAAGACAGGGAACTGGCAGGCACCGAGGCAT- CTCTGCACCGAGGTGAAAC AAGCTGCCATTTCATTACAGGCAAAGCTGAGCAAAAGTAGATATTACAAGACCAGCATGTACTCACCTCTCA- TGAAGCACTGTGGGTACGAA GGAAATGACTCAAATATGCTGTCTGAAGCCATCGCTTCCTCCTGAAAATGCACCCTCTTCTGAAGGCGGGGG- ACTCAATGATTTCTTTTACC TTCGGAGCGAAAACCAAGACAGGTCACTGTTTCAGCCTCACCCCTCTAGCCCTACATCTCTCTTTCTTCTCC- CCTCTGCTGGATACCTCTGG GACTCCCCAAGCCCTATTAAAAAATGCACCTTTGTAAAAACAAATATTCAAATTGTTAAAGATTAAAAAAAA-

AAAAAAAGCCAGCGCCGCCTT GGCTGTGGGTTGGTGATGCTCACCACGCTGCGAAACCCTGTGGTTTGCATTCAGTGTGATTCGTCCTGCCTG- CTGACCACTATGCTGGGTT CAGACTTCTGACACTGCCAGGCTACCCAACTTGTGGTTCTGTGGTTGTTTATGAGGCCCAAAGAAGTTTTCA- CACAACCCAAATTACAAATTT AACTGTTCCCCTTTCCACAGCCCATCTCAATTGGTTCTTGCCAATCATGTGACTTAAGTGATGTCAATTTTT- TTTTTTCTTTTCTGAGCAATGC CCTTCCTTCCCTCCACCTGCCCTCCCCCAGGCTGTGCAAGAAAATAGCCGAGTAGACTTTGCAAGAGGGGGG- GATGTAGAAAAAAGTGACT CAGTCACTTATTATATCTCAATGGTCTTTGCTGATTTAGTACAACTCGGCTCCTGTTGTTATTTGTGGTTTT- TGGAACTACTGATTATTTTGATA AAGATTTCATTGCTGCTTATTCAATAGTAATTCAACGCTGGCATCAAGCCGCTGCTCCGACAGGATGTGGAT- CCCATCATTTAAAATGCTAG GCATCAGCTCCGGGAGAGTTAAGTCCTTGGTAACGTCTATCATGGCATAAGTGAAACTATAAAAGGGAAAAA- TAAATAAAAAGAAATGTTTTG GTGAGAGTCTGACCCCTACAACGGGCTGGCAACTCACAGGTATTTTAAAGCCTGGGAAAGGGAAAGAATTTT- ACTTTTGAAATAAAAGGACT GTTTTAATGAAACCAAAATTATGTGGTTTTATTCCCCCTAAATGGACAACTTTAGTATGTATCTCTTTCAGT- AAAGAGATAAAATCATAGTACA GTCTTAACACACACACACACACACACACACACACACACACACACACAAATTAGGAAGCTAAAGGAAAACAAA- GCAGAGAGAATTTCTGTATT TGGGACAAAGCAGTGGTTACTCTGCAGATGTTTATTTGTATTGTCACTTGGGAAAGCTCCCTGTATTGCCTT- TCTCTAGTTCAATTCAAATCA ATAGGCTAATTTACACCTGTAGGTAAAACTACACTTTGAGCACATGAGGATGCCACAATAGAAGGGGAACCA- GGAGGAGACACTTCTCCTG GGGCTGACTAATGAATATTATATAGCGCGTCCTCTACCTTAGAAAGACATGCCTGTTTGAAGATGCTAAAAA- CAGGATAATTTTGTAAGTGGG CAAACCACTGTGGTCACACGTATTTCATTTTCCGGCCCCACTGGCTTTACCTGCTGACAACTAAAACGTCAT- TTTGTTTTGTAGTTCCAAGAT GAAGAAAGGCTTATTTTCCTGATTTACTACCTTATTCATTTGGCTCTGCTCTGCCTACATCCGCCATAGCAC- TCTGCGCACGTGAAATTTCGA CACATAGGGTCAAGAGAACCTGTGTGATGATGGGTTGTAAATGCCAGTCCTGGATTCTAAGCTGCAGTAGCC- AGCACAGGCACTTCAGAAA GGCTGAACTCCCACAACACTCCCTCGGTTTTCCCTCATCCACTTAATTTCACACACACAAAGACCCACAACG- ATAGTAGCTTCCATGGCACA AGTCTTTCAAAAGGAACAGACACAATTTTTACTTACTCCTGTTTTGACTAAAGCAGGAATTGAAACTCAACA- GACCGCTTTCTCTTACACTTGT GAGAAGTTAGCTGGCCACATGT 201 chr21: 35499200-35499700 AGGGAAAAGAGATAACGAAAGAAAGAAAGAAAAAAAAAAGGGCCGGCAATTTCATGTACATTTGTTTTGGCAT- TCGCTGAATTCTAGAGATG AAAACAATCTCCTGCTTTTAATTCAGTCCACGTGCAACAAAGTTGTACGTTGGGAGATCTGGCTTTTAATAA- GAACGATTAACAAGCGTTTTT GATCACAGGAAGTTGAGAAGAGTCGCTGCTTCTAAGAATACAATAAACATTGACTAGCAGTTAGACGGTCCA- TCTTTCTCTATCAGCCGTTTA GCAGCCTCTACTTTGATTTGGGGCAAATGCGAGATGGGACCAGGAGAGAGCTCCCCACACCCCCACCACCAC- GTGGGCAGTGGTTCTGTT CCAGAGCGCCTTCCTTCCTGTCCAGGGAGGCAGGCTGCTGAGGCCGTTTCTGGGCAAGAGGCCATTGTCGGG- ATATTTGCTTTAGATAGC TTGCAGCTGGGCTGAGTGGGTGTTTCATTCAGACTCAACACA 202 chr21: 35822800-35823500 AGCCTGGCGCACCCGCCCTAATTTGAGTCAGGGACCCTAGGCGCCTGCAGCTCCGGTTCGGGTTGAGTGCCTC- CTGTCAGGATGTGAAGC TGCTGTCCCCCCCGGGGGCCTCCAGCACTGCTGAGGACTCAGCAGTCAGCCTCTCCTCCCACTTGGGCTCAT- TTACAGAGAGCATCTCCA GGAATCAGTCATGGGGAAAGGGGAAACGCGGAGTGACAACACAACACGTAGAAAGTTCTCTGCCGCCTTGGT- CAGGCTTGTCAGCCTCAC AGCCCATCCTGCTCCTGCGGGAGGAAAAGTGAGCAGAACTCAGCCCGGAGATGAGCCGCAGGCCGGCAGCCC- CTGCCTCTGCCCTGCTT GTTGTGACTGCAATGCAAGGCTCTCTGTAGGTGCGGGGGATTCGGGTTAAATGGGTCTCCAGTGGTCCAGCG- CTCCCAGCAAAGGCCGAC CACAAGAATTAGCGGGCTAGTTATTTACCATAACCATATACAAAACCACAAGCATCAGCGTTCCCTCAAATA- CATCCGAGACGCTGTATATCT CTTTATTAAAGCCTGTCAGGGTTTGTTATTGCACAGCTTGGCCTTGAACCCCAACTAAACCAGGCTGCTTGA- GCAAAGAACCAAGCAATGCA AGCATTCAGGCAGGACCATTATAACCCTGAGGCCAAAGGCAGAAGCAGGGAGAGGAGACGTCTTCC 203 CBR1 AGACCAGCCTCGGTCTTCGGCCTGCGGGTTCTGCAAAGTCAGGCTAGCTGGCTCTCCGCCTGCTC- CGCACCCCGGCGAGGTTCCGGTGG GGAGGGGTAGGGATGGTTCAGCCCCGCCCCGCTAGGGCGGGGCCTGCGCCTGCGCGCTCAGCGGCCGGGCGT- GTAACCCACGGGTGC GCGCCCACGACCGCCAGACTCGAGCAGTCTCTGGAACACGCTGCGGGGCTCCCGGGCCTGAGCCAGGTCTGT- TCTCCACGCAGGTGTTC CGCGCGCCCCGTTCAGCCATGTCGTCCGGCATCCATGTAGCGCTGGTGACTGGAGGCAACAAGGGCATCGGC- TTGGCCATCGTGCGCGA CCTGTGCCGGCTGTTCTCGGGGGACGTGGTGCTCACGGCGCGGGACGTGACGCGGGGCCAGGCGGCCGTACA- GCAGCTGCAGGCGGA GGGCCTGAGCCCGCGCTTCCACCAGCTGGACATCGACGATCTGCAGAGCATCCGCGCCC 204 DOPEY2 AAACGTTTAAAATATATTTCTAAACAGAATGGGCCAATTCAGTCACAGTAACTGTTGATCTCC- ATAGCAGAGCAACCCACAAAGACAGAACTG ATTTTTTTCCCATAATCAGGGGTGAAAAATATACAACTTGTTTCTGAACCAAAACCACAATTTCTGCAGTTT- AAAATGTTTCACTGCTAATATG GCCCTGGTAGAAATTATGTAGTTTCTTTTCTTCTTTAAAAAAAAAAAAAATTAAAAAAATTTCCTAAGACAC- TAAATGCTCCATCTGGAATGTAG ATTCTGATCACAAAGCAGCTCAGTTAACCTAAAAAATAAAAAATTCCCATCACCTGTCTCAGTAGGGCCTGA- GAGTAGTGTGGGGAACCCCA GCTTTGGTATGGAGAGTCATGGCCCCTTGAACCAGATAGAGACCTTGAATAGCCATAGCTGGTGCTTCTCTC- AGGATAAACTCTGATGTAG GAAGTATCACCCTCATGAGAGTGGAATTTGGTCATCCAGTTGACGCAGGGCATATTCCATGTCTTCTTTTCT- GAGACACCCAACCATCCCCA CTCCATCCTTCTGCACATCCGTGTAACAGGCATCCCCAGCTTCTCGCGTGTGATCCTTCAGGTCCTGCCAGC- TGCCTGATGGAAGAAGTCC ATTTCTTCCATAAATAGCATCCTCTGCATCTCGAGGGTCCTCGAAGCGCACGGAGGCGAAGGGCACAAGGCC- GTACCGGCTCTTGAGCTC GATCTCGCGGATGCGGCTGTACTTGTAGAACAGGTCCTGCGGCTCCTTCTCGCGCACGTGGGTCGGAAGGTT- TCCCCACGTAGATGCACC CGTCGCCCTCCCAGCCGCGCTCGTGTCCGCCCAGCCGGACAACCGCACCGCCCGACGCTGCTGGCCAGCCGC- AGCCCGCATCCGCCCG TATCGCCGCCGCTGCCGCCTCAGCACGGCTGCCCCCGCAGCGTCTGTTTTGTTTTATTCTAACAGGGTCTCT- CTCTGTCGCCCAGGCTGGA GTGCAGTGGCGTGATCTTGGCTCCCTGCAACCTCTGCCTCCCGGGTTCAAGCGATTCACCTGCCTCAGCCTC- CCAAGTAGTGGGCATTATA GGTGCCAGCTAACCATGGCCGGCTAATTTTTTTTTTTTTTTTTTTTTTTTTTTGAGACAGAGTCTTGCTCTG- TCACCCAGGCTGGAGTGCAGT GGCGCGATCTCGGCTCCCTGCAACCTCCGCCTCCTGGGTTCAAGCGATTCTCCTGCCTCAGCCTCCTGAGTA- GCTGGGATTACAGCTATGT ACAGCGATGTCTGCAAAGATAGGGATTTAACAGCACTCATATCTTCATGTTCATAAAAAAGTCCTACACGCG- TGATGTACGTCTAGATCTTTC CTTTTGTCACAGGATATAGCACGGTAGTTACGGATATAGTCTCCGCAGTGCCTGGGTTTGACTCAGCTTCCC- CACGTACTGTCCTGCGCATA TTTTGTGTCTCAGTTTCCTCATCTTTAAGGTAG 205 SIM2 CACGCGCCCCGGCCTGGCTGGAGGGGCCAACCCAGCGGGGCCCGCCTGCCCGCCGGCCTTTCTGT- AACTTTCTCTCTTTAAACTTCCAAT GAATGAACGTGCCTCTTCTTACGGATTTGTTTAGATTAGGGAATAGATTCCTCGCTGATAGCGTTGCTTTGC- AAATAAGACCTCCTATATTAT TCAAACCAAACGAGTTTGTGTCTTTAAAGGACTATAGCAGCCCCATTCTATGTTAAGGGTTGGCTATTACAA- TTATTATATGCTTAGGGAAAA AATGTAAGCCCCGTAGTTTGTGCTTTTCTTGATGTACAGAAAGGTTTATCTTAGGTGGATAGGTTTTGTTTT- GTTTCTTAAATGGGATTTTTTT GGTTCGTGTCTTTGAAGGGCTGTTTCGCGACGTCATTAATGAACTAATCGGTTTTCAGATTTCAAGACGGTG- TGTAATTGATGTAACCACTGA GGAATTTCAGTGCACACCAGACTAAGACTCTTCCAGCGCAGGGGATTCCAGATGCTTCTTGGGCCCTCTGGA- AGCCATGGGGATGTTTCCA GACCGAAAGGAGGGCTTTGCTGGGGAGCAGATGTGCTGCCTCTCCCCGACCCAGGATTTTGAGGCCATGTTT- CCGTTAATCTGGACCGAG AGCCCTCTGGGAGAGGGAGGCAGGTCGTAGGGGGCGGGGGTGAGGGGGAGCGAGATGAGGTCGTCGCTGGAC- GCTGGGCTCCCTTGT CGTTGTCCTTTTCCCCAGAATCCATGGTCAGGCCTAGGGAGCCACCCCTGGGTGCTCGAGATGAGTCCCCAC- CCTCACTGAAGGTCGGTC ACTGGATGTTTGTGTGCATCGTAAGGGGCCCACCGAAGTCCCGAAGCCTTCTCAGGGACCAGCGAGAAAGAG- GAGCAGGCTTGGGAGAC AGGGAAGGAAAATGCAGGGGAAAGGGCTCACCCCTCGACCCCAGGTAAAATTAGAAGGAACGTGTGGCAACC- CAGGTGCAGCTTTGGTCG CTCGCTCAAGGACTTTGCTAGTCACTACCATTAATTAATTAATCACTATCATTAACTACCAAGGACACCGTT- TTTATTCCCCTAAAAGCGTCAC CTTGAGGGGAATGGAGAATTGGGCAGCAGCTATGCAAATCCTGGGACAGGAGACACTGCCTGAGGACCCTCT- CTCACTCCCAATCCCAGA ACCCGAAGTTATCCCCGACAACCAAGTCCAAGCACATGAACCAAGACGATCAGCTTCAGGCAGCTCCTTACC- CCCACAAGCGGCCCAGGA GGTGGGCATTATCCCCCACCCCTGGGATTTCTCCATCCCTCCCTCTTCTCTCCTGCGGGAGAGAGAGCTGTG- GTCACCCAGTTGGGCGCG ATGGCTCTGGACTAATGGGGTCTCTAGACCCAGGGCACAAAGGCCAATCTGCCAGGGGTTACTGCATGTAAT- GAGATAATCAGACATGTTG ACCAACCTAAAAGAAAAGACTCTCCCAGGGAGTAACTCCCAGTGAAATAATTTATTAAAAAAAGCAAAAAAG- AGACATAAATTTCTCTCTACT ACTTGAGGAAACAGCAAACAGAACGAATTAGGGTCTTGGCCTCTGCAGGAATAAATTATTTCCGACTTGGTC- TGGATACCTGTAATTATTTGT AAGCTGTGGGTAGTAATACTGTAATTGTCCCCCGGTCCTTTCTGGAAGTAGCAATGACCCCAAGGACAATTG- GTGACGTCTCCACAGGGTT TACACATGGAAAGGAGTGAAAAATCGAGGAATTCTTTCAGATAGCCCAGACCAAAAATCCTCTCAGCCATGA- AAAGGTCATATATGTGATGC TGGGCCAAGCGGACTTTTCTGGAGTAACCATATCATAACTGATTGCGGATGTAGACAAGAGCGTATAAACCA- AATAGGCTTGAATCAACGCA GTCCTGGATTTTCTGTTGCCTCTGCTTGCTGGGGCAGTGGAAGTTCTTAAACTCCACTTCAGAGGTTGGAAA- TTCTTCCCCCTCCCCCACCT CCTTAGTGACAAGGTCTCTGATCTCCTGCTGCCACTGCAATAGCCTCTCCCATCCCGCGGGGAACGGCCGGA- GTTCTTCCCTTGATCTCTC CCGAGTCGGCTTCCGCTGGGGATGGATCGCAGGTAGGCGCCGGCGCGGCCTGGGGAAGAACAGTTGCGGAGC- ATCTGAAGCGGAAAAT CCAAGCAGATGTGAGGCGATCCGGGCCCGCCTCGTTCCTCTTGGGGCCTGAATTTCTTCCAGATAAGTTTCC- TAATGGAACATTTCTAAGA GGTGGGGTACGAGGCGGCTTGCTCGCACGCGCAGTGGGACAGACTGCGGGTGGGGACGTACTGAGAGGTCCG- GACCTCAATGCGTCCG ACCCGTCTCCACACCGCCCTTTTCCAGCCCCCAGTCTCCTTTCATTCCCTACTCTTCAGGCTCCTTTGGGGC- CAGTGGGTGAACCGCCATT TAGAACGGTGCCTCGGACTCGGGGGTCGTGCGCTCCATCTCTGCCTCCCCCCTGGGGCCCGCGAGGCTGGTC- CGGGCTTTCTGAGCTGG GCGTTCGGCTTTAGGCCCAATACCTGGACCAGGAATTTCTTCTCCCCGCGCCAGAAGGGAAAGACATAGGAG- GTGTCCCAATCTGCGGTC ACCGCCGATGCTCCTGACCACTCTAGTGAGCACCTGCCCGGTACTTTTCCATTCCAACAGAGCTTCCAGCTT- CATACTAACTATCCCACATA CGGCCTGTGGGTATTAGCTCTAAGTGTCCTTTTCCGAGGGCCCGAGGCTCCCCCTCCAGCAGGGAGAGCTCC- GGGACGGCCCCCACCAA GGGTTGGGTTTCTTCCTTCACAATTCCACAGAGGCATCCCTGTCCTTCCTACCTGGGAAACCTCGAGGTGCG- GTGCCCGTGTACTTCTGGT ACTTTGCGTGGTGCCATCAGGGACCCCAGAGCCACAGCTGCGTGTGTGTGTGGATGTGTGTGTGTGTGTGCG- CGCGCGCGCGTGTACGG CGAAAGGATGTGCTTGGGGGAGCCGAGTACACAACGTCTGCTTGGGCAGCTGCTGGGCAGGCGTTGGGCCTG- GAGGTATCTCACACCCA CGTATCTTCCAGTCTTCAAACACGGCATTGCTCTGCCTCCCGTAGCGCGCTTCGAACCTGCCTCGCGGACAC- GTGAACAGAGGCTGTCCCT GGGAAGATAAGTGCGCTTTCCCGTAAAATCCGGGAAATTTGCCTTGAGGAAAGTTTCCGTTCTTGTTACTTG- TCGGGTTTCTCCCACTTCCA CTTAGCCATGTTTCTGCGATCTGGGTAATCCCTTTCAAGCCCAGGAGGAATTCTCCCGGGTCCATAATTGAG- GGTCGGAAGCCGTGGGGGT GAGAAACGCATTAAATCCTCCCGAAGCCCAGGAGGTGCCAGAGCGGGCTCAGGGGGCCGCCTGCGGAAGCTG- CGGCAGGGGCTGGGTC CGTAGCCTCTAACCCCTTGGAGCTCCTTCTCCCAGAGGCCCGGAGCCGGCAGCTGTCAGCGCAGCCAGGAGC- GGGATCCTGGGCGCGGA GGTGGGTCCGACTCGCCAGGCTTGGGCATTGGAGACCCGCGCCGCTAGCCCATGGCCCTCTGCTCAAGCCGC- TGCAACAGGAAAGCGCT CCTGGATCCGAAACCCCAAAGGAAAGCGCTGTTACTCTGTGCGTCCGGCTCGCGTGGCGTCGCGGTTTCGGA- GCACCAAGCCTGCGAGC CCTGGCCACGATGTGGACTCCGCAAGGGGCTAGGGACAGGCAGGGGGAGAGCCCGGGTTTGCGCACACCTTC- CAGCCCCTGGAGGGAG CCTGCTCGGCTTCGAACGCCTTCGAACTTTTGACCTTCAAAGGAGTCCCTGGAAAAGGTCAGGAGCGCCTGC- TGCAGGCACGGTTGCCGA AGGCCAGGCCTTCCTGGCGCAGGGGAGGGCCAGGGGAGGGAAGCGGATACTCAGTCGCTGTCCGACGGCGAG- TTTTCGGAGCAGCAGG CTCATGATCCCGGGCCAGTGGCGAGAGCAGTGACACCGAGAACCCAAATCTCCGCGCCCCCATCCGCGGCCC- GGTGTCCTCCCGGCCCC TGCTGACCTCCAGGTCACGCACCCCACTGCTCCACGGCTCTGCAGCCTGTGGCACACGGCCGAGAGTCCCCA- CATGATCTCGACGCCAAG GTAAGGAATTGCCCTGCGTCCTCTGAGCCTGTCTCTGGCCTGGGGGGCCGGGAAAGCTGCACTCCTGGAAGA- GGTGGGGTTATGTGACC GCCGCTGCAGGGGTGCGCGGAGGACTCCTGGGCCGCACACCCATTTCCAGGCTGCGGGAGCCGGACAGGGGA- GGGCAGAGGGGGGAC AAAAGGACTCTTTAGGTCCAAAATGACCCTGAAGGAGAGTCCAGAATGCCCAGTGGCCGCGTCTGCAACGGA- GTCTTCTTTCTCCAATTGC CTTCTGCCCCATCACCATGGGCCCCACCTGCGCCACCTGCGCCCACCCTGTGACCCTGGCTCAGCGACCTTG- GCCCTTAATCGCCCAACG CCGATTCCTCAAAATTCCGGCTGCGCTGAATCGGGCTGCTTTTGCCGCCGCCCCGGCAGTTGGGCCCTGTTT- CCGCCGGCGCCCTGGGA GAGGCCTCACCACTCGGCTGGGCTCCCTGGCCCCTCCCTTCCCCTGGCCTGAGCGCCCCTGCGGCCTCCCGC- TCCTCCTGAGAAGGCGA CAATCTCTTTGCACCTTAGTGTTTCGAGGACAGAAAGGGCAGAAGGGTCACTTCGGAGCCACTCGCGCCGTT- TTCACGTGTGTGTGTAATG GGGGGAGGGGGGCTCCCGGCTTTCCCCTTTTCAGCTCTTGGACCTGCAACACCGGGAGGGCGAGGACGCGGG- ACCAGCGCACCCTCGG AAGGCTCGATCCTCCCCGGCAGGGCGCCTGGCCAACGAGTCGCGCCGCCTCCTCTCGGCCGCGCCTGCTGGT- GACCTTCCCGAGAGCCA CAGGGGCGGCCTCGGCACCCCTCCTTCCCTCGCCCTCCCTGCCGCCCATCCTAGCTCCGGGGTCCGGCGACC- GGCGCTCAGGAGCGGG TCCCCGCGGCGCGCCGTGTGCACTCACCGCGACTTCCCCGAACCCGGGAGCGCGCGGGTCTCTCCCGGGAGA- GTCCCTGGAGGCAGCG ACGCGGAGGCGCGCCTGTGACTCCAGGGCCGCGGCGGGGTCGGAGGCAAGATTCGCCGCCCCCGCCCCCGCC- GCGGTCCCTCCCCCC TCCCGCTCCCCCCTCCGGGACCCAGGCGGCCAGTGCTCCGCCCGAAGGCGGGTCTGCCATAAACAAACGCGG- CTCGGCCGCACGTGGA CAGCGGAGGTGCTGCGCCTAGCCACACATCGCGGGCTCCGGCGCTGCGTCTCCAGGCACAGGGAGCCGCCAG- GAAGGGCAGGAGAGCG CGCCCGGGCCAGGGCCCGGCCCCAGCCGCCTGCGACTCGCTCCCCTCCGCTGGGCTCCCGCTCCATGGCTCC- GCGGCCACCGCCGCCC CTGTCGCCCTCCGGTCCGGAGGGGCCTTGCCGCAGCCGGTTCGAGCACTCGACGAAGGAGTAAGCAGCGCCT- CCGCCTCCGCGCCGGC CGCCCCCACCCCCCAGGAAGGCCGAGGCAGGAGAGGCAGGAGGGAGGAAACAGGAGCGAGCAGGAACGGGGC- TCCGGTTGCTGCAGG ACGGTCCAGCCCGGAGGAGGCTGCGCTCCGGGCAGCGGCGGGCGGCGCCGCCGGGTTGCTCGGAGCTCAGGC- CCGGCGGCTGCGGG GAGGCGTCTCGGAACCCCGGGAGGCCCCCCGCACCTGCCCGCGGCCCACTCCGCGGACTCACCTGGCTCCCG- GCTCCCCCTTCCCCAT CCCCGCCGCCGCAGCCCGAGCGGGGCTCCGCGGGCCTGGAGCACGGCCGGGTCTAATATGCCCGGAGCCGAG- GCGCGATGAAGGAGA AGTCCAAGAATGCGGCCAAGACCAGGAGGGAGAAGGAAAATGGCGAGTTTTACGAGCTTGCCAAGCTGCTCC- CGCTGCCGTCGGCCATCA CTTCGCAGCTGGACAAAGCGTCCATCATCCGCCTCACCACGAGCTACCTGAAGATGCGCGCCGTCTTCCCCG- AAGGTGAGGCCTCAGGTG

GGCGGCCGGGGACGCTGGGGAGCCCGGCGGCCCCGGCCCAGGCGGGAAGCGCAAGCCAGCCCGCCCAGAGGG- GTTGCCGCGGCCTG GCGTCCAGAGCTGGGGCGTCTGAGGGAGGTTGCGTGAGGGTCTTCGGCTTCGGCGCTGGCTTGGGGCGAGGG- GCCAGGGCCTTGGCGG CCCAGGCGACCAAACCCTCTCCTGGTCCAGGGCTGGGTGAGGGCGAATTACGAATTGTTCCAGGGGCAGGCA- GTCCCCCAGCCCGCACG GCCAGCGAGTTCTTTCTGGTTTTGTTCTTTCTCCCTTTCCTCCTTCCTTCCTTCGCCAGTGCATTCTGGTTT- GGTTTGGATTTTTTTCTCTCTT TCTTTCCTTTCTTTCTTTCTTTCTCTTTCTTTTTCTTTCTTTCTTCCTCTTTCTTTCATTCTCCCCTTCCTT- CCTTCCTTGGCCCCCTCTCTCCCT CCCTCCTTCCTTCCTTCCTTTGCCAATGCATTGGTTTGTTTTCTTTCCTTTTCTGCTTTCCTTCCTTTCTTT- GGAAGTTCACTCTGGTTTTGCTT TCTTTCTTTCCCCATCCCTTCCTTTCTTTATCCCTCCTTCCCTTCCTCCTTTTCTTTCTACGATTCCCTTTA- TTTTTCCTTCATTCCTCCCTCTTT TTGTCTCTTCTGGAGGAGGTGAAGGAGGGTCAGCTTCAGGCGCTGCGAGTCAGCGGGGATCACGGTGAGGCC- CAAGCACTGCAGGCTGA GGCCACAGAGCGAACACTTGTGCTGAGCCGGGCCCTCTCGTGAGGCTGGGGTGCGGGAAGTCCGGGCAGGAG- AGACCCGCCCCCGCCG TTGCTGAGCTGAGACCCGGCTGAAAGAGAGGGGTCCGATTAATTCGAAAATGGCAGACAGAGCTGAGCGCTG- CCGTTCTTTTCAGGATTGA AAATGTGCCAGTGGGCCAGGGGCGCTGGGACCCGCGGTGCGGAAGACTCGGAACAGGAAGAAATAGTGGCGC- GCTGGGTGGGCTGCCC CGCCGCCCACGCCGGTTGCCGCTGGTGACAGTGGCTGCCCGGCCAGGCACCTCCGAGCAGCAGGTCTGAGCG- TTTTTGGCGTCCCAAGC GTTCCGGGCCGCGTCTTCCAGAGCCTCTGCTCCCAGCGGGGTCGCTGCGGCCTGGCCCGAAGGATTTGACTC- TTTGCTGGGAGGCGCGC TGCTCAGGGTTCTGGTGGGTCCTCTGGGCCCAGGAGCTGGGAGGGCTGCGCCGGCCTCTGGAGCCCCGGGAG- CCAGTGCCGAGGTAGG GAGACAACTTCCGCCGCAGGGCGCCGGACGGTCGGGGCAGAGCAGGCGACAGGTGTCCCTAGGCCGCAGGGC- GCTTCCATAGCGCCAT CCCCACCAGGCACTCTACTCGAAATCGGAAAGCTCGACCTTTTGCGTTCGCCTCTGCCAAGCCTGTTATTTG- TGCTGGCCGCTGGGTCTGG AGCTGCGCTTCTCGGCCCCTCCCCGGTGGAGCGCAGAGGGCTGGTCTGCAAGCGCGGCCTCCAGCCCCGCGG- CTCCCCGGCCCAGGAG CCAGGCGCGGGCTGACCCGGGAGCACCCGGCAGCGGAGGGGGCTGGAAGCGGACCCTAGGCCTCTCCTGTGC- CACCCGGCCCTACCG CGCGGCCGCGGGGCGCTCTCCTCTCGGGCGCAGCGGTCCTTCAGCCCAGGGCAGGTTCCTCCCTTTCCTACT- CGGAACGTGGCAAAGAT ACCCCAGTCCCAGCCCCTCCAGCTGAGAGCTGTTGCCCAAGGTCGTCGCTACTTGTCCGCTCAATGGTGACC- CCTTGGCAGAGAACTAGG GATGATTCCACTCCGGTTGATGTTTTAGGGGAAATTAAAAGAACATTCGGTTTTCTGAGTCTCCTTCCGGGG- AGGCGTGGTGGTAACTGGTT TGCTGGGAAGAGCCGTTCCTTAACCGCATGCAACAAAGCAGGTGTGGAATCCGGACGAGAGGGCACTCACTG- CCTTCTGCCCCCTTTGGA AATAGAAAAAGCCTTCGAAGCAGCAATCCAAAGATCAAATGATTTGCGGTCAATGATTTCAATTAAACCAGA- AATTAGTAAGGGAGGGCCGA GAAGACACGGCTGCTCAGAAGCTGTTCGCTGTTTGAGGGATTTCCCGGAGAGCCTGTTAAAAGATGCGAAGT- GGTGGGTGTACCGCTCAG CCACCTTTAAACCGGCTCTGTGCGTTCTGGCTCTGGAAAGCAAGTCTCCAGGCATTTGGGCTCAGAATTGCT- GGGCCCCGAGTTTGGGCG GGGGTGGTCCTTCTGGGGGTCAGGCCTTGAGCAGCTTGCACTGGTGGCAGGTTTGGGAGCAGTTGAGGGGCT- TCCTGTGTGTCTTTTGGA GGGGGTGACCCTGGAAGTTGGCACTCTGGAAGGGAGCTGTTTGGCCCTAGAGTTTTGGAAAGGGCCCTGAAC- CTGTTCGGTCCCCCTCGG AAAGGGAAGGGAGCAGTGGCTTAGTCCCTCCCTCCTCCATTCGTGCAATGCCTGGGGTAGGGGTAGACCTGG- AGCCGGTGGACTCATATC CTTGGAATTCGTCAGGACAGCTGCTCCGGGGCCTTGGCCCTCAGTCAGTCTGGGGCTGAGGAGTAGGGAAGC- TGGGAACTTGGGGCAGA GGAAGAAGATGCGTTTAGAAAGACCTCCATTATGCAAACTGGAGTCCATTTATGCAAACTGGTCACCCTTCC- AGTAGCTCCAAAGAGTGGCA GTGGAGTGGCATCTTGATTGATTTAACCTCTTCTCAGGGGACCTGGGTCTGCGAGGGAGGATATGGCTGCGG- GGTTGGAATAGGATCTGT CTGAGCTGCCAGGGTCAGGGTGGTGGCCCTAGGGAGGTTTTAGGGCCAGGGTGGTCCCGGGCTGTGGCAGGG- GCTCTCAGATCGCCTC GGGCTCTCAGCTGCAAGGTGAAAAATACCATGAGGAATTGATCTGCCAAGGGCGGTCTTGTCTCAAAGCAAG- TGGATTGCTGGGGTAAAGA ATCTAGAGACCAGCTTAGGACTCTGGGAGGAAGAAAAAAAAAAAAAGAATAGCATAGTCCTAAGGAACTGCA- AGGATCACCAGATTAACCCT TCATACCTGGGGAAATTAAGGCCAGACATGACACAGGCCTTTCCCAAGGCTCTGTAGCAAGGGCAATAGCAG- GCCAGTTGCTGCCACTGC GGTCCTGTGGGGCATGTTCTCACTCCACTGCACCCAGGAGGCTGCCAGCCTCTGTTCCTTTTAACATAGATC- TCCTCAGTTGTTAAGACAGA AAGAGGAACTCAGAGGGGTCCCTGTGTGCAAGGCAGAGGGAGACCACCAGAACCAGGGTAAGCACCCCACTT- GGTAGCCAGTTCAAGGA CTTGGGGATGTTTTCAACATTTACAGCGAGGTTTGAGGCCCCATTGTCATGCAGCGCTACTCGGCCTTGGTC- TCCTTATCTGTAAAATGGGC CCATTAGCAATGCACAGGGTTGCTGTGATGAAGGGTGAGGTCCCACAAGCAAAAGCTGTGCAGTGAGGGGGG- AATCCTAAGCATTGTTCC TATGCCATTCACCCCTTCCTGTGAGCTCCCCATATTCCCTGGCTCAAAGGAGTCTTGAATGGCAGGGATGGA- GGACTCACTGCCTGGACTT TGAAGACCCCTGCTTTCTGGGTGACCACCTTTTCTTCCCTTTGACAGTGAACTAATACATTGGAGGTAGATA- GTGCTGGGAAGAGGACAGG AGACCACGGCTGACTTTGGACATGGGCTCGAAATTGATAACTTGATGAGTCTTGGAGGGTGGTTAAGATAAG- CTCGGGGCTGGGGCAGCG CTGAGGTCTGATGGTCAGCCAGCCCTCCCCAAAGTGTGGCCCTCCGTTCTGGAGATAGGGGCTTTGGAAACT- GCAAAAGCGTCCTGGCAG GCCAGCTCTGGTTGCTCCCTGGCCATAGCTGCTCTGACTACAGGCAGCAGGACGCAGGTCGGCCTCTGCCCA- TCGGAGGTCAGAGGCAG GGCCTCCAGCACCAGACTCAGCAGTGCCACTGCAAACCTGGCACAACAGGCTGGTCCCAGGACTCAGCTCAG- CAGTGAAGTTGGAAACCA AGGTTGAGTCTCCCCATCTCCCTTTCCCCAACCCGAAAGACCCAAGATGGGTGTGGGTGAAAGAGGGAGAAA- GAATTGCTACTCCAGAAAC TGTCATTTGCCCACACGAAACGAGGTGGGGTTCAAGGTCTGAACTCTTCCAGTGCCTGGGTGCCTTTGGGTT- TAAATTCAGCTGCAGGTGC CCCCATCACCACTTCCACCTGAGCACACCACGAGAAGCCAGGTTATCTTAGAAACTGTTTCCCGGAATCAAA- GCGACTTGATTTGGAGAGTT GGGTGAGGAGAAACTCACCCCTATACCCCTCAGGGCGTCAGAGATGTGAGGCAATTCTCTACCTCCGCTGGA- AAAAATGCAGATTTATTAA AGGTCGACTGTTTAGCAGAACAACGTAGATTTTTTACAACGCTTTCCCCGTCTCTGCTTTGAAGCCTGCCAG- GCTGCAGCTGGGGATCCAG GAGGGAAAGCCCGCAGGCGCAGAGGGGACAATCCGGGAAGTGGTAAAGGGGACACCCGGGCACAGGGCCTGT- GCTTTCGTTGCAGGCG AGGAAGTGGAGCGCGCGCTGCAGATTCAGCGCGGGGCTAGAGGAGGGGACCTGGATCCCTGAACCCCGGGGC- GGAAAGGGAGCCTCCG GGCGGCTGTGGGTGCCGCGCTCCTCGGAGCCAGCAGCTGCTGGGGCGGCGTCCGAACTCCCCAGGTCTGCGC- ACGGCAATGGGGGCAC CGGGCCTTCTGTCTGTCCTCAGAATACGTAGGATACCCGCGGGCGACAAGCCGGGCCAGGCTAGGAGCCTCC- TTCCCTGCCCCTCCCCAT CGGCCGCGGGAGGCTTTCTTGGGGCGTCCCCACGACCACCCCCTTCTCACCCGGTCCCCAGTTTGGAAAAAG- GCGCAAGAAGCGGGCTT TTCAGGGACCCCGGGGAGAACACGAGGGCTCCGACGCGGGAGAAGGATTGAAGCGTGCAGAGGCGCCCCAAA- TTGCGACAATTTACTGG GATCCTTTTGTGGGGAAAGGAGGCTTAGAGGCTCAAGCTATAGGCTGTCCTAGAGCAACTAGGCGAGAACCT- GGCCCCAAACTCCCTCCTT ACGCCCTGGCACAGGTTCCCGGCGACTGGTGTTCCCAAGGGAGCCCCCTGAGCCTACCGCCCTTGCAGGGGG- TCGTGCTGCGGCTTCTG GGTCATAAACGCCGAGGTCGGGGGTGGCGGAGCTGTAGAGGCTGCCCGCGCAGAAAGCTCCAGGATCCCAAT- ATGTGCTTGCGTGGAGC AGGGAGCGGAAGAGGCAGCCGGTCCTCACCCTCCTCTCCCGCCACGCACATATCCTTCTTGACTTCGAAGTG- GTTTGCAATCCGAAAGTG AGACCTTGAGTCCTCAGATGGCCGGCAACGCGCCGAGGTCACGCTCCCCAGAAACACCCCTCTCCCCTCCCC- TACCCCAGCTCCCCCTGG GGCGGGTGGTAATTGGGGGAGGAGAGGCCGCAGGCAGGGAAGGGGTGGGAAAGCCAGAGAGGGAGGCACAAA- GTGATGGCAGCCCGG CAAACACTGGGGCTTCGGGCTGGGCCGCGCTCGTTTAATCCCACAAAAATCCCATTTTGGAGGTGAGAAATA- GAGGTTAGAGGTCGGGCC CTTCTGGAGATCAGACCGAGGAGACGGGCCCAGCTGGCGTCTTAAAGCAAGGAGGGGGAGTCGGGAGGAGGT- GAGACCCCTGCACCCA GGTGGGGCTCCCAAACCGTTCTGGATTTACCACACTCCCAGGTCCGATTTTCCATGGAGGGCTGGGGTTAGG- GACTGGCACCTTCTTGTTG TTAACCGCATTTGATATTCACAAGAACCCTGTGAGGAGACTTTGTCACCGTTTTTAGATGCCTGAGGTTGCC- GGAGGGGCAGTGAGAGAAT CGTCTAACCTGGTGTTCCTACCACAGTCCAGGCCCTGTGTCCTGGGCTGGACCCACAGCCCCTGCCACCACC- CAGAGGAAGGCGCGAAG CTGGCTGCCTCCTTTACGGGTCTCCCTTAGGTGCCCTCATGAAGGGGGACGGCCACCTCACAGTGCAGGAAC- TATCTCCCCGTTTGCTCC CAAATAGTCTTCTTGGTGTGGTGCTGTCTATGGTCTGTGACCTGCATCTGGAGTTACCCCCAGGACCAGCTT- CGGAAGAGGAGGGATCGCT TGGAGGCCGTGCAGTGTGAGGAACGGCAGGCAGGGTGTGGGACCAACATGCACACACTCGCAGGTGCTGGGG- CCAGGGAGGAATGAGG CGCTGGCTCCCTTTCCCTCCATTTCTCCCTGGGGGTCCCAGCAACCTGGCCATCCCTGACTTCCAACAGCAC- AGCGTCCCCACAGGTCCT GCAGTGCTCTGCAGGGGTGCAGGGAGCTCCCCTCCCCCCAGCCGCAACCTCACCTTCCTCACCCCCACCCCT- CCGGCAGGAAACCACAG GCTGGGTTGGGGACCCCTGGTGCTCCAAGAGAGCAGTGAGTGCTGGGAGCCGCTAACCCCGAGGCGCCTAGC- ACAGACTCTTCTCACCC CTTATTTCTGAAATAAAGCCCTTCCTTAGGTCCAGATGAGGACCACGTGCTCAGTGCCTCACTTTCGTGGGA- GTGTATATCACTTTACAGTAT CAAGACAATTTTCTTTCGTTACAAATCTTTATTTAGTCTCTGCGTTTAGACCAAAGTAGATTTTTATGGGCT- GAGTGAAAAAACCTCGCCCGCA TTGGTTTCTGATGGAACAGCTGGCAGCGCCACGGCCCCGGGTGGGGTGGCCTAGAGGCAGGGGTGCTTGGGA- GGAACATCTAGCACCCG ACCACCTCCACCAGGTGGGAAAGGGACGTTTGCACCAAATCTCCGCCGGCAAAGCAGAGGCTTTGGGGAATT- ACAGAAAAACTATAATGAT CTAAAAGAGAACAAGTTATCTTGAACTGTGCGGGTATTTGAATCATACAGAAAATTGTCCTGTGTGCCCAAT- GCACTTTTGCATGTAGAGCCA GGGCCTTCGAGGAAGCTTTCAGGAGATCCCGGGCAGCGGAGTCTGGTCTGGAGTTTCATTTCCGTAGGTGCA- GATTTCTCCCCAAGTCTTC CCGCCATGGGCTTTGCAAGAAGCCAGGGCCCAGAGGCCACGCTCACCGTTAACACTGCACAGGGCAAAGGTG- GCTCCAGGACAACTGCC CAACCCCAGGAACGACCCAGCAGCAGAGAAAAGGACAGCTGCCAGGGTGCCTTTGTCGCTTTTTGGAAATCA- GAATTCCTGGGTCCTTAGT TAAGTCTTACTTCACCAAATCCCAGGACCTTCACATTTTGGTTCTTGCCATTGCTAACAGTTGTAAATGCTG- CCGCCACGAGGCCTGGGAGG AAGGACCCGCTGGTGAGAGCACAGGGAGTGCTGCTGTGATCACGGTGGTGATGCGGGGTGAGCGCGATTTCC- CGGGATTAAAAAGCCAC CGCTGCCCCCGTGGTGGAGGCTGGGGGCCCCCGAATAATGAGCTGTGATTGTATTCCCGGGATCGTGTATGT- GGAAATTAGCCACCTCCT CAGCCAGGATAAGCCCCTAATTCCTTGAGCCCAGGAGGAGAAATTAAAGGTCATCCCTTTTTAAATTGAGGA- ATAGTGGTTTTTTTTAACTTT TTTTTTTTTAGGTTTTTAGTTGCCGAATAGGGAAGGGTTTGCGAAGCCGCTGCCCTGGGCCGAGGTGCATTT- TACGCTTCCAGAGGTCGAG GCCTCCAGAGACCGCGATGCCCAGGGCGTTCCCGGGGAGGCTGAGAGACCCAGGGTGCTCTGGGTGACTGCA- CGGCGACTCCTCGGGA ACCCACTCGTGGCTGCCCGCTTGGAAGGGCTTTGCGGCCCCGGGAACGATCTCCAGGATCTCCACGGCTGGT- CAGGTTCCCCGTCCCTC GTATCCCGCGCTGCCCGGGGGCTCCTGCCTTTGGTTCAGTGCTCGCGGCACCACCGCACTCAGGACGGCAGT- GGGGGGCTGGGGCTGG GGCTGGGCCTGGCCCAGCGTGGGTTGGGGCGGGGGACGCGCCAGCAGCGCCCGCAGCTCGCTCCGCAGGGGT- CGCAGCCAGGGGTCG GGAGCTAGGCTCGTGGGCCGGGAGACGCCGGGCGCGTTGTCCTCCGGGGAGGTTGGGGTGCAGGCGGTGCAC- CGACCCTCGCCATCTG GCGCTGCAGCCACCAGCCACGGCGCTTAGTGGAGGGTCTGCGGCCAGGCTCCCGGCGGAAAGATTCCGGGGA- GGGCTCGGGGGTTGTC CCAGCCCGCGCTAAGCGCCGCAGCCTCGCCCGGCTTTCCTGCTTCCTCGGACTGTGCAGGGGAAGCCTGGGG- TCTCGCGGGGCGCAGC AGTCAGGTCGAGGGTGCAGCAGGAGGGGAGTCCTGACGGGCAGGTCCCTCTTTCCCCTGGTGCGCAACACTG- GTTGGTAGCTTTTGCGG AGGTGGTGAAGAAGGGCAGGAGGCCTGTTGAGCGGAGGAGTCCGGGGATCCCTAATTATGTGACAGGAGACC- CTTTCCAGTTCGGCCTGT GGCCCATCCCTCTCTCACCGCCGGCAGATTGGAGTCTGCTCTCGGGGAGCCCCCAGGTAAACCCCTCACAGG- GAGAAGGTTTCGGATTGG AAGGAGGACCGCGCTCGTGGGGCGCCTGTGAGAGCTGGGAAGCCCAAGGGGTAGCGTGTAGGGGGTTTTTTA- TGCGGGAGGAGCTGCC TCCTGGGCGGCGGGGACTTTCTGTCTCAGCCTGTCTGCCTTTGGGAAAACAAGGAGTTGCCGGAGAAGCAGG- GAAAGAAAGGAGGGAGG GAAGGAGGGTCCTTGGGGGAATATTTGCGGGTCAAATCGATATCCCCGTTTGGCCACGAGAATGGCGATTTC- AAAGCAGATTAGATTACTT TGTGGCATTTCAAATAAAACGGCAATTTCAGGGCCATGAGCACGTGGGCGACCCGCGGGAGCTGTGGGCCTG- GCAGGCTCGCACAGGCG CCCGGGCTGCCGGCCGCTGCGGGGATTTCTCCCCCAGCCTTTTCTTTTTAACAGAGGGCAAAGGGGCGACGG- CGAGAGCACAGATGGCG GCTGCGGAGCCGGGGAGGCGGCGGGGAGACGCGCGGGACTCGTGGGGAGGGCTGGCAGGGTGCAGGGGTTCC- GCGTGACCTGCCCG GCTCCCAGGCATCGGGCTGGGCGCTGCAGTTTACCGATTTGCTTTCGTCCCTCGTCCAGGTTTAGGAGACGC- GTGGGGACAGCCGAGCC GCGCCGGGCCCCTGGACGGCGTCGCCAAGGAGCTGGGATCGCACTTGCTGCAGGTAGAGCGGCCTCGCCGGG- GGAGGAGCGCAGCCG CCGCAGGCTCCCTTCCCACCCCGCCACCCCAGCCTCCAGGCGTCCCTTCCCCAGGAGCGCCAGGCAGATCCA- GAGGCTGCCGGGGGCT GGGGATGGGGTGGTCCCCACTGCGGAGGGATGGACGCTTAGCATGTCGGATGCGGCCTGCGGCCAACCCTAC- CCTAACCCTACGTCTGC CCCCACACCCCGCCGAAGGCCCCAGGACTCCCCAGGCCACCTGAGACCTACGCCAGGGGCGCCTCCCGAGCG- TGGTCAAGTGCTTTCCA ATCTCACTTCCCTCAGCAGGTTCCACCCAGCGCTTGCTCTGTGCCAGGCGCCAGGGCTGGAGCAGCAGAAAT- GATTGGGCTGCTCTGAGC TCTGAAGCATTCGGCCGCTGTGTGTGTGCAAGGGGCGCAAGGACGGAGAGACAGCATCAATAATACAATATT- AACAGGAGCACTTGTCCAG AGCTTACTGCAAGCCACATTCAGTTCCGGACCTTATTGACTTCCCCCTCCCATCTAGAGTGGATTCTGGTTT- TTCAATTTGTTTTGTTTTGTTT TTTGTTTGTTTGTTTGTTTTTGAGACGGAGTCTCACTCTGTGGCCCAGGCTAGAGTGCAATGGCGCGATCTC- GGCTCACTCCAACCTCCGCC TCCCGGGTTCAAGCGATTCTCCCGCTTCAGCCTCCCGAGTAGCCAGGATTGCAGGCACCCGCCATCATGCCT- GGCTAATTTTTGTAGAGAC AGGGTTTCACCCAGGCTGGTCTCGATCTCCTGACCTCCGATGATCCGCCCACCTCAGCCTTCCAAAGTGTTG- GGATTACAGGCGTGAGCCA ACGCGTCCTGCCTTGATTCTGTTTTTAACTCCATTTTTTAGAGGAGGAAATTGAGGCACAGAGAGGTTAAAT- AACATGTCTAAGGTCACACAG CAAGGGGTGGAGCGGAGTTAGCCCACTGGCCTAGCTCTAGAGCCCACCCGGATAACCAGAACTTGGTGAGGC- CTCCGGGCTCTTGCTTG GTTTGGAGCCAGGTGCTTAGCGCCCCGAGCCCGGGGCCATTCACCCTGCAGGAGCTGCACGCGCCCCTGACC- TCGGCTTTTCCCTGGCA GCAGAGGGGCTTTGCGGGTCGGCCGGGTAGCCCTGAGCACAGCTCGCCACTTCCAGGTGGGCTGTTGGCGCT- GGCTGGGGACACATCC CGATCTTTCAAATGCCCTTTACAGAGCCTCATCAACGACCCGATTCATTCCCCCCTCCTGTCATTTGTCTCT- GCCATCGAAAAATGCCTACC GAGAGCTGCTCTGCATTTCCGCCCTCTATTTTGTGTTTTACTTTAAAATAATAATAAAAAAAATGTTGGCTG- CAGGACGCCATGACTTAGGTC AGCGAGTCAGCCGCTAGCTCTGCATTTCCAAAAAGCAGATCTTTTCACAACTCTCTTGCCCCAAGTGCCCTG- GTGTGGTTTATTTTTTAAAAT GCATGCCTGCGGAAGAGAAGACCCGGGGAATATTCGAAACCCCGAGCTTTTACAACATAAAGCGCATGGTGT- GGCCGCGGCGAGTAATGG CGCT 206 HLCS CAAATCACTTGAACTCAAGTTCAAGACCAGCCTGGGCAACATGGTGAAACCACATCTCTACAAAA- GTAAAGAAAATTAGCCAGGCATGGTGC TGTGTGCCTGTAGTTCCAGCTACTCCTGGGGAGGTCGAGGCTGCAGTGAGCCGCAATCACGCCACTTGTACT- CCAGCCTGGGCGACAGAG CAAGTCCCCATCTCAAAAAAAAAAAAAAAAAAAAAAAAAAAAGGCTGGGTGTGGTGGTCCCAGATACTCAGA- GGCTGAAAAGGGAGGATTG CTTGAGCCCAGGAGTTCAAGGCTGCAGTGAGCTGCGATCACATCAATGCACTCCATCCAGCCTGAGCAATGG-

AGTGAGACCCTGACTATAT TTAAAAAAAAAAAAAATAGGAAGAAACAACTCAACCACAGGGCTAGTATGTTACTCGGTTATAAAATGATAA- AGCCCTAAACAGAGAATTAGC CCGTTTCCAGAAGAGGCCAAGAACAGATGATACAGCTGAACTGAACTCCTGCCTGTACAGCTCGTTTTCTAC- AAGATTCCAGACCTGGAAG ATGATGGCATCCAGCCCCCATTGAAGCACCTCGAACAAGAAAAACGCCGAGTCCGAAGAGCCAGGCCTTGAA- CACACGATTCCTGTCTATA AATAACTCCCCCTGGGGAATAAAAAGCAGGATCCAAGGCAGGAAACCCGAGCCGTGGAATCTGGTAAGTTCT- TAGGAAACCCACTCACGG GCCTGAGTCCCCCGTGGAAGCGGCGACTTCGGCACCTGGACACCCGAGTCCCCAGAGCCCCGGGCGGCCGCG- CGTCCCTACCTGCAGG CCTGATACCGGCCGCGGAGCGCTCCTGGCCCCGCTCCCGCCAGGCTCCGGGACCGCTGAAACGCACCCAGGG- GGGTGAAGGCGTAGTC GCCAAGGACAGCGCAGATGGCAGCGGAGGCATGGGAGCCGGAACCTACCGTGGCAAAGGGCCAGGTCGGGAC- GCCCCTCGGCGCAGC CCCAAATCCTGCCCGCGCCCCAGCCCCGCTCAGGCCGCGCCCCTGCCACCTCTGGCCACACGGGCTGAGACG- TCTGGCTCCTGCACAGC GCACTTCCCGCTGCCCTTCTCCACTGGCTGCTCAGGCCCTGCCTCGCCAGCACGGCATCCGCGGGGGATCCC- TACCTGTCCTTTAGGGCT TGCCTCATAGGTCAAACGTCACCTCCCAGGGAGGTATGGCCTGCCCCCTGGCCAGGTGGGCCCCTTCCACGC- TCGCCTGCAACACCACCC ACCCACCTTGATAACTGCTTGTAAAGGTTGTACTGCTTTCCCCCTTGAGACTGCAAACCTTCAAGGGCAGGA- AATGGGTCTGTTTTCCTGGC AAAATAATGAAGTTGGCTTAAGGTTTTGCTGAATAAAATGAGTGACAGACAAAAGTAGCCAAATTTGGCACT- CCTGATGGGTTATTTGATGAA GGAGGTGCAATGTATGGGCTTAACTAGTTATTCTGGATTTCTTTCCCCATGTTA 207 DSCR6 CAAGGCCGGTGCACGCGGACCCGAGGATTCGGTAGATGTCCCCGAAGACCCGCTGCCGCTCTAA- GGCGGTGGAAGCGAGATTCTCCGGA AACCCAGGGAATCCGATGCTCGCACAGGACCAAAGCCCGAGGCCGCGGGGACCACAGAGGGACGGAGAAGCC- GGGACTCCTCACATCC CACATCCGGCAGGGGAAGCCCAG 208 DSCR3 CTGATAATAAAGTTTTACCATTTTATAATTTAAAAATGTAAATATGGAGTTGGGCATGGTGGTT- GGGAGGCTGAGACCAGAAGATCGCTTGAG CCCAGGGGTTTGAGACCAGCCTGGGCAACATGCAGAAACCCTGTCTCTACAAATAAAAAATTAGCCAAGCGT- GGTAGCACGCACCTGTAAT CCCAGCTACTCGGGAGGCTGAGGCAGGAGAATCGCTTGAGCCTGGGAGGTGGAGGCTGCAGTGAGCTGAGAC- TGTACCACTGCACTCCA GCCTGGGTGACAGAGTGAGGCTCTGTCTCAAAAAAACAAAACACAAAAAAACAAACAAAAAAAAGCAAATAT- ATGTAAAAATAGGAAGTGCG GTTTCCCAAAATGAGGTCTGTAAACAACTGATCTAGAAAATGTTCTGGAAAAAGTAAAAAAGGATCAGGATC- TGAGGTCAACTGACCTCTCC CTGCGCTCTGGACAGGCAAACAGGCAAGGTTCCCTCTGAGGCCGTAGCGGCTTCTCGTGGGCGAGTCCCTGT- TCGCAGGTGACGTGTGG ACCACGCTCTTCCGAAGCGTCTGGCCTGTGTGCTCTCGGGGAGGGGACGCAGGTCAGCCCACCTAGCCGATG- GCTAACAAGTCAGTTTGT TTTCTGAACGGAAGCTTAAACCTAGAAAAGTAACTGGGTTGGGGTGGGGGTGTAGCCACATGCAGTAAAAGC- ACTGCCTGTCTGTATAACA ACGACCTGATGAAAAAAGGAACGCGTGAAATGGGGAGTGTTAGGGCGTCACAAACTCCAGTGTGGTTGAAAT- GAAAGCAGAAAGCAAATG GCAAGCTGGCTTCCCCTTCCAGCTTTTCACAACCCTGCCTTGCTCATGGTCAGCCCCAAGCACGGGCGGAAG- AAAGGACTGGAGGGGAGG GAAAGGGGTGGGGAGCGAGGGTACCAGAGGCGTGGGAGGACGGGGACAAAGGGGCAGCAAGGGACCGGCGGA- AAGGAAAGTCGGCGT TAGCTGGATTGGAAACAGTCCAGACAGAACGATGGGCTCTGCTGCCTCCGGGTGGGGCACCAAGCGGGGAGC- GGGGCCACGAGGCAGG GGACAGTGAAGCACCATGCAGCGCCCACCAGCCGGCAGCGCCCACCAGCCTGCGCTGCGCTGCACATGGTAC- CCGCGGCCCCAGCTGG CCAGTGTGTGGCGGAGATGAGACCCTCGTGAAGAGACTAAGCGGCCACAGCAGGGGGAAGGGTTGCTCACAT- AACCCCATACTGCTCACA CTACGAGGTTAACTGCCGTGAGATCTGCCTGCAGCCAGCAGAAACCCGTTCTAGGAAAACGTTGCCCAGTGA- CTTCAGTGAGTGCCACTGA CCCGGGCGCCTCCGCCCCGGCGTCCGGCAGCAGCACCGATTGCGCAGGAGGCACCTTGCAAACAACCTTTCC- TGATCCGCGCTGCAGTT CCCAGGCCGGTTGCAGCCGTTTCACAGAGACTGCGCACACAAAGCGTCTCCGTGCCCTGCCATTCACCTTTC- GACACAGCCGCAACCCCTCTT TTCAGTGTTAAAACCTGGCGCCAAAAGGAACATGCGATGTGACGTGTTACCTCTGCGCATGCGCCGGGCATT- CCCAGCGCCCCGAACCTGATG AACGCGCGGTGGGGACCCCAGGCTTCCGTGCTTTCGTTTTCCTGGAAGCTACGTGTCCTCAGTCTACATATT- GTTACCTGGAAAATAAAGTTT TCTCCTTTTTTCTTCCTTTGTTAACAGGCAGAAGGTGTAGGCTGCAGGTTTCGGGCCTAAGAGAGGGCATGG- CTGGCGACACGGAGTAGACTCC TAGATGACATAACGGAGGCGAGTCTGCACCGGGGACTCGGCATTAGGAGGAGGCAGAGGAAAAGCCCACCAC- CGTGGCCGAGGGAGATCTA GCAAGCAGCTTGCAGGGGGTGAAGTGTGTGCAAAGCAGGCTGAGACCTGTCCAGTATCGAAACACGCCGCGG- TGGTCAAGCAGGCTTTACCATGCT 209 chr21: 37841100-37841800 TGAGGCTCAAAACAGGTGTCTGTGAGCTTCACAGGCGGTAAGGCCGTGTCTACATGGCCGGGACATGCATCCC- GGGGCTGCCCCTGCCG TGCTGCCCGAGTGCACGGGGGATGAGGACCTGACAAGGCCATTGATCTTGCGGGAGCTTCCTGAACTACTCC- AGCGTGAAAATCTTCCAG AAGGATTCTCCACAGGGCAATGAGGCAAGAAATTTACAGCTTAGCCTGATTAATGGGCCAGGCAGTTAAGAG- TTCTTTGCCAAGCTATGAG CATAATTTATAGTCATCACGGCAGGAGGAAAGGCCACATAACTCACATCCTTAAAGGGCCCTTAGAACAAGA- GACACGCCGGATCATTGAAA ACGTCTCCACTCCTGGCGCCAAAAGAGATCGGCACGTTTCTGGGTATTCTGGTCAAAGAACAGGGAGTCTGG- ATTAATATACACGGCAGAA AAAAGCGAAGAAAAGACACACAGGTCATATATTTCTGACTGATATTCCGTTTGTTGTTTTCGGAGGGACTTG- GTATTTATTTAACCACATTCT CACTTGACACGCCCCCTCCCCACACCTTGTAAATGCCTTCCTCTTTAGCCGAGTCATTTTTCATCACATAGA- ATTGAAATGTTGCCAGGAAG GCGGTTTATGAGATTGTAGAAATGGCACTAGAGAAAGCAGTGTGAAAAGAGGCCTAGAACGT 210 ERG TCTCTACATGCTATCTACTAAAAACTTAGGCAAGGAAATGCATCAGACCAAACACCCCACAGCACA- GAGAACCGACCGGCCATTGCTTTCCA ATCTCCGCAAACCTAACCATTGCTGGAAGAAATCTTACTCACAGTGCACAGACAGTAGGTATTTTATTGAAG- ATAAACATATAGTGGAACAAA CCAAATTACCCCCATTTGAGTTACGTGAGCACTCAGTTCTCAGCGTGGATGTCCCACAAATCAAGTCAACAT- TTGCGTCCCATTACCAGCAG CCACTTGCCGAGTATCTCTTCGCTTCCACTGGGACTGCCTGGCATCCCTGATGCTAAGGAGCCACTGAAGAG- CCTCCAAATGTCTGACATT CACAAACGCATCTTTTGCTTTGACCCGACCCTTCAACCTCTCCGAGTCTGCTGCCTTTTCTCAGACACACAT- CCAGGCACCGTTAGGGATAG TTAGAGAATCTGAAAATTCAGAAGCGCTCCGAAAAGCCTTTCCAAAAGTAATCCACAGCACTCAACAGTGAA- TTTAGAAACCCCAATTTTTTT CTGAGTTTGAAGTTTTTAAGCCTTGCGGATGGTTGGAGTAGGAAAAA 211 chr21: 39278700-39279800 TCAGACAAGCTCTGTGCAGTCGGAATTTTTTAAAGATGCACTGTCACTTGAGGAAGACAGGTGATCTTCCTGC- GGCACAAATAGAAGCAAAG AGATTTCTCTTCTTCTCTGTAGAGCAACACAATTGATAAATGGCCGATAATCTCCACCAAATTGGCAGCAGT- AGGCTGCCCGAAGGCAGCAG GCATATTCGTCTTTGTGAATTGTTTTACTATGATGCTGTCACATTTCCAGGAATAAGACGGTTAAAATGATA- TATTGTTGTGGTTTGGCATTTG CAGCTTTGCTCTGACTTCCCTGGTAACTGCCAACATCTGCAAATTATTATGTGCTTAAAAAAAAAATCAACC- GCCACCGCAGGCTGCCCCCA CGGTCCCTGGCTGGGCCAGGCCTCCTGCCAGGCCACAGGGCAGAGTTCTTGGACCAGGAGGCAGCAGGGTCA- AAACCCAGGTTGCCTAG GAAGCCCCCAAAGACAGTTATGGATAGAGCTGGGAGCCCGAAACACATGCGGCAGTCTCTCAGTTTCCAGGT- ACCGGTTCTCACATCATCC ATGCATGTGTTTGAGGAAAAACAAAAAAAAATTGATGGTTGCCAAAAACAAAAATGCTTCCATATCAAAGTT- TATCAGTGTCAATGTCAAGAG ACTTCTGGTTCGTAGACTCATTTTGGCTTGAGGCCACCAGAAGTGAACTCTGGTTTCTAAATGCAGAAGCAG- AGGCACTGGCCGATCATGG AAGATGCAGGGAACTGTTCAAGAGGCCCAAGCCTGGTGCTCAGAAACTTGGCAGGATCAAGCATCTCGCCCA- GGAATTCATCCCCTGCTTG TCTAAGCCGGCTGGCTCTCGTGACTGACTCGGAACAACAGAGCAGATGTTTGCGTGGGAGGCAAGCCTCACC- CAACATCTGTCCTGCGGC GGGAAGGCCTGGGTGTTCACAGATAGAGCTGGAGTTCCCCGGTGGGTGGCACAGACAATTAGCTGGGGCTGC- CTCACATGTAATCTAATT ACAGGGGAAACAGGCTCAAACACCGGGTGATAAGCAGCGCAACTGTTTCGGGTGACTCTGTAATTTTTCCTC- CATTAATTTTCTCCATAACGCAC 212 C21orf129 GTTGCCTGGGATATGCTTATATCAAAAACTTACGTGTCACTTACCTAGCATTTGCATTTCACTGGGCCTCCTA- AATTCTGTGTGGTAACCGAC TGCCACCGGACATGCTGTTTACTTCTCTATCCTCACGCAGCCAGTTGCCACATTCAACATAACACTGCAAAT- ATTGCCGGTGGATCCTGACT TCCTCGTGGACCCTACTGTGTCGGGAAAAACAAACAAACGAACCCTGGAAGGAAACACCATGAGT 213 C2CD2 TCATAAATATTTCCAAATGTATTCCTATTTGTCTCTACAGAGTCTAACAGACATAAATAGCGAA- TTGAAGGTTCTGTCTTAAAACCCAGCAGAA AGAAAAACAATGACCAGAAAAAAAAAACAATTGTCTTTGGCTTCCCAAGAACAGCATCGGATTTCAACTGGA- ACCACAGATGGTCCGTTGAT AGAAGCGACTACTTTTTAGCTCTGGAGGACGACAAAAGGAACCAGCTTCTTCCTGTGGGTGTCACAGCGAGG- TCGCCTGGCCACATCAGGT ACCAGAGCGAGCGCCCTCACCTGATAGGCCCTGTACAACCTCAGCCACAGCACTGTCAGGAGGAACACGCGG- AACTAGCAACCTAGGAG GGTAAAGGCGGAGTTGGGAGGGAACACGAGGCAGGCAGGTCGGCTGGCTGCTGAGCTACAGGCTGCACTCCT- AGGACGTCTACGTGTAA TTGAGAAAAATAAGACAAAAATAACTTACTGTGCAGGCAATTAATTCTGGTTGGCATAGCGATCCTCTTAAG- TTAAAGGGAATGAGCATGAGA TGAAGAGAAGTAAGAGGCAGAAAGAATTATGCAAGAGCAACATCAGAGTGGA 214 UMODL1 ACGCCGAGCCGCCTCTGCAGGGGAAACCGAAGCAGATGTGGTGAGATAATACATCCAACCCTG- AGTGCTACTCTAACCTGCCAGAGGCGG AGGGTTCTCAGTGAGATGAAAGCATTACAGATGCGTTAGATCTAAGGGAGGGGCCTGCAGATGCGCAGCTGG- CAGAGAAACCAGGGAGG GGCTGAACTGTCAGTCGCGACCACCAGGGATCTGAATCAGTTCACCGACAGCCTTGGGGACATTCACCTTGG- GCTCCACAACCTGTCAGA AATGCCCCCAAGCCCAAAGGCGTCGAGAGAATGGCCAGGTTGTTTCAGATTGACACATATCCTAATGTACAA- GTCAGCCCACACACCCCAC GTGCACTGAGCGTCTCTTGTTGTTCACCCCAAATAAACTCTGCCGGAACTGGGGCGGGACTCGCAGGGGCGG- AGAAGGGGGGAGACGGG CAGAGGGCAGAAGTGGATGGTGAGAAGAGCCAATGGAGGGGCCCCGTGAGAGTGAGCAAGGCTGCACCCCTA- ACCGACGTCCTGGGGC TACTGTACAAACAAAGAACCACAGGCTGGGAGGCTGAACAACAGACCTGCACTCTCTCGCAGCTCGGAGGCT- GCAGGTCTGAAATCGAGG GGCTGACAGCGCTGGTTTCCTCTGGAGGCTGCGAGGGAGAAACCGTCCCCTGCCTCTCCCAGGCTCTGGGGT- GAGCCCTTCCTGGCATC CCGGGCTCATTGTAGATGGATCACTCCAATCTCCATGGCTTCTCAGGGCTTCCCTCCATGCACCTCAAATCT- CTCTCTCCTTCCTTTTGTAA GGATGCCAGTCATTGGATTTAGGTTCACCTTAAATCCAGGATGATCTCATCTAAATTACATCTGCAAAAAGA- CCCTTTTTCCAAGTAAGTTGA CATTCACAGGTACCTGGGGTTAGGATTGGACATATCTTTTGCAGGGGTGCAGGGGGCTGCCACTGAGCCCGC- TGCACAGGGTGACCTGGG CCAAGGGCCCTTCACTTTCACTTCCTCATTGGCAAGCTGCCCTGTGTTTGGACTGGGTCGAGGCTGTCAACC- TTGCTGCCCCTCGGAGTCC CCCCTGGTGTCCCCCAAACAGATTCTAAGCTGCTTTCCTGGGGCTGGAGGCCAGGCATTGGGATTTTTTAAA- GAGCTTCCCAGCAGGTGAG CAGCCTTTCATGGGTATCAGGAGACCTTCCTGGCAAATGTGGTGAAGGTCCTTCCTCCTGAGCGATGCCTTA- GACCCAGGAGCCCAGGGA GGCTGCTCACCTGATCGTTAGGACAGGAGCAGTGGAAACCTCTGGCCTCAGACCCCCTGGAGGAATCCCTCC- CTCTAAGACTCTGGGACT GGTGCACGCAAGGAGCTATCGTGAACATTGCTCCCAACTGGCCGCTTGCTTGTCCCCCGGCTCCCCTTGGCC- CCAGTGGCGGCTTTGCCT GAATTAGAGGGCGTGAGAGCCACCTGTGTCTCAGCACTGCAATTAAAGCAGGAAGCCCTTTCGGAAGCAGCC- GTGTGCACCAGCCTCCCA TGGGTGGAGCAGAGCAAACCACCCACTTCTGCCCTCTGCCCTTCTTCCCTTTTCTCGACACCCTGCGGCCCC- CCAGTTTCAGCAGAGTTTA TTTGGGGTGAAAAACAAGAGATGCTCAGCGCCTGTGGGATGTGTGGGCTGACTCGTACATTAGGATGTGTGT- CAATCTGAAATAACCTGGC CGTTATATGGATGCCTTGGGGCTTGGGGGGTTTCTGGCAGTCTGTCGAGCCCGAGGTGAATGTCCCCAAGGC- TGCTGGTGAATCAGATCC CTGGCGTTCTCCGTTGGCAGTTCAGCCCAACAGTTTCTCTGCCGGCCGTGCCTCTGCAGGTCCCTCCTCTGA- TCTGATTGGATTAATATTTG AATCAATAGACTGAGTCAAGCAGAATGTGGGTGGGCCTCATGCAATCAGCTGAAGCCCTGAAAAGAGCAAAA- GGGCTGCCCCTTCCCCCG AGGAGGAGAGAAC 215 UMODL1/ CACATTTCAGAGCTGAGGTGCTGGTGCGGGCAGGTCTCCTGAGCTGGGGGGTCAGCTGTGTGGCCAGTGATGG- TGACGCCTCAGGCCGT C21orf128 GCATGGCCGGGGAGGCGGCCCTGCCTCTGCACTCTTTTGACTCCATGACTACTGGTGTCTTCG- GACGCCAGAGTCGGGGGAGCAACCAT GGGGCACCGCCCCTGCCTGGGGAGGCAGCACGAGGCCTGAGCCCAGCTTACAGGGGGACATCCACCCCCGCT- GAGAGCCCCACCTTCA CGGCGAGGATCTGTAGAAGAAGACATTTGATATTACTCGGCAAAAAAAACAAGAAACGAAAACACAAAAAGA- GCTCCTCTGAAGAAGAAAAG GTATTTGCGCTGTGGTCCACCTAGAAATAATGTTGTTGGCACAACTAGAGCATTCCTCAGTCATTCAGGAGC- ACTCCCTGCCGGTGCGTCC ACATGTCCCAACCCCGATAGATGAGGCGCTGTTCGCCCGTGGAGGGGTCAGGTTGTCGTGACCTTATCTTTA- CCCTTAGGCCGTCCATCCC GGGGCCTGGGGTTTCCTGCGCCAGTCACGGTGGGCTGTGTAGGTGGCCATGTGTTCGGTCTTTCCCCAGGAG- GTACGTACCATGTGCTG GGAGGCCTGGAGGCTGAGCCGCCCCCCGCGCCTATGAGTTGCACCCTCACAGCGGCGGCCAAACCTCCTGC 216 ABCG1 CAGGCTTGAGCGGTGACTGGGAGACCCCGGGAATGGAAATGGCGCTCAAATGCTGGTGTGGTGT- CCGCAGGGGAACGGCCCGCGGGTG TGTGGAGTCTGCGCCCCTGTGGCTTCAGCTGCGTCGGGGGACTGCGGGAATCTTCCAGACTCCAGTTTAAAT- CAGAGAGGTGTGTCCACG AAAAGAGTCAAACTAAAACATT 217 chr21: 42598300-42599600 AACGAGACAGTGCAAAAAGCCGCTGCCTGGTGACCTGGCATGCAGACTCGGCCCTCCCACTTGCACGGTGATC- CACTGAAGACAACAGCT GCCTCTGTACTCACGCTCCCCCACACTCCCCTCCTTCCTGCCCTGGTTTCTCCATCCCTAGATGCCATCCCA- TGCCCCAAACCATCCGCCA AGCACAATAACCTCGCCCCCACCCACCCCATGAGGTCACTCGAGTTGACAACCAGATAACAGTTTTTGTTTT- GTTTTGTTTTGTTTTGTTTTG TTTGTTTTTGAGACGGGGTCTCGCTCTGTTGCCCAGGCTGGAGTGCAATGACGTTATCTCGGCTCACCACAA- CCTCCGCCTCCCGGGTTCA AGAGATTCTTCTGCCTCAGCTGCCTGAGTAGCTGGGACTACAGGCGCGTGCCACCATTCTCAGCTAACTTTT- GTATTTTTAGTAGAGACAGG GTTTCATTATATTGGCCAGGCTGGTCTCGAACTCCTGACCTCTTGATCCGCCCACCTCAGCCTCTCAAAGTG- CAGGGATTACAGGCGTGAG CCACCGCGCCCAATAGCAATTTGATGACCCATCCCCTCCACTGCTGGGAAAAGGCTGGGCACCGCCCACACT- CCATGCAGCTCTCTTTCCC TGGCTCGGAATCGCTGCAGGCGCCACAGACCAGACGCGCACTGTTCCCCACTCCTGCTTATCGGCCGCGCGG- CATCCCCTTGTCGCAGC ACTCCAGCATCCATGCAGCCGCGCGGCACCCCGTCTTCGGAGCACTCCAGAATCCATGCAGAGCGCAGCACC- CCACATCCAGAGCGCTC CAGAATCCATGAAGCACGCGGCACCCCCTCGTCAGAGTGCTCCAGAATCCATGAAGTGCGCAGCACCCCTTA- ATCGGAGCGCTCTAGAAC CCGTGCAGCGAGCAGCACCCCACACCCGGAGCGCTCCAGAATCCATGAAGCCAGCAGCACCCCACACCCGGA- GTGCTCCAGAATCCACG CAGCACGTGGCATCTCCTCGTCATAGCGTTCTAGAATCCATGCAGCGAGCAGTACCCCACACCGGGAGCGCT- CCAGAATCCACGCAGCGT CTGGCACATCTTTATCAGAGCGCTCCAGAGTCCATGCAGCCACAGTCCTCCAACGGACCCTGAGATTGTTTC-

TGCAAAAGGCCATGCCTTC ATAAATCTGAAAATTTGGAAAACATCCTTCTACTTATATCCTTACAACCCACCATTCAAGCTGTAGAAGCCT- TTCTGGAACCCCAAGCAGAAG GATATCCAAAATGTAAAAACGGTGGGGCCT 218 chr21: 42910000-42911000 ATAGTGCGACTGTTCCGAAGTCTTTATCACAGTTACTGGTGATGCTTTTTTCCAGATGTCCTCGACGTGCACC- CATGAAGGGCTCCACCTGA GAGTGCCAGGGTCCTCCGTGGGATGGGGCTGGAGGGGGTGCTCTTGCCGTCCTGGGCTCCCAAGCAGCCATA- GGAACAATAGGGTGATG GGGTCCCAGAGATAGAGGCCAGTGACAGCAGCGCTTTGAACCCCTCACACGGGCACGGGCCCTCTGGCAGGG- ATGGGCGTCCCGGTCAC ACGGAGATGGGGGCTGCTGCTGCCTGCAGGTAGAGGAAGGGACGTGTTTGGCAGTCCTGTGACCCCTGGGCA- CCTCGCCTCCCCCACGG CCGGCTCTGCTTGTAAACAGACAAGTGCACAAGCGCAGCCCGGTGAAGGCACAGCGGTCCCAGGAGGCATCT- GGGCTGCACCCCAGCGA GCCGCCCATACACGTGGAGATGCCGGCCAAGGCCCTGCAGCACACGGCAGAGGAAGGCGCGATGGGAGCCAT- GCTGGGCCCGGAAGGT GCCGCCGCCCGGAGCTGTAGCCATCACTCCAGCTCTTCTTTTAAGTGTTCCCAGAAATTGTGACCCACCAAA- ATCTGAGAGCACCCGACAG TAAGCCAGAGGACCTTGATGTGAGATCCCAGCACGGTGTGGGGGCGGACTGTGGTGGGTGCTGTCTCGGCCC- CCACCCCTTCCACAGGT CGGTGTGCACATCCCACGGCGCCTGCTAAGCTGCAGTCTTCTCCAAAGGGGTCACTCTCCGTGGGAAGGGAG- CCACCCGCCCCCGGGTG ATGTCCCCAGTCAGTGACTGACGACAGTCCCCAGCCGAGGTGAGGGACCAGCTCCTGCATCCCTCACTCCGG- GGCTTGCCTGTGGGCCA GGGTGGGGGCGAGCCTCAGCAGAGACCGCGTCCCCCTTGCCTGTCCTGCCCTGCCTCCCCTGCCTCCCCCGC- GCCTCTGCTGAGCACGC CCAGAGGGAGCTGCTTG 219 PDE9A CACTTGAAAAGCACAACTCATGGTGCCAAAGCTCTGACACGGACTCCACTGGAGCTGTGGGCAG- GGGGTGCCAAGGTACCGAGTTCCAAG CCGTTGTTATTTGAGAGCGTGCCCCCCGCCATGAGAGCAGGTGGGGGGACATAAAGTGACACAGGATGGACT- GGCCAAAGGCTGAGGAC GATCACTTACCTCACAGGATGATGCCACCCCCACGGACAGGCAAGGAGCTCTCACCTTCCCCAGGACCCCAG- CTGCCACCAGAGCTCCAG ATGGCCCTGGGGGTGTCTGTAAAGCCTGTGACCGTCCACCAGGTGGAGACCAGGCTGGCCAGGGGAGGGAGA- GGAAGTGACCACTGGC CCTGGCACTGGCTGGCCGGCTCCAGCAGGCCCGAAGGGGAGGGAGGAGCCTGGGTGCACCAGACTCTCTCAA- TAAGCAGCACCCAGACA CTTAACAGATGGAAAGCGGTGGCTTGGAACTCACTTCCAACGAAACAATAGCAC 220 PDE9A AGCACCTCCTACCCCACCCTCCCCATTCCTGCCATCCCCAGGGTCCAGGGAGCCCAGATTCCAG- GGAAGGGTTGCATTAGCTCCCACTCG GAGTCCTGATGCAGCAGAGACAGACAGAGGCCCTGGGAGAAGTGAGCATGAATTATTAAGACAAGACAAGGG- TGAGGCCCCAGAGAGGG GGTGGCGGAAGGGTCATGTTCATGCAGCGAGAGTTGCTTCGAGCTTGAACCGCGTATCCAGGAGTCAAGCAG- ATTGCAACTGGCGAGAGG CCTTCAGAAATGCCCCGTGAGAGTCCTGTGTGCAGAGCTCCATCTCAGCACACTTCCTGTTCTTTTGGTTCG- TCGATTTTTGCATTTTCAGTC CCCTGTGATCCATTATTTATAACAGTGGAGATTGGCCTCAGACACTAGCAGTGAGGAAAACAAAAGCGAAGC- TACGCAGAAAAATGACAAGA GTGATGAGCACAGCAGTCATGACAAATGAGCCCTGTGCGGAGGCCCGGGATCCGCGCAGATGCCGGCGCGGG- GGAAATGGGCCCTGAA ATCCCACCGTCAGGCCAGGCAGCTCTGAGCGTGACCTGGAGGGCTGTTCAGACGGTCTGGGTAGCCGTGTCC- TGCGCATGAACATCCTCC GTCGGGAGAGGAATTCCCCACGGATTATCAGAGCTGCTCCCTCCACCCCCCGCCACGTCCCACGCGGGCCAC- ATCAACTCCCTCTGCAGC CTCTGGCCAGCGGCTGAGCCCTCCGTGTCTCCCCTCGTTAATGCCTCCTTCACCATCCCCTCCTGAAGTTTC- CCCCATTGCATACACGCGC TGAGGCCCACCCGGTATCAAGGACTCCCATTGCTTGCGAAAAAGATTCCACCCCTCTTAGAACAGAGACCAG- GGCCGCTGTAGCAAATGG CCATAAATGCCACAGCTTAAAACAACAGAAACGGATTATCTCGCAGCTCTGGAGGATGGAGTCCAAAATCTG- AATCGCTGGGCTGAAATCC AGGTGTGGGCAGGGCCGCGCTCCCTCTAGAGGCTCCCCCGGAGATTCCCTTCCTTGCCTCTTCCAGCTGCTG- GTGGCTGCCAGCAGTTTG GGAATTGCGGCCGCATCACACCACCTTTCTGTTTGTTGTTGACATCCCCGCCTCCCCTGCCTGCGGGGTCTT- AGATGTCTCTCTCCTTCCC ACTGAGTTTCACTCCACATTTGAATTGGATTAACTCATGCCATGTTAGGCAAACGTGCCCCTCAAATCCTTC- CACTTAACAGACATTTATTGA AGGTTCCTGTGTGCGGGGCCCAAGAGAAGGGA 221 PDE9A GAATGTTCAAAGAAAGAGCCCTCCTTGCCTTCCTCTTCTTCCACCCCTGCCCTCTGCAGACTGG- GGTTCTGTAGACCCCCAAAGTAAGTCC GCCACACCGGAAGGAAGTGAGTTACACAGGGGCCCACATGGGAACCGCTTTTTGTCCTGTCTTGGTGGGAAA- ATGGCCACGACCCCAGCC CAGGCTCTGCCACGCCACA 222 PDE9A CCATCTTCCTAGGCCTGCGTTTCCCCCACACCGGGGACTTGTGCTGGAAAGAAAAGCTGCGTTG- GCAGCCAGGAGCCGGGGAAACTGTCC AGGGAGGCATCCTCTGCGATGAAGGCGGGGCCTCGGCGTGGCCCGTTCCGCGCTCTGTCCAGCCCTGGAGAA- GCCCCACCCTCACCGA GCTCGAAATACCCCCTCCCTGAGAGCCGAGACTCATGGCCGGGACCCCTTGGACAGAAGATGCGGATGCTAA- CCCGGCGCTTCCACCACA GCCCCGGCGGCACTGGGGAGCGAGCGCGGCCATCCCGCGCGTAGGTGGTGTTTCTCTGCAGGCGCCAGTTTC- ACCGCGGGCGCCCAGG ATCCTCAACGGTTCTGTTGTGATGTGATTCCCCTCTTCGACTTCGTCATTCAGCCTCAGTCCCTCAGTCCCC- AAATACCGAAAGGCAGTCTT TTTTTTTTTTTTTTGAGACGGAGTTTCACTCTTGTTGCCCAGGCTGGAGTGCAATGGTGCGATCTCGGTTCA- CTGCAACCTCCGTCTCCCTG GCTCAAGCGATTCTCCCGGCTCAGCCTCCCGAGTAGCTGGGATTACAGGCACCTGCCACCACGCCCGGCTAA- TTTTTTGTATTTTTAGTAG AGACGGGGTTTCACCATGTTGGCCAGGATGGTCTGGAACTCCTGATCTCAGGTGATCCACCCGCCTCTGCCT- CCCAAAGTGCTGGGATTAC AGGCGTGAGCCACCGCGCCCGGCCTTTTTTTCTTTTTTCTTTTGAAGTTAATGAACTTGAATTTTATTTTAT- TTACAGAATAGCCCCCATGAGA TACTTGAAGACCCGGTGCCAAGCGACAGTGTTGACCCCAGGTGGTCAGTCCTGCCTGGCCCCTTCCGAGGGA- TGCGCCTTCACCATAACC ATGTCACGGACAGGCGTGTGGGCAAGGGGGCATCGCTGTATTTTTCACAACTCTTTCCACTGAACACGACAA- TGACATTTTTCACCACCCGT ATGCATCAACCAAATGAAAAGATGAGCCTGTGACATTCCCGTGCGTAGAGTTACAGCTTTTCTTTTCAAAAC- GAACCTTCAGTTTGGAGCCG AAGCGGAAGCACGTGGCGTCTGACGTCTCCAGGGAGACCCGCCGCCCTCGCTGCCGCCTCACCGCGCTTCTG- TTTTGCAGGTAATCTTCA GCAAGTACTGCAACTCCAGCGACATCATGGACCTGTTCTGCATCGCCACCGGCCTGCCTCGGTGAGTGCGCG- CTGCGGGCTCTGCCCGG TGACGCCACGCGGCCTCCTCGCCTTTTCGGGATGGCTGGGAGGGGCGGGAAGAGGCGCTGAAGGGCCCGAGG- CACCGGCCTTCTACAA GGGGCTCTTCGAAATCAATCAATGCGCAGAATCCCGAGGGAGGCTCAGCCGCCCTCCGGGCCTCTCTGCCTC- CACAGGTGATGGCTGTGT CCACAAGGAGGAAACCGTCGGGCTGAATTAAACAGAACCGCCCTCCTAAGAGTGTGGGTTTTTCTGCCGGGC- GTGGTGTCTCACACCTGT AATCCCAACACTTTGAGAGGCCGAGGTGGGCAGATCACCTGAGGTCAGGAGTTCGAGACCAGC 223 PDE9A AGGCAGCAGGGTTAGGACTTCAACATACAACTTTTGGGGGGAGATGTACTTCAGCCCATAACAC- ACCACGTGGGAGGATAACACCGATTTC AGAGCTTGCAGAGGAAGCCGCCAGGAACTCCAGTGAGACATCAGCCCCCAGGTGCCTGTCAGGCACGCCGGG- CTGTGGGGGGCACCTG GGCCCATCTGAGTAACGGAGGCGCATCCGCACTTCCCCCAGGAGTACATTTTTAGAACCCACAGCGCCATAA- ACCAAAGACAAGGAGACTT CCTGGTGCCCCGTCAGCTTCTGGAGGCGACGTTCTCGGCTGACAGCTCTGGCAGCCTCCCCTGTAGGTGAGA- GACAGGTAAATGGGACTC TTGCTTCCAAAACGGAACAGGGTAAAAATTCTCAAGCGTT 224 chr21: 43130800-43131500 TGCTGCACCCCCGCTGCCCTCCCTCCCGCTGGCCGGCAGCACCTTCTCCACCCGGGCCCCTCTGCTCACAGCG- CTCCCCGCCCCCGTCT CCCCGAGGGGCGGGGAGCCAGGACATGGCCCTGAAAGCCTAGCCCTGGCCTTGACCTCCCCAGAGCGCCCTC- CCCACCCTCCGCCCTCT GCCAACCCTGGCCCCTGCCCTGGCCCCGTCCTTGTCCTCTGCTGCTGGCCTTGGGGTCGCGCCCCGCAGACT- GGGCTGTGCGTGGGGGT CCTGGCGGCCTGTGCCGTCCCACGCCTACGGGGATGGGCGAGGTCCTTCTTGGGGCTTCTCTTACCCACTCT- CCAGTCACCTGAGGGCG CTGCTTCCCTGCGGCCACCCCAGGTTTCTGTGCAGCCGAAGCCTCTGCCTCTGCGGCCGGGTGATCCCAAGA- CCCCGGGGTCCAGGGAG GCACGGGATCTGCTCCCCCGGTCCCAAATGCACCGGCTGCGCCTTAGGAGGGACGGCCTCCACCCATGGCGC- TGGCGCCCAGGGGCCG CTCCTCGGACTACAGCACTTGCTCGTCGCCCTGCGCCCTGTTTAGTTCTCATCACCAGCAGCCTGGACTAGG- GCCCTGGTCCTTCTGGCCT CCTTCCACAGCCCGCTGCACATCTCACCCACTTCCCCGAGGTGCTGTCATTGTTTAGCTGGGCCCCTCAGCC- TCCG 225 U2AF1 TTAAAGGGGAGTGGTTGTATGAAGAGTTCCTCAGTCAAAGGTGTGCAGCTGGGAAGCCCACCCC- ACCTAAGAGGGAGGTCTGACAAACTG TCCACACTGAACCACTCAGACCTGCATCAGGGCCCCGTTTCTTCCATAAGCCGCCAAGTACAGCCCTGAGTC- AACTGAACTCAGGCCTGGG AGGCTTCCCAAAGCTGACTTGACTCAGCTTTGAACTGAAATGACCGTACCATGACAACCCTGATGAAAAGCT- AAACTGAGCCCAATTATTCA ACAGTAAAATTCAGTTGGTCTCACTCA 226 U2AF1 TGCTACCAGCTGCTTGGGCTTGGGCAAGTCACCCTAGCTCTCAGATGTCATCTGTAAATGATGA- CAATGCCAATGTGGCACTGTTCTGAGA GTCAGACAGAACGTATGTGTGCTTCACATATGGTGCTCATGAAGTGCTATCATTATCTAAGGAAAACAGAAA- ACGAAGTTCAGAGTCTCTCT AAACGCATGACACCAGACCAACAGGGAGTTTCAAAAAATAGGTCTGAAGTAAATCAATTCTCCTGGTCTCAA- TACACTGAAAACAAACTATTA GGGGACTGACCGAACCCACCTTAGGAACCACCTTACGTCACCTTCTGTCTCTACTGCAAAACCCTCCCTTAA- TACTGTTCAAATACGCTGAC AATCCAGATCCATATCCAATGGAACCAGCAATCATGCCTGTGTGCCAGCAATGTCAGGGAGGGAAGCCGATC- TCTGATGAAT 227 chr21: 43446600-43447600 CAGGTGCCGGCCACCACACCCGGCTAATTTTTGTGTTTTTAGTGGAGACAGGGTTTCGCCATGTTGGCCGGGC- TGGTCTCAAACTCCTGAC CTCATGTGATCCACCCGCCTCGGCCTTCCAAAGTGCTGGGATTACAAGTGTAAGCCACTGCGCCCGGCCAAG- AGTGAAGTTCTGATAGCTG GGGTAAGAAAGGCCGTGGGAACAGCCGGTTTCAGACACGCTGGGTCTAAGACGCTGCGTCTGGCGCTGCTCG- GCATCCAATGGGAGCCG TGGAGAAGCCAGGCGAGTGCGTAGGGCGGAGCCAGCGCACAGGAAATAGGACGTGATGAGGTCAACCGGCTG- GTCCAAGTGTGGACGG AAGTAGAGGATGCAAGCACCGAGCCCCGGGGCCCCCAGCATTGGCGGGGAGGAGCTCGCGGTGCGGGAGAAG- CAGGGGACCGCGCAT CCTGGAGACCAGGTGGAGCCAGTGCGCCCGGAAGGGGCGTGGCCCGCTGACAGCCGCCCAGGAGGCCGGGGG- AGGCCTGGAGCCGAG GGCCGCGCGTGGCAATGTGGAGAGACATTTTGGTGGAGTCATGGGGCCACAGCCTGATTGGTGAGAACAGGA- AGGGAAATTGCAGATGG GCCTGGGCCCCCTGGCTCCCGCATACTCCAGGACCAGGGCTGAGTCATCGTTCACCGTGTGTGACCAGGGCC- CCGTGTGGCCGGCTGTC ACTCGGTATCCAGTTACCCTGGGCAGACCACTGGCGGCACCCCCCAGCCAGAGGCCGCAGCAACACACACGC- CTGCAGGCGACCAGGCC GGACTGCATGCCCCGTGGGGGAACTGAGGGCGTTTCAGTAACAGAGTGTTAGGGGACACGGGTTGGGTGGCT- TGGAAAGGGCCTAAGGT GGGGTTTGTTTTAGATTGGGGTGGTGAGGGCGCAGGGGCCCGGTAGGATTCTCTAACAGGGCAGCAGCCACT- CATTTAGCAACAGGAGAG GCGTCCAGCGTTTCGTGGGCT 228 CRYAA ACCCAACCACAGGCCTCCTCTCTGAGCCACGGGTGAGCGGTGCAGGTTCTGCTGTTCTGGAGGG- CCTGAGTCCCACCCAGCACCTCATAA ACAGGGTCCTCCCCAGGGCTGCTGCAGTAGGCATCAACGCCAGGGTGCAAAATGCCTCAGGGAGCCAAGGCT- GAGCCAGGGGAGTGAGA AGGAGCATGTGGAAGTGCGTTTTGGAGAGGCAGCTGCGCAGGCTGTCAGCAGGCTCCGGCCGCTTCTATAGA- CAGCATGACACCAAGGG CAGTGACCTCATTCCACAGGCTGAGTCCAGCCAGCCAGCCAAGCATCACCAGCCAGACGATTGACCCTAACG- GACCAACCAACCCGTAAC GACCCCTCCTACCATAACCAGTAGCCAGCCAGCCCATAACCAGCCAACTTATCTATAACCAGCCACCTGACC- ATAGCCAAACAACCAGCCG GCCCACCAGTAGCATTCAGCCCCTCAGCTGGCCCTGAGGGTTTGGAGACAGGTCGAGGGTCATGCCTGTCTG- TCCAGGAGACAGTCACAG GCCCCCGAAAGCTCTGCCCCACTTGGTGTGTGGGAGAAGAGGCCGGCAGGTGACCGAAGCATCTCTGTTCTG- ATAACCGGGACCCGCCC TGTCTCTGCCAACCCCAGCAGGGACGGCACCCTCTGGGCAGCTCCACATGGCACGTTTGGATTTCAGGTTCG- ATCCGACCGGGACAAGTT CGTCATCTTCCTCGATGTGAAGCACTTCTCCCCGGAGGACCTCACCGTGAAGGTGCAGGACGACTTTGTGGA- GATCCACGGAAAGCACAA CGAGCGCCAGGTGAGCCCAGGCACTGAGAGGTGGGAGAGGGGGGCGAGTTGGGCGCGAGGACAAGGGGGTCA- CGGCGGGCACGACCG GGCCTGCACACCTGCACCATGCCTTCAACCCTGGGAGAGGGACGCTCTCCAGGGGACCCCGAATCAGGCCTG- GCTTTTCCCCAAGGGAG GGGCCGTGCCCACCTGAGCACAGCCAGCCCCTCCCGGTGACAGAGGTCACCATTCCCGAGCTAATGTGGCTC- AGGGATCCAGGTTAGGG TCCCTTCCCGGGCTGCACCCAGCCGTCGCCAGCTCCATCCCTGTCACCTGGATGCCAGGGTGGTCTTAGAAA- GAACCCCAGGAAGTGGGA GTGCCCCGGGTGGCCGCCTCCTAGCCAGTGTACATCTTCACATGAACCCTACCTGAGGAAGCCAGTCCCCGA- CGGCATAGCTGCATCCGC TTGGAATGCTTTACAGGCATTGACACCTTCGCCTCACAGCAGCACTTTGGAACCAGTGTCCTCATTATTCCA- GGGCACGGCTGGGGAACAA GGGGGTCCTCAGCCTGCTGGGTCCCACAGCTAGTACCGGGCAGGTGGACGGGAGCTTCTCCCCACAGTCACC- CTGATGCCCCGCTCTTG CTCGGCTGGAGGCCTCGGATCTCCGTGGTGTTGAGGGAGCCGGGGCACTGGAGCCCTGGTGACCTGCATCTC- CTGGCGGAGCCGGGAA GAGCTCATGGACTGTCACAGATGGACAGTGCCCCGCGGGGGCTGGAGAGCAGAGTGGGGCTGGAAGGTGGAA- CTCTTAGCCAAAGTCTT GGTTTCTTTTGGCCAGGGTCCTCTTTCAATGGCTGGAGAAGGTGGTGCTGGGGGGTGAACGCTGACCTCCTC- ATGTGCTGCCCCTCCCTC GCCTGGGCCCGGTAAAGCCCCCACGTAGCCCCAGCCAGCCTGGAACATGCTTCCTGAGCTCCCAGCTCTTGG- TCTTTGCACCCAGTGGAG GAGGAGGTCAGCCCAGGGAGCTGAGTCTGCGGTTTAGGGCGTCCAGGGGACGTGGAAGCATGTGGGTCGTCT- GGCCACATTAGGTAGGG CTGCAGAGACCTGGGCTAGAGCAGTCCTGCGGGGTCTGGAAGGGGAAGACTGGCTGAGGTGCGGGGCCTGGT- CTGGAATGATCCTGCGA TTTTGGAGTGAAGCCATGGAGCGGGAAGAGACAACCCCCCGCGGGGAATAGCCCGGCAAGTGGCCACGAGGC- CAGGCTGAGGTCCAGA GAAGCAGGGGCATGAATCCATAAATCCCAGGGGGCCTGGCCATGGGATGTGCTGGCTGCACCCGGCCCCTGT- GAGAGCCCCCGCAGGCT GGCCCCCTTCTGCAGTCAGTGGGGCTGGGGCAGCTTCTCTGGCATGGGGCGAGGCAGCCGCCTGCACAGTGG- CCCCCCTGACTGTGCG CCCCCACCCTCTCCAGGACGACCACGGCTACATTTCCCGTGAGTTCCACCGCCGCTACCGCCTGCCGTCCAA- CGTGGACCAGTCGGCCCT CTCTTGCTCCCTGTCTGCCGATGGCATGCTGACCTTCTGTGGCCCCAAGATCCAGACTGGCCTGGATGCCAC- CCACGCCGAGCGAGCCAT CCCCGTGTCGCGGGAGGAGAAGCCCACCTCGGCTCCCTCGTCCTAAGCAGGCATTGCCTCGGCTGGCTCCCC- TGCAGCCCTGGCCCATC ATGGGGGGAGCACCCTGAGGGCGGGGTGTCTGTCTTCCTTTGCTTCCCTTTTTTCCTTTCCACCTTCTCACA- TGGAATGAGGGTTTGAGAG AGCAGCCAGGAGAGCTTAGGGTCTCAGGGTGTCCCAGACCCCGACACCGGCCAGTGGCGGAAGTGACCGCAC- CTCACACTCCTTTAGATA GCAGCCTGGCTCCCCTGGGGTGCAGGCGCCTCAACTCTGCTGAGGGTCCAGAAGGAGGGGGTGACCTCCGGC- CAGGTGCCTCCTGACA CACCTGCAGCCTCCCTCCGCGGCGGGCCCTGCCCACACCTCCTGGGGCGCGTGAGGCCCGTGGGGCCGGGGC- TTCTGTGCACCTGGGC TCTCGCGGCCTCTTCTCTCAGACCGTCTTCCTCCAACCCCTCTATGTAGTGCCGCTCTTGGGGACATGGGTC-

