Genetic polymorphisms associated with coronary stenosis, methods of detection and uses thereof

Abstract

The present invention is based on the discovery of genetic polymorphisms that are associated with coronary stenosis. In particular, the present invention relates to nucleic acid molecules containing the polymorphisms, variant proteins encoded by such nucleic acid molecules, reagents for detecting the polymorphic nucleic acid molecules and proteins, and methods of using the nucleic acids and proteins as well as methods of using reagents for their detection.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional application of U.S. non-provisional application Ser. No. 10/741,601, filed Dec. 22, 2003, which claims priority to provisional application Ser. No. 60/434,741, filed Dec. 20, 2002, provisional application Ser. No. 60/453,050, filed Mar. 10, 2003, and provisional application Ser. No. 60/466,437, filed Apr. 30, 2003, the contents of which are hereby incorporated by reference in its entirety into this application.

FIELD OF THE INVENTION

[0002] The present invention is in the field of stenosis diagnosis and therapy. In particular, the present invention relates to specific single nucleotide polymorphisms (SNPs) in the human genome, and their association with stenosis and related pathologies. Based on differences in allele frequencies in the stenosis patient population relative to normal individuals, the naturally-occurring SNPs disclosed herein can be used as targets for the design of diagnostic reagents and the development of therapeutic agents, as well as for disease association and linkage analysis. In particular, the SNPs of the present invention are useful for identifying an individual who is at an increased or decreased risk of developing stenosis and for early detection of the disease, for providing clinically important information for the prevention and/or treatment of stenosis, and for screening and selecting therapeutic agents. The SNPs disclosed herein are also useful for human identification applications.

[0003] Methods, assays, kits, and reagents for detecting the presence of these polymorphisms and their encoded products are provided.

BACKGROUND OF THE INVENTION

[0004] Stenosis

[0005] Coronary stenosis is the narrowing of coronary arteries by obstructive atherosclerotic plaques. The coronary arteries supply oxygenated blood flow to the myocardium. Although mild and moderate coronary stenosis do not impede resting coronary flow, stenosis >30-45% starts to restrict maximal coronary flow. Severe coronary stenosis (>70% reduction in luminal diameter) causes stable angina (ischemic chest pain upon exertion). Significant stenosis contributes, along with plaque rupture and thrombus formation, coronary spasm, or inflammation/infection, to unstable angina as well as myocardial infarction. Together with arrhythmia, coronary stenosis is a major factor of sudden cardiac deaths, as evidenced by its presence in two or more major coronary arteries in 90% of adult sudden cardiac death victims.

[0006] Coronary stenosis is a prevalent disease. Each year in the United States, 440,000 new cases of stable angina and 150,000 new cases of unstable angina occur. This year, an estimated 1.1 million Americans will have a new or recurrent heart attack. These incidences result in over six million individuals in the U.S. living with stable or unstable angina pectoris, a debilitating condition, and over seven million individuals in the U.S. living with a history of myocardial infarction. Coronary stenosis is frequently a deadly disease. It is a major underlying cause of coronary heart disease (CHD), which is the single largest cause of death in the U.S. Over half a million coronary deaths, including 250,000 sudden cardiac deaths, occur each year in U.S. Coronary stenosis is also a costly disease. It is the major reason for 1.2 million cardiac catheterizations, 0.4 million angioplasties, and 0.6 million bypass surgeries, contributing to the estimated 110 billion dollar total costs of CHD in the U.S. for the year 2002. Still, these statistics underestimate the true prevalence of the disease since coronary stenosis often remains clinically asymptomatic for decades, and only becomes symptomatic when the disease has progressed to a severe, and sometime fatal, state.

[0007] There is therefore an unmet need in early diagnosis and prognosis of asymptomatic coronary stenosis. This need is particularly significant given that early diagnosis or prognosis results can significantly influence the course of disease by influencing treatment choices (for example, those with genetic risks can be treated to modify risk factors such as hypertension, diabetes, inactivity, dyslipidemia, etc.), thresholds (e.g., lipid levels used to trigger the use of lipid-lowering drugs), and goals (e.g., target blood pressure or lipid levels), and possibly enhance compliance.

[0008] Diagnosis of coronary stenosis currently starts by assessing if the risk profiles (e.g., hypertension, dyslipidemia, family history, diabetes, etc.) and symptoms (e.g., angina) of patients are consistent with coronary heart disease, followed most commonly by resting and exercise EKGs. However, risk assessments and EKGs are imperfect diagnostic tests for stenosis since they can be both insensitive (giving false negatives) and non-specific (giving false positives). Coronary arteriography is the definitive test for assessing the severity of coronary stenosis, however, it is not very sensitive in early detection of mild stenosis. It is also an invasive procedure with a small risk of death due to the catheterization procedure and the contrast dye. Because of this risk, it is typically only used at a time when coronary stenosis is considered likely from symptoms or other tests, which is hardly an ideal time to start intervention.

[0009] Coronary stenosis risk is presumed to have a strong genetic component. It is well known that several major risk factors of coronary disease are heritable, e.g. serum lipid levels (Perusse L. et. al., Arterioscler Thromb Vasc Biol (1997): 17(11) 3263-9) and obesity (Rice T. et. al., Int J Obes Relat Metab Disord (1997):21(11) 1024-31). Indeed, several known genetic defects are individually sufficient to cause elevated serum LDL-cholesterol (e.g., familial hypercholesterolemia) leading to premature coronary disease (Goldstein and Brown, Science 292 (2001): 1310-12). In addition, linkage studies in humans have replicated the findings of the link of several chromosomal regions (quantitative trait loci) to coronary heart disease and related diseases and risk factors (Pajukanta P. et. al., Am J Hum Genet. 67 (2000):1481-93, Francke S. et. al., Human Molecular Genetics (2001): (24) 2751-65). Finally, a family history of premature coronary disease is a significant factor in the risk assessment and diagnosis of coronary disease (Braunwald E., Zipes D. and Libby P., Heart Disease, 6.sup.th ed. W.B. Saunders Company, 2001, 28).

[0010] Although many risk factors for coronary stenosis have been identified, including age, diabetes, hypertension, high serum cholesterol, smoking, etc., and genetic factors play significant roles in several of these risk factors, significant genetic risk factors are likely to exist which have not been identified to date. In addition to the anecdotal coronary disease patients that exhibit few traditional risk factors, a study of multiple existing risk factors showed that only half of the "population-attributable risk" was attributable to known risk factors (Change M. et. al., J Clin Epidemiol (2001) 54 (6) 634-44). Therefore, the presently known risk factors are inadequate for predicting coronary stenosis risk in individuals. Given the magnitude of the disease, there is an urgent need for genetic markers that are predictive of coronary stenosis risk. Such genetic markers could increase the prognostic ability of existing risk assessment methods and complement current diagnostic methods such as exercise EKG, especially in early detection of disease when intervention is most effective and should ideally start.

[0011] SNPs

[0012] The genomes of all organisms undergo spontaneous mutation in the course of their continuing evolution, generating variant forms of progenitor genetic sequences (Gusella, Ann. Rev. Biochem. 55, 831-854 (1986)). A variant form may confer an evolutionary advantage or disadvantage relative to a progenitor form or may be neutral. In some instances, a variant form confers an evolutionary advantage to the species and is eventually incorporated into the DNA of many or most members of the species and effectively becomes the progenitor form. Additionally, the effects of a variant form may be both beneficial and detrimental, depending on the circumstances. For example, a heterozygous sickle cell mutation confers resistance to malaria, but a homozygous sickle cell mutation is usually lethal. In many cases, both progenitor and variant forms survive and co-exist in a species population. The coexistence of multiple forms of a genetic sequence gives rise to genetic polymorphisms, including SNPs.

[0013] Approximately 90% of all polymorphisms in the human genome are SNPs. SNPs are single base positions in DNA at which different alleles, or alternative nucleotides, exist in a population. The SNP position (interchangeably referred to herein as SNP, SNP site, or SNP locus) is usually preceded by and followed by highly conserved sequences of the allele (e.g., sequences that vary in less than 1/100 or 1/1000 members of the populations). An individual may be homozygous or heterozygous for an allele at each SNP position. A SNP can, in some instances, be referred to as a "cSNP" to denote that the nucleotide sequence containing the SNP is an amino acid coding sequence.

[0014] A SNP may arise from a substitution of one nucleotide for another at the polymorphic site. Substitutions can be transitions or transversions. A transition is the replacement of one purine nucleotide by another purine nucleotide, or one pyrimidine by another pyrimidine. A transversion is the replacement of a purine by a pyrimidine, or vice versa. A SNP may also be a single base insertion or deletion variant referred to as an "indel" (Weber et al., "Human diallelic insertion/deletion polymorphisms", Am J Hum Genet. 2002 October; 71(4):854-62).

[0015] A synonymous codon change, or silent mutation/SNP (terms such as "SNP", "polymorphism", "mutation", "mutant", "variation", and "variant" are used herein interchangeably), is one that does not result in a change of amino acid due to the degeneracy of the genetic code. A substitution that changes a codon coding for one amino acid to a codon coding for a different amino acid (i.e., a non-synonymous codon change) is referred to as a missense mutation. A nonsense mutation results in a type of non-synonymous codon change in which a stop codon is formed, thereby leading to premature termination of a polypeptide chain and a truncated protein. A read-through mutation is another type of non-synonymous codon change that causes the destruction of a stop codon, thereby resulting in an extended polypeptide product. While SNPs can be bi-, tri-, or tetra-allelic, the vast majority of the SNPs are bi-allelic, and are thus often referred to as "bi-allelic markers", or "di-allelic markers".

[0016] As used herein, references to SNPs and SNP genotypes include individual SNPs and/or haplotypes, which are groups of SNPs that are generally inherited together. Haplotypes can have stronger correlations with diseases or other phenotypic effects compared with individual SNPs, and therefore may provide increased diagnostic accuracy in some cases (Stephens et al. Science 293, 489-493, 20 Jul. 2001).

[0017] Causative SNPs are those SNPs that produce alterations in gene expression or in the expression, structure, and/or function of a gene product, and therefore are most predictive of a possible clinical phenotype. One such class includes SNPs falling within regions of genes encoding a polypeptide product, i.e. cSNPs. These SNPs may result in an alteration of the amino acid sequence of the polypeptide product (i.e., non-synonymous codon changes) and give rise to the expression of a defective or other variant protein. Furthermore, in the case of nonsense mutations, a SNP may lead to premature termination of a polypeptide product. Such variant products can result in a pathological condition, e.g., genetic disease. Examples of genes in which a SNP within a coding sequence causes a genetic disease include sickle cell anemia and cystic fibrosis.

[0018] Causative SNPs do not necessarily have to occur in coding regions; causative SNPs can occur in, for example, any genetic region that can ultimately affect the expression, structure, and/or activity of the protein encoded by a nucleic acid. Such genetic regions include, for example, those involved in transcription, such as SNPs in transcription factor binding domains, SNPs in promoter regions, in areas involved in transcript processing, such as SNPs at intron-exon boundaries that may cause defective splicing, or SNPs in mRNA processing signal sequences such as polyadenylation signal regions. Some SNPs that are not causative SNPs nevertheless are in close association with, and therefore segregate with, a disease-causing sequence. In this situation, the presence of a SNP correlates with the presence of, or predisposition to, or an increased risk in developing the disease. These SNPs, although not causative, are nonetheless also useful for diagnostics, disease predisposition screening, and other uses.

[0019] An association study of a SNP and a specific disorder involves determining the presence or frequency of the SNP allele in biological samples from individuals with the disorder of interest, such as stenosis, and comparing the information to that of controls (i.e., individuals who do not have the disorder; controls may be also referred to as "healthy" or "normal" individuals) who are preferably of similar age and race. The appropriate selection of patients and controls is important to the success of SNP association studies. Therefore, a pool of individuals with well-characterized phenotypes is extremely desirable.

[0020] A SNP may be screened in diseased tissue samples or any biological sample obtained from a diseased individual, and compared to control samples, and selected for its increased (or decreased) occurrence in a specific pathological condition, such as pathologies related to stenosis. Once a statistically significant association is established between one or more SNP(s) and a pathological condition (or other phenotype) of interest, then the region around the SNP can optionally be thoroughly screened to identify the causative genetic locus/sequence(s) (e.g., causative SNP/mutation, gene, regulatory region, etc.) that influences the pathological condition or phenotype. Association studies may be conducted within the general population and are not limited to studies performed on related individuals in affected families (linkage studies).

[0021] Clinical trials have shown that patient response to treatment with pharmaceuticals is often heterogeneous. There is a continuing need to improve pharmaceutical agent design and therapy. In that regard, SNPs can be used to identify patients most suited to therapy with particular pharmaceutical agents (this is often termed "pharmacogenomics"). Similarly, SNPs can be used to exclude patients from certain treatment due to the patient's increased likelihood of developing toxic side effects or their likelihood of not responding to the treatment. Pharmacogenomics can also be used in pharmaceutical research to assist the drug development and selection process. (Linder et al. (1997), Clinical Chemistry, 43, 254; Marshall (1997), Nature Biotechnology, 15, 1249; International Patent Application WO 97/40462, Spectra Biomedical; and Schafer et al. (1998), Nature Biotechnology, 16, 3).

SUMMARY OF THE INVENTION

[0022] The present invention relates to the identification of novel SNPs, unique combinations of such SNPs, and haplotypes of SNPs that are associated with stenosis and related pathologies. The polymorphisms disclosed herein are directly useful as targets for the design of diagnostic reagents and the development of therapeutic agents for use in the diagnosis and treatment of stenosis and related pathologies.

[0023] Based on the identification of SNPs associated with stenosis, the present invention also provides methods of detecting these variants as well as the design and preparation of detection reagents needed to accomplish this task. The invention specifically provides novel SNPs in genetic sequences involved in stenosis, variant proteins encoded by nucleic acid molecules containing such SNPs, antibodies to the encoded variant proteins, computer-based and data storage systems containing the novel SNP information, methods of detecting these SNPs in a test sample, methods of identifying individuals who have an altered (i.e., increased or decreased) risk of developing stenosis based on the presence of a SNP disclosed herein or its encoded product, methods of identifying individuals who are more or less likely to respond to a treatment, methods of screening for compounds useful in the treatment of a disorder associated with a variant gene/protein, compounds identified by these methods, methods of treating disorders mediated by a variant gene/protein, and methods of using the novel SNPs of the present invention for human identification.

[0024] In Tables 1-2, the present invention provides gene information, transcript sequences (SEQ ID NOS:1-12), encoded amino acid sequences (SEQ ID NOS:13-24), genomic sequences (SEQ ID NOS:37-40), transcript-based context sequences (SEQ ID NOS:25-36) and genomic-based context sequences (SEQ ID NOS:41-44) that contain the SNPs of the present invention, and extensive SNP information that includes observed alleles, allele frequencies, populations/ethnic groups in which alleles have been observed, information about the type of SNP and corresponding functional effect, and, for cSNPs, information about the encoded polypeptide product. The transcript sequences (SEQ ID NOS:1-12), amino acid sequences (SEQ ID NOS:13-24), genomic sequences (SEQ ID NOS:37-40), transcript-based SNP context sequences (SEQ ID NOS: 25-36), and genomic-based SNP context sequences (SEQ ID NOS:41-44) are also provided in the Sequence Listing.

[0025] In a specific embodiment of the present invention, naturally-occurring SNPs in the human genome are provided. These SNPs are associated with stenosis such that they can have a variety of uses in the diagnosis and/or treatment of stenosis. One aspect of the present invention relates to an isolated nucleic acid molecule comprising a nucleotide sequence in which at least one nucleotide is a SNP disclosed in Tables 3 and/or 4. In an alternative embodiment, a nucleic acid of the invention is an amplified polynucleotide, which is produced by amplification of a SNP-containing nucleic acid template. In another embodiment, the invention provides for a variant protein which is encoded by a nucleic acid molecule containing a SNP disclosed herein.

[0026] In yet another embodiment of the invention, a reagent for detecting a SNP in the context of its naturally-occurring flanking nucleotide sequences (which can be, e.g., either DNA or mRNA) is provided. In particular, such a reagent may be in the form of, for example, a hybridization probe or an amplification primer that is useful in the specific detection of a SNP of interest. In an alternative embodiment, a protein detection reagent is used to detect a variant protein which is encoded by a nucleic acid molecule containing a SNP disclosed herein. A preferred embodiment of a protein detection reagent is an antibody or an antigen-reactive antibody fragment.

[0027] Also provided in the invention are kits comprising SNP detection reagents, and methods for detecting the SNPs disclosed herein by employing detection reagents. In a specific embodiment, the present invention provides for a method of identifying an individual having an increased or decreased risk of developing stenosis by detecting the presence or absence of a SNP allele disclosed herein. In another embodiment, a method for diagnosis of stenosis by detecting the presence or absence of a SNP allele disclosed herein is provided.

[0028] The nucleic acid molecules of the invention can be inserted in an expression vector, such as to produce a variant protein in a host cell. Thus, the present invention also provides for a vector comprising a SNP-containing nucleic acid molecule, genetically-engineered host cells containing the vector, and methods for expressing a recombinant variant protein using such host cells. In another specific embodiment, the host cells, SNP-containing nucleic acid molecules, and/or variant proteins can be used as targets in a method for screening and identifying therapeutic agents or pharmaceutical compounds useful in the treatment of stenosis.

[0029] An aspect of this invention is a method for treating stenosis in a human subject wherein said human subject harbors a gene, transcript, and/or encoded protein identified in Tables 1-2, which method comprises administering to said human subject a therapeutically or prophylactically effective amount of one or more agents counteracting the effects of the disease, such as by inhibiting (or stimulating) the activity of the gene, transcript, and/or encoded protein identified in Tables 1-2.

[0030] Another aspect of this invention is a method for identifying an agent useful in therapeutically or prophylactically treating stenosis in a human subject wherein said human subject harbors a gene, transcript, and/or encoded protein identified in Tables 1-2, which method comprises contacting the gene, transcript, or encoded protein with a candidate agent under conditions suitable to allow formation of a binding complex between the gene, transcript, or encoded protein and the candidate agent and detecting the formation of the binding complex, wherein the presence of the complex identifies said agent.

[0031] Another aspect of this invention is a method for treating stenosis in a human subject, which method comprises:

[0032] (i) determining that said human subject harbors a gene, transcript, and/or encoded protein identified in Tables 1-2, and

[0033] (ii) administering to said subject a therapeutically or prophylactically effective amount of one or more agents counteracting the effects of the disease.

[0034] Many other uses and advantages of the present invention will be apparent to those skilled in the art upon review of the detailed description of the preferred embodiments herein. Solely for clarity of discussion, the invention is described in the sections below by way of non-limiting examples.

DESCRIPTION OF THE FILES CONTAINED ON THE CD-R NAMED CL1500DIV1 CDR

[0035] The CD-R named CL1500DIV1 CDR contains the following text (ASCII) file:

[0036] 1) File SEQLIST_CL1500DIV1.txt provides the Sequence Listing. The Sequence Listing provides the transcript sequences (SEQ ID NOS:1-12) and protein sequences (SEQ ID NOS:13-24) as shown in Table 1, and genomic sequences (SEQ ID NOS:37-40) as shown in Table 2, for each stenosis-associated gene that contains one or more SNPs of the present invention. Also provided in the Sequence Listing are context sequences flanking each SNP, including both transcript-based context sequences as shown in Table 1 (SEQ ID NOS:25-36) and genomic-based context sequences as shown in Table 2 (SEQ ID NOS:41-44). The context sequences generally provide 100 bp upstream (5') and 100 bp downstream (3') of each SNP, with the SNP in the middle of the context sequence, for a total of 200 bp of context sequence surrounding each SNP. File SEQLIST_CL1500DIV1.txt is 307 KB in size.

[0037] The material contained on the CD-R labeled "CL 1500DIV1" is hereby incorporated by reference pursuant to 37 CFR 1.77(b)(4).

DESCRIPTION OF TABLE 1 AND TABLE 2

[0038] Table 1 and Table 2 disclose the SNP and associated gene/transcript/protein information of the present invention. For each gene, Table 1 and Table 2 each provide a header containing gene/transcript/protein information, followed by a transcript and protein sequence (in Table 1) or genomic sequence (in Table 2), and then SNP information regarding each SNP found in that gene/transcript.

[0039] NOTE: SNPs may be included in both Table 1 and Table 2; Table 1 presents the SNPs relative to their transcript sequences and encoded protein sequences, whereas Table 2 presents the SNPs relative to their genomic sequences (in some instances Table 2 may also include, after the last gene sequence, genomic sequences of one or more intergenic regions, as well as SNP context sequences and other SNP information for any SNPs that lie within these intergenic regions). SNPs can readily be cross-referenced between Tables based on their hCV (or, in some instances, hDV) identification numbers.

[0040] The gene/transcript/protein information includes: [0041] a gene number (1 through n, where n=the total number of genes in the Table) [0042] a Celera hCG and UID internal identification numbers for the gene [0043] a Celera hCT and UID internal identification numbers for the transcript (Table 1 only) [0044] a public Genbank accession number (e.g., RefSeq NM number) for the transcript (Table 1 only) [0045] a Celera hCP and UID internal identification numbers for the protein encoded by the hCT transcript (Table 1 only) [0046] a public Genbank accession number (e.g., RefSeq NP number) for the protein (Table 1 only) [0047] an art-known gene symbol [0048] an art-known gene/protein name [0049] Celera genomic axis position (indicating start nucleotide position-stop nucleotide position) [0050] the chromosome number of the chromosome on which the gene is located [0051] an OMIM (Online Mendelian Inheritance in Man; Johns Hopkins University/NCBI) public reference number for obtaining further information regarding the medical significance of each gene [0052] alternative gene/protein name(s) and/or symbol(s) in the OMIM entry

[0053] NOTE: Due to the presence of alternative splice forms, multiple transcript/protein entries can be provided for a single gene entry in Table 1; i.e., for a single Gene Number, multiple entries may be provided in series that differ in their transcript/protein information and sequences.

[0054] Following the gene/transcript/protein information is a transcript sequence and protein sequence (in Table 1), or a genomic sequence (in Table 2), for each gene, as follows: [0055] transcript sequence (Table 1 only) (corresponding to SEQ ID NOS:1-12 of the Sequence Listing), with SNPs identified by their IUB codes (transcript sequences can include 5' UTR, protein coding, and 3' UTR regions). (NOTE: If there are differences between the nucleotide sequence of the hCT transcript and the corresponding public transcript sequence identified by the Genbank accession number, the hCT transcript sequence (and encoded protein) is provided, unless the public sequence is a RefSeq transcript sequence identified by an NM number, in which case the RefSeq NM transcript sequence (and encoded protein) is provided. However, whether the hCT transcript or RefSeq NM transcript is used as the transcript sequence, the disclosed SNPs are represented by their IUB codes within the transcript.) [0056] the encoded protein sequence (Table 1 only) (corresponding to SEQ ID NOS:13-24 of the Sequence Listing) [0057] the genomic sequence of the gene (Table 2 only), including 6 kb on each side of the gene boundaries (i.e., 6 kb on the 5' side of the gene plus 6 kb on the 3' side of the gene) (corresponding to SEQ ID NOS:37-40 of the Sequence Listing).

[0058] After the last gene sequence, Table 2 may include additional genomic sequences of intergenic regions (in such instances, these sequences are identified as "Intergenic region:" followed by a numerical identification number), as well as SNP context sequences and other SNP information for any SNPs that lie within each intergenic region (and such SNPs are identified as "INTERGENIC" for SNP type).

[0059] NOTE: The transcript, protein, and transcript-based SNP context sequences are provided in both Table 1 and in the Sequence Listing. The genomic and genomic-based SNP context sequences are provided in both Table 2 and in the Sequence Listing. SEQ ID NOS are indicated in Table 1 for each transcript sequence (SEQ ID NOS:1-12), protein sequence (SEQ ID NOS:13-24), and transcript-based SNP context sequence (SEQ ID NOS:25-36), and SEQ ID NOS are indicated in Table 2 for each genomic sequence (SEQ ID NOS:37-40), and genomic-based SNP context sequence (SEQ ID NOS:41-44).

[0060] The SNP information includes: [0061] context sequence (taken from the transcript sequence in Table 1, and taken from the genomic sequence in Table 2) with the SNP represented by its IUB code, including 100 bp upstream (5') of the SNP position plus 100 bp downstream (3') of the SNP position (the transcript-based SNP context sequences in Table 1 are provided in the Sequence Listing as SEQ ID NOS:25-36; the genomic-based SNP context sequences in Table 2 are provided in the Sequence Listing as SEQ ID NOS:41-44). [0062] Celera hCV internal identification number for the SNP (in some instances, an "hDV" number is given instead of an "hCV" number) [0063] SNP position [position of the SNP within the given transcript sequence (Table 1) or within the given genomic sequence (Table 2)] [0064] SNP source (may include any combination of one or more of the following five codes, depending on which internal sequencing projects and/or public databases the SNP has been observed in: "Applera"=SNP observed during the re-sequencing of genes and regulatory regions of 39 individuals, "Celera"=SNP observed during shotgun sequencing and assembly of the Celera human genome sequence, "Celera Diagnostics"=SNP observed during re-sequencing of nucleic acid samples from individuals who have stenosis or a related pathology, "dbSNP"=SNP observed in the dbSNP public database, "HGBASE"=SNP observed in the HGBASE public database, "HGMD"=SNP observed in the Human Gene Mutation Database (HGMD) public database) (NOTE: multiple "Applera" source entries for a single SNP indicate that the same SNP was covered by multiple overlapping amplification products and the re-sequencing results (e.g., observed allele counts) from each of these amplification products is being provided) [0065] Population/allele/allele count information in the format of [population1(allele1,count|allele2,count) population2(allele 1,count|allele2,count) total (allele 1,total count|allele2,total count)]. The information in this field includes populations/ethnic groups in which particular SNP alleles have been observed ("cau"=Caucasian, "his"=Hispanic, "chn"=Chinese, and "afr"=African-American, "jpn"=Japanese, "ind"=Indian, "mex"=Mexican, "ain"="American Indian, "cra"=Celera donor, "no_pop"=no population information available), identified SNP alleles, and observed allele counts (within each population group and total allele counts), where available ["-" in the allele field represents a deletion allele of an insertion/deletion ("indel") polymorphism (in which case the corresponding insertion allele, which may be comprised of one or more nucleotides, is indicated in the allele field on the opposite side of the "|"); "-" in the count field indicates that allele count information is not available].

[0066] NOTE: For SNPs of "Applera" SNP source, genes/regulatory regions of 39 individuals (20 Caucasians and 19 African Americans) were re-sequenced and, since each SNP position is represented by two chromosomes in each individual (with the exception of SNPs on X and Y chromosomes in males, for which each SNP position is represented by a single chromosome), up to 78 chromosomes were genotyped for each SNP position. Thus, the sum of the African-American ("afr") allele counts is up to 38, the sum of the Caucasian allele counts ("cau") is up to 40, and the total sum of all allele counts is up to 78.

[0067] (NOTE: semicolons separate population/allele/count information corresponding to each indicated SNP source; i.e., if four SNP sources are indicated, such as "Celera", "dbSNP", "HGBASE", and "HGMD", then population/allele/count information is provided in four groups which are separated by semicolons and listed in the same order as the listing of SNP sources, with each population/allele/count information group corresponding to the respective SNP source based on order; thus, in this example, the first population/allele/count information group would correspond to the first listed SNP source (Celera) and the third population/allele/count information group separated by semicolons would correspond to the third listed SNP source (HGBASE); if population/allele/count information is not available for any particular SNP source, then a pair of semicolons is still inserted as a place-holder in order to maintain correspondence between the list of SNP sources and the corresponding listing of population/allele/count information) [0068] SNP type (e.g., location within gene/transcript and/or predicted functional effect) ["MIS-SENSE MUTATION"=SNP causes a change in the encoded amino acid (i.e., a non-synonymous coding SNP); "SILENT MUTATION"=SNP does not cause a change in the encoded amino acid (i.e., a synonymous coding SNP); "STOP CODON MUTATION"=SNP is located in a stop codon; "NONSENSE MUTATION"=SNP creates or destroys a stop codon; "UTR 5"=SNP is located in a 5' UTR of a transcript; "UTR 3"=SNP is located in a 3' UTR of a transcript; "PUTATIVE UTR 5"=SNP is located in a putative 5' UTR; "PUTATIVE UTR 3"=SNP is located in a putative 3' UTR; "DONOR SPLICE SITE"=SNP is located in a donor splice site (5' intron boundary); "ACCEPTOR SPLICE SITE"=SNP is located in an acceptor splice site (3' intron boundary); "CODING REGION"=SNP is located in a protein-coding region of the transcript; "EXON"=SNP is located in an exon; "INTRON"=SNP is located in an intron; "hmCS"=SNP is located in a human-mouse conserved segment; "TFBS"=SNP is located in a transcription factor binding site; "UNKNOWN"=SNP type is not defined; "INTERGENIC"=SNP is intergenic, i.e., outside of any gene boundary] [0069] Protein coding information (Table 1 only), where relevant, in the format of [protein SEQ ID NO:#, amino acid position, (amino acid-1, codon1) (amino acid-2, codon2)]. The information in this field includes SEQ ID NO of the encoded protein sequence, position of the amino acid residue within the protein identified by the SEQ ID NO that is encoded by the codon containing the SNP, amino acids (represented by one-letter amino acid codes) that are encoded by the alternative SNP alleles (in the case of stop codons, "X" is used for the one-letter amino acid code), and alternative codons containing the alternative SNP nucleotides which encode the amino acid residues (thus, for example, for missense mutation-type SNPs, at least two different amino acids and at least two different codons are generally indicated; for silent mutation-type SNPs, one amino acid and at least two different codons are generally indicated, etc.). In instances where the SNP is located outside of a protein-coding region (e.g., in a UTR region), "None" is indicated following the protein SEQ ID NO.

DESCRIPTION OF TABLE 3 AND TABLE 4

[0070] Tables 3 and 4 provide a list of a subset of SNPs from Table 1 (in the case of Table 3) or Table 2 (in the case of Table 4) for which the SNP source falls into one of the following three categories: 1) SNPs for which the SNP source is only "Applera" and none other, 2) SNPs for which the SNP source is only "Celera" and none other, and 3) SNPs for which the SNP source is both "Applera" and "Celera" but none other.

[0071] These SNPs have not been observed in any of the public databases (dbSNP, HGBASE, and HGMD), and were also not observed during shotgun sequencing and assembly of the Celera human genome sequence (i.e., "Celera" SNP source). Tables 3 and 4 provide the hCV identification number (or hDV identification number for SNPs having "Celera" SNP source) and the SEQ ID NO of the context sequence for each of these SNPs.

DESCRIPTION OF TABLE 5

[0072] Table 5 provides sequences (SEQ ID NOS:45-56) of primers that have been synthesized and used in the laboratory to carry out allele-specific PCR reactions in order to assay the SNPs disclosed in Tables 6-7 during the course of stenosis association studies.

[0073] Table 5 provides the following: [0074] the column labeled "hCV" provides an hCV identification number for each SNP site [0075] the column labeled "Alleles" designates the two alternative alleles at the SNP site identified by the hCV identification number that are targeted by the allele-specific primers (the allele-specific primers are shown as "Sequence A" and "Sequence B" in each row) [0076] the column labeled "Sequence A (allele-specific primer)" provides an allele-specific primer that is specific for the first allele designated in the "Alleles" column [0077] the column labeled "Sequence B (allele-specific primer)" provides an allele-specific primer that is specific for the second allele designated in the "Alleles" column [0078] the column labeled "Sequence C (common primer)" provides a common primer that is used in conjunction with each of the allele-specific primers (the "Sequence A" primer and the "Sequence B" primer) and which hybridizes at a site away from the SNP position.

[0079] All primer sequences are given in the 5' to 3' direction.

[0080] Each of the alleles designated in the "Alleles" column matches the 3' nucleotide of the allele-specific primer that is specific for that allele. Thus, the first allele designated in the "Alleles" column matches the 3' nucleotide of the "Sequence A" primer, and the second allele designated in the "Alleles" column matches the 3' nucleotide of the "Sequence B" primer.

DESCRIPTION OF TABLE 6 AND TABLE 7

[0081] Tables 6-7 provide results of statistical analyses for SNPs disclosed in Tables 1-5 (SNPs can be cross-referenced between Tables based on their hCV identification numbers). The statistical results provide support for the association of these SNPs with coronary stenosis.

[0082] NOTE: SNPs can be cross-referenced between Tables 1-7 based on the hCV identification number of each SNP. However, six of the SNPs that are included in Tables 1-7 possess two different hCV identification numbers, as follows: [0083] hCV1129436 is equivalent to hCV26581155 [0084] hCV15954277 is equivalent to hCV22272408 [0085] hCV16173091 is equivalent to hCV25473098 [0086] hCV16179628 is equivalent to hCV22272980 [0087] hCV16195242 is equivalent to hCV22274712

[0088] hCV7482175 is equivalent to hCV26546221 TABLE-US-00001 Column heading Definition Marker Internal hCV identification number for the tested SNP Gene HUGO gene symbol for the gene in which the SNP Name resides Sample Sample set used in the analysis ("Sample Set 1" or Set "Sample Set 2") p-value The result of the asymptotic chi square test for allelic, dominant, or recessive (based on the genotype reported in the "Mode" column) genotypic association, or the results of Armitage trendtest for additive genotypic association. For SNPs for which information is provided in an "Adjust" column, it is the result of allelic, additive, dominant, or recessive (based on the genotype reported in the "Mode" column) p-value of the stratified analysis with Cochran Mantel Haenszel test. OR Allelic, dominant, recessive, or additive (based on the genotype reported in Mode column) odds ratio 95% CI 95% confidence interval of the OR reported Case Frequency of Allele1, or genotype containing Allele1, in Freq. the case group Cntrl Frequency of Allele1, or genotype containing Allele1, in Freq. the control group Allele1 Nucleotide (allele) of the tested SNP for which statistics are being reported Mode Mode of inheritance for which p-values are reported: Dom: dominant Rec: recessive Add: Additive Allelic Strata Stratum in which the association study analysis was based All: unstratified M: in male F: in female Age T1: age tertile 1 Age T2: age tertile 2 Age T3: age tertile 3 Smoke+: people who are past or current smoker Smoke-: people who never smoked MI-: people without heart attack Adjust Adjustments that were done for the Cochran Mantel Haenszel test (Indicates that the p-value was determined using a Cochran Mantel Haenszel test that was adjusted for confounders)

DETAILED DESCRIPTION OF THE INVENTION

[0089] The present invention provides SNPs associated with stenosis, nucleic acid molecules containing SNPs, methods and reagents for the detection of the SNPs disclosed herein, uses of these SNPs for the development of detection reagents, and assays or kits that utilize such reagents. The stenosis-associated SNPs disclosed herein are useful for diagnosing, screening for, and evaluating predisposition to stenosis and related pathologies in humans. Furthermore, such SNPs and their encoded products are useful targets for the development of therapeutic agents.

[0090] A large number of SNPs have been identified from re-sequencing DNA from 39 individuals, and they are indicated as "Applera" SNP source in Tables 1-2. Their allele frequencies observed in each of the Caucasian and African-American ethnic groups are provided. Additional SNPs included herein were previously identified during shotgun sequencing and assembly of the human genome, and they are indicated as "Celera" SNP source in Tables 1-2. Furthermore, the information provided in Table 1-2, particularly the allele frequency information obtained from 39 individuals and the identification of the precise position of each SNP within each gene/transcript, allows haplotypes (i.e., groups of SNPs that are co-inherited) to be readily inferred. The present invention encompasses SNP haplotypes, as well as individual SNPs.

[0091] Thus, the present invention provides individual SNPs associated with stenosis, as well as combinations of SNPs and haplotypes in genetic regions associated with stenosis, polymorphic/variant transcript sequences (SEQ ID NOS:1-12) and genomic sequences (SEQ ID NOS:37-40) containing SNPs, encoded amino acid sequences (SEQ ID NOS:13-24), and both transcript-based SNP context sequences (SEQ ID NOS: 25-36) and genomic-based SNP context sequences (SEQ ID NOS:41-44) (transcript sequences, protein sequences, and transcript-based SNP context sequences are provided in Table 1 and the Sequence Listing; genomic sequences and genomic-based SNP context sequences are provided in Table 2 and the Sequence Listing), methods of detecting these polymorphisms in a test sample, methods of determining the risk of an individual of having or developing stenosis, methods of screening for compounds useful for treating disorders associated with a variant gene/protein such as stenosis, compounds identified by these screening methods, methods of using the disclosed SNPs to select a treatment strategy, methods of treating a disorder associated with a variant gene/protein (i.e., therapeutic methods), and methods of using the SNPs of the present invention for human identification.

[0092] The present invention provides novel SNPs associated with stenosis, as well as SNPs that were previously known in the art, but were not previously known to be associated with stenosis. Accordingly, the present invention provides novel compositions and methods based on the novel SNPs disclosed herein, and also provides novel methods of using the known, but previously unassociated, SNPs in methods relating to stenosis (e.g., for diagnosing stenosis, etc.). In Tables 1-2, known SNPs are identified based on the public database in which they have been observed, which is indicated as one or more of the following SNP types: "dbSNP"=SNP observed in dbSNP, "HGBASE"=SNP observed in HGBASE, and "HGMD"=SNP observed in the Human Gene Mutation Database (HGMD). Novel SNPs for which the SNP source is only "Applera" and none other, i.e., those that have not been observed in any public databases and which were also not observed during shotgun sequencing and assembly of the Celera human genome sequence (i.e., "Celera" SNP source), are indicated in Tables 3-4.

[0093] Particular SNP alleles of the present invention can be associated with either an increased risk of having or developing stenosis, or a decreased risk of having or developing stenosis. SNP alleles that are associated with a decreased risk of having or developing stenosis may be referred to as "protective" alleles, and SNP alleles that are associated with an increased risk of having or developing stenosis may be referred to as "susceptibility" alleles or "risk factors". Thus, whereas certain SNPs (or their encoded products) can be assayed to determine whether an individual possesses a SNP allele that is indicative of an increased risk of having or developing stenosis (i.e., a susceptibility allele), other SNPs (or their encoded products) can be assayed to determine whether an individual possesses a SNP allele that is indicative of a decreased risk of having or developing stenosis (i.e., a protective allele). Similarly, particular SNP alleles of the present invention can be associated with either an increased or decreased likelihood of responding to a particular treatment or therapeutic compound, or an increased or decreased likelihood of experiencing toxic effects from a particular treatment or therapeutic compound. The term "altered" may be used herein to encompass either of these two possibilities (e.g., an increased or a decreased risk/likelihood).

[0094] Those skilled in the art will readily recognize that nucleic acid molecules may be double-stranded molecules and that reference to a particular site on one strand refers, as well, to the corresponding site on a complementary strand. In defining a SNP position, SNP allele, or nucleotide sequence, reference to an adenine, a thymine (uridine), a cytosine, or a guanine at a particular site on one strand of a nucleic acid molecule also defines the thymine (uridine), adenine, guanine, or cytosine (respectively) at the corresponding site on a complementary strand of the nucleic acid molecule. Thus, reference may be made to either strand in order to refer to a particular SNP position, SNP allele, or nucleotide sequence. Probes and primers, may be designed to hybridize to either strand and SNP genotyping methods disclosed herein may generally target either strand. Throughout the specification, in identifying a SNP position, reference is generally made to the protein-encoding strand, only for the purpose of convenience.

[0095] References to variant peptides, polypeptides, or proteins of the present invention include peptides, polypeptides, proteins, or fragments thereof, that contain at least one amino acid residue that differs from the corresponding amino acid sequence of the art-known peptide/polypeptide/protein (the art-known protein may be interchangeably referred to as the "wild-type", "reference", or "normal" protein). Such variant peptides/polypeptides/proteins can result from a codon change caused by a nonsynonymous nucleotide substitution at a protein-coding SNP position (i.e., a missense mutation) disclosed by the present invention. Variant peptides/polypeptides/proteins of the present invention can also result from a nonsense mutation, i.e. a SNP that creates a premature stop codon, a SNP that generates a read-through mutation by abolishing a stop codon, or due to any SNP disclosed by the present invention that otherwise alters the structure, function/activity, or expression of a protein, such as a SNP in a regulatory region (e.g. a promoter or enhancer) or a SNP that leads to alternative or defective splicing, such as a SNP in an intron or a SNP at an exon/intron boundary. As used herein, the terms "polypeptide", "peptide", and "protein" are used interchangeably.

Isolated Nucleic Acid Molecules and SNP Detection Reagents & Kits

[0096] Tables 1 and 2 provide a variety of information about each SNP of the present invention that is associated with stenosis, including the transcript sequences (SEQ ID NOS:1-12), genomic sequences (SEQ ID NOS:37-40), and protein sequences (SEQ ID NOS:13-24) of the encoded gene products (with the SNPs indicated by IUB codes in the nucleic acid sequences). In addition, Tables 1 and 2 include SNP context sequences, which generally include 100 nucleotide upstream (5') plus 100 nucleotides downstream (3') of each SNP position (SEQ ID NOS:25-36 correspond to transcript-based SNP context sequences disclosed in Table 1, and SEQ ID NOS:41-44 correspond to genomic-based context sequences disclosed in Table 2), the alternative nucleotides (alleles) at each SNP position, and additional information about the variant where relevant, such as SNP type (coding, missense, splice site, UTR, etc.), human populations in which the SNP was observed, observed allele frequencies, information about the encoded protein, etc.

[0097] Isolated Nucleic Acid Molecules

[0098] The present invention provides isolated nucleic acid molecules that contain one or more SNPs disclosed Table 1 and/or Table 2. Preferred isolated nucleic acid molecules contain one or more SNPs identified in Table 3 and/or Table 4. Isolated nucleic acid molecules containing one or more SNPs disclosed in at least one of Tables 1-4 may be interchangeably referred to throughout the present text as "SNP-containing nucleic acid molecules". Isolated nucleic acid molecules may optionally encode a full-length variant protein or fragment thereof. The isolated nucleic acid molecules of the present invention also include probes and primers (which are described in greater detail below in the section entitled "SNP Detection Reagents"), which may be used for assaying the disclosed SNPs, and isolated full-length genes, transcripts, cDNA molecules, and fragments thereof, which may be used for such purposes as expressing an encoded protein.

[0099] As used herein, an "isolated nucleic acid molecule" generally is one that contains a SNP of the present invention or one that hybridizes to such molecule such as a nucleic acid with a complementary sequence, and is separated from most other nucleic acids present in the natural source of the nucleic acid molecule. Moreover, an "isolated" nucleic acid molecule, such as a cDNA molecule containing a SNP of the present invention, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized. A nucleic acid molecule can be fused to other coding or regulatory sequences and still be considered "isolated". Nucleic acid molecules present in non-human transgenic animals, which do not naturally occur in the animal, are also considered "isolated". For example, recombinant DNA molecules contained in a vector are considered "isolated". Further examples of "isolated" DNA molecules include recombinant DNA molecules maintained in heterologous host cells, and purified (partially or substantially) DNA molecules in solution. Isolated RNA molecules include in vivo or in vitro RNA transcripts of the isolated SNP-containing DNA molecules of the present invention. Isolated nucleic acid molecules according to the present invention further include such molecules produced synthetically.

[0100] Generally, an isolated SNP-containing nucleic acid molecule comprises one or more SNP positions disclosed by the present invention with flanking nucleotide sequences on either side of the SNP positions. A flanking sequence can include nucleotide residues that are naturally associated with the SNP site and/or heterologous nucleotide sequences. Preferably the flanking sequence is up to about 500, 300, 100, 60, 50, 30, 25, 20, 15, 10, 8, or 4 nucleotides (or any other length in-between) on either side of a SNP position, or as long as the full-length gene or entire protein-coding sequence (or any portion thereof such as an exon), especially if the SNP-containing nucleic acid molecule is to be used to produce a protein or protein fragment.

[0101] For full-length genes and entire protein-coding sequences, a SNP flanking sequence can be, for example, up to about 5 KB, 4 KB, 3 KB, 2 KB, 1 KB on either side of the SNP. Furthermore, in such instances, the isolated nucleic acid molecule comprises exonic sequences (including protein-coding and/or non-coding exonic sequences), but may also include intronic sequences. Thus, any protein coding sequence may be either contiguous or separated by introns. The important point is that the nucleic acid is isolated from remote and unimportant flanking sequences and is of appropriate length such that it can be subjected to the specific manipulations or uses described herein such as recombinant protein expression, preparation of probes and primers for assaying the SNP position, and other uses specific to the SNP-containing nucleic acid sequences.

[0102] An isolated SNP-containing nucleic acid molecule can comprise, for example, a full-length gene or transcript, such as a gene isolated from genomic DNA (e.g., by cloning or PCR amplification), a cDNA molecule, or an mRNA transcript molecule. Polymorphic transcript sequences are provided in Table 1 and in the Sequence Listing (SEQ ID NOS: 1-12), and polymorphic genomic sequences are provided in Table 2 and in the Sequence Listing (SEQ ID NOS:37-40). Furthermore, fragments of such full-length genes and transcripts that contain one or more SNPs disclosed herein are also encompassed by the present invention, and such fragments may be used, for example, to express any part of a protein, such as a particular functional domain or an antigenic epitope.

[0103] Thus, the present invention also encompasses fragments of the nucleic acid sequences provided in Tables 1-2 (transcript sequences are provided in Table 1 as SEQ ID NOS:1-12, genomic sequences are provided in Table 2 as SEQ ID NOS:37-40, transcript-based SNP context sequences are provided in Table 1 as SEQ ID NO:25-36, and genomic-based SNP context sequences are provided in Table 2 as SEQ ID NO:41-44) and their complements. A fragment typically comprises a contiguous nucleotide sequence at least about 8 or more nucleotides, more preferably at least about 12 or more nucleotides, and even more preferably at least about 16 or more nucleotides. Further, a fragment could comprise at least about 18, 20, 22, 25, 30, 40, 50, 60, 100, 250 or 500 (or any other number in-between) nucleotides in length. The length of the fragment will be based on its intended use. For example, the fragment can encode epitope-bearing regions of a variant peptide or regions of a variant peptide that differ from the normal/wild-type protein, or can be useful as a polynucleotide probe or primer. Such fragments can be isolated using the nucleotide sequences provided in Table 1 and/or Table 2 for the synthesis of a polynucleotide probe. A labeled probe can then be used, for example, to screen a cDNA library, genomic DNA library, or mRNA to isolate nucleic acid corresponding to the coding region. Further, primers can be used in amplification reactions, such as for purposes of assaying one or more SNPs sites or for cloning specific regions of a gene.

[0104] An isolated nucleic acid molecule of the present invention further encompasses a SNP-containing polynucleotide that is the product of any one of a variety of nucleic acid amplification methods, which are used to increase the copy numbers of a polynucleotide of interest in a nucleic acid sample. Such amplification methods are well known in the art, and they include but are not limited to, polymerase chain reaction (PCR) (U.S. Pat. Nos. 4,683,195; and 4,683,202; PCR Technology: Principles and Applications for DNA Amplification, ed. H.A. Erlich, Freeman Press, NY, N.Y., 1992), ligase chain reaction (LCR) (Wu and Wallace, Genomics 4:560, 1989; Landegren et al., Science 241:1077, 1988), strand displacement amplification (SDA) (U.S. Pat. Nos. 5,270,184; and 5,422,252), transcription-mediated amplification (TMA) (U.S. Pat. No. 5,399,491), linked linear amplification (LLA) (U.S. Pat. No. 6,027,923), and the like, and isothermal amplification methods such as nucleic acid sequence based amplification (NASBA), and self-sustained sequence replication (Guatelli et al., Proc. Natl. Acad. Sci. USA 87: 1874, 1990). Based on such methodologies, a person skilled in the art can readily design primers in any suitable regions 5' and 3' to a SNP disclosed herein. Such primers may be used to amplify DNA of any length so long that it contains the SNP of interest in its sequence.

[0105] As used herein, an "amplified polynucleotide" of the invention is a SNP-containing nucleic acid molecule whose amount has been increased at least two fold by any nucleic acid amplification method performed in vitro as compared to its starting amount in a test sample. In other preferred embodiments, an amplified polynucleotide is the result of at least ten fold, fifty fold, one hundred fold, one thousand fold, or even ten thousand fold increase as compared to its starting amount in a test sample. In a typical PCR amplification, a polynucleotide of interest is often amplified at least fifty thousand fold in amount over the unamplified genomic DNA, but the precise amount of amplification needed for an assay depends on the sensitivity of the subsequent detection method used.

[0106] Generally, an amplified polynucleotide is at least about 16 nucleotides in length. More typically, an amplified polynucleotide is at least about 20 nucleotides in length. In a preferred embodiment of the invention, an amplified polynucleotide is at least about 30 nucleotides in length. In a more preferred embodiment of the invention, an amplified polynucleotide is at least about 32, 40, 45, 50, or 60 nucleotides in length. In yet another preferred embodiment of the invention, an amplified polynucleotide is at least about 100, 200, or 300 nucleotides in length. While the total length of an amplified polynucleotide of the invention can be as long as an exon, an intron or the entire gene where the SNP of interest resides, an amplified product is typically no greater than about 1,000 nucleotides in length (although certain amplification methods may generate amplified products greater than 1000 nucleotides in length). More preferably, an amplified polynucleotide is not greater than about 600 nucleotides in length. It is understood that irrespective of the length of an amplified polynucleotide, a SNP of interest may be located anywhere along its sequence.

[0107] In a specific embodiment of the invention, the amplified product is at least about 201 nucleotides in length, comprises one of the transcript-based context sequences or the genomic-based context sequences shown in Tables 1-2. Such a product may have additional sequences on its 5' end or 3' end or both. In another embodiment, the amplified product is about 101 nucleotides in length, and it contains a SNP disclosed herein. Preferably, the SNP is located at the middle of the amplified product (e.g., at position 101 in an amplified product that is 201 nucleotides in length, or at position 51 in an amplified product that is 101 nucleotides in length), or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, or 20 nucleotides from the middle of the amplified product (however, as indicated above, the SNP of interest may be located anywhere along the length of the amplified product).

[0108] The present invention provides isolated nucleic acid molecules that comprise, consist of, or consist essentially of one or more polynucleotide sequences that contain one or more SNPs disclosed herein, complements thereof, and SNP-containing fragments thereof.

[0109] Accordingly, the present invention provides nucleic acid molecules that consist of any of the nucleotide sequences shown in Table 1 and/or Table 2 (transcript sequences are provided in Table 1 as SEQ ID NOS:1-12, genomic sequences are provided in Table 2 as SEQ ID NOS:37-40, transcript-based SNP context sequences are provided in Table 1 as SEQ ID NO:25-36, and genomic-based SNP context sequences are provided in Table 2 as SEQ ID NO:41-44), or any nucleic acid molecule that encodes any of the variant proteins provided in Table 1 (SEQ ID NOS:13-24). A nucleic acid molecule consists of a nucleotide sequence when the nucleotide sequence is the complete nucleotide sequence of the nucleic acid molecule.

[0110] The present invention further provides nucleic acid molecules that consist essentially of any of the nucleotide sequences shown in Table 1 and/or Table 2 (transcript sequences are provided in Table 1 as SEQ ID NOS:1-12, genomic sequences are provided in Table 2 as SEQ ID NOS:37-40, transcript-based SNP context sequences are provided in Table 1 as SEQ ID NO:25-36, and genomic-based SNP context sequences are provided in Table 2 as SEQ ID NO:41-44), or any nucleic acid molecule that encodes any of the variant proteins provided in Table 1 (SEQ ID NOS:13-24). A nucleic acid molecule consists essentially of a nucleotide sequence when such a nucleotide sequence is present with only a few additional nucleotide residues in the final nucleic acid molecule.

[0111] The present invention further provides nucleic acid molecules that comprise any of the nucleotide sequences shown in Table 1 and/or Table 2 or a SNP-containing fragment thereof (transcript sequences are provided in Table 1 as SEQ ID NOS:1-12, genomic sequences are provided in Table 2 as SEQ ID NOS:37-40, transcript-based SNP context sequences are provided in Table 1 as SEQ ID NO:25-36, and genomic-based SNP context sequences are provided in Table 2 as SEQ ID NO:41-44), or any nucleic acid molecule that encodes any of the variant proteins provided in Table 1 (SEQ ID NOS:13-24). A nucleic acid molecule comprises a nucleotide sequence when the nucleotide sequence is at least part of the final nucleotide sequence of the nucleic acid molecule. In such a fashion, the nucleic acid molecule can be only the nucleotide sequence or have additional nucleotide residues, such as residues that are naturally associated with it or heterologous nucleotide sequences. Such a nucleic acid molecule can have one to a few additional nucleotides or can comprise many more additional nucleotides. A brief description of how various types of these nucleic acid molecules can be readily made and isolated is provided below, and such techniques are well known to those of ordinary skill in the art (Sambrook and Russell, 2000, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, NY).

[0112] The isolated nucleic acid molecules can encode mature proteins plus additional amino or carboxyl-terminal amino acids or both, or amino acids interior to the mature peptide (when the mature form has more than one peptide chain, for instance). Such sequences may play a role in processing of a protein from precursor to a mature form, facilitate protein trafficking, prolong or shorten protein half-life, or facilitate manipulation of a protein for assay or production. As generally is the case in situ, the additional amino acids may be processed away from the mature protein by cellular enzymes.

[0113] Thus, the isolated nucleic acid molecules include, but are not limited to, nucleic acid molecules having a sequence encoding a peptide alone, a sequence encoding a mature peptide and additional coding sequences such as a leader or secretory sequence (e.g., a pre-pro or pro-protein sequence), a sequence encoding a mature peptide with or without additional coding sequences, plus additional non-coding sequences, for example introns and non-coding 5' and 3' sequences such as transcribed but untranslated sequences that play a role in, for example, transcription, mRNA processing (including splicing and polyadenylation signals), ribosome binding, and/or stability of mRNA. In addition, the nucleic acid molecules may be fused to heterologous marker sequences encoding, for example, a peptide that facilitates purification.

[0114] Isolated nucleic acid molecules can be in the form of RNA, such as mRNA, or in the form DNA, including cDNA and genomic DNA, which may be obtained, for example, by molecular cloning or produced by chemical synthetic techniques or by a combination thereof (Sambrook and Russell, 2000, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, NY). Furthermore, isolated nucleic acid molecules, particularly SNP detection reagents such as probes and primers, can also be partially or completely in the form of one or more types of nucleic acid analogs, such as peptide nucleic acid (PNA) (U.S. Pat. Nos. 5,539,082; 5,527,675; 5,623,049; 5,714,331). The nucleic acid, especially DNA, can be double-stranded or single-stranded. Single-stranded nucleic acid can be the coding strand (sense strand) or the complementary non-coding strand (anti-sense strand). DNA, RNA, or PNA segments can be assembled, for example, from fragments of the human genome (in the case of DNA or RNA) or single nucleotides, short oligonucleotide linkers, or from a series of oligonucleotides, to provide a synthetic nucleic acid molecule. Nucleic acid molecules can be readily synthesized using the sequences provided herein as a reference; oligonucleotide and PNA oligomer synthesis techniques are well known in the art (see, e.g., Corey, "Peptide nucleic acids: expanding the scope of nucleic acid recognition", Trends Biotechnol. 1997 June; 15(6):224-9, and Hyrup et al., "Peptide nucleic acids (PNA): synthesis, properties and potential applications", Bioorg Med. Chem. 1996 January; 4(1):5-23). Furthermore, large-scale automated oligonucleotide/PNA synthesis (including synthesis on an array or bead surface or other solid support) can readily be accomplished using commercially available nucleic acid synthesizers, such as the Applied Biosystems (Foster City, Calif.) 3900 High-Throughput DNA Synthesizer or Expedite 8909 Nucleic Acid Synthesis System, and the sequence information provided herein.

[0115] The present invention encompasses nucleic acid analogs that contain modified, synthetic, or non-naturally occurring nucleotides or structural elements or other alternative/modified nucleic acid chemistries known in the art. Such nucleic acid analogs are useful, for example, as detection reagents (e.g., primers/probes) for detecting one or more SNPs identified in Table 1 and/or Table 2. Furthermore, kits/systems (such as beads, arrays, etc.) that include these analogs are also encompassed by the present invention. For example, PNA oligomers that are based on the polymorphic sequences of the present invention are specifically contemplated. PNA oligomers are analogs of DNA in which the phosphate backbone is replaced with a peptide-like backbone (Lagriffoul et al., Bioorganic & Medicinal Chemistry Letters, 4: 1081-1082 (1994), Petersen et al., Bioorganic & Medicinal Chemistry Letters, 6: 793-796 (1996), Kumar et al., Organic Letters 3(9): 1269-1272 (2001), WO96/04000). PNA hybridizes to complementary RNA or DNA with higher affinity and specificity than conventional oligonucleotides and oligonucleotide analogs. The properties of PNA enable novel molecular biology and biochemistry applications unachievable with traditional oligonucleotides and peptides.

[0116] Additional examples of nucleic acid modifications that improve the binding properties and/or stability of a nucleic acid include the use of base analogs such as inosine, intercalators (U.S. Pat. No. 4,835,263) and the minor groove binders (U.S. Pat. No. 5,801,115). Thus, references herein to nucleic acid molecules, SNP-containing nucleic acid molecules, SNP detection reagents (e.g., probes and primers), oligonucleotides/polynucleotides include PNA oligomers and other nucleic acid analogs. Other examples of nucleic acid analogs and alternative/modified nucleic acid chemistries known in the art are described in Current Protocols in Nucleic Acid Chemistry, John Wiley & Sons, N.Y. (2002).

[0117] The present invention further provides nucleic acid molecules that encode fragments of the variant polypeptides disclosed herein as well as nucleic acid molecules that encode obvious variants of such variant polypeptides. Such nucleic acid molecules may be naturally occurring, such as paralogs (different locus) and orthologs (different organism), or may be constructed by recombinant DNA methods or by chemical synthesis. Non-naturally occurring variants may be made by mutagenesis techniques, including those applied to nucleic acid molecules, cells, or organisms. Accordingly, the variants can contain nucleotide substitutions, deletions, inversions and insertions (in addition to the SNPs disclosed in Tables 1-2). Variation can occur in either or both the coding and non-coding regions. The variations can produce conservative and/or non-conservative amino acid substitutions.

[0118] Further variants of the nucleic acid molecules disclosed in Tables 1-2, such as naturally occurring allelic variants (as well as orthologs and paralogs) and synthetic variants produced by mutagenesis techniques, can be identified and/or produced using methods well known in the art. Such further variants can comprise a nucleotide sequence that shares at least 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with a nucleic acid sequence disclosed in Table 1 and/or Table 2 (or a fragment thereof) and that includes a novel SNP allele disclosed in Table 1 and/or Table 2. Further, variants can comprise a nucleotide sequence that encodes a polypeptide that shares at least 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with a polypeptide sequence disclosed in Table 1 (or a fragment thereof) and that includes a novel SNP allele disclosed in Table 1 and/or Table 2. Thus, the present invention specifically contemplates isolated nucleic acid molecule that have a certain degree of sequence variation compared with the sequences shown in Tables 1-2, but that contain a novel SNP allele disclosed herein. In other words, as long as an isolated nucleic acid molecule contains a novel SNP allele disclosed herein, other portions of the nucleic acid molecule that flank the novel SNP allele can vary to some degree from the specific transcript, genomic, and context sequences shown in Tables 1-2, and can encode a polypeptide that varies to some degree from the specific polypeptide sequences shown in Table 1.

[0119] To determine the percent identity of two amino acid sequences or two nucleotide sequences of two molecules that share sequence homology, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, at least 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more of the length of a reference sequence is aligned for comparison purposes. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein, amino acid or nucleic acid "identity" is equivalent to amino acid or nucleic acid "homology"). The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

[0120] The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. (Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part 1, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991). In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch algorithm (J. Mol. Biol. (48):444-453 (1970)) which has been incorporated into the GAP program in the GCG software package, using either a Blossom 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.

[0121] In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (Devereux, J., et al., Nucleic Acids Res. 12(1):387 (1984)), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. In another embodiment, the percent identity between two amino acid or nucleotide sequences is determined using the algorithm of E. Myers and W. Miller (CABIOS, 4:11-17 (1989)) which has been incorporated into the ALIGN program (version 2.0), using a PAM 120 weight residue table, a gap length penalty of 12, and a gap penalty of 4.

[0122] The nucleotide and amino acid sequences of the present invention can further be used as a "query sequence" to perform a search against sequence databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (J. Mol. Biol. 215:403-10 (1990)). BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12 to obtain nucleotide sequences homologous to the nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to the proteins of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al. (Nucleic Acids Res. 25(17):3389-3402 (1997)). When utilizing BLAST and gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. In addition to BLAST, examples of other search and sequence comparison programs used in the art include, but are not limited to, FASTA (Pearson, Methods Mol. Biol. 25, 365-389 (1994)) and KERR (Dufresne et al., Nat Biotechnol 2002 December; 20(12):1269-71). For further information regarding bioinformatics techniques, see Current Protocols in Bioinformatics, John Wiley & Sons, Inc., N.Y.

[0123] The present invention further provides non-coding fragments of the nucleic acid molecules disclosed in Table 1 and/or Table 2. Preferred non-coding fragments include, but are not limited to, promoter sequences, enhancer sequences, intronic sequences, 5' untranslated regions (UTRs), 3' untranslated regions, gene modulating sequences and gene termination sequences. Such fragments are useful, for example, in controlling heterologous gene expression and in developing screens to identify gene-modulating agents.

[0124] SNP Detection Reagents

[0125] In a specific aspect of the present invention, the SNPs disclosed in Table 1 and/or Table 2, and their associated transcript sequences (provided in Table 1 as SEQ ID NOS:1-12), genomic sequences (provided in Table 2 as SEQ ID NOS:37-40), and context sequences (transcript-based context sequences are provided in Table 1 as SEQ ID NOS:25-36; genomic-based context sequences are provided in Table 2 as SEQ ID NOS:41-44), can be used for the design of SNP detection reagents. As used herein, a "SNP detection reagent" is a reagent that specifically detects a specific target SNP position disclosed herein, and that is preferably specific for a particular nucleotide (allele) of the target SNP position (i.e., the detection reagent preferably can differentiate between different alternative nucleotides at a target SNP position, thereby allowing the identity of the nucleotide present at the target SNP position to be determined). Typically, such detection reagent hybridizes to a target SNP-containing nucleic acid molecule by complementary base-pairing in a sequence specific manner, and discriminates the target variant sequence from other nucleic acid sequences such as an art-known form in a test sample. An example of a detection reagent is a probe that hybridizes to a target nucleic acid containing one or more of the SNPs provided in Table 1 and/or Table 2. In a preferred embodiment, such a probe can differentiate between nucleic acids having a particular nucleotide (allele) at a target SNP position from other nucleic acids that have a different nucleotide at the same target SNP position. In addition, a detection reagent may hybridize to a specific region 5' and/or 3' to a SNP position, particularly a region corresponding to the context sequences provided in Table 1 and/or Table 2 (transcript-based context sequences are provided in Table 1 as SEQ ID NOS:25-36; genomic-based context sequences are provided in Table 2 as SEQ ID NOS:41-44). Another example of a detection reagent is a primer which acts as an initiation point of nucleotide extension along a complementary strand of a target polynucleotide. The SNP sequence information provided herein is also useful for designing primers, e.g. allele-specific primers, to amplify (e.g., using PCR) any SNP of the present invention.

[0126] In one preferred embodiment of the invention, a SNP detection reagent is an isolated or synthetic DNA or RNA polynucleotide probe or primer or PNA oligomer, or a combination of DNA, RNA and/or PNA, that hybridizes to a segment of a target nucleic acid molecule containing a SNP identified in Table 1 and/or Table 2. A detection reagent in the form of a polynucleotide may optionally contain modified base analogs, intercalators or minor groove binders. Multiple detection reagents such as probes may be, for example, affixed to a solid support (e.g., arrays or beads) or supplied in solution (e.g., probe/primer sets for enzymatic reactions such as PCR, RT-PCR, TaqMan assays, or primer-extension reactions) to form a SNP detection kit.

[0127] A probe or primer typically is a substantially purified oligonucleotide or PNA oligomer. Such oligonucleotide typically comprises a region of complementary nucleotide sequence that hybridizes under stringent conditions to at least about 8, 10, 12, 16, 18, 20, 22, 25, 30, 40, 50, 60, 100 (or any other number in-between) or more consecutive nucleotides in a target nucleic acid molecule. Depending on the particular assay, the consecutive nucleotides can either include the target SNP position, or be a specific region in close enough proximity 5' and/or 3' to the SNP position to carry out the desired assay.

[0128] Other preferred primer and probe sequences can readily be determined using the transcript sequences (SEQ ID NOS:1-12), genomic sequences (SEQ ID NOS:37-40), and SNP context sequences (transcript-based context sequences are provided in Table 1 as SEQ ID NOS:25-36; genomic-based context sequences are provided in Table 2 as SEQ ID NOS:41-44) disclosed in the Sequence Listing and in Tables 1-2. It will be apparent to one of skill in the art that such primers and probes are directly useful as reagents for genotyping the SNPs of the present invention, and can be incorporated into any kit/system format.

[0129] In order to produce a probe or primer specific for a target SNP-containing sequence, the gene/transcript and/or context sequence surrounding the SNP of interest is typically examined using a computer algorithm which starts at the 5' or at the 3' end of the nucleotide sequence. Typical algorithms will then identify oligomers of defined length that are unique to the gene/SNP context sequence, have a GC content within a range suitable for hybridization, lack predicted secondary structure that may interfere with hybridization, and/or possess other desired characteristics or that lack other undesired characteristics.

[0130] A primer or probe of the present invention is typically at least about 8 nucleotides in length.

[0131] In one embodiment of the invention, a primer or a probe is at least about 10 nucleotides in length. In a preferred embodiment, a primer or a probe is at least about 12 nucleotides in length. In a more preferred embodiment, a primer or probe is at least about 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 nucleotides in length. While the maximal length of a probe can be as long as the target sequence to be detected, depending on the type of assay in which it is employed, it is typically less than about 50, 60, 65, or 70 nucleotides in length. In the case of a primer, it is typically less than about 30 nucleotides in length. In a specific preferred embodiment of the invention, a primer or a probe is within the length of about 18 and about 28 nucleotides. However, in other embodiments, such as nucleic acid arrays and other embodiments in which probes are affixed to a substrate, the probes can be longer, such as on the order of 30-70, 75, 80, 90, 100, or more nucleotides in length (see the section below entitled "SNP Detection Kits and Systems").

[0132] For analyzing SNPs, it may be appropriate to use oligonucleotides specific for alternative SNP alleles. Such oligonucleotides which detect single nucleotide variations in target sequences may be referred to by such terms as "allele-specific oligonucleotides", "allele-specific probes", or "allele-specific primers". The design and use of allele-specific probes for analyzing polymorphisms is described in, e.g., Mutation Detection A Practical Approach, ed. Cotton et al. Oxford University Press, 1998; Saiki et al., Nature 324, 163-166 (1986); Dattagupta, EP235,726; and Saiki, WO 89/11548.

[0133] While the design of each allele-specific primer or probe depends on variables such as the precise composition of the nucleotide sequences flanking a SNP position in a target nucleic acid molecule, and the length of the primer or probe, another factor in the use of primers and probes is the stringency of the condition under which the hybridization between the probe or primer and the target sequence is performed. Higher stringency conditions utilize buffers with lower ionic strength and/or a higher reaction temperature, and tend to require a more perfect match between probe/primer and a target sequence in order to form a stable duplex. If the stringency is too high, however, hybridization may not occur at all. In contrast, lower stringency conditions utilize buffers with higher ionic strength and/or a lower reaction temperature, and permit the formation of stable duplexes with more mismatched bases between a probe/primer and a target sequence. By way of example and not limitation, exemplary conditions for high stringency hybridization conditions using an allele-specific probe are as follows: Prehybridization with a solution containing 5.times. standard saline phosphate EDTA (SSPE), 0.5% NaDodSO.sub.4 (SDS) at 55.degree. C., and incubating probe with target nucleic acid molecules in the same solution at the same temperature, followed by washing with a solution containing 2.times.SSPE, and 0.1% SDS at 55.degree. C. or room temperature.

[0134] Moderate stringency hybridization conditions may be used for allele-specific primer extension reactions with a solution containing, e.g., about 50 mM KCl at about 46.degree. C. Alternatively, the reaction may be carried out at an elevated temperature such as 60.degree. C. In another embodiment, a moderately stringent hybridization condition suitable for oligonucleotide ligation assay (OLA) reactions wherein two probes are ligated if they are completely complementary to the target sequence may utilize a solution of about 100 mM KCl at a temperature of 46.degree. C.

[0135] In a hybridization-based assay, allele-specific probes can be designed that hybridize to a segment of target DNA from one individual but do not hybridize to the corresponding segment from another individual due to the presence of different polymorphic forms (e.g., alternative SNP alleles/nucleotides) in the respective DNA segments from the two individuals. Hybridization conditions should be sufficiently stringent that there is a significant detectable difference in hybridization intensity between alleles, and preferably an essentially binary response, whereby a probe hybridizes to only one of the alleles or significantly more strongly to one allele. While a probe may be designed to hybridize to a target sequence that contains a SNP site such that the SNP site aligns anywhere along the sequence of the probe, the probe is preferably designed to hybridize to a segment of the target sequence such that the SNP site aligns with a central position of the probe (e.g., a position within the probe that is at least three nucleotides from either end of the probe). This design of probe generally achieves good discrimination in hybridization between different allelic forms.

