Cytochrome P450 Genetic Variations

Abstract

A primer set used to screen a polynucleotide sample to detect and identify variants in the Cytochrome P450 isoenzyme 2D6 (CYP2D6) gene. A method of screening a polynucleotide sample to detect and identify the presence of one or more than one variant in the CYP2D6 gene in the sample. A method of predicting the potential for altered metabolism of a substance, including one or more than one pharmaceutical drug, by a first individual compared to a second control individual, where the substance is metabolized by the CYP2D6 isoenzyme, and where the second control individual is homozygous for the wild type allele of the CYP2D6*1, SEQ ID NO:1. A method of screening a population to detect and identify the presence of one or more than one variant in the CYP2D6 gene. A purified or isolated variant of SEQ ID NO:1. A purified or isolated variant of SEQ ID NO:3.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application is a continuation of U.S. patent application Ser. No. 10/712,363, filed Nov. 12, 2003, now U.S. Pat. No. 7,195,877, issued Mar. 27, 2007, which is both a continuation of International Patent Application No. PCT/US03/21468 filed Jul. 9, 2003, which claims the benefit of U.S. Provisional Patent Application No. 60/397,010 filed Jul. 18, 2002, and a continuation-in-part of U.S. patent application Ser. No. 10/360,790 filed Jul. 18, 2002, which claims the benefit of U.S. Provisional Patent Application No. 60/306,675 filed Jul. 20, 2001, the contents of which are incorporated herein by reference in their entirety.

BACKGROUND

[0002] Adverse reactions to pharmaceutical drugs cause significant morbidity and mortality. Further, when the rate or severity of the adverse reactions causes the withdrawal of a pharmaceutical drug from the market, adverse reactions also cause considerable financial losses to pharmaceutical companies.

[0003] A large portion of endobiotics and xenobiotics, including many classes of pharmaceutical drugs, is metabolized by cytochrome p450 super family of enzymes present in human liver tissue. Cytochrome P450 2D6 (CYP2D6) is an isoenzyme of the cytochrome p450 super family and is responsible for the metabolism of many pharmaceutical drugs in commonly prescribed drug classes such as antiarrhythmics, .beta.-receptor blockers, neuroleptics, selective serotonin reuptake inhibitors and antidepressants. Examples of pharmaceutical drugs metabolized by CYP2D6 include amitriptyline, codeine, desipramine, haloperidol, metopropol, tamoxifen and timolol.

[0004] There is considerable genetic polymorphism in CYP2D6. Polymorphic variants of CYP2D6 can result in altered metabolism of pharmaceutical drugs due to impaired CYP2D6 function. The altered metabolism can be increased metabolism, decreased metabolism or a shift in the metabolic ratio of enantiomeric forms of a pharmaceutical drug in a mixture of enantiomers. The rate of altered pharmaceutical drugs metabolism due to polymorphic variants of CYP2D6 has been estimated at 7% of Caucasian Americans, 2% of African American and 1% of Asian Americans. However, the true rate of altered pharmaceutical drugs metabolism due to polymorphic variants of CYP2D6 and the distribution of CYP2D6 variants remains poorly understood, especially in individuals of non-northern European descent. Further, there remain large numbers of CYP2D6 variants that are, as yet, uncharacterized.

[0005] Due to time and cost limitations, phenotypic drug response variation due to the presence of CYP2D6 variants is not adequately characterized during clinical trials of pharmaceutical drugs, but is only fully characterized once the pharmaceutical drug is used by the general population. There is currently no adequate method of screening a population prior to administration of pharmaceutical drugs in the general population to identify CYP2D6 variants in the population predictive of phenotypes likely to result in adverse reactions.

[0006] Therefore, there is a need for a method of screening a population to identify CYP2D6 variants in the population. Further, there is a need for a method of predicting adverse reactions to a pharmaceutical drug that is metabolized by the Cytochrome p450 isoenzyme CYP2D6. Additionally, there is a need to identify all variants of the Cytochrome p450 isoenzyme CYP2D6 that cause altered pharmaceutical drugs metabolism.

SUMMARY

[0007] In one embodiment of the present invention, there is provided a primer set that can be used to screen a polynucleotide sample to detect and identify variants in the Cytochrome P450 isoenzyme 2D6 (CYP2D6) gene. The primer set comprises one or more than one primer group of the three primer groups of sequences selected from the primer groups consisting of Primer Group I (16 or more than 16 consecutive nucleotides of SEQ ID NO:9, 16 or more than 16 consecutive nucleotides of SEQ ID NO:10, 16 or more than 16 consecutive nucleotides of SEQ ID NO:11, 16 or more than 16 consecutive nucleotides of SEQ ID NO:12, 16 or more than 16 consecutive nucleotides of SEQ ID NO:13 and 16 or more than 16 consecutive nucleotides of SEQ ID NO:14); Primer Group 11 (16 or more than 16 consecutive nucleotides of SEQ ID NO:15, 16 or more than 16 consecutive nucleotides of SEQ ID NO:16; 16 or more than 16 consecutive nucleotides of SEQ ID NO:17, 16 or more than 16 consecutive nucleotides of SEQ ID NO:18, 16 or more than 16 consecutive nucleotides of SEQ ID NO:19, 16 or more than 16 consecutive nucleotides of SEQ ID NO:20, 16 or more than 16 consecutive nucleotides of SEQ ID NO:21, 16 or more than 16 consecutive nucleotides of SEQ ID NO:22, 16 or more than 16 consecutive nucleotides of SEQ ID NO:23 and 16 or more than 16 consecutive nucleotides of SEQ ID NO:24); and Primer Group III (16 or more than 16 consecutive nucleotides of SEQ ID NO:25; 16 or more than 16 consecutive nucleotides of SEQ ID NO:26; 16 or more than 16 consecutive nucleotides of SEQ ID NO:27, 16 or more than 16 consecutive nucleotides of SEQ ID NO:28, 16 or more than 16 consecutive nucleotides of SEQ ID NO:29, 16 or more than 16 consecutive nucleotides of SEQ ID NO:30, 16 or more than 16 consecutive nucleotides of SEQ ID NO:31, and 16 or more than 16 consecutive nucleotides of SEQ ID NO:32).

[0008] In one embodiment, the primer set comprises two primer groups selected from the group consisting of Primer Group I, Primer Group II and Primer Group III. In another embodiment, the primer set comprises all three primer groups, Primer Group I, Primer Group II and Primer Group III. In one embodiment, each sequence consists of at least 17 consecutive nucleotides. In another embodiment, each sequence consists of at least 18 consecutive nucleotides. In another embodiment, each sequence consists of at least 19 consecutive nucleotides. In another embodiment, each sequence consists of at least 20 consecutive nucleotides. In another embodiment, each sequence consists of at least 21 consecutive nucleotides. In another embodiment, one or more than one sequence additionally comprises a tail sequence. In another embodiment, one or more than one sequence has one or more than one dUTP substituted for TTP.

[0009] In another embodiment of the present invention, there is provided a method of screening a polynucleotide sample to detect and identify the presence of one or more than one variant in the CYP2D6 gene in the sample. The method comprises a) providing a polynucleotide sample potentially comprising a sequence comprising at least about 50 consecutive nucleotides from one or more than one of the sequences of the wild type CYP2D6*1, SEQ ID NO:1, one or more than one variant of wild type CYP2D6*1, SEQ ID NO:1 or both wild type CYP2D6*1, SEQ ID NO:1 and one or more than one variant of wild type CYP2D6*1, SEQ ID NO:1; b) providing a primer set according to the present invention; c) amplifying the polynucleotide sample using the provided primer set to produce a set of amplicons; and d) analyzing the amplicons to identify the presence of CYP2D6*1 gene, SEQ ID NO:1, the presence of one or more than one variant of the CYP2D6*1 gene, SEQ ID NO:1 or to identify one or more than one specific variant of the CYP2D6*1 gene, SEQ ID NO:1 in the sample.

[0010] In another embodiment of the present invention, there is provided a method of predicting the potential for altered metabolism of a substance, including one or more than one pharmaceutical drug, by a first individual compared to a second control individual, where the substance is metabolized by the CYP2D6 isoenzyme, and where the second control individual is homozygous for the wild type allele of the CYP2D6*1, SEQ ID NO:1. The method comprises a) providing a polynucleotide sample from the first individual; b) providing a primer set according to the present invention; c) amplifying the polynucleotide sample using the provided primer set to produce a set of amplicons; d) analyzing the amplicons to detect and identify one or more than one variant in the CYP2D6 gene from the first individual; and e) analyzing the one or more than one variant in the CYP2D6 gene detected and identified to determine if it constitutes a silent variant or non-silent variant; where the absence of a non-silent variant means that the first individual will not have the potential for altered metabolism of the substance, and where the presence of a non-silent variant means that the first individual will have the potential for altered metabolism of the substance.

[0011] In another embodiment of the present invention, there is provided a method of screening a population to detect and identify the presence of one or more than one variant in the CYP2D6 gene. The method comprises a) providing a plurality of polynucleotide samples from the population; b) providing a primer set according to the present invention; c) amplifying the polynucleotide sample using the provided primer set to produce a set of amplicons; and d) analyzing the amplicons to detect and identify of one or more than one variant of the CYP2D6*1 gene, SEQ ID NO:1 in the sample. In one embodiment, the plurality of polynucleotide samples is a plurality of random samples of individuals in the population. In another embodiment, the plurality of polynucleotide samples is one or more than one sample from each individual in the population. In another embodiment, the method of screening a population further comprises determining the distribution of the variants in the CYP2D6 gene in the population. In another embodiment, the method of screening a population further comprises recording the presence and identity, or recording the distribution of the variants in the CYP2D6 gene in the population sample, in writing or another suitable media.

[0012] In a preferred embodiment, amplifying the polynucleotide sample in a method of the present invention comprises using modified nucleotides. In a particularly preferred embodiment, the modified nucleotides are selected from the group consisting of deaza dATP, deaza dGTP, and nucleotides labeled with one or more than one label selected from the group consisting of biotin, digoxigenin, and a fluorescent dye.

[0013] In a preferred embodiment, amplifying the polynucleotide sample in a method of the present invention comprises using dUTP in place of TTP. In another preferred embodiment, the amplification step in a method of the present invention is performed in two stages. In another preferred embodiment, analyzing the amplicons in a method of the present invention is performed using a method selected from the group consisting of dideoxy sequencing, pyrosequencing and SSCP.

[0014] In another embodiment of the present invention, there is provided a kit for screening a polynucleotide sample to detect and identify the presence of one or more than one variant in the CYP2D6 gene in the sample, comprising suitable amounts of a primer set according to the present invention. In one embodiment, the kit further comprises one or more than one additional reagent or one or more than one vessel to amplify the polynucleotide sample, to analyze the amplicons, or both to amplify the polynucleotide sample and to analyze the amplicons. In a preferred embodiment, the additional reagent is selected from the group consisting of one or more than one DNA dependent polymerase, one or more than one buffer, one or more than one detergents and one or more than one stabilizing agent.

[0015] In another embodiment of the present invention, there is provided a purified or isolated variant of SEQ ID NO:1 having one or more than one of the alterations selected from the group consisting of C>T at position 1522, G insert at position 1576, G>C at position 1851, A>C at position 1852, A>G at position 1864, T>A at position 3230, C>T at position 3232, G>A at position 3335, C>T at position 3542, T>C at position 3617, A>G at position 3716, C>T at position 3922, G>T at position 4221, G>A at position 4280, G>A at position 4282, T>A at position 4379, T>C at position 4555, G>A at position 4607, C>T at position 4820, A>G at position 4854, T>C at position 4873, insert GT at position 4878, C>A at position 5003, T>C at position 5027, C>A at position 5054, C>T at position 5409, G>A at position 5496, C>T at position 5774, C>T at position 5791, C>T at position 5948, C>T at position 6020 and an exon 9 gene conversion.

[0016] In another embodiment of the present invention, there is provided a method of predicting the potential for altered metabolism of a substance, including one or more than one pharmaceutical drug, by a first individual compared to a second control individual, where the substance is metabolized by the CYP2D6 isoenzyme, and where the second control individual is homozygous for the wild type allele of the CYP2D6*1, SEQ ID NO:1. The method comprises a) detecting and identifying one or more than one variant in the CYP2D6 gene from the first individual; and b) analyzing the one or more than one variant in the CYP2D6 gene detected and identified to determine if it constitutes one or more than one variant according to the present invention; where the presence of the one or more than one variant means that the first individual will have the potential for altered metabolism of the substance.

[0017] In another embodiment of the present invention, there is provided a purified or isolated variant of SEQ ID NO:3 having one or more than one of the alterations selected from the group consisting of F>I at position 120, F>F at position 120, E>K at position 155, R>R at position 194, F>F at position 219, L>L at position 276, H>H at position 324, R>STOP at position 344, Y>C at position 355, H>H at position 361, V>FRAMESHIFT at position 363, E>K at position 418, H>Y at position 478, F>F at position 483.

[0018] In another embodiment of the present invention, there is provided a method of predicting the potential for altered metabolism of a substance, including one or more than one pharmaceutical drug, by a first individual compared to a second control individual, where the substance is metabolized by the CYP2D6 isoenzyme, and where the second control individual is homozygous for the wild type allele of the CYP2D6*1, SEQ ID NO:1. The method comprises a) detecting and identifying one or more than one variant in the CYP2D6 isoenzyme from the first individual; and b) analyzing the one or more than one variant in the CYP2D6 isoenzyme detected and identified to determine if it constitutes one or more than one variant according to the present invention; where the presence of the one or more than one variant means that the first individual will have the potential for altered metabolism of the substance.

DESCRIPTION

[0019] According to one embodiment of the present invention, there is provided a primer set that can be used to screen a polynucleotide sample to detect and identify variants in the Cytochrome P450 isoenzyme 2D6 (CYP2D6) gene. According to another embodiment of the present invention, there is provided a method of screening a polynucleotide sample to detect and identify the presence of one or more than one variant in the CYP2D6 gene in the sample. According to another embodiment of the present invention, there is provided a method of screening a population to detect and identify the presence of one or more than one variant in the CYP2D6 gene. According to another embodiment of the present invention, there is provided a method of predicting the potential for altered metabolism of a substance, including one or more than one pharmaceutical drug, by a first individual compared to a second individual, where the substance is metabolized by the CYP2D6 isoenzyme. According to another embodiment of the present invention, there is provided a kit for performing a method of the present invention. According to another embodiment of the present invention, there are provided novel purified and isolated variants of the Cytochrome p450 CYP2D6 gene and the CYP2D6 isoenzyme, including both silent variants and non-silent variants.

[0020] As used in this disclosure, the term "non-silent variant" refers to a CYP2D6 gene variant that causes a change in the production, regulation, length or sequence of the wild type CYP2D6 isoenzyme. As used in this disclosure, the term "silent variant" refers to a CYP2D6 gene variant that causes a change in the production, regulation, length or sequence of the wild type CYP2D6 isoenzyme. Both a non-silent variant and a silent variant can be the result of one or more than one point mutation that is a single nucleotide polymorphism, a deletion of one or more than one nucleotide, an insertion of one or more than one nucleotide, a gene conversion, or a combination of the preceding.

[0021] As used in this disclosure, the term "comprise" and variations of the term, such as "comprising" and "comprises," are not intended to exclude other additives, components, integers or steps.

[0022] The wild type allele of the CYP2D6 gene is designated as CYP2D6*1, GenBank accession number M33388, SEQ ID NO:1, and contains 9432 base pairs. The CYP2D6 gene is located on chromosome 22q13.1. The CYP2D6*1 gene, SEQ ID NO:1, is transcribed into an mRNA, GenBank accession number NM-000106, SEQ ID NO:2, that contains 9 exons, residues 1532-1799 of SEQ ID NO:1 (exon 1); residues 2503-2674 of SEQ ID NO:1 (exon 2); residues 3225-3377 of SEQ ID NO:1 (exon 3); residues 3466-3626 of SEQ ID NO:1 (exon 4); residues 4060-4236 of SEQ ID NO:1 (exon 5); residues 4427-4568 of SEQ ID NO:1 (exon 6); residues 4776-4963 of SEQ ID NO:1 (exon 7); residues 5418-5559 of SEQ ID NO:1 (exon 8); and residues 5658-5909 of SEQ ID NO:1 (exon 9). The CYP2D6 mRNA, SEQ ID NO:2, is translated into the wild type CYP2D6 isoenzyme, GenBank accession number AAA53500, SEQ ID NO:3, containing 497 amino acids.

[0023] There are a number of pseudogenes in the human genome on chromosome 22q close to the location of functional CYP2D6*1 gene, SEQ ID NO:1. These pseudogenes include GenBank accession number M33387, SEQ ID NO:4; GenBank accession number X58467, SEQ ID NO:5; GenBank accession number X58468, SEQ ID NO:6; GenBank accession number NG-000853, SEQ ID NO:7; and GenBank accession number NG-000854; SEQ ID NO:8. These pseudogenes can cause false positive results in tests for variants of the CYP2D6 gene.

[0024] In one embodiment, the present invention is a primer set that can be used to interrogate a polynucleotide sample to detect and identify variants in the Cytochrome P450 isoenzyme 2D6 (CYP2D6) gene, and thereby, to detect and identify variants in the Cytochrome P450 2D6 (CYP2D6) isoenzyme. The variants include differences in the sequence of the CYP2D6 gene that can affect the function of the translated CYP2D6 isoenzyme by changing the production, regulation, length or sequence of the CYP2D6 isoenzyme compared to the wild type CYP2D6 isoenzyme, and differences in the sequence of the CYP2D6 gene that code for 5' and 3' untranslated regions and for flanking intronic sequences that effect the production, regulation, length or sequence of the transcribed messenger RNA, and combinations of the preceding. The primer set permits amplification from a small polynucleotide sample of selected portions of the coding portion of the CYP2D6 gene, or amplification of the entire coding portion of the CYP2D6 gene, as well as the flanking intronic sequences that are relevant to recognition of splice sites. The primer set further permits the detection of genetic variants of the CYP2D6 gene without interference from pseudogenes, or from homologous or paralogous genes of non-CYP2D6 Cytochrome p450 genes. The primer set also permits the detection of low frequency variants that affect pharmaceutical drugs metabolism, thereby decreasing the false negative rate in variant screening.

[0025] The primer set of the present invention comprises a plurality of primers selected from the group consisting of the primers shown in Table I. In a preferred embodiment, the present invention comprises one or more than one primer group of the three primer groups selected from the primer groups consisting of Primer Group I (SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13 and SEQ ID NO:14); Primer Group II (SEQ ID NO:15, SEQ ID NO:16; SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23 and SEQ ID NO:24); and Primer Group III (SEQ ID NO:25; SEQ ID NO:26; SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 and SEQ ID NO:32). In a preferred embodiment of the present invention, the primer set comprises two primer groups selected from the group consisting of Primer Group I, Primer Group II and Primer Group III. In a particularly preferred embodiment, the primer set comprises all three primer groups, Primer Group I, Primer Group II and Primer Group III. TABLE-US-00001 TABLE I EXAMPLES OF PRIMERS SEQ ID AMPLIFICATION AMPLIFICATION AMPLICON NO: REGION DIRECTION SEQUENCE SIZE GROUP 9 EXON 1-2 FORWARD 5'AGCAGAGGGCAAAGGCCATCA 1281 I 10 EXON 1-2 REVERSE 5'CTCTCTGCCCAGCTCGGACTA 1281 I 11 EXON 1 FORWARD 5'CTTTATAAGGGAAGGGTCACG 346 I 12 EXON 1 REVERSE 5'AGGGGAGCCTCAGCACCTCTG 346 I 13 EXON 2 FORWARD 5'GGTGATCCTGGCTTGACAAGA 251 I 14 EXON 2 REVERSE 5'CCACGGAAATCTGTCTCTGTC 251 I 15 EXON 3-6 FORWARD 5'TGGTGGGGCTAATGCCTTCAT 1559 II 16 EXON 3-6 REVERSE 5'CCGGCCCCTGACACTCCTTCT 1559 II 17 EXON 3 FORWARD 5'GGTGGATGGTGGGGCTAATGC 252 II 18 EXON 3 REVERSE 5'CTTCCCAGTTCCCGCTTTGTG 252 II 19 EXON 4 FORWARD 5'ACGGGGAAGGCGACCCCTTAC 242 II 20 EXON 4 REVERSE 5'GAGCTCGCCCTGCAGAGACTC 242 II 21 EXON 5 FORWARD 5'AGAGCACAGGAGGGATTGAGA 277 II 22 EXON 5 REVERSE 5'ATTCCTCCTGGGACGCTCAAC 277 II 23 EXON 6 FORWARD 5'CCGTTCTGTCCCGAGTATGCT 207 II 24 EXON 6 REVERSE 5'CCCCTGCACTGTTTCCCAGAT 207 II 25 EXON 7-9 FORWARD 5'GGAGGCAAGAAGGAGTGTCAG 1397 III 26 EXON 7-9 REVERSE 5'ACCAATCTGGGCAGTCAGAGT 1397 III 27 EXON 7 FORWARD 5'GGCCGGACCCCCTGGGTGCTG 277 III 28 EXON 7 REVERSE 5'GCTGGTGCTGAGCTGGGGTGA 277 III 29 EXON 8 FORWARD 5'TAGAGTCCAGTCCCCACTCTC 227 III 30 EXON 8 REVERSE 5'AGACTCCACGGAAGGGGACAG 227 III 31 EXON 9 FORWARD 5'TCACCCAGGAGCCAGGCTCAC 332 III 32 EXON 9 REVERSE 5'TGATCCCAACGAGGGCGTGAG 332 III

[0026] Each primer, SEQ ID NO:9 through SEQ ID NO:32, is shown having exactly 21 nucleotides. However, as will be understood by those with skill in the art with reference to this disclosure, each primer can be truncated to contain less than 21 nucleotides. In one embodiment, one or more than one primer consists of only 16 consecutive nucleotides, only 17 consecutive nucleotides, only 18 consecutive nucleotides, only 19 consecutive nucleotides, or only 20 consecutive nucleotides of the sequences disclosed. Truncating the primer will usually decrease the binding efficiency of the primer and can cause less specific binding. Thus, in a preferred embodiment, the primer set comprises primers having the full sequences shown in Table I for maximum efficiency. However, truncated primers will usually still work in the methods of the present invention.

[0027] Additionally, primers from the primer set of the present invention can include added tail sequences, in particular at their 5' ends. Examples of suitable include -40 M13 Forward Promer, -21 M13 Forward Primer, -28 M13 Reverse Primer, -28 M13 Reverse 2 Primer, -29 M13 Reverse Primer, SP6 Primer, T7 Primer, T3 Primer, and Poly T (16-24 nucleotides) Primer. However, other tail sequences can also be used, as will be understood by those with skill in the art with reference to this disclosure. The addition of tail sequences is particularly preferred when the primers are truncated, in order to increase their binding efficiency as will be understood by those with skill in the art with reference to this disclosure. Further, dUTP can be substituted for TTP in a primer, as will be understood by those with skill in the art with reference to this disclosure.