GCCCATGAGAGCGCAGCC CGCGGCAATCAATAAACAGCAGGTGATACAAGCAACCCGCCGTCTGCTGGTGCTGTCTCCATCAGGGGCGCG- AGGGGCAGGAGGGCGGC GCCGGGAGGGAGGACAGCGGGGTCTCCTGCTCGCGTTGGACCCGGTGGCCTCGGAACGATGG 229 chr21: 43545000-43546000 TTTTTGTGTTTTTAGTAGAGATGGGATTTCACCATGTTGGCCAGGCTGGTCTCAAACTCCTGGCCTCATGCAA- TCCTCCTGCCTCAGTAGTA GTAGTTGGGATTACAGGTGTGAGCTGCCATGCCCAGCTGCAGGTGCGGAAGCTGGGGGCCTCAGAGACTGTG- GACTCCTGGCCGGTGAG GAGCGGCATGGGCCGGGAGAGCTGACTCTTCAGCGGGACTGAGGTGGCTGGAGCGTGACCCTTTCCTGAGGG- CAAACAGGGAGGGCCT TGGAGCCCGGCGCTCAGGACAGGCCCCTGCTGGCCCGGCAGCCTGAGCTTCCACACTTTTCCAGGGCGTCTC- GAGTTCGCCCACAGAGC TGTTGTTTCAGGATAAAAAATGCCCTTGTATTCCACGTTCCAGTTCAGAGGCCCGTCTGTTCCCAAGAGCGG- AGGCGTCAGCCGCATGAGT CCCACCGGAAGCCGGGTTGCCGGGTCCCCGTCCCTGCCCTGCAGACGACGCATTCCGGAGCCCCCTTGGGAA- GCTGCCTGGCTCTCCCA GGCCTGGCTGCCTTCGCACGAGGGCTCCGAGGCATGCTCATCCTACGTGACTGCCCGAGTGTGCACACGCCT- GGCCGTGTGTGGGCGTG TGCCTGGGGCCCGAGCTCAGGAGCAAGGCCTGCGTGGACCTGTTGTCTGAAACAAGCCAGTAGACAGCTGCG- TCAATGCAGGCAAGCTG AACAGGGCTGCTTTTTCAGCCTGACAACCCCAGGGGCTGAACAGGAGCTGGGGGAGGAGCAAGGGGCCGTTC- CCCTGCCCCACAGCACA GCACACGACCCCGCCTTGGAACCTGGGGCCCGGGGTGAATCGAGGGTCCTGGAGCAAGAGGGGCTGCTCCAC- AGGAGAGCCTGTCCCG CCACCCCTCAGCCACCAGATTCGGGGCTGCTGGACTTGTTCTCAAACCTGCACAGTGAGTGACAGCTGCTGA- GACGGAGGTCTCAGGCAG TGCAGGTGAATCAGCAT 230 chr21: 43606000-43606500 TCCTTATTTTTTAGTTCTCAAGCCCTGTAGGGTGTTTTCGGTCGCAGTTGTTTGGGCTGTGGTCCTGACCCTC- CTGAGTTCCAGTGGCTCTG TTCAGGAGAGCTGCCTGGGGCCGGGACTTCTGAAACACACACTGAGCCACAGGCCGGCCCGGCGGCTTGGGT- TCACCGCCGCCTCTTTG TGTGTGATGTCCTGGGATAGGCCCGTGCACGTTCAGATGACACTGTACATATAAATAACTTGTAGCCGAGAA- CAGGATGGGGCGGGGAGG AGGGGAGGGCAGAACGTACCACAGCAGCAGAAGTCACTGTGGATGCCTTCGTAAGTTGCATGGAAGGTTTTT- AAACCTAGCCCTGCCGAG CAGCCCTCTCCTGGTCCGGGAGAACGATGGGGAGAGAGCTGGCGTTCAGCTTTCATCACTGGAGCCGTTCCT- TCTTCCGGCCCCCCGAGG GCCTGTCCATGATCACACTTTGTCTTGTTTCGGGGGTGGCCCCTGTGAC 231 chr21: 43643000-43644300 CAAGCCTGTGGTAGGGACCAGGTCAGAGTAAACAGGAAGACAGCTTTCGGCCAGGCGGTGCACCTCGGTGCCG- GTGAGTGTGAGCGTGT GTGCGTGTGCACGTGTGCAGATGTGTGTGGACGCTCCCTTCTCCGCAGCAGCTCCTGACCCCCTGCAGGTGA- CCCTCAGCCAGCCCCAG GGCTGCCCCCACTCTCCCCTGTGGACACCTACCTCATTTGGGGTGAAGTGGGGGGACTGGGGTGTGAGGGGT- GCTTTGGGGGGCACACT TCGACCCCTCTCTCTGCAGGCCAAGTCCTGAGGCTCAGTTTCCTCCTCTGTGCCCCGGCGACGTGGTGCAGG- CCTCGCGAGTGACGTGAG GGTTCATGACCCAGGTGTGGGCAGCCAGCCCTTCACGGGAGGCCACCCACCTGGCCACAGTGCCTGGGAATT- TAGGTCGGGCACTGCCG ATATGTCGCCTTCCACAAGGCGGGCCCGGGCCTCTGCTGACCGTGCACCGGTCCTGGGGCTGGGTAATTCTG- CAGCAGCAGCGCAGCCC ATGCCGGGGAATTTGCGGGCAGAGGAGACAGTGAGGCCCGCGTTCTGTGCGGGAACTCCCGAGCTCACAGAG- CCCAAGACCACACGGCT GCATCTGCTTGGCTGACTGGGCCAGGCCCACGCGTAGTAACCCGGACGTCTCTCTCTCACAGTCCCCTTGCG- TCTGGCCAGGGAGCTGCC AGGCTGCACCCCGCGGTGGGGATCGGGAGAGGGGCAGTGTCGCCCATCCCCGGAAGGCTGAGCCTGGTGCAG- CCAGGGAGTGAGGGG GCGGGAAGCCGGGGTGCTGCCCTGAGGGTGCCCCGACACGCTCTCCTGGGGCCCTGAGCGGCTGCCACGTGC- GTCCAGGGTTCTGGCC ACAGGGTGGGCAGGGGCCCTGTGCTCCTCACTGGAGGCCCCTGAGGCTCTGGAACTGAGACCATCCACCCGC- CGGCCCCCTCTCGCCG GCTCCGGCACCCCTGCCTACTGTGACTTCCTGCCCCGGACTCGCTCTGCCAGCTTGGGGCAAACCACTTCCC- TCTGGGGTTTTCACTTCCC TCTTTCCCAAGTGGGGAAAGACCACCTGTCCCCGACCCAGAAAGGGCCCCTGCCCGAGGGCAGCAGCAGTGC- CAGGCTGGCATGTGAGG CTTGGGGCAGGCCCGGCCCCCAGAGGCACAGGGCGATGCTCTGTGGGACGCTGTGTCGTTTCTAAGTACAAG- GTCAGGAGAGGAGCCCC CTGACCCCGGAGGGGAGGAGAGGCAGGGCAGGAAACCGCCACCATCTCAGCCCA 232 C21orf125 GCCCACTGTGGGTGTGCCCGTGTGTGTGGCTGTGAGGCGTGAGTGCAGGCGTGAAGTGTCTGGGAGTGGGAGC- GGGCATGAGTGTGTG CCACGGGCCTGCTGTTGGGTCCTTGGAGGCCACGGTTGCCCCTGAAGGGACTGCAAGCTCTTTTTTGATTTG- TAGTTATTTGAGAAGTCTA TACAGGAAGAAAATTAAACCG 233 C21orf125 AGCGCCCAGCGCAGGGCCGGGACCCAGAGTGGACTCTACCGTGGGGCTGCCTCAAAGAAATCTCAGCAAACAC- AGGAAGCCAGCCCACC CGTGCAGCCATGGGGCCAGGAAGCCCGCCCTTTACCAAGTCATTTGGGCATTTTTTCTCTGTGCTAACAGCC- CAGATGGAGCCATAGCCTC AACCTCTGTGTTCTGATAACACCAAGCTGGGACGCCGGAGCCATGCAGGGGACAGTGCCCGGCCTGAGGCTG- CAGCCTGGGTCTGGATG CCTTTCTAATTCAGGGCCTCCTCATGGCCTGGTTCCATAAATGGTCAAATGCAGCCTGACAGCGCAGCCTCC- TATCAGCGCTGGGCTCCGT ACCGCCACACAGCCCACATACCCCGTTCCCCAGGAGACGCCCGCAGGTGGGCAGCGTCACTCCCACCCGCCG- AGCACACGCTGTCCCCG TCTCGTGTCCCGAGGAGCCGGAAGCAGCTGCTTCCTCCCAGCCTGAAAGCTGCACCTCGGGCTGCACTCGGC- TCCCCGAACCCGCCCTC CGCTGCCCTGCAATTCGCCAAGGGAGCTACCCTTCCCATATAAAAATTTCACCTCCATTTCCTTGTAGAGAA- GAAACATTTCTGACAGCAAG GAAGATTCTAATTTGAAAAGCAAGTGATTCATCTCCCGGTGCCAAACAGCAGACGCAGGCGTTACCAGTCTG- GGTGGGGCGCCCGAGCTG GGGACCTGGGGTCCTCTGGGAGGGGCAAGAAGGCAGCGATGCTGGCCCCCGCCTCCATCTGCCCATCCCATC- TGCTTCCACACACCGCC CTGCCGTAGCTGCTTGCAGCCCTTCTCTGTCAGTTTCTCCATCTTTTGGTTTGGTGATAAATGAGAGTTCCC- ATCGGGTGTGCCACCCTCTG TGTGACGGGGAGCAGAGAAGACCCTGCGTCCAAGTCCTCCTGGGGGAAGAGCGAAGATGCTGGGACCAGCCC- CAGCTGTCAGGGGGTCT CCAATCCCAG 234 HSF2BP GGAACGGAGAGCCGCCAGGCCCAAACCTCCCAGAATTTGCGCAGTATTCTCGGCCTAGAGAGC- GAGGAGTGGCCTTGGCGAGGTCCCTC TTTGGCTCTTCTGGCTTAGCCGGGGTTTTAAACTTGTTATCTGCAAAGCAGAAGGAAAGTCAGCCCCTGATG- TAAGTGTCAAGTAAAATAAA TCGGATGGGTCCTTTCCTGTTTGGCGAGGAATGCTACACTAAGGGGGACTGCGTTCAAATGGGCAGTCTTTG- CTGGAAACCTCGCCTCCGC GCGCCTTCCCTCGCTCGGATTCAGGCGCTTTTACGTTAAGGGTTGAATTTTTGTGTCAACAGGCACCTCGGG- AGGTCGCCTAGACAACTGA GCGGAGCAACTGAGATAACCCCCGCTACGTGTGGAGTGACCTAGTCCATTAACTTGCCCCAGCACGCCCGCT- GAGTCCGCAAAATATAGG ATGGCCTCGGGTTTTAGATGAACCCAAAGCTAAGATTTCTTCCCTCTCTGGAATTAGCAAGCAGCCCGCCCT- GCCCAACTCCCCTGGAAGC GCGCGTGCTCGCCAGGCCTCGGGACGCCTGCGCGGGCGCCCTTGCACTGGCACCAGGGCTCCGGGGTAGGGG- CGCACCGATCTGCCCA AGCCTCTGCAGGCACTGGAGGAAGGCGAGCCCTCCACCCGCTCAACAGGCCCCAGTGCCGGCCTTTCCTTCC- AGTCTCAACTCCACCCG GGGGCCCGGGGGCTCCACAGTTAAAAACTCCACGCCACGGAGATCGCAGGTAAGCTGCTGGCTCAACGAGGT- GTGCTAAATGGGATTAAA GATCCTGGACCGTGGCCAGGCGCGGCGGCTCAAGCCTGTAATCCCAGCGATCAGGGAGGCCGCCGCGGGAGG- ATTGCTTGAGCCCAGG AGTTTGAGACCAGCTTGGGCAACATAGCGAGACACCGTCTCTACAAAAAAATAACAAATAGTGGGGCGTGAT- GGCGCGCGCCTGTAGTCTC AGCTACTTGGGCGGTCGAGATGGGAGGATCGATCGAGTCTGGGAGGTCGAGGCTGCAGTGAGCCAGGATCAC- CGCCAAGATCGCGCCAC TGCATTCCAGCCTGGGCGACAGAGGGAGACCCTGTCTCAAAAACAAACAAAAAATCCTAGACCGTTTACAAA- CAGCCTTCCGTCTCTTCCTG GTCAAGTCCTAACCCTGGCTAACCTCGCCGTCTACAGCCTGAATTTTGGCAACCGAAAGGCAGCGCCGGCGC- CACGTGCACACGGGCTGG GCCGCTCCGCCAGCTGCCAGGGCCACTGCCGCGCTCACT 235 AGPAT3 CGCACACACAGCACAGACGCCTGCATCTTCCCATGCGTGGTTTCTGCTCTTGCCTCTCTGGGT- TTTTGTTTCACTTCGGTCGAGTTTTTGGT GGTGTTGAGCGGATAGCCGGGGAAGTTGGAGTCTTGTTTGTGGCCGCCTCGTGCTCGTGTCTGTATCTAAGA- TCCTCAGGCTGCTCCTTTT TGGGTAAGGTCTGTTGCTTCTCTAGGAACAGTGACGGTGGCAGAGCCCGTGGCCCCTCTCTCCTGTCCCAGA- GCCAAGCTGTTTCCTCTCC CCACTCCCGGGCACCCTGCGGGCAAG 236 chr21: 44446500-44447500 CACAGCCCAGCTTCAAGCCTGGCCGACCAGGGGTTTGGCATGAAGACCCCGGCAGGGCTGGGGCTGTGCTGGA- ATCCACCCGGAAGTTT CCTGCCCCTTGGGCTGCCCACCAGGTCCCCTTTCTGCTCTGATCAAGCTGGACAAAACGTCGTGGGGCCACA- GCACAGGGGGCCAACGC AAGCTGGGATCGTCAGACGTTAGGAAATCCCAAGGAAGAAGAGAAAGGGGACACATTCGGGAGACGTCGGCA- CACGCTCGAAGCAGCGG ACAGGCACCTCTCTGTGGACAAGGCAGACTGGGCGGCCGAGATTCCGCATAGATGCCTGCTTCCTCCACGAC- CTCCACGTGTGGCTGGCC CAGTCCGGGTCCCCCTCACCTCCTCTGTCTGTCTTGGTGGCCTCACGCCGTGGGCTGTGATGCCGGCTACGC- TGCTTGGGTGGCCAAGG GTCTGAGCTGCAAGACGCCCAGCCTGGGTCTCTCCCGAGCTCTCCCACGTCCTGTCTGCTCCTCCTCCGAGC- TCCCGGTTGACTCTCACG ACTGCACCAGCCTCTCCCCCAGGAAGGCGTGGAAACAACCTCCTTCTCCCAGGCCCGCTCTGCCTCCTGCGT- TTCAAGGCAAATCCGTTCCTC CAGGAGATGATGCAACCACATCCTGTTGGAGCCCAGAGAAGTGCGGATGCAGCCCGGGGCTCTTTCTTTCCT- AGAACCCTGCCTGGGAGTGGCTT CCCTGAACTAAGGACAGAGACTTTGTCTTCGTTGCCTCTCGGCCTGTGGGCACTGAGCATACAGTAGGTGCT- CAGTAAATGCTTGCAGGCCG ATGCCCAGAGCCATTAGCCCTCATCATGGTGAGCTCGGCAGCCGGTGTTGGGGCTGGGCTGGGCCTAGGTGT- GCGTGGGGGCGGTGCTGGT CTGCTTTGCTGGGAGCCATGGACACCGGAGGAACAGGGCCCCATCAGTGCGGTCAGAGTGCAAACTCGGAGC- GTCCTTCTCTGGAAAACGAAT 237 TRPM2 GGGAGGGGGCGTGGCCAGCAGGCAGCTGGGTGGGGCTGAGCCAGGGCGATCCGACCCCGAACCG- GAGCTTTTAGCACTTTGAGTCCCT GTACTCAGAGGTCTCCTGCAGCCGGGAATCCCACTGTGCTGTGGTCCCTGGCAGCCAGCACCCACCCCCAGC- TTCTCCGTCAAGGTTGAG GACGGAGCACTCCTGCCTCTGATTAACTGGACGCAGGAGAAGCAGTTGCTTTAATCCGGAGCCTTGAGTTGG- GACAGATAATGAGTCATTC AACCAGATTTTCCAAGGACACACTAACTTTGGTATGATGCGTGTGTGCCCCTGAATCCACGTGGTCAGGAAA- GCCCAGGGAACACTGGCCT GTGACTCACTGAGCAGGTTCCCTTGTTACCCCGAGGGGTGATTTACTCCTCTGACAGTGACACGGACACTGT- GCGTCCATTCCCCGGGCG GGCAGAGGACACTCCCAGATGCCCACGAGGGGCCCAGCAAGCACTGGCCA 238 C21orf29 CTGCAGGACCTGCTCGTTCACAGATGTTCTCCTAGAAGCAGAAGCTGTTTCTTGTTGCAAACAAATTTGCTGT- GTCCTGTCTTAGGAGTCTC ACCTGAATTTACCAAGGATGCATCTGTGCTTGGGGATGGCTCGGTTTGAGGGGTCTGAGGAGCGGCTCCCCT- GGATCCTTTCCTCCCCAG GAGCCCACCTGCCGAGCTGTCAGCGTCAGCCCCACATCTCAAGATGAGGAAATGGAGGTCGAAGCCATGCAC- ACGCAGGCGTCCTGCTG ACATGCAGGCCAGGCGGGTGCCTCTGTATTCAGCAGCCTCAGGGCTGTGGCCAGTTCAGGCAGCAGAGGGGC- CTCATCCCGGTGCTTCC CTGCAGGCAGTTGTGGGGCCGGCCTGCAGCAGGGGCTCAGACAGGGCCTTGGGAGAGGGAGGGATCACAGAG- GTGTCCAGTGACAGGC AGGGCGGGCAGAGCCCATGGGGCCTTGGGCTCCTCACTCCTTCGGTCAGTCAGGGTGACATCTGGAGCCACC- TCCATTAATGGTGGGTTA TGATTTGGTTCCCATGCAGCCCGTGCCAGCTCGCTGGGAGGAGGACGAGGACGCCTGTGATC 239 C21orf29 AAGAGGAAATTCCCACCTAATAAATTTTGGTCAGACCGGTTGATCTCAAAACCCTGTCTCCTGATAAGATGTT- ATCAATGACAATGGTGCCC GAAACTTCATTAGCAATTTTAATTTCGCCTTGGAGCTGTGGTCCTGTGATCTCGCCCTGCCTCCACTGGCCT- TGTGATATTCTATTACCCTGT TAAGTACTTGCTGTCTGTCACCCACACCTATTCGCACACTCCTTCCCCTTTTGAAACTCCCTAATAAAAACT- TGCTGGTTTTTGCGGCTTGTG GGGCATCACAGATCCTACCAACGTGTGATGTCTCCCCCGGACGCCCAGCTTTAAAATTTCTCTCTTTTGTAC- TCTGTCCCTTTATTTCTCAAG CCAGTCGATGCTTAGGAAAATAGAAAAGAACCTACGTGATTATCGGGGCAGGTCCCCCGATAACCCCCAGCT- GCAGATCGAGGCCTAGTG CGAGCACAGGTCCCCCCAGACCCTTCCCAGTGCCCACCAACCGGCGGCCTAGGCCAGGTAGAACTGGCAGCG- CCTCCCCTGCTGCAACA CCAGGCTCTGGTAGAAACTTCAGAAAACATGCACCGGCAAAACCAAGGAAGGGTGGCTGCGTCCCGGGTTCT- TCCGCGCAGCTGTGTGTA CACGCATGCACACACCCACACGCACACACCCACGTGCACACCCCCATGCACACGCACCCACTTGCACGCCCA- TGCACGCACACACGCGC GTGCACCCATGCGCACGCACCCATGCACACACACGCGCGCACACACCCACGTGCGCACCCACATGTACACAC- CCACGTGCACACACCCAC GCGTACACACCCACGCGCACACACCGCTGTCCCCAGCCGTGCAGAACGATCCTCCCTGAGTCCCCGGCTCCG- ACCCACACGCAGCACTC GCTAAACGCTTCCCACGCAGTCGTTTTGCTGGGTTGCGCTTCACCCACTTCTCAGAGGGGGCGGCCGAGGCA- GAGGTGTCGGGGATCGA GCAGCTCCGGGCCTCAGGGGTCGCCCCGCCACCGTTTTCCTTTCCCAGATGCTGGGACGGGGGCAGGGAGGG- GCTCCCCAGGCTGAAC CCGACTAGGTCACCCTAGAAGCGAGGCGAGCTTCTCTTCTGTTTTTCTTCGGCGCCCCTGAGCCCCTGACAG- TGCCCAAGCTGCCCATGG GATTGGATTCGCCAGAGCCTCCTACGCAGACCCCACCCAGGGCCAAAGCCAACCCCAAGCCCCACCACCTTG- GTGGTGTGGGATGAAAAG TGAGCCATCGAGAGATGGGGTCCCCCCACCCCCAACCCCTCCAAGGACAAAGGCGGGCTGGGAAGCACCCGC- TTTCACGTCCGCCCCTG CCCGGCTTTCCTAGCGGAATTGGCGCCGGCATCAGTTGGGGGTTGTGGGATCAGTGAGGAATCCCGTGGGGT- CGCCTCCATTTATCAGTT GTGTGGGGTTGGGCGAGCACCCCTAGCCCCAGCCCAGGCGATCAGGGCGCGAAGCCCACTGGACGCGGATTT- GGGATTAGGACGGGGG TGACAGCCAGGAGGACCGCACCTGCCCTCCCCACTCCTGCCGCTCCACCCCTGCCCCCACCGCAACACCAAG- GTCTCCACCAGGAAGAT GGGGGTGGGGAAAGGACGCGGGGTGGGGGGGGGTGCGGGGAGAGAGGACACAGGGTCGGAAGGGTGAGGGGT- AGTGGCAGAGGCGG AGGCCGAGGCCACGCAGCTGCGGGGCGCAGGGAGGGGCAGAGGAGGGGCGTTCAGATGGGAACCTAGTCCAG- ACCCGTCGGGGCCCT CGTGTGCGGCTCGTTATCCTGGAACCAGAGAGGCTGGAGACCCTTGGCTTGTCTGGAGCGGAACCGTAGTGT- CCAATAGAGTGTGTGGGG CTCAGCCCTAAAGCTAAACATTCTTTATTTCCTGATGACCATGGGGGCGGAGCGGGGGAAAAGCCCTGGCCT- TATAGTTTAGAATTTTATAA AAGGAAAGGCGTGGCCACTGACAATTTGCGCTTCAGGAGTCCCAGAGTGACCGCCTGGCTCGGAGCAGGGAA- TGAGGGGGTCCTTAACT CTGAGATTTGTTTTCTGAGAGACAAAGGTGATGGGTGAGGCGGCTAAGCCTCTGATTCTCTATAGGTGGCGG- TCATTCATTTCAGAACATGA ATGGATTCAGTAAATAAACATGATAGAAAAATGCCACAAGCCCTAGGCCCATTGGAGTGGACTGGACAGTCT- GTTCCCAGTGTGTCCCTCA GCCTCGGTCCCCCACCCTTCCCGGAGCCCTGGGGGTCACACACATCCCTCCTGGCTGCCTAGCCTGTGCCCC- CCGATTCCCCCCCTCCC CGCCCCGCGCGTGCACACACACACACACACACACACACACACACACACACACCACACAGCACGAGGCGACAG- AGATATGAGAGAGAGCG AGCGAGAGAGGACGGGAGAGAGAGGGAGTGCAAGTGTGCGCTGGGGGTAACCCGTGCATGCATGCATTGGGG-

GTAACAGGCTGGAGCT CAGATCCCTCCCCCAGCCCCCAGCAGGGGGGACTGCAGGCTCCTGGTCTGAGTGGGGAGCTGGGCCCCCTGG- ACAGAGGACTGGGCTG CGGGGTCAGGAATGGGCACACTTCCTAACTGCAGGACACTCTAAGGGCTTTGGTCATGCACACGCAGCCAAG- AGAAGGTGTCGCTGGCAC ACAGCCTTCCAGGAGCGGACTTGGAGACCTCGCCAAGGACCAGGACTCCCCAGCACTCACACTCCCTTAGGC- GCTGAAGTCCAGAGGACA GAGGTTGAGGGCAGAGCTCCTGGGAGCACCAGTGGAAGTAGGAGGGCTGGGCTGGAAAACCTCCCCCAACCT- CCTATTGCAAAGAGGCT CCAGCCAGCAGCCTCCACACCCCAGTGATCTTTTAAGATGCAAATCTGCGCCATCATTTATTTCCTCAGTGC- CTTCTCCAGCTCCTGGGATG CACACTGCCCGTCCCCAGGCCCAGAGACCTGACCACCCTCATTCCTCCCTCAGCCCACCCTGGGGTCTCTCC- ACCAGCTGACAGCCTTCC TGCAGTCCCCTCCCCGAATGCTGCTCCCTGAGGCCCTCCTGGACACCTGCAGGGCAGGCACAGCCCGCGGGA- CCTCACAGCACTTGCTC CGGGCAGAGCTGCAGTTTGGCCAAGTTGCCAGCTCCGTGTGGGCAGGGGCCCTGGCCTGTGGCTGCCACATC- CCGGGTGGGGGCACGG CCTTTCCTGGCGTGGATGCTGAGCAAACGTAGGGGGAAGGGGAGTGAATGAGGAGAGCCAGGTAGCTCAGGG- GCTGAGGCCTCACTGAG CAGGGTCCCGCGTGACCGGTCCCCACCGCTGACGGTTCCTGGGGTAACACTCAGGACAGGGAGAGGCAATGG- AAAGAGACGTGGCCGC CCTCGCATCCTGCAGCTCCCGCACTCCCAGCCTCCCAGCCTCCCACCCAGCCCCCCAGAGCCCACCAGTGAC- CCCGCCCACTGGGTCCT CAGATGGCTCCCACGGGATCTCCTGCCTTGATCTCCTGTCCACATGGAGGTGAAGTGGGTTGCTCTGAATGA- GGGGTGCCGAGCCTAGGG CGCAGCCCACTCTCCTGGGTCCGCAGCATCACGCAGCCCGGACCACAGGCTCCTTACAAGAATCGGAAGGGT- CCCTGCAATCGCCCTTCG CACTGAGGCTTCCTACTGTGTGGTGTAAAAACACAGGCTTGTCCTCCCTTGCTGCCCACGGGGCTGGAGCCG- CCTGAAAATCCCAGCCCA CAACTTCCCCAAAGCCTGGCAGTCACTTGAATAGCCAAATGAGTCCTAGAAAGCGAGAGACGAGAGGGGAAT- GAGCGCCGAAAATCAAAG CAGGTTCCCCTCCTGACAACTCCAGAGAAGGCGCATGGGCCCCGTGGCAGACCCGAACCCCCAGCCTCGCGA- CCGCCTGTGACCTGCGG GTCAACCACCCGCCGCGGCTCCACGCCGTGGGCACAGACTCAGGGAGCAGGATGAGAAAGCTGAGACGGCGC- AGCCACGGCCCGGTGC CTTCACGCGCACAGCGACACAGCCCCAGCCAGCGGGGCCCACGCTAAGGCGGAATCCCACAGAAGCCTACAG- AGCGAGCGCGCGCCTG TGCTTCCCAAAACGGAATGGAACCAAGGTGACTTCTACAGAACGATCTGAAGCCCTGGCTGGCCCTTATGCT- AGTCTCTTGGGAGCGTTCC AAATGCAGCTCAATATTACTTACTTGACTTTTATCTTTCCTCCCTGGTTCGTGGTATTTATAACTGGGTCAT- CTTTTAACTATTTGCAACGTAG CTTCAGGGGAGAGGGGGAGGGCTTTATAAATAACCTGTATTATTATTATGCAGGTTGATTCTGTTCCCTGAG- CTAAAGGGAACATGAAAATA CATGTCTGTGACTCATGCCCCCCCACCCCCACTCCAGGGTGTGCTGAGGAGTCTCTCAGCTGCCCCGGGGTC- CTCGAGCAGGGGAGGGA GAAAGGCTGGCGCTGCGCCCTCCATCGCGTGAAGCCAGGGGATTTTGCTCTGCGACAAGCTGACTTGGCTCT- CGTATTGTTTGCAGAATCA CCCAGTTCCAAGGCAGTCCCTGCGGGCAGGTGCAGCTGTGCGGGAGCTTCAGTCCTGTCCCCAACACCCAGG- CAGTAATGGTTCCAGCAC GGAAGGTCTACCTACCTCCCACTGCACAGCCCGAGGGCTGTCCTGGAGGCACAGCCATCCGTCCCTGGGTGG- GCAGGCACGTTTATGAC CCCCACCCCCACCCCCACCCCCCACGCGAGTCAGCACGTTCCATACTCGGGTGATCGTGCTCATCCCCTGGT- CATGTCATCGGGATCTGA GTGCCATCCGAGCAGAGAGCTGTGGCCCGGTGCCGGGGGTGGACTTCATCTATTCCAGGGAACCAAGGATGC- ATGATTTGCAAACAAAAC CAGAAGCGCAAGCCATCTCCTCGCCTCCCCTGATAGCCGTGCTGCGGAGCCTGAGTGCTGGAG 240 ITGB2 CAGGAACCACGGGACCTGCTGCCTAGCGGCCCTGTTCCACCCTTGGCCGCTCGCAAAATGTTTA- GGCTTCATAAGGTTTGCCCAGGGTCA CAAATTTAACTCACAGCAAACAATGAAATCAGCGCATGATTTTCGAGCCCTCGTGGTCACCCTCCCTTCCTC- CTGCCCTTTCCTGCATGGGC AGCAGCAGGGTGAGGAGCTGCTCTCCCCAGGCCCAGGCTGGAGTCCCTCAGACGACCTGCCGGCCAGGGTAC- CCCCCTGCCCCCACACA GCGCCTGACAGAGCCCCCCACACTGGGGGAACGTGGGGACCCAAGCAGGGGCAGCGGCCTCACCGGGCAGGC- GGCGACCTGCATCATG GCGTCCAGCCCACCCTCGGGTGCATCCAGGTTTCCGGAAATCAGCTGCTTCCCGACCTCGGTCTGAAACTGG- TTGGAGTTGTTGGTCAGC TTCAGCACGTGCCTGAAGGCAAACGGGGGCTGGCACTCTTTCTCCTTGTTGGGGCATGGGTTTCGCAGCTTA- TCAGGGTGCGTGTTCACG AACGGCAGCACGGTCTTGTCCACGAAGGACCCGAAGCCTGCAGGGCACATGGAGGGGCTGG 241 ITGB2 TGCGTTTAGTGTAAAAATATCAGGTGTGGCTGCACGGAGTGAAAAATCACAGGCTCCACGGAGC- CGGGAGGCCTGCTGCCCTGCCCTCTT GCTTTGATGAGGAAATGGCGACCGCAGAAGGAAATGTAGCAGCACCGGCAACCGGCATCCGTGGGGCCACGC- CGGGCTGCTTCCCAGGG CCCTCCAGCCAAGCAGCCACAGGAAAGAGTAGATGTTGATCCCAAGCTAGGACTGAGGAGTCCGTCCCTAAG- AGCCGAGGGAGTCAGGTG GGCGAAACTGGCCGCATGTCTGGGTACAACTGCTCAGGGTTTCTCATCTGCTGAATCACCAAGCTAGGTTCT- GAAGCCAGGCGTGAGTGA GCAGGACTGGAGCAGGATTCTGGGAACAATCTTTTCCCTCC 242 POFUT2 GCTGGGGAACTGAAGGAAGGGCTGTGGAGCCTGAAGCCTGGGCCTGGCCTGTGCTGCGGCCGC- ACCGCTGGGTGATGCAGGAGCCACT CCACCTCCCTGGCACCCCAGCCTCATCCGGCAACCTGGGAGCGTGGGCCTCCTGCCCCTCCAGGGAGGCCCT- GGCCGTGTCCTCATGGG GCCCCTCCAGGTCCTTGTGGCTCCAGGTCGGGACAGTGGCTGTGAGATCTGACCCTCCCGTTCCCCCTCCAC- CAAGTAGGAGAAACCCCG GAGCATGAGCCCTCGTCCTTCACCGTCCCGGGGACAGGGGGACCCCCAGATGCTGCACGGCTGACAGGCCAA- CGTGGCAGAAGCTCCAG CTTCACAGGAAGCCAGTGACCATGAGAGTCTGTAGCTGTAACGAAGCCACAGAGCTGTGGCTTTCTTTCCCC- TTCAGCTCTAGGAAAGGTT ATCTGCCCTGCACAGATCTCCGGAGGCCTGGCTGGGCTCTGAGAGCATCAGACTGATTATCGTAAGAAAATA- ATCTCTGCAGACACATTCC TTGCTAGAAGCAGGGGACAAAGCCCAGCTTCAAAGACAATTCCACACACGCCCTCCCTGCCCTGCACAGCTG- CCTGCCGGGTGGGAGCAG AGCCCTTGCAGCCGGGCTCAGGGGCCTGGGCAGGGACAGCGTGTGGCAGGGGCACAGCTGAGACAGGAGCCT- CAAAGCGACACCAACC CGACGTGAAGCTACAGTTGAGGAGACACAGCTGCCCCCATTCCCGGGCCTCATCTCCACAGTGAGACGCTGG- ACTCTCTCCCTGACCCAC CGTCTCTTAGAACCTCCCCTCCATCCGGAGCAGTTCGGCAGCCCCAGGGCAGCCAGGGGAACCCTGCCGAGT- GCCTCTGGGCCGCCACA GACCGCAGAGCCCGCGGGAGCCTTGCTCACACAGCCTCAGGTCCACTGTGGTCTTGGGGGAAAGCCCTGTCC- TGGGACAGGGGAGCCG GGGGTCCTGGCCCTGGACCACCATCTGGGGACCACGTTGTCACGCCTGCAAAGCTCCCTGCCCCACCCCCAT- GTGCCGGCTGGTGTTGA CACCTTTGTAGAGTGGGAACCTGCCTCCGACCCCAGCCTGCAGCCACAGGGCAGGTTATAGACCAGGTGAGA- GGGCGCCGCGCCCAGAA CCAAGGAGCACAAGTCCGCAGTGCCCATGAGATCCTCATGCTGGCCGGCGCAGGAGCCATCCTCGGCCTCTG- CAGGTCCTCGTGGGAAA CCGCGGGGGCACGTGGGGCGGCTGCAGGGTCCGCAAAGCCGGCTGTTTGCGAAGGGCGCAGCTCCACCTGGA- ACAGCCGAGGCCGCC CACGCGCTTCCCGCGGGATCAGAGCAGCCTCCACGGCTGTTGTCTCAGGCACCACGGGATGCCTTTCTTCGT- TTCAATAGCTGTGGGAAA GCCTCAATCGGTCCTGAAAGAACCCAGATGTGCAGCAATGACAAGGCCTTCTCTGAGACTCTAGAACCTTCT- GCCATCTCAGACAGGAGGG AGCCGTGAGGCAGGCGGGAGATTTGCAGTCAGCAAAGGACGGGCAGGTGGGGCAGCTGCACACCCAGGGCCC- TCTCCACGGTCTTCCC GGGCCCACCCCTCCCGCGGTCCTGGGTCATCCACCTGCTGGCCTCACTCTGCCCACGCGGCCAGGTCCCACC- GGCCCCTGAGCTCAACA GACCAAAGCTGGCCCGACCCCACCCCCAAGAAGAATGAAACAATTTTTTTTTACCTCTTGCAGAAAAGTAAA- AGATCATTTATTCATTCTGTT TCTAGATAGCAAAACTAAGTGTCAAAAGCACCTTCTGCACACAGTCTGCACACACTGGCCGGTGGTCCTGTT- CCCGCAAGGTTGAGCTGTG TTCCAGAGACATGGGTCCTCCGGGTGATGAGGAGCCGCTGGAGGGCCCTGAGCTGCACGTGCTAATGATTAA- CGCCCCGTCCGTGCTGG CCGGTTTCTCAAATGCCTCCTGACGATTGCGC 243 chr21: 45571500-45573700 GGCCTGAGGAGTCAAACGGTGCAAACCCTGCCCCACTCTGTTTGGGAAGCACCTGCTGTGTGGCAGGCGCTGC- GCTTGGTGCTGGGGAT AGACCATGGGGAAGAAACACACAGAACCTGCCCTGCTCTCAAGGAACAGGCCCTGGGGGCGGCCAGGGGCAG- AGACCCAAGGCAGACAC CCACACAGTGGCGTAATGACAGTGCTTATGGTGGGGACCTGGCTGCACAGCAGGTCAGCAAGGGGATGTTCA- GGTGACACTGGGGGCAC GGAGACCCAGGGGAGAGTGGATTGACAGAGGGGACGCTGGGCAAATGTCCCGAGGCTGAGGTGGAGTTGCGG- GAAGGAGGAGGCTGCC GGGCAGAGGCGCAGAGAGCTTTGCAGGTGTTGGCAGAGACCAGCAGGCCCTGCGAGGCCTGGGGTGTGTCCT- CAGCTGGGAGGGCCAT AGAAGGATCTGGGCTTGCAGATGCTGGTGCAGACTGGAGGCCTGGGGTGTGAGAGTCCAGGCGGGGCTCCTG- CCAACACCCAGGGGAGT GGGCCTGGGCCAGGTGGACCGGGAGCTGGCACGGTGGTCAGGTGCTTGGAGGCTGCGTGCCACGCTGGGGAC- CTGGAGGTGTGTGAG GAGGTGTCTGTTGCTCCTGGGGCTGCCGCCTGCAGGGCTGGGTGTGCAGCAGTGCGGGGCAATGAAGTGGGC- GGGTTCTGGGATGGTG GACGTTCCCTTTGTTGGGAACGTGTTGGTGCCAAGCTGCCATTTGAGTTTGGCTCTGAGGGGTCTGGGCAGG- GGACACACAGGGAATCAC ACAGGATGGAGTGAGTTCCCAGGGACCCAGGGTGGCTTGGCCTGAGAACAGCTCCCACTCCCAGATGTGTGG- GAAGCCCTCGGCACCAA GCCTCAGCCTCTCCATCTGTGAAATGGAGACAACGTCACTGGACTTGCAGGCTGTCCATGAGGGTGATGCGA- TCAGAAAGGGTGGAGTTC CTGAACGCCCCGGGGTCGGGGTCTCACAGCAGGAGCTTAGCTGGTGTCGGCATCTCCTGGACCCGTCCTCAG- CTCCGAGCGCCCAGTCC TGCCACCTGTGTCCAAGTCTGCACTGTGCCCACGAGGCCCTCAAGGCCGCAGACAGCCCCACACTTCTCGGA- CGCCGCCCCAGCACGGT CCTTGTGTGAGGTGGACACTCCTTCTGGACGCCGCCCCAGCACGGTCCTTGTGTGAGGTGGACACTCCTTCT- GGACGCCGCCCCAGTACG GTCCTTGTGTGAGGTGGACACTCCTTCTAGGGAAGGAGTAGTAACTCTTGGGTGGTCGGGTAGTTGCCATGG- AAAGGGGCAGTAATGCCC AGGTATTGCCGTGGCAACCGTAAACTGACATGGCGCACTGGAGGGCGTGCCTCATGGAAAGCTACCTGTGCC- CCTGCCCTGTGTTAGCTA GGCCTCAATGTGGTCCAGTATCTGAGCACCGCCTCCTGCCTCAGATGTTCCCGTCTGTCACCCCATTACCAG- GGCGGCACTTCGGGTCCTT TCCAGCCATCATTGTCCTGGCATTGCCACAGTGGACACTGCCACACAGGCTTGTGTGCTTGCGCGTACCCAG- GTCCTCACCTCTCTGGGAT AAACCAGGCACGTGGCGGCCGCCCCATTTTCCACCCGCCAGCGGTGGAGGAGTTGCCCAGCCTTGCAGGAAA- ACAGCTCTCATGCCAGC AGCGGAGCATCCTATTCAAGTTTTCTCAGGGCTGCCAGCACAAATGCTGCATGCCGGGCGGCTTCCTCAGCA- GACCGTTGTTTCTCTGCGT CCTGGAGGCTGGACGTCCCAGGTCCCCGTGTGGCAGGCCCGGTTCCTCCCGCAGCCTCTCCTTGGCTTGTGG- GCGGCGTCTCCTCCCTG GGTCCTCGCAGGGCCACCCCTCCGTGTGTCTGTGTCCTCCCTCCCCTTATAAGGACCCCAGGCAGACTGGAT- CAGGGCCTGCCCTAAGGA CTGAATTTTACCTTAATCACCTCTTTAAAAGCTGTCTCCAAATACAGTCACCTTCTGGGGTCCTGGCTGTTA- GGGCTTTGATGCATGGATTTG GGGGACACCGCTCAGCCCCTAACAGCCCCCATCCTCTGCCTGCCTTTACCATGGGGCTGAGCCCAGCCCTGC- AGGAGTCCCCTGGTTTGA TGTCTGCTGTGGCCACGGCGACCCTCAGGCTGCTCCAGCCGCACTTGTGCTT 244 chr21: 45609000-45610600 GGGGAGTCTCCAGGGGCTGGGGCTGGAGCCGCATCAGAGAGGAAAGGGGTGTTTGAAAAAGGGGCAGGGCCTG- GGACCCAGGAAACTG TTCTTCCAGAGACACCCGTGAAGCTGAGCTTTGCCTCTCAGGGAAGCTGTGACCCCACGGGTGCTGCCCAGA- GAGATCGGGCCAGGTGGA GCCAAGATGGACTGGAATTCCCCGACGGGGACAAGGGGCCGGACGAGGCTGACTTGCCCTGTCTGATGAATG- GTCAGGTTTGCTTTTTCT CCTGAAAACACGAGGCAGTGATCCCGGCCAGCTAATTCCAGCAGACTGGAGACGGGATGGTGGAGAATGAGG- CTGTGGGCGGGAAGAGC AGATGGGACTCGCCAGCATCCTCACGGCAGGGCCGCGCTATTGCCCTCCCTCCCCTCCTACTCTCTGGGGTC- CCAGGAGCCCCAGATACG CAATGCTGCCAGGCGATTTCTGGCGCCCCGCAGACCCCTGCCCCTGGAGTTGGGCCAGGTCCCGGCTGGAGC- AAAGGGGGCTCCTTCAA GCCCGCTCCTCCCTGTCAAACCCGAGGAGCCTGACAGGCGCAGCGTCACCAGCGTCACCGGGCCATAGTGAG- CGGCCAAGCCAGCGTCA CCGGGCCATAGTGAGCGGCCAAGCCAGCGTCACCGGGCCATAGTGAGCCGCCAAGCCAGCGTCACCGGGCCA- TAGTGAGCCGCCAAGC CAGTGTCACCGGGCCATAGTGAGCGGCCAAGCCTTGGTCTGCCAGAGCCGGCCGCACCAGAAGGATTTCTGG- GTCCCCAGTCCTGGAGG AGCACACGGTTTACACCAGGCCTTGGGAGGGGAAGAGGCAAGGCGTGGGCCCAGCCCTCACTCCCCAGGAGA- AACCCTGTTTGAGCGGC AGAGGAGACTGGAGAGACCCCAGGGCGGGGATCCCTGAGAGGAGAGAAACCCGGAATTCATCCACGGAGGCG- TTCACCCAGAGGAGACC CGGAGCTTCTCCAGGAGAGGCTGGATTGCTCCAACAGGGGCCCTGAGGAGCTGATGGCAAGAGCGGAAGGCA- GCTCTGACTCGTGCGTC TGACTCCAGGTGTGGCCGTTGGGGCTACAGTGGGACCAGCCTGTTGTCACTGAACCCACAAAGTGCCTCCGA- GCGCGGGTGGAGAGAGG GGGACCTCCCACCGTCTGCTGGCCTTGAATCTTGAATCTAATTCCCGTCTGTGCTTTGATGGGAGAGGCACT- GGGAGCGGGCGGCTTTTTC AGTTCCTTTTATCTTGAATGGCCTTTGGGGGATTTTCACAGATTCTGAGTTCAAAGCCCAGGGAGGTGTGGG- AACGTGACATTCCTCACCGC ATTCCTCACCGCATTCCTCTGTAAACCAGGCGGTGTTGGCACCCATGAGCCTGTGTCTTCTATGACATCAGG- AGTTTTATCCCTCACGTCAG AAATCAGGGTTCCAGGCGCCTTGGTTTTTCTTGGCGCCAGCGGCTTGGCTATAGAAGAAAAACTGAAGGGGC- CAGGTGCGGTGGCTCACA CCTGTAATCCCAGCACTTTGGAAGGCCAAGGCGGGTGGATCACGAGGTCAGGGGTTCGAGACCAGCCAACAT- GGCAA 245 COL18A1 GCTCCTCAGGGGGAGGTTCGGGGCCTTTGGTCTCTGGACTTGGGCAGCAGAAAGGAAACATCCCTGGGGGCCT- GTGGTGACCCCCATCC TCCCCAGGGTGGTCTGGCAGGGGACACTGTTTTCCAAAGCAAAGCCAGAGCGCCAAGGGCTCTCGGGATTCA- CGAGATCCACATTTATCC CAAGTTAGAACAGCACATCTGTGCGTGCAAACTTCATTCTGACTTCGGCCGGCTGTCCTTCTTGCCCAAAGC- ACCGTGAGGCCTCATCCCT GCATCCCTGTTGCTTCTTTCATGTGGGATGAGAACCCAGGAAGGGGCTGAGTGTGACTCCTCTGGTTTTTAG- AGAGCACTGCCCCCGCCCC GCCCCCTCCTGCTTCCCCACCTTTTCACAGTTGCCTGGCTGGGGCGTAAGTGAATTGACAGCATTTAGTTTG- AGTGACTTTCGAGTTACTTT TTTTCTTTTTTTGAGACAGAGTCTCGCTCTGTCGCCCAGGGTGGACTGCAGTGGTGTAATCTTGGCTCACTG- CAACCTCTACCTCCCGGGTT CAAGCGATTCTCACATCTCAGCCTCTGGAGTAGCTGGAATTACAGGCGCCCGCCACCACACCTGGCTAATTT- TTGTGTTTTTAGTAGAGATG GGGTTTCACCATGTTGGCCAGGCTGGTCTCGAACTCCTGACCTCAGGTGATCCGCCTGCCTTGGCCTCCCAA- AGTGCTGGGATTACAGGT GTGAGCCACCGAGCCTGGCCTGGAGTTATTTTGGGAGAGGGCAGCCCCTGGTTCAGCGTGGCGAGGCTGCGC- TTGCTCTCCCGGGCGGG CGTCCACACCCTCCTCGCCGAGATGGAGAAGCCCAAACCCCTGCAGCGCTCCCCCATCACGTCCGGCCCTGG- AAGCCCCCGGAAACCCT GCCACGCCCTGAGTGGGAGAGCGCAGGTCCCTTTCCGGCCCTGGAAGCCCCCAGAAACCCTTGGGTGCCAGG- CCTGGCCGGGACAGCA GCGACACTGCATGCTCAGCCCTTGCGTGAGACCACGGGAGTGTCCGCCCTCTGCACGTGCTGCTGATTGCCC- ACTTCGTCCAGCAGGTTT GGGAGCTTGTGGCTGCATCCTCCTGCAGACACTTGCCCATTCTGGGGCCTCCTCTCTGTCTTTTCTCCTCTG- TTGAGGGGTCTGGGAGGGA GGCCTTGGAGGGTACCCATGCTGCTGGGACTGATGCTCCCCGCGGTGGAAGGAGCTGCCTCTTGAACAGCAG- GGGGCTGAGCAGAGGG GAGGGGATGCGGGGGTGCCGTGCACACAGGTGCTCTCAGGACGCAGGGGCTTCTCAGCCCTGCTGTCCCAGG- GCTGCACTCCAGCAGG GCAGACTCCTGAGGTGCAGACACCCCAGCTTCACGCTCACACTTCTGGAAGGCGATGTCTGTGCGTTTGCTT- TCTGCTGCAGTTTAAAAAG CCGGGCTCTCTCCGGAGCGTGTGTAGGGCCTGGTCACTGGAATATCTGGACTCAGTGTTAATGGCAGCCACG- CTGGGGGCTGGGCCCAG

CTTTCTGTTCTCCGTGTGGGTGCCATATCCACCTCCATCGCAGCCCTTTCTCTCTCGACCTTTTAAATCACA- GTGTCACCTCCCCCTGCTGT CCTGCCAGTGGCCCCTGGAGGCTTCTCCCCACCCCTTTCTTCTGGGGCAATTCTTAAGGCTGGCATTGAATC- AGGAGGCCAGATGTGGCC CCTAGTAACTCACCAGCAGTCCCTGAGGCTTCTGGCTCCCCTGGCCCACCAGCCTCCCATGTCTGCCTCAGG- CCTCTTGACCCGCCTGGC ACTGACCAGACTGTGTGCCCGGGTGCCGTGCCCATGGGCTCCGCCTCCCCCAGGCAGGCCCCCTCTTGCTCC- GCGGCCACCCCTGCTCT TGACCTCACACCTCTGCGGTGTGTCTGGACACACCAGCACCACGGCGGGCGGGGAGCGGAATTCTCCAGGTG- GGGTGGGCAGGCCGGC GGGTGTTGAGGTCTCTGTGCATGCTTGTGCGTACCCTGGACTTTGCCGTGAGGGGTGGCCAGTGCTCTGGGT- GCCTTTGCCAGACAACTG GTCTGCCGGGCCGAGCATTCATGCTGGTCGCCATCACGTGACTCCCATGCGCCCTGGCCCTGGGGTTGGGTC- TGCAGGACTGAGAACCA GCGGAAGGGGGGCGAGGCCTCGGGAATGCGCCGGCAACTGGCGATGAGCTCAGGCCTGACTAATGAGCCCAG- GTGACTCATACACCCG GGGCCTGGATGAGTCTGACTGGGTCAGGACTTCCCTGCTTGTTCTGTCCTGGGAGATGTTGTCCCTGGCCCT- GCAGAGCCGGGAGGACAC GAGGCCTCCTGGGTCACAGCCAACGCAGCCTACTCCTGCCCACTGCTCGCGCCGGCCAAGGCCCGTCGGCAC- CACCTCCTCCATGAAGC CTTCCTGACTGCCCCCATCCCTCTGTGGGCAGCTCGAGTGTGCATCTTGAGTGCTGTGCAGGTTGGGGTCCG- GCGCTCCTGCAGGCAGGC GGCGTCTGGGCCTGGGGGCTCTCAGAGTTTGAGGAGCGTGTGGTGAGGGTGGCCTCGGGCCTCAAAGACGCA- GCGCTGTGGGAACCGG GAGACTGGCTGAGCCCGCTCTGAGGAAGGTGGGGCCAGGGGCACCCTCAGCTGACCCGGCGTGCAGGGGTGA- CCAGCCAGGCGTGGCC AAGGATGGGGTCTCTGGGATCAGGAGACTTCAGTAGCAGCCAGGACCGAGGCCACCAGTTTCCACCCTGGCA- TTTTCCATCTTTTGAAGGA CTGGAAACGATTGGATTCTTTAACTTTTTTAAGTTGAGGTGAAATTCACAACGCATAAAATTAACCATCTTA- AAGCGAACAATTCGGTGACATT TAGTACAGCCAGAAGGCTGTGCAGCCATCACCACTGCCCAACTCTAGAACATTCACACGCCGGAGAGAGGGA- GCCCTGGGCCATCACGCA GCCACCGCCCGGCCCCAAGAACCTGCGAGTCCACTTTCCACCTCTGGATCGGCGGTTCTGGACGTTCATGCA- GGTGGTTCCCGCAGTGCG AGGCCTTTTGTTTCGGGCTCCTCTCACAAGCCTCACGTTTCCAGGTACGTCGTGGTGTTGTGCAGACCCACA- ATTCATCCCTTTTCATGGGT GTGTAATAGTCCACCATAGATTCTCTACGTTTTAAAGCATGTTTTATGTGCCTGAAATGTCTCTGCACTCGA- GACTATAGCTTGCTTTCTTTCT TTTCTTTTTTTTTTTTTAATTTGAGACGGAGTCTTGCTCTGTTTTCAGGCTGGAGTGCAGTGGTGCGATCTC- GGCTCACTATAACCTCTGCCT CCCAGGTTCAACTGATTCTTTTGCCTCAGCCTCCCGAGTAGCTGGGACTATAGGCGCGCCACCCCACCCGGC- CAATTTTTTTGTATTTTTAG TAGAGATGGGGTTTCATCATGTTGGCCAGGATGGTCTCGATCTTCCGACCTTGTGATCTGCCCGCCTCGGCC- TCCCAAATTGTTGGGATTA CAGGCGTGAGCCACCGCGCCCAGCCGAGACTACAGCTTTCTTTAACTGCATCCCTGGAGGGATCTGAGAGTC- TCTTTCCCTGTCTCCTTTC CTTTGGAAAACATTTCAGCCAGGGCTCCCCAAGATGAAAGGCCAGAGTCCCAGGCATGGGCGTTGCAGGTGC- ACAGTTGCCACGGGGAGC TGTGGGTGATGGTCGCTGTCAGCGATGGCTGCTGCAGGTCCCTGTGAGGAAGGGGCAGTGCCACAGCAGGAG- GAGAGGGAGTCAGCGG ACGTTGATTGGCAGTGCCCGCCCATTCCATCATTCAGTCACCCACTGTGCACCCAGCACCCAGGCTCGGCTG- CATAGAACATGGCCCAGG AAGGCTCCACTTCCTGTCTCCTCTTCTCCCCTCTCCAGTCTCATGATGGGGCTGGAGGCATCTTCTAGTTTT- GAGTTCTGAGCTAATGAACA TGCTCATGAGCAGGCGGCAGGATCCCAGGACGGTGGAGCTGGGAGCCTGACTGCGGGTGACGGACAGGCTCT- GGCAGCCCCTGTCAGC ATCCTCTCCAGGGCATGTGAAAGCCAGTGTGTCCTCAGCTGCCAGTGCCCCCTCCCCACCTCCTCTGGGCCC- ATGTGCACGGGACCTGGG CTCCCCCAACCAAGCCTGCCCGCCTTGGTTCAGCAGAACGGCTCCTGTCTCTACAGCGGTGCCAGGCCAGGA- GTGCTGTGTCTGTGAAGC GGGGTCATGGTTTTGGGGCCCTCATCTCCCTCGCGCCCTCTCATTGGGGACCCCCCGTCTCCCTAGCGCCCT- CTCGTCCTCTCCTGCATG TGCTGTGTCTGTGAAGCGGGGTCATGGTTTTGGGGCCCCCCGTCTCCCTAGCGTTCTCTCGCCCTCTCCAGC- ATGTGAAGTGGGGTCATG GTTTGGGGGCCCCCATCTCCCTAGCGCCCTCTCGTTGGGGACCCCCCGTCTCCCTAGCGCCCTCTCGCCCTC- GCCTGCATGTGCTGTGTC CATGAAGTGGGGTCATGGTTTGGGGGCCCCCTATCTTTCTAGCACCCTCTCGCCCTCTCCTGTATGTGAAGT- GGGGTCATGGTTTGGGGG CCGCCATCTTTCTAGCGCCCTCTCGCCTTCTCCTGAGCGTGTGGAACTCTGTGGTGGTCAGAGCTAAGGTTC- TGAATAGGTCGAAGCACCT CCCCGGTGCCTCTCACCCTGAATGCTCTGGGAGGACACAGCCTTTTCATAGGCTACGACTGACATGGCAGGA- GGGGCCTGCCTGCCACCC GGGTCCTCTGCTGCCTGCTGCTTGCTGGGGAGGGGGCTCGAGACTGGGATCCTGGGCTTCTGCTCCAGCTGT- GCCCAAGGGAGCTGCTG AGGAGGGACCGGGTGGGGCATCCACTCTGGGCAGGTTCAGGGTCATTCTTGGTGACCCCGGGTCCGGTTACA- AAGGCTGATGGAGCGCG TGGGTGGCTGCCTAAGTCTCTGGAAGCCCAAGAATGTGGAGATGGCGCGTCTCGGCCCGGGGTCTCGTGGCT- GGTCTGGGAGAACTTGC CTTTATTTCTAGGCAGGAGGCTGCACTGCAAGGGAGCGTCAGTGGCCCGGCTGGCTTTCCCCGGCCCTCAGC- CCGCACTCGTCCACCAAA GCAAGCTCCTTTGTGGGGCTGCCCTGGGAAGCCGGGATCACGAGGCTCTGCCGGCCGTGGTCACCCCATGAG- GCAGGGTCAGCTCGGG AGCAAGGCGGATCAGATGGAACAGAACACGTAGACCACCTCGCCCGCCCTTAGTCAGCTGGGCCATTGAAAA- TCAAGTCCGTAGAAAGAC CTAGAAATAAGTCCCGGGGTGCCCTTGCCTGTTGACGGGCGGGCCGAGCAGGACTGTTCTCAGGCAGGCACT- GGTCTCTTGGCTTCCAGG TGGTTTGTTTGCTGGTTTGAGGCTGGGGGTGACGCTCCTGTGCGGGAGGAGGTCGCATTCCATTCATAGCGG- CTTATCTGGGCTGTCAGG CAGGCCTGGGAGGGAGCCTGCCTCTGTGCTCTCCAAGGGTGGGCGACGGACAGACAGGGTGTCCCACCCCTT- CTGGGCCAAGGACAGA GGGTCAGTGTTTGCAGAGACCTGGGGAGGCCCAGGTGACCTCCACCGAGCACCTGCTGTGTGCAGGGCCAGT- GCTGGCTGCAGAGACAG CGGAGCGTGTGTGGACCCGGCGGCCCAGGGGAGGGGGGCAGGCAGGACCCGGCGGCCCAGGGGAGGGGGGCA- GGCAGGACCCGGCG GCCCAGGGGAGGTGGGCAGGCAGGACCCGGCGGCCCAGGGGAGGGGGGCAGGCAGGACCCGGCGGCCCAGGG- GAGGGGGCAGGCA GGACCCGGCGGCCCAGGGGAGGGGGGCAGGCAGGACTCGGCGGCCCAGGGGAGGGGGGCAGGCAGGACCAGG- CGGCCCTGGGGGTC AGGGGTGGAGGCCAGGCCTAGACGGCCCACAGGAGGGTGGACTCATTCTGACCGATTCCTGGAAGCCCCCGG- AAAGTGGTGATGTTCTG GAGGGCCCAGCAGACCCCAAGGCCCCCAAGACAATCCCAGCTGGCTCTCTGCGGCTCTCGGTGTCTGCCATT- TGAGACAATTTGGGCACA GGCAGGGCAGGCCGTCGCGGACGGTCTAAGCCGCGCGCATTGGTGGGGGCAGCAGAGCCCCTGCTCTCAGCT- CCTCGGGGTACAGCGG GGGTACCAGGCGGGTGAGTGGGTGGGTGGTCACTGCTCCTGCCAAGGGCAGCCCTGGTTTGGTTTGCACTTG- CTGCCCTGGTGACGGCT GCTCTCATTCCTGCCCCATTGCTAACAAGGGTGTCATAAGCTACTTTCCCGGCCCACATCCTATTAAGCCCA- TGGAGACCCTCCCACAGCT GAGCCTGCTGTGGGCTGCAGGCCCTGGGCGGTGCCCACCTCGGTCCCCACTGGCCTCCTTCCAGCACTTTAG- AGCAGACACAGGTTGGA GATAAGGAAAGTTCCAGAGCACAGACTGGAACAAGCCCCAGGCCTCTCCCTGCCCCAGCAGGGCCTCCCTGG- ATTTGGGGGACAGGTGC CCTCATGGGGGGTCCTGAAGGTCAGAGCTGGGGCTGGGGCTGGGCTGGCGGAGGTGGCCTTGGCGGAGGCCA- CATTCCAGGGTCTCAG TGAGAGTCTGTGGCAGGCAGCCTTGCAGATGCCGCTGAGGGACCCCCCACTTCATGTTGTGGGTGATGTGGT- CCATTGATTGCCTCCAGG TTTAAATCAGGTGGATATTTACCTAGCGGCCTCCTCTCCCTCTGCACAGGGCCTGGAGTGGGATGGACTGGG- GTGCTCAGCTGGAGGCTC TGCAGACACAGCCCCCTGGGCTATGCAGGCCCTGCTGGGAGCCACATTGCCATTTTTCATCACCCACTTTTT- GGGTGAGAACCCCCTCGAG TCCTAACATCTGCCGCATCTCAGAGCCTGTGGCTCCAGTCAGAGCATCTGGACCATACTGCTGGGGTCAGAG- CGCGGCAGGACAATGGC 246 COL18A1 TGCCACCACCATCTTCAGGTAGAGCTTCTCTCTCCTCCTTGCTGGGCGGGGCCCCTCCCTGGGGAAGCCTGCA- GGACCCAGACAGCCAAG GACTCTCGCCCGCCGCAGCCGCTCCCAGCCAGCAGCTCCAACGCCCTGACGTCCGCCTGCGCACGCCACTTC- TGCACCCCCTGGTGATG GGCTCCCTGGGCAAGCACGCGGCCCCCTCCGCCTTCTCCTCTGGGCTCCCGGGCGCACTGTCTCAGGTCGCA- GTCACCACTTTAACCAG GGACAGCGGTGCTTGGGTCTCCCACGTGGCTAACTCTGTGGGGCCGGGTCTTGCTAATAACTCTGCCCTGCT- CGGGGCTGACCCCGAGG CCCCCGCCGGTCGCTGCCTGCCCCTGCCACCCTCCCTGCCAGTCTGCGGCCACCTGGGCATCTCACGCTTCT- GGCTGCCCAACCACCTC CACCACGAGAGCGGCGAGCAGGTGCGGGCCGGGGCACGGGCGTGGGGGGGCCTGCTGCAGACGCACTGCCAC- CCCTTCCTCGCCTGG TTCTTCTGCCTGCTGCTGGTCCCCCCATGCGGCAGCGTCCCGCCGCCCGCCCCGCCACCCTGCTGCCAGTTC- TGCGAGGCCCTGCAGGA TGCGTGTTGGAGCCGCCTGGGCGGGGGCCGGCTGCCCGTCGCCTGTGCCTCGCTCCCGACCCAGGAGGATGG- GTACTGTGTGCTCATTG GGCCGGCTGCAGGTAACTGGCCGGCCCCGATCTCCCCACCCTTTCCTTTTTGCCTTGCCAGGTAAGTGTGGG- CGGGGCTGACGTGAGCCT GGTACAGGTTCCCCCCACATCGAATCTCTACGTTCAGGGGCCCGTGGCCCTCGGGAGGTGGGAGAGCTGGGA- GTGAGGCCTCCTGTGTG GGGAGGAGGCCGGCGTCTGGACAGGAAGAGGGCTGGATGAACCGCAGCCGATGTGTCCAGGTGCCACCTGGG- CCTGGAGCTCCCTGAG CATTTTAGCGCATTTAGTCCTCAGCACGGTCCCGAGATACCCTGCCATGCCCCGAGTCACAGAGGGGAAACT- GAGGCGTGGGGCAGTGGC GTGACTCACCCCAGGGAGCCGAGATTCCCGCTCAGGTGTGGCTGCATCGACCTTGCTCCGGTCACTAAGCTG- CACGGTTCGATGCGCTTC CTGGGAGCCCCAGCGTGCTCGGGCCAAGGGTGCTGCCGCGTGGGCAGTGCAGAGACCCTACCAGCGTGGGGA- CCAGGGAGGTCTGCAG GGCCCGTCCTGAGAGGGAGCCTTTCATGTCCCCCTCCCCATCCTGAAGCACACAGCCTCCCTGCCACAGTGG- GGGCCGCTTCTGGGCCC AGGGGACGTTGCCCCATCACCGTGTGGCCTGGCCTTGTTGCTGGCTGGACAGTTGGGGGCAGGAAGAGGAGG- GAAAGGGGGACTCTTTA ACCTCCTGGGGGCAGGGGCAGCCCAGAAAGGACCCCAGCAGATCCCTCCTCTGTGTCCGGGAGTAGACGGGG- CCCC 247 COL18A1 GGGCTCCACAGCGGCCTGTCTCCTCACAGGGTTCAGCCCAGTCTGCTCTCACTCATTTGCTGATTCATTCTTT- CATTCAGCCAGTCAATAGT CATGGCCCCTCCTGTGTGCCGGGTGGCCATGGATATTGCCCTGGGTAACACACAGCCTGGCCCTGTGGAGCA- GACAGTGGGGACAGCCA TGTGGACAGGGTGCAGGTGGATGGCAATGGCAGCTGGGTCAGGAGGGGCTGAGGGCCGTGGGGAAAGGTGCA- GAATCAATAGGGGCAT CCGGACTGGGGTGCAGGCCTGGGGGCTGGGATTTCTAGGGTGGAGGTCACCTCTGAGGGAGACAGAGCAAGG- CCCTGGGAGATTAGAA GGTCGAAGGTCGCCGTGTTGAGGTCAGGGGCCCTGAATTGGAGCCGCGGCAAAGGAGAGGGCAGGTCAGGGC- ACGTGGTGAGTGATTG CTGCGGCTTCTGAGCACGGCTGGGTCTGTGGGGCCTGAGCAGAGGTGACCCGCGATCCGGCGCCACGGCAGG- CAGGACTCCCCACCCT TGCTGCTGCCTACACCCCCAGGGCAGCCCCAGAGTCGGGGGCGCAGCTCCCTGCTTGCCAGTTCAGAGCCCA- GCCCCTCTCACCCAGCC CAGAGGAGGACACAGATGGAGGAGGGGCACCCGGAGGGTCCCCCCGCCGACAGGCCCCACGTCTCCCACCTG- CAGGACAATGAAGTGG CCGCCTTGCAGCCCCCCGTGGTGCAGCTGCACGACAGCAACCCCTACCCGCGGCGGGAGCACCCCCACCCCA- CCGCGCGGCCCTGGCG GGCAGATGACATCCTGGCCAGCCCCCCTCGCCTGCCCGAGCCCCAGCCCTACCCCGGAGCCCCGCACCACAG- CTCCTACGTGCACCTGC GGCCGGCGCGACCCACAAGCCCACCCGCCCACAGCCACCGCGACTTCCAGCCGGTGGTGAGTGCCCCCCCAA- AGTGGGCTTGGCTCCAT CTAGCCCCTCGGCTCTCGGCAGCAGAAGAGGGCCCAGCCCCTGCAGAGCTGCTGGGGGTCCCAGGCTTCGGC- CATGGGTGGGGGTCTG GCGGCTCAGGGCCACTCAGGGCGGCTTGGCTGGCCCTGGGACTTGCCCTCTGGTGGCCAAGCAGTGGTCATG- AAAGTCCAGCCGCTGTC ACATCCTTGAGGAACCGGCGTACCTCCGCCTACAGCGGCAGCTGGGGGCACCCACGTGGCCCGGGGCTGCTC- TGACCTGGCAGCGTATG GGGGCTGCTGCCTGGGCCCCTCAGTGTGTCACTTGCGCGCCTCCCGCTCAGCGCCCCTCGGCCGTGCCTGTC- CACACAGGTGCGGGGC CGGGGTGGTGCGCCCGGGGCCTGGGTGCAGGGGGCAGCGTGGGACACAGCCCGTGACGCGCCCCTCTCCCCG- CAGCTCCACCTGGTT GCGCTCAACAGCCCCCTGTCAGGCGGCATGCGGGGCATCCGCGGGGCCGACTTCCAGTGCTTCCAGCAGGCG- CGGGCCGTGGGGCTGG CGGGCACCTTCCGCGCCTTCCTGTCCTCGCGCCTGCAGGACCTGTACAGCATCGTGCGCCGTGCCGACCGCG- CAGCCGTGCCCATCGTC AACCTCAAGGTGGGTCAGTCCAGTCCTGAGGGCGCGGGCTCCTCGGCCCCCACTTGACCTCTGGGGTGAACT- CCCAGCGGGGAGCTCCC CTCTAGGGCCTCTGGAGGCCACCATGTTACAGACACTGGCGCCTAGGCTGGCGACTTCAGGGCAGGCTCCGG- GTGGGTCACACCCCTCC AGGCTCAGGCCAGGCCTCTGCATCCCTGGGCACTGCCACGTCCCCCAGGGCATCCCATGAGGCCCCCCCGTG- GCCCCCTGACCCCCCGC TCCCCCGGCAGTGCCCCTCAGAGGGTCCCATGCTGCTGGACCAAGTGTCCACACAGGTGATAGGGCTCACAT- ACAAGCCTGGAATCAGGA ACCGTCCTTTGGGCCTCTAGTGCCATGCGGGCTGGTGGCCCCTCTGCCA 248 chr21: 45885000-45887000 GCCTGGAGTGTAGTCCTGCTGAAGGCCAGAGACCACACACTCCACCCAGACTCCGGATCTCCCTCCCCAGCAG- GGGGATGGAGGCCCTG CCGCTGGGAGTGCTGGTGTTATGTGGAAGGGCTGGGCTTCTCCAGGGCTCCTGGGAGGCCTAAACATCTTGC- AAGGTTTTGACGTTAATTA CTATTATGATTGCTTTCTGTGTGTTACTGTTTTCCCCACACTTTAGCCAGCTAATGTGGAGCTACAGAAGGC- CCTCGCCCCTACCCCTCCAG ATGTCCCAGCCCATGACAAGCAGGAAGGCCGGGTGCTGGGAGACTTCCTGGGGCTGGATCTGACATCATTCC- AAGCAGATGATAACCTGC CTTCCCGATTTCCAAACCCACAGCAAGACACCCTGGAGTTATTTATAAATGCGAGCCCCTGGGTGCACTTCT- GACGGGACCAGCACCCTGA CGGCCATGAGAGGGTGGAGACAGCGCACCCCGAGCTCAGGGAGGCAGGAAACTCTGGACCTGGAGGCCGGGC- ACCATGAGGGACACGC TGCAGGCCCAGCTGCTGCCGCCTGGGGCGGGGCTGCCCTGCAGGCTCCGGGAAAACCCAGAACCAGGCCGGA- TCAGCGTGTGTCAAGA GGCGGGGCGTGAGAGATGAGCTGCTTTTTTTCTTCACAGGGTTGGCAGGAACTGCAAATAATAGAAAGTCTT- TAGGGTCTAACACGCTGCC CTGAAAACACTATCATTACTTTCCTAATGACTAACTGTGTCTTTCAGCCGGCGGGGCAGGCAGCTGAGGCCG- CAGGCTCCCGCAGAGGAC CGGGGGAGGCTGGCAGCCTGTAATCTGGGGGCGCTGACAGTGCTCTGCCCAGACCCTCGCGCCAGCTCCAGC- TCCAGCACAGCAGCCCT GGGTCCCTCTGGCCCCCTGCCCGCAGAGTCCAGGTGTGGCAGAGGCCGCCCAGTATCCCTTCTCCTCCTCCT- TTTCTAAAAACAGAGTCT CACGATGTTTCCCATGCGGGTCTCCAACGCCTGGGCTCAAGCGATCCTTCTGCCTCGGCCTCCCAAAGCGTT- GGGATTAAGGGGCGAGCC ACCGCGCCCGGCCCACCTTCCCTTCTGGTTCATTTCCAGTAAGGTCCTGTCCACAGCGTCCTTCCCAGCATT- CCCACCAGGCTGCAGGCCT TGGCCTCCCTCCCCTCCATTCTCATTCTCCCCGAAACCGCCAAGCGCGTCCAAAGCACGGGTTCGCCAAGCG- CCCCCCCCGCCCCACTCC ACATTCCCTTCCCCGCCGACTCAGCCTCCGTAGCTCGCGGACGGCCCCTCCTCACGCCAGCCCAGGCTTTTT- TTTTTTTTTTTTCTTCTATTT TAAGGTTGTCTTTTAATGACACAAGCGACATTTGGAGACAAAAGGACACATCTCTTCCTGACCCACCTCCAA- CCCCAGCTGACGGCCGCCC TGAGCCTGGCGTAGACGGCCCGGAACGTTCCCTGCGTGGGTTCCGTCCATCCCGAACCCCTGTCCCCGCGCC- GGCTCCGGGGGTGCTCG GGGGGCCGCGTGGGGTCTGTGACGTCGCCTCGAGGCTGCATCCCGGTGACCCGGCAGCCCCTGGCGCTCGCG- GGAGGCGGGCGGGCG CGGACCCCAGGCTTTAGGGCGCGATTCCTGCAGCTGGCTGCCGGCCCGAGGTTCTGGGGTGTCTGAGGTCTC- GGGCGGGGCGAGGACG TTTCTCCGGCTCAGCCCCCCCACCTCCTGCCCTGCCGCCCCCCACACCCAGCTCCCCACGGACGCCAAGAGG- CGCCTCCCACCCCGGCG AGGACCCGCGGGGAAACGGGGCCCAGGCGCGGCGACTGCGGAGGACGCGCCTCGGCCCCAGCGCCCTGGTCC- TCGGGGCGTCCGGCT GCCCTTGCCCGAGGCCGGGGCGGGCGCTCAGCGCCGCGGAAGAAACGCCCGGGCGGGGACGCACAGCGAGGC- GGGCTCCGCGGGAA

GTACCGGGAAAACGGCGCGGAGCGGAACAG 249 PCBP3 TGGAGCAATCCCAGAGAGGCTGAGGTGTTCAGGCTGGCCCCAGATGCACACGAGCGTGAAGCCT- GTTCAGAAGCCAGCTCCTCACACCCT CTCCCCTGCCAGAGGCTCCAGCACCCCCTCCCCTCTCCTCTCCCCTCCCTTCCCTGTGGTCCTCCTGCCCAC- CCCACCCCCGTCTGCATG TGCACCGTCACGGAGATGCGTGTACTAGGGCGGAGGTCGGGGACAGTCGTCAGAAGGACACAGGAAAGAAGG- GAACAGGAATCCCATAA CAGAACATTATCCGGCAGGAGTAATTAACACAGGCAGGACTGGAGGCTTTGTTTTGTTTTGCTTAAAAAACA- GTGGTATTTAAATTAATGGGC ATGGGAAGACTATTCAGTGAAAGACATCGGTCATTGAGGTATCTATTCAAAAACACGGTTTAGTACTCTGCC- ACACACCGAACGCAACGCCA CAGCAGCCATAGAAGCGTGTGTGGCTGTTTAACGTGGTCTTTTTGGGGAGGGCATCCTAGGCAGAGCAGGCG- TGGAAGGGAAGGCGGCG GACGGAACAAAACGCGGGCACGCAACGGCTGCTGCGCCGGATCTGAGGCAGGGCCAGCCTGTGGGAGCAGCA- ACATCGCTCGCAGGAC AGCGATGGAGCCCCCACGAATCCGCGTGAAAGCAGCAACCACCTAGAAATGAACGTACAGCTGCTTAGAAAC- AGAATACGGATGACCCGA AAGACTTCCCGATGGTAGTCACCAGCATACAGGACCTGACACGGGCGTGCGGGCAGGGTGTGCCGCTACGGG- GTCCCTGGCGCACCTGC TACCCCTGCTACCCGCATTCACCGCACGCGGAGGGTGCGGGCCGTGAAGGTTATACATGCAAATATCCTTCC- ACCAGCCAGTTCTCCTTCC AGGAATCTGCCACCCGACCCTTGTGTTGTGCACAGACATGGTCCAGGTGTTTGCGACGTGATTGTTTATCAG- AGAGAGAGAAGGGAAATCT CCAGGCTCGCTGTAGCTGCAGGAGCTCTGGGGGCTGCGCCCATCGTGGAGACGGATAGCTGTCTCTCATGAA- CACAGGACAGCAAGTCC GGCTGCGGCCACAGAAGACTCGCCCTCCTGGACGCAGCGTCTTCCTTCCTCAGCCCCACACTGGAGGTGGCC- AGTGCCATCCACAGCAG AAGGGGCCAGCCGGGACCAGGCTCACGCCGTGGAATTCTGCTCTGTGGTAAGAGGAAGAGCGATAGCTGGAA- CCCAGCGCCGTCGCACA CACAGCGGGGAAGAGTCTCAGAAATGTTACTTTGAGTCAAAAAGCTGGACAAAAAAAGGCGCAAGCCAGATG- GTGCTGAAGAGGCCACAG GAGGCTGGCAGCCAGGGGGTCTGGCACCTCACTCGGAGGCGCAGTGGGCCCGTCCGGAATTAGTGGCCATAC- GGCAAGTGCCGAGTGG ACATCAAACCGTCACTTCAGACTCCTGCGCTTCACTGCCTGTCGGTTATGCCTGGGTTTTGAAATCAAGTCA- CAGAACACCTGGAATGTGGT GTTTACGCAGAACAAAGCGGGTGCCTCGGAGGAGAGAGCCTAGGGACAGGGGCACCTCCCGGTGTGGGTGCC- CAGGGTTGCAGGGTGG CTTCCTCTGTCTGCGCGGTTTTCAGAGCCCCAGGGTCCTGCCTGCCCGGCTGCCTGGAGGCGGCCCACATCC- TGCTCTGCGCCGCCGAA TCTCAGCCTGAACAGCTTCGCTGGTGTTTGTGTTGACTTATTTGTTCTTTTTTTTTTTTTTTTTTTTTAAAT- AAAGGATTCCGATGCTGTTACAG TCAATAAAAGCCACAGGTCTGGGTGACCTACAAATGTGTGTGTCTGACTTTCTGCAGTTTAAATCGCCACTG- AGCCTTAAGGCGTCTGGCCC GCGCATTGAGGAATCCACGTGGGTCTCGGGGTCCCCATGCCTGCCCAGCTCCCTGCTTCAGCCTGGGCGGGT- CTGGCGGGCATTTCTGC GAGCCTGTCCCTGGGCCCGCCTCCTGGCCAGACTTCCAGAAACATTGTCCACATCCCCGTTGCACGTCCCCC- CGTCACCGGAAACTGCAG CCCACAGCACTGGGAAGAACCCGGGAGGCAGGCGTTAGGACGGGGTGGCCGAGACAGGGAAGGGAGCCATGG- CGGACGTCCTCACCCA AGCCAGGGCTTCCTGCCCCTGTGGTACTGACAGGAGCCCCGCAGGACGTGGGGTTGGCTTTGGGCAGCTCGG- TGGACACTTCTCTTTCAG ATCCTGCCACAGCAAAGCTCACGAGACTCACTTCTTCCCATTGGAATTCACTAAGAACAAATTCAACAATTC- AGACGCCCCAGCTGGAGGTT TATTTTATGGATTTTACCTGTGCGGTATTTAGGGTTGTGTTTATGAATAAAGGTGTGCGTTCTGGCAAGTAG- AAATACAGAGCTTGTCTTTCA CCCAAGTATCTGTAACTTTCTCCAATGCAGACACTAAAATGCAATAAAAACAAACCAAACCCATTAAACATG- AATTAGATGAGGCAGGCTGAT GGGAGGTTGTGGGATTAACAGGCCGTCAGCGGATTGAAGCTGCGCACATCGCTGGGATGCTGCTGCGGGAGG- ATTCGGTCTAATCCGGG AGCATCTGGCTGGGCAGTGGGCAGCGTCTGCAGTCGTGGCTGCTTGAAGGTATGAAGGTTGTGGCCTTTGCT- TCCCCCCATCAGGCTGCC CCACCCTGGACCCCACCCAGACCCCTCGGGCACCCTGGGGTCATCTTCAGCTCCCCCTTCTCTTCCTTCCTT- CTCTTCCGCCTGGGCCCCT ACTGTGACCCGAGGTCAGCAGAGGACCCTGGCAGGTGGCTGCTCCCTGGGACTCGACTGTGCAGGTGAGGCT- TGGGGTGACCGCTGCTC CTGCTCCTGCTCCTCTCGCCGTCCCCACCCTCCTCCATCATGCTGTCAACATGCATGTGGGCTGCAGCCCTC- AGCCTGCAGGACGCTGTC AGTGCAGCTCCTCAGTGGCCAGG 250 PCBP3 ATCTTGTCTTCCTTGTCCCAGTCCTGGAACCAGCCACTGCCCCAGCAGCTCCTGTGTGTGGTGG- CATGTTCTGGAAGCCAGGATGCATGGT GCTCCTGGGCTGCTGTGGGTCCTGGGCTGCTGTGGGTCCCGAGCTGCTGTGGGTCCTGGGCTGCACCCCTGC- AGAACACTTCCTTCCAT GTTCAGCTCCCTATATGGAACCCCAGTTCCAGCCCCACAGCACAGGGTCCCCCAGTTCTTCCTGCCTCAGGT- GTGCACCACGAGGAATCCA ACTGCCAGTATCTGTGCGTGGCCTCCCGCCGGGAGGAGGCTGCCGGAGGCTCTGAGCTCTAGCCCCACAGCA- CTGGCACATCCTAGATTT CCGGGAAGACACGGCCTCCTCCCCAGGGGAAGGTGGTGGTGCCCACACCCAGAGCATTCATTCCTGCAGTGG- AGACAGAGGGACCTGCC TCTCCAACTGTGGGTGTCAGGAGCCAAGGCGCATGGTAAATGGGGCTCTCTGTGAGGCCAGGTGCACGGCCC- CATCTCCAGCAGCAGCG GCCATGCCACCCAGCTGCACTCTGTGGGGGAGGTGCCATGATTGACGGGGGCCCCTCCCTGTGTCCAGTGTC- CTCCTCCCTCCACGGGC CCCTCTGCACACCGTCCTCACAGTCTCCCTCTGCACACCGTCCTCACAGCCTCCCTCTGCACACCATCCTCA- TGGTCTCCCTCTGCACACC GTCCTCACAGCCTCCCTCTGCACACCGTCCTCACAGCCTCCCTCTGCACACCGTCCTCACAGCCTCCCTCTG- CACACCATCCTCATGGTCT CCCTCTCCTTCCACAGACCCCTCTGCTCGCCATCCTGACGGCCTCCCTCTCCCTCCACGGACCCCTCTACAC- ACTGTCCTCCCAGCCTCCC TCTACACGCCATCCTCACAGCCTCCCTCTCCCTCCACGGGCCCCTCTACACACCGTCCTCACGGCCTCCCTC- TCCCTCCACGGGCCCCTCT GCACACCGTCCTCACAGCCTCCCTCTCCCTCCACGGGCCCCTCTGCACGCCGTCCTCACGGCCTCCCTCTGC- CTCCACGGGCCCCTCTGC ACGCCGTCCTCACGGCCTCCCTCTGCCTCCACGGGCCCCTCTGCATGCCGTCCTCACGGCCTCCCTCTCTCT- CCACGGGCCCCTCTGCAC GCCGTCCTCACGGCCTCCCTCTCTCTCCACGGGCCCCTCTGCACGCCGTCCTCACAGCCTTCCTCTTTTTCC- ACAGACCCCTCTGCACGCC GTCCTCACGGCCTCCCTCTCCCTCCACGGGCCCCTCTGCATGCCGTCCTCACAGCCTCACCGACGTCACCAT- TGCTGGCCCCGCTTCAGG TGACAGGCCACAGTAGCACCTGTCAGCTCTGTCCCGCTGCTGGACAGGGAGATACTGGGCCACTCAGCCCAG- CGGGGAACGTGTGTCCC GAAACTGCCTTGGGCTCGCCATCAGAACTGTGGCAGCATCTTCCAGCGTTCCTTTTAACAGGCTGCCGTTGG- AATAGGAGTCACGGAGCAA TTGCAGTGCTAAGTTTTCTTTAAGTCACACAATTGAAGGAGGCTTTATTTTTCACACATTTCTTCCAGAGTT- TCCTGGTAGCCTGAGTGCATG GGTGATGCCCCCTGAGTTATTTATCAGGGGCAGCCAGCTGCCCTCCCCCGGGGCACTTACAGTCAGCCCATC- TCTGTCCTGGTCAGGTGG GCGCCAAGGAAGACCCGGCTCAGGGCCTCTGTATGGGCAGCCTGGCTTGTACACACACCCCTCCCCACCAGC- AGATTCTGAATTCTCCCT TCTTCATGCACACCGGGAAGGTCCCTTCTGCACTCATACCGGGAAGGTAGGCAGGTTTCGGTAGTGTCTGCC- TCCAGTGTTTTCCTCCTCC TGCTCTATGACATCATCTTTCTGTGATTTTTTTTTTCTTGCAGGAAGTTGGAAGCATCATCGGGAAGGTAAT- TATTGATTGAATCTCTGCCTCT CCTGGGGTCTCTGTAAGGGGATGGTGAGGATGGCAGCCTCCCTGGGTACTAGGTGGCACCCAGTAGGTGCGC- CTTTCCCAGTTGGTGGG TGGTCTGTGTTCCATGAAGACAGGACCCCAGAGGTGTCGCCTTTATGCTGTATGACATTGAAGCTGGTCCCT- GGCTCTGCGTGGCCTGAGG GGAAGGGGTTCACTCCAGCTGGTCACCTCGCTGCCCCCTGCCCGTGGCCTTGGTGGCCAGTCCTTCTTTCCC- GGTTGAAGACCCCACGAA GAATGATTTCTCACGCCTTCTTCAGCCGGCTGTGTAGTCTGGGTGGTCTCCAGGAGTGCCAGTGGAGGCAGC- AGCCCCCAGACAATTCCTT TCCAAATCAGGGCTGGCCCGGGGGAAGTAAGGCCCAGTTTGGAAGCCTGCTGCCCCGGGAGGCCGAGCAGTG- AGGGCCACCTCCCTGTC TTCATCACATTTTCACCGCTTCCGGGGGTCCTTCCCCTCAGTCCCACCATGGGGGCGCC 251 COL6A1 GCTGGACACCTCTGAGAGCGTGGCCCTGAGGCTGAAGCCCTACGGGGCCCTCGTGGACAAAGT- CAAGTCCTTCACCAAGCGCTTCATCGA CAACCTGAGGGACAGGTAGGAGGGACGCCCCGTGACCTTCCTCCTGTGCTTCTGGGCCTCTTGGAGGGAGGG- GTGGGGGCCCAGGGGA ACACGGGTGCGACGGCCTCAACCTCCTAAGGTTGGGCGAGCGTTGCCCTGACCGGGGCCCCTCCCGGCGCCC- TCCAGAGTGAGGCCGG GGCCCTTTCCGGCGCCCTCCAGAGTGAGCTGGTCTGAGCCTCTCCCAGCGCCTTCCAGAGTGAGCTGGTTTG- AGACCCTGCTCGCGGGG GTGGCACCTGTTCAGCAGGGCCGAGGTGACAGTGAGGCTGAGATGTAGGGAAGAGAGGCTCCCGCAGGCTGA- CCGAGAGGGCTCAGCG CACTGGCCCAGACACGCAGTCCTGCCTGGTGCGCGGGAGCCCCTCACTAACCACCTGGACCCTGGTTTGTTC- CGTGGGCAGTGAGAGCC TCTACCTGGGTCCTGGATCCCACGTTCTGAAGGTCCCCGACTCGGGAGCCAGGAGGGGTGTCGCTCTGCAGC- CCCAGGGCCCCCAGGCT TGGTTCTGGGCTTGGGACACGGCACCCTCTGCTCCACGTTCCTCCATCTGTGCGTGTGGCTGAGGACAGACC- GGGGGGAGAGGGGAGTC GGTCCTGTGGGTGCACAGGGCCGCTGAGGGGGGGGCATGTAGAACGGGGCTCCCCCACTGAGACGGGTCCTG- GCAGTGGGGACACAGC TTAGCCGGCGTAGGAACCCCCGTCCTCCTTGACCCTGCTGACTGGCCGCTGGGCCGGAGCCTCCCGCCACCA- GAAGGGGCACAGTCAGA GGCTGCCGGTAACAGCAGGGTGGACCTTCCAGCCCACACCGTGCCCAGCAGGAGCCATTGGTACCAGGAACC- CTGAGCTTAGTGGACAT GGCCAGGCCCGTGCGGCAGTGTTTGGGGGGGGGTCTGGCTGTGGATGGCACCGGGGAGGGGCGGCCGCGTGG- CCCAGCGTCCCCCGA GTCGCCCTTGTTGCCTTTACTCAGTCTCCCCATGACTCAGTTTCCCACCTGTGAAATGGGGCGGAGTCATCC- CCATGTCGCTGCCACTGGA TTCCTGCAGGCGCCGTGGTCACTCTGCTGAATGGATGGGAGGGTGGGTGGGGCAGAGGTGGGCCCACCCCAG- GCTGGGGCAGAGCAGA CCCCTGAGAGCCTCAGGCTCAGGTGCTCAGAGGGCAGCGAGGGGGCTGCTCAGATCCCCGGGGTGCCTCCTT- CCCCCACTGTCATGCTG CCCCACTGCAGGCCCAAGGACCCCACCCCAGCAGGGCCACACACTCAGGGCTCCTGGTCTGAGGGCCTGAGG- GATCGGGGCGCAGGTC GCTTGCTGGCCACACCCGCCTGCACAGCCTTCCAGGAGGGCCGGCCTCAGGGCCACAGGGCAAGTCCAGCTG- TGTGTCAGCCACGGCCA GGGTGGGGCAGCCTGTCCATCTGGGTGACGTCGCGCCCTGGGACGGGTAGCGATGGCGCCAGGGGCCGCCCG- CCTCACGCCCGCCGT GCCTGTTCCTGGCAGGTACTACCGCTGTGACCGAAACCTGGTGTGGAACGCAGGCGCGCTGCACTACAGTGA- CGAGGTGGAGATCATCCA AGGCCTCACGCGCATGCCTGGCGGCCGCGACGCACTCAAAAGCAGCGTGGACGCGGTCAAGTACTTTGGGAA- GGGCACCTACACCGACT GCGCTATCAAGAAGGGGCTGGAGCAGCTCCTCGTGGGGTGAGTGGCCCCCAGCCTCCTGCCCACGCCAGTTC- TCACGCGTGGTACCCAG CCTGGGCTGGGGTTGGCCTGGGGTCCCTGTGCGGCTTCAGCTGCAGCCTCCCTGTTCTCTTGGAGGCTGCAC- GGCCTCCCTGACCCACTT TGTGGGCAGGAAAGAGACGGAGACAGACAGAGACAGAGAGAAACAGAAACAGGGAGAAACAGACACAGAGAG- AGACAGAGACAGAGAGA GATAGAGACAGAGACAGAGAGAGACAGAGACAAAGAGTGACAGAGGGACCAAGACAGGCAGACAGAGACAAA- CAGAGACAGAGACAGAG ACACAGAGAGAGACACAGAGAGACAGAGACGGGAACAGAGACAGGCAGACAGAGACAGAGAGAGACAGAGAC- AGAAACAGAGACAGAGG GACAGAGACAGGCAGAGAGAGACAGAGAGACAGAGACAGAGACAGACAAACAGAGACAGAGAGACAGAAACA- GGGACAGAGACAGAAAG AGAGAGAGACAGAGGGAAACAGAGAGAGACAGAGACAGATAGAAAAAGACAGAGGCAGAGAGAAGCAGAGAC- AGAGAAACAAAGACAGT CAGAGACAGACAGAGACAGAGACAGAAACAGAGACAGAGAGACAGAGACAGAGGGGCAGAGACAGGCAGACA- GAGAGACAGAGACAGAG ACAGCGAAACAGAGACAGAAACATACAGAGACAGAGAGACAGAGAGAAGCAGAGACAGACAGAGGCAGAGAG- ACAGAGAGAAGCAGAGA CAGGGACAGAGACAGAGACAGAAATAGAGAGATAGAGACAGAGGGACAGAGACAGAGAGATAGAGACAGAGA- GGGAGACAGAGAGATAG AAGCAGAGAGAGAGAGACAAAGACAGAGGCAGAGAGACAGAGAGAGAAGCACAGACAGAGACAGACAGAGAG- ACAGGGACAGACAGAGA CAGAGAGACCGGAAACAGAGGCAGAGAGACTGAGAGACTGAGAGAGACGGGGTGGTTTTCCCCACAGCATCA- ACACCAAGCAGGGCTAG GATCACTGAAACAGACTCATCAGACCCGAAGCATGCGCTTTCTCGGGGTTTTTCTGGACTGAGGGGTTTCCT- CTCATCCCAGTGTCCAGCT GTGGGGACGCAGGGGCCGCAAGCCCCGGAGTGTCCAGAGGGGAACGTGGCCTCCCCACACCCAGCCCTTCAC- GAGGCCTCAGGATCCC AGTGGGGGTACCCGAGGCTGCCCTGTCCAGCCAGGCGGTGCGGGGGGTTTGGGGAGAGCCTCTCCCCGAGGT- CGGTCTCAGAGGGCCA CATGGCCGGTGTGGGCCGGACATTCCCTTTCCAATGGTTGTGCCCACTTCCCTCCAGAGTTGGTGCCAAGCT- GGGACCTGGGGGACTTGG AGTCTCAGGAAGTCGTCCGCTGTCTGCAGGGGGTGCATGGGGGATGTGGCCACACACGTCAGAGTGCGGCCC- CCTGTGGAAGCCACAGA CAGACACGACTCCCCTAAATGAGCTCGCCCTTCTGGCCGAGATGCTCAGCGTCCCCAGCAGGCTGCCCGACT- GCCCTGCGATACTGCCCT CCTTCCTGCTGCTCCCACTTTCCCTTTCGGGGGGTTGGATTTGGGGCATTCAGGGATCGCCCTGTTGTTTGC- TCATCACACCCATTTCCTGC AAGAGCCACGGTGACCGAGCAGCCTTGAGTTGAGGCAGCTTGTGGGTAGACGCGGCGGGCATCTCGGAGGGG- CACGCTCCCTGCCACC CTCAGCCTCCACTCACTGGTCAGGGGCTTTGCGCCCCAGGGCACCCCAGGAACCGAGCCTCCTTTGGGGTCA- TGGGTGCCTCTCCTGGG AGGGCGTGGATTTTCCAAAGCAGTTTAGAGAAATGAGACCCACAGGCGTTATTTCCCATGGTGAGGTTCTTT- TCAGTAACCCCCACCGTATA GCCAGGATCAGCAAAGAGAGGCGGCTCCTCCCGGTGAGACAGGGACCAGCACCTCCCGGACAGGCTTGGGTC- TCCCTCCAGTTCCCCCA CCTAGTCTCGAGGTCTCACGCTGCCCTCTCCTGTCCAGGGGCTCCCACCTGAAGGAGAATAAGTACCTGATT- GTGGTGACCGACGGGCAC CCCCTGGAGGGCTACAAGGAACCCTGTGGGGGGCTGGAGGATGCTGTGAACGAGGCCAAGCACCTGGGCGTC- AAAGTCTTCTCGGTGGC CATCACACCCGACCACCTGGTAGGCACCGGCCCCCCCCGGCAGATGCCCCCAACCACAGGGAGTGGCGGCTG- CAAGGCCCCCGGCAGC TGGGACCGTCTTTTGGTCCTCGGGAGGGTGTGGGTTCTCCAGCCGGCCACCCTTGCCCCTGAGAGGCCAGCC- CCTCCTGCTGAGGAGCC TGGAGCGCCCCAGCCCAGCCTCCCCTCTGGCCCTGTGGGAAGCGGCCCCGGCCGTCAGGGGTCCCAGCCCTG- CTCAGCCCACCCTGAA CACTGCCCCCAGGAGCCGCGTCTGAGCATCATCGCCACGGACCACACGTACCGGCGCAACTTCACGGCGGCT- GACTGGGGCCAGAGCCG CGACGCAGAGGAGGCCATCAGCCAGACCATCGACACCATCGTGGACATGATCGTGAGGCCCCTGCCCAGGAG- ACGGGGAGGCCCGCGG CGGCCGCAGGTGGAAAGTAATTCTGCGTTTCCATTTCTCTTTCCAGAAAAATAACGTGGAGCAAGTGGTAAG- AGCCCTCCCCACCACCCCC AGCCGTGAGTCTGCACACGTCCACCCACACGTCCACCTGTGTGTTCAGGACGCATGTCCCTATGCATATCCG- CCCATGTGCCCGGGACAC ATGTCCCCTGCGTGTCTGCCCGTGTGCCCGGGATGTGTGTCCCCCTGCGTGTCCACCTGTGTGTCTGCCCAT- GTGCCTGGGACATGTGTC CGCCTGTGCGTCCATCCGTGTGTCCGTCTGCCCATGTGCCTGGGTCGCATGTCACCCTGTGTCCCAGCCGTA- TGTCCGTGGCTTTCCCAC TGACTCGTCTCCATGCTTTCCCCCCACAGTGCTGCTCCTTCGAATGCCAGGTGAGTGTGCCCCCCGACCCCT- GACCCCGCGCCCTGCACC CTGGGAACCTGAGTCTGGGGTCCTGGCTGACCGTCCCCTCTGCCTTGCAGCCTGCAAGAGGACCTCCGGGGC- TCCGGGGCGACCCCGG CTTTGAGGTGAGTGGTGACTCCTGCTCCTCCCATGTGTTGTGGGGCCTGGGAGTGGGGGTGGCAGGACCAAA- GCCTCCTGGGCACCCAA GTCCACCATGAGGATCCAGAGGGGACGGCGGGGGTCCAGATGGAGGGGACGGCGGGGGTCCAGATGGAGGGG- ACGGCGGGAGTCCAG ATGGAGGGGATGGCGGGGTCCAGATGGAGGGGACGGCGGGGTCCAGATGGAGGGGACGGCGGGGTCCAGATG- GAGGGGATGGCGGG GTCCAGATGGAGGGGACGGCGGGGTCCAGATGGAGGGGACGGCGGGGTCCAGATGGAGGGGACGTCGGGGCT- CCAGATGGAGGGGAC GGCGGGAGTCCAGATGGAGGGGACGGCGGGGTCCAGATGGAGGGGACGGCGGGGTCCAGATGGAGGGGACGG- CGGGGTCCAGATGGA GGGGACGTCGGGGCTCCAGATGGAGGGGACGGCGGGAGTCCAGATGGAGGGGACGGCGTGGTCCAGATGGAG- GGGACGGCGGGGTCC AGATGGAGGGGACGTCGGGGCTCCAGATGGAGGGGACGGCGGGGGTCCAGATGGAGGGGACGGCGGGGTCCA-

GATGGAGGGGACGGC GGGGTCCAGATGGAGGGGACGGCGGGGTCCAGATGGAGGGGACGGCGGGGTCCAGATGGAGGGGACGGCGGG- GTCCAGATGGAGGG GACGGCGGGAGTCCAGATGGAGGGGACGGCGTGGTCCAGATGGAGGGGACGGCGGGGTCCAGATGGAGGGGA- CGTCGGGGCTCCAGA TGGAGGGGACGGCGGGGTCCAGATGGAGGGGATGTCGGGGTCCAGATGGAAGGGACGGCGGGGTCCAGCAGG- CAGGCTCCGGCCGTG CAGGGTGTGGACTGTCCCGGGGGCGCTGGGGGCTTCTGAGGGTGTCTCTGTCCGCCCTGCCCTCAGCCGCAC- TCTGTTCAGAAGGACCT TTCTGGAGGTAGGAGGGTGAGAATGTGGGTCCCCTGCTTCTGTGTGGCTCAC 252 COL6A1 GGCCGGGGAGGCGGGGAGGCTGCCCCAAGAGTAAAAGCCTTTCTGACGTGCGCAGGACGCGGC- CCTGACTGGTCTAACTGACTCTTTCT CTTCTCCTCAGCTTGCTGTGGTGAGACCCAGGCTCTAGCTCCTGAGAGAATGGATCCCGGGGGTCGGGGAGC- GAGGCCTGGGTCCCACA CATGTCACAGGACAGCACATGGCACTCTGGTCCCCGCCCGCAGCTCCCTGCACCTGCCCGCCCCCTCTGGGG- CCTGCTCCAAGCCAGCA GGGTTCCCGGGTGTTGGGCTGGGCCCCGCCCTCTTTCACCCATAACTGAAATAACCAGGAGCAGGCTTGGGG- GGGTCCCTGCTCCATCAT TCTGGCCCACAGGCCCCACCCTAGCCTGGCTGAGCAACGCCAGCCCTGACCAGCCGCCGGACAGAGCAGCCT- TTACGGGGCCATGGGAG GGGGTGGGCTTTTCTGGGGCTGAGACGGGGGGACCCCAACGTGTCAGGTGAGGATGTGGCAGCCAAGGAGGG- GCCAGGGCGGTGGAG GGGAGGGGCCAGGGCACTGGAGGGGAGGGGCGTGCTCTGCTGACACCGCCCCCGCCTGCAGAATGCAAGTGC- GGCCCCATCGACCTCC TGTTCGTGCTGGACAGCTCAGAGAGCATTGGCCTGCAGAACTTCGAGATTGCCAAGGACTTCGTCGTCAAGG- TCATCGACCGGCTGAGCC GGGACGAGCTGGTCAAGGTGAGGCCTCGCCCCGCCCGGCTTTCTCAAGCCCAGGTGCACCCCGACCCTGCCG- GCCGCCCCTGCCCGCG CCAGACCTCAGCCTCCCGAGGCCACCGCTGCATCCCTGTGACTTCCCTACTCATGACAAGGATGCCAGGCAC- GCGCCAGCCCGTCCAGG CCTCCAGCTCCACCTGGCGAGGCTGGCCCATTGTACACAGGCGCCCCAGATGAGGGAGGGTCTCCCCCTCTC- CTTGAAGGGCGGTAGTC TGGGGTCCTGAGTGCTGGGTGTGGGCTTGTCCCTCGTGGACAGAACCCAGGAGGGCTTCATCCACCAAGGAA- GATTGCTTTGCAGGGTAC CCAGGTCCCGGGGGCTGTGCCACCCTCTGGGCACCCGGAGCCAATCGCAGGGTACCCAGGTCCCGGGGGCTG- TGCCACCCTCTGTGCA CCCAGAGCCAATCGCAGGGGACCCAGGTCCTGAGGTCCTGGGGGCCATGCCACCCTCTGGGCACCCGCAGCC- AATAGAGTCACCCTTGG GAAGCTTATGCGGACCTGGGGCAGCACTCGCGTCCTGACCCCGGTGCCGGTCCCACAGTTCGAGCCAGGGCA- GTCGTACGCGGGTGTGG TGCAGTACAGCCACAGCCAGATGCAGGAGCACGTGAGCCTGCGCAGCCCCAGCATCCGGAACGTGCAGGAGC- TCAAGGAGTGAGTGCCC CACGCGGCCAGGACCCTCCCACCCCTCGCCCCGACCGCTGTTCCCACGGCAGGTCGGCCCTGACCCCTGATC- CCAGGTGGGCTCGGCC CCGCGGCAGGCCTGGCCCCAACCGGCCCTTCCTGCCCTTTGCTATGCAGAGCCATCAAGAGCCTGCAGTGGA- TGGCGGGCGGCACCTTC ACGGGGGAGGCCCTGCAGTACACGCGGGACCAGCTGCTGCCGCCCAGCCCGAACAACCGCATCGCCCTGGTC- ATCACTGACGGGCGCT CAGACACTCAGAGGGACACCACACCGCTCAACGTGCTCTGCAGCCCCGGCATCCAGGTGGGGTGGCCACCCC- CAGGCTGCACCTGCCCC GCCTAGGGCGCCCCGCCAGCCAGGGTGGCCTTGTCCCCAGAAAGACGAGGGCAGAGCAGGCTGCGCCACACC- GATACTGTCTGTCCCCA CAGGTGGTCTCCGTGGGCATCAAAGACGTGTTTGACTTCATCCCAGGCTCAGACCAGCTCAATGTCATTTCT- TGCCAAGGCCTGGCACCAT CCCAGGGCCGGCCCGGCCTCTCGCTGGTCAAGGAGAACTATGCAGAGCTGCTGGAGGATGCCTTCCTGAAGA- ATGTCACCGCCCAGATCT GCATAGGTGCGCATGGGGCCACCCGGGCAGTCCCAGATCTGCGTAGGTGCGCGCGGGGCCGCCCGGGCAGTC- CCAGATCTGCGTAGGT GCACGCGGGGCCGCCCGGGCAGTCCCAGATCTGCGTAGGTGCACGCGGGGCCGCCCAGGGCCGTCCCAGATC- TGTGTAGGTGCGCGCA GGCGCCCAGGGCTGTCCCAGAGGCCTCCTCCCAGCTCACTGTTACCTCCAGGGGCACGGCCACCCTGTAGGT- GCGCACGGGGCCGCCT GGGGCTGTCCCACAGGCATCCTCCTCCCGGCTCGCTGTGACTTCCGGGGGCACGGCCACCCCTGTGCTCGGC- CGGGAGGTCCTGTGACA TCTCCTTGCGGGGTTATAGGTGGAGCAGTGGGCTCACACTGCACGGCTTTTCTCTTTTACAGACAAGAAGTG- TCCAGATTACACCTGCCCC AGTGAGTACCTCGGCGGCCGGGACACGTGGGGAGGAGGGCACCGTGGTTGGGGCGAGGGCTCTGAGAGGACG- GGGCTCTGGGAGGAG GGCCTGGCGGTCACGAGAGTAGGTGCATGGCTCACTCCGGTGGCTGAGCACCACCGTGCCGTGCCCTCTCTG- GGGAGCTTAGACGCTCT CTGGCCGGCCCACTGCGGCTGCATCACCAGGGCCTCATGCTAACGGCTGCCCACCCCGCCCCGCAGTCACGT- TCTCCTCCCCGGCTGAC ATCACCATCCTGCTGGACGGCTCCGCCAGCGTGGGCAGCCACAACTTTGACACCACCAAGCGCTTCGCCAAG- CGCCTGGCCGAGCGCTT CCTCACAGCGGGCAGGACGGACCCCGCCCACGACGTGCGGGTGGCGGTGGTGCAGTACAGCGGCACGGGCCA- GCAGCGCCCAGAGCG GGCGTCGCTGCAGTTCCTGCAGAACTACACGGCCCTGGCCAGTGCCGTCGATGCCATGGACTTTATCAACGA- CGCCACCGACGTCAACGA TGCCCTGGGCTATGTGACCCGCTTCTACCGCGAGGCCTCGTCCGGCGCTGCCAAGAAGAGGCTGCTGCTCTT- CTCAGATGGCAACTCGCA GGGCGCCACGCCCGCTGCCATCGAGAAGGCCGTGCAGGAAGCCCAGCGGGCAGGCATCGAGATCTTCGTGGT- GGTCGTGGGCCGCCAG GTGAATGAGCCCCACATCCGCGTCCTGGTCACCGGCAAGACGGCCGAGTACGACGTGGCCTACGGCGAGAGC- CACCTGTTCCGTGTCCC CAGCTACCAGGCCCTGCTCCGCGGTGTCTTCCACCAGACAGTCTCCAGGAAGGTGGCGCTGGGCTAGCCCAC- CCTGCACGCCGGCACCA AACCCTGTCCTCCCACCCCTCCCCACTCATCACTAAACAGAGTAAAATGTGATGCGAATTTTCCCGACCAAC- CTGATTCGCTAGATTTTTTTT AAGGAAAAGCTTGGAAAGCCAGGACACAACGCTGCTGCCTGCTTTGTGCAGGGTCCTCCGGGGCTCAGCCCT- GAGTTGGCATCACCTGCG CAGGGCCCTCTGGGGCTCAGCCCTGAGCTAGTGTCACCTGCACAGGGCCCTCTGAGGCTCAGCCCTGAGCTG- GCGTCACCTGTGCAGGG CCCTCTGGGGCTCAGCCCTGAGCTGGCCTCACCTGGGTTCCCCACCCCGGGCTCTCCTGCCCTGCCCTCCTG- CCCGCCCTCCCTCCTGC CTGCGCAGCTCCTTCCCTAGGCACCTCTGTGCTGCATCCCACCAGCCTGAGCAAGACGCCCTCTCGGGGCCT- GTGCCGCACTAGCCTCCC TCTCCTCTGTCCCCATAGCTGGTTTTTCCCACCAATCCTCACCTAACAGTTACTTTACAATTAAACTCAAAG- CAAGCTCTTCTCCTCAGCTTG GGGCAGCCATTGGCCTCTGTCTCGTTTTGGGAAACCAAGGTCAGGAGGCCGTTGCAGACATAAATCTCGGCG- ACTCGGCCCCGTCTCCTG AGGGTCCTGCTGGTGACCGGCCTGGACCTTGGCCCTACAGCCCTGGAGGCCGCTGCTGACCAGCACTGACCC- CGACCTCAGAGAGTACT CGCAGGGGCGCTGGCTGCACTCAAGACCCTCGAGATTAACGGTGCTAACCCCGTCTGCTCCTCCCTCCCGCA- GAGACTGGGGCCTGGAC TGGACATGAGAGCCCCTTGGTGCCACAGAGGGCTGTGTCTTACTAGAAACAACGCAAACCTCTCCTTCCTCA- GAATAGTGATGTGTTCGAC GTTTTATCAAAGGCCCCCTTTCTATGTTCATGTTAGTTTTGCTCCTTCTGTGTTTTTTTCTGAACCATATCC- ATGTTGCTGACTTTTCCAAATAA AGGTTTTCACTCCTCTCCCTGTGGTTATCTTCCCCACAAAGTAAAATCCTGCCGTGTGCCCCAAAGGAGCAG- TCACAGGAGGTTGGGGGGC GTGTGCGTGCGTGCTCACTCCCAACCCCCATCACCACCAGTCCCAGGCCAGAACCAGGGCTGCCCTTGGCTA- CAGCTGTCCATCCATGCC CCTTATCTGCGTCTGCGTCGGTGACATGGAGACCATGCTGCACCTGTGGACAGAGAGGAGCTGAGAAGGCAA- CACCCTGGGCTTTGGGGT CGGGAGCAGATCAGGCCTCAGTGGGCTGGGGCCGGCCACATCCACCGAGGTCAACCACAGAGGCCGGCCACA- GGTTCTAGGCTTGGTAC TGAAATACCCCTGGGAGCTCGGAAGGGGAGTTGAGATACTGCAGGGCCCATAGGAAGAAGTCTTGGGAGGCT- CCACCTTTGGGGCAGAG GAAGAAGTCTTGGGAGGCTCCACCTTTGGGGCAGAGCAAGAAGAGGGCGGAGGGCAGAGGCAGCGAGGGCTC- ATCCTCAAAAGAAAGAA GTTAGTGGCCCCTGAATCCCAGAATCCGGGGTGCACGGCTGTTCTGGGGGCCGCTAGGGGACTAAGAGGATC- GGCCGAGGGCTGGGCT GGAGGAGGGCAGCAGGGATGGGCGGCGAGGGTGAGGGTGGGGCTTCCTGAAGGCCTTCACCTGCGGGGACCC- CGGCGAGCCCCTCAG GTGCCACAGGCAGGGACACGCCTCGCTCGATGCGTCACACCATGTGGCCACCAGAGCTGCGGGAAAATGCTG- GGGACCCTGCATTTCCG TTTCAGGTGGCGAACAAGCGCCCCTCACAGAACTGCAGGTAGAGACGGGCCCGGGGCAGACGCAGTGAGGCG- GTGGGCGGGGCCCGGG GCAGATGCAGTGAGGCGGTGGGCGGGGCCCGGGGCAGAGGCAGCGAGCGGTGGGCGGGGCCCGGGGCAGACG- CAGTGAGGCGGTGG GCGGGGCCCGGGGCAGAGGCAGCGGGTGGTGGCCGGGGCCCGGGGCAGACGCAGTGAGGCGGTGGGCGGGGC- CCGGGGTAGTCGCA GTAGGTGGTGGGCGGGGCCCGGGGCAGACGCAGTGAGGTGGTGGGCGGGGCCCGGGGCAGACGCAGTGAGGC- GGTGGGAGGGGCCC GGGGCAGACGCAGTGAGGCGGTGGGCGGGGCCCGGGTCAGAGGCAACGGGTGGTGGGCGGGGCCCGGGGCAG- ACGCAGTGAGGCGG TGGGCGGGGCCCGGGGCAGATGCAGTGAGGCGGTGGGCGGGGCCCGGGGCAGATGCAGTGAGGCGGTGGGAG- GGGCCCGGGGCAGA CGCAGTGAGGCGGTGGGCGGGGCCCGGGGCAGACGCAGTGAGGCGGTGGGCGGGGCCCGGGGCAGACGCAGT- GAGGCAGTTGCCAG CCTCTCTCAGCTGCCTCATGGGATTCGCACTGCAGCTGCGGCCCTGGCGCGACAAGGGCTGGACTTGGCCAG- CGGGACGGTCCCTCACG GCGCTGAGGCCCACACTCTGCGTGGAGCCTCCCCGTGCCCAGGCTACCCTGCAAGGTCCTCGGAGAGGCTTC- CTCCAGCCCCAGCCCCC ACACAGCTCCGGCCCAGGCCCGCTCTTCCCCATCCCAGTTGCTTTGCGCTGTATACGGCCAGGTGACCCCGA- GCCGGCCCTGAGCCCTC GTCCCGGCTTCCTCCCCTGTAAGCTGGGTGAAGGACTCCATGGCACCCACCTGAGAGGGTTGTGGCGAGGCC- CAGGCCCCTCGTGCCCA CACGGCCGGCGGCCCATGCCTGGCAGGGGCTGGGAGGAGGCTGGGGCGACCAGAGGGGAGCGGCCTGTCCTG- GAGGAGGCCCAGGGA CCCTGGTGAGAGGGTCTCTCCCAAGTGCTCTCTATGGGACCCCCTTCCTCTGCGCCCGTCCTTCACGGACCT- CTCCGGGTCACCCCTGGG CTGCACACTGGGTTCAGGGGGGCCTTGAGGTGGGGCCCCTGTTCCCAAGTCCCGGCGGGGTTTCTCCTGAAC- CTCAACCCATCCTCACCT GCGGGCATTCCCATCCCCCAACGCCTGGGTCACCAGGATTCCAGGCAGGAGGGGCGGTGGGGGTTACCAAGG- CCCGGGTTGCCATGCA GAACCCCCAGCCACCACGCAGACCCCCACGGGGCCCAGGGAAGCTCCTGGTCTCACACTGCACCTCACACTT- CCTGTGGGGGCAGACTC CAAGGTCCCGGCCTCTCATCTTGTAGAAACTGAGGCACAGGAGGGACACACACTCCCACGGCCGGTCACCGT- GGCCCCCACACCTCCCAC TGGACTGACACCTGGCCAGGCTCCGGACACCCGTGGCACAGCCTCAGCCCCTGCGGCCCCTGCTCCGTGGCC- CCCAGGCCCCAGCTCC CATGTGCACGTCCTGCCTCAGGCCTGGAGGCCCCTCGGCCCCAAATAATCAGACAATTCAACAGCAAAACTA- CTTTTTTCAGGCTGGCAGG ACTCTGGGCAACCCCCTGCAACAGCCCCCTGCCCTATCACAGCCACCCTTGCCTCCCAGGCACGGAGACCCC- ACCATCAGGTCCCAGCCT TGGTTCATCCCCAAGCACCCTGTGTGTTGGGATGGCGATGCTGGCTGAGCCCCTGCATCC 253 chr21: 46280500-46283000 AGGGCGTTTGGGAACACCCCTCCCGGAGGGGTGAGGCGGCCCAGCCTGCGGCTGCCAGAGGACACAGGTTCTG- CTGCGGAACCTGCAG ACATGGCCATAACAGGCCACAGTGCTCGGGCCCACACAGCCTGGACCCACATGGCCCTGTGTCACCTCCTCA- GGGGCAGGCTTCAGGGC CTCGACCCTAGAGGCTGCCCCTCGGTTCTGCTCCATGGACGGCGCAGGCAGGCCCAGGCCTGTGACGAGTTC- ACGGAAGCTCCAGGATG ACCCCCGCTCTGCGCCCTCCTCCAGCATTCCAGACCACAAACCACTCTGGGCTAAAACGAGGCATCGCCAGA- GCATCCCACTTCCTCGGA AAGCTGCGGTCTGGGGACGCGTCTTGGCCCTGAAGAGGCTCCAGATGGCTCCCATCAGGCCTCTCCGCCTAC- GTGCGGCCGACATGGAG TGACAGAGCGTCGGGGACACAGAATTCAGAGCTGGGCCTGGGGCTGCTTTGAGATACTGATGGCTGCCAGGG- GGCACAGAGACCCGTCC TGCAGACAGGGCTGTGAGGGCCACAGGGGGCCTCGGGGAGAGGCAGTGGGAGGGAGGACAGTGGGGGCCTCC- AGCTGGGTGAGCAGC TGGAGCGAGGGGGGCCCGGGGCTTGTGATGGTGCTGCCGACCCTAGAGGTGCCGGCCCCACGATGGAGAGCA- CGTAGTGCCCCCCGGG AGTCAGGAGGCCGGGCCTGACCTCGGGGGCTGCAGCCAGGGGAGGCCGGCACCCCAGATAACCCCCAAAGAA- CTGCAGGCCCTGAGGC GAGGCCAGAGTGGGGGCGGGGGCAGGTCCCAGCCGAGGAGGTGCTCCGTGCTGCCTCAGCAGAACCCATGAT- GGGCTGGCCCAAGGCT CTGAAGGTGGAAAGGCCTCACACATTCTGCCCCGGCTGACGCCTTCCTTGGGCCAGTGCTCGGGGGTGTGTA- ACAAACGCCAAGACGCAT TGTAAAGAAGGAAGCCTGCGTTTCCATCACCGGCTTAATATCAAACAAAAGTGCAATTTTGAAAATGTAGTC- CAAGGTTTTCTGTGGTGCGG AAATGGCCAGGCCAGACCTCCGTGGGTGGTCCTTCGTGTCCACGTCAGCGCCCTACATCCACACTGTGGGCA- CCATGACCTCACATGCGG AGCGGAGCAGGGCCGGCGCCCGGAGAGCCAGGCTGGTCACGAACGAGGCCTAGAGGGCGTCAGGCCCCAAAG- CACTCACAGGCTTCTC CTCTGTCCTCGGGGCCTTCAGACACCTGCATGCGCCGATTCAGCCACCCGCGCGCGCCGATTCCCCTGGCCA- TGGGGTTTCCAAAGTGTG TGCTCAGAGGACAGTTTCCTCCAGGATGACCTGTCAGTGGCTCTCTGTGCCGGGGACGTCGCGTGCTGGGTC- CCGGTCTGAATGCTTCCT AACGATTTACCCAGTTCCTTTTCTCCACTCAGGAGGCGTTTGCTGAGAGGCACAGGCTGAGCCCCCGTGCTG- ATGCCACGACCGAGGGAA CGGGTCTCCCTGTCGGCGTGAACTGACCCGGCCAGGCGTCCACTGCCACTCGGACTGTCTCCCAGGCACGTG- GCGCCCACACGGGCAGA ACACGCCCTCCACACACGCGGCTTCGGGCAGAACACGAGGCGCCCTCCACACACGCGGCTTCGGGGCTTGTC- ATGAAAAAAGCTGAATG CTGGGGGTGCAGCTTTCACCAACAGAATCCCGTTTGGAAGGGACGCGGTGAGACATGATCCACCCTAAGTTG- TGATCCTGGGTGAGCCGC CGTCCACACCCTGCTGAGGGTCCCTTCACCCACTTTATTCTCCAGAAAACCCTGCCCATCAGGGCTGAGTCC- CACGCCTTCCCTCTCCGTC CAGGCCTGGCTTTGACCTCTGGGGTCGTGTGGGGCACAGGGGACACCCTATCCAGGCAGAGGCCCTACGGCT- ATCTGGAGGAAGTGGTG GGAGCTGGGCTTCTGCCTGGAGGATGCACCCAGAGGGGTCACAGTCCACACAGAGACACACGGGTGCCTTCC- AGATGGCTGAGCCAGTC CAGCCCAGAAGGGCCTGGGGGTTGGGGGCTGCACCTGGCCTGTCCCCACCAGCAGGGCTCAGGGCTTCCCAA- GGTGTGTGGGGGACGG GGCAGCACCTCTCAACCAGGTCACCTGAAACCCGAACTGAAAGGCATCCTAAGTTAAGACATTAACTCCCAT- TGTCAAGGTGCCATCGTCA ATTCTGTCTCCAAATCCTTCTTTGTTATTTCATGTATTCACAGAGTGACGCTCCGTGTTTCGTTCAGCCTGC- AGGCCTGCAGAAGCTGCATCT CGGGATGGCCAAGAGCCCGGCCAGGCCCCACGGCTGCACCCAGGACGGGATTCATGCCCCATGCCTGGCTTC- TCACGACCACAGAGTGC CTTTCCCGGGACTGGATGGAGGCAGAGTGAGAGAAGAGCCTGGAGCAAGTGTTTTGGACCACAGTGATCAAA- CACGGAGCCCGTGGG 254 COL6A2 AAGAAAGGCCAGACCGGGCACGGTGGCTCACGCCTGTAATCCCAACACTTGGGGAGGCCGAGG- CGGGCAGATCACCTGAGGTCAGGAGT TCGAGACCAGCCTGGCCAACAGGGTGAAACCCCGTCTCTACTAAAAATACAAAAAAAAATTAGCCGGGCGTG- GTGGCAGGCACCTGTAATC CCAGCTAATCGGGAGGCTGAGGCAGGAGAAAATCACTTGAACCTGGGAGGCGGAGGCTGCAGTGAGCTGAGA- TCGCGCCACTGCACTCC AGCCTGGGTGAGGGAGCGAGACTGTCTCAAAAAAAAAAAAAAAAAAAAAAAAAAAGGAAAGAAAGGCCCGGT- GAGATGCTTTCTCTTAAAC ACGGCCCTGCACGTTGAGTTGCTGCCTCCTGTGGCCTATTTCACGTTTATGCAAAGTCGGGCGCCTGATGCG- GGGCTCACCCGCCACAAG CAGGGGTCCTGGTGCTGCTCATGGAAGGGGCCCTACCCAGCCCGCGGGGCACTGGCTGGGACGGGGCTGCCC- AGGTCCGCCCAGGATC CAAACACCCAGCCCCGCCCAGCGGCCCTTCCTGGCCTGCAGTGGAGGCTGTAATGGGCAGGGGTGGTGGGAA- TCCCAGCTCACAGGGC GCCTGCTCTTAGAAGGGCGGCATCTGGGTCCAGAGGTCAGAAACGTCAGATGCCCATCCCAGAAGTGGCGGG- GA 255 COL6A2 GGGTGAATGAGTAGATGTATGGGTGAGTAGGTGGGTAGGTGGGTAGATGGATGGGTGGGTGGG- CGAGTGTGTGGTTAGATGATGGATGG CTGAATGGATGAGTGGGGGGATGGATGGGTGAGTGGGTGTATGTATGGATGGGTTAGTGGGTGGGTGGATGA- ATGGATGGGTGCATAAA GGATGGATGGATGAATGAGTTAGTGGGTTGGCAGATGGATGGATGGGTGAGTCAGTGGATAGATGGATGGGT- GGGTGGATAGAGGATGG ATGGTTGGGTAGGTGATGGGTGGATGAGTGGATAGATGGGTATGTGAGTGAGTGGGGGGATGGGTAGGTGGG-