[0136] In another embodiment, a probe or primer may be designed to hybridize to a segment of target DNA such that the SNP aligns with either the 5' most end or the 3' most end of the probe or primer. In a specific preferred embodiment which is particularly suitable for use in a oligonucleotide ligation assay (U.S. Pat. No. 4,988,617), the 3' most nucleotide of the probe aligns with the SNP position in the target sequence.

[0137] Oligonucleotide probes and primers may be prepared by methods well known in the art. Chemical synthetic methods include, but are limited to, the phosphotriester method described by Narang et al., 1979, Methods in Enzymology 68:90; the phosphodiester method described by Brown et al., 1979, Methods in Enzymology 68:109, the diethylphosphoamidate method described by Beaucage et al., 1981, Tetrahedron Letters 22:1859; and the solid support method described in U.S. Pat. No. 4,458,066.

[0138] Allele-specific probes are often used in pairs (or, less commonly, in sets of 3 or 4, such as if a SNP position is known to have 3 or 4 alleles, respectively, or to assay both strands of a nucleic acid molecule for a target SNP allele), and such pairs may be identical except for a one nucleotide mismatch that represents the allelic variants at the SNP position. Commonly, one member of a pair perfectly matches a reference form of a target sequence that has a more common SNP allele (i.e., the allele that is more frequent in the target population) and the other member of the pair perfectly matches a form of the target sequence that has a less common SNP allele (i.e., the allele that is rarer in the target population). In the case of an array, multiple pairs of probes can be immobilized on the same support for simultaneous analysis of multiple different polymorphisms.

[0139] In one type of PCR-based assay, an allele-specific primer hybridizes to a region on a target nucleic acid molecule that overlaps a SNP position and only primes amplification of an allelic form to which the primer exhibits perfect complementarity (Gibbs, 1989, Nucleic Acid Res. 17 2427-2448). Typically, the primer's 3'-most nucleotide is aligned with and complementary to the SNP position of the target nucleic acid molecule. This primer is used in conjunction with a second primer that hybridizes at a distal site. Amplification proceeds from the two primers, producing a detectable product that indicates which allelic form is present in the test sample. A control is usually performed with a second pair of primers, one of which shows a single base mismatch at the polymorphic site and the other of which exhibits perfect complementarity to a distal site. The single-base mismatch prevents amplification or substantially reduces amplification efficiency, so that either no detectable product is formed or it is formed in lower amounts or at a slower pace. The method generally works most effectively when the mismatch is at the 3'-most position of the oligonucleotide (i.e., the 3'-most position of the oligonucleotide aligns with the target SNP position) because this position is most destabilizing to elongation from the primer (see, e.g., WO 93/22456). This PCR-based assay can be utilized as part of the TaqMan assay, described below.

[0140] In a specific embodiment of the invention, a primer of the invention contains a sequence substantially complementary to a segment of a target SNP-containing nucleic acid molecule except that the primer has a mismatched nucleotide in one of the three nucleotide positions at the 3'-most end of the primer, such that the mismatched nucleotide does not base pair with a particular allele at the SNP site. In a preferred embodiment, the mismatched nucleotide in the primer is the second from the last nucleotide at the 3'-most position of the primer. In a more preferred embodiment, the mismatched nucleotide in the primer is the last nucleotide at the 3'-most position of the primer.

[0141] In another embodiment of the invention, a SNP detection reagent of the invention is labeled with a fluorogenic reporter dye that emits a detectable signal. While the preferred reporter dye is a fluorescent dye, any reporter dye that can be attached to a detection reagent such as an oligonucleotide probe or primer is suitable for use in the invention. Such dyes include, but are not limited to, Acridine, AMCA, BODIPY, Cascade Blue, Cy2, Cy3, Cy5, Cy7, Dabcyl, Edans, Eosin, Erythrosin, Fluorescein, 6-Fam, Tet, Joe, Hex, Oregon Green, Rhodamine, Rhodol Green, Tamra, Rox, and Texas Red.

[0142] In yet another embodiment of the invention, the detection reagent may be further labeled with a quencher dye such as Tamra, especially when the reagent is used as a self-quenching probe such as a TaqMan (U.S. Pat. Nos. 5,210,015 and 5,538,848) or Molecular Beacon probe (U.S. Pat. Nos. 5,118,801 and 5,312,728), or other stemless or linear beacon probe (Livak et al., 1995, PCR Method Appl. 4:357-362; Tyagi et al., 1996, Nature Biotechnology 14: 303-308; Nazarenko et al., 1997, Nucl. Acids Res. 25:2516-2521; U.S. Pat. Nos. 5,866,336 and 6,117,635).

[0143] The detection reagents of the invention may also contain other labels, including but not limited to, biotin for streptavidin binding, hapten for antibody binding, and oligonucleotide for binding to another complementary oligonucleotide such as pairs of zipcodes.

[0144] The present invention also contemplates reagents that do not contain (or that are complementary to) a SNP nucleotide identified herein but that are used to assay one or more SNPs disclosed herein. For example, primers that flank, but do not hybridize directly to a target SNP position provided herein are useful in primer extension reactions in which the primers hybridize to a region adjacent to the target SNP position (i.e., within one or more nucleotides from the target SNP site). During the primer extension reaction, a primer is typically not able to extend past a target SNP site if a particular nucleotide (allele) is present at that target SNP site, and the primer extension product can readily be detected in order to determine which SNP allele is present at the target SNP site. For example, particular ddNTPs are typically used in the primer extension reaction to terminate primer extension once a ddNTP is incorporated into the extension product (a primer extension product which includes a ddNTP at the 3'-most end of the primer extension product, and in which the ddNTP corresponds to a SNP disclosed herein, is a composition that is encompassed by the present invention). Thus, reagents that bind to a nucleic acid molecule in a region adjacent to a SNP site, even though the bound sequences do not necessarily include the SNP site itself, are also encompassed by the present invention.

[0145] SNP Detection Kits and Systems

[0146] A person skilled in the art will recognize that, based on the SNP and associated sequence information disclosed herein, detection reagents can be developed and used to assay any SNP of the present invention individually or in combination, and such detection reagents can be readily incorporated into one of the established kit or system formats which are well known in the art. The terms "kits" and "systems", as used herein in the context of SNP detection reagents, are intended to refer to such things as combinations of multiple SNP detection reagents, or one or more SNP detection reagents in combination with one or more other types of elements or components (e.g., other types of biochemical reagents, containers, packages such as packaging intended for commercial sale, substrates to which SNP detection reagents are attached, electronic hardware components, etc.). Accordingly, the present invention further provides SNP detection kits and systems, including but not limited to, packaged probe and primer sets (e.g., TaqMan probe/primer sets), arrays/microarrays of nucleic acid molecules, and beads that contain one or more probes, primers, or other detection reagents for detecting one or more SNPs of the present invention. The kits/systems can optionally include various electronic hardware components; for example, arrays ("DNA chips") and microfluidic systems ("lab-on-a-chip" systems) provided by various manufacturers typically comprise hardware components. Other kits/systems (e.g., probe/primer sets) may not include electronic hardware components, but may be comprised of, for example, one or more SNP detection reagents (along with, optionally, other biochemical reagents) packaged in one or more containers.

[0147] In some embodiments, a SNP detection kit typically contains one or more detection reagents and other components (e.g., a buffer, enzymes such as DNA polymerases or ligases, chain extension nucleotides such as deoxynucleotide triphosphates, and in the case of Sanger-type DNA sequencing reactions, chain terminating nucleotides, positive control sequences, negative control sequences, and the like) necessary t6 carry out an assay or reaction, such as amplification and/or detection of a SNP-containing nucleic acid molecule. A kit may further contain means for determining the amount of a target nucleic acid, and means for comparing the amount with a standard, and can comprise instructions for using the kit to detect the SNP-containing nucleic acid molecule of interest. In one embodiment of the present invention, kits are provided which contain the necessary reagents to carry out one or more assays to detect one or more SNPs disclosed herein. In a preferred embodiment of the present invention, SNP detection kits/systems are in the form of nucleic acid arrays, or compartmentalized kits, including microfluidic/lab-on-a-chip systems.

[0148] SNP detection kits/systems may contain, for example, one or more probes, or pairs of probes, that hybridize to a nucleic acid molecule at or near each target SNP position. Multiple pairs of allele-specific probes may be included in the kit/system to simultaneously assay large numbers of SNPs, at least one of which is a SNP of the present invention. In some kits/systems, the allele-specific probes are immobilized to a substrate such as an array or bead. For example, the same substrate can comprise allele-specific probes for detecting at least 1; 10; 100; 1000; 10,000; 100,000 (or any other number in-between) or substantially all of the SNPs shown in Table 1 and/or Table 2.

[0149] The terms "arrays", "microarrays", and "DNA chips" are used herein interchangeably to refer to an array of distinct polynucleotides affixed to a substrate, such as glass, plastic, paper, nylon or other type of membrane, filter, chip, or any other suitable solid support. The polynucleotides can be synthesized directly on the substrate, or synthesized separate from the substrate and then affixed to the substrate. In one embodiment, the microarray is prepared and used according to the methods described in U.S. Pat. No. 5,837,832, Chee et al., PCT application WO95/11995 (Chee et al.), Lockhart, D. J. et al. (1996; Nat. Biotech. 14: 1675-1680) and Schena, M. et al. (1996; Proc. Natl. Acad. Sci. 93: 10614-10619), all of which are incorporated herein in their entirety by reference. In other embodiments, such arrays are produced by the methods described by Brown et al., U.S. Pat. No. 5,807,522.

[0150] Nucleic acid arrays are reviewed in the following references: Zammatteo et al., "New chips for molecular biology and diagnostics", Biotechnol Annu Rev. 2002; 8:85-101; Sosnowski et al., "Active microelectronic array system for DNA hybridization, genotyping and pharmacogenomic applications", Psychiatr Genet. 2002 December; 12(4):181-92; Heller, "DNA microarray technology: devices, systems, and applications", Annu Rev Biomed Eng. 2002; 4:129-53. Epub 2002 Mar. 22; Kolchinsky et al., "Analysis of SNPs and other genomic variations using gel-based chips", Hum Mutat. 2002 April; 19(4):343-60; and McGall et al., "High-density genechip oligonucleotide probe arrays", Adv Biochem Eng Biotechnol. 2002; 77:21-42.

[0151] Any number of probes, such as allele-specific probes, may be implemented in an array, and each probe or pair of probes can hybridize to a different SNP position. In the case of polynucleotide probes, they can be synthesized at designated areas (or synthesized separately and then affixed to designated areas) on a substrate using a light-directed chemical process. Each DNA chip can contain, for example, thousands to millions of individual synthetic polynucleotide probes arranged in a grid-like pattern and miniaturized (e.g., to the size of a dime). Preferably, probes are attached to a solid support in an ordered, addressable array.

[0152] A microarray can be composed of a large number of unique, single-stranded polynucleotides, usually either synthetic antisense polynucleotides or fragments of cDNAs, fixed to a solid support. Typical polynucleotides are preferably about 6-60 nucleotides in length, more preferably about 15-nucleotides in length, and most preferably about 18-25 nucleotides in length. For certain types of microarrays or other detection kits/systems, it may be preferable to use oligonucleotides that are only about 7-20 nucleotides in length. In other types of arrays, such as arrays used in conjunction with chemiluminescent detection technology, preferred probe lengths can be, for example, about 15-80 nucleotides in length, preferably about 50-70 nucleotides in length, more preferably about 55-65 nucleotides in length, and most preferably about 60 nucleotides in length. The microarray or detection kit can contain polynucleotides that cover the known 5' or 3' sequence of a gene/transcript or target SNP site, sequential polynucleotides that cover the full-length sequence of a gene/transcript; or unique polynucleotides selected from particular areas along the length of a target gene/transcript sequence, particularly areas corresponding to one or more SNPs disclosed in Table 1 and/or Table 2. Polynucleotides used in the microarray or detection kit can be specific to a SNP or SNPs of interest (e.g., specific to a particular SNP allele at a target SNP site, or specific to particular SNP alleles at multiple different SNP sites), or specific to a polymorphic gene/transcript or genes/transcripts of interest.

[0153] Hybridization assays based on polynucleotide arrays rely on the differences in hybridization stability of the probes to perfectly matched and mismatched target sequence variants. For SNP genotyping, it is generally preferable that stringency conditions used in hybridization assays are high enough such that nucleic acid molecules that differ from one another at as little as a single SNP position can be differentiated (e.g., typical SNP hybridization assays are designed so that hybridization will occur only if one particular nucleotide is present at a SNP position, but will not occur if an alternative nucleotide is present at that SNP position). Such high stringency conditions may be preferable when using, for example, nucleic acid arrays of allele-specific probes for SNP detection. Such high stringency conditions are described in the preceding section, and are well known to those skilled in the art and can be found in, for example, Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6.

[0154] In other embodiments, the arrays are used in conjunction with chemiluminescent detection technology. The following patents and patent applications, which are all hereby incorporated by reference, provide additional information pertaining to chemiluminescent detection: U.S. patent application Ser. Nos. 10/620,332 and 10/620,333 describe chemiluminescent approaches for microarray detection; U.S. Pat. Nos. 6,124,478, 6,107,024, 5,994,073, 5,981,768, 5,871,938, 5,843,681, 5,800,999, and 5,773,628 describe methods and compositions of dioxetane for performing chemiluminescent detection; and U.S. published application US2002/0110828 discloses methods and compositions for microarray controls.

[0155] In one embodiment of the invention, a nucleic acid array can comprise an array of probes of about 15-25 nucleotides in length. In further embodiments, a nucleic acid array can comprise any number of probes, in which at least one probe is capable of detecting one or more SNPs disclosed in Table 1 and/or Table 2, and/or at least one probe comprises a fragment of one of the sequences selected from the group consisting of those disclosed in Table 1, Table 2, the Sequence Listing, and sequences complementary thereto, said fragment comprising at least about 8 consecutive nucleotides, preferably 10, 12, 15, 16, 18, 20, more preferably 22, 25, 30, 40, 47, 50, 55, 60, 65, 70, 80, 90, 100, or more consecutive nucleotides (or any other number in-between) and containing (or being complementary to) a novel SNP allele disclosed in Table 1 and/or Table 2. In some embodiments, the nucleotide complementary to the SNP site is within 5, 4, 3, 2, or 1 nucleotide from the center of the probe, more preferably at the center of said probe.

[0156] A polynucleotide probe can be synthesized on the surface of the substrate by using a chemical coupling procedure and an ink jet application apparatus, as described in PCT application WO95/251116 (Baldeschweiler et al.) which is incorporated herein in its entirety by reference. In another aspect, a "gridded" array analogous to a dot (or slot) blot may be used to arrange and link cDNA fragments or oligonucleotides to the surface of a substrate using a vacuum system, thermal, UV, mechanical or chemical bonding procedures. An array, such as those described above, may be produced by hand or by using available devices (slot blot or dot blot apparatus), materials (any suitable solid support), and machines (including robotic instruments), and may contain 8, 24, 96, 384, 1536, 6144 or more polynucleotides, or any other number which lends itself to the efficient use of commercially available instrumentation.

[0157] Using such arrays or other kits/systems, the present invention provides methods of identifying the SNPs disclosed herein in a test sample. Such methods typically involve incubating a test sample of nucleic acids with an array comprising one or more probes corresponding to at least one SNP position of the present invention, and assaying for binding of a nucleic acid from the test sample with one or more of the probes. Conditions for incubating a SNP detection reagent (or a kit/system that employs one or more such SNP detection reagents) with a test sample vary. Incubation conditions depend on such factors as the format employed in the assay, the detection methods employed, and the type and nature of the detection reagents used in the assay. One skilled in the art will recognize that any one of the commonly available hybridization, amplification and array assay formats can readily be adapted to detect the SNPs disclosed herein.

[0158] A SNP detection kit/system of the present invention may include components that are used to prepare nucleic acids from a test sample for the subsequent amplification and/or detection of a SNP-containing nucleic acid molecule. Such sample preparation components can be used to produce nucleic acid extracts (including DNA and/or RNA), proteins or membrane extracts from any bodily fluids (such as blood, serum, plasma, urine, saliva, phlegm, gastric juices, semen, tears, sweat, etc.), skin, hair, cells (especially nucleated cells), biopsies, buccal swabs or tissue specimens. The test samples used in the above-described methods will vary based on such factors as the assay format, nature of the detection method, and the specific tissues, cells or extracts used as the test sample to be assayed. Methods of preparing nucleic acids, proteins, and cell extracts are well known in the art and can be readily adapted to obtain a sample that is compatible with the system utilized. Automated sample preparation systems for extracting nucleic acids from a test sample are commercially available, and examples are Qiagen's BioRobot 9600, Applied Biosystems' PRISM 6700, and Roche Molecular Systems'COBAS AmpliPrep System.

[0159] Another form of kit contemplated by the present invention is a compartmentalized kit. A compartmentalized kit includes any kit in which reagents are contained in separate containers. Such containers include, for example, small glass containers, plastic containers, strips of plastic, glass or paper, or arraying material such as silica. Such containers allow one to efficiently transfer reagents from one compartment to another compartment such that the test samples and reagents are not cross-contaminated, or from one container to another vessel not included in the kit, and the agents or solutions of each container can be added in a quantitative fashion from one compartment to another or to another vessel. Such containers may include, for example, one or more containers which will accept the test sample, one or more containers which contain at least one probe or other SNP detection reagent for detecting one or more SNPs of the present invention, one or more containers which contain wash reagents (such as phosphate buffered saline, Tris-buffers, etc.), and one or more containers which contain the reagents used to reveal the presence of the bound probe or other SNP detection reagents. The kit can optionally further comprise compartments and/or reagents for, for example, nucleic acid amplification or other enzymatic reactions such as primer extension reactions, hybridization, ligation, electrophoresis (preferably capillary electrophoresis), mass spectrometry, and/or laser-induced fluorescent detection. The kit may also include instructions for using the kit. Exemplary compartmentalized kits include microfluidic devices known in the art (see, e.g., Weigl et al., "Lab-on-a-chip for drug development", Adv Drug Deliv Rev. 2003 Feb. 24; 55(3):349-77). In such microfluidic devices, the containers may be referred to as, for example, microfluidic "compartments", "chambers", or "channels".

[0160] Microfluidic devices, which may also be referred to as "lab-on-a-chip" systems, biomedical micro-electro-mechanical systems (bioMEMs), or multicomponent integrated systems, are exemplary kits/systems of the present invention for analyzing SNPs. Such systems miniaturize and compartmentalize processes such as probe/target hybridization, nucleic acid amplification, and capillary electrophoresis reactions in a single functional device. Such microfluidic devices typically utilize detection reagents in at least one aspect of the system, and such detection reagents may be used to detect one or more SNPs of the present invention. One example of a microfluidic system is disclosed in U.S. Pat. No. 5,589,136, which describes the integration of PCR amplification and capillary electrophoresis in chips. Exemplary microfluidic systems comprise a pattern of microchannels designed onto a glass, silicon, quartz, or plastic wafer included on a microchip. The movements of the samples may be controlled by electric, electroosmotic or hydrostatic forces applied across different areas of the microchip to create functional microscopic valves and pumps with no moving parts. Varying the voltage can be used as a means to control the liquid flow at intersections between the micro-machined channels and to change the liquid flow rate for pumping across different sections of the microchip. See, for example, U.S. Pat. Nos. 6,153,073, Dubrow et al., and 6,156,181, Parce et al.

[0161] For genotyping SNPs, an exemplary microfluidic system may integrate, for example, nucleic acid amplification, primer extension, capillary electrophoresis, and a detection method such as laser induced fluorescence detection. In a first step of an exemplary process for using such an exemplary system, nucleic acid samples are amplified, preferably by PCR. Then, the amplification products are subjected to automated primer extension reactions using ddNTPs (specific fluorescence for each ddNTP) and the appropriate oligonucleotide primers to carry out primer extension reactions which hybridize just upstream of the targeted SNP. Once the extension at the 3' end is completed, the primers are separated from the unincorporated fluorescent ddNTPs by capillary electrophoresis. The separation medium used in capillary electrophoresis can be, for example, polyacrylamide, polyethyleneglycol or dextran. The incorporated ddNTPs in the single nucleotide primer extension products are identified by laser-induced fluorescence detection. Such an exemplary microchip can be used to process, for example, at least 96 to 384 samples, or more, in parallel.

[0162] Uses of Nucleic Acid Molecules

[0163] The nucleic acid molecules of the present invention have a variety of uses, especially in the diagnosis and treatment of stenosis. For example, the nucleic acid molecules are useful as hybridization probes, such as for genotyping SNPs in messenger RNA, transcript, cDNA, genomic DNA, amplified DNA or other nucleic acid molecules, and for isolating full-length cDNA and genomic clones encoding the variant peptides disclosed in Table 1 as well as their orthologs.

[0164] A probe can hybridize to any nucleotide sequence along the entire length of a nucleic acid molecule provided in Table 1 and/or Table 2. Preferably, a probe of the present invention hybridizes to a region of a target sequence that encompasses a SNP position indicated in Table 1 and/or Table 2. More preferably, a probe hybridizes to a SNP-containing target sequence in a sequence-specific manner such that it distinguishes the target sequence from other nucleotide sequences which vary from the target sequence only by which nucleotide is present at the SNP site. Such a probe is particularly useful for detecting the presence of a SNP-containing nucleic acid in a test sample, or for determining which nucleotide (allele) is present at a particular SNP site (i.e., genotyping the SNP site).

[0165] A nucleic acid hybridization probe may be used for determining the presence, level, form, and/or distribution of nucleic acid expression. The nucleic acid whose level is determined can be DNA or RNA. Accordingly, probes specific for the SNPs described herein can be used to assess the presence, expression and/or gene copy number in a given cell, tissue, or organism. These uses are relevant for diagnosis of disorders involving an increase or decrease in gene expression relative to normal levels. In vitro techniques for detection of mRNA include, for example, Northern blot hybridizations and in situ hybridizations. In vitro techniques for detecting DNA include Southern blot hybridizations and in situ hybridizations (Sambrook and Russell, 2000, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, N.Y.).

[0166] Probes can be used as part of a diagnostic test kit for identifying cells or tissues in which a variant protein is expressed, such as by measuring the level of a variant protein-encoding nucleic acid (e.g., mRNA) in a sample of cells from a subject or determining if a polynucleotide contains a SNP of interest.

[0167] Thus, the nucleic acid molecules of the invention can be used as hybridization probes to detect the SNPs disclosed herein, thereby determining whether an individual with the polymorphisms is at risk for stenosis or has developed early stage stenosis. Detection of a SNP associated with a disease phenotype provides a diagnostic tool for an active disease and/or genetic predisposition to the disease.

[0168] The nucleic acid molecules of the invention are also useful as primers to amplify any given region of a nucleic acid molecule, particularly a region containing a SNP identified in Table 1 and/or Table 2.

[0169] The nucleic acid molecules of the invention are also useful for constructing recombinant vectors (described in greater detail below). Such vectors include expression vectors that express a portion of, or all of, any of the variant peptide sequences provided in Table 1. Vectors also include insertion vectors, used to integrate into another nucleic acid molecule sequence, such as into the cellular genome, to alter in situ expression of a gene and/or gene product. For example, an endogenous coding sequence can be replaced via homologous recombination with all or part of the coding region containing one or more specifically introduced SNPs.

[0170] The nucleic acid molecules of the invention are also useful for expressing antigenic portions of the variant proteins, particularly antigenic portions that contain a variant amino acid sequence (e.g., an amino acid substitution) caused by a SNP disclosed in Table 1 and/or Table 2.

[0171] The nucleic acid molecules of the invention are also useful for constructing vectors containing a gene regulatory region of the nucleic acid molecules of the present invention.

[0172] The nucleic acid molecules of the invention are also useful for designing ribozymes corresponding to all, or a part, of an mRNA molecule expressed from a SNP-containing nucleic acid molecule described herein.

[0173] The nucleic acid molecules of the invention are also useful for constructing host cells expressing a part, or all, of the nucleic acid molecules and variant peptides.

[0174] The nucleic acid molecules of the invention are also useful for constructing transgenic animals expressing all, or a part, of the nucleic acid molecules and variant peptides. The production of recombinant cells and transgenic animals having nucleic acid molecules which contain the SNPs disclosed in Table 1 and/or Table 2 allow, for example, effective clinical design of treatment compounds and dosage regimens.

[0175] The nucleic acid molecules of the invention are also useful in assays for drug screening to identify compounds that, for example, modulate nucleic acid expression.

[0176] The nucleic acid molecules of the invention are also useful in gene therapy in patients whose cells have aberrant gene expression. Thus, recombinant cells, which include a patient's cells that have been engineered ex vivo and returned to the patient, can be introduced into an individual where the recombinant cells produce the desired protein to treat the individual.

[0177] SNP Genotyping Methods

[0178] The process of determining which specific nucleotide (i.e., allele) is present at each of one or more SNP positions, such as a SNP position in a nucleic acid molecule disclosed in Table 1 and/or Table 2, is referred to as SNP genotyping. The present invention provides methods of SNP genotyping, such as for use in screening for stenosis or related pathologies, or determining predisposition thereto, or determining responsiveness to a form of treatment, or in genome mapping or SNP association analysis, etc.

[0179] Nucleic acid samples can be genotyped to determine which allele(s) is/are present at any given genetic region (e.g., SNP position) of interest by methods well known in the art. The neighboring sequence can be used to design SNP detection reagents such as oligonucleotide probes, which may optionally be implemented in a kit format. Exemplary SNP genotyping methods are described in Chen et al., "Single nucleotide polymorphism genotyping: biochemistry, protocol, cost and throughput", Pharmacogenomics J. 2003; 3(2):77-96; Kwok et al., "Detection of single nucleotide polymorphisms", Curr Issues Mol. Biol. 2003 April; 5(2):43-60; Shi, "Technologies for individual genotyping: detection of genetic polymorphisms in drug targets and disease genes", Am J. Pharmacogenomics. 2002; 2(3):197-205; and Kwok, "Methods for genotyping single nucleotide polymorphisms", Annu Rev Genomics Hum Genet. 2001; 2:235-58. Exemplary techniques for high-throughput SNP genotyping are described in Mamellos, "High-throughput SNP analysis for genetic association studies", Curr Opin Drug Discov Devel. 2003 May; 6(3):317-21. Common SNP genotyping methods include, but are not limited to, TaqMan assays, molecular beacon assays, nucleic acid arrays, allele-specific primer extension, allele-specific PCR, arrayed primer extension, homogeneous primer extension assays, primer extension with detection by mass spectrometry, pyrosequencing, multiplex primer extension sorted on genetic arrays, ligation with rolling circle amplification, homogeneous ligation, OLA (U.S. Pat. No. 4,988,167), multiplex ligation reaction sorted on genetic arrays, restriction-fragment length polymorphism, single base extension-tag assays, and the Invader assay. Such methods may be used in combination with detection mechanisms such as, for example, luminescence or chemiluminescence detection, fluorescence detection, time-resolved fluorescence detection, fluorescence resonance energy transfer, fluorescence polarization, mass spectrometry, and electrical detection.

[0180] Various methods for detecting polymorphisms include, but are not limited to, methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA duplexes (Myers et al., Science 230:1242 (1985); Cotton et al., PNAS 85:4397 (1988); and Saleeba et al., Meth. Enzymol. 217:286-295 (1992)), comparison of the electrophoretic mobility of variant and wild type nucleic acid molecules (Orita et al., PNAS 86:2766 (1989); Cotton et al., Mutat. Res. 285:125-144 (1993); and Hayashi et al., Genet. Anal. Tech. Appl. 9:73-79 (1992)), and assaying the movement of polymorphic or wild-type fragments in polyacrylamide gels containing a gradient of denaturant using denaturing gradient gel electrophoresis (DGGE) (Myers et al., Nature 313:495 (1985)). Sequence variations at specific locations can also be assessed by nuclease protection assays such as RNase and S1 protection or chemical cleavage methods.

[0181] In a preferred embodiment, SNP genotyping is performed using the TaqMan assay, which is also known as the 5' nuclease assay (U.S. Pat. Nos. 5,210,015 and 5,538,848). The TaqMan assay detects the accumulation of a specific amplified product during PCR. The TaqMan assay utilizes an oligonucleotide probe labeled with a fluorescent reporter dye and a quencher dye. The reporter dye is excited by irradiation at an appropriate wavelength, it transfers energy to the quencher dye in the same probe via a process called fluorescence resonance energy transfer (FRET). When attached to the probe, the excited reporter dye does not emit a signal. The proximity of the quencher dye to the reporter dye in the intact probe maintains a reduced fluorescence for the reporter. The reporter dye and quencher dye may be at the 5' most and the 3' most ends, respectively, or vice versa. Alternatively, the reporter dye may be at the 5' or 3' most end while the quencher dye is attached to an internal nucleotide, or vice versa. In yet another embodiment, both the reporter and the quencher may be attached to internal nucleotides at a distance from each other such that fluorescence of the reporter is reduced.

[0182] During PCR, the 5' nuclease activity of DNA polymerase cleaves the probe, thereby separating the reporter dye and the quencher dye and resulting in increased fluorescence of the reporter. Accumulation of PCR product is detected directly by monitoring the increase in fluorescence of the reporter dye. The DNA polymerase cleaves the probe between the reporter dye and the quencher dye only if the probe hybridizes to the target SNP-containing template which is amplified during PCR, and the probe is designed to hybridize to the target SNP site only if a particular SNP allele is present.

[0183] Preferred TaqMan primer and probe sequences can readily be determined using the SNP and associated nucleic acid sequence information provided herein. A number of computer programs, such as Primer Express (Applied Biosystems, Foster City, Calif.), can be used to rapidly obtain optimal primer/probe sets. It will be apparent to one of skill in the art that such primers and probes for detecting the SNPs of the present invention are useful in diagnostic assays for stenosis and related pathologies, and can be readily incorporated into a kit format. The present invention also includes modifications of the Taqman assay well known in the art such as the use of Molecular Beacon probes (U.S. Pat. Nos. 5,118,801 and 5,312,728) and other variant formats (U.S. Pat. Nos. 5,866,336 and 6,117,635).

[0184] Another preferred method for genotyping the SNPs of the present invention is the use of two oligonucleotide probes in an OLA (see, e.g., U.S. Pat. No. 4,988,617). In this method, one probe hybridizes to a segment of a target nucleic acid with its 3' most end aligned with the SNP site. A second probe hybridizes to an adjacent segment of the target nucleic acid molecule directly 3' to the first probe. The two juxtaposed probes hybridize to the target nucleic acid molecule, and are ligated in the presence of a linking agent such as a ligase if there is perfect complementarity between the 3' most nucleotide of the first probe with the SNP site. If there is a mismatch, ligation would not occur. After the reaction, the ligated probes are separated from the target nucleic acid molecule, and detected as indicators of the presence of a SNP.

[0185] The following patents, patent applications, and published international patent applications, which are all hereby incorporated by reference, provide additional information pertaining to techniques for carrying out various types of OLA: U.S. Pat. Nos. 6,027,889, 6,268,148, 5,494,810, 5,830,711, and 6054564 describe OLA strategies for performing SNP detection; WO 97/31256 and WO 00/56927 describe OLA strategies for performing SNP detection using universal arrays, wherein a zipcode sequence can be introduced into one of the hybridization probes, and the resulting product, or amplified product, hybridized to a universal zip code array; U.S. application US01/17329 (and 09/584,905) describes OLA (or LDR) followed by PCR, wherein zipcodes are incorporated into OLA probes, and amplified PCR products are determined by electrophoretic or universal zipcode array readout; U.S. applications 60/427,818, 60/445,636, and 60/445,494 describe SNPlex methods and software for multiplexed SNP detection using OLA followed by PCR, wherein zipcodes are incorporated into OLA probes, and amplified PCR products are hybridized with a zipchute reagent, and the identity of the SNP determined from electrophoretic readout of the zipchute. In some embodiments, OLA is carried out prior to PCR (or another method of nucleic acid amplification). In other embodiments, PCR (or another method of nucleic acid amplification) is carried out prior to OLA.

[0186] Another method for SNP genotyping is based on mass spectrometry. Mass spectrometry takes advantage of the unique mass of each of the four nucleotides of DNA. SNPs can be unambiguously genotyped by mass spectrometry by measuring the differences in the mass of nucleic acids having alternative SNP alleles. MALDI-TOF (Matrix Assisted Laser Desorption Ionization--Time of Flight) mass spectrometry technology is preferred for extremely precise determinations of molecular mass, such as SNPs. Numerous approaches to SNP analysis have been developed based on mass spectrometry. Preferred mass spectrometry-based methods of SNP genotyping include primer extension assays, which can also be utilized in combination with other approaches, such as traditional gel-based formats and microarrays.

[0187] Typically, the primer extension assay involves designing and annealing a primer to a template PCR amplicon upstream (5') from a target SNP position. A mix of dideoxynucleotide triphosphates (ddNTPs) and/or deoxynucleotide triphosphates (dNTPs) are added to a reaction mixture containing template (e.g., a SNP-containing nucleic acid molecule which has typically been amplified, such as by PCR), primer, and DNA polymerase. Extension of the primer terminates at the first position in the template where a nucleotide complementary to one of the ddNTPs in the mix occurs. The primer can be either immediately adjacent (i.e., the nucleotide at the 3' end of the primer hybridizes to the nucleotide next to the target SNP site) or two or more nucleotides removed from the SNP position. If the primer is several nucleotides removed from the target SNP position, the only limitation is that the template sequence between the 3' end of the primer and the SNP position cannot contain a nucleotide of the same type as the one to be detected, or this will cause premature termination of the extension primer. Alternatively, if all four ddNTPs alone, with no dNTPs, are added to the reaction mixture, the primer will always be extended by only one nucleotide, corresponding to the target SNP position. In this instance, primers are designed to bind one nucleotide upstream from the SNP position (i.e., the nucleotide at the 3' end of the primer hybridizes to the nucleotide that is immediately adjacent to the target SNP site on the 5' side of the target SNP site). Extension by only one nucleotide is preferable, as it minimizes the overall mass of the extended primer, thereby increasing the resolution of mass differences between alternative SNP nucleotides. Furthermore, mass-tagged ddNTPs can be employed in the primer extension reactions in place of unmodified ddNTPs. This increases the mass difference between primers extended with these ddNTPs, thereby providing increased sensitivity and accuracy, and is particularly useful for typing heterozygous base positions. Mass-tagging also alleviates the need for intensive sample-preparation procedures and decreases the necessary resolving power of the mass spectrometer.

[0188] The extended primers can then be purified and analyzed by MALDI-TOF mass spectrometry to determine the identity of the nucleotide present at the target SNP position. In one method of analysis, the products from the primer extension reaction are combined with light absorbing crystals that form a matrix. The matrix is then hit with an energy source such as a laser to ionize and desorb the nucleic acid molecules into the gas-phase. The ionized molecules are then ejected into a flight tube and accelerated down the tube towards a detector. The time between the ionization event, such as a laser pulse, and collision of the molecule with the detector is the time of flight of that molecule. The time of flight is precisely correlated with the mass-to-charge ratio (m/z) of the ionized molecule. Ions with smaller m/z travel down the tube faster than ions with larger m/z and therefore the lighter ions reach the detector before the heavier ions. The time-of-flight is then converted into a corresponding, and highly precise, m/z. In this manner, SNPs can be identified based on the slight differences in mass, and the corresponding time of flight differences, inherent in nucleic acid molecules having different nucleotides at a single base position. For further information regarding the use of primer extension assays in conjunction with MALDI-TOF mass spectrometry for SNP genotyping, see, e.g., Wise et al., "A standard protocol for single nucleotide primer extension in the human genome using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry", Rapid Commun Mass Spectrom. 2003; 17(11):1195-202.

[0189] The following references provide further information describing mass spectrometry-based methods for SNP genotyping: Bocker, "SNP and mutation discovery using base-specific cleavage and MALDI-TOF mass spectrometry", Bioinformatics. 2003 July; 19 Suppl 1:I44-I53; Storm et al., "MALDI-TOF mass spectrometry-based SNP genotyping", Methods Mol. Biol. 2003; 212:241-62; Jurinke et al., "The use of MassARRAY technology for high throughput genotyping", Adv Biochem Eng Biotechnol. 2002; 77:57-74; and Jurinke et al., "Automated genotyping using the DNA MassArray technology", Methods Mol. Biol. 2002; 187:179-92.

[0190] SNPs can also be scored by direct DNA sequencing. A variety of automated sequencing procedures can be utilized ((1995) Biotechniques 19:448), including sequencing by mass spectrometry (see, e.g., PCT International Publication No. WO94/16101; Cohen et al., Adv. Chromatogr. 36:127-162 (1996); and Griffin et al., Appl. Biochem. Biotechnol. 38:147-159 (1993)). The nucleic acid sequences of the present invention enable one of ordinary skill in the art to readily design sequencing primers for such automated sequencing procedures. Commercial instrumentation, such as the Applied Biosystems 377, 3100, 3700, 3730, and 3730x1 DNA Analyzers (Foster City, Calif.), is commonly used in the art for automated sequencing.

[0191] Other methods that can be used to genotype the SNPs of the present invention include single-strand conformational polymorphism (SSCP), and denaturing gradient gel electrophoresis (DGGE) (Myers et al., Nature 313:495 (1985)). SSCP identifies base differences by alteration in electrophoretic migration of single stranded PCR products, as described in Orita et al., Proc. Nat. Acad. Single-stranded PCR products can be generated by heating or otherwise denaturing double stranded PCR products. Single-stranded nucleic acids may refold or form secondary structures that are partially dependent on the base sequence. The different electrophoretic mobilities of single-stranded amplification products are related to base-sequence differences at SNP positions. DGGE differentiates SNP alleles based on the different sequence-dependent stabilities and melting properties inherent in polymorphic DNA and the corresponding differences in electrophoretic migration patterns in a denaturing gradient gel (Erlich, ed., PCR Technology, Principles and Applications for DNA Amplification, W.H. Freeman and Co, New York, 1992, Chapter 7).

[0192] Sequence-specific ribozymes (U.S. Pat. No. 5,498,531) can also be used to score SNPs based on the development or loss of a ribozyme cleavage site. Perfectly matched sequences can be distinguished from mismatched sequences by nuclease cleavage digestion assays or by differences in melting temperature. If the SNP affects a restriction enzyme cleavage site, the SNP can be identified by alterations in restriction enzyme digestion patterns, and the corresponding changes in nucleic acid fragment lengths determined by gel electrophoresis

[0193] SNP genotyping can include the steps of, for example, collecting a biological sample from a human subject (e.g., sample of tissues, cells, fluids, secretions, etc.), isolating nucleic acids (e.g., genomic DNA, mRNA or both) from the cells of the sample, contacting the nucleic acids with one or more primers which specifically hybridize to a region of the isolated nucleic acid containing a target SNP under conditions such that hybridization and amplification of the target nucleic acid region occurs, and determining the nucleotide present at the SNP position of interest, or, in some assays, detecting the presence or absence of an amplification product (assays can be designed so that hybridization and/or amplification will only occur if a particular SNP allele is present or absent). In some assays, the size of the amplification product is detected and compared to the length of a control sample; for example, deletions and insertions can be detected by a change in size of the amplified product compared to a normal genotype.

[0194] SNP genotyping is useful for numerous practical applications, as described below. Examples of such applications include, but are not limited to, SNP-disease association analysis, disease predisposition screening, disease diagnosis, disease prognosis, disease progression monitoring, determining therapeutic strategies based on an individual's genotype ("pharmacogenomics"), developing therapeutic agents based on SNP genotypes associated with a disease or likelihood of responding to a drug, stratifying a patient population for clinical trial for a treatment regimen, predicting the likelihood that an individual will experience toxic side effects from a therapeutic agent, and human identification applications such as forensics.

[0195] Analysis of Genetic Association Between SNPs and Phenotypic Traits

[0196] SNP genotyping for disease diagnosis, disease predisposition screening, disease prognosis, determining drug responsiveness (pharmacogenomics), drug toxicity screening, and other uses described herein, typically relies on initially establishing a genetic association between one or more specific SNPs and the particular phenotypic traits of interest.

[0197] Different study designs may be used for genetic association studies (Modern Epidemiology, Lippincott Williams & Wilkins (1998), 609-622). Observational studies are most frequently carried out in which the response of the patients is not interfered with. The first type of observational study identifies a sample of persons in whom the suspected cause of the disease is present and another sample of persons in whom the suspected cause is absent, and then the frequency of development of disease in the two samples is compared. These sampled populations are called cohorts, and the study is a prospective study. The other type of observational study is case-control or a retrospective study. In typical case-control studies, samples are collected from individuals with the phenotype of interest (cases) such as certain manifestations of a disease, and from individuals without the phenotype (controls) in a population (target population) that conclusions are to be drawn from. Then the possible causes of the disease are investigated retrospectively. As the time and costs of collecting samples in case-control studies are considerably less than those for prospective studies, case-control studies are the more commonly used study design in genetic association studies, at least during the exploration and discovery stage.

[0198] In both types of observational studies, there may be potential confounding factors that should be taken into consideration. Confounding factors are those that are associated with both the real cause(s) of the disease and the disease itself, and they include demographic information such as age, gender, ethnicity as well as environmental factors. When confounding factors are not matched in cases and controls in a study, and are not controlled properly, spurious association results can arise. If potential confounding factors are identified, they should be controlled for by analysis methods explained below.

[0199] In a genetic association study, the cause of interest to be tested is a certain allele or a SNP or a combination of alleles or a haplotype from several SNPs. Thus, tissue specimens (e.g., whole blood) from the sampled individuals may be collected and genomic DNA genotyped for the SNP(s) of interest. In addition to the phenotypic trait of interest, other information such as demographic (e.g., age, gender, ethnicity, etc.), clinical, and environmental information that may influence the outcome of the trait can be collected to further characterize and define the sample set. In many cases, these factors are known to be associated with diseases and/or SNP allele frequencies. There are likely gene-environment and/or gene-gene interactions as well. Analysis methods to address gene-environment and gene-gene interactions (for example, the effects of the presence of both susceptibility alleles at two different genes can be greater than the effects of the individual alleles at two genes combined) are discussed below.

[0200] After all the relevant phenotypic and genotypic information has been obtained, statistical analyses are carried out to determine if there is any significant correlation between the presence of an allele or a genotype with the phenotypic characteristics of an individual. Preferably, data inspection and cleaning are first performed before carrying out statistical tests for genetic association. Epidemiological and clinical data of the samples can be summarized by descriptive statistics with tables and graphs. Data validation is preferably performed to check for data completion, inconsistent entries, and outliers. Chi-squared tests and t-tests (Wilcoxon rank-sum tests if distributions are not normal) may then be used to check for significant differences between cases and controls for discrete and continuous variables, respectively. To ensure genotyping quality, Hardy-Weinberg disequilibrium tests can be performed on cases and controls separately. Significant deviation from Hardy-Weinberg equilibrium (HWE) in both cases and controls for individual markers can be indicative of genotyping errors. If HWE is violated in a majority of markers, it is indicative of population substructure that should be further investigated. Moreover, Hardy-Weinberg disequilibrium in cases only can indicate genetic association of the markers with the disease (Genetic Data Analysis, Weir B., Sinauer (1990)).

[0201] To test whether an allele of a single SNP is associated with the case or control status of a phenotypic trait, one skilled in the art can compare allele frequencies in cases and controls. Standard chi-squared tests and Fisher exact tests can be carried out on a 2.times.2 table (2 SNP alleles.times.2 outcomes in the categorical trait of interest). To test whether genotypes of a SNP are associated, chi-squared tests can be carried out on a 3.times.2 table (3 genotypes.times.2 outcomes). Score tests are also carried out for genotypic association to contrast the three genotypic frequencies (major homozygotes, heterozygotes and minor homozygotes) in cases and controls, and to look for trends using 3 different modes of inheritance, namely dominant (with contrast coefficients 2, -1, -1), additive (with contrast coefficients 1, 0, -1) and recessive (with contrast coefficients 1, 1, -2). Odds ratios for minor versus major alleles, and odds ratios for heterozygote and homozygote variants versus the wild type genotypes are calculated with the desired confidence limits, usually 95%.

[0202] In order to control for confounders and to test for interaction and effect modifiers, stratified analyses may be performed using stratified factors that are likely to be confounding, including demographic information such as age, ethnicity, and gender, or an interacting element or effect modifier, such as a known major gene (e.g., APOE for Alzheimer's disease or HLA genes for autoimmune diseases), or environmental factors such as smoking in lung cancer. Stratified association tests may be carried out using Cochran-Mantel-Haenszel tests that take into account the ordinal nature of genotypes with 0, 1, and 2 variant alleles. Exact tests by StatXact may also be performed when computationally possible. Another way to adjust for confounding effects and test for interactions is to perform stepwise multiple logistic regression analysis using statistical packages such as SAS or R. Logistic regression is a model-building technique in which the best fitting and most parsimonious model is built to describe the relation between the dichotomous outcome (for instance, getting a certain disease or not) and a set of independent variables (for instance, genotypes of different associated genes, and the associated demographic and environmental factors). The most common model is one in which the logit transformation of the odds ratios is expressed as a linear combination of the variables (main effects) and their cross-product terms (interactions) (Applied Logistic Regression, Hosmer and Lemeshow, Wiley (2000)). To test whether a certain variable or interaction is significantly associated with the outcome, coefficients in the model are first estimated and then tested for statistical significance of their departure from zero.

[0203] In addition to performing association tests one marker at a time, haplotype association analysis may also be performed to study a number of markers that are closely linked together. Haplotype association tests can have better power than genotypic or allelic association tests when the tested markers are not the disease-causing mutations themselves but are in linkage disequilibrium with such mutations. The test will even be more powerful if the disease is indeed caused by a combination of alleles on a haplotype (e.g., APOE is a haplotype formed by 2 SNPs that are very close to each other). In order to perform haplotype association effectively, marker-marker linkage disequilibrium measures, both D' and R.sup.2, are typically calculated for the markers within a gene to elucidate the haplotype structure. Recent studies (Daly et al, Nature Genetics, 29, 232-235, 2001) in linkage disequilibrium indicate that SNPs within a gene are organized in block pattern, and a high degree of linkage disequilibrium exists within blocks and very little linkage disequilibrium exists between blocks. Haplotype association with the disease status can be performed using such blocks once they have been elucidated.

[0204] Haplotype association tests can be carried out in a similar fashion as the allelic and genotypic association tests. Each haplotype in a gene is analogous to an allele in a multi-allelic marker. One skilled in the art can either compare the haplotype frequencies in cases and controls or test genetic association with different pairs of haplotypes. It has been proposed (Schaid et al, Am. J. Hum. Genet., 70, 425-434, 2002) that score tests can be done on haplotypes using the program "haplo.score". In that method, haplotypes are first inferred by EM algorithm and score tests are carried out with a generalized linear model (GLM) framework that allows the adjustment of other factors.

[0205] An important decision in the performance of genetic association tests is the determination of the significance level at which significant association can be declared when the p-value of the tests reaches that level. In an exploratory analysis where positive hits will be followed up in subsequent confirmatory testing, an unadjusted p-value <0.1 (a significance level on the lenient side) may be used for generating hypotheses for significant association of a SNP with certain phenotypic characteristics of a disease. It is preferred that a p-value <0.05 (a significance level traditionally used in the art) is achieved in order for a SNP to be considered to have an association with a disease. It is more preferred that a p-value <0.01 (a significance level on the stringent side) is achieved for an association to be declared. When hits are followed up in confirmatory analyses in more samples of the same source or in different samples from different sources, adjustment for multiple testing will be performed as to avoid excess number of hits while maintaining the experiment-wise error rates at 0.05. While there are different methods to adjust for multiple testing to control for different kinds of error rates, a commonly used but rather conservative method is Bonferroni correction to control the experiment-wise or family-wise error rate (Multiple comparisons and multiple tests, Westfall et al, SAS Institute (1999)). Permutation tests to control for the false discovery rates, FDR, can be more powerful (Benjamini and Hochberg, Journal of the Royal Statistical Society, Series B 57, 1289-1300, 1995, Resampling-based Multiple Testing, Westfall and Young, Wiley (1993)). Such methods to control for multiplicity would be preferred when the tests are dependent and controlling for false discovery rates is sufficient as opposed to controlling for the experiment-wise error rates.

[0206] In replication studies using samples from different populations after statistically significant markers have been identified in the exploratory stage, meta-analyses can then be performed by combining evidence of different studies (Modern Epidemiology, Lippincott Williams & Wilkins, 1998, 643-673). If available, association results known in the art for the same SNPs can be included in the meta-analyses.

[0207] Since both genotyping and disease status classification can involve errors, sensitivity analyses may be performed to see how odds ratios and p-values would change upon various estimates on genotyping and disease classification error rates.

[0208] It has been well known that subpopulation-based sampling bias between cases and controls can lead to spurious results in case-control association studies (Ewens and Spielman, Am. J. Hum. Genet. 62, 450-458, 1995) when prevalence of the disease is associated with different subpopulation groups. Such bias can also lead to a loss of statistical power in genetic association studies. To detect population stratification, Pritchard and Rosenberg (Pritchard et al. Am. J. Hum. Gen. 1999, 65:220-228) suggested typing markers that are unlinked to the disease and using results of association tests on those markers to determine whether there is any population stratification. When stratification is detected, the genomic control (GC) method as proposed by Devlin and Roeder (Devlin et al. Biometrics 1999, 55:997-1004) can be used to adjust for the inflation of test statistics due to population stratification. GC method is robust to changes in population structure levels as well as being applicable to DNA pooling designs (Devlin et al. Genet. Epidem. 20001, 21:273-284).

[0209] While Pritchard's method recommended using 15-20 unlinked microsatellite markers, it suggested using more than 30 biallelic markers to get enough power to detect population stratification. For the GC method, it has been shown (Bacanu et al. Am. J. Hum. Genet. 2000, 66:1933-1944) that about 60-70 biallelic markers are sufficient to estimate the inflation factor for the test statistics due to population stratification. Hence, 70 intergenic SNPs can be chosen in unlinked regions as indicated in a genome scan (Kehoe et al. Hum. Mol. Genet. 1999, 8:237-245).

[0210] Once individual risk factors, genetic or non-genetic, have been found for the predisposition to disease, the next step is to set up a classification/prediction scheme to predict the category (for instance, disease or no-disease) that an individual will be in depending on his genotypes of associated SNPs and other non-genetic risk factors. Logistic regression for discrete trait and linear regression for continuous trait are standard techniques for such tasks (Applied Regression Analysis, Draper and Smith, Wiley (1998)). Moreover, other techniques can also be used for setting up classification. Such techniques include, but are not limited to, MART, CART, neural network, and discriminant analyses that are suitable for use in comparing the performance of different methods (The Elements of Statistical Learning, Hastie, Tibshirani & Friedman, Springer (2002)).

[0211] Disease Diagnosis and Predisposition Screening

[0212] Information on association/correlation between genotypes and disease-related phenotypes can be exploited in several ways. For example, in the case of a highly statistically significant association between one or more SNPs with predisposition to a disease for which treatment is available, detection of such a genotype pattern in an individual may justify immediate administration of treatment, or at least the institution of regular monitoring of the individual. Detection of the susceptibility alleles associated with serious disease in a couple contemplating having children may also be valuable to the couple in their reproductive decisions. In the case of a weaker but still statistically significant association between a SNP and a human disease, immediate therapeutic intervention or monitoring may not be justified after detecting the susceptibility allele or SNP. Nevertheless, the subject can be motivated to begin simple life-style changes (e.g., diet, exercise) that can be accomplished at little or no cost to the individual but would confer potential benefits in reducing the risk of developing conditions for which that individual may have an increased risk by virtue of having the susceptibility allele(s).

[0213] The SNPs of the invention may contribute to stenosis in an individual in different ways. Some polymorphisms occur within a protein coding sequence and contribute to disease phenotype by affecting protein structure. Other polymorphisms occur in noncoding regions but may exert phenotypic effects indirectly via influence on, for example, replication, transcription, and/or translation. A single SNP may affect more than one phenotypic trait. Likewise, a single phenotypic trait may be affected by multiple SNPs in different genes.

[0214] As used herein, the terms "diagnose", "diagnosis", and "diagnostics" include, but are not limited to any of the following: detection of stenosis that an individual may presently have, predisposition screening (i.e., determining the increased risk of an individual in developing stenosis in the future, or determining whether an individual has a decreased risk of developing stenosis in the future), determining a particular type or subclass of stenosis in an individual known to have stenosis, confirming or reinforcing a previously made diagnosis of stenosis, pharmacogenomic evaluation of an individual to determine which therapeutic strategy that individual is most likely to positively respond to or to predict whether a patient is likely to respond to a particular treatment, predicting whether a patient is likely to experience toxic effects from a particular treatment or therapeutic compound, and evaluating the future prognosis of an individual having stenosis. Such diagnostic uses are based on the SNPs individually or in a unique combination or SNP haplotypes of the present invention.

[0215] Haplotypes are particularly useful in that, for example, fewer SNPs can be genotyped to determine if a particular genomic region harbors a locus that influences a particular phenotype, such as in linkage disequilibrium-based SNP association analysis.

[0216] Linkage disequilibrium (LD) refers to the co-inheritance of alleles (e.g., alternative nucleotides) at two or more different SNP sites at frequencies greater than would be expected from the separate frequencies of occurrence of each allele in a given population. The expected frequency of co-occurrence of two alleles that are inherited independently is the frequency of the first allele multiplied by the frequency of the second allele. Alleles that co-occur at expected frequencies are said to be in "linkage equilibrium". In contrast, LD refers to any non-random genetic association between allele(s) at two or more different SNP sites, which is generally due to the physical proximity of the two loci along a chromosome. LD can occur when two or more SNPs sites are in close physical proximity to each other on a given chromosome and therefore alleles at these SNP sites will tend to remain unseparated for multiple generations with the consequence that a particular nucleotide (allele) at one SNP site will show a non-random association with a particular nucleotide (allele) at a different SNP site located nearby. Hence, genotyping one of the SNP sites will give almost the same information as genotyping the other SNP site that is in LD.

[0217] For diagnostic purposes, if a particular SNP site is found to be useful for diagnosing stenosis, then the skilled artisan would recognize that other SNP sites which are in LD with this SNP site would also be useful for diagnosing the condition. Various degrees of LD can be encountered between two or more SNPs with the result being that some SNPs are more closely associated (i.e., in stronger LD) than others. Furthermore, the physical distance over which LD extends along a chromosome differs between different regions of the genome, and therefore the degree of physical separation between two or more SNP sites necessary for LD to occur can differ between different regions of the genome.

[0218] For diagnostic applications, polymorphisms (e.g., SNPs and/or haplotypes) that are not the actual disease-causing (causative) polymorphisms, but are in LD with such causative polymorphisms, are also useful. In such instances, the genotype of the polymorphism(s) that is/are in LD with the causative polymorphism is predictive of the genotype of the causative polymorphism and, consequently, predictive of the phenotype (e.g., stenosis) that is influenced by the causative SNP(s). Thus, polymorphic markers that are in LD with causative polymorphisms are useful as diagnostic markers, and are particularly useful when the actual causative polymorphism(s) is/are unknown.

[0219] Linkage disequilibrium in the human genome is reviewed in: Wall et al., "Haplotype blocks and linkage disequilibrium in the human genome", Nat Rev Genet. 2003 August; 4(8):587-97; Garner et al., "On selecting markers for association studies: patterns of linkage disequilibrium between two and three diallelic loci", Genet Epidemiol. 2003 January; 24(1):57-67; Ardlie et al., "Patterns of linkage disequilibrium in the human genome", Nat Rev Genet. 2002 April; 3(4):299-309 (erratum in Nat Rev Genet. 2002 July; 3(7):566); and Remm et al., "High-density genotyping and linkage disequilibrium in the human genome using chromosome 22 as a model"; Curr Opin Chem. Biol. 2002 February; 6(1):24-30.

[0220] The contribution or association of particular SNPs and/or SNP haplotypes with disease phenotypes, such as stenosis, enables the SNPs of the present invention to be used to develop superior diagnostic tests capable of identifying individuals who express a detectable trait, such as stenosis, as the result of a specific genotype, or individuals whose genotype places them at an increased or decreased risk of developing a detectable trait at a subsequent time as compared to individuals who do not have that genotype. As described herein, diagnostics may be based on a single SNP or a group of SNPs. Combined detection of a plurality of SNPs (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30, 32, 48, 50, 64, 96, 100, or any other number in-between, or more, of the SNPs provided in Table 1 and/or Table 2) typically increases the probability of an accurate diagnosis. For example, the presence of a single SNP known to correlate with stenosis might indicate a probability of 20% that an individual has or is at risk of developing stenosis, whereas detection of five SNPs, each of which correlates with stenosis, might indicate a probability of 80% that an individual has or is at risk of developing stenosis. To further increase the accuracy of diagnosis or predisposition screening, analysis of the SNPs of the present invention can be combined with that of other polymorphisms or other risk factors of stenosis, such as disease symptoms, pathological characteristics, family history, diet, environmental factors or lifestyle factors.

[0221] It will, of course, be understood by practitioners skilled in the treatment or diagnosis of stenosis that the present invention generally does not intend to provide an absolute identification of individuals who are at risk (or less at risk) of developing stenosis, and/or pathologies related to stenosis, but rather to indicate a certain increased (or decreased) degree or likelihood of developing the disease based on statistically significant association results. However, this information is extremely valuable as it can be used to, for example, initiate preventive treatments or to allow an individual carrying one or more significant SNPs or SNP haplotypes to foresee warning signs such as minor clinical symptoms, or to have regularly scheduled physical exams to monitor for appearance of a condition in order to identify and begin treatment of the condition at an early stage. Particularly with diseases that are extremely debilitating or fatal if not treated on time, the knowledge of a potential predisposition, even if this predisposition is not absolute, would likely contribute in a very significant manner to treatment efficacy.

[0222] The diagnostic techniques of the present invention may employ a variety of methodologies to determine whether a test subject has a SNP or a SNP pattern associated with an increased or decreased risk of developing a detectable trait or whether the individual suffers from a detectable trait as a result of a particular polymorphism/mutation, including, for example, methods which enable the analysis of individual chromosomes for haplotyping, family studies, single sperm DNA analysis, or somatic hybrids. The trait analyzed using the diagnostics of the invention may be any detectable trait that is commonly observed in pathologies and disorders related to stenosis.

[0223] Another aspect of the present invention relates to a method of determining whether an individual is at risk (or less at risk) of developing one or more traits or whether an individual expresses one or more traits as a consequence of possessing a particular trait-causing or trait-influencing allele. These methods generally involve obtaining a nucleic acid sample from an individual and assaying the nucleic acid sample to determine which nucleotide(s) is/are present at one or more SNP positions, wherein the assayed nucleotide(s) is/are indicative of an increased or decreased risk of developing the trait or indicative that the individual expresses the trait as a result of possessing a particular trait-causing or trait-influencing allele.

[0224] In another embodiment, the SNP detection reagents of the present invention are used to determine whether an individual has one or more SNP allele(s) affecting the level (e.g., the concentration of mRNA or protein in a sample, etc.) or pattern (e.g., the kinetics of expression, rate of decomposition, stability profile, Km, Vmax, etc.) of gene expression (collectively, the "gene response" of a cell or bodily fluid). Such a determination can be accomplished by screening for mRNA or protein expression (e.g., by using nucleic acid arrays, RT-PCR, TaqMan assays, or mass spectrometry), identifying genes having altered expression in an individual, genotyping SNPs disclosed in Table 1 and/or Table 2 that could affect the expression of the genes having altered expression (e.g., SNPs that are in and/or around the gene(s) having altered expression, SNPs in regulatory/control regions, SNPs in and/or around other genes that are involved in pathways that could affect the expression of the gene(s) having altered expression, or all SNPs could be genotyped), and correlating SNP genotypes with altered gene expression. In this manner, specific SNP alleles at particular SNP sites can be identified that affect gene expression.

[0225] Pharmacogenomics and Therapeutics/Drug Development

[0226] The present invention provides methods for assessing the pharmacogenomics of a subject harboring particular SNP alleles or haplotypes to a particular therapeutic agent or pharmaceutical compound, or to a class of such compounds. Pharmacogenomics deals with the roles which clinically significant hereditary variations (e.g., SNPs) play in the response to drugs due to altered drug disposition and/or abnormal action in affected persons. See, e.g., Roses, Nature 405, 857-865 (2000); Gould Rothberg, Nature Biotechnology 19, 209-211 (2001); Eichelbaum, Clin. Exp. Pharmacol. Physiol. 23(10-11):983-985 (1996); and Linder, Clin. Chem. 43(2):254-266 (1997). The clinical outcomes of these variations can result in severe toxicity of therapeutic drugs in certain individuals or therapeutic failure of drugs in certain individuals as a result of individual variation in metabolism. Thus, the SNP genotype of an individual can determine the way a therapeutic compound acts on the body or the way the body metabolizes the compound. For example, SNPs in drug metabolizing enzymes can affect the activity of these enzymes, which in turn can affect both the intensity and duration of drug action, as well as drug metabolism and clearance.

[0227] The discovery of SNPs in drug metabolizing enzymes, drug transporters, proteins for pharmaceutical agents, and other drug targets has explained why some patients do not obtain the expected drug effects, show an exaggerated drug effect, or experience serious toxicity from standard drug dosages. SNPs can be expressed in the phenotype of the extensive metabolizer and in the phenotype of the poor metabolizer. Accordingly, SNPs may lead to allelic variants of a protein in which one or more of the protein functions in one population are different from those in another population. SNPs and the encoded variant peptides thus provide targets to ascertain a genetic predisposition that can affect treatment modality. For example, in a ligand-based treatment, SNPs may give rise to amino terminal extracellular domains and/or other ligand-binding regions of a receptor that are more or less active in ligand binding, thereby affecting subsequent protein activation. Accordingly, ligand dosage would necessarily be modified to maximize the therapeutic effect within a given population containing particular SNP alleles or haplotypes.

[0228] As an alternative to genotyping, specific variant proteins containing variant amino acid sequences encoded by alternative SNP alleles could be identified. Thus, pharmacogenomic characterization of an individual permits the selection of effective compounds and effective dosages of such compounds for prophylactic or therapeutic uses based on the individual's SNP genotype, thereby enhancing and optimizing the effectiveness of the therapy. Furthermore, the production of recombinant cells and transgenic animals containing particular SNPs/haplotypes allow effective clinical design and testing of treatment compounds and dosage regimens. For example, transgenic animals can be produced that differ only in specific SNP alleles in a gene that is orthologous to a human disease susceptibility gene.

[0229] Pharmacogenomic uses of the SNPs of the present invention provide several significant advantages for patient care, particularly in treating stenosis. Pharmacogenomic characterization of an individual, based on an individual's SNP genotype, can identify those individuals unlikely to respond to treatment with a particular medication and thereby allows physicians to avoid prescribing the ineffective medication to those individuals. On the other hand, SNP genotyping of an individual may enable physicians to select the appropriate medication and dosage regimen that will be most effective based on an individual's SNP genotype. This information increases a physician's confidence in prescribing medications and motivates patients to comply with their drug regimens. Furthermore, pharmacogenomics may identify patients predisposed to toxicity and adverse reactions to particular drugs or drug dosages. Adverse drug reactions lead to more than 100,000 avoidable deaths per year in the United States alone and therefore represent a significant cause of hospitalization and death, as well as a significant economic burden on the healthcare system (Pfost et. al., Trends in Biotechnology, August 2000.). Thus, pharmacogenomics based on the SNPs disclosed herein has the potential to both save lives and reduce healthcare costs substantially.

[0230] Pharmacogenomics in general is discussed further in Rose et al., "Pharmacogenetic analysis of clinically relevant genetic polymorphisms", Methods Mol. Med. 2003; 85:225-37. Pharmacogenomics as it relates to Alzheimer's disease and other neurodegenerative disorders is discussed in Cacabelos, "Pharmacogenomics for the treatment of dementia", Ann Med. 2002; 34(5):357-79, Maimone et al., "Pharmacogenomics of neurodegenerative diseases", Eur J. Pharmacol. 2001 Feb. 9; 413(1): 11-29, and Poirier, "Apolipoprotein E: a pharmacogenetic target for the treatment of Alzheimer's disease", Mol. Diagn. 1999 December; 4(4):335-41. Pharmacogenomics as it relates to cardiovascular disorders is discussed in Siest et al., "Pharmacogenomics of drugs affecting the cardiovascular system", Clin Chem Lab Med. 2003 April; 41(4):590-9, Mukherjee et al., "Pharmacogenomics in cardiovascular diseases", Prog Cardiovasc Dis. 2002 May-June; 44(6):479-98, and Mooser et al., "Cardiovascular pharmacogenetics in the SNP era", J Thromb Haemost. 2003 July; 1(7): 1398-402. Pharmacogenomics as it relates to cancer is discussed in McLeod et al., "Cancer pharmacogenomics: SNPs, chips, and the individual patient", Cancer Invest. 2003; 21(4):630-40 and Watters et al., "Cancer pharmacogenomics: current and future applications", Biochim Biophys Acta. 2003 Mar. 17; 1603(2):99-111.

[0231] The SNPs of the present invention also can be used to identify novel therapeutic targets for stenosis. For example, genes containing the disease-associated variants ("variant genes") or their products, as well as genes or their products that are directly or indirectly regulated by or interacting with these variant genes or their products, can be targeted for the development of therapeutics that, for example, treat the disease or prevent or delay disease onset. The therapeutics may be composed of, for example, small molecules, proteins, protein fragments or peptides, antibodies, nucleic acids, or their derivatives or mimetics which modulate the functions or levels of the target genes or gene products.

[0232] The SNP-containing nucleic acid molecules disclosed herein, and their complementary nucleic acid molecules, may be used as antisense constructs to control gene expression in cells, tissues, and organisms. Antisense technology is well established in the art and extensively reviewed in Antisense Drug Technology. Principles, Strategies, and Applications, Crooke (ed.), Marcel Dekker, Inc.: New York (2001). An antisense nucleic acid molecule is generally designed to be complementary to a region of mRNA expressed by a gene so that the antisense molecule hybridizes to the mRNA and thereby blocks translation of mRNA into protein. Various classes of antisense oligonucleotides are used in the art, two of which are cleavers and blockers. Cleavers, by binding to target RNAs, activate intracellular nucleases (e.g., RNaseH or RNase L) that cleave the target RNA. Blockers, which also bind to target RNAs, inhibit protein translation through steric hindrance of ribosomes. Exemplary blockers include peptide nucleic acids, morpholinos, locked nucleic acids, and methylphosphonates (see, e.g., Thompson, Drug Discovery Today, 7 (17): 912-917 (2002)). Antisense oligonucleotides are directly useful as therapeutic agents, and are also useful for determining and validating gene function (e.g., in gene knock-out or knock-down experiments).

[0233] Antisense technology is further reviewed in: Lavery et al., "Antisense and RNAi: powerful tools in drug target discovery and validation", Curr Opin Drug Discov Devel. 2003 July; 6(4):561-9; Stephens et al., "Antisense oligonucleotide therapy in cancer", Curr Opin Mol. Ther. 2003 April; 5(2): 118-22; Kurreck, "Antisense technologies. Improvement through novel chemical modifications", Eur J. Biochem. 2003 April; 270(8):1628-44; Dias et al., "Antisense oligonucleotides: basic concepts and mechanisms", Mol Cancer Ther. 2002 March; 1(5):347-55; Chen, "Clinical development of antisense oligonucleotides as anti-cancer therapeutics", Methods Mol. Med. 2003; 75:621-36; Wang et al., "Antisense anticancer oligonucleotide therapeutics", Curr Cancer Drug Targets. 2001 November; 1 (3): 177-96; and Bennett, "Efficiency of antisense oligonucleotide drug discovery", Antisense Nucleic Acid Drug Dev. 2002 June; 12(3):215-24.

[0234] The SNPs of the present invention are particularly useful for designing antisense reagents that are specific for particular nucleic acid variants. Based on the SNP information disclosed herein, antisense oligonucleotides can be produced that specifically target mRNA molecules that contain one or more particular SNP nucleotides. In this manner, expression of mRNA molecules that contain one or more undesired polymorphisms (e.g., SNP nucleotides that lead to a defective protein such as an amino acid substitution in a catalytic domain) can be inhibited or completely blocked. Thus, antisense oligonucleotides can be used to specifically bind a particular polymorphic form (e.g., a SNP allele that encodes a defective protein), thereby inhibiting translation of this form, but which do not bind an alternative polymorphic form (e.g., an alternative SNP nucleotide that encodes a protein having normal function).

[0235] Antisense molecules can be used to inactivate mRNA in order to inhibit gene expression and production of defective proteins. Accordingly, these molecules can be used to treat a disorder, such as stenosis, characterized by abnormal or undesired gene expression or expression of certain defective proteins. This technique can involve cleavage by means of ribozymes containing nucleotide sequences complementary to one or more regions in the mRNA that attenuate the ability of the mRNA to be translated. Possible mRNA regions include, for example, protein-coding regions and particularly protein-coding regions corresponding to catalytic activities, substrate/ligand binding, or other functional activities of a protein.