[0028] Primer Group 1 is used to amplify the region of the CYP2D6 gene, SEQ ID NO:1, containing residues 1532-1799 of SEQ ID NO:1 (exon 1); and residues 2503-2674 of SEQ ID NO:1 (exon 2). Primer Group II is used to amplify the region of the CYP2D6 gene, SEQ ID NO:1, containing residues 3225-3377 of SEQ ID NO:1 (exon 3); residues 3466-3626 of SEQ ID NO:1 (exon 4); residues 4060-4236 of SEQ ID NO:1 (exon 5); and residues 4427-4568 of SEQ ID NO:1 (exon 6). Primer Group III is used to amplify the region of the CYP2D6 gene, SEQ ID NO:1, containing residues 4776-4963 of SEQ ID NO:1 (exon 7); residues 5418-5559 of SEQ ID NO:1 (exon 8); and residues 5658-5909 of SEQ ID NO:1 (exon 9).

[0029] In another embodiment, the present invention is a method of screening a polynucleotide sample to detect and identify the presence of one or more than one variant in the CYP2D6 gene in the sample. The method comprises, first, providing a polynucleotide sample potentially comprising a sequence comprising at least about 50 consecutive nucleotides from one or more than one of the sequences of the wild type CYP2D6*1, SEQ ID NO:1, one or more than one variant of wild type CYP2D6*1, SEQ ID NO:1 or both wild type CYP2D6*1, SEQ ID NO:1 and one or more than one variant of wild type CYP2D6*1, SEQ ID NO:1. The polynucleotide sample can originate from a human, a nonhuman animal including a transgenic animal or clone, or from another suitable source, as will be understood by those with skill in the art with reference to this disclosure. The polynucleotide sample can be in the form of one or more than one peripheral whole blood sample, buccal swab, Guthrie blood spot, preserved tissues sample such as a liver sample, paraffin embedded tissue, or from a clone library, or from another suitable source, as will be understood by those with skill in the art with reference to this disclosure.

[0030] Next, the method comprises providing a primer set according to the present invention. Then, the method comprises amplifying the polynucleotide sample using the provided primer set. Amplification can be performed using standard PCR, using the method as disclosed in U.S. Pat. No. 6,322,988 to Dawson et al, the contents of which are incorporated into this disclosure by reference in their entirety, or using another amplification method as will be understood by those with skill in the art with reference to this disclosure.

[0031] Additionally, as will be understood by those with skill in the art with reference to this disclosure, modified nucleotides, such as deaza dATP or deaza dGTP, can be used in the amplification step in conjunction with high denaturation temperatures, or for other reasons such as when the sequence of the CYP2D6 gene to be amplified contains high G/C or high A/T, and dUTP can be substituted for TTP. Further, modified bases in the form of their deoxynucleotide triphosphate can be used in the amplification step to introduce labels, such as biotin, digoxigenin or fluorescent dyes, such as fluoresceine, to produce labeled amplification products. The labeled amplification products can then be identified using array technology or can be used for other purposes, as will be understood by those with skill in the art with reference to this disclosure.

[0032] In a preferred embodiment, the amplification step is performed in two stages. The amplification step can be used to amplify a region of the CYP2D6 gene containing 1532-1799 of SEQ ID NO:1 (exon 1) and residues 2503-2674 of SEQ ID NO:1 (exon 2) using Primer Group I; or containing residues 3225-3377 of SEQ ID NO:1 (exon 3), residues 3466-3626 of SEQ ID NO:1 (exon 4), residues 4060-4236 of SEQ ID NO:1 (exon 5) and residues 4427-4568 of SEQ ID NO:1 (exon 6) using Primer Group II; or containing residues 4776-4963 of SEQ ID NO:1 (exon 7), residues 5418-5559 of SEQ ID NO:1 (exon 8) and residues 5658-5909 of SEQ ID NO:1 (exon 9) using Primer Group III; or containing 1532-1799 of SEQ ID NO:1 (exon 1), residues 2503-2674 of SEQ ID NO:1 (exon 2), residues 3225-3377 of SEQ ID NO:1 (exon 3), residues 3466-3626 of SEQ ID NO:1 (exon 4), residues 4060-4236 of SEQ ID NO:1 (exon 5) and residues 4427-4568 of SEQ ID NO:1 (exon 6) using Primer Group I and Primer Group II; or containing 1532-1799 of SEQ ID NO:1 (exon 1), residues 2503-2674 of SEQ ID NO:1 (exon 2), residues 4776-4963 of SEQ ID NO:1 (exon 7), residues 5418-5559 of SEQ ID NO:1 (exon 8) and residues 5658-5909 of SEQ ID NO:1 (exon 9) using Primer Group I and Primer Group III; or containing residues 3225-3377 of SEQ ID NO:1 (exon 3), residues 3466-3626 of SEQ ID NO:1 (exon 4), residues 4060-4236 of SEQ ID NO:1 (exon 5), residues 4427-4568 of SEQ ID NO:1 (exon 6), residues 4776-4963 of SEQ ID NO:1 (exon 7), residues 5418-5559 of SEQ ID NO:1 (exon 8) and residues 5658-5909 of SEQ ID NO:1 (exon 9) using Primer Group II and Primer Group III; or containing 1532-1799 of SEQ ID NO:1 (exon 1), residues 2503-2674 of SEQ ID NO:1 (exon 2), residues 3225-3377 of SEQ ID NO:1 (exon 3), residues 3466-3626 of SEQ ID NO:1 (exon 4), residues 4060-4236 of SEQ ID NO:1 (exon 5), residues 4427-4568 of SEQ ID NO:1 (exon 6), residues 4776-4963 of SEQ ID NO:1 (exon 7), residues 5418-5559 of SEQ ID NO:1 (exon 8) and residues 5658-5909 of SEQ ID NO:1 (exon 9) using Primer Group I, Primer Group II and Primer Group III. In a preferred embodiment, the amplification step is used to amplify a region of the CYP2D6 gene containing 1532-1799 of SEQ ID NO:1 (exon 1), residues 2503-2674 of SEQ ID NO:1 (exon 2), residues 3225-3377 of SEQ ID NO:1 (exon 3), residues 3466-3626 of SEQ ID NO:1 (exon 4), residues 4060-4236 of SEQ ID NO:1 (exon 5), residues 4427-4568 of SEQ ID NO:1 (exon 6), residues 4776-4963 of SEQ ID NO:1 (exon 7), residues 5418-5559 of SEQ ID NO:1 (exon 8) and residues 5658-5909 of SEQ ID NO:1 (exon 9) using Primer Group I, Primer Group II and Primer Group III.

[0033] Though the amplification step will now be disclosed in the context of using all three primer groups, Primer Group I, Primer Group II and Primer Group III, to amplify regions of the CYP2D6 gene containing 1532-1799 of SEQ ID NO:1 (exon 1), residues 2503-2674 of SEQ ID NO:1 (exon 2), residues 3225-3377 of SEQ ID NO:1 (exon 3), residues 3466-3626 of SEQ ID NO:1 (exon 4), residues 4060-4236 of SEQ ID NO:1 (exon 5), residues 4427-4568 of SEQ ID NO:1 (exon 6), residues 4776-4963 of SEQ ID NO:1 (exon 7), residues 5418-5559 of SEQ ID NO:1 (exon 8) and residues 5658-5909 of SEQ ID NO:1 (exon 9), amplifying shorter regions of the CYP2D6 gene can be performed with corresponding procedures using either one primer group or two primer groups, as will be understood by those with skill in the art with reference to this disclosure.

[0034] In the first amplification stage, three regions of the CYP2D6 gene are amplified using the six primers, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:25 and SEQ ID NO:26. The first amplification stage can be performed, for example, using standard PCR as follows, though other methods can also be used as will be understood by those with skill in the art with reference to this disclosure. By way of example only, first, a sample of 1 .mu.l of 1>T.E. buffer containing 20 ng of a polynucleotide sample is provided potentially comprising at least 50 consecutive nucleotides from one or more than one sequence selected from the group consisting of the wild type CYP2D6*1, SEQ ID NO:1, one or more than one variant of wild type CYP2D6*1, SEQ ID NO:1 and both the wild type CYP2D6*1, SEQ ID NO:1 and one or more than one variant of wild type CYP2D6*1, SEQ ID NO:1. Then, 19 .mu.l of buffer is added to the polynucleotide sample. The 19 .mu.l of buffer contains 0.2-2.0 units of Taq Gold, 200 .mu.M each of dATP, dCTP, dGTP and TTP, 2 mM MgCl.sub.2, 50 mM KCl, 5 mM dithiothreitol 2% DMSO, 10 mM TR1S/TR1S HCl, pH 9.0, and 10 pMoles of one primer pair selected from the group consisting of SEQ ID NO:9 and SEQ ID NO:10; SEQ ID NO:15 and SEQ ID NO:16; and SEQ ID NO:25 and SEQ ID NO:26. The buffered polynucleotide sample is then thermocycled using a standard thermocycler and standard vessels, and using a first cycle of 95.degree. C. for 12 minutes to activate the Taq Gold, followed by 30-40 cycles consisting of denaturation at 95.degree. C. for 30 seconds, annealing at 62.degree. C. for 30 seconds, extension at 72.degree. C. for 2 minutes, and a final extension at 72.degree. C. for 8 minutes. Then, the amplification is repeated twice more on the same sample using each additional primer pair of the three primer pairs until the sample has been amplified using all three primer pairs. In a preferred embodiment, the first amplification stage is performed using two of the three primer pairs simultaneously, rather than sequentially, following by an amplification using the third primer pair. In a particularly preferred embodiment, the amplification is performed using all three primer pairs simultaneously. Performing the amplification using each of the three primer pairs sequentially rather than simultaneously is particularly preferred if the analysis method to be used to sequence the amplicons disclosed below, such as SSCP, would function less optimally on the amplicons produced by all three primer pairs simultaneously, as will be understood by those with skill in the art with reference to this disclosure. This first amplification stage results in a sample comprising three amplicons containing 1532-1799 of SEQ ID NO:1 exons 1-2; exons 3-6; and exons 7-9, as well as the four flanking intronic sequences that effect the production, regulation, length or sequence of the transcribed messenger RNA (or in a sample comprising one or two of these amplicons and flaking intronic sequences, if less than all three primer pairs are used in the first amplification stage, as will be understood by those with skill in the art with reference to this disclosure).

[0035] Next, the sample comprising the amplicons resulting from the first amplification stage is subjected to a second amplification stage using some or all of the 18 remaining primers from the primer set of the present invention; SEQ ID NO:11 through SEQ ID NO:14, SEQ ID NO:17 through SEQ ID NO:24, and SEQ ID NO:27 through SEQ ID NO:32. First, 1 .mu.l of sample resulting from the first amplification stage is diluted 1:1000 in 0.1.times. T.E. buffer. Then, 19 .mu.l of buffer is added to the diluted sample. The 19 .mu.l of buffer contains 0.2-2.0 units of Taq Gold, 200 .mu.M each of dATP, dCTP, dGTP and TTP, 2 mM MgCl.sub.2, 50 mM KCl, 5 mM dithiothreitol 2% DMSO, 10 mM TR1S/TR1S HCl, pH 9.0, and 10 pMoles each of one or more than one primer pair, depending on the exon or exons of interest as follows: SEQ ID NO:11 and SEQ ID NO:12 for 1532-1799 of SEQ ID NO:1 (exon 1); SEQ ID NO:13 and SEQ ID NO:14 for residues 2503-2674 of SEQ ID NO:1 (exon 2); SEQ ID NO:17 and SEQ ID NO:18 for residues 3225-3377 of SEQ ID NO:1 (exon 3); SEQ ID NO:19 and SEQ ID NO:20 for residues 3466-3626 of SEQ ID NO:1 (exon 4); SEQ ID NO:21 and SEQ ID NO:22 for residues 4060-4236 of SEQ ID NO:1 (exon 5); SEQ ID NO:23 and SEQ ID NO:24 for residues 4427-4568 of SEQ ID NO:1 (exon 6); SEQ ID NO:27 and SEQ ID NO:28 for residues 4776-4963 of SEQ ID NO:1 (exon 7); SEQ ID NO:29 and SEQ ID NO:30 for residues 5418-5559 of SEQ ID NO:1 (exon 8); or SEQ ID NO:31 and SEQ ID NO:32 for residues 5658-5909 of SEQ ID NO:1 (exon 9), as will be understood by those with skill in the art with reference to this disclosure. The sample is then thermocycled using a standard thermocycler and standard vessels, and using a first cycle of 95.degree. C. for 12 minutes to activate the Taq Gold, followed by 30-40 cycles consisting of denaturation at 95.degree. C. for 30 seconds, annealing at 62.degree. C. for 30 seconds, extension at 72.degree. C. for 2 minutes final extension at 72.degree. C. for 8 minutes. Then, the one or more than one primer pair used depends on the amplicons in the sample that resulted from the first amplification stage. If, for example, all three primer pairs, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:25 and SEQ ID NO:26, were used in the first amplification stage, and the amplicons of interest include all 9 exons, then all remaining nine primer pairs are used in the second amplification stage. If only one or only two primer pairs were used in the first amplification stage, then fewer than all nine remaining primer pairs can be used in the second amplification stage, as will be understood by those with skill in the art with reference to this disclosure. In a preferred embodiment, the second amplification stage is performed using all nine primer pairs, SEQ ID NO:11 through SEQ ID NO:14, SEQ ID NO:17 through SEQ ID NO:24, and SEQ ID NO:27 through SEQ ID NO:32, simultaneously. In another preferred embodiment, the second amplification stage is performed using all nine primer pairs but where one or more than one of the nine primer pairs is used sequentially rather than simultaneously. When all nine primer pairs are used in the second amplification stage after a first amplification stage involving three primer pairs, the second amplification results in nine amplicons, each amplicon containing one exon as well as the four flanking intronic sequences that affect the production, regulation, length or sequence of the transcribed messenger RNA (or in fewer than nine amplicons and flaking intronic sequences if less than all eighteen primer pairs are used in the second amplification stage, as will be understood by those with skill in the art with reference to this disclosure).

[0036] The amplicons produced using the present method represent polynucleotides distinct from CYP2D6 pseudogenes, and from homologous or paralogous genes related to the CYP2D6 gene, thereby eliminating these sources of potential false positive results of the presence of variants. Further, since the present method amplifies only exons and their adjacent flanking intronic sequences, the method produces amplicons that are relevant to identifying only variants of the CYP2D6 gene having an effect of the CYP2D6 isoenzyme, SEQ ID NO:3.

[0037] Next, the method comprises analyzing the amplicons produced in the second amplification stage to identify the presence of CYP2D6*1 gene, SEQ ID NO:1, the presence of a variant of the CYP2D6*1 gene, SEQ ID NO:1 or to identify the specific variant of the CYP2D6*1 gene, SEQ ID NO:1 in the sample. This analysis step can be performed using any suitable method, such as dideoxy sequencing, pyrosequencing, SSCP or another suitable method, as will be understood by those with skill in the art with reference to this disclosure.

[0038] According to another embodiment of the present invention, there is provided a method of screening a population to detect and identify the presence of one or more than one variant in the CYP2D6 gene. The method comprises providing a plurality of polynucleotide samples from the population, where the plurality of polynucleotide samples is selected from a representative group of individuals from the population, such as for example, a plurality of random samples of individuals in the population or one or more than one sample from each individual in the population. Next, each of the pluralities of polynucleotide samples is subjected to a method of screening a polynucleotide sample to detect and identify the presence of one or more than one variant in the CYP2D6 gene in the polynucleotide sample according to the present invention. In a preferred embodiment, the method further comprises determining the distribution of the variants in the CYP2D6 gene in the population. In another preferred embodiment, the method comprises recording the presence and identity, or recording the distribution of the variants in the CYP2D6 gene in the population sample, in writing or another suitable media.

[0039] According to another embodiment of the present invention, there is provided a method of predicting the potential for altered metabolism of a substance, including one or more than one pharmaceutical drug, by a first individual compared to a second control individual, where the substance is metabolized by the CYP2D6 isoenzyme, and where the second control individual is homozygous for the wild type allele of the CYP2D6*1, SEQ ID NO:1. In one embodiment, the method comprises, first, providing a polynucleotide sample from the first individual. Next, the polynucleotide sample from the first individual is subjected to a method of screening a polynucleotide sample to detect and identify the presence of one or more than one variant in the CYP2D6 gene in the polynucleotide sample according to the present invention. Then, the one or more than one variant in the CYP2D6 gene detected and identified is analyzed to determine if it constitutes a silent variant or non-silent variant, where the absence of a non-silent variant means that the first individual will not have the potential for altered metabolism of the substance, and where the presence of a non-silent variant means that the first individual will have the potential for altered metabolism of the substance.

[0040] According to another embodiment of the present invention, there are provided novel purified and isolated variants of the Cytochrome p450 CYP2D6 gene and corresponding variants in the CYP2D6 isoenzyme, including both silent variants and non-silent variants. The variants were detected and identified using the methods of the present invention. The variants are disclosed in Table II. Further, some individuals had a plurality of the variants listed in Table I. The present invention, therefore, includes both the 32 variants of the Cytochrome p450 CYP2D6 gene and corresponding variants in the CYP2D6 isoenzyme, if any, as well as variants of the Cytochrome p450 CYP2D6 gene having a plurality of the variants listed in Table I, and corresponding variants in the CYP2D6 isoenzyme, if any. TABLE-US-00002 TABLE II VARIANTS OF THE CYTOCHROME P450 CYP2D6 GENE AND CORRESPONDING VARIANTS IN THE CYP2D6 ISOENZYME POSITION CHANGE POSITION CHANGE IN IN WILD TYPE POSITION CHANGE IN WILD TYPE WILD TYPE VARIANT SEQUENCE, SEQUENCE, SEQ ID NO: 1, POLYPEPTIDE NUMBER SEQ ID NO: 1 NUMBERED FROM ATG (MET) VARIANT SEQUENCE, SEQ ID NO: 3 VARIANT 1 1522 -98 C > T 2 1576 -44 insert GUIDING TUBE 3 1851 232 G > C 4 1852 233 A > C 5 1864 245 A > G 6 3230 1611 T > A 120 F > I 7 3232 1613 C > T 120 F > F 8 3335 1716 G > A 155 E > K 9 3542 1923 C > T 194 R > R 10 3617 1998 T > C 219 F > F 11 3716 2097 A > G 12 3922 2303 C > T 13 4221 2602 G > T 276 L > L 14 4280 2661 G > A 15 4282 2663 G > A 16 4379 2760 T > A 17 4555 2936 T > C 324 H > H 18 4607 2988 G > A 19 4820 3201 C > T 344 R > STOP 20 4854 3235 A > G 355 Y > C 21 4873 3254 T > C 361 H > H 22 4878 3259 insert GT 363 V > FRAME SHIFT 23 5003 3384 C > A 24 5027 3408 T > C 25 5054 3435 C > A 26 5409 3790 C > T 27 5496 3877 G > A 418 E > K 28 5774 4155 C > T 478 H > Y 29 5791 4172 C > T 483 F > F 30 5948 4329 C > T 31 6020 4401 C > T 32 EXON9 GENE CONVERSION

[0041] According to another embodiment of the present invention, there is provided a method of predicting the potential for altered metabolism of a substance, including one or more than one pharmaceutical drug, by a first individual compared to a second control individual, where the substance is metabolized by the CYP2D6 isoenzyme, and where the second control individual is homozygous for the wild type allele of the CYP2D6*1, SEQ ID NO:1. In one embodiment, the method comprises, first, providing a polynucleotide sample from the first individual. Next, the polynucleotide sample from the first individual is subjected to a method of screening a polynucleotide sample to detect and identify the presence of one or more than one variant in the CYP2D6 gene in the polynucleotide sample according to the present invention. Then, the one or more than one variant in the CYP2D6 gene detected and identified is analyzed to determine if it constitutes one of the novel non-silent variants of the present invention, where the presence of one of the novel non-silent variants of the present invention means that the first individual will have the potential for altered metabolism of the substance.

[0042] In another embodiment, the present invention is a kit for performing a method of the present invention. The kit comprises suitable amounts of one or more than one primer group selected from the group consisting of Primer Group I, Primer Group II and Primer Group III to perform the amplification step of a method of the present invention. In one embodiment, the kit comprises suitable amounts of two primer groups selected from the group consisting of Primer Group I and Primer Group II; and Primer Group I and Primer Group III; and Primer Group II and Primer Group III. In a preferred embodiment, the kit comprises suitable amounts of all three primer groups, Primer Group I, Primer Group II and Primer Group III. Additionally, the kit can comprise additional reagents or vessels for performing a method of the present invention, such as one or more than one DNA dependent polymerase, one or more than one buffer, one or more than one detergents and one or more than one stabilizing agent. Further, the kit can comprise reagents or vessels for analyzing or sequencing the amplicons resulting from a method of the present invention. Additionally, the kit can comprise written or recorded directions for performing a method of the present invention.

EXAMPLE

Method of Screening a Polynucleotide Sample to Detect and Identify the Presence of One or More than One Variant in the CYP2D6 Gene in the Sample

[0043] A polynucleotide sample was screened to detect and identify the presence of one or more than one variant in the CYP2D6 gene in the sample according to the present invention as follows. First, polynucleotide samples were provided that potentially comprises a sequence comprising at least about 50 consecutive nucleotides from one or more than one of the sequences of the wild type CYP2D6*1, SEQ ID NO:1, one or more than one variant of wild type CYP2D6*1, SEQ ID NO:1 or both wild type CYP2D6*1, SEQ ID NO:1 and one or more than one variant of wild type CYP2D6*1, SEQ ID NO:1. The polynucleotide samples provided were human diversity panels of genomic DNA obtained from Corriel Laboratories. The panels consisted of 10 .mu.g of genomic DNA each from a first group of 100 African Americans, a second group of 10 African Americans, 100 Caucasians, 10 Chinese Asians, 10 Japanese Asians, 10 non-Chinese, non-Japanese Asians, and 20 aged controls. Next, the samples were dried in a SpeedVac.TM. (Thermo Savant, Inc., Holbrook, N.Y. US) and then, resuspended in 1.times. T.E. buffer (1.times. T.E.=1 mM EDTA, 10 mM TrisHCl) having a pH 7.6 to a concentration of 200 ng/.mu.l per sample. Stock samples were stored at -20.degree. C. until ready for dispensing.

[0044] Once the samples were ready for dispensing, the samples were thawed and allowed to come to room temperature. Then, the samples were further diluted with 0.1.times. T.E. to a concentration of 2 ng/.mu.l. The samples were then dispensed in 10 .mu.l increments to individual wells of 96 well 200 .mu.l PCR plates. The plated samples were then dried in an oven at between 60.degree. C. and 70.degree. C. for one hour until no visible moisture was observed in the wells of the plates. The dried samples in plates were then stored with a desiccant at room temperature in sealed containers until ready for amplification.

[0045] Next, the samples were subjected to a two-stage amplification procedure according to the present invention, using PCR. First, 20 .mu.l of a master mix was added to each well. The master mix consisted of an aqueous buffer of 0.25 units of TAQ Gold.TM. (PE Applied Biosystems, Inc. Foster City, Calif. US), 2 mM MgCl.sub.2, 50 mM KCl, 10 mM TrisHCl, pH 9.0 and 10 pMoles of each primer of the six primers, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:25 and SEQ ID NO:26 as appropriate for the specific region of the CYP2D6 gene being amplified. The first amplification stage was conducted on thermocyclers (MJ Research, Inc., Cambridge, Mass. US) using a set of cycles consisting of 95.degree. C. for 12 minutes, followed by a cycle consisting of denaturation at 95.degree. C. for 30 seconds, a cycle of annealing at 60.degree. C. for 20 seconds, and cycles of extension at 72.degree. C. for 1 minute and 40 seconds. These three steps of cycling were repeated 34 additional times followed by a final cycle of extension at 72.degree. C. for 8 minutes.