TGGATGGATGGTTAGGT GAATGAGTGGATGGACAGACGGACAGTGGGTGGATGGATGAGTGAACGGATGGACCGATGGATGAATGGGTG- GGTGGGTAGAGGATGGA CGGACAGGTGAGTGGGTGGGTGGATGGATAGATGGGTAAGTGAGTGGATAGATAGATGGGTGGGTGGACAGA- GGATGGGTGGATGAATG GATGGGTTAGTGGGTGGCTGGGTGGATGGATGATGGATGGGTGACTGGGTGGATGGATGGATGGGTTAGTGG- GTGGCTGGGTGGATAGA TGGATGGGTGATTGGGCGAATGGGCGAATGGGTGGATGGGTGGGCGTGGAGTTGGTGGGTACATGATAATGG- GGTGGAATACCCATGGA TTGGAATGAGCTGTTTTGGCTGCTATTTCTGGGACACCCAGCTCTGCCAGGCCCCTACCCCTCTGGTGGGCC- AGGCTCTGACGGTGGCCA CTCATGGCCTTTCTAGCTCTGGTGCCAGCATAGGGAAGGAGGAGGCACAGCCTTGTCTTACTCCTTGCACCT- GTTAGCCCCCCCCCCCGC CAAGGGAGGACCCGTGGTTGGGGACAGCACAGGGGGCCCTGCTGTGTGCAGGGACTGTCCCTGGGGCCACTG- AAGCCCACCTGTTCTTG TTCCTTCTCAGGCGGATCCTGGTCCCCCTGGTGAGCCAGGCCCTCGGGGGCCAAGAGGAGTCCCAGGACCCG- AGGTAGGTTGGTGGCCA GTCCCCATGCCCTCCCCCCAACCTGCCAGGCCAACACACACCCAAGCCTCGTGGTTCTGCCCACGGTGGACC- CACGTATCAGTGGGCAGT GGCCTGGGAGAGACTCAGCCACCCAGCCTTGGCCCCAGAGTCTCAGCCTCATCCTTCCTTCCCCAGGGTGAG- CCCGGCCCCCCTGGAGA CCCCGGTCTCACGGTAGGTGTCACATGGGGCAGAACCAGTGTCCTTCTCCTGCCAAAACTAGACACCAAGAG- CAGCAGGGGTGGGGGAA GGTCAGCTGGCACGGTCAGAGAGCAAGATCAGTGGAGGAGGTCAGAGGGCAAGGTCAGAGAGCAAGCTTGGT- TGGGGAAGGTCACAGG GCAAGGTTGGTGGGGGGAGGAGGGTGGCAGCGAGGTTGGTAGGGACAGGACCCGCCAGCCTCCCCGCATGGC- TGCCTCCACACGTGGG CTGGAATGTCCCGGGACCCCCAGGCCAGGACCTTGCTGTGGAAACTCTTCTGGGGCCCCGGGGGGACTACCC- TGCCTGCCGTGTGCATT GCAGGAGTGTGACGTCATGACCTACGTGAGGGAGACCTGCGGGTGCTGCGGTGAGGCACTGCCCACGGCAGG- GTCGGGGCCCATGCAC CGGGTGGAGGGCGGGAGTGCAGCAGGGCTGGGTCATCGCTGGGTCCTGCATGTGCACGTGACCCTAGGGTCT- GAGGTCTCCCCGGTAC CCCCCGATGACCCTGCCACCCCCCCAGACTGTGAGAAGCGCTGTGGCGCCCTGGACGTGGTCTTCGTCATCG- ACAGCTCCGAGAGCATT GGGTACACCAACTTCACACTGGAGAAGAACTTCGTCATCAACGTGGTCAACAGGCTGGGTGCCATCGCTAAG- GACCCCAAGTCCGAGACA GGTCAGCGGGGCAGGGGCGGGTGCAGCATTGCGGGGGGCCGGGCGGGGCGTGGGAGGCGATGAGATGGGAGA- AGTCCAGACGCGTCC CTCCAACGAGGGCCTCTGCATGGCTGGGGATGCCCCAGACCCCGAGGCCTCTGGCAACGACCTCACGCGTGC- GGCTTGCAGGGACGCGT GTGGGCGTGGTGCAGTACAGCCACGAGGGCACCTTTGAGGCCATCCAGCTGGACGACGAACGTATCGACTCC- CTGTCGAGCTTCAAGGA GGCTGTCAAGAACCTCGAGTGGATTGCGGGCGGCACCTGGACACCCTCAGCCCTCAAGTTTGCCTACGACCG- CCTCATCAAGGAGAGCCG GCGCCAGAAGACACGTGTGTTTGCGGTGGTCATCACGGACGGGCGCCACGACCCTCGGGACGATGACCTCAA- CTTGCGGGCGCTGTGCG ACCGCGACGTCACAGTGACGGCCATCGGCATCGGGGACATGTTCCACGAGAAGCACGAGAGTGAAAACCTCT- ACTCCATCGCCTGCGACA AGCCACAGCAGGTGCGCAACATGACGCTGTTCTCCGACCTGGTCGCTGAGAAGTTCATCGATGACATGGAGG- ACGTCCTCTGCCCGGGTG AGCGTGTGGGCGCGGGGCAGTCGGCCGAGGAGCAGCAGGCCCCAGCCGCTGTCTAGCGTGAGCCCCAGGGAC- ACCCCTCACCTGAGGG ATGAATGTGCAGCCCAGGATCTTGGGCTGTGGGTGGGAAGGGGTCGGGCCCTCTCGGGGCTGCAGGGCAGAG- GCCAGCTGCACCCTGA GCCTGTCTAGGCAGATCAGTGAACGGCCGCTGAGGGTTCGCTAGGGACTGACCCTGGCCTGGCCCGGCCTCT- CTCCTCTCTTCCAGACCC TCAGATCGTGTGCCCAGACCTTCCCTGCCAAACAGGTAATGCAGGGCACCCTGAGCCACCACCCCAGACTAG- CAAAGCAGCCCTGGTGTC CTTCCTCCTCGAGGGCCGGGCTGGGGGAGGGGCCGTGCAGGGACCCGGGGGGCGGCGGAGCCACTGCGGAGG- CTGCTCCTTAGGGAG ATGGCCCCAGGATGGCAGCACAGGGGAGGAGGGGCTTGGGGAAGGCAGGCTCCCAGGAACGCAGGAACAGCA- TCACGAGGCCATGAGG TGGGTGCTGCTAGCCTGGCGCTGTGCTCGGCATGTGGCCACTGGTCTTGAAGGCCCACCATGGGCCTTGCAG- TCTCCCTCAGCTGCCGC CCAGCTCCCATGGGCTGGCCGTGCATGTGCCACTCGGAGGAAGCCCTGGATTCAGTGAGTGAAACCATCCCG- GGGTGGAAGCACTGACA CCCCCCAGCACCAGCAGGTCTTGCTCCAACCCTGGCCTGCCTCGGAGCTGCAGCTGCGGCTCTCACATCTCT- GGGAGTGGGGGAGCCCA TGTCCCGGATGTGGCCCACGTGGGTGTGAAGCTGGAGCTGGGGGTGCCGTCCAGGCTCTGCTGGACGTGGTG- CTGCCCCCATGGTGCAC TGCTGCACCGTACCTGGGCCCACAGGAGGTCCCCGGGGGCGTTAGGAGCTGAGTCCCCCTCAGTGAGCCGTC- CCCTCCAGGAGTGTGAG GGTAGGGATGCCATGGAGACAGGGTGGGAGGGTCCGACCTGGAGGACCACAGGGAGGAAACCTCAGGGTCTG- CGGTACGAAGTCAGCG CTTCCTCAGCACGCGGGTCGCGGTGTGCGTTCGGGCGTTCCATGGGGAGCTCCCGGTGGGTGAGCTGGGCCA- CTGAGCACATTCACAGG CCCTGAGGCTGCCCCAGGGGAGGAGCCGTGGACTCAGAGCCGAGGTTCCCCATACGTGCTGCGACAGAGAAC- CTAGGGCTTGCACCTGG GTCTGGCTGCCCTTCAGCAGGCGGGCAGCCTCTGGCCCCACAACAGTGGGCTGTGCTTCTGCCGCCAAGGTG- CAGGCGTCCTCCCCCAG GGTCCACATCAGCAGCAGGGGCACCTGGACCCTGAGGGCAGGAACCAGACCTTGGCTCCTCCACCCACCCCC- TCGTTCCTGATGGGGCA GGGAAGTCTCGGGACCCCATGATGGGCGACATGGCGATGGTCACTGTGGGTGCTTTGCTATCAGGTGGGGGG- CCTTCCTCTCCACTCTGG GTCCAGTGTGAGTGGCCGCTATGGCTTCCCCTCCACTCCAGGTTCTATCGTGAGTGGGTGGGTGCTGCGTCT- GTGGATGTCACGTGACCT TTCCTCTTTAGCCTATCATTGTAGTTGGGAGTTAGTTAGCCCGTTGAGCGTCATTGAATTTCCAGTGTTGAG- CCAGCCCTGCGTGCCCGGGA TAAACCCACCTGGCCGTGGTGTGTGGCCCTGTTTATGCACGTGGGCCCTGATTCGCTGATGCCTGCCTGAGG- GTTTGCGCTTATCGGCGA CATCAGCCTGCACTTTTCTTTTCTCGTGATCTCTCTGGTTCTGGCCTCAGGGTGACGTGGGCCTCGTAGGGT- CCTGTGGTGGCTCCTCCCC AGACGGTGACATGGAGTGAGCCCATTCTCCCTCCTGGGAGTGGGTCACTCAGGCCACCAGAGCACCACAGGG- AAAGCAGCCAGGGAGGA CACGGAGGCCCTTGAAGCTCTGGCCTCTTCTGAGGCCTCCAGGACCTGACAGTGAGTGGGAGCAGCCCTGGC- AGAACCCCTCCCCTCCT CTCGGCCGCCCTGACACCTCATCCCCGACACTCAGAGCTCATCCTCCTTCCCAGCTGTTTCCAATTTCAAAG- TGAACTCGACCTTGTGGCT CCAGGAGATGCAGCAGGGACAGTGTTAAATCGGCTTTCACCAGCCCACACGGCCAGGCATCCTCCTCGGCCC- TCCTGGGCACTGGGTGG ACACCACTGGCTGTGGCCTGGCCCTGGCCTTCTCCAGACAGCCCTGTCCACCCCAAAGCCCAGCCACCCTGG- GCCTGCAGCAGGCCTGT GGAGTTCTCAGTTGCGTGGGGACCAGAGGGTGCTGGAGAAACAAACCAGACGCAGCTGAAGGCAGTCAGGGC- AGGGCGCAATCAGCGAT AAGAGCTGCATAGGGGCCACAGCGTAACCTGAGCTCCAGTCGGTGGAAAGAAAAGGCAGAGACGTTGCAGAG- GCCAGGTCTGCTCAGGG GAAGACAGTTCTGGGTGTAGAGGACTCACATCCCAGAGAGGCTGAGGAAGGGTTTACCACCGCAAGCTTTCT- CAGGCGGGCTCTTGAGGG GTGGCTGGGGTCTTCCTGGCGACGGGCCTGCGGCACTGGAAGCCCTACTGGAGTTTGGCCTGTCTCCGGCAC- AGGTTTGGACGGAGCTG TTTTGTGCTGAAAGGTTTTCTCGGGGTCCGTGGTGTCCCCCAAAGGTGCCACCGTGCGGGTCTCCTAGCTCC- CTGCCAGCTTCCTGTCCCT GTGCTCACTGCCCCCACGCCTCCTGCCAAGGCCGAGCCACACACCCGCTCCACCTGCATTTCCTCTACCGAC- TCGCCAGCCCAAATGCCG CTCTTCACTCTGGCCTCGCTGAGCGGCTGCCCGAGGAGGAGCTCTAGGCCGACGCCCACCGCAGGCCTTACA- GTCTTCTCTGGACGCTCC CTTGCAGATGCACCGTGGCCTGGCGGCGAGCCCCCGGTCACCTTCCTCCGCACGGAAGAGGGGCCGGACGCC- ACCTTCCCCAGGACCAT TCCCCTGATCCAACAGTTGCTAAACGCCACGGAGCTCACGCAGGACCCGGCCGCCTACTCCCAGCTGGTGGC- CGTGCTGGTCTACACCGC CGAGCGGGCCAAGTTCGCCACCGGGGTAGAGCGGCAGGACTGGATGGAGCTGTTCATTGACACCTTTAAGCT- GGTGCACAGGGACATCG TGGGGGACCCCGAGACCGCGCTGGCCCTCTGCTAAAGCCCGGGCACCCGCCCAGCCGGGCTGGGCCCTCCCT- GCCACACTAGCTTCCC AGGGCTGCCCCCGACAGGCTGGCTCTCAGTGGAGGCCAGAGATCTGGAATCGGGGTCAGCGGGGCTACAGTC- CTTCCAGGGGCTCTGG GGCAGCTCCCAGCCTCTTCCCATGCTGGTGGCCACCGTGTCCCTTGCTGCGGCTGCATCTTCCAGTCTCTCC- TCCGTCTTCCTGTGGCCG CTCTCTTTATAAGAACCCTGGTCATTGAATTTAAGGCCCACCCCAAGTCCAGAATGACCTCGCAAGACCCTT- AACTCACTCCCGTCTGCAGA GTCCTTCTTTGCTGCATCAGGTCACCCTCACAGGCTCCAGGGTTTGGGTGTGGAAGTCTTTGGAGGCCCTTA- CTTAGCGGCCCAGCTGGG CTGCCGTGCGTCTGGGATGGGGCTGAGGGAGGGTGCTGCCCAGGTGCTGGAGGATGTTCCAGCACCAGGTTC- CAGCGGAGCCTCGGAA ACAGGCCCCAGAGGCTGGTGAGCCTCGCTGGGTGTGGGCACTAATCCCGTGCATGGTGACTCGTGGGCGCTC- ACGGCCCACCTGGTGGC AGGTGAAGGCTTCCGGTTGGGCAGCAGATAGTCCTGGGGGAAGCTGGCAGTCCTGGCACCATGACGTATCTG- GGCTGGTGTCATGCACA GTAGGGCGAATGGCCACAGCTGCCTGCCAGCAGCCCTGATCCCGGGGTGTCTGCACCCTTCCAGCCCAACCT- CTGGGTCTCCAAAAGCAC AGTCGGGGGAGCATCCACCAGGCACAACCTCTGCGGTCCTCAGAGGACTGAGCAGAGAATCCCAGGGTCCAC- AATGTTGGGGAGCGGCA GGGATCACCATCCAAAGGGAGCGGCCCCCACGGCGAGCTGACCCCGACGTTCTGACTGCAGGAGCCCTCATC- CAGGCTGGGCTCCTGCC GGGCACGGCTGTGACCATTTCTCAGGGCCAGGTTCTCGTCCCCACACCCACTGCACAGGGCAGGCCAGGCTG- GTCTTCCCACTGTGGGG ATGAAGGATCCTCCACAGGAGGAGGAGAGCAGAGTCCACAGACATCCCAACAGCCTCAGCCTCCCTGTGCCT- GGCCGGCCCCCACAGCTT CCCCGTCTCCTCCAGGCCCCACAGACACTGATGAATGGACAGAGACCCCCAAAACCAGCTGCCCCTTGCATG- TCTGTCTCCATATGTTTGG TGACAGCAGTGAAAATGTTATTAGTTTTGAGGGGGTTTGGGAAGCCCAGCGGTACCTGAGGAGTTTCTGGAC- ATTTAAGCCGGTTCCTAGG TGTGGCCTTAACAGGGAGGCTGCCCTTCCTTTCACTGAATGAGCTGCGTCACTCATAAGCTCACTGAGGGAA- CCCCATCTGCCAGCTCGTG CGTGCTCAGACGGCGTCCATGTCTCAAGCGTTCTGTGAAGGCTGCGGTGCAGCGTGAGGTCACCCTGCTGTG- TTCAGAGCTTTGCTCACT GCCTGCGGGGCTGGACCGTTGCACCTCCAGGGCCCCCAGAAACCGAGTTTCGGGTCAGGGTCCTCTGTGTGC- ATTCCTGGGGGTCCATG TACCAGCTGTGACGACGTCCAGGGGTTGGGCTGAGAAGCAGACACCCTTGGGGAAACTGGCTCTGTCCCTCC- CCTCCCCCATCCCAGGAG CTGAGGTCTTGGTGAGGCCACAGGGCCAGGTCCACGCAAGGACTGTCCGTGTCCTGTCCTGTGGTCTCTGGC- CCCACGTGACACCCACAC GTGTGGTAGGCAGCCTGGCCTGGGTTGTGGCTATGGCCAGGCCCCCAAGCTGTCCCCGATGCCCAGGGCTGG- TGACCACCCAGGCAGGT GGGGGCCCCACTTGGTAACAGAGTCATAGGGCAGAACCCACCTGGGCTGCCACAGAAGGTCTGGCTGCCCCT- GTGCCCACTGCTCCCCA CCATGGCCAATCAGAAGAGTCAGGGGCTCCTGGTCTTTCCGGGAGGGACGTGGCCCAGCCAGCTCTAGGTGT- TCTGAGCAGCTCTGGGA CCCAGCGATTGAGGGGTCAGGCTGGGGGTGTCAGAGCCAGGGTCCTCCTTAAGTACCTCCCACACTACACAG- ACAGTGGCCCTTTTGTGG GCAGCAAATTCTTGAGCCATGAAAGGATGCTTTGGGCCCCTTCCCTCCCAGGAGGGCAGCCTGTGCAGGGAT- GGTGCTCAGCAGGTGGAC AGGGCCTGGGGCCTGTGTCAGGGTCTCAGGCCTGGGAGCACCAGCAGAGGAGATGGCGGCTCCCAGCAGTGC- CGCCTGAAAGTGTCTTG GGCTAAGGACCCACACCCAGGGCTGCCCTGCAGAAACGCCCCCGCAGAGCCCAGTGGTCTGTGAGGTTGCAG- GCAGGGTGCGAATGGAA GGGCACAGGTGCGGGGCTGGCACCTGCCCGGTCCTGCCCACCTCCCCTCCGCCCAGCCCGCACCTGCGTCTC- CCCACAGAGCTGTCCGT GGCACAGTGCACGCAGCGGCCCGTGGACATCGTCTTCCTGCTGGACGGCTCCGAGCGGCTGGGTGAGCAGAA- CTTCCACAAGGCCCGGC GCTTCGTGGAGCAGGTGGCGCGGCGGCTGACGCTGGCCCGGAGGGACGACGACCCTCTCAACGCACGCGTGG- CGCTGCTGCAGTTTGG TGGCCCCGGCGAGCAGCAGGTGGCCTTCCCGCTGAGCCACAACCTCACGGCCATCCACGAGGCGCTGGAGAC- CACACAATACCTGAACT CCTTCTCGCACGTGGGCGCAGGCGTGGTGCACGCCATCAATGCCATCGTGCGCAGCCCGCGTGGCGGGGCCC- GGAGGCACGCAGAGCT GTCCTTCGTGTTCCTCACGGACGGCGTCACGGGCAACGACAGTCTGCACGAGTCGGCGCACTCCATGCGCAA- GCAGAACGTGGTACCCA CCGTGCTGGCCTTGGGCAGCGACGTGGACATGGACGTGCTCACCACGCTCAGCCTGGGTGACCGCGCCGCCG- TGTTCCACGAGAAGGAC TATGACAGCCTGGCGCAACCCGGCTTCTTCGACCGCTTCATCCGCTGGATCTGCTAGCGCCGCCGCCCGGGC- CCCGCAGTCGAGGGTCG TGAGCCCACCCCGTCCATGGTGCTAAGCGGGCCCGGGTCCCACACGGCCAGCACCGCTGCTCACTCGGACGA- CGCCCTGGGCCTGCAC CTCTCCAGCTCCTCCCACGGGGTCCCCGTAGCCCCGGCCCCCGCCCAGCCCCAGGTCTCCCCAGGCCCTCCG- CAGGCTGCCCGGCCTC CCTCCCCCTGCAGCCATCCCAAGGCTCCTGACCTACCTGGCCCCTGAGCTCTGGAGCAAGCCCTGACCCAAT- AAAGGCTTTGAACCCATT GCGTGCCTGCTTGCGAGCTTCTGTGCGCAGGAGAGACCTCAAAGGTGTCTTGTGGCCAGGAGGGAAACACTG- CAGCTGTCGCTCGCCCA CCAGGGTCAATGGCTCCCCCGGGCCCAGCCCTGACCTCCTAGGACATCAACTGCAGGTGCTGGCTGACCCCG- CCTGTGCAGACCCCACA GCCTTGATCAGCAAACTCTCCCTCCAGCCCCAGCCAGGCCCAAAGTGCTCTAAGAAGTGTCACCATGGCTGA- GGGTCTTCTGTGGGTGGA CGCATGATTAACACTAGACGGGGAGACAGCAGGTGCTGAGCCTGTTGTGTTCTGTGTGGAGATCTCAGTGAG- TTTTTGCTGTTCAGACCCC AGGGTCCTTCAGGCTCAGCTCAGGAGCCCCACAGTGAACCAGAGGCTCCACAGGCAGGTGCTGACCTGACAG- GAGTGGGCTTGGTGGCC ATCACAGGGCACCACAGACACAGCTTGAACAACTACCAGTATCGGCCACAGGCCTGGAGGCATCAGCCGGGC- CATGCTTCCTCTGGAGGG CTAGAGGAGGACTAGAGAAGGGCCTGCCCCGGCCTCTCCCCAGCATCCCAGGGTTCCTGATCTCCTGGATAA- GGATACAAGTCACCACAC TGGACTGGGGCTCAGCCTGCTCTAGAATACCTCACCTAAGTCACAGTGGACCAGGCTCAGCCTGCTCTAAGG- TGAGCTTACCCGAGACACT GGACCAGAGATCAGCCTATCCTGGGATAAGCTCACCCGAGTCACACTGGACCAGGGCTCAGCCTATTCCGGG- ATGAGCTCACCCGAGTC 256 C21orf56 GACACTTCCATGACTGCAGCTGACCAGTCCACCTGCCAGCGGTTGACCACTCCCACTTCGCCAGCGACCGAAG- GGGAGGGGAGGGGCCT CACCTGAGGGCAACAGCAGAACCCACCACCTGGTCTTGCTTTACTCAGACCTGAGGGTGTGAAAGGTGCCCG- TGACCTCCCGCATCAGGG AGCTGGCCGCCACCCTCGACTCCCGGGGAGCAGGCGTCCCGCGACCCCCTCATCTACCAGGCCATCTGAGCT- GGGCGGCGCCTCACCTC CGCTCCCGGGGGAGCCGGCCTCAGGGTAGGCATGCGCCCTGGGTGGGAGCAGGTCGTGGCCGCCGCCCTCCT- GGCAGCTCTGGCTGAG CAGCCGCCGCAGCATCTGATTCTCCTTCAGGAGGCGCACCTGCTTCTTCAGGTCCGCGTTCTCGCTCAGGAG- CCGGCTCATCAGCTCGCC GCCTTCAGCCATGGCGGGTGCGTCCCTCCTTGTCCCTCACGGCTCCTGCAGCCCCATGGAGGTGGGAGCCCA- GAGCCCGCAGGCACCAC AGAAACAGCCCAGGCACGGAGTTCCGTAGCCACCACCGCCTTCCACGCCTTGTGATGTCACTGCCCTAGTGA- TGAGGTGCCCAGCACCCT GCCTGCCCCCGCGATGGCTCATGGCCCCGTTGAGGCAGTGAAGCTGGAGGCCCGTGGCGTGCACAGGCAGCC- ACTCCCACATTATGACC AGGGCCCGAGAATGCCAAGGACATTAGGCAGCTACGGGATGTAGCGACTGTACTCCAAGAGGGGCGTCCAAG- CCACTCCCCATTGA 257 C21orf57 AGGTGGAGGTTGCAGTGAGCCCTCCTCCCCTCCTCCCCCTTCCCTTCCCACCTCCCATGCCCCCCTTTCTTCC- TCCCACTCCCCTCCCGAGGCCCCG CTTATTCTCCCGGCCTGTGGCGGTTCGTGCACTCGCTGAGCTCAGGTTCTGGTGAAGGTGCCCGGAGCCGGG- TCCCGCCTTCGGCCTGAGCTAGAGCCGC GCGGGCGGCCGGCTTCCCCCAAACCCTGTGGGAGGGGCATCCCGAGGAGGCGACCCCAGAGAGTGGGGCGCG- GACACCTTCCCTGGGGAGGGCCAG 258 C21orf57 CCTTCCAGATGTTCCAGAAGGAGAAGGCGGTGCTGGACGAGCTGGGCCGACGCACGGGGACCCGGCTGCAGCC- CCTGACCCGGGGCCT CTTCGGAGGGAGCTGAGGGCCGCGTTCCTTCTGAAAGCGGGACGCGGGAGGGGTGGAGGCTGCGGGGAGCCG- GGGTCGCACACGAATA

AATAACGAATGAACGTACGAGGGGAACCTCCTCTTATTTCCTTCACGTTGCATCGGGTATTTTTCGTTATTG- TAAATAAAACGGTTCCGAGCC GTGGCATCGAGAGGGCGTCTGGAGTTCAGGGAACGCGTGGCCCCCGCCCGGGAGCACCGCGCAGCGCTCGCC- TCTCGCCCTTCAAGGG GGTCCCTGCCCGGAGCCTGCGCCCCCGGAGAGGAAGGGGCTCGAGGGGCTTGGGTGCCGCAGCGCGTCCTTC- CGTAGAAAAGGCTTGC GTCAGTATTTCCTGCTTTTACCTCCTGAG 259 C21orf57 CAGTATTTCCTGCTTTTACCTCCTGAGTATTGGAATATTCGAGTAAACCCTGGAGTTTCAGCGCCAGCGCACG- CCTCTTCATCAGGGCAGCG CGTCGCGAGCGCGCTGGTTCCCCGGGGCCTCCCGGCCACGGACACCGCTCTAGCCAGGGCCACGGCGAGGCC- GCCGAGCAGCACCTCA GAGACCTGCGTGAGTTCTAAAGCCTGGGGCTACTACAATTCTGCTCATCTGTTTGTCCTGTGAAATGATTCA- GGGACATGAAAATGCCTTCC CACTGACTTGCGTCCTGTCTTAGCCTGGACTTGTCCCCTTGGGAACACGGGCCAGGCCCCTCTGTTCCTGAA- GT 260 C21orf58 ATGTCTGCAGGGAAGAAGCAGGGGGACCCTGAATAAAGTTTCCGTTTTTCCTATTTGTTAAAGTGATAGAGCA- TTATAGGACCAGAGAACAG GTGTGTCTGTACACTGTGCAGGTCCCCGGGGCAGGCTCTGAGTCCGTCTGCACACGGTGCGGGTCCCCGGGG- CGCGCCCTGAGCCCGT CTGCACACGGTGCGGGTCCCCGGGGCGCGCCCTGAGCCCGTCTGCACACGGTGCGGGTCCCCGGGGCGCGCC- CTGAGCCCGTCTGCA CACGGTGCGGGTCCCCGGGGCGCGCCCTGAGCCCGTCTGCACACGGTGCGGGTCCCCGGGGCGCGCCCTGAG- CCCGTCTGCACACGG TGCGGGTCCCCGGGGCGCGCCCTGAGCCCGTCTGTACACGGTGCGGGTCCCCGGGGCGCGCCCTGAGTCTCT- ACTAAAAATACAAAAAT TAGCCAGGCGTGGTGGTTCAAGCCTGTAATCCCAGCTCCTTGGGAGG 261 PRMT2 CATACATGGTTATTAGAAAAGGCATCTCATCCAAATGTGGTGGCTCGTGCTTGTAATCCCAGTG- CTTCAGGAGGCCAAGGGAGGAGGATTA CTTGAGCCTAAGAGTTTGAGACCAGCCTGGGCAACACAACAAGACCTTGCCTCTACAAAAAACTTAAAAACT- AGCTGGGTATGATGGTGCAC ACCTGTAGTCCCAGCTACTTGGGAGGCGGAGGCGGGCAGATCGCCTGAGGTCAGGAGTTCGAGACCAGCCTG- GCCAACATGATGAAACC CCGTCTCTACTAAAAATACAAAAATTAGCCGAGTGTGGTGGTGCATGCCTGTAATCCCAGCTACTCAGGAGG- CTGAGGCAGGAGAATCACT TGAACCCGGGAGGCGGAGGTTGCCATGAGCCGAGATCACGTCACTGCACTCCAGCCTGGGTGACAGAGCACA- AAAGACAGGCATGACTTT GTACTTAACTGCTCAGCTTTGTAATCACTGGGGGCCCAGATGCTCACTTGGATTCTAACTTTGTTGGCATCT- GGGCCTAAAAGCCGTGATGC AGGTGAGCAATGATGCAGAGGGCTCTGTGCGCCTGGCGGGCTCTGTTTGCCTGCTGGGCTCTGTGCGCCTGC- TGGGCTCTGTGCGCCCG GGAAGGTGCGGCCACCCTCACGCGGAAGGCGGCCAGCGGATCCCGGTGCGCGCAGCTCCCAGCGCTGGGGTT- CCAGCGCCCCGCCTCT TCCTATAGCAACCAGCGGGACCTGCCGTCCCCCGGGGCACCCCGAGGGGTCTGCGCCCGCTTCTTTCCGAAA- CGGGAAGGCGCTGGGG GCTCGGCAGCCAGAGGGACGGGTTCAGGGAGCGTCCGGTGAGCCTAAGACGCGCCTTTGCCGGGGTTGCCGG- GTGTCTGCCTCTCACTT AGGTATTAGGAACCGTGGCACAAATCTGTAGGTTTTCCTCTGGGGGTGGGCGGAGGCTCCAAACCGGACGGT- TTTCTCCTGGAGGACTGT GTTCAGACAGATACTGGTTTCCTTATCCGCAGGTGTGCGCGGCGCTCGCAAGTGGTCAGCATAACGCCGGGC- GAATTCGGAAAGCCCGTG CGTCCGTGGACGACCCACTTGGAAGGAGTTGGGAGAAGTCCTTGTTCCCACGCGCGGACGCTTCCCTCCGTG- TGTCCTTCGAGCCACAAA AAGCCCAGACCCTAACCCGCTCCTTTCTCCCGCCGCGTCCATGCAGAACTCCGCCGTTCCTGGGAGGGGAAG- CCCGCGAGGCGTCGGGA GAGGCACGTCCTCCGTGAGCAAAGAGCTCCTCCGAGCGCGCGGCGGGGACGCTGGGCCGACAGGGGACCGCG- GGGGCAGGGCGGAGA GGACCCGCCCTCGAGTCGGCCCAGCCCTAACACTCAGGACCGCCTCCAGCCGGAGGTCTGCGCCCTTCTGAG- GACCCTGCCTGGGGGAGCT TATTGCGGTTCTTTTGCAAATACCCGCTGCGCTTGGACGGAGGAAGCGCCCACGCGTCGACCCCGGAAACGA- AGGCCTCCCTGATGGGAACGCA TGCGTCCAGGAGCCTTTATTTACTCTTAATTCTGCCCGATGCTTGTACGTGTGTGAAATGCTTCAGATGCTT- TTGGGAGCGAGGTGTTACATAAA TCATGGAAATGCCTCCTGGTCTCACCACACCCAGGGTGACAGCTGAGATGCGGCTTCTCCAGGGTGGAGCCT- CCTCGTTTTCCAGAGCTGC TTGTTGAAGTCTTCCCAGGGCCCCTGACTTGCACTGGAAACTGCTCACCTTGGCATCGGGATGTGGAGCAAG- AAATGCTTTTGTTTTCATTCAT CCTAGTGTTCATAAAATGGAAAACAAATAAGGACATACAAAAACATTAATAAAATAAATTAATGGAACTAGA- TTTTTCAGAAAGCACAACAAACA CAAAATCCAAGTATTGCCATGTCAGCAACACATTCCTACTTTAAGTTTTATGAAGTTAATTGGAGTAGTGGA- GAACAAAAGTGGATGTGGGGCAG

Example 4

Fetal DNA Quantification Using Massively Parallel Shotgun Sequencing

[0469] In this example, fetal-specific DNA methylation markers were utilized to quantify the fraction of circulating cell-free fetal DNA in maternal plasma, using a massively parallel shotgun sequencing (MPSS) platform. For this Example, four types of DNA markers were assayed: 1) fetal-specific methylation markers which allowed selective enrichment and subsequent quantification of fetal DNA (e.g., SOX14, TBX), 2) Y-chromosome markers which confirmed fetal DNA quantification (for samples with a male fetus; e.g., SRY1, SRY2, UTY), 3) total markers avoid of restriction sites which were used to quantify total cell-free DNA, including fetal and maternal DNA (e.g., ALB, APOE, RNAseP, and 4) digestion control markers which monitored the completeness of restriction digestion and hence the accuracy of methylation marker-based fetal quantification (e.g., LDHA, POP5).

Methylation-Specific Restriction Digestion

[0470] Fetal methylation DNA markers were enriched by selective digestion of unmethylated maternal DNA, using methylation-sensitive restriction enzymes. Digestion was performed according to the parameters specified in Table 5 below.

TABLE-US-00017 TABLE 5 Methylation-specific restriction digestion Concentration in Reagent Volume Reagent reaction (.mu.L) for n = 1 H2O N/A 16.7 10x PCR Buffer 1 3.5 (20 mM MgCl2, Roche) 25 mM MgCl2 (Roche) 2 2.8 Exol [U/.mu.l] (NEB) 0.2857 0.5 Hhal [U/.mu.l] (NEB) 0.2857 0.5 Hpall [U/.mu.l] (NEB) 1.4285 1 DNA [.mu.l] 10 Final Vol: 35 Reaction conditions: Digestion 41.degree. C. 60' Inactivation 98.degree. C. 10'

Competitive PCR

[0471] The digested samples were amplified by PCR together with known copy numbers of competitor oligonucleotides. The competitors were synthetic oligonucleotides having the same nucleotide sequences as the target DNA, except for one base difference at the synthetic target site, which differentiated the target DNA from the competitor. Competitive PCR using target-specific primers allowed for independent quantification of each marker. Competitive PCR was performed according to the parameters specified in Table 6 below.

TABLE-US-00018 TABLE 6 PCR amplification Concentration in Reagent Volume Reagent reaction (.mu.L) for n = 1 Water, HPLC grade N/A 6.64 10x PCR Buffer (20 mM 1x (2 mM MgCl2) 1.5 MgCL2, Roche) 25 mM MgCl2 (Roche) 2 mM 1.2 dNTPs (25 mM, Roche) 500 .mu.M 1 PCR primer (1 uM each) 0.1 .mu.M 5 FASTSTART PCR Enzyme 0.1 U/.mu.l 1 (5U/.mu.l, Roche) Competitor MIX (8000/800 c/ul)(1:0.1 c/u1) 0.38 DNA (from restriction digestion) 35 Total 50 PCR Cycling conditions: 95.degree. C., 5 min 95.degree. C., 45 sec 35 cycles 60.degree. C., 30 sec 72.degree. C., 45 sec 72.degree. C., 3 min 4.degree. C. hold

Adaptor Oligonucleotide Ligation

[0472] Illumina adaptor oligonucleotides (TRUSEQ adaptors) were ligated to the amplicons generated in the competitive PCR described above. The adaptor-ligated amplicons were subsequently sequenced using the Illumina HISEQ 2000 platform (Illumina, San Diego Calif.). Two different ligation-based approaches were used to flank the amplicons with the adaptors. The ligation procedure was optimized to maximize the amount of double ligation products (i.e., adaptor oligonucleotides ligated to both ends of the amplicon), and minimize single ligation and/or empty ligation (i.e., two adaptor oligonucleotides ligate to each other without amplicon insertion).

[0473] Direct Ligation of Adaptors

[0474] To render the PCR amplicons compatible for MPSS, the amplicons (which had 3' adenine (A) overhangs generated by Taq polymerase during the PCR reaction) were ligated to adaptor oligonucleotides having 3' thymine (T) overhangs (see FIG. 21). Prior to the ligation reaction, AMPURE XP beads at 2-fold volume of PCR reaction volume were used to remove single-stranded primers and amplicons generated by asymmetric PCR. Cleaned amplicons were quantified by Agilent Bioanalyzer and mixed with Illumina TRUSEQ library adaptors at an 8:1 ratio. 2 .mu.L of T4 DNA ligase (Enzymatics) and 17.5 .mu.L of 2.times. ligase buffer (Enzymatics) were added, and the ligation reaction was carried out at room temperature for 15 minutes.

[0475] Unidirectional Adaptor Ligation

[0476] In some cases, a modified protocol to improve ligation efficiency and to ensure unidirectional ligation was used. Single base overhang ligation can be less efficient compared to ligation of longer cohesive ends. Additionally, using single base overhang ligation, PCR amplicons can ligate with Illumina TRUSEQ adaptors in either orientation such that, when the ligated product were sequenced, only about half of the sequence reads covered the target sites for copy number calculation. Modifications of the ligation procedure were thus developed to overcome such limitations. First, tag sequences that were 5 nucleotides long were designed to replace the original tag sequence (10 nucleotides long) in the PCR primers (for the competitive PCR above; provided in Table 7 below). The tags were of different sequences for reverse or forward PCR primers and each had a deoxyuridine at the junction between tag sequence and target-specific sequence. The modified primers were used at equal molar ratio in the competitive PCR reaction above.

[0477] After PCR amplification, the tags were cleaved from the amplicons by uracil N-glycosylase (UNG; UDG) and EndoVIII digestion, creating a 5 base overhang that selectively ligated the PCR amplicon to universal or indexed adaptors (provided in Table 7 below) with high efficiency (see FIG. 22). Specifically, 1 .mu.L UDG (5 U/.mu.L, NEB) and 5 .mu.L EndoVIII (10 U/.mu.L, NEB) were added to each reaction and incubated at 37.degree. C. for 30 minutes. The reaction was stopped by heating at 95.degree. C. for 10 minutes to inactivate UDG, after which it was gradually cooled to 25.degree. C. The amplicons were cleaned by AMPURE XP beads prior to the ligation reaction.

TABLE-US-00019 TABLE 7 Primer and adaptor sequences Target Forward_Primer (SEQ ID NOS 350-362) Reverse_Primer (SEQ ID NOS 363-375) ALB TAGCUGCGTAGCAACCTGTTACATATT GATCUATACTGAGCAAAGGCAATCAAC APOE TAGCUCAGTTTCTCCTTCCCCAGAC GATCUGAATGTGACCAGCAACGCAG RNAseP TAGCUGGTCAGCTCTTCCCTTCATC GATCUCCTCCCACATGTAATGTGTTG CDC42EP1 TAGCUAGCTGGTGCGGAGGGTGGG GATCUATGGGGGAGATGGCCGGTGGA LDHA TAGCUGGCCTTTGCAACAAGGATCAC GATCUCGCAATACTAGAAACCAGGGC MGC15523 TAGCUTCTGGTGACCCCCGCGCTTC GATCUCATCTCTGGGTGCGCCTTG POP5 TAGCUCCCTCCACATCCCGCCATC GATCUCAGCCGCCTGCTCCATCG SOX14 TAGCUACGGAATCCCGGCTCTGTG GATCUCCTTCCTAGTGTGAGAACCG SPN TAGCUGGCCCTGCTGGCGGTCATA GATCUTGCTCAGCACGAGGGCCCCA SRY1 TAGCUAGCAACGGGACCGCTACAG GATCUTCTAGGTAGGTCTTTGTAGCC SRY2 TAGCUTAAGTTTCGAACTCTGGCACC GATCUGAAGCATATGATTGCATTGTCAA TBX3 TAGCUCTCCTCTTTGTCTCTGCGTG GATCUTTAATCACCCAGCGCATGGC UTY TAGCUTGATGCCCGATGCCGCCCTT GATCUGTCTGTGCTGGGTGTTTTTGC Adaptors (SEQ ID NOS 376-378) Universal_adaptor AATGATACGGCGACCACCGAGATCTACACTCTTTCCCTACACGACGCTCTTCCGATCT Index_linker GCTCTTCCGATCTATAGCT Index_adaptor 5'phos/ GATCGGAAGAGCACACGTCTGAACTCCAGTCACAGTCAACAATCTCGTATGCCGTCTTCTGCTTG

[0478] Pre-annealed index adaptor and index-linker was prepared by mixing at equal molar ratio, heating to 95.degree. C. for 5 minutes, and gradually cooled to 25.degree. C. Universal adaptor and pre-annealed index adaptor at equal molar ratio were mixed with the UDG/EndoVIII-digested PCR amplicons (having 5 nucleotide overhangs). The ratio of adaptor to amplicon varied from 8:1 to 2:1. 2 .mu.L of T4 DNA ligase (Enzymatics) and 17.5 .mu.L of 2.times. ligase buffer (Enzymatics) were added, and the ligation reaction was carried out at room temperature for 15 minutes.

[0479] For both ligation approaches, the ligated product (5 .mu.L) was amplified using Illumina TRUSEQ PCR mixture and primers as specified in Table 8 below. Amplified libraries were purified using AMPURE XP beads to remove free primers/adaptors and DNA fragments of smaller size.

TABLE-US-00020 TABLE 8 PCR amplification of ligation products Reagent Reagent Volume (.mu.L) for n = 1 Water, HPLC grade 11 TRUSEQ PCR master mix 20 TRUSEQ PCR primers 4 Ligation product 5 Total 40 PCR Cycling conditions 98.degree. C., 5 min 98.degree. C., 10 sec 10 cycles 65.degree. C., 30 sec 72.degree. C., 30 sec 72.degree. C., 3 min 4.degree. C. hold

[0480] Amplified libraries were retained on an Illumina flow cell and bridge amplified to generate clusters for subsequent sequencing on Illumina's HISEQ 2000. Use of indexed adaptors allowed for sequencing of multiple samples in a single lane on the flow cell.

Nucleotide Sequence Read Analysis and Fetal DNA Quantification

[0481] Nucleotide sequence reads were analyzed and used to calculate copy number of individual markers and fetal percentage. 50 base pair (bp) nucleotide sequence reads were uniquely aligned to expected chromosome positions, allowing up to 5 mismatches outside the target sites/synthetic target sites. Reads having quality score greater than 13 at the target site with expected target DNA or competitor alleles were used to calculate the copy number of each marker. Specifically, the following formula was used:

Copy ( DNA ) = Copy ( comp ) .times. Read Counts ( expected DNA allele ) Read Counts ( expected comp allele ) ##EQU00001##

[0482] Fetal DNA, Y-chromosome DNA and total DNA copy numbers were represented by the mean value of methylation markers, Y-markers and total DNA markers, respectively. Fetal percentage was calculated according to the following formulas:

Fetal Fraction ( methyl ) = mean copy number ( methylation markers ) mean copy number ( total markers ) ##EQU00002## and ##EQU00002.2## Fetal Fraction ( Y ) = 2 .times. mean copy number ( y markers ) mean copy number ( total markers ) ##EQU00002.3##

[0483] Digestion efficiency was calculated by

digestion efficiency = 1 - mean copy number ( digestion markers ) mean copy number ( total markers ) ##EQU00003##

Results

[0484] The fetal DNA quantification method using MPSS described in this Example was applied to ccfDNA extracted from 48 plasma samples from pregnant women. The results were compared to those obtained from another method that used mass spectrometry (e.g., MASSARRAY) as a detection method instead of MPSS. The results from both methods were highly correlated (see FIGS. 23 and 24). With exception of digestion markers (LDHA and POP5, which were detected at higher levels by the MPSS method), the R.sup.2 values were in the range of 0.965-0.998. The fetal fractions derived from methylation markers also were highly correlated between MPSS and mass spectrometry methods (see FIG. 25).

Example 5

SNP Allele Frequency Based Method for Fetal Fraction Quantification

[0485] In this example, single nucleotide polymorphism (SNP) markers were utilized to detect and quantify circulating cell-free (CCF) fetal DNA in maternal plasma (i.e. fetal fraction). In some cases, fetal fraction was determined by measuring single nucleotide polymorphism alleles using a single tube multiplex PCR for amplicon sequencing via massively parallel shotgun sequencing (MPSS). Advantages of this methodology include, for example: 1) the ability to detect CCF fraction of DNA from both male and female fetuses without prior knowledge of maternal or paternal SNP genotypes; 2) a simplified workflow that generates MPSS ready products without the need for traditional library generation and 3) an ability to perform MPSS fetal fraction quantification on samples multiplexed with genomic libraries on the same flow cell lane.

Materials and Methods

[0486] CCF DNA was extracted from 4 mL plasma from 46 pregnant women using QIAAMP Circulating Nucleic Acid kit in an elution volume of 55 .mu.l. DNA also was extracted from maternal buffy coat samples for confirmation of maternal genotypes. Gestational age at collection ranged from 10-17 weeks. Maternal age ranged from 18-42 years. Ethnic background of samples included African American, Asian, Caucasian and Hispanic ethnicities. 15 .mu.l of CCF DNA underwent PCR for each SNP panel using a single tube multiplex of forward and reverse PCR primers that included adapter sequences to allow secondary amplification with universal PCR primers designed to incorporate index tags. Amplicon libraries with index tags were clustered on the cBOT and sequenced on the HiSeq 2000 for 36 cycles or 27 cycles to generate amplicon sequence reads and 7 cycles to determine the index tag sequence. Reads were aligned to the human genome (hg19) and matched read counts for expected SNP alleles were used to calculate the allele ratio of each SNP within each CCF DNA. 15 .mu.l of CCF DNA also was used for quantification of fetal fraction by fetal specific methylation patterns for comparison with SNP based quantification.

Detection of Paternally Inherited Alleles

[0487] CCF fetal DNA in maternal plasma contains both maternally and paternally inherited DNA (e.g., SNP alleles). Detection of paternal SNP alleles not present in the maternal genome can allow confirmation of the presence of fetal DNA. Additionally, quantification of paternal:maternal SNP allele ratios can provide for a determination of fetal DNA fraction in maternal plasma. The likelihood of detecting a paternally inherited allele at a single locus is dependent upon allele frequency and individual inheritance patterns. FIG. 26, for example, provides a summary of expected genotypes and the associated population frequency of each genotype based a SNP having a minor allele population frequency of 0.4. A SNP with a high minor allele frequency may increase the chance that paternal and maternal alleles will differ at a given SNP locus. Provided enough SNPs are interrogated, a high probability can be established that the fetus will contain some paternal alleles that differ from the maternal alleles. Thus, use of multiple SNP alleles increases the likelihood of informative fetal and maternal genotype combinations. Often, no prior knowledge of the paternal genotypes is required because paternal alleles can be inferred by the presence of non-maternal alleles in the maternal/fetal cell free DNA mixture. FIGS. 27 and 28 show how fetal fraction can be calculated using SNP allele frequency.

SNP Panels

[0488] High minor allele frequency SNPs that contain only 2 known alleles were identified. Two panels of SNPs were generated: a 67 SNP panel (SNP panel 1) and an 86 SNP panel (SNP panel 2). Individual SNP identifiers for each panel are provided in Table 9A and Table 10A below. Tables 9B and 10B include chromosome identity for each SNP.

TABLE-US-00021 TABLE 9A SNP Panel 1 rs10413687 rs2001778 rs4453265 rs539344 rs7176924 rs10949838 rs2323659 rs447247 rs551372 rs7525374 rs1115649 rs2427099 rs4745577 rs567681 rs870429 rs11207002 rs243992 rs484312 rs585487 rs949312 rs11632601 rs251344 rs499946 rs600933 rs9563831 rs11971741 rs254264 rs500090 rs619208 rs970022 rs12660563 rs2827530 rs500399 rs622994 rs985462 rs13155942 rs290387 rs505349 rs639298 rs1444647 rs321949 rs505662 rs642449 rs1572801 rs348971 rs516084 rs6700732 rs17773922 rs390316 rs517316 rs677866 rs1797700 rs3944117 rs517914 rs683922 rs1921681 rs425002 rs522810 rs686851 rs1958312 rs432586 rs531423 rs6941942 rs196008 rs444016 rs537330 rs7045684

TABLE-US-00022 TABLE 9B SNP Panel 1 Chro- Chro- Chro- SNP_ID mosome SNP_ID mosome SNP_ID mosome rs10413687 chr19 rs290387 chr20 rs537330 chr8 rs10949838 chr7 rs321949 chr19 rs539344 chr19 rs1115649 chr21 rs348971 chr2 rs551372 chr11 rs11207002 chr1 rs390316 chr14 rs567681 chr11 rs11632601 chr15 rs3944117 chr7 rs585487 chr19 rs11971741 chr7 rs425002 chr4 rs600933 chr1 rs12660563 chr6 rs432586 chr12 rs619208 chr11 rs13155942 chr5 rs444016 chr5 rs622994 chr13 rs1444647 chr12 rs4453265 chr11 rs639298 chr1 rs1572801 chr6 rs447247 chr6 rs642449 chr1 rs17773922 chr19 rs4745577 chr9 rs6700732 chr1 rs1797700 chr12 rs484312 chr13 rs677866 chr13 rs1921681 chr4 rs499946 chr7 rs683922 chr15 rs1958312 chr14 rs500090 chr11 rs686851 chr6 rs196008 chr16 rs500399 chr10 rs6941942 chr6 rs2001778 chr11 rs505349 chr11 rs7045684 chr9 rs2323659 chr17 rs505662 chr6 rs7176924 chr15 rs2427099 chr20 rs516084 chr1 rs7525374 chr1 rs243992 chr4 rs517316 chr1 rs870429 chr3 rs251344 chr5 rs517914 chr4 rs949312 chr18 rs254264 chr19 rs522810 chr13 rs9563831 chr13 rs2827530 chr21 rs531423 chr1 rs970022 chr4 rs985462 chr10

TABLE-US-00023 TABLE 10A SNP Panel 2 rs1005241 rs1432515 rs2906237 rs654065 rs849084 rs1006101 rs1452396 rs2929724 rs6576533 rs873870 rs10745725 rs1518040 rs3742257 rs6661105 rs9386151 rs10776856 rs16853186 rs3764584 rs669161 rs9504197 rs10790342 rs1712497 rs3814332 rs6703320 rs9690525 rs11076499 rs1792205 rs4131376 rs675828 rs9909561 rs11103233 rs1863452 rs4363444 rs6814242 rs11133637 rs1991899 rs4461567 rs6989344 rs11974817 rs2022958 rs4467511 rs7120590 rs12102203 rs2099875 rs4559013 rs7131676 rs12261 rs2108825 rs4714802 rs7214164 rs12460763 rs2132237 rs4775899 rs747583 rs12543040 rs2195979 rs4817609 rs768255 rs12695642 rs2248173 rs488446 rs768708 rs13137088 rs2250246 rs4950877 rs7828904 rs13139573 rs2268697 rs530913 rs7899772 rs1327501 rs2270893 rs6020434 rs7900911 rs13438255 rs244887 rs6442703 rs7925270 rs1360258 rs2736966 rs6487229 rs7975781 rs1421062 rs2851428 rs6537064 rs8111589

TABLE-US-00024 TABLE 10B SNP Panel 2 Chro- Chro- Chro- SNP_ID mosome SNP_ID mosome SNP_ID mosome rs1518040 chr1 rs11974817 chr7 rs10745725 chr12 rs16853186 chr1 rs13438255 chr7 rs2250246 chr12 rs2268697 chr1 rs2736966 chr7 rs2270893 chr12 rs3814332 chr1 rs2906237 chr7 rs6487229 chr12 rs4363444 chr1 rs4131376 chr7 rs7975781 chr12 rs4950877 chr1 rs849084 chr7 rs12261 chr13 rs6661105 chr1 rs9690525 chr7 rs3742257 chr13 rs6703320 chr1 rs12543040 chr8 rs675828 chr13 rs1432515 chr2 rs1863452 chr8 rs12102203 chr15 rs12695642 chr3 rs2022958 chr8 rs4775899 chr15 rs2132237 chr3 rs6989344 chr8 rs6576533 chr15 rs6442703 chr3 rs7828904 chr8 rs11076499 chr16 rs13137088 chr4 rs10776856 chr9 rs244887 chr16 rs13139573 chr4 rs11103233 chr9 rs654065 chr16 rs1452396 chr4 rs1327501 chr9 rs7214164 chr17 rs1712497 chr4 rs1360258 chr9 rs9909561 chr17 rs4461567 chr4 rs1421062 chr10 rs12460763 chr19 rs4467511 chr4 rs2248173 chr10 rs2108825 chr19 rs6537064 chr4 rs768255 chr10 rs2195979 chr19 rs6814242 chr4 rs7899772 chr10 rs3764584 chr19 rs747583 chr4 rs7900911 chr10 rs8111589 chr19 rs1006101 chr5 rs10790342 chr11 rs873870 chr19 rs11133637 chr5 rs1792205 chr11 rs530913 chr20 rs2929724 chr5 rs1991899 chr11 rs6020434 chr20 rs4559013 chr5 rs2099875 chr11 rs4817609 chr21 rs4714802 chr6 rs2851428 chr11 rs1005241 chr22 rs669161 chr6 rs488446 chr11 rs9386151 chr6 rs7120590 chr11 rs9504197 chr6 rs7131676 chr11 rs768708 chr11 rs7925270 chr11

Generation of Illumina Sequencer Ready Amplicons

[0489] For SNP panel 1, PCR primers were designed to amplify the 67 targeted SNPs plus a flanking region of 35 base pairs (bp) surrounding the SNP site. The 67 targeted regions were amplified in a single multiplex reaction. For SNP panel 2, PCR primers were designed to amplify the 86 targeted SNPs plus a flanking region of 26 base pairs (bp) surrounding the SNP site. The 86 targeted regions were amplified in a single multiplex reaction.

[0490] PCR primers were modified such that Illumina sequencing adapters could be added via universal tag sequences incorporated onto the 5' end of the SNP-specific PCR primers. Illumina tags were added using two separate PCR reactions (see FIG. 29 and Table 11 below): 1) a loci-specific PCR which incorporated a section of the Illumina sequencing adapters followed by 2) a universal PCR whose primers annealed to the tags in the loci-specific PCR to complete the addition of the adapters whilst allowing the addition of a sample specific index sequence via the reverse primer in the universal PCR. A 3.sup.rd single cycle PCR was performed to remove heteroduplex secondary structure that can arise in the amplicons during the universal PCR stage due to cross-annealing of shared adapter sequences between different amplicons in the same multiplex. Loci-specific PCR and universal PCR were performed under standard conditions using primers synthesized from Integrated DNA Technologies (IDT; Coralville, Iowa) with no special modifications.

TABLE-US-00025 TABLE 11 Name Sequence Squencing adaptors, loci specific PCR primer tags and universal PCR primer tags (SEQ ID NOS 379-385) TRUSEQ P5 Adapter 5'- AATGATACGGCGACCACCGAGATCTACACTCTTTCCCTACACGA CGCTCTTCCGATCT-3' TRUSEQ Read 1 5'-ACACTCTTTCCCTACACGACGCTCTTCCGATCT-3' sequencing primer TRUSEQ P7 adapter, 5'- Index 13 GATCGGAAGAGCACACGTCTGAACTCCAGTCACAGTCAAATCTC GTATGCCGTCTTCTGCTTG-3' TRUSEQ index read 5'-GATCGGAAGAGCACACGTCTGAACTCCAGTCAC-3' primer Loci PCR forward tag 5'-TCTTTCCCTACACGACGCTCTTCCGATCT-3' Loci PCR reverse tag 5'-GTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT-3' UNIV PCR forward 5'- primer AATGATACGGCGACCACCGAGATCTACACTCTTTCCCTACACGA CGCTC-3' Sequencing adaptors, loci specific PCR primer tags and universal PCR primer tags (SEQ ID NOS 386) UNIV PCR reverse index 5'- 13 primer CAAGCAGAAGACGGCATACGAGATTTGACTGTGACTGGAGTTCA GACGTG-3'

Amplicon Sequencing by Illumina NGS

[0491] Universal PCR products were quantified using standard DNA fragment analysis methods such as Caliper LabChip GX or Agilent Bioanalyzer. The sequencer-ready amplicons from up to 12 samples were pooled and sequenced on an Illumina HISEQ apparatus. For SNP panel 1, 36 cycles were used to sequence the target SNP plus the 35 bp flanking region. For SNP panel 2, 27 cycles were used to sequence the target SNP plus the 26 bp flanking region. Samples were de-multiplexed using a 6 bp index identifier incorporated at the universal PCR stage.

Assignment of Informative Alleles and Fetal Fraction Determination

[0492] Reads were aligned to the human genome (hg19) with up to 3 mismatches in each read to allow for sequencing error and variant alleles at target SNP position. The frequency of each SNP allele was determined by counting the number of reads having the allele of interest and dividing it by the total number of reads for each SNP locus (i.e., (# reads allele 1)/(# reads allele 1+# reads allele 2)). Based on the frequency value generated from this data, the sequenced genotypes were assigned as Type 0 non-informative genotypes, Type 1 informative genotypes or Type 2 informative genotypes. A Type 0 non-informative genotype is a fetal genotype that cannot be distinguished from the maternal genotype because the fetus has the same genotype as the mother (e.g., mother is "Aa" and fetus is "Aa"). A Type I informative genotype is the situation where the mother is homozygous (AA) and the fetus is heterozygous (Aa). This genotype is informative because allele "a" is from the father. The frequency of a Type 1 informative allele can be indicative of the percentage fetal DNA in the mixture. A Type 2 informative genotype is the situation where the mother is heterozygous (Aa) and the fetus is homozygous (AA). The genotype is informative because the frequency of the maternal allele "a" will deviate from the expected Mendelian frequency of 0.5 when there is fetal DNA contributing additional "A" alleles. This deviation in value from 0.5 can be used to compute the fetal fraction.

[0493] Allele frequencies for each of the SNPs was calculated for each sample based on the number of reads containing each allele, as described above. Variation of expected allele frequency could be due to the presence of fetal DNA with a different paternal allele or could be due to mis-incorporated sequences by the Illumina Sequencer (e.g., background noise). In some cases, the amount of background noise associated with each particular SNP amplicon was determined to establish a dynamic cutoff value for each SNP. Maternal DNA (i.e. buffy coat) samples were sequenced and the deviations from the expected Mendelian ratios of 1 for homozygotes and 0.5 for heterozygotes were observed. From these values a median-adjusted deviation (MAD score) was identified for each SNP assay. In some cases, a genotype was identified as being a Type I informative genotype when the paternal allele frequency measured was greater than 3.times.MAD score. In some cases, multiple Type 1 informative genotypes were identified and an average allele frequency was determined. Fetal fraction was calculated by multiplying the average Type 1 informative allele frequency by 2. For example, an average informative allele frequency of 4.15% indicated a fetal fraction of 8.3%. Fetal Fraction also can be calculated from Type 2 informative genotypes by determining maternal allele "a" frequencies deviating from 0.5 by greater than 3.times.MAD, for example. Fetal fraction can be identified by multiplying this deviation by 2.

[0494] In some cases, informative genotypes were assigned without prior knowledge of maternal or paternal genotypes. Allele frequencies for each SNP (of SNP panel 1) were plotted as shown in FIG. 30 and FIG. 31 for two of the 46 samples tested. Homozygous allele frequencies in maternal buffy coat were close to 0 or 1. Type 1 informative SNPs were identified by allele frequencies that deviated from the expected allele frequency of 0 or 1 due to the presence of a paternal allele from the fetus. The size of the deviation was dependent on the size of the fetal fraction of CCF DNA. A maximum background allele frequency of 0.007 was observed for maternal buffy coat DNA. For this approach, fixed cutoff frequency value of 0.01 was used to distinguish non-informative homozygotes from informative genotypes in plasma samples (see FIGS. 32 and 33, showing the assignment of certain Type 1 informative genotypes). A fixed cutoff value of 0.25 was used to distinguish non-informative heterozygotes from other genotypes. Fetal fractions were calculated for 46 plasma samples by taking the mean of the informative genotype allele frequencies and multiplying this value by 2. Informative genotypes assigned per sample ranged from 1 to 26. Fetal fractions ranged from 2.5% to 14% (see FIG. 34).

[0495] To assess performance of the above method, fetal fractions also were determined for the 46 plasma samples using a differential methylation-based fetal quantifier assay. SNP-based fetal fraction estimates showed a linear association with the methylation-based estimates (r.sup.2=0.72). FIG. 35 shows linear regression of fetal fraction estimate methods as a diagonal line.

Amplicon Sequence Coverage

[0496] Various amounts of SNP amplicon libraries were combined (i.e. diluted) with TRUSEQ libraries to demonstrate that allele frequency determinations can be made at varying levels of amplicon sequence coverage. SNP amplicon libraries from 6 plasma samples and 6 buffy coat samples were combined with 11 TRUSEQ libraries and co-sequenced on a HISEQ 2000 apparatus in the same flowcell lane. Percent (%) of SNP amplicon library combined with TRUSEQ libraries ranged from 50% to 0.8%. After alignment coverage per SNP for each amplicon library ranged from 71619.times. per SNP (50% amplicon library) to 1413.times. per SNP (0.8% amplicon library). Fetal fraction estimates were not significantly different even at lowest coverage level (see FIG. 36). These findings indicate that less than 1% of the flowcell clusters on a HISEQ 2000 apparatus can be used to co-sequence amplicon libraries and that high levels of sample multiplexing (e.g., greater than 96) can be achieved.

Example 6

Examples of Embodiments

[0497] Provided hereafter are non-limiting examples of certain embodiments of the technology.

[0498] A1. A method for determining the amount of fetal nucleic acid in a sample comprising: [0499] (a) contacting a sample nucleic acid with one or more agents that differentially modify methylated nucleic acid and unmethylated nucleic acid, which sample nucleic acid comprises differentially methylated fetal nucleic acid and maternal nucleic acid, the combination of the fetal nucleic acid and the maternal nucleic acid comprising total nucleic acid in the sample, thereby generating differentially modified sample nucleic acid; [0500] (b) contacting under amplification conditions the differentially modified sample nucleic acid with: [0501] (i) a first set of amplification primers that specifically amplify a first region in sample nucleic acid comprising one or more loci that are differentially methylated between the fetal nucleic acid and maternal nucleic acid, and [0502] (ii) a second set of amplification primers that amplify a second region in the sample nucleic acid allowing for a determination of total nucleic acid in the sample, wherein the first region and the second region are different, thereby generating fetal nucleic acid amplification products and total nucleic acid amplification products; [0503] (c) incorporating adaptor oligonucleotides into the amplification products in (b); thereby generating adaptor-modified amplification products; [0504] (d) obtaining nucleotide sequences of the adaptor-modified amplification products in (c) by a sequencing process, thereby generating sequence reads; [0505] (e) quantifying the sequence reads; and [0506] (f) determining the amount of fetal nucleic acid in the sample based on a quantification of the sequence reads in (e).

[0507] A2. The method of embodiment A1, wherein the first region comprises one or more loci which each contain a restriction site for a methylation-sensitive restriction enzyme.

[0508] A3. The method of embodiment A2, wherein the one or more agents that differentially modify methylated nucleic acid and unmethylated nucleic acid comprise one or more methylation sensitive restriction enzymes.

[0509] A4. The method of embodiment A2 or A3, wherein the second region comprises one or more loci which do not contain a restriction site for a methylation-sensitive restriction enzyme.

[0510] A5. The method of embodiment A1, wherein the one or more agents that differentially modify methylated nucleic acid and unmethylated nucleic acid comprise bisulfite.

[0511] A6. The method of any one of embodiments A1 to A5, wherein the adaptor oligonucleotides are incorporated into the amplification products by ligation.

[0512] A7. The method of embodiment A6, wherein the ligation is unidirectional ligation.

[0513] A8. The method of any one of embodiments A1 to A5, wherein the adaptor oligonucleotides are incorporated into the amplification products using amplification primers comprising the adaptor oligonucleotide sequences.

[0514] A9. The method of any one of embodiments A1 to A8, wherein the adaptor oligonucleotides comprise one or more index sequences.

[0515] A10. The method of embodiment A9, wherein the one or more index sequences comprise a sample-specific index.

[0516] A11. The method of embodiment A9, wherein the one or more index sequences comprise an aliquot-specific index.

[0517] A12. The method of any one of embodiments A1 to A11, wherein at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NOs:1-261, or a fragment thereof.

[0518] A13. The method of embodiment A12, wherein at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NOs:1-89, or a fragment thereof.

[0519] A14. The method of embodiment A12, wherein at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NOs:90-261, or a fragment thereof.

[0520] A15. The method of embodiment A12, wherein at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NOs:1-59 and SEQ ID NOs:86-89, or a fragment thereof.

[0521] A16. The method of embodiment A12, wherein at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NOs:1-59, or a fragment thereof.

[0522] A17. The method of embodiment A12, wherein at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:154, SEQ ID NO:158 and SEQ ID NO:163.

[0523] A18. The method of any one of embodiments A1 to A17, wherein the sequencing process is a sequencing by synthesis method.

[0524] A19. The method of any one of embodiments A1 to A18, wherein the sequencing process is a reversible terminator-based sequencing method.

[0525] A20. The method of any one of embodiments A1 to A19, wherein the amount of fetal nucleic acid determined is the fraction of fetal nucleic acid in the sample based on the amount of each of the fetal nucleic acid amplification products and total nucleic acid amplification products.

[0526] A21. The method of embodiment A20, wherein the fraction of fetal nucleic acid is a ratio of fetal nucleic acid amplification product amount to total nucleic acid amplification product amount.

[0527] A22. The method of any one of embodiments A1 to A21, further comprising contacting under amplification conditions the nucleic acid sample with a third set of amplification primers that amplify a third region in the sample nucleic acid allowing for a determination of the presence or absence of fetal specific nucleic acid.

[0528] A23. The method of embodiment A22, wherein the fetal specific nucleic acid is Y chromosome nucleic acid.

[0529] A24. The method of embodiment A23, wherein the third region comprises one or more loci within chromosome Y.

[0530] A25. The method of any one of embodiments A3 to A24, further comprising contacting under amplification conditions the nucleic acid sample with a fourth set of amplification primers that amplify a fourth region in the sample nucleic acid allowing for a determination of the amount of digested or undigested nucleic acid, as an indicator of digestion efficiency.

[0531] A26. The method of embodiment A25, wherein the fourth region comprises one or more loci present in both fetal nucleic acid and maternal nucleic acid and unmethylated in both fetal nucleic acid and maternal nucleic acid.

[0532] A27. The method of any one of embodiments A1 to A26, further comprising contacting under amplification conditions the nucleic acid sample with a predetermined copy number of one or more first competitor oligonucleotides that compete with the first region for hybridization of primers of the first amplification primer set.

[0533] A28. The method of any one of embodiments A1 to A27, further comprising contacting under amplification conditions the nucleic acid sample with a predetermined copy number of one or more second competitor oligonucleotides that compete with the second region for hybridization of primers of the second amplification primer set.

[0534] A29. The method of any one of embodiments A22 to A28, further comprising contacting under amplification conditions the nucleic acid sample with a predetermined copy number of one or more third competitor oligonucleotides that compete with the third region for hybridization of primers of the third amplification primer set.

[0535] A30. The method of any one of embodiments A25 to A29, further comprising contacting under amplification conditions the nucleic acid sample with a predetermined copy number of one or more fourth competitor oligonucleotides that compete with the fourth region for hybridization of primers of the fourth amplification primer set.

[0536] A31. The method of any one of embodiments A27 to A30, wherein the amount of fetal nucleic acid determined is the copy number of fetal nucleic acid based on the amount of competitor oligonucleotide used.

[0537] A32. The method of any one of embodiments A1 to A26, wherein the amount of fetal nucleic acid determined is the copy number of fetal nucleic acid based on a quantification of sequence reads.

[0538] A33. The method of any one of embodiments A1 to A32, wherein the sample nucleic acid is extracellular nucleic acid.

[0539] A34. The method of any one of embodiments A1 to A33, wherein the nucleic acid sample is obtained from a pregnant female subject.

[0540] A35. The method of embodiment A34, wherein the subject is human.

[0541] A36. The method of any one of embodiments A1 to A35, wherein the sample nucleic acid is from plasma or serum.

[0542] A37. The method of any one of embodiments A1 to A36, wherein two or more independent loci in the first region are assayed.

[0543] A38. The method of any one of embodiments A1 to A37, wherein the amount of fetal nucleic acid is substantially equal to the amount of fetal nucleic acid determined using a mass spectrometry method.

[0544] A39. The method of any one of embodiments A1 to A38, wherein the amount of fetal nucleic acid is determined with an R.sup.2 value of 0.97 or greater when compared to an amount of fetal nucleic acid determined using a mass spectrometry method.

[0545] B1. A method for determining the amount of fetal nucleic acid in a sample comprising: [0546] (a) contacting a sample nucleic acid with one or more methylation sensitive restriction enzymes, which sample nucleic acid comprises differentially methylated fetal nucleic acid and maternal nucleic acid, the combination of the fetal nucleic acid and the maternal nucleic acid comprising total nucleic acid in the sample, thereby generating differentially digested sample nucleic acid; [0547] (b) contacting under amplification conditions the digested sample nucleic acid with: [0548] (i) a first set of amplification primers that specifically amplify a first region in sample nucleic acid comprising one or more loci that are differentially methylated between the fetal nucleic acid and maternal nucleic acid, and [0549] (ii) a second set of amplification primers that amplify a second region in the sample nucleic acid allowing for a determination of total nucleic acid in the sample, wherein the first region and the second region are different, thereby generating fetal nucleic acid amplification products and total nucleic acid amplification products; [0550] (c) incorporating adaptor oligonucleotides into the amplification products in (b); thereby generating adaptor-modified amplification products; [0551] (d) obtaining nucleotide sequences of the adaptor-modified amplification products in (c) by a sequencing process, thereby generating sequence reads; [0552] (e) quantifying the sequence reads; and [0553] (f) determining the amount of fetal nucleic acid in the sample based on a quantification of the sequence reads in (e).

[0554] B2. The method of embodiment B1, wherein the adaptor oligonucleotides are incorporated into the amplification products by ligation.

[0555] B3. The method of embodiment B2, wherein the ligation is unidirectional ligation.

[0556] B4. The method of any one of embodiments B1 to B3, wherein the adaptor oligonucleotides are incorporated into the amplification products using amplification primers comprising the adaptor oligonucleotide sequences.

[0557] B5. The method of any one of embodiments B1 to B4, wherein the adaptor oligonucleotides comprise one or more index sequences.

[0558] B6. The method of embodiment B5, wherein the one or more index sequences comprise a sample-specific index.

[0559] B7. The method of embodiment B5, wherein the one or more index sequences comprise an aliquot-specific index.

[0560] B8. The method of any one of embodiments B1 to B7, wherein at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NOs:1-261, or a fragment thereof.

[0561] B9. The method of embodiment B8, wherein at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NOs:1-89, or a fragment thereof.

[0562] B10. The method of embodiment B8, wherein at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NOs:90-261, or a fragment thereof.

[0563] B11. The method of embodiment B8, wherein at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NOs:1-59 and SEQ ID NOs:86-89, or a fragment thereof.

[0564] B12. The method of embodiment B8, wherein at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NOs:1-59, or a fragment thereof.

[0565] B13. The method of embodiment B8, wherein at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:154, SEQ ID NO:158 and SEQ ID NO:163.

[0566] B14. The method of any one of embodiments B1 to B13, wherein the sequencing process is a sequencing by synthesis method.

[0567] B15. The method of any one of embodiments B1 to B13, wherein the sequencing process is a reversible terminator-based sequencing method.

[0568] B16. The method of any one of embodiments B1 to B15, wherein the amount of fetal nucleic acid determined is the fraction of fetal nucleic acid in the sample based on the amount of each of the fetal nucleic acid amplification products and total nucleic acid amplification products.

[0569] B17. The method of embodiment B16, wherein the fraction of fetal nucleic acid is a ratio of fetal nucleic acid amplification product amount to total nucleic acid amplification product amount.

[0570] B18. The method of any one of embodiments B1 to B17, further comprising contacting under amplification conditions the nucleic acid sample with a third set of amplification primers that amplify a third region in the sample nucleic acid allowing for a determination of the presence or absence of fetal specific nucleic acid.

[0571] B19. The method of embodiment B18, wherein the fetal specific nucleic acid is Y chromosome nucleic acid.

[0572] B20. The method of embodiment B19, wherein the third region comprises one or more loci within chromosome Y.

[0573] B21. The method of any one of embodiments B1 to B20, further comprising contacting under amplification conditions the nucleic acid sample with a fourth set of amplification primers that amplify a fourth region in the sample nucleic acid allowing for a determination of the amount of digested or undigested nucleic acid, as an indicator of digestion efficiency.

[0574] B22. The method of embodiment B21, wherein the fourth region comprises one or more loci present in both fetal nucleic acid and maternal nucleic acid and unmethylated in both fetal nucleic acid and maternal nucleic acid.

[0575] B23. The method of any one of embodiments B1 to B22, further comprising contacting under amplification conditions the nucleic acid sample with a predetermined copy number of one or more first competitor oligonucleotides that compete with the first region for hybridization of primers of the first amplification primer set.

[0576] B24. The method of any one of embodiments B1 to B23, further comprising contacting under amplification conditions the nucleic acid sample with a predetermined copy number of one or more second competitor oligonucleotides that compete with the second region for hybridization of primers of the second amplification primer set.

[0577] B25. The method of any one of embodiments B18 to B24, further comprising contacting under amplification conditions the nucleic acid sample with a predetermined copy number of one or more third competitor oligonucleotides that compete with the third region for hybridization of primers of the third amplification primer set.

[0578] B26. The method of any one of embodiments B21 to B25, further comprising contacting under amplification conditions the nucleic acid sample with a predetermined copy number of one or more fourth competitor oligonucleotides that compete with the fourth region for hybridization of primers of the fourth amplification primer set.

[0579] B27. The method of any one of embodiments B23 to B26, wherein the amount of fetal nucleic acid determined is the copy number of fetal nucleic acid based on the amount of competitor oligonucleotide used.

[0580] B28. The method of any one of embodiments B1 to B27, wherein the amount of fetal nucleic acid determined is the copy number of fetal nucleic acid based on a quantification of sequence reads.

[0581] B29. The method of any one of embodiments B1 to B28, wherein the sample nucleic acid is extracellular nucleic acid.

[0582] B30. The method of any one of embodiments B1 to B29, wherein the nucleic acid sample is obtained from a pregnant female subject.

[0583] B31. The method of embodiment B30, wherein the subject is human.

[0584] B32. The method of any one of embodiments B1 to B31, wherein the sample nucleic acid is from plasma or serum.

[0585] B33. The method of any one of embodiments B1 to B32, wherein two or more independent loci in the first region are assayed.

[0586] B34. The method of any one of embodiments B1 to B33, wherein the amount of fetal nucleic acid is substantially equal to the amount of fetal nucleic acid determined using a mass spectrometry method.

[0587] B35. The method of any one of embodiments B1 to B34, wherein the amount of fetal nucleic acid is determined with an R.sup.2 value of 0.97 or greater when compared to an amount of fetal nucleic acid determined using a mass spectrometry method.

[0588] C1. A method for determining the copy number of fetal nucleic acid in a sample comprising: [0589] (a) contacting a sample nucleic acid with one or more agents that differentially modify methylated nucleic acid and unmethylated nucleic acid, which sample nucleic acid comprises differentially methylated fetal nucleic acid and maternal nucleic acid, the combination of the fetal nucleic acid and the maternal nucleic acid comprising total nucleic acid in the sample, thereby generating differentially modified sample nucleic acid; [0590] (b) contacting under amplification conditions the differentially modified sample nucleic acid with: [0591] (i) a first set of amplification primers that specifically amplify a first region in sample nucleic acid comprising one or more loci that are differentially methylated between the fetal nucleic acid and maternal nucleic acid, and [0592] (ii) a predetermined copy number of one or more first competitor oligonucleotides that compete with the first region for hybridization of primers of the first amplification primer set, thereby generating fetal nucleic acid amplification products and competitor amplification products; [0593] (c) incorporating adaptor oligonucleotides into the amplification products in (b); thereby generating adaptor-modified amplification products; [0594] (d) obtaining nucleotide sequences of the adaptor-modified amplification products in (c) by a sequencing process, thereby generating sequence reads; [0595] (e) quantifying the sequence reads; and [0596] (f) determining the copy number of fetal nucleic acid in the sample based on a quantification of the sequence reads in (e) and the amount of competitor oligonucleotide used.

[0597] C2. The method of embodiment C1, wherein the first region comprises one or more loci which each contain a restriction site for a methylation-sensitive restriction enzyme.

[0598] C3. The method of embodiment C2, wherein the one or more agents that differentially modify methylated nucleic acid and unmethylated nucleic acid comprise one or more methylation sensitive restriction enzymes.

[0599] C4. The method of embodiment C1, wherein the one or more agents that differentially modify methylated nucleic acid and unmethylated nucleic acid comprise bisulfite.

[0600] C5. The method of any one of embodiments C1 to C4, wherein the adaptor oligonucleotides are incorporated into the amplification products by ligation.

[0601] C6. The method of embodiment C5, wherein the ligation is unidirectional ligation.

[0602] C7. The method of any one of embodiments C1 to C4, wherein the adaptor oligonucleotides are incorporated into the amplification products using amplification primers comprising the adaptor oligonucleotide sequences.

[0603] C8. The method of any one of embodiments C1 to C7, wherein the adaptor oligonucleotides comprise one or more index sequences.

[0604] C9. The method of embodiment C8, wherein the one or more index sequences comprise a sample-specific index.

[0605] C10. The method of embodiment C8, wherein the one or more index sequences comprise an aliquot-specific index.

[0606] C11. The method of any one of embodiments C1 to C10, wherein at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NOs:1-261, or a fragment thereof.

[0607] C12. The method of embodiment C11, wherein at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NOs:1-89, or a fragment thereof.

[0608] C13. The method of embodiment C11, wherein at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NOs:90-261, or a fragment thereof.

[0609] C14. The method of embodiment C11, wherein at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NOs:1-59 and SEQ ID NOs:86-89, or a fragment thereof.

[0610] C15. The method of embodiment C11, wherein at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NOs:1-59, or a fragment thereof.

[0611] C16. The method of embodiment C11, wherein at least one of the one or more loci in the first region comprises a nucleotide sequence selected from among SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:154, SEQ ID NO:158 and SEQ ID NO:163.

[0612] C17. The method of any one of embodiments C1 to C16, wherein the sequencing process is a sequencing by synthesis method.

[0613] C18. The method of any one of embodiments C1 to C16, wherein the sequencing process is a reversible terminator-based sequencing method.

[0614] C19 The method of any one of embodiments C1 to C18, further comprising contacting under amplification conditions the nucleic acid sample with a second set of amplification primers that amplify a second region in the sample nucleic acid allowing for a determination of total nucleic acid in the sample, wherein the first region and the second region are different.

[0615] C20. The method of embodiment C19, wherein the second region comprises one or more loci which do not contain a restriction site for a methylation-sensitive restriction enzyme.

[0616] C21. The method of any one of embodiments C1 to C20, further comprising contacting under amplification conditions the nucleic acid sample with a third set of amplification primers that amplify a third region in the sample nucleic acid allowing for a determination of the presence or absence of fetal specific nucleic acid.

[0617] C22. The method of embodiment C21, wherein the fetal specific nucleic acid is Y chromosome nucleic acid.

[0618] C23. The method of embodiment C22, wherein the third region comprises one or more loci within chromosome Y.

[0619] C24. The method of any one of embodiments C3 to C23, further comprising contacting under amplification conditions the nucleic acid sample with a fourth set of amplification primers that amplify a fourth region in the sample nucleic acid allowing for a determination of the amount of digested or undigested nucleic acid, as an indicator of digestion efficiency.

[0620] C25. The method of embodiment C24, wherein the fourth region comprises one or more loci present in both fetal nucleic acid and maternal nucleic acid and unmethylated in both fetal nucleic acid and maternal nucleic acid.

[0621] C26. The method of any one of embodiments C19 to C25, further comprising contacting under amplification conditions the nucleic acid sample with a predetermined copy number of one or more second competitor oligonucleotides that compete with the second region for hybridization of primers of the second amplification primer set.

[0622] C27. The method of any one of embodiments C21 to C26, further comprising contacting under amplification conditions the nucleic acid sample with a predetermined copy number of one or more third competitor oligonucleotides that compete with the third region for hybridization of primers of the third amplification primer set.

[0623] C28. The method of any one of embodiments C24 to C27, further comprising contacting under amplification conditions the nucleic acid sample with a predetermined copy number of one or more fourth competitor oligonucleotides that compete with the fourth region for hybridization of primers of the fourth amplification primer set.

[0624] C29. The method of any one of embodiments C1 to C28, wherein the sample nucleic acid is extracellular nucleic acid.

[0625] C30. The method of any one of embodiments C1 to C29, wherein the nucleic acid sample is obtained from a pregnant female subject.

[0626] C31. The method of embodiment C30, wherein the subject is human.

[0627] C32. The method of any one of embodiments C1 to C31, wherein the sample nucleic acid is from plasma or serum.

[0628] C33. The method of any one of embodiments C1 to C32, wherein two or more independent loci in the first region are assayed.

[0629] C34. The method of any one of embodiments C1 to C33, wherein the copy number of fetal nucleic acid is substantially equal to the copy number of fetal nucleic acid determined using a mass spectrometry method.

[0630] C35. The method of any one of embodiments C1 to C34, wherein the copy number of fetal nucleic acid is determined with an R.sup.2 value of 0.97 or greater when compared to a copy number of fetal nucleic acid determined using a mass spectrometry method.

[0631] D1. A method for detecting the presence or absence of a fetal aneuploidy in a sample comprising: [0632] (a) contacting a sample nucleic acid with one or more agents that differentially modify methylated nucleic acid and unmethylated nucleic acid, which sample nucleic acid comprises differentially methylated fetal nucleic acid and maternal nucleic acid, the combination of the fetal nucleic acid and the maternal nucleic acid comprising total nucleic acid in the sample, thereby generating differentially modified sample nucleic acid; [0633] (b) contacting under amplification conditions the differentially modified sample nucleic acid with: [0634] (i) a first set of amplification primers that specifically amplify one or more loci in a target chromosome that are differentially methylated between the fetal nucleic acid and maternal nucleic acid, and [0635] (ii) a second set of amplification primers that specifically amplify one or more loci in a reference chromosome that are differentially methylated between the fetal nucleic acid and maternal nucleic acid, thereby generating target chromosome amplification products and reference chromosome amplification products; [0636] (c) incorporating adaptor oligonucleotides into the amplification products in (b); thereby generating adaptor-modified amplification products; [0637] (d) obtaining nucleotide sequences of the adaptor-modified amplification products in (c) by a sequencing process, thereby generating sequence reads; [0638] (e) quantifying the sequence reads; and [0639] (f) detecting the presence or absence of a fetal aneuploidy in the sample based on a quantification of the sequence reads in (e).

[0640] D2. The method of embodiment D1, wherein the target chromosome comprises one or more loci which each contain a restriction site for a methylation-sensitive restriction enzyme.

[0641] D3. The method of embodiment D1 or D2, wherein the reference chromosome comprises one or more loci which each contain a restriction site for a methylation-sensitive restriction enzyme.

[0642] D4. The method of embodiment D2 or D3, wherein the one or more agents that differentially modify methylated nucleic acid and unmethylated nucleic acid comprise one or more methylation sensitive restriction enzymes.

[0643] D5. The method of embodiment D1, wherein the one or more agents that differentially modify methylated nucleic acid and unmethylated nucleic acid comprise bisulfite.

[0644] D6. The method of any one of embodiments D1 to D5, wherein the adaptor oligonucleotides are incorporated into the amplification products by ligation.

[0645] D7. The method of embodiment D6, wherein the ligation is unidirectional ligation.

[0646] D8. The method of any one of embodiments D1 to D5, wherein the adaptor oligonucleotides are incorporated into the amplification products using amplification primers comprising the adaptor oligonucleotide sequences.

[0647] D9. The method of any one of embodiments D1 to D8, wherein the adaptor oligonucleotides comprise one or more index sequences.

[0648] D10. The method of embodiment D9, wherein the one or more index sequences comprise a sample-specific index.

[0649] D11. The method of embodiment D9, wherein the one or more index sequences comprise an aliquot-specific index.

[0650] D12. The method of any one of embodiments D1 to D11, wherein at least one of the one or more loci in the target chromosome comprises a nucleotide sequence selected from among SEQ ID NOs:1-261, or a fragment thereof.

[0651] D13. The method of embodiment D12, wherein at least one of the one or more loci in the target chromosome comprises a nucleotide sequence selected from among SEQ ID NOs:1-89, or a fragment thereof.

[0652] D14. The method of embodiment D12, wherein at least one of the one or more loci in the target chromosome comprises a nucleotide sequence selected from among SEQ ID NOs:90-261, or a fragment thereof.

[0653] D15. The method of embodiment D12, wherein at least one of the one or more loci in target chromosome comprises a nucleotide sequence selected from among SEQ ID NOs:1-59 and SEQ ID NOs:86-89, or a fragment thereof.

[0654] D16. The method of embodiment D12, wherein at least one of the one or more loci in the target chromosome comprises a nucleotide sequence selected from among SEQ ID NOs:1-59, or a fragment thereof.

[0655] D17. The method of embodiment D12, wherein at least one of the one or more loci in the target chromosome comprises a nucleotide sequence selected from among SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:154, SEQ ID NO:158 and SEQ ID NO:163.

[0656] D18. The method of any one of embodiments D1 to D17, wherein at least one of the one or more loci in the reference chromosome comprises a nucleotide sequence selected from among SEQ ID NOs:1-261, or a fragment thereof.

[0657] D19. The method of embodiment D18, wherein at least one of the one or more loci in the reference chromosome comprises a nucleotide sequence selected from among SEQ ID NOs:1-89, or a fragment thereof.

[0658] D20. The method of embodiment D18, wherein at least one of the one or more loci in the reference chromosome comprises a nucleotide sequence selected from among SEQ ID NOs:90-261, or a fragment thereof.

[0659] D21. The method of embodiment D18, wherein at least one of the one or more loci in reference chromosome comprises a nucleotide sequence selected from among SEQ ID NOs:1-59 and SEQ ID NOs:86-89, or a fragment thereof.

[0660] D22. The method of embodiment D18, wherein at least one of the one or more loci in the reference chromosome comprises a nucleotide sequence selected from among SEQ ID NOs:1-59, or a fragment thereof.

[0661] D23. The method of embodiment D18, wherein at least one of the one or more loci in the reference chromosome comprises a nucleotide sequence selected from among SEQ ID NO:42, SEQ ID NO:52, SEQ ID NO:154, SEQ ID NO:158 and SEQ ID NO:163.

[0662] D24. The method of any one of embodiments D1 to D23, wherein the sequencing process is a sequencing by synthesis method.

[0663] D25. The method of any one of embodiments D1 to D23, wherein the sequencing process is a reversible terminator-based sequencing method.

[0664] D26. The method of any one of embodiments D1 to D25, further comprising contacting under amplification conditions the nucleic acid sample with a predetermined copy number of one or more first competitor oligonucleotides that compete with the target chromosome for hybridization of primers of the first amplification primer set.

[0665] D27. The method of any one of embodiments D1 to D26, further comprising contacting under amplification conditions the nucleic acid sample with a predetermined copy number of one or more second competitor oligonucleotides that compete with the reference chromosome for hybridization of primers of the second amplification primer set.

[0666] D28. The method of any one of embodiments D1 to D27, wherein the sample nucleic acid is extracellular nucleic acid.

[0667] D29. The method of any one of embodiments D1 to D28, wherein the nucleic acid sample is obtained from a pregnant female subject.

[0668] D30. The method of embodiment D29, wherein the subject is human.

[0669] D31. The method of any one of embodiments D1 to D30, wherein the sample nucleic acid is from plasma or serum.

[0670] D32. The method of any one of embodiments D1 to D31, wherein two or more independent loci in the target chromosome are assayed.

[0671] D33. The method of any one of embodiments D1 to D32, wherein two or more independent loci in the reference chromosome are assayed.

[0672] D34. The method of any one of embodiments D1 to D33, wherein the target chromosome is chromosome 13.

[0673] D35. The method of any one of embodiments D1 to D33, wherein the target chromosome is chromosome 18.

[0674] D36. The method of any one of embodiments D1 to D33, wherein the target chromosome is chromosome 21.

[0675] E1. A method for determining fetal fraction in a sample comprising: [0676] (a) enriching a sample nucleic acid for a plurality of polymorphic nucleic acid targets, which sample nucleic acid comprises fetal nucleic acid and maternal nucleic acid; [0677] (b) obtaining nucleotide sequences for some or all of the nucleic acid targets by a sequencing process; [0678] (c) analyzing the nucleotide sequences of (b); and [0679] (d) determining fetal fraction based on the analysis of (c), wherein the polymorphic nucleic acid targets and number thereof result in at least five polymorphic nucleic acid targets being informative for determining the fetal fraction for at least 90% of samples.

[0680] E2. The method of embodiment E1, wherein the enriching comprises amplifying the plurality of polymorphic nucleic acid targets.

[0681] E3. The method of embodiment E1 or E2, wherein the enriching comprises generating amplification products in an amplification reaction.

[0682] E4. The method of embodiment E3, wherein the amplification reaction is performed in a single vessel.

[0683] E5. The method of any one of embodiments E1 to E4, wherein the maternal genotype and the paternal genotype at each of the polymorphic nucleic acid targets are not known prior to (a).

[0684] E5.1 The method of any one of embodiments E1 to E5, wherein polymorphic nucleic acid targets having a minor allele population frequency of about 40% or more are selected.

[0685] E6. The method of any one of embodiments E1 to E5.1, comprising determining an allele frequency in the sample for each of the polymorphic nucleic acid targets.

[0686] E7. The method of embodiment E6, wherein determining which polymorphic nucleic acid targets are informative comprises identifying informative genotypes by comparing each allele frequency to one or more fixed cutoff frequencies.

[0687] E7.1 The method of embodiment E7, wherein the fixed cutoff for identifying informative genotypes from non-informative homozygotes is about a 1% or greater shift in allele frequency.

[0688] E7.2 The method of embodiment E7, wherein the fixed cutoff for identifying informative genotypes from non-informative homozygotes is about a 2% or greater shift in allele frequency.

[0689] E7.3 The method of embodiment E7, wherein the fixed cutoff for identifying informative genotypes from non-informative heterozygotes is about a 25% or greater shift in allele frequency.

[0690] E7.4 The method of embodiment E7, wherein the fixed cutoff for identifying informative genotypes from non-informative heterozygotes is about a 50% or greater shift in allele frequency.

[0691] E8. The method of embodiment E6, wherein determining which polymorphic nucleic acid targets are informative comprises identifying informative genotypes by comparing each allele frequency to one or more target-specific cutoff frequencies.

[0692] E9. The method of embodiment E8, wherein the one or more target-specific cutoff frequencies are determined for each polymorphic nucleic acid target.

[0693] E10. The method of embodiment E8 or E9, wherein each target-specific cutoff frequency is determined based on the allele frequency variance for the corresponding polymorphic nucleic acid target.

[0694] E11. The method of any one of embodiments E6 to E10, further comprising determining an allele frequency mean.

[0695] E12. The method of embodiment E11, wherein fetal fraction is determined based, in part, on the allele frequency mean.

[0696] E13. The method of any one of embodiments E1 to E12, wherein the fetal genotype at one or more informative polymorphic nucleic acid targets is heterozygous.

[0697] E14. The method of any one of embodiments E1 to E13, wherein the fetal genotype at one or more informative polymorphic nucleic acid targets is homozygous.

[0698] E15. The method of any one of embodiments E1 to E14, wherein fetal fraction is determined with a coefficient of variance (CV) of 0.20 or less.

[0699] E16. The method of embodiment E15, wherein fetal fraction is determined with a coefficient of variance (CV) of 0.10 or less.

[0700] E17. The method of embodiment E16, wherein fetal fraction is determined with a coefficient of variance (CV) of 0.05 or less.

[0701] E18. The method of any one of embodiments E1 to E17, wherein the polymorphic nucleic acid targets each comprise at least one single nucleotide polymorphism (SNP).

[0702] E19. The method of embodiment E18, wherein the SNPs are selected from:

rs10413687, rs10949838, rs1115649, rs11207002, rs11632601, rs11971741, rs12660563, rs13155942, rs1444647, rs1572801, rs17773922, rs1797700, rs1921681, rs1958312, rs196008, rs2001778, rs2323659, rs2427099, rs243992, rs251344, rs254264, rs2827530, rs290387, rs321949, rs348971, rs390316, rs3944117, rs425002, rs432586, rs444016, rs4453265, rs447247, rs4745577, rs484312, rs499946, rs500090, rs500399, rs505349, rs505662, rs516084, rs517316, rs517914, rs522810, rs531423, rs537330, rs539344, rs551372, rs567681, rs585487, rs600933, rs619208, rs622994, rs639298, rs642449, rs6700732, rs677866, rs683922, rs686851, rs6941942, rs7045684, rs7176924, rs7525374, rs870429, rs949312, rs9563831, rs970022, rs985462, rs1005241, rs1006101, rs10745725, rs10776856, rs10790342, rs11076499, rs11103233, rs11133637, rs11974817, rs12102203, rs12261, rs12460763, rs12543040, rs12695642, rs13137088, rs13139573, rs1327501, rs13438255, rs1360258, rs1421062, rs1432515, rs1452396, rs1518040, rs16853186, rs1712497, rs1792205, rs1863452, rs1991899, rs2022958, rs2099875, rs2108825, rs2132237, rs2195979, rs2248173, rs2250246, rs2268697, rs2270893, rs244887, rs2736966, rs2851428, rs2906237, rs2929724, rs3742257, rs3764584, rs3814332, rs4131376, rs4363444, rs4461567, rs4467511, rs4559013, rs4714802, rs4775899, rs4817609, rs488446, rs4950877, rs530913, rs6020434, rs6442703, rs6487229, rs6537064, rs654065, rs6576533, rs6661105, rs669161, rs6703320, rs675828, rs6814242, rs6989344, rs7120590, rs7131676, rs7214164, rs747583, rs768255, rs768708, rs7828904, rs7899772, rs7900911, rs7925270, rs7975781, rs8111589, rs849084, rs873870, rs9386151, rs9504197, rs9690525, and rs9909561.

[0703] E20. The method of embodiment E19, wherein the SNPs are selected from:

rs10413687, rs10949838, rs1115649, rs11207002, rs11632601, rs11971741, rs12660563, rs13155942, rs1444647, rs1572801, rs17773922, rs1797700, rs1921681, rs1958312, rs196008, rs2001778, rs2323659, rs2427099, rs243992, rs251344, rs254264, rs2827530, rs290387, rs321949, rs348971, rs390316, rs3944117, rs425002, rs432586, rs444016, rs4453265, rs447247, rs4745577, rs484312, rs499946, rs500090, rs500399, rs505349, rs505662, rs516084, rs517316, rs517914, rs522810, rs531423, rs537330, rs539344, rs551372, rs567681, rs585487, rs600933, rs619208, rs622994, rs639298, rs642449, rs6700732, rs677866, rs683922, rs686851, rs6941942, rs7045684, rs7176924, rs7525374, rs870429, rs949312, rs9563831, rs970022, and rs985462.

[0704] E21. The method of embodiment E19, wherein the SNPs are selected from:

rs1005241, rs1006101, rs10745725, rs10776856, rs10790342, rs11076499, rs11103233, rs11133637, rs11974817, rs12102203, rs12261, rs12460763, rs12543040, rs12695642, rs13137088, rs13139573, rs1327501, rs13438255, rs1360258, rs1421062, rs1432515, rs1452396, rs1518040, rs16853186, rs1712497, rs1792205, rs1863452, rs1991899, rs2022958, rs2099875, rs2108825, rs2132237, rs2195979, rs2248173, rs2250246, rs2268697, rs2270893, rs244887, rs2736966, rs2851428, rs2906237, rs2929724, rs3742257, rs3764584, rs3814332, rs4131376, rs4363444, rs4461567, rs4467511, rs4559013, rs4714802, rs4775899, rs4817609, rs488446, rs4950877, rs530913, rs6020434, rs6442703, rs6487229, rs6537064, rs654065, rs6576533, rs6661105, rs669161, rs6703320, rs675828, rs6814242, rs6989344, rs7120590, rs7131676, rs7214164, rs747583, rs768255, rs768708, rs7828904, rs7899772, rs7900911, rs7925270, rs7975781, rs8111589, rs849084, rs873870, rs9386151, rs9504197, rs9690525, and rs9909561.

[0705] E22. The method of any one of embodiments E1 to E21, wherein the polymorphic nucleic acid targets and number thereof result in at least five polymorphic nucleic acid targets being informative for determining the fetal fraction for at least 95% of samples.

[0706] E23. The method of embodiment E22, wherein the polymorphic nucleic acid targets and number thereof result in at least five polymorphic nucleic acid targets being informative for determining the fetal fraction for at least 99% of samples.

[0707] E24. The method of any one of embodiments E1 to E21, wherein the polymorphic nucleic acid targets and number thereof result in at least ten polymorphic nucleic acid targets being informative for determining the fetal fraction for at least 90% of samples.

[0708] E25. The method of embodiment E24, wherein the polymorphic nucleic acid targets and number thereof result in at least ten polymorphic nucleic acid targets being informative for determining the fetal fraction for at least 95% of samples.

[0709] E26. The method of embodiment E25, wherein the polymorphic nucleic acid targets and number thereof result in at least ten polymorphic nucleic acid targets being informative for determining the fetal fraction for at least 99% of samples.

[0710] E27. The method of any one of embodiments E1 to E26, wherein 10 or more polymorphic nucleic acid targets are enriched.

[0711] E27.1 The method of embodiment E27, wherein about 40 to about 100 polymorphic nucleic acid targets are enriched.

[0712] E28. The method of embodiment E27, wherein 50 or more polymorphic nucleic acid targets are enriched.

[0713] E29. The method of embodiment E28, wherein 100 or more polymorphic nucleic acid targets are enriched.

[0714] E30. The method of embodiment E29, wherein 500 or more polymorphic nucleic acid targets are enriched.

[0715] E31. The method of any one of embodiments E1 to E30, wherein the sequencing process comprises a sequencing by synthesis method.

[0716] E31.1 The method of embodiment E31, wherein the sequencing by synthesis method comprises a plurality of synthesis cycles.

[0717] E31.2 The method of embodiment E31.1, wherein the sequencing by synthesis method comprises about 36 cycles.

[0718] E31.3 The method of embodiment E31.1, wherein the sequencing by synthesis method comprises about 27 cycles.

[0719] E32. The method of any one of embodiments E1 to E30, wherein the sequencing process comprises a sequencing by ligation method.

[0720] E33. The method of any one of embodiments E1 to E30, wherein the sequencing process comprises a single molecule sequencing method.

[0721] E34. The method of any one of embodiments E1 to E33, wherein the sequencing process comprises sequencing a plurality of samples in a single compartment.

[0722] E35. The method of embodiment E34, wherein the fetal fraction is determined for 10 or more samples.

[0723] E36. The method of embodiment E35, wherein the fetal fraction is determined for 100 or more samples.

[0724] E37. The method of embodiment E36, wherein the fetal fraction is determined for 1000 or more samples.

[0725] E38. The method of any one of embodiments E1 to E37, wherein the sample nucleic acid is cell-free DNA.

[0726] E39. The method of any one of embodiments E1 to E38, wherein the sample nucleic acid is obtained from a pregnant female subject.

[0727] E40. The method of embodiment E39, wherein the subject is human.

[0728] E41. The method of any one of embodiments E1 to E40, wherein the sample nucleic acid is from plasma or serum.

[0729] The entirety of each patent, patent application, publication and document referenced herein hereby is incorporated by reference. Citation of the above patents, patent applications, publications and documents is not an admission that any of the foregoing is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents.

[0730] Modifications may be made to the foregoing without departing from the basic aspects of the technology. Although the technology has been described in substantial detail with reference to one or more specific embodiments, those of ordinary skill in the art will recognize that changes may be made to the embodiments specifically disclosed in this application, yet these modifications and improvements are within the scope and spirit of the technology.

[0731] The technology illustratively described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein. Thus, for example, in each instance herein any of the terms "comprising," "consisting essentially of," and "consisting of" may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and use of such terms and expressions do not exclude any equivalents of the features shown and described or portions thereof, and various modifications are possible within the scope of the technology claimed. The term "a" or "an" can refer to one of or a plurality of the elements it modifies (e.g., "a reagent" can mean one or more reagents) unless it is contextually clear either one of the elements or more than one of the elements is described. The term "about" as used herein refers to a value within 10% of the underlying parameter (i.e., plus or minus 10%), and use of the term "about" at the beginning of a string of values modifies each of the values (i.e., "about 1, 2 and 3" refers to about 1, about 2 and about 3). For example, a weight of "about 100 grams" can include weights between 90 grams and 110 grams. Further, when a listing of values is described herein (e.g., about 50%, 60%, 70%, 80%, 85% or 86%) the listing includes all intermediate and fractional values thereof (e.g., 54%, 85.4%). Thus, it should be understood that although the present technology has been specifically disclosed by representative embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered within the scope of this technology.

[0732] Certain embodiments of the technology are set forth in the claim(s) that follow(s).