[0236] The SNPs of the present invention are also useful for designing RNA interference reagents that specifically target nucleic acid molecules having particular SNP variants. RNA interference (RNAi), also referred to as gene silencing, is based on using double-stranded RNA (dsRNA) molecules to turn genes off. When introduced into a cell, dsRNAs are processed by the cell into short fragments (generally about 21-22 bp in length) known as small interfering RNAs (siRNAs) which the cell uses in a sequence-specific manner to recognize and destroy complementary RNAs (Thompson, Drug Discovery Today, 7 (17): 912-917 (2002)). Thus, because RNAi molecules, including siRNAs, act in a sequence-specific manner, the SNPs of the present invention can be used to design RNAi reagents that recognize and destroy nucleic acid molecules having specific SNP alleles/nucleotides (such as deleterious alleles that lead to the production of defective proteins), while not affecting nucleic acid molecules having alternative SNP alleles (such as alleles that encode proteins having normal function). As with antisense reagents, RNAi reagents may be directly useful as therapeutic agents (e.g., for turning off defective, disease-causing genes), and are also useful for characterizing and validating gene function (e.g., in gene knock-out or knock-down experiments).

[0237] The following references provide a further review of RNAi: Agami, "RNAi and related mechanisms and their potential use for therapy", Curr Opin Chem. Biol. 2002 December; 6(6):829-34; Lavery et al., "Antisense and RNAi: powerful tools in drug target discovery and validation", Curr Opin Drug Discov Devel. 2003 July; 6(4):561-9; Shi, "Mammalian RNAi for the masses", Trends Genet. 2003 January; 19(1):9-12), Shuey et al., "RNAi: gene-silencing in therapeutic intervention", Drug Discovery Today 2002 October; 7(20):1040-1046; McManus et al., Nat Rev Genet. 2002 October; 3(10):737-47; Xia et al., Nat Biotechnol 2002 October; 20(10):1006-10; Plasterk et al., Curr Opin Genet Dev 2000 October; 10(5):562-7; Bosher et al., Nat Cell Biol 2000 February; 2(2):E31-6; and Hunter, Curr Biol 1999 Jun. 17; 9(12):R440-2).

[0238] A subject suffering from a pathological condition, such as stenosis, ascribed to a SNP may be treated so as to correct the genetic defect (see Kren et al., Proc. Natl. Acad. Sci. USA 96:10349-10354 (1999)). Such a subject can be identified by any method that can detect the polymorphism in a biological sample drawn from the subject. Such a genetic defect may be permanently corrected by administering to such a subject a nucleic acid fragment incorporating a repair sequence that supplies the normal/wild-type nucleotide at the position of the SNP. This site-specific repair sequence can encompass an RNA/DNA oligonucleotide that operates to promote endogenous repair of a subject's genomic DNA. The site-specific repair sequence is administered in an appropriate vehicle, such as a complex with polyethylenimine, encapsulated in anionic liposomes, a viral vector such as an adenovirus, or other pharmaceutical composition that promotes intracellular uptake of the administered nucleic acid. A genetic defect leading to an inborn pathology may then be overcome, as the chimeric oligonucleotides induce incorporation of the normal sequence into the subject's genome. Upon incorporation, the normal gene product is expressed, and the replacement is propagated, thereby engendering a permanent repair and therapeutic enhancement of the clinical condition of the subject.

[0239] In cases in which a cSNP results in a variant protein that is ascribed to be the cause of, or a contributing factor to, a pathological condition, a method of treating such a condition can include administering to a subject experiencing the pathology the wild-type/normal cognate of the variant protein. Once administered in an effective dosing regimen, the wild-type cognate provides complementation or remediation of the pathological condition.

[0240] The invention further provides a method for identifying a compound or agent that can be used to treat stenosis. The SNPs disclosed herein are useful as targets for the identification and/or development of therapeutic agents. A method for identifying a therapeutic agent or compound typically includes assaying the ability of the agent or compound to modulate the activity and/or expression of a SNP-containing nucleic acid or the encoded product and thus identifying an agent or a compound that can be used to treat a disorder characterized by undesired activity or expression of the SNP-containing nucleic acid or the encoded product. The assays can be performed in cell-based and cell-free systems. Cell-based assays can include cells naturally expressing the nucleic acid molecules of interest or recombinant cells genetically engineered to express certain nucleic acid molecules.

[0241] Variant gene expression in a stenosis patient can include, for example, either expression of a SNP-containing nucleic acid sequence (for instance, a gene that contains a SNP can be transcribed into an mRNA transcript molecule containing the SNP, which can in turn be translated into a variant protein) or altered expression of a normal/wild-type nucleic acid sequence due to one or more SNPs (for instance, a regulatory/control region can contain a SNP that affects the level or pattern of expression of a normal transcript).

[0242] Assays for variant gene expression can involve direct assays of nucleic acid levels (e.g., mRNA levels), expressed protein levels, or of collateral compounds involved in a signal pathway. Further, the expression of genes that are up- or down-regulated in response to the signal pathway can also be assayed. In this embodiment, the regulatory regions of these genes can be operably linked to a reporter gene such as luciferase.

[0243] Modulators of variant gene expression can be identified in a method wherein, for example, a cell is contacted with a candidate compound/agent and the expression of mRNA determined. The level of expression of mRNA in the presence of the candidate compound is compared to the level of expression of mRNA in the absence of the candidate compound. The candidate compound can then be identified as a modulator of variant gene expression based on this comparison and be used to treat a disorder such as stenosis that is characterized by variant gene expression (e.g., either expression of a SNP-containing nucleic acid or altered expression of a normal/wild-type nucleic acid molecule due to one or more SNPs that affect expression of the nucleic acid molecule) due to one or more SNPs of the present invention. When expression of mRNA is statistically significantly greater in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of nucleic acid expression. When nucleic acid expression is statistically significantly less in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of nucleic acid expression.

[0244] The invention further provides methods of treatment, with the SNP or associated nucleic acid domain (e.g., catalytic domain, ligand/substrate-binding domain, regulatory/control region, etc.) or gene, or the encoded mRNA transcript, as a target, using a compound identified through drug screening as a gene modulator to modulate variant nucleic acid expression. Modulation can include either up-regulation (i.e., activation or agonization) or down-regulation (i.e., suppression or antagonization) of nucleic acid expression.

[0245] Expression of mRNA transcripts and encoded proteins, either wild type or variant, may be altered in individuals with a particular SNP allele in a regulatory/control element, such as a promoter or transcription factor binding domain, that regulates expression. In this situation, methods of treatment and compounds can be identified, as discussed herein, that regulate or overcome the variant regulatory/control element, thereby generating normal, or healthy, expression levels of either the wild type or variant protein.

[0246] The SNP-containing nucleic acid molecules of the present invention are also useful for monitoring the effectiveness of modulating compounds on the expression or activity of a variant gene, or encoded product, in clinical trials or in a treatment regimen. Thus, the gene expression pattern can serve as an indicator for the continuing effectiveness of treatment with the compound, particularly with compounds to which a patient can develop resistance, as well as an indicator for toxicities. The gene expression pattern can also serve as a marker indicative of a physiological response of the affected cells to the compound. Accordingly, such monitoring would allow either increased administration of the compound or the administration of alternative compounds to which the patient has not become resistant. Similarly, if the level of nucleic acid expression falls below a desirable level, administration of the compound could be commensurately decreased.

[0247] In another aspect of the present invention, there is provided a pharmaceutical pack comprising a therapeutic agent (e.g., a small molecule drug, antibody, peptide, antisense or RNAi nucleic acid molecule, etc.) and a set of instructions for administration of the therapeutic agent to humans diagnostically tested for one or more SNPs or SNP haplotypes provided by the present invention.

[0248] The SNPs/haplotypes of the present invention are also useful for improving many different aspects of the drug development process. For example, individuals can be selected for clinical trials based on their SNP genotype. Individuals with SNP genotypes that indicate that they are most likely to respond to the drug can be included in the trials and those individuals whose SNP genotypes indicate that they are less likely to or would not respond to the drug, or suffer adverse reactions, can be eliminated from the clinical trials. This not only improves the safety of clinical trials, but also will enhance the chances that the trial will demonstrate statistically significant efficacy. Furthermore, the SNPs of the present invention may explain why certain previously developed drugs performed poorly in clinical trials and may help identify a subset of the population that would benefit from a drug that had previously performed poorly in clinical trials, thereby "rescuing" previously developed drugs, and enabling the drug to be made available to a particular stenosis patient population that can benefit from it.

[0249] SNPs have many important uses in drug discovery, screening, and development. A high probability exists that, for any gene/protein selected as a potential drug target, variants of that gene/protein will exist in a patient population. Thus, determining the impact of gene/protein variants on the selection and delivery of a therapeutic agent should be an integral aspect of the drug discovery and development process. (Jazwinska, A Trends Guide to Genetic Variation and Genomic Medicine, 2002 March; S30-S36).

[0250] Knowledge of variants (e.g., SNPs and any corresponding amino acid polymorphisms) of a particular therapeutic target (e.g., a gene, mRNA transcript, or protein) enables parallel screening of the variants in order to identify therapeutic candidates (e.g., small molecule compounds, antibodies, antisense or RNAi nucleic acid compounds, etc.) that demonstrate efficacy across variants (Rothberg, Nat Biotechnol 2001 March; 19(3):209-11). Such therapeutic candidates would be expected to show equal efficacy across a larger segment of the patient population, thereby leading to a larger potential market for the therapeutic candidate.

[0251] Furthermore, identifying variants of a potential therapeutic target enables the most common form of the target to be used for selection of therapeutic candidates, thereby helping to ensure that the experimental activity that is observed for the selected candidates reflects the real activity expected in the largest proportion of a patient population (Jazwinska, A Trends Guide to Genetic Variation and Genomic Medicine, 2002 March; S30-S36).

[0252] Additionally, screening therapeutic candidates against all known variants of a target can enable the early identification of potential toxicities and adverse reactions relating to particular variants. For example, variability in drug absorption, distribution, metabolism and excretion (ADME) caused by, for example, SNPs in therapeutic targets or drug metabolizing genes, can be identified, and this information can be utilized during the drug development process to minimize variability in drug disposition and develop therapeutic agents that are safer across a wider range of a patient population. The SNPs of the present invention, including the variant proteins and encoding polymorphic nucleic acid molecules provided in Tables 1-2, are useful in conjunction with a variety of toxicology methods established in the art, such as those set forth in Current Protocols in Toxicology, John Wiley & Sons, Inc., N.Y.

[0253] Furthermore, therapeutic agents that target any art-known proteins (or nucleic acid molecules, either RNA or DNA) may cross-react with the variant proteins (or polymorphic nucleic acid molecules) disclosed in Table 1, thereby significantly affecting the pharmacokinetic properties of the drug. Consequently, the protein variants and the SNP-containing nucleic acid molecules disclosed in Tables 1-2 are useful in developing, screening, and evaluating therapeutic agents that target corresponding art-known protein forms (or nucleic acid molecules). Additionally, as discussed above, knowledge of all polymorphic forms of a particular drug target enables the design of therapeutic agents that are effective against most or all such polymorphic forms of the drug target.

[0254] Pharmaceutical Compositions and Administration Thereof

[0255] Any of the stenosis-associated proteins, and encoding nucleic acid molecules, disclosed herein can be used as therapeutic targets (or directly used themselves as therapeutic compounds) for treating stenosis and related pathologies, and the present disclosure enables therapeutic compounds (e.g., small molecules, antibodies, therapeutic proteins, RNAi and antisense molecules, etc.) to be developed that target (or are comprised of) any of these therapeutic targets.

[0256] In general, a therapeutic compound will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the therapeutic compound of this invention, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.

[0257] Therapeutically effective amounts of therapeutic compounds may range from, for example, approximately 0.01-50 mg per kilogram body weight of the recipient per day; preferably about 0.1-20 mg/kg/day. Thus, as an example, for administration to a 70 kg person, the dosage range would most preferably be about 7 mg to 1.4 g per day.

[0258] In general, therapeutic compounds will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal, or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. The preferred manner of administration is oral or parenteral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Oral compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.

[0259] The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills, or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area, i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a cross-linked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.

[0260] Pharmaceutical compositions are comprised of, in general, a therapeutic compound in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the therapeutic compound. Such excipients may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one skilled in the art.

[0261] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[0262] Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.

[0263] Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).

[0264] The amount of the therapeutic compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of the therapeutic compound based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt %.

[0265] Therapeutic compounds can be administered alone or in combination with other therapeutic compounds or in combination with one or more other active ingredient(s). For example, an inhibitor or stimulator of a stenosis-associated protein can be administered in combination with another agent that inhibits or stimulates the activity of the same or a different stenosis-associated protein to thereby counteract the affects of stenosis.

[0266] For further information regarding pharmacology, see Current Protocols in Pharmacology, John Wiley & Sons, Inc., N.Y.

[0267] Human Identification Applications

[0268] In addition to their diagnostic and therapeutic uses in stenosis and related pathologies, the SNPs provided by the present invention are also useful as human identification markers for such applications as forensics, paternity testing, and biometrics (see, e.g., Gill, "An assessment of the utility of single nucleotide polymorphisms (SNPs) for forensic purposes", Int J Legal Med. 2001; 114(4-5):204-10). Genetic variations in the nucleic acid sequences between individuals can be used as genetic markers to identify individuals and to associate a biological sample with an individual. Determination of which nucleotides occupy a set of SNP positions in an individual identifies a set of SNP markers that distinguishes the individual. The more SNP positions that are analyzed, the lower the probability that the set of SNPs in one individual is the same as that in an unrelated individual. Preferably, if multiple sites are analyzed, the sites are unlinked (i.e., inherited independently). Thus, preferred sets of SNPs can be selected from among the SNPs disclosed herein, which may include SNPs on different chromosomes, SNPs on different chromosome arms, and/or SNPs that are dispersed over substantial distances along the same chromosome arm.

[0269] Furthermore, among the SNPs disclosed herein, preferred SNPs for use in certain forensic/human identification applications include SNPs located at degenerate codon positions (i.e., the third position in certain codons which can be one of two or more alternative nucleotides and still encode the same amino acid), since these SNPs do not affect the encoded protein. SNPs that do not affect the encoded protein are expected to be under less selective pressure and are therefore expected to be more polymorphic in a population, which is typically an advantage for forensic/human identification applications. However, for certain forensics/human identification applications, such as predicting phenotypic characteristics (e.g., inferring ancestry or inferring one or more physical characteristics of an individual) from a DNA sample, it may be desirable to utilize SNPs that affect the encoded protein.

[0270] For many of the SNPs disclosed in Tables 1-2 (which are identified as "Applera" SNP source), Tables 1-2 provide SNP allele frequencies obtained by re-sequencing the DNA of chromosomes from 39 individuals (Tables 1-2 also provide allele frequency information for "Celera" source SNPs and, where available, public SNPs from dbEST, HGBASE, and/or HGMD). The allele frequencies provided in Tables 1-2 enable these SNPs to be readily used for human identification applications. Although any SNP disclosed in Table 1 and/or Table 2 could be used for human identification, the closer that the frequency of the minor allele at a particular SNP site is to 50%, the greater the ability of that SNP to discriminate between different individuals in a population since it becomes increasingly likely that two randomly selected individuals would have different alleles at that SNP site. Using the SNP allele frequencies provided in Tables 1-2, one of ordinary skill in the art could readily select a subset of SNPs for which the frequency of the minor allele is, for example, at least 1%, 2%, 5%, 10%, 20%, 25%, 30%, 40%, 45%, or 50%, or any other frequency in-between. Thus, since Tables 1-2 provide allele frequencies based on the re-sequencing of the chromosomes from 39 individuals, a subset of SNPs could readily be selected for human identification in which the total allele count of the minor allele at a particular SNP site is, for example, at least 1, 2, 4, 8, 10, 16, 20, 24, 30, 32, 36, 38, 39, 40, or any other number in-between.

[0271] Furthermore, Tables 1-2 also provide population group (interchangeably referred to herein as ethnic or racial groups) information coupled with the extensive allele frequency information. For example, the group of 39 individuals whose DNA was re-sequenced was made-up of 20 Caucasians and 19 African-Americans. This population group information enables further refinement of SNP selection for human identification. For example, preferred SNPs for human identification can be selected from Tables 1-2 that have similar allele frequencies in both the Caucasian and African-American populations; thus, for example, SNPs can be selected that have equally high discriminatory power in both populations. Alternatively, SNPs can be selected for which there is a statistically significant difference in allele frequencies between the Caucasian and African-American populations (as an extreme example, a particular allele may be observed only in either the Caucasian or the African-American population group but not observed in the other population group); such SNPs are useful, for example, for predicting the race/ethnicity of an unknown perpetrator from a biological sample such as a hair or blood stain recovered at a crime scene. For a discussion of using SNPs to predict ancestry from a DNA sample, including statistical methods, see Frudakis et al., "A Classifier for the SNP-Based Inference of Ancestry", Journal of Forensic Sciences 2003; 48(4):771-782.

[0272] SNPs have numerous advantages over other types of polymorphic markers, such as short tandem repeats (STRs). For example, SNPs can be easily scored and are amenable to automation, making SNPs the markers of choice for large-scale forensic databases. SNPs are found in much greater abundance throughout the genome than repeat polymorphisms. Population frequencies of two polymorphic forms can usually be determined with greater accuracy than those of multiple polymorphic forms at multi-allelic loci. SNPs are mutationaly more stable than repeat polymorphisms. SNPs are not susceptible to artifacts such as stutter bands that can hinder analysis. Stutter bands are frequently encountered when analyzing repeat polymorphisms, and are particularly troublesome when analyzing samples such as crime scene samples that may contain mixtures of DNA from multiple sources. Another significant advantage of SNP markers over STR markers is the much shorter length of nucleic acid needed to score a SNP. For example, STR markers are generally several hundred base pairs in length. A SNP, on the other hand, comprises a single nucleotide, and generally a short conserved region on either side of the SNP position for primer and/or probe binding. This makes SNPs more amenable to typing in highly degraded or aged biological samples that are frequently encountered in forensic casework in which DNA may be fragmented into short pieces.

[0273] SNPs also are not subject to microvariant and "off-ladder" alleles frequently encountered when analyzing STR loci. Microvariants are deletions or insertions within a repeat unit that change the size of the amplified DNA product so that the amplified product does not migrate at the same rate as reference alleles with normal sized repeat units. When separated by size, such as by electrophoresis on a polyacrylamide gel, microvariants do not align with a reference allelic ladder of standard sized repeat units, but rather migrate between the reference alleles. The reference allelic ladder is used for precise sizing of alleles for allele classification; therefore alleles that do not align with the reference allelic ladder lead to substantial analysis problems. Furthermore, when analyzing multi-allelic repeat polymorphisms, occasionally an allele is found that consists of more or less repeat units than has been previously seen in the population, or more or less repeat alleles than are included in a reference allelic ladder. These alleles will migrate outside the size range of known alleles in a reference allelic ladder, and therefore are referred to as "off-ladder" alleles. In extreme cases, the allele may contain so few or so many repeats that it migrates well out of the range of the reference allelic ladder. In this situation, the allele may not even be observed, or, with multiplex analysis, it may migrate within or close to the size range for another locus, further confounding analysis.

[0274] SNP analysis avoids the problems of microvariants and off-ladder alleles encountered in STR analysis. Importantly, microvariants and off-ladder alleles may provide significant problems, and may be completely missed, when using analysis methods such as oligonucleotide hybridization arrays, which utilize oligonucleotide probes specific for certain known alleles. Furthermore, off-ladder alleles and microvariants encountered with STR analysis, even when correctly typed, may lead to improper statistical analysis, since their frequencies in the population are generally unknown or poorly characterized, and therefore the statistical significance of a matching genotype may be questionable. All these advantages of SNP analysis are considerable in light of the consequences of most DNA identification cases, which may lead to life imprisonment for an individual, or re-association of remains to the family of a deceased individual.

[0275] DNA can be isolated from biological samples such as blood, bone, hair, saliva, or semen, and compared with the DNA from a reference source at particular SNP positions. Multiple SNP markers can be assayed simultaneously in order to increase the power of discrimination and the statistical significance of a matching genotype. For example, oligonucleotide arrays can be used to genotype a large number of SNPs simultaneously. The SNPs provided by the present invention can be assayed in combination with other polymorphic genetic markers, such as other SNPs known in the art or STRs, in order to identify an individual or to associate an individual with a particular biological sample.

[0276] Furthermore, the SNPs provided by the present invention can be genotyped for inclusion in a database of DNA genotypes, for example, a criminal DNA databank such as the FBI's Combined DNA Index System (CODIS) database. A genotype obtained from a biological sample of unknown source can then be queried against the database to find a matching genotype, with the SNPs of the present invention providing nucleotide positions at which to compare the known and unknown DNA sequences for identity. Accordingly, the present invention provides a database comprising novel SNPs or SNP alleles of the present invention (e.g., the database can comprise information indicating which alleles are possessed by individual members of a population at one or more novel SNP sites of the present invention), such as for use in forensics, biometrics, or other human identification applications. Such a database typically comprises a computer-based system in which the SNPs or SNP alleles of the present invention are recorded on a computer readable medium (see the section of the present specification entitled "Computer-Related Embodiments").

[0277] The SNPs of the present invention can also be assayed for use in paternity testing. The object of paternity testing is usually to determine whether a male is the father of a child. In most cases, the mother of the child is known and thus, the mother's contribution to the child's genotype can be traced. Paternity testing investigates whether the part of the child's genotype not attributable to the mother is consistent with that of the putative father. Paternity testing can be performed by analyzing sets of polymorphisms in the putative father and the child, with the SNPs of the present invention providing nucleotide positions at which to compare the putative father's and child's DNA sequences for identity. If the set of polymorphisms in the child attributable to the father does not match the set of polymorphisms of the putative father, it can be concluded, barring experimental error, that the putative father is not the father of the child. If the set of polymorphisms in the child attributable to the father match the set of polymorphisms of the putative father, a statistical calculation can be performed to determine the probability of coincidental match, and a conclusion drawn as to the likelihood that the putative father is the true biological father of the child.

[0278] In addition to paternity testing, SNPs are also useful for other types of kinship testing, such as for verifying familial relationships for immigration purposes, or for cases in which an individual alleges to be related to a deceased individual in order to claim an inheritance from the deceased individual, etc. For further information regarding the utility of SNPs for paternity testing and other types of kinship testing, including methods for statistical analysis, see Krawczak, "Informativity assessment for biallelic single nucleotide polymorphisms", Electrophoresis 1999 June; 20(8):1676-81.

[0279] The use of the SNPs of the present invention for human identification further extends to various authentication systems, commonly referred to as biometric systems, which typically convert physical characteristics of humans (or other organisms) into digital data. Biometric systems include various technological devices that measure such unique anatomical or physiological characteristics as finger, thumb, or palm prints; hand geometry; vein patterning on the back of the hand; blood vessel patterning of the retina and color and texture of the iris; facial characteristics; voice patterns; signature and typing dynamics; and DNA. Such physiological measurements can be used to verify identity and, for example, restrict or allow access based on the identification. Examples of applications for biometrics include physical area security, computer and network security, aircraft passenger check-in and boarding, financial transactions, medical records access, government benefit distribution, voting, law enforcement, passports, visas and immigration, prisons, various military applications, and for restricting access to expensive or dangerous items, such as automobiles or guns (see, for example, O'Connor, Stanford Technology Law Review and U.S. Pat. No. 6,119,096).

[0280] Groups of SNPs, particularly the SNPs provided by the present invention, can be typed to uniquely identify an individual for biometric applications such as those described above. Such SNP typing can readily be accomplished using, for example, DNA chips/arrays. Preferably, a minimally invasive means for obtaining a DNA sample is utilized. For example, PCR amplification enables sufficient quantities of DNA for analysis to be obtained from buccal swabs or fingerprints, which contain DNA-containing skin cells and oils that are naturally transferred during contact.

[0281] Further information regarding techniques for using SNPs in forensic/human identification applications can be found in, for example, Current Protocols in Human Genetics, John Wiley & Sons, N.Y. (2002), 14.1-14.7.

Variant Proteins, Antibodies, Vectors & Host Cells, & Uses Thereof

[0282] Variant Proteins Encoded by SNP-Containing Nucleic Acid Molecules

[0283] The present invention provides SNP-containing nucleic acid molecules, many of which encode proteins having variant amino acid sequences as compared to the art-known (i.e., wild-type) proteins. Amino acid sequences encoded by the polymorphic nucleic acid molecules of the present invention are provided as SEQ ID NOS: 13-24 in Table 1 and the Sequence Listing. These variants will generally be referred to herein as variant proteins/peptides/polypeptides, or polymorphic proteins/peptides/polypeptides of the present invention. The terms "protein", "peptide", and "polypeptide" are used herein interchangeably.

[0284] A variant protein of the present invention may be encoded by, for example, a nonsynonymous nucleotide substitution at any one of the cSNP positions disclosed herein. In addition, variant proteins may also include proteins whose expression, structure, and/or function is altered by a SNP disclosed herein, such as a SNP that creates or destroys a stop codon, a SNP that affects splicing, and a SNP in control/regulatory elements, e.g. promoters, enhancers, or transcription factor binding domains.

[0285] As used herein, a protein or peptide is said to be "isolated" or "purified" when it is substantially free of cellular material or chemical precursors or other chemicals. The variant proteins of the present invention can be purified to homogeneity or other lower degrees of purity. The level of purification will be based on the intended use. The key feature is that the preparation allows for the desired function of the variant protein, even if in the presence of considerable amounts of other components.

[0286] As used herein, "substantially free of cellular material" includes preparations of the variant protein having less than about 30% (by dry weight) other proteins (i.e., contaminating protein), less than about 20% other proteins, less than about 10% other proteins, or less than about 5% other proteins. When the variant protein is recombinantly produced, it can also be substantially free of culture medium, i.e., culture medium represents less than about 20% of the volume of the protein preparation.

[0287] The language "substantially free of chemical precursors or other chemicals" includes preparations of the variant protein in which it is separated from chemical precursors or other chemicals that are involved in its synthesis. In one embodiment, the language "substantially free of chemical precursors or other chemicals" includes preparations of the variant protein having less than about 30% (by dry weight) chemical precursors or other chemicals, less than about 20% chemical precursors or other chemicals, less than about 10% chemical precursors or other chemicals, or less than about 5% chemical precursors or other chemicals.

[0288] An isolated variant protein may be purified from cells that naturally express it, purified from cells that have been altered to express it (recombinant host cells), or synthesized using known protein synthesis methods. For example, a nucleic acid molecule containing SNP(s) encoding the variant protein can be cloned into an expression vector, the expression vector introduced into a host cell, and the variant protein expressed in the host cell. The variant protein can then be isolated from the cells by any appropriate purification scheme using standard protein purification techniques. Examples of these techniques are described in detail below (Sambrook and Russell, 2000, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.).

[0289] The present invention provides isolated variant proteins that comprise, consist of or consist essentially of amino acid sequences that contain one or more variant amino acids encoded by one or more codons which contain a SNP of the present invention.

[0290] Accordingly, the present invention provides variant proteins that consist of amino acid sequences that contain one or more amino acid polymorphisms (or truncations or extensions due to creation or destruction of a stop codon, respectively) encoded by the SNPs provided in Table 1 and/or Table 2. A protein consists of an amino acid sequence when the amino acid sequence is the entire amino acid sequence of the protein.

[0291] The present invention further provides variant proteins that consist essentially of amino acid sequences that contain one or more amino acid polymorphisms (or truncations or extensions due to creation or destruction of a stop codon, respectively) encoded by the SNPs provided in Table 1 and/or Table 2. A protein consists essentially of an amino acid sequence when such an amino acid sequence is present with only a few additional amino acid residues in the final protein.

[0292] The present invention further provides variant proteins that comprise amino acid sequences that contain one or more amino acid polymorphisms (or truncations or extensions due to creation or destruction of a stop codon, respectively) encoded by the SNPs provided in Table 1 and/or Table 2. A protein comprises an amino acid sequence when the amino acid sequence is at least part of the final amino acid sequence of the protein. In such a fashion, the protein may contain only the variant amino acid sequence or have additional amino acid residues, such as a contiguous encoded sequence that is naturally associated with it or heterologous amino acid residues. Such a protein can have a few additional amino acid residues or can comprise many more additional amino acids. A brief description of how various types of these proteins can be made and isolated is provided below.

[0293] The variant proteins of the present invention can be attached to heterologous sequences to form chimeric or fusion proteins. Such chimeric and fusion proteins comprise a variant protein operatively linked to a heterologous protein having an amino acid sequence not substantially homologous to the variant protein. "Operatively linked" indicates that the coding sequences for the variant protein and the heterologous protein are ligated in-frame. The heterologous protein can be fused to the N-terminus or C-terminus of the variant protein. In another embodiment, the fusion protein is encoded by a fusion polynucleotide that is synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers which give rise to complementary overhangs between two consecutive gene fragments which can subsequently be annealed and re-amplified to generate a chimeric gene sequence (see Ausubel et al., Current Protocols in Molecular Biology, 1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST protein). A variant protein-encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the variant protein.

[0294] In many uses, the fusion protein does not affect the activity of the variant protein. The fusion protein can include, but is not limited to, enzymatic fusion proteins, for example, beta-galactosidase fusions, yeast two-hybrid GAL fusions, poly-His fusions, MYC-tagged, HI-tagged and Ig fusions. Such fusion proteins, particularly poly-His fusions, can facilitate their purification following recombinant expression. In certain host cells (e.g., mammalian host cells), expression and/or secretion of a protein can be increased by using a heterologous signal sequence. Fusion proteins are further described in, for example, Terpe, "Overview of tag protein fusions: from molecular and biochemical fundamentals to commercial systems", Appl Microbiol Biotechnol. 2003 January; 60(5):523-33. Epub 2002 Nov. 7; Graddis et al., "Designing proteins that work using recombinant technologies", Curr Pharm Biotechnol. 2002 December; 3(4):285-97; and Nilsson et al., "Affinity fusion strategies for detection, purification, and immobilization of recombinant proteins", Protein Expr Purif. 1997 October; 11(1):1-16.

[0295] The present invention also relates to further obvious variants of the variant polypeptides of the present invention, such as naturally-occurring mature forms (e.g., alleleic variants), non-naturally occurring recombinantly-derived variants, and orthologs and paralogs of such proteins that share sequence homology. Such variants can readily be generated using art-known techniques in the fields of recombinant nucleic acid technology and protein biochemistry. It is understood, however, that variants exclude those known in the prior art before the present invention.

[0296] Further variants of the variant polypeptides disclosed in Table 1 can comprise an amino acid sequence that shares at least 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence disclosed in Table 1 (or a fragment thereof) and that includes a novel amino acid residue (allele) disclosed in Table 1 (which is encoded by a novel SNP allele). Thus, the present invention specifically contemplates polypeptides that have a certain degree of sequence variation compared with the polypeptide sequences shown in Table 1, but that contain a novel amino acid residue (allele) encoded by a novel SNP allele disclosed herein.

[0297] In other words, as long as a polypeptide contains a novel amino acid residue disclosed herein, other portions of the polypeptide that flank the novel amino acid residue can vary to some degree from the polypeptide sequences shown in Table 1.

[0298] Full-length pre-processed forms, as well as mature processed forms, of proteins that comprise one of the amino acid sequences disclosed herein can readily be identified as having complete sequence identity to one of the variant proteins of the present invention as well as being encoded by the same genetic locus as the variant proteins provided herein.

[0299] Orthologs of a variant peptide can readily be identified as having some degree of significant sequence homology/identity to at least a portion of a variant peptide as well as being encoded by a gene from another organism. Preferred orthologs will be isolated from non-human mammals, preferably primates, for the development of human therapeutic targets and agents. Such orthologs can be encoded by a nucleic acid sequence that hybridizes to a variant peptide-encoding nucleic acid molecule under moderate to stringent conditions depending on the degree of relatedness of the two organisms yielding the homologous proteins.

[0300] Variant proteins include, but are not limited to, proteins containing deletions, additions and substitutions in the amino acid sequence caused by the SNPs of the present invention. One class of substitutions is conserved amino acid substitutions in which a given amino acid in a polypeptide is substituted for another amino acid of like characteristics. Typical conservative substitutions are replacements, one for another, among the aliphatic amino acids Ala, Val, Leu, and Ile; interchange of the hydroxyl residues Ser and Thr; exchange of the acidic residues Asp and Glu; substitution between the amide residues Asn and Gln; exchange of the basic residues Lys and Arg; and replacements among the aromatic residues Phe and Tyr. Guidance concerning which amino acid changes are likely to be phenotypically silent are found in, for example, Bowie et al., Science 247:1306-1310 (1990).

[0301] Variant proteins can be fully functional or can lack function in one or more activities, e.g. ability to bind another molecule, ability to catalyze a substrate, ability to mediate signaling, etc. Fully functional variants typically contain only conservative variations or variations in non-critical residues or in non-critical regions. Functional variants can also contain substitution of similar amino acids that result in no change or an insignificant change in function. Alternatively, such substitutions may positively or negatively affect function to some degree. Non-functional variants typically contain one or more non-conservative amino acid substitutions, deletions, insertions, inversions, truncations or extensions, or a substitution, insertion, inversion, or deletion of a critical residue or in a critical region.

[0302] Amino acids that are essential for function of a protein can be identified by methods known in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis (Cunningham et al., Science 244:1081-1085 (1989)), particularly using the amino acid sequence and polymorphism information provided in Table 1. The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for biological activity such as enzyme activity or in assays such as an in vitro proliferative activity. Sites that are critical for binding partner/substrate binding can also be determined by structural analysis such as crystallization, nuclear magnetic resonance or photoaffinity labeling (Smith et al., J. Mol. Biol. 224:899-904 (1992); de Vos et al. Science 255:306-312 (1992)).

[0303] Polypeptides can contain amino acids other than the 20 amino acids commonly referred to as the 20 naturally occurring amino acids. Further, many amino acids, including the terminal amino acids, may be modified by natural processes, such as processing and other post-translational modifications, or by chemical modification techniques well known in the art. Accordingly, the variant proteins of the present invention also encompass derivatives or analogs in which a substituted amino acid residue is not one encoded by the genetic code, in which a substituent group is included, in which the mature polypeptide is fused with another compound, such as a compound to increase the half-life of the polypeptide (e.g., polyethylene glycol), or in which additional amino acids are fused to the mature polypeptide, such as a leader or secretory sequence or a sequence for purification of the mature polypeptide or a pro-protein sequence.

[0304] Known protein modifications include, but are not limited to, acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent crosslinks, formation of cystine, formation of pyroglutamate, formylation, gamma carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination.

[0305] Such protein modifications are well known to those of skill in the art and have been described in great detail in the scientific literature. Several particularly common modifications, glycosylation, lipid attachment, sulfation, gamma-carboxylation of glutamic acid residues, hydroxylation and ADP-ribosylation, for instance, are described in most basic texts, such as Proteins--Structure and Molecular Properties, 2nd Ed., T.E. Creighton, W. H. Freeman and Company, New York (1993); Wold, F., Posttranslational Covalent Modification of Proteins, B. C. Johnson, Ed., Academic Press, New York 1-12 (1983); Seifter et al., Meth. Enzymol. 182: 626-646 (1990); and Rattan et al., Ann. N.Y Acad. Sci. 663:48-62 (1992).

[0306] The present invention further provides fragments of the variant proteins in which the fragments contain one or more amino acid sequence variations (e.g., substitutions, or truncations or extensions due to creation or destruction of a stop codon) encoded by one or more SNPs disclosed herein. The fragments to which the invention pertains, however, are not to be construed as encompassing fragments that have been disclosed in the prior art before the present invention.

[0307] As used herein, a fragment may comprise at least about 4, 8, 10, 12, 14, 16, 18, 20, 25, 30, 50, 100 (or any other number in-between) or more contiguous amino acid residues from a variant protein, wherein at least one amino acid residue is affected by a SNP of the present invention, e.g., a variant amino acid residue encoded by a nonsynonymous nucleotide substitution at a cSNP position provided by the present invention. The variant amino acid encoded by a cSNP may occupy any residue position along the sequence of the fragment. Such fragments can be chosen based on the ability to retain one or more of the biological activities of the variant protein or the ability to perform a function, e.g., act as an immunogen. Particularly important fragments are biologically active fragments. Such fragments will typically comprise a domain or motif of a variant protein of the present invention, e.g., active site, transmembrane domain, or ligand/substrate binding domain. Other fragments include, but are not limited to, domain or motif-containing fragments, soluble peptide fragments, and fragments containing immunogenic structures. Predicted domains and functional sites are readily identifiable by computer programs well known to those of skill in the art (e.g., PROSITE analysis) (Current Protocols in Protein Science, John Wiley & Sons, N.Y. (2002)).

[0308] Uses of Variant Proteins

[0309] The variant proteins of the present invention can be used in a variety of ways, including but not limited to, in assays to determine the biological activity of a variant protein, such as in a panel of multiple proteins for high-throughput screening; to raise antibodies or to elicit another type of immune response; as a reagent (including the labeled reagent) in assays designed to quantitatively determine levels of the variant protein (or its binding partner) in biological fluids; as a marker for cells or tissues in which it is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in a disease state); as a target for screening for a therapeutic agent; and as a direct therapeutic agent to be administered into a human subject. Any of the variant proteins disclosed herein may be developed into reagent grade or kit format for commercialization as research products. Methods for performing the uses listed above are well known to those skilled in the art (see, e.g., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Sambrook and Russell, 2000, and Methods in Enzymology: Guide to Molecular Cloning Techniques, Academic Press, Berger, S. L. and A. R. Kimmel eds., 1987).

[0310] In a specific embodiment of the invention, the methods of the present invention include detection of one or more variant proteins disclosed herein. Variant proteins are disclosed in Table 1 and in the Sequence Listing as SEQ ID NOS: 13-24. Detection of such proteins can be accomplished using, for example, antibodies, small molecule compounds, aptamers, ligands/substrates, other proteins or protein fragments, or other protein-binding agents. Preferably, protein detection agents are specific for a variant protein of the present invention and can therefore discriminate between a variant protein of the present invention and the wild-type protein or another variant form. This can generally be accomplished by, for example, selecting or designing detection agents that bind to the region of a protein that differs between the variant and wild-type protein, such as a region of a protein that contains one or more amino acid substitutions that is/are encoded by a non-synonymous cSNP of the present invention, or a region of a protein that follows a nonsense mutation-type SNP that creates a stop codon thereby leading to a shorter polypeptide, or a region of a protein that follows a read-through mutation-type SNP that destroys a stop codon thereby leading to a longer polypeptide in which a portion of the polypeptide is present in one version of the polypeptide but not the other.

[0311] In another specific aspect of the invention, the variant proteins of the present invention are used as targets for diagnosing stenosis or for determining predisposition to stenosis in a human. Accordingly, the invention provides methods for detecting the presence of, or levels of, one or more variant proteins of the present invention in a cell, tissue, or organism. Such methods typically involve contacting a test sample with an agent (e.g., an antibody, small molecule compound, or peptide) capable of interacting with the variant protein such that specific binding of the agent to the variant protein can be detected. Such an assay can be provided in a single detection format or a multi-detection format such as an array, for example, an antibody or aptamer array (arrays for protein detection may also be referred to as "protein chips"). The variant protein of interest can be isolated from a test sample and assayed for the presence of a variant amino acid sequence encoded by one or more SNPs disclosed by the present invention. The SNPs may cause changes to the protein and the corresponding protein function/activity, such as through non-synonymous substitutions in protein coding regions that can lead to amino acid substitutions, deletions, insertions, and/or rearrangements; formation or destruction of stop codons; or alteration of control elements such as promoters. SNPs may also cause inappropriate post-translational modifications.

[0312] One preferred agent for detecting a variant protein in a sample is an antibody capable of selectively binding to a variant form of the protein (antibodies are described in greater detail in the next section). Such samples include, for example, tissues, cells, and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject.

[0313] In vitro methods for detection of the variant proteins associated with stenosis that are disclosed herein and fragments thereof include, but are not limited to, enzyme linked immunosorbent assays (ELISAs), radioimmunoassays (RIA), Western blots, immunoprecipitations, immunofluorescence, and protein arrays/chips (e.g., arrays of antibodies or aptamers). For further information regarding immunoassays and related protein detection methods, see Current Protocols in Immunology, John Wiley & Sons, N.Y., and Hage, "Immunoassays", Anal Chem. 1999 Jun. 15; 71(12):294R-304R.

[0314] Additional analytic methods of detecting amino acid variants include, but are not limited to, altered electrophoretic mobility, altered tryptic peptide digest, altered protein activity in cell-based or cell-free assay, alteration in ligand or antibody-binding pattern, altered isoelectric point, and direct amino acid sequencing.

[0315] Alternatively, variant proteins can be detected in vivo in a subject by introducing into the subject a labeled antibody (or other type of detection reagent) specific for a variant protein. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.

[0316] Other uses of the variant peptides of the present invention are based on the class or action of the protein. For example, proteins isolated from humans and their mammalian orthologs serve as targets for identifying agents (e.g., small molecule drugs or antibodies) for use in therapeutic applications, particularly for modulating a biological or pathological response in a cell or tissue that expresses the protein. Pharmaceutical agents can be developed that modulate protein activity.

[0317] As an alternative to modulating gene expression, therapeutic compounds can be developed that modulate protein function. For example, many SNPs disclosed herein affect the amino acid sequence of the encoded protein (e.g., non-synonymous cSNPs and nonsense mutation-type SNPs). Such alterations in the encoded amino acid sequence may affect protein function, particularly if such amino acid sequence variations occur in functional protein domains, such as catalytic domains, ATP-binding domains, or ligand/substrate binding domains. It is well established in the art that variant proteins having amino acid sequence variations in functional domains can cause or influence pathological conditions. In such instances, compounds (e.g., small molecule drugs or antibodies) can be developed that target the variant protein and modulate (e.g., up- or down-regulate) protein function/activity.

[0318] The therapeutic methods of the present invention further include methods that target one or more variant proteins of the present invention. Variant proteins can be targeted using, for example, small molecule compounds, antibodies, aptamers, ligands/substrates, other proteins, or other protein-binding agents. Additionally, the skilled artisan will recognize that the novel protein variants (and polymorphic nucleic acid molecules) disclosed in Table 1 may themselves be directly used as therapeutic agents by acting as competitive inhibitors of corresponding art-known proteins (or nucleic acid molecules such as mRNA molecules).

[0319] The variant proteins of the present invention are particularly useful in drug screening assays, in cell-based or cell-free systems. Cell-based systems can utilize cells that naturally express the protein, a biopsy specimen, or cell cultures. In one embodiment, cell-based assays involve recombinant host cells expressing the variant protein. Cell-free assays can be used to detect the ability of a compound to directly bind to a variant protein or to the corresponding SNP-containing nucleic acid fragment that encodes the variant protein.

[0320] A variant protein of the present invention, as well as appropriate fragments thereof, can be used in high-throughput screening assays to test candidate compounds for the ability to bind and/or modulate the activity of the variant protein. These candidate compounds can be further screened against a protein having normal function (e.g., a wild-type/non-variant protein) to further determine the effect of the compound on the protein activity. Furthermore, these compounds can be tested in animal or invertebrate systems to determine in vivo activity/effectiveness. Compounds can be identified that activate (agonists) or inactivate (antagonists) the variant protein, and different compounds can be identified that cause various degrees of activation or inactivation of the variant protein.

[0321] Further, the variant proteins can be used to screen a compound for the ability to stimulate or inhibit interaction between the variant protein and a target molecule that normally interacts with the protein. The target can be a ligand, a substrate or a binding partner that the protein normally interacts with (for example, epinephrine or norepinephrine). Such assays typically include the steps of combining the variant protein with a candidate compound under conditions that allow the variant protein, or fragment thereof, to interact with the target molecule, and to detect the formation of a complex between the protein and the target or to detect the biochemical consequence of the interaction with the variant protein and the target, such as any of the associated effects of signal transduction.

[0322] Candidate compounds include, for example, 1) peptides such as soluble peptides, including Ig-tailed fusion peptides and members of random peptide libraries (see, e.g., Lam et al., Nature 354:82-84 (1991); Houghten et al., Nature 354:84-86 (1991)) and combinatorial chemistry-derived molecular libraries made of D- and/or L-configuration amino acids; 2) phosphopeptides (e.g., members of random and partially degenerate, directed phosphopeptide libraries, see, e.g., Songyang et al., Cell 72:767-778 (1993)); 3) antibodies (e.g., polyclonal, monoclonal, humanized, anti-idiotypic, chimeric, and single chain antibodies as well as Fab, F(ab').sub.2, Fab expression library fragments, and epitope-binding fragments of antibodies); and 4) small organic and inorganic molecules (e.g., molecules obtained from combinatorial and natural product libraries).

[0323] One candidate compound is a soluble fragment of the variant protein that competes for ligand binding. Other candidate compounds include mutant proteins or appropriate fragments containing mutations that affect variant protein function and thus compete for ligand. Accordingly, a fragment that competes for ligand, for example with a higher affinity, or a fragment that binds ligand but does not allow release, is encompassed by the invention.

[0324] The invention further includes other end point assays to identify compounds that modulate (stimulate or inhibit) variant protein activity. The assays typically involve an assay of events in the signal transduction pathway that indicate protein activity. Thus, the expression of genes that are up or down-regulated in response to the variant protein dependent signal cascade can be assayed. In one embodiment, the regulatory region of such genes can be operably linked to a marker that is easily detectable, such as luciferase. Alternatively, phosphorylation of the variant protein, or a variant protein target, could also be measured. Any of the biological or biochemical functions mediated by the variant protein can be used as an endpoint assay. These include all of the biochemical or biological events described herein, in the references cited herein, incorporated by reference for these endpoint assay targets, and other functions known to those of ordinary skill in the art.

[0325] Binding and/or activating compounds can also be screened by using chimeric variant proteins in which an amino terminal extracellular domain or parts thereof, an entire transmembrane domain or subregions, and/or the carboxyl terminal intracellular domain or parts thereof, can be replaced by heterologous domains or subregions. For example, a substrate-binding region can be used that interacts with a different substrate than that which is normally recognized by a variant protein. Accordingly, a different set of signal transduction components is available as an end-point assay for activation. This allows for assays to be performed in other than the specific host cell from which the variant protein is derived.

[0326] The variant proteins are also useful in competition binding assays in methods designed to discover compounds that interact with the variant protein. Thus, a compound can be exposed to a variant protein under conditions that allow the compound to bind or to otherwise interact with the variant protein. A binding partner, such as ligand, that normally interacts with the variant protein is also added to the mixture. If the test compound interacts with the variant protein or its binding partner, it decreases the amount of complex formed or activity from the variant protein. This type of assay is particularly useful in screening for compounds that interact with specific regions of the variant protein (Hodgson, Bio/technology, 1992, Sep. 10(9), 973-80).

[0327] To perform cell-free drug screening assays, it is sometimes desirable to immobilize either the variant protein or a fragment thereof, or its target molecule, to facilitate separation of complexes from uncomplexed forms of one or both of the proteins, as well as to accommodate automation of the assay.

[0328] Any method for immobilizing proteins on matrices can be used in drug screening assays. In one embodiment, a fusion protein containing an added domain allows the protein to be bound to a matrix. For example, glutathione-S-transferase/.sup.125I fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) or glutathione derivatized microtitre plates, which are then combined with the cell lysates (e.g., .sup.35S-labeled) and a candidate compound, such as a drug candidate, and the mixture incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads can be washed to remove any unbound label, and the matrix immobilized and radiolabel determined directly, or in the supernatant after the complexes are dissociated. Alternatively, the complexes can be dissociated from the matrix, separated by SDS-PAGE, and the level of bound material found in the bead fraction quantitated from the gel using standard electrophoretic techniques.

[0329] Either the variant protein or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin. Alternatively, antibodies reactive with the variant protein but which do not interfere with binding of the variant protein to its target molecule can be derivatized to the wells of the plate, and the variant protein trapped in the wells by antibody conjugation. Preparations of the target molecule and a candidate compound are incubated in the variant protein-presenting wells and the amount of complex trapped in the well can be quantitated. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the protein target molecule, or which are reactive with variant protein and compete with the target molecule, and enzyme-linked assays that rely on detecting an enzymatic activity associated with the target molecule.

[0330] Modulators of variant protein activity identified according to these drug screening assays can be used to treat a subject with a disorder mediated by the protein pathway, such as stenosis. These methods of treatment typically include the steps of administering the modulators of protein activity in a pharmaceutical composition to a subject in need of such treatment.

[0331] The variant proteins, or fragments thereof, disclosed herein can themselves be directly used to treat a disorder characterized by an absence of, inappropriate, or unwanted expression or activity of the variant protein. Accordingly, methods for treatment include the use of a variant protein disclosed herein or fragments thereof.

[0332] In yet another aspect of the invention, variant proteins can be used as "bait proteins" in a two-hybrid assay or three-hybrid assay (see, e.g., U.S. Pat. No. 5,283,317; Zervos et al. (1993) Cell 72:223-232; Madura et al. (1993) J. Biol. Chem. 268:12046-12054; Bartel et al. (1993) Biotechniques 14:920-924; Iwabuchi et al. (1993) Oncogene 8:1693-1696; and Brent WO94/10300) to identify other proteins that bind to or interact with the variant protein and are involved in variant protein activity. Such variant protein-binding proteins are also likely to be involved in the propagation of signals by the variant proteins or variant protein targets as, for example, elements of a protein-mediated signaling pathway. Alternatively, such variant protein-binding proteins are inhibitors of the variant protein.

[0333] The two-hybrid system is based on the modular nature of most transcription factors, which typically consist of separable DNA-binding and activation domains. Briefly, the assay typically utilizes two different DNA constructs. In one construct, the gene that codes for a variant protein is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein ("prey" or "sample") is fused to a gene that codes for the activation domain of the known transcription factor. If the "bait" and the "prey" proteins are able to interact, in vivo, forming a variant protein-dependent complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) that is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected, and cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene that encodes the protein that interacts with the variant protein.

[0334] Antibodies Directed to Variant Proteins

[0335] The present invention also provides antibodies that selectively bind to the variant proteins disclosed herein and fragments thereof. Such antibodies may be used to quantitatively or qualitatively detect the variant proteins of the present invention. As used herein, an antibody selectively binds a target variant protein when it binds the variant protein and does not significantly bind to non-variant proteins, i.e., the antibody does not significantly bind to normal, wild-type, or art-known proteins that do not contain a variant amino acid sequence due to one or more SNPs of the present invention (variant amino acid sequences may be due to, for example, nonsynonymous cSNPs, nonsense SNPs that create a stop codon, thereby causing a truncation of a polypeptide or SNPs that cause read-through mutations resulting in an extension of a polypeptide).

[0336] As used herein, an antibody is defined in terms consistent with that recognized in the art: they are multi-subunit proteins produced by an organism in response to an antigen challenge. The antibodies of the present invention include both monoclonal antibodies and polyclonal antibodies, as well as antigen-reactive proteolytic fragments of such antibodies, such as Fab, F(ab)'.sub.2, and Fv fragments. In addition, an antibody of the present invention further includes any of a variety of engineered antigen-binding molecules such as a chimeric antibody (U.S. Pat. Nos. 4,816,567 and 4,816,397; Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851, 1984; Neuberger et al., Nature 312:604, 1984), a humanized antibody (U.S. Pat. Nos. 5,693,762; 5,585,089; and 5,565,332), a single-chain Fv (U.S. Pat. No. 4,946,778; Ward et al., Nature 334:544, 1989), a bispecific antibody with two binding specificities (Segal et al., J. Immunol. Methods 248:1, 2001; Carter, J. Immunol. Methods 248:7, 2001), a diabody, a triabody, and a tetrabody (Todorovska et al., J. Immunol. Methods, 248:47, 2001), as well as a Fab conjugate (dimer or trimer), and a minibody.

[0337] Many methods are known in the art for generating and/or identifying antibodies to a given target antigen (Harlow, Antibodies, Cold Spring Harbor Press, (1989)). In general, an isolated peptide (e.g., a variant protein of the present invention) is used as an immunogen and is administered to a mammalian organism, such as a rat, rabbit, hamster or mouse. Either a full-length protein, an antigenic peptide fragment (e.g., a peptide fragment containing a region that varies between a variant protein and a corresponding wild-type protein), or a fusion protein can be used. A protein used as an immunogen may be naturally-occurring, synthetic or recombinantly produced, and may be administered in combination with an adjuvant, including but not limited to, Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substance such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin, dinitrophenol, and the like.

[0338] Monoclonal antibodies can be produced by hybridoma technology (Kohler and Milstein, Nature, 256:495, 1975), which immortalizes cells secreting a specific monoclonal antibody. The immortalized cell lines can be created in vitro by fusing two different cell types, typically lymphocytes, and tumor cells. The hybridoma cells may be cultivated in vitro or in vivo. Additionally, fully human antibodies can be generated by transgenic animals (He et al., J. Immunol., 169:595, 2002). Fd phage and Fd phagemid technologies may be used to generate and select recombinant antibodies in vitro (Hoogenboom and Chames, Immunol. Today 21:371, 2000; Liu et al., J. Mol. Biol. 315:1063, 2002). The complementarity-determining regions of an antibody can be identified, and synthetic peptides corresponding to such regions may be used to mediate antigen binding (U.S. Pat. No. 5,637,677).

[0339] Antibodies are preferably prepared against regions or discrete fragments of a variant protein containing a variant amino acid sequence as compared to the corresponding wild-type protein (e.g., a region of a variant protein that includes an amino acid encoded by a nonsynonymous cSNP, a region affected by truncation caused by a nonsense SNP that creates a stop codon, or a region resulting from the destruction of a stop codon due to read-through mutation caused by a SNP). Furthermore, preferred regions will include those involved in function/activity and/or protein/binding partner interaction. Such fragments can be selected on a physical property, such as fragments corresponding to regions that are located on the surface of the protein, e.g., hydrophilic regions, or can be selected based on sequence uniqueness, or based on the position of the variant amino acid residue(s) encoded by the SNPs provided by the present invention. An antigenic fragment will typically comprise at least about 8-contiguous amino acid residues in which at least one of the amino acid residues is an amino acid affected by a SNP disclosed herein. The antigenic peptide can comprise, however, at least 12, 14, 16, 20, 25, 50, 100 (or any other number in-between) or more amino acid residues, provided that at least one amino acid is affected by a SNP disclosed herein.

[0340] Detection of an antibody of the present invention can be facilitated by coupling (i.e., physically linking) the antibody or an antigen-reactive fragment thereof to a detectable substance. Detectable substances include, but are not limited to, various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, .beta.-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include .sup.125I, .sup.131I, .sup.35S or .sup.3H.

[0341] Antibodies, particularly the use of antibodies as therapeutic agents, are reviewed in: Morgan, "Antibody therapy for Alzheimer's disease", Expert Rev Vaccines. 2003 February; 2(1):53-9; Ross et al., "Anticancer antibodies", Am J Clin Pathol. 2003 April; 119(4):472-85; Goldenberg, "Advancing role of radiolabeled antibodies in the therapy of cancer", Cancer Immunol Immunother. 2003 May; 52(5):281-96. Epub 2003 Mar. 11; Ross et al., "Antibody-based therapeutics in oncology", Expert Rev Anticancer Ther. 2003 February; 3(1): 107-21; Cao et al., "Bispecific antibody conjugates in therapeutics", Adv Drug Deliv Rev. 2003 Feb. 10; 55(2):171-97; von Mehren et al., "Monoclonal antibody therapy for cancer", Annu Rev Med. 2003; 54:343-69. Epub 2001 Dec. 3; Hudson et al., "Engineered antibodies", Nat. Med. 2003 January; 9(1):129-34; Brekke et al., "Therapeutic antibodies for human diseases at the dawn of the twenty-first century", Nat Rev Drug Discov. 2003 January; 2(1):52-62 (Erratum in: Nat Rev Drug Discov. 2003 March; 2(3):240); Houdebine, "Antibody manufacture in transgenic animals and comparisons with other systems", Curr Opin Biotechnol. 2002 December; 13(6):625-9; Andreakos et al., "Monoclonal antibodies in immune and inflammatory diseases", Curr Opin Biotechnol. 2002 December; 13(6):615-20; Kellermann et al., "Antibody discovery: the use of transgenic mice to generate human monoclonal antibodies for therapeutics", Curr Opin Biotechnol. 2002 December; 13(6):593-7; Pini et al., "Phage display and colony filter screening for high-throughput selection of antibody libraries", Comb Chem High Throughput Screen. 2002 November; 5(7):503-10; Batra et al., "Pharmacokinetics and biodistribution of genetically engineered antibodies", Curr Opin Biotechnol. 2002 December; 13(6):603-8; and Tangri et al., "Rationally engineered proteins or antibodies with absent or reduced immunogenicity", Curr Med. Chem. 2002 December; 9(24):2191-9.

[0342] Uses of Antibodies

[0343] Antibodies can be used to isolate the variant proteins of the present invention from a natural cell source or from recombinant host cells by standard techniques, such as affinity chromatography or immunoprecipitation. In addition, antibodies are useful for detecting the presence of a variant protein of the present invention in cells or tissues to determine the pattern of expression of the variant protein among various tissues in an organism and over the course of normal development or disease progression. Further, antibodies can be used to detect variant protein in situ, in vitro, in a bodily fluid, or in a cell lysate or supernatant in order to evaluate the amount and pattern of expression. Also, antibodies can be used to assess abnormal tissue distribution, abnormal expression during development, or expression in an abnormal condition, such as stenosis. Additionally, antibody detection of circulating fragments of the full-length variant protein can be used to identify turnover.

[0344] Antibodies to the variant proteins of the present invention are also useful in pharmacogenomic analysis. Thus, antibodies against variant proteins encoded by alternative SNP alleles can be used to identify individuals that require modified treatment modalities.

[0345] Further, antibodies can be used to assess expression of the variant protein in disease states such as in active stages of the disease or in an individual with a predisposition to a disease related to the protein's function, particularly stenosis. Antibodies specific for a variant protein encoded by a SNP-containing nucleic acid molecule of the present invention can be used to assay for the presence of the variant protein, such as to screen for predisposition to stenosis as indicated by the presence of the variant protein.

[0346] Antibodies are also useful as diagnostic tools for evaluating the variant proteins in conjunction with analysis by electrophoretic mobility, isoelectric point, tryptic peptide digest, and other physical assays well known in the art.

[0347] Antibodies are also useful for tissue typing. Thus, where a specific variant protein has been correlated with expression in a specific tissue, antibodies that are specific for this protein can be used to identify a tissue type.

[0348] Antibodies can also be used to assess aberrant subcellular localization of a variant protein in cells in various tissues. The diagnostic uses can be applied, not only in genetic testing, but also in monitoring a treatment modality. Accordingly, where treatment is ultimately aimed at correcting the expression level or the presence of variant protein or aberrant tissue distribution or developmental expression of a variant protein, antibodies directed against the variant protein or relevant fragments can be used to monitor therapeutic efficacy.

[0349] The antibodies are also useful for inhibiting variant protein function, for example, by blocking the binding of a variant protein to a binding partner. These uses can also be applied in a therapeutic context in which treatment involves inhibiting a variant protein's function. An antibody can be used, for example, to block or competitively inhibit binding, thus modulating (agonizing or antagonizing) the activity of a variant protein. Antibodies can be prepared against specific variant protein fragments containing sites required for function or against an intact variant protein that is associated with a cell or cell membrane. For in vivo administration, an antibody may be linked with an additional therapeutic payload such as a radionuclide, an enzyme, an immunogenic epitope, or a cytotoxic agent. Suitable cytotoxic agents include, but are not limited to, bacterial toxin such as diphtheria, and plant toxin such as ricin. The in vivo half-life of an antibody or a fragment thereof may be lengthened by pegylation through conjugation to polyethylene glycol (Leong et al., Cytokine 16:106, 2001).

[0350] The invention also encompasses kits for using antibodies, such as kits for detecting the presence of a variant protein in a test sample. An exemplary kit can comprise antibodies such as a labeled or labelable antibody and a compound or agent for detecting variant proteins in a biological sample; means for determining the amount, or presence/absence of variant protein in the sample; means for comparing the amount of variant protein in the sample with a standard; and instructions for use.

[0351] Vectors and Host Cells

[0352] The present invention also provides vectors containing the SNP-containing nucleic acid molecules described herein. The term "vector" refers to a vehicle, preferably a nucleic acid molecule, which can transport a SNP-containing nucleic acid molecule. When the vector is a nucleic acid molecule, the SNP-containing nucleic acid molecule can be covalently linked to the vector nucleic acid. Such vectors include, but are not limited to, a plasmid, single or double stranded phage, a single or double stranded RNA or DNA viral vector, or artificial chromosome, such as a BAC, PAC, YAC, or MAC.

[0353] A vector can be maintained in a host cell as an extrachromosomal element where it replicates and produces additional copies of the SNP-containing nucleic acid molecules. Alternatively, the vector may integrate into the host cell genome and produce additional copies of the SNP-containing nucleic acid molecules when the host cell replicates.

[0354] The invention provides vectors for the maintenance (cloning vectors) or vectors for expression (expression vectors) of the SNP-containing nucleic acid molecules. The vectors can function in prokaryotic or eukaryotic cells or in both (shuttle vectors).

[0355] Expression vectors typically contain cis-acting regulatory regions that are operably linked in the vector to the SNP-containing nucleic acid molecules such that transcription of the SNP-containing nucleic acid molecules is allowed in a host cell. The SNP-containing nucleic acid molecules can also be introduced into the host cell with a separate nucleic acid molecule capable of affecting transcription. Thus, the second nucleic acid molecule may provide a trans-acting factor interacting with the cis-regulatory control region to allow transcription of the SNP-containing nucleic acid molecules from the vector. Alternatively, a trans-acting factor may be supplied by the host cell. Finally, a trans-acting factor can be produced from the vector itself. It is understood, however, that in some embodiments, transcription and/or translation of the nucleic acid molecules can occur in a cell-free system.

[0356] The regulatory sequences to which the SNP-containing nucleic acid molecules described herein can be operably linked include promoters for directing mRNA transcription. These include, but are not limited to, the left promoter from bacteriophage .lamda., the lac, TRP, and TAC promoters from E. coli, the early and late promoters from SV40, the CMV immediate early promoter, the adenovirus early and late promoters, and retrovirus long-terminal repeats.

[0357] In addition to control regions that promote transcription, expression vectors may also include regions that modulate transcription, such as repressor binding sites and enhancers. Examples include the SV40 enhancer, the cytomegalovirus immediate early enhancer, polyoma enhancer, adenovirus enhancers, and retrovirus LTR enhancers.

[0358] In addition to containing sites for transcription initiation and control, expression vectors can also contain sequences necessary for transcription termination and, in the transcribed region, a ribosome-binding site for translation. Other regulatory control elements for expression include initiation and termination codons as well as polyadenylation signals. A person of ordinary skill in the art would be aware of the numerous regulatory sequences that are useful in expression vectors (see, e.g., Sambrook and Russell, 2000, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.).

[0359] A variety of expression vectors can be used to express a SNP-containing nucleic acid molecule. Such vectors include chromosomal, episomal, and virus-derived vectors, for example, vectors derived from bacterial plasmids, from bacteriophage, from yeast episomes, from yeast chromosomal elements, including yeast artificial chromosomes, from viruses such as baculoviruses, papovaviruses such as SV40, Vaccinia viruses, adenoviruses, poxviruses, pseudorabies viruses, and retroviruses. Vectors can also be derived from combinations of these sources such as those derived from plasmid and bacteriophage genetic elements, e.g., cosmids and phagemids. Appropriate cloning and expression vectors for prokaryotic and eukaryotic hosts are described in Sambrook and Russell, 2000, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.

[0360] The regulatory sequence in a vector may provide constitutive expression in one or more host cells (e.g., tissue specific expression) or may provide for inducible expression in one or more cell types such as by temperature, nutrient additive, or exogenous factor, e.g., a hormone or other ligand. A variety of vectors that provide constitutive or inducible expression of a nucleic acid sequence in prokaryotic and eukaryotic host cells are well known to those of ordinary skill in the art.

[0361] A SNP-containing nucleic acid molecule can be inserted into the vector by methodology well-known in the art. Generally, the SNP-containing nucleic acid molecule that will ultimately be expressed is joined to an expression vector by cleaving the SNP-containing nucleic acid molecule and the expression vector with one or more restriction enzymes and then ligating the fragments together. Procedures for restriction enzyme digestion and ligation are well known to those of ordinary skill in the art.

[0362] The vector containing the appropriate nucleic acid molecule can be introduced into an appropriate host cell for propagation or expression using well-known techniques. Bacterial host cells include, but are not limited to, E. coli, Streptomyces, and Salmonella typhimurium. Eukaryotic host cells include, but are not limited to, yeast, insect cells such as Drosophila, animal cells such as COS and CHO cells, and plant cells.

[0363] As described herein, it may be desirable to express the variant peptide as a fusion protein. Accordingly, the invention provides fusion vectors that allow for the production of the variant peptides. Fusion vectors can, for example, increase the expression of a recombinant protein, increase the solubility of the recombinant protein, and aid in the purification of the protein by acting, for example, as a ligand for affinity purification. A proteolytic cleavage site may be introduced at the junction of the fusion moiety so that the desired variant peptide can ultimately be separated from the fusion moiety. Proteolytic enzymes suitable for such use include, but are not limited to, factor Xa, thrombin, and enterokinase. Typical fusion expression vectors include pGEX (Smith et al., Gene 67:31-40 (1988)), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) which fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein. Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amann et al., Gene 69:301-315 (1988)) and pET 11d (Studier et al., Gene Expression Technology: Methods in Enzymology 185:60-89 (1990)).

[0364] Recombinant protein expression can be maximized in a bacterial host by providing a genetic background wherein the host cell has an impaired capacity to proteolytically cleave the recombinant protein (Gottesman, S., Gene Expression Technology. Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990) 119-128). Alternatively, the sequence of the SNP-containing nucleic acid molecule of interest can be altered to provide preferential codon usage for a specific host cell, for example, E. coli (Wada et al., Nucleic Acids Res. 20:2111-2118 (1992)).

[0365] The SNP-containing nucleic acid molecules can also be expressed by expression vectors that are operative in yeast. Examples of vectors for expression in yeast (e.g., S. cerevisiae) include pYepSec1 (Baldari, et al., EMBO J. 6:229-234 (1987)), pMFa (Kujan et al., Cell 30:933-943 (1982)), pJRY88 (Schultz et al., Gene 54:113-123 (1987)), and pYES2 (Invitrogen Corporation, San Diego, Calif.).

[0366] The SNP-containing nucleic acid molecules can also be expressed in insect cells using, for example, baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., Sf 9 cells) include the pAc series (Smith et al., Mol. Cell. Biol. 3:2156-2165 (1983)) and the pVL series (Lucklow et al., Virology 170:31-39 (1989)).

[0367] In certain embodiments of the invention, the SNP-containing nucleic acid molecules described herein are expressed in mammalian cells using mammalian expression vectors. Examples of mammalian expression vectors include pCDM8 (Seed, B. Nature 329:840 (1987)) and pMT2PC (Kaufman et al., EMBO J. 6:187-195 (1987)).

[0368] The invention also encompasses vectors in which the SNP-containing nucleic acid molecules described herein are cloned into the vector in reverse orientation, but operably linked to a regulatory sequence that permits transcription of antisense RNA. Thus, an antisense transcript can be produced to the SNP-containing nucleic acid sequences described herein, including both coding and non-coding regions. Expression of this antisense RNA is subject to each of the parameters described above in relation to expression of the sense RNA (regulatory sequences, constitutive or inducible expression, tissue-specific expression).

[0369] The invention also relates to recombinant host cells containing the vectors described herein. Host cells therefore include, for example, prokaryotic cells, lower eukaryotic cells such as yeast, other eukaryotic cells such as insect cells, and higher eukaryotic cells such as mammalian cells.

[0370] The recombinant host cells can be prepared by introducing the vector constructs described herein into the cells by techniques readily available to persons of ordinary skill in the art. These include, but are not limited to, calcium phosphate transfection, DEAE-dextran-mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, lipofection, and other techniques such as those described in Sambrook and Russell, 2000, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.).

[0371] Host cells can contain more than one vector. Thus, different SNP-containing nucleotide sequences can be introduced in different vectors into the same cell. Similarly, the SNP-containing nucleic acid molecules can be introduced either alone or with other nucleic acid molecules that are not related to the SNP-containing nucleic acid molecules, such as those providing trans-acting factors for expression vectors. When more than one vector is introduced into a cell, the vectors can be introduced independently, co-introduced, or joined to the nucleic acid molecule vector.

[0372] In the case of bacteriophage and viral vectors, these can be introduced into cells as packaged or encapsulated virus by standard procedures for infection and transduction. Viral vectors can be replication-competent or replication-defective. In the case in which viral replication is defective, replication can occur in host cells that provide functions that complement the defects.

[0373] Vectors generally include selectable markers that enable the selection of the subpopulation of cells that contain the recombinant vector constructs. The marker can be inserted in the same vector that contains the SNP-containing nucleic acid molecules described herein or may be in a separate vector. Markers include, for example, tetracycline or ampicillin-resistance genes for prokaryotic host cells, and dihydrofolate reductase or neomycin resistance genes for eukaryotic host cells. However, any marker that provides selection for a phenotypic trait can be effective.

[0374] While the mature variant proteins can be produced in bacteria, yeast, mammalian cells, and other cells under the control of the appropriate regulatory sequences, cell-free transcription and translation systems can also be used to produce these variant proteins using RNA derived from the DNA constructs described herein.

[0375] Where secretion of the variant protein is desired, which is difficult to achieve with multi-transmembrane domain containing proteins such as G-protein-coupled receptors (GPCRs), appropriate secretion signals can be incorporated into the vector. The signal sequence can be endogenous to the peptides or heterologous to these peptides.