[0046] Then, 2 .mu.l of the resulting amplicons were electrophoresed on 1% precast agarose gel containing ethidium bromide. The amplicons were stored at -20.degree. C. until the second amplification stage.

[0047] Next, the amplicons from the first amplification stage were subjected to a second amplification stage. First, the amplicons were treated with ExoSap.RTM. (USB Corporation, Cleveland, Ohio US) using 1 .mu.l of the enzyme mixture added directly to the amplicons in the wells of the 96 well plate in which they were originally subjected to the first amplification stage, and the plated amplicons were heated for 1 hour at 37.degree. C., followed by heat inactivation at 65.degree. C. for 30 minutes, followed by heating at 80.degree. C. for 10 minutes, and then followed by cooling to 4.degree. C.

[0048] One group of the ExoSap.RTM. treated samples were amplified using components from a core cycle sequencing kit (PE Applied Biosystems, Inc., Foster City, Calif. US). The amplification reaction was performed on 20 .mu.l of substrate comprising the 2 .mu.l treated sample (containing about 100 ng of amplicons), 10 pMoles each of exon specific primer pairs according to the present invention, (SEQ ID NO:11 through SEQ ID NO:14, SEQ ID NO:17 through SEQ ID NO:24, and SEQ ID NO:27 through SEQ ID NO:32), 2 units of FS polymerase, 4 .mu.l of 5.times. reaction buffer and 1 .mu.l each of the A and C terminator mixes, with the balance consisting of 18 megaohm water. The amplification reactions were performed in the wells of a 96 well PCR plate or in 200 .mu.l PCR strip tubes (Fisher Scientific L.L.C., Pittsburgh, Penn. US) using cycling conditions consisting of a first denaturation step of 95.degree. C. for 5 minutes, followed by 35 cycles of three steps consisting of heating at 95.degree. C. for 30 seconds, annealing at 55.degree. C. for 20 seconds, and extension at 60.degree. C. for 4 minutes, followed by cooling to 4.degree. C. Reactions were then cleaned to remove unincorporated terminators using a microtiter cleanup system (Millipore Corporation, Bedford, Mass. US).

[0049] The recovered 20 .mu.l filtrates were then dried in the wells of a fresh 96 well plate under vacuum at 60.degree. C. in a SpeedVac.TM. after the addition of 1 .mu.l and a tetramethylrhodamine labeled MapMarker.RTM. TMR 650 (BioVentures, Inc., Murfreesboro, Tenn. US). The dried products were resuspended in 3 .mu.l of 18 megaohm water and 3 .mu.l of a mix of deionized formamide (American Bioanalytical Products, Natick, Mass. US). Next, the samples were denatured and concentrated to about 3 .mu.l by heating at 95.degree. C. for 10 minutes without an evaporation barrier and then cooled to 4.degree. C.

[0050] 1.2 .mu.l of the denatured and concentrated samples were loaded onto individual teeth of a 50 tooth gel loading comb (The Gel Company, San Francisco, Calif. US) and then loaded onto the gels of an ABI Prism 377 DNA Sequencer (PE Applied Biosystems, Inc. Foster City, Calif. US) using the comb manufacturer's suggested protocol. The terminated polynucleotide fragments were analyzed on 0.2 mm thick 36 cm denaturing Long Ranger.RTM. polyacrylamide gels (FMC Corporation, Philadelphia, Pa. US) prepared using the instrument manufacturer's and the gel manufacturer's instructions. The gels were prepared 18 hours prior to use to assure complete polymerization of the acrylamide. The run conditions utilized were those recommended by the instrument manufacturer for performing dye terminated sequencing reactions for the core kit.

[0051] Sequencing reactions were also performed using 1 .mu.l of sample (comprising about 50 ng of amplicons) of the treated PCR products and components from a Big Dye sequencing kit (PE Applied Biosystems, Inc. Foster City, Calif. US) setting up separate forward and reverse sequencing reactions using the exon specific forward or reverse primers, (SEQ ID NO:11 through SEQ ID NO:14, SEQ ID NO:17 through SEQ ID NO:24, and SEQ ID NO:27 through SEQ ID NO:32), according to the present invention specific for the region being sequenced. Modifications were made to the manufacturer's suggested protocol consisting of reducing the primer concentrations to 2.4 pMoles per reaction and using 4 .mu.l of the supplied Ready Reaction Mix.TM. for each 20 .mu.l reaction. Cycle sequencing was performed in 96 well plates using the recommended thermocycling conditions on a thermocycler. The reaction components were then cleaned to remove unincorporated terminators using a microtiter cleanup system.

[0052] Following the sequencing reaction, the terminated products were obtained by precipitation using the manufacturer's suggested procedure. The dried fragments obtained by this procedure were resuspended in 3 .mu.l of 18 megaohm water and 3 .mu.l of formamide. Samples were denatured uncapped at 95.degree. C. for 10 minutes which reduced volume to about 3 .mu.l. 1.2 .mu.l of each sample was loaded onto the teeth of a 50-lane loading comb following manufacturer's protocol. Terminated fragments were electrophoresed on an ABI Prism 377 DNA Sequencer using the manufacturer's recommended procedure using 0.2 mm thick Long Ranger.RTM. polyacrylamide gels.

[0053] The sequence data obtained from both sequencing procedures were analyzed using fragment analysis software and compared to sequence data for the wild type CYP2D6*1 gene sequence, SEQ ID NO:1. The data obtained from the procedures revealed a plurality of variants of the CYP2D6 gene present in the samples that were not previously reported, especially in samples from Asians and African Americans.

[0054] Although the present invention has been discussed in considerable detail with reference to certain preferred embodiments, other embodiments are possible. Therefore, the scope of the appended claims should not be limited to the description of preferred embodiments contained in this disclosure.

Sequence CWU 1

1

32 1 9432 DNA Homo sapiens 1 gaattcaaga ccagcctgga caacttggaa gaacccggtc tctacaaaaa atacaaaatt 60 agctgggatt gggtgcggtg gctcatgcct ataatcccag cactttggga gcctgaggtg 120 ggtggatcac ctgaagtcag gagttcaaga ctagcctggc caacatggtg aaaccctatc 180 tctactgaaa atacaaaaag ctagacgtgg tggcacacac ctgtaatccc agctacttag 240 gaggctgagg caggagaatt gcttgaagcc tagaggtgaa ggttgtagtg agccgagatt 300 gcatcattgc acaatggagg ggagccacca gcctgggcaa caagaggaaa tctccgtctc 360 caaaaaaaaa aaaaaaaaaa aaagaattag gctgggtggt gcctgtagtc ccagctactt 420 gggaggcagg gggtccactt gatgtcgaga ctgcagtgag ccatgatcct gccactgcac 480 tccggcctgg gcaacagagt gagaccctgt ctaaagaaaa aaaaaataaa gcaacatatc 540 ctgaacaaag gatcctccat aacgttccca ccagatttct aatcagaaac atggaggcca 600 gaaagcagtg gaggaggacg accctcaggc agcccgggag gatgttgtca caggctgggg 660 caagggcctt ccggctacca actgggagct ctgggaacag ccctgttgca aacaagaagc 720 catagcccgg ccagagccca ggaatgtggg ctgggctggg agcagcctct ggacaggagt 780 ggtcccatcc aggaaacctc cggcatggct gggaagtggg gtacttggtg ccgggtctgt 840 atgtgtgtgt gactggtgtg tgtgagagag aatgtgtgcc ctaagtgtca gtgtgagtct 900 gtgtatgtgt gaatattgtc tttgtgtggg tgattttctg cgtgtgtaat cgtgtccctg 960 caagtgtgaa caagtggaca agtgtctggg agtggacaag agatctgtgc accatcaggt 1020 gtgtgcatag cgtctgtgca tgtcaagagt gcaaggtgaa gtgaagggac caggcccatg 1080 atgccactca tcatcaggag ctctaaggcc ccaggtaagt gccagtgaca gataagggtg 1140 ctgaaggtca ctctggagtg ggcaggtggg ggtagggaaa gggcaaggcc atgttctgga 1200 ggaggggttg tgactacatt agggtgtatg agcctagctg ggaggtggat ggccgggtcc 1260 actgaaaccc tggttatccc agaaggcttt gcaggcttca ggagcttgga gtggggagag 1320 ggggtgactt ctccgaccag gcccctccac cggcctaccc tgggtaaggg cctggagcag 1380 gaagcagggg caagaacctc tggagcagcc catacccgcc ctggcctgac tctgccactg 1440 gcagcacagt caacacagca ggttcactca cagcagaggg caaaggccat catcagctcc 1500 ctttataagg gaagggtcac gcgctcggtg tgctgagagt gtcctgcctg gtcctctgtg 1560 cctggtgggg tgggggtgcc aggtgtgtcc agaggagccc atttggtagt gaggcaggta 1620 tggggctaga agcactggtg cccctggccg tgatagtggc catcttcctg ctcctggtgg 1680 acctgatgca ccggcgccaa cgctgggctg cacgctaccc accaggcccc ctgccactgc 1740 ccgggctggg caacctgctg catgtggact tccagaacac accatactgc ttcgaccagg 1800 tgagggagga ggtcctggag ggcggcagag gtgctgaggc tcccctacca gaagcaaaca 1860 tggatggtgg gtgaaaccac aggctggacc agaagccagg ctgagaaggg gaagcaggtt 1920 tgggggacgt cctggagaag ggcatttata catggcatga aggactggat tttccaaagg 1980 ccaaggaaga gtagggcaag ggcctggagg tggagctgga cttggcagtg ggcatgcaag 2040 cccattgggc aacatatgtt atggagtaca aagtcccttc tgctgacacc agaaggaaag 2100 gccttgggaa tggaagatga gttagtcctg agtgccgttt aaatcacgaa atcgaggatg 2160 aagggggtgc agtgacccgg ttcaaacctt ttgcactgtg ggtcctcggg cctcactgcc 2220 tcaccggcat ggaccatcat ctgggaatgg gatgctaact ggggcctctc ggcaattttg 2280 gtgactcttg caaggtcata cctgggtgac gcatccaaac tgagttcctc catcacagaa 2340 ggtgtgaccc ccacccccgc cccacgatca ggaggctggg tctcctcctt ccacctgctc 2400 actcctggta gccccggggg tcgtccaagg ttcaaatagg actaggacct gtagtctggg 2460 gtgatcctgg cttgacaaga ggccctgacc ctccctctgc agttgcggcg ccgcttcggg 2520 gacgtgttca gcctgcagct ggcctggacg ccggtggtcg tgctcaatgg gctggcggcc 2580 gtgcgcgagg cgctggtgac ccacggcgag gacaccgccg accgcccgcc tgtgcccatc 2640 acccagatcc tgggtttcgg gccgcgttcc caaggcaagc agcggtgggg acagagacag 2700 atttccgtgg gacccgggtg ggtgatgacc gtagtccgag ctgggcagag agggcgcggg 2760 gtcgtggaca tgaaacaggc cagcgagtgg ggacagcggg ccaagaaacc acctgcacta 2820 gggaggtgtg agcatgggga cgagggcggg gcttgtgacg agtgggcggg gccactgccg 2880 agacctggca ggagcccaat gggtgagcgt ggcgcatttc ccagctggaa tccggtgtcg 2940 aagtgggggc ggggaccgca cctgtgctgt aagctcagtg tgggtggcgc ggggcccgcg 3000 gggtcttccc tgagtgcaaa ggcggtcagg gtgggcagag acgaggtggg gcaaagcctg 3060 ccccagccaa gggagcaagg tggatgcaca aagagtgggc cctgtgacca gctggacaga 3120 gccagggact gcgggagacc agggggagca tagggttgga gtgggtggtg gatggtgggg 3180 ctaatgcctt catggccacg cgcacgtgcc cgtcccaccc ccaggggtgt tcctggcgcg 3240 ctatgggccc gcgtggcgcg agcagaggcg cttctccgtg tccaccttgc gcaacttggg 3300 cctgggcaag aagtcgctgg agcagtgggt gaccgaggag gccgcctgcc tttgtgccgc 3360 cttcgccaac cactccggtg ggtgatgggc agaagggcac aaagcgggaa ctgggaaggc 3420 gggggacggg gaaggcgacc ccttacccgc atctcccacc cccaggacgc ccctttcgcc 3480 ccaacggtct cttggacaaa gccgtgagca acgtgatcgc ctccctcacc tgcgggcgcc 3540 gcttcgagta cgacgaccct cgcttcctca ggctgctgga cctagctcag gagggactga 3600 aggaggagtc gggctttctg cgcgaggtgc ggagcgagag accgaggagt ctctgcaggg 3660 cgagctcccg agaggtgccg gggctggact ggggcctcgg aagagcagga tttgcataga 3720 tgggtttggg aaaggacatt ccaggagacc ccactgtaag aagggcctgg aggaggaggg 3780 gacatctcag acatggtcgt gggagaggtg tgcccgggtc agggggcacc aggagaggcc 3840 aaggactctg tacctcctat ccacgtcaga gatttcgatt ttaggtttct cctctgggca 3900 aggagagagg gtggaggctg gcacttgggg agggacttgg tgaggtcagt ggtaaggaca 3960 ggcaggccct gggtctacct ggagatggct ggggcctgag acttgtccag gtgaacgcag 4020 agcacaggag ggattgagac cccgttctgt ctggtgtagg tgctgaatgc tgtccccgtc 4080 ctcctgcata tcccagcgct ggctggcaag gtcctacgct tccaaaaggc tttcctgacc 4140 cagctggatg agctgctaac tgagcacagg atgacctggg acccagccca gcccccccga 4200 gacctgactg aggccttcct ggcagagatg gagaaggtga gagtggctgc cacggtgggg 4260 ggcaagggtg gtgggttgag cgtcccagga ggaatgaggg gaggctgggc aaaaggttgg 4320 accagtgcat cacccggcga gccgcatctg ggctgacagg tgcagaattg gaggtcattt 4380 gggggctacc ccgttctgtc ccgagtatgc tctcggccct gctcaggcca aggggaaccc 4440 tgagagcagc ttcaatgatg agaacctgcg catagtggtg gctgacctgt tctctgccgg 4500 gatggtgacc acctcgacca cgctggcctg gggcctcctg ctcatgatcc tacatccgga 4560 tgtgcagcgt gagcccatct gggaaacagt gcaggggccg agggaggaag ggtacaggcg 4620 ggggcccatg aactttgctg ggacacccgg ggctccaagc acaggcttga ccaggatcct 4680 gtaagcctga cctcctccaa cataggaggc aagaaggagt gtcagggccg gaccccctgg 4740 gtgctgaccc attgtgggga cgcatgtctg tccaggccgt gtccaacagg agatcgacga 4800 cgtgataggg caggtgcggc gaccagagat gggtgaccag gctcacatgc cctacaccac 4860 tgccgtgatt catgaggtgc agcgctttgg ggacatcgtc cccctgggtg tgacccatat 4920 gacatcccgt gacatcgaag tacagggctt ccgcatccct aaggtaggcc tggcgccctc 4980 ctcaccccag ctcagcacca gcacctggtg atagccccag catggctact gccaggtggg 5040 cccactctag gaaccctggc cacctagtcc tcaatgccac cacactgact gtccccactt 5100 gggtgggggg tccagagtat aggcagggct ggcctgtcca tccagagccc ccgtctagtg 5160 gggagacaaa ccaggacctg ccagaatgtt ggaggaccca acgcctgcag ggagaggggg 5220 cagtgtgggt gcctctgaga ggtgtgactg cgccctgctg tggggtcgga gagggtactg 5280 tggagcttct cgggcgcagg actagttgac agagtccagc tgtgtgccag gcagtgtgtg 5340 tcccccgtgt gtttggtggc aggggtccca gcatcctaga gtccagtccc cactctcacc 5400 ctgcatctcc tgcccaggga acgacactca tcaccaacct gtcatcggtg ctgaaggatg 5460 aggccgtctg ggagaagccc ttccgcttcc accccgaaca cttcctggat gcccagggcc 5520 actttgtgaa gccggaggcc ttcctgcctt tctcagcagg tgcctgtggg gagcccggct 5580 ccctgtcccc ttccgtggag tcttgcaggg gtatcaccca ggagccaggc tcactgacgc 5640 ccctcccctc cccacaggcc gccgtgcatg cctcggggag cccctggccc gcatggagct 5700 cttcctcttc ttcacctccc tgctgcagca cttcagcttc tcggtgccca ctggacagcc 5760 ccggcccagc caccatggtg tctttgcttt cctggtgagc ccatccccct atgagctttg 5820 tgctgtgccc cgctagaatg gggtacctag tccccagcct gctccctagc cagaggctct 5880 aatgtacaat aaagcaatgt ggtagttcca actcgggtcc cctgctcacg ccctcgttgg 5940 gatcatcctc ctcagggcaa ccccacccct gcctcattcc tgcttacccc accgcctggc 6000 cgcatttgag acaggggtac gttgaggctg agcagatgtc agttaccctt gcccataatc 6060 ccatgtcccc cactgaccca actctgactg cccagattgg tgacaaggac tacattgtcc 6120 tggcatgtgg ggaaggggcc agaatgggct gactagaggt gtcagtcagc cctggatgtg 6180 gtggagaggg caggactcag cctggaggcc catatttcag gcctaactca gcccacccca 6240 catcagggac agcagtcctg ccagcaccat cacaacagtc acctcccttc atatatgaca 6300 ccccaaaacg gaagacaaat catggcgtca gggagctata tgccagggct acctacctcc 6360 cagggctcag tcggcaggtg ccagaacgtt ccctgggaag gccccatgga agcccaggac 6420 tgagccacca ccctcagcct cgtcacctca ccacaggact ggctacctct ctgggccctc 6480 agggatgctg ctgtacagac ccctgaccag tgacgagttc gcactcaggg ccaggctggc 6540 gctggaggag gacacttgtt tggctccaac cctaggtacc atcctcccag tagggatcag 6600 gcagggccca caggcctgcc ctagggacag gagtcaacct tggacccata aggcactggg 6660 gcgggcagag aaggaggagg tggcatgggc agctgagagc cagagaccct gaccctagtc 6720 cttgctctgc cattaccccg tgtgaccccg ggcccaccct tccccaccct tccccacccc 6780 gggcttctgt ttccttctgc caacgagaag gctgcttcac ctgccccgag tcctgtcttc 6840 ctgctctgcc ttctggggct gtggcccttg ctggcctgga gccccaacca agggcaggga 6900 ctgctgtcct ccacgtctgt cctcaccgac ataatgggct gggctgggca cacaggcagt 6960 gcccaagagt ttctaatgag catatgatta cctgagtcct gggcagacct tcttagggaa 7020 cagcctggga cagagaacca cagacactct gaggagccac cctgaggcct cttttgccag 7080 aggaccctac agcctccctg gcagcagttc cgccagcatt tctgtaaatg ccctcatgcc 7140 agggtgcggc ccggctgtca gcacgagagg gacgttggtc tgtcccctgg caccgagtca 7200 gtcagaaggg tggccagggc ccccttgggc ccctccagag acaatccact gtggtcacac 7260 ggctcggtgg caggaagtgc tgttcctgca gctgtgggga cagggagtgt ggatgaagcc 7320 aggctgggtt tgtctgaaga cggaggcccc gaaaggtggc agcctggcct atagcagcag 7380 caactcttgg atttattgga aagattttct tcacggttct gagtcttggg ggtgttagag 7440 gctcagaacc agtccagcca gagctctgtc atgggcacgt agacccggtc ccagggcctt 7500 tgctctttgc tgtcctcaga ggcctctgca aagtagaaac aggcagcctt gtgagtcccc 7560 tcctgggagc aaccaaccct ccctctgaga tgccccgggg ccaggtcagc tgtggtgaaa 7620 ggtagggatg cagccagctc agggagtggc ccagagttcc tgcccaccca aggaggctcc 7680 caggaaggtc aaggcacctg actcctgggc tgcttccctc ccctcccctc cccaggtcag 7740 gaaggtggga aagggctggg gtgtctgtga ccctggcagt cactgagaag cagggtggaa 7800 gcagccccct gcagcacgct gggtcagtgg tcttaccaga tggatacgca gcaacttcct 7860 tttgaacctt tttattttcc tggcaggaag aagagggatc cagcagtgag atcaggcagg 7920 ttctgtgttg cacagacagg gaaacaggct ctgtccacac aaagtcggtg gggccaggat 7980 gaggcccagt ctgttcacac atggctgctg cctctcagct ctgcacagac gtcctcgctc 8040 ccctgggatg gcagcttggc ctgctggtct tggggttgag ccagcctcca gcactgcctc 8100 cctgccctgc tgcctcccac tctgcagtgc tccatggctg ctcagttgga cccacgctgg 8160 agacgttcag tcgaagcccc gggctgtcct tacctcccag tctggggtac ctgccacctc 8220 ctgctcagca ggaatggggc taggtgcttc ctcccctggg gacttcacct gctctccctc 8280 ctgggataag acggcagcct cctccttggg ggcagcagca ttcagtcctc caggtctcct 8340 gggggtcgtg acctgcagga ggaataagag ggcagactgg gcagaaaggc cttcagagca 8400 cctcatcctc ctgttctcac actggggtgt cacagtcctg ggaagttctt ccttttcagt 8460 tgagctgtgg taaccttgtg agtttcctgg agggggcctg ccactaccct tgggactccc 8520 tgccgtgtgt ctgggtctaa ctgagctctg aaaggagaga gccccagccc tgggccttcc 8580 aggggaagcc ttacctcaga ggttggcttc ttcctactct tgactttgcg tctctgcaga 8640 gggaggtggg aggggtgaca caaccctgac acccacacta tgagtgatga gtagtcctgc 8700 cccgactggc ccatcctttc caggtgcagt cccccttact gtgtctgcca agggtgccag 8760 cacagccgcc ccactccagg ggaagaggag tgccagccct taccacctga gtgggcacag 8820 tgtagcattt attcattagc ccccacactg gcctgaccat ctcccctgtg ggctgcatga 8880 caaggagaga gaacaggctg aggtgagagc tactgtcaac acctaaacct aaaaaatcta 8940 taattgggct gggcagggtg gctcacgcct gtaatcccag cactttggga ggccgagatg 9000 ggtggatcac ctgaggtcag atgttcgaga ccagcctggc caacatggtg aaaccccgtc 9060 tctactaaaa atacaaaaaa ttagctgggc gtggtggtgg gtgcctgtaa tcccagctac 9120 tcaggaggct gaggcaggag aattgcttga acctgggagg cagaggctgc agtgagccga 9180 gatcgcatca ttgcactcca gcctggtcaa caagagtgaa actgtcttaa aaaaaaaatc 9240 tataattgat atctttagaa agataaaact ttgcattcat gaaataagaa taggagggtc 9300 taaaataaaa atgttcaaac acccaccacc actaattctt gacaaaaata tagtctgggt 9360 gccttagctc atgcctgtaa tcccagcatt ttgggaggct aaggcaggag gattgtttga 9420 gcctaggaat tc 9432 2 1655 RNA Homo sapiens 2 gcugagagug uccugccugg uccucugugc cugguggggu gggggugcca ggugugucca 60 gaggagccca uuugguagug aggcagguau ggggcuagaa gcacuggugc cccuggccgu 120 gauaguggcc aucuuccugc uccuggugga ccugaugcac cggcgccaac gcugggcugc 180 acgcuaccca ccaggccccc ugccacugcc cgggcugggc aaccugcugc auguggacuu 240 ccagaacaca ccauacugcu ucgaccaguu gcggcgccgc uucggggacg uguucagccu 300 gcagcuggcc uggacgccgg uggucgugcu caaugggcug gcggccgugc gcgaggcgcu 360 ggugacccac ggcgaggaca ccgccgaccg cccgccugug cccaucaccc agauccuggg 420 uuucgggccg cguucccaag ggguguuccu ggcgcgcuau gggcccgcgu ggcgcgagca 480 gaggcgcuuc uccgugucca ccuugcgcaa cuugggccug ggcaagaagu cgcuggagca 540 gugggugacc gaggaggccg ccugccuuug ugccgccuuc gccaaccacu ccggacgccc 600 cuuucgcccc aacggucucu uggacaaagc cgugagcaac gugaucgccu cccucaccug 660 cgggcgccgc uucgaguacg acgacccucg cuuccucagg cugcuggacc uagcucagga 720 gggacugaag gaggagucgg gcuuucugcg cgaggugcug aaugcugucc ccguccuccu 780 gcauauccca gcgcuggcug gcaagguccu acgcuuccaa aaggcuuucc ugacccagcu 840 ggaugagcug cuaacugagc acaggaugac cugggaccca gcccagcccc cccgagaccu 900 gacugaggcc uuccuggcag agauggagaa ggccaagggg aacccugaga gcagcuucaa 960 ugaugagaac cugcgcauag ugguggcuga ccuguucucu gccgggaugg ugaccaccuc 1020 gaccacgcug gccuggggcc uccugcucau gauccuacau ccggaugugc agcgccgugu 1080 ccaacaggag aucgacgacg ugauagggca ggugcggcga ccagagaugg gugaccaggc 1140 ucacaugccc uacaccacug ccgugauuca ugaggugcag cgcuuugggg acaucguccc 1200 ccuggguaug acccauauga caucccguga caucgaagua cagggcuucc gcaucccuaa 1260 gggaacgaca cucaucacca accugucauc ggugcugaag gaugaggccg ucugggagaa 1320 gcccuuccgc uuccaccccg aacacuuccu ggaugcccag ggccacuuug ugaagccgga 1380 ggccuuccug ccuuucucag caggccgccg ugcaugccuc ggggagcccc uggcccgcau 1440 ggagcucuuc cucuucuuca ccucccugcu gcagcacuuc agcuucucgg ugcccacugg 1500 acagccccgg cccagccacc auggugucuu ugcuuuccug gugagcccau cccccuauga 1560 gcuuugugcu gugccccgcu agaauggggu accuaguccc cagccugcuc cuagcccaga 1620 ggcucuaaug uacaauaaag caauguggua guucc 1655 3 497 PRT Homo sapiens 3 Met Gly Leu Glu Ala Leu Val Pro Leu Ala Val Ile Val Ala Ile Phe 1 5 10 15 Leu Leu Leu Val Asp Leu Met His Arg Arg Gln Arg Trp Ala Ala Arg 20 25 30 Tyr Pro Pro Gly Pro Leu Pro Leu Pro Gly Leu Gly Asn Leu Leu His 35 40 45 Val Asp Phe Gln Asn Thr Pro Tyr Cys Phe Asp Gln Leu Arg Arg Arg 50 55 60 Phe Gly Asp Val Phe Ser Leu Gln Leu Ala Trp Thr Pro Val Val Val 65 70 75 80 Leu Asn Gly Leu Ala Ala Val Arg Glu Ala Leu Val Thr His Gly Glu 85 90 95 Asp Thr Ala Asp Arg Pro Pro Val Pro Ile Thr Gln Ile Leu Gly Phe 100 105 110 Gly Pro Arg Ser Gln Gly Val Phe Leu Ala Arg Tyr Gly Pro Ala Trp 115 120 125 Arg Glu Gln Arg Arg Phe Ser Val Ser Thr Leu Arg Asn Leu Gly Leu 130 135 140 Gly Lys Lys Ser Leu Glu Gln Trp Val Thr Glu Glu Ala Ala Cys Leu 145 150 155 160 Cys Ala Ala Phe Ala Asn His Ser Gly Arg Pro Phe Arg Pro Asn Gly 165 170 175 Leu Leu Asp Lys Ala Val Ser Asn Val Ile Ala Ser Leu Thr Cys Gly 180 185 190 Arg Arg Phe Glu Tyr Asp Asp Pro Arg Phe Leu Arg Leu Leu Asp Leu 195 200 205 Ala Gln Glu Gly Leu Lys Glu Glu Ser Gly Phe Leu Arg Glu Val Leu 210 215 220 Asn Ala Val Pro Val Leu Leu His Ile Pro Ala Leu Ala Gly Lys Val 225 230 235 240 Leu Arg Phe Gln Lys Ala Phe Leu Thr Gln Leu Asp Glu Leu Leu Thr 245 250 255 Glu His Arg Met Thr Trp Asp Pro Ala Gln Pro Pro Arg Asp Leu Thr 260 265 270 Glu Ala Phe Leu Ala Glu Met Glu Lys Ala Lys Gly Asn Pro Glu Ser 275 280 285 Ser Phe Asn Asp Glu Asn Leu Arg Ile Val Val Ala Asp Leu Phe Ser 290 295 300 Ala Gly Met Val Thr Thr Ser Thr Thr Leu Ala Trp Gly Leu Leu Leu 305 310 315 320 Met Ile Leu His Pro Asp Val Gln Arg Arg Val Gln Gln Glu Ile Asp 325 330 335 Asp Val Ile Gly Gln Val Arg Arg Pro Glu Met Gly Asp Gln Ala His 340 345 350 Met Pro Tyr Thr Thr Ala Val Ile His Glu Val Gln Arg Phe Gly Asp 355 360 365 Ile Val Pro Leu Gly Val Thr His Met Thr Ser Arg Asp Ile Glu Val 370 375 380 Gln Gly Phe Arg Ile Pro Lys Gly Thr Thr Leu Ile Thr Asn Leu Ser 385 390 395 400 Ser Val Leu Lys Asp Glu Ala Val Trp Glu Lys Pro Phe Arg Phe His 405 410 415 Pro Glu His Phe Leu Asp Ala Gln Gly His Phe Val Lys Pro Glu Ala 420 425 430 Phe Leu Pro Phe Ser Ala Gly Arg Arg Ala Cys Leu Gly Glu Pro Leu 435 440 445 Ala Arg Met Glu Leu Phe Leu Phe Phe Thr Ser Leu Leu Gln His Phe 450 455 460 Ser Phe Ser Val Pro Thr Gly Gln Pro Arg Pro Ser His His Gly Val 465 470 475 480 Phe Ala Phe Leu Val Ser Pro Ser Pro Tyr Glu Leu Cys Ala Val Pro 485 490 495 Arg 4 17060 DNA Homo sapiens 4 tcatgctgcc atatcttgaa ttacaggcct ctggctggta aggagggcac tcgggaggac 60 actgcccaca ttgcaggcat gcctgtccct gcccttcaca cccccatcat gattcatgat 120 gactgcttgg ggagggcctg acacctcaaa aggccaagag tgcatacagg taatgtataa 180 agggccacat gtaacaagca cccacccaga ccatcctgct gtccctgcac cttgattctc 240 tcacagtccc aaatagaaca gtgctgccat gtaggacagg aacattcatt cagctgaggc 300 cagtttggga gaccacaagc cagatctgca gaagtcccca gataggcatg ggtcttgctc 360 tctctgtcag ttgagtagct tcaaaacttc tgttgggcca ggtggctcat gcctctattt 420 ccaacacttt gggaggccaa ggcaggagga tcacttgaag ccaggagttc cagaccagcg 480 tgggcaacat agtgaggacc catctcaaca aaaaaattag ccgagcgtaa tgatgtgcac 540 ctgtagttcc agctactcgg gacgctaaaa taggatctct tgattgaggc acaggagttt 600 gagtgagcta tgatcacagc tctgcactcc agcctgggca acagagcaag atcttgtctc 660 taaaaaatat atatatattt ttaaatttta aataaactgt tctccctgcc ttttgttccc 720 cagatccagt cttcatccag