Sequence CWU 1

1

3881305DNAHomo sapiens 1cagcaggcgc gctcccggcg aatctgcctg aatcgccgtg aatgcggtgg ggtgcagggc 60aggggctggt tttctcagcc ggtcttggct tttctctttc tctcctgctc caccagcagc 120ccctccgcgg gtcccatggg ctccgcgctc agaacagccc ggaaccaggc gccgctcgcc 180gctcgctggg ggccacccgc ctctccccgg aacagcctcc cgcgggcctc ttggcctcgc 240actggcgccc tcacccacac atcgtccctt tatccgctca gacgctgcaa agggccttct 300gtctc 3052336DNAHomo sapiens 2gctttggatt tatcctcatt ggctaaatcc ctcctgaaac atgaaactga aacaaagccc 60tgaaccccct caggctgaaa agacaaaccc cgcctgaggc cgggtcccgc tccccacctg 120gagggaccca attctgggcg ccttctggcg acggtccctg ctagggacgc tgcgctctcc 180gagtgcgagt tttcgccaaa ctgataaagc acgcagaacc gcaatcccca aactaacact 240gaacccggac ccgcgatccc caaactgaca agggacccgg aacagcgacc cccaaaccga 300cacgggactc gggaaccgct atctccaaag ggcagc 3363139DNAHomo sapiens 3tttccacaac agggagccag cattgaggcg cccagatggc atctgctgga aatcacgggc 60cgctggtgaa gcaccacgcc ttacccgacg tggggaggtg atcccccacc tcatcccacc 120cccttctgtc tgtctcctt 1394292DNAHomo sapiens 4gctggacaag gagcgctcac tgtagctctg ctgtggattg tgttggggcg aagagatggg 60taagaggtca aagtcgtagg attctggcga ccgcctacca agggattggg tccacagcac 120agaggtctga tcgcttcctt ctctgctctg ccacctccag acagcagctc taaccagctg 180cccagcagca agaggatgcg cacggctttc accagcacgc agctgctaga gctggagcgc 240gagttcgctt ctaatatgta cctgtcccgc ctacgtcgca tcgagatcgc ga 2925190DNAHomo sapiens 5tgcctgacac tgaccccagg cgcagccagg aggggctttg tgcgggagag ggagggggac 60cccagcttgc ctggggtcca cgggactctc ttcttcctag ttcactttct tgctaaggcg 120aaggtcctga ggcaggacga gggctgaact gcgctgcaat cgtccccacc tccagcgaaa 180cccagttgac 1906706DNAHomo sapiens 6tcggcggaga gacctcgagg agagtatggg gaaaggaatg aatgctgcgg agcgcccctc 60tgggctccac ccaagcctcg gaggcgggac ggtgggctcc gtcccgaccc cttaggcagc 120tggaccgata cctcctggat cagaccccac aggaagactc gcgtggggcc cgatatgtgt 180acttcaaact ctgagcggcc accctcagcc aactggccag tggatgcgaa tcgtgggccc 240tgaggggcga gggcgctcgg aactgcatgc ctgtgcacgg tgccgggctc tccagagtga 300gggggccgta aggagatctc caaggaagcc gaaaaaagca gccagttggg cttcgggaaa 360gacttttctg caaaggaagt gatctggtcc cagaactcca gggttgaccc cagtacctga 420cttctccggg agctgtcagc tctcctctgt tcttcgggct tggcgcgctc ctttcataat 480ggacagacac cagtggcctt caaaaggtct ggggtggggg aacggaggaa gtggccttgg 540gtgcagagga agagcagagc tcctgccaaa gctgaacgca gttagcccta cccaagtgcg 600cgctggctcg gcatatgcgc tccagagccg gcaggacagc ccggccctgc tcaccccgag 660gagaaatcca acagcgcagc ctcctgcacc tccttgcccc agagac 7067325DNAHomo sapiens 7agatcccggt gcatttaaag gccggcgtga tctgcaccac gtacctatct cggattctca 60gtttcacttc gctggtgtct gccaccatct ttaccacatc ccggtagcta catttgtcta 120ccgcttgagc caccagcgtc tgaaacctgg accggatttt gcgcgccgag aggtagccgg 180aggcggtaat gaattccacc cagagggaca tgctcctctt gcgcccgtcg ctcaacttca 240gcaccgcgca gccgggcagt gagccatcgt ccacgaagtt gaacaccccc atttggttga 300gataaagcac cacttcaaat tcggt 3258663DNAHomo sapiens 8actatgcctt gagggtcaaa acgtctggat ttcctgatcg atgctgtcgt cgctgtccac 60ggagctactg tcgccgtcag agcgggaagg cacgttcagg gagtagaagc gtgggcttgc 120agaaagggac ctgttgctgc cttacatggg ggccggcagg gtagtcttgg aaatgcccaa 180gattgcttcc gcgcgcgtca gttcagcgga cgtgtctgcc tggcacgagg accgttctac 240aaactcgttc ctggaagccg ggctcgctgg aggcggagct ttggtttcct tcgggagctt 300gtggggaatg gtcagcgtct aggcaccccg ggcaagggtc tgtggccttg gtggccactg 360gcttcctcta gctgggtgtt ttcctgtggg tctcgcgcaa ggcacttttt tgtggcgctg 420cttgtgctgt gtgcggggtc aggcgtcctc tctcctcccg gcgctgggcc ctctggggca 480ggtccccgtt ggcctccttg cgtgtttgcc gcagctagta cacctggatg gcctcctcag 540tgccgtcgtt gctgctggag tctgacgcct cgggcgcctg cgccgcactt gtgacttgct 600ttccccttct cagggcgcca gcgctcctct tgaccccgct tttattctgt ggtgcttctg 660aag 66391985DNAHomo sapiens 9gcaagtcggg tagctaccgg gtgctggaga actccgcacc gcacctgctg gacgtggacg 60cagacagcgg gctcctctac accaagcagc gcatcgaccg cgagtccctg tgccgccaca 120atgccaagtg ccagctgtcc ctcgaggtgt tcgccaacga caaggagatc tgcatgatca 180aggtagagat ccaggacatc aacgacaacg cgccctcctt ctcctcggac cagatcgaaa 240tggacatctc ggagaacgct gctccgggca cccgcttccc cctcaccagc gcacatgacc 300ccgacgccgg cgagaatggg ctccgcacct acctgctcac gcgcgacgat cacggcctct 360ttggactgga cgttaagtcc cgcggcgacg gcaccaagtt cccagaactg gtcatccaga 420aggctctgga ccgcgagcaa cagaatcacc atacgctcgt gctgactgcc ctggacggtg 480gcgagcctcc acgttccgcc accgtacaga tcaacgtgaa ggtgattgac tccaacgaca 540acagcccggt cttcgaggcg ccatcctact tggtggaact gcccgagaac gctccgctgg 600gtacagtggt catcgatctg aacgccaccg acgccgatga aggtcccaat ggtgaagtgc 660tctactcttt cagcagctac gtgcctgacc gcgtgcggga gctcttctcc atcgacccca 720agaccggcct aatccgtgtg aagggcaatc tggactatga ggaaaacggg atgctggaga 780ttgacgtgca ggcccgagac ctggggccta accctatccc agcccactgc aaagtcacgg 840tcaagctcat cgaccgcaac gacaatgcgc cgtccatcgg tttcgtctcc gtgcgccagg 900gggcgctgag cgaggccgcc cctcccggca ccgtcatcgc cctggtgcgg gtcactgacc 960gggactctgg caagaacgga cagctgcagt gtcgggtcct aggcggagga gggacgggcg 1020gcggcggggg cctgggcggg cccgggggtt ccgtcccctt caagcttgag gagaactacg 1080acaacttcta cacggtggtg actgaccgcc cgctggaccg cgagacacaa gacgagtaca 1140acgtgaccat cgtggcgcgg gacgggggct ctcctcccct caactccacc aagtcgttcg 1200cgatcaagat tctagacgag aacgacaacc cgcctcggtt caccaaaggg ctctacgtgc 1260ttcaggtgca cgagaacaac atcccgggag agtacctggg ctctgtgctc gcccaggatc 1320ccgacctggg ccagaacggc accgtatcct actctatcct gccctcgcac atcggcgacg 1380tgtctatcta cacctatgtg tctgtgaatc ccacgaacgg ggccatctac gccctgcgct 1440cctttaactt cgagcagacc aaggcttttg agttcaaggt gcttgctaag gactcggggg 1500cgcccgcgca cttggagagc aacgccacgg tgagggtgac agtgctagac gtgaatgaca 1560acgcgccagt gatcgtgctc cccacgctgc agaacgacac cgcggagctg caggtgccgc 1620gcaacgctgg cctgggctat ctggtgagca ctgtgcgcgc cctagacagc gacttcggcg 1680agagcgggcg tctcacctac gagatcgtgg acggcaacga cgaccacctg tttgagatcg 1740acccgtccag cggcgagatc cgcacgctgc accctttctg ggaggacgtg acgcccgtgg 1800tggagctggt ggtgaaggtg accgaccacg gcaagcctac cctgtccgca gtggccaagc 1860tcatcatccg ctcggtgagc ggatcccttc ccgagggggt accacgggtg aatggcgagc 1920agcaccactg ggacatgtcg ctgccgctca tcgtgactct gagcactatc tccatcatcc 1980tccta 198510213DNAHomo sapiens 10atgcgccctc tgcaccccta gagccagaag acgctaggtg ggctgcgcgc tctgccaggc 60gaaggctgga gcgcagacgg caaagccgcg cgtttcagcc gtggtcgggt ccgcaggacc 120tgggcgtggg gacaccacca ggcaggagca gaggcaggac tgggacgcca aaagctgaga 180atcctcgatg cccgcgcgag agccccgtgt tat 213111558DNAHomo sapiens 11ttctggaaac cgggccccac ttgcaggccc ggccaccttg ggttctggtg gccgaagccg 60gagctgtgtt tctcgcagac tcggggagct acattgtgcg taggcaattg tttagtttga 120aaggaggcac atttcaccac gcagccagcg ccctgcatgc aggagaagcc cccagggccc 180agggtcggct ggctttagag gccacttagg ttgttttaag cacatgtgaa agggcagaca 240gcaggggagc aggatatggg taagatcttc gggtctcaga acaggggctg cccttgggct 300gtcccggcgc cctgggctct gacactgaag ggtggaatgg aggaaggaat ggagaaagga 360cggtggaact ttcgcttccc ctctgggccg ccttcccagg gtcatgcctg agctgctttg 420atcccagtgt cgcgcatctt ggtccgctac ctcccaggcg atagctactg ggctcctcgc 480tggcctcact gggggccatc ccgggcagtg gcctgccctc cgaggcccgc gggacccagc 540ccagagctga ggttggagtt ctccgggcca cgttccgggt cgcttaggct cggagatttc 600ccggagaccg tcgtcctccc tttctgcttg gcactgcgga gctccctcgg cctctctcct 660cctctggtcc ctaaggcccg gagtggttgg cggtactggg gcccgtcgtc atctctgctt 720ctaaggcatt cagactgggc tccagctggg accggcagag gaggttctca aggaaactgg 780tgggaaatat agttttcttt cgtctggtcg tttaatttaa atgcaacttc ccttggggac 840attttcctgg acgttaacca gaccaccttg agatgtcgtt gatgacctag agacccagat 900gatgcgtccc aggaaagttc actgctgact attgtcactc ttggcgttat atctatagat 960atagacctat gtacatatct ccaccctgat ctctccgtgg acatgaaacc cacctacctt 1020gtgaaagccc tacgggtgac acatgactac tacgtctctg tcccaacagg ggctgggcct 1080cccctgccta atagttgcca ggagtttcgc agcccaagtg aataatgtct tatggctgaa 1140cgtggccaag gactcctgtg atttaggtcc caggaggagc agagacgtcc ccgccccgcc 1200tgggccctgc cgcattcaaa gctggaagaa ggcgctgatc agagaagggg cttccaggtc 1260ctgggttaga acaacaacaa acaaacgaaa ctccacaaca gacacgcctg cccatgaccc 1320cacgcaagga cataggaagt tctgtcgcct tcctgctccg cggatagccg cctgccgtct 1380gctgccacca gaacgcacgg acgctcgggg tggaggtagt caatgggcag caggggaccc 1440ccagccccca caagcgcggc tccgaggacc tggaagcggg tgcctgtcgc tctccgcagg 1500ctccgctctg cctccaggag caagatcccc aaaagggtct ggaagctgtg gagaaaac 1558121264DNAHomo sapiens 12ttttttaaac acttcttttc cttctcttcc tcgttttgat tgcaccgttt ccatctgggg 60gctagaggag caaggcagca gccttcccag ccagcccttg ttggcttgcc atcgtccatc 120tggcttataa aagtttgctg agcgcagtcc agagggctgc gctgctcgtc ccctcggctg 180gcagaagggg gtgacgctgg gcagcggcga ggagcgcgcc gctgcctctg gcgggctttc 240ggcttgaggg gcaaggtgaa gagcgcaccg gccgtggggt ttaccgagct ggatttgtat 300gttgcaccat gccttcttgg atcggggctg tgattcttcc cctcttgggg ctgctgctct 360ccctccccgc cggggcggat gtgaaggctc ggagctgcgg agaggtccgc caggcgtacg 420gtgccaaggg attcagcctg gcggacatcc cctaccagga gatcgcaggt aagcgcgggc 480gcgctgcagg ggcaggctgc agccctcggc tgccgcacgt cccactggcc gcccggcgtc 540cccttccttc cccctgttgc tgagttggtg ctcactttct gccaccgcta tgggactccg 600cgtctccgtg ttgggcggcg gatgctcctg cggcttcttc ggcgggggaa ggtgtgcgtc 660tccgccgcct cattgtgtgc acacgcggga gcaccctggc tcccgcctcc cgctgctctc 720gcgcccttct accccttagt tgatggctca ggcccggctg gccagggagc ccgggtcact 780ccggggcggc tgcaaggcgc agacggagag ccgagccggg cgctcactcc gcgttctggt 840tcgggcaaac ttggaagaac tgcgaccgca gtttgcccag cgccacagtc tgagtggcgc 900cttctccact cccgcccttg cgccggcagg ggcggtggag agacgcggag ggctccccca 960gcccctctct cccctatccg tccttcgggc gacagagcgc ccggcgctcg ggccgggggc 1020gggcaaggct gggagggacc ctcgccgggg acctggcctc tggacgccgg cgtttcaagg 1080ctggtttggg gacttcacgg gctgcctgtt tcagatgtgg ggcgggcttt cccgttaggg 1140ttcctcagtg cttccccagt tgctgttggc cactcagggc ccggggacac cctgccaccc 1200ggtctggagc cggcctcgtc tgccagcgaa cagccaactt tagcgggtgg ctcagctggg 1260gatt 126413761DNAHomo sapiens 13cactcagtgt gtgcatatga gagcggagag acagcgacct ggaggccatg ggtgggggcg 60ggtggtgaag ctgccgaagc ctacacatac acttagcttt gacacttctc gtaggttcca 120aagacgaaga cacggtggct tcagggagac aagtcgcaag ggcgactttt ccaagcggga 180gatggtgaag tctttggacg tgtagtgggt aggtgatgat ccccgcagcc gcctgtaggc 240ccgcagactt cagaaaacaa gggccttctg tgagcgctgt gtcctccccg gaatccgcgg 300cttaacacat tctttccagc tgcggggcca ggatctccac cccgcgcatc cgtggacaca 360cttagggtcg cctttgtttt gcgcagtgat tcaagttggg taacccttgc tcaacacttg 420ggaaatgggg agaatctccc ccacccgcaa cctcccgcac cccaggttcc caaaatctga 480atctgtatcc tagagtggag gcagcgtcta gaaagcaaag aaacggtgtc caaagacccc 540ggagagttga gtgagcgcag atccgtgacg cctgcggtac gctagggcat ccaggctagg 600gtgtgtgtgt gcgggtcggg gggcgcacag agaccgcgct ggtttaggtg gacccgcagt 660cccgcccgca tctggaacga gctgcttcgc agttccggct cccggcgccc cagagaagtt 720cggggagcgg tgagcctagc cgccgcgcgc tcatgtttat t 761141198DNAHomo sapiens 14agtcactcca ggatcagagg ccgcgtcggt tctgcttggg gcatgggcag agggaggctg 60ctggggccaa gccccggctg gacgcgaggg aagaaactcg tcccaggacc cgcacgccca 120tacctggctg tcccagagct cttccctagg ccggcacctt cgctcttcct cttccccacc 180ccctagccct tttgtctctt tttcagacgg atgttttcag tctcaagtgg ttttattttc 240cgcacaaaac cctgagatca agggcagatc acagactgta ccggaggctc gggtttccct 300ggactctgtg ctgttctgcg tcccagggtt ggctaggaag gaaggcctgg gccggcgagg 360tgacgggtct cccgcccagg tcggcaggac ggggggaggt gtgtcccggt aggtccctgg 420tgagctcacc cgtggcatcg gggacccgcg ggaacccacc gggcgcccac tagagactcg 480ggtcctaccc tcccccacac tactccaccg aaatgatcgg aagggcgcgc taggcctgct 540tccaagggct cagtgataaa ggcctcaaaa tcacactcca tcaagacttg gttgaagctt 600tgggtaggtt tgttgttgtt gttgttgttg tttgtttgtt tgttttagca gacacgtcct 660ggaaagaggt cctcagaacc caaaggttca ataatgattt gtggatggat tgattatagt 720ctgatatcgc tctggttcca cagaaacccg gagctccttg gcccactgtt accccagcag 780acctaaatgg acggtttctg tttttcactg gcagctcaga actggaccgg aagaagttcc 840cctccacttc ccccctcccg acaccagatc attgctgggt ttttattttc gggggaaaaa 900caacaacaac aacaacaaaa aaaacactag gtccttccag actggatcag gtgatcgggc 960aaaaaccctc aggctagtcc ggctgggtgc ccgagcatga aaaggcctcc gtggccgttt 1020gaacagggtg ttgcaaatga gaacttttgt aagccataac cagggcatcc tgagggtctg 1080agttcacggt caaggctgtg ggctactagg tccagcgagt ccaggcctcg ccccgccccc 1140gagctgccac agccaagatc ttcggcaggg aattcgagac cagggtcctc ccactcct 119815377DNAHomo sapiens 15tttcgtgccg ctgttttcaa tgcgctaacg aggcacgtta ttcttagccg cgtccgggag 60gggatcacat tcctgcgcag ttgcgctgct ggcggaagtg acttgttttc taacgaccct 120cgtgacagcc agagaatgtc cgtttctcgg agcgcagcac agcctgtccc atcgagaagc 180ctcgggtgag gggcccggtg ggcgcccgga ggccgctgga gggctgtggg agggacggtg 240gctccccact cccgtggcga agggcaggca aaccagaagc ctcttttgag agccgtttgg 300gattgagacg agtaagccac agcgagtggt tagaagtagg ttaggaagaa ggggaggtaa 360gaaagccgag tagggtt 37716256DNAHomo sapiens 16gttcggtgga caagggggca gcgcccacag caagccggaa agagggaggc gcggggccgc 60gcttggggcc tgccgctgca cgccagcctg ggcaaagagc tgccaccttc tgcgggcgaa 120gcgggtcggg acgcaggacg gcagcggggc tggaggcagc tacgtgggtc cacaccccca 180tgccctgcaa ggctccttgg ccctgcttct cctctgtctc ggcgggagag gagcagcctc 240ggttttacag aatttc 25617189DNAHomo sapiens 17tgtgccattt agtgagaggt gttttgggca aagaatcaat ttaactgtga ctgaccgacg 60ggcttgactg tattaattct gctaccgaaa aaaaaaaaaa aaaaaaagca atgagccgca 120agccttggac tcgcagagct gccggtgccc gtccgagagc cccaccagcg cggctcacgc 180ctcagtctc 18918707DNAHomo sapiens 18agagtcccag ttctgcaggc cgctccaggg ctaggggtag agatggtggc aggtggtgcg 60tcaactctct agggaagagg aacttgcatt acaaagactt gtctttctga gctgaagtca 120aaacgggggc gtcaagcgcg ctccgtttgg cggcggtgga ggggccgcgc gcccgcgctg 180tcccagccgg agctgccctg gctggtgatt ggaggtttaa cgtccggaat tcaggcgctt 240ctgcagctca gatttgccgg ccaaggggcc tcagttgcaa cttttcaaaa tggtgtttct 300ggaaaataac aaattcagac tcaactggtg acagcttttg gctatagaga atgaaactgc 360ttccctttgg cggtggaact cttaaacttc gaagagtgaa agaatacaat gaaataaaat 420gccataagat cactggattt ttcagaaaaa ggaagacccc aaattactcc caaaatgagg 480ctttgtaaat tcttgttaaa aatctttaaa tctcgaattt ccccctacaa catctgatga 540gtgctttaag agcaaacgag caaatcccac ctcgagaatc aacaaaccca agctctggcc 600aaggctctcc ccgcgttttc ttctcgtgac ctggggaatg tcccgcccca tcgctcacct 660ggctcttgtc atctcgctca tcttgaagtg acccgtggac aatgctg 70719182DNAHomo sapiens 19agctgccctc tgtggccatg agcgggtgtc cagccccttc caaggctgca ccggggagac 60gctggttttc tgctcgctgt gaccgaacaa agcccctaag agtcagtgcg cggaacagaa 120gagccggacc ccgacgggcc gagtcccaac gtgaggcacc cggcagagaa aacacgttca 180cg 18220179DNAHomo sapiens 20cctcggcagc accggcatgg ctggaggcca gtacggccag gtgtggcggg agggagcgcc 60gtctggcttg ggtcgtccat cctgacagga cgctgcaagg gcaggagccc cgcgccccgt 120gtcctgcgcc cccgctcgag gacaagcccc agccgccggt ctccgctggg ttccgacag 17921369DNAHomo sapiens 21ctttaagagg ctgtgcaggc agacagacct ccaggcccgc taggggatcc gcgccatgga 60ggccgcccgg gactatgcag gagccctcat caggcgagtg ccccgcgtcc ccctgattgc 120cgtgcgcttc caatcgcctt gcgttcggtg gcctcatatt cccctgtgcg cctctagtac 180cgtaccccgc tcccttcagc cccctgctcc ccgcattctc ttgcgctccg cgaccccgcg 240cacacaccca tccgccccac tggtgcccaa gccgtccagc cgcgcccgcg ggcagagccc 300aatcccgtcc cgcgcctcct caccctcttg cagctgggca caggtaccag gtgtggctct 360tgcgaggtg 36922176DNAHomo sapiens 22agacttgcag aactcgggcc ccctggagga gacctaaccg ccacggtctt ggggaggttc 60cggagggcct cggttgtctg cactcccaac accaagaaac ccctgagacg cgaagctgcc 120agcgtgctgc cctcagagca gggcgacgca aagccagcgg accccggggt ggcggg 17623167DNAHomo sapiens 23tgctcggctg gggggctcgc tccgcacttt cggtgccaga aaatgcccag aggagcgggg 60cggccccaga gcctcctttc ggggcgcgag gcccggcgcg tgtgtacgga gtccagtccc 120cccagggagt ggggtgcccg caccttcccc tccgcgctcg gagccac 167241205DNAHomo sapiens 24tcttgcacac ctgcttgtag ttctgcaccg agatctggtc gttgaggaac tgcacgcaga 60gcttggtgac ctgggggatg tgcaggatct tgctgaccga cagcacctcc tccaccgtgt 120ccagggacag ggtcacgttg gccgtgtaga ggtactcgag caccaggcgc agcccgatgg 180acgagcagcc ctgcagcacc aggttgttga tggcccgggg gctggtcagc agcttgtcgt 240cgggggagga agaaggagtc ccgggctcct cctgcggcgg cggctgctgc tgctgtgacg 300gctgctgctg cggcggctgc tgctggtcct tgggggcccc caggccgtcc tggccgccga 360cccctccccc gagagggggg tggctggaga agagcgatcg gaagtactgc gagcaggagg 420ccagcacggc cttgtggcaa tggaactgct ggccctgggc cgtcagggtc acgtcgcaaa 480acagctgctt cctccacagc aggttgaggc cgtgcagcag gttgtcgctg tggctggggt 540cgaaggtgga ggtcctgtcc ccggatctgg acatggcgag ctgactcggt gcacctggct 600ttaaaccctc ctccaacctg gcagacaggg gtgggggatg ggagggaggg gagcagggtg 660gtggagcggg tggggtgtgg tcggggtggg gaagggtgtg gaggggaggg gagggcgaag 720aacaagaatc aaggctcagc ttgactccct cctggcgcgc tccggacccc gaccctagga 780ggaaagtccg aagacgctgg atccgtgagc gccaccagaa gggccctgtc tggggtcccg 840gcgccggttc tgcgccctgc ggctcctctc gccacctccc acacacttcg tccctcactt 900tcctaaaacc aaccacctca gctcggctgt tggcagcaac agcagtggca gcagcgacgg 960caaagtggcg gctgaggccg aggcacctcg tgggctcgtg tccatgccgg gccagatgaa 1020gggaaaggcc gggaagtggg gagccggggg tgccctgaaa gctcagaggc gaccgacggc 1080gaaggttcca ggtcaacttg tgcccgaagc tttgcttttc gcagttggcc cagtttgggg 1140gagggggtag gaacaggggc ccgaccagcg tgcggggtgt gcgaatctta gctctccaaa 1200agctg 12052544DNAHomo sapiens 25cctctgtgtt agtgccctcg ggaatttggt tgatggggtg

tttg 44265002DNAHomo sapiens 26tgatgtcgca cctgaacggc ctgcaccacc cgggccacac tcagtctcac gggccggtgc 60tggcacccag tcgcgagcgg ccaccctcgt cctcatcggg ctcgcaggtg gccacgtcgg 120gccagctgga agaaatcaac accaaagagg tggcccagcg catcacagcg gagctgaagc 180gctacagtat cccccaggcg atctttgcgc agagggtgct gtgccggtct caggggactc 240tctccgacct gctccggaat ccaaaaccgt ggagtaaact caaatctggc agggagacct 300tccgcaggat gtggaagtgg cttcaggagc ccgagttcca gcgcatgtcc gccttacgcc 360tggcaggtaa ggccggggct agccaggggc caggctgctg ggaagagggc tccgggtccg 420gtgcttgtgg cccaagtctg cgcgccgagt cacttctctt gattctttcc ttctctttcc 480tatacacgtc ctctttcttc tcgtttttat ttcttcttcc attttctctt tctcttccgc 540tcttccccta ctttcccttc tcccttttct ttttctttct tactctctcc ttgtccctga 600gctttcattg accgaccccc ccccatttca ttcgccctcc cctcaatgtg ccaacctttg 660ccctatttcc gatcttccca ggtactggga ggcgggatgg gggtgtgcgt tttcctctag 720gagccctgtc tttccaagac ccacagaaac caggacctgc ccttattcaa aaccccatgc 780acttcaagtc tcttttagac aacacatttc aattttccgg gctgactagt ctccctgtgc 840agaggcagtt gagaggcttt gctctgcaga gggaaaagag ctctctactc tcccacccac 900catataggca aacttatttg gtcattggct gaaggcacag ccttgccccc gcggggaacc 960ggcggccagg atacaacagc gctcctggag cccatctctg gccttggcgt tggcgcaggg 1020actttctgac cgggcttgag gggctcgggc cagctccaat gtcactacct acagcgaggg 1080cagggtgtaa ggttgagaag gtcacattca ccgctttggg aggacgtggg agaagagact 1140gaggtggaaa gcgctttgcc ttgctcaccg gccgtccttg ccccggtccc agcgtttgct 1200gggatttgcc aggatttgcc ggggctccgg gagaccctga gcactcgcag gaagaggtgc 1260tgagaaatta aaaattcagg ttagttaatg catccctgcc gccggctgca ggctccgcct 1320ttgcattaag cgggcgctga ttgtgcgcgc ctggcgaccg cggggaggac tggcggcccg 1380cgggagggga cgggtagagg cgcgggttac attgttctgg agccggctcg gctctttgtg 1440cctcctctag cggccaagct gcgaggtaca gccctctatt gttctaggag cacagaaacc 1500tcctgtgtgg gcggcgggtg cgcgagctag agggaaagat gcagtagtta ctgcgactgg 1560cacgcagttg cgcgcttttg tgcgcacgga ccccgcgcgg tgtgcgtggc gactgcgctg 1620cccctaggag caagccacgg gcccagaggg gcaaaatgtc caggtccccc gctgggaagg 1680acacactata ccctatggca agccagggtg ggcgacttcc catggatcgg gtggaggggg 1740gtatctttca ggatcggcgg gcggtctagg ggaacaattc gtggtggcga tgatttgcat 1800agcgcgggtc ttgggatgcg cgcggttccg agccagcctc gcacagctcg cttccggagc 1860tgcgagctca ggtttccacc cccgatcccc cgggctttcc tcgcaccgct gagcccagct 1920tgtggggtgc actcgaccaa cgcccgacag ggctggggaa tgtgacaggc agcaggttca 1980cccgggcttg gggaggggga gtttccgctt tgacagcatt ttcctttgcc gtctgctggt 2040ggattcctat tcccagtcgg taatcgcccc gcagtgttga tctaagaagg taaagaaaac 2100taggtttccc tgcaaagagc ctcccccaaa tcggcggact ccggatactt tgagtggatt 2160tagaaattta tgtaatcttt ctcctttagt ttatttttca tcctctccta cagttttctc 2220tgatttgctg ttggttcggg gcaagataaa gcagccagta gagagcgata ataatagcgg 2280cgggaaatga actggagact ggctgacagt tcttaacatt ttgtcataga tccccccgaa 2340tgtcccaggc tgtctctggt gggttttagt acccgccggc ttcttgggca ccggggacca 2400gaaggaactt ggcagctggt cttaggggta cagttaaagg caggatgaca gctattctcc 2460tgctcatctc agagcgctgc cgccccctca tgccggtcgc gcaaagaaca cagcttttaa 2520aaaacacgtg ccttctgccc atataggtct gaaagtgatg aggaaagtaa tgcttcgcct 2580attagcgagt ttcagctttt aaaatgatcc caagcgttgc tgagatgaga aagcgtggca 2640tcccgggggt cctcagcccc acccgcgccc atggtgcaag tctgcaggga caggcccggg 2700acagcactgc ccacgctgct agattttccg cagaggatcg ctgaagctgc cttcgtggga 2760gacagaatgc ctcctccagc gagtggaaaa ggcctgctga ggaccccgct ttgctcgagc 2820attcaaatgt gtgtctgttt tattaccctg ggttgaaaag ggacaagagc tttagccttt 2880ttatctggcc attttatcag caactacaag tgtgttgagt ggttattatt acataggagg 2940cttttcagtt tggggtcagt agatcagtct cttcagacac tgatgcagaa gctgggactg 3000gtaagtaggt attatgtgct cggagcgcta ggggacagga gcaaatggag aagaaaagcg 3060gaggctttct ccgcccggag tatcgatcgg aatccccgcc ggtacgccgc agagggccct 3120cgccgttggg ccccgggggt ttaacaagcc cagccgctcc gcaggcggct cggccggact 3180ctcagaccgg tgcctggaag acaccgtccc tgcccccctc ccgccaaacc tgcctcttct 3240ctttctctca taggttatag gttccctttc tctctcattt tggccccgcc cccgggtcct 3300gccaaacagc caagcaggcc ggggtttagg gggctcagaa tgaagaggtc tgatttggcc 3360agcgccggca aagctcaccc ttaggcgagg tcacaacaga ggcaggtcct tcctgcccag 3420cctgccggtg tagtcacagc caagggtggc acttgaaagg aaaagggaga aaacttcgga 3480gaaatttaga ttgccccaac gttagatttc agagaaattg actccaaatg cacggattcg 3540ttcggaaagg gcggctaagt ggcaggtggt tgcaaccccg cccggtcggg ccttcgcaga 3600ggttccccaa gaccagccct tgcagggcgg ttttcagcaa cctgacaaga ggcggccaag 3660acaaatttct gcgggttcga gcacacactc tcgggcgttg ggccccagag acctctaaac 3720caagcacaaa caagaaggga gtgagagaac ccaggctaga acttgcacgg gcatcccact 3780gaggaaaagc gaggcctcgg tggcaggcat gttttcttcc gacgcccgaa aatcgagccg 3840agcgcccgac tacatttact gcagaggttt ccgcctccag tgagcccgga tcccccagcg 3900gcctgcccgg agctggtctc cagtccccgc cgtagtccga cgcacggccc tctcctggca 3960gcaagctccc agcggccagt ctgaagccaa ttctgttcag gcggccgagg gcccttagcc 4020aacccaccat gatgtcgcct gggccacctg atgcccgcag cggcgggaca cggcccgggc 4080agtgcgcagt ggctcctgct aggggcaccg cgtgcgtgct tgtctcccgc tgcgccgggg 4140acgtccttgg gtgacacggg ccgctgggca cctcccaagc cgaggaaacg gacccccttc 4200gcagagtctc gcgcccaccc cccaacctcc cacctcgttt ctcgctgcta gggctcccga 4260ctcagcccac ctctcctggc ggtttagtta gggatcagag ctggagaggc tgaacgcaac 4320ccgtgccagt acggaacaga cgatatgttt gcctgctagc tgcttggatg aataattgaa 4380aagttcgctg cagtctgtgc ttcgtcaagt cccgggtgcc gggagaacac cttcccaaca 4440cgcatcaggg tgggcgggag cgggcagagg aggcgggacc cgagggagga gagtgaaccc 4500gagcaggaga agcagcccag gcagccaggc gccctcgatg cgagaggctg ggcatttatt 4560tttattccag gctttccact gtgtggttat gtcactttct caaacaaatg tgtatatgga 4620gggagatcga tgctgataat gtttagaaga ttaaaagagc attaatgctg gcaacaataa 4680cgtaaacgtg tggacccaga tttcattgat ctggaacttg atccggcgcg tttccagtaa 4740gcccgacggc gcgctcttcc cagcagagcg ctcaccagcg ccacggcccc gcggttttcc 4800agcggtgccg cttcgccagc tctgcgcggg ttctcccgtc tgaccgcagc tcctcccccg 4860cgaggcccca gcccgcctta cttccccgag gttttctcct cctctcgcgg ggctctctgc 4920cctctgcacc ccctcccccg acctctgcac cacccgcccc tgtgcgcaca caccgctact 4980tgcgcttccg gcgatccgcc tg 500227150DNAHomo sapiens 27aaccggagat ctgcttggtg aactgagagg agtccttagg agagcgggga cgccaggggc 60cgggggacac ttcgctctcg ccctagggaa ggtggtcttg acgctttcta ttgaagtcaa 120acttgaaaat atcagctgcc gctggactat 15028339DNAHomo sapiens 28cgtgagcaga acgcccgccc tggagcagtt aggaccgaag gtctccggag agtcgccggc 60ggtgccaggt aacgcagagg gctcgggtcg ggccccgctt ctggggcttg ggactccggg 120cgcgcggagc cagccctctg gggcgaaatc cccgggcggc gtgcgcggtc cctctccgcg 180ctgtgctctc ccagcaactc cctgccacct cgacgagcct accggccgct ccgagttcga 240cttcctcgga cttagtggga gaaggggttg gaaatgggct gccgggactg ggggagctgc 300tctctggaag cagggaagct ggggcgcacc ggggcaggt 339291961DNAHomo sapiens 29tagaagagga agactcctct ggccccacta ggtatcatcc gcgctctccc gctttccacc 60tgcgccctcg cttgggccaa tctctgccgc acgtgtccat ccctgaactg cacgctatcc 120tccacccccg gggggttcct gcgcactgaa agaccgttct ccggcaggtt ttgggatccg 180gcgacggctg accgcgcgcc gcccccacgc ccggttccac gatgctgcaa tacagaaagt 240ttacgtcggc cccgacccgc gcgggactgc agggtccgcc ggagcgcggc gcagaggctt 300ttcctgcgcg ttcggccccg ggaaaggggc gggagggctg gctccgggag cgcacgggcg 360cggcggggag ggtactcact gtgaagcacg ctgcgcccat ggatcatgtc tgtgcgttac 420accagaggct ccgggctcca ctaattccat ttagagacgg gaagacttcc agtggcgggg 480ggaggacagg gtcgagaggt gttaaagacg caaagcaaga aggaaataaa ggggggccga 540gagggagacc gagaggaagg gggagctccg agcccacgct gcagccagat ccggatgagt 600ccgtcctccg ccccgggcgg gctctcgctc tcgctggccc tcagcgccgc gcagccagca 660gcatccccac cgtgacgctc gcatcacacc cgggcgccgg ccgccaccat ccgcgccgcc 720gccgtcagga ccctcctccc gggcatcgtc gccgccgcgg ggtcgggagg acgcggcgcg 780cgggaggcgg cggtcgcagg gcgagccccg ggacgccccg agccggggcc ggggccgggg 840agagggcgca gcgaggtggg ggccagtcca gaccgacggc agcgacggag cgggcggcgg 900cggcggcgcc ggcggcggcg gggtggctca gtccccagtc tcagacgcgc cgcgcagcag 960gtcggagcag cctccccggg aggatgtcca gcggcagcgc tcctcgctcc agcccttggg 1020gatcttccgc tgaggcattg aaggcaggaa gaaggggtcc gtcatcggct cgccgggctg 1080cgcgccacct ctgctatctt gcggaaagag gagcgggtgg gtgggcgtct gggaggcggg 1140ctggagggcg gtgcagggga gcggggcggc cggggggggg gccggggggc ggggaaggga 1200gggaggagaa aggagccgga agagggcaga gttaccaaat gggctcctta gtcatggctt 1260ggggctccac gaccctcctg gaagcccgga gcctgggtgg gatagcgagg ctgcgcgcgg 1320ccggcgcccc ggggctggtg cgcggcagaa tggggccgcg gcggcggcag caaggacatc 1380ccagccgcgc ggatctgggg gaggggcggg gagggggtga ggacccggct gggatccgcg 1440gctcggcccg ccagggcgca gagagaggat gcagccgcaa atcccgagcc ggatcctcgt 1500gccggacgga aggcgtggaa gcgggagggg ccttcgtgtg aaaatccctt gtggggtttg 1560gtgtttcact ttttaaaggt tagaccttgc gggctctctg cctcccaccc cttcttttcc 1620atccgcgtaa aggaactggg cgccccctct ccctccctcc ctggggcgca ggtttcgccg 1680cggactccgc gctcagcttg ggagacacgg caggggcgcg ccccagggaa aggcggccgt 1740aaaagtttcg cggttgagca ctgggcctga tgtccagtcc ccccaccaaa ttactcctgc 1800aaagacgcgg gcttcttgca attgagcccc ccacctcgag gtatttaaaa ccaccccaag 1860gcacacacgg acccccgttc ccccgcgcca cttcctccta caggctcgcg cggcgcgtta 1920aagtctggga gacacgagtt gcggggaaac agcaccggaa g 196130314DNAHomo sapiens 30aagaaacagc tcatttcgga gctgaggaca aggcgtggga agaagacgcg tttggtttca 60cccaggcggg tggcggcaaa gctgtgggat gcgcgctgca cactccttcc gtcatcccgt 120tcccaccttc cacacacacc tgcgggaggt cggacatgtc ctgattgcgt gttcatcacg 180atggcaaacc gaacatgagg agaacgccac tgacgctggg tgcgccggct ttcccagccc 240tcgtgcataa cggggaggga gatgcagaag ttttttccaa catcggtgca aaggggaagc 300tgaggttttc ctat 31431584DNAHomo sapiens 31tctgtcagct gctgccatgg ggcagcggga aggccctgga gggtgcctgg gctgtgtctg 60gtcccggcca cgcgtccctg cagcgtctga gaccttgtgg aacacacttg acccggcgct 120gggacggggt cggcccacac gcaccgccag cccgcaggag tgaggtgcag gctgccgctg 180gctccttagg cctcgacagc tctcttgagg tcggccctcc tcccctcccg agagctcagc 240agccgcagac ccaggcagag agagcaaagg aggctgtggt ggcccccgac gggaacctgg 300gtggccgggg gacacaccga ggaactttcc gccccccgac gggctctccc accgaggctc 360aggtgctcgt gggcagcaag gggaagcccc atggccatgc cgcttccctt tcaccctcag 420cgacgcgccc tcctgtgccc gcggggaaca agacggctct cggcggccat gcaggcggcc 480tgtcccacga acacgatgga gacctcagac gccgtcccca ccctgtcact gtcaccatca 540cccatcctgt cccctcacgc ctccccacat cccatcatta ctac 58432349DNAHomo sapiens 32gaagtagaat cacagtaaat gaggagttag ggaatttagg gtagagatta aagtaatgaa 60cagaggagga ggcctgagac agctgcagag agaccctgtg ttccctgtga ggtgaagcgt 120ctgctgtcaa agccggttgg cgctgagaag aggtaccggg ggcagcaccc gcctcctggg 180agagggatgg gcctgcgggc acctggggga accgcacgga cacagacgac actataaacg 240cgggcgagac atcagggacc gggaaacaga aggacgcgcg tttcgagcag ctgcccagtg 300ggccacaagc cccgccacgc cacagcctct tcccctcagc acgcagaga 349333510DNAHomo sapiens 33tactccggcg acgggaggat gttgagggaa gcctgccagg tgaagaaggg gccagcagca 60gcacagagct tccgactttg ccttccaggc tctagactcg cgccatgcca agacgggccc 120ctcgactttc acccctgact cccaactcca gccactggac cgagcgcgca aagaacctga 180gaccgcttgc tctcaccgcc gcaagtcggt cgcaggacag acaccagtgg gcagcaacaa 240aaaaagaaac cgggttccgg gacacgtgcc ggcggctgga ctaacctcag cggctgcaac 300caaggagcgc gcacgttgcg cctgctggtg tttattagct acactggcag gcgcacaact 360ccgcgccccg actggtggcc ccacagcgcg caccacacat ggcctcgctg ctgttggcgg 420ggtaggcccg aaggaggcat ctacaaatgc ccgagccctt tctgatcccc acccccccgc 480tccctgcgtc gtccgagtga cagattctac taattgaacg gttatgggtc atccttgtaa 540ccgttggacg acataacacc acgcttcagt tcttcatgtt ttaaatacat atttaacgga 600tggctgcaga gccagctggg aaacacgcgg attgaaaaat aatgctccag aaggcacgag 660actggggcga aggcgagagc gggctgggct tctagcggag accgcagagg gagacatatc 720tcagaactag gggcaataac gtgggtttct ctttgtattt gtttattttg taactttgct 780acttgaagac caattattta ctatgctaat ttgtttgctt gtttttaaaa ccgtacttgc 840acagtaaaag ttccccaaca acggaagtaa cccgacgttc ctcacactcc ctaggagact 900gtgtgcgtgt gtgcccgcgc gtgcgctcac agtgtcaagt gctagcatcc gagatctgca 960gaaacaaatg tctgaattcg aaatgtatgg gtgtgagaaa ttcagctcgg ggaagagatt 1020agggactggg ggagacaggt ggctgcctgt actataagga accgccaacg ccagcatctg 1080tagtccaagc agggctgctc tgtaaaggct tagcaatttt ttctgtaggc ttgctgcaca 1140cggtctctgg cttttcccat ctgtaaaatg ggtgaatgca tccgtacctc agctacctcc 1200gtgaggtgct tctccagttc gggcttaatt cctcatcgtc aagagttttc aggtttcaga 1260gccagcctgc aatcggtaaa acatgtccca acgcggtcgc gagtggttcc atctcgctgt 1320ctggcccaca gcgtggagaa gccttgccca ggcctgaaac ttctctttgc agttccagaa 1380agcaggcgac tgggacggaa ggctctttgc taacctttta cagcggagcc ctgcttggac 1440tacagatgcc agcgttgccc ctgccccaag gcgtgtggtg atcacaaaga cgacactgaa 1500aatacttact atcatccggc tcccctgcta ataaatggag gggtgtttaa ctacaggcac 1560gaccctgccc ttgtgctagc gcggttaccg tgcggaaata actcgtccct gtacccacac 1620catcctcaac ctaaaggaga gttgtgaatt ctttcaaaac actcttctgg agtccgtccc 1680ctccctcctt gcccgccctc tacccctcaa gtccctgccc ccagctgggg gcgctaccgg 1740ctgccgtcgg agctgcagcc acggccatct cctagacgcg cgagtagagc accaagatag 1800tggggacttt gtgcctgggc atcgtttaca tttggggcgc caaatgccca cgtgttgatg 1860aaaccagtga gatgggaaca ggcggcggga aaccagacag aggaagagct agggaggaga 1920ccccagcccc ggatcctggg tcgccagggt tttccgcgcg catcccaaaa ggtgcggctg 1980cgtggggcat caggttagtt tgttagactc tgcagagtct ccaaaccatc ccatccccca 2040acctgactct gtggtggccg tattttttac agaaatttga ccacgttccc tttctccctt 2100ggtcccaagc gcgctcagcc ctccctccat cccccttgag ccgcccttct cctccccctc 2160gcctcctcgg gtccctcctc cagtccctcc ccaagaatct cccggccacg ggcgcccatt 2220ggttgtgcgc agggaggagg cgtgtgcccg gcctggcgag tttcattgag cggaattagc 2280ccggatgaca tcagcttccc agccccccgg cgggcccagc tcattggcga ggcagcccct 2340ccaggacacg cacattgttc cccgcccccg cccccgccac cgctgccgcc gtcgccgctg 2400ccaccgggct ataaaaaccg gccgagcccc taaaggtgcg gatgcttatt atagatcgac 2460gcgacaccag cgcccggtgc caggttctcc cctgaggctt ttcggagcga gctcctcaaa 2520tcgcatccag agtaagtgtc cccgccccac agcagccgca gcctagatcc cagggacaga 2580ctctcctcaa ctcggctgtg acccagaatg ctccgataca gggggtctgg atccctactc 2640tgcgggccat ttctccagag cgactttgct cttctgtcct ccccacactc accgctgcat 2700ctccctcacc aaaagcgaga agtcggagcg acaacagctc tttctgccca agccccagtc 2760agctggtgag ctccccgtgg tctccagatg cagcacatgg actctgggcc ccgcgccggc 2820tctgggtgca tgtgcgtgtg cgtgtgtttg ctgcgtggtg tcgatggaga taaggtggat 2880ccgtttgagg aaccaaatca ttagttctct atctagatct ccattctccc caaagaaagg 2940ccctcacttc ccactcgttt attccagccc gggggctcag ttttcccaca cctaactgaa 3000agcccgaagc ctctagaatg ccacccgcac cccgagggtc accaacgctc cctgaaataa 3060cctgttgcat gagagcagag gggagataga gagagcttaa ttataggtac ccgcgtgcag 3120ctaaaaggag ggccagagat agtagcgagg gggacgagga gccacgggcc acctgtgccg 3180ggaccccgcg ctgtggtact gcggtgcagg cgggagcagc ttttctgtct ctcactgact 3240cactctctct ctctctccct ctctctctct ctcattctct ctcttttctc ctcctctcct 3300ggaagttttc gggtccgagg gaaggaggac cctgcgaaag ctgcgacgac tatcttcccc 3360tggggccatg gactcggacg ccagcctggt gtccagccgc ccgtcgtcgc cagagcccga 3420tgaccttttt ctgccggccc ggagtaaggg cagcagcggc agcgccttca ctgggggcac 3480cgtgtcctcg tccaccccga gtgactgccc 351034333DNAHomo sapiens 34ttaattcgaa aatggcagac agagctgagc gctgccgttc ttttcaggat tgaaaatgtg 60ccagtgggcc aggggcgctg ggacccgcgg tgcggaagac tcggaacagg aagaaatagt 120ggcgcgctgg gtgggctgcc ccgccgccca cgccggttgc cgctggtgac agtggctgcc 180cggccaggca cctccgagca gcaggtctga gcgtttttgg cgtcccaagc gttccgggcc 240gcgtcttcca gagcctctgc tcccagcggg gtcgctgcgg cctggcccga aggatttgac 300tctttgctgg gaggcgcgct gctcagggtt ctg 33335385DNAHomo sapiens 35ccggtcccca gtttggaaaa aggcgcaaga agcgggcttt tcagggaccc cggggagaac 60acgagggctc cgacgcggga gaaggattga agcgtgcaga ggcgccccaa attgcgacaa 120tttactggga tccttttgtg gggaaaggag gcttagaggc tcaagctata ggctgtccta 180gagcaactag gcgagaacct ggccccaaac tccctcctta cgccctggca caggttcccg 240gcgactggtg ttcccaaggg agccccctga gcctaccgcc cttgcagggg gtcgtgctgc 300ggcttctggg tcataaacgc cgaggtcggg ggtggcggag ctgtagaggc tgcccgcgca 360gaaagctcca ggatcccaat atgtg 38536105DNAHomo sapiens 36gcgcaggtcc ccccagtccc cgagggagtg cgcccgacgg aaacgcccct agcccgcggg 60cctcgctttc ctctcccggg ttcctgggtc acttcccgct gtctc 10537147DNAHomo sapiens 37ttccctcgcg gctttggaaa gggggtgcaa atgcaccctt ctgcgggccc gctacccgct 60gcaacacctg tgtttccttt ctgggcacct tctaggtttc tagatattgc tgtgaatacg 120gtcctccgct gtacagttga aaacaaa 14738365DNAHomo sapiens 38tgggaattta ggtcgggcac tgccgatatg tcgccttcca caaggcgggc ccgggcctct 60gctgaccgtg caccggtcct ggggctgggt aattctgcag cagcagcgca gcccatgccg 120gggaatttgc gggcagagga gacagtgagg cccgcgttct gtgcgggaac tcccgagctc 180acagagccca agaccacacg gctgcatctg cttggctgac tgggccaggc ccacgcgtag 240taacccggac gtctctctct cacagtcccc ttgcgtctgg ccagggagct gccaggctgc 300accccgcggt ggggatcggg agaggggcag tgtcgcccat ccccggaagg ctgagcctgg 360tgcag 36539418DNAHomo sapiens 39cggttttctc ctggaggact gtgttcagac agatactggt ttccttatcc gcaggtgtgc 60gcggcgctcg caagtggtca gcataacgcc gggcgaattc ggaaagcccg tgcgtccgtg 120gacgacccac ttggaaggag ttgggagaag tccttgttcc cacgcgcgga cgcttccctc 180cgtgtgtcct tcgagccaca aaaagcccag accctaaccc gctcctttct cccgccgcgt 240ccatgcagaa ctccgccgtt cctgggaggg gaagcccgcg aggcgtcggg agaggcacgt 300cctccgtgag caaagagctc ctccgagcgc gcggcgggga cgctgggccg acaggggacc 360gcgggggcag ggcggagagg acccgccctc gagtcggccc agccctaaca ctcaggac 41840906DNAHomo sapiens 40agggaatcgg gctgaccagt cctaaggtcc cacgctcccc tgacctcagg gcccagagcc 60tcgcattacc ccgagcagtg cgttggttac tctccctgga aagccgcccc cgccggggca 120agtgggagtt gctgcactgc ggtctttgga ggcctaggtc gcccagagta ggcggagccc 180tgtatccctc ctggagccgg cctgcggtga ggtcggtacc cagtacttag ggagggagga 240cgcgcttggt gctcagggta ggctgggccg ctgctagctc ttgatttagt ctcatgtccg 300cctttgtgcc ggcctctccg atttgtgggt ccttccaaga aagagtcctc tagggcagct 360agggtcgtct cttgggtctg gcgaggcggc aggccttctt

cggacctatc cccagaggtg 420taacggagac tttctccact gcagggcggc ctggggcggg catctgccag gcgagggagc 480tgccctgccg ccgagattgt ggggaaacgg cgtggaagac accccatcgg agggcaccca 540atctgcctct gcactcgatt ccatcctgca acccaggaga aaccatttcc gagttccagc 600cgcagaggca cccgcggagt tgccaaaaga gactcccgcg aggtcgctcg gaaccttgac 660cctgacacct ggacgcgagg tctttcagga ccagtctcgg ctcggtagcc tggtccccga 720ccaccgcgac caggagttcc ttcttccctt cctgctcacc agccggccgc cggcagcggc 780tccaggaagg agcaccaacc cgcgctgggg gcggaggttc aggcggcagg aatggagagg 840ctgatcctcc tctagccccg gcgcattcac ttaggtgcgg gagccctgag gttcagcctg 900actttc 90641860DNAHomo sapiens 41cactacggat ctgcctggac tggttcagat gcgtcgttta aagggggggg ctggcactcc 60agagaggagg gggcgctgca ggttaattga tagccacgga agcacctagg cgccccatgc 120gcggagccgg agccgccagc tcagtctgac ccctgtcttt tctctcctct tccctctccc 180acccctcact ccgggaaagc gagggccgag gtaggggcag atagatcacc agacaggcgg 240agaaggacag gagtacagat ggagggacca ggacacagaa tgcaaaagac tggcaggtga 300gaagaaggga gaaacagagg gagagagaaa gggagaaaca gagcagaggc ggccgccggc 360ccggccgccc tgagtccgat ttccctcctt ccctgaccct tcagtttcac tgcaaatcca 420cagaagcagg tttgcgagct cgaatacctt tgctccactg ccacacgcag caccgggact 480gggcgtctgg agcttaagtc tgggggtctg agcctgggac cggcaaatcc gcgcagcgca 540tcgcgcccag tctcggagac tgcaaccacc gccaaggagt acgcgcggca ggaaacttct 600gcggcccaat ttcttcccca gctttggcat ctccgaaggc acgtacccgc cctcggcaca 660agctctctcg tcttccactt cgacctcgag gtggagaaag aggctggcaa gggctgtgcg 720cgtcgctggt gtggggaggg cagcaggctg cccctccccg cttctgcagc gagttttccc 780agccaggaaa agggagggag ctgtttcagg aatttcagtg ccttcaccta gcgactgaca 840caagtcgtgt gtataggaag 86042452DNAHomo sapiens 42ggagcctgaa gtcagaaaag atggggcctc gttactcact ttctagccca gcccctggcc 60ctgggtcccg cagagccgtc atcgcaggct cctgcccagc ctctggggtc gggtgagcaa 120ggtgttctct tcggaagcgg gaagggctgc gggtcgggga cgtcccttgg ctgccacccc 180tgattctgca tccttttcgc tcgaatccct gcgctaggca tcctccccga tcccccaaaa 240gcccaagcac tgggtctggg ttgaggaagg gaacgggtgc ccaggccgga cagaggctga 300aaggaggcct caaggttcct ctttgctaca aagtggagaa gttgctctac tctggagggc 360agtggccttt tccaaacttt tccacttagg tccgtaagaa aagcaattca tacacgatca 420gcgctttcgg tgcgaggatg gaaagaaact tc 452431992DNAHomo sapiens 43ttttcctgtt acagagctga gcccactcat gtggtgccaa gtagcgacta tctctcggcc 60acctccaccc agagcaatgt gggcgccccc agcgggtggg agcgattgcc gagcggcgca 120agggcgttta acgcctaacc ccctcctcct gggttgccaa gccgctaggt cgccgtttcc 180aacgtggctg cgcgggactg aagtccgacg actcctcgtc ctcagtagga gacacacctc 240ccactgcccc cagccacgcg agctatgggc agaatcgggg caacggtaat atctggatgg 300ggcaggctcc cctgaggctg tgcttaagaa aaaaggaatc tggagtagcc tgaggggccc 360cacgaggggg cctcctttgc gatcgtctcc cagccttagg ccaaggctac ggaggcaggc 420ggccgagtgt tggcgcccag cccggccgag gactggatgg aggacgagaa gcagcctgcc 480tctgggcgac agctgcggac gcagcctcgc cgcctcgccg cctcagcctc ggtcccagcg 540tctctaaagc cgcgcccatt ttacagatgc agggcaggga gacaagaggc atctccgggg 600gccgagtaga atgatggcgc gggttctccc ggcgccctga tttcgaggct gcgcccgggg 660ccctacatgc aggcggggag gcctgggccg aaggcgtctg caaggagggg cgagtctgcc 720cggtccgggc agggagtgag gccacagtca gttctcccta ggaggccgcg cagcgggtag 780ggtatgggac tgggggacgc aacggggacc tggccgaatc agagccctca gcagagaacg 840ccgaaaactc tggggccggc cgctcgcttc ccgctagtgg gaatggtttc cggtcatccg 900ttcccagtcc agccccgggt agggagctct gatttgcaat gcacagcact tgcgaggttc 960gaatgccccc gcaatttgca gatggaaata ctaagcctag gccgggcgtg gtggctcaag 1020cctatcatct cagccctttg ggaggccaag ccgggaggat tgtttgagcc caagaattca 1080aaaccagcct gagcaacata gcgaccccgt ctctacaaaa taaaataaaa taaattatcc 1140gggcgtggtg gcacgcgcct gtggttccag ctactccgga ggctgaggtg ggaggatcgc 1200ttgagtccgg gaggtcgagg ctacagtgag ccgtgatcgc accactgcac tccagcctgg 1260gcgacagagt gagaccttgt ctcaaaaaag gaaaaaaaga aaaagaaagt aagcttcaaa 1320gaagctctga taatagttct gggtcgtgca gcggtggcgg ccccgcgctc tcgcccctaa 1380agcaagcgct ctttgtactg ggtggaggag ctttgagtag tgagggtgga gatgcagctt 1440cggggtggcg cagccaccct gacactaggc ccggggtcgc agtgggacag aagagtctgc 1500cgctctgact tgggctctga gttccaaggg cgcccggcac ttctagcctc ccaggcttgc 1560gcgctggcgc ctttgccatc cgtgccgaag tggggagacc tagccgcgac caccacgagc 1620gcagcggtga cacccagagg tcccaccggg cccctgggca gggtaacctt agcctgtccg 1680cttcggcagc tttgcgaaga gtggcgcgca gctagggctg aggctcttgc ggacctgcgg 1740tcgaagcagg cggctgagcc agttcgatcg ccaaggcctg ggctgccgac agtggtgcgc 1800gctctgttcc gccgcggccg ggccaggcgc tctggaatag cgatgggggg acacggcctc 1860caactttctg cagagaccat cgggcagctc cgggcctaag cagcgacctc accgaaggtt 1920cctgggaacc tttgccaaaa tcccagcctc tgcctcggtc cagctaaacc gtgtgtaaac 1980aagtgcacca ag 199244448DNAHomo sapiens 44ataaaggacc gggtaatttc gcggaatgcg gattttgaga caggcccaga cggcggcgga 60ttccctgtgt cccccaactg gggcgatctc gtgaacacac ctgcgtccca ccccgatcct 120aggttggggg gaaagggtat gggaaccctg agcccagagc gcgccccgct ctttcctttg 180ctccccggct tccctggcca gccccctccc ggctggtttc ctcgctcact cggcgcctgg 240cgtttcgggc gtctggagat caccgcgtgt ctggcacccc aacgtctagt ctccccgcag 300gttgaccgcg gcgcctggag ccgggaatag gggtggggag tccggagaac caaacccgag 360cctgaagttg ccattcgggt gactcccgag aaagcccggg agcattttgg ccaatgcggg 420tttttacctg aacttcagca tcttcacc 44845395DNAHomo sapiens 45aattggaaaa ccctggtatt gtgcctgttt gggggaagaa aacgtcaata aaaattaatt 60gatgagttgg cagggcgggc ggtgcgggtt cgcggcgagg cgcagggtgt catggcaaat 120gttacggctc agattaagcg attgttaatt aaaaagcgac ggtaattaat actcgctacg 180ccatatgggc ccgtgaaaag gcacaaaagg tttctccgca tgtggggttc cccttctctt 240ttctccttcc acaaaagcac cccagcccgt gggtcccccc tttggcccca aggtaggtgg 300aactcgtcac ttccggccag ggaggggatg gggcggtctc cggcgagttc caagggcgtc 360cctcgttgcg cactcgcccg cccaggttct ttgaa 39546491DNAHomo sapiens 46gggaagcgat cgtctcctct gtcaactcgc gcctgggcac ttagcccctc ccgtttcagg 60gcgccgcctc cccggatggc aaacactata aagtggcggc gaataaggtt cctcctgctg 120ctctcggttt agtccaagat cagcgatatc acgcgtcccc cggagcatcg cgtgcaggag 180ccatggcgcg ggagctatac cacgaagagt tcgcccgggc gggcaagcag gcggggctgc 240aggtctggag gattgagaag ctggagctgg tgcccgtgcc ccagagcgct cacggcgact 300tctacgtcgg ggatgcctac ctggtgctgc acacggccaa gacgagccga ggcttcacct 360accacctgca cttctggctc ggtaagggac ggcgggcggc gggaccccga cgcaccaagg 420ccggcgaggg gagggcgtag gggtctgaga tttgcaggcg tgggagtaaa ggggaccgca 480aactgagcta g 491471284DNAHomo sapiens 47ctcaggggcg ggaagtggcg ggtgggagtc acccaagcgt gactgcccga ggcccctcct 60gccgcggcga ggaagctcca taaaagccct gtcgcgaccc gctctctgca ccccatccgc 120tggctctcac ccctcggaga cgctcgcccg acagcatagt acttgccgcc cagccacgcc 180cgcgcgccag ccaccgtgag tgctacgacc cgtctgtcta ggggtgggag cgaacggggc 240gcccgcgaac ttgctagaga cgcagcctcc cgctctgtgg agccctgggg ccctgggatg 300atcgcgctcc actccccagc ggactatgcc ggctccgcgc cccgacgcgg accagccctc 360ttggcggcta aattccactt gttcctctgc tcccctctga ttgtccacgg cccttctccc 420gggcccttcc cgctgggcgg ttcttctgag ttacctttta gcagatatgg agggagaacc 480cgggaccgct atcccaaggc agctggcggt ctccctgcgg gtcgccgcct tgaggcccag 540gaagcggtgc gcggtaggaa ggtttccccg gcagcgccat cgagtgagga atccctggag 600ctctagagcc ccgcgccctg ccacctccct ggattcttgg gctccaaatc tctttggagc 660aattctggcc cagggagcaa ttctctttcc ccttccccac cgcagtcgtc accccgaggt 720gatctctgct gtcagcgttg atcccctgaa gctaggcaga ccagaagtaa cagagaagaa 780acttttcttc ccagacaaga gtttgggcaa gaagggagaa aagtgaccca gcaggaagaa 840cttccaattc ggttttgaat gctaaactgg cggggccccc accttgcact ctcgccgcgc 900gcttcttggt ccctgagact tcgaacgaag ttgcgcgaag ttttcaggtg gagcagaggg 960gcaggtcccg accggacggc gcccggagcc cgcaaggtgg tgctagccac tcctgggttc 1020tctctgcggg actgggacga gagcggattg ggggtcgcgt gtggtagcag gaggaggagc 1080gcggggggca gaggagggag gtgctgcgcg tgggtgctct gaatccccaa gcccgtccgt 1140tgagccttct gtgcctgcag atgctaggta acaagcgact ggggctgtcc ggactgaccc 1200tcgccctgtc cctgctcgtg tgcctgggtg cgctggccga ggcgtacccc tccaagccgg 1260acaacccggg cgaggacgca ccag 128448554DNAHomo sapiens 48tggagaacct tgggctctgt ggcctcaaag gtaggggtga tttcgagggg ccggcacctc 60acagggcagg ttccaccgcg gaaacgcagt catcgcccag cgaccctgct cctggccctc 120agcctccccc caggtttctt tttctcttga atcaagccga ggtgcgccaa tggccttcct 180tgggtcggat ccggggggcc agggccagct tacctgcttt caccgagcag tggatatgtg 240ccttggactc gtagtacacc cagtcgaagc cggcctccac cgccaggcgg gccagcatgc 300cgtacttgct gcggtcgcgg tcagacgtgg tgatgtccac tgcgcggccc tcgtagtgca 360gagactcctc tgagtggtgg ccatcttcgt cccagccctc ggtcacccgc agtttcactc 420ctggccactg gttcatcacc gagatggcca aagcgttcaa cttgtcctta cacctctgcg 480aagacaaggg gacccccacc gacggacacg ttagcctggg caaccgccac ccctcccggc 540ccctccatca gcct 55449772DNAHomo sapiens 49tctcacgacc catccgttaa cccaccgttc ccaggagctc cgaggcgcag cggcgacaga 60ggttcgcccc ggcctgctag cattggcatt gcggttgact gagcttcgcc taacaggctt 120ggggagggtg ggctgggctg ggctgggctg ggctgggtgc tgcccggctg tccgcctttc 180gttttcctgg gaccgaggag tcttccgctc cgtatctgcc tagagtctga atccgacttt 240ctttcctttg ggcacgcgct cgccagtgga gcacttcttg ttctggcccc gggctgatct 300gcacgcggac ttgagcaggt gccaaggtgc cacgcagtcc cctcacggct ttcggggggt 360cttggagtcg ggtggggagg gagacttagg tgtggtaacc tgcgcaggtg ccaaagggca 420gaaggagcag ccttggatta tagtcacggt ctctccctct cttccctgcc atttttaggg 480ctttctctac gtgctgttgt ctcactgggt ttttgtcgga gccccacgcc ctccggcctc 540tgattcctgg aagaaagggt tggtcccctc agcaccccca gcatcccgga aaatggggag 600caaggctctg ccagcgccca tcccgctcca cccgtcgctg cagctcacca attactcctt 660cctgcaggcc gtgaacacct tcccggccac ggtggaccac ctgcagggcc tgtacggtct 720cagcgcggta cagaccatgc acatgaacca ctggacgctg gggtatccca at 772501362DNAHomo sapiens 50tggtttcctt tcgcttctcg cctcccaaac acctccagca agtcggaggg cgcgaacgcg 60gagccagaaa cccttcccca aagtttctcc cgccaggtac ctaattgaat catccatagg 120atgacaaatc agccagggcc aagatttcca gacacttgag tgacttcccg gtccccgagg 180tgacttgtca gctccagtga gtaacttgga actgtcgctc ggggcaaggt gtgtgtctag 240gagagagccg gcggctcact cacgctttcc agagagcgac ccgggccgac ttcaaaatac 300acacagggtc atttataggg actggagccg cgcgcaggac aacgtctccg agactgagac 360attttccaaa cagtgctgac attttgtcgg gccccataaa aaatgtaaac gcgaggtgac 420gaacccggcg gggagggttc gtgtctggct gtgtctgcgt cctggcggcg tgggaggtta 480tagttccaga cctggcggct gcggatcgcc gggccggtac ccgcgaggag tgtaggtacc 540ctcagcccga ccacctcccg caatcatggg gacaccggct tggatgagac acaggcgtgg 600aaaacagcct tcgtgaaact ccacaaacac gtggaacttg aaaagacaac tacagccccg 660cgtgtgcgcg agagacctca cgtcacccca tcagttccca cttcgccaaa gtttcccttc 720agtggggact ccagagtggt gcgccccatg cccgtgcgtc ctgtaacgtg ccctgattgt 780gtacccctct gcccgctcta cttgaaatga aaacacaaaa actgttccga attagcgcaa 840ctttaaagcc ccgttatctg tcttctacac tgggcgctct taggccactg acagaaacat 900ggtttgaacc ctaattgttg ctatcagtct cagtcagcgc aggtctctca gtgacctgtg 960acgccgggag ttgaggtgcg cgtatcctta aacccgcgcg aacgccaccg gctcagcgta 1020gaaaactatt tgtaatccct agtttgcgtc tctgagcttt aactccccca cactctcaag 1080cgcccggttt ctcctcgtct ctcgcctgcg agcaaagttc ctatggcatc cacttaccag 1140gtaaccggga tttccacaac aaagcccggc gtgcgggtcc cttcccccgg ccggccagcg 1200cgagtgacag cgggcggccg gcgctggcga ggagtaactt ggggctccag cccttcagag 1260cgctccgcgg gctgtgcctc cttcggaaat gaaaaccccc atccaaacgg ggggacggag 1320cgcggaaacc cggcccaagt gccgtgtgtg cgcgcgcgtc tg 136251476DNAHomo sapiens 51gaaagccatc cttaccattc ccctcaccct ccgccctctg atcgcccacc cgccgaaagg 60gtttctaaaa atagcccagg gcttcaaggc cgcgcttctg tgaagtgtgg agcgagcggg 120cacgtagcgg tctctgccag gtggctggag ccctggaagc gagaaggcgc ttcctccctg 180catttccacc tcaccccacc cccggctcat ttttctaaga aaaagttttt gcggttccct 240ttgcctccta cccccgctgc cgcgcggggt ctgggtgcag acccctgcca ggttccgcag 300tgtgcagcgg cggctgctgc gctctcccag cctcggcgag ggttaaaggc gtccggagca 360ggcagagcgc cgcgcgccag tctattttta cttgcttccc ccgccgctcc gcgctccccc 420ttctcagcag ttgcacatgc cagctctgct gaaggcatca atgaaaacag cagtag 47652300DNAHomo sapiens 52atcgaaaatg tcgacatctt gctaatggtc tgcaaacttc cgccaattat gactgacctc 60ccagactcgg ccccaggagg ctcgtattag gcagggaggc cgccgtaatt ctgggatcaa 120aagcgggaag gtgcgaactc ctctttgtct ctgcgtgccc ggcgcgcccc cctcccggtg 180ggtgataaac ccactctggc gccggccatg cgctgggtga ttaatttgcg aacaaacaaa 240agcggcctgg tggccactgc attcgggtta aacattggcc agcgtgttcc gaaggcttgt 300531246DNAHomo sapiens 53atcaacatcg tggctttggt cttttccatc atggtgagtg aatcacggcc agaggcagcc 60tgggaggaga gacccgggcg gctttgagcc cctgcagggg agtccgcgcg ctctctgcgg 120ctcccttcct cacggcccgg cccgcgctag gtgttctttg tcctcgcacc tcctcctcac 180ctttctcggg ctctcagagc tctccccgca atcatcagca cctcctctgc actcctcgtg 240gtactcagag ccctgatcaa gcttccccca ggctagcttt cctcttcttt ccagctccca 300gggtgcgttt cctctccaac ccggggaagt tcttccgtgg actttgctga ctcctctgac 360cttcctaggc acttgcccgg ggcttctcaa ccctcttttc tagagcccca gtgcgcgcca 420ccctagcgag cgcagtaagc tcataccccg agcatgcagg ctctacgttc ctttccctgc 480cgctccgggg gctcctgctc tccagcgccc aggactgtct ctatctcagc ctgtgctccc 540ttctctcttt gctgcgccca agggcaccgc ttccgccact ctccgggggg tccccaggcg 600attcctgatg ccccctcctt gatcccgttt ccgcgctttg gcacggcacg ctctgtccag 660gcaacagttt cctctcgctt cttcctacac ccaacttcct ctccttgcct ccctccggcg 720cccccttttt aacgcgcccg aggctggctc acacccacta cctctttagg cctttcttag 780gctccccgtg tgcccccctc accagcaaag tgggtgcgcc tctcttactc tttctaccca 840gcgcgtcgta gttcctcccc gtttgctgcg cactggccct aacctctctt ctcttggtgt 900cccccagagc tcccaggcgc ccctccaccg ctctgtcctg cgcccggggc tctcccggga 960atgaactagg ggattccacg caacgtgcgg ctccgcccgc cctctgcgct cagacctccc 1020gagctgcccg cctctctagg agtggccgct ggggcctcta gtccgccctt ccggagctca 1080gctccctagc cctcttcaac cctggtagga acacccgagc gaaccccacc aggagggcga 1140cgagcgcctg ctaggccctc gccttattga ctgcagcagc tggcccgggg gtggcggcgg 1200ggtgaggttc gtaccggcac tgtcccggga caacccttgc agttgc 124654984DNAHomo sapiens 54acaaataaaa caccctctag cttcccctag actttgttta actggccggg tctccagaag 60gaacgctggg gatgggatgg gtggagagag ggagcggctc aaggacttta gtgaggagca 120ggcgagaagg agcacgttca ggcgtcaaga ccgatttctc cccctgcttc gggagacttt 180tgaacgctcg gagaggcccg gcatctcacc actttacttg gccgtagggg cctccggcac 240ggcaggaatg agggaggggg tccgattgga cagtgacggt ttggggccgt tcggctatgt 300tcagggacca tatggtttgg ggacagcccc agtagttagt aggggacggg tgcgttcgcc 360cagtccccgg atgcgtaggg aggcccagtg gcaggcagct gtcccaagca gcgggtgcgc 420gtccctgcgc gctgtgtgtt cattttgcag agccagcctt cggggaggtg aaccagctgg 480gaggagtgtt cgtgaacggg aggccgctgc ccaacgccat ccggcttcgc atcgtggaac 540tggcccaact gggcatccga ccgtgtgaca tcagccgcca gctacgggtc tcgcacggct 600gcgtcagcaa gatcctggcg cgatacaacg agacgggctc gatcttgcca ggagccatcg 660ggggcagcaa gccccgggtc actaccccca ccgtggtgaa acacatccgg acctacaagc 720agagagaccc cggcatcttc gcctgggaga tccgggaccg cctgctggcg gacggcgtgt 780gcgacaagta caatgtgccc tccgtgagct ccatcagccg cattctgcgc aacaagatcg 840gcaacttggc ccagcagggt cattacgact catacaagca gcaccagccg acgccgcagc 900cagcgctgcc ctacaaccac atctactcgt accccagccc tatcacggcg gcggccgcca 960aggtgcccac gccacccggg gtgc 98455545DNAHomo sapiens 55aggaggcgca acgcgctgcc agggcggctt tatcctgccg ccacagggcg gggaccagcc 60cggcagccgg gtgtccagcg ccgctcacgt gcctcgcctg gagcttagct ctcagactcc 120gaagagggcg actgagactt gggcctggga gttggcttcg gggtacccaa ggcgacgaca 180gctgagttgt accacgaagc tcaggccgag gcctcctccc ttgtctggcc ttcgaatcca 240tactggcagc ctctcctctc aggcactccg cgggccgggc cactaggccc cctgctcctg 300gagctgcgct atgatccggg tcttgagatg cgcgcgattc tctctgaacc ggtggagagg 360aggctctgcc ccgcgcggag cgaggacagc ggcgcccgag cttcccgcgc ctctccaggg 420cccaatggca agaacagcct ccgaagtgcg cggatgacag gaaaagatct tcagttcttc 480tgccgctaga gaagtgcggg atacaagcct ctattggatc cacaacctgg agtcctgcct 540tcgga 545561533DNAHomo sapiens 56atctgcgtgc ccttttctgg gcgagccctg ggagatccag ggagaactgg gcgctccaga 60tggtgtatgt ctgtaccttc acagcaaggc ttcccttgga tttgaggctt cctattttgt 120ctgggatcgg ggtttctcct tgtcccagtg gcagccccgc gttgcgggtt ccgggcgctg 180cgcggagccc aaggctgcat ggcagtgtgc agcgcccgcc agtcgggctg gtgggttgtg 240cactccgtcg gcagctgcag aaaggtggga gtgcaggtct tgcctttcct caccgggcgg 300ttggcttcca gcaccgaggc tgacctatcg tggcaagttt gcggcccccg cagatcccca 360gtggagaaag agggctcttc cgatgcgatc gagtgtgcgc ctccccgcaa agcaatgcag 420accctaaatc actcaaggcc tggagctcca gtctcaaagg tggcagaaaa ggccagacct 480aactcgagca cctactgcct tctgcttgcc ccgcagagcc ttcagggact gactgggacg 540cccctggtgg cgggcagtcc catccgccat gagaacgccg tgcagggcag cgcagtggag 600gtgcagacgt accagccgcc gtggaaggcg ctcagcgagt ttgccctcca gagcgacctg 660gaccaacccg ccttccaaca gctggtgagg ccctgcccta cccgccccga cctcgggact 720ctgcgggttg gggatttagc cacttagcct ggcagagagg ggagggggtg gccttgggct 780gaggggctgg gtacagccct aggcggtggg ggagggggaa cagtggcggg ctctgaaacc 840tcacctcggc ccattacgcg ccctaaacca ggtctccctg gattaaagtg ctcacaagag 900aggtcgcagg attaaccaac ccgctccccc gccctaatcc ccccctcgtg cgcctgggga 960cctggcctcc ttctccgcag ggcttgctct cagctggcgg ccggtcccca agggacactt 1020tccgactcgg agcacgcggc cctggagcac cagctcgcgt gcctcttcac ctgcctcttc 1080ccggtgtttc cgccgcccca ggtctccttc tccgagtccg gctccctagg caactcctcc 1140ggcagcgacg tgacctccct gtcctcgcag ctcccggaca cccccaacag tatggtgccg 1200agtcccgtgg agacgtgagg gggacccctc cctgccagcc cgcggacctc gcatgctccc 1260tgcatgagac tcacccatgc tcaggccatt ccagttccga aagctctctc gccttcgtaa 1320ttattctatt gttatttatg agagagtacc gagagacacg gtctggacag cccaaggcgc 1380caggatgcaa cctgctttca ccagactgca gacccctgct ccgaggactc ttagtttttc 1440aaaaccagaa tctgggactt accagggtta gctctgccct ctcctctcct ctctacgtgg 1500ccgccgctct gtctctccac gccccacctg tgt 153357702DNAHomo sapiens

57aggtctcttc agactgccca ttctccgggc ctcgctgaat gcgggggctc tatccacagc 60gcgcggggcc gagctcaggc aggctggggc gaagatctga ttctttcctt cccgccgcca 120aaccgaatta atcagtttct tcaacctgag ttactaagaa agaaaggtcc ttccaaataa 180aactgaaaat cactgcgaat gacaatacta tactacaagt tcgttttggg gccggtgggt 240gggatggagg agaaagggca cggataatcc cggagggccg cggagtgagg aggactatgg 300tcgcggtgga atctctgttc cgctggcaca tccgcgcagg tgcggctctg agtgctggct 360cggggttaca gacctcggca tccggctgca ggggcagaca gagacctcct ctgctagggc 420gtgcggtagg catcgtatgg agcccagaga ctgccgagag cactgcgcac tcaccaagtg 480ttaggggtgc ccgtgataga ccgccaggga aggggctggt tcggagggaa ttcccgctac 540cgggaaggtc ggaactcggg gtgatcaaac aaggaatgca tctcacctcc gtgggtgctt 600gtgctgcgca aggaattatt accggagcgg ttgcgatggc ctttgcccgg cgacccaaga 660agagtaagca aactaccgtc cacccagcgg atcaggtcca at 702583180DNAHomo sapiens 58gatgtcctgt ttctagcagc ctccagagcc aagctaggcg agaggcgtag gaggcagaga 60gagcgggcgc gggaggccag ggtccgcctg ggggcctgag gggacttcgt ggggtcccgg 120gagtggccta gaaacaggga gctgggaggg ccgggaagag cttgaggctg agcgggggac 180gaacgggcag cgcaaagggg agatgaacgg aatggccgag gagccacgca ttcgccttgt 240gtccgcggac ccttgttccc gacaggcgac caagccaagg ccctccggac tgacgcggcc 300tgagcagcag cgagtgtgaa gtttggcacc tccggcggcg agacggcgcg ttctggcgcg 360cggctcctgc gtccggctgg tggagctgct gcgccctatg cggcctgccg agggcgccgc 420cgagggcccg cgagctccgt ggggtcgggg tggggggacc cgggagcgga cagcgcggcc 480cgaggggcag gggcaggggc gcgcctggcc tggggtgtgt ctgggccccg gctccgggct 540cttgaaggac cgcgagcagg aggcttgcgc aatcccttgg ctgagcgtcc acggagaaag 600aaaaagagca aaagcagagc gagagtggag cgagggatgg gggcgggcaa agagccatcc 660gggtctccac caccgccctg acacgcgacc cggctgtctg ttggggaccg cacgggggct 720cgggcgagca ggggagggag gagcctgcgc ggggctcgtg ttcgcccagg aatcccggag 780aagctcgaag acggtctggt gttgaacgca cacgtggact ccatttcatt accaccttgc 840agctcttgcg ccacggaggc tgctgctgcc cggcggctgc tacccaccga gacccacgtg 900gcccctcccc aggggtgtag gggtgacggt tgtcttctgg tgacagcaga ggtgttgggt 960ttgcgactga tctctaacga gcttgaggcg caaacctagg attccctgag tgttggggtg 1020cggcgggggg gcaagcaagg tgggacgacg cctgcctggt ttccctgact agttgcgggg 1080ggtgggggcc ggctctcagg ggccaccaga agctgggtgg gtgtacagga aaatattttt 1140ctcctgccgt gtttggcttt ttcctggcat ttttgcccag ggcgaagaac tgtcgcgcgg 1200ggcagctcca ccgcggaggg agaggggtcg cgaggctggc gcgggaagcg ctgtaggtgg 1260cagtcatccg tccacgccgc acaggccgtc tgcgccgtcg gaccatcggg aggtctgcag 1320caactttgtc ccggccagtc cccttgtccg ggaaggggct gagcttcccg acactctacc 1380ctccccctct tgaaaatccc ctggaaaatc tgtttgcaat gggtgtttcc gcggcgtcca 1440ggtctgggct gccgggggag gccgagcggc tgctgcagcc tccctgctgc caggggcgtc 1500ggactccgct tcgctcacta cgcccaggcc cctcaggggc ccacgctcag gacttcgggg 1560ccacacagca ggacccggtg ccccgacgac gagtttgcgc aggacccggg ctgggccagc 1620cgcggagctg gggaggaagg ggcgggggtc ggtgcagcgg atcttttctg ttgctgcctg 1680tgcggcggca ggaagcgtct tgaggctccc caagactacc tgaggggccg cccaagcact 1740tcagaagccc aaggagcccc cggccacccc cgctcctggc ctttttgcca acgactttga 1800aagtgaaatg cacaagcacc agcaattgac ttcccttccg tggttattta ttttgtcttt 1860gtggatggtg ggcagatggg gagagaggcc cctacctaac ctcggtggct ggtccctaga 1920ccacccctgc cagccggtgt ggggaggagc tcaggtccgc gggagagcga atgggcgcca 1980ggaggtggga cagaatcctg ggaaggtaca gcggacgccc tggaagctcc cctgatgccc 2040cagagggccc ttcctgggaa acctcccggg ggggtgcccc ataccatccc acccggctgt 2100cttggcccct cccagggagc cgcaggagaa actagcccta cacctgggat tcccagagcc 2160ttctgctggg gctcctgccc ccgacttcgg ataaccagct ccgcacaggt ccccgagaag 2220ggccgctggc ctgcttattt gatactgccc cctcccagac aggggctggt cgagcccctg 2280gttctgctgc cagactgaag ccttccagac gccacctcgg tttgggcccc cagggccctc 2340aggggcccca ggagaggaga gctgctatct agctcagcca caggctcgct cctggtgggg 2400gccaggctga aggagtggac cctggagagg tcgggaacct tttaacagcc gtgggctgga 2460gggtggctac taagtgttcg gtctgggaag aggcatgacc cgcaccatcc cggggaaata 2520aacgacttct taagggaatc ttctcgctga gcgggtgctc tgggccagga gattgccacc 2580gccagcccac ggaacccaga tttgggctct gccttgagcg ggccgcctgt ggcttcccgg 2640gtcgctcccc cgactcagaa agctctcaag ttggtatcgt tttcccggcc ctcggaggtg 2700gattgcagat caccgagagg ggatttacca gtaaccacta cagaatctac ccgggcttta 2760acaagcgctc atttctctcc cttgtcctta gaaaaacttc gcgctggcgt tgatcatatc 2820gtacttgtag cggcagctta ggggcagcgg aactggtggg gttgtgcgtg cagggggagg 2880ctgtgaggga gccctgcact ccgcccctcc acccttctgg aggagtggct ttgtttctaa 2940gggtgccccc ccaacccccg ggtccccact tcaatgtttc tgctctttgt cccaccgccc 3000gtgaaagctc ggctttcatt tggtcggcga agcctccgac gcccccgagt cccaccctag 3060cgggccgcgc ggcactgcag ccgggggttc ctgcggactg gcccgacagg gtgcgcggac 3120ggggacgcgg gccccgagca ccgcgacgcc agggtccttt ggcagggccc aagcacccct 3180591038DNAHomo sapiens 59tggcggccgg cgggcacagc cggctcattg ttctgcacta caaccactcg ggccggctgg 60ccgggcgcgg ggggccggag gatggcggcc tgggggccct gcgggggctg tcggtggccg 120ccagctgcct ggtggtgctg gagaacttgc tggtgctggc ggccatcacc agccacatgc 180ggtcgcgacg ctgggtctac tattgcctgg tgaacatcac gctgagtgac ctgctcacgg 240gcgcggccta cctggccaac gtgctgctgt cgggggcccg caccttccgt ctggcgcccg 300cccagtggtt cctacgggag ggcctgctct tcaccgccct ggccgcctcc accttcagcc 360tgctcttcac tgcaggggag cgctttgcca ccatggtgcg gccggtggcc gagagcgggg 420ccaccaagac cagccgcgtc tacggcttca tcggcctctg ctggctgctg gccgcgctgc 480tggggatgct gcctttgctg ggctggaact gcctgtgcgc ctttgaccgc tgctccagcc 540ttctgcccct ctactccaag cgctacatcc tcttctgcct ggtgatcttc gccggcgtcc 600tggccaccat catgggcctc tatggggcca tcttccgcct ggtgcaggcc agcgggcaga 660aggccccacg cccagcggcc cgccgcaagg cccgccgcct gctgaagacg gtgctgatga 720tcctgctggc cttcctggtg tgctggggcc cactcttcgg gctgctgctg gccgacgtct 780ttggctccaa cctctgggcc caggagtacc tgcggggcat ggactggatc ctggccctgg 840ccgtcctcaa ctcggcggtc aaccccatca tctactcctt ccgcagcagg gaggtgtgca 900gagccgtgct cagcttcctc tgctgcgggt gtctccggct gggcatgcga gggcccgggg 960actgcctggc ccgggccgtc gaggctcact ccggagcttc caccaccgac agctctctga 1020ggccaaggga cagctttc 103860374DNAHomo sapiens 60tagtaaggca ccgaggggtg gctcctctcc ctgcagcggc tgtcgcttac catcctgtag 60accgtgacct cctcacacag cgccaggacg aggatcgcgg tgagccagca ggtgactgcg 120atcctggagc tggtcgcagc aggccatcct gcacgcggtg gaggcgcccc ctgcaggccg 180cagcgcatcc ccagcttctg gacgcactgt gagcggttat gcagcagcac gctcatatga 240gatgccccgc agggtgctat gcaggcccac gtccccacaa agcccatggc aggcgcccgg 300gtgccggagc acgcacttgg ccccatggat ctctgtgccc agggctcagc caggcatctg 360gccgctaaag gttt 37461246DNAHomo sapiens 61tctcatctga gcgctgtctt tcaccagagc tctgtaggac tgaggcagta gcgctggccc 60gcctgcgaga gcccgaccgt ggacgatgcg tcgcgccctt cccatcgcgg cctgggcggg 120cccgcctgcc ctcggctgag cccggtttcc ctaccccggg gcacctcccc tcgcccgcac 180ccggccccag tccctcccag gcttgcgggt agagcctgtc tttgcccaga aggccgtctc 240caagct 24662222DNAHomo sapiens 62cagtccccga ggccctcccc ggtgactcta accagggatt tcagcgcgcg gcgcggggct 60gcccccaggc gtgacctcac ccgtgctctc tccctgcaga atctcctacg acccggcgag 120gtaccccagg tacctgcctg aagcctactg cctgtgccgg ggctgcctga ccgggctgtt 180cggcgaggag gacgtgcgct tccgcagcgc ccctgtctac at 222632209DNAHomo sapiens 63agagagacat tttccacgga ggccgagttg tggcgcttgg ggttgtgggc gaaggacggg 60gacacggggg tgaccgtcgt ggtggaggag aaggtctcgg aactgtggcg gcggcggccc 120ccctgcgggt ctgcgcggat gaccttggcg ccgcggtggg ggtccggggg ctggctggcc 180tgcaggaagg cctcgactcc cgacacctgc tccatgaggc tcagcctctt cacgcccgac 240gtcgggctgg ccacgcgggc agcttctggc ttcggggggg ccgcgatagg ttgcggcggg 300gtggcggcca caccaaaagc catctcggtg tagtcaccat tgtccccggt gtccgaggac 360aacgatgagg cggcgcccgg gccctgggcg gtggcaacgg ccgaggcggg gggcaggcgg 420tacagctccc ccggggccgg cggcggtggc ggcggctgca gagacgacga cggggacgcg 480gacggacgcg ggggcaacgg cggatacggg gaggaggcct cgggggacag gaggccgtcc 540aaggagccca cggggtggcc gctcggggcg cccggcttag gagacttggg ggagctgaag 600tcgaggttca tgtagtcgga gagcggagac cgctgccggc tgtcgctgct ggtgcccggg 660gtgcctgagc ccagcgacga ggccgggctg ctggcggaca agagcgagga ggacgaggcc 720gccgacgcca gcaggggagg cgcgggcggc gacaggcggg ccccgggctc gccaaagtcg 780atgttgatgt actcgccggg gctcttgggc tccggtggca gtgggtactc gtgcatgctg 840ggcaggctgg gcagcccctc cagggacagg cgcgtgggcc tcaccgcccg gccgcgctgg 900cccaagaagc cctccgggcg gccgccgcta ggccgcacgg gcgaaggcac tacagggtga 960gggggctgcg tggggccggc cccgaaggcg ctggccgcct ggctgggccc tggcgtggcc 1020tgaggctcca gacgctcctc ctccaggatg cgccccacgg gggagctcat gagcacgtac 1080tggtcgctgt ccccgccaca ggtgtagggg gccttgtagg agcggggcaa ggagctgtag 1140cagcagccgg gaacgcccct gagcggctcc ccgccggggt gcagggctgc ggagaagaag 1200tcgggcgggg tgcccgtggt gaccgcgtcg ctgggggaca cgttgaggta gtccccgttg 1260ggcagcagct tgccatctgc atgctccatg gacagcttgg aaccgcacca catgcgcatg 1320tacccactgt cctcggggga gctctcggcg ggcgagctgg ccttgtagcc gcccccgctc 1380gccgggaatg tcctgcccgc cgcagaggtg ggtgctggcc ccgcaggccc cgcagaaggc 1440acggcggcgg cggcggcggc ggcggccctg ggctgcaaga tctgcttggg ggcggacacg 1500ctggcggggc tcatgggcat gtagtcgtcg ctcctgcagc tgccgctccc actgcccgcg 1560agggccgcgc cgggcgtcat gggcatgtag ccgtcgtctg cccccaggtt gctgctggag 1620ctcctgtggg agccgatctc gatgtctccg tagtcctctg ggtaggggtg gtaggccacc 1680ttgggagagg acgcggggca ggacgggcag aggcggcccg cgctgcccga gaaggtggcc 1740cgcatcaggg tgtattcatc cagcgaggca gaggagggct ggggcaccgg ccgctgccgg 1800gctggcgtgg tcagggagta ggtcctcttg cgcagccctc ggtccaggtc ctgggccgcg 1860tcccccgaga cccggcggta ggagcggcca cagtggctca ggggcctgtc catggtcatg 1920tacccgtaga actcaccgcc gccgccgccg tctcgggccg ggggcgtctc cgcgatggac 1980tcgggcgtgt tgcttcggtg gctgcagaag gcgcgcaggt cgcctgggct ggagccgtac 2040tcgtccaggg acatgaagcc ggggtcgctg ggggagcccg aggcggaggc gctgccgctg 2100gagggccgct ggccggggcc gtggtgcagc ggatgcggca gaggcgggtg cgggccgggc 2160ggcggcgggt aggagcccga gccgtggccg ctgctggacg acagggagc 220964149DNAHomo sapiens 64taacctaaag aatgaagtca tgccccggcc tgcacccggg aaactgcaca cagcgaaaga 60tcgccactga gataaagagc tgaaagctat tccccaattc agctgtttca gccgtgcggt 120ctcacaatgg gctcacagac ggcagcatc 14965832DNAHomo sapiens 65gtttccacaa tccacctcgt agctggggcg tgccgcttgc ctcggcttgt cccggcagaa 60cactcttacc tttaatggcg actgaaaagt tgccacgagt tcctgatcat tgtggtaggt 120gctgcgtgaa gctgagacgt gcgtgagcca catcccaggg ggctttgagc ccccaccgcg 180gcggcggctg aggggaggct tgtcgtactc gcacaggagg acacagggct gcagtgttca 240ctccagggcc tcttatcatt gggatctgag gaattttccg agaggaagtg cgaattaaca 300atgatgaaag gtttgtgagt gagtgacagg cacgttctat tgagcactgc atggggcatt 360atgtgccacc agagacgggg gcagaggtca agagccctcg agggctggga gagttcggag 420gatagaagtc atcagagcac aatgaagcca gaccctgcag ccgccttccc cttcgggggc 480ttccttagaa tgcagcattg cggggactga gctgtcccag gtgaaggggg gccgtcacgg 540tgtgtggacg cccctcggct cagccctcta agagactcgg cagccaggat gggctcaagg 600catgagccct caaaggaggt taggaaggag cgagggagaa aagatatgct tgtgtgacgt 660cctggccgaa gtgagaacaa ttgtatcaga taatgagtca tgtcccattg aggggtgccg 720acaaggactc gggaggaggc cacggagccc tgtactgagg agacgcccac agggagcctc 780gggggcccag cgtcccggga tcactggatg gtaaagccgc cctgcctggc gt 83266256DNAHomo sapiens 66tccagctgca gcgagggcgg ccaggccccc ttctccgacc tgcaggggta gcgcggcctc 60ggcgccggag acccgcgcgc tgtctggggc tgcggtggcg tggggagggc gcggcccccg 120gacgccccga ggaaggggca cctcaccgcc cccacccaga gcgcctggcc gtgcgggctg 180cagaggaccc ctccggggca gaggcaggtt ccacggaaga ccccggcccg ctggggcttc 240cccggagact ccagag 25667184DNAHomo sapiens 67acttactgct tccaaaagcg ctgggcacag ccttatatga ctgaccccgc ccccgagtcc 60caggccgccc catgcaaccg cccaaccgcc caaccgccac tccaaaggtc accaaccact 120gctccaggcc acgggctgcc tctccccacg gctctagggc ccttcccctc caccgcaggc 180tgac 18468118DNAHomo sapiens 68tgccacaccc aggtaccgcc cgcccgcgcg agagccgggc aggtgggccg cggatgctcc 60cagaggccgg cccagcagag cgatggactt ggacaggcta agatggaagt gacctgag 118691534DNAHomo sapiens 69tcgccagcgc agcgctggtc catgcaggtg ccacccgagg tgagcgcgga ggcaggcgac 60gcggcagtgc tgccctgcac cttcacgcac ccgcaccgcc actacgacgg gccgctgacg 120gccatctggc gcgcgggcga gccctatgcg ggcccgcagg tgttccgctg cgctgcggcg 180cggggcagcg agctctgcca gacggcgctg agcctgcacg gccgcttccg gctgctgggc 240aacccgcgcc gcaacgacct ctcgctgcgc gtcgagcgcc tcgccctggc tgacgaccgc 300cgctacttct gccgcgtcga gttcgccggc gacgtccatg accgctacga gagccgccac 360ggcgtccggc tgcacgtgac aggcgaggcg gcgtgggagc gggtccccgg cctcccttcc 420cgccctcccg cctgccccgc cccaagggct acgtgggtgc caggcgctgt gctgagccag 480gaagggcaac gagacccagc cctctcctct accccaggga tctcacacct gggggtagtt 540taggaccacc tgggagcttg acacaaatgc agaatccagg tcccaggaag ggctgaggtg 600ggcccgggaa taggcattgc cgtgactctc gtagagtgac tgtccccagt ggctctcaga 660cgaagaggcg agaaagacaa gtgaatggca atcctaaata tgccaagagg tgcaatgtgg 720tgtgtgctac cagcccggaa agacactcgc agcccctcta cccaggggtg cacagacagc 780ccaccaagta gtgcctagca ctttgccaga ccctgatata caaagatgcc tgaaccaggg 840tcccgtccct agagcagtgg ctctccactc tagcccccac cctgctctgc gacaataatg 900gccacttagc atttgctagg gagccgggac ctagtccaag cacccacaag catgaatttg 960ccaaatcttt tcagcaacct cttaaggcaa ctgctatcat gatcctcact ttacacatgg 1020agaagcagaa gcagagatga tagaatcttt cgcccaaggc cacatctgta ttgggacggg 1080ggcagcctgg cacccaagtg cccattcctc ccttctgacc agcccccacc cctccggctc 1140tggcgtccaa agggctaagg ggaggggtgc ccttgtgaca gtcacccgcc ttctcccctg 1200cagccgcgcc gcggatcgtc aacatctcgg tgctgcccag tccggctcac gccttccgcg 1260cgctctgcac tgccgaaggg gagccgccgc ccgccctcgc ctggtccggc ccggccctgg 1320gcaacagctt ggcagccgtg cggagcccgc gtgagggtca cggccaccta gtgaccgccg 1380aactgcccgc actgacccat gacggccgct acacgtgtac ggccgccaac agcctgggcc 1440gctccgaggc cagcgtctac ctgttccgct tccatggcgc cagcggggcc tcgacggtcg 1500ccctcctgct cggcgctctc ggcttcaagg cgct 153470269DNAHomo sapiens 70atgaacttca agggcgacat catcgtggtc tacgtcagcc agacctcgca ggagggcgcg 60gcggcggctg cggagcccat gggccgcccg gtgcaggagg agaccctggc gcgccgagac 120tccttcgcgg ggaacggccc gcgcttcccg gacccgtgcg gcggccccga ggggctgcgg 180gagccggaga aggcctcgag gccggtgcag gagcaaggcg gggccaaggc ttgagcgccc 240cccatggctg ggagcccgaa gctcggagc 26971282DNAHomo sapiens 71tcagtgttat gtggggagcg ctagatcgtg cacacagtag gcgtcaggaa gtgttttccc 60cagtaattta ttctccatgg tactttgcta aagtcatgaa ataactcaga ttttgttttc 120caaggaagga gaaaggccca gaatttaaga gcaggcagac acacaaccgg gcacccccag 180accctggccc ttccagcagt caggaattga cttgccttcc aaagccccag cccggagctt 240gaggaacgga ctttcctgcg cagggggatc ggggcgcact cg 28272142DNAHomo sapiens 72gtggaaacac aacctgcctt ccattgtctg cgcctccaaa acacaccccc cgcgcatccg 60tgaagctgtg tgtttctgtg ttactacagg ggccggctgt ggaaatccca cgctccagac 120cgcgtgccgg gcaggcccag cc 14273741DNAHomo sapiens 73tccacacctc gggcagtcac taggaaaagg gtcgccaact gaaaggcctg caggaaccag 60gatgatacct gcgtcagtcc cgcggctgct gcgagtgcgc gctctcctgc cagggggacc 120tcagaccctc ctttacagca caccgagggc cctgcagaca cgcgagcggg ccttcagttt 180gcaaaccctg aaagcgggcg cggtccacca ggacgatctg gcagggctct gggtgaggag 240gccgcgtctt tatttggggt cctcgggcag ccacgttgca gctctggggg aagactgctt 300aaggaacccg ctctgaactg cgcgctggtg tcctctccgg ccctcgcttc cccgaccccg 360cacaggctaa cgggagacgc gcaggcccac cccaccggct ggagaccccg gcacggcccg 420catccgccag gattgaagca gctggcttgg acgcgcgcag ttttcctttg gcgacattgc 480agcgtcggtg cggccacaat ccgtccactg gttgtgggaa cggttggagg tcccccaaga 540aggagacacg cagagctctc cagaaccgcc tacatgcgca tggggcccaa acagcctccc 600aaggagcacc caggtccatg cacccgagcc caaaatcaca gacccgctac gggcttttgc 660acatcagctc caaacacctg agtccacgtg cacaggctct cgcacagggg actcacgcac 720ctgagttcgc gctcacagat c 741744498DNAHomo sapiens 74ctgccctcgc ggatctcccc cggcctcgcc ggcctccgcc tgtcctccca ccaccctctc 60cgggccagta ccttgaaagc gatgggcagg gtcttgttgc agcgccagtg cgtaggcagc 120acggagcaga ggaagttggg gctgtcggtg cgcaccagct cgcccgggtg gtcggccagc 180acctccacca tgctgcggtc gccgctcctc agcttgccgg ccagggcagc gccggcgtcc 240ggggcgccca gcggcaacgc ctcgctcatc ttgcctgggc tcagcgcggt ggaaggcggc 300gtgaagcggc ggctcgtgct ggcatctacg gggatacgca tcacaacaag ccgattgagt 360taggaccctg caaacagctc ctaccagacg gcgacagggg cgcggatctt cagcaagcag 420ctcccgggag accaacatac acgttcaggg gcctttatta ctgcgggggg tggggggggg 480cgggggtggt taggggagga gggagactaa gttactaaca gtccaggagg ggaaaacgtt 540ctggttctgc ggatcggcct ctgacccagg atgggctcct agcaaccgat tgcttagtgc 600attaaaaagt ggagactatc ttccacgaat cttgcttgca gaggttaagt tctgtctttg 660gctgttagaa aagttcctga aggcaaaatt ctcatacact tcctaaaata tttatgcgaa 720gagtaaaacg atcagcaaac acattatttg gaagttccag tagttaatgc ctgtcagttt 780tttgcaggtg agttttgtct aaagtcccaa cagaacacaa ttatctcccg taacaaggcc 840acttttatca tgcaaaactg gcttcagtcc cgaaaagcaa gagctgagac ttccaaaggt 900agtgctacta atgtatgtgc acgtatatat aaatatatac atatgctcta cttcataaaa 960tatttacaat acaatctgtg gagaatttaa acacaacaga aatccattaa tgtacgctgc 1020agattttttt aagtagcctt gaaaatcagc ttcagtagtt ggagcagtgc tgagctagaa 1080gtacttgtca tgttctctgt tctctcaatg aattctgtca aaacgctcag tgcagaaaat 1140tcagcgtttc agagatcttc agctaatctt aaaacaacaa tcataagaag gcccagtcga 1200tgacactcag ggttctacag ctctcccaca tctgtgaact cgggtttggg gatgttggtt 1260aagtttgtgg ctggtcctct ggtttgttgg gagttgagca gccgcagagt cacacacatg 1320caaacacgca ctcttcggaa ggcagccact gtctacatca gctgggtgac tcagccctga 1380ctcgggcagc agcgagacga tactcctcca ccgtcgccca gcacccgccg gttagctgct 1440ccgaggcacg aacacccacg agcgccgcgt aaccgcagca ggtggagcgg gccttgaggg 1500agggctccgc ggcgcagatc gaaacagatc gggcggctcg ggttacacac gcacgcacat 1560cctgccacgc acactgccac gcacacgcaa cttcacggct cgcctcggac cacagagcac 1620tttctccccc tgttgtaaaa ggaaaacaat tggggaaaag ttcgcagcca ggaaagaagt 1680tgaaaacatc cagccaagaa gccagttaat tcaaaaggaa gaaaggggaa aaacaaaaaa 1740aaacaacaaa aaaaggaagg