[0376] Where the variant protein is not secreted into the medium, the protein can be isolated from the host cell by standard disruption procedures, including freeze/thaw, sonication, mechanical disruption, use of lysing agents, and the like. The variant protein can then be recovered and purified by well-known purification methods including, for example, ammonium sulfate precipitation, acid extraction, anion or cationic exchange chromatography, phosphocellulose chromatography, hydrophobic-interaction chromatography, affinity chromatography, hydroxylapatite chromatography, lectin chromatography, or high performance liquid chromatography.

[0377] It is also understood that, depending upon the host cell in which recombinant production of the variant proteins described herein occurs, they can have various glycosylation patterns, or may be non-glycosylated, as when produced in bacteria. In addition, the variant proteins may include an initial modified methionine in some cases as a result of a host-mediated process.

[0378] For further information regarding vectors and host cells, see Current Protocols in Molecular Biology, John Wiley & Sons, N.Y.

[0379] Uses of Vectors and Host Cells, and Transgenic Animals

[0380] Recombinant host cells that express the variant proteins described herein have a variety of uses. For example, the cells are useful for producing a variant protein that can be further purified into a preparation of desired amounts of the variant protein or fragments thereof. Thus, host cells containing expression vectors are useful for variant protein production.

[0381] Host cells are also useful for conducting cell-based assays involving the variant protein or variant protein fragments, such as those described above as well as other formats known in the art. Thus, a recombinant host cell expressing a variant protein is useful for assaying compounds that stimulate or inhibit variant protein function. Such an ability of a compound to modulate variant protein function may not be apparent from assays of the compound on the native/wild-type protein, or from cell-free assays of the compound. Recombinant host cells are also useful for assaying functional alterations in the variant proteins as compared with a known function.

[0382] Genetically-engineered host cells can be further used to produce non-human transgenic animals. A transgenic animal is preferably a non-human mammal, for example, a rodent, such as a rat or mouse, in which one or more of the cells of the animal include a transgene. A transgene is exogenous DNA containing a SNP of the present invention which is integrated into the genome of a cell from which a transgenic animal develops and which remains in the genome of the mature animal in one or more of its cell types or tissues. Such animals are useful for studying the function of a variant protein in vivo, and identifying and evaluating modulators of variant protein activity. Other examples of transgenic animals include, but are not limited to, non-human primates, sheep, dogs, cows, goats, chickens, and amphibians. Transgenic non-human mammals such as cows and goats can be used to produce variant proteins which can be secreted in the animal's milk and then recovered.

[0383] A transgenic animal can be produced by introducing a SNP-containing nucleic acid molecule into the male pronuclei of a fertilized oocyte, e.g., by microinjection or retroviral infection, and allowing the oocyte to develop in a pseudopregnant female foster animal. Any nucleic acid molecules that contain one or more SNPs of the present invention can potentially be introduced as a transgene into the genome of a non-human animal.

[0384] Any of the regulatory or other sequences useful in expression vectors can form part of the transgenic sequence. This includes intronic sequences and polyadenylation signals, if not already included. A tissue-specific regulatory sequence(s) can be operably linked to the transgene to direct expression of the variant protein in particular cells or tissues.

[0385] Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described in, for example, U.S. Pat. Nos. 4,736,866 and 4,870,009, both by Leder et al., U.S. Pat. No. 4,873,191 by Wagner et al., and in Hogan, B., Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986). Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the transgene in its genome and/or expression of transgenic mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene can further be bred to other transgenic animals carrying other transgenes. A transgenic animal also includes a non-human animal in which the entire animal or tissues in the animal have been produced using the homologously recombinant host cells described herein.

[0386] In another embodiment, transgenic non-human animals can be produced which contain selected systems that allow for regulated expression of the transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage P1 (Lakso et al. PNAS 89:6232-6236 (1992)). Another example of a recombinase system is the FLP recombinase system of S. cerevisiae (O'Gorman et al. Science 251:1351-1355 (1991)). If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are generally needed. Such animals can be provided through the construction of "double" transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected variant protein and the other containing a transgene encoding a recombinase.

[0387] Clones of the non-human transgenic animals described herein can also be produced according to the methods described in, for example, Wilmut, I. et al. Nature 385:810-813 (1997) and PCT International Publication Nos. WO 97/07668 and WO 97/07669. In brief, a cell (e.g., a somatic cell) from the transgenic animal can be isolated and induced to exit the growth cycle and enter Go phase. The quiescent cell can then be fused, e.g., through the use of electrical pulses, to an enucleated oocyte from an animal of the same species from which the quiescent cell is isolated. The reconstructed oocyte is then cultured such that it develops to morula or blastocyst and then transferred to pseudopregnant female foster animal. The offspring born of this female foster animal will be a clone of the animal from which the cell (e.g., a somatic cell) is isolated.

[0388] Transgenic animals containing recombinant cells that express the variant proteins described herein are useful for conducting the assays described herein in an in vivo context. Accordingly, the various physiological factors that are present in vivo and that could influence ligand or substrate binding, variant protein activation, signal transduction, or other processes or interactions, may not be evident from in vitro cell-free or cell-based assays. Thus, non-human transgenic animals of the present invention may be used to assay in vivo variant protein function as well as the activities of a therapeutic agent or compound that modulates variant protein function/activity or expression. Such animals are also suitable for assessing the effects of null mutations (i.e., mutations that substantially or completely eliminate one or more variant protein functions).

[0389] For further information regarding transgenic animals, see Houdebine, "Antibody manufacture in transgenic animals and comparisons with other systems", Curr Opin Biotechnol. 2002 December; 13(6):625-9; Petters et al., "Transgenic animals as models for human disease", Transgenic Res. 2000; 9(4-5):347-51; discussion 345-6; Wolf et al., "Use of transgenic animals in understanding molecular mechanisms of toxicity", J Pharm Pharmacol. 1998 June; 50(6):567-74; Echelard, "Recombinant protein production in transgenic animals", Curr Opin Biotechnol. 1996 October; 7(5):536-40; Houdebine, "Transgenic animal bioreactors", Transgenic Res. 2000; 9(4-5):305-20; Pirity et al., "Embryonic stem cells, creating transgenic animals", Methods Cell Biol. 1998; 57:279-93; and Robl et al., "Artificial chromosome vectors and expression of complex proteins in transgenic animals", Theriogenology. 2003 Jan. 1; 59(1):107-13.

EXAMPLES

Statistical Analysis of SNP Association with Coronary Stenosis

[0390] A case-control genetic study to determine the association of SNPs in the human genome with coronary stenosis was carried out using genomic DNA extracted from 2 independently collected case-control sample sets. A sample set from the University of California, San Francisco (UCSF), referred to as "Sample Set 1", consisted of DNA from 1,654 Caucasian patients with varying degrees of coronary artery stenosis as evidenced by coronary angiography. A sample set from the Cleveland Clinic (CCF), referred to as "Sample Set 2", consisted of DNA from 1,501 Caucasian patients with very little or severe coronary artery stenosis, also evidenced by coronary angiography. All samples were obtained from people between the ages of 18 to 75. All individuals who were included in each study had signed a written informed consent form. The study protocols were IRB approved.

[0391] DNA was extracted from blood samples using conventional DNA extraction methods such as the QIA-amp kit from Qiagen. SNP markers in the extracted DNA samples were analyzed by genotyping. While some samples were individually genotyped, the same samples were also used for pooling studies, in which DNA samples from about 50 individuals were pooled, and allele frequencies were determined in pooled DNA. Genotypes and pool allele frequencies were obtained using a PRISM 7900HT sequence detection PCR system (Applied Biosystems, Foster City, Calif.) by allele-specific PCR, similar to the method described by Germer et al (Germer S., Holland M. J., Higuchi R. 2000, Genome Res. 10: 258-266). Primers for the allele-specific PCR reactions are provided in Table 5.

[0392] Genotype or allele frequency results from 287 SNPs in Sample Set 1 and 177 SNPs in Sample Set 2 were analyzed for association with coronary stenosis. Analysis of the Sample Set 1 data was performed by placing individuals into groups based on quartiles of the sum score and using the two extreme quartiles as a binary endpoint. For Sample Set 2 samples, analysis was done in two ways. One method placed individuals into groups based on quartiles of the sum scores and used the two extreme quartiles as a binary endpoint. The other method placed individuals into groups of sum score "0" (the control group) or the sum score ">0" (the case group). The "sum score" is a measure of the overall extent of coronary artery stenosis and was determined by summing measures of percent stenosis from various arterial locations. The percent stenosis was determined from images obtained using coronary angiography. The case and control groups were further stratified by sex (F, M), age (tertile 1, 2, or 3) and smoking status ("never smoked" and "ever smoked"). The allele or genotype frequencies for the tested SNPs were obtained, and compared between cases and controls. No multiple testing corrections were made.

[0393] Several tests of association were calculated for both unstratified and stratified settings: 1) Fisher's exact test or asymptotic chi-square test for allelic association, 2) asymptotic chi-square test of genotypic association of two different modes of inheritance: dominant and recessive, and 3) Armitage trendtest for the additive mode of genotypic association.

[0394] Effect sizes were estimated through genotypic or allelic odds ratios, including 95% confidence intervals. The reported allele (Allele1) or genotype may be under-represented in cases (with a lower frequency in cases than in controls, indicating that the reported allele or genotype is associated with decreased risk and the other allele or genotype is a risk factor for disease) or over-represented in cases (indicating that the reported allele or genotype is a risk factor for disease).

[0395] The replicated coronary stenosis markers are reported in Table 6. A SNP is considered a replicated marker if the association analyses in two studies showed that the risk allele is the same, the p-values are each less than or equal to 0.05, and the significant association is seen in either the same stratum or in a stratum and its substratum. Table 6 also includes SNPs for which Cochran Mantel Haenszel test showed that the adjusted p-value of the meta analysis was less than 0.05, although the p-value for the individual sample sets might be greater than 0.05. Table 7 provides SNPs having a significant association (p-value of less than or equal to 0.05) with coronary stenosis in either the Sample Set 1 or the Sample Set 2 study.

[0396] An example of a replicated marker, where the homozygous reported allele is associated with a decreased risk for coronary stenosis is hCV1608777 (Table 6). Individuals in the second age tertile (Age T2) with 2 copies of the reported allele of HCV1608777 (Mode Rec) showed significant association (p-values 0.0344 and 0.0076) with decreased risk (odds ratios of 0.51 and 0.19 times of the reference) when compared to those carrying one or none of the reported allele (heterozygotes and major homozygotes) in both the Sample Set 1 and the Sample Set 2 studies.

[0397] An example of a replicated marker, where the reported allele is associated with increased risk for coronary stenosis is hCV16165996 (Table 6). Among the whole study population (Strata=ALL), carriers of one or two copies of the reported allele (Mode Dom) of HCV16165996 showed significant association (p-values of 0.0306 and 0.0037) with coronary stenosis with an increased risk (odds ratios of 1.31 and 1.69) compared with those carrying none of the reported allele (major homozygotes) in both the Sample Set 1 and the Sample Set 2 studies.

[0398] All publications and patents cited in this specification are herein incorporated by reference in their entirety. Various modifications and variations of the described compositions, methods and systems of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments and certain working examples, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the above-described modes for carrying out the invention that are obvious to those skilled in the field of molecular biology, genetics and related fields are intended to be within the scope of the following claims. TABLE-US-00002 TABLE 1 Gene Number: 1 Celera Gene: hCG1811758 - 63000132574665 Celera Transcript: hCT1954383 - 63000132574666 Public Transcript Accession: Celera Protein: hCP1766736 - 197000069463822 Public Protein Accession: Gene Symbol: CD163 Protein Name: CD163 antigen Celera Genomic Axis: GA_x5YUV32W234 (5436647 . . . 5489410) Chromosome: 12 OMIM NUMBER: 605545 OMIM Information: Transcript Sequence (SEQ ID NO: 1): Protein Sequence (SEQ ID NO: 13): SNP Information Context (SEQ ID NO: 25): GGCTGTGCAGACAAAGGGAAAATCAACCCTGCATCTTTAGACAAGGCCAT GTCCATTCCCATGTGGGTGGACAATGTTCAGTGTCCAAAAGGACCTGACA Y GCTGTGGCAGTGCCCATCATCTCCATGGGAGAAGAGACTGGCCAGCCCCT CGGAGGAGACCTGGATCACATGTGACAACAAGATAAGACTTCAGGAAGGA Celera SNP ID: hCV25591528 Public SNP ID: SNP in Transcript Sequence SEQ ID NO: 1 SNP Position Transcript: 2788 SNP Source: Applera Population (Allele, Count): Caucasian (T,8|C,32) african american (T,1|C,37) total (T,9|C,69) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 13, at position 901, (T,ACG)(M,ATG) Gene Number: 1 Celera Gene: hCG1811758 - 63000132574665 Celera Transcript: hCT2286904 - 63000132574686 Public Transcript Accession: Celera Protein: hCP1900559 - 197000069463823 Public Protein Accession: Gene Symbol: CD163 Protein Name: CD163 antigen Celera Genomic Axis: GA_x5YUV32W234 (5436647 . . . 5489410) Chromosome: 12 OMIM NUMBER: 605545 OMIM Information: Transcript Sequence (SEQ ID NO: 2): Protein Sequence (SEQ ID NO: 14): SNP Information Context (SEQ ID NO: 26): GGCTGTGCAGACAAAGGGAAAATCAACCCTGCATCTTTAGACAAGGCCAT GTCCATTCCCATGTGGGTGGACAATGTTCAGTGTCCAAAAGGACCTGACA Y GCTGTGGCAGTGCCCATCATCTCCATGGGAGAAGAGACTGGCCAGCCCCT CGGAGGAGACCTGGATCACATGTGACAACAAGATAAGACTTCAGGAAGGA Celera SNP ID: hCV25591528 Public SNP ID: SNP in Transcript Sequence SEQ ID NO: 2 SNP Position Transcript: 2788 SNP Source: Applera Population (Allele, Count): caucasian (T,8|C,32) african american (T,1|C,37) total (T,9|C,69) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 14, at position 901, (T,ACG)(M,ATG) Gene Number: 1 Celera Gene: hCG1811758 - 63000132574665 Celera Transcript: hCT2286906 - 63000132574728 Public Transcript Accession: Celera Protein: hCP1900561 - 197000069463825 Public Protein Accession: Gene Symbol: CD163 Protein Name: CD163 antigen Celera Genomic Axis: GA_x5YUV32W234 (5436647 . . . 5489410) Chromosome: 12 OMIM NUMBER: 605545 OMIM Information: Transcript Sequence (SEQ ID NO: 3): Protein Sequence (SEQ ID NO: 15): SNP Information Context (SEQ ID NO: 27): GGCTGTGCAGACAAAGGGAAAATCAACCCTGCATCTTTAGACAAGGCCAT GTCCATTCCCATGTGGGTGGACAATGTTCAGTGTCCAAAAGGACCTGACA Y GCTGTGGCAGTGCCCATCATCTCCATGGGAGAAGAGACTGGCCAGCCCCT CGGAGGAGACCTGGATCACATGTGACAACAAGATAAGACTTCAGGAAGGA Celera SNP ID: hCV25591528 Public SNP ID: SNP in Transcript Sequence SEQ ID NO: 3 SNP Position Transcript: 2887 SNP Source: Applera Population (Allele, Count): caucasian (T,8|C,32) african american (T,1|C,37) total (T,9|C,69) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 15, at position 934, (T,ACG)(M,ATG) Gene Number: 1 Celera Gene: hCG1811758 - 63000132574665 Celera Transcript: hCT2286907 - 63000132574707 Public Transcript Accession: Celera Protein: hCP1900560 - 197000069463824 Public Protein Accession: Gene Symbol: CD163 Protein Name: CD163 antigen Celera Genomic Axis: GA_x5YUV32W234 (5436647 . . . 5489410) Chromosome: 12 OMIM NUMBER: 605545 OMIM Information: Transcript Sequence (SEQ ID NO: 4): Protein Sequence (SEQ ID NO: 16): SNP Information Context (SEQ ID NO: 28): GGCTGTGCAGACAAAGGGAAAATCAACCCTGCATCTTTAGACAAGGCCAT GTCCATTCCCATGTGGGTGGACAATGTTCAGTGTCCAAAAGGACCTGACA Y GCTGTGGCAGTGCCCATCATCTCCATGGGAGAAGAGACTGGCCAGCCCCT CGGAGGAGACCTGGATCACATGTGACAACAAGATAAGACTTCAGGAAGGA Celera SNP ID: hCV25591528 Public SNP ID: SNP in Transcript Sequence SEQ ID NO: 4 SNP Position Transcript: 2788 SNP Source: Applera Population (Allele, Count): caucasian (T,8|C,32) african american (T,1|C,37) total (T,9|C,69) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 16, at position 901, (T,ACG)(M,ATG) Gene Number: 2 Celera Gene: hCG19417 - 79000075877786 Celera Transcript: hCT10488 - 79000075877787 Public Transcript Accession: NM_001278 Celera Protein: hCP37140 - 197000069450514 Public Protein Accession: NP_001269 Gene Symbol: CHUK Protein Name: conserved helix-loop-helix ubiquitous kinase Celera Genomic Axis: GA_x54KRFTF114 (32119433 . . . 32180761) Chromosome: 10 OMIM NUMBER: 600664 OMIM Information: Transcript Sequence (SEQ ID NO: 5): Protein Sequence (SEQ ID NO: 17): SNP Information Context (SEQ ID NO: 29): TAAGAAGAAGGATCCAAAGTGTATATTTGCATGTGAAGAGATGTCAGGAG AAGTTCGGTTTAGTAGCCATTTACCTCAACCAAATAGCCTTTGTAGTTTA R TAGTAGAACCCATGGAAAACTGGCTACAGTTGATGTTGAATTGGGACCCT CAGCAGAGAGGAGGACCTGTTGACCTTACTTTGAAGCAGCCAAGATGTTT Celera SNP ID: hCV1345898 Public SNP ID: rs2230804 SNP in Transcript Sequence SEQ ID NO: 5 SNP Position Transcript: 877 SNP Source: Celera; HGBASE; dbSNP Population (Allele, Count): no_pop (G,-|A,-) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 17, at position 268, (V,GTA)(I,ATA) Gene Number: 3 Celera Gene: hCG27811 - 66000116063099 Celera Transcript: hCT18953 - 66000116063100 Public Transcript Accession: NM_001168 Celera Protein: hCP43533 - 197000064921779 Public Protein Accession: NP_001159 Gene Symbol: BIRC5 Protein Name: baculoviral IAP repeat-containing 5 (survivin) Celera Genomic Axis: GA_x5YUV32W262 (13301753 . . . 13333146) Chromosome: 17 OMIM NUMBER: OMIM Information: Transcript Sequence (SEQ ID NO: 6): Protein Sequence (SEQ ID NO: 18): SNP Information Context (SEQ ID NO: 30): ATTAACCCTTGGTGAATTTTTGAAACTGGACAGAGAAAGAGCCAAGAACA AAATTGCAAAGGAAACCAACAATAAGAAGAAAGAATTTGAGGAAACTGCG R AGAAAGTGCGCCGTGCCATCGAGCAGCTGGCTGCCATGGATTGAGGCCTC TGGCCGGAGCTGCCTGGTCCCAGAGTGGCTGCACCACTTCCAGGGTTTAT Celera SNP ID: hCV16266313 Public SNP ID: rs2071214 SNP in Transcript Sequence SEQ ID NO: 6 SNP Position Transcript: 459 SNP Source: Applera Population (Allele, Count): caucasian (A,35|G,3) african american (A,30|G,0) total (A,65|G,3) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 18, at position 129, (K,AAG)(E,GAG) SNP Source: dbSNP; HapMap; HGBASE Population (Allele, Count: caucasian (G,6|A,114) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 18, at position 129, (K,AAG)(E,GAG) Gene Number: 3 Celera Gene: hCG27811 - 66000116063099 Celera Transcript: hCT1958629 -66000116063116 Public Transcript Accession: NM_001012271 Celera Protein: hCP1766717 - 197000064921781 Public Protein Accession: NP_001012271 Gene Symbol: BIRC5 Protein Name: baculoviral IAP repeat-containing 5 (survivin) Celera Genomic Axis: GA_x5YUV32W262 (13301753 . . . 13333146) Chromosome: 17 OMIM NUMBER: OMIM Information: Transcript Sequence (SEQ ID NO: 7): Protein Sequence (SEQ ID NO: 19): SNP Information Context (SEQ ID NO: 31): ATTAACCCTTGGTGAATTTTTGAAACTGGACAGAGAAAGAGCCAAGAACA AAATTGCAAAGGAAACCAACAATAAGAAGAAAGAATTTGAGGAAACTGCG R AGAAAGTGCGCCGTGCCATCGAGCAGCTGGCTGCCATGGATTGAGGCCTC TGGCCGGAGCTGCCTGGTCCCAGAGTGGCTGCACCACTTCCAGGGTTTAT Celera SNP ID: hCV16266313 Public SNP ID: rs2071214

SNP in Transcript Sequence SEQ ID NO: 7 SNP Position Transcript: 528 SNP Source: Applera Population (Allele, Count): caucasian (A,35|G,3) african american (A,30|G,0) total (A,65|G,3) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 19, at position 152, (K,AAG)(E,GAG) SNP Source: dbSNP; HapMap; HGBASE Population (Allele, Count): caucasian (G,6|A,114) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 19, at position 152, (K,AAG)(E,GAG) Gene Number: 3 Celera Gene: hCG27811 - 66000116063099 Celera Transcript: hCT1962326 - 66000116063125 Public Transcript Accession: NM_001012270 Celera Protein: hCP1778153 - 197000064921782 Public Protein Accession: NP_001012270 Gene Symbol: BIRC5 Protein Name: baculoviral IAP repeat-containing 5 (survivin) Celera Genomic Axis: GA_x5YUV32W262 (13301753 . . . 13333146) Chromosome: 17 OMIM NUMBER: OMIM Information: Transcript Sequence (SEQ ID NO: 8): Protein Sequence (SEQ ID NO: 20): SNP Information Context (SEQ ID NO: 32): AGTGTTTCTTCTGCTTCAAGGAGCTGGAAGGCTGGGAGCCAGATGACGAC CCCATGCAAAGGAAACCAACAATAAGAAGAAAGAATTTGAGGAAACTGCG R AGAAAGTGCGCCGTGCCATCGAGCAGCTGGCTGCCATGGATTGAGGCCTC TGGCCGGAGCTGCCTGGTCCCAGAGTGGCTGCACCACTTCCAGGGTTTAT Celera SNP ID: hCV16266313 Public SNP ID: rs2071214 SNP in Transcript Sequence SEQ ID NO: 8 SNP Position Transcript: 341 SNP Source: Applera Population (Allele, Count): caucasian (A,35|G,3) african american (A,30|G,0) total (A,65|G,3) SNP Type: Silent Mutation Protein Coding: SEQ ID NO: 20, at position 89, (R,CGA)(R,CGG) SNP Source: dbSNP; HapMap; HGBASE Population (Allele, Count): caucasian (G,6|A,114) SNP Type: Silent Mutation Protein Coding: SEQ ID NO: 20, at position 89, (R,CGA)(R,CGG) Gene Number: 3 Celera Gene: hCG27811 - 66000116063099 Celera Transcript: hCT1967440 - 66000116063140 Public Transcript Accession: NM_001168 Celera Protein: hCP1781899 - 197000064921785 Public Protein Accession: NP_001159 Gene Symbol: BIRC5 Protein Name: baculoviral IAP repeat-containing 5 (survivin) Celera Genomic Axis: GA_x5YUV32W262 (13301753 . . . 13333146) Chromosome: 17 OMIM NUMBER: OMIM Information: Transcript Sequence (SEQ ID NO: 9): Protein Sequence (SEQ ID NO: 21): SNP Information Context (SEQ ID NO: 33): ATTAACCCTTGGTGAATTTTTGAAACTGGACAGAGAAAGAGCCAAGAACA AAATTGCAAAGGAAACCAACAATAAGAAGAAAGAATTTGAGGAAACTGCG R AGAAAGTGCGCCGTGCCATCGAGCAGCTGGCTGCCATGGATTGAGGCCTC TGGCCGGAGCTGCCTGGTCCCAGAGTGGCTGCACCACTTCCAGGGTTTAT Celera SNP ID: hCV16266313 Public SNP ID: rs2071214 SNP in Transcript Sequence SEQ ID NO: 9 SNP Position Transcript: 459 SNP Source: Applera Population (Allele, Count): caucasian (A,35|G,3) african american (A,30|G,0) total (A,65|G,3) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 21, at position 129, (K,AAG)(E,GAG) SNP Source: dbSNP; HapMap; HGBASE Population (Allele, Count): caucasian (G,6|A,114) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 21, at position 129, (K,AAG)(E,GAG) Gene Number: 3 Celera Gene: hCG27811 - 66000116063099 Celera Transcript: hCT2336835 - 66000116063149 Public Transcript Accession: NM_001012271 Celera Protein: hCP1789145 - 197000064921786 Public Protein Accession: NP_001012271 Gene Symbol: BIRC5 Protein Name: baculoviral IAP repeat-containing 5 (survivin) Celera Genomic Axis: GA_x5YUV32W262 (13301753 . . . 13333146) Chromosome: 17 OMIM NUMBER: OMIM Information: Transcript Sequence (SEQ ID NO: 10): Protein Sequence (SEQ ID NO: 22): SNP Information Context (SEQ ID NO: 34): ATTAACCCTTGGTGAATTTTTGAAACTGGACAGAGAAAGAGCCAAGAACA AAATTGCAAAGGAAACCAACAATAAGAAGAAAGAATTTGAGGAAACTGCG R AGAAAGTGCGCCGTGCCATCGAGCAGCTGGCTGCCATGGATTGAGGCCTC TGGCCGGAGCTGCCTGGTCCCAGAGTGGCTGCACCACTTCCAGGGTTTAT Celera SNP ID: hCV16266313 Public SNP ID: rs2071214 SNP in Transcript Sequence SEQ ID NO: 10 SNP Position Transcript: 528 SNP Source: Applera Population (Allele, Count): caucasian (A,35|G,3) african american (A,30|G,0) total (A,65|G,3) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 22, at position 152, (K,AAG)(E,GAG) SNP Source: dbSNP; HapMap; HGBASE Population (Allele, Count): caucasian (G,6|A,114) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 22, at position 152, (K,AAG)(E,GAG) Gene Number: 3 Celera Gene: hCG27811 - 66000116063099 Celera Transcript: hCT2336837 - 66000116063132 Public Transcript Accession: NM_001012270 Celera Protein: hCP1789143 - 197000064921784 Public Protein Accession: NP_001012270 Gene Symbol: BIRC5 Protein Name: baculoviral IAP repeat-containing 5 (survivin) Celera Genomic Axis: GA_x5YUV32W262 (13301753 . . . 13333146) Chromosome: 17 OMIM NUMBER: OMIM Information: Transcript Sequence (SEQ ID NO: 11): Protein Sequence (SEQ ID NO: 23): SNP Information Context (SEQ ID NO: 35): AGTGTTTCTTCTGCTTCAAGGAGCTGGAAGGCTGGGAGCCAGATGACGAC CCCATGCAAAGGAAACCAACAATAAGAAGAAAGAATTTGAGGAAACTGCG R AGAAAGTGCGCCGTGCCATCGAGCAGCTGGCTGCCATGGATTGAGGCCTC TGGCCGGAGCTGCCTGGTCCCAGAGTGGCTGCACCACTTCCAGGGTTTAT Celera SNP ID: hCV16266313 Public SNP ID: rs2071214 SNP in Transcript Sequence SEQ ID NO: 11 SNP Position Transcript: 341 SNP Source: Applera Population (Allele, Count): caucasian (A,35|G,3) african american (A,30|G,0) total (A,65|G,3) SNP Type: Silent Mutation Protein Coding: SEQ ID NO: 23, at position 89, (R,CGA)(R,CGG) SNP Source: dbSNP; HapMap; HGBASE Population (Allele, Count): caucasian (G,6|A,114) SNP Type: Silent Mutation Protein Coding: SEQ ID NO: 23, at position 89, (R,CGA)(R,CGG) Gene Number: 4 Celera Gene: hCG38633 -226000018878110 Celera Transcript: hCT29876 - 226000018878111 Public Transcript Accession: NM_000134 Celera Protein: hCP48455 - 197000069464429 Public Protein Accession: NP_000125 Gene Symbol: FABP2 Protein Name: fatty acid binding protein 2, intestinal Celera Genomic Axis: GA_x5YUV32VYAM (759337 . . . 784251) Chromosome: 4 OMIM NUMBER: 134640 OMIM Information: Transcript Sequence (SEQ ID NO: 12): Protein Sequence (SEQ ID NO: 24): SNP Information Context (SEQ ID NO: 36): AATGGGTGTTAATATAGTGAAAAGGAAGCTTGCAGCTCATGACAATTTGA AGCTGACAATTACACAAGAAGGAAATAAATTCACAGTCAAAGAATCAAGC R CTTTTCGAAACATTGAAGTTGTTTTTGAACTTGGTGTCACCTTTAATTAC AATCTAGCAGACGGAACTGAACTCAGGGGGACCTGGAGCCTTGAGGGAAA Celera SNP ID: hCV761961 Public SNP ID: rs1799883 SNP in Transcript Sequence SEQ ID NO: 12 SNP Position Transcript: 224 SNP Source: HGMD; dbSNP; HapMap; HGBASE Population (Allele, Count): caucasian (A,44|G,74) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 24, at position 55, (A,GCT)(T,ACT)

[0399] TABLE-US-00003 TABLE 2 Gene Number: 1 Celera Gene: hCG1811758 -63000132574665 Gene Symbol: CD163 Protein Name: CD163 antigen Celera Genomic Axis: GA_x5YUV32W234 (5436647 . . . 5489410) Chromosome: 12 OMIM NUMBER: 605545 OMIM Information: Genomic Sequence (SEQ ID NO: 37): SNP Information Context (SEQ ID NO: 41): CATATAGGTCGATGGATACTCACTGTCACATGTGATCCAGGTCTCCTCCG AGGGGCTGGCCAGTCTCTTCTCCCATGGAGATGATGGGCACTGCCACAGC R TGTCAGGTCCTTTTGGACACTGAACATTGTCCACCCACATGGGAATGGAC ATGGCCTTGTCTAAAGATGCAGGGTTGATTTTCCCTTTGTCTGCACAGCC Celera SNP ID: hCV25591528 Public SNP ID: SNP in Genomic Sequence: SEQ ID NO: 37 SNP Position Genomic: 24287 SNP Source: Applera Population (Allele, Count): caucasian (A,8|G,32) african american (A,1|G,37) total (A,9|G,69) SNP Type: MISSENSE MUTATION; HUMAN-MOUSE SYNTENIC REGION Gene Number: 2 Celera Gene: hCG19417 - 79000075877786 Gene Symbol: CHUK Protein Name: conserved helix-loop-helix ubiquitous kinase Celera Genomic Axis: GA_x54KRFTF114 (32119433 . . . 32180761) Chromosome: 10 OMIM NUMBER: 600664 OMIM Information: Genomic Sequence (SEQ ID NO: 38): SNP Information Context (SEQ ID NO: 42): AAACATCTTGGCTGCTTCAAAGTAAGGTCAACAGGTCCTCCTCTCTGCTG AGGGTCCCAATTCAACATCAACTGTAGCCAGTTTTCCATGGGTTCTACTA Y TAAACTAGAAAACATACAAAATAGGGTGAAAATCAAATCATTATGTTCCA ATTTCCCTTTATACTGTTAGAAAGGTAATTTTGCAGGTTGTCCATTTTCT Celera SNP ID: hCV1345898 Public SNP ID: rs2230804 SNP in Genomic Sequence: SEQ ID NO: 38 SNP Position Genomic: 39847 SNP Source: Celera; HGBASE; dbSNP Population (Allele, Count): no_pop (C,-|T,-) SNP Type: MISSENSE MUTATION; HUMAN-MOUSE SYNTENIC REGION; SILENT MUTATION Gene Number: 3 Celera Gene: hCG27811 - 66000116063099 Gene Symbol: BIRC5 Protein Name: baculoviral IAP repeat-containing 5 (survivin) Celera Genomic Axis: GA_x5YUV32W262 (13301753 . . . 13333146) Chromosome: 17 OMIM NUMBER: OMIM Information: Genomic Sequence (SEQ ID NO: 39): SNP Information Context (SEQ ID NO: 43): GGATGTGACTGGGAAGCTCTGGTTTCAGTGTCATGTGTCTATTCTTTATT TCCAGGCAAAGGAAACCAACAATAAGAAGAAAGAATTTGAGGAAACTGCG R AGAAAGTGCGCCGTGCCATCGAGCAGCTGGCTGCCATGGATTGAGGCCTC TGGCCGGAGCTGCCTGGTCCCAGAGTGGCTGCACCACTTCCAGGGTTTAT Celera SNP ID: hCV16266313 Public SNP ID: rs2071214 SNP in Genomic Sequence: SEQ ID NO: 39 SNP Position Genomic: 19267 SNP Source: Applera Population (Allele, Count): caucasian (A,35|G,3) african american (A,30|G,0) total (A,65|G,3) SNP Type: MISSENSE MUTATION; HUMAN-MOUSE SYNTENIC REGION; SILENT MUTATION SNP Source: dbSNP; HapMap; HGBASE Population (Allele, Count): caucasian (G,6|A,114) SNP Type: MISSENSE MUTATION; HUMAN-MOUSE SYNTENIC REGION; SILENT MUTATION Gene Number: 4 Celera Gene: hCG38633 - 226000018878110 Gene Symbol: FABP2 Protein Name: fatty acid binding protein 2, intestinal Celera Genomic Axis: GA_x5YUV32VYAM (759337 . . . 784251) Chromosome: 4 OMIM NUMBER: 134640 OMIM Information: Genomic Sequence (SEQ ID NO: 40): SNP Information Context (SEQ ID NO: 44): CTCATAAAAAAAAAAATTCTTACCCTGAGTTCAGTTCCGTCTGCTAGATT GTAATTAAAGGTGACACCAAGTTCAAAAACAACTTCAATGTTTCGAAAAG Y GCTTGATTCTTTGACTGTGAATTTATTTCCTTCTTGTGTAATTGTCAGCT TCAAATTGTCATGAGCTGCAAGCTTCCTTTTCACTATATTAACACCTGTA Celera SNP ID: hCV761961 Public SNP ID: rs1799883 SNP in Genomic Sequence: SEQ ID NO: 40 SNP Position Genomic: 13498 SNP Source: HGMD; dbSNP; HapMap; HGBASE Population (Allele, Count): caucasian (T,44|C,74) SNP Type: MISSENSE MUTATION; HUMAN-MOUSE SYNTENIC REGION

[0400] TABLE-US-00004 TABLE 3 hCV25591528 SEQ ID NO: 25 hCV25591528 SEQ ID NO: 26 hCV25591528 SEQ ID NO: 27 hCV25591528 SEQ ID NO: 28

[0401] TABLE-US-00005 TABLE 4 hCV25591528 SEQ ID NO: 41

[0402] TABLE-US-00006 TABLE 5 Primers Sequence A Sequence B Sequence C hCV Alleles (Allele-specific Primer) (Allele-specific Primer) (Common Primer) hCV1345898 C/T CAGTTTTCCATGGGTTCTACTAC CAGTTTTCCATGGGTTCTACTAT TTATGAAATGGTACAGACAAGTGAT (SEQ ID NO:45) (SEQ ID NO:46) (SEQ ID NO:47) hCV16266313 A/G CACGGCGCACTTTCTT CACGGCGCACTTTCTC TGTTTTTTCCTTTGTCATCTTATCTA (SEQ ID NO:48) (SEQ ID NO:49) (SEQ ID NO:50) hCV25591528 A/G TCCAAAAGGACCTGACAT TCCAAAAGGACCTGACAC GGCTGCAGAATGGAATTT (SEQ ID NO:51) (SEQ ID NO:52) (SEQ ID NO:53) hCV761961 C/T CACAGTCAAAGAATCAAGCG TCACAGTCAAAGAATCAAGCA AAATTCTTACCCTGAGTTCAGTTC (SEQ ID NO:54) (SEQ ID NO:55) (SEQ ID NO:56)

[0403] TABLE-US-00007 TABLE 6 Gene Case Cntrl Marker Name Sample Set p-value OR 95% CI Freq. Freq. Allele1 Mode Strata Adjust hCV1608777 PLSCR1 Sample Set 2 0.0344 0.51 0.27-0.96 5.1 9.6 T Rec Age T2 hCV1608777 PLSCR1 Sample Set 1 0.0076 0.19 0.05-0.72 2.8 13.2 T Rec Age T2 hCV16165996 LRP2 Sample Set 2 0.0306 1.31 1.03-1.68 49.0 42.3 T Dom ALL hCV16165996 LRP2 Sample Set 2 0.0281 1.31 1.02-1.68 28.3 23.2 T Add Smoke+ hCV16165996 LRP2 Sample Set 1 0.0037 1.69 1.18-2.4 47.9 35.2 T Dom ALL hCV16165996 LRP2 Sample Set 1 0.0321 1.67 1.04-2.7 48.3 35.9 T Dom Smoke+ hCV16181123 ACADL Sample Set 2 0.0182 1.74 1.09-2.77 19.3 12.1 G Rec MI- hCV16181123 ACADL Sample Set 1 0.0072 1.87 1.18-2.96 66.9 52.0 G Dom MI- hCV2143203 CD44 Sample Set 2 0.0394 4.00 0.97-16.49 6.7 1.8 T Rec Age T1 hCV2143203 CD44 Sample Set 2 0.0326 2.08 1.05-4.11 26.0 14.5 T Add MI-Age T1 hCV2143203 CD44 Sample Set 1 0.0274 6.00 0.7-50.8 5.5 0.0 T Rec Age T1 hCV2143203 CD44 Sample Set 1 0.0163 8.90 0.8-88.9 6.7 0.0 T Rec MI-Age T1 hCV2143205 CD44 Sample Set 2 0.0090 1.68 1.12-2.52 39.8 28.3 A Add MI-Smoke- hCV2143205 CD44 Sample Set 1 0.0123 3.88 1.3-12 18.2 5.4 A Rec MI-Smoke- hCV22273419 GP6 Sample Set 2 0.0332 0.81 0.67-0.99 15.5 18.4 C Add ALL hCV22273419 GP6 Sample Set 1 0.0229 0.51 0.29-0.92 27.7 42.7 C Dom Smoke- hCV25591528 CD163 Sample Set 2 0.0285 0.73 0.55-0.97 9.7 12.8 A Add ALL hCV25591528 CD163 Sample Set 2 0.0356 0.20 0-1.5 0.0 1.9 A Rec Male hCV25591528 CD163 Sample Set 2 0.0105 0.51 0.3-0.88 7.3 13.4 A Add Smoke- hCV25591528 CD163 Sample Set 1 0.0096 0.10 0-1 0.0 2.2 A Rec ALL hCV25591528 CD163 Sample Set 1 0.0328 0.20 0-1.4 0.0 2.5 A Rec Male hCV25591528 CD163 Sample Set 1 0.0457 0.52 0.28-0.99 7.8 14.0 A Allelic Smoke- hCV25603879 SCNN1A Sample Set 2 0.0330 2.24 1.05-4.76 11.1 5.3 T Dom Smoke- hCV25603879 SCNN1A Sample Set 2 0.0243 2.71 1.08-6.8 6.7 2.6 T Add MI-Age T1 hCV25603879 SCNN1A Sample Set 2 0.0429 1.65 1.01-2.68 9.5 6.0 T Dom MI- hCV25603879 SCNN1A Sample Set 2 0.0100 2.26 1.18-4.32 4.8 2.2 T Add MI-Male hCV25603879 SCNN1A Sample Set 2 0.0474 1.83 1-3.33 10.4 6.0 T Dom MI- hCV25603879 SCNN1A Sample Set 2 0.0054 3.22 1.36-7.62 15.3 5.3 T Dom MI-Smoke- hCV25603879 SCNN1A Sample Set 1 0.0147 3.67 1.2-11.5 6.4 1.8 T Add Smoke- hCV25603879 SCNN1A Sample Set 1 0.0201 5.99 1.07-33.6 6.7 1.2 T Add MI-Age T1 hCV25603879 SCNN1A Sample Set 1 0.0035 3.62 1.43-9.2 5.4 1.6 T Add MI- hCV25603879 SCNN1A Sample Set 1 0.0165 3.93 1.2-13.3 6.3 1.7 T Add MI-Male hCV25603879 SCNN1A Sample Set 1 0.0035 3.62 1.43-9.2 5.4 1.6 T Add MI- hCV25603879 SCNN1A Sample Set 1 0.0020 5.53 1.6-18.9 9.3 1.8 T Add MI-Smoke- hCV25627634 SMTN Sample Set 2 0.0396 1.82 1.02-3.24 64.4 49.8 G Dom MI-Smoke- hCV25627634 SMTN Sample Set 1 0.0068 2.62 1.28-5.4 15.7 6.6 G Rec MI- hCV3084793 APOE Sample Set 2 0.0487 1.62 1-2.64 30.5 21.3 C Dom MI-Female hCV3084793 APOE Sample Set 2 0.0299 1.82 1.06-3.14 38.5 25.6 C Dom MI-Age T2 hCV3084793 APOE Sample Set 1 0.0069 2.25 1.2-4.2 23.2 11.8 C Add MI-Female hCV3084793 APOE Sample Set 1 0.0137 8.40 0.9-78.2 7.9 0.0 C Rec MI-Age T2 hCV5478 TCF1 Sample Set 2 0.0100 3.07 1.24-7.57 3.5 1.3 T Allelic Age T2 hCV5478 TCF1 Sample Set 1 0.0152 12.21 1.18-126.50 4.6 0.6 T Allelic Age T2 hCV598677 EDN1 Sample Set 2 0.0065 1.82 1.18-2.79 45.8 31.7 T Dom Age T1 hCV598677 EDN1 Sample Set 2 0.0048 3.23 1.38-7.53 60.0 31.7 T Dom MI-Age T1 hCV598677 EDN1 Sample Set 1 0.0372 4.60 0.97-22 9.9 2.3 T Rec Age T1 hCV598677 EDN1 Sample Set 1 0.0048 8.31 1.5-45.4 16.7 2.4 T Rec MI-Age T1 hCV7482175 HLA-A Sample Set 2 0.0163 0.66 0.47-0.93 25.7 34.4 A Dom Smoke+ hCV7482175 HLA-A Sample Set 1 0.0132 0.61 0.4-0.9 14.3 21.6 A Add Smoke+ hCV7530616 WRN Sample Set 2 0.0027 14.10 1.46-136.45 1.9 0.1 A Rec MI- hCV7530616 WRN Sample Set 1 0.0492 5.90 0.5-57.9 3.6 0.0 A Rec MI-Female hCV7530616 WRN Sample Set 1 0.0230 2.43 1.1-5.2 11.7 5.2 A Add MI-Smoke+ hCV7584364 PTGS1 Sample Set 2 0.0006 9.32 1.97-44.18 2.7 0.3 T Rec MI- hCV7584364 PTGS1 Sample Set 2 0.0051 11.90 1.2-117 3.6 0.0 T Rec MI-Age T1 hCV7584364 PTGS1 Sample Set 1 0.0209 1.99 1.10-3.6 10.0 5.3 T Add MI- hCV7584364 PTGS1 Sample Set 1 0.0282 3.11 1.1-8.7 13.3 4.7 T Add MI-Age T1 hCV761961 FABP2 Sample Set 2 0.0360 1.48 1.03-2.14 50.0 40.3 T Dom Age T3 hCV761961 FABP2 Sample Set 1 0.0397 6.73 0.84-53.9 9.5 1.5 T Rec Age T3 hCV790057 CETP Sample Set 2 0.0121 0.78 0.64-0.95 26.3 31.4 G Allelic ALL hCV790057 CETP Sample Set 2 0.0443 0.61 0.37-0.99 6.9 11.0 G Rec MI- hCV790057 CETP Sample Set 1 0.0033 0.27 0.11-0.67 30.0 61.2 G Dom MI-Age T1 hCV790057 CETP Sample Set 1 0.0186 0.49 0.27-0.89 44.0 61.6 G Dom Age T1 hCV790057 CETP Sample Set 1 0.0482 0.49 0.24-1.0 37.2 55.0 G Dom MI-Smoke- hCV8705506 KLK1 Sample Set 2 0.0122 0.58 0.38-0.89 45.6 59.2 C Dom Smoke- hCV8705506 KLK1 Sample Set 1 0.0388 0.57 0.34-0.98 9.2 15.0 C Rec ALL hCV8921288 GAPD Sample Set 2 0.0130 1.38 1.07-1.77 40.9 33.5 G Dom ALL hCV8921288 GAPD Sample Set 1 0.0486 6.45 0.78-53.3 5.8 1.0 G Rec Female hCV9458082 NOS2A Sample Set 2 0.0092 1.47 1.1-1.96 17.8 12.9 T Rec ALL hCV9458082 NOS2A Sample Set 1 0.0406 1.87 1.02-3.4 66.4 51.3 T Dom Age T2 hCV9458082 NOS2A Sample Set 1 0.0200 1.49 1.06-2.1 41.3 32.1 T Add Smoke+ hCV9458082 NOS2A Sample Set 1 0.0228 1.74 1.08-2.8 68.0 55.0 T Dom Male hCV9506149 FN1 Sample Set 2 0.0058 1.32 1.08-1.6 28.7 23.4 T Add ALL hCV9506149 FN1 Sample Set 1 0.0152 1.60 1.08-2.4 27.3 19.0 T Add Male hCV1552900 ALOX12 Sample Set 2 0.1180 1.38 0.92-2.06 50.0 42.1 A Allelic Smoke- gender, age_group_lt54_le64 hCV1552900 ALOX12 Sample Set 1 0.2066 1.40 0.83-2.33 50.0 42.5 A Allelic Smoke- gender, age_group_lt54_le64 hCV1552900 ALOX12 Meta 0.0445 1.38 1.01-1.90 50.0 42.2 A Allelic Smoke- source, gender, age_group_lt54_le6 hCV16266313 BIRC5 Sample Set 2 0.3686 1.37 0.69-2.72 6.1 4.9 G Allelic Age T3 gender, smoke hCV16266313 BIRC5 Sample Set 1 0.0280 3.21 1.08-9.60 9.5 3.1 G Allelic Age T3 gender, smoke hCV16266313 BIRC5 Meta 0.0359 1.83 1.04-3.22 7.7 4.5 G Allelic Age T3 source, gender, smoke hCV1985480 AGT Sample Set 2 0.2513 0.84 0.63-1.13 11.8 14.2 A Allelic ALL gender, age_group_lt54_le64, smoke hCV1985480 AGT Sample Set 1 0.0447 0.57 0.32-0.99 7.5 12.1 A Allelic ALL gender, age_group_lt54_le64, smoke hCV1985480 AGT Meta 0.0478 0.77 0.59-1.00 10.6 13.7 A Allelic ALL source, gender, age_group_lt54_le64, smoke hCV22274624 HDLBP Sample Set 2 0.0348 0.67 0.47-0.97 40.1 48.7 C Dom ALL gender, age_group_lt54_le64 hCV22274624 HDLBP Sample Set 1 0.4815 0.85 0.54-1.34 38.8 43.3 C Dom ALL gender, age_group_lt54_le64 hCV22274624 HDLBP Meta 0.0369 0.74 0.55-0.98 39.6 47.4 C Dom ALL source, gender, age_group_lt54_le64 hCV2548962 PON1 Sample Set 2 0.1393 0.85 0.69-1.05 27.2 30.4 C Allelic Smoke+ gender, age_group_lt54_le64, smoke hCV2548962 PON1 Sample Set 1 0.0545 0.71 0.50-1.01 28.1 35.9 C Allelic Smoke+ gender, age_group_lt54_le64, smoke hCV2548962 PON1 Meta 0.0238 0.81 0.68-0.97 27.4 31.7 C Allelic Smoke+ source, gender, age_group_lt54_le64, smoke hCV11660791 MTHFD1 Sample Set 2 0.01 1.5 1.1-2.1 86 81 C Allelic ALL hCV11660791 MTHFD1 Sample Set 1 0.0364 0.58 0.3-1.0 14 21 T Allelic Age T3

[0404] TABLE-US-00008 TABLE 7 Gene Case Cntrl Marker Name Sample Set p-value OR 95% CI Freq. Freq. Allele1 Mode Strata hCV11975277 SELP Sample Set 1 0.039 n/a* G Rec Age T3 hCV1575287 IL8RA Sample Set 1 0.027 n/a* G Dom Older hCV1575287 IL8RA Sample Set 1 0.046 n/a* G Dom Smoke- hCV1603656 HSPG2 Sample Set 1 0.037 1.13 T Allelic Female hCV1639938 F13A1 Sample Set 1 0.04 n/a* A Dom Age T2 hCV3216553 APOB Sample Set 1 0.047 n/a* A Dom Age T2 hCV3216553 APOB Sample Set 1 0.034 1.55 A Allelic Age T1 hCV7582933 PLA2G7 Sample Set 1 0.019 5.95 T Rec Age T3 hCV1129436 APOL3 Sample Set 1 0.02463 C Allelic Smoke+ hCV1129436 APOL3 Sample Set 1 0.02409 C Allelic male/Age T2 hCV1129436 APOL3 Sample Set 1 0.02811 C Allelic male/no hypertension hCV1129436 APOL3 Sample Set 1 0.00455 C Allelic MaleSmoke+ hCV11623862 TBXAS1 Sample Set 1 0.04724 T Allelic All hCV11972321 F13A1 Sample Set 1 0.04190 G Allelic Smoke+ hCV11972321 F13A1 Sample Set 1 0.04755 G Allelic female/no hypertension hCV11972321 F13A1 Sample Set 1 0.02064 G Allelic male/Age T1 hCV11972321 F13A1 Sample Set 1 0.01487 G Allelic MaleSMoke+ hCV1202883 MTHFR Sample Set 1 0.01357 A Allelic MI+ hCV1202883 MTHFR Sample Set 1 0.03654 A Allelic MaleMI+ hCV1345898 CHUK Sample Set 1 0.02992 C Allelic male/Age T3 hCV15954277 PRKCQ Sample Set 1 0.03260 A Allelic female/no hypertension hCV15963704 ITGA3 Sample Set 1 0.03398 A Allelic Hypertension hCV15963704 ITGA3 Sample Set 1 0.02997 A Allelic male/hypertension hCV16170982 SREBF2 Sample Set 1 0.04406 C Allelic female/Age T2 hCV16170982 SREBF2 Sample Set 1 0.04529 C Allelic FemaleMI- hCV16170993 SELPLG Sample Set 1 0.04733 G Allelic Smoke+ hCV16172262 FABP6 Sample Set 1 0.04577 G Allelic MI- hCV16172262 FABP6 Sample Set 1 0.02549 G Allelic No hypertension hCV16172262 FABP6 Sample Set 1 0.04855 G Allelic MaleMI- hCV16172262 FABP6 Sample Set 1 0.03227 G Allelic male/no hypertension hCV16179628 ABCC2 Sample Set 1 0.03322 T Allelic female/Age T2 hCV16195242 MTP Sample Set 1 0.00814 G Allelic MI- hCV16195242 MTP Sample Set 1 0.01728 G Allelic Smoke+ hCV16195242 MTP Sample Set 1 0.00212 G Allelic MaleMI- hCV16195242 MTP Sample Set 1 0.02587 G Allelic MaleSmoke+ hCV1932478 P2RY12 Sample Set 1 0.04012 T Allelic MI- hCV2213764 MMP11 Sample Set 1 0.02493 C Allelic Smoke+ hCV2213764 MMP11 Sample Set 1 0.02596 C Allelic FemaleMI+ hCV22271841 PDGFRA Sample Set 1 0.04281 C Allelic MI+ hCV22271841 PDGFRA Sample Set 1 0.03142 C Allelic female/hypertension hCV22272408 PRKCQ Sample Set 1 0.02252 A Allelic female/no hypertension hCV22272408 PRKCQ Sample Set 1 0.04503 A Allelic MaleSmoke- hCV22272567 ABCC2 Sample Set 1 0.03614 A Allelic MI- hCV22272567 ABCC2 Sample Set 1 0.01204 A Allelic MaleMI- hCV22272567 ABCC2 Sample Set 1 0.01309 A Allelic male/hypertension hCV22274307 MTP Sample Set 1 0.03426 C Allelic age T2 hCV22274307 MTP Sample Set 1 0.04299 C Allelic MI- hCV22274307 MTP Sample Set 1 0.02673 C Allelic male/age T2 hCV25472673 NPC1 Sample Set 1 0.02505 C Allelic MI+ hCV25591743 ABCC2 Sample Set 1 0.02414 T Allelic MI- hCV25591743 ABCC2 Sample Set 1 0.03752 T Allelic male/hypertension hCV25614474 PLG Sample Set 1 0.01528 A Allelic female hCV25614474 PLG Sample Set 1 0.02338 A Allelic MI- hCV25614474 PLG Sample Set 1 0.00122 A Allelic FemaleMI- hCV25614474 PLG Sample Set 1 0.02906 A Allelic female/hypertension hCV25629888 TIMP2 Sample Set 1 0.01835 G Allelic age T 1 hCV25638153 APOA5 Sample Set 1 0.03379 G Allelic age T3 hCV25646316 LRP2 Sample Set 1 0.04595 G Allelic male/no hypertension hCV25652767 LRP1 Sample Set 1 0.02443 A Allelic MI+ hCV25652767 LRP1 Sample Set 1 0.00243 A Allelic MI- hCV2705229 ITGA10 Sample Set 1 0.03914 T Allelic Hypertension hCV2705229 ITGA10 Sample Set 1 0.00468 T Allelic male/hypertension hCV2822674 CUBN Sample Set 1 0.02925 T Allelic female hCV2822674 CUBN Sample Set 1 0.00076 T Allelic female/age T3 hCV2822674 CUBN Sample Set 1 0.03335 T Allelic FemaleMI+ hCV3135085 CUBN Sample Set 1 0.00245 T Allelic No hypertension hCV3135085 CUBN Sample Set 1 0.01122 T Allelic female/no hypertension hCV3135085 CUBN Sample Set 1 0.02797 T Allelic male/age T3 hCV342590 F5 Sample Set 1 0.04203 C Allelic FemaleSmoke- hCV342590 F5 Sample Set 1 0.03999 C Allelic MaleSmoke+ hCV5687 CX3CR1 Sample Set 1 0.03556 T Allelic male hCV7490135 NPC1 Sample Set 1 0.01191 G Allelic age T2 hCV7490135 NPC1 Sample Set 1 0.04298 G Allelic MI+ hCV7490135 NPC1 Sample Set 1 0.02428 G Allelic male/age T2 hCV7900503 CX3CR1 Sample Set 1 0.02118 C Allelic female/age T1 hCV7900503 CX3CR1 Sample Set 1 0.03188 C Allelic FemaleSmoke+ hCV7900503 CX3CR1 Sample Set 1 0.02491 C Allelic MaleMI+ hCV1361979 ACAT2 Sample Set 2 0.0027 1.71388 1.2-2.4 0.7342 0.6171 A Dom Age T2 hCV1361979 ACAT2 Sample Set 2 0.0298 1.37325 1-1.8 0.7114 0.6422 A Dom Male hCV1361979 ACAT2 Sample Set 2 0.0152 1.2601 1-1.5 0.4429 0.3869 A Add Smoke+ hCV1361979 ACAT2 Sample Set 2 0.0198 1.1936 1-1.4 0.4431 0.4 A Add ALL hCV1361979 ACAT2 Sample Set 2 0.00753 1.73944 1.2-2.6 0.7371 0.6171 A Dom Age T2 hCV1361979 ACAT2 Sample Set 2 0.0301 1.47134 1-2.1 0.7253 0.6422 A Dom Male hCV1361979 ACAT2 Sample Set 2 0.0181 1.49327 1.1-2.1 0.7153 0.6272 A Dom Smoke+ hCV1361979 ACAT2 Sample Set 2 0.0358 1.32885 1-1.7 0.7 0.6371 A Dom ALL hCV1361979 ACAT2 Sample Set 2 0.0126 2.1026 1.2-3.8 0.7722 0.6171 A Dom MI-AgeT2 hCV1361979 ACAT2 Sample Set 2 0.00369 1.9409 1.2-3 0.7578 0.6171 A Dom MI-AgeT2 hCV1361979 ACAT2 Sample Set 2 0.0373 1.2953 1-1.7 0.4497 0.3869 A Add MI-Smoke+ hCV22274712 MTP Sample Set 2 0.0403 1.41589 1-2 0.6321 0.5482 G Dom Age T2 hCV22274712 MTP Sample Set 2 0.0369 1.43566 1-2 0.6596 0.5745 G Dom Female hCV22274712 MTP Sample Set 2 0.0498 1.4498 1-2.1 0.6733 0.5871 G Dom MI- hCV2531431 THBD Sample Set 2 0.0111 0.22613 0.1-0.8 0.0149 0.0625 T Rec Age T3 hCV2531431 THBD Sample Set 2 0.0299 0.42323 0.2-0.9 0.0202 0.0464 T Rec Male hCV2531431 THBD Sample Set 2 0.00295 0.5156 0.3-0.8 0.1186 0.207 T Allelic Age T3 hCV25608818 SLC10A2 Sample Set 2 0.00737 6.0214 1.3-27 0.021 0.0035 A Add Female hCV25608818 SLC10A2 Sample Set 2 0.0363 3.5574 1.1-11.6 0.022 0.0063 A Add Smoke- hCV25608818 SLC10A2 Sample Set 2 0.0212 5.3694 1.1-26.8 0.0188 0.0035 A Add Female hCV25608818 SLC10A2 Sample Set 2 0.0263 4.208 1.2-15 0.0259 0.0063 A Allelic Smoke- hCV25608818 SLC10A2 Sample Set 2 0.0101 7.4602 1.2-45.2 0.0259 0.0035 A Add MI-Female hCV25608818 SLC10A2 Sample Set 2 0.0341 -- -- 0.0104 0 A Rec MI-Male hCV25608818 SLC10A2 Sample Set 2 0.0156 5.5614 1.4-22.6 0.0339 0.0063 A Add MI-Smoke- hCV25608818 SLC10A2 Sample Set 2 0.0314 -- -- 0.0065 0 A Rec MI- hCV25608818 SLC10A2 Sample Set 2 0.00132 8.5895 1.8-41.7 0.0297 0.0035 A Add MI-Female hCV25608818 SLC10A2 Sample Set 2 0.0239 4.3227 1.2-15.5 0.0265 0.0063 A Allelic MI-Smoke- hCV25653599 WDR12 Sample Set 2 0.00488 1.77148 1.2-2.6 0.2868 0.185 C Dom Age T2 hCV25653599 WDR12 Sample Set 2 0.0125 1.4324 1.1-1.9 0.148 0.1081 C Add Male hCV25653599 WDR12 Sample Set 2 0.0011 2.06754 1.3-3.2 0.3194 0.185 C Dom Age T2 hCV25653599 WDR12 Sample Set 2 0.00925 1.5412 1.1-2.1 0.1574 0.1081 C Add Male hCV25653599 WDR12 Sample Set 2 0.0449 1.33735 1-1.8 0.2716 0.218 C Dom ALL hCV25653599 WDR12 Sample Set 2 0.00797 2.1608 1.2-3.8 0.3291 0.185 C Dom MI-AgeT2 hCV25653599 WDR12 Sample Set 2 0.00341 2.0357 1.3-3.3 0.3438 0.2047 C Dom MI-Male hCV25653599 WDR12 Sample Set 2 0.0204 1.5756 1.1-2.3 0.3052 0.218 C Dom MI- hCV25653599 WDR12 Sample Set 2 0.00334 1.6595 1.2-2.3 0.1675 0.1081 C Add MI-Male hCV25653599 WDR12 Sample Set 2 0.0106 1.4203 1.1-1.9 0.1571 0.116 C Add MI- hCV25653599 WDR12 Sample Set 2 0.0257 1.7171 1.1-2.8 0.2805 0.185 C Dom MI-AgeT2 hCV25653599 WDR12 Sample Set 2 0.0289 1.4654 1-2.1 0.1559 0.112 C Add MI-Smoke+ hCV25963638 SRPX Sample Set 2 0.0333 1.51 1-2.2 0.079 0.0538 A Allelic Smoke+ hCV25963638 SRPX Sample Set 2 0.0246 1.9735 1.1-3.5 0.1392 0.0758 A Allelic MI-AgeT2 hCV25963638 SRPX Sample Set 2 0.00997 2.0235 1.2-3.4 0.1237 0.0652 A Allelic MI-Male hCV25963638 SRPX Sample Set 2 0.0465 1.8005 1-3.2 0.0928 0.0538 A Allelic MI-Smoke+ hCV25963638 SRPX Sample Set 2 0.048 1.9943 1-4 0.0769 0.0401 A Rec MI- hCV25963638 SRPX Sample Set 2 0.00373 1.8731 1.2-2.8 0.1156 0.0652 A Allelic MI-Male hCV25963638 SRPX Sample Set 2 0.00569 1.893 1.2-3 0.0971 0.0538 A Allelic MI-Smoke+ hCV25963638 SRPX Sample Set 2 0.0174 1.9469 1.1-3.4 0.0752 0.0401 A Rec MI- hCV25963638 SRPX Sample Set 2 0.0204 1.7792 1.1-2.9 0.1273 0.0758 A Allelic MI-AgeT2 hCV2782570 PTGIS Sample Set 2 0.0202 0.7282 0.6-0.9 0.3184 0.3908 G Allelic Smoke- hCV2782570 PTGIS Sample Set 2 0.0439 0.3075 0.1-1 0.0526 0.153 G Rec MI-Female hCV2782570 PTGIS Sample Set 2 0.0345 1.4814 1-2.1 0.697 0.6082 G Dom MI-Smoke+ hCV2782570 PTGIS Sample Set 2 0.0428 0.4656 0.2-1 0.0776 0.153 G Rec MI-Female hCV2908485 none Sample Set 2 0.00678 0.6959 0.5-0.9 0.3621 0.4492 G Add Age T3 hCV2908485 none Sample Set 2 0.00146 0.63584 0.5-0.8 0.5955 0.6984 G Dom Male hCV2908485 none Sample Set 2 0.00761 0.7751 0.6-0.9 0.3935 0.4557 G Allelic Smoke+ hCV2908485 none Sample Set 2 0.015 0.76396 0.6-0.9 0.6211 0.6821 G Dom ALL hCV2908485 none Sample Set 2 0.00553 0.6407 0.5-0.9 0.3432 0.4492 G Add Age T3 hCV2908485 none Sample Set 2 0.00236 0.59936 0.4-0.8 0.5812 0.6984 G Dom Male hCV2908485 none Sample Set 2 0.0142 0.66644 0.5-0.9 0.6187 0.7089 G Dom Smoke+ hCV2908485 none Sample Set 2 0.0181 0.73421 0.6-0.9 0.6117 0.6821 G Dom ALL hCV2908485 none Sample Set 2 0.0473 1.9907 1-4 0.2414 0.1378 G Rec MI-Female hCV2908485 none Sample Set 2 0.0102 0.5553 0.4-0.9 0.5625 0.6984 G Dom MI-Male hCV2908485 none Sample Set 2 0.00378 2.5953 1.3-5 0.2712 0.1254 G Rec MI-Smoke- hCV2908485 none Sample Set 2 0.00978 0.6506 0.5-0.9 0.3526 0.4557 G Add MI-Smoke+ hCV2908485 none Sample Set 2 0.0432 0.6917 0.5-1 0.5974 0.6821 G Dom MI- hCV2908485 none Sample Set 2 0.00684 0.6135 0.4-0.9 0.599 0.7089 G Dom MI-Smoke+ hCV2908485 none Sample Set 2 0.007 0.6185 0.4-0.9 0.5888 0.6984 G Dom MI-Male hCV2908485 none Sample Set 2 0.00798 0.69 0.5-0.9 0.5968 0.6821 G Dom MI- hCV2908485 none Sample Set 2 0.0178 0.5526 0.3-0.9 0.5761 0.7109 G Dom MI-AgeT3 hCV2908485 none Sample Set 2 0.0431 1.7825 1-3.1 0.2035 0.1254 G Rec MI-Smoke- hCV783138 F7 Sample Set 2 0.0245 0 -- 0 0.0177 A Rec Female hCV11592758 BDNF Sample Set 2 0.003689 1.418521 0.85736073 0.8090617 C Allelic ALL hCV11592758 BDNF Sample Set 2 0.015578 1.442573 0.85240696 0.8001411 C Allelic Male hCV11592758 BDNF Sample Set 2 0.048839 1.410359 0.85028022 0.8010637 C Allelic Younger hCV2531086 CD22 Sample Set 2 0.016484 1.45531 0.80197937 0.7356524 G Allelic Younger hCV25474320 LCP1 Sample Set 2 0.003797 0.421814 0.04477473 0.1000101 T Allelic Female hCV25474320 LCP1 Sample Set 2 0.040595 0.609457 0.05770926 0.0913129 T Allelic Older hCV25608809 TLR5 Sample Set 2 0.033066 1.352714 0.58624226 0.5115828 A Allelic Female hCV25608809 TLR5 Sample Set 2 0.001546 1.482234 0.59272859 0.4954267 A Allelic Older hCV25608809 TLR5 Sample Set 2 0.037258 1.249806 0.56389988 0.5085033 A Allelic Smoke+ hCV2676030 EDG2 Sample Set 2 0.047657 1.202427 0.35389562 0.3129634 G Allelic ALL hCV2676030 EDG2 Sample Set 2 0.047791 1.250291 0.359831 0.310138 G Allelic Smoke+ hCV7490119 NPC1 Sample Set 2 8.66E-05 0.684841 0.27083028 0.3516384 C Allelic ALL hCV7490119 NPC1 Sample Set 2 0.020383 0.703492 0.28775573 0.3647954 C Allelic Female hCV7490119 NPC1 Sample Set 2 0.001487 0.672101 0.25987035 0.3431481 C

Allelic Male hCV7490119 NPC1 Sample Set 2 0.000415 0.502755 0.23248743 0.3759751 C Allelic Smoke- hCV7490119 NPC1 Sample Set 2 0.005119 0.690612 0.28847403 0.3699039 C Allelic Older hCV7490119 NPC1 Sample Set 2 0.002153 0.640858 0.24675175 0.3382584 C Allelic Younger hCV7490119 NPC1 Sample Set 2 0.039905 0.787741 0.28126535 0.3318993 C Allelic Smoke+ hCV8827241 SPARCL1 Sample Set 2 0.011283 0.716295 0.57830575 0.6568944 C Allelic Younger hCV8932279 SERPINB5 Sample Set 2 0.026358 1.465232 0.48857258 0.3946682 G Allelic Smoke- hCV9482394 KIAA1608 Sample Set 2 0.04301 1.74935 0.12036092 0.0725434 A Allelic Smoke- hCV9482394 KIAA1608 Sample Set 2 0.02777 0.641196 0.06323883 0.0952556 A Allelic Smoke+ hCV9578831 TNFRSF6 Sample Set 2 0.034212 0.615467 0.07409659 0.115064 T Allelic Younger hCV1309246 PPP1R12A Sample Set 2 0.03147 0.339874 0.01228995 0.0353173 C Allelic Male hCV1309246 PPP1R12A Sample Set 2 0.032389 0.187827 0.00861413 0.0442151 C Allelic Smoke- hCV1403468 IL12A Sample Set 2 0.032773 0.663131 0.13769986 0.1940753 G Allelic Male hCV1487384 CD33 Sample Set 2 0.008942 1.597195 0.83948062 0.7660464 G Allelic Male hCV16173091 FABP1 Sample Set 2 0.04212 0.66867 0.27076982 0.3570351 C Allelic Female hCV16173091 FABP1 Sample Set 2 0.040581 0.738459 0.29386913 0.3604351 C Allelic Smoke+ hCV25594815 LRP3 Sample Set 2 0.003239 1.690589 0.14376135 0.0903416 A Allelic ALL hCV25594815 LRP3 Sample Set 2 0.002488 1.960164 0.16132547 0.0893639 A Allelic Male hCV25594815 LRP3 Sample Set 2 0.019092 1.672316 0.14861088 0.094512 A Allelic Smoke+ hCV25944011 EGLN2 Sample Set 2 0.047039 1.264556 0.37561049 0.322361 A Allelic ALL hCV25944011 EGLN2 Sample Set 2 0.036898 1.366324 0.39094994 0.319636 A Allelic Male hCV313778 GOLGA5 Sample Set 2 0.022064 0.751072 0.2535017 0.3113598 A Allelic ALL hCV313778 GOLGA5 Sample Set 2 0.002363 0.52557 0.19889103 0.3208284 A Allelic Female hCV313778 GOLGA5 Sample Set 2 0.019467 0.696256 0.24191677 0.314285 A Allelic Smoke+ Note: * Odds Ratio (OR) not applicable because sum score is a continuous end point

[0405]