acctgaaaag acccaggctc cagctgctgg cctcctgctg 780 cccctcaggc cacctgcaca ggaaattcca ggggtgggtt ggtcccactg ccagtgccgt 840 ggcctacagt gctaggcagc ccctcagtca gctagacaaa gttctccatg aatccttccc 900 agaaagtcct gttccagcct gggacaacgt ccccatggac cctcatggca ctgctggctt 960 gtcatgtcag ctatgttacc ttcctactcc ccgtggtcat cattacgttg gggcattgac 1020 tcacagcctt accaccatgc tcccagtaca cagcccagca cccagtacaa tccatacctc 1080 caacttgggt ggagctccca tgccaggcca cctctcgccc accaccctaa tctgggtagg 1140 caactagagc gagcaggggc aaggacctct gcagcagccc atacccgccc tggcctgacc 1200 ctgcacccac tggcagcaca gtcaacacag caggttggct cacagcagaa ggcaaaggcc 1260 atcatcagct ccctttataa gggaacggtc acgcgctcgg tgtgctgaga gtgtcctgcc 1320 tggtcctctg tgcctggtgg ggtgggggtg ccaggtgtgt ccagaggagc ccagttggta 1380 gtgaggcagc catggggctg gatgcactgg tgcccctggc agtgacagtg gccatcttcc 1440 tgctcctggt ggacctgatg cagcagcacc aacgctggac tgcacgctac ccgccaggcc 1500 ccctgccact gcccgggctg ggcaacttgc tgcatgtgga cttccagaac atatacacct 1560 tcaaccaggt gaggggagga ggtccgtgag gatcccccac caccagcaaa catgggtggt 1620 gggtggagcc acagtctgga caagaagcca ggctgagaag gggaagcaga tttgagggac 1680 ttcctgggga gggcatttat gcatggcatg aaagatggga ttttccaaag gccaaggaag 1740 agtagggcaa gggcctggag gtggagctgg acttggcagt gggcgtgcaa gcccattggg 1800 cagcatatgt taggagcaca aagtcccctc tgctgacacc agaaggaaag gccttgggaa 1860 tggaagacga gtcagggtcc tgtgtgccgt ttaaatcagg aaatcaggct gtgcgtggtg 1920 ctcacgctat aatcccagca cttaaggaag ccaaggtggg cggatcacct gaggtcaggg 1980 gttccagatg agtctggcca acatggcaaa aaccggtctc tactaaacat acaaaaaatg 2040 agctgggcac agtggtgcac gcctgcaatc ccagctactt gggaggctga ggcaggagaa 2100 ttgcttgaac ttaggaggca gaggttgtag tgagtggaga ttgtgccatt gccttgcaac 2160 ctcggtgaca cagccagaca atgtctaaat aaacgaataa gaaatcaggc cgggcgcggt 2220 ggctcacgcc tgtaatcccg gccctttgga ggctaaggcg ggcggatcat gaggttagga 2280 gatcgagacc atcctggcta acacaatgaa acccgtctct actaaagata caaaccaatt 2340 agccaggcga ggtggtgggc acctgtagtc ccagctactt gggaggctga ggcaggagaa 2400 tggcatgaac ccatgaggca gagcttgaag tgagctgaga acacaccatt acactccagt 2460 ctgggcgaca gagcgagact ctgtctcaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaat 2520 caacggctgg gcgcggtggc tcacacctgt aatcccagca tcttgggaga ccaaggtggg 2580 gggatcacaa ggtcaggagt tcgagaccag cctggccaac atggtgaaac cctgcctcta 2640 ctaaaaatac aaaaattagc ggggcacggt ggtgggcacc tgtaatccca gctacatggg 2700 aggctgaggc aggtgaattg cttgaacccg ggaggtggag gttgcagtga gccaagatcg 2760 cgcattgcgt ccagcctggg tgacagagcc agacatggtc taaataaatg agtaagttag 2820 aaatcaagga tgaagggata tagtggaccc ggttcaaacc ttttgcactg tgggtcctcg 2880 ggcctcactg ctcaccggca tggaccatca tctgggaatg ggatgctaac tggggcctct 2940 cggcaatttt ggtgactctt gcaaggtcat acctgggtga cgcatccaaa ctgagttcct 3000 ccatcacaga aggtgtgacc ccatccccgc cccaggatcg ggaggctggg tctcctcctt 3060 ccacctgctc actcctggta gccccgaggg tcgtctaagg ttcaaatagg actaggacct 3120 gcagtctggg gggaccctgg cctgatggag gccctgaccc aacggaggcc ctgaccctcc 3180 ctctacagct gcggcaccgc tttggggacg tgttcagcct gcagctggcc tggatgccgg 3240 tggtcgtgct caatgggctg gcggccgtgc gtgaggctct ggtgacctgc ggcgaggaca 3300 ccgccgaccg cccgcctgcg cccatctacc aggtcctggg catcgggccg cgctcccaag 3360 gcaagcggcg gtgggggaca gagactgcgt ttccgtgggt cctgggtggg cggtgaccgt 3420 agcccaagct gggctgagag ggcgtggggt tgtggacttg ggacacatag aaaggccagt 3480 gagtgggttg gggacagcga gccaggaaac cacttccact ggggaggtgc gagtctgtgg 3540 gcgggaggaa gaggggcttg tgagtgggcg gggcaactgc cgagacccac caggaaccgg 3600 gtgggcggac tggcgccttt cccagctgga agcgggtgtc tagaagccgg gatggactct 3660 gctgtgggct catatgggcg gggcgggacg ggcgggatct tccctgagtg gaaaggcagt 3720 cagggtcgga agagccaagg tggggccaag acccaagcaa ggtgagtgag caaagagcag 3780 gccctgtgcc cagctggaca gggccaggga ctgcgggaga ccaggaaaag cacagggttg 3840 gagtgggcgg cggagggcgg ggccaaggcc tccatgacca cgtccatgtg tccgtcccgc 3900 ccccaggggt gtttctggca cactacggac acgcgtggcg cgagcagagg cgcttctccg 3960 tgtccacctt gcgcaacttg ggcctgggca agaagtccct ggagcggtgg gtgaccgagg 4020 aggccgcctg cctctgtgcc gccttcgccg accaagccag tgggtgatgg gcagaggggc 4080 acaaagcggg aactgggaag gtggaggact gggaaggcga cccctgaccc gcatctcccg 4140 cccccaggac gcccctttca ccccaacggc ctcctgaaca aagcggcgag caacgtgatc 4200 gcctccctca cctgcgggtg ccgcttcgag tacgacgacc ctcgcttcct caggctactg 4260 gacctagctc agaagggatt gaaggaggag ctgggctttc tgtgagagat gtggagcgag 4320 ggaccgcagg gtctctgcag ggcgagctcc tgagaggtgc cgggactgca gccggacctc 4380 caaggagcag ggtttgcata gagtggtttg ggaaaggaca ttccagaaga gctcactgct 4440 agaggaaggg ccttgaggag gaggagacat ctcagatacg gtcgtgggag aggtgtgccc 4500 gggtcagggg gcaccaagaa aggccaagga ccctgtgcct cctgtccaca ttggagattt 4560 tgatttttag gtttctcctc tggcagccca gggcaaggag agagggtgga ggctggcact 4620 tggggaggga cttggggagg tgagtggtgg ggacaggcag gccctgggtc ttccctggag 4680 gcagctgggg cctgagactg gtccaggtga acgcagagca caggagggat tgagaccccg 4740 ttctgtgtca gctgtagatg ctgaatgttg tccccctcct cctgcgcatc ccagggctgg 4800 ctggcaaggt cctacgctcc caaaaggctt tcctgaccca gctggatgag ctgctgaccg 4860 agcacagaat gatctgggac ccagcctagc caccccgaga cctgactgag gccttcctgg 4920 cagagaagga gaaggtgaga gtggctgaca cggtagggac caggggtggt gggttgagcg 4980 tccgggagga atgaggcagg caaaaggtgg gtccattgga tcacttggca agtggcacct 5040 gggctgacag gtgcagaatg tggaggtcat ttgggggctt tcccgttctg tcccctgagt 5100 accctctcag ccctgctcag gccaagggga accctgagag cagcttcaat gatgagaacc 5160 tgcgcatggt ggtggctgac ctgttctttg ccgggatggt gaccacctcg atcacgctgg 5220 cctggggcct cctgctcatg atcctacgcc cggatgtgca gcgtgagccc agctggggcc 5280 cagtgcaggg ggcaagggag gaagggtaca ggtgggggcc cctgagctta gctgggacac 5340 ccgggactcc aagcacaggc ttggccaggt tcctgtaagc ctaacctcct ccaacacagg 5400 aggcaggaga gtgtcagggc tggtcccctg ggtgctgacc cattgtgggg acgcgtgtct 5460 gtccaggccg tgtccaacag atcgacaacg tgatagggca ggtgtggtga ccagagatgg 5520 gtgaccaggc tcgcatgccc tgcaccactg ccgtgattca cgaggtgcag cgctttgggg 5580 acatcgtccc cctgggtgtg acccatatga catcccgtga catcgaagta cagggcttcc 5640 gcatccctaa ggtaggcctg gcaccctcct caccccagct cagcaccagc ccctggtgat 5700 agccccagca tggccactgc caggtgggcc cagtctagga accctggcca cccagtcctc 5760 aatgccacca catcgactgt cccagcctgg gtgtggggtg cagagtatag gcagggctgg 5820 cctgtccatc cagagcccca gtctagtggg gaaggcagac caggacctgc cagaatgttg 5880 gaggacccca atacctgtag ggagaggggt agcgtgggcg ctcccaggag gtgtgactgc 5940 gccctgccgt ggggtcggag agggtgctct ggagcttctc gggcacagga ctagttgaca 6000 gagtccagct gtgtgccagg cagtgtgtgt cccctgtgtg cttgggggtc ccagcatcct 6060 agagtccagt ccccactctc accctgcatc tcctgcccag gggatgatgc tcttcaccaa 6120 cctgtcatcg gtgctgaagg atgaggccgt ctggaagaag cccttccgct tccaccccga 6180 acacttcctg gatgcccagg gccactttgt gaagccggag gccttcctgc ctttctcagc 6240 aggtgcctgt ggggagcccg gctcctgtcc ccttccgtgg agtcttgcag gggtatcacc 6300 cgggagccag gctcactgac gccctcccct ccccacaggc cgccgtgcat gcctcgggcc 6360 agcccctggc ccgcatagag ctcttcctct tcttcacctc cctgctgcag cacttcagct 6420 tctcggtgcc caccggacag ccccggccca gccactctcg tgtcgtcggc tttctggtga 6480 cgccatcccc ctatgagctt tgtgctgtgc cccgctagag ttgctcctca gctgggaccc 6540 tgttgtacaa taaattagtc tagtggctcc cacttggttt ctgtatccag tctgggcccc 6600 tgccaaggtc ctggttgtgt tgggtcgtca gtcacctgcc tgatgtcagt gctcacccct 6660 cacccctcac ccctcacctc attcattcat tttttttttt ttttttttga gatggagcct 6720 actctgtcac ccaggctgga gtgcagtggt gcaatctcag ctcactgcaa cctccgcctc 6780 cagagttcaa gcgattctcg tgcctcagct tcctgagtag ctgggattac aggcaccggg 6840 taccaccccc ggctcatttt tgtcttttta gtagtgatgg gtttcgccat gttggccagt 6900 ctggtttcaa actcctgact tcacgtgacc accagcctca gcctcccaaa gtgctgggat 6960 tacaggcgtg agccaccgag accagcctca cctcattcac tcttacctgg acgcctgact 7020 ttacttgaga tacaggcata gtgattctca gcaggaaaca gcctgccccc acgtcacgcc 7080 cagagaccca tcactggctg cctggcttgg tgacaaagtc catgcgtaag tcttggctgg 7140 ggtggatatg aataggcata tgccaagaat caacccattc cctggctagg gtgggagact 7200 gtgttgtgct cccccagacc accctcaggt tcagtgattt ctagaaggtc tcacagccct 7260 agaaaagctg ttattctccc tgttaacagt ttattacaga gaagggtaca gattaaagtc 7320 agcaaagatg aaaggcacag ggaccagagt ccagaatgac caggccaagg ctgcagctct 7380 cttttctggt ggactcctac aggcagtgct taattctccc ccaacagtaa gtgaggcagc 7440 agagagccct gccagccacg gaagctcacc tgggccttgg tgtccatggt ttttgttggg 7500 agttggtcat cctaggcttg agcccccgca gcatggctga ccttggtcat cctaggcttg 7560 agcccccgca gcatggctga cctcagttac tcagtctcca gcccctcctg aagtcagatg 7620 gatacacgtg acggccccac cctcgatcac attgttggca taaactgtgt tgtacggtcc 7680 aaggccctag ctatgtacaa agacactatt tcaggcagga cattccaagg ccttagcaga 7740 tatctcccag cctcctgtca agagtcagtt tggactcttg gtccagtggc ttgcattgtg 7800 caaggaatga cttccccact ttttactaca caggccaccc ctcttggctc taacagcaaa 7860 atgatattag tttgagcatc tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtttt 7920 cttgagacag ggtcttgctc tgtcaccgag gctggagtgc agtgatgcca tcagggctca 7980 ctgcagcctt gacttcctgg gttcaagcaa tcctcccatc tcagcctccc tagtagctgg 8040 gactgcaggc acatgccacc atgctttgct aatttttgta ttttttgtag agacggagtt 8100 tcaccatgtt ggccaggctg ctttcgaact ccctatctca ggtcatctga ctgcctcagc 8160 ccccagagtg ctgggattac aggtgtaagc tactgtgccc agccaaattt ccttcctaat 8220 ttcttcattg aaccactggc cattccggac catattgttt aattttcacg tgtatgtata 8280 gtttccagaa ttcctcttgt tgttgatttc cacttttatt ctgttgtggt cagagaagat 8340 gcttgatatt attttaacat ttgtaatgtt ttaagacttg ccttgtgacc taacatatgg 8400 tgtatccttg agaatgatcc atgtgctgag gagaagaatg tgtattctgc agactttaga 8460 cgaagtgttc tgtaagtatc tagtaggtcc atttcttttg tagtgcagat taagtctaat 8520 gttttcttat tgggtttcca tctgggacac ccgtccaatg ctgaatgtgg ggtgttgacg 8580 tctttagctg ttattgcgtt aacgtctctc ttgggctcca ataacatttg ctttacgtgc 8640 tccagtgttg tgtgcatatg tatttacaat tgttatattc tgttgctgga tgaccttctt 8700 tgtctcctct tacagttttt ttggttgttg ttgtttgttt gttttgtttt ggagagggag 8760 tctcgctctg tcacccaggc tggagtgcag tggcgcgatc ttggctcact gcaagcttcg 8820 cctcccaggt tgacgccatt ctcctgcctc agcctcctga gtagctggga ctacaggcgc 8880 ccgccaccac gcctggctaa ttttttgtat ttttagtaga gacggggttt caccatgtta 8940 gccaggatag tctcaatctc ctgacctcgt gatccgcccg cctcagcctc ccaaagtgct 9000 gggattacag gcgtgagcca ccacacccgg cctcctctta cagtttttgt tttaaaatct 9060 gttctgtcta agtattgcta ctcctgctct tttttgtttt ccattggcat ggagtatctt 9120 tttccatccc tttattttca gtctatgtgt atctttacag gtgaagtgtg tttcttctag 9180 acaaaagagc attgagcttt gctttttcat ccattcagcc actctgtgtc tttgtattgg 9240 agagtttagt ccatttacat tcaatgttat tattgctaag cagggactta ctcctgctat 9300 tttgttattt cttttctcac tgttttgtgg tcttctcttt tttttttttt ttccttgtct 9360 tccttttaat gaaggtgatt ttctctggtg gtatgattta atttcttgct tttttttgtg 9420 tgtgtatcca ttgtgtgttt tttcttcttt tctttttgag acacagtctc acttattgtg 9480 tgctttttga tttgaggttg ccgtgaggct tggcaaatat tatcttataa ctcattattt 9540 taaacggatg acaacactga ttgcgtaaac aaacataaag caaaaggaag actaataaaa 9600 actctacact ttaagttcat cttagtgctt tttaactttt tgttgtttct ctttttttgt 9660 ttttgagata aagtcttgct ctgttgccca ggctagagtg cagtggcacg atctcagctc 9720 actgtaacct ccacttccca ggttcaaccg attctcctgc ctcagcctcc tgggtagcag 9780 gcgcccacca ccatgcccag ctaaattttt tgtattttta gtagagatgg ggtttcacca 9840 tgttggccag gcttgtctcg aactcctgcc ctcaggtgat ccacccacct cagccttaca 9900 aagtgctggg attacctgcg tgagccaccg ggtccggcct ctttatgtct tactgtactg 9960 tctgtcttga aaagtactta ttatttttga ttggttcatc atttagtcta attaaaataa 10020 gagtagttta cacaccacaa ttacagtatt ataatactct gtttttctgt gtgcttacta 10080 ttaccagtga gttttgtacc tttagatgat ttcttcttgc tcattaatat cctttttttt 10140 ttcagattga aaaactccct ttagcatttc ttgtgggata taggtctggt gttgatgaaa 10200 tctcgcagct tttgtttgtc tgggaaggtc tttatttctc cttcctgttg gaaggatatt 10260 tttgccagat acgttattct aggctaaaag ttttttttcc ttcagcactt taaatatgtc 10320 atgccactcc cccctggcct gtaaggtttc cactggaaag gtggctgccc catgtcatgt 10380 attggagctc tactgcatgt tatttgtttc ttttctcttg ctgcttttag gatccacgtg 10440 acagctttga ggctcaccgg gagcagcctc tggacaggag aggtcccatc caggaaacct 10500 cgggcatggc tgggaagtgg ggtacttggt gccgggtctg tatgtgtgtg tgactggtgt 10560 gtgtgagaga gaatgtgtgc cctgagtgtc agtgtgagtc tgtgtatgtg tgaatattgt 10620 ctttgtgtgg gtgattttct gcatgtgtaa tcgtgtccct gcaagtgtga acaagtggac 10680 aagtgtctgg gagtggacaa gagatctgtg caccatcagg tgtgtgcata gcgtctgtgc 10740 atgtcaagag tgcaaggtga agtgaaggga ccaggcccat gatgccactc atcatcagga 10800 gctctaaggc cccaggtaag tgccagtgac agataagggt gctgaaggtc actctggagt 10860 gggcaggtgg gggtagggaa agggcaaggt catgttctgg aggaggggtt gtgactacat 10920 tagggtgtat gagcctagct gggaggtgga tggccgggtc cactgagacc ctggttatcc 10980 cagaagcctg tgtgggcttg gggagcttgg agtggggaga gggggtgact tctccgacca 11040 ggcctttcta ccaccctacc ctgggtaagg gcctggagca ggaagcagcg gcaaggacct 11100 ctgcagcagc ccatacccgc cctggcctga ccctgcaccc actggcagca cagtcaacac 11160 agcaggttgg ctcacagcag agggcgaagg ccatcatcag ctccctttat aagggaaggg 11220 tcacgcgctc ggtgtgctga gagtgtcctg cctggtcctc tgtgcctggt ggggtggggg 11280 tgccaggtgt gtccagagga gcccagttgg tagtgaggca gccatggggc tagaagcact 11340 ggtgcccctg gccatgatag tggccatctt cctgctcctg gtggacctga tgcaccggca 11400 ccaacgctgg gctgcacgct acccgccagg tcccctgcca ctgcccgggc tgggcaacct 11460 tgctgcatgt ggacttccag aacacaccat actgcttcga ccaggtgagg gaggaggtcc 11520 tggagggcgg cagaggtcct gaggatgccc caccaccagc aaacatgggt ggtgggttaa 11580 accacaggct ggatcagaag ccaggctgag aaggggaagc aggtttgggg gactcctggg 11640 gaaggacatt tatacatggc atgaaggact ggattttcca aaggccaagg aagagtaggg 11700 caagggcctg gaggtggagc tggacttggc agtgggcatg caagcccatt gggcaacata 11760 tgttatggag tacaaagtcc cttctgctga caccagaagg aaaggccttg ggaatggaag 11820 atgagttagt cctgagtgcc gtttaaatca cgaaatcgag gatgaagggg gtgcagtgac 11880 ccggttcaaa ccttttgcac tgtgggtcct cgggcctcac tgctcaccgg catggaccat 11940 catctgggaa tgggatgcta actggggcct ctcggcaatt ttggtgactc ttgcaaggtc 12000 atacctgggt gacgcatcca aactgagttc ctccatcaca gaaggtgtga cccccacccc 12060 cgccccagga tcaggaggct gggtctcctc cttccacctg ctcactcctg gtagccccgg 12120 gggtcgtcca aggttcaaat aggactagga cctgtagtct ggggggatcc tggcttgaca 12180 agaggccctg accctccctc tgcagttgcg gcgccgcttc ggggacgtgt tcagcctgca 12240 gctggcctgg acgccggtgg tcgtgctcaa tgggctggcg gccgtgcgcg aggcgatggt 12300 gacccgcggc gaggacacgg ccgaccgccc gcctgcgccc atctaccagg tcctgggctt 12360 cgggccgcgt tcccaaggca agcggcggtg ggggacagag accgcgtttc cgtgggcccc 12420 gggtggacag tgaccgtagc ccaagcagcg ccgacagggc gtggggtcct ggacgtgaaa 12480 cagagataaa ggccagcgag tgggctgagg acagtgggcc aggaaaccac ctgcacgggg 12540 gaggtgcgag tctgtgggct gggagggggc ggggctactg cccagacccg ccagaagccc 12600 ggtgggcgag gctgatgcgt cgaagtggcg gtggcgggga cgcgcctatg ctgcgggctc 12660 agtgtgggcg ggacgggcgg gatcttcctt gagtggaaag gtggtcaggg tgggcagaga 12720 cgaggtgggg ccaaaccccg ccccaggcag gggagcaatg tgggtgagca aagagtgggc 12780 cctgtgccca gctggaccgg gctagggact gcgggagacc ttgtggagcg ccagggttgg 12840 agtgggtggc ggagggtggg gccaaggcct tcatggcaac gcccacgtgt ccgtcccgcc 12900 cccaggggtg ttcctggcgc gctatgggcc cgcgtggcgc gagcagaggc gcttctccgt 12960 gtccaccttg cgcaacttgg gcctgggcaa gaagtcgctg gagcagtggg tgaccgagga 13020 ggccgcctgc ctttgtgccg ccttcgccga ccaagccggt gggtgatggg cagaagggca 13080 cacagcggga actgggaagg cgggggacgg agaaggcgac cccttacccg catctcccac 13140 ccccaggacc gccctttcgc cccaacggtc tcttggacaa agccgtgagc aacgtgatcg 13200 cctccctcac ctgcgggcgc cgcttcgagt acgacgaccc tcgcttcctc aggctgctgg 13260 acctagctca ggagggactg aaggaggagt cgggcttcct gcgcgaggtg cggagcaagg 13320 gtctttgcag ggcgagctcc tgagaggtgc cggggctgga ctggggcctc cgaagggcag 13380 gatttgcgta gatgggtttg ggaaaggaca ttccaggaga ccccactgta agaagggcct 13440 ggaggaggag gggacatctc agacatggtc gtgggagagg tgtgcccggg tcagggggca 13500 ccaggagagg ccaaggactc tgtacccccg tccacgttgg agatttcgat tttaggtctc 13560 tcctctgggc aaggagagag agggtggagg ctggcacttg gggagggact tggtgaggtc 13620 agtggtaagg acaggcaggc cctgggtctt cctggagatg gctggggcct gagactggtc 13680 cagatgaacg cagagcacag gagggattga gaccccgttc tgtctggtgt aggtgctgaa 13740 tgctgtcccc gtcctcctgc acatcccagc gctggctggc aaggtcctac gcttccaaaa 13800 ggctttcctg acccagctgg atgagctgct aactgagcac aggatgacct gggacccagc 13860 ccagcccccc cgagacctga ctgaggcctt cctggcagag atggagaagg tgagagtggc 13920 tgccacggtg gggggcaagg gtggtgggtt gaacgtccca ggaggaatga ggggaggctg 13980 ggcaaaaggt tggaccagtg catcacccgg cgagccgcat ctgggctgac aggtgcagaa 14040 ttggaggtca tttgggggct accccgttct atcccctgag tatcctctcg gccctgctca 14100 ggccaagggg agccctgaga gcagcttcaa tgatgagaac ctgcgcatag tggtgggtaa 14160 cctgttcctt gccgggatgg tgaccacctt gaccacgctg gcctggggcc tcctgctcat 14220 gatcctacac ctggatgtgc agcgtgagcc cagctggggc ccaaggcagg gactgaggga 14280 ggaagggtac agctgggggc ccctgggctt agctgggaca cccggggctt ccagcacagg 14340 cgtggccagg ctcctgtaag cctaacttcc tccaacacag gacgaaggag agtgtcccct 14400 gggtgctgac ccattgtggg gacgcatgtc tgtccagtcc gtgtccaaca ggagatcgac 14460 gacgtgatag ggcaggtgcg gcgaccagag atgggtgacc aggctcacat gccctacacc 14520 actgccgtga ttcacgaggt gcagcgcttt ggggacatca tccccctgag tgtgacccat 14580 atgacatccc atgacatcga agtacagggc ttccgcatcc ctaaggtagg cctggcgccc 14640 tcctcacccc agctcagcat cagccccggt ggtagcccca gcatggctac tgccaggtgg 14700 gcccactcta ggaaccctgg ccacctagtc ctcaatgcca ccacactgac tgtccccgct 14760 tgggtggggg gtccagagta taggcagggc tggcctgtcc atccagagcc cccgtctagt 14820 ggggaagaca aatcaggacc tgccagaatg ttggaggacc cagcgcctgc agggagaggg 14880 ggcagtgtgg gtgcctctga gaggtgtgac tgcgccctgc tgtggggtcg gagagggtac 14940 tgtggagctt ctcgggcgca ggactagttg acagagtcca gctgtgtgcc aggcagtgtg 15000 tgtcccccgt gtgtttggtg gcaggggtcc cagcatccta gagtccagtc cccactctca 15060 ccctgcatct cctgcccagg gaacgacact catcaccaac ctgtcatcgg tgctgaagga 15120 tgaggccgtc tggaagaagc ccttccgctt ccaccccgaa cacttcctgg atgcccaggg 15180 ccactttgtg aagccggagg ccttcctgcc tttctcagca ggtgcctgtg gggagcccgg 15240 ctccctgtcc ccttccgtgg agtcttgcag gggtatcacc caggagccag gctcactgac 15300 gcccctcccc tccccacagg ccgccgtgca tgcctcgggg agcccctggc ccgcatggag 15360 ctcttcctct tcttcacctc cctgctgcag cacttcagct tctccgtggc cgccggacag 15420 ccccggccca gccactctcg tgtcgtcagc tttctggtga ccccatcccc ctacgagctt 15480 tgtgctgtgc cccgctagaa tggggtacct agtccccagc ctgctcccta gccagaggct 15540 ctaatgtaca ataaagcaat gtggtagttc caactcgggt cccctgctca cgccctcgtt 15600 gggatcatcc tcctcagggc aaccccaccc ctgcctcatt cctgcttacc ccaccgcctg 15660 gccgcatttg agacgggtac gttgaggctg agcagatgtc agttaccctt gcccataatc 15720 ccatgtcccc cactgaccca actctgactg cccagattgg tgacaaggac tacattgtcc 15780 tggcatgtgg ggaaggggcc