tccaacgcag gccaaggaga agcagcagag gttgacttcc 1800ttctggcgtc cctaggagcc ccggaaagaa gtgcctggcg gcgcagggcc gggcagcgtg 1860gtgccctggc tgggtccggc cgcggggcgc ccgtcccgcc cgcgcccgct ggctctatga 1920atgagagtgc ctggaaatga acgtgctttt actgtaagcc cggccggagg aattccattc 1980cctcagctcg tttgcatagg ggcggccggc ggccaatcac aggcctttcc ggtatcagcc 2040agggcgcggc tcgccgccgc cggctcctgg aattggcccg cgcgcccccg ccgccgcgcc 2100gcgcgctact gtacgcagcc cgggcgggga gtcggaggcc acccccgcgc cccgcatcca 2160agcctgcatg ctggcccggg gccccgcccg cgtgcggacc cctttccgca gccacacgca 2220ggcttgtgcg gctccgcgag tggccacggt ccggagacct ggaaaaagaa agcaggcccc 2280gccggcccga ggaggacccg gccggcgcgc cgcacccgga gaggcccggc cccgcgagcc 2340gctgcaggca ggcgcagtgg ccgccacgag gctcccgaac cgggctgcag cccgcggacg 2400gccccagatc ctgcgcggcc gcccagggcc aggcctccgc ttccagggcg ggggtgcgat 2460ttggccgcgg ggcccggggg agccactccg cgctcctgca ccgtccggct ggcagctgcg 2520gcgaagcggc gctgattcct tgcatgaggc cggacggcgt ccgcgcgtgc cgtttgctct 2580cagcgtcttc ccttgggtcg gtttctgtaa tgggtgtttt ttaccgctgc gcccgggccg 2640cggctcgatc cctccgcgcg tctcacttgc tgcgtgcgtc agcggccagc gaagagtttc 2700ctagtcagga aagaccccaa gaacgcgcgg ctggaaggaa agttgaaagc agccacgcgg 2760cttgctcccg ggccttgtag cgccggcacc cgcagcagcc ggacagcctg cccgggcccc 2820gcgtctcccc tccggctccc cggaagcggc ccccgctcct ctccccgccc ccgtgcgctc 2880gagcggcccc aggtgcggaa cccaccccgg cttcgcgtgc gggcggccgc ttccccctgc 2940gccggtcccc gcggtgctgc gggcattttc gcggagctcg gagggccccg cccccggtcc 3000ggcgtgcgct gccaactccg accccgcccg gcggggctcc ctcccagcgg aggctgctcc 3060cgtcaccatg agtccctcca cgccctccct gccgggccct gcacctcccg gggcctctca 3120tccaccccgg ggctgcaacc cagtccccgg atcccggccc cgttccaccg cgggctgctt 3180tgtggtcccc gcggagcccc tcaattaagc tccccggcgc gggggtccct cgccgacctc 3240acggggcccc tgacgcccgc tcctccctcc cccagggcta gggtgctgtg gccgctgccg 3300cgcagggact gtccccgggc gttgccgcgg gcccggacgc aggagggggc cggggttgac 3360tggcgtggag gcctttcccg ggcgggcccg gactgcgcgg agctgtcggg acgcgccgcg 3420ggctctggcg gacgccaggg ggcagcagcc gccctccctg gacgccgcgc gcagtccccg 3480gagctcccgg aacgcccccg acggcgcggg gctgtgcggc ccgcctcgtg gccttcgggt 3540cgcccgggaa gaactagcgt tcgaggataa aagacaggaa gccgccccag agcccacttg 3600agctggaacg gccaaggcgc gtttccgagg ttccaatata gagtcgcagc cggccaggtg 3660gggactctcg gaccaggcct ccccgctgtg cggcccggtc ggggtctctt cccgaagccc 3720ctgttcctgg ggcttgactc gggccgctct tggctatctg tgcttcagga gcccgggctt 3780ccggggggct aaggcgggcg gcccgcggcc tcaaccctct ccgcctccgc tccccctggg 3840cactgccagc acccgagttc agttttgttt taatggacct ggggtctcgg aaagaaaact 3900tactacattt ttcttttaaa atgatttttt taagcctaat tccagttgta aatccccccc 3960tccccccgcc caaacgtcca ctttctaact ctgtccctga gaagagtgca tcgcgcgcgc 4020ccgcccgccc gcaggggccg cagcgccttt gcctgcgggt tcggacgcgg cccgctctag 4080aggcaagttc tgggcaaggg aaaccttttc gcctggtctc caatgcattt ccccgagatc 4140ccacccaggg ctcctggggc cacccccacg tgcatccccc ggaacccccg agatgcggga 4200gggagcacga gggtgtggcg gctccaaaag taggcttttg actccagggg aaatagcaga 4260ctcgggtgat ttgcccctcg gaaaggtcca gggaggctcc tctgggtctc gggccgcttg 4320cctaaaaccc taaaccccgc gacgggggct gcgagtcgga ctcgggctgc ggtctcccag 4380gagggagtca agttccttta tcgagtaagg aaagttggtc ccagccttgc atgcaccgag 4440tttagccgtc agaggcagcg tcgtgggagc tgctcagcta ggagtttcaa ccgataaa 449875453DNAHomo sapiens 75ttcggaagtg agagttctct gagtcccgca cagagcgagt ctctgtcccc agcccccaag 60gcagctgccc tggtgggtga gtcaggccag gcccggagac ttcccgagag cgagggaggg 120acagcagcgc ctccatcaca gggaagtgtc cctgcgggag gccctggccc tgattgggcg 180ccggggcgga gcggcctttg ctctttgcgt ggtcgcgggg gtataacagc ggcgcgcgtg 240gctcgcagac cggggagacg ggcgggcgca cagccggcgc ggaggcccca cagccccgcc 300gggacccgag gccaagcgag gggctgccag tgtcccggga cccaccgcgt ccgccccagc 360cccgggtccc cgcgcccacc ccatggcgac ggacgcggcg ctacgccggc ttctgaggct 420gcaccgcacg gagatcgcgg tggccgtgga cag 45376560DNAHomo sapiens 76acgcacactg ggggtgtgat ggaaaggggg acgcgatgga taggggtggg cgcacactgg 60gggacgcgac ggggaggggt gagcacacac tgggggtgtg atggagaggg cgacgcaata 120gggaggggtg ggcgcacacc agggacgcga tgatggggac gggtgggcgc acaccaggtg 180gcatgatggg gaggagtggg tacacaccat ggggggcgtg atggggaggc gtgggcgtac 240accggggggc gcgatgggga ggggtgggcg cacaccgggg gacgcgatgg aggcggtggg 300tgcacacggg gcgcgatggg tgggagtagg tgcacactga gggcacgatt ggggagacac 360gaaggagagg ggtgggcgca cactggggga cgcgatggcc gggacacgat gcggagaagt 420gggtgaatac cggggtcgcg atgggcgccc tggaaggacg gcagtgctgc tcacaggggc 480caggcccctc agagcgcgcc ccttgggggt aaccccagac gcttgttccc gagccgactc 540cgtgcactcg acacaggatc 56077157DNAHomo sapiens 77ccacagggtg gggtgcgccc acctgccctg tccatgtggc cttgggcctg cgggggagag 60ggaatcagga cccacagggc gagccccctc cgtagcccgc ggcaccgact ggatctcagt 120gaacacccgt cagcccatcc agaggctaga aggggga 15778114DNAHomo sapiens 78ttgaggtctc tgtgcatgct tgtgcgtacc ctggactttg ccgtgagggg tggccagtgc 60tctgggtgcc tttgccagac aactggtctg ccgggccgag cattcatgct ggtc 11479104DNAHomo sapiens 79tgacgcgccc ctctccccgc agctccacct ggttgcgctc aacagccccc tgtcaggcgg 60catgcggggc atccgcgggg ccgacttcca gtgcttccag cagg 10480659DNAHomo sapiens 80aacacactgt ctcgcactag gtgctcgcgg aagagcgcgg cgtcgatgct gcggctcagg 60ttgatgggcg atggcggccg cagatccagc tcgctcagcg atggcgccgg tcccacaccg 120ttgcgggaca gtcccgggcc accctggggt ccgcgaccca acgacgcagc cgagccccag 180gcgcctgaac tgggcgtggc cagctgccca ctctccgccg ggttgcggat gaggctcttg 240ctgatgtcca agctgcctgc accaacgttg ctgggccctg catagcagtt attgggtcgc 300tccggcacct cgctctttcc tgacggcgcc gggcacgcca gacgcatcag cttagcccag 360caagcgtgct ccgtgggcgg cctgggtctc gcggcagcca ccgcggccaa cgccagggcg 420agcgcccatg tcagctccag gaggcgcagc cagaagtgga caccccacca ggcccacgag 480aagcggccca cgcggcctgg gcccgggtac agccagagcg cagccgccag ctgcaagccg 540ctagccagca gccccagcgc gcccgccaca gccaacagcc gagggcccgg gctggcatcc 600cagccccgtg ggccgtccag caggcggcga cggcacaggc agagcgtgcc cagagccac 65981813DNAHomo sapiens 81gtctgcacga agcccgcggc ggcctgcagg gggcccagcg actcgtccag ggaaccggtg 60cgcaggagca gccgggggcg cggcgcgccg gccgcccttg ggggactctg gggccggggg 120cgcagctcga tctgacgctt gggcactgtc cggggcctgg cgggcgcggc gccctcctcc 180agagccacct ccacacactc gaactgcgct ggggcggcag gacttggccc acggggccgc 240agctctaggt aggtggccca gcgggagcca ccatcgggga cctgggactg gcgtgggacc 300gcggcgggag acgctggccc cggcggcaag gggctgatga aggccggctc cgtgaactgt 360tgttgcgcct cgcgatcgtc tgcgccggag cagccgaaca ggggtccgac gccgaagatg 420acttccatct cccccgacgg cagcgtgcgc agctggggct ggggtggccg tgggccggaa 480cctgggcctc gcgggaaacc cgagccgggc ccgtgccgct ggcggctatt ctgggcgctg 540acggacaggc gaggctgcgc gcccgccccc cgcccaggag ccacccaggg ccaattcgct 600gggcctttcg cgtccggccc aacgtccggg ggctccggag aacctggagc cgtgtagtag 660gagcctgacg aaccggagga gtcctggcgc cgcgcggggg ccgtgggcag ctgcctcggg 720atcccaggca gggctggcgg ggcgagcgcg gtcagcatgg tggggccgga cgccgtgcac 780tatctccctc gcattcgcct ccgctggtgg cgc 81382440DNAHomo sapiens 82ctggagagaa ctatacgggc tgtgggagtc accgggcgac tatcaccggg cctcctttcc 60acatcctcct ccgggaaggg accccgttcc gggcctcgac cggcgcagac tgggctgacc 120cactttcttg ggcccactga gtcacctcga aacctccagg ccggtagcgg ggaggagagg 180aggagcaggc gggggtgcca aggtgtgggc tgcgccctgg ttagggggcg agcccggctt 240gtttatgagg aggagcgcgg aggaggatcc agacacacag gcttgcgcgc ccagactcgc 300ccggccagcg gctggcggcc tccgacgtca ccaaaccggt tgggtgagag ggcagagagc 360agggggaagg gccgcagtcc cgcccgcgcc ccccggcacg caccgtacat cttgccctcg 420tctgacagga tgatcttccg 44083252DNAHomo sapiens 83gagtgcggag tgaaggggtg cactgggcac tcagcgcggc ccttgggagg cagggccgcc 60ccagcctgcc ctcctgtctg ggaaggccgt ccagaagcag gagccccggg gaaaacaact 120ggctggacgg ggcggccttc agtgtctctc ccagcctgag agtcgcttcc caccacctgg 180gcacgaacct gctctgcgat ctccggcaag ttcctgcgcc tcctgtcggt aaaatgcaga 240tcgtggcgtc tt 252841539DNAHomo sapiens 84tcttctttcc gcccctaggg ggcacaagcg ggcatgtcca agcgcctagg agcccgtacc 60gctggggacc tccccttccg cgaaccccga gcgggtagac ccagagcaat ccgagtgtgg 120aaacaatgga gagggggcgt gttgagctgg ggtctccatg cctcgttggg gagagggagg 180tgagtttgtg tcttctggaa ggcgtggggg ctgtgccctc gtgggggtag gaagtgctcc 240cgtggggcgg ggtgcggatc ggagaggtga gtgggtgcgt ctgtccagcg gtccgcccgg 300tgtggtcgtg cccggcccgc gtggggatgg gggtgtctct cccgctgggc aactatacca 360gcgcaaccgg ggcgtcggcg cggcccacgc tagcggcgct gctccggcgg cgggggctgg 420gcgtggcggt gatgctgggc gtggtggccg cgctgggcgt ggtggccgcg ctgccgccct 480cacccgggca gccgtgctgg agaaggatgt cggcgcacag ctggcttcca gcctggcggg 540cgtagaacag cgccgtgcgg ccctgggcgt cacgggccgc cacgtccgcg ccgtactaga 600gggcggaaac ggccgcgtga ccgcgcgtcc ccagggcgcc cacacccggc gccgcctccc 660ccacatggcc aagcctactt ccggggtccc tctgggaatt tcgggctttc ccgcgccagg 720cgttttccga gatgaagcct caaagacccc ctttcctccc cccagctcac gtacccacag 780cagcagttgc gtgatgacga cgtgggcgag ctcggccgcc aggtggagtg gggagcgcag 840ctgtgggtcc tctacgctgg tgtcgagcgg cccgtgtcgc gcatgggcca aaagcaggag 900aacggtagcc acgtcctggg cctgcacggc ggcccacagc tggcggccca gcggctcctc 960cgaggtgctc agcggcgcca ggaacagtag ctgctcgtac ttggcgcgaa tccacgactc 1020gcgctcctcc ctgcaagacc agggatcaac ggaaaaggct ctagggaccc ccagccagga 1080cttctgcccc tacccacggg accgtctcag gttcgcacac cctcagcaac cctccccccg 1140ctctgttccc tcacgcttac cgcgaagagt cccgcgaggg cttggcacgg cctcgcgtgt 1200cgctttccca cacgcggttg gccgtgtcgt tgccaatagc cgtcagcacc agggtcagct 1260cccgtggcca gtcgtccaag tccagcgagc gaacgcggga caggtgtgtg cccaggttgc 1320ggtggatgcc agaacactcg atgcagatga gggcgcccag gttcaagctg gcccacgtgg 1380ggtctgcgga aggagcgtag aggtcggctc ccagccgggc agcacaggca ccccggcatt 1440cactacactc cctagcccct ccgctgcctc ctggcactca ctgggggccc cgcagtccac 1500gcagattgaa ttccccttgg cgttccggat cgcctggat 1539852648DNAHomo sapiens 85agccaggtcc agcccccgcg cctgacaccg gccggacgtt cccggggcgc cgcagctgcg 60gcgggaactc tgggatccgg agccatctgc tcccacccgc tccggagcca aaccccgggg 120gccgcctccg ctcccggacc cgcctcctct cccgggagtg tgagccgaac caagagtctc 180ctgcctatct cctccagtag gaaaatagta ataataatag acaccctgcc cccgtaaaaa 240acactacctt ccccgtaccg cctcccaagt ctcccggggt acggattgcc tttgcagcag 300ttccgcccca cctgactcac tccagggtca gccccgggtg ggtttcaatg cggctctggg 360gagggggtgg gcagtggggg aagtgaggct tcctatccgc cccctctcac ttcacattta 420aatattctgc acgttccagc ccccgcggac tcgcgtaccg cccaatccgc cttcaccgca 480cgaaaaacat cactagcctg ctctcagccc aggggacgac tagtccctgg cgagaagctg 540cctgcaaggt cactgtcatg ccacctgccc caagtgctca ggggaaactg aggcttcctc 600atccccttca ccttcaacgt cgctctaaac acggcaaagc cccgtttcca tgctcccaga 660gttcagctga ggctggaagt ggggtcctgg gcttctctgg gagcaatttt ctagtcactc 720tgatcaagga cgttactttc ccagaaagct ctgaggctga gtccctctga aatcaagtcc 780tttctcctgt cgcacaatgt agctactcgc cccgcttcag gactcctatt ctttgcccca 840atccttgaca gaggggtgag cttggttcat ccgcccaccc cagagaaaag cttccctagt 900ttcctggacc tcgctcctcc accccaagct gagcattcca ggtacccttc cctccctgtt 960ctcaagccct gactcaactc actaggggaa gcgcggagct cggcgcccag cagctccctg 1020gacccgctgc cagaagacag gctggggggt ccgggaaggg gcccggagcc aggaggccct 1080cctgtgctct tggtgaagat gccgctgata aacttgagca tcttgcggtc acgagtggat 1140gctcggcccc cctcccggcc ccgtttcagc cccggagctg gaggctccag agtgattgga 1200ggtgcaggcc cggggggctg cgcggaagca gcggtgacag cagtggctgg actcggagtt 1260ggtgggaggg ttagcggagg aggagagccg gcaggcggtc ccggatgcaa gtcactgttg 1320tccaaggtct tactcttgcc tttccgaggg gacaacttcc ctcgggctcc agccccagcc 1380ccgaccccac cagaggtcga agctgtagag ccccctcccc cggcggcggc ggcggtggcg 1440gcggcagaga ccgaagctcc agtcccggcg ctgctctttg accccttgac cctgggcttg 1500ccctcgcttt cgggccatga caggcggcta cccgcgccct tgcccccgcc ggctttggct 1560ccactcgtgg tcacggtctt gcaaggcttg ggagccggcg gaggaggcgc caccttgagc 1620ctccggctgc cggtgccagg gtgcggagag gatgagccag ggatgccgcc gcccgcccgg 1680ccttcgggct ccgggccgcc ccagctcggg ctgctgagca gggggcgccg ggaggaggtg 1740ggggcgcccc caggcttggg gtcggggctc agtcccccgg agagcggggg tcccggaggg 1800acggcccaga gggagaggcg gcggccggga gcgggggaga ctgggcgggc cggactggcc 1860ggagccgggg acagggctgg gggctccgcg cccccggtgc ccgcgctgct cgtgctgatc 1920cacagcgcat cctgccggtg gaagagacgt tcgtgccgct tcttgcccgg ctcctccgcg 1980cctcgggggc tgccaggatc cccagtctcg gagcctctgg caccggcggc gccggccgcg 2040gccgcagacg gagaaggcgg cggcggaggc accgactcga gcttaaccag ggtcagcgag 2100atgaggtagg tcgttgtccg gcgctgaagc gcgcccgcgc cccggctcat ggggcccgga 2160gacccccgag ctggggaggg gaggggactc ccccggactg cctcaggggg gcccggccat 2220ggggccgccc tgctcgctgc ccccagcccc cggaccccgc tgagcccccg gcccggctcc 2280gctgtcgccg ccgcctccgc cgcctccgct tgcgcccccc tcccatcaca tggggcgccc 2340cctccccatg ctccccgccc tgcgccccca ccctcttgga gccccgggac cttggtgctg 2400ctccagggag gcgcgccgga ccgtccaccc cggcctgggt gggggcgctg agatgggtgg 2460gggagggcgg ggaggacagt agtgggggca aatgggggag agagaggaaa agggagcaga 2520aaaggggacc ggaggctagg ggaaacgaac ctgtgcgggg gaggcagggg cggggaattg 2580ggactcaagg gacaggggcc gcggatgcgg tcggaaagag ggtctagagg agggtgggaa 2640gctagtgg 264886452DNAHomo sapiens 86aggagcgcaa ggcttgcagg gcatgctggg agagcgcagg gaacgctggg agagcgcggg 60aaatactggg attggctccc gagggctgtg aggagggcac gaggggacac tccgatgaag 120gcagggcacg cggggcgagc cgggagcgtc tcctgagggc agcgaggagg gagctgaggc 180acgcgggctc tcaatcgacg ccccacagag accaagaggc ctggccttgg ggggcagctg 240cttgaaggag gcagagcgga agcgagggag actgctggag gccctgccgc ccacccgccc 300tttcctcccc ctgaggagac gcctgacgca tctgcagtgc aggaggccgt gggcgttaga 360agtgttgctt ttccagtttg taagaccatt ttcctgattc tcttccccac ggttgcggag 420gagcaggtca gggccgccat gagggcagga tc 45287232DNAHomo sapiens 87tcgaccgcta ctattatgaa aacagcgacc agcccattga cttaaccaag tccaagaaca 60agccgctggt gtccagcgtg gctgattcgg tggcatcacc tctgcgggag agcgcactca 120tggacatctc cgacatggtg aaaaacctca caggccgcct gacgcccaag tcctccacgc 180cctccacagt ttcagagaag tccgatgctg atggcagcag ctttgaggag gc 23288221DNAHomo sapiens 88tgtgccgtcg cacacagacg ccctcaacgt cggagagctg tgagcggggc cgtgctcttg 60ggatgggagc ccccgggaga gctgcccgcc aacaccactc cgacgtgatc catgctggac 120ataaagtgct cttccctccg ctagtcatcg gccgagcggg cccctcgctc ctgggtgtaa 180gttctttctg tgcgtccttc tcccatctcc gtgcagttca g 22189477DNAHomo sapiens 89ccatgcgccg ctgcgcgcgc gagttcgggc tgctgctgct gttcctctgc gtggccatgg 60cgctcttcgc gccactggtg cacctggccg agcgcgagct gggcgcgcgc cgcgacttct 120ccagcgtgcc cgccagctat tggtgggccg tcatctccat gaccaccgtg ggctacggcg 180acatggtccc gcgcagcctg cccgggcagg tggtggcgct cagcagcatc ctcagcggca 240tcctgctcat ggccttcccg gtcacctcca tcttccacac cttttcgcgc tcctactccg 300agctcaagga gcagcagcag cgcgcggcca gccccgagcc ggccctgcag gaggacagca 360cgcactcggc cacagccacc gaggacagct cgcagggccc cgacagcgcg ggcctggccg 420acgactccgc ggatgcgctg tgggtgcggg cagggcgctg acgcctgcgc cgcccac 477901200DNAHomo sapiens 90gtcctaacat cccaggtggc ggcgcgctgg ctccctggag cggggcggga cgcggccgcg 60cggactcacg tgcacaaccg cgcgggacgg ggccacgcgg actcacgtgc acaaccgcgg 120gaccccagcg ccagcgggac cccagcgcca gcgggacccc agcgccagcg ggaccccagc 180gccagcggga ccccagcgcc agcgggaccc cagcgccagc gggaccccag cgccagcggg 240tctgtggccc agtggagcga gtggagcgct ggcgacctga gcggagactg cgccctggac 300gccccagcct agacgtcaag ttacagcccg cgcagcagca gcaaagggga aggggcagga 360gccgggcaca gttggatccg gaggtcgtga cccaggggaa agcgtgggcg gtcgacccag 420ggcagctgcg gcggcgaggc aggtgggctc cttgctccct ggagccgccc ctccccacac 480ctgccctcgg cgcccccagc agttttcacc ttggccctcc gcggtcactg cgggattcgg 540cgttgccgcc agcccagtgg ggagtgaatt agcgccctcc ttcgtcctcg gcccttccga 600cggcacgagg aactcctgtc ctgccccaca gaccttcggc ctccgccgag tgcggtactg 660gagcctgccc cgccagggcc ctggaatcag agaaagtcgc tctttggcca cctgaagcgt 720cggatcccta cagtgcctcc cagcctgggc gggagcggcg gctgcgtcgc tgaaggttgg 780ggtccttggt gcgaaaggga ggcagctgca gcctcagccc caccccagaa gcggccttcg 840catcgctgcg gtgggcgttc tcgggcttcg acttcgccag cgccgcgggg cagaggcacc 900tggagctcgc agggcccaga cctgggttgg aaaagcttcg ctgactgcag gcaagcgtcc 960gggaggggcg gccaggcgaa gccccggcgc tttaccacac acttccgggt cccatgccag 1020ttgcatccgc ggtattgggc aggaaatggc agggctgagg ccgaccctag gagtataagg 1080gagccctcca tttcctgccc acatttgtca cctccagttt tgcaacctat cccagacaca 1140cagaaagcaa gcaggactgg tggggagacg gagcttaaca ggaatatttt ccagcagtga 120091900DNAHomo sapiens 91caccttcccc gaggtaatta ttttctgggg ggtaggggtg ggggttggga gggtgaagaa 60aggaagaaaa agaaggccga tcacactggg caccggcgga ggaagcgtgg agtccattga 120tctaggtact tgtggggagg ggagaacccg agcagcagct gcaaacggaa gggctgtgag 180cgagcgggcg ggcgggtggc tggcagcgag gccaccagca gggggggccc gggccgaggc 240cgcgccacct cggcaccacg cgggcagccg gtgcggcggg gtcgccacgg ccaggggagc 300gctgggtgcc caccatggca gttatgcaag cggtgacccc ctggtcttgc ctccccgccg 360ccctgcactc cttcctcccc gctgccgaca cttggatctc tctagctctt tctctcccct 420gtgttttcaa acaggaagtg cacggctgtc tataacgtgc tgccgggtct caggatggag 480gagtgaagtc tcctgtcgcc gtggttccag cctccggagc tcgcccaagc cgcgtcccca 540gagagcgccc tgagagaaca gggtggccgc ttggtccagg tgcgcggggt cgggtctggg 600tccagggagc gggtcgggaa gtctgcggca cggagcactg ctagtgtcgg atctgcatct 660ccagctctgt gctgcagctt cacttgcccg ccccccacca ctggcttctc acccggggtc 720tctgccaaac tctggctgct gccgccctgg gttcgggccg gcggaaggcc ctgggcgtgc 780gctgcggagc cgcctgcgag gactccacta gggcgctttc caggctggac tgccccgggc 840tgcgctggag ctgccagtgc tcggggagtc ttcctggagt ccccagctgc cctctccacc 90092200DNAHomo sapiens 92ctcttcccaa gttacgccac cggtcgagga cggcaggaga cccccgagtg cagagaaagc 60tcaaaccggc agcgaagtcg gtcctagcca agctgaaaaa acgtctcgga tttcgcggac 120agcggcctag acacagcccg atcttccagt cctagtgccc tggtcgagac ggttctatcc 180ttttgcaaag aagccggaaa 20093400DNAHomo sapiens 93tctcggttgc aatccccacc ctcctcaccc agcagggcag gaggcaccca acttggagga 60gaaaggggtg ggggaggtga aacagagacc ggagagtcac gagggctggg ccgccgagag

120caggagaata taccgtgtca cacacctcca ttctctcaca cacgttgcag acacaaatca 180ctgacggttt ccacgtgctg cgctcgtgag cggaggtgtt caaagagggg gcagatgagt 240tacttcccga gacggaaccg ggggtcccac gtccgccgcc ttcagtagca caaccaatct 300ctgaacactc aaaccgcgca tctctggcgc atcaccatcc tatttaaggc cacgggctcc 360gcccttttcc tcccctccct tcttttccac tctttttcca 40094700DNAHomo sapiens 94ctgccagaga tgtgtctgtc ttgcgccccg catgcactgc ctgcggggct gcgctgcact 60ccccggcggc gccacgggtc tggcccccgc gcttctacgt gttgggggga tgcatggacc 120ttggagatcc gtagttggcc ctaaccttct cggaatctcc tctgcacgcg ctgcctgttc 180ctcctctgca cgctctgtcc gttcctttgc aacttctgtg ggaattgtcc tggcgtggga 240aacgcccccg cgctctttgg cacttagggt gtgagtgttg cgccccttgc cgcagcgctc 300agggcagcat cccgctcgag gatgcagggt tctcaccaag cagtgagggg gactcacgcg 360ccgccgggga gcggagccag gctccgagaa gggagcaggc tcgagccgct gggttttcgc 420aagccttggg gcctctggcc gcccttccat gcctccgggc gcgggcggct cagcaggtcc 480ccggcttcgg gaagttttgt gcgcggatcg ctggtgggga gggcgcgcgg gccagtggct 540gagcttgcag cgaagtttcc gtgaaggaaa ctgcatgtgc ctttggaggc gactcgggac 600tgctgtaggg tggactgggt gtctatggag ttgcgggtca gagcgagtag ggtgggtcct 660ttcctgggac aggactggga attggggctc gaagtagggg 70095200DNAHomo sapiens 95aggggtgtcc tccaacatct ctgaaccgcc ttcccttcct cctcactggc gccctcttgc 60ctcagtcgtc ggagatggag aggcggctga agattggcag gcggcggcca gggtcgaggc 120tgggagactc agagccgctg aggctgccgg agctcaggga gccgcttagg tagctgtcgc 180ggtccgacag cgagtccggg 200965000DNAHomo sapiens 96tctgactctc gggctggagc agccgagaca gcgctcccca gcgggactac agaatcccgg 60gtgtcggcct gggggccctg gattggcagt ggtggagtct tctgagccta acagctacta 120ggaatgacag agttgcagat ggctttgtcg cccgcggggc ggctcaagcg tcctgggtcc 180caggcctctg tcctacggcc aggccgccgg ctcaacgggc cgaagggaat cgggctgacc 240agtcctaagg tcccacgctc ccctgacctc agggcccaga gcctcgcatt accccgagca 300gtgcgttggt tactctccct ggaaagccgc ccccgccggg gcaagtggga gttgctgcac 360tgcggtcttt ggaggcctag gtcgcccaga gtaggcggag ccctgtatcc ctcctggagc 420cggcctgcgg tgaggtcggt acccagtact tagggaggga ggacgcgctt ggtgctcagg 480gtaggctggg ccgctgctag ctcttgattt agtctcatgt ccgcctttgt gccggcctct 540ccgatttgtg ggtccttcca agaaagagtc ctctagggca gctagggtcg tctcttgggt 600ctggcgaggc ggcaggcctt cttcggacct atccccagag gtgtaacgga gactttctcc 660actgcagggc ggcctggggc gggcatctgc caggcgaggg agctgccctg ccgccgagat 720tgtggggaaa cggcgtggaa gacaccccat cggagggcac ccaatctgcc tctgcactcg 780attccatcct gcaacccagg agaaaccatt tccgagttcc agccgcagag gcacccgcgg 840agttgccaaa agagactccc gcgaggtcgc tcggaacctt gaccctgaca cctggacgcg 900aggtctttca ggaccagtct cggctcggta gcctggtccc cgaccaccgc gaccaggagt 960tccttcttcc cttcctgctc accagccggc cgccggcagc ggctccagga aggagcacca 1020acccgcgctg ggggcggagg ttcaggcggc aggaatggag aggctgatcc tcctctagcc 1080ccggcgcatt cacttaggtg cgggagccct gaggttcagc ctgactttcc cgactccgcc 1140gggcgcttgg tgggctcctg ggcttctggg ctcaccctta cacctgtgta ctaaagggct 1200gctaccctcc cgaggtgtac gtccgccgcc tcggcgctca tcggggtgtt ttttcaccct 1260ctcgcggtgc acgctttttc tctcacgtca gctcacatct ttcagtacac agccactggg 1320tctccctgcc cctccagcct ttcctaggca gctttgaggg cccagacgac tgaagtctta 1380ctgctaggat gggaacacga tgaaaaagga aggggcccag tcaaaagtcc tctcctcttc 1440ggtttttctt caactgtcct tcacaaaaac atttatttct gtcccagcgc cctggcggat 1500ttcggcagat gggccctagg gggttgtgga ggccaaattc ccaggatgct ggtcctgcct 1560ttttcattgg ccaaaactgt atttcctaca acgactaaag ataaccaaga actgagtaga 1620ccctgttctc tcaccagatc tccctggctc tgtttaactt ttcctggtgc aatgcgatgg 1680caccaccagc tccccaggca ggcaccactc cctcaagata ccatttgggg tagggatttg 1740agtcctggag agggtcagcg gggcgccggg gtgggggtgg gaaggagact gacagggaca 1800caccgcgagc tccgcatact ctcctctgcc ccctgtagcc cggggcttta atgaccccaa 1860gcagatttcc tgtctctggt ctagccagct gcccctaggg ctggatttta tttcttcatg 1920gggtttcacc ctaaagggcc ccctggtcat gggacctggt tgggaacaaa tgaaagatgt 1980cttgtagcaa atgctttcag gggagcagaa aagaagattg ggcacttcca gtcacttggt 2040cactttaggt ggctggaaca aaactggtga ctttcacgac tgctacaggg tgagggggtg 2100aagggtggca gagaggtgac aagccactgg gaatcctatt cagtggggat gccgacaggg 2160agtggctgta atcaactgag caacatctgt gtgaatgtta ttcacaggtc aggacagcag 2220cttggtcttc ccaggtgagg aactgaggac tggcctgcat agatttgtgc agtaggtgag 2280tagcttccaa atttattttc agaacttcca tgtagtacct gcctctccat ttaaatattt 2340tttaaaattt tatttattta aatattttct tggttagctt tccaagaggg aggaaaagag 2400gggagttgca acaagtagtg cccctatgct gggattcatt ttccagagta aagcctggga 2460ctggcaccct gacccctacc ggcaggtgaa aactccaggc aaactgctga gatcccacct 2520gggctggctg agatagtgcc tggggtgcat ccctcagcag ctgccacctg ggccctgggg 2580ccatctcttt ctctggcatc aagcagccag gtgtcaaggc cttcccagca atccatgctg 2640catggctggg tcttgttcta gcaggtcgat gggcagggac tggtagctta gccagggcac 2700cagtgcgtgg ctgtgggttt gtgtgcttct gtggagaagc atgatgtgta tgtgtgtgtg 2760tgggcacagg catgaggaag ggttcatttg tgcaggtatc tcccatgtat atcagtgtgg 2820gagagtgcct gaggatgtgt ttgtgtgtct gaaaatgggc ggagggtctg ttgtgctaat 2880gtgtgcaggg gtgaacatgt gtgtgacagt ctgtgtgttt ccctgagtgg tggctgcgtg 2940agagggtgag gggatttggt gttgtctacc atgcccggca catagcaggc tcttaataat 3000cttgaattta attaatgtta aatgtgtatg ttcccatcct tgtggaagtt ggtatagagc 3060ctgttttcct gtgattgtga gactggaaaa tgggggacgg gcaggggcga gacaggatac 3120agaggctact gttttcttcc tccctagaag taagtacata gaagagtggg ctctggcacc 3180tcacgggaca tcaccaagtc ctgtgtggct ggctaggctg tcccaaggtg gcttcaggca 3240tcacttgaat cttttgagac cttcaggcag tagcctgcca ttcaccctgt cagtcagcag 3300aagttgggcc cacacaggcc atagaaacac agagcagttc ccgggaggac ctgagctgtc 3360cctgagagca gagcttccag gagaggccgc aggaactgcc ttgaccggaa ttcctcttgg 3420ggtgcaaagg tggagggaca catggtgcga ccccaggcag aggactgcag ccactccgtg 3480cagtcccagc ctctggggta gccccttgac ctccaggcct gcacagatcc aaggccgagg 3540tccaggctcc agcgccaaat tagctggcct agcagcctgc agccgctcta atctcaacta 3600ggaaggaatc cttgcgctta gaaagtccaa gcgaaagggt attctgattt tatcccggtt 3660ttaccagaaa atgctgaaag gaaaagcccc gagaggacac agtgctctag gaactcgggg 3720cgccacgagc gcctcatccc ctcccttccg cccggccgcg gtgccctggt cgctgaggga 3780cgcggtcagt acctaccgcc actgcgaccc gagaagggaa agcctcaact tcttcctctc 3840ggagtcctgc ccactacgga tctgcctgga ctggttcaga tgcgtcgttt aaaggggggg 3900gctggcactc cagagaggag ggggcgctgc aggttaattg atagccacgg aagcacctag 3960gcgccccatg cgcggagccg gagccgccag ctcagtctga cccctgtctt ttctctcctc 4020ttccctctcc cacccctcac tccgggaaag cgagggccga ggtaggggca gatagatcac 4080cagacaggcg gagaaggaca ggagtacaga tggagggacc aggacacaga atgcaaaaga 4140ctggcaggtg agaagaaggg agaaacagag ggagagagaa agggagaaac agagcagagg 4200cggccgccgg cccggccgcc ctgagtccga tttccctcct tccctgaccc ttcagtttca 4260ctgcaaatcc acagaagcag gtttgcgagc tcgaatacct ttgctccact gccacacgca 4320gcaccgggac tgggcgtctg gagcttaagt ctgggggtct gagcctggga ccggcaaatc 4380cgcgcagcgc atcgcgccca gtctcggaga ctgcaaccac cgccaaggag tacgcgcggc 4440aggaaacttc tgcggcccaa tttcttcccc agctttggca tctccgaagg cacgtacccg 4500ccctcggcac aagctctctc gtcttccact tcgacctcga ggtggagaaa gaggctggca 4560agggctgtgc gcgtcgctgg tgtggggagg gcagcaggct gcccctcccc gcttctgcag 4620cgagttttcc cagccaggaa aagggaggga gctgtttcag gaatttcagt gccttcacct 4680agcgactgac acaagtcgtg tgtataggaa ggcgtctggc tgtttcggga ctcaccagag 4740agcatcgcca accagaacgg cccacccggg gtgtcgagtc ttggtaggga aatcagacac 4800agctgcactc ccggcccgcg ggccttgtgg catataacca tttatatatt tatgatttct 4860aattttatta taaaataaaa gcagaaatat ttcccgaaga acattcacat gagggcatta 4920cggggagacg gcaagtcggc ggctcggggg gcgcgctcag ccgggagcgc tgtagtcaca 4980gtcccgggag gaagagcgcg 5000971500DNAHomo sapiens 97tggaacaagt gtcagagagt aagcaaacga ctttctgagc tgtgactctg ctcctcgact 60gcccacgtgc tctccgctgt ctgcactcct gcctcacctg ggctgactcg gactctccac 120ctcctttgct gcttccggca tgagctaccc aggagcctaa ggcgctcctt cccgcaactc 180cggtccccgc gccccgggac tgcaaatcct ttaaacagag gccccagagc taggggtttt 240cccaggctct ggtgggcgtg ggctgacagt cgctgggagc cccgcaacag gggggatgtc 300caggcaggta tgcacccagc tcccggcgtt tcccggagtc accacaatgt ttccctttct 360ctctccccca cgtatgctgc taggggtact ccccagatag gattttcttt gtcttttctc 420ctagtaacac cgaagccctc tcgtgcccgg ggactgcaga ggaacgccag accatccgga 480ccttgcggga tggctcggtg tgtgtgtttt actgtgtgtc ggagtgtcgc gcatgtgtgc 540gtgttggggc gcgttatcaa caggggccta gggcaccccc actctttctt gctctcttcc 600cccatcactt catggacctc cgaggcgcaa agcgctcgac cctctcctgg gctcagtggc 660ttgggtactc cgggctgagc tcagctgggg agtcccctta cccagcccgc accggcaccc 720cgaagcttca aagttgcggc aaacagttgc ggggagcaga ggaactgagg tccaggccag 780cgcgcccgcg gtcgctcgcc ttggggagca ggctgagccg agggtcgtgc gggtgcgcgg 840cagaggcggt aggaggcgga ggagaggggg gagaaagagg gggcggtggg gaacagctgc 900cggggtaggc gaggcgcaag gtggctcccc gcggccccgc gccccgcggc tctcggacgc 960accaggcagc caatggctgc gcagaggtgt acagcagatg gcgtctgact gcgccgttcc 1020ttcctcctcc tcctcctcct ccttctcttc ctcctcctcc ttctcttcct cctcctcctc 1080cttcagtgct gaggagccag agtcgccgcc gggttgccag acgctggaat gggtggtctt 1140ccgacacaca ccaccatctt tcttgcgctc gggaagctcg gggctcagcg gctcccagag 1200gttacggcgg cggctctggc gagacgggtg agtgcaagca cgcggagccc cgagtcgggg 1260atgccgggcc ccctggccgg ccgactgggg cgcggggtgg cagcgccggg gaagggggcg 1320cgctgccggc gcagactttg ctctttcctc gccggacagc catcgtcgcc ccttctccca 1380gccagacgcg ggaacttgga agcggatctt ctcggacgcc tctggcttgg ggctgcggga 1440agcgtgggct gcccggggcg cagtgtgcgg agaccctcta ggcgggcggg gacgccccac 150098800DNAHomo sapiens 98gttattatcc acggggtcct aattaaagct tgattaaaat gcccttcttt ctctaaaaaa 60ttacgaacta ggcaacttca tacattttga atggcgcagt gtttcctctt ccaactgttt 120agtttgtagt atactatgta agcaacatca attatcaacc cttgcaagat gacaacatga 180gcctgtgggg gaagcacttg aggggaggga ggagaaactt ctctttttta ataatcagcc 240ggaaacaatg tttaacaaga atctgatgag gtcactgcag taaatatttt tcctcttaca 300gagccaatca tcacggaggg atcccctgaa tttaaagtcc tggaggatgc atggactgtg 360gtctccctag acaatcaaag gtgtttgctt tctgctctgt tgcttttaaa ttgtatggga 420aaggaagatt ggtccgacgg cgcgcttgtg gcccggccgg agcttgcgtg cgcgttctga 480cggctgggtg ctgtgttaca ggtcggcgca gttcgagcac acggttctga tcacgtcgag 540gggcgcgcag atcctgacca aactacccca tgaggcctga ggagccgccc gaaggtcgcg 600gtgacctggt gcctttttaa ataaattgct gaaatttggc tggagaactt ttagaagaaa 660cagggaaatg accggtggtg cggtaacctg cgtggctcct gatagcgttt ggaagaacgc 720gggggagact gaagagcaac tgggaactcg gatctgaagc cctgctgggg tcgcgcggct 780ttggaaaaac aaatcctggc 8009940DNAHomo sapiens 99tccctgctgt gggacccgag gagaggagaa ctggttcgct 40100500DNAHomo sapiens 100tctctctctc tctcttgctt ggtttctgta atgaggaagt tctccgcagc tcagtttcct 60ttccctcact gagcgcctga aacaggaagt cagtcagtta agctggtggc agcagccgag 120gccaccaaga ggcaacgggc ggcaggttgc agtggagggg cctccgctcc cctcggtggt 180gtgtgggtcc tgggggtgcc tgccggcccg gccgaggagg cccacgccca ccatggtccc 240ctgctggaac catggcaaca tcacccgctc caaggcggag gagctgcttt ccaggacagg 300caaggacggg agcttcctcg tgcgtgccag cgagtccatc tcccgggcat acgcgctctg 360cgtgctgtga gtacaacctg ctccctcccc gggcacagat atgacagagg ggcttagagg 420gggcccagct ttgagatggg ttgttcttat gtcacaggac agagtgatct gacatgcaca 480cttccccgcc accctgtcat 500101500DNAHomo sapiens 101tgtcctcgaa gaagggcctg agcagcagca gaggacccca ggcgaccgtg cctgagccgg 60gcgccgacga cgactgagca cctgatatgt ccccggcact cgcagccccg cggccggagt 120cgctgtgggt gagcggtcgt cgagcttcac agaggccggg ctctgtgcca gggccccgac 180agggcaggaa gcagatagag tcccacaagc acaagcccag tgcgcagaaa gggttactta 240aaaaataagt tctgtgataa aatcaaacag ggtgaagggc tggaaacagg tcatgagggc 300gcaaacaggt cgtgagggcg caaacaggtc gtgagggcgc aaacaggtcg tgagggcgca 360aacaggtcgt gagggcgcaa acaggtcgtg agggcgcaaa cagatcgtga gggcgcaaac 420aggtcgtgag ggcgcaaaca ggtcgtgagg gtgcaaacag gtcgtgaggg cgcaaacagg 480tcgtgagggt gcaaacaggt 500102300DNAHomo sapiens 102aaatgagacc tctggggaga ctgtcaaccc caggggtaaa acaaaaattc tgatcagaaa 60ctgagtttcc caaagaaggg gctaaatgtt ttccaacact ttcggggctc agggaagatg 120actctgtaag gacactgaga atcttcctcg cgtgccacgg ggaggaggac tgggggcgtt 180tgaggggctc agcgcaccag aggagtgagg tggaggaggg cgttcccgcg tcctcctctt 240caatccagag cagctcaacg acgtggctcc ctttctatgt atccctcaaa gccttcgcgt 300103600DNAHomo sapiens 103taggctctag tggacctagc agtgggagag ctacttgggc tggtttcttt cctgacgctg 60cagggatggg catcggcctg gaaccagaag cgcaggagct gggccacggc agagtaatta 120agaaaataat gaaattgatg gcggatgggg gcgctagaaa tcctggggcg tctacttaaa 180accagagatt cgcggtcggc cccacggaat cccggctctg tgtgcgccca ggttccgggg 240cttgggcgtt gccggttctc acactaggaa ggagcctgaa gtcagaaaag atggggcctc 300gttactcact ttctagccca gcccctggcc ctgggtcccg cagagccgtc atcgcaggct 360cctgcccagc ctctggggtc gggtgagcaa ggtgttctct tcggaagcgg gaagggctgc 420gggtcgggga cgtcccttgg ctgccacccc tgattctgca tccttttcgc tcgaatccct 480gcgctaggca tcctccccga tcccccaaaa gcccaagcac tgggtctggg ttgaggaagg 540gaacgggtgc ccaggccgga cagaggctga aaggaggcct caaggttcct ctttgctaca 600104800DNAHomo sapiens 104gaggttgctg actcaggagc caggagctga gaaactccta ggctagcagc cgttgagcct 60aattttattt tctggctttc tccgaaatgt ctcgtttccc tcatctttct ggtccttttc 120gtctctctta ttttccccaa aacgtctacc tcacttcgtc ttcctttctc ctcccctccc 180cctctctttc ctctatactc tcttcccatt tagccttgca ggcccctcct ccccggtgtt 240ggagagctca aagacgcgcg aaactcaagg atctggccct gaccagggac gggattaggc 300gggaagtggt gacggcctga aaaggctggg ctcgaacccg tgccttcctg aaaggactct 360ccccgccaca agtcacaccc acccgcaggc ctgctggcca aagaaacaaa ggagtcgggc 420gtggatccag gagaaacagg ttttcgctct cggatctccc tgggcaaatc agggatcctg 480agcgctatac cccgcagtcg tacggagcct ctgggaaagg ggatttaagg gtgacttcca 540ctttcagctt cggctacttg ttgcctgcgg tccaagcctt ctctgcttcc tcctacctcg 600tcttaggcct ctgtagaaag tgcacgccgc gtttcccctt ccaggctctg agagggcctg 660caggcccgtg gccgcctccg acaagatgcc ttccagtgct aggggggcca ctttggcggg 720atgggggtcg gttggttaaa aaaaacttaa gttctggctc agtcgagtgt ggcaaaagcc 780gagggtcggg ggttgggggg 8001052000DNAHomo sapiens 105tactgacctg gtctccgcct caccggcctc ttgcggccgc tgcagaagcg cactttgctg 60aacaccccga ggacgtgcct ctcgcacagg gagcgcccgt ctttgctggg gctggagcgg 120cgcttggagg ccgacactcg gtcgctgttg gactccctcg cctgccgctt ctgccggatc 180aaggagctgg ctatcgccgc agccatagct gctcagcgag ggcctcaggc cccagcctct 240actgcgccct ccggcttgcg ctccgccggg gcgagggcag gacctgggcg gccagggaaa 300gggcagtcgc ggggaggcag tgctaaaatt tgaggaggct gcagtatcga aaacccggcg 360ctcacaaggt tagtcaaagt ctgggcagtg gcgacaaaat gtgtgaaaat ccagatgtaa 420acttccccaa cctctggcgg ccggggggcg gggcggggcg gtcccaggcc ctcttgcgaa 480gtagacgttt gcaccccaaa cttgcacccc aaggcgatcg gcgtccaagg ggcagtgggg 540agtttagtca cactgcgttc ggggtaccaa gtggaagggg aagaacgatg cccaaaataa 600caagacgtgc ctctgttgga gaggcgcaag cgttgtaagg tgtccaaagt atacctacac 660atacatacat agaaaacccg tttacaaagc agagtctgga cccaggcggg tagcgcgccc 720ccggtagaaa atactaaaaa gtgaataaaa cgttccttta gaaaacaagc caccaaccgc 780acgagagaag gagaggaagg cagcaattta actccctgcg gcccgcggtt ctgaagatta 840ggaggtccgt cccagcaggg tgaggtctac agaatgcatc gcgccggctg cggctttcca 900ggggccggcc acccgagttc tggaattccg agaggcgcga agtgggagcg gttacccgga 960gtctgggtag gggcgcgggg cgggggcagc tgtttccagc tgcggtgaga gcaactcccg 1020gccagcagca ctgcaaagag agcgggaggc gagggagggg ggagggcgcg agggagggag 1080ggagatcctc gagggccaag cacccctcgg ggagaaacca gcgagaggcg atctgcgggg 1140tcccaagagt gggcgctctt tctctttccg cttgctttcc ggcacgagac gggcacagtt 1200ggtgattatt tagggaatcc taaatctgga atgactcagt agtttaaata agccccctca 1260aaaggcagcg atgccgaagg tgtcctctcc agctcggcgc ccacacgcct ttaactggag 1320ctccccgcca tggtccaccc ggggccgccg caccgagctg gtctccgcac aggctcagag 1380ggagcgaggg aagggaggga aggaaggggc gccctggcgg gctcgggatc aggtcatcgc 1440cgcgctgctg cccgtgcccc ctaggctcgc gcgccccggc agtcagcagc tcacaggcag 1500cagatcagat ggggattacc cgccggacgc aaggccgatc actcagtccc gcgccgccca 1560tcccggccga ggaaggaagt gacccgcgcg ctgcgaatac ccgcgcgtcc gctcgggtgg 1620ggcgggggct ggctgcaggc gatgttggct cgcggcggct gaggctcctg gccggagctg 1680cccaccatgg tctggcgcca ggggcgcagg cggggcccct aggcctcctg gggctacctc 1740gcgaggcagc cgagggcgca acccgggcgc ttggggccgg aggcggaatc aggggccggg 1800gccaggaggc aggtgcaggc ggctgccaac tcgcccaact tgctgcgcgg gtggccgctc 1860agagccgcgg gcttgcgggg cgccccccgc cgccgcgccg ccgcctcccc aggcccggga 1920gggggcgctc agggtggagt cccattcatg ggctgaggct ctgggcgcgc ggagccgccg 1980ccgcccctcc ggctggctca 2000106800DNAHomo sapiens 106gggggacaca gagaggaggg gttgcgggcc tgtgagaatg aagagcacag agcggagagg 60gggaggagga gggaaaggaa ggcgtggcag tgagagagaa gaggaagaag agaggaggag 120tggggagggg agggagagca agacagcagc gggtctggat tcccctccga gccacatctg 180gtcaggttct aagtaattag aagattttcc cattggttta cccaagggct ctctctctga 240ttaattttcg aaagagttgg ccaattttaa tcatagcaaa cacgatgatc acggtgatca 300tggcctgaac agctaaaagc agaaaataaa acccccagaa cggactatga tcttgacctt 360tgcccgtggt caccggctgg gcccacaccc agggttctga gctgttggga gccaaggctg 420ggtggacagg ggcttccgag gagctgtccg cagcggggcg gggaggcggg ccccgggggc 480ccgggcactc cgcgtcaccc cccggcaggg cccagagcgg caggccggcg tgcgccccag 540ggcctgcgca ccgtgggggc tcttccccgc ccacgaggcc taggtgctgc cgcagccacc 600ccaggaaggg ccccaggcca cagtcgcagc gccaggagtt gtgccccaac aggacctccg 660tcagccgggg cagagcccca aacacgtcgc caggcagggt ctccagctgg ttgtggtcga 720gctggacgct ctccaggctg ctgagattgc ggaagagggc acggggcagg gcgcgcagcc 780tgttgcggcg cagggacacc 800107550DNAHomo sapiens 107gccccggtgc accgcgcgtc cagccggccc aactcgagct agaagcccca accactgccc 60agtgcctgag ttgcagtctt gggtccttta gaaacctgga gatgtgcgta aaattcagat 120gccggtattc ccgaacttcc ccaggcctca gcatatctcg gcggcctgtg gacagatggg 180aggctaccaa tcgctccggc gtccgcagcc cgacccctgc cgccagaccc cggacgtctt 240ccggataata aagttcccgc tctaattcat tttccctaat ctggacgccc ctaatctaca 300gcttttattg cgcccagtta aaagtcgagg gaattcgctg tccctccgcg ctcggataat

360tacccctaaa tggccacggc agccccttgt gtttcctgga gattagaacc ccgcagtcat 420caatggcagg gccgagtgag ccgccaatca cctccgctca ctccctgaga gccgctggcc 480tgggccgcag gaggagaggc cataaagcga caggcgcaga aaatggccaa gccccgaccc 540cgcttcaggc 5501082000DNAHomo sapiens 108agggtgcctc tgttcaaatt agaaaaaggc gccccctcag ggcagactca gcccagctgc 60caggggacaa gtcctggcta acgggagctg gagctgggtt tcacctccag gtgcctcctt 120ggcggggcgc cccgtgcagg ctacagccta cagctgtcag cgccggtccg gagccggagc 180gcgggaatca ctcgctgcct cagcccaagc gggttcactg ggtgcctgcg gcagctgcgc 240aggtggagag cgcccagcct gggaggcagt agtacgggta atagtaggag ggctgcagtg 300gcagaagcga gggtggccgc agcacttcgc cgggcaggta ttgtctctgg tcgtcgcgca 360ccagcacctt tacggccacc ttcttggcgg cgggcgccga ggccagcagg tcggctgcca 420tctgccggcg ctttgtcttg tagcgacggt tctggaacca gattttcacc tgcgtctcgg 480tgagcttcag cgacgcggcc aggtctgcgc gctcgggccc ggacaggtag cgctggtggt 540taaagcggcg ctccagctcg aagacctgcg cgtgggagaa agcggcccgc gagcgcttct 600tgcgtggctt gggcgccgcc ggctcctcct cctcctccgc gacgcctgcc ggcccgctgc 660cgcccccgcc gccggccccg ctgcacagcg cggacacgtg tgcacctctg gggccaacac 720cgtcgtcctc ggtccttggg ctgcggtcgc ctgcggaccc cggtgggaac agaaacaaga 780gactgtcagc gccacagacg aggtgaggcc gggcctcaac tgcaggggtc acgggagtgg 840ggcggaaata cactttgatc ccactcaagc ggagcggagg tctgggaggc cctgggcccg 900ggagaccagt cttagactct tgccccactg ggtatcccat ctaggcctct tctggggagg 960gcggcagact cagccgctgt gtcaacgctg tgttgtcgag accagctccc caccctctct 1020gggccccagg ctcccctcag taacttgggg cactcgaccc gagcatccgc gaaagccctc 1080ccggctctca gcgttgagca ttgggattct agactgcatt tccgtctctc tgcttgggtt 1140cacgcgcctc tccacactta gttcacacgc acacacgcgc gcgtcctcgc agcacacact 1200tgtctggtgc aggtaaggga aggtggaggc ggatcctggg gccaaaggta tttagaatct 1260ttcaccctca gccgcctggg attgctgtga gagacatgga aacaggctga gccgaggcct 1320tagatgagag gatggactgg agagtaaaga gggagggttg cccctgcatc gagtttttgg 1380accctgatcc cacaccagct tctcggtctc gtacccgccc ttccgaagaa ctccagcaga 1440aaggtccagc ggtcccctgt gcttgaggcc tacagaagct tgtacccaac tagggcaggc 1500acccgggtct tccagaccac aggacaggac aggccacggc tgaggaggcc tctctcctgc 1560ctccaggatg aactaaagac ccaatccggg atcttcggcc tagggctgct ctcccagacc 1620tggggtctga gaaagccaaa ccagcccttt ccccaaagct ctagttctgc agattctcag 1680ctctggccca ctcggaggtg ttcttcacca cctatccacc tactgtgggg cccggccctg 1740ggaccttgaa ctggcaggtc tctggtccag agctaggtca ctggctacct gaggtctctg 1800aacccctcac ttttccgctt ccctgatttt ggggatttgg ggacagacac ggcagaaagc 1860actggcgacg aactcaaaaa ctcccgaacg caaggggcag cggttctccc aacccagtct 1920aatgcacatt ggcccaggat gtctcaggcc tcaccccagg acgtagggct ctgaggagct 1980actccggtct ctcgcgggct 20001091000DNAHomo sapiens 109gagaagggat gtggcggggg gctcctccgg ccctggactc cctgggtgga ctagaaaagg 60gcaaagaagt ggtcacatct gtgggccaga ctggtgcgcg atctttggag gcgcagcagc 120aaggccgcgc cagggctgag cccagaccgc ccacgaggag gcccgccagg cccggagcag 180cggcgcgtgc gggggcgtgc cgagcgcagg ctctagggcc cctgcttcgc cccagctgga 240ccccgcgggc ggtcggtgca gctcgagcgt gtgggctgcg atgccctgcc tgagacttcg 300ggctagggat gcgggcggga agtgggggtg cggcggcagc tgcagattag attccttttt 360tttttggccg gagggacgtg caaacttcta gtgcccgggc caagagggcg accccggagg 420tgcgtaggtg gccctccggg ttcccgcttc tcctagtgcc tctgaaaata ccgtcagggt 480aaagggagac aggcagtaag tcttaccacc accgcccttt ccccatgtca ttggccaaaa 540actgaacatt aagataaagc agctgtttca gtcaatggaa agcggtaggg cgaggttgta 600cccaaaaccc ggtttagacg gccaatgaag tcctaggaaa agccgccccg ggggcacgtt 660caggtggagc ggctgcacct cgggtcgttc taagggatgg gctgcgtggt acccacggaa 720ttcatgggtc caaaaggtcc tggtcacctg tccaaacatc catcccctgg cgcatggcgg 780ttgacaagat ggcccggcca cccagaggaa ggaggatccg ggacggggaa cttcgcgccg 840ggaagctgta gcccagagct gcagctcagc attcgcaaga gattcatctt ttttttctct 900cgtgttcgga gaaacagata aacaagacac cgcctcatca gataagaacg tctccttcga 960tgtcacggat ttcaagaggt agctggagaa actgacgtca 10001101300DNAHomo sapiens 110caggtcaggc agaacttctg cccttcccgc tactggcacc ccaagcaggg atgcactggg 60atgcgtggca ggggcgggat ctcctgggag cgtctcagcc cagcagggag tggggaagca 120agagggaagg cttaccttcc tcggtggctg gcaggaggtg gtcgctgcta gcgaggggga 180tgcaaaggtc gttgtcctgg gggaaacggt cgcactcaag catgtcgggc caggggaagc 240cgaaggcgga catgaccggg gcgcagcggt ccttcacctg cacgcagagc gagtggcatg 300gctggatggt ctcgtctagg tcatcgaggc agacgggggc gaagagcgag cacaggaact 360tcttggtgtc cgggtggcac tgcttcatga ccagcgggat ccaagcgccg gcctgctcca 420gcacctcctt catggtctcg tggcccagca ggttgggcag ccgcatgttc tggtattcga 480tgccgtggca cagctgcagg ttggcaggga tgggcttgca attgctgcgc ttgtaggaga 540agtcgggctg gccaaagagg aagagcccgc gcgccgagcc caggcagcag tgcgaggcga 600ggaagagcag cagcagcgag ccagggccct gcagcatcgt gggcgcgcga ccccgagggg 660gcagagggag cggagccggg gaagggcgag gcggccggag ttcgagcttg tcccgggccc 720gctctcttcg ctgggtgcga ctcggggccc cgaaaagctg gcagccggcg gctggggcgc 780ggagaagcgg gacaccggga ggacagcgcg ggcgaggcgc tgcaagcccg cgcgcagctc 840cggggggctc cgacccgggg gagcagaatg agccgttgct ggggcacagc cagagttttc 900ttggcctttt ttatgcaaat ctggagggtg gggggagcaa gggaggagcc aatgaagggt 960aatccgagga gggctggtca ctactttctg ggtctggttt tgcgttgaga atgcccctca 1020cgcgcttgct ggaagggaat tctggctgcg ccccctcccc tagatgccgc cgctcgcccg 1080ccctaggatt tctttaaaca acaaacagag aagcctggcc gctgcgcccc cacagtgagc 1140gagcagggcg cgggctgcgg gagtgggggg cacgcagggc accccgcgag cggcctcgcg 1200accaggtact ggcgggaacg cgcctagccc cgcgtgccgc cggggcccgg gcttgttttg 1260ccccagtccg aagtttctgc tgggttgcca ggcatgagtg 1300111500DNAHomo sapiens 111tgcgatcatt aaaatcagtt ccttccctcc tgtcctgagg gtaggggcgg gcagatttta 60ttacttctct tttcctgata gcagaactga ggcggggttg tggaggagcg acggaggacc 120acctctaact tcccttcact tcctggattt gaagcctcag ggccaccggc ctcagtcctg 180ttacggtggc ggactcgcga ggttttccag cagctcattc cgggacggcg gtgtctagtc 240cagtccaggg taactgggct ctctgagagt ccgacctcca tcggtctggg agcgagtggt 300tcgagttcag atgctgggaa ccgtcgcttc tccccggccg ggctcgctgt tttctcctcc 360gctcgccgtc atcaagcccg gctatgagca gggctttaaa tcctccctcc ctcacccgca 420ggtttaccga gcagccccgg agctctcaga catgctgcgc tgcggcggcc agaggagggg 480tgggggcatt gccctctgca 500112500DNAHomo sapiens 112gggcttgggc cgcaggcttc cctggacttc cgcagtcccc cttctcccca ttccagaacc 60tgccgagccc ctgctgcatc tgggacccgc cttcaccgtt tcccaatccc agcggttagc 120ccctgcgccc cctttttggt ctccactttg ccgttcgaaa atgcctaggt tggtggatcg 180accctccgcg gagcaaagac ggatggctgg caggagcagg ttcaggagct gggccaaggt 240attctctgct tccgcctttg tgtccgcccc cccgccccct gctccccgct tcccgccagc 300atctctcctt ttctgctcag gagtgtttgg cccggcggtc caccccggct tcccgagata 360cgctagagtt gcccccacgt cctgtccgcc gcgcccctac ccaccgggtt gccttcgggg 420cccttcggtg ctgtgtagtc ggcgtggcgc tgtgagctag gcgaacagga acccccaggc 480ccgccacgtc tacgctatta 500113600DNAHomo sapiens 113ttctggggcc tggatgggtg cgagcgggac ccgggggagt gggagtcgcc aggctctgag 60caagcaaggg ctgcacctgc acctctgccg ggcatgaaga aaggtaagga aggaaggagc 120tcacccgggt gggagacaga gccggggcgc gcgagcttgg tgtgggggcg ccactccggg 180gcggagggga ggggctacca gtgacttctc cgagtcggga gctagaaaga ggcttccggc 240caggttccct tggaacaggt gtcggagttg ttgggagagg gggctgcaag aaagaggggt 300gcagaaactg gttcattaga tggaggctct gggcggaacc gcgaggacac cctggcagcg 360cgctgtgcct gcgttaggcc gggaggggag aggcctccgg acggcgaagt gtccctaggg 420acccagacgc ctcgggagcg atccgggccg ctgcgaagcc ctgcccacca ggagtggatc 480cccaggattc acctcccggc tgcctgctct gagctgagaa ggggatctgg ttcttcacaa 540taccgtggat ggcggggaag gggagggagc ctggggtaaa atcccatctt ggtttcctcg 6001141300DNAHomo sapiens 114tgtcacagaa accccagcag cgcagccacc ggactgggtt ctggaggccg agccgcagtc 60cgtgcggcgg cgctgggaag agaaggcgcc ccggcagctc ccctgccacc ggccccgagg 120agcggctggc tcccccagcc cagcgccgcc gccgcccggt aactccaggc gcaactgggc 180gcaactgggg cagctgcgac accgaatccc tcacatctgc aacctgggtg ctgcggccac 240tgagaaaatg gaggcgcaga ccaacgagcg gtgccgcgac cgagagacct cggctggcga 300aatggtggtg ccgggagcct gcgagtgacg ccagccggcg gggttgtcaa ggacaacatt 360cgttttgacg cagccaatgg cgccgtcacc aagaaaccat cgactctgag aaaaaagaga 420ggttcggcca ccgagaaact ccgtacgaca agtgctgtgg cagaaaaacc gcctactccg 480cgccacaggc aaaacagcca atggaaaccc caggtgctgc gaccgtgaca ccggcactag 540agggtctcgg atggagaaag cggcgcacgg agaccaggaa actatgtgta gcacaactag 600cagaaaaccg tctggtcggc catccgggag aaagcgcgga tcagaaacaa gcgacttcga 660tgcagggaac cgcgcagcca ctgaagaaag tgacccacgt ggcagtggtg ccagcgaaac 720actgcagttt ggacggcagc tgtggggatg ccacagagaa acatgcactg ccactgaagt 780acatccagct ccgcggagct agtgttcata tgatcaagaa accgccagtt gggctctgct 840agaaactttt agtcctccct taacggctat cctacccaca acagacaatg cctttaccca 900gcacctagcg gtgctgagac ccgcctgggc cagcacagag cgcagagcag tacgggtacg 960gagaaacgcc ggactcagtg aaaccagcct tgcctccagc ggattccccg gcttcgccgg 1020acgccacagg cagagtgccg cggggaaacc tctggctccc taaaccgatt agattgtggg 1080agtggggggg acactcacaa gttgtgtgga agggaaccag cggcaatggg acccggcgag 1140cacttgcccg cagcaaatgc ctgcgctgct gcaaaaaaaa caacttttgg cgcaaagaat 1200gttgcggcca gagagcatcc gctgtcgctg acaaaggagt agcaatggca atgagaaacc 1260gccggcgcca cggccgaccg cggcggctca cgcctatgat 13001152100DNAHomo sapiens 115caaacgctga gagacaaaaa gacaccaaca cccaccagga ctgcgtcctg ccagctcttc 60actccgctga cctgaccttc cacgccccta gtcctcgagc ggacttgacc tgtgggggag 120taccgaaccg tccccatgag gccctccaag cggccaggtg gcctccgcca ctctctccac 180ccccacctcc tccacccccc agcccatcgg tccatcttcg atctgcaaaa cacgccgggt 240cagcgacgca tcggtcccag gcttgtgacc acctctttct ctgttacttg gggagccagg 300cccaccgctc aggatcacag tgaggagaaa aaagacacaa acgccaggac agggcggctg 360gggaaggaaa ctgctaggga ccgctcattg tcagcctggc gtgtcccacg gatcgcagga 420cccgtcgagg ctttgctctc tgcgacccga atactcctgg gcctctcgac ctcctcctcg 480gactcaggcg tccgcgtctc cggtcatcac gggagaccaa ttggtttaca aatagtgatg 540ataaacctgg gaccgacctt ggggctgtgt aaaagtctac tgacagatgt aatggagggt 600tgttagcagt cacaaagcct gtcggacccg tagcattagt tcaagagact attttcgtgt 660cgcaccaaaa ttactgcgcg tgtaaaccaa tttccccgac ggaagaataa acagagattc 720gtttgaagcg cgagatgaaa acagatgggg tatcgcaaac agttccccaa aatacaacag 780acttctgggc caattacacg tggttagctc tgaatggcag aggaaatagt tttctttgct 840gctaaatgtc acaaaagtca cctaaaggca cagaggaggc cgctctgttt ttgcgaaact 900tgctaaaatt aatctgcgct gggccacttg cagaaagcag aaccacctcc cgcccccacc 960tcgcctccag ccgccggggt tcaggcgttt gtgaaagaca gaacctttgg gctagggacc 1020cgggcactgg tgcttcgaag tccgaatccg ccggccgaga aaacgacaag agaaagaaaa 1080tccagcgggc gctctctcca gcgccaggcc ggtgtaggag ggcgctgggg ctcggcctgc 1140cacccctacc cgacattggg aagcagcccc tgcgctcccg cggcgcctca gcctccggtc 1200cccgccccga ggtgcgcgtt cctcctcccg catgcccgtc tcgggcccca cggagcaaga 1260agatagacga tgacgaggcg cgcccatcca tccgggccga cgaggtcagg cccgcgccac 1320aggcaaaaat tgcgcaagcc cggccgcagg gatttcgcgg gcgcctgggt cccaggtgcg 1380cggccgaaat cctcagggaa aatcccgagg ggccaacggt ctaggccaca gggctgctgg 1440gcccgggcct ggctcagagc gcattcgggc ggggaggccg cacgccgcac ccgggcctct 1500cctccgagcc cgaggcaggc actgagctcc gggccagcca ggtgcctccc ggctggtgcg 1560agaccccggg cctgctggga ggcgtgggca gggcagggca gggctgaacc ccagcgactg 1620aatctcgaag gcaggaggcc tcggaggtca tcggcccagc tcgcctgaaa ctgtccctgc 1680tcgtgccagg gcgcgggcag aggagaaagg acagggcgga gcaagcccac tgcagaactg 1740cggtcggtgg ctgcgaaggg tccgggtcac cgcgctcccg gacgccggaa gccgcgctgg 1800cggggccgcg gggagggagg ctgggtaccg gggccgtccg gccggaggaa gcggctccgg 1860ccgcgctgtc cgcgcttggg agccgcgtgc agggttcagc cgtgtttcag ttgccctctg 1920acctgacccc gggcgcacaa aggcctcccg ggtgcgccgc catggcccag tcttccagtc 1980gctgccaaat taatgagccc acgtcaggtt gggtttacag ctcggccggg aagcagccga 2040gtggaaaatg agctcggggc cgctccagag gctcccgcac aactgcagag gctgcccgcg 2100116250DNAHomo sapiens 116tttccaagac agaaggaggg aactaggcgc cttttttcca ctccgctgac cccaacgtct 60gggctgtgcg ttgtaacgca gttggcgggg ccttcagctt gggatgaggg cgaaggggct 120cgggatgggt gggaaagcaa ggaccgggca acaggtgggg aggtggcgga cttttgtctc 180ggggaaggaa atcggctgtg ctgaaagggc ggaaagcagt agcgcacaga actagtgtct 240gcggggtccc 250117250DNAHomo sapiens 117ccctcctgtg gctgcttggg cagacgcctg tggcctgtcg gatgcggccc acatcgagag 60cctgcaggag aagtcgcagt gcgcactgga ggagtacgtg aggagccagt accccaacca 120gcccagccgt tttggcaaac tgctgctgcg actgccctcg ctgcgcaccg tgtcctcctc 180cgtcatcgag cagctcttct tcgtccgttt ggtaggtaaa acccccatcg aaactctcat 240ccgcgatatg 2501182000DNAHomo sapiens 118tcctcctttg tgtatgtcaa cccagaggat ggacggatct ttgcccagcg tacctttgac 60tatgaattgc tgcagatgct gcagattgtg gtgggggttc gagactccgg ctctccccca 120ttgcatgcca acacatctct gcatgtgttt gtcctagacg agaatgataa tgccccagct 180gtgctgcacc cacggccaga ctgggaacac tcagcccccc agcgtctccc tcgctctgct 240cctcctggct ccttggtcac caaggtgaca gccgtggatg ctgatgcagg ccacaatgcg 300tggctctcct actcactgtt gccacagtcc acagccccag gactgttcct cgtgtctaca 360cacactggtg aggtgcgcac agcccgggcc ttactggagg atgactctga cacccagcag 420gtggtggtcc tggtgaggga caatggtgac ccttcactct cctccacagc cacagtgctg 480ctggttctgg aggatgagga ccctgaggaa atgcccaaat ccagtgactt cctcatacac 540cctcctgagc gttcagacct taccctttac ctcattgtgg ctctagcgac cgtcagtctc 600ttatccctag tcaccttcac ctttctgtca gcgaagtgcc ttcagggaaa cgcagacggg 660gacgggggtg gagggcagtg ctgcaggcgc caggactcac cctccccgga cttctataag 720cagtccagcc ccaacctgca ggtgagctcg gacggcacgc tcaagtacat ggaggtgacg 780ctgcggccca cagactcgca gagccactgc tacaggacgt gcttttcacc ggcctcggac 840ggcagtgact tcacttttct aagacccctc agcgttcagc agcccacagc tctggcgctg 900gagcctgacg ccatccggtc ccgctctaat acgctgcggg agcggagcca ggtgaggggc 960tcggcgccgc cccgggcgac ccctgggggc ggcactggag aagccgcccg tcctcataag 1020ggattgaact tgcatccact cctctccggc cggcttggtc gctggctgcg ctccacccga 1080ttctcgggat cattggaccg tttgcgcgaa accagagtgg ccgattaagg gatggggctc 1140cgagcaccgg gggtggtggc gactgtgggc gaggggaggt gggaccgacc cccaccccta 1200cactcaaaaa aggccggggc ctccttcgag cttccggtga atttcgggcg atttccgcgg 1260gtgtcggggg tcccgggagg aggcagtcac agatccaccc ctgcagccag cctcctaggc 1320gccggctccg gcacgcttcg ccggtctgta gatttcctct tcgatttctc cccagctccc 1380agcatctgtg acttcactgt taccctccct atccccgcat cacccaaccg cacctgtctg 1440cgggacttag gtgtgcgcgc ggggctcatg cgtgtcctcc ctgctggcca cccccacggc 1500ccacacaagt tgcacgggct cgccacgccc cgccaacacg tgcgcggacg cacgcacgca 1560ctcctcgcac gtgggcttac gcgaatacca gctttcactg ccactcgctc gcggccagat 1620tcacaggcct gttccggtcc actcgcagct cccctctgcc gctccctccg ccgggctcag 1680gagtactcgt agctgattgt gcgcgcctga gggtcccaga tcgcggccgc ccaggaccag 1740gcgaggactc cggagcctcc tctcacctct cccacctgcg ccccgggctg ggccgggtcg 1800cctggggggc ggcctgagcg aggcgcgggg ccaggagcgc tggagcgact gccgctctaa 1860gtgccgggcg ggcaggactc tacgatcctt gggccagagg tccggatggt cccgggactc 1920cgtctcaagg gtcggcgacc cctcaaccca gaagcctcga gcaggcggac aggcagagct 1980gcccagtggc cgaggcgcgg 20001191100DNAHomo sapiens 119atttgtcgtt gtgccattgc tgccactgtt gttcttgtcc agggaaacac cggtggccaa 60cccagatcgg atacaatggt gcggctctgg actgagcctc caaccacatt agccatgggc 120agcattgttg ctgccgctgc tgttatttta attatgattg tacgttaacc accaccttcc 180ttcctctgcc tcccttcagc tgcaatgatg tatgttactt tttggtaact ggatttcatt 240aacatttatg aactctcata aagtagtaga aaaagcaatt tgtgtggaag aattttccac 300ctcattaaac agtgttcttt tgggggtcaa gctgatattt tttttgttgt tagatttttt 360ttataggtcc tttgtccttc cctaagccct gggggatgaa aggagagccg tccacccagc 420gaggggcttg tgtgccctag agggcgctgg gccccgcgcg ctttcctggc tgtccccgcc 480ggctttccac cctccccaaa gcccaggtgc ccaccgtggg tcgctgcggc ctttcccctt 540cttggccaaa tccgattact tcgcagcctg cagatggcat cgccggctaa gggcagcctg 600cggcaggtcc ccgagcctga gcactcctcc tatctggggc ctgagaggac gctctgggct 660ttttcccagg cccagggtgc gcggcctgct agcgcctttc gaggcacagt cccaagatag 720gctcttgtcc ttcgacgccc ccttggcaca agcgcactgg cgccctccgc tcaacccacc 780ttgcctttgg ggcgggcttc aaccctggga agacaggcct gggggaagcg agaggagagg 840cccgaataga ggttccggct caatctttcc cagacggagg cctggtgttt ccagctcagt 900tgcatcttcc agccgcgggc tcctggccca aacagaatgt gtttgctttc acaccgggac 960ggcaagcgga gtccgcctca gtgagcagcg agctgcgcag tccggacggg tgtcgccccc 1020agagactcgc cagccgcccc cagacactcg ccagccgtcc ccatctctaa tccaccgtcc 1080aggcccgggc cctgggaaga 1100120800DNAHomo sapiens 120ccgtgtctcc cttaagaact ggggcctcat ctccactcca gctgcgcgtg cacgtgtgct 60cccggcagga cgcgcgccca ggagcgcgct gggggctgcc ccgcccctct ctccctcccc 120cgcgggtaaa ctccgggcat ccatcagtct gttaattgca ctaattagag atcgcagagg 180tgttaattgg aaaaccctgg tattgtgcct gtttggggga agaaaacgtc aataaaaatt 240aattgatgag ttggcagggc gggcggtgcg ggttcgcggc gaggcgcagg gtgtcatggc 300aaatgttacg gctcagatta agcgattgtt aattaaaaag cgacggtaat taatactcgc 360tacgccatat gggcccgtga aaaggcacaa aaggtttctc cgcatgtggg gttccccttc 420tcttttctcc ttccacaaaa gcaccccagc ccgtgggtcc cccctttggc cccaaggtag 480gtggaactcg tcacttccgg ccagggaggg gatggggcgg tctccggcga gttccaaggg 540cgtccctcgt tgcgcactcg cccgcccagg ttctttgaag agccaggagc ctccggggaa 600gtgggagccc ccagcggccc gcagactgcc tcagagcgga agaggcagcc gcggctttga 660cccagcttcc ttccgacggc atctgcagga gcctctaggc ctgacatagg ctccgaggtg 720ccctggctcc cccacgggga atgctgaggg ttgggccact aggtcctgcc taagtgcagg 780acctgagcct cagacaaatc 800121300DNAHomo sapiens 121gggattgccg gctttgagaa aatatgaaga aaccgatttc tccttccact ttgccagtgc 60actttccttc cactttcact ggtgctgggg gcggcgcact ctttacgaca tataagcgga 120aaattctgca aaagtggccc ccggggatcc ccgcccgacc cctgtctgtc gctaatgtgg 180gcctgtctcc ggaaattcga ggttgggcct ttgcctgaat ctgttgctat tgctcccctt 240gctaccgctg acacttggca ccgccgcctc ctagcagcgg ccagacgcgg ggctgggggc 300122400DNAHomo sapiens 122gttgcgagcg cggcacaggt tgctggtagc ttctggactc tggaggcttg gccttccttc 60taagccgatg gcggggaaag aacctcgttt ccacagcttc cccgaccccc gccgcttgcc

120atttggggac gggaagcgcg cccgggtcgc ttcacgtccc tctgggccgg agccctttcc 180atggctggct cctctggggg cccttgggcc tgtgagcagc gtctacttcc ctcagagaag 240aatcctttcc ttcccccatc gaagtgtccc tttctgtatc ctgaaataac ccctcctggg 300tgaggccagt tcccctctgt cgccctcctc ccgcaggcgt ccgggagcct cgtgaggacc 360ccgtgcagtt gagtccaggc gacaggtgcc tccccaggtg 400123800DNAHomo sapiens 123cagtgcgccc cttaccggag cacccatggc ctcccgcgtt accccaaatt ttgtaggcag 60actgtcagag ttcgaagcca gctgtgtcct ctgcgggccg tgtgacccta ggctatctgg 120gctgctcgga gccttagttt ccctagttgt gaagagggag ggtgtgacca tggcccggag 180ctctccgaaa ggctgtgcgg attgctcggt ggcgggatgt ggagcgcgtc ttctatgatg 240ccaggtgctg gccaagcgct cgatgcaggc tgctccagtt aggtcgatgc gatggcggga 300agcactttcc tctgcaatgg agagacgccg acaccccgag cccgaaggct tgcaaggcgc 360gctctcgcca ctggggtcgg ggatccgtgg gttctctatc ccgcttaccc actccatcct 420tagcagctgt cgtcggtccc agacctctac cttggagaga ccaaggcggc ccagagccca 480ggagactact gcgcggtacg ccaggatcca gaagtggatt ctgacttcta aagacccctc 540ccaagccaac gctatcaggg tccctgcaag cggttgactg tggcggaggc agaaccaaaa 600cctttgctct gcccgcggcg ctccagcctc tcacccagga cagtgctctg ggctccagcc 660gctgcagtgg ggtcgggaca cagacgccga gttagaagcc ccgccgctgc aggtccctgc 720ttggtcggcg cggtgacggt gtcgctggcg gcggcggggg ccttcctttg gctgcccggc 780catttaatca gagctattat 8001241000DNAHomo sapiens 124tttagtattt aaggagaaaa gcctcatttt ccagaatcga ataagcgaat taatcgcaca 60attgtgtaga atggaactca gtctgtaaaa aatcaagacc aacgtacttt ttaatattct 120aacatctcca agtagtagtt acaagtattg tacccatgaa gtccaggtaa ttaatttgtt 180caatgtcaca ctgttaaaag tcaggtgggc tccaaagcac agtcctaacc agcatgctct 240actgcctcct ctgaggcaac agccgaagtg cagaccactg ggaataaata gctgcccggt 300cttccccact cctaaattct cccgacagac cccaaagcct ctctgagagc ctctctgacc 360gccctgcggc ccaccccgag ttcccggcat cctctgggat ccctcttcct ggagccaaaa 420cctacgcagg ctcctttcct ccgagctggt tgctaggtga tctccgaagg ctgtccgaag 480tctcgcgagg gcggacccgt tgcctgatga cgagagttgg gagtgtggct ggggctgcgg 540atctccagca gtggcgttac ttctagcggc tggataccgg gttctccgcg agatcgcgag 600atcccgagat attctccccg cacggaagcg acgactggcc tggccagagg actcgcgtgg 660gagcgaggtg ccggccccga caggacggtg aggtatgcag aagtaaggcg gggcgccccc 720tgcgggaagc gagcgcgccc cggaaaatga gcgcctcccc acaccaaggt gtccaggagt 780gagtgcggga aggaactcgg ccgcccggag ttgtggcctc atcgtgcttc ccgccaaaaa 840cgccttggta ctgtcgggac gcggctaagc gtggacgcgc ccgcatctgc ccctcctccg 900cagtggtgga agacacccgc ggagcgccgg tggataaggg ccgtttcctg agaccagagc 960tgtatccgca gcaggtcagc acttcgtgcg ccctgtgtgc 1000125300DNAHomo sapiens 125agcggcgctg ttcccgggct gggtgcagct gctaaggaca aggcccctgc tccgaagaac 60gcggtggctc ggggataccc tgaaagggac ggccatggcg cacatgggat gccctagggt 120tcgtgggagg gcatgcaggc gcagcccccg caggggttgg cctgccagag aaggcagggg 180agagcactcg gggctgcaca aatggtgtgg ccggagggaa ggtgcagcct tgtgtgtgtc 240tggatgaggg ctgggcatag gagcttggta tttgatcctg aaagctctgc gtttccaaag 300126600DNAHomo sapiens 126gagtcatact tgtagtcaca tccttttcct ttctccaacc cactggttaa tcatgaaagg 60ctcttctgat tggctgcctc ctggcagtag tgcctcagcg cgacggttcg ggagcaaata 120aataattccc gctgggaagc tgtttctcag acaggagcag cgacacccct gccacgcctg 180ccgcctggag ttgagtgggg taagcacgcc ggcctccagg aatcgacggt gccacgtggt 240tcttcttgca cttctcttct tctccagttt caggggacac cgtggggtgt gcgagcccgg 300gggagcgcag ggaagggcgg gttgggctgc aggtgggaat gtgcggtcct tctgcgccct 360caacagagct tccttccttt ttgccaaggt ccccgtgccg ccttcagcgc gcctccttat 420gcacctctac ctctgctgca gcgtacctct tccgcagccc tagcggcctc cccgaggggc 480gccgcggcct cggctgtccc tcccctgcct ggcacgacca cctgaccccc agcgacccaa 540gaagcaagtt gtgtttgcag acgcaaaggg gctgtcgttg gtatcggtgc actggtttga 6001271700DNAHomo sapiens 127acactttctg tgtgggaggg cacaagacat gggctatgac atggccagag accccacctt 60ctttacacat gtaaaaacca accaaatcaa gatgcgtcaa cggtgattct tcctcccaca 120ttgtttccct ttttaaactg ttattttttc aatccatgga gcagttgaga aacgggtatg 180catctctcct cccctcccct tctatcaaag cctgtaagac acataaggaa atccaaagcc 240acagtaatag agagagagag agagagagag agagagagag agagagagag agagaaaaca 300gaacaaaaga aatcctcctt ggcttgtttt tccagggtgg ccaggcaagg tgtgaaaatc 360catatttccc tctgggctgg caggtagaag ttactgggaa ggctgcgctc ccttctctcc 420caccggctct cacatccagg ctgttccctc accctcagcc tcccccagcg ccagcttcct 480cctccgcctc tctgcagcca ggcctcccct gcaaggcgga ccttggccca ccttggttcc 540gggccaaggc ggcgggaaag gcaccgctac ctgcagccgc acgactccac caccatgtcc 600tcgtactgct tgtagaccac attattgccc gcgtcgatgt atagaatgct gatgggagtc 660aatttggtgg gcacgcagca gctgggcggg gtggagccgg ggtccatgga gttcatcagc 720gtctggatga tggcgtggtt ggtgggctcc aggtgcgagc gcagcgggaa gtcgcataca 780ccctcgcagt gataggcctc gtactccagg ggcgcgataa tccagtcgtc ccagcccagc 840tccttgaagt tcacgtgcag gggcttcttg ctgcagcgta gcctggactt cttgccgtgc 900cgcttgccat ggcgactggc gaaggccgtg cgccgccgcc ggcggccggg cgagggcagc 960caaggcctgg catccggggc gcccgacggc ggcggccacg acccctcggc gcccgcgccc 1020gggcccgcag cctcggccga gcccagctgc tcgcgcatct ctgcgaacag gttcttgcgc 1080tgggatctgg tgaataccac cagcagggcc cgctcctggg gaggccgcac cctccggccg 1140aagcccagac tccgcaggtc cgggggcggc ggttgctggg gtccccgcgc gcgcgcctcg 1200gcctccccgg cgtccagctc gccccatgcg gcccgcagct ccaagcacag ctgcttccag 1260ggctggtggc gcaggccctg ccacacgtcg aagacttccc agccggccgg cggcgccccc 1320tgcgggtcca gggtccgcgc gtccagcagt aggggcgaaa ggcaagggaa gagctgcacg 1380tggagcggcc cggctggtgg cccccagggc gctgagggcg cctggcgaaa gagccgcagc 1440tccgcgccca ccagctcttc tttgtctgag agcatggaca catcaaacaa atacttctgt 1500ctccggagag gagtgtgcga gagatcgtct gcgagataaa aaataattac agtcagtttc 1560acttaagggg gagatcagcc cggtgctctt cggccgcccc gggaggaaaa gggcggggag 1620tgggggcagg tcggccgggc agtccagctt gcccggccca gggcctgacc accccggctc 1680cccatctggc tggtgcatgg 17001282000DNAHomo sapiens 128gcccgctgtg aatgtaggtg aggtgatccc gggaacctgg gtctgaaatc agacctgtgt 60tgccattggg agcacggaga gaggggaagc gccctgctta ggcccaggcc gggcgtcctg 120gtggtgggac cgcagccgca ctcacctcca ggccaacgga caaggttcct gcaagccagc 180agggccactc tgtgcttggc ctactgcagc tcccctgcag ctcctttcct ctccctcccc 240ggagcgctct cctctctcct ctcccctctc ttctctctcc tctctcgtct cctggggcat 300cccgggtgga gggatgtagg ggtcgctcct cggtgccagg ccgggaagca gctcaggcct 360cccaagagct tggcgctcag tctgggaaaa ggggttcctc tggcctcagg gacgttctcc 420gcccccaccc caccccctgg gagcctgaac catctggaag ggatcttagt cgggggttgg 480gaggagagcc cgtggatagg aggagggggc gattctaggc cgaatccagc ccctgaggtg 540tcacttttct ttcctgcggc ccgtcaccgc tgatagatgg ggctgagggc agaggaagga 600aaaagaaaac ctccgaggtc agtgcggggc gaggtgagcc cctcccaggg ccctctggcc 660caggaggatg aagcgcgccg gcttcgctct tgcacgccgg cttgccatcc gggtaagcgc 720gggaaaggcg gccacagggc gcggcggcag cgcagcgcgt gggatctcac gacccatccg 780ttaacccacc gttcccagga gctccgaggc gcagcggcga cagaggttcg ccccggcctg 840ctagcattgg cattgcggtt gactgagctt cgcctaacag gcttggggag ggtgggctgg 900gctgggctgg gctgggctgg gtgctgcccg gctgtccgcc tttcgttttc ctgggaccga 960ggagtcttcc gctccgtatc tgcctagagt ctgaatccga ctttctttcc tttgggcacg 1020cgctcgccag tggagcactt cttgttctgg ccccgggctg atctgcacgc ggacttgagc 1080aggtgccaag gtgccacgca gtcccctcac ggctttcggg gggtcttgga gtcgggtggg 1140gagggagact taggtgtggt aacctgcgca ggtgccaaag ggcagaagga gcagccttgg 1200attatagtca cggtctctcc ctctcttccc tgccattttt agggctttct ctacgtgctg 1260ttgtctcact gggtttttgt cggagcccca cgccctccgg cctctgattc ctggaagaaa 1320gggttggtcc cctcagcacc cccagcatcc cggaaaatgg ggagcaaggc tctgccagcg 1380cccatcccgc tccacccgtc gctgcagctc accaattact ccttcctgca ggccgtgaac 1440accttcccgg ccacggtgga ccacctgcag ggcctgtacg gtctcagcgc ggtacagacc 1500atgcacatga accactggac gctggggtat cccaatgtgc acgagatcac ccgctccacc 1560atcacggaga tggcggcggc gcagggcctc gtggacgcgc gcttcccctt cccggccctg 1620ccttttacca cccacctatt ccaccccaag cagggggcca ttgcccacgt cctcccagcc 1680ctgcacaagg accggccccg ttttgacttt gccaatttgg cggtggctgc cacgcaagag 1740gatccgccta agatgggaga cctgagcaag ctgagcccag gactgggtag ccccatctcg 1800ggcctcagta aattgactcc ggacagaaag ccctctcgag gaaggttgcc ctccaaaacg 1860aaaaaagagt ttatctgcaa gttttgcggc agacacttta ccaaatccta caatttgctc 1920atccatgaga ggacccacac ggacgagagg ccgtacacgt gtgacatctg ccacaaggcc 1980ttccggaggc aagatcacct 20001292000DNAHomo sapiens 129cactcccccg ccgcctccgc ccctaaccct cggccccgtg cgcgagcgag cgagggagcg 60aacgcagcgc aacaaaacaa actagtgccg gcttcctgtt gtgcaactcg ctcctgagtg 120agtcgggggc cgaaagggtg ctgcggctgg gaagcccggg cgccggggac ctgcgcgcgc 180tgcccggcct ggccggagcc tgtagcccgg gggcgccacg gccgggctcg cagtcccccc 240acgccggccc cccggtcccc gccgagccag tgtcctcacc ctgtggtttc ctttcgcttc 300tcgcctccca aacacctcca gcaagtcgga gggcgcgaac gcggagccag aaacccttcc 360ccaaagtttc tcccgccagg tacctaattg aatcatccat aggatgacaa atcagccagg 420gccaagattt ccagacactt gagtgacttc ccggtccccg aggtgacttg tcagctccag 480tgagtaactt ggaactgtcg ctcggggcaa ggtgtgtgtc taggagagag ccggcggctc 540actcacgctt tccagagagc gacccgggcc gacttcaaaa tacacacagg gtcatttata 600gggactggag ccgcgcgcag gacaacgtct ccgagactga gacattttcc aaacagtgct 660gacattttgt cgggccccat aaaaaatgta aacgcgaggt gacgaacccg gcggggaggg 720ttcgtgtctg gctgtgtctg cgtcctggcg gcgtgggagg ttatagttcc agacctggcg 780gctgcggatc gccgggccgg tacccgcgag gagtgtaggt accctcagcc cgaccacctc 840ccgcaatcat ggggacaccg gcttggatga gacacaggcg tggaaaacag ccttcgtgaa 900actccacaaa cacgtggaac ttgaaaagac aactacagcc ccgcgtgtgc gcgagagacc 960tcacgtcacc ccatcagttc ccacttcgcc aaagtttccc ttcagtgggg actccagagt 1020ggtgcgcccc atgcccgtgc gtcctgtaac gtgccctgat tgtgtacccc tctgcccgct 1080ctacttgaaa tgaaaacaca aaaactgttc cgaattagcg caactttaaa gccccgttat 1140ctgtcttcta cactgggcgc tcttaggcca ctgacagaaa catggtttga accctaattg 1200ttgctatcag tctcagtcag cgcaggtctc tcagtgacct gtgacgccgg gagttgaggt 1260gcgcgtatcc ttaaacccgc gcgaacgcca ccggctcagc gtagaaaact atttgtaatc 1320cctagtttgc gtctctgagc tttaactccc ccacactctc aagcgcccgg tttctcctcg 1380tctctcgcct gcgagcaaag ttcctatggc atccacttac caggtaaccg ggatttccac 1440aacaaagccc ggcgtgcggg tcccttcccc cggccggcca gcgcgagtga cagcgggcgg 1500ccggcgctgg cgaggagtaa cttggggctc cagcccttca gagcgctccg cgggctgtgc 1560ctccttcgga aatgaaaacc cccatccaaa cggggggacg gagcgcggaa acccggccca 1620agtgccgtgt gtgcgcgcgc gtctgcgagg gcagcggcgg cagggggagg aggaggcaga 1680ggcggggtgg ctggaccctc ggcatcagct cattctcccc tgctacacac atacacacac 1740aaataatgtt tctaaaaagt tcagttgcga ctttgtgcct cgcctgtcct gttcatcctc 1800gtcctgggcc ggggaatgct tctgggggcc gaccccggga tgctggctaa ttgctgccgg 1860cgggttccgt cgccggtgtg accctggacg gcgcggacgg cgtacagggg gtcccgggag 1920gggcagtggc cgcggcactc gccgccggtg cccgtgcgcg ccgcgctctg ggctgcccgg 1980gcggcgcagt gtggacgcgg 2000130800DNAHomo sapiens 130ctgaaaagcc gtcagggaaa ccacacatgt tcaacccctg gcggctcccc caaacctctc 60atttccagta actgtgtgtt tccgctcgtc aacagctgaa accgagcgga acttgggggg 120ccccaccacg cggccctgct gtgcggcacg gggctcatct gtcccccggc tgcggggagt 180cagctctcac cgcccacctc cttcccagat agtctctgtg cccactcgac ggcccggcaa 240gcccagcccc tgcctgccac ggccacagca gcctcagaga gctgccctct ctggccaggg 300tcagggcctg agctgctgcc tcccgcaggg tcgagggcag gacacttgtc tgaggcttgg 360gtggggcaat ggcacctcct cagggcctca gcccccgggc aggctcggtg accatgggcc 420tacagcaggg aaaattctgg gccaaaagct ccagcctcct actagggcat ctgtctgcaa 480atgcacctta acctgaccgc ttgggctgtg ggggagcctg tttcagggaa agtgagggac 540gcgccagttt cctcctttgg acttgatgag gcacgaacgc atctctaata aagccaggtc 600tccccgccgt ggctccctgg gcgggtgcct gtggctcggg ccatgagtca cgctgggtaa 660ccccactacg gggaagaggg caggaagctg ggagccaccg cctctgtgcc cggttgtcat 720ctcggcacga gggcgaccgt cggcttcgtc ctgccctcat ggctgagggc ttttgggatg 780tggcgggaga cgggggagtc 800131500DNAHomo sapiens 131aaatcatcag aatggctaaa atgaaaaaga cagacaacag caagtgctga caagggtgtg 60gggcggccaa atgctcctgc actgctggca ggggacctga gaactgcagg gcattccctg 120gcttcctgcc cctcctggga ctggggaccc cccagggaca gcctaaggga actgcattta 180tcttcacgtc tgccaaaaga taacacgaag atgttcaaag ctaagccccc aggctggtaa 240gagctccaag gcaccagcag tgtgtgcaga actgggggga gtctgttctc ccagggatgc 300tcccatcacc tgctgccagc agtggggcat gccggtcccc tggggtgtgg ccaaggggct 360gtgtctcctg cccgggctgc cggcccctct caggttcact ttcccatctc taagcccacg 420tctcgctgca gttcaagttt gccaggccac caacgggtga cacgcccggc gcagtggggg 480actccgcact ttctgcgcac 5001321200DNAHomo sapiens 132accctttgtg cctgggtccc ataaacaatg tgctttttaa aggggagccc cctcccagct 60ccggcctttt tctccagcgt gggcagccaa tcagctgcgc agagctgcat agctggaccg 120ctttccattc tgagtagcaa caacgtacta atttgatgca cacatggatg cctcgcgcac 180tctgcaaatt catcacccgc atcttgcatt agtcatctga cggactgcca agtgtttcat 240tttctttcca tgtgacttta ttattaccac ctctctcctc tcttccaaaa acctcccaaa 300aagggcggtg gggcgggggg cggggcaggg agagggagag aaatccagca gacatctagc 360tctgcctttc tttcccagcc acagccaggg tagggctgat aaggcgctga tgcgttgatg 420gcagccttgc agagctagac ctgcacttaa cttgcagctg cctcccgagc ctccaagatg 480tccacgccct gggtgacagg cggcagggcg ctgccccgtg ctcccccggc tctgctcgac 540agcagcacgc agtgagagcc tcgccgccgc cgaggagcaa ctcatggtgc ctccgctttg 600ttttagttca tcaaatttct acgactcatt aggcactttg ccactgctct tcttcctcct 660ccttccgcct ccccgctccc ccacccccac tattttttct tcctgtccct catcgtgccg 720ccctaactct ggctcccggt tccgtttttg acagtaacgg cacagccaac aagatgaacg 780gagctttgga tcactcagac caaccagacc cagatgccat taagatgttt gtcggacaga 840tcccccggtc atggtcggaa aaggagctga aagaactttt tgagccttac ggagccgtct 900accagatcaa cgtcctccgg gaccggagtc agaaccctcc gcagagtaaa ggtacagagc 960gcggggcggg ggtcgccagg cgtccaggtg ggcgtcgcgg ggcactgggg ctgtccgagc 1020ccccagcctg caggaggaag ggcgggtagg caggagggct ggaagcagcc ggtgctggcg 1080gcccctgtgc tccaggggct gctcccgact cctccccgca cccccgcccg cctgcccgcc 1140gggacaggtt ggaggcggga gagagggacc gaggcagggc gggagcgcag aggctcggtc 1200133800DNAHomo sapiens 133taacaaataa gccgcccgtg gtccgcgctg tgggtgaccc ttggcgcctt cgaggtctgg 60agccctaggg taaataagga aacggggcgc ctctagagtt ttaaatgaac tctgttattg 120gaagcttcag tagggaccct gaaaacaatt aacgtcttaa ttagcatttt aatgtctcca 180ttattacggc gcgggctcta gctcagccct ttaccttacc ttctcaccgt taacagggga 240gggggattgt atttttagtt catcttttta tgtttttgag ttgttatcct gtctgtctga 300ttccagcctc gagggtttga tgatgcggcc cgagcctggc tgtggtcgcc tgtcggggct 360ggagcgggac cctcagccgg gccgggcctg ggggctaacg ttttcacagt gcgccctgag 420tttccttggg ttactgctgg gaccgcgcag gaggaagcaa agagtttttc gagctagacc 480aacaggaaac acattgacgg aaatgttgcc atagcccatg gggtggcttt aactggccgc 540ccccgcgggc tgggtgtgaa atcagaggag gccgcggctc ccccggccag gattggaggc 600tcctcgcgca acctaatgcg ggtgtccggg cccgagcgct tcccgcgcag ccaggccttg 660tcggtgcagc agccccgctc ctccccaaca cgcacacacc cggtgttcgc aagtgcggct 720caccaaggga gatccaaggg ggcaaaaagt tatgtataaa tccgagagcc actggggaaa 780gagggtcgtg gtattgtaag 800134500DNAHomo sapiens 134ctaccctgtg ctatcctgag ctgtagtctt ctgaaatgat cgtttggctt cccagccaag 60gcagggctcc cccaaagttc attcccactc ttgcagtttc acctcgggat gcttccgcag 120aatttcagcg cctaagcaga caaggtcaaa gtaaaccgct tcaccgctgc ttctggcgca 180ggggcccaga gcgcgtgcag ctccccagca cagaccaaca gcaggagagg ggtccgggcg 240ggagccctgg gctgtagata agcaaaacgc acccattttc tctcctattt actccagagg 300cacctctcct cccccactcc tggcatctct ttatcactgg ctccctctcc ctgtggcata 360tttttgggta gtagaatgct gaggtcacag ggagcggctc tttatccaag cagtggggac 420atcagcctgg agccctgagc atgaaccagc aagatgcaga ctctcgctct tgactttggg 480ctccaggagc tgccccgacc 5001351100DNAHomo sapiens 135cagtgctccg ctccgggaaa ttgcatcgtc acgacaaacg ggaccgtgat aaaacgaccc 60tttccgtcct tatttgtaga tcactcagac gagattgaac tgcacttgtt tccccttcga 120ggggagccgc gttttcaggg tagccgaagg cttggggctg agggggggcc ctcaccaagg 180cgcgggtggg ggccggagcc tcaactcgat gagaagtgac aggcgtttgg gggatctggg 240ctccggccgg gaccagcgca agcagggact ttgcggggac accgcttctc caacagagca 300aggcctggcc cacgtttccg gtttctccta acttcctttt attgccttcc tttgcttcgc 360aagttccatc tacccctcca gctacagagc cccacctcta ggcacaggaa gcttcccgga 420aaaagaaagg ctgtcccaga aagagaccga gagagacttt ccaaacttcg ggcatagcca 480cggcaattcc cagtctgcta atgccaaggc gggcgcgtaa ggccgcctaa atctagacct 540ccctcctcac tcatttcaaa aaataacaac gtgccagcca cctccgcaga taccgccggc 600tggtgcttgc ccaggagacg ccagggccag agcgccactc ccagcatcga aatggcagag 660agaaagcgca gctccaaatt ccccttcaga ggttaagcct caatcattgt gtcccttccc 720tagggactgc tggcgctctc gcccactggc gatgattatg cgcctagaac tcgaccgcga 780agcaactaat aggaaaacat atggtgtcaa tttggatgct ccgcgcctcg cgcacacccg 840ggaacgagcg gcacaaagcc ctgccggccg gcccgcgacc ccgcgcccct cggggcctgc 900cagccgggcc gcagcgacaa acgctcaggg ctgcgcgccc tggctggggc ccgcccgaga 960gacagcctgc ggctggggag tctgagctcc aaggggagag cccagccgcc gaaggcgagc 1020ctaccggcca agccctgggg tccggcaggt tctgcacaac tactcccgca aagctcgcca 1080cctttgtgcc ctttcctcag 1100136500DNAHomo sapiens 136gggccctcgc ggctcaagcg ccagcgctgg agagagagtc tgagggtacc acgggcgtgc 60tggcctgggt gctcactccc gccctccttc atgagcggct ttcctctggg tgtgtccagg 120gcatcacaga gctcttctgc ccaaacccgg aggcctacca gggcctgccc accttgcctc 180cttccacact ctctgtagca gcagccgcag ccatggcggg gatgaagaca gcctccgggg 240actacatcga ctcgtcatgg gagctgcggg tgtttgtggg agaggaggac ccagaggccg 300agtcggtcac cctgcgggtc actggggagt cgcacatcgg cggggtgctc ctgaagattg 360tggagcagat cagtgagtgt ccgctgcccg cttgctgaac tcggcaccat gggcggccgc 420cacgggtgtc tctgggcact tccgggccat ccctgctgct cagctcccga taatggtgtc 480acggtgactc aggcattagc 500137600DNAHomo sapiens 137tgtttacgga atcgggatcg aggggccgat aagtagttta cacgccggcc agagcagagg 60gctggaggtc ggagttgggg gctggaggaa cgggtggcgt ttttaggatt cagtaacagg 120atcacagctt tttcttgtgg tggaagctat tggaatttgg ggagggtagc acgaggggtc 180ctgcagctcc gcgtgtgaaa aagcgtttag gtaggcgatg

aaagtagttg atctgagcca 240tggcaggcga gccccgaatt tttgctgctt ccccctgaaa gtgtttcttt aggaggagag 300gacttgggcc acacaggacc cggtcctaag agagcgattc cgggaagcgg acagatcgaa 360gagaccttct gggcgaagcg gcagggcagc ctcgcggggc tgggagtgga tctgaggtcc 420cgacccaggc ggctcggagt gctccaggag ccacctgggt ctgcgggcgc agcgcggcgg 480ggcgggagcg gtggcccgca ggggccgcgg cctgcgatga aggccggggg gcagcgctag 540cagcgaggtg ccacagtggg ccgaggagtc tgggctgtgg cccagggtag gaccggctca 600138150DNAHomo sapiens 138acctaaacca agctctccct ccctgccgtc tccttccctg gcctgggtct gaaggagagg 60aggtgcccag aagttcagag cggcataacc acagagatac tacctaatta acataccaga 120agcataaaga actcatttgc attggagagt 150139900DNAHomo sapiens 139ataactacgg gggtgggggt ggggaaggaa gagatccaag gaggcagaag gctgcggtca 60aaatattttg gggtggcaga gtcacgtagg atgtggctgt gggttctggc agcccagaga 120ttcagctccc gcctcctccc tcagagcgag tccatagcta ccctcacgtc ccccgtggcg 180gtcctcgcca cgctccggag cgggttaccc atgagggtgc tagacctggg cagcgggaac 240ctcgaagagg tggagattgc aggctgggac tccagatttc gggcagggat gcggggaagg 300gaagacgcct cgctggaggc ggaatggagg gcaaggcgaa ggaggatggt gcaggaaacg 360gcgacaaggc gcccggccag gcccgcgagc taccgagacc cgggttccaa tcctcccccc 420ttccgcaaac gcccgggttc gaggtacctg gcgggcaagg gccgcagcgg agcgaagcgg 480gctggccatg gggaggctgc ggggacgcgg ggctgcagag agcggcagtg gcacggagcg 540cgcggctgga agcgaaagca ggcggtgtgg ccaagccccg gcgcacggcc catagggcgc 600tgggtaccac gacctggggc cgcgcgccag ggccaggcgc agggtacgac gcaacccctc 660cagcatccct tggggaggag cctccaaccg tctcgtccca gtctgtctgc agtcgctaaa 720accgaagcgg ttgtccctgt caccggggtc gcttgcggag gcccgagaat gcgcgccacg 780aacgagcgcc tttccaagcg cagatatttc gcgagcatcc ttgtttatta aacaacctct 840aggtgaatgg ccgggaagcg cccctcggtc aaggctaagg aaacctcgga gaaactacat 900140600DNAHomo sapiens 140cagtccagcc gcttgcctca cttcttcccg cttgccttat ctccccgcag acgtggttcc 60cctgcagccc gaggtgagca gctaccggcg cgggcgcaag aaacgcgtgc cctacactaa 120ggtgcagctg aaggagctag agaaggaata cgcggctagc aagttcatca ccaaagagaa 180gcgccggcgc atctccgcca ccacgaacct ctctgagcgc caggtaacca tctggttcca 240gaaccggcgg gtcaaagaga agaaggtggt cagcaaatcg aaagcgcctc atctccactc 300cacctgacca cccacccgct gcttgcccca tctatttatg tctccgcttt gtaccataac 360cgaacccacg gaaagacgct gcgcgggtgc agaagagtat ttaatgttaa ggaaagagaa 420gaaccgcgcc gcccggaggc agagaggctc catggccgtg ctgctgggcc atccccaact 480ccctatccca tccccagcct ccacccccat ccagatggga ctcacgtggc ttcaacagct 540ttggaaatgg gtcccgagtg ggccgtgcga ggaaggctgt cgacctctac tcctccttgc 6001411500DNAHomo sapiens 141caagatcgac tttcttagga agggggagag gagggaactc ttcacgaagg gaggtgggag 60tccacctcag acctctattg gaaggaaatc gagttgttcc gggggactga ggtctcttgc 120ataaggcatg ggatccttat tattattatt attattttta aatcccccgc ggaggagctc 180tgggcaaatg aataccgagg cgccgctcta gctggttagg cttgggatgc gataactcag 240tgccctcttg cagacttgca tagaaataat tactgggttg tcgtggaggg gacacgagac 300agagggagtt ctccgtaatg tgccttgcgg agagaaaggt ccaagaatgc aattcgtccc 360agagtggccc ggcaggggcg gggtgcgagt gggtggtgga gtaggggtgg gagtggagag 420aggtggtttc tgtagagaat aattattgta ccagggcccg ccgaggcacg aggcactcta 480ttttgttttg taatcacgac gactattatt tttagtctga tcaatgggca caatttctaa 540gcagcgcagt ggtggatgct cgcaaacttt tgcgcaccgc tggaaaccca ctaggttgag 600ttgcaaaacg taccgcgtag acgcccctgg tggcgccgag agaagagcta ggcctgccca 660gcacagagcc ggagagcgtc gggccttccg gaagggtaag ttctccgcca aggggtcccg 720agggagctgg acgtctgaat ctggacttgc ccccagcttc ggggttcgat tctgggtttt 780gcgcgtcccc aacccccagg gctttccgaa gcatggcctg gctccaggcc cggtcctgta 840aggactggaa cggcagcaaa atgtgcaggg aggcagtcgg ccggcagagc tgcggcggga 900gccaaggtca ggcccgcggg gagagcgggc agcttccagc gccggccaca agctcccagg 960ccagctgggc cgcagacccc tttgcttcca gagagcacaa cccgcgtcct ttctctcagc 1020caggctgcag tggctgcccc gagcttcgct ttcgtttccc aagctgttaa taacgatatg 1080tccccaaatc cgaggctcgt gtttgctccc agatgccaag aacgcaaccc gaaatccttc 1140tcccaaaccc taggtcgacg agatgagttc ctacttgacc tctgagccga ggtgggccgg 1200aaaccgaggc ctaggccccg ccggggctgc aaggaaaagg ggaaactccg agcgtagcgt 1260cttttccttg tggttccttt ctccggcatc ccggactgcg ggccctgcag ccacctggac 1320cggcattcaa aggattctgc aagtccagct tcacagactg gctttcccag acgctccgaa 1380gcccgcacca cgaacagaat aaaggagaga cgagagatcg caactagatt tgagaatcct 1440cgttcttttc cccaatcgtt cgggcagtaa actccggagc cggctacagc gcgcatcctc 1500142500DNAHomo sapiens 142actgtcctcc tccctcaatt gcctattttt tgcccatagc tctaacttaa ccctgtgatc 60accccagatc gctacttctg acccccatct cctctcccac accaacctcc agcgcgcgaa 120gcagagaacg agaggaaagt ttgcggggtt cgaatcgaaa atgtcgacat cttgctaatg 180gtctgcaaac ttccgccaat tatgactgac ctcccagact cggccccagg aggctcgtat 240taggcaggga ggccgccgta attctgggat caaaagcggg aaggtgcgaa ctcctctttg 300tctctgcgtg cccggcgcgc ccccctcccg gtgggtgata aacccactct ggcgccggcc 360atgcgctggg tgattaattt gcgaacaaac aaaagcggcc tggtggccac tgcattcggg 420ttaaacattg gccagcgtgt tccgaaggct tgtgctgggc ctggcctcca ggagaaccca 480cgaggccagc gctccccgga 500143900DNAHomo sapiens 143ctcagggaat cacatgtccg cctggcctgg cctggtacca aatgtttata gacaggacga 60gggtcgctgg aatcgcctcg ctcctttcag cttggcgcta aggcgcgaat ctcgatcctc 120ctagtatttc tctggcgtct gtctctatct cagtctctgc ttttgtctct ttctccctcc 180ctccgcccca gtctttccgt ctctttttcc tcgaatgcac gtggaattcg gaattgaaaa 240ttgaggtcag aatctccctt tttcttccag ttatccgcgc cgctgcccca cgcctagcgg 300cttggatctg catagacatc tatctacccg caacaagatc cgagctgcag aagcaaacct 360aatctgtctc cgcaccatcc cctgctctgt agacccactg ccccatccca cgccacatcc 420ttgaggttca agtagcgact ccagcggatg attcggagaa tgccctgctt tccaaaggcc 480ccaacccgtg tttttatttt ctttttcctt tgcccgcttg accaactttg gtttctttca 540gggcccggag gtgcctgcgc cgcgcttggc tttgctttcc gccgccccag gagacccggg 600actgtggttt ccgctcgcca catcccagcc tggtgcgcac acaagagcct ggcgagcttc 660cctcgcgcgc ttacagtcaa ctactttggg cctcggtttc cctgctcctt gtagatcaga 720gaagggacgg gcgaaatgcc tgcgagggag ggttggcgaa tgggttggtt ggtggcaaga 780ctgcagttct tgtacatgga cgggggttgg ggggtcaaca ctggaagaac tcctgcctga 840cgccaagagc cacccgcttt ccagctcgtc ccactccgcg gatgtttacc caccttcatg 900144500DNAHomo sapiens 144tttggggcac ccaacccttc ccaagcctcg gttttcccga tcttgtggga tccttgcggc 60gcgaatgggg ttggaagcac cttggaagct acagagtacc gggtcgggac aatttccggc 120actgccccag ttcagtggtt tatagaaaat ttctttctct ctctcaggtc cactaagacc 180gagagagaga gagaagtcga ctctggcaca cccgggcgag gggctgccgg gattcgggag 240ctggcgcggt tgattttttc cgagaatcct ccacttgggg tgacgtcggg cagcgcgcgc 300gggccgtgag gttaatgccc aggcttttct ctaaagcgtc cgggaatgat ccggcgaata 360aaacgggtgt ctgcaaagtt aatgaattgt acaaggaggc tgagggtggg gacttcgacc 420cggggagcca gaggcggttc tggtggacgc ttccccgtgc gcctaggggt gcgctgggct 480ttcccagccg aggtctgcag 5001452000DNAHomo sapiens 145ccagacagtt aaggtaaaac gttgaagtca agaggaagta gtgagtctgt tgccaactgg 60atagggttgg tcctgtccca tctaaatgta ttagaattaa gtggctttta aaaatgagct 120ggtcatcttc agcccacggg ctggccaatt tggaacttaa tgggcctttg cgtcctcctt 180ccctgagcct ccttttattc cagacttctc agtgtgagtc tgtgcgtccc tccgacgatc 240tcagggagtg gggtgccttc atctgcctgt tccctgttcc tcaggctgac gctcccgctg 300tcctccccgc ctcccctcac tccttttctc cctcccttcc tccttgtggg gaggctcttg 360gccagggtcc ctgagcccgg gcgggtgctg gcagaggacg cagaaggggt gaggtcacgt 420ctcccttgag ccccgagccg ctggcttttc agagcctcgc cacaagccgg cggccagagc 480cccagaccac acagaccgtg cgctcctccg ccctcccggc gccgccggcc tcgcccatgt 540ctcagtacgc ccctagcccg gacttcaaga gggctttgga cagcagtccc gaggccaaca 600ctgaagatga caagaccgag gaggacgtgc ccatgcccaa gaactacctg tggctcacca 660tcgtctcgtg tttttgccct gcgtacccca tcaacatcgt ggctttggtc ttttccatca 720tggtgagtga atcacggcca gaggcagcct gggaggagag acccgggcgg ctttgagccc 780ctgcagggga gtccgcgcgc tctctgcggc tcccttcctc acggcccggc ccgcgctagg 840tgttctttgt cctcgcacct cctcctcacc tttctcgggc tctcagagct ctccccgcaa 900tcatcagcac ctcctctgca ctcctcgtgg tactcagagc cctgatcaag cttcccccag 960gctagctttc ctcttctttc cagctcccag ggtgcgtttc ctctccaacc cggggaagtt 1020cttccgtgga ctttgctgac tcctctgacc ttcctaggca cttgcccggg gcttctcaac 1080cctcttttct agagccccag tgcgcgccac cctagcgagc gcagtaagct cataccccga 1140gcatgcaggc tctacgttcc tttccctgcc gctccggggg ctcctgctct ccagcgccca 1200ggactgtctc tatctcagcc tgtgctccct tctctctttg ctgcgcccaa gggcaccgct 1260tccgccactc tccggggggt ccccaggcga ttcctgatgc cccctccttg atcccgtttc 1320cgcgctttgg cacggcacgc tctgtccagg caacagtttc ctctcgcttc ttcctacacc 1380caacttcctc tccttgcctc cctccggcgc ccccttttta acgcgcccga ggctggctca 1440cacccactac ctctttaggc ctttcttagg ctccccgtgt gcccccctca ccagcaaagt 1500gggtgcgcct ctcttactct ttctacccag cgcgtcgtag ttcctccccg tttgctgcgc 1560actggcccta acctctcttc tcttggtgtc ccccagagct cccaggcgcc cctccaccgc 1620tctgtcctgc gcccggggct ctcccgggaa tgaactaggg gattccacgc aacgtgcggc 1680tccgcccgcc ctctgcgctc agacctcccg agctgcccgc ctctctagga gtggccgctg 1740gggcctctag tccgcccttc cggagctcag ctccctagcc ctcttcaacc ctggtaggaa 1800cacccgagcg aaccccacca ggagggcgac gagcgcctgc taggccctcg ccttattgac 1860tgcagcagct ggcccggggg tggcggcggg gtgaggttcg taccggcact gtcccgggac 1920aacccttgca gttgcgctcc ctcccccacc ggctcacctc gcctgcagct gggccacgga 1980actccccggc cacagacgca 2000146600DNAHomo sapiens 146ctctctgggc cttaggaaaa tggaaatgac acctgtacct gcccttccag gactgacagg 60aggggctgct ccatgaaacc tcactgctgc ggtcataatg tcattatctt ttgccttaaa 120gggatttctt ctgcaccagc acctaaagtg gcagcccctt acccttggcc atcagctgga 180ccctggtgct ctcctggagc ccaaaacctc tgttttgtgt tgcatcctgc tgaccagcca 240cagtccacac ccatctgagt gtctgagcag aacagcccag aggccacacc aggatggctt 300tccaccggtc accttccccc acccactcat aaaccctgcg tctctggggg agagggtggc 360gaggtcccct ccccacatag atggaaacac tgaggcctga ttcatggtgc cccctgtgaa 420gcgcctcatg gccagcaccg gggggcagca ggccagggcg gggacacata cccggttctc 480gtcgtagatg atctgcacca ggctgcggtg cttcgactcg atgggcggcg gtgacacggg 540cttctcaggc tcgggcggct tggcagcctc ctcctccagc tgttgctgtg gggagaggca 600147400DNAHomo sapiens 147cttgaaaact cccagccccc tttgtccaga tggggatgga ggtggccagg ctgccccgtt 60gattgtgtgc cgaggagccc tccccgggaa ggctgtgatt tatacgcgca ggcttgtcac 120ggggtgaaag gaagggccac tttttcattt tgatccaatg ttaggtttga aagccaccca 180ctgctgtaaa ctcagctgga tccgcgggcc gtgattaaac acattgcccg ctttgttgcc 240gagatggtgt ttcggaaggc gctgtgaatg cacttccctt tgcggggctc acacagacaa 300gatgtgtgtt gcaaggatga ggcgcctgct cggcctccag cccagggccg ggaagggaga 360aggtgctgtg cgtcgctgcc tgtgtcgccc gcggctctcc 4001481200DNAHomo sapiens 148cgcgtcaggg ccgagctctt cactggcctg ctccgcgctc ttcaatgcca gcgccaggcg 60ctcaccctgc agagcgtccc gcctctcaaa gaggggtgtg acccgcgagt ttagatagga 120ggttcctgcc gtggggaaca ccccgccgcc ctcggagctt tttctgtggc gcagcttctc 180cgcccgagcc gcgcgcggag ctgccggggg ctccttagca cccgggcgcc ggggccctcg 240cccttccgca gccttcactc cagccctctg ctcccgcacg ccatgaagtc gccgttctac 300cgctgccaga acaccacctc tgtggaaaaa ggcaactcgg cggtgatggg cggggtgctc 360ttcagcaccg gcctcctggg caacctgctg gccctggggc tgctggcgcg ctcggggctg 420gggtggtgct cgcggcgtcc actgcgcccg ctgccctcgg tcttctacat gctggtgtgt 480ggcctgacgg tcaccgactt gctgggcaag tgcctcctaa gcccggtggt gctggctgcc 540tacgctcaga accggagtct gcgggtgctt gcgcccgcat tggacaactc gttgtgccaa 600gccttcgcct tcttcatgtc cttctttggg ctctcctcga cactgcaact cctggccatg 660gcactggagt gctggctctc cctagggcac cctttcttct accgacggca catcaccctg 720cgcctgggcg cactggtggc cccggtggtg agcgccttct ccctggcttt ctgcgcgcta 780cctttcatgg gcttcgggaa gttcgtgcag tactgccccg gcacctggtg ctttatccag 840atggtccacg aggagggctc gctgtcggtg ctggggtact ctgtgctcta ctccagcctc 900atggcgctgc tggtcctcgc caccgtgctg tgcaacctcg gcgccatgcg caacctctat 960gcgatgcacc ggcggctgca gcggcacccg cgctcctgca ccagggactg tgccgagccg 1020cgcgcggacg ggagggaagc gtcccctcag cccctggagg agctggatca cctcctgctg 1080ctggcgctga tgaccgtgct cttcactatg tgttctctgc ccgtaattgt gagtccccgg 1140gccccgaggc agcagggcac tgagactgtc cggccgcgga tgcggggcgg gaagggtgga 12001492000DNAHomo sapiens 149cttccgccgc ggtatctgcg tgcccttttc tgggcgagcc ctgggagatc cagggagaac 60tgggcgctcc agatggtgta tgtctgtacc ttcacagcaa ggcttccctt ggatttgagg 120cttcctattt tgtctgggat cggggtttct ccttgtccca gtggcagccc cgcgttgcgg 180gttccgggcg ctgcgcggag cccaaggctg catggcagtg tgcagcgccc gccagtcggg 240ctggtgggtt gtgcactccg tcggcagctg cagaaaggtg ggagtgcagg tcttgccttt 300cctcaccggg cggttggctt ccagcaccga ggctgaccta tcgtggcaag tttgcggccc 360ccgcagatcc ccagtggaga aagagggctc ttccgatgcg atcgagtgtg cgcctccccg 420caaagcaatg cagaccctaa atcactcaag gcctggagct ccagtctcaa aggtggcaga 480aaaggccaga cctaactcga gcacctactg ccttctgctt gccccgcaga gccttcaggg 540actgactggg acgcccctgg tggcgggcag tcccatccgc catgagaacg ccgtgcaggg 600cagcgcagtg gaggtgcaga cgtaccagcc gccgtggaag gcgctcagcg agtttgccct 660ccagagcgac ctggaccaac ccgccttcca acagctggtg aggccctgcc ctacccgccc 720cgacctcggg actctgcggg ttggggattt agccacttag cctggcagag aggggagggg 780gtggccttgg gctgaggggc tgggtacagc cctaggcggt gggggagggg gaacagtggc 840gggctctgaa acctcacctc ggcccattac gcgccctaaa ccaggtctcc ctggattaaa 900gtgctcacaa gagaggtcgc aggattaacc aacccgctcc cccgccctaa tccccccctc 960gtgcgcctgg ggacctggcc tccttctccg cagggcttgc tctcagctgg cggccggtcc 1020ccaagggaca ctttccgact cggagcacgc ggccctggag caccagctcg cgtgcctctt 1080cacctgcctc ttcccggtgt ttccgccgcc ccaggtctcc ttctccgagt ccggctccct 1140aggcaactcc tccggcagcg acgtgacctc cctgtcctcg cagctcccgg acacccccaa 1200cagtatggtg ccgagtcccg tggagacgtg agggggaccc ctccctgcca gcccgcggac 1260ctcgcatgct ccctgcatga gactcaccca tgctcaggcc attccagttc cgaaagctct 1320ctcgccttcg taattattct attgttattt atgagagagt accgagagac acggtctgga 1380cagcccaagg cgccaggatg caacctgctt tcaccagact gcagacccct gctccgagga 1440ctcttagttt ttcaaaacca gaatctggga cttaccaggg ttagctctgc cctctcctct 1500cctctctacg tggccgccgc tctgtctctc cacgccccac ctgtgtcccc atctcggccg 1560gcccggagct cgcccacgcg gacccccgcc ctgccccagc tcagcgctcc ctggcggctt 1620cgcccgggct cctagcgggg aaaaggaagg ggataactca gaggaacaga cactcaaact 1680cccaaagcgc atgattgctg ggaaacagta gaaaccagac ttgccttgaa agtgtttaag 1740ttattcgacg gaggacagag tatgtgagcc tttgccgaac aaacaaacgt aagttattgt 1800tatttattgt gagaacagcc agttcatagt gggacttgta ttttgatctt aataaaaaat 1860aataacccgg ggcgacgcca ctcctctgtg ctgttggcgc ggcgggaggg ccggcggagg 1920ccagttcagg ggtcaggctg gcgtcggctg ccggggctcc gcgtgctgcg ggcggggcgg 1980gcccggtggg gattgggcgc 20001501000DNAHomo sapiens 150agtttgggga gccttttctc catttgagaa aaaacaaact tacagcgagg ggtgaggggt 60tagggtttgg gattggggaa aatgtgggtg gggagccccc ccaaggaagt gaggaggggg 120ctgcaaggat tacacctggg catacgtttc cctagaaatc acattcattg tatttttata 180atttattcta aatctttcat gcgaagaaag tcagtagtga gtgttagtac tggtggccct 240cctgatcaca cttgcatctc ttgagtgtgc cttaaaggtc ttgggaatgg aaaatataaa 300aactgcttcg tgatgcgtca tctttatccc ccactccccc acccattcca atatattttc 360tacttccagc ctaaattcgg ggccccctac cgaggccggc catgatcttg agggcggcat 420aggggaggcc gcgctctgtc caccccagcc tggtgatgcc gttcgcttct tgtgcccggt 480attgtgggct acatgccttt ccggcgtacg gagctgagcg tccaggccag tgcccctcaa 540cctctcagta atgtttaccc gaggccgtcg tgcaatgaga ctattcgcat ggcattgtca 600acgcggcggc gcgcgcgtct cggccctccg cggcttgcca gactgtcctg caaaccacct 660cacccgtctc tttggcgcag gagactcagg ctgtaaccgg agaaaacact tcaccctgga 720accctaactc aggtcctggc aaaagatgcg agaggaagac ttgctctctt aataaatctc 780ggccgcccgc acatctggcc cctagacctg ctcggtagag gactggctgg tggatgcgcg 840gtccaggccg tgggcactcg acccacctct attttccttc ccgaggcgcc cctggattac 900cactttcggt ttgcgcttac atccgggatg tcgaatttcc cagggaatca taattatttt 960atctataatt tattctaacc ccaaggttcc aagaaaatct 10001511100DNAHomo sapiens 151acattccttc taaaatgtgg gctttctgtg tacatgggcg cgcattccca ggactcggtt 60ccctgggtgg aattcaccca ggaatacaat cgattttctg aacctgcgta aggccacagg 120cagctctgaa aatgaaagcg tttgctaagt gggggagatc tcaccgatcg aacgtttaaa 180aatggctttg tcttcattca gctctcccga tttattctgt gttttacaaa tagaagctca 240gagcttctgt cgcccagtcc ttgcatgact catggcggtg gccacacggg tttcagggat 300aacgggatgt ttagaaaatc gctgcatatc ggagtttcct agcacgttcc atttatactg 360aacgcaggcg gccgctgaaa atccagcctc gactcttgct aatgactggg taggaccctc 420ggggtcctgc gacggtgctg gagggtgttc ccggctccga tgtggggagg cctgcgcggg 480gactaggttc tcgagaggcg agcgggcgcg ccagagaacc cgagactgct gcggggccgg 540atgcgggatc cctgggctgc ggttctacgc agaaacgcca atggccatgc ctccccagct 600cctcccagcc ccagtcacta ggccggcgcc tggcccggag atcctcccag agccctggcg 660gtgccatcat gccggagaag acaagctcgg ccccgctgga attcgctcca aacacagatg 720ctcatttttg gaatattcta gaaaaataac aagatcttgt ttgtcgttat gattcacggg 780aggtaactga tgggagggcc atttacatga gggcagacac tgtggggcga aggtgacttc 840tggacgtagg ctttaaagta ggaacggctc caaattccca atatctccgg ccttaccggt 900tgcaaatcgg acccctgcgg gaaaaccaga cacttctgtt tcgtggcttt cgggctgcct 960ccagcccacg caggctcgtt tagtccccgt ggagtcagcc ccgagccttc ctagtcctgg 1020aacaagggct ccaggtcgcg gccgcgggaa gccgccaaga gggcggggag tagggattcc 1080ctccagctcc gcagggcatc 11001521500DNAHomo sapiens 152tcctcctcgg cctcagatgt cgtcccacct gcccacgagc agggaacctg gaacccactc 60tcccggcagt ccccagcggg ttccgccacc cggcggccgc ccctgacacc gagtgggtgg 120gaggaagagg cagctggcgg ggatgggcca ttgagacctc ttgaaaaata ttaaaagaca 180ggatgggtag agatttctcc gggagaaagt tcgagggtgc atcgggtcgc ggctgggagg 240agtacccgaa atgccagcag gagaaatgca acctgtttag gccacacctt caatccccga 300ggctgtctgg agagactgcg tgcgggggac ttgccggcgt tcccacaccg cgcctgcaat 360ccactcccgc ggctgcctgg cctctgccac tcgcggcttg aagccagtgg ctctcaagcc 420ctcggccccg cggcggcccg cgcagccttc acccggcgcc ggcaccacga agcctggccg 480cagtggactc cccgcagctc gctgcgccct ggcgtctccc gtcgaggagg gagggacgga 540ggcctgagcc gggagctccc tggcggtggt cgggccgccc cccttgaggc ctgctccccc 600ctctcggcct cgccaaatcc ctgaaagccc agtccccctt cgtcaccccg ggggcttcta