Sequence CWU 1

1

56 1 5313 DNA Homo sapien 1 gaattcttag ttgttttctt tagaagaaca tttctaggga ataatacaag aagatttagg 60 aatcattgaa gttataaatc tttggaatga gcaaactcag aatggtgcta cttgaagact 120 ctggatctgc tgacttcaga agacattttg tcaacctgag tcccttcacc attactgtgg 180 tcttacttct cagtgcctgt tttgtcacca gttctcttgg aggaacagac aaggagctga 240 ggctagtgga tggtgaaaac aagtgtagcg ggagagtgga agtgaaagtc caggaggagt 300 ggggaacggt gtgtaataat ggctggagca tggaagcggt ctctgtgatt tgtaaccagc 360 tgggatgtcc aactgctatc aaagcccctg gatgggctaa ttccagtgca ggttctggac 420 gcatttggat ggatcatgtt tcttgtcgtg ggaatgagtc agctctttgg gattgcaaac 480 atgatggatg gggaaagcat agtaactgta ctcaccaaca agatgctgga gtgacctgct 540 cagatggatc caatttggaa atgaggctga cgcgtggagg gaatatgtgt tctggaagaa 600 tagagatcaa attccaagga cggtggggaa cagtgtgtga tgataacttc aacatagatc 660 atgcatctgt catttgtaga caacttgaat gtggaagtgc tgtcagtttc tctggttcat 720 ctaattttgg agaaggctct ggaccaatct ggtttgatga tcttatatgc aacggaaatg 780 agtcagctct ctggaactgc aaacatcaag gatggggaaa gcataactgt gatcatgctg 840 aggatgctgg agtgatttgc tcaaagggag cagatctgag cctgagactg gtagatggag 900 tcactgaatg ttcaggaaga ttagaagtga gattccaagg ggaatggggg acaatatgtg 960 atgacggctg ggacagttac gatgctgctg tggcatgcaa gcaactggga tgtccaactg 1020 ccgtcacagc cattggtcga gttaacgcca gtaagggatt tggacacatc tggcttgaca 1080 gcgtttcttg ccagggacat gaacctgctg tctggcaatg taaacaccat gaatggggaa 1140 agcattattg caatcacaat gaagatgctg gcgtgacatg ttctgatgga tcagatctgg 1200 agctaagact tagaggtgga ggcagccgct gtgctgggac agttgaggtg gagattcaga 1260 gactgttagg gaaggtgtgt gacagaggct ggggactgaa agaagctgat gtggtttgca 1320 ggcagctggg atgtggatct gcactcaaaa catcttatca agtgtactcc aaaatccagg 1380 caacaaacac atggctgttt ctaagtagct gtaacggaaa tgaaacttct ctttgggact 1440 gcaagaactg gcaatggggt ggacttacct gtgatcacta tgaagaagcc aaaattacct 1500 gctcagccca cagggaaccc agactggttg gaggggacat tccctgttct ggacgtgttg 1560 aagtgaagca tggtgacacg tggggctcca tctgtgattc ggacttctct ctggaagctg 1620 ccagcgttct atgcagggaa ttacagtgtg gcacagttgt ctctatcctg gggggagctc 1680 actttggaga gggaaatgga cagatctggg ctgaagaatt ccagtgtgag ggacatgagt 1740 cccatctttc actctgccca gtagcacccc gcccagaagg aacttgtagc cacagcaggg 1800 atgttggagt agtctgctca agatacacag aaattcgctt ggtgaatggc aagaccccgt 1860 gtgagggcag agtggagctc aaaacgcttg gtgcctgggg atccctctgt aactctcact 1920 gggacataga agatgcccat gttctttgcc agcagcttaa atgtggagtt gccctttcta 1980 ccccaggagg agcacgtttt ggaaaaggaa atggtcagat ctggaggcat atgtttcact 2040 gcactgggac tgagcagcac atgggagatt gtcctgtaac tgctctaggt gcttcattat 2100 gtccttcaga gcaagtggcc tctgtaatct gctcaggaaa ccagtcccaa acactgtcct 2160 cgtgcaattc atcgtctttg ggcccaacaa ggcctaccat tccagaagaa agtgctgtgg 2220 cctgcataga gagtggtcaa cttcgcctgg taaatggagg aggtcgctgt gctgggagag 2280 tagagatcta tcatgagggc tcctggggca ccatctgtga tgacagctgg gacctgagtg 2340 atgcccacgt ggtttgcaga cagctgggct gtggagaggc cattaatgcc actggttctg 2400 ctcattttgg ggaaggaaca gggcccatct ggctggatga gatgaaatgc aatggaaaag 2460 aatcccgcat ttggcagtgc cattcacacg gctgggggca gcaaaattgc aggcacaagg 2520 aggatgcggg agttatctgc tcagaattca tgtctctgag actgaccagt gaagccagca 2580 gagaggcctg tgcagggcgt ctggaagttt tttacaatgg agcttggggc actgttggca 2640 agagtagcat gtctgaaacc actgtgggtg tggtgtgcag gcagctgggc tgtgcagaca 2700 aagggaaaat caaccctgca tctttagaca aggccatgtc cattcccatg tgggtggaca 2760 atgttcagtg tccaaaagga cctgacacgc tgtggcagtg cccatcatct ccatgggaga 2820 agagactggc cagcccctcg gaggagacct ggatcacatg tgacaacaag ataagacttc 2880 aggaaggacc cacttcctgt tctggacgtg tggagatctg gcatggaggt tcctggggga 2940 cagtgtgtga tgactcttgg gacttggacg atgctcaggt ggtgtgtcaa caacttggct 3000 gtggtccagc tttgaaagca ttcaaagaag cagagtttgg tcaggggact ggacccgata 3060 tggctcaatg aagtgaagtg caaagggaat gagtcttcct tgtgggattg tcctgccaga 3120 cgctggggcc atagtgagtg tgggcacaag gaagacgctg cagtgaattg cacagatatt 3180 tcagtgcaga aaaccccaca aaaagccaca acaggtcgct catcccgtca gtcatccttt 3240 attgcagtcg ggatccttgg ggttgttctg ttggccattt tcgtcgcatt attcttcttg 3300 actaaaaagc gaagacagag acagcggctt gcagtttcct caagaggaga gaacttagtc 3360 caccaaattc aataccggga gatgaattct tgcctgaatg cagatgatct ggacctaatg 3420 aattcctcag gtctgtgggt tcttggaggg tctattgccc aggggttcag atcagtggct 3480 gcagttgagg cacagacatt ctactttgat aaacagttaa aaaagtctaa aaatgtaata 3540 ggaagcttag atgcatataa tggacaagaa tgactgaaaa ttattcttgg agaatatcaa 3600 aattgcaatc atagggaggc ctttagctta agaggcctgt gattattcct gatagaggta 3660 tggaaagaac catgcagagg aatattatga cttggacctc attttattaa aacagaaatt 3720 aatcttacaa aagattgtca taagtgacag tttaactttt ttctttaaat tttgttgtgt 3780 atatttaagg tatacaacat gattttatgg gatgtatata gatagtaaaa agcttactaa 3840 agcaaagcaa atgaacacac ccatcatctg acatagttac ccttttttgt gttgttcttg 3900 tggcaagagc agctaaaacc tactcactta gcatgaatcc tacatacagc acaatgttat 3960 tacctataat cctcatgttg tacattagac ctctagactg gttcattcta cgtatctgct 4020 actttgtatc ctctgaccta catacgtctt tcacagtttc ttccattccc atttcctgtc 4080 attttttttc tctagcttga tatttattat atttttccct aaaagtctaa aaccttaaac 4140 tttcaatatc tttattgcat gagaagccat acaaatccac agaactagcc ttatttctca 4200 tcacatcatg ctgttttatc cttgaacttc tatttagcac cagtgcacta attctgcatc 4260 tgggcaggat gactttactg ggttggaaga aatatcccaa aacccattgt ctttactcca 4320 tgaagggtcc ctgaccttct gagaggggcc tgcctcactt cttccatcca aagaattatg 4380 catctgctac tgtgtcaggg aacatattta aggaacatgt actgttactg tgtcaggaaa 4440 catatttaag aaataggaaa gactttctct gccccttaaa tcacacatgc ttttcttcct 4500 agttatgggt ggtgttttta gttgctcaaa gagcctcaca gttacgtgag aagaggtctg 4560 gtttatttcc cagtaattat tttcttcctt tcagaaaatt cccatgagtc agctgatttc 4620 agtgctgctg aactaatttc tgtgtctaaa tttcttccta tttctggaat ggaaaaggag 4680 gccattctga gccacactga aaaggaaaat gggaatttat aacccagtga gttcagcctt 4740 taagatacct tgatgaagac ctggactatt gaatggagca gaaattcacc tctctcactg 4800 actattacag ttgcattttt atggagttct tcttctccta ggattcctaa gactgctgct 4860 gaatttataa aaattaagtt tgtgaatgtg actacttagt ggtgtatatg agactttcaa 4920 gggaattaaa taaataaata agaatgttat tgatttgagt ttgctttaat tacttgtcct 4980 taattctatt aatttctaaa cgggcttcct aattttttgt agagtttcct agatgtatta 5040 taatgtgttt tatttgacag tgtttcaatt tgcatataca gtactgtata ttttttctta 5100 tttggtttga ataattttcc tattaccaaa taaaaataaa tttattttta ctttagtttt 5160 tctaagacag gaaaagttaa tgatattgaa gggtctgtaa ataatatatg gctaacttta 5220 taaggcatga ctcacaacga ttctttaact gctttttgtt actgtaattc tgttcactag 5280 aataaaatgc agagccacac ctggtgaggg cac 5313 2 4066 DNA Homo sapien 2 gaattcttag ttgttttctt tagaagaaca tttctaggga ataatacaag aagatttagg 60 aatcattgaa gttataaatc tttggaatga gcaaactcag aatggtgcta cttgaagact 120 ctggatctgc tgacttcaga agacattttg tcaacctgag tcccttcacc attactgtgg 180 tcttacttct cagtgcctgt tttgtcacca gttctcttgg aggaacagac aaggagctga 240 ggctagtgga tggtgaaaac aagtgtagcg ggagagtgga agtgaaagtc caggaggagt 300 ggggaacggt gtgtaataat ggctggagca tggaagcggt ctctgtgatt tgtaaccagc 360 tgggatgtcc aactgctatc aaagcccctg gatgggctaa ttccagtgca ggttctggac 420 gcatttggat ggatcatgtt tcttgtcgtg ggaatgagtc agctctttgg gattgcaaac 480 atgatggatg gggaaagcat agtaactgta ctcaccaaca agatgctgga gtgacctgct 540 cagatggatc caatttggaa atgaggctga cgcgtggagg gaatatgtgt tctggaagaa 600 tagagatcaa attccaagga cggtggggaa cagtgtgtga tgataacttc aacatagatc 660 atgcatctgt catttgtaga caacttgaat gtggaagtgc tgtcagtttc tctggttcat 720 ctaattttgg agaaggctct ggaccaatct ggtttgatga tcttatatgc aacggaaatg 780 agtcagctct ctggaactgc aaacatcaag gatggggaaa gcataactgt gatcatgctg 840 aggatgctgg agtgatttgc tcaaagggag cagatctgag cctgagactg gtagatggag 900 tcactgaatg ttcaggaaga ttagaagtga gattccaagg ggaatggggg acaatatgtg 960 atgacggctg ggacagttac gatgctgctg tggcatgcaa gcaactggga tgtccaactg 1020 ccgtcacagc cattggtcga gttaacgcca gtaagggatt tggacacatc tggcttgaca 1080 gcgtttcttg ccagggacat gaacctgctg tctggcaatg taaacaccat gaatggggaa 1140 agcattattg caatcacaat gaagatgctg gcgtgacatg ttctgatgga tcagatctgg 1200 agctaagact tagaggtgga ggcagccgct gtgctgggac agttgaggtg gagattcaga 1260 gactgttagg gaaggtgtgt gacagaggct ggggactgaa agaagctgat gtggtttgca 1320 ggcagctggg atgtggatct gcactcaaaa catcttatca agtgtactcc aaaatccagg 1380 caacaaacac atggctgttt ctaagtagct gtaacggaaa tgaaacttct ctttgggact 1440 gcaagaactg gcaatggggt ggacttacct gtgatcacta tgaagaagcc aaaattacct 1500 gctcagccca cagggaaccc agactggttg gaggggacat tccctgttct ggacgtgttg 1560 aagtgaagca tggtgacacg tggggctcca tctgtgattc ggacttctct ctggaagctg 1620 ccagcgttct atgcagggaa ttacagtgtg gcacagttgt ctctatcctg gggggagctc 1680 actttggaga gggaaatgga cagatctggg ctgaagaatt ccagtgtgag ggacatgagt 1740 cccatctttc actctgccca gtagcacccc gcccagaagg aacttgtagc cacagcaggg 1800 atgttggagt agtctgctca agatacacag aaattcgctt ggtgaatggc aagaccccgt 1860 gtgagggcag agtggagctc aaaacgcttg gtgcctgggg atccctctgt aactctcact 1920 gggacataga agatgcccat gttctttgcc agcagcttaa atgtggagtt gccctttcta 1980 ccccaggagg agcacgtttt ggaaaaggaa atggtcagat ctggaggcat atgtttcact 2040 gcactgggac tgagcagcac atgggagatt gtcctgtaac tgctctaggt gcttcattat 2100 gtccttcaga gcaagtggcc tctgtaatct gctcaggaaa ccagtcccaa acactgtcct 2160 cgtgcaattc atcgtctttg ggcccaacaa ggcctaccat tccagaagaa agtgctgtgg 2220 cctgcataga gagtggtcaa cttcgcctgg taaatggagg aggtcgctgt gctgggagag 2280 tagagatcta tcatgagggc tcctggggca ccatctgtga tgacagctgg gacctgagtg 2340 atgcccacgt ggtttgcaga cagctgggct gtggagaggc cattaatgcc actggttctg 2400 ctcattttgg ggaaggaaca gggcccatct ggctggatga gatgaaatgc aatggaaaag 2460 aatcccgcat ttggcagtgc cattcacacg gctgggggca gcaaaattgc aggcacaagg 2520 aggatgcggg agttatctgc tcagaattca tgtctctgag actgaccagt gaagccagca 2580 gagaggcctg tgcagggcgt ctggaagttt tttacaatgg agcttggggc actgttggca 2640 agagtagcat gtctgaaacc actgtgggtg tggtgtgcag gcagctgggc tgtgcagaca 2700 aagggaaaat caaccctgca tctttagaca aggccatgtc cattcccatg tgggtggaca 2760 atgttcagtg tccaaaagga cctgacacgc tgtggcagtg cccatcatct ccatgggaga 2820 agagactggc cagcccctcg gaggagacct ggatcacatg tgacaacaag ataagacttc 2880 aggaaggacc cacttcctgt tctggacgtg tggagatctg gcatggaggt tcctggggga 2940 cagtgtgtga tgactcttgg gacttggacg atgctcaggt ggtgtgtcaa caacttggct 3000 gtggtccagc tttgaaagca ttcaaagaag cagagtttgg tcaggggact ggacccgata 3060 tggctcaatg aagtgaagtg caaagggaat gagtcttcct tgtgggattg tcctgccaga 3120 cgctggggcc atagtgagtg tgggcacaag gaagacgctg cagtgaattg cacagatatt 3180 tcagtgcaga aaaccccaca aaaagccaca acaggtcgct catcccgtca gtcatccttt 3240 attgcagtcg ggatccttgg ggttgttctg ttggccattt tcgtcgcatt attcttcttg 3300 actaaaaagc gaagacagag acagcggctt gcagtttcct caagaggaga gaacttagtc 3360 caccaaattc aataccggga gatgaattct tgcctgaatg cagatgatct ggacctaatg 3420 aattcctcag gaggccattc tgagccacac tgaaaaggaa aatgggaatt tataacccag 3480 tgagttcagc ctttaagata ccttgatgaa gacctggact attgaatgga gcagaaattc 3540 acctctctca ctgactatta cagttgcatt tttatggagt tcttcttctc ctaggattcc 3600 taagactgct gctgaattta taaaaattaa gtttgtgaat gtgactactt agtggtgtat 3660 atgagacttt caagggaatt aaataaataa ataagaatgt tattgatttg agtttgcttt 3720 aattacttgt ccttaattct attaatttct aaacgggctt cctaattttt tgtagagttt 3780 cctagatgta ttataatgtg ttttatttga cagtgtttca atttgcatat acagtactgt 3840 atattttttc ttatttggtt tgaataattt tcctattacc aaataaaaat aaatttattt 3900 ttactttagt ttttctaaga caggaaaagt taatgatatt gaagggtctg taaataatat 3960 atggctaact ttataaggca tgactcacaa cgattcttta actgcttttt gttactgtaa 4020 ttctgttcac tagaataaaa tgcagagcca cacctggtga gggcac 4066 3 4248 DNA Homo sapien 3 gaattcttag ttgttttctt tagaagaaca tttctaggga ataatacaag aagatttagg 60 aatcattgaa gttataaatc tttggaatga gcaaactcag aatggtgcta cttgaagact 120 ctggatctgc tgacttcaga agacattttg tcaacctgag tcccttcacc attactgtgg 180 tcttacttct cagtgcctgt tttgtcacca gttctcttgg aggaacagac aaggagctga 240 ggctagtgga tggtgaaaac aagtgtagcg ggagagtgga agtgaaagtc caggaggagt 300 ggggaacggt gtgtaataat ggctggagca tggaagcggt ctctgtgatt tgtaaccagc 360 tgggatgtcc aactgctatc aaagcccctg gatgggctaa ttccagtgca ggttctggac 420 gcatttggat ggatcatgtt tcttgtcgtg ggaatgagtc agctctttgg gattgcaaac 480 atgatggatg gggaaagcat agtaactgta ctcaccaaca agatgctgga gtgacctgct 540 cagatggatc caatttggaa atgaggctga cgcgtggagg gaatatgtgt tctggaagaa 600 tagagatcaa attccaagga cggtggggaa cagtgtgtga tgataacttc aacatagatc 660 atgcatctgt catttgtaga caacttgaat gtggaagtgc tgtcagtttc tctggttcat 720 ctaattttgg agaaggctct ggaccaatct ggtttgatga tcttatatgc aacggaaatg 780 agtcagctct ctggaactgc aaacatcaag gatggggaaa gcataactgt gatcatgctg 840 aggatgctgg agtgatttgc tcaaagggag cagatctgag cctgagactg gtagatggag 900 tcactgaatg ttcaggaaga ttagaagtga gattccaagg ggaatggggg acaatatgtg 960 atgacggctg ggacagttac gatgctgctg tggcatgcaa gcaactggga tgtccaactg 1020 ccgtcacagc cattggtcga gttaacgcca gtaagggatt tggacacatc tggcttgaca 1080 gcgtttcttg ccagggacat gaacctgctg tctggcaatg taaacaccat gaatggggaa 1140 agcattattg caatcacaat gaagatgctg gcgtgacatg ttctgatgga tcagatctgg 1200 agctaagact tagaggtgga ggcagccgct gtgctgggac agttgaggtg gagattcaga 1260 gactgttagg gaaggtgtgt gacagaggct ggggactgaa agaagctgat gtggtttgca 1320 ggcagctggg atgtggatct gcactcaaaa catcttatca agtgtactcc aaaatccagg 1380 caacaaacac atggctgttt ctaagtagct gtaacggaaa tgaaacttct ctttgggact 1440 gcaagaactg gcaatggggt ggacttacct gtgatcacta tgaagaagcc aaaattacct 1500 gctcagccca cagggaaccc agactggttg gaggggacat tccctgttct ggacgtgttg 1560 aagtgaagca tggtgacacg tggggctcca tctgtgattc ggacttctct ctggaagctg 1620 ccagcgttct atgcagggaa ttacagtgtg gcacagttgt ctctatcctg gggggagctc 1680 actttggaga gggaaatgga cagatctggg ctgaagaatt ccagtgtgag ggacatgagt 1740 cccatctttc actctgccca gtagcacccc gcccagaagg aacttgtagc cacagcaggg 1800 atgttggagt agtctgctca agtaagaccc agaaaacatc tttaattggt tctcatactg 1860 tgaaagggac agggttaggg agtcatagct gtctttttct aaagccctgt ctccttccag 1920 gatacacaga aattcgcttg gtgaatggca agaccccgtg tgagggcaga gtggagctca 1980 aaacgcttgg tgcctgggga tccctctgta actctcactg ggacatagaa gatgcccatg 2040 ttctttgcca gcagcttaaa tgtggagttg ccctttctac cccaggagga gcacgttttg 2100 gaaaaggaaa tggtcagatc tggaggcata tgtttcactg cactgggact gagcagcaca 2160 tgggagattg tcctgtaact gctctaggtg cttcattatg tccttcagag caagtggcct 2220 ctgtaatctg ctcaggaaac cagtcccaaa cactgtcctc gtgcaattca tcgtctttgg 2280 gcccaacaag gcctaccatt ccagaagaaa gtgctgtggc ctgcatagag agtggtcaac 2340 ttcgcctggt aaatggagga ggtcgctgtg ctgggagagt agagatctat catgagggct 2400 cctggggcac catctgtgat gacagctggg acctgagtga tgcccacgtg gtttgcagac 2460 agctgggctg tggagaggcc attaatgcca ctggttctgc tcattttggg gaaggaacag 2520 ggcccatctg gctggatgag atgaaatgca atggaaaaga atcccgcatt tggcagtgcc 2580 attcacacgg ctgggggcag caaaattgca ggcacaagga ggatgcggga gttatctgct 2640 cagaattcat gtctctgaga ctgaccagtg aagccagcag agaggcctgt gcagggcgtc 2700 tggaagtttt ttacaatgga gcttggggca ctgttggcaa gagtagcatg tctgaaacca 2760 ctgtgggtgt ggtgtgcagg cagctgggct gtgcagacaa agggaaaatc aaccctgcat 2820 ctttagacaa ggccatgtcc attcccatgt gggtggacaa tgttcagtgt ccaaaaggac 2880 ctgacacgct gtggcagtgc ccatcatctc catgggagaa gagactggcc agcccctcgg 2940 aggagacctg gatcacatgt gacaacaaga taagacttca ggaaggaccc acttcctgtt 3000 ctggacgtgt ggagatctgg catggaggtt cctgggggac agtgtgtgat gactcttggg 3060 acttggacga tgctcaggtg gtgtgtcaac aacttggctg tggtccagct ttgaaagcat 3120 tcaaagaagc agagtttggt caggggactg gacccgatat ggctcaatga agtgaagtgc 3180 aaagggaatg agtcttcctt gtgggattgt cctgccagac gctggggcca tagtgagtgt 3240 gggcacaagg aagacgctgc agtgaattgc acagatattt cagtgcagaa aaccccacaa 3300 aaagccacaa caggtcgctc atcccgtcag tcatccttta ttgcagtcgg gatccttggg 3360 gttgttctgt tggccatttt cgtcgcatta ttcttcttga ctaaaaagcg aagacagaga 3420 cagcggcttg cagtttcctc aagaggagag aacttagtcc accaaattca ataccgggag 3480 atgaattctt gcctgaatgc agatgatctg gacctaatga attcctcaga aaattcccat 3540 gagtcagctg atttcagtgc tgctgaacta atttctgtgt ctaaatttct tcctatttct 3600 ggaatggaaa aggaggccat tctgagccac actgaaaagg aaaatgggaa tttataaccc 3660 agtgagttca gcctttaaga taccttgatg aagacctgga ctattgaatg gagcagaaat 3720 tcacctctct cactgactat tacagttgca tttttatgga gttcttcttc tcctaggatt 3780 cctaagactg ctgctgaatt tataaaaatt aagtttgtga atgtgactac ttagtggtgt 3840 atatgagact ttcaagggaa ttaaataaat aaataagaat gttattgatt tgagtttgct 3900 ttaattactt gtccttaatt ctattaattt ctaaacgggc ttcctaattt tttgtagagt 3960 ttcctagatg tattataatg tgttttattt gacagtgttt caatttgcat atacagtact 4020 gtatattttt tcttatttgg tttgaataat tttcctatta ccaaataaaa ataaatttat 4080 ttttacttta gtttttctaa gacaggaaaa gttaatgata ttgaagggtc tgtaaataat 4140 atatggctaa ctttataagg catgactcac aacgattctt taactgcttt ttgttactgt 4200 aattctgttc actagaataa aatgcagagc cacacctggt gagggcac 4248 4 4149 DNA Homo sapien 4 gaattcttag ttgttttctt tagaagaaca tttctaggga ataatacaag aagatttagg 60 aatcattgaa gttataaatc tttggaatga gcaaactcag aatggtgcta cttgaagact 120 ctggatctgc tgacttcaga agacattttg tcaacctgag tcccttcacc attactgtgg 180 tcttacttct cagtgcctgt tttgtcacca gttctcttgg aggaacagac aaggagctga 240 ggctagtgga tggtgaaaac aagtgtagcg ggagagtgga agtgaaagtc caggaggagt 300 ggggaacggt gtgtaataat ggctggagca tggaagcggt ctctgtgatt tgtaaccagc 360 tgggatgtcc aactgctatc aaagcccctg gatgggctaa ttccagtgca ggttctggac 420 gcatttggat ggatcatgtt tcttgtcgtg ggaatgagtc agctctttgg gattgcaaac 480 atgatggatg gggaaagcat agtaactgta ctcaccaaca agatgctgga gtgacctgct 540 cagatggatc caatttggaa atgaggctga cgcgtggagg gaatatgtgt tctggaagaa 600 tagagatcaa attccaagga cggtggggaa cagtgtgtga tgataacttc aacatagatc 660 atgcatctgt catttgtaga caacttgaat gtggaagtgc tgtcagtttc tctggttcat 720 ctaattttgg agaaggctct ggaccaatct ggtttgatga tcttatatgc aacggaaatg 780 agtcagctct ctggaactgc aaacatcaag gatggggaaa gcataactgt gatcatgctg 840 aggatgctgg agtgatttgc tcaaagggag cagatctgag cctgagactg gtagatggag 900 tcactgaatg ttcaggaaga ttagaagtga gattccaagg ggaatggggg acaatatgtg 960 atgacggctg ggacagttac gatgctgctg tggcatgcaa gcaactggga tgtccaactg 1020 ccgtcacagc cattggtcga gttaacgcca gtaagggatt tggacacatc tggcttgaca 1080 gcgtttcttg ccagggacat gaacctgctg tctggcaatg taaacaccat gaatggggaa 1140 agcattattg caatcacaat gaagatgctg gcgtgacatg ttctgatgga tcagatctgg 1200 agctaagact tagaggtgga ggcagccgct gtgctgggac agttgaggtg gagattcaga 1260 gactgttagg gaaggtgtgt

gacagaggct ggggactgaa agaagctgat gtggtttgca 1320 ggcagctggg atgtggatct gcactcaaaa catcttatca agtgtactcc aaaatccagg 1380 caacaaacac atggctgttt ctaagtagct gtaacggaaa tgaaacttct ctttgggact 1440 gcaagaactg gcaatggggt ggacttacct gtgatcacta tgaagaagcc aaaattacct 1500 gctcagccca cagggaaccc agactggttg gaggggacat tccctgttct ggacgtgttg 1560 aagtgaagca tggtgacacg tggggctcca tctgtgattc ggacttctct ctggaagctg 1620 ccagcgttct atgcagggaa ttacagtgtg gcacagttgt ctctatcctg gggggagctc 1680 actttggaga gggaaatgga cagatctggg ctgaagaatt ccagtgtgag ggacatgagt 1740 cccatctttc actctgccca gtagcacccc gcccagaagg aacttgtagc cacagcaggg 1800 atgttggagt agtctgctca agatacacag aaattcgctt ggtgaatggc aagaccccgt 1860 gtgagggcag agtggagctc aaaacgcttg gtgcctgggg atccctctgt aactctcact 1920 gggacataga agatgcccat gttctttgcc agcagcttaa atgtggagtt gccctttcta 1980 ccccaggagg agcacgtttt ggaaaaggaa atggtcagat ctggaggcat atgtttcact 2040 gcactgggac tgagcagcac atgggagatt gtcctgtaac tgctctaggt gcttcattat 2100 gtccttcaga gcaagtggcc tctgtaatct gctcaggaaa ccagtcccaa acactgtcct 2160 cgtgcaattc atcgtctttg ggcccaacaa ggcctaccat tccagaagaa agtgctgtgg 2220 cctgcataga gagtggtcaa cttcgcctgg taaatggagg aggtcgctgt gctgggagag 2280 tagagatcta tcatgagggc tcctggggca ccatctgtga tgacagctgg gacctgagtg 2340 atgcccacgt ggtttgcaga cagctgggct gtggagaggc cattaatgcc actggttctg 2400 ctcattttgg ggaaggaaca gggcccatct ggctggatga gatgaaatgc aatggaaaag 2460 aatcccgcat ttggcagtgc cattcacacg gctgggggca gcaaaattgc aggcacaagg 2520 aggatgcggg agttatctgc tcagaattca tgtctctgag actgaccagt gaagccagca 2580 gagaggcctg tgcagggcgt ctggaagttt tttacaatgg agcttggggc actgttggca 2640 agagtagcat gtctgaaacc actgtgggtg tggtgtgcag gcagctgggc tgtgcagaca 2700 aagggaaaat caaccctgca tctttagaca aggccatgtc cattcccatg tgggtggaca 2760 atgttcagtg tccaaaagga cctgacacgc tgtggcagtg cccatcatct ccatgggaga 2820 agagactggc cagcccctcg gaggagacct ggatcacatg tgacaacaag ataagacttc 2880 aggaaggacc cacttcctgt tctggacgtg tggagatctg gcatggaggt tcctggggga 2940 cagtgtgtga tgactcttgg gacttggacg atgctcaggt ggtgtgtcaa caacttggct 3000 gtggtccagc tttgaaagca ttcaaagaag cagagtttgg tcaggggact ggacccgata 3060 tggctcaatg aagtgaagtg caaagggaat gagtcttcct tgtgggattg tcctgccaga 3120 cgctggggcc atagtgagtg tgggcacaag gaagacgctg cagtgaattg cacagatatt 3180 tcagtgcaga aaaccccaca aaaagccaca acaggtcgct catcccgtca gtcatccttt 3240 attgcagtcg ggatccttgg ggttgttctg ttggccattt tcgtcgcatt attcttcttg 3300 actaaaaagc gaagacagag acagcggctt gcagtttcct caagaggaga gaacttagtc 3360 caccaaattc aataccggga gatgaattct tgcctgaatg cagatgatct ggacctaatg 3420 aattcctcag aaaattccca tgagtcagct gatttcagtg ctgctgaact aatttctgtg 3480 tctaaatttc ttcctatttc tggaatggaa aaggaggcca ttctgagcca cactgaaaag 3540 gaaaatggga atttataacc cagtgagttc agcctttaag ataccttgat gaagacctgg 3600 actattgaat ggagcagaaa ttcacctctc tcactgacta ttacagttgc atttttatgg 3660 agttcttctt ctcctaggat tcctaagact gctgctgaat ttataaaaat taagtttgtg 3720 aatgtgacta cttagtggtg tatatgagac tttcaaggga attaaataaa taaataagaa 3780 tgttattgat ttgagtttgc tttaattact tgtccttaat tctattaatt tctaaacggg 3840 cttcctaatt ttttgtagag tttcctagat gtattataat gtgttttatt tgacagtgtt 3900 tcaatttgca tatacagtac tgtatatttt ttcttatttg gtttgaataa ttttcctatt 3960 accaaataaa aataaattta tttttacttt agtttttcta agacaggaaa agttaatgat 4020 attgaagggt ctgtaaataa tatatggcta actttataag gcatgactca caacgattct 4080 ttaactgctt tttgttactg taattctgtt cactagaata aaatgcagag ccacacctgg 4140 tgagggcac 4149 5 3618 DNA Homo sapien 5 gacgcgcgag catcggcggc ccggaaccgg ccttggaaca actgtggaac ctgaggccgc 60 ttgccctccc gccccatgga gcggcccccg gggctgcggc cgggcgcggg cgggccctgg 120 gagatgcggg agcggctggg caccggcggc ttcgggaacg tctgtctgta ccagcatcgg 180 gaacttgatc tcaaaatagc aattaagtct tgtcgcctag agctaagtac caaaaacaga 240 gaacgatggt gccatgaaat ccagattatg aagaagttga accatgccaa tgttgtaaag 300 gcctgtgatg ttcctgaaga attgaatatt ttgattcatg atgtgcctct tctagcaatg 360 gaatactgtt ctggaggaga tctccgaaag ctgctcaaca aaccagaaaa ttgttgtgga 420 cttaaagaaa gccagatact ttctttacta agtgatatag ggtctgggat tcgatatttg 480 catgaaaaca aaattataca tcgagatcta aaacctgaaa acatagttct tcaggatgtt 540 ggtggaaaga taatacataa aataattgat ctgggatatg ccaaagatgt tgatcaagga 600 agtctgtgta catcttttgt gggaacactg cagtatctgg ccccagagct ctttgagaat 660 aagccttaca cagccactgt tgattattgg agctttggga ccatggtatt tgaatgtatt 720 gctggatata ggcctttttt gcatcatctg cagccattta cctggcatga gaagattaag 780 aagaaggatc caaagtgtat atttgcatgt gaagagatgt caggagaagt tcggtttagt 840 agccatttac ctcaaccaaa tagcctttgt agtttagtag tagaacccat ggaaaactgg 900 ctacagttga tgttgaattg ggaccctcag cagagaggag gacctgttga ccttactttg 960 aagcagccaa gatgttttgt attaatggat cacattttga atttgaagat agtacacatc 1020 ctaaatatga cttctgcaaa gataatttct tttctgttac cacctgatga aagtcttcat 1080 tcactacagt ctcgtattga gcgtgaaact ggaataaata ctggttctca agaacttctt 1140 tcagagacag gaatttctct ggatcctcgg aaaccagcct ctcaatgtgt tctagatgga 1200 gttagaggct gtgatagcta tatggtttat ttgtttgata aaagtaaaac tgtatatgaa 1260 gggccatttg cttccagaag tttatctgat tgtgtaaatt atattgtaca ggacagcaaa 1320 atacagcttc caattataca gctgcgtaaa gtgtgggctg aagcagtgca ctatgtgtct 1380 ggactaaaag aagactatag caggctcttt cagggacaaa gggcagcaat gttaagtctt 1440 cttagatata atgctaactt aacaaaaatg aagaacactt tgatctcagc atcacaacaa 1500 ctgaaagcta aattggagtt ttttcacaaa agcattcagc ttgacttgga gagatacagc 1560 gagcagatga cgtatgggat atcttcagaa aaaatgctaa aagcatggaa agaaatggaa 1620 gaaaaggcca tccactatgc tgaggttggt gtcattggat acctggagga tcagattatg 1680 tctttgcatg ctgaaatcat ggagctacag aagagcccct atggaagacg tcagggagac 1740 ttgatggaat ctctggaaca gcgtgccatt gatctatata agcagttaaa acacagacct 1800 tcagatcact cctacagtga cagcacagag atggtgaaaa tcattgtgca cactgtgcag 1860 agtcaggacc gtgtgctcaa ggagctgttt ggtcatttga gcaagttgtt gggctgtaag 1920 cagaagatta ttgatctact ccctaaggtg gaagtggccc tcagtaatat caaagaagct 1980 gacaatactg tcatgttcat gcagggaaaa aggcagaaag aaatatggca tctccttaaa 2040 attgcctgta cacagagttc tgcccggtcc cttgtaggat ccagtctaga aggtgcagta 2100 acccctcaga catcagcatg gctgcccccg acttcagcag aacatgatca ttctctgtca 2160 tgtgtggtaa ctcctcaaga tggggagact tcagcacaaa tgatagaaga aaatttgaac 2220 tgccttggcc atttaagcac tattattcat gaggcaaatg aggaacaggg caatagtatg 2280 atgaatcttg attggagttg gttaacagaa tgagttgtca cttgttcact gtccccaaac 2340 ctatggaagt tgttgctata catgttggaa atgtgttttt cccccatgaa accattcttc 2400 agacatcagt caatggaaga aatggctatg aacagaaact acatttctac tatgatcaga 2460 agaacatgat tttacaagta taacagtttt gagtaattca agcctctaaa cagacaggaa 2520 tttagaaaaa gtcaatgtac ttgtttgaat atttgtttta ataccacagc tatttagaag 2580 catcatcacg acacatttgc cttcagtctt ggtaaaacat tacttattta actgattaaa 2640 aataccttct atgtattagt gtcaactttt aacttttggg cgtaagacca aatgtagttt 2700 tgtatacaga gaagaaaacc tcaagtaata ggcattttaa gtaaaagtct acctgtgttt 2760 ttttctaaaa aggctgctca caagttctat ttcttgaaga ataaattcta cctccttgtg 2820 ttgcactgaa caggttctct tcctggcatc ataaggagtt ggtgtaatca ttttaaattc 2880 cactgaaaat ttaacagtat ccccttctca tcgaagggat tgtgtatctg tgcttctaat 2940 attagttggc tttcataaat catgttgttg tgtgtatatg tatttaagat gtacatttaa 3000 taatatcaaa gagaagatgc ctgttaattt ataatgtatt tgaaaattac atgttttttc 3060 atttgtaaaa atgagtcatt tgtttaaaca atctttcatg tcttgtcata caaatttata 3120 aaggtctgca ctcctttatc tgtaattgta attccaaaat ccaaaaagct ctgaaaacaa 3180 ggtttccata agcttggtga caaaattcat ttgcttgcaa tctaatctga actgaccttg 3240 aatcttttta tcccatttag tgtgaatatt cctttatttt gctgcttgat gatgagaggg 3300 agggctgctg ccacagactg tggtgagggc tggttaatgt agtatggtat atgcacaaaa 3360 ctacttttct aaaatctaaa atttcataat tctgaaacaa cttgccccaa gggtttcaga 3420 gaaaggactg tggacctcta tcatctgcta agtaatttag aagatattat ttgtcttaaa 3480 aaatgtgaaa tgcttttata ttctaatagt ttttcacttt gtgtattaaa tggtttttaa 3540 attactttct tgatctctat tcattataaa aatcagatta taataaaaca gttgaatatg 3600 gcttaggaaa atatgaag 3618 6 2585 DNA Homo sapien 6 gacatgcccc gcggcgcgcc attaaccgcc agatttgaat cgcgggaccc gttggcagag 60 gtggcggcgg cggcatgggt gccccgacgt tgccccctgc ctggcagccc tttctcaagg 120 accaccgcat ctctacattc aagaactggc ccttcttgga gggctgcgcc tgcaccccgg 180 agcggatggc cgaggctggc ttcatccact gccccactga gaacgagcca gacttggccc 240 agtgtttctt ctgcttcaag gagctggaag gctgggagcc agatgacgac cccatagagg 300 aacataaaaa gcattcgtcc ggttgcgctt tcctttctgt caagaagcag tttgaagaat 360 taacccttgg tgaatttttg aaactggaca gagaaagagc caagaacaaa attgcaaagg 420 aaaccaacaa taagaagaaa gaatttgagg aaactgcgaa gaaagtgcgc cgtgccatcg 480 agcagctggc tgccatggat tgaggcctct ggccggagct gcctggtccc agagtggctg 540 caccacttcc agggtttatt ccctggtgcc accagccttc ctgtgggccc cttagcaatg 600 tcttaggaaa ggagatcaac attttcaaat tagatgtttc aactgtgctc ttgttttgtc 660 ttgaaagtgg caccagaggt gcttctgcct gtgcagcggg tgctgctggt aacagtggct 720 gcttctctct ctctctctct tttttggggg ctcatttttg ctgttttgat tcccgggctt 780 accaggtgag aagtgaggga ggaagaaggc agtgtccctt ttgctagagc tgacagcttt 840 gttcgcgtgg gcagagcctt ccacagtgaa tgtgtctgga cctcatgttg ttgaggctgt 900 cacagtcctg agtgtggact tggcaggtgc ctgttgaatc tgagctgcag gttccttatc 960 tgtcacacct gtgcctcctc agaggacagt ttttttgttg ttgtgttttt ttgttttttt 1020 ttttttggta gatgcatgac ttgtgtgtga tgagagaatg gagacagagt ccctggctcc 1080 tctactgttt aacaacatgg ctttcttatt ttgtttgaat tgttaattca cagaatagca 1140 caaactacaa ttaaaactaa gcacaaagcc attctaagtc attggggaaa cggggtgaac 1200 ttcaggtgga tgaggagaca gaatagagtg ataggaagcg tctggcagat actccttttg 1260 ccactgctgt gtgattagac aggcccagtg agccgcgggg cacatgctgg ccgctcctcc 1320 ctcagaaaaa ggcagtggcc taaatccttt ttaaatgact tggctcgatg ctgtggggga 1380 ctggctgggc tgctgcaggc cgtgtgtctg tcagcccaac cttcacatct gtcacgttct 1440 ccacacgggg gagagacgca gtccgcccag gtccccgctt tctttggagg cagcagctcc 1500 cgcagggctg aagtctggcg taagatgatg gatttgattc gccctcctcc ctgtcataga 1560 gctgcagggt ggattgttac agcttcgctg gaaacctctg gaggtcatct cggctgttcc 1620 tgagaaataa aaagcctgtc atttcaaaca ctgctgtgga ccctactggg tttttaaaat 1680 attgtcagtt tttcatcgtc gtccctagcc tgccaacagc catctgccca gacagccgca 1740 gtgaggatga gcgtcctggc agagacgcag ttgtctctgg gcgcttgcca gagccacgaa 1800 ccccagacct gtttgtatca tccgggctcc ttccgggcag aaacaactga aaatgcactt 1860 cagacccact tatttctgcc acatctgagt cggcctgaga tagacttttc cctctaaact 1920 gggagaatat cacagtggtt tttgttagca gaaaatgcac tccagcctct gtactcatct 1980 aagctgctta tttttgatat ttgtgtcagt ctgtaaatgg atacttcact ttaataactg 2040 ttgcttagta attggctttg tagagaagct ggaaaaaaat ggttttgtct tcaactcctt 2100 tgcatgccag gcggtgatgt ggatctcggc ttctgtgagc ctgtgctgtg ggcagggctg 2160 agctggagcc gcccctctca gcccgcctgc cacggccttt ccttaaaggc catccttaaa 2220 accagaccct catggctacc agcacctgaa agcttcctcg acatctgtta ataaagccgt 2280 aggcccttgt ctaagtgcaa ccgcctagac tttctttcag atacatgtcc acatgtccat 2340 ttttcaggtt ctctaagttg gagtggagtc tgggaagggt tgtgaatgag gcttctgggc 2400 tatgggtgag gttccaatgg caggttagag cccctcgggc caactgccat cctggaaagt 2460 agagacagca gtgcccgctg cccagaagag accagcaagc caaactggag cccccattgc 2520 aggctgtcgc catgtggaaa gagtaactca caattgccaa taaagtctca tgtggtttta 2580 tctac 2585 7 2654 DNA Homo sapien 7 gacatgcccc gcggcgcgcc attaaccgcc agatttgaat cgcgggaccc gttggcagag 60 gtggcggcgg cggcatgggt gccccgacgt tgccccctgc ctggcagccc tttctcaagg 120 accaccgcat ctctacattc aagaactggc ccttcttgga gggctgcgcc tgcaccccgg 180 agcggatggc cgaggctggc ttcatccact gccccactga gaacgagcca gacttggccc 240 agtgtttctt ctgcttcaag gagctggaag gctgggagcc agatgacgac cccattgggc 300 cgggcacggt ggcttacgcc tgtaatacca gcactttggg aggccgaggc gggcggatca 360 cgagagagga acataaaaag cattcgtccg gttgcgcttt cctttctgtc aagaagcagt 420 ttgaagaatt aacccttggt gaatttttga aactggacag agaaagagcc aagaacaaaa 480 ttgcaaagga aaccaacaat aagaagaaag aatttgagga aactgcgaag aaagtgcgcc 540 gtgccatcga gcagctggct gccatggatt gaggcctctg gccggagctg cctggtccca 600 gagtggctgc accacttcca gggtttattc cctggtgcca ccagccttcc tgtgggcccc 660 ttagcaatgt cttaggaaag gagatcaaca ttttcaaatt agatgtttca actgtgctct 720 tgttttgtct tgaaagtggc accagaggtg cttctgcctg tgcagcgggt gctgctggta 780 acagtggctg cttctctctc tctctctctt ttttgggggc tcatttttgc tgttttgatt 840 cccgggctta ccaggtgaga agtgagggag gaagaaggca gtgtcccttt tgctagagct 900 gacagctttg ttcgcgtggg cagagccttc cacagtgaat gtgtctggac ctcatgttgt 960 tgaggctgtc acagtcctga gtgtggactt ggcaggtgcc tgttgaatct gagctgcagg 1020 ttccttatct gtcacacctg tgcctcctca gaggacagtt tttttgttgt tgtgtttttt 1080 tgtttttttt tttttggtag atgcatgact tgtgtgtgat gagagaatgg agacagagtc 1140 cctggctcct ctactgttta acaacatggc tttcttattt tgtttgaatt gttaattcac 1200 agaatagcac aaactacaat taaaactaag cacaaagcca ttctaagtca ttggggaaac 1260 ggggtgaact tcaggtggat gaggagacag aatagagtga taggaagcgt ctggcagata 1320 ctccttttgc cactgctgtg tgattagaca ggcccagtga gccgcggggc acatgctggc 1380 cgctcctccc tcagaaaaag gcagtggcct aaatcctttt taaatgactt ggctcgatgc 1440 tgtgggggac tggctgggct gctgcaggcc gtgtgtctgt cagcccaacc ttcacatctg 1500 tcacgttctc cacacggggg agagacgcag tccgcccagg tccccgcttt ctttggaggc 1560 agcagctccc gcagggctga agtctggcgt aagatgatgg atttgattcg ccctcctccc 1620 tgtcatagag ctgcagggtg gattgttaca gcttcgctgg aaacctctgg aggtcatctc 1680 ggctgttcct gagaaataaa aagcctgtca tttcaaacac tgctgtggac cctactgggt 1740 ttttaaaata ttgtcagttt ttcatcgtcg tccctagcct gccaacagcc atctgcccag 1800 acagccgcag tgaggatgag cgtcctggca gagacgcagt tgtctctggg cgcttgccag 1860 agccacgaac cccagacctg tttgtatcat ccgggctcct tccgggcaga aacaactgaa 1920 aatgcacttc agacccactt atttctgcca catctgagtc ggcctgagat agacttttcc 1980 ctctaaactg ggagaatatc acagtggttt ttgttagcag aaaatgcact ccagcctctg 2040 tactcatcta agctgcttat ttttgatatt tgtgtcagtc tgtaaatgga tacttcactt 2100 taataactgt tgcttagtaa ttggctttgt agagaagctg gaaaaaaatg gttttgtctt 2160 caactccttt gcatgccagg cggtgatgtg gatctcggct tctgtgagcc tgtgctgtgg 2220 gcagggctga gctggagccg cccctctcag cccgcctgcc acggcctttc cttaaaggcc 2280 atccttaaaa ccagaccctc atggctacca gcacctgaaa gcttcctcga catctgttaa 2340 taaagccgta ggcccttgtc taagtgcaac cgcctagact ttctttcaga tacatgtcca 2400 catgtccatt tttcaggttc tctaagttgg agtggagtct gggaagggtt gtgaatgagg 2460 cttctgggct atgggtgagg ttccaatggc aggttagagc ccctcgggcc aactgccatc 2520 ctggaaagta gagacagcag tgcccgctgc ccagaagaga ccagcaagcc aaactggagc 2580 ccccattgca ggctgtcgcc atgtggaaag agtaactcac aattgccaat aaagtctcat 2640 gtggttttat ctac 2654 8 2467 DNA Homo sapien 8 gacatgcccc gcggcgcgcc attaaccgcc agatttgaat cgcgggaccc gttggcagag 60 gtggcggcgg cggcatgggt gccccgacgt tgccccctgc ctggcagccc tttctcaagg 120 accaccgcat ctctacattc aagaactggc ccttcttgga gggctgcgcc tgcaccccgg 180 agcggatggc cgaggctggc ttcatccact gccccactga gaacgagcca gacttggccc 240 agtgtttctt ctgcttcaag gagctggaag gctgggagcc agatgacgac cccatgcaaa 300 ggaaaccaac aataagaaga aagaatttga ggaaactgcg aagaaagtgc gccgtgccat 360 cgagcagctg gctgccatgg attgaggcct ctggccggag ctgcctggtc ccagagtggc 420 tgcaccactt ccagggttta ttccctggtg ccaccagcct tcctgtgggc cccttagcaa 480 tgtcttagga aaggagatca acattttcaa attagatgtt tcaactgtgc tcttgttttg 540 tcttgaaagt ggcaccagag gtgcttctgc ctgtgcagcg ggtgctgctg gtaacagtgg 600 ctgcttctct ctctctctct cttttttggg ggctcatttt tgctgttttg attcccgggc 660 ttaccaggtg agaagtgagg gaggaagaag gcagtgtccc ttttgctaga gctgacagct 720 ttgttcgcgt gggcagagcc ttccacagtg aatgtgtctg gacctcatgt tgttgaggct 780 gtcacagtcc tgagtgtgga cttggcaggt gcctgttgaa tctgagctgc aggttcctta 840 tctgtcacac ctgtgcctcc tcagaggaca gtttttttgt tgttgtgttt ttttgttttt 900 ttttttttgg tagatgcatg acttgtgtgt gatgagagaa tggagacaga gtccctggct 960 cctctactgt ttaacaacat ggctttctta ttttgtttga attgttaatt cacagaatag 1020 cacaaactac aattaaaact aagcacaaag ccattctaag tcattgggga aacggggtga 1080 acttcaggtg gatgaggaga cagaatagag tgataggaag cgtctggcag atactccttt 1140 tgccactgct gtgtgattag acaggcccag tgagccgcgg ggcacatgct ggccgctcct 1200 ccctcagaaa aaggcagtgg cctaaatcct ttttaaatga cttggctcga tgctgtgggg 1260 gactggctgg gctgctgcag gccgtgtgtc tgtcagccca accttcacat ctgtcacgtt 1320 ctccacacgg gggagagacg cagtccgccc aggtccccgc tttctttgga ggcagcagct 1380 cccgcagggc tgaagtctgg cgtaagatga tggatttgat tcgccctcct ccctgtcata 1440 gagctgcagg gtggattgtt acagcttcgc tggaaacctc tggaggtcat ctcggctgtt 1500 cctgagaaat aaaaagcctg tcatttcaaa cactgctgtg gaccctactg ggtttttaaa 1560 atattgtcag tttttcatcg tcgtccctag cctgccaaca gccatctgcc cagacagccg 1620 cagtgaggat gagcgtcctg gcagagacgc agttgtctct gggcgcttgc cagagccacg 1680 aaccccagac ctgtttgtat catccgggct ccttccgggc agaaacaact gaaaatgcac 1740 ttcagaccca cttatttctg ccacatctga gtcggcctga gatagacttt tccctctaaa 1800 ctgggagaat atcacagtgg tttttgttag cagaaaatgc actccagcct ctgtactcat 1860 ctaagctgct tatttttgat atttgtgtca gtctgtaaat ggatacttca ctttaataac 1920 tgttgcttag taattggctt tgtagagaag ctggaaaaaa atggttttgt cttcaactcc 1980 tttgcatgcc aggcggtgat gtggatctcg gcttctgtga gcctgtgctg tgggcagggc 2040 tgagctggag ccgcccctct cagcccgcct gccacggcct ttccttaaag gccatcctta 2100 aaaccagacc ctcatggcta ccagcacctg aaagcttcct cgacatctgt taataaagcc 2160 gtaggccctt gtctaagtgc aaccgcctag actttctttc agatacatgt ccacatgtcc 2220 atttttcagg ttctctaagt tggagtggag tctgggaagg gttgtgaatg aggcttctgg 2280 gctatgggtg aggttccaat ggcaggttag agcccctcgg gccaactgcc atcctggaaa 2340 gtagagacag cagtgcccgc tgcccagaag agaccagcaa gccaaactgg agcccccatt 2400 gcaggctgtc gccatgtgga aagagtaact cacaattgcc aataaagtct catgtggttt 2460 tatctac 2467 9 2570 DNA Homo sapien 9 gacatgcccc gcggcgcgcc attaaccgcc agatttgaat cgcgggaccc gttggcagag 60 gtggcggcgg cggcatgggt gccccgacgt tgccccctgc ctggcagccc tttctcaagg 120 accaccgcat ctctacattc aagaactggc ccttcttgga gggctgcgcc tgcaccccgg 180 agcggatggc cgaggctggc ttcatccact gccccactga gaacgagcca gacttggccc 240 agtgtttctt ctgcttcaag gagctggaag gctgggagcc agatgacgac cccatagagg 300 aacataaaaa gcattcgtcc ggttgcgctt tcctttctgt caagaagcag tttgaagaat 360 taacccttgg tgaatttttg aaactggaca gagaaagagc caagaacaaa attgcaaagg 420 aaaccaacaa taagaagaaa gaatttgagg aaactgcgaa gaaagtgcgc cgtgccatcg 480 agcagctggc

tgccatggat tgaggcctct ggccggagct gcctggtccc agagtggctg 540 caccacttcc agggtttatt ccctggtgcc accagccttc ctgtgggccc cttagcaatg 600 tcttaggaaa ggagatcaac attttcaaat tagatgtttc aactgtgctc ttgttttgtc 660 ttgaaagtgg caccagaggt gcttctgcct gtgcagcggg tgctgctggt aacagtggct 720 gcttctctct ctctctctct tttttggggg ctcatttttg ctgttttgat tcccgggctt 780 accaggtgag aagtgaggga ggaagaaggc agtgtccctt ttgctagagc tgacagcttt 840 gttcgcgtgg gcagagcctt ccacagtgaa tgtgtctgga cctcatgttg ttgaggctgt 900 cacagtcctg agtgtggact tggcaggtgc ctgttgaatc tgagctgcag gttccttatc 960 tgtcacacct gtgcctcctc agaggacatg tttttttgtt tttttttttt tggtagatgc 1020 atgacttgtg tgtgatgaga gaatggagac agagtccctg gctcctctac tgtttaacaa 1080 catggctttc ttattttgtt tgaattgtta attcacagaa tagcacaaac tacaattaaa 1140 actaagcaca aagccattct aagtcattgg ggaaacgggg tgaacttcag gtggatgagg 1200 agacagaata gagtgatagg aagcgtctgg cagatactcc ttttgccact gctgtgtgat 1260 tagacaggcc cagtgagccg cggggcacat gctggccgct cctccctcag aaaaaggcag 1320 tggcctaaat cctttttaaa tgacttggct cgatgctgtg ggggactggc tgggctgctg 1380 caggccgtgt gtctgtcagc ccaaccttca catctgtcac gttctccaca cgggggagag 1440 acgcagtccg cccaggtccc cgctttcttt ggaggcagca gctcccgcag ggctgaagtc 1500 tggcgtaaga tgatggattt gattcgccct cctccctgtc atagagctgc agggtggatt 1560 gttacagctt cgctggaaac ctctggaggt catctcggct gttcctgaga aataaaaagc 1620 ctgtcatttc aaacactgct gtggacccta ctgggttttt aaaatattgt cagtttttca 1680 tcgtcgtccc tagcctgcca acagccatct gcccagacag ccgcagtgag gatgagcgtc 1740 ctggcagaga cgcagttgtc tctgggcgct tgccagagcc acgaacccca gacctgtttg 1800 tatcatccgg gctccttccg ggcagaaaca actgaaaatg cacttcagac ccacttattt 1860 ctgccacatc tgagtcggcc tgagatagac ttttccctct aaactgggag aatatcacag 1920 tggtttttgt tagcagaaaa tgcactccag cctctgtact catctaagct gcttattttt 1980 gatatttgtg tcagtctgta aatggatact tcactttaat aactgttgct tagtaattgg 2040 ctttgtagag aagctggaaa aaaatggttt tgtcttcaac tcctttgcat gccaggcggt 2100 gatgtggatc tcggcttctg tgagcctgtg ctgtgggcag ggctgagctg gagccgcccc 2160 tctcagcccg cctgccacgg cctttcctta aaggccatcc ttaaaaccag accctcatgg 2220 ctaccagcac ctgaaagctt cctcgacatc tgttaataaa gccgtaggcc cttgtctaag 2280 tgcaaccgcc tagactttct ttcagataca tgtccacatg tccatttttc aggttctcta 2340 agttggagtg gagtctggga agggttgtga atgaggcttc tgggctatgg gtgaggttcc 2400 aatggcaggt tagagcccct cgggccaact gccatcctgg aaagtagaga cagcagtgcc 2460 cgctgcccag aagagaccag caagccaaac tggagccccc attgcaggct gtcgccatgt 2520 ggaaagagta actcacaatt gccaataaag tctcatgtgg ttttatctac 2570 10 2639 DNA Homo sapien 10 gacatgcccc gcggcgcgcc attaaccgcc agatttgaat cgcgggaccc gttggcagag 60 gtggcggcgg cggcatgggt gccccgacgt tgccccctgc ctggcagccc tttctcaagg 120 accaccgcat ctctacattc aagaactggc ccttcttgga gggctgcgcc tgcaccccgg 180 agcggatggc cgaggctggc ttcatccact gccccactga gaacgagcca gacttggccc 240 agtgtttctt ctgcttcaag gagctggaag gctgggagcc agatgacgac cccattgggc 300 cgggcacggt ggcttacgcc tgtaatacca gcactttggg aggccgaggc gggcggatca 360 cgagagagga acataaaaag cattcgtccg gttgcgcttt cctttctgtc aagaagcagt 420 ttgaagaatt aacccttggt gaatttttga aactggacag agaaagagcc aagaacaaaa 480 ttgcaaagga aaccaacaat aagaagaaag aatttgagga aactgcgaag aaagtgcgcc 540 gtgccatcga gcagctggct gccatggatt gaggcctctg gccggagctg cctggtccca 600 gagtggctgc accacttcca gggtttattc cctggtgcca ccagccttcc tgtgggcccc 660 ttagcaatgt cttaggaaag gagatcaaca ttttcaaatt agatgtttca actgtgctct 720 tgttttgtct tgaaagtggc accagaggtg cttctgcctg tgcagcgggt gctgctggta 780 acagtggctg cttctctctc tctctctctt ttttgggggc tcatttttgc tgttttgatt 840 cccgggctta ccaggtgaga agtgagggag gaagaaggca gtgtcccttt tgctagagct 900 gacagctttg ttcgcgtggg cagagccttc cacagtgaat gtgtctggac ctcatgttgt 960 tgaggctgtc acagtcctga gtgtggactt ggcaggtgcc tgttgaatct gagctgcagg 1020 ttccttatct gtcacacctg tgcctcctca gaggacatgt ttttttgttt tttttttttt 1080 ggtagatgca tgacttgtgt gtgatgagag aatggagaca gagtccctgg ctcctctact 1140 gtttaacaac atggctttct tattttgttt gaattgttaa ttcacagaat agcacaaact 1200 acaattaaaa ctaagcacaa agccattcta agtcattggg gaaacggggt gaacttcagg 1260 tggatgagga gacagaatag agtgatagga agcgtctggc agatactcct tttgccactg 1320 ctgtgtgatt agacaggccc agtgagccgc ggggcacatg ctggccgctc ctccctcaga 1380 aaaaggcagt ggcctaaatc ctttttaaat gacttggctc gatgctgtgg gggactggct 1440 gggctgctgc aggccgtgtg tctgtcagcc caaccttcac atctgtcacg ttctccacac 1500 gggggagaga cgcagtccgc ccaggtcccc gctttctttg gaggcagcag ctcccgcagg 1560 gctgaagtct ggcgtaagat gatggatttg attcgccctc ctccctgtca tagagctgca 1620 gggtggattg ttacagcttc gctggaaacc tctggaggtc atctcggctg ttcctgagaa 1680 ataaaaagcc tgtcatttca aacactgctg tggaccctac tgggttttta aaatattgtc 1740 agtttttcat cgtcgtccct agcctgccaa cagccatctg cccagacagc cgcagtgagg 1800 atgagcgtcc tggcagagac gcagttgtct ctgggcgctt gccagagcca cgaaccccag 1860 acctgtttgt atcatccggg ctccttccgg gcagaaacaa ctgaaaatgc acttcagacc 1920 cacttatttc tgccacatct gagtcggcct gagatagact tttccctcta aactgggaga 1980 atatcacagt ggtttttgtt agcagaaaat gcactccagc ctctgtactc atctaagctg 2040 cttatttttg atatttgtgt cagtctgtaa atggatactt cactttaata actgttgctt 2100 agtaattggc tttgtagaga agctggaaaa aaatggtttt gtcttcaact cctttgcatg 2160 ccaggcggtg atgtggatct cggcttctgt gagcctgtgc tgtgggcagg gctgagctgg 2220 agccgcccct ctcagcccgc ctgccacggc ctttccttaa aggccatcct taaaaccaga 2280 ccctcatggc taccagcacc tgaaagcttc ctcgacatct gttaataaag ccgtaggccc 2340 ttgtctaagt gcaaccgcct agactttctt tcagatacat gtccacatgt ccatttttca 2400 ggttctctaa gttggagtgg agtctgggaa gggttgtgaa tgaggcttct gggctatggg 2460 tgaggttcca atggcaggtt agagcccctc gggccaactg ccatcctgga aagtagagac 2520 agcagtgccc gctgcccaga agagaccagc aagccaaact ggagccccca ttgcaggctg 2580 tcgccatgtg gaaagagtaa ctcacaattg ccaataaagt ctcatgtggt tttatctac 2639 11 2452 DNA Homo sapien 11 gacatgcccc gcggcgcgcc attaaccgcc agatttgaat cgcgggaccc gttggcagag 60 gtggcggcgg cggcatgggt gccccgacgt tgccccctgc ctggcagccc tttctcaagg 120 accaccgcat ctctacattc aagaactggc ccttcttgga gggctgcgcc tgcaccccgg 180 agcggatggc cgaggctggc ttcatccact gccccactga gaacgagcca gacttggccc 240 agtgtttctt ctgcttcaag gagctggaag gctgggagcc agatgacgac cccatgcaaa 300 ggaaaccaac aataagaaga aagaatttga ggaaactgcg aagaaagtgc gccgtgccat 360 cgagcagctg gctgccatgg attgaggcct ctggccggag ctgcctggtc ccagagtggc 420 tgcaccactt ccagggttta ttccctggtg ccaccagcct tcctgtgggc cccttagcaa 480 tgtcttagga aaggagatca acattttcaa attagatgtt tcaactgtgc tcttgttttg 540 tcttgaaagt ggcaccagag gtgcttctgc ctgtgcagcg ggtgctgctg gtaacagtgg 600 ctgcttctct ctctctctct cttttttggg ggctcatttt tgctgttttg attcccgggc 660 ttaccaggtg agaagtgagg gaggaagaag gcagtgtccc ttttgctaga gctgacagct 720 ttgttcgcgt gggcagagcc ttccacagtg aatgtgtctg gacctcatgt tgttgaggct 780 gtcacagtcc tgagtgtgga cttggcaggt gcctgttgaa tctgagctgc aggttcctta 840 tctgtcacac ctgtgcctcc tcagaggaca tgtttttttg tttttttttt tttggtagat 900 gcatgacttg tgtgtgatga gagaatggag acagagtccc tggctcctct actgtttaac 960 aacatggctt tcttattttg tttgaattgt taattcacag aatagcacaa actacaatta 1020 aaactaagca caaagccatt ctaagtcatt ggggaaacgg ggtgaacttc aggtggatga 1080 ggagacagaa tagagtgata ggaagcgtct ggcagatact ccttttgcca ctgctgtgtg 1140 attagacagg cccagtgagc cgcggggcac atgctggccg ctcctccctc agaaaaaggc 1200 agtggcctaa atccttttta aatgacttgg ctcgatgctg tgggggactg gctgggctgc 1260 tgcaggccgt gtgtctgtca gcccaacctt cacatctgtc acgttctcca cacgggggag 1320 agacgcagtc cgcccaggtc cccgctttct ttggaggcag cagctcccgc agggctgaag 1380 tctggcgtaa gatgatggat ttgattcgcc ctcctccctg tcatagagct gcagggtgga 1440 ttgttacagc ttcgctggaa acctctggag gtcatctcgg ctgttcctga gaaataaaaa 1500 gcctgtcatt tcaaacactg ctgtggaccc tactgggttt ttaaaatatt gtcagttttt 1560 catcgtcgtc cctagcctgc caacagccat ctgcccagac agccgcagtg aggatgagcg 1620 tcctggcaga gacgcagttg tctctgggcg cttgccagag ccacgaaccc cagacctgtt 1680 tgtatcatcc gggctccttc cgggcagaaa caactgaaaa tgcacttcag acccacttat 1740 ttctgccaca tctgagtcgg cctgagatag acttttccct ctaaactggg agaatatcac 1800 agtggttttt gttagcagaa aatgcactcc agcctctgta ctcatctaag ctgcttattt 1860 ttgatatttg tgtcagtctg taaatggata cttcacttta ataactgttg cttagtaatt 1920 ggctttgtag agaagctgga aaaaaatggt tttgtcttca actcctttgc atgccaggcg 1980 gtgatgtgga tctcggcttc tgtgagcctg tgctgtgggc agggctgagc tggagccgcc 2040 cctctcagcc cgcctgccac ggcctttcct taaaggccat ccttaaaacc agaccctcat 2100 ggctaccagc acctgaaagc ttcctcgaca tctgttaata aagccgtagg cccttgtcta 2160 agtgcaaccg cctagacttt ctttcagata catgtccaca tgtccatttt tcaggttctc 2220 taagttggag tggagtctgg gaagggttgt gaatgaggct tctgggctat gggtgaggtt 2280 ccaatggcag gttagagccc ctcgggccaa ctgccatcct ggaaagtaga gacagcagtg 2340 cccgctgccc agaagagacc agcaagccaa actggagccc ccattgcagg ctgtcgccat 2400 gtggaaagag taactcacaa ttgccaataa agtctcatgt ggttttatct ac 2452 12 2252 DNA Homo sapien 12 aattctcgcc caaggacaga cctgaatctc tagctgccta gaggctgact caactgaaat 60 catggcgttt gacagcactt ggaaggtaga ccggagtgaa aactatgaca agttcatgga 120 aaaaatgggt gttaatatag tgaaaaggaa gcttgcagct catgacaatt tgaagctgac 180 aattacacaa gaaggaaata aattcacagt caaagaatca agcgcttttc gaaacattga 240 agttgttttt gaacttggtg tcacctttaa ttacaatcta gcagacggaa ctgaactcag 300 ggggacctgg agccttgagg gaaataaact tattggaaaa ttcaaacgga cagacaatgg 360 aaacgaactg aatactgtcc gagaaattat aggtgatgaa ctagtccaga cttatgtgta 420 tgaaggagta gaagccaaaa ggatctttaa aaaggattga gcattattct tggcgcacag 480 tccaaaatac aaattggaca gaagatctat attgtaccag aactatttat ttcaccccat 540 caagtataag gttactgatt gattggtcct tttataaaca ttggtatatt tccattcatg 600 ccaaagcaaa agaagtaaaa gctaattagg atttaatttg ttttatattc tctaagatat 660 atatttacta aaagaatttg tgacatttta aaaaacaaaa ataaatattg cgtccatgtt 720 gctttatatg tagccttgcc ttttaaaaga aaaagtatgt gaatatgaat tgacagactg 780 ttttcgtaga gagagggtct tactctttca ctcaggctgg aatgtagtgg agagatcata 840 gctcactgta acctcaaact cctggactca tgcaatcttc ctgcctcagg cttctgagta 900 gctaggacta tgggtacatt ccacagtgcc cagctaattt ttgttttgtt ttctttttat 960 tttttttaga gatggggtct tgctatattg cccaggctgg tcttgaaccc ctggcctcaa 1020 gcaatcctcc tgcctcagcc tctcaagttg ttttttttct ttacatttga taaactaaaa 1080 gcataggctg catatgagtc tttaacatct tgaactggtt gtgaataatt ttctggcact 1140 ggttgtaagt aatatctatt attataaaaa taatatatgc tcaaccagaa aacttagaaa 1200 taagaaacac aaatgtaaaa taagtatttc cataactcat aatccagaga taattgccat 1260 tctgattttg atagatatcc tctcagctct cttccctggg ggcagatatt tcccaataca 1320 taccactttg aataggatga taggaaataa atgatgtact acattaaatt aaattattgt 1380 attacatttt tgtacacatc agtcattccc acgcttggct gaaaatcagg atcatctgag 1440 aaacttaaac aatttctgca ttcttaatct ccactgttat tctattatat cagaatcgct 1500 aatagaacca agaattctag aaaatttcct ggtgattctg atgcagcctg tccactaact 1560 tgtctttgag aacaatggag atatcagtta tcaatgttat ttttaaccac ccccttcttt 1620 tttgttgttg tgggtttttt cacataaaca catacattgc caattttcca gggctcaaaa 1680 agtttccttt tattcatatt ttcacatgac gtaaaatttt atgtgcttca cataattgta 1740 ttttagcagg gtacatatta ggggatggag agggggtaca atttttaagc atttgcagct 1800 gcaactctat agacttttga caaattcttt ttcacactga tgtagataac agcttaacat 1860 ttacatagtt cttactactt gccacacact gttctaagtg gtatatacat atgacatata 1920 tattaaaatg taggaagaaa aatgtttgag tacctgatga aaatgaatag agagtatgta 1980 atctttgaaa gctgaatact gcgtgttctc acttataagt gggagctaaa taatgtatac 2040 acatggacac accagagtgt agaataatag acactggaga cttggaagag ttggagggtt 2100 ggcagggggc gatgataatt tacttaatgg gtacaatgta cattattcag ggggtgatgg 2160 ttacagccca gactttacca ctatgcaata tatcaatgta acaaaactat acttgtactc 2220 cttaaattta tataaaaata ccttaaatct at 2252 13 994 PRT Homo sapien 13 Met Ser Lys Leu Arg Met Val Leu Leu Glu Asp Ser Gly Ser Ala Asp 1 5 10 15 Phe Arg Arg His Phe Val Asn Leu Ser Pro Phe Thr Ile Thr Val Val 20 25 30 Leu Leu Leu Ser Ala Cys Phe Val Thr Ser Ser Leu Gly Gly Thr Asp 35 40 45 Lys Glu Leu Arg Leu Val Asp Gly Glu Asn Lys Cys Ser Gly Arg Val 50 55 60 Glu Val Lys Val Gln Glu Glu Trp Gly Thr Val Cys Asn Asn Gly Trp 65 70 75 80 Ser Met Glu Ala Val Ser Val Ile Cys Asn Gln Leu Gly Cys Pro Thr 85 90 95 Ala Ile Lys Ala Pro Gly Trp Ala Asn Ser Ser Ala Gly Ser Gly Arg 100 105 110 Ile Trp Met Asp His Val Ser Cys Arg Gly Asn Glu Ser Ala Leu Trp 115 120 125 Asp Cys Lys His Asp Gly Trp Gly Lys His Ser Asn Cys Thr His Gln 130 135 140 Gln Asp Ala Gly Val Thr Cys Ser Asp Gly Ser Asn Leu Glu Met Arg 145 150 155 160 Leu Thr Arg Gly Gly Asn Met Cys Ser Gly Arg Ile Glu Ile Lys Phe 165 170 175 Gln Gly Arg Trp Gly Thr Val Cys Asp Asp Asn Phe Asn Ile Asp His 180 185 190 Ala Ser Val Ile Cys Arg Gln Leu Glu Cys Gly Ser Ala Val Ser Phe 195 200 205 Ser Gly Ser Ser Asn Phe Gly Glu Gly Ser Gly Pro Ile Trp Phe Asp 210 215 220 Asp Leu Ile Cys Asn Gly Asn Glu Ser Ala Leu Trp Asn Cys Lys His 225 230 235 240 Gln Gly Trp Gly Lys His Asn Cys Asp His Ala Glu Asp Ala Gly Val 245 250 255 Ile Cys Ser Lys Gly Ala Asp Leu Ser Leu Arg Leu Val Asp Gly Val 260 265 270 Thr Glu Cys Ser Gly Arg Leu Glu Val Arg Phe Gln Gly Glu Trp Gly 275 280 285 Thr Ile Cys Asp Asp Gly Trp Asp Ser Tyr Asp Ala Ala Val Ala Cys 290 295 300 Lys Gln Leu Gly Cys Pro Thr Ala Val Thr Ala Ile Gly Arg Val Asn 305 310 315 320 Ala Ser Lys Gly Phe Gly His Ile Trp Leu Asp Ser Val Ser Cys Gln 325 330 335 Gly His Glu Pro Ala Val Trp Gln Cys Lys His His Glu Trp Gly Lys 340 345 350 His Tyr Cys Asn His Asn Glu Asp Ala Gly Val Thr Cys Ser Asp Gly 355 360 365 Ser Asp Leu Glu Leu Arg Leu Arg Gly Gly Gly Ser Arg Cys Ala Gly 370 375 380 Thr Val Glu Val Glu Ile Gln Arg Leu Leu Gly Lys Val Cys Asp Arg 385 390 395 400 Gly Trp Gly Leu Lys Glu Ala Asp Val Val Cys Arg Gln Leu Gly Cys 405 410 415 Gly Ser Ala Leu Lys Thr Ser Tyr Gln Val Tyr Ser Lys Ile Gln Ala 420 425 430 Thr Asn Thr Trp Leu Phe Leu Ser Ser Cys Asn Gly Asn Glu Thr Ser 435 440 445 Leu Trp Asp Cys Lys Asn Trp Gln Trp Gly Gly Leu Thr Cys Asp His 450 455 460 Tyr Glu Glu Ala Lys Ile Thr Cys Ser Ala His Arg Glu Pro Arg Leu 465 470 475 480 Val Gly Gly Asp Ile Pro Cys Ser Gly Arg Val Glu Val Lys His Gly 485 490 495 Asp Thr Trp Gly Ser Ile Cys Asp Ser Asp Phe Ser Leu Glu Ala Ala 500 505 510 Ser Val Leu Cys Arg Glu Leu Gln Cys Gly Thr Val Val Ser Ile Leu 515 520 525 Gly Gly Ala His Phe Gly Glu Gly Asn Gly Gln Ile Trp Ala Glu Glu 530 535 540 Phe Gln Cys Glu Gly His Glu Ser His Leu Ser Leu Cys Pro Val Ala 545 550 555 560 Pro Arg Pro Glu Gly Thr Cys Ser His Ser Arg Asp Val Gly Val Val 565 570 575 Cys Ser Arg Tyr Thr Glu Ile Arg Leu Val Asn Gly Lys Thr Pro Cys 580 585 590 Glu Gly Arg Val Glu Leu Lys Thr Leu Gly Ala Trp Gly Ser Leu Cys 595 600 605 Asn Ser His Trp Asp Ile Glu Asp Ala His Val Leu Cys Gln Gln Leu 610 615 620 Lys Cys Gly Val Ala Leu Ser Thr Pro Gly Gly Ala Arg Phe Gly Lys 625 630 635 640 Gly Asn Gly Gln Ile Trp Arg His Met Phe His Cys Thr Gly Thr Glu 645 650 655 Gln His Met Gly Asp Cys Pro Val Thr Ala Leu Gly Ala Ser Leu Cys 660 665 670 Pro Ser Glu Gln Val Ala Ser Val Ile Cys Ser Gly Asn Gln Ser Gln 675 680 685 Thr Leu Ser Ser Cys Asn Ser Ser Ser Leu Gly Pro Thr Arg Pro Thr 690 695 700 Ile Pro Glu Glu Ser Ala Val Ala Cys Ile Glu Ser Gly Gln Leu Arg 705 710 715 720 Leu Val Asn Gly Gly Gly Arg Cys Ala Gly Arg Val Glu Ile Tyr His 725 730 735 Glu Gly Ser Trp Gly Thr Ile Cys Asp Asp Ser Trp Asp Leu Ser Asp 740 745 750 Ala His Val Val Cys Arg Gln Leu Gly Cys Gly Glu Ala Ile Asn Ala 755 760 765 Thr Gly Ser Ala His Phe Gly Glu Gly Thr Gly Pro Ile Trp Leu Asp 770 775 780 Glu Met Lys Cys Asn Gly Lys Glu Ser Arg Ile Trp Gln Cys His Ser 785 790 795 800 His Gly Trp Gly Gln Gln Asn Cys Arg His Lys Glu Asp Ala Gly Val 805 810 815 Ile Cys Ser Glu Phe Met Ser Leu Arg Leu Thr Ser Glu Ala Ser Arg 820 825 830 Glu Ala Cys Ala Gly Arg Leu Glu Val Phe Tyr Asn Gly Ala Trp Gly 835 840 845 Thr Val Gly Lys Ser Ser Met Ser Glu Thr Thr Val Gly Val Val Cys 850 855 860 Arg Gln Leu Gly Cys Ala Asp Lys Gly Lys Ile Asn Pro Ala Ser Leu 865 870 875 880 Asp Lys Ala Met Ser Ile Pro Met Trp Val Asp Asn Val Gln Cys Pro