agaatgggct gactagaggt gtcagtcagc cctggatgtg 15840 gtggagaggg caggactcag cctggaggcc catatttcag gcctaactca gcccacccca 15900 catcagggac agcagtcctg ccagcaccat cacaacagtc acctcccttc atatatgaca 15960 ccccaaaatg gaagacaaat catgtcaggg agctatatgc cagggctacc tcccagggct 16020 cagtcggcag gtgccagaac attccctggg aaggccccag gaaaacccag gaccgagcca 16080 ccgccctcag cctgtcacct tgtgtccaaa attggtgggt tcttggtctc actgacttca 16140 agaatgaagc cgtggaccct cacggtgagt gttacagttc ttaaagatgg tgtgttcaga 16200 gtttgttcct tctgatgtta agacgtgttc agagtttctt ccttctggtg ggtgcgtggt 16260 cttgctggct tcaggagtga agctgcagac cttcacagtg agtgttacgg ctcttaaggc 16320 tgcacgtacg gagttgttca ttcttcctgg tgggtttgtg gtctcactgg cctcaggagt 16380 gaaactgcag tccttccagt gttacaactc ataaaggcag tgtggaccca atgagggagc 16440 agcagcagca agacttactg caaacagcaa aagaatgatg gcaaccaggt tgccgctgct 16500 acttcaggca gcctgctttt attcccttat ctgaccccca cccacatcct gctgattggc 16560 ccattttaca gacagtggat tggtccactt acagagagct gattggtgca tttacaatcc 16620 ctgagctaga cacagagtac tgattggtat atttacaaac cttgagctag acacagagtg 16680 ctgaatggtg tatttacaat cccttagcta gacataaagg ttgtcccagt ccccactaga 16740 ttagctagat agagtagaca gagagcactg attggtgcgt ttacaaacct tgagttagac 16800 acagggtgct gactggtgtg tttacaaacc ttgagctaga cacagagtgc tgattggtgt 16860 atttacaatc ttttagctag aaataaaagt tccccaagtc cccaccagat tagctagata 16920 cagagtgcta attggtgcat gcacaacccg gagctagaca cagagtgctg attggtgcat 16980 atacaatcct ctggctagac ataaaagttc tccaagtccc cacctgactc agagcccagc 17040 cagcttcgcc tagtggatcc 17060 5 13278 DNA Homo sapiens 5 attaccagtg agttttgtac ctttagatga tttcttcttg ctcattaata tccttttttt 60 tttcagattg aaaaactccc tttagcattt cttgtgggat ataggtctgg tgttgatgaa 120 atctcgcagc ttttgtttgt ctgggaaggt ctttatttct ccttcctgtt ggaaggatat 180 ttttgccaga tacgttattc tcggctaaaa gttttttttc cttcagcact ttaaatatgt 240 catgccactc ccccctggcc tgtaaggttt ccactggaaa ggtggctgcc ccatgtcatg 300 tattggagct ctactgcatg ttatttgttt cttttctctt gctgctttta ggatccacgt 360 gacagctttg aggctcactg ggagcagcct ctggacagga gaggtcccat ccaggaaacc 420 ttgggcatgg ctgggaagtg gggtacttgg tgccgggtct gtatgtgtgt gtgactggtg 480 tgtgtgagag agaatgtgtg ccctgagtgt cagtgtgagt ctgtgtatgt gtgaatattg 540 tctttgtgtg ggtgattttc tgcatgtgta atcgtgtccc tgcaagtgtg aacaagtgga 600 caagtgtctg ggagtggaca agagatctgt gcaccatcag gtgtgtgcat agcgtctgtg 660 catgtcaaga gtgcaaggtg aagtgaaggg accaggccca tgatgccact catcatcagg 720 agctctaagg ccccaggtaa gtgccagtga cagataaggg tgctgaaggt cactctggag 780 tgggcaggtg ggggtaggga aagggcaagg ccatgttctg gaggaggggt tgtgactaca 840 ttacggtgta tgagcctagc tgggaggtgg atggccgggt ccactgagac cctggttatc 900 ccagaagcct gtgtgggctt ggggagcttg gagtggggag agggggtgac ttctccgacc 960 aggcctttct accaccctac cctgggtaag ggcctggagc aggaagcagc ggcaaggacc 1020 tctggagcag cccataccca ccctggcctg actctgccac tggcagcaca gtcaacacag 1080 caggttcact cacagcagag ggcaaaggcc atcatcagct ccctttataa gggaagggtc 1140 acgcgctcgg tgtgctgaga gtgtcctgcc tggtcctctg tgcctggtgg ggtgggggtg 1200 ccaggtgtgt ccagaggagc ccagttggta gtgaggcagc catggggcta gaagcactgg 1260 tgcccctggc catgatagtg gccatcttcc tgctcctggt ggacctgatg caccggcacc 1320 aacgctgggc tgcacgctac ccgccaggtc ccctgccact gcccgggctg ggcaaccttg 1380 ctgcatgtgg acttccagaa cacaccatac tgcttcgacc aggtgaggga ggaggtcctg 1440 gagggcggca gaggtcctga ggatgcccca ccaccagcaa acatgggtgg tgggttaaac 1500 cacaggctgg atcagaagcc aggctgagaa ggggaagcag gtttggggga cgtcctgggg 1560 aaggacattt atacatggca tgaaggactg gattttccaa aggccaagga agagtagggc 1620 aagggcctgg aggtggagct ggacttggca gtgggcatgc aagcccattg ggcaacatat 1680 gttatggagt acaaagtccc ttctgctgac accagaagga aaggccttgg gaatggaaga 1740 tgagttagtc ctgagtgccg tttaaatcac gaaatcgagg atgaaggggg tgcagtgacc 1800 cggttcaaac cttttgcact gtgggtcctc gggcctcact gctcaccggc atggaccatc 1860 atctgggaat gggatgctaa ctggggcctc tcggcaattt tggtgactct tgcaaggtca 1920 tacctgggtg acgcatccaa actgagttcc tccatcacag aaggtgtgac ccccaccccc 1980 gccccaggat caggaggctg ggtctcctcc ttccacctgc tcactcctgg tagccccggg 2040 ggtcgtccaa ggttcaaata ggactaggac ctgtagtctg gggggatcct ggcttgacaa 2100 gaggccctga ccctccctct gcagttgcgg cgccgcttcg gggacgtgtt cagcctgcag 2160 ctggcctgga cgccggtggt cgtgctcaat gggctggcgg ccgtgcgcga ggcgatggtg 2220 acccgcggcg aggacacggc cgaccgcccg cctgcgccca tctaccaggt cctgggcttc 2280 gggccgcgtt cccaaggcaa gcggcggtgg gggacagaga ccgcgtttcc gtgggccccg 2340 ggtggacagt gaccgtagcc caagcagcgc cgacagggcg tggggtcctg gacgtgaaac 2400 agagataaag gccagcgagt gggctgagga cagtgggcca ggaaaccacc tgcacggggg 2460 aggtgcgagt ctgtgggctg ggagggggcg ggctactgcc cagacccgcc agaagcccgg 2520 tgggcgaggc tgatgcgtcg aagtggcggt ggcggggacg cgcctatgct gcgggctcag 2580 tgtgggcggg acgggcggga tcttccttga gtggaaaggt ggtcagggtg ggcagagacg 2640 aggtggggcc aaaccccgcc ccaggcaggg gagcaatgtg ggtgagcaaa gagtgggccc 2700 tgtgcccagc tggaccgggc tagggactgc gggagacctt gtggagcgcc agggttggag 2760 tgggtggcgg agggtgggcc aaggccttca tggcaacgcc cacgtgtccg tcccgcccac 2820 aggggtgatc ctgtcgcgct atgggcccgc gtggcgcgag cagaggcgct tctccgtgtc 2880 caccttgcgc aacttgggcc tgggcaagaa gtcgctggag cagtgggtga ccgaggaggc 2940 cgcctgcctt tgtgccgcct tcgccgacca agccggtggg tgatgggcag aagggcacac 3000 agcgggaact gggaaggcgg gggacggaga aggcgacccc ttacccgcat ctcccacccc 3060 caggacgccc ctttcgcccc aacggtctct tggacaaagc cgtgagcaac gtgatcgcct 3120 ccctcacctg cgggcgccgc ttcgagtacg acgaccctcg cttcctcagg ctgctggacc 3180 tagctcaggg agggatcgaa ggaggagtcg ggcttcctgc gcgaggtgcg gagcaagggt 3240 ctttgcaggg cgagctcctg agaggtgccg gggctggact ggggcctccg aagggcagga 3300 tttgcgtaga tgggtttggg aaaggacatt ccaggagacc ccactgtaag aagggcctgg 3360 aggaggaggg gacatctcag acatggtcgt gggagaggtg tgcccgggtc agggggcacc 3420 aggagaggcc aaggactctg tacccccgtc cacgttggag atttcgattt taggtttctc 3480 ctctgggcaa ggagagagag ggtggaggct ggcacttggg gagggacttg gtgaggtcag 3540 tggtaaggac aggcaggccc tgggtcttcc tggagatggc tggggcctga gactggtcca 3600 gatgaacgca gagcacagga aggattgaga cccggttctg tctggtgtag gtgctgaatg 3660 ctgtccccgt cctcccgcac atcccagcgc tggctggcaa ggtcctacgc ttccaaaagg 3720 ctttcctgac ccagctggat gagctgctaa ctgagcacag gatgacctgg gacccagccc 3780 agccaccccg agacctgact gaggccttcc tggcaaagaa ggagaaggtg agagtggctg 3840 ccacggtggg gggcaagggt ggtgggttga acgtcccagg aggaatgagg ggaggctggg 3900 caaaaggttg gaccagtgca tcacccggcg agccgcatct gggctgacag gtgcagaatt 3960 ggaggtcatt tgggggctac cccgttctat cccctgagta tcctctcggc cctgctcagg 4020 ccaaggggag ccctgagagc agcttcaatg atgagaacct gcgcatagtg gtgggtaacc 4080 tgttccttgc cgggatggtg accaccttga ccacgctggc ctggggcctc ctgctcatga 4140 tcctacacct ggatgtgcag cgtgagccca gctggggccc aaggcaggga ctgagggagg 4200 aagggtacag ctgggggccc ctgggcttag ctgggacacc cggggcttcc agcacaggcg 4260 tggccaggct cctgtaagcc taacttcctc caacacagga ggaaggagag tgtcccctgg 4320 gtgctgaccc attgtgggga cgcatgtctg tccagtccgt gtccaacagg agatcgacga 4380 cgtgataggg caggtgcggc gaccagagat gggtgaccag gctcacatgc cctacaccac 4440 tgccgtgatt catgaggtgc agcactttgg ggactcgtcc ccctgggtgt gacccatatg 4500 acatcccgtg acatcgaagt acagggcttc cgcatcccta aggtaggcct ggcgccctcc 4560 tcaccccagc tcagcaccag cccctggtga tagccccagc atggctactg ccaggtgggc 4620 ccactctagg aaccctggcc acctagtcct caatgccacc acactgactg tccccacttg 4680 ggtggggggt ccagagtata ggcagggctg gcctgtccat ccagagcccc cgtctagtgg 4740 ggaagacaaa ccaggacctg ccagaatgtt ggaggaccca gcgcctgcag ggagaggggg 4800 cagtgtgggt gcctctgaga ggtgtgactg cgccctgctg tggggtcgga gagggtactg 4860 tggagcttct cgggcgcagg actagttgac agagtccagc tgtgtgccag gcagtgtgtg 4920 tcccccgtgt gtttggtggc aggggtccca gcatcctaga gtccagtccc cactctcacc 4980 ctgcatctcc tgcccaggga acgacactca tcaccaacct gtcatcggtg ctgaaggatg 5040 aggccgtctg gaagaagccc ttccgcttcc accccgaaca cttcctggat gcccagggcc 5100 actttgtgaa gccggaggcc ttcctgcctt tctcagcagg tgcctgtggg gagcccggct 5160 ccctgtcccc ttccgtggag tcttgcaggg gtatcaccca ggagccaggc tcactgacgc 5220 ccctcccctc cccacaggcc gccgtgcatg cctcggggag cccctggccc gcatggagct 5280 cttcctcttc ttcacctccc tgctgcagca cttcagcttc tccgtggccg ccggacagcc 5340 ccggcccagc cactctcgtg tcgtcagctt tctggtgacc ccatccccct atgagctttg 5400 tgctgtgccc cgctagaatg gggtacctag tccccagcct gttccctagc cagaggctct 5460 aatgtacaat aaagcaatgt ggtagttcca actcgggtcc cctgctcacg ccctcgttgg 5520 gatcatcctc ctcagggcaa ccccacccct gcctcattcc tgcttacccc accgcctggc 5580 cgcatttgag acgggtacgt tgaggctgag cagatgtcag ttacccttgc ccataatccc 5640 gtgtccccca ctgacccaac tctgactgcc cagattggtg acaaggacta cattgtcctg 5700 gcatgtgggg aaggggccag aatgggctga ctagaggtgt cagtcagccc tggatgtggt 5760 ggagagggca ggactcagcc tggaggccca tatttcaggc ctaactcagc ccaccccaca 5820 tcagggacag cagtcctgcc agcaccatca caacagtcac ctcccttcat atatgacacc 5880 ccaaaatgga agacaaatca tgtcagggag ctatatgcca gggctacctc ccagggctca 5940 gtcggcaggt gccagaacat tccctgggaa ggccccagga aaacccagga ccgagccacc 6000 gccctcagcc tgtcaccttg tgtccaaaat tggtgggttc ttggtctcac tgacttcaag 6060 aatgaagctg tggaccctca cggtgagtgt tacagttctt aaagatggtg tgttcagagt 6120 ttgttccttc tgatgttaag acgtgttcag agtttcttcc ttctggtggg tgcgtggtct 6180 tgctggcttc aggagtgaag ctgcagacct tcacagtgag tgttacggct cttaaggctg 6240 cacgtacgga gttgttcatt cttcctggtg ggtttgtggt ctcactggcc tcaggagtga 6300 aactgcagtc cttccagtgt tacaactcat aaaggcagtg tggacccaat gagggagcag 6360 cagcagcaag acttactgca aacagcaaaa gaatgatggc aaccaggttg ccgctgctac 6420 ttcaggcagc ctgcttttat tcccttatct gacccccacc cacatcctgc tgattggccc 6480 attttacaga cagtggattg gtccacttac agagagctga ttggtgcatt tacaatccct 6540 gagctagaca cagagtactg attggtatat ttacaaacct tgagctagac acagagtgct 6600 gaatggtgta tttacaatcc cttagctaga cataaaggtt gtcccagtcc ccactagatt 6660 agctagatag agtagacaga gagcactgat tggtgcgttt acaaaccttg agttagacac 6720 agggtgctga ctggtgtgtt tacaaaccct gagctagaca cagagtgctg attggtgtat 6780 ttacaatctt ttagctagaa ataaaggttc cccaagtccc caccagatta gctagataca 6840 gagtgctaat tggtgcatgc acgaacccgg agctagacac agagtgctga ttggtgcata 6900 tacaatcctc tggctagaca taaaagttct ccaagtcccc acctgactca ggagcccagc 6960 cagcttcgcc tagtggatcc tatgccaggg ccacaggcag agctgcctgc tagtcccaca 7020 ccaggcacct gtactcctca gcccttgggc agtggacggg accaggtgcc gtggagcagt 7080 gggaggcacc catccgggag gcttgggcct cgcagggagc ccaccgtagg gaggcttggg 7140 catggcaggc tgcaagtcct gagccctgcc ccgcggggag gtgactgagg cctggcgaca 7200 attcaagtgt ggtgagcgcc ggcagcagca gtactggggg acccggtgcc ccctctgcag 7260 ctgctggccc aggtgctaag cccctcactg cctggggcca gaggcaccag ccggccgctc 7320 cgagtgcagg gcccgctgag cccctgccca cccagaactg gtgctggccc gcgagcaacc 7380 caggttcccg cacacgcctc tccctccata cctccccgca agcagacgga gccggctcca 7440 gcctccacca gtccagagag gggctcccac agtgcagcgc tgggctgaag ggctcctcaa 7500 gtgtggtcag agcagaagct gaggccgagg aggcgctgag agcgagcgag gaccgccagc 7560 acgttgacac ctctcaacct caccacagga ctggccacct ctctgggccc tcagggatgc 7620 tgctgtctgg acccctgacc agtgacgagt tcgcactcag ggccaggctg gcgctggagg 7680 aggacacttg tttggctcca accctaggta ccatcctccc agtagggatc aggcagggcc 7740 cacaggctgc cctagggaca ggagtcaacc ttggacccat aaggcactgg ggcgggcaga 7800 gaaggaggag gtggcatggg cagctgagag ccagagaccc tgaccctagt ccttgctctg 7860 ccattacccc gtgtgacccc gggcccaccc ttccccaccc ttccccaccc cgggcttctg 7920 tttcccttct gccaacgaga aggctgcttc acctgccccg agtcctgtct tcctgctctg 7980 ccttctgggg ctgtggccct tgctggcctg gagccccaac caagggcagg gactgctgtc 8040 ctccacatct gtcctcaccg acataatggg ctgggctggg cacacaggca gtgcccaaga 8100 gtttctaatg agcatatgat tacctgagtc ctgggcagac cttcttaggg aacagcctgg 8160 gacagagaac cacagacact ctgaggagcc acctgaggcc tcttttgcca gaggacccta 8220 cagcctccct ggcagcagtt ccgccagcat ttctgtaaat gccctcatgc cagggtgcgg 8280 cccggctgtc agcacgagag ggacgttggt ctgtcccctg gcaccgagtc agtcagaagg 8340 gtggccaggg cccccttggg cccctccaga gacaatccac tgtggtcaca cggctcggtg 8400 gcaggaagtg ctgttcctgc agctgtgggg acagggagtg tggatgaagc caggctgggt 8460 ttgtctgaag acggaggccc cgaaaggtgg cagcctggcc tatagcagca gcaactcttg 8520 gatttattgg aaagattttc ttcacggttc tgagtcttgg gggtgttaga ggctcagaac 8580 cagtccagcc agagctctgt catgggcacg tagacccggt cccagggcct ttgctctttg 8640 ctgtcctcag aggcctctgc aaagtagaaa caggcagcct tgtgagtccc ctcctgggag 8700 caaccaaccc tccctctgag atgccccggg gccaggtcag ctgtggtgaa aggtagggat 8760 gcagccagct caggggagtg gcccagagtt cctgcccacc caaggaggct cccaggaagg 8820 tcaaggcacc tgactcctgg gctgcttccc tcccctcccc tccccaggtc aggaaggtgg 8880 gaaagggctg gggtgtctgt gaccctggca gtcactgaga agcagggtgg aagcagcccc 8940 ctgcagcacg ctgggtcaat ggtcttacca gatggatacg cagcaacttc cttttgaacc 9000 tttttatttt cctggcagga agaagaggga tccagcagtg agatcaggca ggttctgtgt 9060 tgcacagaca gggaaacagg ctctgtccac acaaagtcgg tggggccagg atgaggccca 9120 gtctgttcac acatggctgc tgcctctcag ctctgcacag acgtcctcgc tcccctggga 9180 tggcagcttg gcctgctggt cttggggttg agccagcctc cagcactgcc tccctgccct 9240 gctgcctccc actctgcagt gctccatggc tgctcagttg gacccacgct ggagacgttc 9300 agtcgaagcc ccgggctgtc cttacctccc agtctggggt acctgccacc tcctgctcag 9360 caggaatggg gctaggtgct tcctcccctg gggacttcac ctgctctccc tcctgggata 9420 agacggcagc ctcctccttg ggggcagcag cattcagtcc tccaggtctc ctgggggtcg 9480 tgacctgcag gaggaataag agggcagact gggcagaaag gccttcagag cacctcatcc 9540 tcctgttctc acactggggt gtcacagtcc tgggaagttc ttccttttca gttgagctgt 9600 ggtaaccttg tgagtttcct ggaggggcct gccactaccc ttgggactcc ctgccgtgtg 9660 tctgggtcta actgagctct gaaaggagag agccccagcc ctgggccttc caggggaagc 9720 cttacctcag aggttggctt cttcctactc ttgactttgc gtctctgcag agggaggtgg 9780 gaggggtgac acaaccctga cacccacact atgagtgatg agtagtcctg ccccgactgg 9840 cccatccttt ccaggtgcag tcccccttac tgtgtctgcc aagggtgcca gcacagccgc 9900 cccactccag gggaagagga gtgccagccc ttacccacct gagtgggcac agtgtagcat 9960 ttattcatta gcccccacac tggcctgacc atctcccctg tggctgcatg acaaggagag 10020 agaacaggct gaggtgagag ctactgtcaa cacctaaacc taaaaaatct ataattgggc 10080 tgggcagggt ggctcacgcc tgtaatccca gcactttggg aggccgagat gggtggatca 10140 cctgaggtca gatgttcgag accagcctgg ccaacatggt gaaaccccgt ctctactaaa 10200 aatacaaaaa attagctggg cgtggtggtg ggtgcctgta atcccagcta ctcaggaggc 10260 tgaggcagga gaattgcttg aacctgggag gcagaggttg cagtgagccg agatcacacc 10320 attgcactcc agtctgggtg ataagtatga aacgccatct ccaaaacaaa agaaaagcct 10380 aattccccaa gaactgtcag tctttcacct gtctgctagc tcccagggag accccacttg 10440 ccagggctgt ctacatttgt cctgagatct cttctggtgg gaacagcact ttcctcagga 10500 aagtttgttg aaagtcatca gatccatgat tgaaaatcga agctgcctgt ggtgatggat 10560 aacagctggg gttaaaaagc agcagctggg gcatgagcgg tccacagtga gtttttgttg 10620 ttgtttttgt ttttttgggt gggggatggg gtcttgctag gtctcaaact cctggcctca 10680 agtcatcctc ccattacagc cttctgagtc actgacacta caggtgtgag ccaccatgtc 10740 cagcttgtag tggttttgaa cagctcttgc cccttcttgg gaatctaggt gccctgcacg 10800 tgggtaaggc tgtctgcagc tgtgcccata ttcaggaagg ccggcaaggc cctgagccct 10860 cacccgtgac tgacctgagg tgctgtgcag acagcaggtg acggctaagg gaaagttgag 10920 cactgcctag ccgagcactg aagccacgcc cggcacacag agagagaccc actcggcaaa 10980 gacttcgctt ccaggcacct aaggaactct ctgaccagtc attagctgac cactgccgta 11040 actgaagagc ggcttcagtg gccacagctc gcagggaatg gagacattaa tgcttagtca 11100 gaattagttc agaaaagtca cccagcaaag aaacagctcc aacaggcaac aacaacaaca 11160 catccttggc agggaagaga atctgacttc cggagttgcc acattatcgc ccgtgaaatg 11220 tccaggtttt aacaaattat gagacatgga aaggaaaccg aaaggacgac ccagacacgg 11280 gaaaagtcac caatgggacc agcccgatgc tgcaattgct agacaaagac gttcagtcag 11340 ctcatttaaa tatgttcaaa gacctaaaac atgctgcatc tgaggctgca ccggctggaa 11400 cctgctgatc tcggaagcta agcatggtca ggcctggcta gtacttcaaa gggagaaacc 11460 acgtgtaggc ctggtgcagt ggctcacacc tataatccta gcactctggg aagctgaggc 11520 ccgtggattg cttgagccca ggagtttgag agcagcttgg gaaatgtggt gagaccccca 11580 tctctacaaa aaatttaaaa aattagctgg ctgcctatgg tcccagcctc tcaggatgct 11640 gaggtaggag gatcacttca gcccaggaag ttgaggctgc agtgagccat gactgcatca 11700 ctgcactcca gcttgggcga cagagagacc ctctcccaag aaaaagaaaa gaaccatgtc 11760 aaaagaacta acgaaagtgt gggaacaatg tctcaccaat tagagaatat caataatggg 11820 atgaacctta taaaaagggg ctgggcatgg tggctcatgc ctataatccc agcactttgg 11880 gaggctgagg cgggcatatc atgaggtcaa gagattgaga ccagcctggc caacatggtg 11940 aaaccccgtc tctacttaaa atacaaaaat tagccgggcg tggtggcacg tgcctgtaat 12000 cccagctact cgggaggctg aggcaggaga atcgcttgaa cccgagaggc agagattgca 12060 gtgagccgag attgcaccac tgcactacag cctgggtgac agagcgatac tccaaaaaac 12120 aaaacaaaac aaaaaacaaa aaaaaagttt aaaaaggaac caaataaaaa ttctggagtt 12180 gtagggtaaa ataaatgaaa attcatccca ggggcccaag agcagattgg aacaattgga 12240 agaaagagcc tgtgactatg gagagaggcc acctgaggta gtcccctctg aggaacagga 12300 acaagcatga agagcaatgc acagagatcc agagacctgg agacgccgtc aagctttccg 12360 acatacacac aatgggagtc ccaggaaaga agacagggag aaaggagtaa aggaatagtt 12420 gaagaattaa tggctgaaaa acctcccaaa tctgatgaaa aatattaatc cgtacatcca 12480 aaaagctcat caaactccaa gtagggtaaa ctcaaagaga tcttcagcca tacgcatcat 12540 cataatcact gtcaaaagac agatttttct ttttttagaa ttttaaatgt accttttaat 12600 ttgctcctgg ggcaaagagc caggactggt actagagcag tgtctgggat gagaagaatt 12660 taataaaatg ggattaggtc caatggttgg gttaggggag gcaacctgct cggaaggatc 12720 agcctcaacc tatccatgca gcagggcctc cacctgtccc tctccgtagt cccacacctg 12780 gaacccagag ccatctgcct cttcccagat catggccgac agcactccac cggactgctg 12840 ctggagcagg cacaggattc acttattgag ggctgtggcc tggcacagat catagcctat 12900 acccagggac agttgtgtca cttctgccac caccacatcc gccttctgca gccacatcaa 12960 gtaccactca tggatgagcc cgtcaccccc agcggactta tcaaccccgc gtccagctcc 13020 acagccgcca cgtgctcggt gagcactggc tccaagcatg gcagctgcca tacaatccac 13080 ctgtagaggg cccggtcctc ctgtcctcag tggatgatcc cgtagaagtc cagagctcgg 13140 cagctgccct cccacaaaag acaggatttt gaaagcagca agagagaaga gacgtatcag 13200 gtagtcacag tggctcaggc ctgtaatccc agcactttgg gaggcccagg tgggaggatc 13260 gcttcacccc aggaattc 13278 6 13677 DNA Homo sapiens 6 gaattcaaga ccagcctgga caacttggaa gaacccggtc tctacaaaaa atacaaaatt 60 agctgggatt gggtgcggtg gctcatgcct ataatcccag cactttggga gcctgaggtg 120 ggtggatcac ctgaagtcag gagttcaaga ctagcctggc caacatggtg aaaccctatc 180 tctactgaaa atataaaaag ctagacgtgg tggcacacac ctgtaatccc agctacttag 240 gaggctgagg caggagaatt gcttgaagcc tagaggtgaa ggttgtagtg agccgagatt 300 gcatcattgc acaatggagg ggagccacca gcctgggcaa caagaggaaa tctccgtctc 360 caaaaaaaaa aaaaaaaaaa