660atcactcggt atcgatttcc ctaactcttt tcatcctgtt gaagacacat cttaaaacac 720tccagcccgg agtgtgctct gggctttatc cacactaata aaatgattta cccttctctc 780cgcgctctcc tcacagagga aaatcgttcg agccccggct atttgtgtgt gatcagtaaa 840tatttagtgc gctgacatcc ttagctgggc ttcggatcga ttcggggccc accgggaggt 900gcgcacggtc cgggcggggc cgcgccgagc tcgccgaggg ggctcctccc gccctcgccg 960ccggccgctg atttacggcc cctgcaacca gctaaggggg gcgaaagcgc gcctggaaaa 1020ttggcttttc aaccttttac ttttgacatt cagccacttc cccaggctct aattctcgcc 1080cgcactcctc cctcccgccc tactaagggt tgccctgtgc gccctgcgag cccttccagc 1140agcaacgcgc ggcgctcgcg ccccctcggc ccggggacca cctatcacag ccctgagccg 1200cgacgcgggg aggccccggc ccctgctatg ggggtcgcct ccttcgagga gagatgctct 1260ccgcccgccc acacctctga gggaggagag ggggtggaga agcccagagc tgcatctgct 1320ggatgacgag ccgctctccc tgctaccctt tctccgaccc gtcggccttt ctcctactct 1380ggagactgat cctcgacgtc catcgggccg gatggcgtcg ggtggaagcg ttactttcct 1440cgcagaaaaa ctcctcctct ttcctaagat cagaaaaagc gcttagcttg gaattgttag 1500153600DNAHomo sapiens 153cctaggcatt ctcagcccgt tttgctggag ggggcatttg aggcctggcc agcttagcca 60gcctacaagg agtgttactg gggtgaaaac agccagcggg gaccagtctg cttgtggccc 120gccaggtgcc tgggatgggg aagcagcaaa tgcccacctt cctgcccaac cccctcctcc 180ctcttcatgg ggggaactgg gggtggcagc ggctgccggg tgcgagcggg ctcaggcctg 240tggccctgcc tgacgttggt ccccatcaag ccatgtgacg agaccaggcc acaagaaaga 300ggtttcaaca agcgttatcg tttcctggaa ctccaactcg gcgacttccc cgaagaccgg 360ctgtgcctgg cgggcgggct gcgcacagcg gggacaaggc tgcccccttc ctcctccgct 420gcctccgcgg ccgcgtctat ctcagtctga ctacctggaa gcagcactcc accctccagc 480ccagcggccc tcggctcagc tgccaggtca ccggcaaccc cgggagcggt ggggcagggg 540ctgctccgcc agcctctgtg atgttcaggc cgggctgcac cagcccggga cccctaggtg 600154700DNAHomo sapiens 154gcactggttc ccctttacct gagccaacaa cctaccagga agtttccatc aagatgtcat 60cagtgcccca ggaaacccct catgcaacca gtcatcctgc tgttcccata acagcaaact 120ctctaggatc ccacaccgtg acaggtggaa ccataacaac gaactctcca gaaacctcca 180gtaggaccag tggagcccct gttaccacgg cagctagctc tctggagacc tccagaggca 240cctctggacc ccctcttacc atggcaactg tctctctgga gacttccaaa ggcacctctg 300gaccccctgt taccatggca actgactctc tggagacctc cactgggacc actggacccc 360ctgttaccat gacaactggc tctctggagc cctccagcgg ggccagtgga ccccaggtct 420ctagcgtaaa actatctaca atgatgtctc caacgacctc caccaacgca agcactgtgc 480ccttccggaa cccagatgag aactcacgag gcatgctgcc agtggctgtg cttgtggccc 540tgctggcggt catagtcctc gtggctctgc tcctgctgtg gcgccggcgg cagaagcggc 600ggactggggc cctcgtgctg agcagaggcg gcaagcgtaa cggggtggtg gacgcctggg 660ctgggccagc ccaggtccct gaggaggggg ccgtgacagt 700155300DNAHomo sapiens 155tgtccgacag gcacacagag cgccgccagg cacggccctc attcttcacc ccgagctccc 60gcaaggtcgg cgaggaggct ggagcagcgg gtaggaagcg ggccgaggct cccccgacgc 120tgggccgcaa ctgtcatcgc agatccctga aaaacgagct ctgtaatcgt tgccgtcagc 180gggtgtacaa ttgcagcctt atgtttcctg ccgctgttta ccttcctgag cggcgcccag 240agatgcacac acgctgccct gaagcgggac gtgacctctg ggcacctgtg aggtcctggg 300156500DNAHomo sapiens 156gtcggctcct gcgctcccaa cggggtggcc gtttccttcc tcgcaccctc ttctctcccg 60gtgcctgcgg tcccaccttc cagatacccc tcggagagtc cagctgagct ctcgccagag 120ctttcccctt ccaacccgct cgacttgccc agatcccaag ctgggcttct ctctccatcg 180ccccagaaag tgggtcttgg agaccgaggc aagaatttgg gcctccgctt ctgttccaga 240ccccggaccc cttgccaaaa tgcggcagat gtgcagattg ggccgcgctt ggttcctggc 300tgggtttatg gagcctgcgg ctgaggcagg ctccgcagac cccgagccag agtgggattt 360aacggcggcc ggtgcgctgt gcttggtcaa ccccggtaac cgtcacgctg ctagtgatat 420gaaaaaaacc tgccagcgtt ctgcttttct gccccgctgc agtctttagc acccgccagg 480attctgtccg agtgtttgga 5001571000DNAHomo sapiens 157tttagtgtgt gcataaaaca tcccagctaa tctcaaatag acttttcctg agcagaggct 60gaaatttgca agtaatgcaa agaagactcc gggagagcgt cgccgatggt ggagcgggag 120acgggcgtgg ggagccccac tgcagtgctg ggatcgaagt ggtgctgacc ccaagacctc 180tcccctcctc ctcccccggg agcttctcca gggttatttg ggaaatgagg gggaactcca 240atccctgaga aagcgctcag gggcttgctg aggtgagcgc aaatggaagc acaaggccgg 300gctggccgtg ggctcagtaa ccagtcggct gcccggcttg cgccagcact aaatgctcga 360tcagaaagag aaaaagaggc gcaataattc caaatttcag gaaaagtcaa atcggagagg 420ggggacgcag gtctcttcag actgcccatt ctccgggcct cgctgaatgc gggggctcta 480tccacagcgc gcggggccga gctcaggcag gctggggcga agatctgatt ctttccttcc 540cgccgccaaa ccgaattaat cagtttcttc aacctgagtt actaagaaag aaaggtcctt 600ccaaataaaa ctgaaaatca ctgcgaatga caatactata ctacaagttc gttttggggc 660cggtgggtgg gatggaggag aaagggcacg gataatcccg gagggccgcg gagtgaggag 720gactatggtc gcggtggaat ctctgttccg ctggcacatc cgcgcaggtg cggctctgag 780tgctggctcg gggttacaga cctcggcatc cggctgcagg ggcagacaga gacctcctct 840gctagggcgt gcggtaggca tcgtatggag cccagagact gccgagagca ctgcgcactc 900accaagtgtt aggggtgccc gtgatagacc gccagggaag gggctggttc ggagggaatt 960cccgctaccg ggaaggtcgg aactcggggt gatcaaacaa 1000158500DNAHomo sapiens 158catggtgctt caggaaggga ggggacgaga gccctgggct tgtggtgtcc acgtggacag 60ctaatgagga gccttgccga tgaggagcat gcgttcccga cggggcggcc gaatgcggaa 120ggagccgcca ttctctccgc cctgaccgcg ggattctctg cagcagatga gaaacggcgc 180tgactcagca gggtccctcc caggccccga gcggtcatct ggtgaccccc gcgcttcccc 240cacggcccag ccggagaagg gcaaagggaa gtcccggctc caaggcgcac ccagagatgc 300ggtgcatgtg gcaggatggc ccagccccgt cggcagcccc agcttcctgc ccctggtttc 360cttcctccca cgggctacag gcctctgatg agctttggaa agcaggaaac acacaggcta 420gtaactatga atgggtccaa aaaacactcc ttattacttt aaactactta ggaagaagca 480cagcgttgcc aaacgccaga 5001591200DNAHomo sapiens 159gcgcgggggg ccggaggatg gcggcctggg ggccctgcgg gggctgtcgg tggccgccag 60ctgcctggtg gtgctggaga acttgctggt gctggcggcc atcaccagcc acatgcggtc 120gcgacgctgg gtctactatt gcctggtgaa catcacgctg agtgacctgc tcacgggcgc 180ggcctacctg gccaacgtgc tgctgtcggg ggcccgcacc ttccgtctgg cgcccgccca 240gtggttccta cgggagggcc tgctcttcac cgccctggcc gcctccacct tcagcctgct 300cttcactgca ggggagcgct ttgccaccat ggtgcggccg gtggccgaga gcggggccac 360caagaccagc cgcgtctacg gcttcatcgg cctctgctgg ctgctggccg cgctgctggg 420gatgctgcct ttgctgggct ggaactgcct gtgcgccttt gaccgctgct ccagccttct 480gcccctctac tccaagcgct acatcctctt ctgcctggtg atcttcgccg gcgtcctggc 540caccatcatg ggcctctatg gggccatctt ccgcctggtg caggccagcg ggcagaaggc 600cccacgccca gcggcccgcc gcaaggcccg ccgcctgctg aagacggtgc tgatgatcct 660gctggccttc ctggtgtgct ggggcccact cttcgggctg ctgctggccg acgtctttgg 720ctccaacctc tgggcccagg agtacctgcg gggcatggac tggatcctgg ccctggccgt 780cctcaactcg gcggtcaacc ccatcatcta ctccttccgc agcagggagg tgtgcagagc 840cgtgctcagc ttcctctgct gcgggtgtct ccggctgggc atgcgagggc ccggggactg 900cctggcccgg gccgtcgagg ctcactccgg agcttccacc accgacagct ctctgaggcc 960aagggacagc tttcgcggct cccgctcgct cagctttcgg atgcgggagc ccctgtccag 1020catctccagc gtgcggagca tctgaagttg cagtcttgcg tgtggatggt gcagccaccg 1080ggtgcgtgcc aggcaggccc tcctggggta caggaagctg tgtgcacgca gcctcgcctg 1140tatggggagc agggaacggg acaggccccc atggtcttcc cggtggcctc tcggggcttc 1200160600DNAHomo sapiens 160gggcgggttg ccacactgtc ccctttctgc atgggaggaa gggggctcga gaactgagtc 60agccacacaa aacgaggatg gacagaactc ctgagtagcg agggtgcctg ccgggcgcga 120ggaggagggg gaagacgagg aagacgagga ggaggaatag ggagcaccac atgacagagg 180ggctgcctca gaccacaaag cgcttcctca tcctttcctc gccctttgat gccgccggca 240acgtgactct gcgagcagcg gggcagacgc caggtctccc tcgcaggcgg gaaaggggct 300ccaaggcggg tgctgccttg ctcgggtcac atggctacgt gggggccttg ctcaaattca 360cttcctgcct tcattacaaa actgtcaaag gggatcgcac gtttgcaggg tgtcacccaa 420gcattctggt tttgcaaacg acgctgtgcg gcaggcggtc tgatacctga tgagctcggt 480gtggcggggt cggcagcatt tcctccgggg ttttgagctc tggccacttc tccttttgtt 540ccacccaatc tcacccactt ctgggcttcg aggccagagt gtcttaacaa gggggcacgt 600161500DNAHomo sapiens 161gagcgagact ttgtctcaaa aaaaaaaaaa accaaataaa ttgaaagctg agaaattcag 60agcacaagaa gacaagcgcg ccccctcttt tagctgtcaa catggcggag ccgtccctgg 120tgacgcagcc tccaaaggcc tccctgtgcc ctcctgagac cgcaagaggg aaagtggcag 180cgacagtgat cgtggtgtct ttgtggcggt tgtgttgacc tcactgaccc ccgaagtgcc 240gctctagggt ctgtcctcag cggtgacccg gccgggtcga agggcagagt tccgctgtca 300ctagccctcc acccgtcctg tgtgctggga tgccctcgcg gcgccgtcca cgccaccgcc 360gccccctctt gtgggttctg tctcctccgt gtctaggatc ctcctgcatc cgtttttcct 420tcctcccttc tctccctccg tctgtcttgc ccgcacctga ggttgtcgca gaggcgctga 480gacgggccag caggagctgt 500162600DNAHomo sapiens 162tgctgtcccg gtcctgtcgc agtcctcaaa gatgctagag tgacagtcct ctaggggtag 60agatggtcgt cctcccagga gaaggtggcc cggagacttg gaggtgggat caatcctgcc 120agtcctggat caggaggcct ctgtcgggcg ccgcccccct tcctcctcca tcagcaacag 180gcggcgccgg ccagcctcat agtcagcctc atccacactg accagcaggc gaacagcctc 240ccggcccaca gcctctcgca gggcctcagt caggaacacg ccccgcaggg cctgcagcag 300ggcgccactc aggtagtcgc cccagaaggc gtccagatag gagagctctg agaacttgat 360gtcacaaacc acagagccca ggtcccttga gcgcagcact gcggtggcct gcccaaacac 420gtccagctgc cgcgccagcg cctggggccg ccgggatgcc acgccctgct ccaaggctgg 480cccatgctcg cagtactctg ctcgaacccg gagccggatg tctgcagggg aaggagggat 540ttgtcaggga gggggccaac actagacaca cttatgggga acgccaccct tcctccctcc 600163500DNAHomo sapiens 163tgatgcccgg cccccagggg ggcagaggcg ccgccaccat gagcctgggc aagctctcgc 60ctgtgggctg ggtgtccagt tcacagggaa agaggcggct gactgcagac atgatcagcc 120acccactcgg ggacttccgc cacaccatgc atgtgggccg tggcggggat gtcttcgggg 180acacgtcctt cctcagcaac cacggtggca gctccgggag cacccatcgc tcaccccgca 240gcttcctggc caagaagctg cagctggtgc ggagggtggg ggcgcccccc cggaggatgg 300catctccccc tgcaccctcc ccggctccac cggccatctc ccccatcatc aagaacgcca 360tctccctgcc ccagctcaac caggccgcct acgacagcct cgtggttggc aagctcagct 420tcgacagcag ccccaccagc tccacggacg gccactccag ctacggtgag ggcctgggcc 480atcttggccc acttttcaga 500164200DNAHomo sapiens 164ggccgggcaa aaagccgccg caacaaaaag ctgcgctgac gggcggaaaa agccgcggcg 60gcggagccaa aaagccgggg cggcaaaaag ccacggtggc gggcgcaaac agccgcaaaa 120agccgcggtg gtgggggcaa aatcagtggg agcaggggca aaaaaacaca aaaagccgcg 180gcggcggggg caaaaagcca 200165400DNAHomo sapiens 165tggctttgct ggagtgtgat gtgataggaa atgtgcagcc aaagacaaaa gaagatgtaa 60gtaggcttga ctcattgcag ctaagaaccc agatgttacc ttgagggtat taactaataa 120gcagtttaaa tcagaatggc acattctgat ttgttttttg tatgttcaca tttggcaggc 180atagatactg tttgaaaaga gaaaagtcag tacatagagg taacaagctt aaatatgtgc 240caagtctaga aacaagagac tagggggata aggacctttc gaaattaaat gcaagatttg 300aaaactgatt ggctggggga tgaggcaaag gcaggtcttt aaggtcaatc cctgttttgc 360tttaagttgt tagcgggtgg ttttatcata tattgtagaa 400166650DNAHomo sapiens 166ttcctgggaa tgtcagctaa cctgagccta ggggcctgag cccaagggca gactgaggct 60cccccagcac agggaggtgc tgcctgtgac aaggggtagt gctggcacag tgcaggctac 120tccctagaaa gatcagcttg aatatgcagg aagagcagga ccctcgggct gaggcagagg 180tggaatggga agtgcatggt ggtaatttag ttctccagag gccagaagta ggaggagcgg 240ttggaatgct gatggcccaa agggaaaccc tggactaccc tggcctccca caggactctc 300atagtaattg cggctccctg cagtggtgag gccagaagga gtgttgccca atgctgtcat 360catccagtcc accccccacc caccatcaac agatgagtat ggtcatgagt gtggtcacct 420catcagtcat ttgctcagtt gtgaaaaaga aattgttcag agaagagcaa agtgtttttc 480catgagccaa aggtcagcca agttatgcta atgaggagga ctggagacag cgtgtcacag 540acaccgagaa ggagcactgg gcaagggcac ttctcccagg gcagagccca caagaagcgt 600cctggcacca gacactcagg gaactgaagg ctggcagggg cccgcccagt 6501675000DNAHomo sapiens 167tccccccagc tgggtataag caaactttcc tgtctatggg ccgcagagac caccatctag 60ttcccccgcc aaaactttac atgattttaa ttctcctgat gaagatgaga ggataacagc 120caacagagag ggcagaggat gggatgggac tcccttgctc agagacctca cctctaggtc 180tttacctcct attgagaata agtcagttct gtagtaagaa ctctgtgtcc acggcaaccc 240caaacagaat cctagcgctc ttgtgattct tgtagaatgg ggaatagaac gagcttggcc 300caagactgca cagacttaaa aacatactat tctttgaaaa tggcaatcat taaaaagtca 360ggaaacaaca ggtgctggag aggatgtgga gaaataggaa cacttttaca ctgttggtgg 420gactgtaaac tagttcaacc atggtggaag tcagtgtggc gattcctcag ggatctagaa 480ctagaaatac catttgaccc agccatccca ttactgggta tatacccaaa ggactataaa 540tcatgctgct atacagacac atgcacacgt atgtttactg cagcactatt cacaatagca 600aagacttgga accaacccaa atgtccaaca atgatagact ggattaagaa aatgtggcac 660atatacacca tggaatacta tgcagccata aaaaatgatg agttcatgtc ctttgtaggg 720acatggatga aattggaaat cattctcagt aaactatcgc aagaacaaaa aaccaaacac 780tgcatattct cactcatagg tgggaactga acaatgagaa cacgtggacc caggaagggg 840aacatcacac tctggggact gttgtggggt ggggggaggg gggagggata gcattgggag 900atataccaaa tgctagatga ggagtttgtg ggtgcagcgc accagcatgt cacacgttta 960catatgtaac taacctgcac attgtgcaca tgtaccctaa aacttaaagt ataataaaaa 1020aaatactgtt ctgccataca tacagatact cattaaagat gagggagaag ggcatggggt 1080gggggagaat gtaccaaaac caaagaccac aggataataa cctcagagca gagactatct 1140ctctagttat tttttctttt gtatgtaatg gagaggatta ttatttactc tgatgaagaa 1200gtttacatca agtgttcagc ttcctttgtg ggttacagag aataaccaga gggctcagtt 1260atgctctctg aataactatg tttgcttagt gttttctaaa caatattaaa tttcactaaa 1320atagacaagg ttgataggac ttgggggcat aactcattga ctcaagctat cattttatag 1380gattgtgaga aaacaaatag atgaacattt aaaatacact catattctcg ctagaaaaga 1440ggattttgaa tattcttaca tcaaagacat ggtaaatgtt taaggcaatg aatatgctaa 1500ttaccatgat ttgatcatta tgcaatgtaa aatgtactga aacatcacat tgtacctcat 1560aaatatgtac aatttattat gtgcgaatta aaattttgag tataagaaaa aataaacttc 1620aattgtaaga aaacaaccca acttttaaaa aacgggcaaa atacgtgaac agatacttca 1680ctaatagaga tttgcaactg gcaaataagc aaatgaaaaa ctggtcatca tcactatcta 1740ttagagaaat gcagattaaa actacaataa gaaacaatgc tgcccgtcca gacgcattgt 1800tttgaccgtt tccaacttgt cccagccctt cccggggcat cgctggggac cctacgccga 1860cgtcccccct ccgcccgcgc cccaagggcc gactgggcaa attgggagac ccgccccgcg 1920gggcgaccca acttttcgga acagcacccc accgcccacc cccgcagacc cccggacccc 1980cgctcccggc ggagactcag ggaaccccgc accccaagcc cttctaaatc gtgcagcgtg 2040agtgtgacgg ccaagagcgg atgcagcccg ggatcgcccg caccttcccg tgggcggaag 2100cgcaggagcc agctggggag ggggcgccct agaggagcgg ctagaaagca gacacgggga 2160actcaggtca tcctgggggg ggacaagaca acgagagccg ggcgcctcgg gggcggcgcg 2220ggagcctccg caggaccggg cgggcgcccc ggctggcgcg ggcggggggc gcgccccctt 2280tacctgcggc tccggctcct aggccatttc ctcacgcggc ggcggccggg actgagctaa 2340caccactcag gccggccggg tttgaatgag gaggagcggg cgcggagagg aggggacggg 2400gagggcggag ggagggaggg aggcgtcgcg gagtttttct cggccttttg tgcggacacc 2460tcccggattc cgcgcccgca cccggccccc caaaagacac ggggagccgc gggcgagggg 2520ttcagccatc cgccgaggcg cctagtgcct tcgcgcctcc aagacccccc cccaacaaaa 2580aggagcgtcc cccaccccta cccccgcccg gaggacttag ggcctgggct cacctcgggc 2640gcggagctaa gtgtaggcgc cgggggtccc tagagccgcc ggggcgcagc gagtccggcg 2700ctgggtaact gttgggtcag aaactgttca ggtagcagct gttgtgccct cccttggccc 2760cgccgctcgg agacgccccg ccccctgcct tgaacggccg cccggccccg ccccagcgcc 2820cacgtgacta gcataggcgc gcccccgttc cgcccgccgc cgcagactcc gcctccggga 2880cgcgagcgag cggcgagcgc gcgcactacc agttcttgct cggcgactcc cgcgcacgcg 2940cgcgccgtgc caccctcccc gcacccctcc tcccgccatc cggcttaacg tggcgggcgc 3000gcgccgcggc agtagccgtg acaggtaccc ggcggggcgg ggggggaggg ggttggcccg 3060cgagggtgtg cgcaggcaca gacccgggtc ctgtccccgc cgccccctcc tctgcaaggt 3120gtgcctgggc gaggggaggg gcccgcggcc cgaacccctg ggtcaccccc gaattacaaa 3180caaaaacctt aacgccattg ctcgcgggtt agaaggcagc tgtgcgtgct caggaaaaga 3240agccacgcac aagagaccgc acgcggcgtg gatacagtga cacgaaacac ccaaaatctc 3300ttttgaaagg gaaaccaggc acagtggctc atgcctataa tcccagcact ttcgggggcc 3360aaggcgctca cctaaacccg agagttcaag accagcctgg gcaatacagc gaaaccctgt 3420ctctacgaaa aatataaaaa ttagctgggc atagggctgg gcacggtggc tcacgcctgt 3480aatcccagca ttttggaggc cgaggcgggc ggatcacgag gtcaggagtt ccagaccatc 3540ctggctaaca cagtgaaacc ttctctctac taaaaataca aaaaaaatta gccgggcgtg 3600gtggcaggtg cctgtagtcc tagctacttg ggaggttgag gcaggagaat ggcatgaatc 3660agggagcgga ggctgcagtg agctgagatt gcgccactgc actccagcct gggggacaga 3720gtgagactcc gtctcaaaaa aaaaaataat aattagctgg gcatggtggc tggcacacat 3780ggtcccagct actcaggagg ctgaggtgga aggatctctt gatcccgggg aggtcaaggc 3840tgcagtgagc caagatggca tcaccgcact ccagcctggg ccacagaccc tgtctcaaaa 3900aaaaaagaga aagtggggaa gaaaatgtaa tacaaattaa tataccaaca gcaattagtg 3960agtacttttt ccatggagct gggagaggga ataaatgttt gtaaaattaa aatgttctac 4020gctagaaatc aactttcctt ctatgctttc tttacttcac cccttatagc tacttagtaa 4080atctcacaaa tcctatcctt ctgatctctc tgaaatgtat gtaccctttc ccttctattc 4140tcaccaccca tgtttctttg tttccttcta gcctgtgtaa taatctcata atcgcacctc 4200ctgtacctgc cttctttcta gtccagaata cgttttccta aattccacca ataaccatcc 4260tgctactgct ttgtgtgaaa ttctccaaaa aaaattttac ttttccaaaa taagtcaggc 4320tccctctctt aggatacaaa accacaccat ggtcccagcc aatctttcag cctgattcac 4380tcagtatata tttattgacc tctcctttct cccaagcact tggctagata ataattaaag 4440agtgcggcac aaaacaaatt ggattcctcc cctcatggag cttgtatttt cacaggaagc 4500acagacatta aataaattaa aacacaaaaa aatagacaag catataatta cagtatgtat 4560cctagagaaa tatcactcat gcagaaagca tacacaagga tgcagcactg tttccaatag 4620cgaaaagcta gaaacaacct acatgttcac caaaagaaaa tggccacata aactatacca 4680tatccaaatt atccaaattt tagaatatag acaacaggtt gggcgcggtg gctcacacct 4740gtaatcccag cactttggga agccgaggcg ggtggatcac aaggtcagga gttcaagacc 4800agcctggcca acatggtgaa accccgtctc ctctaaaaaa acaaaaaaat cagctgggca 4860ctgtggcagg agcctgtaat cccagctact gaggagactg aggcaggaga atcgcttgaa 4920ccctggaggc agaggttgca gtgagccaag atcgcgccac tgcactctag cctgggtgac 4980agagcaagac tccatctcag 50001681500DNAHomo sapiens 168tgtaggagtc ctccggtgct ggagtccaga gcacagtgag gctgggtcct cccgtgccat 60agtgtagggc atggcgggac agggatcctg ccctgcgata gtccagtgct tgagtccgca 120gtaaggcaat ggtcctccaa tgctggagtt cacggcgttg tggggtcggg gtcctttggt 180gacttagtcc agggcgtacc agggcggggg tccacagttg ccatagtgag gatcttggag 240gaaggtggtt cctgccttgc

tgtagtccgg ggagcagggg gcaggggtcc tctcttgtca 300gagtctctgg cgcggggtgg gggtggaggt gggggttttc ctatgcgata gcccacgggt 360cggtgaagcc gggtcctccc gtgcctttgt ccagggcgca ggggggcgag ggtcttcggt 420ggtggagtcc gcggagcggc aggacggggg tcctccagtg ccatattcca gggcgcggcg 480gagtggggga cctgtcctgc agtggtccag ggcatgtggg agtggtggtc ctgctgtgcc 540tcagtccagt gcgcggtggg acggcggtcc tgctgtgctg tagtgcagga cgcggtggcg 600caggggtagt ccagagagcg ccgtggcagg gggtcctcca gtgctggaat ccagtgcaag 660gcgggtcagg ggtcttaccg tgccgaagtc ggtggcaagg gtcctcccgt gccatagtct 720agggggcgac ggggcagggt tctctagtgc aggtgtccag ggtgtggcag ggcaggagtc 780ctcttgtgca ggagtccagg acgtagccga ggagtcctcc aatgtcagag tccagggctc 840tgcggggccg ggttccccca tgccagagtg tagggcgcgt tcaggtgagg gtcttggcgt 900gcagtaatcc agggtgcggt ggggcagggg tagtccagac ctccatggcg ggcgtccctc 960tgtgcaggag cccagtgcct ggcggatcgg gggtccttct gtgctgtagt ccagggcacc 1020gcaaggtgtg ggtcctctgg tgccctagtc cagggggcgg cgagtcagag gttctcccgt 1080gtctcagtct agggcctggt aggactgggg tcctggagtc cacgtggtag cccaagttgc 1140cgcaggacca ggtactctgg aaccacagtc cagggcgctg aggggcagga gtagttcagg 1200gcgagccggg gcccaggtcc tcgggagcca gagtccaggg tgtggagggg tgggggttct 1260gcagtggcac agtccaggac accgcggggc gggacagggc ggggatcctc ccgtgcctta 1320gtccagggct gagccgcggg agaggtcctt cagtagcaca gtctagcgca cggcgttgca 1380ggtgtcctcc agtgcctgag gccacggcag gtcgcgggtc ccactgtgct ctagttcagg 1440gcggagtggg tctgaggtct tctcctgcct cagtctaggg cgctggagag cggggatcct 15001692500DNAHomo sapiens 169gggttggtcc tagaaagcgt gaggatcgcc gagtgcactg ccctcccagc ctagggtcca 60ctcttccttg gcccgagccc agagctcggg gtttcaggcg ctgggccctg tgcagctgcc 120cagaataggc tgagcggcag gttcccgccc tggcaaggga tccagcagtg gaatcctcac 180tgctgttggc tgcgggcaag gtcagcgggg tttccatcgc tgctggtggg agccacctgg 240cggtggtagc tgcaagtgag cgcgtggcag agactggcag ggctggtccc agacaccctg 300agggtctctg ggtgcatcgc cctaccaccc tagggtctgc tcttccttag cctgctccca 360ggacgcggtg tacgagggct agactctgag cagcctccag gatggggctg agcagcggat 420tcctgccctg ctgcagctac agtctgaatt aggcgccacc gcagtatctg gccctggggt 480acgtgctact gggtggcatg gacagagatg ggggctgcca cagctgctat ggggctgagc 540agccgattct cgccctgctg cagcgggcga ccgctgcaat ccccagcgct atgggaccga 600ccacctgact tagatgcctt ggaggcatcc ggtcctgggg tcttgctgct ggtgtctgcg 660ggcagggtca cggctgccac tactactgct gtgcgccatg ggcaggtgcc agctgcagct 720gagtccgagg cagatgctgt cagggctggt ctgaggttgc ctaagggtgg ctgagtgcac 780cacgcttcca ccccagggtc cgttattcct aggccggctc ccagattgca gggttgtggg 840cgttggacac tgtgcagcca tgaggatctg gttgggtgca gattcccgcc ctcctgcagc 900tgagaagcca atctcataac aggcgctgca gtgacctctg gctctgcggt ccgcgctgct 960gctggagctg gcagagaaca gagctgccac cgctgctgct tccaggagtg tgcagctggc 1020agctgcagct gagcccgtgg cggaggctgg aaggccttat tccagaagcc ttgagggtcc 1080ccgaatgcac cgccctccca ccctaaggtc cagtcttcct tgcccgcgcc cagagagttg 1140gattgcaggc gctgagcaca gtgcaggtgc tgggatgggg ctaagctgaa agtttccgcc 1200ctctggctgc tgcggggccg acagcctgag ttatgcgccg cggcggcttt tggtcatggg 1260atccgcactg ccggtggctt gcacagggtc gggggctgcc acagctgcta tagttcaccg 1320tgtgcacgtg gcagccgccc ctgagcccac cgctgaggct gcagggctgg tccggtccca 1380gacggcctga gggccatttg cccgcgccca gatccgggtg gctgcgctgg gcactgtgca 1440gcctcccgga atccgctgaa gggcacgttc ccgctctcct acagctgtgg gccgactgcc 1500tgattttggc cactaggtgg agtctggctc tagggtttcg aggccgctgg tgttggtggg 1560cggagtccgg gtttgccacc gctgcgctcc atgagcaggt agcagctgca gcggagcttt 1620agaccgaggc tggcagggct ggccccagac ggcctgaggg tcagggagtg cagggtcctc 1680ccaccctagg tccgctcttc ctttcccctt acccagagcg ggttgtgcgg gctctgggct 1740ctgtgccggc gctgggctct gtgcagccgc cgagatgggg ctgagcagcg gatttcctcc 1800ctgctgcagc tggaggacga ttacctgcac tagccgctga ggcggcatct ggccctgggt 1860tactgcagct ggtgacgcgg gcagggtcag ggttggttgc aggtggcagc tgctgctaaa 1920cccattgcga gcctcagggt caccaagttc accgtccttt catcatagta tctgatcttt 1980ggcccgcgcc cagagtgcgg actggcctgc gctggggact gcatagcttc tgggggccgg 2040tcagcgccag tttcacgtcc tcctgcagct gcgtggccta aggtcttagg cgccgcggcg 2100ctatctggcc ctgctgtcga cgctgctggt ggtggggaca gggtcaaggg ttgccactgc 2160tgctcccgtg cgccatcggc aggtggcagt tgcagatgag cccacaattg aggctgttgg 2220ggctgctccc aggttgttag agggtcgccg agttcaccga catgccaccc taggttacgc 2280tcttggcccg cacccagagc gccgggttac gggtcctggg ccctgtgcag ccacggggat 2340ggtgctgagt gcaggttccc gtcttcctga gatgcggggc gaccactgga attagcctct 2400gtggtggtat ctgaccctag ggtccgagct gctggtggcg tgggcggggt cgaagtcgcc 2460tctgttgctg cggcgtgcca tttgcaccgt cctctggtac 25001701600DNAHomo sapiens 170aaatactcta ctgaaaaaac agaaatagta aatgaataca gtaaagtttt agaatacaaa 60atcagcatag aaaaatcagt cgcatttcta tacccaacag cataccatct gaaaaaggaa 120tcaagaaacc aatcccattt aaaatagcta taaaaaaatg cctgggaata aactaagcca 180aataaatatg tctaaaatga aaactataaa acattgataa aaatcaattg aaaaagatac 240aaataaaggg aaagttatcc catttttatg aattagaagt attaatactg ttaaaatgac 300catcatactc aaatcagtct ataggtccaa tacaatctct aacaaatttc caatgtaatt 360cttcagagat gttaaaaaag gttttaaaaa tcgttctgcg gatgttaaaa ggatttttaa 420aacgcttttt tcgttctgca ggcgaaggct gtggccgtgc tcccgccggc cagttcccag 480cagcagcgca ttgcccctgc tccacgcctt cgctccaggc ccgcaggggc gcagccccgc 540gggaatcagc actgagccgg tcccgccgcc gccccagtgt ccgggctgcg actgcgggga 600gccgatcgcc cagcgattgg aggagggcga cgaggccttc cgccagagcg agtaccagaa 660agcagccggg ctcttccgct ccacgctggc ccggctggcg cagcccgacc gcggtcagtg 720cctgaggctg gggaacgcgc tggcccgcgc cgaccgcctc ccggtggccc tgggcgcgtt 780ctgtgtcgcc ctgcggctcg aggcgctgcg gccggaggag ctgggagagc tggcagagct 840ggcgggcggc ctggtgtgcc ccggcctgcg cgaacggcca ctgttcacgg ggaagccggg 900cggcgagctt gaggcgccag gctagggagg gccggccctg gagcccggcg cgccccgcga 960cctgctcggc tgcccgcggc tgctgcacaa gccggtgaca ctgccctgcg ggctcacggt 1020ctgcaagcgc tgcgtggagc cggggccgag cggccacagg cgctgcgcgt gaacgtggtg 1080ctgagccgca agctggagag gtgcttcccg gccaagtgcc cgctgctcag gctggagggt 1140caggcgcgga gcctgcagcg ccagcagcag cccgaggccg cgctgctcag gtgcgaccag 1200gccctgtagc tgtgacttgg ctgtggggct ggcccgcctc cctgacccct gtcaggcgga 1260gcagctggag ctgacccacg ggcctgggct ttcgagcgct ttgtccaggc gctaatgatg 1320ggaaggtgaa aggtgggggt ggccacaccc tgcagtcagg gtggcaggtg tcagaggcca 1380catgcaaccc actggttttg tcttttccag gatgctgata agtttcccgc ggcccccgga 1440gcagctctgt aaggccctgt aattgccttt cgttcccttc tgctctattg aggagtggga 1500agatgacaaa gtgtttttgc tcaacccgaa ggaaaatgca catgggagga cacaccgggt 1560tactatttga gtagcccaga caggagagca gcggtctgct 16001711500DNAHomo sapiens 171tgggtggatt gcttgagccc aggagttcga gaccagcctg gacaaaatgg cagaaactcc 60atgtctacaa aaaatacaaa aattagccgg gcatgatgtt ctgcgcctgt agtcccagct 120actcaggagg ctgaggtggg aggatcgctt gagcccagga ggcggagttt gcagtgagct 180gagatgtcac tgcattccag cctgggagac agagccagac tctgtctcaa aagaaaaaaa 240gaaaaaaaaa aaagaaaaga aaaaacgaaa ttgtattctg aatacatctt ctaaaacact 300acatttactt gcactatatt aaactggttt tatcctgacc acaattgcag gtgaaagata 360ccactgttgt tctatttttc tggtaagtag agtgagccat gtcttcccca gggaaagacg 420cctcctaaaa atttgtagga ccacctttgg ttttcttcca gatatttttt ttgtcatcgc 480ttttcctgcg cccaattccc atctgtctag cccttctgcc tccgctggtc tttttcgcga 540gcctctcccc agccgcaggt attcgtctgg gctgcagccc ctcccatctc ctggggcgtg 600accacctgtc caggccccgc ccccgtccaa cccgcggaga cccgccccct tccccggaca 660ccgggttcag cgcccgagcg tgcgagcgcg tccccgctcg tcgcccggct cggcgtcggg 720agcgcgctct gtgtggtcgc tgctgcagtg ttgttgtggc tgtgagaagg cggcggcggc 780ggcggagcag cagccggacc agactcccta gtagctcagg cgctgccctg cgccggccct 840ggcagggagc ctggtgagat ggtggaggag gaggctgtgc cgtggctggc cttgctgtgt 900cctgctgcct ggttagaacc ccatccccgt cccccgtctc ctccgggggg tgaggaggag 960ctggaagagg ggccggcctc tgtccggccc ggccaggcgg cagtcaccct ctgaggaggc 1020agcgcccggg gaggggcctc ccaggcggcc gccgccgcca gggggaggcg ctgggagtgg 1080gagtgggagc gggacctcag ctgccaagct cggcccggac cctaggtgcg ggggaggcgg 1140ggtcccgggc tcgggctgcc tgcccggacc tggcggggat gggcccgtgc ggctccgggt 1200gtgggacgta ccctcagagc gcccggggtt attcccactg actccaggga ggtgagtgtg 1260cgcccttcgc tccctgccgt gtctgtgagg gtccatcgtt gccggagact ggaggtcggg 1320ggccatggga gccccggggc gaacggtgcg gacatgggcc ttgtggaaag gaggagtgac 1380cgcctgagcg tgcagcagga catcttcctg acctggtaat aattaggtga gaaggatggt 1440tgggggcggt cggcgtaact cagggaacac tggtcaggct gctccccaaa cgattacggt 15001721700DNAHomo sapiens 172gtctctagga caccctaaga tggcggcgag ggagacggtg aaggttggct cccgcctgtc 60tgggctctga tcctctgtct ccccctcccc ctgcggccgg ctcatggcct ggcggaggcc 120cgaaccaaag acctccgcac cgccgtgtac aacgccgccc gtgacggcaa gggggcagct 180gctccagaag ctgctcagca gccggagccg ggaggaactg gacgagctga ctggctaggt 240ggccggcggg gggacgccgc tgctcatcgc cgcctgctac ggccacctgg acgtggtgga 300gtacctggtg gacccgtgcg gcgcgagcgt ggaggccggt ggctcggtgc acttcgatgg 360cgagaccatg gagggtgcgc cgccgctgtg ggcgcggacc acctggacgt ggtgcggagc 420ctgctgcgcc gcggggcctc ggtgaactgc accacgcgca ccaactccac gcccctccgc 480gccgcctgct tcgagggcct cctggaggtg gtgcgctacc tggtcggcga gcaccaggcc 540aacctggagg tggccaaccg gcacggccac atgtgcctca tgatctcgtg ctacaagggc 600caccgtgaga tcgcccgcta cctgctggag cagggcgccc aggtgaactg gcgcagcgcc 660aagggcaaca cggccctgca caactgtgcc gagaccagca gcctggagat cctgcagctg 720ctgctggggt gcaaggccag catggaacgt gatagctacg gcatgacccc gttgctcccg 780gccagcgtga cgggccacac caacatcgtg gagtacctca tccaggagca gcccggccag 840gagcagctca taggggtaga ggctcagctt aggctgcccc aagaaggctc ctccaccagc 900caggggtgtg cgcagcctca gggggctccg tgctgcatct tctcccctga ggtactgaac 960ggggaatctt accaaagctg ctgtcccacc agccgggaag ctgccatgga agccttggaa 1020ttgctgggat ctacctatgt ggataagaaa cgagatctgc ttggggccct taaacactgg 1080aggcgggcca tggagctgcg tcaccagggg ggtgagtacc tgcccaaact ggagccccca 1140cagctggtcc tggcctatga ctattccagg gaggtcaaca ccaccgagga gctggaggcg 1200ctgatcaccg acgccgatga gatgcgtatg caggccttgt tgatccggga gcgcatcctc 1260agtccctcgc accccgacac ttcctattgt atccgttaca ggggcgcagt gtacgccgac 1320tcggggaata tcgagtgcta catccgcttg tggaagtacg ccctggacat gcaacagagc 1380aacctggagc ctctgagccc catgagcgcc agcagcttcc tctccttcgc cgaactcttc 1440tcctacgtgc tgcaggaccc ggctgccaaa ggcagcctgg gcacccagat cggctttgca 1500gacctcatgg gggtcctcac caaaggggtc cgggaagtgg aatgggccct gcagctgctc 1560agggagccta gagactcggc ccagttcaac aaggcgctgg ccatcatcct ccacctgctc 1620tacctgctgg agaaagtgga gtgcaccccc agccaggagc acctgaagca ccagaccatc 1680tatcgcctgc tcaagtgcgc 1700173300DNAHomo sapiens 173taaaaataaa ttgtaataaa tatgccggcg gatggtagag atgccgaccc taccgaggag 60cagatggcag aaacagagag aaacgacgag gagcagttcg aatgccagga acggctcaag 120tgccaggtgc aggtgggggc ccccgaggag gaggaggagg acgcgggcct ggtggccaag 180gccgaggccg tggctgcagg ctggatgctc gatttcctcc gcttctctct ttgccgagct 240ttccgcgacg gccgctcgga ggacttctgc aggatccgca acagggcaga ggctattatt 300174600DNAHomo sapiens 174cgccaccacg tgcgggtagc gccgcatcgc cccagccgtg ttccttggtc tccgtctccg 60ccgcgcccgc ctggtgaact ggagcacagg gaccatagtt ctggaaattt atcctttttc 120tctccatgga ttcagcagca gtgtctaaaa gaaaaaaatt catcaatcat ttatgtatat 180tttaatataa aggtaaaaca ctgcgaacca gtggaaccgg atagaaagta attcagtttt 240acagaacaca actgtttttc aggctctttt attaaatata aaagagccat atatatttct 300gtggaattcc ccttttactt aagaattcat tatcagcgaa ttagtttaag gaggctgttt 360tgttagaggc tgtggttgca ttcaaaaatt ggaataggaa caatgacttg taaaaattca 420acattttatt ttatttttga gatggagtct cgctctgtcg cccaggctgt agtgcagtgg 480cgcgatctcg gctcactgca acctcagcct cccgggttta aggaattctc tgcttcagcc 540tcctgaatag ctgggattac aggcgcatgc caccaagccc agctaatttt ttttgtattt 6001751300DNAHomo sapiens 175ccctgaacag tcagagttta ctgcccactt ttgctggagg agaagctcct gaacaactag 60agagactgtg gttcccaaag agcagcctgt aggcctgagg actgctctat gaccggcgtc 120agtccctgcc tccctccctc cgtccctcct tccctccttc cttcccaggc cttctctgac 180taccagatcc agcagatgac ggccaacttt gtggatcagt ttggcttcaa tgatgaggag 240tttgcagacc atgacaacaa catcaagtga gtccacttgg atgccccctg cacgaggcac 300gactccccct cctcgctgct gaagtcccat gggggcagct cccttagtcc ttgccgggag 360ataacaggtg tttccagttg catgagggtg ctgaggcccc cagtgagaac caggggagga 420gcactgaggc ctcagatgag caccggggga ggagccctga ggccccagat gagcaccagg 480ggaggagcac tgaggcccca gatgagcacc gggggaggag cgttgaagcc ccagatgagc 540accagaggag gagagctgag gccccagatg agccccgggg gaggagctct gaggccccag 600acgagcaccg ggggaggagc gccgaggccc cagatgagca ccgggggagg agcgccgagg 660ccccagatga gcagtggggg aggagccccg aggcccccag atgagcagtg ggcggggcag 720ggagcgccga ggccatcccc cttgctcttg cagcgcccca tttgacagga tcgcggagat 780caacttcaac atcgacactg acgaggacag tgtgagcgag cggggctgtg cggggtcatg 840caggcaccct gttcccaggc agctcaggcc gcgcccatgg ctcggtctgt ggtgggcctg 900tgcggtgggg ctgggagagg cccctctgtg gagctaggaa cagtcgcttt tcttgaccct 960ccccatcatg ccctccagcc catggcgccc acatcctgaa ctaagcccct ctgggagccc 1020tgtggggaga gcgcctcctg tctcccccag accctctgga aactgacctt ggcgttttac 1080tctgcagccc agcgcggctc tgaggcctgc tgcagcgacc gcatccagca ctttgatgag 1140aacgaggaca tctcggagga cagcgacact tgctgtgctg cccaggtgaa ggccagagcc 1200aggtgcgggg cctgcccatc cccccaaagc ctctgccgag gaggtgcagc ccccagaaca 1260cccgtcagat gcccagacgc cctgctgttt gttatgccgg 1300176110DNAHomo sapiens 176tttgggccac gaggcaagtt caaagcggga gacttttgtt ttataaaatg atggtgagca 60gctccggttt tatgtcaaac atcagggttt cgtgcaggat ataaacattt 1101771500DNAHomo sapiens 177attgccgtac tttgcttccc tttgtatgta tttcttgtat gctgccgagt cactgatggc 60tagctctgtc tggcaagtaa ttcaaaaatg ctgtttatgt agaaaggaaa ggtagggact 120ttaccacact ctgtcattaa agggagcaat tgaagaacaa aggaactgag taaataccta 180tatattgcct tttgtgttgc gaaacactgt agcacaaaca catttgtgtt cagccaaatg 240ttttacttcc ttttgtaata acgcatatag taggttgtct ccacatatgt acaagaatcc 300atattttatt taaacgtata tagtcaattg ttcatattta taggctgcaa acatttctca 360atctcaaaga cttttacata tccactccca cacagctatt tgttattatt ttaaaagttc 420ttaaattaaa aaaaaaaata aaatatacta atatctctgt tggttgattt tattaagcaa 480cttaggattt caacacagtt taaatcatat tgatgactca gatcctggca ggtcttacaa 540ttcctgtgaa atgagagcac agctaataaa aatattaagc aattactttt attaaaatca 600tagggttttt ttcattatca catagaaatg attgatctat acagattggt ctcactcatg 660tgtcttttgg gctgcttggg agcttcatgt agaagtggaa agtccccttt gctcttcctt 720cgaccaaggt ggggaaaatg aaggcataga atacaatcta gggctattaa agaattgctg 780gcattacttc tctctatcac gtgtgagcct ggctgcctgc ttcctgaggt aggggatcca 840ggatgagact gtgccggagc ctgtttccac aactgcattt ggagatccgt cttattgatt 900agcgggggaa aggggtgggg atcaggagtg tgaggtgagg ggaggaccaa ctgacgactg 960gctcaatgaa gcacaagaca ttttcttccg gaaagatgtc aaacaactga gaaacagcca 1020gagaggaagt agaaaggtgg aaaaatgagg agaccctgga agaaatgaag gcatttccta 1080tgagacagcc ttggggcttt tttcttttct ttcttttttt ttgcttccat catctgacct 1140gcaaaggcta gagtgacagc gtcatgcaaa tgctgcagtc cagcaggtct gggagagggt 1200ggatgctaga ctgtgagtta atgttaatga tgagcgcagt gaaaatacca gccgctgcca 1260ccccctgctc acagaagcgc tctgagtcag catcagatgc tttgcctcgc ctctcgctgt 1320gtatctgtat gcctgtgtgc gcgcgcgtgc tcgctcgggc atccgtgtct agccgagggg 1380agggggtggc gtgtgagtgc gtggagggta aaagccagtc agtcagtgag aagcaaaggt 1440acgttggaga gcaactaaaa tctgactgat ttccatcttt ggagcatcag atgtattccc 1500178200DNAHomo sapiens 178gcagcctcct cctgaaaaat gtaagccatt tccactttgt aaagctacgt ttatattcca 60ccacgatacg atggaaaaga aaacccaagg caatttaata tacgggttgg gaagaaagtt 120ttgctgatgg aactacatta gcctccactc cagcaaagca aacaaggaac cacactaaag 180aaatgtactg aatcttttaa 200179800DNAHomo sapiens 179tgcctgagcg cagagcggct gctgctgctg tgatccagga ccagggcgca ccggctcagc 60ctctcacttg tcagaggccg gggaagagaa gcaaagcgca acggtgtggt ccaagccggg 120gcttctgctt cgcctctagg acatacacgg gaccccctaa cttcagtccc ccaaacgcgc 180accctcgaag tcttgaactc cagccccgca catccacgcg cggcacaggc gcggcaggcg 240gcaggtcccg gccgaaggcg atgcgcgcag ggggtcgggc agctgggctc gggcggcggg 300agtagggccc ggcagggagg cagggaggct gcagagtcag agtcgcgggc tgcgccctgg 360gcagaggccg ccctcgctcc acgcaacacc tgctgctgcc accgcgccgc gatgagccgc 420gtggtctcgc tgctgctggg cgccgcgctg ctctgcggcc acggagcctt ctgccgccgc 480gtggtcagcg gtgagtcagg ggccgtctcc ccgaagaacg agcggggaga ggggaccacg 540gggcgcggcg ggcagcctgt tctcgggcgg aggctctccg gggcgttgga aacctgcatg 600gtgtaaggac ccgggaggag gcggggagaa attgattgtg ctgttctcct ccctctcttc 660tctaacacac acgcagaaaa gtttaaattt ttgtgaagcg cttgcttacg tagctgcgga 720gcgagcctct gcttcattac gagcggcata gcctttttca ggagtgattt ccactttctt 780tgtgagagag ttgaccacac 800180600DNAHomo sapiens 180ttcaatttac actcgcacac gcgggtacgt gggtgttcgg ggtagggcac tgatctgggg 60aaggtctccc ccccgcgacc caactcatct ttgcacattt gcagtcctcc ctcggtgcac 120tcctggcggg gatctggcca gtgcagcgca ctgggaccga gggcagagcc cgcggagtga 180ggccaggaga gacttcaggc ctctaaggac acagctgagg ctaaggctga gttgaacgca 240gcccctcccg cggctcgtcc cctctccagt gtctctcccg taaggtgccg ctcccaacag 300caatgggtcg agatgtagag gaaacactct gtacgttatt tttccgccca ccctttagcg 360cctgaggaga cagacagtgt agactttagg gtacaattgc ttcccctctg tcgcggcggg 420gtggggagcg tgggaagggg acagccgcgc aaggggccag cctgctccag gtttgagcga 480gagagggaga aggaggtcca cggagagaca agaatctccc tcctcccacg cccaaaagga 540ataagctgcg gggcacaccg cccgcctcca gatcccccat tcacgttgag ccggggcgcg 600181600DNAHomo sapiens 181tcattatccg attgattttc ctggtatcac atcacttaag tttaagtagc tcttatgtta 60cttagtaatg actgcaaaac acgagttgtg atgcgggcaa tttggataca acaaaaagaa 120gccattaagt ttgttcgtta gttaacaggt gaaagctctc aagttattaa ggataaaaat 180gctagtatat atatatatgg tttggaacta tactgcggat tttggatcat atccgccatg 240gataagggag gaatactata atcaggtttg ttttaaattc catgtctaat gacttcgtta 300tctagatcac ctgtagagct gtttttattg taggagtttt ccttggtttt aatcttttga 360tttgtttttc atgttaatac tgaaattttt aaaaattgca tattgtactt cctatatgaa 420aattttacta tgtattttta tttttatttt ccttttcctt taggaagaat tagtttgttc 480cctgacagag ttagagtaag ggcaaattac ttgtctctat aaacaactca gatgttttga 540gccggtgttg taggggttat ctttttctgg ttttgcattt tattatagga catagtgctt 600182140DNAHomo sapiens 182agaaagaaga

aatccggtaa aaggatgtgt tattgagttt gcagttggtg tttgatcttg 60cacagatttt ctcaggggcc ttaagaccgg tgccttggaa ctgccatctg ggcatagaca 120gaagggagca tttatacgcc 140183900DNAHomo sapiens 183cgaagatggc ggaggtgcag gtcctggtgc tcgatggtcg aggccatctc ctggtccgcc 60tggcggccat cgtggctaaa caggtactgc tgggccggaa agtggtggtc gtacgctgcg 120aaggcatcaa catttctggc aatttctaca gaaacaagtt gaagtacctg ggtttcctcc 180gcaagcggat gaacacccac ctttcccgag gtccctacca cttccgggcc ccccagccgc 240atcttctggc ggaccgtgcg aggtatgccg ccccacaaga ccaagcgagg ccaggcttct 300ctggaccgcc tcaaggtgtt tgaccgcatc ccaccgccct acgacaagaa aaagcggatg 360gtgttcctgc tccctcaagg ttgtgcgtct gaagcctaca agaaagtttg cctatctggg 420gcgcctggct cacgaggttg gctggaagta ccaggcagtg acagccaccc tggaggagaa 480gaggaaagag aaagccaaga tccactaccg gaagaagaaa cagctcatga ggctacggaa 540acaggccgag aagaacatgg agaagaaaat tgacaaatac acagaggtcc tcaagaccca 600cagactcctg gtctgagccc aataaagact gttaattcct catgcgtggc ctgcccttcc 660tccatcgtcg ccctggaatg tacgggaccc aggggcagca gcagtccagg cgccacaggc 720agcctcggac acaggaagct gggagcaagg aaagggtctt agtcactgcc tcccgaagtt 780gcttgaaagc actcggagaa ctgtgcaggt gtcatttatc tatgaccaat aggaagagca 840accagttact attagtgaaa gggagccaga agactgattg gagggcccta tcttgtgagc 9001841400DNAHomo sapiens 184gcctgaagac catttcttcc tctcttaggg acctgctggt ctccagctga ttcggtccag 60gaggaaaaac ctcccacttg ctcctctcgg gctccctgca aggagagagt agagacactc 120ctgccaccca gttgcaagaa gtcgccactt ccccctccag ccgactgaaa gttcgggcga 180cgtctgggcc gtcatttgaa ggcgtttcct tttctttaag aacaaaggtt ggagcccaag 240ccttgcggcg cggtgcagga aagtacacgg cgtgtgttga gagaaaaaaa atacacacac 300gcaatgaccc acgagaaagg gaaaggggaa aacaccaact acccgggcgc tgggcttttt 360cgacttttcc tttaaaaaga aaaaagtttt tcaagctgta ggttccaaga acaggcagga 420ggggggagaa gggggggggg gttgcagaaa aggcgcctgg tcggttatga gtcacaagtg 480agttataaaa gggtcgcacg ttcgcaggcg cgggcttcct gtgcgcggcc gagcccgggc 540ccagcgccgc ctgcagcctc gggaagggag cggatagcgg agccccgagc cgcccgcaga 600gcaagcgcgg ggaaccaagg agacgctcct ggcactgcag gtacgccgac ttcagtctcg 660cgctcccgcc cgcctttcct ctcttgaacg tggcagggac gccgggggac ttcggtgcga 720gggtcaccgc cgggttaact ggcgaggcaa ggcgggggca gcgcgcacgt ggccgtggag 780cccggcctgg tcccgcgcgc gcctgcgggt gccccctggg gactcagtgg tgtcgcctcg 840cccgggacca gagattgcgc tggatggatt cccgcgggca gaggcagggg gaaggagggg 900tgttcgaaac ctaatacttg agcttctttg caaagtttcc ttggatggtt ggggacgtac 960ctgtataatg gccctggacc agcttccctg ttggagtggc cagagaagtg tgtaaaacac 1020actagagggg cagggtggaa aaagagactg ccttcaaaac ttgtatcttt tcgatttcat 1080tttgaaaaat aactacaaat ctattttaat tttacaaagt tagactcata gcattttaga 1140tatcaatgtc ttcatttaac agaagtgaag atggagcaaa cgctcaatca gcgtctgtat 1200ttattcgctc ctgttgtgcc agggtgcgtt tttgccgagc ggttgccttt ctttactcac 1260aaaaccccct tgatgtctgt cctccacgtt ttacgaggga gagccggatc ttttgaagtt 1320tgtatcatct aaagcaggta tattgggatg actatggata gaatttaacc tgaaaacact 1380gaagttgaca gctgacaaag 1400185200DNAHomo sapiens 185cataacaaga gtcattctaa tgtgattata aaggacccga agctttgctt ttaaaattca 60atacttaggt agaaagaaaa tgataacttt ttccctttga tttttattca ctatttttat 120aacactagca gccctgagac accggattgg aaatatctat gcctcttgat gttacctggg 180caccactgca tcacagtcct 200186400DNAHomo sapiens 186aatagtaatt gccaacagtc aagatatgta ctaccaccaa attccgtgtt atttgtgatc 60aaaagatata cacagatact tgaaaactga tttctacgtt gcatatggga aaaatacctc 120atttttctca gctgtccatt atttttgaga tattatgtgc agtgatagta agaacaagca 180gatttggaac acatcagcaa taattttttc aatcagagtc ctgccaaaat gaaagaattt 240gacagtatcc ggcaccctgt actcatgctt ggcttctgta gaaactgtgg cttgcaaaag 300ggcagctggg tactgtgttt tggtacctca ttctttaaac gtataatggg aatctggttg 360gttcaggaaa acccttgcct acttattatt actctgtttt 400187250DNAHomo sapiens 187ggcccatact taatgtattt ttaaacgttt taacatttac taatatagaa ccttctattg 60cctatttcct tctggtttat tccctttcct tctgtcattg aagaaatggt tctagtggta 120gaaatactcc acgattgaga agaatgtggg aagaaaggag ggctggtggg taagaattgc 180tcatgatgtc tccctctgaa ttctgtgctc tcacaatgac actccaatgt gtggtttgac 240gcctggaaga 250188250DNAHomo sapiens 188tgcttcaacc ggaaatgtgg ttgaattacc cttacagtga acctgatcag tggtaacagg 60agatgctaga acaggaaaag acaagtttcc cctttcctcc ctatcccatc aattactttg 120aggtgtattt tttctttgca acccctccag agaagtcggc aatgtttaac gagcatgcct 180gccaagtggc ttgccttata cctcattatg aagtgatact cagggccact aacacatcgc 240acagcattgc 250189500DNAHomo sapiens 189tatgattccc tcgatttccc tcaatcttaa ccattgtgga tcacagcagg agggccagaa 60agtgagcttc agcctggcac cgggacctca gcctctccct taaactttcc ctaatcctcg 120gagctagtgt tactcaagtg actccacagt gttgcccgat cccttcagac atggccttga 180tgatctccaa aactcatgct acctttgcca gcctaaagca tccactctgt gccccaaaac 240gtgaatgtca aatacccttc aaggcagaag gctatttcta tttttgtttg tttctgttta 300aggcaacaat caccaacatt tggtacacat gagccatcct gtgaaacatc aaggcgcttc 360gttggcagca agtcaacttc ggtttcagaa gaaagctgca ctatttcctg aggttagagg 420tttaaaccaa aacaagacaa ccacatttta accccaaatc tgccgactga gggtaaccat 480gatccttcct tcacagcacc 500190150DNAHomo sapiens 190tactaaatca acccaaaccc gagaacccgg tcatggagaa ataaatgata gtaatctatg 60ctgttcatct gttccatcac tcactcactc tcttgctgaa caagaaaggg ccacccatgt 120agcaaaccac atgtaaagag ccgggaagac 150191300DNAHomo sapiens 191tattattttg ttcaaagtag acgggtatac taacatctgt gggcaagttt accacacgcc 60acttaaaaca ggctaacagg gtcatatgcc aaaacgttca ggtttgcatt tttgaaaagc 120tcagagatct gacagatgtg ttccggccgc gatttaacat gcggctccag tgagaaggaa 180gcagatatga caaatggttc acttatttca gaactaaaac cccagaggag cagcctgagc 240caaaaaggga agtgatcaat ggaaaagacg gtcgaatctg ctcacaggca aggcaagggg 300192300DNAHomo sapiens 192aagacctgga gtttccatta caccgaattg gcacttaata actgttgtcg gagcatttct 60taagccacat tttcgtaaag tggctttaaa attgctctgc cagtaggcag gttgctaaga 120tggtcagaga caaacttctg aacgactctt gtaaaatata cagaaatatt ttcagaactt 180ttatcagtaa aattacaaaa cgtgttgcaa ggaaggtgct tgtgataaca ctgtccccag 240aaccttagtg aagttaccaa ctggtggaaa attttctctt gcactcggct taaaaatcat 300193400DNAHomo sapiens 193gcaggggtga ctggtcctct ctctctgcac ctcgcaggat ttctctggaa gatctgagcc 60cgagcgtcgt gctgcacatg accgagaagc tgggttacaa gaacagcgac gtgatcaaca 120ctgtgctctc caaccgcgcc tgccacatcc tggccatcta cttcctctta aacaagaaac 180tggagcgcta tttgtcaggg gtaagtgcga ccctagaggc gatcgtctct gctgtctgtg 240gaaaaaagag ctcctacacc caaagtgctt ctcagttgct gacacttgat ccaagctgct 300aatttaatct aatgtgaggc tgagttttct gaatgtggga taaagtcgta gctaaacctg 360cttctcaggg agtgcctttt atctgcaatg tttttcaaat 4001941100DNAHomo sapiens 194aagtaacggg atcaaattaa ttattatttt ggtggccgcc tctcttctcc accccaagcc 60aggcaagact caccctcggc cctgcccgcc ccagcatttc aaatggaata cctaggtggc 120ccagggggac ccctgacccc tatatcctgt ttctttctgc ctgctttgct acttttctcc 180ttgataaaag gagagagtga gagataatta acaaaaaaca tggccccagg acaatgaaac 240aactggcctt ggccggccag aaatgtatcc tggttttcta ggtgaacttt ctcccatcaa 300tctttccttt aacctctctg ttagtggaag caataggaac acccctcccc tcccctgagc 360aaatgctttc ttttgactgg aaacaaaaca ggggctcggc gaaggctgag gtgaaatctg 420ggtggcatgg gcgccgcaca atggggccgc tgttccccgg cccgggcttg tgttttacaa 480caggggaggg gcgggcgtga atggtctgat gattggaaca atccccccga ttcaggccta 540caaacgcatc ttctgttcca caccgagggg acagaaagga gaaaagtgac aaagaacgcg 600gggcgggggg aattaaaaca aaatgcgctc gactaaaaaa tctctcatat cctgcatatt 660ccagaaagcg gctctatgga gagagccttc aggaggcctc agccatatct gaatggcttt 720ctctggcctc tgatttattg atgaagctga agcgacttgc tggagaaagg cctggagcct 780tctttgtctc cgagatgaag tacaataggc cacagggcgg agatctcttg tgatgctctc 840gggtcctgcc tttctcttgc cctctcctcc ctgcaaatac cagcagcggt gacaaacgat 900tggtggtgtg cctgggagag ccggtgacaa gactgggcca cttgaggtct ccttaagagg 960gtattatggc cagggcgacg tttgtgctgt gaagatggca cactccattt tgtcaatggc 1020tctcatcggc ccagataatc gccccctgcc tgcctgtcag gggcgcagcc ggccgattca 1080tggcgccctc ggagaaagta 110019510000DNAHomo sapiens 195gtctttcccg cccccttgtc taaactcaaa accgagtccg ggcgcgcctt gcagggcgcc 60cgagctctgc agcggcgttg cgggctgaac ccatccggca caaactgcgg gccactggcc 120cctcacacct gggagtttgc ggcgctggcc tgcagcccgg ggcccacgtg gcggaagctt 180tcccgggcgc gcgctgcgca gccccgcggg gccggggaga caccgctcgg gagtcctccg 240ctcggctgca gaatctttat cagctgcact ttaccgcagc cctggctagg acgctaggcg 300gtggagcgcc ctatccaggt gcgccgccgc accatggatc accgcgcccg gtcccgcagt 360cccgccatgg cctggggagg cccgaagccc ggggacagtg gccggcccat ctccggctcc 420gcggaccccc ggctcaggcg ggagggcagg cgggtccctg caggccccca gggagcccgg 480gagcctctct ctggcgtcat tcagtcccgg ggcaacctga agcgcggtag atattggaga 540gggggcgtct gttgggggga cctggcgtca ttactgatgg ctagcaggga ggagggaacg 600ggttgtcacc tcggcctcat aaggccgtga gtgagtagtc cagggcctct tcaggcattt 660ttgaaactgg attaactagg ggggaaattg tagcactgaa gccaccgtga ctgtcttttg 720cgctgtgtgg aaactccggt aaaactcttt gggcaacagt cttatcacca gctcttcaac 780gtgtgcagcc cttctggtcc tgtccctgtt ctgggcccca ggaatgcaaa gcaggtccag 840gcactgtgaa gaccctggcg gtggaggaag aggcttcccg gctgtggagg aagccagacc 900cttacaacac aagacgagaa ccagacctgc gtgggggagc tctggatgct acaggggctc 960aaggaggggt ggaggggcct tcccaggcca acccctgaac ggcttggaca agatgctcag 1020atggacggga ggaacggcgt gtgggatggg ggagctggag gcgggtgggt ggggggggga 1080ggatggggaa agcgctggcc cacccagtgt gggaggggta gaggaaaagc ccgcaggggc 1140caggttggga ccccgtaggc cgggttagag ggcttggact tgatcctgac aggcgacagg 1200gagacatatt gctacttatt atgtgcacag tggccagatc tctaaagaaa acaccatccc 1260ccacccccac cccccatata gtaaaccagg tggtccgccc agtgctccca gggaggtgat 1320gggaaatccc actccatacc ctgcggtgag gggttccatg ccctccacgt gtgcaactac 1380tccgggccca gggaaacact gggccccatc cggtaacccc cggcccagtc gggtttccca 1440gttcacatta taaccaaacg gtcttgccag ctagacagac agacacccct gacctgttta 1500ccctgatcct ctgctctcag gattaatcac aacttgtcga agggggtggc ttccagtggg 1560gtggaccgct ctgtcaatgc cagcgtgtgt ctagcatctc ctggggtggg ggtgtgggga 1620agggaggtgt aggatgaagc cctagaagcc tcaggcaatt gtgatccggt gggctggata 1680ctgaagccca cccctgcctt gacctcaatt ttcagtatct tcatctgtaa aatgggaaca 1740acctgccttc ctcctagccc taaaggggct gctgtcaaga ttggctgaga tagctgtttg 1800caagctgagc tcaatgaaag ttcattgtgt ccccctcagt cctatcccaa tatcgtctca 1860ctgcaaaggt ggggggcagc ttaacttcaa gggcacttca aggatagcca ggtggctgtc 1920agcccagctt tccaggatgg gagcaggatc ttgacagaag ggttgactgg gaggggcagt 1980tgctggtttg ggcttcgtta ggttgcattt ttgtttgttg tcctttcatt tccctggggc 2040agcacccctt cctgcaagct ccaggccttc ctctggaatg ctcctagagc ccaacctctg 2100ctggtgcctg agcttaagcc aggccagcta aggggatcct ggattcacac ggcctcacag 2160tcactcagat tgttagcaga agacaaaaat tacaagggga gggcgtcatg tgattcttac 2220acaccctcca aatccagcag acaccttgga agccacaggt agcttcaaga aacccatttt 2280acggatgaga acctgagatg gagaaaggac aactggagat ctctgagtct ctgagcccac 2340actccctacc tccctgcacc tccaggcact ctgctggcag gatcttgggc aaatgcccac 2400agctctctga gagtcagttt tcctgtctgt aaaatgggag tcataccttc ctcctatggc 2460cggtgagaga ctaaattaaa ctatgtctgt caagacacct gaaactcctg gcacaattta 2520ggttgccttc aagtggtcac agttgtcatt aggtggaagt caacacccca atcattgtaa 2580aggtgcccat ataccccaag atccagatta cagctctcac agtttattat atacagcgaa 2640aaaacacata acacaccttt gcccacattt acatgtattt tacggaccat gtttcacatc 2700agtccgcatg cacatctgca cgtgtgtgca ttcggcagta tttaccaagc acctgccaag 2760tgccagggcc tgtcctccgc acccggcgtg aactgtcctg gaccagtccc gggagccgcg 2820gttctgacca gccgtgctga ccctggacga ctccatgagc tgttttgtga gaaagacacg 2880ccatttgttt gcagagttct gacttctgag gggtcatgta gcacatgttt ggtagccaaa 2940cgctgtcatt cacgaccagg agcgatggct gcaatgcctt tttctttgct ttgctttccg 3000gtgccgggag ccttgcctcc cgccgccacc cctggtcagc tctgcgcaag aacgtcgttc 3060tgtttggcag ccaggccgag acgcagcctg aatgtgagca ggaactcgga gaagggaagg 3120gagagaatca gaaagaaggc ccgggaggga cccgggaagc agtgggaggt ctgcgccctg 3180gagccccgcg agagcccgcc ggtttggcac gggctcctcc cgggccgccc ggcggtccaa 3240caaaggccgg ccccgacacg cacccggtct tttgtgggag agaaacacaa agaagaggga 3300aaaacacgga ggaggccaac agcaccagga cgcgggggcc aaccaggaac tcccggagcc 3360ggggcccatt agcctctgca aatgagcact ccattcccca ggaaggggcc ccagctgcgc 3420gcgctggtgg gaaccgcagt gcctgggacc cgcccaggtc gcccaccccg ggcgccgggc 3480gcaggacccg gacaagtcct ggggacgcct ccaggacgca ccagggcaag cttgggcacc 3540gggatctaat ttctagttat tcctgggacg gggtggggag gcataggaga cacaccgaga 3600ggtactcagc atccgattgg caccagggcc aagggagccc aggggcgaca cagacctccc 3660cgacctccca agctactccg gcgacgggag gatgttgagg gaagcctgcc aggtgaagaa 3720ggggccagca gcagcacaga gcttccgact ttgccttcca ggctctagac tcgcgccatg 3780ccaagacggg cccctcgact ttcacccctg actcccaact ccagccactg gaccgagcgc 3840gcaaagaacc tgagaccgct tgctctcacc gccgcaagtc ggtcgcagga cagacaccag 3900tgggcagcaa caaaaaaaga aaccgggttc cgggacacgt gccggcggct ggactaacct 3960cagcggctgc aaccaaggag cgcgcacgtt gcgcctgctg gtgtttatta gctacactgg 4020caggcgcaca actccgcgcc ccgactggtg gccccacagc gcgcaccaca catggcctcg 4080ctgctgttgg cggggtaggc ccgaaggagg catctacaaa tgcccgagcc ctttctgatc 4140cccacccccc cgctccctgc gtcgtccgag tgacagattc tactaattga acggttatgg 4200gtcatccttg taaccgttgg acgacataac accacgcttc agttcttcat gttttaaata 4260catatttaac ggatggctgc agagccagct gggaaacacg cggattgaaa aataatgctc 4320cagaaggcac gagactgggg cgaaggcgag agcgggctgg gcttctagcg gagaccgcag 4380agggagacat atctcagaac taggggcaat aacgtgggtt tctctttgta tttgtttatt 4440ttgtaacttt gctacttgaa gaccaattat ttactatgct aatttgtttg cttgttttta 4500aaaccgtact tgcacagtaa aagttcccca acaacggaag taacccgacg ttcctcacac 4560tccctaggag actgtgtgcg tgtgtgcccg cgcgtgcgct cacagtgtca agtgctagca 4620tccgagatct gcagaaacaa atgtctgaat tcgaaatgta tgggtgtgag aaattcagct 4680cggggaagag attagggact gggggagaca ggtggctgcc tgtactataa ggaaccgcca 4740acgccagcat ctgtagtcca agcagggctg ctctgtaaag gcttagcaat tttttctgta 4800ggcttgctgc acacggtctc tggcttttcc catctgtaaa atgggtgaat gcatccgtac 4860ctcagctacc tccgtgaggt gcttctccag ttcgggctta attcctcatc gtcaagagtt 4920ttcaggtttc agagccagcc tgcaatcggt aaaacatgtc ccaacgcggt cgcgagtggt 4980tccatctcgc tgtctggccc acagcgtgga gaagccttgc ccaggcctga aacttctctt 5040tgcagttcca gaaagcaggc gactgggacg gaaggctctt tgctaacctt ttacagcgga 5100gccctgcttg gactacagat gccagcgttg cccctgcccc aaggcgtgtg gtgatcacaa 5160agacgacact gaaaatactt actatcatcc ggctcccctg ctaataaatg gaggggtgtt 5220taactacagg cacgaccctg cccttgtgct agcgcggtta ccgtgcggaa ataactcgtc 5280cctgtaccca caccatcctc aacctaaagg agagttgtga attctttcaa aacactcttc 5340tggagtccgt cccctccctc cttgcccgcc ctctacccct caagtccctg cccccagctg 5400ggggcgctac cggctgccgt cggagctgca gccacggcca tctcctagac gcgcgagtag 5460agcaccaaga tagtggggac tttgtgcctg ggcatcgttt acatttgggg cgccaaatgc 5520ccacgtgttg atgaaaccag tgagatggga acaggcggcg ggaaaccaga cagaggaaga 5580gctagggagg agaccccagc cccggatcct gggtcgccag ggttttccgc gcgcatccca 5640aaaggtgcgg ctgcgtgggg catcaggtta gtttgttaga ctctgcagag tctccaaacc 5700atcccatccc ccaacctgac tctgtggtgg ccgtattttt tacagaaatt tgaccacgtt 5760ccctttctcc cttggtccca agcgcgctca gccctccctc catccccctt gagccgccct 5820tctcctcccc ctcgcctcct cgggtccctc ctccagtccc tccccaagaa tctcccggcc 5880acgggcgccc attggttgtg cgcagggagg aggcgtgtgc ccggcctggc gagtttcatt 5940gagcggaatt agcccggatg acatcagctt cccagccccc cggcgggccc agctcattgg 6000cgaggcagcc cctccaggac acgcacattg ttccccgccc ccgcccccgc caccgctgcc 6060gccgtcgccg ctgccaccgg gctataaaaa ccggccgagc ccctaaaggt gcggatgctt 6120attatagatc gacgcgacac cagcgcccgg tgccaggttc tcccctgagg cttttcggag 6180cgagctcctc aaatcgcatc cagagtaagt gtccccgccc cacagcagcc gcagcctaga 6240tcccagggac agactctcct caactcggct gtgacccaga atgctccgat acagggggtc 6300tggatcccta ctctgcgggc catttctcca gagcgacttt gctcttctgt cctccccaca 6360ctcaccgctg catctccctc accaaaagcg agaagtcgga gcgacaacag ctctttctgc 6420ccaagcccca gtcagctggt gagctccccg tggtctccag atgcagcaca tggactctgg 6480gccccgcgcc ggctctgggt gcatgtgcgt gtgcgtgtgt ttgctgcgtg gtgtcgatgg 6540agataaggtg gatccgtttg aggaaccaaa tcattagttc tctatctaga tctccattct 6600ccccaaagaa aggccctcac ttcccactcg tttattccag cccgggggct cagttttccc 6660acacctaact gaaagcccga agcctctaga atgccacccg caccccgagg gtcaccaacg 6720ctccctgaaa taacctgttg catgagagca gaggggagat agagagagct taattatagg 6780tacccgcgtg cagctaaaag gagggccaga gatagtagcg agggggacga ggagccacgg 6840gccacctgtg ccgggacccc gcgctgtggt actgcggtgc aggcgggagc agcttttctg 6900tctctcactg actcactctc tctctctctc cctctctctc tctctcattc tctctctttt 6960ctcctcctct cctggaagtt ttcgggtccg agggaaggag gaccctgcga aagctgcgac 7020gactatcttc ccctggggcc atggactcgg acgccagcct ggtgtccagc cgcccgtcgt 7080cgccagagcc cgatgacctt tttctgccgg cccggagtaa gggcagcagc ggcagcgcct 7140tcactggggg caccgtgtcc tcgtccaccc cgagtgactg cccgccggag ctgagcgccg 7200agctgcgcgg cgctatgggc tctgcgggcg cgcatcctgg ggacaagcta ggaggcagtg 7260gcttcaagtc atcctcgtcc agcacctcgt cgtctacgtc gtcggcggct gcgtcgtcca 7320ccaagaagga caagaagcaa atgacagagc cggagctgca gcagctgcgt ctcaagatca 7380acagccgcga gcgcaagcgc atgcacgacc tcaacatcgc catggatggc ctccgcgagg 7440tcatgccgta cgcacacggc ccttcggtgc gcaagctttc caagatcgcc acgctgctgc 7500tggcgcgcaa ctacatcctc atgctcacca actcgctgga ggagatgaag cgactggtga 7560gcgagatcta cgggggccac cacgctggct tccacccgtc ggcctgcggc ggcctggcgc 7620actccgcgcc cctgcccgcc gccaccgcgc acccggcagc agcagcgcac gccgcacatc 7680accccgcggt gcaccacccc atcctgccgc ccgccgccgc agcggctgct gccgccgctg 7740cagccgcggc tgtgtccagc gcctctctgc ccggatccgg gctgccgtcg gtcggctcca 7800tccgtccacc gcacggccta ctcaagtctc cgtctgctgc cgcggccgcc ccgctggggg 7860gcgggggcgg cggcagtggg gcgagcgggg gcttccagca ctggggcggc atgccctgcc 7920cctgcagcat gtgccaggtg ccgccgccgc accaccacgt gtcggctatg ggcgccggca 7980gcctgccgcg cctcacctcc gacgccaagt gagccgactg gcgccggcgc gttctggcga 8040caggggagcc aggggccgcg gggaagcgag gactggcctg cgctgggctc gggagctctg