885 890 895 Lys Gly Pro Asp Thr Leu Trp Gln Cys Pro Ser Ser Pro Trp Glu Lys 900 905 910 Arg Leu Ala Ser Pro Ser Glu Glu Thr Trp Ile Thr Cys Asp Asn Lys 915 920 925 Ile Arg Leu Gln Glu Gly Pro Thr Ser Cys Ser Gly Arg Val Glu Ile 930 935 940 Trp His Gly Gly Ser Trp Gly Thr Val Cys Asp Asp Ser Trp Asp Leu 945 950 955 960 Asp Asp Ala Gln Val Val Cys Gln Gln Leu Gly Cys Gly Pro Ala Leu 965 970 975 Lys Ala Phe Lys Glu Ala Glu Phe Gly Gln Gly Thr Gly Pro Asp Met 980 985 990 Ala Gln 14 994 PRT Homo sapien 14 Met Ser Lys Leu Arg Met Val Leu Leu Glu Asp Ser Gly Ser Ala Asp 1 5 10 15 Phe Arg Arg His Phe Val Asn Leu Ser Pro Phe Thr Ile Thr Val Val 20 25 30 Leu Leu Leu Ser Ala Cys Phe Val Thr Ser Ser Leu Gly Gly Thr Asp 35 40 45 Lys Glu Leu Arg Leu Val Asp Gly Glu Asn Lys Cys Ser Gly Arg Val 50 55 60 Glu Val Lys Val Gln Glu Glu Trp Gly Thr Val Cys Asn Asn Gly Trp 65 70 75 80 Ser Met Glu Ala Val Ser Val Ile Cys Asn Gln Leu Gly Cys Pro Thr 85 90 95 Ala Ile Lys Ala Pro Gly Trp Ala Asn Ser Ser Ala Gly Ser Gly Arg 100 105 110 Ile Trp Met Asp His Val Ser Cys Arg Gly Asn Glu Ser Ala Leu Trp 115 120 125 Asp Cys Lys His Asp Gly Trp Gly Lys His Ser Asn Cys Thr His Gln 130 135 140 Gln Asp Ala Gly Val Thr Cys Ser Asp Gly Ser Asn Leu Glu Met Arg 145 150 155 160 Leu Thr Arg Gly Gly Asn Met Cys Ser Gly Arg Ile Glu Ile Lys Phe 165 170 175 Gln Gly Arg Trp Gly Thr Val Cys Asp Asp Asn Phe Asn Ile Asp His 180 185 190 Ala Ser Val Ile Cys Arg Gln Leu Glu Cys Gly Ser Ala Val Ser Phe 195 200 205 Ser Gly Ser Ser Asn Phe Gly Glu Gly Ser Gly Pro Ile Trp Phe Asp 210 215 220 Asp Leu Ile Cys Asn Gly Asn Glu Ser Ala Leu Trp Asn Cys Lys His 225 230 235 240 Gln Gly Trp Gly Lys His Asn Cys Asp His Ala Glu Asp Ala Gly Val 245 250 255 Ile Cys Ser Lys Gly Ala Asp Leu Ser Leu Arg Leu Val Asp Gly Val 260 265 270 Thr Glu Cys Ser Gly Arg Leu Glu Val Arg Phe Gln Gly Glu Trp Gly 275 280 285 Thr Ile Cys Asp Asp Gly Trp Asp Ser Tyr Asp Ala Ala Val Ala Cys 290 295 300 Lys Gln Leu Gly Cys Pro Thr Ala Val Thr Ala Ile Gly Arg Val Asn 305 310 315 320 Ala Ser Lys Gly Phe Gly His Ile Trp Leu Asp Ser Val Ser Cys Gln 325 330 335 Gly His Glu Pro Ala Val Trp Gln Cys Lys His His Glu Trp Gly Lys 340 345 350 His Tyr Cys Asn His Asn Glu Asp Ala Gly Val Thr Cys Ser Asp Gly 355 360 365 Ser Asp Leu Glu Leu Arg Leu Arg Gly Gly Gly Ser Arg Cys Ala Gly 370 375 380 Thr Val Glu Val Glu Ile Gln Arg Leu Leu Gly Lys Val Cys Asp Arg 385 390 395 400 Gly Trp Gly Leu Lys Glu Ala Asp Val Val Cys Arg Gln Leu Gly Cys 405 410 415 Gly Ser Ala Leu Lys Thr Ser Tyr Gln Val Tyr Ser Lys Ile Gln Ala 420 425 430 Thr Asn Thr Trp Leu Phe Leu Ser Ser Cys Asn Gly Asn Glu Thr Ser 435 440 445 Leu Trp Asp Cys Lys Asn Trp Gln Trp Gly Gly Leu Thr Cys Asp His 450 455 460 Tyr Glu Glu Ala Lys Ile Thr Cys Ser Ala His Arg Glu Pro Arg Leu 465 470 475 480 Val Gly Gly Asp Ile Pro Cys Ser Gly Arg Val Glu Val Lys His Gly 485 490 495 Asp Thr Trp Gly Ser Ile Cys Asp Ser Asp Phe Ser Leu Glu Ala Ala 500 505 510 Ser Val Leu Cys Arg Glu Leu Gln Cys Gly Thr Val Val Ser Ile Leu 515 520 525 Gly Gly Ala His Phe Gly Glu Gly Asn Gly Gln Ile Trp Ala Glu Glu 530 535 540 Phe Gln Cys Glu Gly His Glu Ser His Leu Ser Leu Cys Pro Val Ala 545 550 555 560 Pro Arg Pro Glu Gly Thr Cys Ser His Ser Arg Asp Val Gly Val Val 565 570 575 Cys Ser Arg Tyr Thr Glu Ile Arg Leu Val Asn Gly Lys Thr Pro Cys 580 585 590 Glu Gly Arg Val Glu Leu Lys Thr Leu Gly Ala Trp Gly Ser Leu Cys 595 600 605 Asn Ser His Trp Asp Ile Glu Asp Ala His Val Leu Cys Gln Gln Leu 610 615 620 Lys Cys Gly Val Ala Leu Ser Thr Pro Gly Gly Ala Arg Phe Gly Lys 625 630 635 640 Gly Asn Gly Gln Ile Trp Arg His Met Phe His Cys Thr Gly Thr Glu 645 650 655 Gln His Met Gly Asp Cys Pro Val Thr Ala Leu Gly Ala Ser Leu Cys 660 665 670 Pro Ser Glu Gln Val Ala Ser Val Ile Cys Ser Gly Asn Gln Ser Gln 675 680 685 Thr Leu Ser Ser Cys Asn Ser Ser Ser Leu Gly Pro Thr Arg Pro Thr 690 695 700 Ile Pro Glu Glu Ser Ala Val Ala Cys Ile Glu Ser Gly Gln Leu Arg 705 710 715 720 Leu Val Asn Gly Gly Gly Arg Cys Ala Gly Arg Val Glu Ile Tyr His 725 730 735 Glu Gly Ser Trp Gly Thr Ile Cys Asp Asp Ser Trp Asp Leu Ser Asp 740 745 750 Ala His Val Val Cys Arg Gln Leu Gly Cys Gly Glu Ala Ile Asn Ala 755 760 765 Thr Gly Ser Ala His Phe Gly Glu Gly Thr Gly Pro Ile Trp Leu Asp 770 775 780 Glu Met Lys Cys Asn Gly Lys Glu Ser Arg Ile Trp Gln Cys His Ser 785 790 795 800 His Gly Trp Gly Gln Gln Asn Cys Arg His Lys Glu Asp Ala Gly Val 805 810 815 Ile Cys Ser Glu Phe Met Ser Leu Arg Leu Thr Ser Glu Ala Ser Arg 820 825 830 Glu Ala Cys Ala Gly Arg Leu Glu Val Phe Tyr Asn Gly Ala Trp Gly 835 840 845 Thr Val Gly Lys Ser Ser Met Ser Glu Thr Thr Val Gly Val Val Cys 850 855 860 Arg Gln Leu Gly Cys Ala Asp Lys Gly Lys Ile Asn Pro Ala Ser Leu 865 870 875 880 Asp Lys Ala Met Ser Ile Pro Met Trp Val Asp Asn Val Gln Cys Pro 885 890 895 Lys Gly Pro Asp Thr Leu Trp Gln Cys Pro Ser Ser Pro Trp Glu Lys 900 905 910 Arg Leu Ala Ser Pro Ser Glu Glu Thr Trp Ile Thr Cys Asp Asn Lys 915 920 925 Ile Arg Leu Gln Glu Gly Pro Thr Ser Cys Ser Gly Arg Val Glu Ile 930 935 940 Trp His Gly Gly Ser Trp Gly Thr Val Cys Asp Asp Ser Trp Asp Leu 945 950 955 960 Asp Asp Ala Gln Val Val Cys Gln Gln Leu Gly Cys Gly Pro Ala Leu 965 970 975 Lys Ala Phe Lys Glu Ala Glu Phe Gly Gln Gly Thr Gly Pro Asp Met 980 985 990 Ala Gln 15 1027 PRT Homo sapien 15 Met Ser Lys Leu Arg Met Val Leu Leu Glu Asp Ser Gly Ser Ala Asp 1 5 10 15 Phe Arg Arg His Phe Val Asn Leu Ser Pro Phe Thr Ile Thr Val Val 20 25 30 Leu Leu Leu Ser Ala Cys Phe Val Thr Ser Ser Leu Gly Gly Thr Asp 35 40 45 Lys Glu Leu Arg Leu Val Asp Gly Glu Asn Lys Cys Ser Gly Arg Val 50 55 60 Glu Val Lys Val Gln Glu Glu Trp Gly Thr Val Cys Asn Asn Gly Trp 65 70 75 80 Ser Met Glu Ala Val Ser Val Ile Cys Asn Gln Leu Gly Cys Pro Thr 85 90 95 Ala Ile Lys Ala Pro Gly Trp Ala Asn Ser Ser Ala Gly Ser Gly Arg 100 105 110 Ile Trp Met Asp His Val Ser Cys Arg Gly Asn Glu Ser Ala Leu Trp 115 120 125 Asp Cys Lys His Asp Gly Trp Gly Lys His Ser Asn Cys Thr His Gln 130 135 140 Gln Asp Ala Gly Val Thr Cys Ser Asp Gly Ser Asn Leu Glu Met Arg 145 150 155 160 Leu Thr Arg Gly Gly Asn Met Cys Ser Gly Arg Ile Glu Ile Lys Phe 165 170 175 Gln Gly Arg Trp Gly Thr Val Cys Asp Asp Asn Phe Asn Ile Asp His 180 185 190 Ala Ser Val Ile Cys Arg Gln Leu Glu Cys Gly Ser Ala Val Ser Phe 195 200 205 Ser Gly Ser Ser Asn Phe Gly Glu Gly Ser Gly Pro Ile Trp Phe Asp 210 215 220 Asp Leu Ile Cys Asn Gly Asn Glu Ser Ala Leu Trp Asn Cys Lys His 225 230 235 240 Gln Gly Trp Gly Lys His Asn Cys Asp His Ala Glu Asp Ala Gly Val 245 250 255 Ile Cys Ser Lys Gly Ala Asp Leu Ser Leu Arg Leu Val Asp Gly Val 260 265 270 Thr Glu Cys Ser Gly Arg Leu Glu Val Arg Phe Gln Gly Glu Trp Gly 275 280 285 Thr Ile Cys Asp Asp Gly Trp Asp Ser Tyr Asp Ala Ala Val Ala Cys 290 295 300 Lys Gln Leu Gly Cys Pro Thr Ala Val Thr Ala Ile Gly Arg Val Asn 305 310 315 320 Ala Ser Lys Gly Phe Gly His Ile Trp Leu Asp Ser Val Ser Cys Gln 325 330 335 Gly His Glu Pro Ala Val Trp Gln Cys Lys His His Glu Trp Gly Lys 340 345 350 His Tyr Cys Asn His Asn Glu Asp Ala Gly Val Thr Cys Ser Asp Gly 355 360 365 Ser Asp Leu Glu Leu Arg Leu Arg Gly Gly Gly Ser Arg Cys Ala Gly 370 375 380 Thr Val Glu Val Glu Ile Gln Arg Leu Leu Gly Lys Val Cys Asp Arg 385 390 395 400 Gly Trp Gly Leu Lys Glu Ala Asp Val Val Cys Arg Gln Leu Gly Cys 405 410 415 Gly Ser Ala Leu Lys Thr Ser Tyr Gln Val Tyr Ser Lys Ile Gln Ala 420 425 430 Thr Asn Thr Trp Leu Phe Leu Ser Ser Cys Asn Gly Asn Glu Thr Ser 435 440 445 Leu Trp Asp Cys Lys Asn Trp Gln Trp Gly Gly Leu Thr Cys Asp His 450 455 460 Tyr Glu Glu Ala Lys Ile Thr Cys Ser Ala His Arg Glu Pro Arg Leu 465 470 475 480 Val Gly Gly Asp Ile Pro Cys Ser Gly Arg Val Glu Val Lys His Gly 485 490 495 Asp Thr Trp Gly Ser Ile Cys Asp Ser Asp Phe Ser Leu Glu Ala Ala 500 505 510 Ser Val Leu Cys Arg Glu Leu Gln Cys Gly Thr Val Val Ser Ile Leu 515 520 525 Gly Gly Ala His Phe Gly Glu Gly Asn Gly Gln Ile Trp Ala Glu Glu 530 535 540 Phe Gln Cys Glu Gly His Glu Ser His Leu Ser Leu Cys Pro Val Ala 545 550 555 560 Pro Arg Pro Glu Gly Thr Cys Ser His Ser Arg Asp Val Gly Val Val 565 570 575 Cys Ser Ser Lys Thr Gln Lys Thr Ser Leu Ile Gly Ser His Thr Val 580 585 590 Lys Gly Thr Gly Leu Gly Ser His Ser Cys Leu Phe Leu Lys Pro Cys 595 600 605 Leu Leu Pro Gly Tyr Thr Glu Ile Arg Leu Val Asn Gly Lys Thr Pro 610 615 620 Cys Glu Gly Arg Val Glu Leu Lys Thr Leu Gly Ala Trp Gly Ser Leu 625 630 635 640 Cys Asn Ser His Trp Asp Ile Glu Asp Ala His Val Leu Cys Gln Gln 645 650 655 Leu Lys Cys Gly Val Ala Leu Ser Thr Pro Gly Gly Ala Arg Phe Gly 660 665 670 Lys Gly Asn Gly Gln Ile Trp Arg His Met Phe His Cys Thr Gly Thr 675 680 685 Glu Gln His Met Gly Asp Cys Pro Val Thr Ala Leu Gly Ala Ser Leu 690 695 700 Cys Pro Ser Glu Gln Val Ala Ser Val Ile Cys Ser Gly Asn Gln Ser 705 710 715 720 Gln Thr Leu Ser Ser Cys Asn Ser Ser Ser Leu Gly Pro Thr Arg Pro 725 730 735 Thr Ile Pro Glu Glu Ser Ala Val Ala Cys Ile Glu Ser Gly Gln Leu 740 745 750 Arg Leu Val Asn Gly Gly Gly Arg Cys Ala Gly Arg Val Glu Ile Tyr 755 760 765 His Glu Gly Ser Trp Gly Thr Ile Cys Asp Asp Ser Trp Asp Leu Ser 770 775 780 Asp Ala His Val Val Cys Arg Gln Leu Gly Cys Gly Glu Ala Ile Asn 785 790 795 800 Ala Thr Gly Ser Ala His Phe Gly Glu Gly Thr Gly Pro Ile Trp Leu 805 810 815 Asp Glu Met Lys Cys Asn Gly Lys Glu Ser Arg Ile Trp Gln Cys His 820 825 830 Ser His Gly Trp Gly Gln Gln Asn Cys Arg His Lys Glu Asp Ala Gly 835 840 845 Val Ile Cys Ser Glu Phe Met Ser Leu Arg Leu Thr Ser Glu Ala Ser 850 855 860 Arg Glu Ala Cys Ala Gly Arg Leu Glu Val Phe Tyr Asn Gly Ala Trp 865 870 875 880 Gly Thr Val Gly Lys Ser Ser Met Ser Glu Thr Thr Val Gly Val Val 885 890 895 Cys Arg Gln Leu Gly Cys Ala Asp Lys Gly Lys Ile Asn Pro Ala Ser 900 905 910 Leu Asp Lys Ala Met Ser Ile Pro Met Trp Val Asp Asn Val Gln Cys 915 920 925 Pro Lys Gly Pro Asp Thr Leu Trp Gln Cys Pro Ser Ser Pro Trp Glu 930 935 940 Lys Arg Leu Ala Ser Pro Ser Glu Glu Thr Trp Ile Thr Cys Asp Asn 945 950 955 960 Lys Ile Arg Leu Gln Glu Gly Pro Thr Ser Cys Ser Gly Arg Val Glu 965 970 975 Ile Trp His Gly Gly Ser Trp Gly Thr Val Cys Asp Asp Ser Trp Asp 980 985 990 Leu Asp Asp Ala Gln Val Val Cys Gln Gln Leu Gly Cys Gly Pro Ala 995 1000 1005 Leu Lys Ala Phe Lys Glu Ala Glu Phe Gly Gln Gly Thr Gly Pro Asp 1010 1015 1020 Met Ala Gln 1025 16 994 PRT Homo sapien 16 Met Ser Lys Leu Arg Met Val Leu Leu Glu Asp Ser Gly Ser Ala Asp 1 5 10 15 Phe Arg Arg His Phe Val Asn Leu Ser Pro Phe Thr Ile Thr Val Val 20 25 30 Leu Leu Leu Ser Ala Cys Phe Val Thr Ser Ser Leu Gly Gly Thr Asp 35 40 45 Lys Glu Leu Arg Leu Val Asp Gly Glu Asn Lys Cys Ser Gly Arg Val 50 55 60 Glu Val Lys Val Gln Glu Glu Trp Gly Thr Val Cys Asn Asn Gly Trp 65 70 75 80 Ser Met Glu Ala Val Ser Val Ile Cys Asn Gln Leu Gly Cys Pro Thr 85 90 95 Ala Ile Lys Ala Pro Gly Trp Ala Asn Ser Ser Ala Gly Ser Gly Arg 100 105 110 Ile Trp Met Asp His Val Ser Cys Arg Gly Asn Glu Ser Ala Leu Trp 115 120 125 Asp Cys Lys His Asp Gly Trp Gly Lys His Ser Asn Cys Thr His Gln 130 135 140 Gln Asp Ala Gly Val Thr Cys Ser Asp Gly Ser Asn Leu Glu Met Arg 145 150 155 160 Leu Thr Arg Gly Gly Asn Met Cys Ser Gly Arg Ile Glu Ile Lys Phe 165 170 175 Gln Gly Arg Trp Gly Thr Val Cys Asp Asp Asn Phe Asn Ile Asp His 180 185 190 Ala Ser Val Ile Cys Arg Gln Leu Glu Cys Gly Ser Ala Val Ser Phe 195 200 205 Ser Gly Ser Ser Asn Phe Gly Glu Gly Ser Gly Pro Ile Trp Phe Asp 210 215 220 Asp Leu Ile Cys Asn Gly Asn Glu Ser Ala Leu Trp Asn Cys Lys His 225 230 235 240 Gln Gly Trp Gly Lys His Asn Cys Asp His Ala Glu Asp Ala Gly Val 245 250 255 Ile Cys Ser Lys Gly Ala Asp Leu Ser Leu Arg Leu Val Asp Gly Val 260 265 270 Thr Glu Cys Ser Gly Arg Leu Glu Val Arg Phe Gln Gly Glu Trp Gly 275 280 285 Thr Ile Cys Asp Asp Gly Trp Asp Ser Tyr Asp Ala Ala Val Ala Cys 290 295 300 Lys Gln Leu Gly Cys Pro Thr Ala Val Thr Ala Ile Gly Arg Val Asn 305 310 315 320 Ala Ser

Lys Gly Phe Gly His Ile Trp Leu Asp Ser Val Ser Cys Gln 325 330 335 Gly His Glu Pro Ala Val Trp Gln Cys Lys His His Glu Trp Gly Lys 340 345 350 His Tyr Cys Asn His Asn Glu Asp Ala Gly Val Thr Cys Ser Asp Gly 355 360 365 Ser Asp Leu Glu Leu Arg Leu Arg Gly Gly Gly Ser Arg Cys Ala Gly 370 375 380 Thr Val Glu Val Glu Ile Gln Arg Leu Leu Gly Lys Val Cys Asp Arg 385 390 395 400 Gly Trp Gly Leu Lys Glu Ala Asp Val Val Cys Arg Gln Leu Gly Cys 405 410 415 Gly Ser Ala Leu Lys Thr Ser Tyr Gln Val Tyr Ser Lys Ile Gln Ala 420 425 430 Thr Asn Thr Trp Leu Phe Leu Ser Ser Cys Asn Gly Asn Glu Thr Ser 435 440 445 Leu Trp Asp Cys Lys Asn Trp Gln Trp Gly Gly Leu Thr Cys Asp His 450 455 460 Tyr Glu Glu Ala Lys Ile Thr Cys Ser Ala His Arg Glu Pro Arg Leu 465 470 475 480 Val Gly Gly Asp Ile Pro Cys Ser Gly Arg Val Glu Val Lys His Gly 485 490 495 Asp Thr Trp Gly Ser Ile Cys Asp Ser Asp Phe Ser Leu Glu Ala Ala 500 505 510 Ser Val Leu Cys Arg Glu Leu Gln Cys Gly Thr Val Val Ser Ile Leu 515 520 525 Gly Gly Ala His Phe Gly Glu Gly Asn Gly Gln Ile Trp Ala Glu Glu 530 535 540 Phe Gln Cys Glu Gly His Glu Ser His Leu Ser Leu Cys Pro Val Ala 545 550 555 560 Pro Arg Pro Glu Gly Thr Cys Ser His Ser Arg Asp Val Gly Val Val 565 570 575 Cys Ser Arg Tyr Thr Glu Ile Arg Leu Val Asn Gly Lys Thr Pro Cys 580 585 590 Glu Gly Arg Val Glu Leu Lys Thr Leu Gly Ala Trp Gly Ser Leu Cys 595 600 605 Asn Ser His Trp Asp Ile Glu Asp Ala His Val Leu Cys Gln Gln Leu 610 615 620 Lys Cys Gly Val Ala Leu Ser Thr Pro Gly Gly Ala Arg Phe Gly Lys 625 630 635 640 Gly Asn Gly Gln Ile Trp Arg His Met Phe His Cys Thr Gly Thr Glu 645 650 655 Gln His Met Gly Asp Cys Pro Val Thr Ala Leu Gly Ala Ser Leu Cys 660 665 670 Pro Ser Glu Gln Val Ala Ser Val Ile Cys Ser Gly Asn Gln Ser Gln 675 680 685 Thr Leu Ser Ser Cys Asn Ser Ser Ser Leu Gly Pro Thr Arg Pro Thr 690 695 700 Ile Pro Glu Glu Ser Ala Val Ala Cys Ile Glu Ser Gly Gln Leu Arg 705 710 715 720 Leu Val Asn Gly Gly Gly Arg Cys Ala Gly Arg Val Glu Ile Tyr His 725 730 735 Glu Gly Ser Trp Gly Thr Ile Cys Asp Asp Ser Trp Asp Leu Ser Asp 740 745 750 Ala His Val Val Cys Arg Gln Leu Gly Cys Gly Glu Ala Ile Asn Ala 755 760 765 Thr Gly Ser Ala His Phe Gly Glu Gly Thr Gly Pro Ile Trp Leu Asp 770 775 780 Glu Met Lys Cys Asn Gly Lys Glu Ser Arg Ile Trp Gln Cys His Ser 785 790 795 800 His Gly Trp Gly Gln Gln Asn Cys Arg His Lys Glu Asp Ala Gly Val 805 810 815 Ile Cys Ser Glu Phe Met Ser Leu Arg Leu Thr Ser Glu Ala Ser Arg 820 825 830 Glu Ala Cys Ala Gly Arg Leu Glu Val Phe Tyr Asn Gly Ala Trp Gly 835 840 845 Thr Val Gly Lys Ser Ser Met Ser Glu Thr Thr Val Gly Val Val Cys 850 855 860 Arg Gln Leu Gly Cys Ala Asp Lys Gly Lys Ile Asn Pro Ala Ser Leu 865 870 875 880 Asp Lys Ala Met Ser Ile Pro Met Trp Val Asp Asn Val Gln Cys Pro 885 890 895 Lys Gly Pro Asp Thr Leu Trp Gln Cys Pro Ser Ser Pro Trp Glu Lys 900 905 910 Arg Leu Ala Ser Pro Ser Glu Glu Thr Trp Ile Thr Cys Asp Asn Lys 915 920 925 Ile Arg Leu Gln Glu Gly Pro Thr Ser Cys Ser Gly Arg Val Glu Ile 930 935 940 Trp His Gly Gly Ser Trp Gly Thr Val Cys Asp Asp Ser Trp Asp Leu 945 950 955 960 Asp Asp Ala Gln Val Val Cys Gln Gln Leu Gly Cys Gly Pro Ala Leu 965 970 975 Lys Ala Phe Lys Glu Ala Glu Phe Gly Gln Gly Thr Gly Pro Asp Met 980 985 990 Ala Gln 17 745 PRT Homo sapien 17 Met Glu Arg Pro Pro Gly Leu Arg Pro Gly Ala Gly Gly Pro Trp Glu 1 5 10 15 Met Arg Glu Arg Leu Gly Thr Gly Gly Phe Gly Asn Val Cys Leu Tyr 20 25 30 Gln His Arg Glu Leu Asp Leu Lys Ile Ala Ile Lys Ser Cys Arg Leu 35 40 45 Glu Leu Ser Thr Lys Asn Arg Glu Arg Trp Cys His Glu Ile Gln Ile 50 55 60 Met Lys Lys Leu Asn His Ala Asn Val Val Lys Ala Cys Asp Val Pro 65 70 75 80 Glu Glu Leu Asn Ile Leu Ile His Asp Val Pro Leu Leu Ala Met Glu 85 90 95 Tyr Cys Ser Gly Gly Asp Leu Arg Lys Leu Leu Asn Lys Pro Glu Asn 100 105 110 Cys Cys Gly Leu Lys Glu Ser Gln Ile Leu Ser Leu Leu Ser Asp Ile 115 120 125 Gly Ser Gly Ile Arg Tyr Leu His Glu Asn Lys Ile Ile His Arg Asp 130 135 140 Leu Lys Pro Glu Asn Ile Val Leu Gln Asp Val Gly Gly Lys Ile Ile 145 150 155 160 His Lys Ile Ile Asp Leu Gly Tyr Ala Lys Asp Val Asp Gln Gly Ser 165 170 175 Leu Cys Thr Ser Phe Val Gly Thr Leu Gln Tyr Leu Ala Pro Glu Leu 180 185 190 Phe Glu Asn Lys Pro Tyr Thr Ala Thr Val Asp Tyr Trp Ser Phe Gly 195 200 205 Thr Met Val Phe Glu Cys Ile Ala Gly Tyr Arg Pro Phe Leu His His 210 215 220 Leu Gln Pro Phe Thr Trp His Glu Lys Ile Lys Lys Lys Asp Pro Lys 225 230 235 240 Cys Ile Phe Ala Cys Glu Glu Met Ser Gly Glu Val Arg Phe Ser Ser 245 250 255 His Leu Pro Gln Pro Asn Ser Leu Cys Ser Leu Val Val Glu Pro Met 260 265 270 Glu Asn Trp Leu Gln Leu Met Leu Asn Trp Asp Pro Gln Gln Arg Gly 275 280 285 Gly Pro Val Asp Leu Thr Leu Lys Gln Pro Arg Cys Phe Val Leu Met 290 295 300 Asp His Ile Leu Asn Leu Lys Ile Val His Ile Leu Asn Met Thr Ser 305 310 315 320 Ala Lys Ile Ile Ser Phe Leu Leu Pro Pro Asp Glu Ser Leu His Ser 325 330 335 Leu Gln Ser Arg Ile Glu Arg Glu Thr Gly Ile Asn Thr Gly Ser Gln 340 345 350 Glu Leu Leu Ser Glu Thr Gly Ile Ser Leu Asp Pro Arg Lys Pro Ala 355 360 365 Ser Gln Cys Val Leu Asp Gly Val Arg Gly Cys Asp Ser Tyr Met Val 370 375 380 Tyr Leu Phe Asp Lys Ser Lys Thr Val Tyr Glu Gly Pro Phe Ala Ser 385 390 395 400 Arg Ser Leu Ser Asp Cys Val Asn Tyr Ile Val Gln Asp Ser Lys Ile 405 410 415 Gln Leu Pro Ile Ile Gln Leu Arg Lys Val Trp Ala Glu Ala Val His 420 425 430 Tyr Val Ser Gly Leu Lys Glu Asp Tyr Ser Arg Leu Phe Gln Gly Gln 435 440 445 Arg Ala Ala Met Leu Ser Leu Leu Arg Tyr Asn Ala Asn Leu Thr Lys 450 455 460 Met Lys Asn Thr Leu Ile Ser Ala Ser Gln Gln Leu Lys Ala Lys Leu 465 470 475 480 Glu Phe Phe His Lys Ser Ile Gln Leu Asp Leu Glu Arg Tyr Ser Glu 485 490 495 Gln Met Thr Tyr Gly Ile Ser Ser Glu Lys Met Leu Lys Ala Trp Lys 500 505 510 Glu Met Glu Glu Lys Ala Ile His Tyr Ala Glu Val Gly Val Ile Gly 515 520 525 Tyr Leu Glu Asp Gln Ile Met Ser Leu His Ala Glu Ile Met Glu Leu 530 535 540 Gln Lys Ser Pro Tyr Gly Arg Arg Gln Gly Asp Leu Met Glu Ser Leu 545 550 555 560 Glu Gln Arg Ala Ile Asp Leu Tyr Lys Gln Leu Lys His Arg Pro Ser 565 570 575 Asp His Ser Tyr Ser Asp Ser Thr Glu Met Val Lys Ile Ile Val His 580 585 590 Thr Val Gln Ser Gln Asp Arg Val Leu Lys Glu Leu Phe Gly His Leu 595 600 605 Ser Lys Leu Leu Gly Cys Lys Gln Lys Ile Ile Asp Leu Leu Pro Lys 610 615 620 Val Glu Val Ala Leu Ser Asn Ile Lys Glu Ala Asp Asn Thr Val Met 625 630 635 640 Phe Met Gln Gly Lys Arg Gln Lys Glu Ile Trp His Leu Leu Lys Ile 645 650 655 Ala Cys Thr Gln Ser Ser Ala Arg Ser Leu Val Gly Ser Ser Leu Glu 660 665 670 Gly Ala Val Thr Pro Gln Thr Ser Ala Trp Leu Pro Pro Thr Ser Ala 675 680 685 Glu His Asp His Ser Leu Ser Cys Val Val Thr Pro Gln Asp Gly Glu 690 695 700 Thr Ser Ala Gln Met Ile Glu Glu Asn Leu Asn Cys Leu Gly His Leu 705 710 715 720 Ser Thr Ile Ile His Glu Ala Asn Glu Glu Gln Gly Asn Ser Met Met 725 730 735 Asn Leu Asp Trp Ser Trp Leu Thr Glu 740 745 18 142 PRT Homo sapien 18 Met Gly Ala Pro Thr Leu Pro Pro Ala Trp Gln Pro Phe Leu Lys Asp 1 5 10 15 His Arg Ile Ser Thr Phe Lys Asn Trp Pro Phe Leu Glu Gly Cys Ala 20 25 30 Cys Thr Pro Glu Arg Met Ala Glu Ala Gly Phe Ile His Cys Pro Thr 35 40 45 Glu Asn Glu Pro Asp Leu Ala Gln Cys Phe Phe Cys Phe Lys Glu Leu 50 55 60 Glu Gly Trp Glu Pro Asp Asp Asp Pro Ile Glu Glu His Lys Lys His 65 70 75 80 Ser Ser Gly Cys Ala Phe Leu Ser Val Lys Lys Gln Phe Glu Glu Leu 85 90 95 Thr Leu Gly Glu Phe Leu Lys Leu Asp Arg Glu Arg Ala Lys Asn Lys 100 105 110 Ile Ala Lys Glu Thr Asn Asn Lys Lys Lys Glu Phe Glu Glu Thr Ala 115 120 125 Lys Lys Val Arg Arg Ala Ile Glu Gln Leu Ala Ala Met Asp 130 135 140 19 165 PRT Homo sapien 19 Met Gly Ala Pro Thr Leu Pro Pro Ala Trp Gln Pro Phe Leu Lys Asp 1 5 10 15 His Arg Ile Ser Thr Phe Lys Asn Trp Pro Phe Leu Glu Gly Cys Ala 20 25 30 Cys Thr Pro Glu Arg Met Ala Glu Ala Gly Phe Ile His Cys Pro Thr 35 40 45 Glu Asn Glu Pro Asp Leu Ala Gln Cys Phe Phe Cys Phe Lys Glu Leu 50 55 60 Glu Gly Trp Glu Pro Asp Asp Asp Pro Ile Gly Pro Gly Thr Val Ala 65 70 75 80 Tyr Ala Cys Asn Thr Ser Thr Leu Gly Gly Arg Gly Gly Arg Ile Thr 85 90 95 Arg Glu Glu His Lys Lys His Ser Ser Gly Cys Ala Phe Leu Ser Val 100 105 110 Lys Lys Gln Phe Glu Glu Leu Thr Leu Gly Glu Phe Leu Lys Leu Asp 115 120 125 Arg Glu Arg Ala Lys Asn Lys Ile Ala Lys Glu Thr Asn Asn Lys Lys 130 135 140 Lys Glu Phe Glu Glu Thr Ala Lys Lys Val Arg Arg Ala Ile Glu Gln 145 150 155 160 Leu Ala Ala Met Asp 165 20 137 PRT Homo sapien 20 Met Gly Ala Pro Thr Leu Pro Pro Ala Trp Gln Pro Phe Leu Lys Asp 1 5 10 15 His Arg Ile Ser Thr Phe Lys Asn Trp Pro Phe Leu Glu Gly Cys Ala 20 25 30 Cys Thr Pro Glu Arg Met Ala Glu Ala Gly Phe Ile His Cys Pro Thr 35 40 45 Glu Asn Glu Pro Asp Leu Ala Gln Cys Phe Phe Cys Phe Lys Glu Leu 50 55 60 Glu Gly Trp Glu Pro Asp Asp Asp Pro Met Gln Arg Lys Pro Thr Ile 65 70 75 80 Arg Arg Lys Asn Leu Arg Lys Leu Arg Arg Lys Cys Ala Val Pro Ser 85 90 95 Ser Ser Trp Leu Pro Trp Ile Glu Ala Ser Gly Arg Ser Cys Leu Val 100 105 110 Pro Glu Trp Leu His His Phe Gln Gly Leu Phe Pro Gly Ala Thr Ser 115 120 125 Leu Pro Val Gly Pro Leu Ala Met Ser 130 135 21 142 PRT Homo sapien 21 Met Gly Ala Pro Thr Leu Pro Pro Ala Trp Gln Pro Phe Leu Lys Asp 1 5 10 15 His Arg Ile Ser Thr Phe Lys Asn Trp Pro Phe Leu Glu Gly Cys Ala 20 25 30 Cys Thr Pro Glu Arg Met Ala Glu Ala Gly Phe Ile His Cys Pro Thr 35 40 45 Glu Asn Glu Pro Asp Leu Ala Gln Cys Phe Phe Cys Phe Lys Glu Leu 50 55 60 Glu Gly Trp Glu Pro Asp Asp Asp Pro Ile Glu Glu His Lys Lys His 65 70 75 80 Ser Ser Gly Cys Ala Phe Leu Ser Val Lys Lys Gln Phe Glu Glu Leu 85 90 95 Thr Leu Gly Glu Phe Leu Lys Leu Asp Arg Glu Arg Ala Lys Asn Lys 100 105 110 Ile Ala Lys Glu Thr Asn Asn Lys Lys Lys Glu Phe Glu Glu Thr Ala 115 120 125 Lys Lys Val Arg Arg Ala Ile Glu Gln Leu Ala Ala Met Asp 130 135 140 22 165 PRT Homo sapien 22 Met Gly Ala Pro Thr Leu Pro Pro Ala Trp Gln Pro Phe Leu Lys Asp 1 5 10 15 His Arg Ile Ser Thr Phe Lys Asn Trp Pro Phe Leu Glu Gly Cys Ala 20 25 30 Cys Thr Pro Glu Arg Met Ala Glu Ala Gly Phe Ile His Cys Pro Thr 35 40 45 Glu Asn Glu Pro Asp Leu Ala Gln Cys Phe Phe Cys Phe Lys Glu Leu 50 55 60 Glu Gly Trp Glu Pro Asp Asp Asp Pro Ile Gly Pro Gly Thr Val Ala 65 70 75 80 Tyr Ala Cys Asn Thr Ser Thr Leu Gly Gly Arg Gly Gly Arg Ile Thr 85 90 95 Arg Glu Glu His Lys Lys His Ser Ser Gly Cys Ala Phe Leu Ser Val 100 105 110 Lys Lys Gln Phe Glu Glu Leu Thr Leu Gly Glu Phe Leu Lys Leu Asp 115 120 125 Arg Glu Arg Ala Lys Asn Lys Ile Ala Lys Glu Thr Asn Asn Lys Lys 130 135 140 Lys Glu Phe Glu Glu Thr Ala Lys Lys Val Arg Arg Ala Ile Glu Gln 145 150 155 160 Leu Ala Ala Met Asp 165 23 137 PRT Homo sapien 23 Met Gly Ala Pro Thr Leu Pro Pro Ala Trp Gln Pro Phe Leu Lys Asp 1 5 10 15 His Arg Ile Ser Thr Phe Lys Asn Trp Pro Phe Leu Glu Gly Cys Ala 20 25 30 Cys Thr Pro Glu Arg Met Ala Glu Ala Gly Phe Ile His Cys Pro Thr 35 40 45 Glu Asn Glu Pro Asp Leu Ala Gln Cys Phe Phe Cys Phe Lys Glu Leu 50 55 60 Glu Gly Trp Glu Pro Asp Asp Asp Pro Met Gln Arg Lys Pro Thr Ile 65 70 75 80 Arg Arg Lys Asn Leu Arg Lys Leu Arg Arg Lys Cys Ala Val Pro Ser 85 90 95 Ser Ser Trp Leu Pro Trp Ile Glu Ala Ser Gly Arg Ser Cys Leu Val 100 105 110 Pro Glu Trp Leu His His Phe Gln Gly Leu Phe Pro Gly Ala Thr Ser 115 120 125 Leu Pro Val Gly Pro Leu Ala Met Ser 130 135 24 132 PRT Homo sapien 24 Met Ala Phe Asp Ser Thr Trp Lys Val Asp Arg Ser Glu Asn Tyr Asp 1 5 10 15 Lys Phe Met Glu Lys Met Gly Val Asn Ile Val Lys Arg Lys Leu Ala 20 25 30 Ala His Asp Asn Leu Lys Leu Thr Ile Thr Gln Glu Gly Asn Lys Phe 35 40 45 Thr Val Lys Glu Ser Ser Ala Phe Arg Asn Ile Glu Val Val Phe Glu 50 55 60 Leu Gly Val Thr Phe Asn Tyr Asn Leu Ala Asp Gly Thr Glu Leu Arg 65 70 75 80 Gly Thr Trp Ser Leu Glu Gly Asn Lys Leu Ile Gly Lys Phe Lys Arg 85 90 95 Thr Asp Asn Gly Asn Glu Leu Asn Thr Val Arg Glu Ile Ile Gly Asp 100 105 110 Glu Leu Val

Gln Thr Tyr Val Tyr Glu Gly Val Glu Ala Lys Arg Ile 115 120 125 Phe Lys Lys Asp 130 25 201 DNA Homo sapien 25 ggctgtgcag acaaagggaa aatcaaccct gcatctttag acaaggccat gtccattccc 60 atgtgggtgg acaatgttca gtgtccaaaa ggacctgaca ygctgtggca gtgcccatca 120 tctccatggg agaagagact ggccagcccc tcggaggaga cctggatcac atgtgacaac 180 aagataagac ttcaggaagg a 201 26 201 DNA Homo sapien 26 ggctgtgcag acaaagggaa aatcaaccct gcatctttag acaaggccat gtccattccc 60 atgtgggtgg acaatgttca gtgtccaaaa ggacctgaca ygctgtggca gtgcccatca 120 tctccatggg agaagagact ggccagcccc tcggaggaga cctggatcac atgtgacaac 180 aagataagac ttcaggaagg a 201 27 201 DNA Homo sapien 27 ggctgtgcag acaaagggaa aatcaaccct gcatctttag acaaggccat gtccattccc 60 atgtgggtgg acaatgttca gtgtccaaaa ggacctgaca ygctgtggca gtgcccatca 120 tctccatggg agaagagact ggccagcccc tcggaggaga cctggatcac atgtgacaac 180 aagataagac ttcaggaagg a 201 28 201 DNA Homo sapien 28 ggctgtgcag acaaagggaa aatcaaccct gcatctttag acaaggccat gtccattccc 60 atgtgggtgg acaatgttca gtgtccaaaa ggacctgaca ygctgtggca gtgcccatca 120 tctccatggg agaagagact ggccagcccc tcggaggaga cctggatcac atgtgacaac 180 aagataagac ttcaggaagg a 201 29 201 DNA Homo sapien 29 taagaagaag gatccaaagt gtatatttgc atgtgaagag atgtcaggag aagttcggtt 60 tagtagccat ttacctcaac caaatagcct ttgtagttta rtagtagaac ccatggaaaa 120 ctggctacag ttgatgttga attgggaccc tcagcagaga ggaggacctg ttgaccttac 180 tttgaagcag ccaagatgtt t 201 30 201 DNA Homo sapien 30 attaaccctt ggtgaatttt tgaaactgga cagagaaaga gccaagaaca aaattgcaaa 60 ggaaaccaac aataagaaga aagaatttga ggaaactgcg ragaaagtgc gccgtgccat 120 cgagcagctg gctgccatgg attgaggcct ctggccggag ctgcctggtc ccagagtggc 180 tgcaccactt ccagggttta t 201 31 201 DNA Homo sapien 31 attaaccctt ggtgaatttt tgaaactgga cagagaaaga gccaagaaca aaattgcaaa 60 ggaaaccaac aataagaaga aagaatttga ggaaactgcg ragaaagtgc gccgtgccat 120 cgagcagctg gctgccatgg attgaggcct ctggccggag ctgcctggtc ccagagtggc 180 tgcaccactt ccagggttta t 201 32 201 DNA Homo sapien 32 agtgtttctt ctgcttcaag gagctggaag gctgggagcc agatgacgac cccatgcaaa 60 ggaaaccaac aataagaaga aagaatttga ggaaactgcg ragaaagtgc gccgtgccat 120 cgagcagctg gctgccatgg attgaggcct ctggccggag ctgcctggtc ccagagtggc 180 tgcaccactt ccagggttta t 201 33 201 DNA Homo sapien 33 attaaccctt ggtgaatttt tgaaactgga cagagaaaga gccaagaaca aaattgcaaa 60 ggaaaccaac aataagaaga aagaatttga ggaaactgcg ragaaagtgc gccgtgccat 120 cgagcagctg gctgccatgg attgaggcct ctggccggag ctgcctggtc ccagagtggc 180 tgcaccactt ccagggttta t 201 34 201 DNA Homo sapien 34 attaaccctt ggtgaatttt tgaaactgga cagagaaaga gccaagaaca aaattgcaaa 60 ggaaaccaac aataagaaga aagaatttga ggaaactgcg ragaaagtgc gccgtgccat 120 cgagcagctg gctgccatgg attgaggcct ctggccggag ctgcctggtc ccagagtggc 180 tgcaccactt ccagggttta t 201 35 201 DNA Homo sapien 35 agtgtttctt ctgcttcaag gagctggaag gctgggagcc agatgacgac cccatgcaaa 60 ggaaaccaac aataagaaga aagaatttga ggaaactgcg ragaaagtgc gccgtgccat 120 cgagcagctg gctgccatgg attgaggcct ctggccggag ctgcctggtc ccagagtggc 180 tgcaccactt ccagggttta t 201 36 201 DNA Homo sapien 36 aatgggtgtt aatatagtga aaaggaagct tgcagctcat gacaatttga agctgacaat 60 tacacaagaa ggaaataaat tcacagtcaa agaatcaagc rcttttcgaa acattgaagt 120 tgtttttgaa cttggtgtca cctttaatta caatctagca gacggaactg aactcagggg 180 gacctggagc cttgagggaa a 201 37 52764 DNA Homo sapien misc_feature 6568, 6569, 6570, 6571, 6572, 6573, 6574, 6575, 6576, 6577, 6578, 6579, 6580, 6581, 6582, 6583, 6584, 6585, 6586, 6587, 6588, 6589, 6590, 6591, 6592, 6593, 6594, 6595, 6596, 6597, 6598, 6599, 6600, 6601, 6602, 6603, 6604, 6605, 6606 n = A,T,C or G misc_feature 6607, 6608, 6609, 6610, 6611, 6612, 6613, 6614, 6615, 6616, 6617, 6618, 6619, 6620, 6621, 6622, 6623, 6624, 6625, 6626, 6627, 6628, 6629, 6630, 6631, 6632, 6633, 6634, 6635, 6636, 6637, 6638, 6639, 6640, 6641, 6642, 6643, 6644, 6645 n = A,T,C or G misc_feature 6646, 6647, 6648, 6649, 6650, 6651, 6652, 6653, 6654, 6655, 6656, 6657, 6658, 6659, 6660, 6661, 6662, 6663, 6664, 6665, 6666, 6667, 6668, 6669, 6670, 6671, 6672, 6673, 6674, 6675, 6676, 6677, 6678, 6679, 6680, 6681, 6682, 6683, 6684 n = A,T,C or G misc_feature 6685, 6686, 6687, 6688, 6689, 6690, 6691, 6692, 6693, 6694, 6695, 6696, 6697, 6698, 6699, 6700, 6701, 6702, 6703, 6704, 6705, 6706, 6707, 6708, 6709, 6710, 6711, 6712, 6713, 6714, 6715, 6716, 6717, 6718, 6719, 6720, 6721, 6722, 6723 n = A,T,C or G misc_feature 6724, 6725, 6726, 6727, 6728, 6729, 6730, 6731, 6732, 6733, 6734, 6735, 6736, 6737, 6738, 6739, 6740, 6741, 6742, 6743, 6744, 6745, 6746, 6747, 6748, 6749, 6750, 6751, 6752, 6753, 6754, 6755, 6756, 6757, 6758, 13921, 13922, 13923 n = A,T,C or G misc_feature 13924, 13925, 13926, 13927, 13928, 13929, 13930, 13931, 13932, 13933, 13934, 13935, 13936, 13937, 13938, 13939, 13940, 17414, 17415, 17416, 17417, 17418, 17419, 17420, 17421, 17422, 17423, 17424, 17425, 17426, 17427, 17428, 17429 n = A,T,C or G 37 ctgactttga caaaattagt gactttattc cgaaaaggga cacaatgaga ttactaacaa 60 gcctcaaatc tattccaaaa ttcagaacaa gtttcaaaat ctgataccat tccctttatt 120 tattcctctt ctttttccca ttccccatga atatgcccac ataaaaatgt cacaaatttc 180 tgagtaaatc atctgctaac ctacaggtcc actcaacatt tttgtgtctt cagcttcccc 240 caagcctggc cctttttgga gggtttgact tcacaattgt tgtaaatctt aaagattgag 300 ctgctggtgg acttctctct ttcttttgtc ctccaccaat aatagctcac aaagattttt 360 aaaaacatct ttattggagc atagttaata tacaataagc tgcacatatt taagtgttcc 420 attagtttag ttttgacgta tgtgtatacc tgtgaaatta tcaacacaat aaagacaatg 480 aacatatcaa ttactccaaa aaacttcatc atgattaccc ctcattgtga ttctttcctt 540 gcactccttc ccatccatct ctaagcaacc actgcatcta gtcacagtcg attaattttc 600 actttccaga attctatata aatagaatca cacggtataa gatttgtaag aatatactgt 660 ccaacactgc tattgaaatt aacctatttt ctgtttttac agcaccaata acaattagct 720 tttaaacttt atcttttgcc attatctaga cttgcacact taatcacaac attttacaag 780 agtaaaattt cacagtctct ttcactgtgt cataaaatac cgtaagaagg aatcaatttg 840 gcttccccaa taccaaatct gtattagtca gggtccttca gagaggcgga tccagtaaga 900 catatatata tatagacatt gagagagaat ttattagggg aattggcttg cataattttg 960 gtggctgaaa agtcccatga taggctttct gtaagctgaa gaccatggga tgactgtagc 1020 atgactcagc ccaagtccaa aggcctgagc accaggggag cccatggtgt aactctcagt 1080 ctgagaccaa aagtcttagc attctggagc cactccagat gtaagtgctg aagtcgaaag 1140 gccagtgagc ctgcagttct gctgtccaaa gtagcacaag aaaagtctgg cccagctctc 1200 aaagagagac caattttcct tctgtatttg ttctctctgg atccctgatg caggccagcg 1260 ctgagggaag gtcttcccca cctagtccac tcagactcac acactaatct tatccattat 1320 tttggatgtg tctggaagca ctcttacaga catgaaaaat aatgctttat caagtgtcta 1380 gaatccttaa tccaatcaag ttgacaccta aaattatgtc tataaatcca ccccttgtca 1440 acttggcacc catacttaat tgcatctcct taacctatat ttaatttcca aataaagaca 1500 ataccaaggg aatagttccg cctaacgtgt tgtaaacaac agaatgcaac tatcctgtat 1560 gcaaccaaaa atgtactgat ctgttccaca gaattcaact ttcagaattt caacattctg 1620 aattgtaatt tttgcaattt ttgatgttag gaatttttag atttcagaga tgttgatctt 1680 tagggatttt gaactttggg attttaacat ttaggattat ggcatttgta attgcatgtt 1740 ttgagattat aatcagcact ctccccaact ccccaaaaaa gaaactacac aacatagact 1800 ccgagtttta taaacagcaa tttatttctt tgttttggag gctggaagtt caagatcaag 1860 atgctgtcag attcagtgtc tggtgagagt ccacttccag ggttatagat taccattttt 1920 tagctgtact tcacacggca aaagggatca gtcttctctc agggatctct ttcatgaggg 1980 caataacccc attcatgaag gcagagccct catgacctaa ttatctccca aaggccctac 2040 ctactaatac ctttgaggtt aggatttcaa catatgaatt ttgaggagac acaaacattt 2100 agaccatagc actaagtaat attttgttta attccagaca ttgtaaacta aacttcgctg 2160 agttttaaat tatttttatt gctttagata ttctaacgtt tagtctagaa tgttgttata 2220 ttcttggaaa caatttgatt ctttgggtct tgtctttaaa atttgttagg tgggatctaa 2280 tcagcaagta gctagggcta cttatttccc accactgtgg taagactcat ctgtgaactc 2340 tacccaatac cccatgactt gtgagttttc catgtgaaca gtcacttttc ctggccctgt 2400 gtgtaactct aatcctttca ttattctttc cccaggctca ggtgatttgc tcacatgcat 2460 gcacttaaca atactcagct gaatactcaa aggggactct acagatattc agctctctct 2520 ccttgcctcc tccctactct ctctctctct ctctttctct ctctctttct tcttgcaagt 2580 ttctcctctg tgagactatt tgctgtgaat tctagccacc ttagtctccc agattctcag 2640 ctgcttcttc ccaactctga gactcctctg atcattctct gggtttccta ttccatggta 2700 gcctggaaac tatctcaagg cagtaaactc agcttagctt ctcatctctc atggatcact 2760 atctttgaga tccaggcaac aactcttctt gttgcctcat tttcagtgtc ttgaaaatca 2820 ttgttacaca tgtttggctt tgtttttagt tgtttctggt gggacagtaa acacacttcc 2880 tgtttcttca ttttgaataa aagcaaaaat gtcttgttca cctagctttt taattttgca 2940 ccaatctatt tcttccattt ttctactgta tcttttcaat cgggctctta ttctattaga 3000 tttttgctat aatattcact tgcactgcat ttaatcttgc tcttatttcc atttttaccc 3060 tggccaccaa tcatcctcaa agttgctacc aagatgagat atgtaaaaga caaagcaatt 3120 taatactcat gtttcaaact atttaatgtc attacttgcc tacagtgtaa aattataatt 3180 ctttaacatg gtatataaaa ctcctcttca tgtagtcctt gtttacctca gcaataataa 3240 caacattgtc aacaacaaca acaaaatagg taatattgag cctagcatct ggcagggact 3300 ggtagatatc tttttgaaaa aaacacagtt cctatcctgg tatcttaaga ctagcaagta 3360 agataaacaa taaatataaa aatataattg ggaggggtgg agccaagatg gccaaatagg 3420 aacagctccg gtctacagct cccagcgtga acaacgcaga agacgtgtga tttctgcatt 3480 tccatctgag gtactgggtt catctcacta gggagtgcca gacagtgggt gcaggatagt 3540 gggtgcagcg cactgtgcac aaaccgaagc agggcgaggc attgcctcac tagagaagcg 3600 caagaggtca gggagttccc tttcccagtc aaagaaaggg gtgacagagg gcacctggaa 3660 aatcaggtca ctcccaccct aatactgcgc ttttccaacg ggcttaaaaa acagcacacc 3720 aggagattat atcccgcaca tggctcggag ggtcctacac ccatggagtc tcactgattg 3780 ctagcacagc agtctgagat caaactgcaa ggcagcagcg aagctggggg aggggcgcct 3840 gccattgccc aggctcgatt aggtaaacaa agcagctggg aacctcgaac tgggtggagc 3900 ccaccacagc tcaaggaggc ctgcctgcct ctgtaggctc cacctctggg ggcagggtac 3960 agacaaacaa aaagacagca gtaacctctg cagacttaaa tgtccctgtc tgacaacttt 4020 gaagagagta gtggttctcc cagcacgcag ctggagatct gcgaatgtgc agactgcctc 4080 ctaaagtggg tccatgaccc ccgagcagcc taactgggag gcatccccca gtaggagcag 4140 actgacacct cacacggccg ggtgctcctc tgagacaaaa cttccagagg aacaatcagg 4200 cagcagcatt tgcagttcac caagatccgc tcttctacag ccactgctgt tctgcagcca 4260 ctgctgctga tacacaggca aacagggtct ggagtggacc tccagcaaac tccaacagac 4320 ctgcagctga gggtcctgac tgttagaagg aaaactaaca aacagaaagg acatctgcac 4380 caaaaaccct tctgtacatc atcatcatca aagaccaaaa gtagataaaa ccacaaagat 4440 ggggaagaaa cagagcagaa aaactggaaa ctctaaaaag cagagtgcct ctgctactcc 4500 gaaggaatgc agctcctcac cagcaatgga acaaagctgg atggagaatg actttgacga 4560 gctgagagaa gaagtcttca gatgatcaaa ctactccgag ctacaggagg aaattcaaat 4620 caatggcaaa gaagttaaaa actgtgaaaa aaaaatagat gaatggataa ctagaataac 4680 caacgcagag aagtccttaa aggagctgat ggagctgaaa gccaaggctc aagaactacg 4740 tgaagaatgc agaaggctca ggagccaatg cgatcaactg gaagaaaggt tatcagtgat 4800 ggaagacaaa atgaatgaaa tgaagtgaga agggaagttt agagaaaaaa gaataaaaag 4860 aaacaaagcc tccaagaaat atgggactat gtgaaaagac caaatctacg tctgattggt 4920 gtacctgaaa gtgatgggga gaatggaacc aagttggaaa acactctgca ggatattatc 4980 catgagaact tccccaatct agcaaggcag gccaacatac agattcagga aatacagaga 5040 acaccacaaa gatactcctc gagaagagca actccaagac acataattgt cagattcacc 5100 aaagttgaaa tgaaggaaaa aatgttaagg gcagccagag agaaaggtcg ggttacccac 5160 aaagggaagc ccatcagact aacagcggat ctctcggcag aaactctaca agccagaaga 5220 gagtgggggc caatattcaa cattcttaaa gaaaagaatt ttcaacccag aatttcatat 5280 ccagccaaac taagcttcat aagtgaagga gaaataactt tacagacaag caaatgctga 5340 gagattttgt caccaccagg cctgccctaa aagagctcct gaaggaagca ctaaacatag 5400 aaaggaacaa ctggtaccag ccactgccaa aacatgacaa aatgtaaaga ctatcaaggc 5460 taggaagaaa ctgcatcaac agaaatcata gtaaactgtc tctcagacca cagtgcaatc 5520 aaactagaac tcaggattaa gaaattcact caaaactgct caaccacatg gaaactgaac 5580 aacctgctcc tgaatgacta ctgggtaaat aatgaaatga aggcagaaat aaagatgttc 5640 tttgaaacca acgagaacaa agacacaaca taccagaatc tttgggacac attcaaagca 5700 gtgtgtagag ggaaatttat agcactaaat acccacaaga gaaagcagga aagatccaaa 5760 attgacaccc taacgtcaca attaaaagaa ctagaaaagc aagagcaaac acattcaaaa 5820 gctagcagaa ggcaagaaat aactaaaatc agagcagaac tgaaggaaat agagacacaa 5880 aaaacctttc aaaaaattaa tgaatctggg agctggtttt ttgaaaacgt caacaaaatc 5940 gatagactgc tagcaagact aataaagaag acaagaaaga agaatcaaat agacacaata 6000 aaaattgata aaggggatat caccaccgat cccacagaaa tacaaactac catcagagaa 6060 tactacaaac acctctacgc aaataaacta gaaaatctag aagaaatgga taaattcctc 6120 gacacataca ccctcccaag actaagcgag gaagaaattc aatctctgaa tagaccaata 6180 acaggctctg aaattgtggc aataatcaat agcttaccaa ccaaaaaaag tccaggagca 6240 ggtggattca cagccaaatt ctaccagagg tacaaggagg agttggtacc attccttctg 6300 aaactattcc aatcaataga aaaagaggga atcctcccta actcattatt ttatgaggcc 6360 agcatcatcc tgataccaaa gcctggcaga gacacaacca aaaaagagaa ttttagacca 6420 atatccttga tgaacattga tgcaaaaatc ctcgataaaa tactggcaaa ccaaatccag 6480 cagcacatca aaaagcttat ccaccatgat caagtgggct tcttcgctgg gatgcaaggg 6540 tggttcaaca tactcaaatc aataaatnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 6600 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 6660 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 6720 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnca ccactcctat tcaagatagt 6780 gttagaagtt ctggccatgg caattaggca ggagaagaaa ataaagggta ttcaattagg 6840 aaaagaggaa gtcaaaattg tccctgtttg cagatgacat gattgtatat ttagaaaacc 6900 cccatcgtct cagcccaaaa tctccttaag ctgataagca acttcagcaa agtctcagga 6960 tacaaaatca atgtacaaaa atcacaagca ttcttataca ccaataacag acaaacagag 7020 agccaaatca tgagtgaact cccattcaca attgcttcaa agagaataaa atacctagga 7080 atccaactta caagggatgt gaaggacctc ttcaaggaga actacaaacc actgctcaat 7140 gaaataaaag aggataccaa caaatggaag aacattccat gctcatgggt aggaagaatc 7200 aatatcatga aaatggccat actgcccaag gtaatttata gattcaatgc catccccatc 7260 aagctaccaa tgactttctt cacagaattg gaaaaaacta ctttaaagtt catatggaac 7320 caaaaaagag cccacatccc caagtcaatc ctaagccaaa agaacaaagc tggaggcatc 7380 acgctacctg acttcaaact atactacaag gctacagtaa ccaaaacagc atggtactgg 7440 taccaaaaca gagatataga tcaatggaac agaacagagc cctcagaaat aatgccgcat 7500 atctacaacc atctgatctt tgacaaacct gacaaaaaca agcaatgggg aaaggattcc 7560 ctatttaata aatgttgctg ggaaaactgg ctagccatat gtagaaagct gaaactggat 7620 cccttcctta caccttatac aaaaattaat tcaagatgga ttaaagactt acatgttaga 7680 cctaaaacca taaaaaccct agaagaaaac ctaggcaata ccattcagga cataggcatg 7740 ggcaaggact tcatatctaa aacaccaaaa gcaatggcaa caaaagccaa aatagacaaa 7800 tgggatctaa ttaaactaaa gagcttctgc acagcaaaag aaactaccat cagagtgaac 7860 aggaaatcta caaaatggga gaaaattttc gcaacctact catctgacaa agggttaata 7920 tccagaatct acaatgacct caaacaaatt tacaagaaaa aaacaaacaa ccccatcaaa 7980 aattggcgaa ggatatgaac agatacttct caaaagaaga catttatgca gccaaaaaac 8040 acatgaaaaa atgctcatca tcactggcca tcagagaaac gcaaatcaaa accacaagga 8100 gataccatct cacaccagtt agaatggtga tcattaaaaa gtcaggaaac aataggtgct 8160 ggagaggatg tggagaaata ggcatgcttt tacactgttg gtgggactgt aaactaattc 8220 aaccattgtg gaagtcagtg tggcaattcc tcagggatct agaactagaa ataccatttg 8280 acccagccat cccatttctg ggtatatacc caaaggatta taaatcatgc tgctataaag 8340 acacatgcac acgtacgttt atagcggcac tactcgcaat agcaaagact tggaaccaac 8400 ccaaatgtcc atcaatgata gactggatta agaaaatgtg gcacatatat accatggaat 8460 actatgcagc cataaaaaat gatgagttca tgtcctttgt agggacatgg atgaaactgg 8520 aaaccatcat tctcagcaaa ccatcgcaag gacaaaaaac caaacaccac atgttctcac 8580 tcataggtgg gaattgaaca atgagaacac atggacacag gaaggggaac atcccactcc 8640 agggacggtt gtggggtcag gggagggggg agggataaca ttaggagata tacctaatgc 8700 taaatgacga gttaatgggt gcagcacacc agcattgcac atgtatacat acgtaacaaa 8760 cctgcatgtt gtgcacatgt atcctaaaac ttaaagtata ataataattt aaaaaaagga 8820 aaaaaatata tgtataattg acaaccctca taagtacagg ctatcatgag tgcatatttt 8880 ctggggtctt tcagcgttag agttatttct cctagtgaag ggaggtttaa ctgagaaata 8940 aagtatatgt gagtgagagt tatcttagag aaaggtacgg gtagggaggc agtaaacaca 9000 gaaggaacaa tatgtatgac ataccatgag gcagggagag atttggcatg cccgagaagt 9060 ggaagaaaac tggggtgcct ttgttgactg ggttctagtg aatgtctctc tggaaggctg 9120 gagttgctct ttaattcccc atttcaggcc catcactaac acctgacaat atgtatgcca 9180 tgatgaacta ttagtagttc ttttgagctt atatgttttt atatacaaat attcatttgt 9240 atgtgctatt tttatgcctt aaactccttt atcatttgtc cctttggcaa tgtttttctc 9300 atcttttagg acacaattta agcctgtcct cagagaaaat agttttctga ctgttcattc 9360 ctttctctca atagatagga ctactttgtc cattattttt aacactgcac tttagcttta 9420 tgttcattgt tgttatcata tgtgtttctc ttacttgaat ctgagttata tggagctaaa 9480 atcatgtgtt gctaattttt gtttcaccat ttgtaatatc agtattagtc atggctaatt 9540 ctcttggtgt acttcatccc attagaaaag aaatgacaaa tgctgtgtct caacaactta 9600 cacaaaatta ctcattagac acatttgatt atggaaataa aattaaaagt gcatatgata 9660 aaatgttatt taattatgtt ttgcctgttt tgctttagtt ttttacataa tttttctaca 9720 tgacaattag taattttttg tgtcttatat atttgtccaa aatgaagttc aaaaatgtaa 9780 aatatttaat tcagcaacag cagcatatga gttagtattt cctctaattt ttcgaaatct 9840 gtgggaagtg tttcccaatt tcctttggtt gtttcatgtg ctatattgaa gaaaacatga 9900 gtatgaaatg gaacctcagc tctttcaatg acttcccttt ttgagttgac tccgcctcca 9960 tatgtagcct tttcattttc atgaaagtga agtgattttt agaattctta gttgttttct 10020 ttagaagaac atttctaggg aataatacaa gaagatttag gaatcattga agttataaat 10080 ctttggaatg agcaaactca gaatggtgct acttgaagac tctggatctg ctggtaaaag 10140 cttctcattt attctacatt tcccctttaa tggggtatgt aattattatg acagtcaatg 10200 gatgtgattt aaaagtgatt ggcatcagga gagtaaggag tggaaaaagg acataggctt 10260 atatggcagc acctttgatc tgccatagat tcaaaattga agatgtgata tgggaatcag 10320 agtcggcatt