aaaaaggatt aggctgggtg gtgcctgtag tcccagctac 420 ttgggaggca gggggtccac ttgatgtcga gactgcagtg agccatgatc ctgccactgc 480 actccggcct gggcaacaga gtgagaccct gtctaaagaa aaaaaaaata aagcaacata 540 tcctgaacaa aggatcctcc ataacgttcc caccagattt ctaatcagaa acatggaggc 600 cagaaagcag tggaggagga caaccctcag gcagcccggg aggatgttgt cacaggctgg 660 ggcaagggcc ttccggctac caactgggag ctctgggaac agccctgttg caaacaagaa 720 gccatagccc ggccagagcc caggaatgtg ggctgggctg ggagcagcct ctggacagga 780 gtggtcccat ccaggaaacc tccggcatgg ctgggaagtg gggtacttgg tgccgggtct 840 gtatgtgtgt gtgactggtg tgtgtgagag agaatgtgtg ccctaagtgt cagtgtgagt 900 ctgtgtatgt gtgaatattg tctttgtgtg ggtgattttc tgcgtgtgta atcgtgtccc 960 tgcaagtgtg aacaagtgga caagtgtctg ggagtggaca agagatctgt gcaccatcag 1020 gtgtgtgcat agcgtctgtg catgtcaaga gtgcaaggtg aagtgaaggg accaggccca 1080 tgatgccact catcatcagg agctctaagg ccccaggtaa gtgccagtga cagataaggg 1140 tgctgaaggt cactctggag tgggcaggtg ggggtaggga aagggcaagg ccatgttctg 1200 gaggaggggt tgtgactaca ttagggtgta tgagcctagc tgggaggtgg atggccgggt 1260 ccactgaaac cctggttatc ccagaaggct ttgcaggctt caggagcttg gagtggggag 1320 agggggtgac ttctccgacc aggcccctcc accggcctac cctgggtaag ggcctggagc 1380 aggaagcagg ggcaagaacc tctggagcag cccatacccg ccctggcctg actctgccac 1440 tggcagcaca gtcaacacag caggttcact cacagcagag ggcaaaggcc atcatcagct 1500 ccctttataa gggaagggtc acgcgctcgg tgtgctgaga gtgtcctgcc tggtcctctg 1560 tgcctggtgg ggtgggggtg ccaggtgtgt ccagaggagc ccatttggta gtgaggcagg 1620 tatggggcta gaagcactgg tgcccctggc cgtgatagtg gccatcttcc tgctcctggt 1680 ggacctgatg caccggcgcc aacgctgggc tgcacgctac tcaccaggcc ccctgccact 1740 gcccgggctg ggcaacctgc tgcatgtgga cttccagaac acaccatact gcttcgacca 1800 ggtgagggag gaggtcctgg agggcggcag aggtgctgag gctcccctac cagaagcaaa 1860 catggatggt gggtgaaacc acaggctgga ccagaagcca ggctgagaag gggaagcagg 1920 tttgggggac ttcctggaga agggcattta tacatggcat gaaggactgg attttccaaa 1980 ggccaaggaa gagtagggca agggcctgga ggtggagctg gacttggcag tgggcatgca 2040 agcccattgg gcaacatatg ttatggagta caaagtccct tctgctgaca ccagaaggaa 2100 aggccttggg aatggaagat gagttagtcc tgagtgccgt ttaaatcacg aaatcgagga 2160 tgaagggggt gcagtgaccc ggttcaaacc ttttgcactg tgggtcctcg ggcctcactg 2220 ctcaccggca tggaccatca tctgggaatg ggatgctaac tggggcctct cggcaatttt 2280 ggtgactctt gcaaggtcat acctgggtga cgcatccaaa ctgagttcct ccatcacaga 2340 aggtgtgacc cccacccccg ccccaggatc aggaggctgg gtctcctcct tccacctgct 2400 cactcctggt agccccgggg gtcgtccaag gttcaaatag gactaggacc tgtagtctgg 2460 ggggatcctg gcttgacaag aggccctgac cctccctctg cagttgcggc gccgcttcgg 2520 ggacgtgttc agcctgcagc tggcctggac gccggtggtc gtgctcaatg ggctggcggc 2580 cgtgcgcgag gcgatggtga cccgcggcga ggacacggcc gaccgcccgc ctgcgcccat 2640 ctaccaggtc ctgggcttcg ggccgcgttc ccaaggcaag cggcggtggg ggacagagac 2700 cgcgtttccg tgggccccgg gtggacagtg accgtagccc aagcagcgcc gacagggcgt 2760 ggggtcctgg acgtgaaaca gagataaagg ccagcgagtg ggctgaggac agtgggccag 2820 gaaaccacct gcacggggga ggtgcgagtc tgtgggctgg gagggggcgg gctactgccc 2880 agacccgcca gaagcccggt gggcgaggct gatgcgtcga agtggcggtg gcggggaccg 2940 cgcctatgct gcgggctcag tgtgggcggg acgggcggga tcttccttga gtggaaaggt 3000 ggtcagggtg ggcagagacg aggtggggcc aaaccccgcc ccaggcaggg gagcaatgtg 3060 ggtgagcaaa gagtgggccc tgtgcccagc tggaccgggc tagggactgc gggagacctt 3120 gtggagcgcc agggttggag tgggtggcgg agggtgggcc aaggccttca tggcaacgcc 3180 cacgtgtccg tcccgcccac aggggtgatc ctgtcgcgct atgggcccgc gtggcgcgag 3240 cagaggcgct tctccgtgtc caccttgcgc aacttgggcc tgggcaagaa gtcgctggag 3300 cagtgggtga ccgaggaggc cgcctgcctt tgtgccgcct tcgccgacca agccggtggg 3360 tgatgggcag aagggcacac agcgggaact gggaaggcgg gggacggaga aggcgacccc 3420 ttacccgcat ctcccacccc caggacgccc ctttcgcccc aacggtctct tggacaaagc 3480 cgtgagcaac gtgatcgcct ccctcacctg cgggcgccgc ttcgagtacg acgaccctcg 3540 cttcctcagg ctgctggacc tagctcaggg agggatcgaa ggaggagtcg ggcttcctgc 3600 gcgaggtgcg gagcaagggt ctttgcaggg cgagctcctg agaggtgccg gggctggact 3660 ggggcctccg aagggcagga tttgcgtaga tgggtttggg aaaggacatt ccaggagacc 3720 ccactgtaag aagggcctgg aggaggaggg gacatctcag acatggtcgt gggagaggtg 3780 tgcccgggtc agggggcacc aggagaggcc aaggactctg tacccccgtc cacgttggag 3840 atttcgattt taggtttctc ctctgggcaa ggagagagag ggtggaggct ggcacttggg 3900 gagggacttg gtgaggtcag tggtaaggac aggcaggccc tgggtcttcc tggagatggc 3960 tggggcctga gactggtcca gatgaacgca gagcacagga aggattgaga cccggttctg 4020 tctggtgtag gtgctgaatg ctgtccccgt cctcccgcac atcccagcgc tggctggcaa 4080 ggtcctacgc ttccaaaagg ctttcctgac ccagctggat gagctgctaa ctgagcacag 4140 gatgacctgg gacccagccc agccaccccg agacctgact gaggccttcc tggcaaagaa 4200 ggagaaggtg agagtggctg ccacggtggg gggcaagggt ggtgggttga acgtcccagg 4260 aggaatgagg ggaggctggg caaaaggttg gaccagtgca tcacccggcg agccgcatct 4320 gggctgacag gtgcagaatt ggaggtcatt tgggggctac cccgttctat cccctgagta 4380 tcctctcggc cctgctcagg ccaaggggag ccctgagagc agcttcaatg atgagaacct 4440 gcgcatagtg gtgggtaacc tgttccttgc cgggatggtg accaccttga ccacgctggc 4500 ctggggctcc tgctcatgat cctacacctg gatgtgcagc gtgagcccag ctggggccca 4560 aggcagggac tgagggagga agggtacagc tgggggcccc tgggcttagc tgggacaccc 4620 ggggcttcca gcacaggcgt ggccaggctc ctgtaagcct aacttcctcc aacacaggag 4680 gaaggagagt gtcccctggg tgctgaccca ttgtggggac gcatgtctgt ccagtccgtg 4740 tccaacagga gatcgacgac gtgatagggc aggtgcggcg accagagatg ggtgaccagg 4800 ctcacatgcc ctacaccact gccgtgattc atgaggtgca gcactttggg gacatcgtcc 4860 ccctgggtgt gacccatatg acatcccgtg acatcgaagt acagggcttc cgcatcccta 4920 aggtaggcct ggcgccctcc tcaccccagc tcagcaccag cccctggtga tagccccagc 4980 atggctactg ccaggtgggc ccactctagg aaccctggcc acctagtcct caatgccacc 5040 acactgactg tccccacttg ggtggggggt ccagagtata ggcagggctg gcctgtccat 5100 ccagagcccc cgtctagtgg ggagacaaac caggacctgc cagaatgttg gaggacccag 5160 cgcctgcagg gagagggggc agtgtgggtg cctctgagag gtgtgactgc gccctgctgt 5220 ggggtcggag agggtactgt ggagcttctc gggcgcagga ctagttgaca gagtccagct 5280 gtgtgccagg cagtgtgtgt cccccgtgtg tttggtggca ggggtcccag catcctagag 5340 tccagtcccc actctcaccc tgcatctcct gcccagggaa cgacactcat caccaacctg 5400 tcatcggtgc tgaaggatga ggccgtctgg gagaagccct tccgcttcca ccccgaacac 5460 ttcctggatg cccagggcca ctttgtgaag ccggaggcct tcctgccttt ctcagcaggt 5520 gcctgtgggg agcccggctc cctgtcccct tccgtggagt cttgcagggg tatcacccag 5580 gagccaggct cactgacgcc cctcccctcc ccacaggccg ccgtgcatgc ctcggggagc 5640 ccctggcccg catggagctc ttcctcttct tcacctccct gctgcagcac ttcagcttct 5700 ccgtggccgc cggacagccc cggcccagcc actctcgtgt cgtcagcttt ctggtgaccc 5760 catcccccta tgagctttgt gctgtgcccc gctagaatgg ggtacctagt ccccagcctg 5820 ttccctagcc agaggctcta atgtacaata aagcaatgtg gtagttccaa ctcgggtccc 5880 ctgctcacgc cctcgttggg atcatcctcc tcagggcaac cccacccctg cctcattcct 5940 gcttacccca ccgcctggcc gcatttgaga cgggtacgtt gaggctgagc agatgtcagt 6000 tacccttgcc cataatccag tgtcccccac tgacccaact ctgactgccc agattggtga 6060 caaggactac attgtcctgg catgtgggga aggggccaga atgggctgac tagaggtgtc 6120 agtcagccct ggatgtggtg gagagggcag gactcagcct ggaggcccat atttcaggcc 6180 taactcagcc caccccacat cagggacagc agtcctgcca gcaccatcac aacagtcacc 6240 tcccttcata tatgacaccc caaaatggaa gacaaatcat gtcagggagc tatatgccag 6300 ggctacctcc cagggctcag tcggcaggtg ccagaacatt ccctgggaag gccccaggaa 6360 aacccaggac cgagccaccg ccctcagcct gtcaccttgt gtccaaaatt ggtgggttct 6420 tggtctcact gacttcaaga atgaagctgt gacctcacgg tgagtgttac agttcttaaa 6480 gatggtgtgt tcagagtttg ttccttctga tgttaagacg tgttcagagt ttcttccttc 6540 tggtgggtgc gtggtcttgc tggcttcagg agtgaagctg cagaccttca cagtgagtgt 6600 tacggctctt aaggctgcac atacggagtt gttcattctt cctggtgggt ttgtggtctc 6660 actggcctca ggagtgaaac tgcagtcctt ccagtgttac aactcataaa ggcagtgtgg 6720 acccaatgag ggagcagcag cagcaagact tactgcaaac agcaaaagaa tgatggcaac 6780 caggttgccg ctgctacttc aggcagcctg cttttattcc cttatctgac ccccacccac 6840 atcctgctga ttggcccatt ttacagacag tggattggtc cacttacaga gagctgattg 6900 gtgcatttac aatccctgag ctagacacag agtactgatt ggtatattta caaaccttga 6960 gctagacaca gagtgctgaa tggtgtattt acaatccctt agctagacat aaaggttgtc 7020 ccagtcccca ctagattagc tagatagagt agacagagag cactgattgg tgcgtttaca 7080 aaccttgagt tagacacagg gtgctgactg gtgtgtttac aaaccctgag ctagacacag 7140 agtgctgatt ggtgtattta caatctttta gctagaaata aaggttcccc aagtccccac 7200 cagattagct agatacagag tgctaattgg tgcatgcacg aacccggagc tagacacaga 7260 gtgctgattg gtgcatatac aatcctctgg ctagacataa aagttctcca agtccccacc 7320 tgactcagga gcccagccag cttcgcctag tggatcctat gccagggcca caggcagagc 7380 tgcctgctag tcccacacca ggcacctgta ctcctcagcc cttgggcagt ggacgggacc 7440 aggtgccgtg gagcagtggg aggcacccat ccgggaggct tgggcctcgc agggagccca 7500 ccgtagggag gcttgggcat ggcaggctgc aagtcctgag ccctgccccg cggggaggtg 7560 actgaggcct ggcgacaatt caagtgtggt gagcgccggc aggccagcag tactggggga 7620 cccggtgccc cctctgcagc tgctggccca ggtgctaagc ccctcactgc ctggggccag 7680 aggcaccagc cggccgctcc gagtgcaggg cccgctgagc ccctgcccac ccagaactgg 7740 tgctggcccg cgagcaaccc aggttcccgc acacgcctct ccctccatac ctccccgcaa 7800 gcagacggag ccggctccag cctccaccag tccagagagg ggctcccaca gtgcagcgct 7860 gggctgaagg gctcctcaag tgtggtcaga gcagaagctg aggccgagga ggcgctgaga 7920 gcgagcgagg accgccagca cgttgacacc tctcaacctc accacaggac tggccacctc 7980 tctgggccct cagggatgct gctgtctgga cccctgacca gtgacgagtt cgcactcagg 8040 gccaggctgg cgctggagga ggacacttgt ttggctccaa ccctaggtac catcctccca 8100 gtagggatca ggcagggccc acaggcctgc cctagggaca ggagtcaacc ttggacccat 8160 aaggcactgg ggcgggcaga gaaggaggag gtggcatggg cagctgagag ccagagaccc 8220 tgaccctagt ccttgctctg ccattacccc gtgtgacccc gggcccaccc ttccccaccc 8280 ttccccaccc ttccccaccc ttccccaccc cgggcttctg tttccttctg ccaacgagaa 8340 ggctgcttca cctgccccga gtcctgtctt cctgctctgc cttctggggc tgtggccctt 8400 gctggcctgg agccccaacc aagggcaggg actgctgtcc tccacatctg tcctcaccga 8460 cataatgggc tgggctgggc acacaggcag tgcccaagag tttctaatga gcatatgatt 8520 acctgagtcc tgggcagacc ttcttaggga acagcctggg acagagaacc acagacactc 8580 tgaggagcca cctgaggcct cttttgccag aggaccctac agcctccctg gcagcagttc 8640 cgccagcatt tctgtaaatg ccctcatgcc agggtgcggc ccggctgtca gcacgagagg 8700 gacgttggtc tgtcccctgg caccgagtca gtcagaaggg tggccagggc ccccttgggc 8760 ccctccagag acaatccact gtggtcacac ggctcggtgg caggaagtgc tgttcctgca 8820 gctgtgggga cagggagtgt ggatgaagcc aggctgggtt tgtctgaaga cggaggcccc 8880 gaaaggtggc agcctggcct atagcagcag caactcttgg atttattgga aagattttct 8940 tcacggttct gagtcttggg ggtgttagag gctcagaacc agtccagcca gagctctgtc 9000 atgggcacgt agacccggtc ccagggcctt tgctctttgc tgtcctcaga ggcctctgca 9060 aagtagaaac aggcagcctt gtgagtcccc tcctgggagc aaccaaccct ccctctgaga 9120 tgccccgggg ccaggtcagc tgtggtgaaa ggtagggatg cagccagctc aggggagtgg 9180 cccagagttc ctgcccaccc aaggaggctc ccaggaaggt caaggcacct gactcctggg 9240 ctgcttccct cccctcccct ccccaggtca ggaaggtggg aaagggctgg ggtgtctgtg 9300 accctggcag tcactgagaa gcagggtgga agcagccccc tgcagcacgc tgggtcaatg 9360 gtcttaccag atggatacgc agcaacttcc ttttgaacct ttttattttc ctggcaggaa 9420 gaagagggat ccagcagtga gatcaggcag gttctgtgtt gcacagacag ggaaacaggc 9480 tctgtccaca caaagtcggt ggggccagga tgaggcccag tctgttcaca catggctgct 9540 gcctctcagc tctgcacaga cgtcctcgct cccctgggat ggcagcttgg cctgctggtc 9600 ttggggttga gccagcctcc agcactgcct ccctgccctg ctgcctccca ctctgcagtg 9660 ctccatggct gctcagttgg acccacgctg gagacgttca gtcgaagccc cgggctgtcc 9720 ttacctccca gtctggggta cctgccacct cctgctcagc aggaatgggg ctaggtgctt 9780 cctcccctgg ggacttcacc tgctctccct cctgggataa gacggcagcc tcctccttgg 9840 gggcagcagc attcagtcct ccaggtctcc tgggggtcgt gacctgcagg aggaataaga 9900 gggcagactg ggcagaaagg ccttcagagc acctcatcct cctgttctca cactggggtg 9960 tcacagtcct gggaagttct tccttttcag ttgagctgtg gtaaccttgt gagtttcctg 10020 gagggggcct gccactaccc ttgggactcc ctgccgtgtg tctgggtcta actgagctct 10080 gaaaggagag agccccagcc ctgggccttc caggggaagc cttacctcag aggttggctt 10140 cttcctactc ttgactttgc gtctctgcag agggaggtgg gaggggtgac acaaccctga 10200 cacccacact atgagtgatg agtagtcctg ccccgactgg cccatccttt ccaggtgcag 10260 tcccccttac tgtgtctgcc aagggtgcca gcacagccgc cccactccag gggaagagga 10320 gtgccagccc ttacccacct gagtgggcac agtgtagcat ttattcatta gcccccacac 10380 tggcctgacc atctcccctg tggctgcatg acaaggagag agaacaggct gaggtgagag 10440 ctactgtcaa cacctaaacc taaaaaatct ataattgggc tgggcagggt ggctcacgcc 10500 tgtaatccca gcactttggg aggccgagat gggtggatca cctgaggtca gatgttcgag 10560 accagcctgg ccaacatggt gaaaccccgt ctctactaaa aatacaaaaa attagctggg 10620 cgtggtggtg ggtgcctgta atcccagcta ctcaggaggc tgaggcagga gaattgcttg 10680 aacctgggag gcagaggttg cagtgagccg agatcacacc attgcactcc agtctgggtg 10740 ataagtatga aacgccatct ccaaaacaaa agaaaagcct aattccccaa gaactgtcag 10800 tctttcacct gtctgctagc tcccagggag accccacttg ccagggctgt ctacatttgt 10860 cctgagatct cttctggtgg gaacagcact ttcctcagga aagtttgttg aaagtcatca 10920 gatccatgat tgaaaatcga agctgcctgt ggtgatggat aacagctggg gttaaaaagc 10980 agcagctggg gcatgagcgg tccacagtga gtttttgttg ttgtttttgt ttttttgggt 11040 gggggatggg gtcttgctag gtctcaaact cctggcctca agtcatcctc ccattacagc 11100 cttctgagtc actgacacta caggtgtgag ccaccatgtc cagcttgtag tggttttgaa 11160 cagctcttgc cccttcttgg gaatctaggt gccctgcacg tgggtaaggc tgtctgcagc 11220 tgtgcccata ttcaggaagg ccggcaaggc ctgagccctc acccgtgact gacctgaggt 11280 gctgtgcaga cagcaggtga cggctaaggg aaagttgagc actgcctagc cgagcactga 11340 agccacgccc ggcacacaga gagagaccca ctcggcaaag acttcgcttc caggcaccta 11400 aggaactctc tgaccagtca ttagctgacc actgccgtaa ctgaagagcg gcttcagtgg 11460 ccacagctcg cagggaatgg agacattaat gcttagtcag aattagttca gaaaagtcac 11520 ccagcaaaga aacagctcca acaggcaaca acaacaacac atccttggca gggaagagaa 11580 tctgacttcc ggagttgcca cattatcgcc cgtgaaatgt ccaggtttta acaaattatg 11640 agacatggaa aggaaaccga aaggacgacc cagacacggg aaaagtcacc aatgggacca 11700 gcccgatgct gcaattgcta gacaaagacg ttcagtcagc tcatttaaat atgttcaaag 11760 acctaaaaca tgctgcatct gaggctgcac cggctggaac ctgctgatct cggaagctaa 11820 gcatggtcag gcctggctag tacttcaaag ggagaaacca cgtgtaggcc tggtgcagtg 11880 gctcacacct ataatcctag cactctggga agctgaggcc cgtggattgc ttgagcccag 11940 gagtttgaga gcagcttggg aaatgtggtg agacccccat ctctacaaaa aatttaaaaa 12000 attagctggc tgcctatggt cccagcctct caggatgctg aggtaggagg atcacttcag 12060 cccaggaagt tgaggctgca gtgagccatg actgcatcac tgcactccag cttgggcgac 12120 agagagaccc tctcccaaga aaaagaaaag aaccatgtca aaagaactaa cgaaagtgtg 12180 ggaacaatgt ctcaccaatt agagaatatc aataatggga tgaaccttat aaaaaggggc 12240 tgggcatggt ggctcatgcc tataatccca gcactttggg aggctgaggc gggcatatca 12300 tgaggtcaag agattgagac cagcctggcc aacatggtga aaccccgtct ctacttaaaa 12360 tacaaaaatt agccgggcgt ggtggcacgt gcctgtaatc ccagctactc gggaggctga 12420 ggcaggagaa tcgcttgaac ccgagaggca gagattgcag tgagccgaga ttgcaccact 12480 gcactacagc ctgggtgaca gagcgatact ccaaaaaaca aaacaaaaca aaaaacaaaa 12540 aaaaagttta aaaaggaacc aaataaaaat tctggagttg tagggtaaaa taaatgaaaa 12600 ttcatcccag gggcccaaga gcagattgga acaattggaa gaaagagcct gtgactatgg 12660 agagaggcca cctgaggtag tcccctctga ggaacaggaa caagcatgaa gagcaatgca 12720 cagagatcca gagacctgga gacgccgtca agctttccga catacacaca atgggagtcc 12780 caggaaagaa gacagggaga aaggagtaaa ggaatagttg aagaattaat ggctgaaaaa 12840 cctcccaaat ctgatgaaaa atattaatcc gtacatccaa aaagctcatc aaactccaag 12900 tagggtaaac tcaaagagat cttcagccat acgcatcatc ataatcactg tcaaaagaca 12960 gatttttctt tttttagaat tttaaatgta ccttttaatt tgctcctggg gcaaagagcc 13020 aggactggta ctagagcagt gtctgggatg agaagaattt aataaaatgg gattaggtcc 13080 aatggttggg ttaggggagg caacctgctc ggaaggatca gcctcaacct atccatgcag 13140 cagggcctcc acctgtccct ctccgtagtc ccacacctgg aacccagagc catctgcctc 13200 ttcccagatc atggccgaca gcactccacc ggactgctgc tggagcaggc acaggattca 13260 cttattgagg gctgtggcct ggcacagatc atagcctata cccagggaca gttgtgtcac 13320 ttctgccacc accacatccg ccttctgcag ccacatcaag taccactcat ggatgagccc 13380 gtcaccccca gcggacttat caaccccgcg tccagctcca cagccgccac gtgctcggtg 13440 agcactggct ccaagcatgg cagctgccat acaatccacc tgtagagggc ccggtcctcc 13500 tgtcctcagt ggatgatccc gtagaagtcc agagctcggc agctgccctc ccacaaaaga 13560 caggattttg aaagcagcaa gagagaagag acgtatcagg tagtcacagt ggctcaggcc 13620 tgtaatccca gcactttggg aggcccaggt gggaggatcg cttcacccca ggaattc 13677 7 4375 DNA Homo sapiens 7 cgcgctcggt gtgctgagag tgtcctgcct ggtcctctgt gcctggtggg gtgggggtgc 60 caggtgtgtc cagaggagcc cagttggtag tgaggcagcc atggggctag aagcactggt 120 gcccctggcc atgatagtgg ccatcttcct gctcctggtg gacctgatgc accggcacca 180 acgctgggct gcacgctacc cgccaggtcc cctgccactg cccgggctgg gcaaccttgc 240 tgcatgtgga cttccagaac acaccatact gcttcgacca ggtgagggag gaggtcctgg 300 agggcggcag aggtcctgag gatgccccac caccagcaaa catgggtggt gggttaaacc 360 acaggctgga tcagaagcca ggctgagaag gggaagcagg tttgggggac gtcctgggga 420 aggacattta tacatggcat gaaggactgg attttccaaa ggccaaggaa gagtagggca 480 agggcctgga ggtggagctg gacttggcag tgggcatgca agcccattgg gcaacatatg 540 ttatggagta caaagtccct tctgctgaca ccagaaggaa aggccttggg aatggaagat 600 gagttagtcc tgagtgccgt ttaaatcacg aaatcgagga tgaagggggt gcagtgaccc 660 ggttcaaacc ttttgcactg tgggtcctcg ggcctcactg ctcaccggca tggaccatca 720 tctgggaatg ggatgctaac tggggcctct cggcaatttt ggtgactctt gcaaggtcat 780 acctgggtga cgcatccaaa ctgagttcct ccatcacaga aggtgtgacc cccacccccg 840 ccccaggatc aggaggctgg gtctcctcct tccacctgct cactcctggt agccccgggg 900 gtcgtccaag gttcaaatag gactaggacc tgtagtctgg ggggatcctg gcttgacaag 960 aggccctgac cctccctctg cagttgcggc gccgcttcgg ggacgtgttc agcctgcagc 1020 tggcctggac gccggtggtc gtgctcaatg ggctggcggc cgtgcgcgag gcgatggtga 1080 cccgcggcga ggacacggcc gaccgcccgc ctgcgcccat ctaccaggtc ctgggcttcg 1140 ggccgcgttc ccaaggcaag cggcggtggg ggacagagac cgcgtttccg tgggccccgg 1200 gtggacagtg accgtagccc aagcagcgcc gacagggcgt ggggtcctgg acgtgaaaca 1260 gagataaagg ccagcgagtg ggctgaggac agtgggccag gaaaccacct gcacggggga 1320 ggtgcgagtc tgtgggctgg gagggggcgg gctactgccc agacccgcca gaagcccggt 1380 gggcgaggct gatgcgtcga agtggcggtg gcggggacgc gcctatgctg cgggctcagt 1440 gtgggcggga cgggcgggat cttccttgag tggaaaggtg gtcagggtgg gcagagacga 1500 ggtggggcca aaccccgccc caggcagggg agcaatgtgg gtgagcaaag agtgggccct 1560 gtgcccagct ggaccgggct agggactgcg ggagaccttg tggagcgcca gggttggagt 1620 gggtggcgga gggtgggcca aggccttcat ggcaacgccc acgtgtccgt cccgcccaca 1680 ggggtgatcc tgtcgcgcta tgggcccgcg tggcgcgagc agaggcgctt