8100tcgcgaggag gggcgcagga ccatggactg ggggtggggc atggtgggga ttccagcatc 8160tgcgaaccca agcaatgggg gcgcccacag agcagtgggg agtgagggga tgttctctcc 8220gggacctgat cgagcgctgt ctggctttaa cctgagctgg tccagtagac atcgttttat 8280gaaaaggtac cgctgtgtgc attcctcact agaactcatc cgacccccga cccccacctc 8340cgggaaaaga ttctaaaaac ttctttccct gagagcgtgg cctgacttgc agactcggct 8400tgggcagcac ttcggggggg gagggggtgt tatgggaggg ggacacattg gggccttgct 8460cctcttcctc ctttcttggc gggtgggaga ctccgggtag ccgcactgca gaagcaacag 8520cccgaccgcg ccctccaggg tcgtccctgg cccaaggcca ggggccacaa gttagttgga 8580agccggcgtt cggtatcaga agcgctgatg gtcatatcca atctcaatat ctgggtcaat 8640ccacaccctc ttagaactgt ggccgttcct ccctgtctct cgttgatttg ggagaatatg 8700gttttctaat aaatctgtgg atgttccttc ttcaacagta tgagcaagtt tatagacatt 8760cagagtagaa ccacttgtgg attggaataa cccaaaactg ccgatttcag gggcgggtgc 8820attgtagtta ttattttaaa atagaaacta ccccaccgac tcatctttcc ttctctaagc 8880acaaagtgat ttggttattt tggtacctga gaacgtaaca gaattaaaag gcagttgctg 8940tggaaacagt ttgggttatt tgggggttct gttggctttt taaaattttc ttttttggat 9000gtgtaaattt atcaatgatg aggtaagtgc gcaatgctaa gctgtttgct cacgtgactg 9060ccagccccat cggagtctaa gccggctttc ctctattttg gtttattttt gccacgttta 9120acacaaatgg taaactcctc cacgtgcttc ctgcgttccg tgcaagccgc ctcggcgctg 9180cctgcgttgc aaactgggct ttgtagcgtc tgccgtgtaa cacccttcct ctgatcgcac 9240cgcccctcgc agagagtgta tcatctgttt tatttttgta aaaacaaagt gctaaataat 9300atttattact tgtttggttg caaaaacgga ataaatgact gagtgttgag attttaaata 9360aaatttaaag taaagtcggg ggatttccat ccgtgtgcca ccccgaaaag gggttcagga 9420cgcgatacct tgggaccgga tttggggatc gttcccccag tttggcacta gagacacaca 9480tgcattatct ttcaaacatg ttccgggcaa atcctccggg tctttttcac aacttgcttg 9540tccttatttt tattttctga cgcctaaccc ggaactgcct ttctcttcag ttgagtattg 9600agctccttta taagcagaca tttccttccc ggagcatcgg actttgggac ttgcagggtg 9660agggctgcgc ctttggctgg gggtctgggc tctcaggagt cctctactgc tcgattttta 9720gatttttatt tcctttctgc tcagaggcgg tctcccgtca ccaccttccc cctgcgggtt 9780tccttggctt cagctgcgga cctggattct gcggagccgt agcgttccca gcaaagcgct 9840tggggagtgc ttggtgcaga atctactaac ccttccattc cttttcagcc atctccacta 9900ccctccccca gcggccaccc ccgccttgag ctgcaaagga tcaggtgctc cgcacctctg 9960gaggagcact ggcagcgctt tggcctctgt gctctttcct 10000196500DNAHomo sapiens 196ccggcacggc ccgcatccgc caggattgaa gcagctggct tggacgcgcg cagttttcct 60ttggcgacat tgcagcgtcg gtgcggccac aatccgtcca ctggttgtgg gaacggttgg 120aggtccccca agaaggagac acgcagagct ctccagaacc gcctacatgc gcatggggcc 180caaacagcct cccaaggagc acccaggtcc atgcacccga gcccaaaatc acagacccgc 240tacgggcttt tgcacatcag ctccaaacac ctgagtccac gtgcacaggc tctcgcacag 300gggactcacg cacctgagtt cgcgctcaca gatccacgca caccggtgct tgcacacgca 360agggcctaga actgcaaagc agcggcctct ctggaccgcc tccctccggc cctcctgagc 420cctactgagc cctgctgagt cctggaggcc ctgtgacccg gtgtccttgg accgcaagca 480tcctggttta ccatccctac 5001971000DNAHomo sapiens 197ggacgcggcc cgctctagag gcaagttctg ggcaagggaa accttttcgc ctggtctcca 60atgcatttcc ccgagatccc acccagggct cctggggcca cccccacgtg catcccccgg 120aacccccgag atgcgggagg gagcacgagg gtgtggcggc tccaaaagta ggcttttgac 180tccaggggaa atagcagact cgggtgattt gcccctcgga aaggtccagg gaggctcctc 240tgggtctcgg gccgcttgcc taaaacccta aaccccgcga cgggggctgc gagtcggact 300cgggctgcgg tctcccagga gggagtcaag ttcctttatc gagtaaggaa agttggtccc 360agccttgcat gcaccgagtt tagccgtcag aggcagcgtc gtgggagctg ctcagctagg 420agtttcaacc gataaacccc gagtttgaag cccgacaaaa agctgatagc aatcacagct 480tttgctcctt gactcgatgg gatcgcggga catttgggtt tccccggagc ggcgcaggct 540gttaactgcg cagcgcggtg ccctcttgaa aagaagaaac agaccaacct ctgcccttcc 600ttactgagga tctaaaatga atggaaagag gcaggggctc cggggaaagg gaacccctta 660gtcggccggg cattttacgg agcctgcact ttcaaggaca gccacagcgt gtacgaagtg 720aggaattcct ttccaccaag agcgctcatt ttagcgacaa tacagaattc cccttccttt 780gcctaaggga gaaaggaaag gaaacattac caggttcatt cccagtgttt ccctggagta 840atgctagaat ttacttttgt cataatgcaa aattaaaaaa aaaaaaaata caacgaagcg 900atacgttggg cggatgctac gtgacagatt tttccaaatt ttgttgcggg gagagggagg 960gaggagaatt gaaaacggct cacaacagga atgaaatgta 1000198100DNAHomo sapiens 198tttttaatgc tcagagaagt tcgtattact gattcgggaa cactgagttt ttcagctcct 60gtaaaactat tttcaggttt attttcaagt acattcttta 100199400DNAHomo sapiens 199caccctagag gcaaggacgg ggtctgtgtc aagaggcttc ccagagaagt gaaaactctg 60caggtgcagc cgctgggaga gcatcaagaa gggcagggtg gaggggcagg gggcgaaggg 120agggggtgaa gcccgcaccc tacccccaca tgaaactgat tccactaccc catctctgca 180agcgtccaga ggcagagagg ccaacatttc ggggacagct tggaggcggg agatttaggc 240agggctcctt aaacttttat gtgcatgaaa atcaggccaa tcacggggct cttgagcaaa 300tggggacgat gattcagcag gtctgggctg aggcctcaga ttctgcactt ctaacaagtt 360cccaggtggt agtgatgctg ccagtccaaa gaccacactg 4002005000DNAHomo sapiens 200tgcttcagtg gggtaaactt gaaccgctga gaagacaagc agggagtcgg tctcgctgag 60atttttacct gtggttctag gaacgcagag gcatgtgagt gttcaggctt tgcatagacc 120actaagccac ttctaagaac aaggctacct gagccatttt gcaaaaatat gtacgtgccg 180aggcttttcc tccccacacc tacctcaact ctttctgccg acacactgca cttttcaagg 240gaacccaagt ttgggttcgg caagaattgt acgttgcaca ccgtgtgtga taattccagg 300gaatttcaat cgcatcttgt cttccttcct aagcaaattc ggtgggaacc tggtgtggtg 360tgatagaaaa agccccgagt tctctgtggt agaccacatc aatttcatgt gccagtctct 420cagactccgg cttgcctctc tcaaggaagg gaacaatggt ttgcttggct tcactcctct 480ctttcccccc aatttccaca tgggtatctg gctaaaaatg agttacaggt ttccttctgt 540gagaattgca tggactgata aagtaccatc ccaggaagaa aacaaagatg ctgtcttccc 600tttcggctca cagttgccgt tggggaggga acacacgctg taaattatag gcagccagaa 660gtgaccgcat tgaccactgc gagtggccca gctatggcaa caggctgaga actctggggg 720agagccattt gttggcaggg atggtgattc ttctagcatc aagctctaag atgatgacca 780aacggtatca aaagaaatga tattttgcta cctctccggc ttgggtgaat gatgtggaca 840gttaacctgg acaatttaaa cctttatgtt gatggatcac ttggatgaaa ttaaccagga 900aattgccaag atttcacttg gccctctgac atcaaatctc aatattatat taccaaatta 960gagattctaa agaaccctga gttcctttca ctgaaaggaa ggagtggaaa aacctttcca 1020gatgatccct tttgagtctt ggtgcgagct caggccctcc ctacactgcc tccgtgaaag 1080ctaaccgacc cttgttccta acctagcgca ggtcagctga gtgtccatcg ggcacaggag 1140ccctgggctt gtccgggaga tagccagact cctgctattt cctgatgtct gcatagctca 1200gcgtgtccct caccatcttt gccgttggcc agtaaggaga gccccagggg ccagcactgc 1260acactgaaac ccaacctatt gctcaatgga atgcttaaaa atttcctgaa tctgccttcc 1320tgagttgata aaataggaaa caatacacgt tctgaggggg tactgaaagc agagtaaagc 1380caggaagatc ttttttttct gttattctat acaaatattg cttcctctgc ttgttagcag 1440cccagaggaa atgcagccag ggagccgttt gcagcttttc accagtggcc ggtgtctctg 1500tgttaccaac caaacgacgc tgcaagacta gtgactaacg cacgtctgca tgattcaact 1560tcactaaaat tccctctgct gccagtaaag aagcacttga aaactcttta atttgaaact 1620tgagcttggt taatgacttg ttttcttctc tttctcttta acttctctct tgccatctcc 1680aacacacaca cacacacaca cacacacaca cacacacaca cacacacact ctctctctct 1740ctctctctct ctctctctct ctctcatcaa gttttttaat ttcagggacc cggaaacata 1800cagccccgtg cattcacaat agcatttgct gtgataaagt ggccggcaag ccctctgcat 1860tcccctgctc acttagctgt atgaataaat aatgagtcac agatacaatt tgggtgctca 1920agagagtttg tagccagaaa attaattatt ctcccatccc agcccactcc atctcagctt 1980tgccaaacca tcaagataca ctttgcaggc actggtcaga gtgcgtgccc cgacgcacac 2040ggcaatgcct ttgagacatt ttatgttatt atttttgttt gtttaagcac agccctcttt 2100taccacgaaa gatacacaag acgcacatgc acacacatac tcacacactc acagctcaac 2160cacagctttg tccatttcaa gaggctggtt tcaaaaatgg agacaggttt tccaccctgg 2220ctgttcctat tcataagcct gtaatctaac gacttaagct gcgagaatgc ttaactcggg 2280aaacttctct attgcccttt tccagagaga cctcggtatg ccacaatttg cttcctttct 2340ctcttgaaag atgctggttg tctctttgca ttgaggctac aaggaaaaac acagcacagc 2400cccatgctga tgattttaac ctaaccaagt ctgtcagtct cctgtactct ctgccttata 2460gagacagctg ccttgccact ttggccctga agtccccagg ctggtgcaag gctatctgag 2520agcctccgcc tcctgcccca cactggcacc agccctcctg gctggctctg tgcatgtgcc 2580tgctaagccc cagggcaggc tgcattctgg gccacacagc atgccgagtt aaggataact 2640cagacacagg cattccgggc aagggacagc aaaataaaac ccagggagct tcgtgcaagc 2700ttcataatct ctaagccttt aaacaagacc agcacaactt actcgcactt gacaaagttc 2760tcacgcaccg actgaacact ccaacagcat aactaagtat ttattaaaac atttctgaag 2820agcttccatc tgattagtaa gtaatccaat agacttgtaa tcatatgcct cagtttgaat 2880tcctctcaca aacaagacag ggaactggca ggcaccgagg catctctgca ccgaggtgaa 2940acaagctgcc atttcattac aggcaaagct gagcaaaagt agatattaca agaccagcat 3000gtactcacct ctcatgaagc actgtgggta cgaaggaaat gactcaaata tgctgtctga 3060agccatcgct tcctcctgaa aatgcaccct cttctgaagg cgggggactc aatgatttct 3120tttaccttcg gagcgaaaac caagacaggt cactgtttca gcctcacccc tctagcccta 3180catctctctt tcttctcccc tctgctggat acctctggga ctccccaagc cctattaaaa 3240aatgcacctt tgtaaaaaca aatattcaaa ttgttaaaga ttaaaaaaaa aaaaaaagcc 3300agcgccgcct tggctgtggg ttggtgatgc tcaccacgct gcgaaaccct gtggtttgca 3360ttcagtgtga ttcgtcctgc ctgctgacca ctatgctggg ttcagacttc tgacactgcc 3420aggctaccca acttgtggtt ctgtggttgt ttatgaggcc caaagaagtt ttcacacaac 3480ccaaattaca aatttaactg ttcccctttc cacagcccat ctcaattggt tcttgccaat 3540catgtgactt aagtgatgtc aatttttttt tttcttttct gagcaatgcc cttccttccc 3600tccacctgcc ctcccccagg ctgtgcaaga aaatagccga gtagactttg caagaggggg 3660ggatgtagaa aaaagtgact cagtcactta ttatatctca atggtctttg ctgatttagt 3720acaactcggc tcctgttgtt atttgtggtt tttggaacta ctgattattt tgataaagat 3780ttcattgctg cttattcaat agtaattcaa cgctggcatc aagccgctgc tccgacagga 3840tgtggatccc atcatttaaa atgctaggca tcagctccgg gagagttaag tccttggtaa 3900cgtctatcat ggcataagtg aaactataaa agggaaaaat aaataaaaag aaatgttttg 3960gtgagagtct gacccctaca acgggctggc aactcacagg tattttaaag cctgggaaag 4020ggaaagaatt ttacttttga aataaaagga ctgttttaat gaaaccaaaa ttatgtggtt 4080ttattccccc taaatggaca actttagtat gtatctcttt cagtaaagag ataaaatcat 4140agtacagtct taacacacac acacacacac acacacacac acacacacac acaaattagg 4200aagctaaagg aaaacaaagc agagagaatt tctgtatttg ggacaaagca gtggttactc 4260tgcagatgtt tatttgtatt gtcacttggg aaagctccct gtattgcctt tctctagttc 4320aattcaaatc aataggctaa tttacacctg taggtaaaac tacactttga gcacatgagg 4380atgccacaat agaaggggaa ccaggaggag acacttctcc tggggctgac taatgaatat 4440tatatagcgc gtcctctacc ttagaaagac atgcctgttt gaagatgcta aaaacaggat 4500aattttgtaa gtgggcaaac cactgtggtc acacgtattt cattttccgg ccccactggc 4560tttacctgct gacaactaaa acgtcatttt gttttgtagt tccaagatga agaaaggctt 4620attttcctga tttactacct tattcatttg gctctgctct gcctacatcc gccatagcac 4680tctgcgcacg tgaaatttcg acacataggg tcaagagaac ctgtgtgatg atgggttgta 4740aatgccagtc ctggattcta agctgcagta gccagcacag gcacttcaga aaggctgaac 4800tcccacaaca ctccctcggt tttccctcat ccacttaatt tcacacacac aaagacccac 4860aacgatagta gcttccatgg cacaagtctt tcaaaaggaa cagacacaat ttttacttac 4920tcctgttttg actaaagcag gaattgaaac tcaacagacc gctttctctt acacttgtga 4980gaagttagct ggccacatgt 5000201500DNAHomo sapiens 201agggaaaaga gataacgaaa gaaagaaaga aaaaaaaaag ggccggcaat ttcatgtaca 60tttgttttgg cattcgctga attctagaga tgaaaacaat ctcctgcttt taattcagtc 120cacgtgcaac aaagttgtac gttgggagat ctggctttta ataagaacga ttaacaagcg 180tttttgatca caggaagttg agaagagtcg ctgcttctaa gaatacaata aacattgact 240agcagttaga cggtccatct ttctctatca gccgtttagc agcctctact ttgatttggg 300gcaaatgcga gatgggacca ggagagagct ccccacaccc ccaccaccac gtgggcagtg 360gttctgttcc agagcgcctt ccttcctgtc cagggaggca ggctgctgag gccgtttctg 420ggcaagaggc cattgtcggg atatttgctt tagatagctt gcagctgggc tgagtgggtg 480tttcattcag actcaacaca 500202700DNAHomo sapiens 202agcctggcgc acccgcccta atttgagtca gggaccctag gcgcctgcag ctccggttcg 60ggttgagtgc ctcctgtcag gatgtgaagc tgctgtcccc cccgggggcc tccagcactg 120ctgaggactc agcagtcagc ctctcctccc acttgggctc atttacagag agcatctcca 180ggaatcagtc atggggaaag gggaaacgcg gagtgacaac acaacacgta gaaagttctc 240tgccgccttg gtcaggcttg tcagcctcac agcccatcct gctcctgcgg gaggaaaagt 300gagcagaact cagcccggag atgagccgca ggccggcagc ccctgcctct gccctgcttg 360ttgtgactgc aatgcaaggc tctctgtagg tgcgggggat tcgggttaaa tgggtctcca 420gtggtccagc gctcccagca aaggccgacc acaagaatta gcgggctagt tatttaccat 480aaccatatac aaaaccacaa gcatcagcgt tccctcaaat acatccgaga cgctgtatat 540ctctttatta aagcctgtca gggtttgtta ttgcacagct tggccttgaa ccccaactaa 600accaggctgc ttgagcaaag aaccaagcaa tgcaagcatt caggcaggac cattataacc 660ctgaggccaa aggcagaagc agggagagga gacgtcttcc 700203500DNAHomo sapiens 203agaccagcct cggtcttcgg cctgcgggtt ctgcaaagtc aggctagctg gctctccgcc 60tgctccgcac cccggcgagg ttccggtggg gaggggtagg gatggttcag ccccgccccg 120ctagggcggg gcctgcgcct gcgcgctcag cggccgggcg tgtaacccac gggtgcgcgc 180ccacgaccgc cagactcgag cagtctctgg aacacgctgc ggggctcccg ggcctgagcc 240aggtctgttc tccacgcagg tgttccgcgc gccccgttca gccatgtcgt ccggcatcca 300tgtagcgctg gtgactggag gcaacaaggg catcggcttg gccatcgtgc gcgacctgtg 360ccggctgttc tcgggggacg tggtgctcac ggcgcgggac gtgacgcggg gccaggcggc 420cgtacagcag ctgcaggcgg agggcctgag cccgcgcttc caccagctgg acatcgacga 480tctgcagagc atccgcgccc 5002041500DNAHomo sapiens 204aaacgtttaa aatatatttc taaacagaat gggccaattc agtcacagta actgttgatc 60tccatagcag agcaacccac aaagacagaa ctgatttttt tcccataatc aggggtgaaa 120aatatacaac ttgtttctga accaaaacca caatttctgc agtttaaaat gtttcactgc 180taatatggcc ctggtagaaa ttatgtagtt tcttttcttc tttaaaaaaa aaaaaaatta 240aaaaaatttc ctaagacact aaatgctcca tctggaatgt agattctgat cacaaagcag 300ctcagttaac ctaaaaaata aaaaattccc atcacctgtc tcagtagggc ctgagagtag 360tgtggggaac cccagctttg gtatggagag tcatggcccc ttgaaccaga tagagacctt 420gaatagccat agctggtgct tctctcagga taaactctga tgtaggaagt atcaccctca 480tgagagtgga atttggtcat ccagttgacg cagggcatat tccatgtctt cttttctgag 540acacccaacc atccccactc catccttctg cacatccgtg taacaggcat ccccagcttc 600tcgcgtgtga tccttcaggt cctgccagct gcctgatgga agaagtccat ttcttccata 660aatagcatcc tctgcatctc gagggtcctc gaagcgcacg gaggcgaagg gcacaaggcc 720gtaccggctc ttgagctcga tctcgcggat gcggctgtac ttgtagaaca ggtcctgcgg 780ctccttctcg cgcacgtggg tcggaaggtt tccccacgta gatgcacccg tcgccctccc 840agccgcgctc gtgtccgccc agccggacaa ccgcaccgcc cgacgctgct ggccagccgc 900agcccgcatc cgcccgtatc gccgccgctg ccgcctcagc acggctgccc ccgcagcgtc 960tgttttgttt tattctaaca gggtctctct ctgtcgccca ggctggagtg cagtggcgtg 1020atcttggctc cctgcaacct ctgcctcccg ggttcaagcg attcacctgc ctcagcctcc 1080caagtagtgg gcattatagg tgccagctaa ccatggccgg ctaatttttt tttttttttt 1140tttttttttt tgagacagag tcttgctctg tcacccaggc tggagtgcag tggcgcgatc 1200tcggctccct gcaacctccg cctcctgggt tcaagcgatt ctcctgcctc agcctcctga 1260gtagctggga ttacagctat gtacagcgat gtctgcaaag atagggattt aacagcactc 1320atatcttcat gttcataaaa aagtcctaca cgcgtgatgt acgtctagat ctttcctttt 1380gtcacaggat atagcacggt agttacggat atagtctccg cagtgcctgg gtttgactca 1440gcttccccac gtactgtcct gcgcatattt tgtgtctcag tttcctcatc tttaaggtag 150020517000DNAHomo sapiens 205cacgcgcccc ggcctggctg gaggggccaa cccagcgggg cccgcctgcc cgccggcctt 60tctgtaactt tctctcttta aacttccaat gaatgaacgt gcctcttctt acggatttgt 120ttagattagg gaatagattc ctcgctgata gcgttgcttt gcaaataaga cctcctatat 180tattcaaacc aaacgagttt gtgtctttaa aggactatag cagccccatt ctatgttaag 240ggttggctat tacaattatt atatgcttag ggaaaaaatg taagccccgt agtttgtgct 300tttcttgatg tacagaaagg tttatcttag gtggataggt tttgttttgt ttcttaaatg 360ggattttttt ggttcgtgtc tttgaagggc tgtttcgcga cgtcattaat gaactaatcg 420gttttcagat ttcaagacgg tgtgtaattg atgtaaccac tgaggaattt cagtgcacac 480cagactaaga ctcttccagc gcaggggatt ccagatgctt cttgggccct ctggaagcca 540tggggatgtt tccagaccga aaggagggct ttgctgggga gcagatgtgc tgcctctccc 600cgacccagga ttttgaggcc atgtttccgt taatctggac cgagagccct ctgggagagg 660gaggcaggtc gtagggggcg ggggtgaggg ggagcgagat gaggtcgtcg ctggacgctg 720ggctcccttg tcgttgtcct tttccccaga atccatggtc aggcctaggg agccacccct 780gggtgctcga gatgagtccc caccctcact gaaggtcggt cactggatgt ttgtgtgcat 840cgtaaggggc ccaccgaagt cccgaagcct tctcagggac cagcgagaaa gaggagcagg 900cttgggagac agggaaggaa aatgcagggg aaagggctca cccctcgacc ccaggtaaaa 960ttagaaggaa cgtgtggcaa cccaggtgca gctttggtcg ctcgctcaag gactttgcta 1020gtcactacca ttaattaatt aatcactatc attaactacc aaggacaccg tttttattcc 1080cctaaaagcg tcaccttgag gggaatggag aattgggcag cagctatgca aatcctggga 1140caggagacac tgcctgagga ccctctctca ctcccaatcc cagaacccga agttatcccc 1200gacaaccaag tccaagcaca tgaaccaaga cgatcagctt caggcagctc cttaccccca 1260caagcggccc aggaggtggg cattatcccc cacccctggg atttctccat ccctccctct 1320tctctcctgc gggagagaga gctgtggtca cccagttggg cgcgatggct ctggactaat 1380ggggtctcta gacccagggc acaaaggcca atctgccagg ggttactgca tgtaatgaga 1440taatcagaca tgttgaccaa cctaaaagaa aagactctcc cagggagtaa ctcccagtga 1500aataatttat taaaaaaagc aaaaaagaga cataaatttc tctctactac ttgaggaaac 1560agcaaacaga acgaattagg gtcttggcct ctgcaggaat aaattatttc cgacttggtc 1620tggatacctg taattatttg taagctgtgg gtagtaatac tgtaattgtc ccccggtcct 1680ttctggaagt agcaatgacc ccaaggacaa ttggtgacgt ctccacaggg tttacacatg 1740gaaaggagtg aaaaatcgag gaattctttc agatagccca gaccaaaaat cctctcagcc 1800atgaaaaggt catatatgtg atgctgggcc aagcggactt ttctggagta accatatcat 1860aactgattgc ggatgtagac aagagcgtat aaaccaaata ggcttgaatc aacgcagtcc 1920tggattttct gttgcctctg cttgctgggg cagtggaagt tcttaaactc cacttcagag 1980gttggaaatt cttccccctc ccccacctcc ttagtgacaa ggtctctgat ctcctgctgc 2040cactgcaata gcctctccca tcccgcgggg aacggccgga gttcttccct tgatctctcc 2100cgagtcggct tccgctgggg atggatcgca ggtaggcgcc ggcgcggcct ggggaagaac 2160agttgcggag catctgaagc ggaaaatcca agcagatgtg aggcgatccg ggcccgcctc 2220gttcctcttg gggcctgaat ttcttccaga taagtttcct aatggaacat ttctaagagg 2280tggggtacga ggcggcttgc tcgcacgcgc agtgggacag actgcgggtg gggacgtact 2340gagaggtccg gacctcaatg cgtccgaccc gtctccacac cgcccttttc cagcccccag 2400tctcctttca ttccctactc ttcaggctcc tttggggcca gtgggtgaac cgccatttag 2460aacggtgcct cggactcggg ggtcgtgcgc

tccatctctg cctcccccct ggggcccgcg 2520aggctggtcc gggctttctg agctgggcgt tcggctttag gcccaatacc tggaccagga 2580atttcttctc cccgcgccag aagggaaaga cataggaggt gtcccaatct gcggtcaccg 2640ccgatgctcc tgaccactct agtgagcacc tgcccggtac ttttccattc caacagagct 2700tccagcttca tactaactat cccacatacg gcctgtgggt attagctcta agtgtccttt 2760tccgagggcc cgaggctccc cctccagcag ggagagctcc gggacggccc ccaccaaggg 2820ttgggtttct tccttcacaa ttccacagag gcatccctgt ccttcctacc tgggaaacct 2880cgaggtgcgg tgcccgtgta cttctggtac tttgcgtggt gccatcaggg accccagagc 2940cacagctgcg tgtgtgtgtg gatgtgtgtg tgtgtgtgcg cgcgcgcgcg tgtacggcga 3000aaggatgtgc ttgggggagc cgagtacaca acgtctgctt gggcagctgc tgggcaggcg 3060ttgggcctgg aggtatctca cacccacgta tcttccagtc ttcaaacacg gcattgctct 3120gcctcccgta gcgcgcttcg aacctgcctc gcggacacgt gaacagaggc tgtccctggg 3180aagataagtg cgctttcccg taaaatccgg gaaatttgcc ttgaggaaag tttccgttct 3240tgttacttgt cgggtttctc ccacttccac ttagccatgt ttctgcgatc tgggtaatcc 3300ctttcaagcc caggaggaat tctcccgggt ccataattga gggtcggaag ccgtgggggt 3360gagaaacgca ttaaatcctc ccgaagccca ggaggtgcca gagcgggctc agggggccgc 3420ctgcggaagc tgcggcaggg gctgggtccg tagcctctaa ccccttggag ctccttctcc 3480cagaggcccg gagccggcag ctgtcagcgc agccaggagc gggatcctgg gcgcggaggt 3540gggtccgact cgccaggctt gggcattgga gacccgcgcc gctagcccat ggccctctgc 3600tcaagccgct gcaacaggaa agcgctcctg gatccgaaac cccaaaggaa agcgctgtta 3660ctctgtgcgt ccggctcgcg tggcgtcgcg gtttcggagc accaagcctg cgagccctgg 3720ccacgatgtg gactccgcaa ggggctaggg acaggcaggg ggagagcccg ggtttgcgca 3780caccttccag cccctggagg gagcctgctc ggcttcgaac gccttcgaac ttttgacctt 3840caaaggagtc cctggaaaag gtcaggagcg cctgctgcag gcacggttgc cgaaggccag 3900gccttcctgg cgcaggggag ggccagggga gggaagcgga tactcagtcg ctgtccgacg 3960gcgagttttc ggagcagcag gctcatgatc ccgggccagt ggcgagagca gtgacaccga 4020gaacccaaat ctccgcgccc ccatccgcgg cccggtgtcc tcccggcccc tgctgacctc 4080caggtcacgc accccactgc tccacggctc tgcagcctgt ggcacacggc cgagagtccc 4140cacatgatct cgacgccaag gtaaggaatt gccctgcgtc ctctgagcct gtctctggcc 4200tggggggccg ggaaagctgc actcctggaa gaggtggggt tatgtgaccg ccgctgcagg 4260ggtgcgcgga ggactcctgg gccgcacacc catttccagg ctgcgggagc cggacagggg 4320agggcagagg ggggacaaaa ggactcttta ggtccaaaat gaccctgaag gagagtccag 4380aatgcccagt ggccgcgtct gcaacggagt cttctttctc caattgcctt ctgccccatc 4440accatgggcc ccacctgcgc cacctgcgcc caccctgtga ccctggctca gcgaccttgg 4500cccttaatcg cccaacgccg attcctcaaa attccggctg cgctgaatcg ggctgctttt 4560gccgccgccc cggcagttgg gccctgtttc cgccggcgcc ctgggagagg cctcaccact 4620cggctgggct ccctggcccc tcccttcccc tggcctgagc gcccctgcgg cctcccgctc 4680ctcctgagaa ggcgacaatc tctttgcacc ttagtgtttc gaggacagaa agggcagaag 4740ggtcacttcg gagccactcg cgccgttttc acgtgtgtgt gtaatggggg gaggggggct 4800cccggctttc cccttttcag ctcttggacc tgcaacaccg ggagggcgag gacgcgggac 4860cagcgcaccc tcggaaggct cgatcctccc cggcagggcg cctggccaac gagtcgcgcc 4920gcctcctctc ggccgcgcct gctggtgacc ttcccgagag ccacaggggc ggcctcggca 4980cccctccttc cctcgccctc cctgccgccc atcctagctc cggggtccgg cgaccggcgc 5040tcaggagcgg gtccccgcgg cgcgccgtgt gcactcaccg cgacttcccc gaacccggga 5100gcgcgcgggt ctctcccggg agagtccctg gaggcagcga cgcggaggcg cgcctgtgac 5160tccagggccg cggcggggtc ggaggcaaga ttcgccgccc ccgcccccgc cgcggtccct 5220cccccctccc gctcccccct ccgggaccca ggcggccagt gctccgcccg aaggcgggtc 5280tgccataaac aaacgcggct cggccgcacg tggacagcgg aggtgctgcg cctagccaca 5340catcgcgggc tccggcgctg cgtctccagg cacagggagc cgccaggaag ggcaggagag 5400cgcgcccggg ccagggcccg gccccagccg cctgcgactc gctcccctcc gctgggctcc 5460cgctccatgg ctccgcggcc accgccgccc ctgtcgccct ccggtccgga ggggccttgc 5520cgcagccggt tcgagcactc gacgaaggag taagcagcgc ctccgcctcc gcgccggccg 5580cccccacccc ccaggaaggc cgaggcagga gaggcaggag ggaggaaaca ggagcgagca 5640ggaacggggc tccggttgct gcaggacggt ccagcccgga ggaggctgcg ctccgggcag 5700cggcgggcgg cgccgccggg ttgctcggag ctcaggcccg gcggctgcgg ggaggcgtct 5760cggaaccccg ggaggccccc cgcacctgcc cgcggcccac tccgcggact cacctggctc 5820ccggctcccc cttccccatc cccgccgccg cagcccgagc ggggctccgc gggcctggag 5880cacggccggg tctaatatgc ccggagccga ggcgcgatga aggagaagtc caagaatgcg 5940gccaagacca ggagggagaa ggaaaatggc gagttttacg agcttgccaa gctgctcccg 6000ctgccgtcgg ccatcacttc gcagctggac aaagcgtcca tcatccgcct caccacgagc 6060tacctgaaga tgcgcgccgt cttccccgaa ggtgaggcct caggtgggcg gccggggacg 6120ctggggagcc cggcggcccc ggcccaggcg ggaagcgcaa gccagcccgc ccagaggggt 6180tgccgcggcc tggcgtccag agctggggcg tctgagggag gttgcgtgag ggtcttcggc 6240ttcggcgctg gcttggggcg aggggccagg gccttggcgg cccaggcgac caaaccctct 6300cctggtccag ggctgggtga gggcgaatta cgaattgttc caggggcagg cagtccccca 6360gcccgcacgg ccagcgagtt ctttctggtt ttgttctttc tccctttcct ccttccttcc 6420ttcgccagtg cattctggtt tggtttggat ttttttctct ctttctttcc tttctttctt 6480tctttctctt tctttttctt tctttcttcc tctttctttc attctcccct tccttccttc 6540cttggccccc tctctccctc cctccttcct tccttccttt gccaatgcat tggtttgttt 6600tctttccttt tctgctttcc ttcctttctt tggaagttca ctctggtttt gctttctttc 6660tttccccatc ccttcctttc tttatccctc cttcccttcc tccttttctt tctacgattc 6720cctttatttt tccttcattc ctccctcttt ttgtctcttc tggaggaggt gaaggagggt 6780cagcttcagg cgctgcgagt cagcggggat cacggtgagg cccaagcact gcaggctgag 6840gccacagagc gaacacttgt gctgagccgg gccctctcgt gaggctgggg tgcgggaagt 6900ccgggcagga gagacccgcc cccgccgttg ctgagctgag acccggctga aagagagggg 6960tccgattaat tcgaaaatgg cagacagagc tgagcgctgc cgttcttttc aggattgaaa 7020atgtgccagt gggccagggg cgctgggacc cgcggtgcgg aagactcgga acaggaagaa 7080atagtggcgc gctgggtggg ctgccccgcc gcccacgccg gttgccgctg gtgacagtgg 7140ctgcccggcc aggcacctcc gagcagcagg tctgagcgtt tttggcgtcc caagcgttcc 7200gggccgcgtc ttccagagcc tctgctccca gcggggtcgc tgcggcctgg cccgaaggat 7260ttgactcttt gctgggaggc gcgctgctca gggttctggt gggtcctctg ggcccaggag 7320ctgggagggc tgcgccggcc tctggagccc cgggagccag tgccgaggta gggagacaac 7380ttccgccgca gggcgccgga cggtcggggc agagcaggcg acaggtgtcc ctaggccgca 7440gggcgcttcc atagcgccat ccccaccagg cactctactc gaaatcggaa agctcgacct 7500tttgcgttcg cctctgccaa gcctgttatt tgtgctggcc gctgggtctg gagctgcgct 7560tctcggcccc tccccggtgg agcgcagagg gctggtctgc aagcgcggcc tccagccccg 7620cggctccccg gcccaggagc caggcgcggg ctgacccggg agcacccggc agcggagggg 7680gctggaagcg gaccctaggc ctctcctgtg ccacccggcc ctaccgcgcg gccgcggggc 7740gctctcctct cgggcgcagc ggtccttcag cccagggcag gttcctccct ttcctactcg 7800gaacgtggca aagatacccc agtcccagcc cctccagctg agagctgttg cccaaggtcg 7860tcgctacttg tccgctcaat ggtgacccct tggcagagaa ctagggatga ttccactccg 7920gttgatgttt taggggaaat taaaagaaca ttcggttttc tgagtctcct tccggggagg 7980cgtggtggta actggtttgc tgggaagagc cgttccttaa ccgcatgcaa caaagcaggt 8040gtggaatccg gacgagaggg cactcactgc cttctgcccc ctttggaaat agaaaaagcc 8100ttcgaagcag caatccaaag atcaaatgat ttgcggtcaa tgatttcaat taaaccagaa 8160attagtaagg gagggccgag aagacacggc tgctcagaag ctgttcgctg tttgagggat 8220ttcccggaga gcctgttaaa agatgcgaag tggtgggtgt accgctcagc cacctttaaa 8280ccggctctgt gcgttctggc tctggaaagc aagtctccag gcatttgggc tcagaattgc 8340tgggccccga gtttgggcgg gggtggtcct tctgggggtc aggccttgag cagcttgcac 8400tggtggcagg tttgggagca gttgaggggc ttcctgtgtg tcttttggag ggggtgaccc 8460tggaagttgg cactctggaa gggagctgtt tggccctaga gttttggaaa gggccctgaa 8520cctgttcggt ccccctcgga aagggaaggg agcagtggct tagtccctcc ctcctccatt 8580cgtgcaatgc ctggggtagg ggtagacctg gagccggtgg actcatatcc ttggaattcg 8640tcaggacagc tgctccgggg ccttggccct cagtcagtct ggggctgagg agtagggaag 8700ctgggaactt ggggcagagg aagaagatgc gtttagaaag acctccatta tgcaaactgg 8760agtccattta tgcaaactgg tcacccttcc agtagctcca aagagtggca gtggagtggc 8820atcttgattg atttaacctc ttctcagggg acctgggtct gcgagggagg atatggctgc 8880ggggttggaa taggatctgt ctgagctgcc agggtcaggg tggtggccct agggaggttt 8940tagggccagg gtggtcccgg gctgtggcag gggctctcag atcgcctcgg gctctcagct 9000gcaaggtgaa aaataccatg aggaattgat ctgccaaggg cggtcttgtc tcaaagcaag 9060tggattgctg gggtaaagaa tctagagacc agcttaggac tctgggagga agaaaaaaaa 9120aaaaagaata gcatagtcct aaggaactgc aaggatcacc agattaaccc ttcatacctg 9180gggaaattaa ggccagacat gacacaggcc tttcccaagg ctctgtagca agggcaatag 9240caggccagtt gctgccactg cggtcctgtg gggcatgttc tcactccact gcacccagga 9300ggctgccagc ctctgttcct tttaacatag atctcctcag ttgttaagac agaaagagga 9360actcagaggg gtccctgtgt gcaaggcaga gggagaccac cagaaccagg gtaagcaccc 9420cacttggtag ccagttcaag gacttgggga tgttttcaac atttacagcg aggtttgagg 9480ccccattgtc atgcagcgct actcggcctt ggtctcctta tctgtaaaat gggcccatta 9540gcaatgcaca gggttgctgt gatgaagggt gaggtcccac aagcaaaagc tgtgcagtga 9600ggggggaatc ctaagcattg ttcctatgcc attcacccct tcctgtgagc tccccatatt 9660ccctggctca aaggagtctt gaatggcagg gatggaggac tcactgcctg gactttgaag 9720acccctgctt tctgggtgac caccttttct tccctttgac agtgaactaa tacattggag 9780gtagatagtg ctgggaagag gacaggagac cacggctgac tttggacatg ggctcgaaat 9840tgataacttg atgagtcttg gagggtggtt aagataagct cggggctggg gcagcgctga 9900ggtctgatgg tcagccagcc ctccccaaag tgtggccctc cgttctggag ataggggctt 9960tggaaactgc aaaagcgtcc tggcaggcca gctctggttg ctccctggcc atagctgctc 10020tgactacagg cagcaggacg caggtcggcc tctgcccatc ggaggtcaga ggcagggcct 10080ccagcaccag actcagcagt gccactgcaa acctggcaca acaggctggt cccaggactc 10140agctcagcag tgaagttgga aaccaaggtt gagtctcccc atctcccttt ccccaacccg 10200aaagacccaa gatgggtgtg ggtgaaagag ggagaaagaa ttgctactcc agaaactgtc 10260atttgcccac acgaaacgag gtggggttca aggtctgaac tcttccagtg cctgggtgcc 10320tttgggttta aattcagctg caggtgcccc catcaccact tccacctgag cacaccacga 10380gaagccaggt tatcttagaa actgtttccc ggaatcaaag cgacttgatt tggagagttg 10440ggtgaggaga aactcacccc tatacccctc agggcgtcag agatgtgagg caattctcta 10500cctccgctgg aaaaaatgca gatttattaa aggtcgactg tttagcagaa caacgtagat 10560tttttacaac gctttccccg tctctgcttt gaagcctgcc aggctgcagc tggggatcca 10620ggagggaaag cccgcaggcg cagaggggac aatccgggaa gtggtaaagg ggacacccgg 10680gcacagggcc tgtgctttcg ttgcaggcga ggaagtggag cgcgcgctgc agattcagcg 10740cggggctaga ggaggggacc tggatccctg aaccccgggg cggaaaggga gcctccgggc 10800ggctgtgggt gccgcgctcc tcggagccag cagctgctgg ggcggcgtcc gaactcccca 10860ggtctgcgca cggcaatggg ggcaccgggc cttctgtctg tcctcagaat acgtaggata 10920cccgcgggcg acaagccggg ccaggctagg agcctccttc cctgcccctc cccatcggcc 10980gcgggaggct ttcttggggc gtccccacga ccaccccctt ctcacccggt ccccagtttg 11040gaaaaaggcg caagaagcgg gcttttcagg gaccccgggg agaacacgag ggctccgacg 11100cgggagaagg attgaagcgt gcagaggcgc cccaaattgc gacaatttac tgggatcctt 11160ttgtggggaa aggaggctta gaggctcaag ctataggctg tcctagagca actaggcgag 11220aacctggccc caaactccct ccttacgccc tggcacaggt tcccggcgac tggtgttccc 11280aagggagccc cctgagccta ccgcccttgc agggggtcgt gctgcggctt ctgggtcata 11340aacgccgagg tcgggggtgg cggagctgta gaggctgccc gcgcagaaag ctccaggatc 11400ccaatatgtg cttgcgtgga gcagggagcg gaagaggcag ccggtcctca ccctcctctc 11460ccgccacgca catatccttc ttgacttcga agtggtttgc aatccgaaag tgagaccttg 11520agtcctcaga tggccggcaa cgcgccgagg tcacgctccc cagaaacacc cctctcccct 11580cccctacccc agctccccct ggggcgggtg gtaattgggg gaggagaggc cgcaggcagg 11640gaaggggtgg gaaagccaga gagggaggca caaagtgatg gcagcccggc aaacactggg 11700gcttcgggct gggccgcgct cgtttaatcc cacaaaaatc ccattttgga ggtgagaaat 11760agaggttaga ggtcgggccc ttctggagat cagaccgagg agacgggccc agctggcgtc 11820ttaaagcaag gagggggagt cgggaggagg tgagacccct gcacccaggt ggggctccca 11880aaccgttctg gatttaccac actcccaggt ccgattttcc atggagggct ggggttaggg 11940actggcacct tcttgttgtt aaccgcattt gatattcaca agaaccctgt gaggagactt 12000tgtcaccgtt tttagatgcc tgaggttgcc ggaggggcag tgagagaatc gtctaacctg 12060gtgttcctac cacagtccag gccctgtgtc ctgggctgga cccacagccc ctgccaccac 12120ccagaggaag gcgcgaagct ggctgcctcc tttacgggtc tcccttaggt gccctcatga 12180agggggacgg ccacctcaca gtgcaggaac tatctccccg tttgctccca aatagtcttc 12240ttggtgtggt gctgtctatg gtctgtgacc tgcatctgga gttaccccca ggaccagctt 12300cggaagagga gggatcgctt ggaggccgtg cagtgtgagg aacggcaggc agggtgtggg 12360accaacatgc acacactcgc aggtgctggg gccagggagg aatgaggcgc tggctccctt 12420tccctccatt tctccctggg ggtcccagca acctggccat ccctgacttc caacagcaca 12480gcgtccccac aggtcctgca gtgctctgca ggggtgcagg gagctcccct ccccccagcc 12540gcaacctcac cttcctcacc cccacccctc cggcaggaaa ccacaggctg ggttggggac 12600ccctggtgct ccaagagagc agtgagtgct gggagccgct aaccccgagg cgcctagcac 12660agactcttct caccccttat ttctgaaata aagcccttcc ttaggtccag atgaggacca 12720cgtgctcagt gcctcacttt cgtgggagtg tatatcactt tacagtatca agacaatttt 12780ctttcgttac aaatctttat ttagtctctg cgtttagacc aaagtagatt tttatgggct 12840gagtgaaaaa acctcgcccg cattggtttc tgatggaaca gctggcagcg ccacggcccc 12900gggtggggtg gcctagaggc aggggtgctt gggaggaaca tctagcaccc gaccacctcc 12960accaggtggg aaagggacgt ttgcaccaaa tctccgccgg caaagcagag gctttgggga 13020attacagaaa aactataatg atctaaaaga gaacaagtta tcttgaactg tgcgggtatt 13080tgaatcatac agaaaattgt cctgtgtgcc caatgcactt ttgcatgtag agccagggcc 13140ttcgaggaag ctttcaggag atcccgggca gcggagtctg gtctggagtt tcatttccgt 13200aggtgcagat ttctccccaa gtcttcccgc catgggcttt gcaagaagcc agggcccaga 13260ggccacgctc accgttaaca ctgcacaggg caaaggtggc tccaggacaa ctgcccaacc 13320ccaggaacga cccagcagca gagaaaagga cagctgccag ggtgcctttg tcgctttttg 13380gaaatcagaa ttcctgggtc cttagttaag tcttacttca ccaaatccca ggaccttcac 13440attttggttc ttgccattgc taacagttgt aaatgctgcc gccacgaggc ctgggaggaa 13500ggacccgctg gtgagagcac agggagtgct gctgtgatca cggtggtgat gcggggtgag 13560cgcgatttcc cgggattaaa aagccaccgc tgcccccgtg gtggaggctg ggggcccccg 13620aataatgagc tgtgattgta ttcccgggat cgtgtatgtg gaaattagcc acctcctcag 13680ccaggataag cccctaattc cttgagccca ggaggagaaa ttaaaggtca tcccttttta 13740aattgaggaa tagtggtttt ttttaacttt ttttttttta ggtttttagt tgccgaatag 13800ggaagggttt gcgaagccgc tgccctgggc cgaggtgcat tttacgcttc cagaggtcga 13860ggcctccaga gaccgcgatg cccagggcgt tcccggggag gctgagagac ccagggtgct 13920ctgggtgact gcacggcgac tcctcgggaa cccactcgtg gctgcccgct tggaagggct 13980ttgcggcccc gggaacgatc tccaggatct ccacggctgg tcaggttccc cgtccctcgt 14040atcccgcgct gcccgggggc tcctgccttt ggttcagtgc tcgcggcacc accgcactca 14100ggacggcagt ggggggctgg ggctggggct gggcctggcc cagcgtgggt tggggcgggg 14160gacgcgccag cagcgcccgc agctcgctcc gcaggggtcg cagccagggg tcgggagcta 14220ggctcgtggg ccgggagacg ccgggcgcgt tgtcctccgg ggaggttggg gtgcaggcgg 14280tgcaccgacc ctcgccatct ggcgctgcag ccaccagcca cggcgcttag tggagggtct 14340gcggccaggc tcccggcgga aagattccgg ggagggctcg ggggttgtcc cagcccgcgc 14400taagcgccgc agcctcgccc ggctttcctg cttcctcgga ctgtgcaggg gaagcctggg 14460gtctcgcggg gcgcagcagt caggtcgagg gtgcagcagg aggggagtcc tgacgggcag 14520gtccctcttt cccctggtgc gcaacactgg ttggtagctt ttgcggaggt ggtgaagaag 14580ggcaggaggc ctgttgagcg gaggagtccg gggatcccta attatgtgac aggagaccct 14640ttccagttcg gcctgtggcc catccctctc tcaccgccgg cagattggag tctgctctcg 14700gggagccccc aggtaaaccc ctcacaggga gaaggtttcg gattggaagg aggaccgcgc 14760tcgtggggcg cctgtgagag ctgggaagcc caaggggtag cgtgtagggg gttttttatg 14820cgggaggagc tgcctcctgg gcggcgggga ctttctgtct cagcctgtct gcctttggga 14880aaacaaggag ttgccggaga agcagggaaa gaaaggaggg agggaaggag ggtccttggg 14940ggaatatttg cgggtcaaat cgatatcccc gtttggccac gagaatggcg atttcaaagc 15000agattagatt actttgtggc atttcaaata aaacggcaat ttcagggcca tgagcacgtg 15060ggcgacccgc gggagctgtg ggcctggcag gctcgcacag gcgcccgggc tgccggccgc 15120tgcggggatt tctcccccag ccttttcttt ttaacagagg gcaaaggggc gacggcgaga 15180gcacagatgg cggctgcgga gccggggagg cggcggggag acgcgcggga ctcgtgggga 15240gggctggcag ggtgcagggg ttccgcgtga cctgcccggc tcccaggcat cgggctgggc 15300gctgcagttt accgatttgc tttcgtccct cgtccaggtt taggagacgc gtggggacag 15360ccgagccgcg ccgggcccct ggacggcgtc gccaaggagc tgggatcgca cttgctgcag 15420gtagagcggc ctcgccgggg gaggagcgca gccgccgcag gctcccttcc caccccgcca 15480ccccagcctc caggcgtccc ttccccagga gcgccaggca gatccagagg ctgccggggg 15540ctggggatgg ggtggtcccc actgcggagg gatggacgct tagcatgtcg gatgcggcct 15600gcggccaacc ctaccctaac cctacgtctg cccccacacc ccgccgaagg ccccaggact 15660ccccaggcca cctgagacct acgccagggg cgcctcccga gcgtggtcaa gtgctttcca 15720atctcacttc cctcagcagg ttccacccag cgcttgctct gtgccaggcg ccagggctgg 15780agcagcagaa atgattgggc tgctctgagc tctgaagcat tcggccgctg tgtgtgtgca 15840aggggcgcaa ggacggagag acagcatcaa taatacaata ttaacaggag cacttgtcca 15900gagcttactg caagccacat tcagttccgg accttattga cttccccctc ccatctagag 15960tggattctgg tttttcaatt tgttttgttt tgttttttgt ttgtttgttt gtttttgaga 16020cggagtctca ctctgtggcc caggctagag tgcaatggcg cgatctcggc tcactccaac 16080ctccgcctcc cgggttcaag cgattctccc gcttcagcct cccgagtagc caggattgca 16140ggcacccgcc atcatgcctg gctaattttt gtagagacag ggtttcaccc aggctggtct 16200cgatctcctg acctccgatg atccgcccac ctcagccttc caaagtgttg ggattacagg 16260cgtgagccaa cgcgtcctgc cttgattctg tttttaactc cattttttag aggaggaaat 16320tgaggcacag agaggttaaa taacatgtct aaggtcacac agcaaggggt ggagcggagt 16380tagcccactg gcctagctct agagcccacc cggataacca gaacttggtg aggcctccgg 16440gctcttgctt ggtttggagc caggtgctta gcgccccgag cccggggcca ttcaccctgc 16500aggagctgca cgcgcccctg acctcggctt ttccctggca gcagaggggc tttgcgggtc 16560ggccgggtag ccctgagcac agctcgccac ttccaggtgg gctgttggcg ctggctgggg 16620acacatcccg atctttcaaa tgccctttac agagcctcat caacgacccg attcattccc 16680ccctcctgtc atttgtctct gccatcgaaa aatgcctacc gagagctgct ctgcatttcc 16740gccctctatt ttgtgtttta ctttaaaata ataataaaaa aaatgttggc tgcaggacgc 16800catgacttag gtcagcgagt cagccgctag ctctgcattt ccaaaaagca gatcttttca 16860caactctctt gccccaagtg ccctggtgtg gtttattttt taaaatgcat gcctgcggaa 16920gagaagaccc ggggaatatt cgaaaccccg agcttttaca acataaagcg catggtgtgg 16980ccgcggcgag taatggcgct 170002061500DNAHomo sapiens 206caaatcactt gaactcaagt tcaagaccag cctgggcaac atggtgaaac cacatctcta 60caaaagtaaa gaaaattagc caggcatggt gctgtgtgcc tgtagttcca gctactcctg 120gggaggtcga ggctgcagtg agccgcaatc acgccacttg tactccagcc tgggcgacag 180agcaagtccc catctcaaaa aaaaaaaaaa aaaaaaaaaa aaaaggctgg gtgtggtggt 240cccagatact cagaggctga aaagggagga ttgcttgagc ccaggagttc aaggctgcag 300tgagctgcga tcacatcaat gcactccatc cagcctgagc aatggagtga gaccctgact 360atatttaaaa aaaaaaaaaa taggaagaaa caactcaacc acagggctag tatgttactc 420ggttataaaa tgataaagcc ctaaacagag aattagcccg tttccagaag aggccaagaa 480cagatgatac

agctgaactg aactcctgcc tgtacagctc gttttctaca agattccaga 540cctggaagat gatggcatcc agcccccatt gaagcacctc gaacaagaaa aacgccgagt 600ccgaagagcc aggccttgaa cacacgattc ctgtctataa ataactcccc ctggggaata 660aaaagcagga tccaaggcag gaaacccgag ccgtggaatc tggtaagttc ttaggaaacc 720cactcacggg cctgagtccc ccgtggaagc ggcgacttcg gcacctggac acccgagtcc 780ccagagcccc gggcggccgc gcgtccctac ctgcaggcct gataccggcc gcggagcgct 840cctggccccg ctcccgccag gctccgggac cgctgaaacg cacccagggg ggtgaaggcg 900tagtcgccaa ggacagcgca gatggcagcg gaggcatggg agccggaacc taccgtggca 960aagggccagg tcgggacgcc cctcggcgca gccccaaatc ctgcccgcgc cccagccccg 1020ctcaggccgc gcccctgcca cctctggcca cacgggctga gacgtctggc tcctgcacag 1080cgcacttccc gctgcccttc tccactggct gctcaggccc tgcctcgcca gcacggcatc 1140cgcgggggat ccctacctgt cctttagggc ttgcctcata ggtcaaacgt cacctcccag 1200ggaggtatgg cctgccccct ggccaggtgg gccccttcca cgctcgcctg caacaccacc 1260cacccacctt gataactgct tgtaaaggtt gtactgcttt cccccttgag actgcaaacc 1320ttcaagggca ggaaatgggt ctgttttcct ggcaaaataa tgaagttggc ttaaggtttt 1380gctgaataaa atgagtgaca gacaaaagta gccaaatttg gcactcctga tgggttattt 1440gatgaaggag gtgcaatgta tgggcttaac tagttattct ggatttcttt ccccatgtta 1500207200DNAHomo sapiens 207caaggccggt gcacgcggac ccgaggattc ggtagatgtc cccgaagacc cgctgccgct 60ctaaggcggt ggaagcgaga ttctccggaa acccagggaa tccgatgctc gcacaggacc 120aaagcccgag gccgcgggga ccacagaggg acggagaagc cgggactcct cacatcccac 180atccggcagg ggaagcccag 2002082000DNAHomo sapiens 208ctgataataa agttttacca ttttataatt taaaaatgta aatatggagt tgggcatggt 60ggttgggagg ctgagaccag aagatcgctt gagcccaggg gtttgagacc agcctgggca 120acatgcagaa accctgtctc tacaaataaa aaattagcca agcgtggtag cacgcacctg 180taatcccagc tactcgggag gctgaggcag gagaatcgct tgagcctggg aggtggaggc 240tgcagtgagc tgagactgta ccactgcact ccagcctggg tgacagagtg aggctctgtc 300tcaaaaaaac aaaacacaaa aaaacaaaca aaaaaaagca aatatatgta aaaataggaa 360gtgcggtttc ccaaaatgag gtctgtaaac aactgatcta gaaaatgttc tggaaaaagt 420aaaaaaggat caggatctga ggtcaactga cctctccctg cgctctggac aggcaaacag 480gcaaggttcc ctctgaggcc gtagcggctt ctcgtgggcg agtccctgtt cgcaggtgac 540gtgtggacca cgctcttccg aagcgtctgg cctgtgtgct ctcggggagg ggacgcaggt 600cagcccacct agccgatggc taacaagtca gtttgttttc tgaacggaag cttaaaccta 660gaaaagtaac tgggttgggg tgggggtgta gccacatgca gtaaaagcac tgcctgtctg 720tataacaacg acctgatgaa aaaaggaacg cgtgaaatgg ggagtgttag ggcgtcacaa 780actccagtgt ggttgaaatg aaagcagaaa gcaaatggca agctggcttc cccttccagc 840ttttcacaac cctgccttgc tcatggtcag ccccaagcac gggcggaaga aaggactgga 900ggggagggaa aggggtgggg agcgagggta ccagaggcgt gggaggacgg ggacaaaggg 960gcagcaaggg accggcggaa aggaaagtcg gcgttagctg gattggaaac agtccagaca 1020gaacgatggg ctctgctgcc tccgggtggg gcaccaagcg gggagcgggg ccacgaggca 1080ggggacagtg aagcaccatg cagcgcccac cagccggcag cgcccaccag cctgcgctgc 1140gctgcacatg gtacccgcgg ccccagctgg ccagtgtgtg gcggagatga gaccctcgtg 1200aagagactaa gcggccacag cagggggaag ggttgctcac ataaccccat actgctcaca 1260ctacgaggtt aactgccgtg agatctgcct gcagccagca gaaacccgtt ctaggaaaac 1320gttgcccagt gacttcagtg agtgccactg acccgggcgc ctccgccccg gcgtccggca 1380gcagcaccga ttgcgcagga ggcaccttgc aaacaacctt tcctgatccg cgctgcagtt 1440cccaggccgg ttgcagccgt ttcacagaga ctgcgcacac aaagcgtctc cgtgccctgc 1500cattcacctt tcgacacagc cgcaacccct cttttcagtg ttaaaacctg gcgccaaaag 1560gaacatgcga tgtgacgtgt tacctctgcg catgcgccgg gcattcccag cgccccgaac 1620ctgatgaacg cgcggtgggg accccaggct tccgtgcttt cgttttcctg gaagctacgt 1680gtcctcagtc tacatattgt tacctggaaa ataaagtttt ctcctttttt cttcctttgt 1740taacaggcag aaggtgtagg ctgcaggttt cgggcctaag agagggcatg gctggcgaca 1800cggagtagac tcctagatga cataacggag gcgagtctgc accggggact cggcattagg 1860aggaggcaga ggaaaagccc accaccgtgg ccgagggaga tctagcaagc agcttgcagg 1920gggtgaagtg tgtgcaaagc aggctgagac ctgtccagta tcgaaacacg ccgcggtggt 1980caagcaggct ttaccatgct 2000209700DNAHomo sapiens 209tgaggctcaa aacaggtgtc tgtgagcttc acaggcggta aggccgtgtc tacatggccg 60ggacatgcat cccggggctg cccctgccgt gctgcccgag tgcacggggg atgaggacct 120gacaaggcca ttgatcttgc gggagcttcc tgaactactc cagcgtgaaa atcttccaga 180aggattctcc acagggcaat gaggcaagaa atttacagct tagcctgatt aatgggccag 240gcagttaaga gttctttgcc aagctatgag cataatttat agtcatcacg gcaggaggaa 300aggccacata actcacatcc ttaaagggcc cttagaacaa gagacacgcc ggatcattga 360aaacgtctcc actcctggcg ccaaaagaga tcggcacgtt tctgggtatt ctggtcaaag 420aacagggagt ctggattaat atacacggca gaaaaaagcg aagaaaagac acacaggtca 480tatatttctg actgatattc cgtttgttgt tttcggaggg acttggtatt tatttaacca 540cattctcact tgacacgccc cctccccaca ccttgtaaat gccttcctct ttagccgagt 600catttttcat cacatagaat tgaaatgttg ccaggaaggc ggtttatgag attgtagaaa 660tggcactaga gaaagcagtg tgaaaagagg cctagaacgt 700210600DNAHomo sapiens 210tctctacatg ctatctacta aaaacttagg caaggaaatg catcagacca aacaccccac 60agcacagaga accgaccggc cattgctttc caatctccgc aaacctaacc attgctggaa 120gaaatcttac tcacagtgca cagacagtag gtattttatt gaagataaac atatagtgga 180acaaaccaaa ttacccccat ttgagttacg tgagcactca gttctcagcg tggatgtccc 240acaaatcaag tcaacatttg cgtcccatta ccagcagcca cttgccgagt atctcttcgc 300ttccactggg actgcctggc atccctgatg ctaaggagcc actgaagagc ctccaaatgt 360ctgacattca caaacgcatc ttttgctttg acccgaccct tcaacctctc cgagtctgct 420gccttttctc agacacacat ccaggcaccg ttagggatag ttagagaatc tgaaaattca 480gaagcgctcc gaaaagcctt tccaaaagta atccacagca ctcaacagtg aatttagaaa 540ccccaatttt tttctgagtt tgaagttttt aagccttgcg gatggttgga gtaggaaaaa 6002111100DNAHomo sapiens 211tcagacaagc tctgtgcagt cggaattttt taaagatgca ctgtcacttg aggaagacag 60gtgatcttcc tgcggcacaa atagaagcaa agagatttct cttcttctct gtagagcaac 120acaattgata aatggccgat aatctccacc aaattggcag cagtaggctg cccgaaggca 180gcaggcatat tcgtctttgt gaattgtttt actatgatgc tgtcacattt ccaggaataa 240gacggttaaa atgatatatt gttgtggttt ggcatttgca gctttgctct gacttccctg 300gtaactgcca acatctgcaa attattatgt gcttaaaaaa aaaatcaacc gccaccgcag 360gctgccccca cggtccctgg ctgggccagg cctcctgcca ggccacaggg cagagttctt 420ggaccaggag gcagcagggt caaaacccag gttgcctagg aagcccccaa agacagttat 480ggatagagct gggagcccga aacacatgcg gcagtctctc agtttccagg taccggttct 540cacatcatcc atgcatgtgt ttgaggaaaa acaaaaaaaa attgatggtt gccaaaaaca 600aaaatgcttc catatcaaag tttatcagtg tcaatgtcaa gagacttctg gttcgtagac 660tcattttggc ttgaggccac cagaagtgaa ctctggtttc taaatgcaga agcagaggca 720ctggccgatc atggaagatg cagggaactg ttcaagaggc ccaagcctgg tgctcagaaa 780cttggcagga tcaagcatct cgcccaggaa ttcatcccct gcttgtctaa gccggctggc 840tctcgtgact gactcggaac aacagagcag atgtttgcgt gggaggcaag cctcacccaa 900catctgtcct gcggcgggaa ggcctgggtg ttcacagata gagctggagt tccccggtgg 960gtggcacaga caattagctg gggctgcctc acatgtaatc taattacagg ggaaacaggc 1020tcaaacaccg ggtgataagc agcgcaactg tttcgggtga ctctgtaatt tttcctccat 1080taattttctc cataacgcac 1100212250DNAHomo sapiens 212gttgcctggg atatgcttat atcaaaaact tacgtgtcac ttacctagca tttgcatttc 60actgggcctc ctaaattctg tgtggtaacc gactgccacc ggacatgctg tttacttctc 120tatcctcacg cagccagttg ccacattcaa cataacactg caaatattgc cggtggatcc 180tgacttcctc gtggacccta ctgtgtcggg aaaaacaaac aaacgaaccc tggaaggaaa 240caccatgagt 250213600DNAHomo sapiens 213tcataaatat ttccaaatgt attcctattt gtctctacag agtctaacag acataaatag 60cgaattgaag gttctgtctt aaaacccagc agaaagaaaa acaatgacca gaaaaaaaaa 120acaattgtct ttggcttccc aagaacagca tcggatttca actggaacca cagatggtcc 180gttgatagaa gcgactactt tttagctctg gaggacgaca aaaggaacca gcttcttcct 240gtgggtgtca cagcgaggtc gcctggccac atcaggtacc agagcgagcg ccctcacctg 300ataggccctg tacaacctca gccacagcac tgtcaggagg aacacgcgga actagcaacc 360taggagggta aaggcggagt tgggagggaa cacgaggcag gcaggtcggc tggctgctga 420gctacaggct gcactcctag gacgtctacg tgtaattgag aaaaataaga caaaaataac 480ttactgtgca ggcaattaat tctggttggc atagcgatcc tcttaagtta aagggaatga 540gcatgagatg aagagaagta agaggcagaa agaattatgc aagagcaaca tcagagtgga 6002142000DNAHomo sapiens 214acgccgagcc gcctctgcag gggaaaccga agcagatgtg gtgagataat acatccaacc 60ctgagtgcta ctctaacctg ccagaggcgg agggttctca gtgagatgaa agcattacag 120atgcgttaga tctaagggag gggcctgcag atgcgcagct ggcagagaaa ccagggaggg 180gctgaactgt cagtcgcgac caccagggat ctgaatcagt tcaccgacag ccttggggac 240attcaccttg ggctccacaa cctgtcagaa atgcccccaa gcccaaaggc gtcgagagaa 300tggccaggtt gtttcagatt gacacatatc ctaatgtaca agtcagccca cacaccccac 360gtgcactgag cgtctcttgt tgttcacccc aaataaactc tgccggaact ggggcgggac 420tcgcaggggc ggagaagggg ggagacgggc agagggcaga agtggatggt gagaagagcc 480aatggagggg ccccgtgaga gtgagcaagg ctgcacccct aaccgacgtc ctggggctac 540tgtacaaaca aagaaccaca ggctgggagg ctgaacaaca gacctgcact ctctcgcagc 600tcggaggctg caggtctgaa atcgaggggc tgacagcgct ggtttcctct ggaggctgcg 660agggagaaac cgtcccctgc ctctcccagg ctctggggtg agcccttcct ggcatcccgg 720gctcattgta gatggatcac tccaatctcc atggcttctc agggcttccc tccatgcacc 780tcaaatctct ctctccttcc ttttgtaagg atgccagtca ttggatttag gttcacctta 840aatccaggat gatctcatct aaattacatc tgcaaaaaga ccctttttcc aagtaagttg 900acattcacag gtacctgggg ttaggattgg acatatcttt tgcaggggtg cagggggctg 960ccactgagcc cgctgcacag ggtgacctgg gccaagggcc cttcactttc acttcctcat 1020tggcaagctg ccctgtgttt ggactgggtc gaggctgtca accttgctgc ccctcggagt 1080cccccctggt gtcccccaaa cagattctaa gctgctttcc tggggctgga ggccaggcat 1140tgggattttt taaagagctt cccagcaggt gagcagcctt tcatgggtat caggagacct 1200tcctggcaaa tgtggtgaag gtccttcctc ctgagcgatg ccttagaccc aggagcccag 1260ggaggctgct cacctgatcg ttaggacagg agcagtggaa acctctggcc tcagaccccc 1320tggaggaatc cctccctcta agactctggg actggtgcac gcaaggagct atcgtgaaca 1380ttgctcccaa ctggccgctt gcttgtcccc cggctcccct tggccccagt ggcggctttg 1440cctgaattag agggcgtgag agccacctgt gtctcagcac tgcaattaaa gcaggaagcc 1500ctttcggaag cagccgtgtg caccagcctc ccatgggtgg agcagagcaa accacccact 1560tctgccctct gcccttcttc ccttttctcg acaccctgcg gccccccagt ttcagcagag 1620tttatttggg gtgaaaaaca agagatgctc agcgcctgtg ggatgtgtgg gctgactcgt 1680acattaggat gtgtgtcaat ctgaaataac ctggccgtta tatggatgcc ttggggcttg 1740gggggtttct ggcagtctgt cgagcccgag gtgaatgtcc ccaaggctgc tggtgaatca 1800gatccctggc gttctccgtt ggcagttcag cccaacagtt tctctgccgg ccgtgcctct 1860gcaggtccct cctctgatct gattggatta atatttgaat caatagactg agtcaagcag 1920aatgtgggtg ggcctcatgc aatcagctga agccctgaaa agagcaaaag ggctgcccct 1980tcccccgagg aggagagaac 2000215700DNAHomo sapiens 215cacatttcag agctgaggtg ctggtgcggg caggtctcct gagctggggg gtcagctgtg 60tggccagtga tggtgacgcc tcaggccgtg catggccggg gaggcggccc tgcctctgca 120ctcttttgac tccatgacta ctggtgtctt cggacgccag agtcggggga gcaaccatgg 180ggcaccgccc ctgcctgggg aggcagcacg aggcctgagc ccagcttaca gggggacatc 240cacccccgct gagagcccca ccttcacggc gaggatctgt agaagaagac atttgatatt 300actcggcaaa aaaaacaaga aacgaaaaca caaaaagagc tcctctgaag aagaaaaggt 360atttgcgctg tggtccacct agaaataatg ttgttggcac aactagagca ttcctcagtc 420attcaggagc actccctgcc ggtgcgtcca catgtcccaa ccccgataga tgaggcgctg 480ttcgcccgtg gaggggtcag gttgtcgtga ccttatcttt acccttaggc cgtccatccc 540ggggcctggg gtttcctgcg ccagtcacgg tgggctgtgt aggtggccat gtgttcggtc 600tttccccagg aggtacgtac catgtgctgg gaggcctgga ggctgagccg ccccccgcgc 660ctatgagttg caccctcaca gcggcggcca aacctcctgc 700216200DNAHomo sapiens 216caggcttgag cggtgactgg gagaccccgg gaatggaaat ggcgctcaaa tgctggtgtg 60gtgtccgcag gggaacggcc cgcgggtgtg tggagtctgc gcccctgtgg cttcagctgc 120gtcgggggac tgcgggaatc ttccagactc cagtttaaat cagagaggtg tgtccacgaa 180aagagtcaaa ctaaaacatt 2002171300DNAHomo sapiens 217aacgagacag tgcaaaaagc cgctgcctgg tgacctggca tgcagactcg gccctcccac 60ttgcacggtg atccactgaa gacaacagct gcctctgtac tcacgctccc ccacactccc 120ctccttcctg ccctggtttc tccatcccta gatgccatcc catgccccaa accatccgcc 180aagcacaata acctcgcccc cacccacccc atgaggtcac tcgagttgac aaccagataa 240cagtttttgt tttgttttgt tttgttttgt tttgtttgtt tttgagacgg ggtctcgctc 300tgttgcccag gctggagtgc aatgacgtta tctcggctca ccacaacctc cgcctcccgg 360gttcaagaga ttcttctgcc tcagctgcct gagtagctgg gactacaggc gcgtgccacc 420attctcagct aacttttgta tttttagtag agacagggtt tcattatatt ggccaggctg 480gtctcgaact cctgacctct tgatccgccc acctcagcct ctcaaagtgc agggattaca 540ggcgtgagcc accgcgccca atagcaattt gatgacccat cccctccact gctgggaaaa 600ggctgggcac cgcccacact ccatgcagct ctctttccct ggctcggaat cgctgcaggc 660gccacagacc agacgcgcac tgttccccac tcctgcttat cggccgcgcg gcatcccctt 720gtcgcagcac tccagcatcc atgcagccgc gcggcacccc gtcttcggag cactccagaa 780tccatgcaga gcgcagcacc ccacatccag agcgctccag aatccatgaa gcacgcggca 840ccccctcgtc agagtgctcc agaatccatg aagtgcgcag caccccttaa tcggagcgct 900ctagaacccg tgcagcgagc agcaccccac acccggagcg ctccagaatc catgaagcca 960gcagcacccc acacccggag tgctccagaa tccacgcagc acgtggcatc tcctcgtcat 1020agcgttctag aatccatgca gcgagcagta ccccacaccg ggagcgctcc agaatccacg 1080cagcgtctgg cacatcttta tcagagcgct ccagagtcca tgcagccaca gtcctccaac 1140ggaccctgag attgtttctg caaaaggcca tgccttcata aatctgaaaa tttggaaaac 1200atccttctac ttatatcctt acaacccacc attcaagctg tagaagcctt tctggaaccc 1260caagcagaag gatatccaaa atgtaaaaac ggtggggcct 13002181000DNAHomo sapiens 218atagtgcgac tgttccgaag tctttatcac agttactggt gatgcttttt tccagatgtc 60ctcgacgtgc acccatgaag ggctccacct gagagtgcca gggtcctccg tgggatgggg 120ctggaggggg tgctcttgcc gtcctgggct cccaagcagc cataggaaca atagggtgat 180ggggtcccag agatagaggc cagtgacagc agcgctttga acccctcaca cgggcacggg 240ccctctggca gggatgggcg tcccggtcac acggagatgg gggctgctgc tgcctgcagg 300tagaggaagg gacgtgtttg gcagtcctgt gacccctggg cacctcgcct cccccacggc 360cggctctgct tgtaaacaga caagtgcaca agcgcagccc ggtgaaggca cagcggtccc 420aggaggcatc tgggctgcac cccagcgagc cgcccataca cgtggagatg ccggccaagg 480ccctgcagca cacggcagag gaaggcgcga tgggagccat gctgggcccg gaaggtgccg 540ccgcccggag ctgtagccat cactccagct cttcttttaa gtgttcccag aaattgtgac 600ccaccaaaat ctgagagcac ccgacagtaa gccagaggac cttgatgtga gatcccagca 660cggtgtgggg gcggactgtg gtgggtgctg tctcggcccc caccccttcc acaggtcggt 720gtgcacatcc cacggcgcct gctaagctgc agtcttctcc aaaggggtca ctctccgtgg 780gaagggagcc acccgccccc gggtgatgtc cccagtcagt gactgacgac agtccccagc 840cgaggtgagg gaccagctcc tgcatccctc actccggggc ttgcctgtgg gccagggtgg 900gggcgagcct cagcagagac cgcgtccccc ttgcctgtcc tgccctgcct cccctgcctc 960ccccgcgcct ctgctgagca cgcccagagg gagctgcttg 1000219500DNAHomo sapiens 219cacttgaaaa gcacaactca tggtgccaaa gctctgacac ggactccact ggagctgtgg 60gcagggggtg ccaaggtacc gagttccaag ccgttgttat ttgagagcgt gccccccgcc 120atgagagcag gtggggggac ataaagtgac acaggatgga ctggccaaag gctgaggacg 180atcacttacc tcacaggatg atgccacccc cacggacagg caaggagctc tcaccttccc 240caggacccca gctgccacca gagctccaga tggccctggg ggtgtctgta aagcctgtga 300ccgtccacca ggtggagacc aggctggcca ggggagggag aggaagtgac cactggccct 360ggcactggct ggccggctcc agcaggcccg aaggggaggg aggagcctgg gtgcaccaga 420ctctctcaat aagcagcacc cagacactta acagatggaa agcggtggct tggaactcac 480ttccaacgaa acaatagcac 5002201300DNAHomo sapiens 220agcacctcct accccaccct ccccattcct gccatcccca gggtccaggg agcccagatt 60ccagggaagg gttgcattag ctcccactcg gagtcctgat gcagcagaga cagacagagg 120ccctgggaga agtgagcatg aattattaag acaagacaag ggtgaggccc cagagagggg 180gtggcggaag ggtcatgttc atgcagcgag agttgcttcg agcttgaacc gcgtatccag 240gagtcaagca gattgcaact ggcgagaggc cttcagaaat gccccgtgag agtcctgtgt 300gcagagctcc atctcagcac acttcctgtt cttttggttc gtcgattttt gcattttcag 360tcccctgtga tccattattt ataacagtgg agattggcct cagacactag cagtgaggaa 420aacaaaagcg aagctacgca gaaaaatgac aagagtgatg agcacagcag tcatgacaaa 480tgagccctgt gcggaggccc gggatccgcg cagatgccgg cgcgggggaa atgggccctg 540aaatcccacc gtcaggccag gcagctctga gcgtgacctg gagggctgtt cagacggtct 600gggtagccgt gtcctgcgca tgaacatcct ccgtcgggag aggaattccc cacggattat 660cagagctgct ccctccaccc cccgccacgt cccacgcggg ccacatcaac tccctctgca 720gcctctggcc agcggctgag ccctccgtgt ctcccctcgt taatgcctcc ttcaccatcc 780cctcctgaag tttcccccat tgcatacacg cgctgaggcc cacccggtat caaggactcc 840cattgcttgc gaaaaagatt ccacccctct tagaacagag accagggccg ctgtagcaaa 900tggccataaa tgccacagct taaaacaaca gaaacggatt atctcgcagc tctggaggat 960ggagtccaaa atctgaatcg ctgggctgaa atccaggtgt gggcagggcc gcgctccctc 1020tagaggctcc cccggagatt cccttccttg cctcttccag ctgctggtgg ctgccagcag 1080tttgggaatt gcggccgcat cacaccacct ttctgtttgt tgttgacatc cccgcctccc 1140ctgcctgcgg ggtcttagat gtctctctcc ttcccactga gtttcactcc acatttgaat 1200tggattaact catgccatgt taggcaaacg tgcccctcaa atccttccac ttaacagaca 1260tttattgaag gttcctgtgt gcggggccca agagaaggga 1300221200DNAHomo sapiens 221gaatgttcaa agaaagagcc ctccttgcct tcctcttctt ccacccctgc cctctgcaga 60ctggggttct gtagaccccc aaagtaagtc cgccacaccg gaaggaagtg agttacacag 120gggcccacat gggaaccgct ttttgtcctg tcttggtggg aaaatggcca cgaccccagc 180ccaggctctg ccacgccaca 2002221600DNAHomo sapiens 222ccatcttcct aggcctgcgt ttcccccaca ccggggactt gtgctggaaa gaaaagctgc 60gttggcagcc aggagccggg gaaactgtcc agggaggcat cctctgcgat gaaggcgggg 120cctcggcgtg gcccgttccg cgctctgtcc agccctggag aagccccacc ctcaccgagc 180tcgaaatacc ccctccctga gagccgagac tcatggccgg gaccccttgg acagaagatg 240cggatgctaa cccggcgctt ccaccacagc cccggcggca ctggggagcg agcgcggcca 300tcccgcgcgt aggtggtgtt tctctgcagg cgccagtttc accgcgggcg cccaggatcc 360tcaacggttc tgttgtgatg tgattcccct cttcgacttc gtcattcagc ctcagtccct 420cagtccccaa ataccgaaag gcagtctttt tttttttttt ttgagacgga gtttcactct 480tgttgcccag gctggagtgc aatggtgcga tctcggttca ctgcaacctc cgtctccctg 540gctcaagcga ttctcccggc tcagcctccc gagtagctgg gattacaggc acctgccacc 600acgcccggct aattttttgt

atttttagta gagacggggt ttcaccatgt tggccaggat 660ggtctggaac tcctgatctc aggtgatcca cccgcctctg cctcccaaag tgctgggatt 720acaggcgtga gccaccgcgc ccggcctttt tttctttttt cttttgaagt taatgaactt 780gaattttatt ttatttacag aatagccccc atgagatact tgaagacccg gtgccaagcg 840acagtgttga ccccaggtgg tcagtcctgc ctggcccctt ccgagggatg cgccttcacc 900ataaccatgt cacggacagg cgtgtgggca agggggcatc gctgtatttt tcacaactct 960ttccactgaa cacgacaatg acatttttca ccacccgtat gcatcaacca aatgaaaaga 1020tgagcctgtg acattcccgt gcgtagagtt acagcttttc ttttcaaaac gaaccttcag 1080tttggagccg aagcggaagc acgtggcgtc tgacgtctcc agggagaccc gccgccctcg 1140ctgccgcctc accgcgcttc tgttttgcag gtaatcttca gcaagtactg caactccagc 1200gacatcatgg acctgttctg catcgccacc ggcctgcctc ggtgagtgcg cgctgcgggc 1260tctgcccggt gacgccacgc ggcctcctcg ccttttcggg atggctggga ggggcgggaa 1320gaggcgctga agggcccgag gcaccggcct tctacaaggg gctcttcgaa atcaatcaat 1380gcgcagaatc ccgagggagg ctcagccgcc ctccgggcct ctctgcctcc acaggtgatg 1440gctgtgtcca caaggaggaa accgtcgggc tgaattaaac agaaccgccc tcctaagagt 1500gtgggttttt ctgccgggcg tggtgtctca cacctgtaat cccaacactt tgagaggccg 1560aggtgggcag atcacctgag gtcaggagtt cgagaccagc 1600223400DNAHomo sapiens 223aggcagcagg gttaggactt caacatacaa cttttggggg gagatgtact tcagcccata 60acacaccacg tgggaggata acaccgattt cagagcttgc agaggaagcc gccaggaact 120ccagtgagac atcagccccc aggtgcctgt caggcacgcc gggctgtggg gggcacctgg 180gcccatctga gtaacggagg cgcatccgca cttcccccag gagtacattt ttagaaccca 240cagcgccata aaccaaagac aaggagactt cctggtgccc cgtcagcttc tggaggcgac 300gttctcggct gacagctctg gcagcctccc ctgtaggtga gagacaggta aatgggactc 360ttgcttccaa aacggaacag ggtaaaaatt ctcaagcgtt 400224700DNAHomo sapiens 224tgctgcaccc ccgctgccct ccctcccgct ggccggcagc accttctcca cccgggcccc 60tctgctcaca gcgctccccg cccccgtctc cccgaggggc ggggagccag gacatggccc 120tgaaagccta gccctggcct tgacctcccc agagcgccct ccccaccctc cgccctctgc 180caaccctggc ccctgccctg gccccgtcct tgtcctctgc tgctggcctt ggggtcgcgc 240cccgcagact gggctgtgcg tgggggtcct ggcggcctgt gccgtcccac gcctacgggg 300atgggcgagg tccttcttgg ggcttctctt acccactctc cagtcacctg agggcgctgc 360ttccctgcgg ccaccccagg tttctgtgca gccgaagcct ctgcctctgc ggccgggtga 420tcccaagacc ccggggtcca gggaggcacg ggatctgctc ccccggtccc aaatgcaccg 480gctgcgcctt aggagggacg gcctccaccc atggcgctgg cgcccagggg ccgctcctcg 540gactacagca cttgctcgtc gccctgcgcc ctgtttagtt ctcatcacca gcagcctgga 600ctagggccct ggtccttctg gcctccttcc acagcccgct gcacatctca cccacttccc 660cgaggtgctg tcattgttta gctgggcccc tcagcctccg 700225300DNAHomo sapiens 225ttaaagggga gtggttgtat gaagagttcc tcagtcaaag gtgtgcagct gggaagccca 60ccccacctaa gagggaggtc tgacaaactg tccacactga accactcaga cctgcatcag 120ggccccgttt cttccataag ccgccaagta cagccctgag tcaactgaac tcaggcctgg 180gaggcttccc aaagctgact tgactcagct ttgaactgaa atgaccgtac catgacaacc 240ctgatgaaaa gctaaactga gcccaattat tcaacagtaa aattcagttg gtctcactca 300226450DNAHomo sapiens 226tgctaccagc tgcttgggct tgggcaagtc accctagctc tcagatgtca tctgtaaatg 60atgacaatgc caatgtggca ctgttctgag agtcagacag aacgtatgtg tgcttcacat 120atggtgctca tgaagtgcta tcattatcta aggaaaacag aaaacgaagt tcagagtctc 180tctaaacgca tgacaccaga ccaacaggga gtttcaaaaa ataggtctga agtaaatcaa 240ttctcctggt ctcaatacac tgaaaacaaa ctattagggg actgaccgaa cccaccttag 300gaaccacctt acgtcacctt ctgtctctac tgcaaaaccc tcccttaata ctgttcaaat 360acgctgacaa tccagatcca tatccaatgg aaccagcaat catgcctgtg tgccagcaat 420gtcagggagg gaagccgatc tctgatgaat 4502271000DNAHomo sapiens 227caggtgccgg ccaccacacc cggctaattt ttgtgttttt agtggagaca gggtttcgcc 60atgttggccg ggctggtctc aaactcctga cctcatgtga tccacccgcc tcggccttcc 120aaagtgctgg gattacaagt gtaagccact gcgcccggcc aagagtgaag ttctgatagc 180tggggtaaga aaggccgtgg gaacagccgg tttcagacac gctgggtcta agacgctgcg 240tctggcgctg ctcggcatcc aatgggagcc gtggagaagc caggcgagtg cgtagggcgg 300agccagcgca caggaaatag gacgtgatga ggtcaaccgg ctggtccaag tgtggacgga 360agtagaggat gcaagcaccg agccccgggg cccccagcat tggcggggag gagctcgcgg 420tgcgggagaa gcaggggacc gcgcatcctg gagaccaggt ggagccagtg cgcccggaag 480gggcgtggcc cgctgacagc cgcccaggag gccgggggag gcctggagcc gagggccgcg 540cgtggcaatg tggagagaca ttttggtgga gtcatggggc cacagcctga ttggtgagaa 600caggaaggga aattgcagat gggcctgggc cccctggctc ccgcatactc caggaccagg 660gctgagtcat cgttcaccgt gtgtgaccag ggccccgtgt ggccggctgt cactcggtat 720ccagttaccc tgggcagacc actggcggca ccccccagcc agaggccgca gcaacacaca 780cgcctgcagg cgaccaggcc ggactgcatg ccccgtgggg gaactgaggg cgtttcagta 840acagagtgtt aggggacacg ggttgggtgg cttggaaagg gcctaaggtg gggtttgttt 900tagattgggg tggtgagggc gcaggggccc ggtaggattc tctaacaggg cagcagccac 960tcatttagca acaggagagg cgtccagcgt ttcgtgggct 10002283100DNAHomo sapiens 228acccaaccac aggcctcctc tctgagccac gggtgagcgg tgcaggttct gctgttctgg 60agggcctgag tcccacccag cacctcataa acagggtcct ccccagggct gctgcagtag 120gcatcaacgc cagggtgcaa aatgcctcag ggagccaagg ctgagccagg ggagtgagaa 180ggagcatgtg gaagtgcgtt ttggagaggc agctgcgcag gctgtcagca ggctccggcc 240gcttctatag acagcatgac accaagggca gtgacctcat tccacaggct gagtccagcc 300agccagccaa gcatcaccag ccagacgatt gaccctaacg gaccaaccaa cccgtaacga 360cccctcctac cataaccagt agccagccag cccataacca gccaacttat ctataaccag 420ccacctgacc atagccaaac aaccagccgg cccaccagta gcattcagcc cctcagctgg 480ccctgagggt ttggagacag gtcgagggtc atgcctgtct gtccaggaga cagtcacagg 540cccccgaaag ctctgcccca cttggtgtgt gggagaagag gccggcaggt gaccgaagca 600tctctgttct gataaccggg acccgccctg tctctgccaa ccccagcagg gacggcaccc 660tctgggcagc tccacatggc acgtttggat ttcaggttcg atccgaccgg gacaagttcg 720tcatcttcct cgatgtgaag cacttctccc cggaggacct caccgtgaag gtgcaggacg 780actttgtgga gatccacgga aagcacaacg agcgccaggt gagcccaggc actgagaggt 840gggagagggg ggcgagttgg gcgcgaggac aagggggtca cggcgggcac gaccgggcct 900gcacacctgc accatgcctt caaccctggg agagggacgc tctccagggg accccgaatc 960aggcctggct tttccccaag ggaggggccg tgcccacctg agcacagcca gcccctcccg 1020gtgacagagg tcaccattcc cgagctaatg tggctcaggg atccaggtta gggtcccttc 1080ccgggctgca cccagccgtc gccagctcca tccctgtcac ctggatgcca gggtggtctt 1140agaaagaacc ccaggaagtg ggagtgcccc gggtggccgc ctcctagcca gtgtacatct 1200tcacatgaac cctacctgag gaagccagtc cccgacggca tagctgcatc cgcttggaat 1260gctttacagg cattgacacc ttcgcctcac agcagcactt tggaaccagt gtcctcatta 1320ttccagggca cggctgggga acaagggggt cctcagcctg ctgggtccca cagctagtac 1380cgggcaggtg gacgggagct tctccccaca gtcaccctga tgccccgctc ttgctcggct 1440ggaggcctcg gatctccgtg gtgttgaggg agccggggca ctggagccct ggtgacctgc 1500atctcctggc ggagccggga agagctcatg gactgtcaca gatggacagt gccccgcggg 1560ggctggagag cagagtgggg ctggaaggtg gaactcttag ccaaagtctt ggtttctttt 1620ggccagggtc ctctttcaat ggctggagaa ggtggtgctg gggggtgaac gctgacctcc 1680tcatgtgctg cccctccctc gcctgggccc ggtaaagccc ccacgtagcc ccagccagcc 1740tggaacatgc ttcctgagct cccagctctt ggtctttgca cccagtggag gaggaggtca 1800gcccagggag ctgagtctgc ggtttagggc gtccagggga cgtggaagca tgtgggtcgt 1860ctggccacat taggtagggc tgcagagacc tgggctagag cagtcctgcg gggtctggaa 1920ggggaagact ggctgaggtg cggggcctgg tctggaatga tcctgcgatt ttggagtgaa 1980gccatggagc gggaagagac aaccccccgc ggggaatagc ccggcaagtg gccacgaggc 2040caggctgagg tccagagaag caggggcatg aatccataaa tcccaggggg cctggccatg 2100ggatgtgctg gctgcacccg gcccctgtga gagcccccgc aggctggccc ccttctgcag 2160tcagtggggc tggggcagct tctctggcat ggggcgaggc agccgcctgc acagtggccc 2220ccctgactgt gcgcccccac cctctccagg acgaccacgg ctacatttcc cgtgagttcc 2280accgccgcta ccgcctgccg tccaacgtgg accagtcggc cctctcttgc tccctgtctg 2340ccgatggcat gctgaccttc tgtggcccca agatccagac tggcctggat gccacccacg 2400ccgagcgagc catccccgtg tcgcgggagg agaagcccac ctcggctccc tcgtcctaag 2460caggcattgc ctcggctggc tcccctgcag ccctggccca tcatgggggg agcaccctga 2520gggcggggtg tctgtcttcc tttgcttccc ttttttcctt tccaccttct cacatggaat 2580gagggtttga gagagcagcc aggagagctt agggtctcag ggtgtcccag accccgacac 2640cggccagtgg cggaagtgac cgcacctcac actcctttag atagcagcct ggctcccctg 2700gggtgcaggc gcctcaactc tgctgagggt ccagaaggag ggggtgacct ccggccaggt 2760gcctcctgac acacctgcag cctccctccg cggcgggccc tgcccacacc tcctggggcg 2820cgtgaggccc gtggggccgg ggcttctgtg cacctgggct ctcgcggcct cttctctcag 2880accgtcttcc tccaacccct ctatgtagtg ccgctcttgg ggacatgggt cgcccatgag 2940agcgcagccc gcggcaatca ataaacagca ggtgatacaa gcaacccgcc gtctgctggt 3000gctgtctcca tcaggggcgc gaggggcagg agggcggcgc cgggagggag gacagcgggg 3060tctcctgctc gcgttggacc cggtggcctc ggaacgatgg 31002291000DNAHomo sapiens 229tttttgtgtt tttagtagag atgggatttc accatgttgg ccaggctggt ctcaaactcc 60tggcctcatg caatcctcct gcctcagtag tagtagttgg gattacaggt gtgagctgcc 120atgcccagct gcaggtgcgg aagctggggg cctcagagac tgtggactcc tggccggtga 180ggagcggcat gggccgggag agctgactct tcagcgggac tgaggtggct ggagcgtgac 240cctttcctga gggcaaacag ggagggcctt ggagcccggc gctcaggaca ggcccctgct 300ggcccggcag cctgagcttc cacacttttc cagggcgtct cgagttcgcc cacagagctg 360ttgtttcagg ataaaaaatg cccttgtatt ccacgttcca gttcagaggc ccgtctgttc 420ccaagagcgg aggcgtcagc cgcatgagtc ccaccggaag ccgggttgcc gggtccccgt 480ccctgccctg cagacgacgc attccggagc ccccttggga agctgcctgg ctctcccagg 540cctggctgcc ttcgcacgag ggctccgagg catgctcatc ctacgtgact gcccgagtgt 600gcacacgcct ggccgtgtgt gggcgtgtgc ctggggcccg agctcaggag caaggcctgc 660gtggacctgt tgtctgaaac aagccagtag acagctgcgt caatgcaggc aagctgaaca 720gggctgcttt ttcagcctga caaccccagg ggctgaacag gagctggggg aggagcaagg 780ggccgttccc ctgccccaca gcacagcaca cgaccccgcc ttggaacctg gggcccgggg 840tgaatcgagg gtcctggagc aagaggggct gctccacagg agagcctgtc ccgccacccc 900tcagccacca gattcggggc tgctggactt gttctcaaac ctgcacagtg agtgacagct 960gctgagacgg aggtctcagg cagtgcaggt gaatcagcat 1000230500DNAHomo sapiens 230tccttatttt ttagttctca agccctgtag ggtgttttcg gtcgcagttg tttgggctgt 60ggtcctgacc ctcctgagtt ccagtggctc tgttcaggag agctgcctgg ggccgggact 120tctgaaacac acactgagcc acaggccggc ccggcggctt gggttcaccg ccgcctcttt 180gtgtgtgatg tcctgggata ggcccgtgca cgttcagatg acactgtaca tataaataac 240ttgtagccga gaacaggatg gggcggggag gaggggaggg cagaacgtac cacagcagca 300gaagtcactg tggatgcctt cgtaagttgc atggaaggtt tttaaaccta gccctgccga 360gcagccctct cctggtccgg gagaacgatg gggagagagc tggcgttcag ctttcatcac 420tggagccgtt ccttcttccg gccccccgag ggcctgtcca tgatcacact ttgtcttgtt 480tcgggggtgg cccctgtgac 5002311300DNAHomo sapiens 231caagcctgtg gtagggacca ggtcagagta aacaggaaga cagctttcgg ccaggcggtg 60cacctcggtg ccggtgagtg tgagcgtgtg tgcgtgtgca cgtgtgcaga tgtgtgtgga 120cgctcccttc tccgcagcag ctcctgaccc cctgcaggtg accctcagcc agccccaggg 180ctgcccccac tctcccctgt ggacacctac ctcatttggg gtgaagtggg gggactgggg 240tgtgaggggt gctttggggg gcacacttcg acccctctct ctgcaggcca agtcctgagg 300ctcagtttcc tcctctgtgc cccggcgacg tggtgcaggc ctcgcgagtg acgtgagggt 360tcatgaccca ggtgtgggca gccagccctt cacgggaggc cacccacctg gccacagtgc 420ctgggaattt aggtcgggca ctgccgatat gtcgccttcc acaaggcggg cccgggcctc 480tgctgaccgt gcaccggtcc tggggctggg taattctgca gcagcagcgc agcccatgcc 540ggggaatttg cgggcagagg agacagtgag gcccgcgttc tgtgcgggaa ctcccgagct 600cacagagccc aagaccacac ggctgcatct gcttggctga ctgggccagg cccacgcgta 660gtaacccgga cgtctctctc tcacagtccc cttgcgtctg gccagggagc tgccaggctg 720caccccgcgg tggggatcgg gagaggggca gtgtcgccca tccccggaag gctgagcctg 780gtgcagccag ggagtgaggg ggcgggaagc cggggtgctg ccctgagggt gccccgacac 840gctctcctgg ggccctgagc ggctgccacg tgcgtccagg gttctggcca cagggtgggc 900aggggccctg tgctcctcac tggaggcccc tgaggctctg gaactgagac catccacccg 960ccggccccct ctcgccggct ccggcacccc tgcctactgt gacttcctgc cccggactcg 1020ctctgccagc ttggggcaaa ccacttccct ctggggtttt cacttccctc tttcccaagt 1080ggggaaagac cacctgtccc cgacccagaa agggcccctg cccgagggca gcagcagtgc 1140caggctggca tgtgaggctt ggggcaggcc cggcccccag aggcacaggg cgatgctctg 1200tgggacgctg tgtcgtttct aagtacaagg tcaggagagg agccccctga ccccggaggg 1260gaggagaggc agggcaggaa accgccacca tctcagccca 1300232200DNAHomo sapiens 232gcccactgtg ggtgtgcccg tgtgtgtggc tgtgaggcgt gagtgcaggc gtgaagtgtc 60tgggagtggg agcgggcatg agtgtgtgcc acgggcctgc tgttgggtcc ttggaggcca 120cggttgcccc tgaagggact gcaagctctt ttttgatttg tagttatttg agaagtctat 180acaggaagaa aattaaaccg 2002331000DNAHomo sapiens 233agcgcccagc gcagggccgg gacccagagt ggactctacc gtggggctgc ctcaaagaaa 60tctcagcaaa cacaggaagc cagcccaccc gtgcagccat ggggccagga agcccgccct 120ttaccaagtc atttgggcat tttttctctg tgctaacagc ccagatggag ccatagcctc 180aacctctgtg ttctgataac accaagctgg gacgccggag ccatgcaggg gacagtgccc 240ggcctgaggc tgcagcctgg gtctggatgc ctttctaatt cagggcctcc tcatggcctg 300gttccataaa tggtcaaatg cagcctgaca gcgcagcctc ctatcagcgc tgggctccgt 360accgccacac agcccacata ccccgttccc caggagacgc ccgcaggtgg gcagcgtcac 420tcccacccgc cgagcacacg ctgtccccgt ctcgtgtccc gaggagccgg aagcagctgc 480ttcctcccag cctgaaagct gcacctcggg ctgcactcgg ctccccgaac ccgccctccg 540ctgccctgca attcgccaag ggagctaccc ttcccatata aaaatttcac ctccatttcc 600ttgtagagaa gaaacatttc tgacagcaag gaagattcta atttgaaaag caagtgattc 660atctcccggt gccaaacagc agacgcaggc gttaccagtc tgggtggggc gcccgagctg 720gggacctggg gtcctctggg aggggcaaga aggcagcgat gctggccccc gcctccatct 780gcccatccca tctgcttcca cacaccgccc tgccgtagct gcttgcagcc cttctctgtc 840agtttctcca tcttttggtt tggtgataaa tgagagttcc catcgggtgt gccaccctct 900gtgtgacggg gagcagagaa gaccctgcgt ccaagtcctc ctgggggaag agcgaagatg 960ctgggaccag ccccagctgt cagggggtct ccaatcccag 10002341300DNAHomo sapiens 234ggaacggaga gccgccaggc ccaaacctcc cagaatttgc gcagtattct cggcctagag 60agcgaggagt ggccttggcg aggtccctct ttggctcttc tggcttagcc ggggttttaa 120acttgttatc tgcaaagcag aaggaaagtc agcccctgat gtaagtgtca agtaaaataa 180atcggatggg tcctttcctg tttggcgagg aatgctacac taagggggac tgcgttcaaa 240tgggcagtct ttgctggaaa cctcgcctcc gcgcgccttc cctcgctcgg attcaggcgc 300ttttacgtta agggttgaat ttttgtgtca acaggcacct cgggaggtcg cctagacaac 360tgagcggagc aactgagata acccccgcta cgtgtggagt gacctagtcc attaacttgc 420cccagcacgc ccgctgagtc cgcaaaatat aggatggcct cgggttttag atgaacccaa 480agctaagatt tcttccctct ctggaattag caagcagccc gccctgccca actcccctgg 540aagcgcgcgt gctcgccagg cctcgggacg cctgcgcggg cgcccttgca ctggcaccag 600ggctccgggg taggggcgca ccgatctgcc caagcctctg caggcactgg aggaaggcga 660gccctccacc cgctcaacag gccccagtgc cggcctttcc ttccagtctc aactccaccc 720gggggcccgg gggctccaca gttaaaaact ccacgccacg gagatcgcag gtaagctgct 780ggctcaacga ggtgtgctaa atgggattaa agatcctgga ccgtggccag gcgcggcggc 840tcaagcctgt aatcccagcg atcagggagg ccgccgcggg aggattgctt gagcccagga 900gtttgagacc agcttgggca acatagcgag acaccgtctc tacaaaaaaa taacaaatag 960tggggcgtga tggcgcgcgc ctgtagtctc agctacttgg gcggtcgaga tgggaggatc 1020gatcgagtct gggaggtcga ggctgcagtg agccaggatc accgccaaga tcgcgccact 1080gcattccagc ctgggcgaca gagggagacc ctgtctcaaa aacaaacaaa aaatcctaga 1140ccgtttacaa acagccttcc gtctcttcct ggtcaagtcc taaccctggc taacctcgcc 1200gtctacagcc tgaattttgg caaccgaaag gcagcgccgg cgccacgtgc acacgggctg 1260ggccgctccg ccagctgcca gggccactgc cgcgctcact 1300235300DNAHomo sapiens 235cgcacacaca gcacagacgc ctgcatcttc ccatgcgtgg tttctgctct tgcctctctg 60ggtttttgtt tcacttcggt cgagtttttg gtggtgttga gcggatagcc ggggaagttg 120gagtcttgtt tgtggccgcc tcgtgctcgt gtctgtatct aagatcctca ggctgctcct 180ttttgggtaa ggtctgttgc ttctctagga acagtgacgg tggcagagcc cgtggcccct 240ctctcctgtc ccagagccaa gctgtttcct ctccccactc ccgggcaccc tgcgggcaag 3002361000DNAHomo sapiens 236cacagcccag cttcaagcct ggccgaccag gggtttggca tgaagacccc ggcagggctg 60gggctgtgct ggaatccacc cggaagtttc ctgccccttg ggctgcccac caggtcccct 120ttctgctctg atcaagctgg acaaaacgtc gtggggccac agcacagggg gccaacgcaa 180gctgggatcg tcagacgtta ggaaatccca aggaagaaga gaaaggggac acattcggga 240gacgtcggca cacgctcgaa gcagcggaca ggcacctctc tgtggacaag gcagactggg 300cggccgagat tccgcataga tgcctgcttc ctccacgacc tccacgtgtg gctggcccag 360tccgggtccc cctcacctcc tctgtctgtc ttggtggcct cacgccgtgg gctgtgatgc 420cggctacgct gcttgggtgg ccaagggtct gagctgcaag acgcccagcc tgggtctctc 480ccgagctctc ccacgtcctg tctgctcctc ctccgagctc ccggttgact ctcacgactg 540caccagcctc tcccccagga aggcgtggaa acaacctcct tctcccaggc ccgctctgcc 600tcctgcgttt caaggcaaat ccgttcctcc aggagatgat gcaaccacat cctgttggag 660cccagagaag tgcggatgca gcccggggct ctttctttcc tagaaccctg cctgggagtg 720gcttccctga actaaggaca gagactttgt cttcgttgcc tctcggcctg tgggcactga 780gcatacagta ggtgctcagt aaatgcttgc aggccgatgc ccagagccat tagccctcat 840catggtgagc tcggcagccg gtgttggggc tgggctgggc ctaggtgtgc gtgggggcgg 900tgctggtctg ctttgctggg agccatggac accggaggaa cagggcccca tcagtgcggt 960cagagtgcaa actcggagcg tccttctctg gaaaacgaat 1000237500DNAHomo sapiens 237gggagggggc gtggccagca ggcagctggg tggggctgag ccagggcgat ccgaccccga 60accggagctt ttagcacttt gagtccctgt actcagaggt ctcctgcagc cgggaatccc 120actgtgctgt ggtccctggc agccagcacc cacccccagc ttctccgtca aggttgagga 180cggagcactc ctgcctctga ttaactggac gcaggagaag cagttgcttt aatccggagc 240cttgagttgg gacagataat gagtcattca accagatttt ccaaggacac actaactttg 300gtatgatgcg tgtgtgcccc tgaatccacg tggtcaggaa agcccaggga acactggcct 360gtgactcact gagcaggttc ccttgttacc ccgaggggtg atttactcct ctgacagtga 420cacggacact gtgcgtccat tccccgggcg ggcagaggac actcccagat gcccacgagg 480ggcccagcaa gcactggcca 500238600DNAHomo sapiens 238ctgcaggacc tgctcgttca cagatgttct cctagaagca gaagctgttt cttgttgcaa 60acaaatttgc tgtgtcctgt cttaggagtc tcacctgaat ttaccaagga tgcatctgtg 120cttggggatg gctcggtttg aggggtctga ggagcggctc ccctggatcc tttcctcccc 180aggagcccac ctgccgagct gtcagcgtca gccccacatc tcaagatgag gaaatggagg 240tcgaagccat gcacacgcag gcgtcctgct gacatgcagg ccaggcgggt gcctctgtat 300tcagcagcct cagggctgtg gccagttcag gcagcagagg ggcctcatcc cggtgcttcc

360ctgcaggcag ttgtggggcc ggcctgcagc aggggctcag acagggcctt gggagaggga 420gggatcacag aggtgtccag tgacaggcag ggcgggcaga gcccatgggg ccttgggctc 480ctcactcctt cggtcagtca gggtgacatc tggagccacc tccattaatg gtgggttatg 540atttggttcc catgcagccc gtgccagctc gctgggagga ggacgaggac gcctgtgatc 6002395000DNAHomo sapiens 239aagaggaaat tcccacctaa taaattttgg tcagaccggt tgatctcaaa accctgtctc 60ctgataagat gttatcaatg acaatggtgc ccgaaacttc attagcaatt ttaatttcgc 120cttggagctg tggtcctgtg atctcgccct gcctccactg gccttgtgat attctattac 180cctgttaagt acttgctgtc tgtcacccac acctattcgc acactccttc cccttttgaa 240actccctaat aaaaacttgc tggtttttgc ggcttgtggg gcatcacaga tcctaccaac 300gtgtgatgtc tcccccggac gcccagcttt aaaatttctc tcttttgtac tctgtccctt 360tatttctcaa gccagtcgat gcttaggaaa atagaaaaga acctacgtga ttatcggggc 420aggtcccccg ataaccccca gctgcagatc gaggcctagt gcgagcacag gtccccccag 480acccttccca gtgcccacca accggcggcc taggccaggt agaactggca gcgcctcccc 540tgctgcaaca ccaggctctg gtagaaactt cagaaaacat gcaccggcaa aaccaaggaa 600gggtggctgc gtcccgggtt cttccgcgca gctgtgtgta cacgcatgca cacacccaca 660cgcacacacc cacgtgcaca cccccatgca cacgcaccca cttgcacgcc catgcacgca 720cacacgcgcg tgcacccatg cgcacgcacc catgcacaca cacgcgcgca cacacccacg 780tgcgcaccca catgtacaca cccacgtgca cacacccacg cgtacacacc cacgcgcaca 840caccgctgtc cccagccgtg cagaacgatc ctccctgagt ccccggctcc gacccacacg 900cagcactcgc taaacgcttc ccacgcagtc gttttgctgg gttgcgcttc acccacttct 960cagagggggc ggccgaggca gaggtgtcgg ggatcgagca gctccgggcc tcaggggtcg 1020ccccgccacc gttttccttt cccagatgct gggacggggg cagggagggg ctccccaggc 1080tgaacccgac taggtcaccc tagaagcgag gcgagcttct cttctgtttt tcttcggcgc 1140ccctgagccc ctgacagtgc ccaagctgcc catgggattg gattcgccag agcctcctac 1200gcagacccca cccagggcca aagccaaccc caagccccac caccttggtg gtgtgggatg 1260aaaagtgagc catcgagaga tggggtcccc ccacccccaa cccctccaag gacaaaggcg 1320ggctgggaag cacccgcttt cacgtccgcc cctgcccggc tttcctagcg gaattggcgc 1380cggcatcagt tgggggttgt gggatcagtg aggaatcccg tggggtcgcc tccatttatc 1440agttgtgtgg ggttgggcga gcacccctag ccccagccca ggcgatcagg gcgcgaagcc 1500cactggacgc ggatttggga ttaggacggg ggtgacagcc aggaggaccg cacctgccct 1560ccccactcct gccgctccac ccctgccccc accgcaacac caaggtctcc accaggaaga 1620tgggggtggg gaaaggacgc ggggtggggg ggggtgcggg gagagaggac acagggtcgg 1680aagggtgagg ggtagtggca gaggcggagg ccgaggccac gcagctgcgg ggcgcaggga 1740ggggcagagg aggggcgttc agatgggaac ctagtccaga cccgtcgggg ccctcgtgtg 1800cggctcgtta tcctggaacc agagaggctg gagacccttg gcttgtctgg agcggaaccg 1860tagtgtccaa tagagtgtgt ggggctcagc cctaaagcta aacattcttt atttcctgat 1920gaccatgggg gcggagcggg ggaaaagccc tggccttata gtttagaatt ttataaaagg 1980aaaggcgtgg ccactgacaa tttgcgcttc aggagtccca gagtgaccgc ctggctcgga 2040gcagggaatg agggggtcct taactctgag atttgttttc tgagagacaa aggtgatggg 2100tgaggcggct aagcctctga ttctctatag gtggcggtca ttcatttcag aacatgaatg 2160gattcagtaa ataaacatga tagaaaaatg ccacaagccc taggcccatt ggagtggact 2220ggacagtctg ttcccagtgt gtccctcagc ctcggtcccc cacccttccc ggagccctgg 2280gggtcacaca catccctcct ggctgcctag cctgtgcccc ccgattcccc ccctccccgc 2340cccgcgcgtg cacacacaca cacacacaca cacacacaca cacacacacc acacagcacg 2400aggcgacaga gatatgagag agagcgagcg agagaggacg ggagagagag ggagtgcaag 2460tgtgcgctgg gggtaacccg tgcatgcatg cattgggggt aacaggctgg agctcagatc 2520cctcccccag cccccagcag gggggactgc aggctcctgg tctgagtggg gagctgggcc 2580ccctggacag aggactgggc tgcggggtca ggaatgggca cacttcctaa ctgcaggaca 2640ctctaagggc tttggtcatg cacacgcagc caagagaagg tgtcgctggc acacagcctt 2700ccaggagcgg acttggagac ctcgccaagg accaggactc cccagcactc acactccctt 2760aggcgctgaa gtccagagga cagaggttga gggcagagct cctgggagca ccagtggaag 2820taggagggct gggctggaaa acctccccca acctcctatt gcaaagaggc tccagccagc 2880agcctccaca ccccagtgat cttttaagat gcaaatctgc gccatcattt atttcctcag 2940tgccttctcc agctcctggg atgcacactg cccgtcccca ggcccagaga cctgaccacc 3000ctcattcctc cctcagccca ccctggggtc tctccaccag ctgacagcct tcctgcagtc 3060ccctccccga atgctgctcc ctgaggccct cctggacacc tgcagggcag gcacagcccg 3120cgggacctca cagcacttgc tccgggcaga gctgcagttt ggccaagttg ccagctccgt 3180gtgggcaggg gccctggcct gtggctgcca catcccgggt gggggcacgg cctttcctgg 3240cgtggatgct gagcaaacgt agggggaagg ggagtgaatg aggagagcca ggtagctcag 3300gggctgaggc ctcactgagc agggtcccgc gtgaccggtc cccaccgctg acggttcctg 3360gggtaacact caggacaggg agaggcaatg gaaagagacg tggccgccct cgcatcctgc 3420agctcccgca ctcccagcct cccagcctcc cacccagccc cccagagccc accagtgacc 3480ccgcccactg ggtcctcaga tggctcccac gggatctcct gccttgatct cctgtccaca 3540tggaggtgaa gtgggttgct ctgaatgagg ggtgccgagc ctagggcgca gcccactctc 3600ctgggtccgc agcatcacgc agcccggacc acaggctcct tacaagaatc ggaagggtcc 3660ctgcaatcgc ccttcgcact gaggcttcct actgtgtggt gtaaaaacac aggcttgtcc 3720tcccttgctg cccacggggc tggagccgcc tgaaaatccc agcccacaac ttccccaaag 3780cctggcagtc acttgaatag ccaaatgagt cctagaaagc gagagacgag aggggaatga 3840gcgccgaaaa tcaaagcagg ttcccctcct gacaactcca gagaaggcgc atgggccccg 3900tggcagaccc gaacccccag cctcgcgacc gcctgtgacc tgcgggtcaa ccacccgccg 3960cggctccacg ccgtgggcac agactcaggg agcaggatga gaaagctgag acggcgcagc 4020cacggcccgg tgccttcacg cgcacagcga cacagcccca gccagcgggg cccacgctaa 4080ggcggaatcc cacagaagcc tacagagcga gcgcgcgcct gtgcttccca aaacggaatg 4140gaaccaaggt gacttctaca gaacgatctg aagccctggc tggcccttat gctagtctct 4200tgggagcgtt ccaaatgcag ctcaatatta cttacttgac ttttatcttt cctccctggt 4260tcgtggtatt tataactggg tcatctttta actatttgca acgtagcttc aggggagagg 4320gggagggctt tataaataac ctgtattatt attatgcagg ttgattctgt tccctgagct 4380aaagggaaca tgaaaataca tgtctgtgac tcatgccccc ccacccccac tccagggtgt 4440gctgaggagt ctctcagctg ccccggggtc ctcgagcagg ggagggagaa aggctggcgc 4500tgcgccctcc atcgcgtgaa gccaggggat tttgctctgc gacaagctga cttggctctc 4560gtattgtttg cagaatcacc cagttccaag gcagtccctg cgggcaggtg cagctgtgcg 4620ggagcttcag tcctgtcccc aacacccagg cagtaatggt tccagcacgg aaggtctacc 4680tacctcccac tgcacagccc gagggctgtc ctggaggcac agccatccgt ccctgggtgg 4740gcaggcacgt ttatgacccc cacccccacc cccacccccc acgcgagtca gcacgttcca 4800tactcgggtg atcgtgctca tcccctggtc atgtcatcgg gatctgagtg ccatccgagc 4860agagagctgt ggcccggtgc cgggggtgga cttcatctat tccagggaac caaggatgca 4920tgatttgcaa acaaaaccag aagcgcaagc catctcctcg cctcccctga tagccgtgct 4980gcggagcctg agtgctggag 5000240600DNAHomo sapiens 240caggaaccac gggacctgct gcctagcggc cctgttccac ccttggccgc tcgcaaaatg 60tttaggcttc ataaggtttg cccagggtca caaatttaac tcacagcaaa caatgaaatc 120agcgcatgat tttcgagccc tcgtggtcac cctcccttcc tcctgccctt tcctgcatgg 180gcagcagcag ggtgaggagc tgctctcccc aggcccaggc tggagtccct cagacgacct 240gccggccagg gtacccccct gcccccacac agcgcctgac agagcccccc acactggggg 300aacgtgggga cccaagcagg ggcagcggcc tcaccgggca ggcggcgacc tgcatcatgg 360cgtccagccc accctcgggt gcatccaggt ttccggaaat cagctgcttc ccgacctcgg 420tctgaaactg gttggagttg ttggtcagct tcagcacgtg cctgaaggca aacgggggct 480ggcactcttt ctccttgttg gggcatgggt ttcgcagctt atcagggtgc gtgttcacga 540acggcagcac ggtcttgtcc acgaaggacc cgaagcctgc agggcacatg gaggggctgg 600241400DNAHomo sapiens 241tgcgtttagt gtaaaaatat caggtgtggc tgcacggagt gaaaaatcac aggctccacg 60gagccgggag gcctgctgcc ctgccctctt gctttgatga ggaaatggcg accgcagaag 120gaaatgtagc agcaccggca accggcatcc gtggggccac gccgggctgc ttcccagggc 180cctccagcca agcagccaca ggaaagagta gatgttgatc ccaagctagg actgaggagt 240ccgtccctaa gagccgaggg agtcaggtgg gcgaaactgg ccgcatgtct gggtacaact 300gctcagggtt tctcatctgc tgaatcacca agctaggttc tgaagccagg cgtgagtgag 360caggactgga gcaggattct gggaacaatc ttttccctcc 4002422000DNAHomo sapiens 242gctggggaac tgaaggaagg gctgtggagc ctgaagcctg ggcctggcct gtgctgcggc 60cgcaccgctg ggtgatgcag gagccactcc acctccctgg caccccagcc tcatccggca 120acctgggagc gtgggcctcc tgcccctcca gggaggccct ggccgtgtcc tcatggggcc 180cctccaggtc cttgtggctc caggtcggga cagtggctgt gagatctgac cctcccgttc 240cccctccacc aagtaggaga aaccccggag catgagccct cgtccttcac cgtcccgggg 300acagggggac ccccagatgc tgcacggctg acaggccaac gtggcagaag ctccagcttc 360acaggaagcc agtgaccatg agagtctgta gctgtaacga agccacagag ctgtggcttt 420ctttcccctt cagctctagg aaaggttatc tgccctgcac agatctccgg aggcctggct 480gggctctgag agcatcagac tgattatcgt aagaaaataa tctctgcaga cacattcctt 540gctagaagca ggggacaaag cccagcttca aagacaattc cacacacgcc ctccctgccc 600tgcacagctg cctgccgggt gggagcagag cccttgcagc cgggctcagg ggcctgggca 660gggacagcgt gtggcagggg cacagctgag acaggagcct caaagcgaca ccaacccgac 720gtgaagctac agttgaggag acacagctgc ccccattccc gggcctcatc tccacagtga 780gacgctggac tctctccctg acccaccgtc tcttagaacc tcccctccat ccggagcagt 840tcggcagccc cagggcagcc aggggaaccc tgccgagtgc ctctgggccg ccacagaccg 900cagagcccgc gggagccttg ctcacacagc ctcaggtcca ctgtggtctt gggggaaagc 960cctgtcctgg gacaggggag ccgggggtcc tggccctgga ccaccatctg gggaccacgt 1020tgtcacgcct gcaaagctcc ctgccccacc cccatgtgcc ggctggtgtt gacacctttg 1080tagagtggga acctgcctcc gaccccagcc tgcagccaca gggcaggtta tagaccaggt 1140gagagggcgc cgcgcccaga accaaggagc acaagtccgc agtgcccatg agatcctcat 1200gctggccggc gcaggagcca tcctcggcct ctgcaggtcc tcgtgggaaa ccgcgggggc 1260acgtggggcg gctgcagggt ccgcaaagcc ggctgtttgc gaagggcgca gctccacctg 1320gaacagccga ggccgcccac gcgcttcccg cgggatcaga gcagcctcca cggctgttgt 1380ctcaggcacc acgggatgcc tttcttcgtt tcaatagctg tgggaaagcc tcaatcggtc 1440ctgaaagaac ccagatgtgc agcaatgaca aggccttctc tgagactcta gaaccttctg 1500ccatctcaga caggagggag ccgtgaggca ggcgggagat ttgcagtcag caaaggacgg 1560gcaggtgggg cagctgcaca cccagggccc tctccacggt cttcccgggc ccacccctcc 1620cgcggtcctg ggtcatccac ctgctggcct cactctgccc acgcggccag gtcccaccgg 1680cccctgagct caacagacca aagctggccc gaccccaccc ccaagaagaa tgaaacaatt 1740tttttttacc tcttgcagaa aagtaaaaga tcatttattc attctgtttc tagatagcaa 1800aactaagtgt caaaagcacc ttctgcacac agtctgcaca cactggccgg tggtcctgtt 1860cccgcaaggt tgagctgtgt tccagagaca tgggtcctcc gggtgatgag gagccgctgg 1920agggccctga gctgcacgtg ctaatgatta acgccccgtc cgtgctggcc ggtttctcaa 1980atgcctcctg acgattgcgc 20002432200DNAHomo sapiens 243ggcctgagga gtcaaacggt gcaaaccctg ccccactctg tttgggaagc acctgctgtg 60tggcaggcgc tgcgcttggt gctggggata gaccatgggg aagaaacaca cagaacctgc 120cctgctctca aggaacaggc cctgggggcg gccaggggca gagacccaag gcagacaccc 180acacagtggc gtaatgacag tgcttatggt ggggacctgg ctgcacagca ggtcagcaag 240gggatgttca ggtgacactg ggggcacgga gacccagggg agagtggatt gacagagggg 300acgctgggca aatgtcccga ggctgaggtg gagttgcggg aaggaggagg ctgccgggca 360gaggcgcaga gagctttgca ggtgttggca gagaccagca ggccctgcga ggcctggggt 420gtgtcctcag ctgggagggc catagaagga tctgggcttg cagatgctgg tgcagactgg 480aggcctgggg tgtgagagtc caggcggggc tcctgccaac acccagggga gtgggcctgg 540gccaggtgga ccgggagctg gcacggtggt caggtgcttg gaggctgcgt gccacgctgg 600ggacctggag gtgtgtgagg aggtgtctgt tgctcctggg gctgccgcct gcagggctgg 660gtgtgcagca gtgcggggca atgaagtggg cgggttctgg gatggtggac gttccctttg 720ttgggaacgt gttggtgcca agctgccatt tgagtttggc tctgaggggt ctgggcaggg 780gacacacagg gaatcacaca ggatggagtg agttcccagg gacccagggt ggcttggcct 840gagaacagct cccactccca gatgtgtggg aagccctcgg caccaagcct cagcctctcc 900atctgtgaaa tggagacaac gtcactggac ttgcaggctg tccatgaggg tgatgcgatc 960agaaagggtg gagttcctga acgccccggg gtcggggtct cacagcagga gcttagctgg 1020tgtcggcatc tcctggaccc gtcctcagct ccgagcgccc agtcctgcca cctgtgtcca 1080agtctgcact gtgcccacga ggccctcaag gccgcagaca gccccacact tctcggacgc 1140cgccccagca cggtccttgt gtgaggtgga cactccttct ggacgccgcc ccagcacggt 1200ccttgtgtga ggtggacact ccttctggac gccgccccag tacggtcctt gtgtgaggtg 1260gacactcctt ctagggaagg agtagtaact cttgggtggt cgggtagttg ccatggaaag 1320gggcagtaat gcccaggtat tgccgtggca accgtaaact gacatggcgc actggagggc 1380gtgcctcatg gaaagctacc tgtgcccctg ccctgtgtta gctaggcctc aatgtggtcc 1440agtatctgag caccgcctcc tgcctcagat gttcccgtct gtcaccccat taccagggcg 1500gcacttcggg tcctttccag ccatcattgt cctggcattg ccacagtgga cactgccaca 1560caggcttgtg tgcttgcgcg tacccaggtc ctcacctctc tgggataaac caggcacgtg 1620gcggccgccc cattttccac ccgccagcgg tggaggagtt gcccagcctt gcaggaaaac 1680agctctcatg ccagcagcgg agcatcctat tcaagttttc tcagggctgc cagcacaaat 1740gctgcatgcc gggcggcttc ctcagcagac cgttgtttct ctgcgtcctg gaggctggac 1800gtcccaggtc cccgtgtggc aggcccggtt cctcccgcag cctctccttg gcttgtgggc 1860ggcgtctcct ccctgggtcc tcgcagggcc acccctccgt gtgtctgtgt cctccctccc 1920cttataagga ccccaggcag actggatcag ggcctgccct aaggactgaa ttttacctta 1980atcacctctt taaaagctgt ctccaaatac agtcaccttc tggggtcctg gctgttaggg 2040ctttgatgca tggatttggg ggacaccgct cagcccctaa cagcccccat cctctgcctg 2100cctttaccat ggggctgagc ccagccctgc aggagtcccc tggtttgatg tctgctgtgg 2160ccacggcgac cctcaggctg ctccagccgc acttgtgctt 22002441600DNAHomo sapiens 244ggggagtctc caggggctgg ggctggagcc gcatcagaga ggaaaggggt gtttgaaaaa 60ggggcagggc ctgggaccca ggaaactgtt cttccagaga cacccgtgaa gctgagcttt 120gcctctcagg gaagctgtga ccccacgggt gctgcccaga gagatcgggc caggtggagc 180caagatggac tggaattccc cgacggggac aaggggccgg acgaggctga cttgccctgt 240ctgatgaatg gtcaggtttg ctttttctcc tgaaaacacg aggcagtgat cccggccagc 300taattccagc agactggaga cgggatggtg gagaatgagg ctgtgggcgg gaagagcaga 360tgggactcgc cagcatcctc acggcagggc cgcgctattg ccctccctcc cctcctactc 420tctggggtcc caggagcccc agatacgcaa tgctgccagg cgatttctgg cgccccgcag 480acccctgccc ctggagttgg gccaggtccc ggctggagca aagggggctc cttcaagccc 540gctcctccct gtcaaacccg aggagcctga caggcgcagc gtcaccagcg tcaccgggcc 600atagtgagcg gccaagccag cgtcaccggg ccatagtgag cggccaagcc agcgtcaccg 660ggccatagtg agccgccaag ccagcgtcac cgggccatag tgagccgcca agccagtgtc 720accgggccat agtgagcggc caagccttgg tctgccagag ccggccgcac cagaaggatt 780tctgggtccc cagtcctgga ggagcacacg gtttacacca ggccttggga ggggaagagg 840caaggcgtgg gcccagccct cactccccag gagaaaccct gtttgagcgg cagaggagac 900tggagagacc ccagggcggg gatccctgag aggagagaaa cccggaattc atccacggag 960gcgttcaccc agaggagacc cggagcttct ccaggagagg ctggattgct ccaacagggg 1020ccctgaggag ctgatggcaa gagcggaagg cagctctgac tcgtgcgtct gactccaggt 1080gtggccgttg gggctacagt gggaccagcc tgttgtcact gaacccacaa agtgcctccg 1140agcgcgggtg gagagagggg gacctcccac cgtctgctgg ccttgaatct tgaatctaat 1200tcccgtctgt gctttgatgg gagaggcact gggagcgggc ggctttttca gttcctttta 1260tcttgaatgg cctttggggg attttcacag attctgagtt caaagcccag ggaggtgtgg 1320gaacgtgaca ttcctcaccg cattcctcac cgcattcctc tgtaaaccag gcggtgttgg 1380cacccatgag cctgtgtctt ctatgacatc aggagtttta tccctcacgt cagaaatcag 1440ggttccaggc gccttggttt ttcttggcgc cagcggcttg gctatagaag aaaaactgaa 1500ggggccaggt gcggtggctc acacctgtaa tcccagcact ttggaaggcc aaggcgggtg 1560gatcacgagg tcaggggttc gagaccagcc aacatggcaa 16002457000DNAHomo sapiens 245gctcctcagg gggaggttcg gggcctttgg tctctggact tgggcagcag aaaggaaaca 60tccctggggg cctgtggtga cccccatcct ccccagggtg gtctggcagg ggacactgtt 120ttccaaagca aagccagagc gccaagggct ctcgggattc acgagatcca catttatccc 180aagttagaac agcacatctg tgcgtgcaaa cttcattctg acttcggccg gctgtccttc 240ttgcccaaag caccgtgagg cctcatccct gcatccctgt tgcttctttc atgtgggatg 300agaacccagg aaggggctga gtgtgactcc tctggttttt agagagcact gcccccgccc 360cgccccctcc tgcttcccca ccttttcaca gttgcctggc tggggcgtaa gtgaattgac 420agcatttagt ttgagtgact ttcgagttac tttttttctt tttttgagac agagtctcgc 480tctgtcgccc agggtggact gcagtggtgt aatcttggct cactgcaacc tctacctccc 540gggttcaagc gattctcaca tctcagcctc tggagtagct ggaattacag gcgcccgcca 600ccacacctgg ctaatttttg tgtttttagt agagatgggg tttcaccatg ttggccaggc 660tggtctcgaa ctcctgacct caggtgatcc gcctgccttg gcctcccaaa gtgctgggat 720tacaggtgtg agccaccgag cctggcctgg agttattttg ggagagggca gcccctggtt 780cagcgtggcg aggctgcgct tgctctcccg ggcgggcgtc cacaccctcc tcgccgagat 840ggagaagccc aaacccctgc agcgctcccc catcacgtcc ggccctggaa gcccccggaa 900accctgccac gccctgagtg ggagagcgca ggtccctttc cggccctgga agcccccaga 960aacccttggg tgccaggcct ggccgggaca gcagcgacac tgcatgctca gcccttgcgt 1020gagaccacgg gagtgtccgc cctctgcacg tgctgctgat tgcccacttc gtccagcagg 1080tttgggagct tgtggctgca tcctcctgca gacacttgcc cattctgggg cctcctctct 1140gtcttttctc ctctgttgag gggtctggga gggaggcctt ggagggtacc catgctgctg 1200ggactgatgc tccccgcggt ggaaggagct gcctcttgaa cagcaggggg ctgagcagag 1260gggaggggat gcgggggtgc cgtgcacaca ggtgctctca ggacgcaggg gcttctcagc 1320cctgctgtcc cagggctgca ctccagcagg gcagactcct gaggtgcaga caccccagct 1380tcacgctcac acttctggaa ggcgatgtct gtgcgtttgc tttctgctgc agtttaaaaa 1440gccgggctct ctccggagcg tgtgtagggc ctggtcactg gaatatctgg actcagtgtt 1500aatggcagcc acgctggggg ctgggcccag ctttctgttc tccgtgtggg tgccatatcc 1560acctccatcg cagccctttc tctctcgacc ttttaaatca cagtgtcacc tccccctgct 1620gtcctgccag tggcccctgg aggcttctcc ccaccccttt cttctggggc aattcttaag 1680gctggcattg aatcaggagg ccagatgtgg cccctagtaa ctcaccagca gtccctgagg 1740cttctggctc ccctggccca ccagcctccc atgtctgcct caggcctctt gacccgcctg 1800gcactgacca gactgtgtgc ccgggtgccg tgcccatggg ctccgcctcc cccaggcagg 1860ccccctcttg ctccgcggcc acccctgctc ttgacctcac acctctgcgg tgtgtctgga 1920cacaccagca ccacggcggg cggggagcgg aattctccag gtggggtggg caggccggcg 1980ggtgttgagg tctctgtgca tgcttgtgcg taccctggac tttgccgtga ggggtggcca 2040gtgctctggg tgcctttgcc agacaactgg tctgccgggc cgagcattca tgctggtcgc 2100catcacgtga ctcccatgcg ccctggccct ggggttgggt ctgcaggact gagaaccagc 2160ggaagggggg cgaggcctcg ggaatgcgcc ggcaactggc gatgagctca ggcctgacta 2220atgagcccag gtgactcata cacccggggc ctggatgagt ctgactgggt caggacttcc 2280ctgcttgttc tgtcctggga gatgttgtcc ctggccctgc agagccggga ggacacgagg 2340cctcctgggt cacagccaac gcagcctact cctgcccact gctcgcgccg gccaaggccc 2400gtcggcacca cctcctccat gaagccttcc tgactgcccc catccctctg tgggcagctc 2460gagtgtgcat cttgagtgct gtgcaggttg gggtccggcg ctcctgcagg caggcggcgt 2520ctgggcctgg gggctctcag agtttgagga gcgtgtggtg agggtggcct cgggcctcaa 2580agacgcagcg ctgtgggaac cgggagactg gctgagcccg ctctgaggaa ggtggggcca 2640ggggcaccct cagctgaccc ggcgtgcagg ggtgaccagc caggcgtggc caaggatggg 2700gtctctggga tcaggagact tcagtagcag ccaggaccga