aattttgtaa aactgctgag gtgaaattaa gtcaggaact aaagttaact 10380 gaaatgtact gagtatgaaa aaatagttgt tagaaaagat agaatatgca gaaaggaata 10440 ttgatagaga gttaattaca taaagaaagt tatctactct gataagtgag ttatctattt 10500 taagacttat ttggacatgt taaaatcatt tagcattttt agttttaaat tagtgttggg 10560 ttagagtaac gagaagatat gagagtaata acagcattaa agagtgtatt atgtgataag 10620 gatacaggta gagatgacaa gatttaatat ttgagttttt cagatatgga tatcatcact 10680 taggtattgt tctgctagct actatttggc aagcatcaag ccaggtactg gtgaaattat 10740 ggtgaacatg atagatataa ttcgtttact catggaactt atcctctatc agtgcggcta 10800 ggtagtctta aagatggggg catccataat tgaatatcaa ggtggttagg gaatagagaa 10860 atctcaggat accttccctg tgcctgctgg gagaattgtc cactactaag tttcattgat 10920 gttgtttcca ttttccaggt tttaagggtt gaccttgcaa ttctcgtttc caccaccaac 10980 cttctgctaa tccgtcacct ctaggttgcc tataaacatg aacattttca aaaccatttc 11040 actgaaacta tatgagcctg ggtatgaatg ttttctgcct gccttgcaat ttagattgaa 11100 gagttttctg tcttggtttg agcttctttg ttaattaacc tctgaaacca tctatcttct 11160 ccaaagtctc tttttgggaa gatgctactt ttgccctctt ttctttttca cagacttcag 11220 aagacatttt gtcaacctga gtcccttcac cattactgtg gtcttacttc tcagtgcctg 11280 ttttgtcacc agttctcttg gtgagtactt tgtcaaattt acttacagcc ttagcccact 11340 ctgacaagaa cagttaaaag gcaaacaatt tttctgaagg ccaagtagca tctaaaaact 11400 aggtgacatg ctccatgtat tcaaaggatc agatattatt aaaagcacac aataaaaatc 11460 taaccaaaat attagcatgg ttcctcacca aatgaaataa actcacagga gagaaatgaa 11520 ttttacttaa agattagaaa taatgttgaa ctgaaaaata ggaaagaata caaaggagga 11580 gaaacttcag aatcattaaa acaaaagtga atttgggaaa cacattagta aattcaaatg 11640 ccaaaattta tctaaaaatg tattgagaga tgccaggttg gtgggaccag attcctacat 11700 aaagctaaaa taatgccaag gaggcaactg agatcatcta tcatctgggg atgggaagag 11760 agtacaaaga ggtttatttt atggtagaaa atagcagaaa atatctccat cttaatttta 11820 gataagtttc agtctagcgt ttttaagatt tatgctattt tacatatacg tatgaaataa 11880 gagttaaatt tcttacaact agtcttttca tcttcataaa ttctctatca gccttctttc 11940 tatcgacctt aggattttgg agaaatgtaa aaagttcatc cccataacgt tttgtagcat 12000 cttatttaac tcgaaaatgc ttcacaggaa ttatataaat tgccactatt aaggctttcc 12060 agccataaaa taaagctatt aaacactatt gtgttactta cctttactgg tcatatagca 12120 ctgcttaatt tgaaaccagt gatactgata cttatatttg aatgactgtg aaataacatt 12180 cttctgtttt accatggata ggactaggat ggttctcaaa tctgagtttg aaggataaat 12240 aagtaatgta aaaaaataat tttctacttg ctctttgcga ccttggccaa ttactgtctt 12300 aatccattgt tgcaggagga acagacaagg agctgaggct agtggatggt gaaaacaagt 12360 gtagcgggag agtggaagtg aaagtccagg aggagtgggg aacggtgtgt aataatggct 12420 ggagcatgga agcggtctct gtgatttgta accagctggg atgtccaact gctatcaaag 12480 cccctggatg ggctaattcc agtgcaggtt ctggacgcat ttggatggat catgtttctt 12540 gtcgtgggaa tgagtcagct ctttgggatt gcaaacatga tggatgggga aagcatagta 12600 actgtactca ccaacaagat gctggagtga cctgctcagg taagacttgc attagtcaaa 12660 gcctcaacac aaaatccttg gtgggaaaaa aatatgtaga tgggttaaaa cctagaataa 12720 gccactttcc tgtaagcaat ctagttcatg tataaaagta ctccatccat tgctagaaaa 12780 ccacaaaaca cgaggtcatt tttttttaat aaaaaaaatt ctgaacactg tgattaatga 12840 ggaggtgact ggcttcaatt ttatacatga tcttagccaa aaagccaaga agtggtggtt 12900 taaatttgat attcagtaag cttactgtaa cctactattc ctatatcata aaaatatcat 12960 gacatctaag ttatttcctt gttctttccc agtgacttgt tttgatatgt tgacccacaa 13020 attattacca ttttgtccat taactgataa tcaacttagt gaatcaaaaa acaactattt 13080 ctagcattaa tacatcattt cttgttgtag gaaggattct ttgaaagtat aattgcttga 13140 ccagtgtgca atgctagtca tttcatttac attgtgcttt taatttacaa aacatctcca 13200 tatgttttat tgcaattgac cccacaataa ctgagaaagt catgtgtcag gcctttctgc 13260 tgacaaatcc caagggcaca tttctgatcc aactcagatt cctgggatcc ccatttcttt 13320 ttgtttgttt cattcctttt tttttttttt tttttttttt tgggacgaat tgtcgctctt 13380 gtcccccagg ctggagtgcg atggcgctat ctcggctcac tgcaacctcc acctcccggg 13440 ttcaagcaat tctcctgcct cagtctcccg agtagctggg attataggca cctgccacca 13500 cacctggctg atttttgtat ttttagtaga gacagggttt caccatattg gccaggctgg 13560 tctcgaactc ctgagctcag gtgatccacc tgcctcggcc tcccaaaatc ctgggattac 13620 aggtgtgagc caccgtgact ggcctgtttc attaattttt atacaatcct ctcacctccc 13680 agcctctctc tctcccatag gactgactat agaaaggact tatctctgtc caggcatcat 13740 gatgtgataa gagaaacaca cagtagcatc tagaaaaatg ctgaaataaa ttttcacata 13800 gctaatatcc tgtgattttg tgcaagttgt caaatctctc taaacttcag tttctgagga 13860 ttcaatgata taatacatgt aaaactactg gtacactgtt tggtatgtaa caggtgctga 13920 nnnnnnnnnn nnnnnnnnnn gtgactcagt tctctttctt ctttctccgc ttcctcttcc 13980 tcttccttct cctccttctc ctccttcttt cctcttattt ttaaccacta tgggaggtgt 14040 gaaatgggga ataacaaaag taacatctac tgcaaagttt aaaattatca taaattttag 14100 caggctctta tcataattat tgctgtgtat agaactggct gtttagctaa aacagtgtag 14160 tacttttagc tctttttttc tgttgtttta taactaccag tggagttaat caatttgctt 14220 tttgaaattt atacacttaa agctttaacc tgagtcaaat ttaaataact tgagtcgaat 14280 ttatctattt ctgtacaaaa aagagtattt acatctgtcc tagtaatagg tggaaacaaa 14340 acaaaacaga aagtttaaaa actttaacct gtaaacattt tcctttgtaa gtagatatag 14400 ataaaaatcc taattgcttc ctagatttta acatattaaa attctctact gtgtggagct 14460 gggcaatgtc caaaatcagg caccatttta aggacaacat aaaatcccaa gtgtccagag 14520 gaaacttctt ttctaaaatc acttctaaat gaatgtaact tctgaactct ggtcttttct 14580 ctgctccaga tggatccaat ttggaaatga ggctgacgcg tggagggaat atgtgttctg 14640 gaagaataga gatcaaattc caaggacggt ggggaacagt gtgtgatgat aacttcaaca 14700 tagatcatgc atctgtcatt tgtagacaac ttgaatgtgg aagtgctgtc agtttctctg 14760 gttcatctaa ttttggagaa ggctctggac caatctggtt tgatgatctt atatgcaacg 14820 gaaatgagtc agctctctgg aactgcaaac atcaaggatg gggaaagcat aactgtgatc 14880 atgctgagga tgctggagtg atttgctcaa gtaaggactg atcttggctc attctattct 14940 ccaggagagg acaaaagaaa ggggtaataa atcttaagag cctgaactct taagaacata 15000 atgaagtctg cttcttttgt caccgcattt taacctaact tcaggttcca gttctgatac 15060 ctgtggactt tttaccttaa ctgaaattag gagaaatagg ttagggaagt gcatagtgaa 15120 actgagatcc aggtcataag aaaagaagaa agtgtttagg aaaagcccat aaagaaaggg 15180 agagaccgaa aagaaaaaga ggggaaaaag gaaagaagga agggctttac taggaaattt 15240 tgcactatga agttttatga ccaaaccact ccagttatca tctaatccac aaaagcctcc 15300 tcattagcct cattaaccca ctccttccca aatcattttt caagttcaca gaatcgaatc 15360 acttgttaaa aatcaatatt ggtttctcat taaaacttta tttatactag atatgcattg 15420 tatctgtcta gagactttca cgttgtatac tcagactggg ggcggggaaa atcgtttgtg 15480 tgtgcagaga taccactctt cgtttttctg ttgaattctt agtataaaag gagattgagt 15540 gtgtcttgaa ccccagagaa cacttaggaa aataagagta aaaaatccct atcttcacca 15600 gatccctttc tctctctctc tctctctctc tgtgtgtgtg tgtgtgtgtg tgtaaataaa 15660 ggaacttcca ttcaaacttg tttaaaaaga agagaatact ggctcacaaa actgggaaat 15720 ccagagggta tagttagcct catgcatggt tggattcagg ttcttgaaca atgtcatctg 15780 ggttctatct ctttctgcat gtcttgaaca agctttttct tgttgaacaa tgtgatcagc 15840 tatagcctga accacaatga atggaactcc tacaagaaag atagattttg ttaggttaag 15900 aatgtgaaga atttggagta gaaaaaacac agactgtacc ttccattctc ttttacccat 15960 caacatttct ctaggccccc agttagcaca tgctgacgaa tcacaatccc acaatgaata 16020 acattgtggg aatgaaaacg gaaactgcca gaggaaacaa ccagtttaat ttattacaga 16080 atattcttca gaatcaacgt ctgttctttg aagaatattg atttggggaa ggtgaaaatt 16140 gtagtactga agcctccttt ctctttgctc tgcttttaaa ctaaggaagt ggtcacaaca 16200 ggttcaggtg tacaacacag gctaggtagt atcaatggag aatgcagtca gaggcaaaag 16260 ggattgctaa gtatggaggc aaactgaagg atgagggagt cacctaaaca catgcaaata 16320 tattttaacc agaaaaagta aacagttcta acaagaactc tgtggtggtc aaatagcagg 16380 tctctagatg aaattcagtc cctgtatctc ctgttagaaa cacttcctgt agtatatgct 16440 gtctatactg agatgtccca tcttcttgcc tgatccactc ctccttccat cttgaatgat 16500 ttccagtggt agtacagtac atcacagttt tctctgtctc cacttatatc tctccccttt 16560 tccttaactc atctcaggta tagctattta tagtctcatg ttcttgcttc cttatcgcag 16620 acctgttgtg tgtctctgtt acagagggag cagatctgag cctgagactg gtagatggag 16680 tcactgaatg ttcaggaaga ttagaagtga gattccaagg ggaatggggg acaatatgtg 16740 atgacggctg ggacagttac gatgctgctg tggcatgcaa gcaactggga tgtccaactg 16800 ccgtcacagc cattggtcga gttaacgcca gtaagggatt tggacacatc tggcttgaca 16860 gcgtttcttg ccagggacat gaacctgctg tctggcaatg taaacaccat gaatggggaa 16920 agcattattg caatcacaat gaagatgctg gcgtgacatg ttctggtaag ttaaaaccaa 16980 accaaaacca aaacactaaa caaaaagaaa agcagaaacg gaaagtcctg tgctccttaa 17040 gagtaggaac gtgctcctta agaagtagaa atgcctagta aattccttgc tgggaattcc 17100 tttatacctg taatctttga cacattcttt attcaactag tttggaaggt tgtctgacgg 17160 cattctctgt aataattact cagactgctt ttatggagca cacttcaaac tcagaatcta 17220 cctggagctc agagagacaa aatttcctag gaatctgttt ttaaattttt ttaatttact 17280 tattttttta ctttaagttc tgggatagat gtgttgaatg tgcaggtttg ttacatgggt 17340 aaacatgttc catggtggtc tgcttcacgt atcaacctgt catactaggt tttaaccccc 17400 catgcattag gtannnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 17460 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 17520 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnatggg catttgggtt 17580 ggttccaagt ctttgttatt gtagatagtg ctgcaataaa catacatgtg catgtgtctt 17640 tatagtagaa tgatttataa tcctttgggt atatacccag taatgggatc gctgggtcaa 17700 atggtatttc tagttctaga tccttgagga atcaccacac tgtcttccat aatggttgaa 17760 ctaatttaca ctcccaccaa cagtgtaaaa gctttcctat ttctctacat ccttgccaac 17820 atctgttgtt tccagacttt ttaatgatcg ccattctaac tgggatgaga tggtatctca 17880 ttgtgatttt gatttgcatt tctctaatga ccattgttga taagctattt ttcatatgtt 17940 tgttgtccgc ataaatgcct tcttttcaga agtgtctgtt catacccttc acccactttt 18000 tgaggaatct cttttaaagc tgaattgctc atatctttct gccattgaca atttttatca 18060 acccttgaaa ctacagtccc atttctaaca aaaatttatg gtctatatta ttgtttctta 18120 aaaagtcagg aaataagtta cctataattt tcaatgcatc agtatcagag aagaaaaaag 18180 acaaaaaaaa atcctctgga agctaacctc catatgtatc gatggtttaa gtttatgttt 18240 cttttgcaga tggatcagat ctggagctaa gacttagagg tggaggcagc cgctgtgctg 18300 ggacagttga ggtggagatt cagagactgt tagggaaggt gtgtgacaga ggctggggac 18360 tgaaagaagc tgatgtggtt tgcaggcagc tgggatgtgg atctgcactc aaaacatctt 18420 atcaagtgta ctccaaaatc caggcaacaa acacatggct gtttctaagt agctgtaacg 18480 gaaatgaaac ttctctttgg gactgcaaga actggcaatg gggtggactt acctgtgatc 18540 actatgaaga agccaaaatt acctgctcag gtatgacttt caatcaactt gttaagaaga 18600 agggtgtaaa tttccagtac tacctttgaa attgaaaaga aacattggtc cttatgacta 18660 gatcactctc aagaaaccag gaaatatcta cacaaattcc actgggagag tcagataagt 18720 ttacaattca tgttgcactt tagatagaag tgtttgggtt ttgctcactt tggtttttga 18780 gtaattttta gatcaataga ggtataagat taaggaggat taaaatttaa aaaatagaat 18840 tcaatatttc tttcacagga tgtcaccaaa agatttaaaa aataaccatg ttagataaac 18900 tgacataacc ttcagctccc tctattgtac tgtgaaagaa ttttcttttt ttttggaaaa 18960 cctgtgaata tttcactgca acctctttaa aaagctcaaa aatgagttgt aaactggtta 19020 ggtttgtgga taatctttag tattttatgc taattatatc tatacaaatg ttaactttgt 19080 tgaaaagtga tgctttttaa ataactctaa agtaaatgta acttttactc atgcaacaaa 19140 aaggcttcag aaaacacagt gtacaagaaa accattaaac atgtagagac ctcacagaat 19200 ggaaacttgt acgtgctgca tgtcctctaa ccaacaatat ggctccagat acctcccaac 19260 ctaggcatgc agtgaggggc atttccctga tgttacaaat ggtgcttacc tctagttaag 19320 tagaaattat cctccgattg aaaaaaggca atcatttaag atataaattt gaatttctat 19380 attacttttt aaaaaatatt ctggaccagg caatataatc acatggttta aacttcaaaa 19440 taaaaaagtg taaactcttc ccccactact atccaattct tttcctcaca gacaacttat 19500 gtggttggaa tatttatata tcatttgaga tatttcatgt aaatacaaga aaatacaaac 19560 aaatctatat atagctatca tttgctttca ttatccaaat ggtggcatgt tgtataaatt 19620 gttttgtacc tgaagtattc acttagtaaa atttcttgat caaatttcac atcagtattt 19680 aaagagctgt ctgaaattac ttccatatct ataacatttc ttataattta ttaccgtgtg 19740 tattcattta ttcttttaat tttttacctg acaaggttag ccattctttt acctaaattt 19800 ttttttaaaa aaccattatt tggattttaa aaaattaatg ttacttttat ttcctttcta 19860 attcattaaa atttactttt ctttctaata attctcttca gatttcctaa agtttgattt 19920 ctttttggcc cccaacttct tgagttgaat cttaagtttt atttcttctg atttactaat 19980 ataaatattt taggttatag attttccttc taaatttata atggtttgta tattttctta 20040 ttaattgtat tttacattga ttagcattaa gttctgctgt atctaaaaga gaaacaaata 20100 atagtgactg aagaaagaca gtgttcactt tttctcattt aaaattagtc aaatagataa 20160 gcagtttaag gctgttttgg tgtctctgtt gtcaccaaga aacatccaga atagatttgc 20220 tgcagtaagt atcaaatcct accggacagg aaggataagc caccccgcag ctcagtgagt 20280 tccttggaaa gccaatctgg tagacgaagt gctggcctct gagaaggtgt cttctgtccg 20340 ctgtccttca tgggccccag tgttgctctc agggcagttc ttcctggcac attattcttc 20400 acagttacat ccaagtttgg tttggagagt atctctatct aaggacagca cacctttcac 20460 aacccacttc ctgctaatat tggtttaggg acctttggat taaagattga ctaatcaagg 20520 gctgatgtca gctgccctca aattcaacaa aaaagttctt tccaaggtta ctaagcttct 20580 agtctacttg ctttataacc caatgccatc tgaaagtaac tatagtccaa gagcatataa 20640 atatactttg atctatgctg tgaccagccc ttctctttaa ttattgacca ctgccttaag 20700 gccgtttgaa actgtgggtt tgggaggaag gacaagacct aaattccgtc tttgccggta 20760 gactcattgc ctttgtatct ggagtatcaa ttttatcttc tgacaaggct acagttttac 20820 caccacctca atttgggggg acaggatact tagagttttt tcttcaattc ttcaattcca 20880 aattatagga ctcttgatta acaatataca acacctgcag gcagaccata cccccttata 20940 aaattgatat ttctcctccc atttctgctt gcattctgac tgctggtagt ctgaattcat 21000 ctttcttgta aatgctaaaa gtggcaagga gaatccacgt catgcaaata ttctgatttt 21060 ttgtagtttt gtttcttgta ctttgcccaa taaattctgc attttttaag catcagtgag 21120 cacacggttt tcttttcaaa gtgaggctta cccaaatatt ttaccatgtg taagactcct 21180 taggttttta gtctctcaca cctgagtcat taatgcattc tgcccatcaa ctccattcaa 21240 ccacacccat attttaggtt gcattactag aataccttac ttatggtaac atgttctaaa 21300 ttattcagga ttctattcag atgtgtataa tagaaatcat gaataacata aatttgcaac 21360 ttaaggtggg ctccgtactt cacagagctg tatttttgtt tgctatttgc catgtgcact 21420 ttttgtttcc ttttacaaac tcttttgtta tattgctgta ggttttggaa gttcttctac 21480 ttatgttggg ggccttggtt tttagctttt tacatgtttt gttagtaata tagtttgtac 21540 ttttgtttct ttatttactt gatactttca atgatgacat actgtctctg tcaatgatga 21600 tatgctgtct ctgtgcctgc caaattcaag ctacgaattt gatcatctgt ttaaattgtt 21660 taacttttat atagtacagg gctatacagc ttaaaagaac caggagaatt caactaagca 21720 ggagaattgg aaacaattta agataaattg ttgacagaaa aaggtctagg aaattttggc 21780 cacaaaatta ctttgaatct cagacatttt gtttgtgatg tctgtgtatg tactgtagag 21840 gacatctgac cttaagaaac agttcatttg agctatgctg tcttttaact taggatggag 21900 aaataattct gagattatga tgatctatac ttcttcagag tctgaaaagc attaaatgtt 21960 gaaaatacat taaagcttct ttaaatcata attgtatatt ttatttatca ctaaacaaaa 22020 ggaagtaatt ctagttaatt atgtctctaa ttatgttaaa gctctttgta gatctattta 22080 tttttctaga aaaagaaaga aaaacagatt cagttactta tgccagggga aaactgtagt 22140 tgttgatcaa tggtgctaaa tccaggtgca aaaatttact taatggtttt tatgtaaaaa 22200 cacagtcaga gacttagcag aaaaaaatcc attaaaggga tacatttcca atattctatc 22260 catgtctaaa gagtaacgat ataagcaaag cgacccatag gatagattaa catgttacta 22320 gcagattcac gaaataaagg ctgaggatgg agtctccaag tcactttctg agttggagaa 22380 tttgtcctct gccttgactc aaatatgtta gtacaaagaa aacaagagga tacttataga 22440 agggactttt tctcaattgc ttaatgagtt ttcacaatgg aaaagaaaat atttttgttt 22500 gtttgtttgt ttgtttttca ctggttttct tttggtttat tttgttcaag atgggtccaa 22560 atgaaagagt aagaagttac aagaaaccag aatttggctt gatctaggag actgccttta 22620 cttaaagatt tagggctgtc caaaagaggt tgggatcata tgaatactag ttaatgatat 22680 cttagagaaa tttcatgctt gaataaagat tcaaaaagaa gaaatgaaag accatcccac 22740 tcaagggtca ttaattattt gtattgtaga ggtgttattt gctttaaact ctgagctatg 22800 tttagaaagc aacatgtttt tcatttcaaa tttggatagg aatttgcttt gcgcagattt 22860 aatggataat gggtgaaatt ttgacatgtt gaggtattct atattgctgt agtacagaat 22920 atggtcatat tcgaaacatt ttctaagaca tttttgtatc aggtgaaagg tttatgagag 22980 atgaaaggaa atcagagtat gtagattggc aagggctgat ggtgtatcta tatcattgtg 23040 atagtaacat caagagatta caaaaattgt tgatatttga tagcaggtat ctataaagga 23100 cttaagacct tcagaaggtc taattttcaa ctgcattttc tttatttctc ttaaagaaca 23160 agttaaaaga aatagtttgt atctcttaag tactttatat tgcctctgag tattttcaaa 23220 gaaactcact tatcttgatg attgtgtttc ttaacttgac aaagagcatc ttcataatat 23280 aaattccatt tattatttct ggtgtgtctt ttctttatat tttaaatttc agctacagta 23340 agttacttat aattcttcaa tgacaccatg catttcgtga ccatattcct taaagattgt 23400 ttcacacact gtgtatttgg caaactcctc atcttttttc aagatccagt ttagatctat 23460 ggtattctct cccccatagt ctaaaacaga gtgaatgact cctttatttg ttagttttat 23520 gtctaataca tatttctatt tttgggttca tcactattaa aatatgtata tcttgtagtg 23580 aactgtgttc atggaggaga aggctattag tgagaaattg aacagccttg aaaagaagta 23640 gccttttcct aggtatataa ggtagggaaa taaattttaa gtagagagaa aagtttctac 23700 agaggcacag aagcatgaaa attacggcat gcccaagcat ctttaggctg gagcatcaaa 23760 ttaggttgat aaagtaatag atattaaagc ttttaaggta acagcatact attttaaagt 23820 gtactaaaga attagtgttt atcacctctc cttaatttta atagctggac gaaattaggg 23880 aatctatgaa aactgtttgt gctgcagttt gctcagaaga aaaatgggag tggtaatagg 23940 gcctacctca caggaattac acagtgagct ataaatacat gttagctaat atgattatga 24000 ttattatttt tagtattatc tatcttcact gacagactga attctgtggc ggccttttta 24060 acccacccat catcaaatgc ctaaaataga gtcagagaac attacaggtt gttacattat 24120 aggtcattac attgatactt ttggattaat tattgcatac atgattatta cagaaattat 24180 aagaaattat gtaagggatc attgcataca ttttaaggaa acgttaagtc atctaaagga 24240 aaaacatcac atgaaaatat ttgaaattta ttaatatatt tataatcatg gcataaattt 24300 cttggaaaaa agactttgaa gcaaggaaac aatttacgaa gctattgtag aggtctgcat 24360 gacagatgat gacaaatcac tttatggcaa tagcaacaaa tatgcagaag aagaaatatg 24420 ctggaggacc aacagatatg gtggttttct acatgttcaa tgtatcatga aagtcaacat 24480 tctaggctct ggaatatact gtctggcttc aaattctgtt ctcttactaa ttctgtagta 24540 atttcttgtg tgaccttagc aaattactac acctcacctc tctatgtttc agattccctg 24600 tctgtaaaat cagaatgata ttaacaatta tctcctaagg caattttaag gattgaatga 24660 aataatgttt gttaaatgct tattggaatg ccatatatgt aatataatag acgctcactt 24720 aatattcact gctatcatta ttaccattat ttgtggtgag ataaagtggg tcaattttag 24780 gtggttctaa tttggcctgt atatcattaa ttaagtaaag aatatagtgg gcttgtcata 24840 caataattca ttcaactttg aatactttaa gctccacatg tctaagcaga tacgtttgtg 24900 gatctaaaat taaagaaaaa agtatggatg aaaatatatt tattagcagt tgagacatgt 24960 ccattgagca gatgagaagg ttacggacag aactttgact caaggaatac acgaaatgtt 25020 ttgataaagc actgtcagaa agaatggagg agaaaatggg acaagaaggg tcacgtatac 25080 caaacgtaac agacgtcaaa aggaagaagt ctgatgttca ttctgaaaat tagaagtata 25140 ttgaaaagct ttacatagaa caattcaaaa aggttgagca gaccccagat tgcagtacat 25200 ggaggaatga gtgcaagact aagagatagc gatagtagat acacattgtt tgtggtctct 25260 aatgttatta tgaataaagt aagcaaaatt ttggaagaac agagttatca ttgcctttgg 25320 ggatggttgg ctgcacaagg tgaagtccca gaattctctc agatggatga gttcagctag 25380 gaatggggag

gtctagattt atccataccc aactcgaggc agaaaagcca agacaaacaa 25440 gtgtaggaaa tcactgagca ccctggtctc catttcccac tccacaccac cttcttcacc 25500 ctcatcatga atggaaatct ggaaatcata ttacctctca ctgaaataat atttattttt 25560 cagcccacag ggaacccaga ctggttggag gggacattcc ctgttctgga cgtgttgaag 25620 tgaagcatgg tgacacgtgg ggctccatct gtgattcgga cttctctctg gaagctgcca 25680 gcgttctatg cagggaatta cagtgtggca cagttgtctc tatcctgggg ggagctcact 25740 ttggagaggg aaatggacag atctgggctg aagaattcca gtgtgaggga catgagtccc 25800 atctttcact ctgcccagta gcaccccgcc cagaaggaac ttgtagccac agcagggatg 25860 ttggagtagt ctgctcaagt aagacccaga aaacatcttt aattggttct catactgtga 25920 aagggacagg gttagggagt catagctgtc tttttctaaa gccctgtctc cttccaggat 25980 acacagaaat tcgcttggtg aatggcaaga ccccgtgtga gggcagagtg gagctcaaaa 26040 cgcttggtgc ctggggatcc ctctgtaact ctcactggga catagaagat gcccatgttc 26100 tttgccagca gcttaaatgt ggagttgccc tttctacccc aggaggagca cgttttggaa 26160 aaggaaatgg tcagatctgg aggcatatgt ttcactgcac tgggactgag cagcacatgg 26220 gagattgtcc tgtaactgct ctaggtgctt cattatgtcc ttcagagcaa gtggcctctg 26280 taatctgctc aggtaagagg atgacgggca gccagtgatg ggtcttaaga gaaggtgtac 26340 atagggatga agaacaaaag taaaacgcag tgatccattt tgaagggtca tgagaagaat 26400 gaatactaat tcatgcttca gaatattaac ctcatttgtc ttttcagagg gtgagcaaac 26460 ctaattttga tggacttctt agttatccag tgcttactat gtgccaagcc catctcaaag 26520 cacctgattt atttcaaact tgttgaccat ccaccttccc ctctctctct aagctatgtt 26580 tgtcctcaac tcatccatat aacatttcat ctgactcccc taaccttttg tgtcttgtat 26640 gactgagtac cttggtgttt gcaggaaacc agtcccaaac actgtcctcg tgcaattcat 26700 cgtctttggg cccaacaagg cctaccattc cagaagaaag tgctgtggcc tgcataggta 26760 agactctgtg acaaatctat gaaaatatta ataacaagtg gaatgctcat tattaatagt 26820 ttcatttctc tttgcagaga gtggtcaact tcgcctggta aatggaggag gtcgctgtgc 26880 tgggagagta gagatctatc atgagggctc ctggggcacc atctgtgatg acagctggga 26940 cctgagtgat gcccacgtgg tttgcagaca gctgggctgt ggagaggcca ttaatgccac 27000 tggttctgct cattttgggg aaggaacagg gcccatctgg ctggatgaga tgaaatgcaa 27060 tggaaaagaa tcccgcattt ggcagtgcca ttcacacggc tgggggcagc aaaattgcag 27120 gcacaaggag gatgcgggag ttatctgctc aggtaaatta tgcatatgac ctttggtcat 27180 aattacatag agaaaggact gaggaagggt agtgaggggt attaatctta aagattttcc 27240 tgaaaagttg atccaaaagg aactattgtg ggagtcagga caacagaagt ctgggtttga 27300 tgtgctagtg gtacttcatg agcaaggtag tgcaacattg taaagagaaa agaccagaaa 27360 tggtcttgta tatcatgaaa atgacaacaa agttaataat gaaggttttt aataaatata 27420 tttggggcca gatattagat agcgatccaa tagcaacact tgataattac agtattagta 27480 aagaagtaga tttaaaggga caagaagaaa tatatatgtt gcatcattct acagaaaaaa 27540 agataattac tatgcccaag caatttttca tggcagataa atgagactta cttgtcatag 27600 aaacaaaaag tagcatgagg ttactgccct catactgctt tgtatacatg gtgagtttta 27660 gaaaacattc tgaaatttaa aaatgtacta tttcatatgt attatgggga acagaactat 27720 gattcagtaa cttaaggaag tgaaaaactc tgtatctcag aagtgattta ttcctatttt 27780 aatgacataa atctggtaga agacatgcac tgcaaaactg tgaagtgtca gcaaatgaac 27840 tgtcatttta agagatgtac acaaaacatt gattttagtg cctgagtgtc taacaatttt 27900 aactatcaaa gacagttgca aaaaaaggag aatatttttg ggaaaaaatc caaactatgt 27960 aactgaaaaa agcctattag aatgattgag ggtaatctaa agaggactct gagtccaaaa 28020 ccaaagacca aaaaactata atgtatttat agaataaata aaatatttta ataatatcta 28080 tgaaatcatc cagaagttac taacgaatta ttagtaactg acatattgta ctattgtacc 28140 tatttttaaa gccattctta catcaaggta aagggaagga gtctctgaat cttcagaaaa 28200 gatgcaaaac tactaattct atgttttgct gcagaattca tgtctctgag actgaccagt 28260 gaagccagca gagaggcctg tgcagggcgt ctggaagttt tttacaatgg agcttggggc 28320 actgttggca agagtagcat gtctgaaacc actgtgggtg tggtgtgcag gcagctgggc 28380 tgtgcagaca aagggaaaat caaccctgca tctttagaca aggccatgtc cattcccatg 28440 tgggtggaca atgttcagtg tccaaaagga cctgacacgc tgtggcagtg cccatcatct 28500 ccatgggaga agagactggc cagcccctcg gaggagacct ggatcacatg tgacagtgag 28560 tatccatcga cctatatgaa aattccattc tgcagccccg ctatcatctt ctgataatgg 28620 acactggatt ttattttcct attctcacac tggcttaaat tgttagattg aattaagcaa 28680 gaatgggtaa cttgtgggta atatctattc tacctggata gtgtaactgg ttttatttaa 28740 tttggcctgt agatattcag gatcagctat tattattcta aagaatatca tactccccat 28800 ggtctgcttg aaagatttat tcaattgctt tctctgagga ggagagaata tgtggtttaa 28860 tatttgactg ttgaatggtc taccttacct tcccattttt ctttcaaata ttatcttgtt 28920 acactaatat aaggagaaaa gcagtcagaa atcagaaaga tcaattctga agtatttcca 28980 cattctacag gttttttttt tttttttttt tttgagacag agttttgctc ttgttcccca 29040 ggctggagtg caatggcgtg atcttggctc actgcaacct ctgccttctt ggttcaagca 29100 attctcctgc tccagcctcc tgagtagctg ggattacagg catgagccac catgcccagc 29160 taattttgta tttttagttg agatggggtt tccccatgtt ggccaggctg gtcttgaact 29220 tctgacctca ggtgatccac tccccttggc ctcccaaatt gctgggatta caggtgtgag 29280 ccactgtgcc tggcctctac atcttcttaa actgtgagat ttgtgacaac ctgccagttt 29340 cccaagaatc ttgcctattt gaaagaattt gacatcacat atttataatg ttaactttaa 29400 tcatttaaca tttactgggt cacattatgt atcttatgtg caggatggaa tatacctagt 29460 tggctgtaat gacaagtcct cttataaaag ataaattttg taaaaatata aattttaggc 29520 caggcacggt ggctcacgcc tgtaatcgga ctttgggagt ccgaggtggg tggatcacga 29580 ggtcaggaga tcgagaccat cctggctaac atggtgaaac cccgtctcta ctaaaaatac 29640 aaaaaattag ccgggtgtgg tggtgggcgc ctgtagtccc agctacttgg gaggctgagg 29700 caggagaatg gtgtgaacct gggaggcgga gcttgcagtg agccgagatt gtgccactgc 29760 actccagcct gggtgacaga gcgagactct gtctcaaaaa aaaaaaaaaa atatatatat 29820 atatatatat atacatatat atatataaat tttaatatgc acattcagta aaattttaaa 29880 tagttttttt ttttttttaa gtttcaaatc tctcttttca cctgtgaact cctggaaact 29940 tttagaagtc ttagaaatag gctacatgtc tctgattttt cagacaagat aagacttcag 30000 gaaggaccca cttcctgttc tggacgtgtg gagatctggc atggaggttc ctgggggaca 30060 gtgtgtgatg actcttggga cttggacgat gctcaggtgg tgtgtcaaca acttggctgt 30120 ggtccagctt tgaaagcatt caaagaagca gagtttggtc aggggactgg acccgatatg 30180 gctcaatgaa gtgaagtgca aagggaatga gtcttccttg tgggattgtc ctgccagacg 30240 ctggggccat agtgagtgtg ggcacaagga agacgctgca gtgaattgca caggtaagtg 30300 ccagaagcct ggattgagct tggaatctct ggcagcaaag aggggttggg cagtgatgtg 30360 tgttgtgtaa aaaccggatt tatcagcaca gggatctggt ggggattctc agagaatcat 30420 aatgtctcta ctgaaagaat gatgaaaaca attgttatac aatggccttc accaaggaga 30480 cacatacaac ctatattccc tgtgcagaga aagaaagact agaggactct agttttaggt 30540 gggaaagagt catatacttg gttgagaggt actaaggggt cagacaagga aatcagaagg 30600 cttgttctat atatcatgca aagaattaac cctctctctt tcttttctcc tacagatatt 30660 tcagtgcaga aaaccccaca aaaagccaca acaggtatat catggagttt atgatgatga 30720 gaccaattat ctgcatacat agaatttttc ttgtttagaa attttaggtc agacgttctg 30780 aggatttgat atttacctca gggatcaagt atttgaccta agagagaatc agtaactagg 30840 gaccttgatc ttttcgataa gacatgatca tatctcttga tatttacttt tacttaggtc 30900 gctcatcccg tcagtcatcc tttattgcag tcgggatcct tggggttgtt ctgttggcca 30960 ttttcgtcgc attattcttc ttgactaaaa agcgaagaca gagacagcgg cttgcaggtt 31020 tgagccaaat ttggtttatc taatatgtct acaggataag ggggttcttg taagacgaaa 31080 atattagact caagtctaat ggccagaaag atggactcta aaagaggttt gagcagtttc 31140 tcaaaacaga gggaagggcc aggcacagtg gctcacactt gtaatcccta cactttggga 31200 ggctgaggca ggagaatcgc ttgagtccag gagttcaaga ccagcctggg ccacacaggg 31260 agctcccatt tctacagatt tttttcattt tttaaataga gggaataaga tttcagagga 31320 gaaaaggggt ttaggttgca ttgatgattc cctgtgttct atctacatgc ttaactggaa 31380 cattacagaa ttgaaagttc agaatgaata tgttagatat tgtttagnnn nnnnnnnnnn 31440 nnnnnnncat gggacaataa atcttggtgg aacttcaagt ctagtggaag agatatatat 31500 gtaaacaaat acactacaat gtagccattt tacattaata ggaaaaagga acaaaagtgg 31560 cacagagaag ggagtaatta actgaaaggg gagggggatt actggaggct tcaaagaggc 31620 ttggggacaa atttcgaaca tagaggctca gagaattggg tgaggaacat tctagagaag 31680 aatatgtaca agtctagaga agcctaaagg atgaagcatt tcttgttttt ttcctgaggg 31740 gcggggggag aaaagttgag tgtgaggaga gaggctgcta agtctgaaga agagaaaagg 31800 cacaaattat gaagttctta tgtttcacat aagattcata gtcattaaag agtatcatgt 31860 aggggagtga aatggtcaag atatctttta ggaagatctt ttggcaacgg gatctaggag 31920 gattgaagga ggaccacttg actgacagga atggcatttt gtaacagttg aggtgaaaaa 31980 tgaaaagtac tataacatat atagtgagaa tggaggggag aggaaagact tttagagata 32040 cttaagaaaa gctccagtga gttatggaag actgctggct tcccttgggt aaaaacagtg 32100 ggttgtttat attaatacaa tggcagtggg gaagatttag ccttgtgcct atttcatttg 32160 agtgtgcgga attgtaaggg aagagcttgg tagtagaatg ggatagaaac aatagcaggg 32220 ataaagacga ggtatgtttg cagcgcttgg aaaaaacaca cttacagcaa gggaaatttt 32280 attatgatag ctgatcccta acctagggat ctctgttttc agtttcctca agaggagaga 32340 acttagtcca ccaaattcaa taccgggaga tgaattcttg cctgaatgca gatgatctgg 32400 acctaatgaa ttcctcaggt ctgtgggttc ttggagggtc tattgcccag gggttcagat 32460 cagtggctgc agttgaggca cagacattct actttgataa acagttaaaa aagtctaaaa 32520 atgtaatagg aagcttagat gcatataatg gacaagaatg actgaaaatt attcttggag 32580 aatatcaaaa ttgcaatcat agggaggcct ttagcttaag aggcctgtga ttattcctga 32640 tagaggtatg gaaagaacca tgcagaggaa tattatgact tggacctcat tttattaaaa 32700 cagaaattaa tcttacaaaa gattgtcata agtgacagtt taactttttt ctttaaattt 32760 tgttgtgtat atttaaggta tacaacatga ttttatggga tgtatataga tagtaaaaag 32820 cttactaaag caaagcaaat gaacacaccc atcatctgac atagttaccc ttttttgtgt 32880 tgttcttgtg gcaagagcag ctaaaaccta ctcacttagc atgaatccta catacagcac 32940 aatgttatta cctataatcc tcatgttgta cattagacct ctagactggt tcattctacg 33000 tatctgctac tttgtatcct ctgacctaca tacgtctttc acagtttctt ccattcccat 33060 ttcctgtcat tttttttctc tagcttgata tttattatat ttttccctaa aagtctaaaa 33120 ccttaaactt tcaatatctt tattgcatga gaagccatac aaatccacag aactagcctt 33180 atttctcatc acatcatgct gttttatcct tgaacttcta tttagcacca gtgcactaat 33240 tctgcatctg ggcaggatga ctttactggg ttggaagaaa tatcccaaaa cccattgtct 33300 ttactccatg aagggtccct gaccttctga gaggggcctg cctcacttct tccatccaaa 33360 gaattatgca tctgctactg tgtcagggaa catatttaag gaacatgtac tgttactgtg 33420 tcaggaaaca tatttaagaa ataggaaaga ctttctctgc cccttaaatc acacatgctt 33480 ttcttcctag ttatgggtgg tgtttttagt tgctcaaaga gcctcacagt tacgtgagaa 33540 gaggtctggt ttatttccca gtaattattt tcttcctttc agaaaattcc catgagtcag 33600 ctgatttcag tgctgctgaa ctaatttctg tgtctaaatt tcttcctatt tctggaatgg 33660 aaaaggaggc cattctgagc cacactgaaa aggaaaatgg gaatttataa cccagtgagg 33720 tgagtgatga gaatttatta gtcattgttc aaaacagctg cattcctttt gaggactgag 33780 agctcttctg gcattagaaa gaaagaatgt atataaacat attttatttg cttatgtgca 33840 tatgtttgta tatgtatata tctatattga gaatatataa aagcttataa atataactga 33900 ttcatctctt aattatacac acaaatagta ataacacatc catggagcta aggagaaact 33960 gagtaaacaa atacaaatta atcttttgaa gacattacag gtatcatttc aggaaaaaga 34020 taagacatat tgtacatcta catcgtataa tacatgctat ggtaaagact gtacaaggca 34080 ctacagaaag tttgcctaag aaactttggg gttgttgtaa gatgatatga tatttaaggt 34140 aaactttaaa aataactgaa aaatagacag ttccaaagaa aggacacagt atgtgcaaac 34200 tagaggcaga aaaaagaacc atgcctttag ggaactataa gaagtttttt attcaaaaac 34260 atatattgaa cgtatttatg gtaacaagtg gtaccgtgag cactgaagat agagataaaa 34320 tctactattg gcaaagacat gattgtttaa taaaagatat catagtctat aggtggtaat 34380 atgaagaggc catgtggaga gaagagaggt ggttagaatc taagctgaaa aggctgcata 34440 gagccctgta atgaatggtc ttacctgcta tactttatgt tctctttcac tgggggtctg 34500 ttgaagaggt gatgatgagc tttgaaagtt tcagatgaga caagatgatt agaattgcat 34560 tttacaactt gctttcatga gaaaaacata aaaaaaaatt caaatgtgaa caagacgtat 34620 agttaagcta tacatcaaga gaaaaagatt gtgaaatgag ttactagata cattttctgt 34680 ttttaaaata ataatttggg gaagactaca tctagaaatg aaatgtagaa aaagtatttt 34740 ttatagaaat attatatatt cctataattc atctacatat tatatatcta cattgtataa 34800 tacatgctat ggtaaagact gtacaagaca ctacagaata tttgtatata cgaaatatag 34860 attaagacaa aggataagag ttggaactct taaagtacat gaaatataaa ttgtgaatat 34920 ctataaaatg cagagctaat tttacatact atatatatac acacatagat acatagagtt 34980 cttagaaact gtacagagca caaaagggtt aatatatgtg aatgtaaatt gtatgtatgt 35040 gtatgtgtaa catctaatag ataattgggc aaagctatga aaagacaatt gacacaaaat 35100 gaatttcaaa tgacagacat ttttaaatgt ctggaggatt gaaattataa ttaacaatga 35160 gctatcactt tatacaaatc agactaacaa aaatttgaaa taccatcaat atttattact 35220 ggcgggaata cagagaaaaa ggccatttca aacactgctt ttggaagtgt gagatatggt 35280 aggtagcctt tggagaaagc aatctggcag tttctattaa aaattatttt caaagattca 35340 cagacccttt gacccaataa ttctatccct gagaatttct tcttaccaat aaagtcacta 35400 gtatgtaatg acaaatatac aaagattcct ttctgccatg ttgttgaaag tggcaaaaac 35460 tagaaacaaa gtgaatgcca attgatggag taatgactgg aaaaatgacg gtttaggcaa 35520 ctaaaaaaga aaaaatcatt ataaaatata ataatattcc atttatgtat tggctataat 35580 taaatacaat gcttacatct ataaaattat gcattcatat gtgcataaag aagctaaaaa 35640 ttctagtgtt gtaaactgag aaccatgaat aatatttgat ttataatctg aagcatatga 35700 atgttttctg atgtgataaa tgataattga actacttttc cctgaaagag taatcactgc 35760 tgaataactg cttcagaatc acatgagggt gcttttaaaa aatgacgatt ctttttttgt 35820 ttttaatctt taagttctgg gatacatgtg ttgaatgtgc aggtttgtta cataggtata 35880 cacgtgtcat ggtggtttgt tgtgcctatc aacccgccat ctaggtttta agccctgcat 35940 gcattaggag cttaaatttg tcttaatgct ctccttcccc ttgcccccac cccgcagcag 36000 gccccatgtg tgatgttccc ctccctgtgt ccatgtgttc tcattgttca actccaactt 36060 atgagtgaga acatgcggtg tttggttttc cgttcctgtg ttagtttgct gagaatgatg 36120 gtttccagct tcatccatat ccctgcaaag gacatgaact cattcttttt tatggctcta 36180 tagtattcca tggtgtgtat gtgccacatt ttctttatcc agtctatcat tgatgggcat 36240 ttaagttggt tccatgtctt tgctattgtg aatagtgctg caataaacat gtgtgcctgt 36300 gtctttatag tagaatgatt tataatcctt tgggtgtata cccagtaatg ggattggtgg 36360 gtcaaatggt atttctggtt ctagatcctt gaggaattgc tacattgtct tccacaatgg 36420 ttgaactaat ttacactccc accaacactg taaaagcatt tctatttctc cacatcctct 36480 ccagcatccg ttgtttcctg actttttaat gatcaccatt ctaactggtg tgagatggta 36540 tctcattgtg gttttgattt gcatttctca gatgaccaat gatgatgagc ctttcttcac 36600 atgtttattg gccacataaa tgtcttcttt tgagaagtgt ctgttcatat cctttgccca 36660 ctttttgatg ggttgtttgt gtttctcttg tagatttgtt aaagttcctt gtagattctg 36720 gttattagct ctttgtcaga tgcctagatt gcaaaaattt tctcccattc tgtaggttgc 36780 ctgttcaccc tgatgatagt ttcttttgct gtgtagaagc tatttagttt aattagatcc 36840 catttgtcaa tttttggctt ttgttgccat tgcttttggt gttttagtta tgaagtcttt 36900 gcccatgcct atgtactgaa tggtactgcc taggttttct tctagggttt ttatggtttt 36960 aggtcttatg tttaagtctt taatccatct tgagttaatt tttgtatacg gtgtaaggaa 37020 gtggtccagt ttctgttttc tgcatatggt tagccaattt tcccagcgcc atttattgaa 37080 tagggaatcc tttcctcatt gcttgttttt ggcaggtttg ttgaagatca gatggttgta 37140 gaggtgtggt gttacttctg aggcctctgt cctgtgccat tggtctatat atctgttttg 37200 gtaccagtac catgctgttt tgataactgt agacttgcag taagtttgaa gtcagatagc 37260 gtgatgcttc cagctctgtt ctttttgctt aggattgtct tggctataca ggctctattt 37320 ttgttccata tcaaatttaa agtagatttt tccaattctg taaagaaagt cgatggtagc 37380 ttgatgagaa tagcattgaa tctataaata actttgggca gtatggccat tttcacaata 37440 ttgattcttc ctatctatga gcatggaatg tttttccatt tgtttgtgtc ctcttttctt 37500 tccttgagca ctggttggta gttctccttt aagaggtcct tcacatccct tgtaagttgt 37560 attcctaggt attttattct ctttgtagga attgtgaata ggagttcact aatgatttgg 37620 ctctctgctt gtctattatt ggtgtatagg aatgcttgtg atttttgcac attgattttg 37680 tatcctgaga ctttgctgaa gttgcttatc tgcttaagga gtttttcggc tgagacaatg 37740 gggttttcta aatatacaat tatgtcatct gcaacaagag ataatttgag ttcctattcc 37800 tgtttgaata ccctttattt ctttctcatg cctgattgcc ctggccagaa cttccaatac 37860 tctgttgaat aggagtggtg agagaagaca tccttgtctt gtgctggttt tcaaaaggaa 37920 tgcttctagg ttttgcccat tcaatattat attggctatg ggtttgtcat aattagctct 37980 tattattttg agatacgttt catcaatatc tagtttattg agagttttta gcatgaagca 38040 ctgttgaatt ttatcgaagg cgttttctgc atctgttgag acaatcattt ggtttttgtg 38100 atttgttctg tttatatgat ggattacgtt tattgattta catatgttga accagcctta 38160 catccaggga tgatgccaac ttgattgtgg tggataagct ttttaatgta ctgctggatt 38220 tggtttgcca gtattttatt gaggattttc gcatcaatgt tcatcaggga tattggcctg 38280 gaattttctt ttctttgttg tgtctctgcc aggttttggt gtcaggatga tgctgacctc 38340 ataaaatgag ttagggagga gtctctcttt ttctattgtt tgggatagtt tcagaaggaa 38400 tggtatttgc tcttctttgt acctctggta gaatttggct gtgaattcat ctggtcatgg 38460 tttttttttt tttttttttt ttggttggta ggctattact tactgcctca atttcataac 38520 ttgttattgg tctagtcaga aattcgactt cttcctcgtt tagtcttggg aggatgtatg 38580 tgtccaggaa tttatccatt tcttttagat tttctagttt atttgtgtag aggtgtttat 38640 agcattctct gatggtagtt tgcatttctg tgggatcagc ggtgatatcc cctctatcac 38700 tttttattat atctatttga ttcttctctc ttttcttctt tattagtctg gctagtggtc 38760 tgtcgattct gtttatcttt tcaaaaaacc agctcctggg ttgattgatt tttgaagggt 38820 ttttcatgtc tccatctcct ttggttttgc tctgatctta gttatttctt gtcttctgct 38880 agcttttgaa tttgtttgct cttacttctc tagttctttt aattgtgatg ttagggtgtt 38940 gattctaaat atttcccact ttctgatgtg ggcatttagt gctatacatt tccctcttaa 39000 cactgcttta gctgtgtccc agagattttt gtatgttgtg tctttattct cattggtttc 39060 aaagaacttc attatttctg ccataatttt gttacttatt cagtagtcat tctggagcag 39120 gttgttcagt ttccacgtag ttgtgaggtt tcgagtgagt ttcttaatct tgagttctaa 39180 tttgattgca ctgtggtttg agagactgtt atgatttctg ttcttttgca tttgctgagg 39240 agtgttttat ttccaattat gaggtccatt ttagaataag tgctatgtgg tgctgagaag 39300 aatgtatatt ctgttgattt ggagtggaga gttctgtaga tgtctattag gtccatttgg 39360 tccagagctg tgttcaggtc ctgaatatcc ttgttaattt tctgtctcat tgatctgtct 39420 aatattgaca atggggtttt aaagtctccc actactattg tgtgggagtc taagtctatt 39480 tgtaggtctc taagaacttg ctttatgaat ctgggtgctc ctgtattggg tgcatatgta 39540 tttagtatag ttagctcttc ttgttgcatt gattccttta ccattatgta atgcccttct 39600 gtgtcttttt ttaatcttta ttggcttaag gtctatttta tcatagacta gaattgcaac 39660 ccctgttttc ttttttttgt tttccatttg cttgttatgt tttcctccat ccttttattt 39720 tgagcctgtg tgtgtcttga acatgaggtg ggtctcctga atacagcacg ccgatggatc 39780 ttgactcttt atccaatttg ccagtctgtg tcttttaatt gggggcattt cacccattta 39840 catttaaggt taatattgtt gtgtgtgaat ttgatcctgt catcatgatg ctaactggtt 39900 attttgcaca ttagttgatg tggtttcttc atagtatcat tggtctttat attttggtgt 39960 gtttttgcag tggctggtac tagtttttct tttccatatt tagtgcttcc ttcaggagct 40020 cttgtaaggc aggcctgatg gtgacaaaat ccctcagcat ttgcttttct gtaaaggatc 40080 ttatttatcc ttcactcatg aagcttagct tggctgaata tgaaattctg ggttgaaaat 40140 tgtttccttt atgaatatta aatattggcc cccactctct tctggcttgt atggtgtctg 40200 gagaaagttc tgctgttagt cagatgggct gccctttgta ggtaacctga cgtttctctc 40260 tggtgccctt aacatttttt cattcatttc agccttggag aaacggatga ttatgtgtct 40320 tcgggttgct cttcttgggg agtatcttag tggtgttccc tgtatttcct gaatttgaat 40380 gttggcttgt cttgctaggt tgtggaagtt ctcctggata atatcctgaa gagtgttttc 40440 caacttggtt

ccattctccc catcactttc aggtacacca atcaatcata ggtttgttct 40500 tttcacatag tcccatattt cttggaggct ttgtttgttc cttttcattc ttttttctcc 40560 aatcttgtct tcattccttt tttcagtaag ttgatcttca attactgtta tcctttcttc 40620 cacttgatcg atttggctat tgatacttgt gtatacttca cgaagttctc atgctgtgtt 40680 tttcagctcc atcaggtcat ttgtgttctt ctctaaactg gttattctag ttagcagttc 40740 ctgtaacctt taatcaggtt cttagcctcc ttgcattggg ttagaacatg ctcctttagc 40800 tcagacaagt ttgttagtat ccaccttctg aagcccactt ctgtcaattc atcaacctca 40860 ttatctgtcc agttttgtgc ccttgctgga caggagttgt gatcaattaa aggagaagag 40920 ccattctggt ttttggaatt ttcagcattt atgcactggt ttttcctcat cttcatcgat 40980 ttatctacct ttgatatttg gagctgatga cctttgttgg ggtttttgtg taggggtcct 41040 ttttgttgat gttaatatta ttgatttctg tttgttagtt tttcttataa cagtcaggcc 41100 cctcttctgt aattctgctg cagtttgatg gaggtccact ccagacccta tttgcctggg 41160 tattaccagc gaaggctgca gaacagcaaa gattgctgcc ttctcattcc tctggaagtt 41220 tcgtcccaga ggggtactgg cctgatgcca gccagagctc tcttgcatga ggtgtctgtt 41280 gacccctgct tggaggtctc tcctagtcac taggcatggg ggtcagggac ccacttgagg 41340 aggcagtctg tcccttagca gagctcgagc gctgtgctgg gagaattctc cttgtcagga 41400 tctgctgctc tcttcagagc cagaagacag gaatgtttaa gtgcgctgaa gctgcaccca 41460 cagccgcccc attcccccag gtgctctgtc ccagggagat gggagtttta tctataagcc 41520 cctgaggggg gctgctgcct ttctttcaga gatgccctgc ccagagagga ggaatctaga 41580 gaggcaatct ggccaacggc ctccttggcc tccttagcgc tgtcacggga aaaccgtcta 41640 ctcaagtctc agtgatggca gatgtccctc ccccgaccaa gcttgattgt ccgagttcga 41700 cttcagactg cagtgctagc atcgagaatt tcaagtcagt agttcgtgac ttgctgcgct 41760 ttgtgggagt gggacccgct gagtgagacc acttggctcc cttgcttcag ccccctttcc 41820 aggggagtga aaggttctgt ctccctgggg ttctaggcgc cactcagttg gaaatgcaga 41880 aatgactcag ttggaaatgc agagacttct gcgttggtct cactgggagc tgcagactgg 41940 agctgttcct attcagccat cttgccagct cctataaatg gcatttctta atcttactgt 42000 atttccatgg aataaaagta attcttatgc acactgaagt taaaaaaaaa tagcatttaa 42060 aatttctgct caggaaagta gtataatttt taacataagt gagtttctct ttgtgttata 42120 atgtaatgaa ttcttatacg catatggaga ggaaaatgac atttttctat ttatggtttt 42180 agttcagcct ttaagatacc ttgatgaaga cctggactat tgaatggagc agaaattcac 42240 ctctctcact gactattaca gttgcatttt tatggagttc ttcttctcct aggattccta 42300 agactgctgc tgaatttata aaaattaagt ttgtgaatgt gactacttag tggtgtatat 42360 gagactttca agggaattaa ataaataaat aagaatgtta ttgatttgag tttgctttaa 42420 ttacttgtcc ttaattctat taatttctaa acgggcttcc taattttttg tagagtttcc 42480 tagatgtatt ataatgtgtt ttatttgaca gtgtttcaat ttgcatatac agtactgtat 42540 attttttctt atttggtttg aataattttc ctattaccaa ataaaaataa atttattttt 42600 actttagttt ttctaagaca ggaaaagtta atgatattga agggtctgta aataatatat 42660 ggctaacttt ataaggcatg actcacaacg attctttaac tgctttttgt tactgtaatt 42720 ctgttcacta gaataaaatg cagagccaca cctggtgagg gcacaaagac tcagtggttt 42780 cgtttctcat tcctcaggac attataagta aagcttaaat acatacataa actatgtctt 42840 ttctatgtaa atataatggt tataaagtaa gtttgtatat tactaaaagt tacttatgat 42900 acatattcac ataaagaaaa gatagcattt aaagtagtac aacactaaac ttagggccta 42960 ctaacttgct aaatatccta gttttctatg caattgattt ttttttaatt ttagtgggtc 43020 cactgtaagt gtatatatat atggggtata tgagatattt tgataaaggc acacaatgtg 43080 taatcatcac atcagggtaa attaggtatt catcacctca agcatttatc ctttctttgt 43140 gttatttatt ttttaaatga caaaatttta catatttatc atgttcaata tgatattttg 43200 aaatatgtat acattgtgga atggctagat caagctaatt gacatatgca ttacctaaca 43260 tacttacttt tttctgtgag aacacttaaa acctcctctg agtgattttc gagaatacaa 43320 taccttgtta ttaactgtag tcaccatgtt gtacaataga tctcttgaac tttctcctcc 43380 tacccaatga aaattttgta tcctttgacc aacatcctct agacaccttc ctccagctac 43440 tggtaaccac cactctactc tctgtttcta taagttcaac tttttcacat tccacttata 43500 aatgaggtaa tatgacattt gtctttctgt gcctggctta tttcacttaa cataatgtcc 43560 tctaggatca tttgttttgt tgcaaaggac aggatttccc tctttttaaa ggctaaatag 43620 tattccattg tgtatatgta ccacattttc ttcattcatc catcagcaga cacttaggtt 43680 gattccatat gtgggttatt gtgactagtg ctacaataaa catgagcatg cagatgtctc 43740 ttcaacatgc tgatttcctt tactttggaa atatagacag aagtggaatt gctgaatcat 43800 atggtaattc tatttttaat ttttaaggct gtcctaattt gcattctcac cactagttta 43860 caagggatcc cttttcccca caacctcatc aatcctcatc tttcatgttt ttgattatag 43920 ctatctaata ggtataaggt gaggtgatac tgtggtttta atttgccttt tcctgatgat 43980 tagtgatgtt aaggattttt tttcatatac ctgtttgaca gttgtatgtt ttcctttgac 44040 aaatatctgt tgttctgccc atttttaatg aggttgtttt ctcaatattg ggttgtttga 44100 gttctctcta tattttggat attaacccat tatcagtatg atgtaaactc attcgtttac 44160 gttcatcttt gttgtctgtg ttttatttcc aaagaatcat tgtcatgaaa tttcccgtgc 44220 cccacccttt attattatta ttgttgtact ttaagttctg ggatacacgt gcagaacatg 44280 cagttttgtt gcataggtat acatgtgcca tggtagtttg ctgcacctat caacccatca 44340 tccaggtttt aagccctgca ggttttaagg tatttgtcct aatgctctcc ctctccttgc 44400 acccaactcc ccgacaggcc ccagtgtgtg atgttgctct ccctgtgtcc atgtgttctc 44460 attgttcaac tcccacttat aagtgagaac atgtggtgtt tggttttctg ttcctgtgtt 44520 agtttgctaa taatgatggt ttccagcttc atccatgtcc ctgccaagaa cataaactca 44580 ttctttttta tggctgcata gtattccatg gtgtacatgt gccacatttt ctttatccag 44640 tccatcactg atggacattt gggttggttc caagtctttg ctattgtgaa tagtgctgca 44700 ataaatatac gtgtgcatgt gtgtttatag tggaatgatt tataatcatt tgggtatata 44760 cccagtaatg ggattactgg gtcaaatggt atttctagtt ctagatcctt gaggaatcgc 44820 cacactgtct tccacaatgg ttgaactaat ttacacttat acaatgagtt tggaagtatt 44880 cactcctcct ctattttttg gaatagtttg agtaagattg gtattagttc tcttctttaa 44940 atgcttggca gaatcagcat tgaacccatt ggatcccaga atttttattt tttaatggga 45000 gattttttac tatggcttca atcttattat tgttattgat ctgttcaggt tttggatttc 45060 tttattgttc aatcttcgta ggttgtatgt gtctaggagt ttgtccatgt cttctagatt 45120 ttccaattta ttagcttata gttagtcata gttgccacta atgatccttc gaatttctgc 45180 agtaataatt ttcatgtctt ctttttcatc tctgacttta tttattcgga ttctccctct 45240 ttttcttagt ctagcttact aaactaaagg tttgttaatt ttgtttaatt ttcaaaaaac 45300 caactgtttg atttgttgat cttttgtatt gttttattca ttttaatttt atttatttct 45360 gctctgattt ttattatttt gtttcatctt ctaatttcgg ctttgatttg ctcttgtttt 45420 tgctccagtt ttttaagatg catgattagg ttgcttattt gaagtctttc tacctttttg 45480 atggatgtgt ttattgatat atattttctt cttaatattg cttttgatgt atccaataag 45540 ttttggtatg ttttgtttcc attttcattt gttcacaaaa tttttaaatt ttatttttaa 45600 tttcttcatt gaccaatgtt cattcaagag catatttttt aatatctgtg tatttatagt 45660 ttccaatgtt acttttgtta ctgatttcta gtttttttct actgtggtca gaaaataaaa 45720 ttgatatgat ctcaatttct ttgaacttct tgaggcttgt tttgtcctct aacatgtggt 45780 ctatcttgaa gaatattcta agtgctgaga agaatgtgta ttctgaagct cctgaatgaa 45840 atgttctata aatgtctctt aagtctattt agtctatagt gcagattaac tctgatgttt 45900 ctttgttgat tttctgttgt gatgatctat ccagtgctga aagtggaata ttgaagttcc 45960 caacttcagt tgtattgggt ttatttctct ttaacttaat aacatttaat aacatttgct 46020 ttatgtattt ggggactcca gtactgggtg catatatatt tacaattgtt atatcctctt 46080 gctaagtcga ctcctttatt attatataat gatcttcctt gtttcttttt atagatttgt 46140 cctgaaatct attttgtctg atataagagt gactattccc ttttcttttt tggtttaaat 46200 ttgcatggaa tatcttttct atcctttcat ttttagtcta tgtgtgttta tataggcaaa 46260 gtgaatttct tgtaggaagc atgcagttgg gtctttttgt tattattcat tcagccactc 46320 tatgtgttct aattggagaa tttagtccat taaccgtcaa tgtattattg acaggaaagg 46380 acttactact gccattttgt tatttgtttt ctagttgttt cattggtcct gtcttcattt 46440 cttactgtct tcctttgtgt acaagtgatt ttctctggta gtatgtttta gttttttgct 46500 ttctagtttt tatgtatcta ttttagtttt tcttctcatg gttaccatga ggcttgtaaa 46560 taacatctta taacagattt ttttaagctg atgaaaactt aattatactc ataatagaaa 46620 cggaaacaag caaagagaaa actaaaaaat ctacacttta actttattct ccccttatca 46680 ttttttgagt tgttgtctat atatcttttt atattgcctg tatttaacaa atcattgtag 46740 ttgttattat tcttgatagg cttgtctttt agtcttcata ctaaatatat gcatggttta 46800 cacactgcaa ttacagtgtc agaggtgttc tatatttgtt tgtgtactta cttttactgg 46860 tgagttttat actttcaggt gatttcttgt tgtttgttag caccttatct ttcagactga 46920 aaaattccct tcagcaaatt tttgcaaagc agggctgatg ttaatgaaat cccttaggtt 46980 tttgtttgtc ttggaaagtc tttatttctc cttcatgttt gaaggataat tttgctggat 47040 ataacattct aagttgaaga ggtttttttc ttcactactt tgaatatatt atccccatcc 47100 cacttggcct gtaaggtttc cactaaaaag tcaactgcca gatgtatcag agttccttta 47160 catgttattt gcttcttttc tcttgctgct tttaggatac tttgtccttg aactttgaga 47220 gtttgattat tttgtgtctt gaggtagtct catttgaatt gaatctcctt ggtcttcttt 47280 gagctttatg tacctgggta ttcaaatctt cctctaggtt tgaaaagttg ctatttcttt 47340 gaataaaact tcttcactga tctcttattt tacatccttt ttaaggccaa taactcttag 47400 atttgccctt ttgagggtat tttctagaac ttgtaggtgt tttcactcct tttaactctt 47460 tttttctcct tggactctgt ctttttaata tagctatttt caagctcact aattcttttt 47520 tttctttacg tcttctaaaa aaatgggata catgggcaga atgtgcaggt tggttacata 47580 ggtatatgtg tgccatggtg gtttgctgta actattgacc catcctctaa gttccctccc 47640 ctgactcccc acctcccaat aggctctgat gtgtgttgtt cccctccctg tgtccatgtg 47700 ttctcaatgt tcaactgcaa cttatgagtg agaacatgta ttgtttggtt tactgttcct 47760 gtgttagttt gctgaggatg atggcttcca gcttcatcca tgtccctgca aaggacatga 47820 actcattcct ttttatggct tcatggtatt caatggggta aatgtgccac attttcttta 47880 tccagtgtat cattgatgag catttgggtt ggctccaagt ctttgctatt gcaaatagtg 47940 ctgcaataaa catacctgtg catgtgtcct tatagtagaa tgatttatat tcgtttgggt 48000 atatatccag taatgggatt gccgggtcaa atggtatttc tggttctaga tccttgaaga 48060 atcaccatac tgtcttccac aatggttgaa ctaatttaca ttcccaccaa cagtgtaaaa 48120 gtgtccctca ccagcatcta ttatttcctg actttttaat aattgccatt ctgactggca 48180 tgagatggta tcttattgtg gttttgattt gcatttttct gatgaacagt gatgttgagc 48240 tttttttatg tttgttggca gtgtaaatgt cttcttttgt aagctcatta attctttatt 48300 ctgcttgatc aatactgctg agagacactg ttgtattttc cagcttgtca attgaatttt 48360 tctgctccag aatatctgct ttgtttttta aattatttaa tatctttgtt aaatttctct 48420 gatagaattc tgtacttctt ttctgtgtta tcttgaagtt tgttgagctt ctgaaagaca 48480 gctattttta attccatgtc tgagaggttg catgtctcca tcactctaga attaatcact 48540 ggtgccttat ttaatctact taatgaaatc acattttcct caatgttcct gatgcttgca 48600 aacattcact aatgtctaga cattgcagag tcgattgttt atttcaatct tcacaatctg 48660 ggcttgtttt tattcatcct ttttgaaagg gcttttaaat aattcaaatt agaaattaag 48720 acagagaaat tcacccaaag ccatacagtt acatggaaat tgaataacat gatcctgaat 48780 ggcttttggg taatgaaatt aaggcagaaa tcaagaagtt ctttgaaact aatgagaaca 48840 aagataaata taccagaatc tctgggacac agctaaagca gtgttaagag ggaaactcat 48900 aagactaaat tcccatatca aaaacttaga ccgatctcgt taacaaccta atatcacaac 48960 taaaagaact agagaaccaa atgcaaacaa actccaaaag tagcagaaca caagaaatta 49020 ccagtcagtg ctgaactgaa aaaaatagag acatgaaaga acatccaaaa aatccagaaa 49080 ttcaggggtt ggcgttttga aaaaattaat aaaatagacc actagctaga ctaataaaga 49140 agaaaagaga gaggattcaa acatacacag tcagaaatga taagggggat attaccactg 49200 accccacaga aatacaaaca accatcagag aatattatga acacctctat gcacataaac 49260 tagaaaatct agaagaaatg gataaattcc tgaacacaca acaccatccc aagactgaac 49320 caggaagaaa ttgatttcct aagcagacca ataatgagct ctgaaattaa ggtagtaata 49380 aatagcctac caaacaaaaa aaaaaaaaaa agcccagcac cagagggata gagggattca 49440 cagctgaatt ctaccagctg tgcaaagaaa agatggtact atttatattg aaactattac 49500 aaaaaattga ggagaaggaa ctccttccta actcattcta tgaagttagc atcatcctga 49560 taccaaaaac tggcagagat acaacaaaaa gagaaaactt caggccaata tccttgatga 49620 acatcgatgc aaaaatcctc aacaagatac tggcaaactg aatccagcag cacatcaaaa 49680 agcttatcca ctacgatcaa gtaggcctca tccttgtgat gcaagattgc ttcaacatat 49740 gcaaatcaat aaatgtgatt catcacatac acagaattaa agacaaaaac cacatgatta 49800 tatcaatagg tgcagaaagg actttcaata aaattcatca tcgatttatg ctaaaaactg 49860 tcaataaact agttgttgaa ggaacatacc tcaaaataat aagagccatc tatgacaaac 49920 ccacagccaa catcatactg aatatgcaaa agctagaagc attcaccttg aaagccagca 49980 caagacaagg atgccctctc tcacactcct attcaacata gtattggaag ttctggccag 50040 gccaatcagg caagagaaag aaataaagcg catccaaaca ggaagagagg aagccgaact 50100 atctctgttt gcaggcgaca taatcctata tctacaaaac cccatagtct cagcccaaaa 50160 gcttcttaca ctcataaata tcttcagcaa agtctcagga tacaaaatgt gcaaacatca 50220 ttagcattct tatacaccaa caacagtcaa gcagagagca aaatcaggaa cacaattatc 50280 attcagaatt gccacaaaaa gaatataatg cctaggaatt cagctaacca gggaggcgaa 50340 agatctctac aaggagaact acaaaccact gcttaaagaa atcagagatg aaagaaacaa 50400 attgaaaaac attccatgct catggataga aagaatcaat attattaaaa tggctatagt 50460 gcctgatatg gtttgactct ctgtccccac ccaaatctca ccttggattg taataatccc 50520 cacgtgtcaa gggtgggacc aggtggagat cattgaatca tgggggcagt ttccaccatg 50580 ccgttctgat aatgagtgag tctcttgaga gctgatggtt ttataagaag cttccccctt 50640 cactctgctc tcattctctc ctgccatcct gtgaagaagg atgtatttgc ttccccttcc 50700 accatgattg taagtttcct gaggcctccc cagccatgca gaactgtgag tcaattaaac 50760 ctcttttctt tataacttac ccagtcatgg gcagttcttt atagcagtgt gagaatgaac 50820 taaaacaatg cccaaagcaa tttatagttc aatgctattt ctgttgaacc accattgaca 50880 ttcttcacag aactagaaaa aaactatttt gaaattcata tggaaccaaa aaggagtctg 50940 aatagccaaa gcaatcctaa gtaaaaagaa tgaagctgga gttatcacgc tacttggctt 51000 taaattatac tacagggata cagtaaccaa aacagcatga tactggtatg agaacagaca 51060 catagactga tgaaacagaa tagagaaccc agaaataaga ccacacacct acaactatct 51120 gatctctgac aaacctgata aaaacaggca atggagaaag gattccctat tcaataaatg 51180 gtgctgtggc caggtgtggt ggctcaggcc tctaatccca gcactttggg agaccgaggt 51240 gggtggatca cttgaggtca ggaattcgag gccggcctgg ccaatatggc gaaaccttgt 51300 ctctacaaaa gatacaaaaa ttagccaggt atggtggcag gtgcctgtaa tcccagctgc 51360 ttgggaggct gaggcacgag aattgcttga ccccaggagg cagacattgc agtgagccaa 51420 gatcgcacta ctgcactcca acctgggcaa cagagtgaat ctctgtctca aaaaaaaaaa 51480 aaaatggtgc tgggataact ggctagtcat atgcagaaga ttgaaactag actccttcct 51540 tacactatac acaaaaatta acacaaggtg gattaaagat ttaaatgcaa aacccaaaac 51600 tgtaaaaacc ctgaaagaca acctaggcaa tagagttcag gacatgggca gggcaaagct 51660 ttcatgatga agatgccaaa agcaattgca acaaaaacaa aaacagacaa attgaatcta 51720 attaaagagc ttctgcacag caaaataaac tatcaagaga gtaaacagac aacctacaga 51780 atgggagaaa aattttgcaa actatgcatc caacaaaggt ctaatatcca gcatctataa 51840 ggaacttaaa tttacaagaa aaaaacaacc ccattaaaaa gtggacaaag gacatgaaca 51900 gagacttctt agtagaagat gtacatgcag ccaacaggca tatgaaaaaa gcttgatatc 51960 gctgatcatt agagaaatgc aaattaaagc cacaatgaga taccatctca caccagtcag 52020 aatgactatt attaaaaagt caaaaaataa cggatgctgg caaggttgtg gaaggaaaag 52080 aatgctgttg gtgagggtgt aaattagttt agccattatg gaagacagtg tggcgattcc 52140 tcaaagacct taaagacaga aataccattt gactcagcaa tgccgttact tcgtatatac 52200 ccaaggaata taagtcattc tgttataaag acacattcac gtgtatgttc actgcaacac 52260 attcacaacg gcaaagacac gtaatcaacc taaatgctca tcaatggaag actggataaa 52320 gaaaatgtga tacgtataca ccaaggaatt ctatgcagtg agactaagtc ctttgcaggg 52380 acattattct tggcaaacta agtcaggaac agaaaaccaa atgccacgtg ttctcactta 52440 caagttggag ctaaatgatg aaaacacacg aacacataaa ggggagccac acacactggg 52500 tttttcggaa ggtagaaggt gggaagaggg agaggatcag gaaaaataac taatgggtac 52560 taggcttaat acctgggtgt taagggtagg ctattgggtg ataaaataag ctgtacaaca 52620 agcccccatg acacagcttt atctatgtaa caaacctgca catgaacccc tgaacttaaa 52680 ataaaagtta aacaaaaaaa agagacagag aattcaaatg ggtttgagtg ttgttaccta 52740 agcctgtggt catggcagcc tctc 52764 38 61329 DNA Homo sapien 38 gagtgcagtg gcacgatctc ggctcactgt aacctccgcc ttccaggttc aagcaattca 60 cctgcttcag tctcccaagt agctgggatt ataggcacgt gccaccatgc ccagctaatt 120 tttgtatttt tagtagagac ggggtttcac cttgttggcc aggctggtct tgaactcctg 180 acctcgcgat ccatttgcct tggcctccca aagtgctggg attacagtca tgagccaacg 240 cacccggtct ggataattgt tttctaacgt atctatattt gcctgtactg gtactcattg 300 ggcccttctg tgctcactca tggcatcttc ccatcagaga atatctgagt ggtagaccat 360 tcttgcatgt tttggttttt acagaaatat ttttagttgc cattaaaggc tgacatccat 420 tgttggaaat cattcttttc tgcctctttg gatgcatctg agtttgaggt tttactttcc 480 ttctacccca ttaggttgta tgtttgcttt tgttttgtag aatttagtca gcagcttaag 540 gcttaggaac attagatgct aatcatgcca tcttagcttt ttttgtgagc ccaaggagta 600 tattcggggg tgggggtggg aatgaaagtt actggggagg cagaaagggg tcattttttt 660 tttttttttt tttttggaga cggagtctcg ctctgtcacc caggctggag tgtagtggcg 720 cgatctcggc tcactgcaac ctctgcctcc cgggttcaag caattctcct gtctcagcct 780 cccgagtagc tgggactaca ggcacatgcc atcacaggcc tggctaattt ttgtattttt 840 agtagaaatg aggtttcacc atattggtca gcctagtctg gaacttctga cctcaggcgg 900 tccacctgcc tcggcctctc aaagttttgg gattacaagc gtgagccact atcccagccg 960 aaagtggtca ttttgaaatc agaagttgta tctttttgtg gttgagggtg ataaaaactg 1020 aaaaactgtt ttcaagtttg gagcatggga gggaaaaccc agcgatttgt tctggtctcc 1080 ctcagctcag tgtgtttgaa gccaaaagcc tgcttgtgtg cctctcccaa ttcatttgct 1140 cctagttcat ttgctacttg catagaaatt ttcatgccga atctcactct tcagcggata 1200 cctgagaaca ttgttgctac aatctctaaa atcagatttt ttcaagaaag aatttttatt 1260 aataacctca agtacttttc gcctacaccc tcaggctcac tttttgtata ggtttttctc 1320 cctggagaat cctacatgct gtattgatgt ctcaattctg tgtgctgctt cttcagtgct 1380 accttgccct ggccaaagga ggcttatctg atgaccatgt cctcatcctg cctattggac 1440 actaccagtc agtggtggag ctttcagcag aggtggtaga agaggtggag aagtataagg 1500 ccactctgag acggttcttt aagagtcgag ggaaatggtg tgttgtattt gagagaaatt 1560 ataagagcca tcacctccag ctacaggtag gtggtctgtt catagaaact tggaagggcg 1620 ctatggggac tttgatattg gtaaataagt atttaaatag gctgggcgag gtggctcacg 1680 cctgtaatcc tagcactttg ggaggccgaa gcggttggat tgcctgagct caggagttca 1740 agaccagcct gggcaacacg gtgaaaccct gtctctacta aaagtacaaa aaaattagct 1800 gggcgtggtg gtgcatgcct gtaatcccag ctactcggga ggctgagaca ggagaatagc 1860 ttgaacctgg gaggcagagg ttgcagtgag ccgagattgt gccactgcac tccagcctgg 1920 gcaacagagc gagactccat ctttaaaaaa aaaattatat aaagtttagc tttaatatgt 1980 aaaatattta atatttttat attaatattt aaataacatt catttaaaaa gtttttaaag 2040 agtatctggt ggtaacccca gagacttcac agggaagtgt gtggtcagta catgtaaaca 2100 gcatagatag taagttcctt gtttagaaaa ggaatgggta gttgaggaag ttccaaggaa 2160 gatgtggggc ttgctggata agaatttgga agaaagtgag tattttgtgt ggaggcccag 2220 catgagggaa agcttagtgg taggaaatag tctcaaagcc tgcatggggc tagcagctca 2280 gaaaatcaga ttgtaaatca tttgtagttg tggtggtttt ctttttggca catttgttaa 2340 gttttcaaat gggcctaact ctgccacata tataatatcg gagatggcaa aggcttgtga 2400 cggagatatc tctcttaagc ctttcctgca tcagagaatg gctcccacat gtgtcaggct 2460 atctcataag tttaagtcct tacagacagg ctgacacagg cttgtctggc ctgaggatat 2520 tctgtgctga ggggtgtttc tccacccctg tgatggattt gctacttctc agagactgtg 2580 caggcacaac ttctctggga cctgcacaag gaatttctcc tgtctcccca acccccaggt 2640 cattcctgtc ccaatcagct gctctactac tgatgacatt