ctccgtgtcc 1740 accttgcgca acttgggcct gggcaagaag tcgctggagc agtgggtgac cgaggaggcc 1800 gcctgccttt gtgccgcctt cgccgaccaa gccggtgggt gatgggcaga agggcacaca 1860 gcgggaactg ggaaggcggg ggacggagaa ggcgacccct tacccgcatc tcccaccccc 1920 aggacgcccc tttcgcccca acggtctctt ggacaaagcc gtgagcaacg tgatcgcctc 1980 cctcacctgc gggcgccgct tcgagtacga cgaccctcgc ttcctcaggc tgctggacct 2040 agctcaggga gggatcgaag gaggagtcgg gcttcctgcg cgaggtgcgg agcaagggtc 2100 tttgcagggc gagctcctga gaggtgccgg ggctggactg gggcctccga agggcaggat 2160 ttgcgtagat gggtttggga aaggacattc caggagaccc cactgtaaga agggcctgga 2220 ggaggagggg acatctcaga catggtcgtg ggagaggtgt gcccgggtca gggggcacca 2280 ggagaggcca aggactctgt acccccgtcc acgttggaga tttcgatttt aggtttctcc 2340 tctgggcaag gagagagagg gtggaggctg gcacttgggg agggacttgg tgaggtcagt 2400 ggtaaggaca ggcaggccct gggtcttcct ggagatggct ggggcctgag actggtccag 2460 atgaacgcag agcacaggaa ggattgagac ccggttctgt ctggtgtagg tgctgaatgc 2520 tgtccccgtc ctcccgcaca tcccagcgct ggctggcaag gtcctacgct tccaaaaggc 2580 tttcctgacc cagctggatg agctgctaac tgagcacagg atgacctggg acccagccca 2640 gccaccccga gacctgactg aggccttcct ggcaaagaag gagaaggtga gagtggctgc 2700 cacggtgggg ggcaagggtg gtgggttgaa cgtcccagga ggaatgaggg gaggctgggc 2760 aaaaggttgg accagtgcat cacccggcga gccgcatctg ggctgacagg tgcagaattg 2820 gaggtcattt gggggctacc ccgttctatc ccctgagtat cctctcggcc ctgctcaggc 2880 caaggggagc cctgagagca gcttcaatga tgagaacctg cgcatagtgg tgggtaacct 2940 gttccttgcc gggatggtga ccaccttgac cacgctggcc tggggcctcc tgctcatgat 3000 cctacacctg gatgtgcagc gtgagcccag ctggggccca aggcagggac tgagggagga 3060 agggtacagc tgggggcccc tgggcttagc tgggacaccc ggggcttcca gcacaggcgt 3120 ggccaggctc ctgtaagcct aacttcctcc aacacaggag gaaggagagt gtcccctggg 3180 tgctgaccca ttgtggggac gcatgtctgt ccagtccgtg tccaacagga gatcgacgac 3240 gtgatagggc aggtgcggcg accagagatg ggtgaccagg ctcacatgcc ctacaccact 3300 gccgtgattc atgaggtgca gcactttggg gactcgtccc cctgggtgtg acccatatga 3360 catcccgtga catcgaagta cagggcttcc gcatccctaa ggtaggcctg gcgccctcct 3420 caccccagct cagcaccagc ccctggtgat agccccagca tggctactgc caggtgggcc 3480 cactctagga accctggcca cctagtcctc aatgccacca cactgactgt ccccacttgg 3540 gtggggggtc cagagtatag gcagggctgg cctgtccatc cagagccccc gtctagtggg 3600 gaagacaaac caggacctgc cagaatgttg gaggacccag cgcctgcagg gagagggggc 3660 agtgtgggtg cctctgagag gtgtgactgc gccctgctgt ggggtcggag agggtactgt 3720 ggagcttctc gggcgcagga ctagttgaca gagtccagct gtgtgccagg cagtgtgtgt 3780 cccccgtgtg tttggtggca ggggtcccag catcctagag tccagtcccc actctcaccc 3840 tgcatctcct gcccagggaa cgacactcat caccaacctg tcatcggtgc tgaaggatga 3900 ggccgtctgg aagaagccct tccgcttcca ccccgaacac ttcctggatg cccagggcca 3960 ctttgtgaag ccggaggcct tcctgccttt ctcagcaggt gcctgtgggg agcccggctc 4020 cctgtcccct tccgtggagt cttgcagggg tatcacccag gagccaggct cactgacgcc 4080 cctcccctcc ccacaggccg ccgtgcatgc ctcggggagc ccctggcccg catggagctc 4140 ttcctcttct tcacctccct gctgcagcac ttcagcttct ccgtggccgc cggacagccc 4200 cggcccagcc actctcgtgt cgtcagcttt ctggtgaccc catcccccta tgagctttgt 4260 gctgtgcccc gctagaatgg ggtacctagt ccccagcctg ttccctagcc agaggctcta 4320 atgtacaata aagcaatgtg gtagttccaa ctcgggtccc ctgctcacgc cctcg 4375 8 5325 DNA Homo sapiens 8 cgcgctcggt gtgctgagag tgtcctgcct ggtcctctgt gcctggtggg gtgggggtgc 60 caggtgtgtc cagaggagcc cagttggtag tgaggcagcc atggggctgg atgcactggt 120 gcccctggca gtgacagtgg ccatcttcct gctcctggtg gacctgatgc agcagcacca 180 acgctggact gcacgctacc cgccaggccc cctgccactg cccgggctgg gcaacttgct 240 gcatgtggac ttccagaaca tatacacctt caaccaggtg aggggaggag gtccgtgagg 300 atcccccacc accagcaaac atgggtggtg ggtggagcca cagtctggac aagaagccag 360 gctgagaagg ggaagcagat ttgagggact tcctggggag ggcatttatg catggcatga 420 aagatgggat tttccaaagg ccaaggaaga gtagggcaag ggcctggagg tggagctgga 480 cttggcagtg ggcgtgcaag cccattgggc agcatatgtt aggagcacaa agtcccctct 540 gctgacacca gaaggaaagg ccttgggaat ggaagacgag tcagggtcct gtgtgccgtt 600 taaatcagga aatcaggctg tgcgtggtgc tcacgctata atcccagcac ttaaggaagc 660 caaggtgggc ggatcacctg aggtcagggg ttccagatga gtctggccaa catggcaaaa 720 accggtctct actaaacata caaaaaatga gctgggcaca gtggtgcacg cctgcaatcc 780 cagctacttg ggaggctgag gcaggagaat tgcttgaact taggaggcag aggttgtagt 840 gagtggagat tgtgccattg ccttgcaacc tcggtgacac agccagacaa tgtctaaata 900 aacgaataag aaatcaggcc gggcgcggtg gctcacgcct gtaatcccgg ccctttggag 960 gctaaggcgg gcggatcatg aggttaggag atcgagacca tcctggctaa cacaatgaaa 1020 cccgtctcta ctaaagatac aaaccaatta gccaggcgag gtggtgggca cctgtagtcc 1080 cagctacttg ggaggctgag gcaggagaat ggcatgaacc catgaggcag agcttgaagt 1140 gagctgagaa cacaccatta cactccagtc tgggcgacag agcgagactc tgtctcaaaa 1200 aaaaaaaaaa aaaaaaaaaa aaaaaaaatc aacggctggg cgcggtggct cacacctgta 1260 atcccagcat cttgggagac caaggtgggg ggatcacaag gtcaggagtt cgagaccagc 1320 ctggccaaca tggtgaaacc ctgcctctac taaaaataca aaaattagcg gggcacggtg 1380 gtgggcacct gtaatcccag ctacatggga ggctgaggca ggtgaattgc ttgaacccgg 1440 gaggtggagg ttgcagtgag ccaagatcgc gcattgcgtc cagcctgggt gacagagcca 1500 gacatggtct aaataaatga gtaagttaga aatcaaggat gaagggatat agtggacccg 1560 gttcaaacct tttgcactgt gggtcctcgg gcctcactgc tcaccggcat ggaccatcat 1620 ctgggaatgg gatgctaact ggggcctctc ggcaattttg gtgactcttg caaggtcata 1680 cctgggtgac gcatccaaac tgagttcctc catcacagaa ggtgtgaccc catccccgcc 1740 ccaggatcgg gaggctgggt ctcctccttc cacctgctca ctcctggtag ccccgagggt 1800 cgtctaaggt tcaaatagga ctaggacctg cagtctgggg ggaccctggc ctgatggagg 1860 ccctgaccca acggaggccc tgaccctccc tctacagctg cggcaccgct ttggggacgt 1920 gttcagcctg cagctggcct ggatgccggt ggtcgtgctc aatgggctgg cggccgtgcg 1980 tgaggctctg gtgacctgcg gcgaggacac cgccgaccgc ccgcctgcgc ccatctacca 2040 ggtcctgggc atcgggccgc gctcccaagg caagcggcgg tgggggacag agactgcgtt 2100 tccgtgggtc ctgggtgggc ggtgaccgta gcccaagctg ggctgagagg gcgtggggtt 2160 gtggacttgg gacacataga aaggccagtg agtgggttgg ggacagcgag ccaggaaacc 2220 acttccactg gggaggtgcg agtctgtggg cgggaggaag aggggcttgt gagtgggcgg 2280 ggcaactgcc gagacccacc aggaaccggg tgggcggact ggcgcctttc ccagctggaa 2340 gcgggtgtct agaagccggg atggactctg ctgtgggctc atatgggcgg ggcgggacgg 2400 gcgggatctt ccctgagtgg aaaggcagtc agggtcggaa gagccaaggt ggggccaaga 2460 cccaagcaag gtgagtgagc aaagagcagg ccctgtgccc agctggacag ggccagggac 2520 tgcgggagac caggaaaagc acagggttgg agtgggcggc ggagggcggg gccaaggcct 2580 ccatgaccac gtccatgtgt ccgtcccgcc cccaggggtg tttctggcac actacggaca 2640 cgcgtggcgc gagcagaggc gcttctccgt gtccaccttg cgcaacttgg gcctgggcaa 2700 gaagtccctg gagcggtggg tgaccgagga ggccgcctgc ctctgtgccg ccttcgccga 2760 ccaagccagt gggtgatggg cagaggggca caaagcggga actgggaagg tggaggactg 2820 ggaaggcgac ccctgacccg catctcccgc ccccaggacg cccctttcac cccaacggcc 2880 tcctgaacaa agcggcgagc aacgtgatcg cctccctcac ctgcgggtgc cgcttcgagt 2940 acgacgaccc tcgcttcctc aggctactgg acctagctca gaagggattg aaggaggagc 3000 tgggctttct gtgagagatg tggagcgagg gaccgcaggg tctctgcagg gcgagctcct 3060 gagaggtgcc gggactgcag ccggacctcc aaggagcagg gtttgcatag agtggtttgg 3120 gaaaggacat tccagaagag ctcactgcta gaggaagggc cttgaggagg aggagacatc 3180 tcagatacgg tcgtgggaga ggtgtgcccg ggtcaggggg caccaagaaa ggccaaggac 3240 cctgtgcctc ctgtccacat tggagatttt gatttttagg tttctcctct ggcagcccag 3300 ggcaaggaga gagggtggag gctggcactt ggggagggac ttggggaggt gagtggtggg 3360 gacaggcagg ccctgggtct tccctggagg cagctggggc ctgagactgg tccaggtgaa 3420 cgcagagcac aggagggatt gagaccccgt tctgtgtcag ctgtagatgc tgaatgttgt 3480 ccccctcctc ctgcgcatcc cagggctggc tggcaaggtc ctacgctccc aaaaggcttt 3540 cctgacccag ctggatgagc tgctgaccga gcacagaatg atctgggacc cagcctagcc 3600 accccgagac ctgactgagg ccttcctggc agagaaggag aaggtgagag tggctgacac 3660 ggtagggacc aggggtggtg ggttgagcgt ccgggaggaa tgaggcaggc aaaaggtggg 3720 tccattggat cacttggcaa gtggcacctg ggctgacagg tgcagaatgt ggaggtcatt 3780 tgggggcttt cccgttctgt cccctgagta ccctctcagc cctgctcagg ccaaggggaa 3840 ccctgagagc agcttcaatg atgagaacct gcgcatggtg gtggctgacc tgttctttgc 3900 cgggatggtg accacctcga tcacgctggc ctggggcctc ctgctcatga tcctacgccc 3960 ggatgtgcag cgtgagccca gctggggccc agtgcagggg gcaagggagg aagggtacag 4020 gtgggggccc ctgagcttag ctgggacacc cgggactcca agcacaggct tggccaggtt 4080 cctgtaagcc taacctcctc caacacagga ggcaggagag tgtcagggct ggtcccctgg 4140 gtgctgaccc attgtgggga cgcgtgtctg tccaggccgt gtccaacaga tcgacaacgt 4200 gatagggcag gtgtggtgac cagagatggg tgaccaggct cgcatgccct gcaccactgc 4260 cgtgattcac gaggtgcagc gctttgggga catcgtcccc ctgggtgtga cccatatgac 4320 atcccgtgac atcgaagtac agggcttccg catccctaag gtaggcctgg caccctcctc 4380 accccagctc agcaccagcc cctggtgata gccccagcat ggccactgcc aggtgggccc 4440 agtctaggaa ccctggccac ccagtcctca atgccaccac atcgactgtc ccagcctggg 4500 tgtggggtgc agagtatagg cagggctggc ctgtccatcc agagccccag tctagtgggg 4560 aaggcagacc aggacctgcc agaatgttgg aggaccccaa tacctgtagg gagaggggta 4620 gcgtgggcgc tcccaggagg tgtgactgcg ccctgccgtg gggtcggaga gggtgctctg 4680 gagcttctcg ggcacaggac tagttgacag agtccagctg tgtgccaggc agtgtgtgtc 4740 ccctgtgtgc ttgggggtcc cagcatccta gagtccagtc cccactctca ccctgcatct 4800 cctgcccagg ggatgatgct cttcaccaac ctgtcatcgg tgctgaagga tgaggccgtc 4860 tggaagaagc ccttccgctt ccaccccgaa cacttcctgg atgcccaggg ccactttgtg 4920 aagccggagg ccttcctgcc tttctcagca ggtgcctgtg gggagcccgg ctcctgtccc 4980 cttccgtgga gtcttgcagg ggtatcaccc gggagccagg ctcactgacg ccctcccctc 5040 cccacaggcc gccgtgcatg cctcgggcca gcccctggcc cgcatagagc tcttcctctt 5100 cttcacctcc ctgctgcagc acttcagctt ctcggtgccc accggacagc cccggcccag 5160 ccactctcgt gtcgtcggct ttctggtgac gccatccccc tatgagcttt gtgctgtgcc 5220 ccgctagagt tgctcctcag ctgggaccct gttgtacaat aaattagtct agtggctccc 5280 acttggtttc tgtatccagt ctgggcccct gccaaggtcc tggtt 5325 9 21 DNA Artificial synthetic primer 9 agcagagggc aaaggccatc a 21 10 21 DNA Artificial synthetic primer 10 ctctctgccc agctcggact a 21 11 21 DNA Artificial synthetic primer 11 ctttataagg gaagggtcac g 21 12 21 DNA Artificial synthetic primer 12 aggggagcct cagcacctct g 21 13 21 DNA Artificial synthetic primer 13 ggtgatcctg gcttgacaag a 21 14 21 DNA Artificial synthetic primer 14 ccacggaaat ctgtctctgt c 21 15 21 DNA Artificial synthetic primer 15 tggtggggct aatgccttca t 21 16 21 DNA Artificial synthetic primer 16 ccggcccctg acactccttc t 21 17 21 DNA Artificial synthetic primer 17 ggtggatggt ggggctaatg c 21 18 21 DNA Artificial synthetic primer 18 cttcccagtt cccgctttgt g 21 19 21 DNA Artificial synthetic primer 19 acggggaagg cgacccctta c 21 20 21 DNA Artificial synthetic primer 20 gagctcgccc tgcagagact c 21 21 21 DNA Artificial synthetic primer 21 agagcacagg agggattgag a 21 22 21 DNA Artificial synthetic primer 22 attcctcctg ggacgctcaa c 21 23 21 DNA Artificial synthetic primer 23 ccgttctgtc ccgagtatgc t 21 24 21 DNA Artificial synthetic primer 24 cccctgcact gtttcccaga t 21 25 21 DNA Artificial synthetic primer 25 ggaggcaaga aggagtgtca g 21 26 21 DNA Artificial synthetic primer 26 accaatctgg gcagtcagag t 21 27 21 DNA Artificial synthetic primer 27 ggccggaccc cctgggtgct g 21 28 21 DNA Artificial synthetic primer 28 gctggtgctg agctggggtg a 21 29 21 DNA Artificial synthetic primer 29 tagagtccag tccccactct c 21 30 21 DNA Artificial synthetic primer 30 agactccacg gaaggggaca g 21 31 21 DNA Artificial synthetic primer 31 tcacccagga gccaggctca c 21 32 21 DNA Artificial synthetic primer 32 tgatcccaac gagggcgtga g 21