ggccaccagt ttccaccctg 2760gcattttcca tcttttgaag gactggaaac gattggattc tttaactttt ttaagttgag 2820gtgaaattca caacgcataa aattaaccat cttaaagcga acaattcggt gacatttagt 2880acagccagaa ggctgtgcag ccatcaccac tgcccaactc tagaacattc acacgccgga 2940gagagggagc cctgggccat cacgcagcca ccgcccggcc ccaagaacct gcgagtccac 3000tttccacctc tggatcggcg gttctggacg ttcatgcagg tggttcccgc agtgcgaggc 3060cttttgtttc gggctcctct cacaagcctc acgtttccag gtacgtcgtg gtgttgtgca 3120gacccacaat tcatcccttt tcatgggtgt gtaatagtcc accatagatt ctctacgttt 3180taaagcatgt tttatgtgcc tgaaatgtct ctgcactcga gactatagct tgctttcttt 3240cttttctttt ttttttttta atttgagacg gagtcttgct ctgttttcag gctggagtgc 3300agtggtgcga tctcggctca ctataacctc tgcctcccag gttcaactga ttcttttgcc 3360tcagcctccc gagtagctgg gactataggc gcgccacccc acccggccaa tttttttgta 3420tttttagtag agatggggtt tcatcatgtt ggccaggatg gtctcgatct tccgaccttg 3480tgatctgccc gcctcggcct cccaaattgt tgggattaca ggcgtgagcc accgcgccca 3540gccgagacta cagctttctt taactgcatc cctggaggga tctgagagtc tctttccctg 3600tctcctttcc tttggaaaac atttcagcca gggctcccca agatgaaagg ccagagtccc 3660aggcatgggc gttgcaggtg cacagttgcc acggggagct gtgggtgatg gtcgctgtca 3720gcgatggctg ctgcaggtcc ctgtgaggaa ggggcagtgc cacagcagga ggagagggag 3780tcagcggacg ttgattggca gtgcccgccc attccatcat tcagtcaccc actgtgcacc 3840cagcacccag gctcggctgc atagaacatg gcccaggaag gctccacttc ctgtctcctc 3900ttctcccctc tccagtctca tgatggggct ggaggcatct tctagttttg agttctgagc 3960taatgaacat gctcatgagc aggcggcagg atcccaggac ggtggagctg ggagcctgac 4020tgcgggtgac ggacaggctc tggcagcccc tgtcagcatc ctctccaggg catgtgaaag 4080ccagtgtgtc ctcagctgcc agtgccccct ccccacctcc tctgggccca tgtgcacggg 4140acctgggctc ccccaaccaa gcctgcccgc cttggttcag cagaacggct cctgtctcta 4200cagcggtgcc aggccaggag tgctgtgtct gtgaagcggg gtcatggttt tggggccctc 4260atctccctcg cgccctctca ttggggaccc cccgtctccc tagcgccctc tcgtcctctc 4320ctgcatgtgc tgtgtctgtg aagcggggtc atggttttgg ggccccccgt ctccctagcg 4380ttctctcgcc ctctccagca tgtgaagtgg ggtcatggtt tgggggcccc catctcccta 4440gcgccctctc gttggggacc ccccgtctcc ctagcgccct ctcgccctcg cctgcatgtg 4500ctgtgtccat gaagtggggt catggtttgg gggcccccta tctttctagc accctctcgc 4560cctctcctgt atgtgaagtg gggtcatggt ttgggggccg ccatctttct agcgccctct 4620cgccttctcc tgagcgtgtg gaactctgtg gtggtcagag ctaaggttct gaataggtcg 4680aagcacctcc ccggtgcctc tcaccctgaa tgctctggga ggacacagcc ttttcatagg 4740ctacgactga catggcagga ggggcctgcc tgccacccgg gtcctctgct gcctgctgct 4800tgctggggag ggggctcgag actgggatcc tgggcttctg ctccagctgt gcccaaggga 4860gctgctgagg agggaccggg tggggcatcc actctgggca ggttcagggt cattcttggt 4920gaccccgggt ccggttacaa aggctgatgg agcgcgtggg tggctgccta agtctctgga 4980agcccaagaa tgtggagatg gcgcgtctcg gcccggggtc tcgtggctgg tctgggagaa 5040cttgccttta tttctaggca ggaggctgca ctgcaaggga gcgtcagtgg cccggctggc 5100tttccccggc cctcagcccg cactcgtcca ccaaagcaag ctcctttgtg gggctgccct 5160gggaagccgg gatcacgagg ctctgccggc cgtggtcacc ccatgaggca gggtcagctc 5220gggagcaagg cggatcagat ggaacagaac acgtagacca cctcgcccgc ccttagtcag 5280ctgggccatt gaaaatcaag tccgtagaaa gacctagaaa taagtcccgg ggtgcccttg 5340cctgttgacg ggcgggccga gcaggactgt tctcaggcag gcactggtct cttggcttcc 5400aggtggtttg tttgctggtt tgaggctggg ggtgacgctc ctgtgcggga ggaggtcgca 5460ttccattcat agcggcttat ctgggctgtc aggcaggcct gggagggagc ctgcctctgt 5520gctctccaag ggtgggcgac ggacagacag ggtgtcccac cccttctggg ccaaggacag 5580agggtcagtg tttgcagaga cctggggagg cccaggtgac ctccaccgag cacctgctgt 5640gtgcagggcc agtgctggct gcagagacag cggagcgtgt gtggacccgg cggcccaggg 5700gaggggggca ggcaggaccc ggcggcccag gggagggggg caggcaggac ccggcggccc 5760aggggaggtg ggcaggcagg acccggcggc ccaggggagg ggggcaggca ggacccggcg 5820gcccagggga gggggcaggc aggacccggc ggcccagggg aggggggcag gcaggactcg 5880gcggcccagg ggaggggggc aggcaggacc aggcggccct gggggtcagg ggtggaggcc 5940aggcctagac ggcccacagg agggtggact cattctgacc gattcctgga agcccccgga 6000aagtggtgat gttctggagg gcccagcaga ccccaaggcc cccaagacaa tcccagctgg 6060ctctctgcgg ctctcggtgt ctgccatttg agacaatttg ggcacaggca gggcaggccg 6120tcgcggacgg tctaagccgc gcgcattggt gggggcagca gagcccctgc tctcagctcc 6180tcggggtaca gcgggggtac caggcgggtg agtgggtggg tggtcactgc tcctgccaag 6240ggcagccctg gtttggtttg cacttgctgc cctggtgacg gctgctctca ttcctgcccc 6300attgctaaca agggtgtcat aagctacttt cccggcccac atcctattaa gcccatggag 6360accctcccac agctgagcct gctgtgggct gcaggccctg ggcggtgccc acctcggtcc 6420ccactggcct ccttccagca ctttagagca gacacaggtt ggagataagg aaagttccag 6480agcacagact ggaacaagcc ccaggcctct ccctgcccca gcagggcctc cctggatttg 6540ggggacaggt gccctcatgg ggggtcctga aggtcagagc tggggctggg gctgggctgg 6600cggaggtggc cttggcggag gccacattcc agggtctcag tgagagtctg tggcaggcag 6660ccttgcagat gccgctgagg gaccccccac ttcatgttgt gggtgatgtg gtccattgat 6720tgcctccagg tttaaatcag gtggatattt acctagcggc ctcctctccc tctgcacagg 6780gcctggagtg ggatggactg gggtgctcag ctggaggctc tgcagacaca gccccctggg 6840ctatgcaggc cctgctggga gccacattgc catttttcat cacccacttt ttgggtgaga 6900accccctcga gtcctaacat ctgccgcatc tcagagcctg tggctccagt cagagcatct 6960ggaccatact gctggggtca gagcgcggca ggacaatggc 70002461500DNAHomo sapiens 246tgccaccacc atcttcaggt agagcttctc tctcctcctt gctgggcggg gcccctccct 60ggggaagcct gcaggaccca gacagccaag gactctcgcc cgccgcagcc gctcccagcc 120agcagctcca acgccctgac gtccgcctgc gcacgccact tctgcacccc ctggtgatgg 180gctccctggg caagcacgcg gccccctccg ccttctcctc tgggctcccg ggcgcactgt 240ctcaggtcgc agtcaccact ttaaccaggg acagcggtgc ttgggtctcc cacgtggcta 300actctgtggg gccgggtctt gctaataact ctgccctgct cggggctgac cccgaggccc 360ccgccggtcg ctgcctgccc ctgccaccct ccctgccagt ctgcggccac ctgggcatct 420cacgcttctg gctgcccaac cacctccacc acgagagcgg cgagcaggtg cgggccgggg 480cacgggcgtg ggggggcctg ctgcagacgc actgccaccc cttcctcgcc tggttcttct 540gcctgctgct ggtcccccca tgcggcagcg tcccgccgcc cgccccgcca ccctgctgcc 600agttctgcga ggccctgcag gatgcgtgtt ggagccgcct gggcgggggc cggctgcccg 660tcgcctgtgc ctcgctcccg acccaggagg atgggtactg tgtgctcatt gggccggctg 720caggtaactg gccggccccg atctccccac cctttccttt ttgccttgcc aggtaagtgt 780gggcggggct gacgtgagcc tggtacaggt tccccccaca tcgaatctct acgttcaggg 840gcccgtggcc ctcgggaggt gggagagctg ggagtgaggc ctcctgtgtg gggaggaggc 900cggcgtctgg acaggaagag ggctggatga accgcagccg atgtgtccag gtgccacctg 960ggcctggagc tccctgagca ttttagcgca tttagtcctc agcacggtcc cgagataccc 1020tgccatgccc cgagtcacag aggggaaact gaggcgtggg gcagtggcgt gactcacccc 1080agggagccga gattcccgct caggtgtggc tgcatcgacc ttgctccggt cactaagctg 1140cacggttcga tgcgcttcct gggagcccca gcgtgctcgg gccaagggtg ctgccgcgtg 1200ggcagtgcag agaccctacc agcgtgggga ccagggaggt ctgcagggcc cgtcctgaga 1260gggagccttt catgtccccc tccccatcct gaagcacaca gcctccctgc cacagtgggg 1320gccgcttctg ggcccagggg acgttgcccc atcaccgtgt ggcctggcct tgttgctggc 1380tggacagttg ggggcaggaa gaggagggaa agggggactc tttaacctcc tgggggcagg 1440ggcagcccag aaaggacccc agcagatccc tcctctgtgt ccgggagtag acggggcccc 15002472000DNAHomo sapiens 247gggctccaca gcggcctgtc tcctcacagg gttcagccca gtctgctctc actcatttgc 60tgattcattc tttcattcag ccagtcaata gtcatggccc ctcctgtgtg ccgggtggcc 120atggatattg ccctgggtaa cacacagcct ggccctgtgg agcagacagt ggggacagcc 180atgtggacag ggtgcaggtg gatggcaatg gcagctgggt caggaggggc tgagggccgt 240ggggaaaggt gcagaatcaa taggggcatc cggactgggg tgcaggcctg ggggctggga 300tttctagggt ggaggtcacc tctgagggag acagagcaag gccctgggag attagaaggt 360cgaaggtcgc cgtgttgagg tcaggggccc tgaattggag ccgcggcaaa ggagagggca 420ggtcagggca cgtggtgagt gattgctgcg gcttctgagc acggctgggt ctgtggggcc 480tgagcagagg tgacccgcga tccggcgcca cggcaggcag gactccccac ccttgctgct 540gcctacaccc ccagggcagc cccagagtcg ggggcgcagc tccctgcttg ccagttcaga 600gcccagcccc tctcacccag cccagaggag gacacagatg gaggaggggc acccggaggg 660tccccccgcc gacaggcccc acgtctccca cctgcaggac aatgaagtgg ccgccttgca 720gccccccgtg gtgcagctgc acgacagcaa cccctacccg cggcgggagc acccccaccc 780caccgcgcgg ccctggcggg cagatgacat cctggccagc ccccctcgcc tgcccgagcc 840ccagccctac cccggagccc cgcaccacag ctcctacgtg cacctgcggc cggcgcgacc 900cacaagccca cccgcccaca gccaccgcga cttccagccg gtggtgagtg cccccccaaa 960gtgggcttgg ctccatctag cccctcggct ctcggcagca gaagagggcc cagcccctgc 1020agagctgctg ggggtcccag gcttcggcca tgggtggggg tctggcggct cagggccact 1080cagggcggct tggctggccc tgggacttgc cctctggtgg ccaagcagtg gtcatgaaag 1140tccagccgct gtcacatcct tgaggaaccg gcgtacctcc gcctacagcg gcagctgggg 1200gcacccacgt ggcccggggc tgctctgacc tggcagcgta tgggggctgc tgcctgggcc 1260cctcagtgtg tcacttgcgc gcctcccgct cagcgcccct cggccgtgcc tgtccacaca 1320ggtgcggggc cggggtggtg cgcccggggc ctgggtgcag ggggcagcgt gggacacagc 1380ccgtgacgcg cccctctccc cgcagctcca cctggttgcg ctcaacagcc ccctgtcagg 1440cggcatgcgg ggcatccgcg gggccgactt ccagtgcttc cagcaggcgc gggccgtggg 1500gctggcgggc accttccgcg ccttcctgtc ctcgcgcctg caggacctgt acagcatcgt 1560gcgccgtgcc gaccgcgcag ccgtgcccat cgtcaacctc aaggtgggtc agtccagtcc 1620tgagggcgcg ggctcctcgg cccccacttg acctctgggg tgaactccca gcggggagct 1680cccctctagg gcctctggag gccaccatgt tacagacact ggcgcctagg ctggcgactt 1740cagggcaggc tccgggtggg tcacacccct ccaggctcag gccaggcctc tgcatccctg 1800ggcactgcca cgtcccccag ggcatcccat gaggcccccc cgtggccccc tgaccccccg 1860ctcccccggc agtgcccctc agagggtccc atgctgctgg accaagtgtc cacacaggtg 1920atagggctca catacaagcc tggaatcagg aaccgtcctt tgggcctcta gtgccatgcg 1980ggctggtggc ccctctgcca 20002482000DNAHomo sapiens 248gcctggagtg tagtcctgct gaaggccaga gaccacacac tccacccaga ctccggatct 60ccctccccag cagggggatg gaggccctgc cgctgggagt gctggtgtta tgtggaaggg 120ctgggcttct ccagggctcc tgggaggcct aaacatcttg caaggttttg acgttaatta 180ctattatgat tgctttctgt gtgttactgt tttccccaca ctttagccag ctaatgtgga 240gctacagaag gccctcgccc ctacccctcc agatgtccca gcccatgaca agcaggaagg 300ccgggtgctg ggagacttcc tggggctgga tctgacatca ttccaagcag atgataacct 360gccttcccga tttccaaacc cacagcaaga caccctggag ttatttataa atgcgagccc 420ctgggtgcac ttctgacggg accagcaccc tgacggccat gagagggtgg agacagcgca 480ccccgagctc agggaggcag gaaactctgg acctggaggc cgggcaccat gagggacacg 540ctgcaggccc agctgctgcc gcctggggcg gggctgccct gcaggctccg ggaaaaccca 600gaaccaggcc ggatcagcgt gtgtcaagag gcggggcgtg agagatgagc tgcttttttt 660cttcacaggg ttggcaggaa ctgcaaataa tagaaagtct ttagggtcta acacgctgcc 720ctgaaaacac tatcattact ttcctaatga ctaactgtgt ctttcagccg gcggggcagg 780cagctgaggc cgcaggctcc cgcagaggac cgggggaggc tggcagcctg taatctgggg 840gcgctgacag tgctctgccc agaccctcgc gccagctcca gctccagcac agcagccctg 900ggtccctctg gccccctgcc cgcagagtcc aggtgtggca gaggccgccc agtatccctt 960ctcctcctcc ttttctaaaa acagagtctc acgatgtttc ccatgcgggt ctccaacgcc 1020tgggctcaag cgatccttct gcctcggcct cccaaagcgt tgggattaag gggcgagcca 1080ccgcgcccgg cccaccttcc cttctggttc atttccagta aggtcctgtc cacagcgtcc 1140ttcccagcat tcccaccagg ctgcaggcct tggcctccct cccctccatt ctcattctcc 1200ccgaaaccgc caagcgcgtc caaagcacgg gttcgccaag cgcccccccc gccccactcc 1260acattccctt ccccgccgac tcagcctccg tagctcgcgg acggcccctc ctcacgccag 1320cccaggcttt tttttttttt ttttcttcta ttttaaggtt gtcttttaat gacacaagcg 1380acatttggag acaaaaggac acatctcttc ctgacccacc tccaacccca gctgacggcc 1440gccctgagcc tggcgtagac ggcccggaac gttccctgcg tgggttccgt ccatcccgaa 1500cccctgtccc cgcgccggct ccgggggtgc tcggggggcc gcgtggggtc tgtgacgtcg 1560cctcgaggct gcatcccggt gacccggcag cccctggcgc tcgcgggagg cgggcgggcg 1620cggaccccag gctttagggc gcgattcctg cagctggctg ccggcccgag gttctggggt 1680gtctgaggtc tcgggcgggg cgaggacgtt tctccggctc agccccccca cctcctgccc 1740tgccgccccc cacacccagc tccccacgga cgccaagagg cgcctcccac cccggcgagg 1800acccgcgggg aaacggggcc caggcgcggc gactgcggag gacgcgcctc ggccccagcg 1860ccctggtcct cggggcgtcc ggctgccctt gcccgaggcc ggggcgggcg ctcagcgccg 1920cggaagaaac gcccgggcgg ggacgcacag cgaggcgggc tccgcgggaa gtaccgggaa 1980aacggcgcgg agcggaacag 20002493000DNAHomo sapiens 249tggagcaatc ccagagaggc tgaggtgttc aggctggccc cagatgcaca cgagcgtgaa 60gcctgttcag aagccagctc ctcacaccct ctcccctgcc agaggctcca gcaccccctc 120ccctctcctc tcccctccct tccctgtggt cctcctgccc accccacccc cgtctgcatg 180tgcaccgtca cggagatgcg tgtactaggg cggaggtcgg ggacagtcgt cagaaggaca 240caggaaagaa gggaacagga atcccataac agaacattat ccggcaggag taattaacac 300aggcaggact ggaggctttg ttttgttttg cttaaaaaac agtggtattt aaattaatgg 360gcatgggaag actattcagt gaaagacatc ggtcattgag gtatctattc aaaaacacgg 420tttagtactc tgccacacac cgaacgcaac gccacagcag ccatagaagc gtgtgtggct 480gtttaacgtg gtctttttgg ggagggcatc ctaggcagag caggcgtgga agggaaggcg 540gcggacggaa caaaacgcgg gcacgcaacg gctgctgcgc cggatctgag gcagggccag 600cctgtgggag cagcaacatc gctcgcagga cagcgatgga gcccccacga atccgcgtga 660aagcagcaac cacctagaaa tgaacgtaca gctgcttaga aacagaatac ggatgacccg 720aaagacttcc cgatggtagt caccagcata caggacctga cacgggcgtg cgggcagggt 780gtgccgctac ggggtccctg gcgcacctgc tacccctgct acccgcattc accgcacgcg 840gagggtgcgg gccgtgaagg ttatacatgc aaatatcctt ccaccagcca gttctccttc 900caggaatctg ccacccgacc cttgtgttgt gcacagacat ggtccaggtg tttgcgacgt 960gattgtttat cagagagaga gaagggaaat ctccaggctc gctgtagctg caggagctct 1020gggggctgcg cccatcgtgg agacggatag ctgtctctca tgaacacagg acagcaagtc 1080cggctgcggc cacagaagac tcgccctcct ggacgcagcg tcttccttcc tcagccccac 1140actggaggtg gccagtgcca tccacagcag aaggggccag ccgggaccag gctcacgccg 1200tggaattctg ctctgtggta agaggaagag cgatagctgg aacccagcgc cgtcgcacac 1260acagcgggga agagtctcag aaatgttact ttgagtcaaa aagctggaca aaaaaaggcg 1320caagccagat ggtgctgaag aggccacagg aggctggcag ccagggggtc tggcacctca 1380ctcggaggcg cagtgggccc gtccggaatt agtggccata cggcaagtgc cgagtggaca 1440tcaaaccgtc acttcagact cctgcgcttc actgcctgtc ggttatgcct gggttttgaa 1500atcaagtcac agaacacctg gaatgtggtg tttacgcaga acaaagcggg tgcctcggag 1560gagagagcct agggacaggg gcacctcccg gtgtgggtgc ccagggttgc agggtggctt 1620cctctgtctg cgcggttttc agagccccag ggtcctgcct gcccggctgc ctggaggcgg 1680cccacatcct gctctgcgcc gccgaatctc agcctgaaca gcttcgctgg tgtttgtgtt 1740gacttatttg ttcttttttt tttttttttt ttttaaataa aggattccga tgctgttaca 1800gtcaataaaa gccacaggtc tgggtgacct acaaatgtgt gtgtctgact ttctgcagtt 1860taaatcgcca ctgagcctta aggcgtctgg cccgcgcatt gaggaatcca cgtgggtctc 1920ggggtcccca tgcctgccca gctccctgct tcagcctggg cgggtctggc gggcatttct 1980gcgagcctgt ccctgggccc gcctcctggc cagacttcca gaaacattgt ccacatcccc 2040gttgcacgtc cccccgtcac cggaaactgc agcccacagc actgggaaga acccgggagg 2100caggcgttag gacggggtgg ccgagacagg gaagggagcc atggcggacg tcctcaccca 2160agccagggct tcctgcccct gtggtactga caggagcccc gcaggacgtg gggttggctt 2220tgggcagctc ggtggacact tctctttcag atcctgccac agcaaagctc acgagactca 2280cttcttccca ttggaattca ctaagaacaa attcaacaat tcagacgccc cagctggagg 2340tttattttat ggattttacc tgtgcggtat ttagggttgt gtttatgaat aaaggtgtgc 2400gttctggcaa gtagaaatac agagcttgtc tttcacccaa gtatctgtaa ctttctccaa 2460tgcagacact aaaatgcaat aaaaacaaac caaacccatt aaacatgaat tagatgaggc 2520aggctgatgg gaggttgtgg gattaacagg ccgtcagcgg attgaagctg cgcacatcgc 2580tgggatgctg ctgcgggagg attcggtcta atccgggagc atctggctgg gcagtgggca 2640gcgtctgcag tcgtggctgc ttgaaggtat gaaggttgtg gcctttgctt ccccccatca 2700ggctgcccca ccctggaccc cacccagacc cctcgggcac cctggggtca tcttcagctc 2760ccccttctct tccttccttc tcttccgcct gggcccctac tgtgacccga ggtcagcaga 2820ggaccctggc aggtggctgc tccctgggac tcgactgtgc aggtgaggct tggggtgacc 2880gctgctcctg ctcctgctcc tctcgccgtc cccaccctcc tccatcatgc tgtcaacatg 2940catgtgggct gcagccctca gcctgcagga cgctgtcagt gcagctcctc agtggccagg 30002502500DNAHomo sapiens 250atcttgtctt ccttgtccca gtcctggaac cagccactgc cccagcagct cctgtgtgtg 60gtggcatgtt ctggaagcca ggatgcatgg tgctcctggg ctgctgtggg tcctgggctg 120ctgtgggtcc cgagctgctg tgggtcctgg gctgcacccc tgcagaacac ttccttccat 180gttcagctcc ctatatggaa ccccagttcc agccccacag cacagggtcc cccagttctt 240cctgcctcag gtgtgcacca cgaggaatcc aactgccagt atctgtgcgt ggcctcccgc 300cgggaggagg ctgccggagg ctctgagctc tagccccaca gcactggcac atcctagatt 360tccgggaaga cacggcctcc tccccagggg aaggtggtgg tgcccacacc cagagcattc 420attcctgcag tggagacaga gggacctgcc tctccaactg tgggtgtcag gagccaaggc 480gcatggtaaa tggggctctc tgtgaggcca ggtgcacggc cccatctcca gcagcagcgg 540ccatgccacc cagctgcact ctgtggggga ggtgccatga ttgacggggg cccctccctg 600tgtccagtgt cctcctccct ccacgggccc ctctgcacac cgtcctcaca gtctccctct 660gcacaccgtc ctcacagcct ccctctgcac accatcctca tggtctccct ctgcacaccg 720tcctcacagc ctccctctgc acaccgtcct cacagcctcc ctctgcacac cgtcctcaca 780gcctccctct gcacaccatc ctcatggtct ccctctcctt ccacagaccc ctctgctcgc 840catcctgacg gcctccctct ccctccacgg acccctctac acactgtcct cccagcctcc 900ctctacacgc catcctcaca gcctccctct ccctccacgg gcccctctac acaccgtcct 960cacggcctcc ctctccctcc acgggcccct ctgcacaccg tcctcacagc ctccctctcc 1020ctccacgggc ccctctgcac gccgtcctca cggcctccct ctgcctccac gggcccctct 1080gcacgccgtc ctcacggcct ccctctgcct ccacgggccc ctctgcatgc cgtcctcacg 1140gcctccctct ctctccacgg gcccctctgc acgccgtcct cacggcctcc ctctctctcc 1200acgggcccct ctgcacgccg tcctcacagc cttcctcttt ttccacagac ccctctgcac 1260gccgtcctca cggcctccct ctccctccac gggcccctct gcatgccgtc ctcacagcct 1320caccgacgtc accattgctg gccccgcttc aggtgacagg ccacagtagc acctgtcagc 1380tctgtcccgc tgctggacag ggagatactg ggccactcag cccagcgggg aacgtgtgtc 1440ccgaaactgc cttgggctcg ccatcagaac tgtggcagca tcttccagcg ttccttttaa 1500caggctgccg ttggaatagg agtcacggag caattgcagt gctaagtttt ctttaagtca 1560cacaattgaa ggaggcttta tttttcacac atttcttcca gagtttcctg gtagcctgag 1620tgcatgggtg atgccccctg agttatttat caggggcagc cagctgccct cccccggggc 1680acttacagtc agcccatctc tgtcctggtc aggtgggcgc caaggaagac ccggctcagg 1740gcctctgtat gggcagcctg gcttgtacac acacccctcc ccaccagcag attctgaatt 1800ctcccttctt catgcacacc gggaaggtcc cttctgcact cataccggga aggtaggcag 1860gtttcggtag tgtctgcctc cagtgttttc ctcctcctgc tctatgacat catctttctg 1920tgattttttt tttcttgcag gaagttggaa gcatcatcgg gaaggtaatt attgattgaa 1980tctctgcctc tcctggggtc tctgtaaggg gatggtgagg atggcagcct ccctgggtac 2040taggtggcac ccagtaggtg cgcctttccc agttggtggg tggtctgtgt tccatgaaga

2100caggacccca gaggtgtcgc ctttatgctg tatgacattg aagctggtcc ctggctctgc 2160gtggcctgag gggaaggggt tcactccagc tggtcacctc gctgccccct gcccgtggcc 2220ttggtggcca gtccttcttt cccggttgaa gaccccacga agaatgattt ctcacgcctt 2280cttcagccgg ctgtgtagtc tgggtggtct ccaggagtgc cagtggaggc agcagccccc 2340agacaattcc tttccaaatc agggctggcc cgggggaagt aaggcccagt ttggaagcct 2400gctgccccgg gaggccgagc agtgagggcc acctccctgt cttcatcaca ttttcaccgc 2460ttccgggggt ccttcccctc agtcccacca tgggggcgcc 25002516000DNAHomo sapiens 251gctggacacc tctgagagcg tggccctgag gctgaagccc tacggggccc tcgtggacaa 60agtcaagtcc ttcaccaagc gcttcatcga caacctgagg gacaggtagg agggacgccc 120cgtgaccttc ctcctgtgct tctgggcctc ttggagggag gggtgggggc ccaggggaac 180acgggtgcga cggcctcaac ctcctaaggt tgggcgagcg ttgccctgac cggggcccct 240cccggcgccc tccagagtga ggccggggcc ctttccggcg ccctccagag tgagctggtc 300tgagcctctc ccagcgcctt ccagagtgag ctggtttgag accctgctcg cgggggtggc 360acctgttcag cagggccgag gtgacagtga ggctgagatg tagggaagag aggctcccgc 420aggctgaccg agagggctca gcgcactggc ccagacacgc agtcctgcct ggtgcgcggg 480agcccctcac taaccacctg gaccctggtt tgttccgtgg gcagtgagag cctctacctg 540ggtcctggat cccacgttct gaaggtcccc gactcgggag ccaggagggg tgtcgctctg 600cagccccagg gcccccaggc ttggttctgg gcttgggaca cggcaccctc tgctccacgt 660tcctccatct gtgcgtgtgg ctgaggacag accgggggga gaggggagtc ggtcctgtgg 720gtgcacaggg ccgctgaggg gggggcatgt agaacggggc tcccccactg agacgggtcc 780tggcagtggg gacacagctt agccggcgta ggaacccccg tcctccttga ccctgctgac 840tggccgctgg gccggagcct cccgccacca gaaggggcac agtcagaggc tgccggtaac 900agcagggtgg accttccagc ccacaccgtg cccagcagga gccattggta ccaggaaccc 960tgagcttagt ggacatggcc aggcccgtgc ggcagtgttt gggggggggt ctggctgtgg 1020atggcaccgg ggaggggcgg ccgcgtggcc cagcgtcccc cgagtcgccc ttgttgcctt 1080tactcagtct ccccatgact cagtttccca cctgtgaaat ggggcggagt catccccatg 1140tcgctgccac tggattcctg caggcgccgt ggtcactctg ctgaatggat gggagggtgg 1200gtggggcaga ggtgggccca ccccaggctg gggcagagca gacccctgag agcctcaggc 1260tcaggtgctc agagggcagc gagggggctg ctcagatccc cggggtgcct ccttccccca 1320ctgtcatgct gccccactgc aggcccaagg accccacccc agcagggcca cacactcagg 1380gctcctggtc tgagggcctg agggatcggg gcgcaggtcg cttgctggcc acacccgcct 1440gcacagcctt ccaggagggc cggcctcagg gccacagggc aagtccagct gtgtgtcagc 1500cacggccagg gtggggcagc ctgtccatct gggtgacgtc gcgccctggg acgggtagcg 1560atggcgccag gggccgcccg cctcacgccc gccgtgcctg ttcctggcag gtactaccgc 1620tgtgaccgaa acctggtgtg gaacgcaggc gcgctgcact acagtgacga ggtggagatc 1680atccaaggcc tcacgcgcat gcctggcggc cgcgacgcac tcaaaagcag cgtggacgcg 1740gtcaagtact ttgggaaggg cacctacacc gactgcgcta tcaagaaggg gctggagcag 1800ctcctcgtgg ggtgagtggc ccccagcctc ctgcccacgc cagttctcac gcgtggtacc 1860cagcctgggc tggggttggc ctggggtccc tgtgcggctt cagctgcagc ctccctgttc 1920tcttggaggc tgcacggcct ccctgaccca ctttgtgggc aggaaagaga cggagacaga 1980cagagacaga gagaaacaga aacagggaga aacagacaca gagagagaca gagacagaga 2040gagatagaga cagagacaga gagagacaga gacaaagagt gacagaggga ccaagacagg 2100cagacagaga caaacagaga cagagacaga gacacagaga gagacacaga gagacagaga 2160cgggaacaga gacaggcaga cagagacaga gagagacaga gacagaaaca gagacagagg 2220gacagagaca ggcagagaga gacagagaga cagagacaga gacagacaaa cagagacaga 2280gagacagaaa cagggacaga gacagaaaga gagagagaca gagggaaaca gagagagaca 2340gagacagata gaaaaagaca gaggcagaga gaagcagaga cagagaaaca aagacagtca 2400gagacagaca gagacagaga cagaaacaga gacagagaga cagagacaga ggggcagaga 2460caggcagaca gagagacaga gacagagaca gcgaaacaga gacagaaaca tacagagaca 2520gagagacaga gagaagcaga gacagacaga ggcagagaga cagagagaag cagagacagg 2580gacagagaca gagacagaaa tagagagata gagacagagg gacagagaca gagagataga 2640gacagagagg gagacagaga gatagaagca gagagagaga gacaaagaca gaggcagaga 2700gacagagaga gaagcacaga cagagacaga cagagagaca gggacagaca gagacagaga 2760gaccggaaac agaggcagag agactgagag actgagagag acggggtggt tttccccaca 2820gcatcaacac caagcagggc taggatcact gaaacagact catcagaccc gaagcatgcg 2880ctttctcggg gtttttctgg actgaggggt ttcctctcat cccagtgtcc agctgtgggg 2940acgcaggggc cgcaagcccc ggagtgtcca gaggggaacg tggcctcccc acacccagcc 3000cttcacgagg cctcaggatc ccagtggggg tacccgaggc tgccctgtcc agccaggcgg 3060tgcggggggt ttggggagag cctctccccg aggtcggtct cagagggcca catggccggt 3120gtgggccgga cattcccttt ccaatggttg tgcccacttc cctccagagt tggtgccaag 3180ctgggacctg ggggacttgg agtctcagga agtcgtccgc tgtctgcagg gggtgcatgg 3240gggatgtggc cacacacgtc agagtgcggc cccctgtgga agccacagac agacacgact 3300cccctaaatg agctcgccct tctggccgag atgctcagcg tccccagcag gctgcccgac 3360tgccctgcga tactgccctc cttcctgctg ctcccacttt ccctttcggg gggttggatt 3420tggggcattc agggatcgcc ctgttgtttg ctcatcacac ccatttcctg caagagccac 3480ggtgaccgag cagccttgag ttgaggcagc ttgtgggtag acgcggcggg catctcggag 3540gggcacgctc cctgccaccc tcagcctcca ctcactggtc aggggctttg cgccccaggg 3600caccccagga accgagcctc ctttggggtc atgggtgcct ctcctgggag ggcgtggatt 3660ttccaaagca gtttagagaa atgagaccca caggcgttat ttcccatggt gaggttcttt 3720tcagtaaccc ccaccgtata gccaggatca gcaaagagag gcggctcctc ccggtgagac 3780agggaccagc acctcccgga caggcttggg tctccctcca gttcccccac ctagtctcga 3840ggtctcacgc tgccctctcc tgtccagggg ctcccacctg aaggagaata agtacctgat 3900tgtggtgacc gacgggcacc ccctggaggg ctacaaggaa ccctgtgggg ggctggagga 3960tgctgtgaac gaggccaagc acctgggcgt caaagtcttc tcggtggcca tcacacccga 4020ccacctggta ggcaccggcc ccccccggca gatgccccca accacaggga gtggcggctg 4080caaggccccc ggcagctggg accgtctttt ggtcctcggg agggtgtggg ttctccagcc 4140ggccaccctt gcccctgaga ggccagcccc tcctgctgag gagcctggag cgccccagcc 4200cagcctcccc tctggccctg tgggaagcgg ccccggccgt caggggtccc agccctgctc 4260agcccaccct gaacactgcc cccaggagcc gcgtctgagc atcatcgcca cggaccacac 4320gtaccggcgc aacttcacgg cggctgactg gggccagagc cgcgacgcag aggaggccat 4380cagccagacc atcgacacca tcgtggacat gatcgtgagg cccctgccca ggagacgggg 4440aggcccgcgg cggccgcagg tggaaagtaa ttctgcgttt ccatttctct ttccagaaaa 4500ataacgtgga gcaagtggta agagccctcc ccaccacccc cagccgtgag tctgcacacg 4560tccacccaca cgtccacctg tgtgttcagg acgcatgtcc ctatgcatat ccgcccatgt 4620gcccgggaca catgtcccct gcgtgtctgc ccgtgtgccc gggatgtgtg tccccctgcg 4680tgtccacctg tgtgtctgcc catgtgcctg ggacatgtgt ccgcctgtgc gtccatccgt 4740gtgtccgtct gcccatgtgc ctgggtcgca tgtcaccctg tgtcccagcc gtatgtccgt 4800ggctttccca ctgactcgtc tccatgcttt ccccccacag tgctgctcct tcgaatgcca 4860ggtgagtgtg ccccccgacc cctgaccccg cgccctgcac cctgggaacc tgagtctggg 4920gtcctggctg accgtcccct ctgccttgca gcctgcaaga ggacctccgg ggctccgggg 4980cgaccccggc tttgaggtga gtggtgactc ctgctcctcc catgtgttgt ggggcctggg 5040agtgggggtg gcaggaccaa agcctcctgg gcacccaagt ccaccatgag gatccagagg 5100ggacggcggg ggtccagatg gaggggacgg cgggggtcca gatggagggg acggcgggag 5160tccagatgga ggggatggcg gggtccagat ggaggggacg gcggggtcca gatggagggg 5220acggcggggt ccagatggag gggatggcgg ggtccagatg gaggggacgg cggggtccag 5280atggagggga cggcggggtc cagatggagg ggacgtcggg gctccagatg gaggggacgg 5340cgggagtcca gatggagggg acggcggggt ccagatggag gggacggcgg ggtccagatg 5400gaggggacgg cggggtccag atggagggga cgtcggggct ccagatggag gggacggcgg 5460gagtccagat ggaggggacg gcgtggtcca gatggagggg acggcggggt ccagatggag 5520gggacgtcgg ggctccagat ggaggggacg gcgggggtcc agatggaggg gacggcgggg 5580tccagatgga ggggacggcg gggtccagat ggaggggacg gcggggtcca gatggagggg 5640acggcggggt ccagatggag gggacggcgg ggtccagatg gaggggacgg cgggagtcca 5700gatggagggg acggcgtggt ccagatggag gggacggcgg ggtccagatg gaggggacgt 5760cggggctcca gatggagggg acggcggggt ccagatggag gggatgtcgg ggtccagatg 5820gaagggacgg cggggtccag caggcaggct ccggccgtgc agggtgtgga ctgtcccggg 5880ggcgctgggg gcttctgagg gtgtctctgt ccgccctgcc ctcagccgca ctctgttcag 5940aaggaccttt ctggaggtag gagggtgaga atgtgggtcc cctgcttctg tgtggctcac 60002527000DNAHomo sapiens 252ggccggggag gcggggaggc tgccccaaga gtaaaagcct ttctgacgtg cgcaggacgc 60ggccctgact ggtctaactg actctttctc ttctcctcag cttgctgtgg tgagacccag 120gctctagctc ctgagagaat ggatcccggg ggtcggggag cgaggcctgg gtcccacaca 180tgtcacagga cagcacatgg cactctggtc cccgcccgca gctccctgca cctgcccgcc 240ccctctgggg cctgctccaa gccagcaggg ttcccgggtg ttgggctggg ccccgccctc 300tttcacccat aactgaaata accaggagca ggcttggggg ggtccctgct ccatcattct 360ggcccacagg ccccacccta gcctggctga gcaacgccag ccctgaccag ccgccggaca 420gagcagcctt tacggggcca tgggaggggg tgggcttttc tggggctgag acggggggac 480cccaacgtgt caggtgagga tgtggcagcc aaggaggggc cagggcggtg gaggggaggg 540gccagggcac tggaggggag gggcgtgctc tgctgacacc gcccccgcct gcagaatgca 600agtgcggccc catcgacctc ctgttcgtgc tggacagctc agagagcatt ggcctgcaga 660acttcgagat tgccaaggac ttcgtcgtca aggtcatcga ccggctgagc cgggacgagc 720tggtcaaggt gaggcctcgc cccgcccggc tttctcaagc ccaggtgcac cccgaccctg 780ccggccgccc ctgcccgcgc cagacctcag cctcccgagg ccaccgctgc atccctgtga 840cttccctact catgacaagg atgccaggca cgcgccagcc cgtccaggcc tccagctcca 900cctggcgagg ctggcccatt gtacacaggc gccccagatg agggagggtc tccccctctc 960cttgaagggc ggtagtctgg ggtcctgagt gctgggtgtg ggcttgtccc tcgtggacag 1020aacccaggag ggcttcatcc accaaggaag attgctttgc agggtaccca ggtcccgggg 1080gctgtgccac cctctgggca cccggagcca atcgcagggt acccaggtcc cgggggctgt 1140gccaccctct gtgcacccag agccaatcgc aggggaccca ggtcctgagg tcctgggggc 1200catgccaccc tctgggcacc cgcagccaat agagtcaccc ttgggaagct tatgcggacc 1260tggggcagca ctcgcgtcct gaccccggtg ccggtcccac agttcgagcc agggcagtcg 1320tacgcgggtg tggtgcagta cagccacagc cagatgcagg agcacgtgag cctgcgcagc 1380cccagcatcc ggaacgtgca ggagctcaag gagtgagtgc cccacgcggc caggaccctc 1440ccacccctcg ccccgaccgc tgttcccacg gcaggtcggc cctgacccct gatcccaggt 1500gggctcggcc ccgcggcagg cctggcccca accggccctt cctgcccttt gctatgcaga 1560gccatcaaga gcctgcagtg gatggcgggc ggcaccttca cgggggaggc cctgcagtac 1620acgcgggacc agctgctgcc gcccagcccg aacaaccgca tcgccctggt catcactgac 1680gggcgctcag acactcagag ggacaccaca ccgctcaacg tgctctgcag ccccggcatc 1740caggtggggt ggccaccccc aggctgcacc tgccccgcct agggcgcccc gccagccagg 1800gtggccttgt ccccagaaag acgagggcag agcaggctgc gccacaccga tactgtctgt 1860ccccacaggt ggtctccgtg ggcatcaaag acgtgtttga cttcatccca ggctcagacc 1920agctcaatgt catttcttgc caaggcctgg caccatccca gggccggccc ggcctctcgc 1980tggtcaagga gaactatgca gagctgctgg aggatgcctt cctgaagaat gtcaccgccc 2040agatctgcat aggtgcgcat ggggccaccc gggcagtccc agatctgcgt aggtgcgcgc 2100ggggccgccc gggcagtccc agatctgcgt aggtgcacgc ggggccgccc gggcagtccc 2160agatctgcgt aggtgcacgc ggggccgccc agggccgtcc cagatctgtg taggtgcgcg 2220caggcgccca gggctgtccc agaggcctcc tcccagctca ctgttacctc caggggcacg 2280gccaccctgt aggtgcgcac ggggccgcct ggggctgtcc cacaggcatc ctcctcccgg 2340ctcgctgtga cttccggggg cacggccacc cctgtgctcg gccgggaggt cctgtgacat 2400ctccttgcgg ggttataggt ggagcagtgg gctcacactg cacggctttt ctcttttaca 2460gacaagaagt gtccagatta cacctgcccc agtgagtacc tcggcggccg ggacacgtgg 2520ggaggagggc accgtggttg gggcgagggc tctgagagga cggggctctg ggaggagggc 2580ctggcggtca cgagagtagg tgcatggctc actccggtgg ctgagcacca ccgtgccgtg 2640ccctctctgg ggagcttaga cgctctctgg ccggcccact gcggctgcat caccagggcc 2700tcatgctaac ggctgcccac cccgccccgc agtcacgttc tcctccccgg ctgacatcac 2760catcctgctg gacggctccg ccagcgtggg cagccacaac tttgacacca ccaagcgctt 2820cgccaagcgc ctggccgagc gcttcctcac agcgggcagg acggaccccg cccacgacgt 2880gcgggtggcg gtggtgcagt acagcggcac gggccagcag cgcccagagc gggcgtcgct 2940gcagttcctg cagaactaca cggccctggc cagtgccgtc gatgccatgg actttatcaa 3000cgacgccacc gacgtcaacg atgccctggg ctatgtgacc cgcttctacc gcgaggcctc 3060gtccggcgct gccaagaaga ggctgctgct cttctcagat ggcaactcgc agggcgccac 3120gcccgctgcc atcgagaagg ccgtgcagga agcccagcgg gcaggcatcg agatcttcgt 3180ggtggtcgtg ggccgccagg tgaatgagcc ccacatccgc gtcctggtca ccggcaagac 3240ggccgagtac gacgtggcct acggcgagag ccacctgttc cgtgtcccca gctaccaggc 3300cctgctccgc ggtgtcttcc accagacagt ctccaggaag gtggcgctgg gctagcccac 3360cctgcacgcc ggcaccaaac cctgtcctcc cacccctccc cactcatcac taaacagagt 3420aaaatgtgat gcgaattttc ccgaccaacc tgattcgcta gatttttttt aaggaaaagc 3480ttggaaagcc aggacacaac gctgctgcct gctttgtgca gggtcctccg gggctcagcc 3540ctgagttggc atcacctgcg cagggccctc tggggctcag ccctgagcta gtgtcacctg 3600cacagggccc tctgaggctc agccctgagc tggcgtcacc tgtgcagggc cctctggggc 3660tcagccctga gctggcctca cctgggttcc ccaccccggg ctctcctgcc ctgccctcct 3720gcccgccctc cctcctgcct gcgcagctcc ttccctaggc acctctgtgc tgcatcccac 3780cagcctgagc aagacgccct ctcggggcct gtgccgcact agcctccctc tcctctgtcc 3840ccatagctgg tttttcccac caatcctcac ctaacagtta ctttacaatt aaactcaaag 3900caagctcttc tcctcagctt ggggcagcca ttggcctctg tctcgttttg ggaaaccaag 3960gtcaggaggc cgttgcagac ataaatctcg gcgactcggc cccgtctcct gagggtcctg 4020ctggtgaccg gcctggacct tggccctaca gccctggagg ccgctgctga ccagcactga 4080ccccgacctc agagagtact cgcaggggcg ctggctgcac tcaagaccct cgagattaac 4140ggtgctaacc ccgtctgctc ctccctcccg cagagactgg ggcctggact ggacatgaga 4200gccccttggt gccacagagg gctgtgtctt actagaaaca acgcaaacct ctccttcctc 4260agaatagtga tgtgttcgac gttttatcaa aggccccctt tctatgttca tgttagtttt 4320gctccttctg tgtttttttc tgaaccatat ccatgttgct gacttttcca aataaaggtt 4380ttcactcctc tccctgtggt tatcttcccc acaaagtaaa atcctgccgt gtgccccaaa 4440ggagcagtca caggaggttg gggggcgtgt gcgtgcgtgc tcactcccaa cccccatcac 4500caccagtccc aggccagaac cagggctgcc cttggctaca gctgtccatc catgcccctt 4560atctgcgtct gcgtcggtga catggagacc atgctgcacc tgtggacaga gaggagctga 4620gaaggcaaca ccctgggctt tggggtcggg agcagatcag gcctcagtgg gctggggccg 4680gccacatcca ccgaggtcaa ccacagaggc cggccacagg ttctaggctt ggtactgaaa 4740tacccctggg agctcggaag gggagttgag atactgcagg gcccatagga agaagtcttg 4800ggaggctcca cctttggggc agaggaagaa gtcttgggag gctccacctt tggggcagag 4860caagaagagg gcggagggca gaggcagcga gggctcatcc tcaaaagaaa gaagttagtg 4920gcccctgaat cccagaatcc ggggtgcacg gctgttctgg gggccgctag gggactaaga 4980ggatcggccg agggctgggc tggaggaggg cagcagggat gggcggcgag ggtgagggtg 5040gggcttcctg aaggccttca cctgcgggga ccccggcgag cccctcaggt gccacaggca 5100gggacacgcc tcgctcgatg cgtcacacca tgtggccacc agagctgcgg gaaaatgctg 5160gggaccctgc atttccgttt caggtggcga acaagcgccc ctcacagaac tgcaggtaga 5220gacgggcccg gggcagacgc agtgaggcgg tgggcggggc ccggggcaga tgcagtgagg 5280cggtgggcgg ggcccggggc agaggcagcg agcggtgggc ggggcccggg gcagacgcag 5340tgaggcggtg ggcggggccc ggggcagagg cagcgggtgg tggccggggc ccggggcaga 5400cgcagtgagg cggtgggcgg ggcccggggt agtcgcagta ggtggtgggc ggggcccggg 5460gcagacgcag tgaggtggtg ggcggggccc ggggcagacg cagtgaggcg gtgggagggg 5520cccggggcag acgcagtgag gcggtgggcg gggcccgggt cagaggcaac gggtggtggg 5580cggggcccgg ggcagacgca gtgaggcggt gggcggggcc cggggcagat gcagtgaggc 5640ggtgggcggg gcccggggca gatgcagtga ggcggtggga ggggcccggg gcagacgcag 5700tgaggcggtg ggcggggccc ggggcagacg cagtgaggcg gtgggcgggg cccggggcag 5760acgcagtgag gcagttgcca gcctctctca gctgcctcat gggattcgca ctgcagctgc 5820ggccctggcg cgacaagggc tggacttggc cagcgggacg gtccctcacg gcgctgaggc 5880ccacactctg cgtggagcct ccccgtgccc aggctaccct gcaaggtcct cggagaggct 5940tcctccagcc ccagccccca cacagctccg gcccaggccc gctcttcccc atcccagttg 6000ctttgcgctg tatacggcca ggtgaccccg agccggccct gagccctcgt cccggcttcc 6060tcccctgtaa gctgggtgaa ggactccatg gcacccacct gagagggttg tggcgaggcc 6120caggcccctc gtgcccacac ggccggcggc ccatgcctgg caggggctgg gaggaggctg 6180gggcgaccag aggggagcgg cctgtcctgg aggaggccca gggaccctgg tgagagggtc 6240tctcccaagt gctctctatg ggaccccctt cctctgcgcc cgtccttcac ggacctctcc 6300gggtcacccc tgggctgcac actgggttca ggggggcctt gaggtggggc ccctgttccc 6360aagtcccggc ggggtttctc ctgaacctca acccatcctc acctgcgggc attcccatcc 6420cccaacgcct gggtcaccag gattccaggc aggaggggcg gtgggggtta ccaaggcccg 6480ggttgccatg cagaaccccc agccaccacg cagaccccca cggggcccag ggaagctcct 6540ggtctcacac tgcacctcac acttcctgtg ggggcagact ccaaggtccc ggcctctcat 6600cttgtagaaa ctgaggcaca ggagggacac acactcccac ggccggtcac cgtggccccc 6660acacctccca ctggactgac acctggccag gctccggaca cccgtggcac agcctcagcc 6720cctgcggccc ctgctccgtg gcccccaggc cccagctccc atgtgcacgt cctgcctcag 6780gcctggaggc ccctcggccc caaataatca gacaattcaa cagcaaaact acttttttca 6840ggctggcagg actctgggca accccctgca acagccccct gccctatcac agccaccctt 6900gcctcccagg cacggagacc ccaccatcag gtcccagcct tggttcatcc ccaagcaccc 6960tgtgtgttgg gatggcgatg ctggctgagc ccctgcatcc 70002532500DNAHomo sapiens 253agggcgtttg ggaacacccc tcccggaggg gtgaggcggc ccagcctgcg gctgccagag 60gacacaggtt ctgctgcgga acctgcagac atggccataa caggccacag tgctcgggcc 120cacacagcct ggacccacat ggccctgtgt cacctcctca ggggcaggct tcagggcctc 180gaccctagag gctgcccctc ggttctgctc catggacggc gcaggcaggc ccaggcctgt 240gacgagttca cggaagctcc aggatgaccc ccgctctgcg ccctcctcca gcattccaga 300ccacaaacca ctctgggcta aaacgaggca tcgccagagc atcccacttc ctcggaaagc 360tgcggtctgg ggacgcgtct tggccctgaa gaggctccag atggctccca tcaggcctct 420ccgcctacgt gcggccgaca tggagtgaca gagcgtcggg gacacagaat tcagagctgg 480gcctggggct gctttgagat actgatggct gccagggggc acagagaccc gtcctgcaga 540cagggctgtg agggccacag ggggcctcgg ggagaggcag tgggagggag gacagtgggg 600gcctccagct gggtgagcag ctggagcgag gggggcccgg ggcttgtgat ggtgctgccg 660accctagagg tgccggcccc acgatggaga gcacgtagtg ccccccggga gtcaggaggc 720cgggcctgac ctcgggggct gcagccaggg gaggccggca ccccagataa cccccaaaga 780actgcaggcc ctgaggcgag gccagagtgg gggcgggggc aggtcccagc cgaggaggtg 840ctccgtgctg cctcagcaga acccatgatg ggctggccca aggctctgaa ggtggaaagg 900cctcacacat tctgccccgg ctgacgcctt ccttgggcca gtgctcgggg gtgtgtaaca 960aacgccaaga cgcattgtaa agaaggaagc ctgcgtttcc atcaccggct taatatcaaa 1020caaaagtgca attttgaaaa tgtagtccaa ggttttctgt ggtgcggaaa tggccaggcc 1080agacctccgt gggtggtcct tcgtgtccac gtcagcgccc tacatccaca ctgtgggcac 1140catgacctca catgcggagc ggagcagggc cggcgcccgg agagccaggc tggtcacgaa 1200cgaggcctag agggcgtcag gccccaaagc actcacaggc ttctcctctg tcctcggggc 1260cttcagacac ctgcatgcgc cgattcagcc acccgcgcgc gccgattccc ctggccatgg 1320ggtttccaaa gtgtgtgctc agaggacagt ttcctccagg atgacctgtc agtggctctc 1380tgtgccgggg acgtcgcgtg ctgggtcccg gtctgaatgc ttcctaacga tttacccagt 1440tccttttctc cactcaggag gcgtttgctg agaggcacag gctgagcccc cgtgctgatg 1500ccacgaccga gggaacgggt ctccctgtcg gcgtgaactg

acccggccag gcgtccactg 1560ccactcggac tgtctcccag gcacgtggcg cccacacggg cagaacacgc cctccacaca 1620cgcggcttcg ggcagaacac gaggcgccct ccacacacgc ggcttcgggg cttgtcatga 1680aaaaagctga atgctggggg tgcagctttc accaacagaa tcccgtttgg aagggacgcg 1740gtgagacatg atccacccta agttgtgatc ctgggtgagc cgccgtccac accctgctga 1800gggtcccttc acccacttta ttctccagaa aaccctgccc atcagggctg agtcccacgc 1860cttccctctc cgtccaggcc tggctttgac ctctggggtc gtgtggggca caggggacac 1920cctatccagg cagaggccct acggctatct ggaggaagtg gtgggagctg ggcttctgcc 1980tggaggatgc acccagaggg gtcacagtcc acacagagac acacgggtgc cttccagatg 2040gctgagccag tccagcccag aagggcctgg gggttggggg ctgcacctgg cctgtcccca 2100ccagcagggc tcagggcttc ccaaggtgtg tgggggacgg ggcagcacct ctcaaccagg 2160tcacctgaaa cccgaactga aaggcatcct aagttaagac attaactccc attgtcaagg 2220tgccatcgtc aattctgtct ccaaatcctt ctttgttatt tcatgtattc acagagtgac 2280gctccgtgtt tcgttcagcc tgcaggcctg cagaagctgc atctcgggat ggccaagagc 2340ccggccaggc cccacggctg cacccaggac gggattcatg ccccatgcct ggcttctcac 2400gaccacagag tgcctttccc gggactggat ggaggcagag tgagagaaga gcctggagca 2460agtgttttgg accacagtga tcaaacacgg agcccgtggg 2500254700DNAHomo sapiens 254aagaaaggcc agaccgggca cggtggctca cgcctgtaat cccaacactt ggggaggccg 60aggcgggcag atcacctgag gtcaggagtt cgagaccagc ctggccaaca gggtgaaacc 120ccgtctctac taaaaataca aaaaaaaatt agccgggcgt ggtggcaggc acctgtaatc 180ccagctaatc gggaggctga ggcaggagaa aatcacttga acctgggagg cggaggctgc 240agtgagctga gatcgcgcca ctgcactcca gcctgggtga gggagcgaga ctgtctcaaa 300aaaaaaaaaa aaaaaaaaaa aaaaggaaag aaaggcccgg tgagatgctt tctcttaaac 360acggccctgc acgttgagtt gctgcctcct gtggcctatt tcacgtttat gcaaagtcgg 420gcgcctgatg cggggctcac ccgccacaag caggggtcct ggtgctgctc atggaagggg 480ccctacccag cccgcggggc actggctggg acggggctgc ccaggtccgc ccaggatcca 540aacacccagc cccgcccagc ggcccttcct ggcctgcagt ggaggctgta atgggcaggg 600gtggtgggaa tcccagctca cagggcgcct gctcttagaa gggcggcatc tgggtccaga 660ggtcagaaac gtcagatgcc catcccagaa gtggcgggga 70025510000DNAHomo sapiens 255gggtgaatga gtagatgtat gggtgagtag gtgggtaggt gggtagatgg atgggtgggt 60gggcgagtgt gtggttagat gatggatggc tgaatggatg agtgggggga tggatgggtg 120agtgggtgta tgtatggatg ggttagtggg tgggtggatg aatggatggg tgcataaagg 180atggatggat gaatgagtta gtgggttggc agatggatgg atgggtgagt cagtggatag 240atggatgggt gggtggatag aggatggatg gttgggtagg tgatgggtgg atgagtggat 300agatgggtat gtgagtgagt ggggggatgg gtaggtgggt ggatggatgg ttaggtgaat 360gagtggatgg acagacggac agtgggtgga tggatgagtg aacggatgga ccgatggatg 420aatgggtggg tgggtagagg atggacggac aggtgagtgg gtgggtggat ggatagatgg 480gtaagtgagt ggatagatag atgggtgggt ggacagagga tgggtggatg aatggatggg 540ttagtgggtg gctgggtgga tggatgatgg atgggtgact gggtggatgg atggatgggt 600tagtgggtgg ctgggtggat agatggatgg gtgattgggc gaatgggcga atgggtggat 660gggtgggcgt ggagttggtg ggtacatgat aatggggtgg aatacccatg gattggaatg 720agctgttttg gctgctattt ctgggacacc cagctctgcc aggcccctac ccctctggtg 780ggccaggctc tgacggtggc cactcatggc ctttctagct ctggtgccag catagggaag 840gaggaggcac agccttgtct tactccttgc acctgttagc cccccccccc gccaagggag 900gacccgtggt tggggacagc acagggggcc ctgctgtgtg cagggactgt ccctggggcc 960actgaagccc acctgttctt gttccttctc aggcggatcc tggtccccct ggtgagccag 1020gccctcgggg gccaagagga gtcccaggac ccgaggtagg ttggtggcca gtccccatgc 1080cctcccccca acctgccagg ccaacacaca cccaagcctc gtggttctgc ccacggtgga 1140cccacgtatc agtgggcagt ggcctgggag agactcagcc acccagcctt ggccccagag 1200tctcagcctc atccttcctt ccccagggtg agcccggccc ccctggagac cccggtctca 1260cggtaggtgt cacatggggc agaaccagtg tccttctcct gccaaaacta gacaccaaga 1320gcagcagggg tgggggaagg tcagctggca cggtcagaga gcaagatcag tggaggaggt 1380cagagggcaa ggtcagagag caagcttggt tggggaaggt cacagggcaa ggttggtggg 1440gggaggaggg tggcagcgag gttggtaggg acaggacccg ccagcctccc cgcatggctg 1500cctccacacg tgggctggaa tgtcccggga cccccaggcc aggaccttgc tgtggaaact 1560cttctggggc cccgggggga ctaccctgcc tgccgtgtgc attgcaggag tgtgacgtca 1620tgacctacgt gagggagacc tgcgggtgct gcggtgaggc actgcccacg gcagggtcgg 1680ggcccatgca ccgggtggag ggcgggagtg cagcagggct gggtcatcgc tgggtcctgc 1740atgtgcacgt gaccctaggg tctgaggtct ccccggtacc ccccgatgac cctgccaccc 1800ccccagactg tgagaagcgc tgtggcgccc tggacgtggt cttcgtcatc gacagctccg 1860agagcattgg gtacaccaac ttcacactgg agaagaactt cgtcatcaac gtggtcaaca 1920ggctgggtgc catcgctaag gaccccaagt ccgagacagg tcagcggggc aggggcgggt 1980gcagcattgc ggggggccgg gcggggcgtg ggaggcgatg agatgggaga agtccagacg 2040cgtccctcca acgagggcct ctgcatggct ggggatgccc cagaccccga ggcctctggc 2100aacgacctca cgcgtgcggc ttgcagggac gcgtgtgggc gtggtgcagt acagccacga 2160gggcaccttt gaggccatcc agctggacga cgaacgtatc gactccctgt cgagcttcaa 2220ggaggctgtc aagaacctcg agtggattgc gggcggcacc tggacaccct cagccctcaa 2280gtttgcctac gaccgcctca tcaaggagag ccggcgccag aagacacgtg tgtttgcggt 2340ggtcatcacg gacgggcgcc acgaccctcg ggacgatgac ctcaacttgc gggcgctgtg 2400cgaccgcgac gtcacagtga cggccatcgg catcggggac atgttccacg agaagcacga 2460gagtgaaaac ctctactcca tcgcctgcga caagccacag caggtgcgca acatgacgct 2520gttctccgac ctggtcgctg agaagttcat cgatgacatg gaggacgtcc tctgcccggg 2580tgagcgtgtg ggcgcggggc agtcggccga ggagcagcag gccccagccg ctgtctagcg 2640tgagccccag ggacacccct cacctgaggg atgaatgtgc agcccaggat cttgggctgt 2700gggtgggaag gggtcgggcc ctctcggggc tgcagggcag aggccagctg caccctgagc 2760ctgtctaggc agatcagtga acggccgctg agggttcgct agggactgac cctggcctgg 2820cccggcctct ctcctctctt ccagaccctc agatcgtgtg cccagacctt ccctgccaaa 2880caggtaatgc agggcaccct gagccaccac cccagactag caaagcagcc ctggtgtcct 2940tcctcctcga gggccgggct gggggagggg ccgtgcaggg acccgggggg cggcggagcc 3000actgcggagg ctgctcctta gggagatggc cccaggatgg cagcacaggg gaggaggggc 3060ttggggaagg caggctccca ggaacgcagg aacagcatca cgaggccatg aggtgggtgc 3120tgctagcctg gcgctgtgct cggcatgtgg ccactggtct tgaaggccca ccatgggcct 3180tgcagtctcc ctcagctgcc gcccagctcc catgggctgg ccgtgcatgt gccactcgga 3240ggaagccctg gattcagtga gtgaaaccat cccggggtgg aagcactgac accccccagc 3300accagcaggt cttgctccaa ccctggcctg cctcggagct gcagctgcgg ctctcacatc 3360tctgggagtg ggggagccca tgtcccggat gtggcccacg tgggtgtgaa gctggagctg 3420ggggtgccgt ccaggctctg ctggacgtgg tgctgccccc atggtgcact gctgcaccgt 3480acctgggccc acaggaggtc cccgggggcg ttaggagctg agtccccctc agtgagccgt 3540cccctccagg agtgtgaggg tagggatgcc atggagacag ggtgggaggg tccgacctgg 3600aggaccacag ggaggaaacc tcagggtctg cggtacgaag tcagcgcttc ctcagcacgc 3660gggtcgcggt gtgcgttcgg gcgttccatg gggagctccc ggtgggtgag ctgggccact 3720gagcacattc acaggccctg aggctgcccc aggggaggag ccgtggactc agagccgagg 3780ttccccatac gtgctgcgac agagaaccta gggcttgcac ctgggtctgg ctgcccttca 3840gcaggcgggc agcctctggc cccacaacag tgggctgtgc ttctgccgcc aaggtgcagg 3900cgtcctcccc cagggtccac atcagcagca ggggcacctg gaccctgagg gcaggaacca 3960gaccttggct cctccaccca ccccctcgtt cctgatgggg cagggaagtc tcgggacccc 4020atgatgggcg acatggcgat ggtcactgtg ggtgctttgc tatcaggtgg ggggccttcc 4080tctccactct gggtccagtg tgagtggccg ctatggcttc ccctccactc caggttctat 4140cgtgagtggg tgggtgctgc gtctgtggat gtcacgtgac ctttcctctt tagcctatca 4200ttgtagttgg gagttagtta gcccgttgag cgtcattgaa tttccagtgt tgagccagcc 4260ctgcgtgccc gggataaacc cacctggccg tggtgtgtgg ccctgtttat gcacgtgggc 4320cctgattcgc tgatgcctgc ctgagggttt gcgcttatcg gcgacatcag cctgcacttt 4380tcttttctcg tgatctctct ggttctggcc tcagggtgac gtgggcctcg tagggtcctg 4440tggtggctcc tccccagacg gtgacatgga gtgagcccat tctccctcct gggagtgggt 4500cactcaggcc accagagcac cacagggaaa gcagccaggg aggacacgga ggcccttgaa 4560gctctggcct cttctgaggc ctccaggacc tgacagtgag tgggagcagc cctggcagaa 4620cccctcccct cctctcggcc gccctgacac ctcatccccg acactcagag ctcatcctcc 4680ttcccagctg tttccaattt caaagtgaac tcgaccttgt ggctccagga gatgcagcag 4740ggacagtgtt aaatcggctt tcaccagccc acacggccag gcatcctcct cggccctcct 4800gggcactggg tggacaccac tggctgtggc ctggccctgg ccttctccag acagccctgt 4860ccaccccaaa gcccagccac cctgggcctg cagcaggcct gtggagttct cagttgcgtg 4920gggaccagag ggtgctggag aaacaaacca gacgcagctg aaggcagtca gggcagggcg 4980caatcagcga taagagctgc ataggggcca cagcgtaacc tgagctccag tcggtggaaa 5040gaaaaggcag agacgttgca gaggccaggt ctgctcaggg gaagacagtt ctgggtgtag 5100aggactcaca tcccagagag gctgaggaag ggtttaccac cgcaagcttt ctcaggcggg 5160ctcttgaggg gtggctgggg tcttcctggc gacgggcctg cggcactgga agccctactg 5220gagtttggcc tgtctccggc acaggtttgg acggagctgt tttgtgctga aaggttttct 5280cggggtccgt ggtgtccccc aaaggtgcca ccgtgcgggt ctcctagctc cctgccagct 5340tcctgtccct gtgctcactg cccccacgcc tcctgccaag gccgagccac acacccgctc 5400cacctgcatt tcctctaccg actcgccagc ccaaatgccg ctcttcactc tggcctcgct 5460gagcggctgc ccgaggagga gctctaggcc gacgcccacc gcaggcctta cagtcttctc 5520tggacgctcc cttgcagatg caccgtggcc tggcggcgag cccccggtca ccttcctccg 5580cacggaagag gggccggacg ccaccttccc caggaccatt cccctgatcc aacagttgct 5640aaacgccacg gagctcacgc aggacccggc cgcctactcc cagctggtgg ccgtgctggt 5700ctacaccgcc gagcgggcca agttcgccac cggggtagag cggcaggact ggatggagct 5760gttcattgac acctttaagc tggtgcacag ggacatcgtg ggggaccccg agaccgcgct 5820ggccctctgc taaagcccgg gcacccgccc agccgggctg ggccctccct gccacactag 5880cttcccaggg ctgcccccga caggctggct ctcagtggag gccagagatc tggaatcggg 5940gtcagcgggg ctacagtcct tccaggggct ctggggcagc tcccagcctc ttcccatgct 6000ggtggccacc gtgtcccttg ctgcggctgc atcttccagt ctctcctccg tcttcctgtg 6060gccgctctct ttataagaac cctggtcatt gaatttaagg cccaccccaa gtccagaatg 6120acctcgcaag acccttaact cactcccgtc tgcagagtcc ttctttgctg catcaggtca 6180ccctcacagg ctccagggtt tgggtgtgga agtctttgga ggcccttact tagcggccca 6240gctgggctgc cgtgcgtctg ggatggggct gagggagggt gctgcccagg tgctggagga 6300tgttccagca ccaggttcca gcggagcctc ggaaacaggc cccagaggct ggtgagcctc 6360gctgggtgtg ggcactaatc ccgtgcatgg tgactcgtgg gcgctcacgg cccacctggt 6420ggcaggtgaa ggcttccggt tgggcagcag atagtcctgg gggaagctgg cagtcctggc 6480accatgacgt atctgggctg gtgtcatgca cagtagggcg aatggccaca gctgcctgcc 6540agcagccctg atcccggggt gtctgcaccc ttccagccca acctctgggt ctccaaaagc 6600acagtcgggg gagcatccac caggcacaac ctctgcggtc ctcagaggac tgagcagaga 6660atcccagggt ccacaatgtt ggggagcggc agggatcacc atccaaaggg agcggccccc 6720acggcgagct gaccccgacg ttctgactgc aggagccctc atccaggctg ggctcctgcc 6780gggcacggct gtgaccattt ctcagggcca ggttctcgtc cccacaccca ctgcacaggg 6840caggccaggc tggtcttccc actgtgggga tgaaggatcc tccacaggag gaggagagca 6900gagtccacag acatcccaac agcctcagcc tccctgtgcc tggccggccc ccacagcttc 6960cccgtctcct ccaggcccca cagacactga tgaatggaca gagaccccca aaaccagctg 7020ccccttgcat gtctgtctcc atatgtttgg tgacagcagt gaaaatgtta ttagttttga 7080gggggtttgg gaagcccagc ggtacctgag gagtttctgg acatttaagc cggttcctag 7140gtgtggcctt aacagggagg ctgcccttcc tttcactgaa tgagctgcgt cactcataag 7200ctcactgagg gaaccccatc tgccagctcg tgcgtgctca gacggcgtcc atgtctcaag 7260cgttctgtga aggctgcggt gcagcgtgag gtcaccctgc tgtgttcaga gctttgctca 7320ctgcctgcgg ggctggaccg ttgcacctcc agggccccca gaaaccgagt ttcgggtcag 7380ggtcctctgt gtgcattcct gggggtccat gtaccagctg tgacgacgtc caggggttgg 7440gctgagaagc agacaccctt ggggaaactg gctctgtccc tcccctcccc catcccagga 7500gctgaggtct tggtgaggcc acagggccag gtccacgcaa ggactgtccg tgtcctgtcc 7560tgtggtctct ggccccacgt gacacccaca cgtgtggtag gcagcctggc ctgggttgtg 7620gctatggcca ggcccccaag ctgtccccga tgcccagggc tggtgaccac ccaggcaggt 7680gggggcccca cttggtaaca gagtcatagg gcagaaccca cctgggctgc cacagaaggt 7740ctggctgccc ctgtgcccac tgctccccac catggccaat cagaagagtc aggggctcct 7800ggtctttccg ggagggacgt ggcccagcca gctctaggtg ttctgagcag ctctgggacc 7860cagcgattga ggggtcaggc tgggggtgtc agagccaggg tcctccttaa gtacctccca 7920cactacacag acagtggccc ttttgtgggc agcaaattct tgagccatga aaggatgctt 7980tgggcccctt ccctcccagg agggcagcct gtgcagggat ggtgctcagc aggtggacag 8040ggcctggggc ctgtgtcagg gtctcaggcc tgggagcacc agcagaggag atggcggctc 8100ccagcagtgc cgcctgaaag tgtcttgggc taaggaccca cacccagggc tgccctgcag 8160aaacgccccc gcagagccca gtggtctgtg aggttgcagg cagggtgcga atggaagggc 8220acaggtgcgg ggctggcacc tgcccggtcc tgcccacctc ccctccgccc agcccgcacc 8280tgcgtctccc cacagagctg tccgtggcac agtgcacgca gcggcccgtg gacatcgtct 8340tcctgctgga cggctccgag cggctgggtg agcagaactt ccacaaggcc cggcgcttcg 8400tggagcaggt ggcgcggcgg ctgacgctgg cccggaggga cgacgaccct ctcaacgcac 8460gcgtggcgct gctgcagttt ggtggccccg gcgagcagca ggtggccttc ccgctgagcc 8520acaacctcac ggccatccac gaggcgctgg agaccacaca atacctgaac tccttctcgc 8580acgtgggcgc aggcgtggtg cacgccatca atgccatcgt gcgcagcccg cgtggcgggg 8640cccggaggca cgcagagctg tccttcgtgt tcctcacgga cggcgtcacg ggcaacgaca 8700gtctgcacga gtcggcgcac tccatgcgca agcagaacgt ggtacccacc gtgctggcct 8760tgggcagcga cgtggacatg gacgtgctca ccacgctcag cctgggtgac cgcgccgccg 8820tgttccacga gaaggactat gacagcctgg cgcaacccgg cttcttcgac cgcttcatcc 8880gctggatctg ctagcgccgc cgcccgggcc ccgcagtcga gggtcgtgag cccaccccgt 8940ccatggtgct aagcgggccc gggtcccaca cggccagcac cgctgctcac tcggacgacg 9000ccctgggcct gcacctctcc agctcctccc acggggtccc cgtagccccg gcccccgccc 9060agccccaggt ctccccaggc cctccgcagg ctgcccggcc tccctccccc tgcagccatc 9120ccaaggctcc tgacctacct ggcccctgag ctctggagca agccctgacc caataaaggc 9180tttgaaccca ttgcgtgcct gcttgcgagc ttctgtgcgc aggagagacc tcaaaggtgt 9240cttgtggcca ggagggaaac actgcagctg tcgctcgccc accagggtca atggctcccc 9300cgggcccagc cctgacctcc taggacatca actgcaggtg ctggctgacc ccgcctgtgc 9360agaccccaca gccttgatca gcaaactctc cctccagccc cagccaggcc caaagtgctc 9420taagaagtgt caccatggct gagggtcttc tgtgggtgga cgcatgatta acactagacg 9480gggagacagc aggtgctgag cctgttgtgt tctgtgtgga gatctcagtg agtttttgct 9540gttcagaccc cagggtcctt caggctcagc tcaggagccc cacagtgaac cagaggctcc 9600acaggcaggt gctgacctga caggagtggg cttggtggcc atcacagggc accacagaca 9660cagcttgaac aactaccagt atcggccaca ggcctggagg catcagccgg gccatgcttc 9720ctctggaggg ctagaggagg actagagaag ggcctgcccc ggcctctccc cagcatccca 9780gggttcctga tctcctggat aaggatacaa gtcaccacac tggactgggg ctcagcctgc 9840tctagaatac ctcacctaag tcacagtgga ccaggctcag cctgctctaa ggtgagctta 9900cccgagacac tggaccagag atcagcctat cctgggataa gctcacccga gtcacactgg 9960accagggctc agcctattcc gggatgagct cacccgagtc 10000256800DNAHomo sapiens 256gacacttcca tgactgcagc tgaccagtcc acctgccagc ggttgaccac tcccacttcg 60ccagcgaccg aaggggaggg gaggggcctc acctgagggc aacagcagaa cccaccacct 120ggtcttgctt tactcagacc tgagggtgtg aaaggtgccc gtgacctccc gcatcaggga 180gctggccgcc accctcgact cccggggagc aggcgtcccg cgaccccctc atctaccagg 240ccatctgagc tgggcggcgc ctcacctccg ctcccggggg agccggcctc agggtaggca 300tgcgccctgg gtgggagcag gtcgtggccg ccgccctcct ggcagctctg gctgagcagc 360cgccgcagca tctgattctc cttcaggagg cgcacctgct tcttcaggtc cgcgttctcg 420ctcaggagcc ggctcatcag ctcgccgcct tcagccatgg cgggtgcgtc cctccttgtc 480cctcacggct cctgcagccc catggaggtg ggagcccaga gcccgcaggc accacagaaa 540cagcccaggc acggagttcc gtagccacca ccgccttcca cgccttgtga tgtcactgcc 600ctagtgatga ggtgcccagc accctgcctg cccccgcgat ggctcatggc cccgttgagg 660cagtgaagct ggaggcccgt ggcgtgcaca ggcagccact cccacattat gaccagggcc 720cgagaatgcc aaggacatta ggcagctacg ggatgtagcg actgtactcc aagaggggcg 780tccaagccac tccccattga 800257293DNAHomo sapiens 257aggtggaggt tgcagtgagc cctcctcccc tcctccccct tcccttccca cctcccatgc 60ccccctttct tcctcccact cccctcccga ggccccgctt attctcccgg cctgtggcgg 120ttcgtgcact cgctgagctc aggttctggt gaaggtgccc ggagccgggt cccgccttcg 180gcctgagcta gagccgcgcg ggcggccggc ttcccccaaa ccctgtggga ggggcatccc 240gaggaggcga ccccagagag tggggcgcgg acaccttccc tggggagggc cag 293258474DNAHomo sapiens 258ccttccagat gttccagaag gagaaggcgg tgctggacga gctgggccga cgcacgggga 60cccggctgca gcccctgacc cggggcctct tcggagggag ctgagggccg cgttccttct 120gaaagcggga cgcgggaggg gtggaggctg cggggagccg gggtcgcaca cgaataaata 180acgaatgaac gtacgagggg aacctcctct tatttccttc acgttgcatc gggtattttt 240cgttattgta aataaaacgg ttccgagccg tggcatcgag agggcgtctg gagttcaggg 300aacgcgtggc ccccgcccgg gagcaccgcg cagcgctcgc ctctcgccct tcaagggggt 360ccctgcccgg agcctgcgcc cccggagagg aaggggctcg aggggcttgg gtgccgcagc 420gcgtccttcc gtagaaaagg cttgcgtcag tatttcctgc ttttacctcc tgag 474259346DNAHomo sapiens 259cagtatttcc tgcttttacc tcctgagtat tggaatattc gagtaaaccc tggagtttca 60gcgccagcgc acgcctcttc atcagggcag cgcgtcgcga gcgcgctggt tccccggggc 120ctcccggcca cggacaccgc tctagccagg gccacggcga ggccgccgag cagcacctca 180gagacctgcg tgagttctaa agcctggggc tactacaatt ctgctcatct gtttgtcctg 240tgaaatgatt cagggacatg aaaatgcctt cccactgact tgcgtcctgt cttagcctgg 300acttgtcccc ttgggaacac gggccaggcc cctctgttcc tgaagt 346260490DNAHomo sapiens 260atgtctgcag ggaagaagca gggggaccct gaataaagtt tccgtttttc ctatttgtta 60aagtgataga gcattatagg accagagaac aggtgtgtct gtacactgtg caggtccccg 120gggcaggctc tgagtccgtc tgcacacggt gcgggtcccc ggggcgcgcc ctgagcccgt 180ctgcacacgg tgcgggtccc cggggcgcgc cctgagcccg tctgcacacg gtgcgggtcc 240ccggggcgcg ccctgagccc gtctgcacac ggtgcgggtc cccggggcgc gccctgagcc 300cgtctgcaca cggtgcgggt ccccggggcg cgccctgagc ccgtctgcac acggtgcggg 360tccccggggc gcgccctgag cccgtctgta cacggtgcgg gtccccgggg cgcgccctga 420gtctctacta aaaatacaaa aattagccag gcgtggtggt tcaagcctgt aatcccagct 480ccttgggagg 4902612000DNAHomo sapiens 261catacatggt tattagaaaa ggcatctcat ccaaatgtgg tggctcgtgc ttgtaatccc 60agtgcttcag gaggccaagg gaggaggatt acttgagcct aagagtttga gaccagcctg 120ggcaacacaa caagaccttg cctctacaaa aaacttaaaa actagctggg tatgatggtg 180cacacctgta gtcccagcta cttgggaggc ggaggcgggc agatcgcctg aggtcaggag 240ttcgagacca gcctggccaa catgatgaaa ccccgtctct actaaaaata caaaaattag 300ccgagtgtgg tggtgcatgc ctgtaatccc agctactcag gaggctgagg caggagaatc 360acttgaaccc gggaggcgga ggttgccatg agccgagatc acgtcactgc actccagcct 420gggtgacaga gcacaaaaga caggcatgac tttgtactta actgctcagc tttgtaatca 480ctgggggccc agatgctcac ttggattcta actttgttgg catctgggcc taaaagccgt 540gatgcaggtg agcaatgatg cagagggctc tgtgcgcctg gcgggctctg tttgcctgct 600gggctctgtg cgcctgctgg gctctgtgcg cccgggaagg tgcggccacc

ctcacgcgga 660aggcggccag cggatcccgg tgcgcgcagc tcccagcgct ggggttccag cgccccgcct 720cttcctatag caaccagcgg gacctgccgt cccccggggc accccgaggg gtctgcgccc 780gcttctttcc gaaacgggaa ggcgctgggg gctcggcagc cagagggacg ggttcaggga 840gcgtccggtg agcctaagac gcgcctttgc cggggttgcc gggtgtctgc ctctcactta 900ggtattagga accgtggcac aaatctgtag gttttcctct gggggtgggc ggaggctcca 960aaccggacgg ttttctcctg gaggactgtg ttcagacaga tactggtttc cttatccgca 1020ggtgtgcgcg gcgctcgcaa gtggtcagca taacgccggg cgaattcgga aagcccgtgc 1080gtccgtggac gacccacttg gaaggagttg ggagaagtcc ttgttcccac gcgcggacgc 1140ttccctccgt gtgtccttcg agccacaaaa agcccagacc ctaacccgct cctttctccc 1200gccgcgtcca tgcagaactc cgccgttcct gggaggggaa gcccgcgagg cgtcgggaga 1260ggcacgtcct ccgtgagcaa agagctcctc cgagcgcgcg gcggggacgc tgggccgaca 1320ggggaccgcg ggggcagggc ggagaggacc cgccctcgag tcggcccagc cctaacactc 1380aggaccgcct ccagccggag gtctgcgccc ttctgaggac cctgcctggg ggagcttatt 1440gcggttcttt tgcaaatacc cgctgcgctt ggacggagga agcgcccacg cgtcgacccc 1500ggaaacgaag gcctccctga tgggaacgca tgcgtccagg agcctttatt tactcttaat 1560tctgcccgat gcttgtacgt gtgtgaaatg cttcagatgc ttttgggagc gaggtgttac 1620ataaatcatg gaaatgcctc ctggtctcac cacacccagg gtgacagctg agatgcggct 1680tctccagggt ggagcctcct cgttttccag agctgcttgt tgaagtcttc ccagggcccc 1740tgacttgcac tggaaactgc tcaccttggc atcgggatgt ggagcaagaa atgcttttgt 1800tttcattcat cctagtgttc ataaaatgga aaacaaataa ggacatacaa aaacattaat 1860aaaataaatt aatggaacta gatttttcag aaagcacaac aaacacaaaa tccaagtatt 1920gccatgtcag caacacattc ctactttaag ttttatgaag ttaattggag tagtggagaa 1980caaaagtgga tgtggggcag 200026288DNAHomo sapiens 262gattgacagt ttctccttcc ccagactggc caatcacagg caggaagatg aaggttctgt 60gggctgcgtt gctggtcaca ttcctggc 8826330DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 263acgttggatg ttgacagttt ctccttcccc 3026430DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 264acgttggatg gaatgtgacc agcaacgcag 3026518DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 265gcaggaagat gaaggtty 1826688DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 266gattgacagt ttctccttcc ccagactggc caatcacagg caggaagatg aaggttttgt 60gggctgcgtt gctggtcaca ttcctggc 8826790DNAHomo sapiens 267gagttttgga tagtaaaata agtttcgaac tctggcacct ttcaattttg tcgcactctc 60cttgtttttg acaatgcaat catatgcttc 9026831DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 268acgtggatag taaaataagt ttcgaactct g 3126927DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 269gaagcatatg attgcattgt caaaaac 2727020DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 270atttcaattt tgtcgcacty 2027190DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 271gagttttgga tagtaaaata agtttcgaac tctggcacct ttcaattttg tcgcactttc 60cttgtttttg acaatgcaat catatgcttc 9027297DNAHomo sapiens 272gaactcctct ttgtctctgc gtgcccggcg cgcccccctc ccggtgggtg ataaacccac 60tctggcgccg gccatgcgct gggtgattaa tttgcga 9727329DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 273acgttggatg tctttgtctc tgcgtgccc 2927430DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 274acgttggatg ttaatcaccc agcgcatggc 3027522DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 275cccctcccgg tgggtgataa ay 2227697DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 276gaactcctct ttgtctctgc gtgcccggcg cgcccccctc ccggtgggtg ataaatccac 60tctggcgccg gccatgcgct gggtgattaa tttgcga 9727786DNAHomo sapiens 277ccattggccg tccgccgtgg cagtgcgggc gggagcgcag ggagagaacc acagctggaa 60tccgattccc accccaaaac ccagga 8627829DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 278acgttggatg ccattggccg tccgccgtg 2927931DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 279acgttggatg tcctgggttt tggggtggga a 3128019DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 280ttccagctgt ggttctctc 1928186DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 281ccattggccg tccgccgtgg cagtgcgggc gggagcgcag agagagaacc acagctggaa 60tccgattccc accccaaaac ccagga 8628231DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 282acgttggatg acatggtcgg ccccacggaa t 3128330DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 283acgttggatg acccattggc cgtccgccgt 3028431DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 284acgttggatg gaactcctct ttgtctctgc g 3128531DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 285acgttggatg cgcagcaacg ggaccgctac a 3128629DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 286acgttgcgta gcaacctgtt acatattaa 2928731DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 287acgttggatg catagaggcc catgatggtg g 3128833DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 288acgttggatg gtgtggtcag ctcttccctt cat 3328932DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 289acgttggatg ctccttccta gtgtgagaac cg 3229031DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 290acgttggatg ttttggggtg ggaatcggat t 3129129DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 291acgttggatg tggcatggcc ggcgccaga 2929232DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 292acgttggcat ctaggtaggt ctttgtagcc aa 3229332DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 293acgttggatc tgagcaaagg caatcaacac cc 3229432DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 294acgttggatg accttctgcc cctctactcc aa 3229533DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 295acgttggccc acatgtaatg tgttgaaaaa gca 3329618DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 296caggttccgg ggcttggg 1829719DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 297cgcagggaga gaaccacag 1929821DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 298cccctcccgg tgggtgataa a 2129921DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 299aaagctgtag gacaatcggg t 2130022DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 300catttttcta catcctttgt tt 2230123DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 301agaagatcac caggcagaag agg 2330225DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 302acttggagaa caaaggacac cgtta 2530381DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 303ggtcggcccc acggaatccc ggctctgtgt gcgcccaggt tccggggctt gggtgttgcc 60ggttctcaca ctaggaagga g 8130479DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 304ccattggccg tccgccgtgg cagtgcgggc gggagcgcag agagagaacc acagctggaa 60tccgattccc accccaaaa 7930577DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 305gaactcctct ttgtctctgc gtgcccggcg cgcccccctc ccggtgggtg ataaatccac 60tctggcgccg gccatgc 7730681DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 306gcagcaacgg gaccgctaca gccactggac aaagccgtag gacaatcggg taacattggc 60tacaaagacc tacctagatg c 8130795DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 307gcgtagcaac ctgttacata ttaaagtttt attatactac atttttctac atcctttgtt 60tcagagtgtt gattgccttt gctcagtatc ttcag 9530886DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 308ccttctgccc ctctactcca agcgctacac cctcttctgc ctggtgatct ttgccggcgt 60cctggccacc atcatgggcc tctatg 8630983DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 309gtgtggtcag ctcttccctt catcacatac ttggagaaca aaggacaccg ttatccatgc 60tttttcaaca cattacatgt ggg 8331030DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 310acgttggatg ttctgcccct ctactccaag 3031130DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 311acgttggatg tcagctcttc ccttcatcac 3031230DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 312acgttggatg ttgacagttt ctccttcccc 3031328DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 313acgttggatg cggtcggccc cacggaat 2831431DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 314acgtggatag taaaataagt ttcgaactct g 3131530DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 315acgttggatg cacagctcac cgcagcaacg 3031629DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 316acgttggatg tctttgtctc tgcgtgccc 2931729DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 317acgttggatg gactgagccc cagaactcg 2931829DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 318acgttggatg aagccaagtt tccctccgc 2931930DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 319acgttagcgt agcaacctgt tacatattaa 3032030DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 320acgttggatg catagaggcc catgatggtg 3032131DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 321acgttggatg cctacctccc acatgtaatg t 3132230DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 322acgttggatg gaatgtgacc agcaacgcag 3032332DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 323acgttggatg ctccttccta gtgtgagaac cg 3232427DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 324gaagcatatg attgcattgt caaaaac 2732532DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 325acgttggatg ctaggtaggt ctttgtagcc aa 3232630DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 326acgttggatg ttaatcaccc agcgcatggc 3032730DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 327acgttggatg gtgggtttgt gctttccacg 3032830DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 328acgttggatg cttttgcttt cccagccagg 3032930DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 329acgttggatg ctgagcaaag gcaatcaaca 3033017DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 330ttctgcctgg tgatctt 1733117DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 331aacaaaggac accgtta 1733217DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 332gcaggaagat gaaggtt 1733318DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 333aaggttccgg ggcttggg 1833419DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 334atttcaattt tgtcgcact 1933519DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 335agctgtagga caatcgggt 1933620DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 336ccctcccggt gggtgataaa 2033720DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 337agggccgggg tctgcgcgtg 2033821DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 338gaggcactgc ccggacaaac c 2133922DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 339catttttcta catcctttgt tt 2234086DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 340ccttctgccc ctctactcca agcgctacac cctcttctgc ctggtgatct ttgccggcgt 60cctggccacc atcatgggcc tctatg 8634190DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 341gtgtggtcag ctcttccctt catcacatac ttggagaaca aaggacaccg ttatccatgc 60tttttcaaca cattacatgt gggaggtagg 9034288DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 342gattgacagt ttctccttcc ccagactggc caatcacagg caggaagatg aaggttttgt 60gggctgcgtt gctggtcaca ttcctggc 8834398DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 343aaaaccagag attcgcggtc ggccccacgg aatcccggct ctgtgtgcgc ccaggttccg 60gggcttgggt gttgccggtt ctcacactag gaaggagc 9834490DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 344gagttttgga tagtaaaata agtttcgaac tctggcacct ttcaattttg tcgcactttc 60cttgtttttg acaatgcaat catatgcttc 9034595DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 345gcagccagct caccgcagca acgggaccgc tacagccact ggacaaagct gtaggacaat 60cgggtgacat tggctacaaa gacctaccta gatgc 9534697DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 346gaactcctct ttgtctctgc gtgcccggcg cgcccccctc ccggtgggtg ataaatccac 60tctggcgccg gccatgcgct gggtgattaa tttgcga 9734786DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 347gtgggtttgt gctttccacg cgtgcacaca cacgcgcaga ccccggccct tgccccgcct 60acctccccga gttctggggc tcagtc 8634889DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 348gcgccagctt ttgctttccc agccagggcg cggtgaggtt tgtccgggca gtgcctcgag 60caactgggaa ggccaaggcg gagggaaac 8934996DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 349gcgtagcaac ctgttacata ttaaagtttt attatactac atttttctac atcctttgtt 60ttagggtgtt gattgccttt gctcagtatc ttcagc 9635027DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 350tagcugcgta gcaacctgtt acatatt 2735125DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer

351tagcucagtt tctccttccc cagac 2535225DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 352tagcuggtca gctcttccct tcatc 2535324DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 353tagcuagctg gtgcggaggg tggg 2435426DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 354tagcuggcct ttgcaacaag gatcac 2635525DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 355tagcutctgg tgacccccgc gcttc 2535624DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 356tagcuccctc cacatcccgc catc 2435724DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 357tagcuacgga atcccggctc tgtg 2435824DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 358tagcuggccc tgctggcggt cata 2435924DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 359tagcuagcaa cgggaccgct acag 2436026DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 360tagcutaagt ttcgaactct ggcacc 2636125DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 361tagcuctcct ctttgtctct gcgtg 2536225DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 362tagcutgatg cccgatgccg ccctt 2536327DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 363gatcuatact gagcaaaggc aatcaac 2736425DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 364gatcugaatg tgaccagcaa cgcag 2536526DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 365gatcucctcc cacatgtaat gtgttg 2636626DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 366gatcuatggg ggagatggcc ggtgga 2636726DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 367gatcucgcaa tactagaaac cagggc 2636824DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 368gatcucatct ctgggtgcgc cttg 2436923DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 369gatcucagcc gcctgctcca tcg 2337025DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 370gatcuccttc ctagtgtgag aaccg 2537125DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 371gatcutgctc agcacgaggg cccca 2537226DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 372gatcutctag gtaggtcttt gtagcc 2637328DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 373gatcugaagc atatgattgc attgtcaa 2837425DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 374gatcuttaat cacccagcgc atggc 2537526DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 375gatcugtctg tgctgggtgt ttttgc 2637658DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 376aatgatacgg cgaccaccga gatctacact ctttccctac acgacgctct tccgatct 5837719DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 377gctcttccga tctatagct 1937865DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 378gatcggaaga gcacacgtct gaactccagt cacagtcaac aatctcgtat gccgtcttct 60gcttg 6537958DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 379aatgatacgg cgaccaccga gatctacact ctttccctac acgacgctct tccgatct 5838033DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 380acactctttc cctacacgac gctcttccga tct 3338163DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 381gatcggaaga gcacacgtct gaactccagt cacagtcaaa tctcgtatgc cgtcttctgc 60ttg 6338233DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 382gatcggaaga gcacacgtct gaactccagt cac 3338329DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 383tctttcccta cacgacgctc ttccgatct 2938434DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 384gtgactggag ttcagacgtg tgctcttccg atct 3438549DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 385aatgatacgg cgaccaccga gatctacact ctttccctac acgacgctc 4938650DNAArtificial SequenceDescription of Artificial Sequence Synthetic primer 386caagcagaag acggcatacg agatttgact gtgactggag ttcagacgtg 5038710DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 387cgcaaccact 1038810DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 388cgcgaccact 10

Claims

1. A method for determining fetal fraction in a sample comprising: (a) enriching a sample nucleic acid for a plurality of polymorphic nucleic acid targets, which sample nucleic acid comprises fetal nucleic acid and maternal nucleic acid; (b) obtaining nucleotide sequences for some or all of the nucleic acid targets by a sequencing process; (c) analyzing the nucleotide sequences of (b); and (d) determining fetal fraction based on the analysis of (c), wherein the polymorphic nucleic acid targets and number thereof result in at least five polymorphic nucleic acid targets being informative for determining the fetal fraction for at least 90% of samples.

2. The method of claim 1, wherein the enriching comprises amplifying the plurality of polymorphic nucleic acid targets.

3. The method of claim 1, wherein the maternal genotype and the paternal genotype at each of the polymorphic nucleic acid targets are not known prior to (a).

4. The method of claim 1, wherein polymorphic nucleic acid targets having a minor allele population frequency of about 40% or more are selected.

5. The method of claim 1, comprising determining an allele frequency in the sample for each of the polymorphic nucleic acid targets.

6. The method of claim 5, wherein determining which polymorphic nucleic acid targets are informative comprises identifying informative genotypes by comparing each allele frequency to one or more fixed cutoff frequencies.

7. The method of claim 6, wherein the fixed cutoff for identifying informative genotypes from non-informative homozygotes is about a 1% or greater shift in allele frequency.

8. The method of claim 6, wherein the fixed cutoff for identifying informative genotypes from non-informative heterozygotes is about a 25% or greater shift in allele frequency.

9. The method of claim 5, wherein determining which polymorphic nucleic acid targets are informative comprises identifying informative genotypes by comparing each allele frequency to one or more target-specific cutoff frequencies.

10. The method of claim 9, wherein each target-specific cutoff frequency is determined based on the allele frequency variance for the corresponding polymorphic nucleic acid target.

11. The method of claim 5 further comprising determining an allele frequency mean.

12. The method of claim 11, wherein fetal fraction is determined based, in part, on the allele frequency mean.

13. The method of claim 1, wherein the fetal genotype at one or more informative polymorphic nucleic acid targets is heterozygous or the fetal genotype at one or more informative polymorphic nucleic acid targets is homozygous.

14. The method of claim 1, wherein fetal fraction is determined with a coefficient of variance (CV) of 0.20 or less.

15. The method of claim 1, wherein the polymorphic nucleic acid targets each comprise at least one single nucleotide polymorphism (SNP).

16. The method of claim 15, wherein the SNPs are selected from: rs10413687, rs10949838, rs1115649, rs11207002, rs11632601, rs11971741, rs12660563, rs13155942, rs1444647, rs1572801, rs17773922, rs1797700, rs1921681, rs1958312, rs196008, rs2001778, rs2323659, rs2427099, rs243992, rs251344, rs254264, rs2827530, rs290387, rs321949, rs348971, rs390316, rs3944117, rs425002, rs432586, rs444016, rs4453265, rs447247, rs4745577, rs484312, rs499946, rs500090, rs500399, rs505349, rs505662, rs516084, rs517316, rs517914, rs522810, rs531423, rs537330, rs539344, rs551372, rs567681, rs585487, rs600933, rs619208, rs622994, rs639298, rs642449, rs6700732, rs677866, rs683922, rs686851, rs6941942, rs7045684, rs7176924, rs7525374, rs870429, rs949312, rs9563831, rs970022, rs985462, rs1005241, rs1006101, rs10745725, rs10776856, rs10790342, rs11076499, rs11103233, rs11133637, rs11974817, rs12102203, rs12261, rs12460763, rs12543040, rs12695642, rs13137088, rs13139573, rs1327501, rs13438255, rs1360258, rs1421062, rs1432515, rs1452396, rs1518040, rs16853186, rs1712497, rs1792205, rs1863452, rs1991899, rs2022958, rs2099875, rs2108825, rs2132237, rs2195979, rs2248173, rs2250246, rs2268697, rs2270893, rs244887, rs2736966, rs2851428, rs2906237, rs2929724, rs3742257, rs3764584, rs3814332, rs4131376, rs4363444, rs4461567, rs4467511, rs4559013, rs4714802, rs4775899, rs4817609, rs488446, rs4950877, rs530913, rs6020434, rs6442703, rs6487229, rs6537064, rs654065, rs6576533, rs6661105, rs669161, rs6703320, rs675828, rs6814242, rs6989344, rs7120590, rs7131676, rs7214164, rs747583, rs768255, rs768708, rs7828904, rs7899772, rs7900911, rs7925270, rs7975781, rs8111589, rs849084, rs873870, rs9386151, rs9504197, rs9690525, and rs9909561.

17. The method of claim 16, wherein the SNPs are selected from: rs10413687, rs10949838, rs1115649, rs11207002, rs11632601, rs11971741, rs12660563, rs13155942, rs1444647, rs1572801, rs17773922, rs1797700, rs1921681, rs1958312, rs196008, rs2001778, rs2323659, rs2427099, rs243992, rs251344, rs254264, rs2827530, rs290387, rs321949, rs348971, rs390316, rs3944117, rs425002, rs432586, rs444016, rs4453265, rs447247, rs4745577, rs484312, rs499946, rs500090, rs500399, rs505349, rs505662, rs516084, rs517316, rs517914, rs522810, rs531423, rs537330, rs539344, rs551372, rs567681, rs585487, rs600933, rs619208, rs622994, rs639298, rs642449, rs6700732, rs677866, rs683922, rs686851, rs6941942, rs7045684, rs7176924, rs7525374, rs870429, rs949312, rs9563831, rs970022, and rs985462.

18. The method of claim 16, wherein the SNPs are selected from: rs1005241, rs1006101, rs10745725, rs10776856, rs10790342, rs11076499, rs11103233, rs11133637, rs11974817, rs12102203, rs12261, rs12460763, rs12543040, rs12695642, rs13137088, rs13139573, rs1327501, rs13438255, rs1360258, rs1421062, rs1432515, rs1452396, rs1518040, rs16853186, rs1712497, rs1792205, rs1863452, rs1991899, rs2022958, rs2099875, rs2108825, rs2132237, rs2195979, rs2248173, rs2250246, rs2268697, rs2270893, rs244887, rs2736966, rs2851428, rs2906237, rs2929724, rs3742257, rs3764584, rs3814332, rs4131376, rs4363444, rs4461567, rs4467511, rs4559013, rs4714802, rs4775899, rs4817609, rs488446, rs4950877, rs530913, rs6020434, rs6442703, rs6487229, rs6537064, rs654065, rs6576533, rs6661105, rs669161, rs6703320, rs675828, rs6814242, rs6989344, rs7120590, rs7131676, rs7214164, rs747583, rs768255, rs768708, rs7828904, rs7899772, rs7900911, rs7925270, rs7975781, rs8111589, rs849084, rs873870, rs9386151, rs9504197, rs9690525, and rs9909561.

19. The method of claim 1, wherein the polymorphic nucleic acid targets and number thereof result in at least five polymorphic nucleic acid targets being informative for determining the fetal fraction for at least 95% of samples.

20. The method of claim 1, wherein the polymorphic nucleic acid targets and number thereof result in at least ten polymorphic nucleic acid targets being informative for determining the fetal fraction for at least 90% of samples.

21. The method of claim 1, wherein 10 or more polymorphic nucleic acid targets are enriched.

22. The method of claim 21, wherein about 40 to about 100 polymorphic nucleic acid targets are enriched.

23. The method of claim 1, wherein the sequencing process comprises a sequencing by synthesis method.

24. The method of claim 23, wherein the sequencing by synthesis method comprises about 36 cycles or about 27 cycles.

25. The method of claim 1, wherein the sample nucleic acid is cell-free DNA.

26. The method of claim 1, wherein the sample nucleic acid is obtained from a pregnant human female subject.

27. The method of claim 1, wherein the sample nucleic acid is from plasma or serum.