Claims

1. A primer set that can be used to screen a polynucleotide sample to detect and identify variants in the Cytochrome P450 isoenzyme 2D6 (CYP2D6) gene comprising one or more than one primer group of the three primer groups of sequences selected from the primer groups consisting of Primer Group I (16 or more than 16 consecutive nucleotides of SEQ ID NO:9, 16 or more than 16 consecutive nucleotides of SEQ ID NO:10, 16 or more than 16 consecutive nucleotides of SEQ ID NO:11, 16 or more than 16 consecutive nucleotides of SEQ ID NO:12, 16 or more than 16 consecutive nucleotides of SEQ ID NO:13 and 16 or more than 16 consecutive nucleotides of SEQ ID NO:14); and Primer Group III (16 or more than 16 consecutive nucleotides of SEQ ID NO:25; 16 or more than 16 consecutive nucleotides of SEQ ID NO:26; 16 or more than 16 consecutive nucleotides of SEQ ID NO:27, 16 or more than 16 consecutive nucleotides of SEQ ID NO:28, 16 or more than 16 consecutive nucleotides of SEQ ID NO:29, 16 or more than 16 consecutive nucleotides of SEQ ID NO:30, 16 or more than 16 consecutive nucleotides of SEQ ID NO:31, and 16 or more than 16 consecutive nucleotides of SEQ ID NO:32).

2. The primer set of claim 1, comprising two primer groups selected from the group consisting of Primer Group I, Primer Group 11 (16 or more than 16 consecutive nucleotides of SEQ ID NO:15, 16 or more than 16 consecutive nucleotides of SEQ ID NO:16; 16 or more than 16 consecutive nucleotides of SEQ ID NO:17, 16 or more than 16 consecutive nucleotides of SEQ ID NO:18, 16 or more than 16 consecutive nucleotides of SEQ ID NO:19, 16 or more than 16 consecutive nucleotides of SEQ ID NO:20, 16 or more than 16 consecutive nucleotides of SEQ ID NO:21, 16 or more than 16 consecutive nucleotides of SEQ ID NO:22, 16 or more than 16 consecutive nucleotides of SEQ ID NO:23 and 16 or more than 16 consecutive nucleotides of SEQ ID NO:24), and Primer Group III.

3. The primer set of claim 1, comprising all three primer groups Primer Group I, Primer Group II (16 or more than 16 consecutive nucleotides of SEQ ID NO:15, 16 or more than 16 consecutive nucleotides of SEQ ID NO:16; 16 or more than 16 consecutive nucleotides of SEQ ID NO:17, 16 or more than 16 consecutive nucleotides of SEQ ID NO:18, 16 or more than 16 consecutive nucleotides of SEQ ID NO:19, 16 or more than 16 consecutive nucleotides of SEQ ID NO:20, 16 or more than 16 consecutive nucleotides of SEQ ID NO:21, 16 or more than 16 consecutive nucleotides of SEQ ID NO:22, 16 or more than 16 consecutive nucleotides of SEQ ID NO:23 and 16 or more than 16 consecutive nucleotides of SEQ ID NO:24) and Primer Group III.

4. The primer set of claim 1, where each sequence consists of at least 17 consecutive nucleotides.

5. The primer set of claim 1, where each sequence consists of at least 18 consecutive nucleotides.

6. The primer set of claim 1, where each sequence consists of at least 19 consecutive nucleotides.

7. The primer set of claim 1, where each sequence consists of at least 20 consecutive nucleotides.

8. The primer set of claim 1, where each sequence consists of at least 21 consecutive nucleotides.

9. The primer set of claim 1, where one or more than one sequence additionally comprises a tail sequence.

10. The primer set of claim 1, where one or more than one sequence has one or more than one dUTP substituted for TTP.

11. A method of screening a polynucleotide sample to detect and identify the presence of one or more than one variant in the CYP2D6 gene in the sample, comprising: a) providing a polynucleotide sample potentially comprising a sequence comprising at least about 50 consecutive nucleotides from one or more than one of the sequences of the wild type CYP2D6*1, SEQ ID NO:1, one or more than one variant of wild type CYP2D6*1, SEQ ID NO:1 or both wild type CYP2D6*1, SEQ ID NO:1 and one or more than one variant of wild type CYP2D6*1, SEQ ID NO:1; b) providing a primer set according to claim 1; c) amplifying the polynucleotide sample using the provided primer set to produce a set of amplicons; and d) analyzing the amplicons to identify the presence of CYP2D6*1 gene, SEQ ID NO:1, the presence of one or more than one variant of the CYP2D6*1 gene, SEQ ID NO:1 or to identify one or more than one specific variant of the CYP2D6*1 gene, SEQ ID NO:1 in the sample.

12. A method of predicting the potential for altered metabolism of a substance, including one or more than one pharmaceutical drug, by a first individual compared to a second control individual, where the substance is metabolized by the CYP2D6 isoenzyme, and where the second control individual is homozygous for the wild type allele of the CYP2D6*1, SEQ ID NO:1, the method comprising: a) providing a polynucleotide sample from the first individual; b) providing a primer set according to claim 1; c) amplifying the polynucleotide sample using the provided primer set to produce a set of amplicons; d) analyzing the amplicons to detect and identify one or more than one variant in the CYP2D6 gene from the first individual; and e) analyzing the one or more than one variant in the CYP2D6 gene detected and identified to determine if it constitutes a silent variant or non-silent variant; where the absence of a non-silent variant means that the first individual will not have the potential for altered metabolism of the substance, and where the presence of a non-silent variant means that the first individual will have the potential for altered metabolism of the substance.

13. A method of screening a population to detect and identify the presence of one or more than one variant in the CYP2D6 gene, comprising: a) providing a plurality of polynucleotide samples from the population; b) providing a primer set according to claim 1; c) amplifying the polynucleotide sample using the provided primer set to produce a set of amplicons; and d) analyzing the amplicons to detect and identify of one or more than one variant of the CYP2D6*1 gene, SEQ ID NO:1 in the sample.

14. The method of claim 13, where the plurality of polynucleotide samples is a plurality of random samples of individuals in the population.

15. The method of claim 13, where the plurality of polynucleotide samples is one or more than one sample from each individual in the population.

16. The method of claim 13, where the method of screening a population further comprises determining the distribution of the variants in the CYP2D6 gene in the population.

17. The method of claim 13, where the method of screening a population further comprises recording the presence and identity, or recording the distribution of the variants in the CYP2D6 gene in the population sample, in writing or another suitable media.

18. The method of claim 11, 12 or 13, where the amplifying the polynucleotide sample comprises using modified nucleotides.

19. The method of claim 11, 12 or 13, where the modified nucleotides are selected from the group consisting of deaza dATP, deaza dGTP, and nucleotides labeled with one or more than one label selected from the group consisting of biotin, digoxigenin, and a fluorescent dye.

20. The method of claim 11, 12 or 13, where the amplifying the polynucleotide sample comprises using dUTP in place of TTP.

21. The method of claim 11, 12 or 13, where the amplification step is performed in two stages.

22. The method of claim 11, 12 or 13, where analyzing the amplicons is performed using a method selected from the group consisting of dideoxy sequencing, pyrosequencing and SSCP.

23. A kit for screening a polynucleotide sample to detect and identify the presence of one or more than one variant in the CYP2D6 gene in the sample, comprising suitable amounts of a primer set according to claim 1.

24. The kit of claim 23, further comprising one or more than one additional reagent or one or more than one vessel to amplify the polynucleotide sample, to analyze the amplicons, or both to amplify the polynucleotide sample and to analyze the amplicons.

25. The kit of claim 24, where the additional reagent is selected from the group consisting of one or more than one DNA dependent polymerase, one or more than one buffer, one or more than one detergents and one or more than one stabilizing agent.

26. A purified or isolated variant of SEQ ID NO:1 having one or more than one of the alterations selected from the group consisting of G insert at position 1576, G>C at position 1851, A>C at position 1852, A>G at position 1864, T>A at position 3230, C>T at position 3232, G>A at position 3335, C>T at position 3542, T>C at position 3617, A>G at position 3716, C>T at position 3922, G>T at position 4221, G>A at position 4280, G>A at position 4282, T>A at position 4379, T>C at position 4555, G>A at position 4607, C>T at position 4820, A>G at position 4854, T>C at position 4873, insert GT at position 4878, C>A at position 5003, T>C at position 5027, C>A at position 5054, C>T at position 5409, G>A at position 5496, C>T at position 5774, C>T at position 5791, C>T at position 5948, C>T at position 6020 and an exon 9 gene conversion.

27. A method of predicting the potential for altered metabolism of a substance, including one or more than one pharmaceutical drug, by a first individual compared to a second control individual, where the substance is metabolized by the CYP2D6 isoenzyme, and where the second control individual is homozygous for the wild type allele of the CYP2D6*1, SEQ ID NO:1, the method comprising: a) detecting and identifying one or more than one variant in the CYP2D6 gene from the first individual; and b) analyzing the one or more than one variant in the CYP2D6 gene detected and identified to determine if it constitutes one or more than one variant according to claim 26; where the presence of the one or more than one variant means that the first individual will have the potential for altered metabolism of the substance.

28. A purified or isolated variant of SEQ ID NO:3 having one or more than one of the alterations selected from the group consisting of F>I at position 120, F>F at position 120, E>K at position 155, R>R at position 194, F>F at position 219, L>L at position 276, H>H at position 324, R>STOP at position 344, Y>C at position 355, H>H at position 361, V>FRAMESHIFT at position 363, E>K at position 418, H>Y at position 478, F>F at position 483.

29. A method of predicting the potential for altered metabolism of a substance, including one or more than one pharmaceutical drug, by a first individual compared to a second control individual, where the substance is metabolized by the CYP2D6 isoenzyme, and where the second control individual is homozygous for the wild type allele of the CYP2D6*1, SEQ ID NO:1, the method comprising: a) detecting and identifying one or more than one variant in the CYP2D6 isoenzyme from the first individual; and b) analyzing the one or more than one variant in the CYP2D6 isoenzyme detected and identified to determine if it constitutes one or more than one variant according to claim 28; where the presence of the one or more than one variant means that the first individual will have the potential for altered metabolism of the substance.