aaagatgcct tcattaccca 2700 ggcacaggag cagcagatag agctgttgga aatcccagag cactctgaca tcaagcaggt 2760 gaaacagggg atggtgatat tcagggaaga gtaaatatct gttttttttg ttgttgtttg 2820 ttgtttgttt gtttgtttga gacagagtct tgctctgttg cctaggttgg agtgcagtgg 2880 catgatcttg gctcactgca acctccgcct tccgggttca agtgattctc ctgcctcagc 2940 ctccccagta gctgggacta caggcatgcg ccaccatacc tggctacttt ttgtattttt 3000 agtcgagacg gggtttcacc atattggcca ggctggtctc gaactcctga ccttgtgatc 3060 tgcctgcctt ggcctcccga aggtattaca ggcatgagcc acccacgcct ggcaagatct 3120 ggtttttgac atgttgagcc taaggttttt gacatgttga gctatcaagg cattccaaaa 3180 atgttattaa ataggcaatg ggttgggcat ggtagctcac acctgtaatc caacactttg 3240 ggaggctgag gcgggaggag cacttgaagc caggagtttg ataccagcct gggcaacaaa 3300 gtgagacacc ttgtctctac aaaaaataaa aaaataagct tggcatggtg gcatgtgcct 3360 gtagtcttag ctactcagga ggctgagagt caggaggatc acttaagcct aggagtttga 3420 ggatgcagtg aggtatgatt gcaccactgt acttcagcct gggcaacatc gcaagaccct 3480 gtctctaaaa aaaaaaaaaa aaaaaagagg cagtggacaa tttggaacta gagcactggg 3540 tattgactag actggagatg aacagggcat tactccaaag tttagtgctt tcctgggaag 3600 agcaagaaat tagaatttcc taaggtagga acttagaagg atagacgcca ctgggaggat 3660 attgttagta tcttccagtt agacttttta agccctagtt ccactaagtg gcttgggatc 3720 tatagcaaca tacatatctt tttttcttgt gcatttagac tgaattattt gcctagagat 3780 gaactcagat tatagatttt taaagcatta ttggacatcc tcatacaact ctgtttactt 3840 tagattgcac agccaggagc agcatatttt tatgttgaac ttgacacagg agaaaagctt 3900 ttccacagaa ttaaaaagaa ttttcctttg cagtttggaa ggtatgtttt tcttcttttc 3960 aatgtatttt cactagacct gctatgaaca gagtggtggg ctacatggga caattgataa 4020 aaagctaaat tgtaaacagt ccttgcccca gaggacccat ggtcttaggg cagatgttta 4080 catatatgac agtaatgtaa tgtagaatgt gaagagtacc atgacagagt tttggagaac 4140 aatgtgctgt agaaattcag aaaagggaca gctcatttct agttggtgaa agccttcatg 4200 aaagtggcaa agttgaacct gagaggcata tttagagggc aaagattgag gtgagggcat 4260 tctagccaga agtgctaggg aactttaatt gagcacatac tctgtgccaa gaactgtacc 4320 aagaacttta cacatacatg actcatttaa tcttcataac tctgtaaggt aggtactgtc 4380 atcccgattt accagtgtgg aaaatgaggc tctagagcag tgcccggtag acttttcaca 4440 acgatggaaa tgctcaaata tctgcactgt ccaatacagt tgtgactagc cacttgtggc 4500 cactgagtgc tgaaatgtgg ctaatgtgac tgaggaacta aatttttgat tttatttaat 4560 taattagaat ttaaatttaa atagccatac ctggctaatg gttaccccac tggatagcag 4620 gctgtagaga gcttaggtag cttgtcctag tcacacagtg gtaggttcaa acccaggcct 4680 gttggacctc aaaacttgag gtcttaacct cagtgttcta cagtatggta aaggcctaga 4740 ggaggcttca gttctgttcc tcgtatcagg caaaacatga ctgcaaaacc atagagggag 4800 taacataact taagcaaaga ttgaagatgg gaagttgctg gcaagaagat acagtttgaa 4860 ggggagtgga aaatgtgtag aacagagtat ctgatgctgg tgtctgtgat ttgcagctgt 4920 tttttctccc ctagttaaaa atgggctttg agtgagcctt gaacctgtct tggactaatt 4980 cagaaagcct ccaagagatt gcccccttag ataagtccag taaatgtagt tgtctacatt 5040 tttcaaaaag ataaatggga acaagtgtgc tacgagattc agacatctga cgtgatgttt 5100 tcgttgttgc ctcagcaaca gatgcggtta tgaacattga caacataagc acacgattgc 5160 agatacacat aggcgtataa agcacacaaa aagaagattc tctgaatggt tttgtgctta 5220 tgatgtattt tcaatattga gtaattatca agatactaat ttatagttat atagcatttt 5280 atagttaaca aaatatttga aatggcatat ttttttcagc tgtacaagaa aggtagttct 5340 attttccttt tatatttgaa ataggctcaa agtttgccca gggagcttag gttctttgac 5400 ttatagagaa ttcatgattt gtttctaact cttctattta ctgtaacttc aaagtggaaa 5460 atgaaccata taaatgtgta atagaattat ttctaatata tcaaaataag taaaaataaa 5520 aatataaagc aatggcgatt agaaggcagc ttgtgtgtga gtgtgtctgt atgtagttat 5580 tctttagtcc taagagccaa gatagttgtt ttgttgacat tgggcttgtg ctgctgttac 5640 gtgggcctga gtcccctaga aggagaggca gaggaatttt aaatcagagt gggtatgact 5700 aggctcctga ctctgcaaac tcatgtctag ttgaggtgac aaaactacag tttaaggcag 5760 gttgtaatca cagctaatat ggcactttga ctgtgttatc tctgtacctc acaaaaaccc 5820 tgtatggtgg gtgttcttat ttgcatttca taggtgagga aatcaagact cagagatgaa 5880 atcatctgtc tagatcatag atagcaagtg gcaaagctgg aaatgggatc cagtctctga 5940 tctttctcac accagggcct gccctttttc tatgtggtgt tgcttctcta agtaccaata 6000 atatagttcc aagtttttta agagagggag aagcaagtgg ggtttgaagg atcaggaaat 6060 atatagtacc tgagctggtc atttaaaacg ggtatgattt tgatcaatag tatggcagag 6120 atggcactca gggcaggaga gcaaagtcag agaaatttgc atacctcctt tgggtgatgt 6180 tgaggagagc tcaggctgat agtttccatt ttgacttctt tgtgctattt ctgcagggag 6240 gtcctggcca gtgaagccat ccttaatgtt cctgataagt ctgactggag gcagtgtcag 6300 atcagcaagg aagacgagga gaccctggct cgccgcttcc ggaaagactt tgagccctat 6360 gactttactc tggatgacta aaacaaaggg aagaactttt tatgaactcc acaggaagta 6420 gtaaagcttt tttttttttt taattaaaag aatttttttt gagacaaagt ctcgctctgt 6480 cacccaagca ggattgcagt ggcataactg tggctcactg tagcctcaac ctcctgggct 6540 ctagagttcc tcccacctca gcctcatgag tagctgggac cacaggcgca tgctaccatg 6600 cctggcaaac ttttttgatt ttttatagag acaggagggt ctccctgtgt tgcccaggct 6660 ggtctgtaat gcctaggctc aagggatcct ctgccttggc ttcttaacct gctgggatta 6720 caagcatgag acaccattcc tggcctagaa gcctattttt aaagaaacta caatctccca 6780 tggggactgt ttccctgcct cttttgtgca gtcccatgga acttgcctac agcaagaggc 6840 ctaagattga atctttttgg ggaaaagtca ttctaggatg aaaatcctat gttaaggccg 6900 ggcgcagtgg ctcacgcctg taatcccagt actttgggaa gccgaggcag gtggatcacc 6960 tgaggtgagg agtttgagac cagcctggcc aacatggtga aaccccgtct ttactaaagc 7020 tacaaaaatt agctgggcgt ggtgccaggc acttgtaatc ccagctactc aggaggctga 7080 ggcaggagaa ttgcttgagc ctgggaggtg gaggttgcag tgagccaaga tcgctccatt 7140 gcactccagc ctgggtgaca gtgaaactcc atctcaaaaa taaaagaata aaagtatgtc 7200 tgtcatccag ctcctatgtc tgttatccag ctccaagtac agcttgtgta tatcaacatt 7260 ttcaaaaacc tttaaactac caaatgaaat ccagatgttt ttccatggtt gagaagtgtc 7320 ttgtgttcat gttgcctgtg accgttgaaa tgaagtagta tgtgtaatag caggggctag 7380 agctttaggc ccagctgtta ctccaaaatc acacagggca gtttctccct gaacaaccca 7440 aagtggaaaa gggatccaag gcttttgcta tttttctctt aaagcattca tcttattcat 7500 agataagagc ccatttagtc cttcggatat ttaactccta tgtgccaggc atttttctaa 7560 gctccaggac catagtcatg tcccaatatg gtccctgttg tcccagagat tacagtttaa 7620 tggggaatag aagggacaga tttaagaaaa aaaagataat tctcctttgg atattgtttt 7680 aggtgcttga tatatctaat atgtgtctgt tgtgctgctg ggcagttcta aactcatcag 7740 tacctgggtt ggttacaggg ctttggggat catcagggta taggccatag gtgaaattaa 7800 gatagggtaa atacagtcct gagctgaaga tgattacctg agaaatatca gtatttaagg 7860 agtgcttgaa aatagtgatc taacatttac atagagaagg agcaaagaga atgctacata 7920 ttaggcgcaa aaagaaaaat atttttacct ttatattggg cacttatggt ccagacactg 7980 tttcatttaa tcttcacaaa atctctgtga ggtaggtatt acctctattt tactcatgaa 8040 aaaaaaactg agactcggaa aattgaagat tgtggagcct ggggtcaaca ggcttaggct 8100 ttttaaaaaa caggccaggt ggctcatgcc tgtgattgca gcactttggg aggctgaggc 8160 aggcagatga cctgagatca ggagtttgag accagcctag ccaacacggt gaaaccccgt 8220 ctctactaaa aatgcaaaaa attagctggg cgtggttgca tgcgcctgta atgccagcta 8280 ctcgggaggc tgaggcagta gaattgcttg aaccctggag gtggaggttg cagtgagctg 8340 agatcacacc attgcactcc agcctgggtg acaagagtga aactccatct caaacaataa 8400 caacaacaac aacaaaaaac aactcaaatt actcatggcc ctgggaatgg gggcatttaa 8460 aaagttaacc aagggaacca acctggtttc cacaaagatg gccacttctg ggtcagccca 8520 atcatcagta tccctgggtc ctcagcatcc cttcctacct cttttgactg ggaattacga 8580 gattacagcc ccacctacgg aaattgagca cattagcact ggccatgctg tacatacagc 8640 aaatgagagg gcttcatact gttacaacaa tctgtaccac aattctctgt gcggtctgcc 8700 cagctctaaa tgacatgtcc tcagaggcat catcatctcc aagtccatgg aaaccatgca 8760 cttacagaaa ccagaacctc ccataccaca tgttactaat gacctacaac atcgacttcg 8820 tctgtatcat gcagtgctca acattctggt tgcagcatca catttatcaa taatttgatt 8880 ccatgctgat tcctttactt ggagtattga gatcccccag gtacagtgaa ggtatgaccc 8940 tcttaaatgg aagaccagga gttgtttccc ctatgctatg gcaatccgcc acccggaagc 9000 acttgctgca ccaacagcat tcccaaagct tgcctctgca gccctgtagc acccattaga 9060 aacacttctc acaatgaact actgtgctgg caaacccata actggactgc cggacagcaa 9120 gctctgtgag gcatctagga aaaaagctcg cgaaatcccg agaaacactc ttcactccgg 9180 aatagcgtca cattcttgag tcatttggga tgacagggga tatcctggag caggtgtatt 9240 gggaagtcag tgaacaagaa ggctaattca ttagtgggcc tgctagcgta gtattttaac 9300 gatttcgcag cctttaaatc attggtggtc tttagcgtgc cggatcagct ggtggtggag 9360 ttggaggata gatggcaggg atctgaagaa aggtgaagtg tagataggag tagagacaat 9420 atgaagttta gaaaagacta attgctggac gcggtggctc atgtctataa tcccagcact 9480 ctgggatgcc aaggtgggag gactacttga gaccaggagt tcgggaccag cctgggcaac 9540 gtagcaagac catgtctcta caaaaaataa aaaattagcc aagcgaggtg gtgcgcgcct 9600 gcaatcccag ctactcggga ggtgagaaga tcgcttaatt ccgggaggtc gaggctgcag 9660 tgagccgtga tcgtgccatt gcactccagc ctgggcaacg gagcgagacc ccatcttaat 9720 taaaaagaaa aaaatacagg agagactggg ctgctttgaa aagtggattt gacgggaatg 9780 tggggtttgg agagatctta tgttttccaa gactagaaaa acattgtggt tccgttcagc 9840 cctcccggaa aatacgtagg ggacttaaag agcggaccga gtacctgttt gtttccccat 9900 cccttagccg gcagggctct ggcagcgccc tgggagaact tagggaaggg ccttctcgca 9960 gcggttaccg gaagtgacgc attcattctc gcgagaacaa agacgcgcga gcatcggcgg 10020 cccggaaccg gccttggaac aactgtggaa cctgaggccg cttgccctcc cgccccatgg 10080 agcggccccc ggggctgcgg ccgggcgcgg gcgggccctg ggagatgcgg gagcggctgg 10140 gcaccggcgg cttcgggaac gtctgtctgt accagcatcg ggtgaggcgg ggcgtgagag 10200 ggagcggcgg tgggttggag cggcggtggg tttgagcgtc tgtggaacac agggctgaca 10260 gtgtgggata gatggttggt gggaccttgg gcagtatttg ggggccagtg ggcttgtgtg 10320 tgtgtattag agagaaagat actatgcctg tgtgtccaaa gttgtatttg aggtactggg 10380 catagataga gctgttgcgg ggaacttggg tatgactgtc aggctgtgac caggtgttta 10440 gtgagtgtga cagtgcgtgt gtgtctctgt gaatgtggag tgtcagggtg tgtgaggcag 10500 atgcacgtca cagtgtgtat gtaggagcac gaatgtgtga gaagagggct gaaggggact 10560 gcctttggga atgtgtgcgt ccgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgtgcgcgc 10620 gcgcgcgcgc gcttggaggc catatgatat cagtggggac tggagtagac aaggaaggct 10680 tcatgatggg tccagagtta agcctttgga agcatggatg ggctttggaa ttggggatgt 10740 attccaggtc gggacagtat gagggtgagt tggtgcagag catggcttca aacgaaaggc 10800 tatattagta gatggagatg gggggcgctc tagtaggtgg aggacagtta acatcagact 10860 caagaatttt actttgattt aatagagaat gtttaaccat tgtagtagca gttaaaaaat 10920 catatttggg tcttgtttgt ttgtttttgt ttttgagacg gagtctcact ctgtcgccca 10980 ggctggaatg cagggcgcga tctcggctca ctgcagcctc ctcctcccga gttcaagcga 11040 ttctcctgcc acagcctcct gagtagctgg gattacaggc gcccgccacc gtgcctggct 11100 aatttttttg tatttttagt agagacgggg tttcaccatg ttggccaggc tggtctcgaa 11160 ctcctgacct caggcgatcc acctgtctca ggctcccaaa gtgcagagat tataggcgtg 11220 agccacggca ccaggcctgg gacatgtatt ttttgatata ccgataaaag ctgtgaaccc 11280 tttccccaga aaaatgcaca gatgcacatt cacacaacca tgcattgcca tttgagaggt 11340 tcgtgccttc ctaaaggaca ttttaggtaa atagaccctg gactaataat tcctgtaata 11400 taggctttgt tttgttgcct gtaaagtaag tatagtataa taattacatg catcatggat 11460 ttgagagtta aataaaatag taatgtgtgt aaagctaaat acggtacctg acccatgaaa 11520 gccctcaact gttagcacct gctgctactt tgttgttgtt gctgctatga tcataatgct 11580 cctcattaat tggccttaag gaaatgtcaa gataaaaagt gttgttctag gaaaatggtt 11640 ttgtaaagga taaatttgag tggaacaaca tatgggacaa gatgaacagg taagatctta 11700 ctaaaatgcc tgggcttggc ttgtgaatag agaagttaat tcaagaggaa aagtaataat 11760 ttgttatcta aaggaacatg ggtgtagtga gaaagctcgt aatttggggt gggagaaagg 11820 ggagatagga gtctaccttg ggaaaatagg catatttagg gtaattagaa tgacaactga 11880 aactgttaga actgaggaag ttttgtgaac caggtttcta gatagggcat aggagaaaat 11940 cttggagaaa gagaatggaa ggtgaaggac taaggcatta agtcctgtga tagcaggata 12000 agtagtaaat ttaataattc tcaccatcag agggaacata acacactaaa aaaaaaaaaa 12060 agtgggagcc aagtgcttcc agtggcatgt tgcctgtgtt acctaagcct gcctatccgc 12120 ctggtcataa ggaaaaagga tgcatgctgg cagcttttgt gacttctttt cttggtccct 12180 gggtggggat ggatgaatta atcacttttt gttttattat ggtaaagtat acataacaca 12240 acatttatca ctttattttt aagtgtacag ttaggtggca ttaagtacat tgacgttgtt 12300 gtacagccat aaccctatct ccagaatatt ccgacttttt tgttgttgtt gtacatctat 12360 aaacttccca tagaatattc tttgtgaaaa ggtagaattt cacagagttg atgaaatata 12420 aattaaggag ttgaaggatc ttacaaagtg ggatttttga aatagataac ttattgctcc 12480 attaacatga gcattcaggg ctcagtgttg ttcatggttg tgcctgattc tcatttccat 12540 ggtggtaaag gcctgcatgg gacatagata taactggtca cctgctcata acaaaaggaa 12600 gattgaaggg agtgagaact gtgggtaggc tagcatgcag tctatcctag tttccttctt 12660 ctctatgcac caggtatcat cttatctcta gcttcttttt tcctctcacc ctccaattca 12720 cactacccta tccaagctat gtcttgcttc cccacctata atatattttt tctgtcctgg 12780 cccctgggct cttctctctg tattcataca cagcctttat tacaactctg gtttgtgtca 12840 gagattacat atgttggaaa ttcttttgaa ctctccttgt gatatcagaa acatagtgta 12900 gcctgtttag ccctgactgc tatttctgag ctgcattatt aatgttgcca gaatatgatg 12960 gggtctggct atttcctgta atatgcatca gaatgggttt aatttcagtc agaattggct 13020 aaattactag tcacaggcaa gagatgttag gttcattatg tagctatgga agcagaagta 13080 cactcattgg taggattttt tttcttcatg tcatttgaaa tgcatacatt aggattggag 13140 ttttttgctt taggcttggt tatattaaaa ctttctcttg ctgtttggag tccaggaagc 13200 cctgaattac cttcttcatt ttagttatgc tagaagctgg ggcacatatt agttgtcttg 13260 attaagctct gaaaggggtt tgctgaggag acaggatctt tttttttcta acattatata 13320 tgagagagag ttctgaaaag acctgttata aaatcagttt caggcacttt tcccttgtat 13380 gctgttgtgt gtttgaaggt cagttttaaa gcattggtgt aatagtctca tggtttatct 13440 ttttaaaaag cattgcctca agagagctgt ggataaatat atttaattag taaagctaaa 13500 aagttttgtt gtcttaagtt atttctttgg tagcaaataa atcttcacaa gaacctaatt 13560 ttttttttct gttgattttc tattttggca ggaacttgat ctcaaaatag caattaagtc 13620 ttgtcgccta gagctaagta ccaaaaacag agaacgatgg tgccatgaaa tccagattat 13680 gaagaagtaa gtgtattcct tgacttacat ttccctggtt ctacagccca accagatgtc 13740 atcatgggga aagaggccag gaatccactc ttctcaggat ctttttggga acatatattt 13800 ttttctctca ttaaatatat tctatttcaa ataataatat cacattaaga ttaagaaggt 13860 ttagttaaaa tcagctagga cacttacaca ctgttggtgg gaatgtaaaa ttgtgcaact 13920 gttacggaaa acagtacggt gattcctaaa aaattaaaaa tagaattacc atatgatcca 13980 gcaattccat ttctgggtat atacaaaaat gaattgaaag cagggactta aagagtaatt 14040 tgtacactca tattcataac attattattc acaatagctg aaaggtaaaa gcaacccagt 14100 atctaccagc agagacatgt ataaacaaaa tgtggtatat tcatgaaacg gaatatcatg 14160 cagccttaaa aaggaatgaa actctgacac atgccacagc atggatgaat cttgtggaca 14220 ttatgctaaa tgaaataagc cagtcacaaa aagacaaata ctgtgtcatt ccacttatgt 14280 gtggtaccta gagtagtcaa actcacagtg aaagaaagta gaatggtgtt tgccagaggg 14340 tgaagggacc agcaaataga gaataatttt taataggtgc ggagtttcag ctttgcagaa 14400 ttaaacagtt ttgtgcagta tagtgatagt agcaaaacat tgtgaaagta tttgatgcca 14460 ggctgggcat gttggctcac actgtaattc caacactttg agaggctgag gtgggtggat 14520 tgcttgagct caggagttcg agaccagcct gggcaacatg gcaaaacccc atctctacaa 14580 aaaatataaa aactagctat gtgtggtggt gcatgcccgt agtcccagtt acttgggagg 14640 ctgaggtggg aagattgctt gagcccagga ggtcaaggct acagtgagct gagatcatac 14700 cactgtactc cagcctgggt gacaagagca agaccctgtc tgaaaaaaaa ggaaagcatc 14760 ttgatgccac taaactgtac acttaaaaat ggttaaggtg gtaaatttta tgctatgtgt 14820 gttttaccac aatcaaaaaa ctatttcatt tcagttaaca aaagtcagct agggccgggc 14880 gtggtggctc acacctataa tcccagcact ttgggaggcc aaggcggatg gattacctga 14940 ggtcaggagt ttgagaccag cccggtcaac atggcaaaac cccatctcta ctaaaaatac 15000 aaaaattagc caggtgtggt ggcgggtgcc tgtaatccca gctacttggg aggccgaggg 15060 aggagaattg cttgaacccg ggaggcggag gttgcggtaa gctgagatca taccactgca 15120 ctccagcctg ggcgactccg tctctaaata aataaataaa taataaaaaa taaattaccc 15180 caacatttag tggcttaaaa tagcaaacat ttagtatctt atagtttctg tgacttagga 15240 atttgggagt ggcttagctg ggtgattcta gcttagagtc tttcctgaga catctcagga 15300 tattggtcgg agctgcagta atccaaaggc ttgactgggg ctggagtatc tgcttccatg 15360 ctcacttata tgaatgttgg ccaaaagcat cagttcttcg ccatgtgggc ctcttcatgg 15420 ggaagcttga atgttttcat gacatggaag ctagctttcc ccagaaagat cttttcctca 15480 gaaagagtga gtgatctgag agagagagag agagagagag agtgaacgag cgagcaagat 15540 gaaaaccgac gtatctttta tgatctttac ttggaagtga gactccatcc ttttccacca 15600 cattctgttt gttacagtga gtcactaagt acagcctaca ttcaagggga ggagagttaa 15660 gctcttaaaa agagaagtag acatatttta aaacttccac aggtagtgtg ctaagtactt 15720 tacagatcat tcttccagtt atcacagcaa tcttatattt aggtattatt ttgcaaatga 15780 ggaagttgaa gcttatagaa tcacatagct ggtggttggt aaagtgtgga tttgaaataa 15840 atactttctg actctaatat ctgtgcttaa ttccattttg attctcaaac ttggttatgt 15900 ggcagaatca ccaggaaagc ttaatagtat aaattatcag gtcctacatg tacatggaaa 15960 ttctgtttgc ttctttttct ttttttcttt ttttttttaa aagagatgtg gtcttgctat 16020 gttacccagg cttgacttga actcctgggc tcaagcagtc ctcccacctc agcctctgga 16080 gtagctggga ctataggcat gcgccaccac acccggctaa tttttaattt tttgtagaga 16140 tgaggtctca ctgtgttacc catgctgatc tcgaactcct ggcctcaagc aatcctccca 16200 cctcagcctc ccaaattgtt gggattacag ttacaactac acccagccta gaacgccaga 16260 tttgacttac tcactgtgtg atcttgttac ttagccaatt tgtgcttcaa ttttctcctg 16320 tgtggtgaaa gtattaataa atctacctat aataggatta ttgtgacaag taactgagtt 16380 aatatattta aaatgtttac tgcttggcac ttagaaatgt aatagtagta atagtgatgg 16440 tatttttatg tgtgttttct tttaaaaaat tactaatttt taattataca aatcagaaat 16500 tagaatatta taaataatac tgatctttcc ccctctgttc atccacccac aattaagtag 16560 catttcaaat ccagtccctt tttattggaa ataatttttt ttattgtaat gtttttcttt 16620 cttattaggt tgaaccatgc caatgttgta aaggcctgtg atgttcctga agaattgaat 16680 attttgattc atgatgtgcc tcttctagca atggaatact gttctggagg agatctccga 16740 aaggtagtgt ggatgttttg agatgagaga gagtaaatca caaactttag caatgtttga 16800 atcatgttaa atataataaa ctagaataag aatcggaaaa actatggtct gcttcctgtt 16860 ttgtaaataa agttttattg gaacacagcc acattcattt ctttacacat tgtctatggc 16920 tgctttctta tggctgcaga agtgagtagt tttaacagag actatgtgac ttgcaaaacc 16980 taaagtattt accatatggt tccttacaga aaatgttgac tcctgattta gaaaatgcat 17040 ttttgttgtt gctgtttgat gggactatag caatggtgtt agatgaaaat ttcagtggtt 17100 aaggtgctta taaaaagttg ttttctgtat tgcaatcttt tttttctacc taattttaaa 17160 tgtgcccata tgaccatttt tatatatatc catgagattt gtcagccttt tccagtttca 17220 aatgcttttt gcctcttttt acttttatga gccttatcat gaaatttaca tgccctcagt 17280 atggatttgg taattttatt cccttgtatt ttattatgac ttattttctc atttgaatat 17340 tcttttagag tatagtaatt aatgtgtggt cactattgca gcccagcaat ttgcagaaca 17400 gatttttaga tttctttctt tttttagctg ctcaacaaac cagaaaattg ttgtggactt 17460 aaagaaagcc agatactttc tttactaagt gatataggta cgtatcagta ttaaaatacc 17520 attgtaatgt aatgtccctt tggcccataa aagatctttt tgggaattca ggagaattgt 17580 tgatacacta tacaaagtct atagaatttc aacatctata agaagttata aaaatctatt 17640 actattgatg ctaaattaaa actaggatat tttggctagg tgcggtggct cacgcctgta 17700 atcccagcac tttgggaggc caaggtaggc ggatcacaag

gtcaggagtt caagaccagc 17760 ctggccaaca tagtgaaacc ccatctctac taaaaataca aaaattagct gggcacaatg 17820 ccgcatgcct gtagtcccag ctactcggga ggctgaggca ggagaatcgc ttgaacccag 17880 gagatagagg ttgcagtgag ccgagattgc accactgcac tccagcttgg acaacagagt 17940 gagactttgt cacacacaca caaaaagaaa ctaggatatt ttattattta tttgtggcta 18000 agagtccttt ttttgtctaa tagatgttcc aatagctgac aaaaaaatca tgtgaaatga 18060 ccttactcaa tttctctccc cccctaccat tgacatagta attttgttta cagtggaatt 18120 acatctcctt gagggatggg tcctcaagtc aactcttttt tgtttgtttg ttttgagacg 18180 gagtctagct ctgttgccca ggctggagtg cagtggtgcg atctcagctt actgtaacct 18240 ctgcctccca ggttcaagcg attctcctgc ctcagcctcc cgagtagctg ggattacagg 18300 tgcccgccat cacacctggc taatttttgt atttttaaca gagacggggt ttcactgtgt 18360 tggccaggct ggtctcaaac tcctgacctc gtgatctgcc cgcctcggcc tcccaaagtg 18420 ctgggattac aagcgtgagc caccgcaccc agccaagtca actcttcagg gtgaaaaatc 18480 tctgcttaat cagaatgact ccagaaaaat tcctaaaata accagtacct aaccttttgg 18540 aggaacctca aaaaccaaaa atttgtttcc ccatagattt tggttttgcc tcttttccaa 18600 ggtcatgagg gctaaagtcc aattgaaatg agtgatttag gtgggagaaa gaggcttata 18660 agagtttcag ggattttccc aattgcttgt tgcatttcta tttggtgtta attctaatga 18720 gttaaatgaa catatagtat aattttgtag tatttgttta atgttacttt tttttctgtg 18780 aagaaaacct ggacactgta gtattagttg tgtagttacg atgatccata taaacttgag 18840 catcagagta gatttgtaca aaatgtgagg tgaatttttc ttttaactca atgatttctg 18900 ttacttcaaa gtatatttta aactttattt agggtctggg attcgatatt tgcatgaaaa 18960 caaaattata catcgagatc taaaacctga aaacatagtt cttcaggatg ttggtggaaa 19020 ggtaggtgaa acctgaagta atgtttcatg cctattgaat atagtctctc tgatatagtt 19080 agtccttgag ctttggtgtc tttgctgtat gcccataaca gtcttacttt ttccatttca 19140 gacctcacca cactgaactg tagttttgtg tttagttttt ttgtcccttc tgctaaacag 19200 tggttccatc agagaaggaa cagcacctgc tttttttttc tttttctttt ttttcatttt 19260 tcatacttaa cccagctcct agacttcacc tgtcttgttc aagtctgttt ttccatcata 19320 gtatctagca aagatacagg ctgtgaatac ataatatgtt aacacttatt attttattct 19380 tatgaagcac atccaaaaca catacatgca catcctgggt ccactttaag aaaaaaaaga 19440 aagtatatat atttttaaaa cttattttcc ttcccccaat ttaaatgagt catctggaga 19500 agaaccagaa attgtgaatt gactcttaaa atgttcattt cattggtaac ttaagcagtt 19560 ttcttgtttc cagcatccaa atttcattcc aataaagact taaaggccaa gagtctgaac 19620 cttgtgttga gttgtgtgtg ccgtctcttt agttagtgaa aatagttgtt ggcctcttgg 19680 aggtgttgga accttggtga tgcctcttct cttaggaacc tttcacgtat gcttggcacc 19740 aaatatctct gctttttttt tttttaatcc aaagacttca ggacattcct gaagttagat 19800 ctaagtattt actcacattt aatctactat aaggaggtat gatgcttctt caagtttgga 19860 agtcaccctt gcctttactt tccagtttaa tggattgagc ttattttgaa tatagtaaaa 19920 taaaaattaa tagcccacct gtattcaatt tttaccatgt accaagcact gtgttacctt 19980 ctttactttc gttatttcat tggatcctaa taacaattct gtgaagcagg gactgttagt 20040 catccaatta gattactgag agaggttaaa taacttggta gatcacatgc ctagttaagt 20100 ggtggcactc agacttgaaa tatttttgtg ttattacaga gcccaaggtc ctcaccacta 20160 ccctgtctac agcctcgtaa ggatattgtt gtctttcctt tttaaatttc tctaccattt 20220 aatacttaat ctgtcttatt attttgcaga taatacataa aataattgat ctgggatatg 20280 ccaaagatgt tgatcaagga agtctgtgta catcttttgt gggaacactg cagtatctgg 20340 tgagacctgt tttgtttctt tgaatttaag tgtgtatagg attctcttat ttctgaagat 20400 catgaatata gtaggtcaaa aataaagtag cttttcccat acagtgttgg tgtttaaagc 20460 attttctctt ttgaaggccc cagagctctt tgagaataag ccttacacag ccactgttga 20520 ttattggagc tttgggacca tggtatttga atgtattgct ggatataggc cttttttgca 20580 tcatctgcag ccatttacct ggtaagaaat ggatgagaac ttgggcatgc ttaatgggaa 20640 tggaaatttt ttcatttgtc tttttttttc tttctttaat tgtttaattg cctttgaaat 20700 atacaattaa atataattaa atggcaagaa atcttaattt gtgagaatca ctttgtcaac 20760 tgaggtagct tttgatttta taggcatgag aagattaaga agaaggatcc aaagtgtata 20820 tttgcatgtg aagagatgtc aggagaagtt cggtttagta gccatttacc tcaaccaaat 20880 agcctttgta ggtaagtata ttttagttaa ggaagtttgc ctcagtttct ccagagttgt 20940 aaaggagcag gagagtagtt gtctgtttca agttgcatta tccagtagaa ctttctgtga 21000 tgatgtagaa accttctata tttctgttgg ccacatgagg ttattgacta cttgacatgt 21060 agctagtttg gctagagaac gaattttgaa taaatagtaa atataaatag ccacttggga 21120 ctagtggcta ccattttgga cagcacaggt ctggtggaaa caagaactgc catttaactg 21180 tttgacatat gtcctaagaa ggctcttagg ataatgaagt aaatgggtta tttgcagaat 21240 ggatttggac tcatccgtca gagttgtcag taactaacat atgtggagtt ttgagtagtt 21300 tttgatggaa aaaagtttgt cccctgtcat ttcatgaatt tgaaagtaat ttatgaaatg 21360 gtacagacaa gtgatgtggg aaagaaaatg gacaacctgc aaaattacct ttctaacagt 21420 ataaagggaa attggaacat aatgatttga ttttcaccct attttgtatg ttttctagtt 21480 tagtagtaga acccatggaa aactggctac agttgatgtt gaattgggac cctcagcaga 21540 gaggaggacc tgttgacctt actttgaagc agccaagatg ttttgtatta atggatcaca 21600 ttttgaattt gaaggttagt cttaatgggt ctactgcata agaccagcat tgaaagtaac 21660 aagtttattt ggaaaattag cataaataca gtttaataat cttttcctgt tgcttattta 21720 tttatttatt ttgagacagg gtctcactct gtcacctagg ctggagtgca gtggcatgtt 21780 tttggctcac tgcaacctgc gcctcccagg ttcaagcgat tctcttgcct cagcctcccg 21840 agtagttggg actaaaggtg tgcaccacca tgcccagcta atttttgtat ttttagtaga 21900 ggtagggttt cgctatgttg tccaggctgg tctcgcactc ctgacctcag gtgatctgcc 21960 cgcctccacc tcccaaagtg ggattacagg cgtgagccat tgcgtccagc cctgatgctt 22020 atttgaaaaa gaaaattata ttcttagagc tgatttttta aaaagtttat ttagcaagct 22080 gtctcagttt gcttctctgt ggtctttgtt aattactcct ttgaagcaac ttttttattt 22140 accttttccc atgttgttgc cattatcctc gattcattta tgtctagtca tactggattt 22200 gatttggtaa ggaaggttcc tatctgcctt tcatggctct gcacttactc cttaacctat 22260 agttcattca atatgtacta cctatctcat cttctgaaaa tgctttttta ttcttctgcc 22320 caagaaacta acatagttct tttttttttt ttttttaaca agtcaagtgt aaactgatct 22380 gcttggtttt ttgggggggc tttccctaac caagttttgc cttgtacctg cttctcttaa 22440 cctttacctc atacaagacc agcttgtcac tgctccttat gcctcaaacc cgttatctac 22500 ctttgtgctt tgacagatgc tatccttctg cctggatatc catttctgtg tatcttctca 22560 cctacactgg catatcttta agagcttttc tttaaatggt ctctgccaca aaatttgtca 22620 tttaaaggct atattctctt tctcgtcttc cattcatgca tcttcatata gactgttgtc 22680 ttcttcaatg ttgggattgt tttacttctt ttattaacaa tcacccaccc tacccttcct 22740 aaccatggca ttctgtacag agcagggcat gtatcaggtt cttagtaaat tatttattga 22800 tatgaatgag agctatagat agttctatta tgcagtgtac ccagaaacaa ctctcatcaa 22860 tagtctttac atttgtattg attgtttgta gtatacaggt ttctaaaatt gaaatgagaa 22920 attataatca tgtaatgttg gagtacatgg cgagatagct cactttagtc tgcaacccct 22980 gagctcaagt gattctcctg cttcagcctc cagagtaaat gggactacag gtgtgcgcca 23040 cctctcctgc ctaattttta aatttttggt agaaatgggg tctcactgtg ttgagcaggt 23100 tggttttgaa ctcctggcct caagtaatcc tcctacctcg acttcccaaa gtgctgagat 23160 tacagatgtg ggctactgtg cccgaccttg gcatacttta ttaaatagaa acttgaggcc 23220 atgtggatgt cattcttggc taacactgaa aagatacctg gcttcttctt gatttggttt 23280 ccttctaatg tgccaaagaa taaattatcc ctcagtgtgt taggaaagca gggctttagt 23340 tctgtgttgc ctctgaaaca tttcagctgt gaatgaacca catctcgcat ttgtttcata 23400 cttgtcatag gaatcatagc atagtttctg ctctgaaggg catctgtgag cctcttgtta 23460 tagggcacgg ggaaagagtc cacattatgg agtttatagt ttacagactt taattcagtt 23520 tgcagcacca ctatttacct atctgtgaac ctgagcaaat gtctctctat ctcaaggaca 23580 gtaatatctt cctcaaagca tcaatattat tatgaggtta tgcagaataa ggtatgtata 23640 aggtactagt tatagtagtt caagaagctt caaggatgct tgttagacat gataatagga 23700 ctgaattttg aagaatgaga gtttttaggg aaagggtgag ggcgggagag atttataggc 23760 agcagagcat catgagcaaa agtacagaag catgaactgc aaaacagctt ggtgttactg 23820 taggacattt tcccaaaatg tttatatata ttgtacaaga aaggaatgat gtctgtttga 23880 ttttcactta aaaaaggaag caacaaaaca gttactgaaa tatttccctt ttgaaaaaat 23940 agcttagcaa gtctgattgt atgcatattt tccaactgtt tattatgaac atctttagat 24000 atgtagaaga gttgaaagaa gtgtactgaa cctaccacta aaaataatga tgaaacagta 24060 gcatttaatt attatttttt tttgcctcct ctttcacgcc cctaaatgta actatattct 24120 gagtctcttc ttggttctct ctttttccat tacatttcct ttcttttatt aggcagcctc 24180 ttcaactgta tagctttact tataaactac atatggctaa ctcctaaagt tatttatctc 24240 tgtagctgtg actcttctgc caaggactta taactgctgt ataactgtat aactacctgg 24300 ctgttccact ggcacttaca acttaattta ttaaaaactg aacatatttg ttctatccat 24360 taaatctact tctttttttt tttttttttt ttttgatatg gagcctcact ctgtctcacg 24420 atctcaactc actgcaacct acacctcctg ggttcaagtg attctcgtgc ctcagcctcc 24480 cgagtagctg ggattacagg tgcctgccac cgtgtccagc taatttttat atttttggta 24540 gaaatggggt ttcaccatgt tggccaggct ggtcttgaca ccctgacctc aggtgatctg 24600 ctcacctcgg ccttccaaag tgctgggatt acaggcatga gccactgcac ctggcccatt 24660 aaatctacct ctatagattt cctacacttc ttatttgcac tgtcaccttt ccagttaccc 24720 aggtgggaaa ctttggatgt gttgactctt cctttctctt caatcgatat atccaattat 24780 tttatcaaat ttatcttttg aatatcttaa caattttgag cttgccaggt tctcaattta 24840 gaaaggcttg catagttttc tttcacttat tgaataaagt ccagaccctt tcattggtac 24900 tcaaaaccta tcttggtttc atatcaactt acactcctgg acttatctct tactaatgcc 24960 ctgagaggcc atcattttag gtacatttga actggattaa ttgtattctc tgattatgcc 25020 catccctttc tacttttctg cttctgctca ccttgttttc tgcctaaagg aactcttttc 25080 agtcttttcc catttcagtc tttcatttca aagtttagct caagtagtgc ctcctttatg 25140 aagtgcctgc ttcctactgc caagtgtatg atactttaca ctgattataa cacctatcac 25200 attttgcctg gtaccttagt tctcttagta tatcttaata tcttctgttt gactataact 25260 gtatggaagg caaggatcat aaggtactca gtttgtatac ccactactac caccacaaca 25320 cacttaatag tatgtaccaa tagtatgtac ctaccaatag taggtactca ttaaatatta 25380 tagtgagcaa aaagataaat ttaggttgta tttcctcttc tttcttttgc ttccttctgg 25440 cctggagctt tggtagtgag atgccatgat gacatactct aatatcctgt gtaaaagtag 25500 atgtccatta taggattttc tattgctata agtggcagct gtcatagtgt gaaatctgcc 25560 taaattggga aggcatggaa agtctcaggt agtataattg tattgcaaat ccgtatcagt 25620 tttgaagatt tccctactcc ccttttaaac ataaagattt atattaaaga aaagtctctt 25680 aataagagaa atactggcaa ttgtgttatg acatttggaa ttcacatgaa aaggatcagc 25740 ttcaggttat aaaaacagtt tggtatttct tttttaaaat tttgttgata caggtgtggt 25800 ggctcatgcc tgtaatccca gcactttggg aggtggaggc aggcagatca cttgaggtct 25860 ggagttcgag accagcctgg ccaacatggt gaaaccccat ctctactaag aatacaaaaa 25920 ttagccaggg atggtggtgc atgcctgtag tcccagctac acgggaggct gaggcagaag 25980 agttgcttga acctgggagg tggaggctgc attgaaccaa gatcgcacca ctgcactcca 26040 gcctgggtga cagagagaga ctctgtctca aaaacaaaca aacaaaattg ttaatacgct 26100 tttaattttt tttttttttt ttgagataag agtcttgttc tatcacccag gctagagtac 26160 catggtgcaa tctccactca ctgcaacttt cacctcccag actcaagtga ttctctcgtg 26220 cctcagcctc ccgcgtagtt ggaattacag gtgtgcgcca tcatggccaa ctaatttttt 26280 gtgtgttttt agtagagaca gggttttgcc atgttggcca ggatgttctc aaactcctgt 26340 cctcaagtga tctacctgtc ttggcctccc aaagggctgg gattacaggt gtgagccacc 26400 gcgcccagcc taatttttta aattgacaaa taattataca aattaatggg gtaaatagtg 26460 atgtttcaat acatgcactg tgtagtgatc agattagggt aattagcata tccatcagct 26520 aaaacataat ttctctgtgt tgggaatatt cagtatccct ttcttttttc tttttttttc 26580 tttttcttct ttcttttttt ttttttttga gacaaagtct cactctgtcg cctggagtgc 26640 agtggcgcga tcttggctca ctgcagcctt gatctcccag gttcaggcga ttctcctgcc 26700 tcagccttct gagtagctgg gattataggc gttgtgccac caagcccagc taatttttgt 26760 gtttttagta gagacaaggt ttcaccatgt tggccaggct ggtcttgaac tcctgacctt 26820 aagtgatcta cttgtcttgt aatcccaaag tgctgggatt acaggcgtga gccaccacgc 26880 ccagcctcag tttagtattt ctgtagcacc acttatttgg gcatctgtgt taggatttgt 26940 aagtggaaat aatagtgggc cttcaaacta aaaagtgtac agtagaaaaa ataatcaaca 27000 aaacgaaaaa gcaacccaac ccatggattg ggaaaagata tttgcatacc atacatccaa 27060 taagaaatta atatcctaaa tttataagaa actcatgcaa ctcaatacca aaaatgtaaa 27120 taacccaatt taaaaatgtg caaaggacct gaattagaca cttctcaaaa gaagaaattc 27180 agatggtcaa caaacatatg aaaaggtgct caacaactct tagcatcagg gcgatgcaaa 27240 tcaaaaccac actaagatat caccccccac ctgttgggat ggctattatc caaaagaaaa 27300 aagataagcg ttagtgagga tgtgggagaa aagaaatccc ttgtacactg ttggtgggaa 27360 tgtaaattat tacagctatt gtgggaaaca gtacaaaggt tcctcaaaat taaaaataga 27420 actactggcc gggcatggtg gctcatgcct gtaatcccag cactttggga ggttgagaca 27480 ggtggatcac atgaggccag gagttcgaga ccagactggg caacatgcag aaaccccatc 27540 tcaactaaaa ttacaaaaat tagctgggca tggtggtgca catctgtaat cccagctact 27600 ccgtaggctg aggcaggata attgcttgaa ttcaggaggt ggaagttgta gtgagctgag 27660 agatcatgcc actgcacatc agcctgcgtg acacagcaag actctgtctc aaaagaaaaa 27720 aaaaaaaaat agaactgtaa gattcaacaa tgtcatttct tggtatatat ccaaaggatt 27780 ttaaagcagg cttgtgaaga gatatttgca ctcccatgtt cattgcagca ttattcacaa 27840 tagtcaagat ctggaaatag cctaaatgtc ctttgacaga tgaatggata gggaaaaagt 27900 ggtatatata cacagtggaa tagtattcaa ccttaagaaa aagaaggaaa ttctgccatt 27960 taggacaatg tggatgaacc tggaggacat gttaagtaaa ataagcaagt cacagaaaga 28020 gaaatactgc gtgatctcac ttacatgtgg aatctataat agttaaattt aatagaagca 28080 gaccatagca tcatagttgc caggggctgc agggatgcgg gtgcgggggt gtatgtagag 28140 atgtttatca aaaggtccaa aaattacggc agcaaaagaa aaaaaaggta caaaaatgac 28200 aactatgaag aggtgacaga tatattaatt agctgaaatg tgataatttc acaacgtata 28260 tcaaaacatc aagttgtata actcaaatat ataacatttt tatatgtcaa attaaattgt 28320 cacaaaataa aatatgtaaa agataaagca ataaatcagg agagggggct atgatagatg 28380 aaacaagata ggctctatgt aaatgatggt tgaaactagg tgaggcattc acagggttgg 28440 gagggggctt attgtactgt tgtctatagt tttgtgtctt tgaaaacatc aattcagatt 28500 tgtgttttaa agggaaaaaa ataatagtgg acttggatta atgccttacc tttgtagtaa 28560 ggattttcag cagagagaat tttaatcatt tgcatatact agtcaatgta aggcatggag 28620 aatgtaggca ttaatttcgt atggcttttc taaggatact ggaaggaaga gaatttaaaa 28680 tcatgttctt ttcaaaagac tgaagtccaa ctctgtggct gtccgcgctg acaggtgggg 28740 acagagcccc acctgactca gcctcacact cacttggcat gtatcaggct acttttactg 28800 gggctttagg tgagagtgat aaaacggttc ttacttgatt tggggccctt aagcaggttg 28860 ctgctctggg attaggttgt cttataaaaa ggtaactcac cacgcataac aatgcttttt 28920 cctgtttaaa gagagaccta gttcttctat cagatgattt cttaaggcag catgaagtag 28980 ccagacacaa aaagagttaa gatccaagct ctaccagtta ttagctgtgt gatccctaac 29040 aagttattta acttagaact ctggtttctt tctctgttta aaatggagat taaaagatct 29100 aattattggg gatgttatgt gaaagtggtt tatgcctgtg gttgtcttct gttaggcact 29160 tcatgaattg gaatgtttcc ttttcggtct atgataatgt ttttttcaaa ataaataact 29220 taggccgggc gcggtggctc acgcctgtaa tcccagcact ttgggaggcc gaggcgggcg 29280 gatcacgagg tcaggagatc gagaccatcc cggctaaaac ggtgaaaccc cgtctctact 29340 aaaaatacaa aaaattagcc gggcgtagtg gcgggcgcct gtagtcccag ctacttggga 29400 ggctgaggca ggagaatggc gtgaacccgg gaggcggagc ttgcagtgag ccgagatccc 29460 gccactgcac tccagcctgg gcgacagagc gagactccgt ctcaaaaaaa aaaaaaaaaa 29520 ataaataaat aaataaataa ataaataaat aaataacttg ttcttttaaa ttgggatttt 29580 tcttaatttt gaaaatttct taactttgaa attttattgt tggaactaac atctattgta 29640 gaaaaggaaa ttgttcagtt ttcagaatgt cattttataa ttataaaagg agatctcact 29700 ttggagaatg agtgagcctt gtttaatgta gaaataatgc cttttgccca tattcacctt 29760 ttagtatctg gcagcgaatc ttttatgtaa caaataatca ataactttac ctttttttct 29820 tatttataca gatagtacac atcctaaata tgacttctgc aaagataatt tcttttctgt 29880 taccacctga tgaaagtctt cattcactac agtctcgtat tgagcgtgaa actggaataa 29940 atactggttc tcaagaactt ctttcagaga caggaatttc tctggatcct cggaaaccag 30000 cctctcaatg tgttctagat ggagttgtaa gaaaattaat tataatatcc ctagagtatg 30060 tgaaatctag agggattgcg tgccctgcaa tttttatgca tacttggaat tccttgggag 30120 gccgcacatt ttgttttggt tttgtccttc tcccaactct tatcattgct ttgcaaggtg 30180 aacaggatag aaatgaaaca tttgttgttt tgaactttgc aagacttttt ctttggtgcc 30240 agttttctgc tcctgttccc agaccaaact gagggtcagg ctgcttactc tcgcggccca 30300 ataacgagat gcagatgaat tgggagagat gggagttttt atttctgtaa ccagttacag 30360 gtagaaggcc tggaaattac cgccagacca actcaaaatt acaaagtttt tccgtagttt 30420 atttatcttc taagctatat gtctatgtgt aagtttgcat tcatctaaag acataagtga 30480 ttaacttctt ttaatctgta gctgaggtct gagtcttgaa gacattcctc tggagcctca 30540 gtaaatttac ttactctaaa tgggtccagg tgctggggtg attaccctta tcttgtctcc 30600 tattaaatca cagaggttta aggagttcct tcagaccccc aataaacttg tttgtggagg 30660 cctggggttt cttcagaccc ccaataaaac ttatttaatt ctgaacgggt cctgttaaga 30720 attcctttgt tattttgctt ttaggcctgg gaaaggcctg ggcagaactc ttggtaggct 30780 ttggctacat ttcagccttt gtgtaagggc actggctctt ccagtttttt ttttttttag 30840 acagtcttgc tctgttgccc aggctgaagt gcaatggcac aatctcagct cactgcaacc 30900 tccgcctcct gggttcaagt gattctccct gccacagcct cccaagtagc tgggattata 30960 ggtgcccacc accatgccta gctaattttt tgtatcttta gtagagacgg ggttttgcca 31020 ctcctgaccg acctcaggcg atctgcctac ctcggcctcc tgaagtgttg ggattacagg 31080 cgtgagccac tgcacccggc cactctttca gcttttaata tttaacttca ccactcagtc 31140 gtgctgaaac agttgttatt taggcctgca ttagtgagac ctggcctgcc acactcccag 31200 ttaatattcc ttcttggctt ggtgcagtgg cccatgcctg taatcccggg actttgggaa 31260 cccaaggtgg gtggattgct gagttcaaga gttcgagacc tgcctgagca acatgttgaa 31320 gccctgtctc tacaaaaact acaaaaatta gcggggtttg gtggtgcacc cctgtagtcc 31380 tagctacttg ggagattgag gtgggagaat cacttgagcc cagggaggtt gaggctgcaa 31440 tgagccatga tcacgccgct gcactccagc atgggtgaca gagcaagacc ctgtctcaaa 31500 aaaaaaaatt tctttttgta tttgaagccc agtactctga aactactgtg agaacagcag 31560 tctcataggt cctgccaaag gataaatggg tggtaaaata tgactgtggt catgactttt 31620 tcccccattt ttctttttat gactttattg aggcatatta tcatgttagt tcccatttaa 31680 ggtgtacaat atagtgattt tttatttctt ttttattaac ttgtcactga cttgatgctc 31740 aattacagtg attttttttt aaagtaaatt taccaaattt tgcagctgtc accataaatc 31800 agcttaaaaa catttccatt aacagtccat taactgttaa tctccattct gtccacccca 31860 ggaaaccagg aatctatttt ttatctccac aagtttgcct tttctgaaca ttccatataa 31920 atggaattat gtaatatata gtcttgtgtc tgactttttt tacttgcctt gtatttttga 31980 agcccgtgca tgttgtagca tgtatcagta cttcattcgt tttgattacc gattagtttt 32040 ttcactgtat atatcttttt gcatttgttc tttgggtttt ggtgattgtt cactttagcc 32100 catacaaaag tttgggtctt ttttcctcaa caaaagtttg gactctgtta tctgtaagag 32160 atatggtaat acacattgat tttgttcatt tgcatttcaa agtaggaaat ctggtgcata 32220 agtatttaga aaacctagga ttttcaaaga tccttgaaca ggattttaac tgtttgtttc 32280 tttttcagag aggctgtgat agctatatgg tttatttgtt tgataaaagt aaaactgtat 32340 atgaagggcc atttgcttcc agaagtttat ctgattgtgt aaattatatt ggtaagtcca 32400 gtccatttag tggctgagct ttaaacatga attaatataa ctttgactct cagtatgatt 32460 agtagaaatg gacttttggt gttgtgttct gtatctcata cttgaagttt ctatatggag 32520 ttatatgaga actctgaaaa atggatttat atagtttgga aggtgaaaag gtagatatta 32580 aatctccatg agatcattca agagaagatt tactttcttg aggatagggc tctcacagga 32640 gaatgaaact tcactattag ttgaacctgc tttttaattg tctcttcata gtctaagcat 32700 gttcaagtat ttatttcatt tttcctgtga atactgcttg atgttcaaat gttttaattt 32760 atcctgtgaa aattattctt ttcttttgaa caagttaagt

gtttgatcac tgtatatctg 32820 tccaaataaa gtaaagcaca aaattgtaaa atcaagaaca aaattgagca gaggggctaa 32880 aatgtatgta atcttacttt tttaaaagtc tttttattag ttttcttttg aatttttctt 32940 ttaaattgag gcagtttaca tagagtgaaa ttcacagatc atatagtttg ataacttttg 33000 acaaatttag atacttgtgt aatccacacc acagtcatca tgtagaacat ttctttcacc 33060 ttagaaagtt ccctcatgtc tcttttcagt caactcccct tgccccagac tttattacta 33120 ttttactaat ggactttttt tttttaagaa tggttttaga tttgccaaaa aattgggcag 33180 atagtacaga gttctcatat aactcccctc actcacgcat gtagtttttc ctattgttaa 33240 cattttacct gggaggcgga ggttgcagtg agccaatgtc acaccactgc acttcagcct 33300 gggcaacaga gtgagacctt tctcaaaaaa ataaataaaa aacataaaat atttaaaaat 33360 attaaaaagt aaaaaaaaat ctattttaca ttagtatgat gtatttgtta catttaatga 33420 acccatttat tattaattga agcccatact ttattcacat ttccttcatt tttacctaat 33480 atcctttttc tgttctaaga tctcatctta gaacacatta catttggttg tcatgtctct 33540 ttagctcctc tttgctgtga cattttgtca gacttcaaat agtccttgtt tttgatgacc 33600 ttgacaatga cctgaggaat actagtcaag tattttgtaa gatgtccctc tgctgaaatt 33660 tgtctttttg tttttgtttt tgttttgttt ttgagatgga gtttcactct tgtcgcccag 33720 gctggagtgc aatggcacaa tcttggctca ctgcaacccc cacctcccgg gtacaagcga 33780 ttctcctgtc tcagtctccc gagtagctgg gattataggt gcacaccacc acgcccagct 33840 aatttttgca tttttagtag agacagggtt tcaccgtgtt ggccaggctg ctcttgaact 33900 cctgacctca agggatctgc ccgccttggc ttcccaaagt gctgggatta caggcgtgag 33960 ccatcacacc tggctcttgt gtgtattctt aaacctggat tgttggtcca gaatatgaaa 34020 tttattattc agaggtagga aagactcaga ggagatggga cttgatttag aacttgaaag 34080 aaataatttg gattagcaga gagaaaaaga gtattccagg ttgcagaaaa gcaagcaaaa 34140 aagacagata caggaataat ctcaagctct gtgagtgtag cgattgtgtc atttttattt 34200 ccccccttgt atgtggagcg gggcttaagt attgcaggtg ctctgtaaat gtatattgaa 34260 ctgaattaaa tggaaacaag tggttctttt agcatcagtt tctagcatct atgggaatcc 34320 tgtttgtgtg gacaggaaat cacaaagaat gataaatcaa ctctaaaatc ctcaaaagta 34380 actaacctcc cttgcccttt ttctcatctt cttgtatata gtacaggaca gcaaaataca 34440 gcttccaatt atacagctgc gtaaagtgtg ggctgaagca gtgcactatg tgtctggact 34500 aaaagaagac tatagcaggc tctttcaggg acaaagggca gcaatgtaag tggattctgt 34560 tgtttataag cacaatgcaa tgtgcatcat atactcaaga attaatcttg ccggttttca 34620 ctaatcaata ttgcatgtaa tagtaacata ctgggccaat ttgaagtgta atgttctgat 34680 aaacttgtag aattcttact aatggactga gaccattcta ttgtaatggc ttgagggtaa 34740 taattcccat acggtcctag tataaaaaga ttgtttatca caaaatatta taggcaggaa 34800 gtctttagag atcagattct agagctcagt tatttctcat agattgataa tagaaactta 34860 ggctttggcc ttgtggcagt ttatgttttt acattattgt tcaatgtttc tgaatgctga 34920 taatatcttt tttctttttc ttttttttct tgctgtggtt taggttaagt cttcttagat 34980 ataatgctaa cttaacaaaa atgaagaaca ctttgatctc agcatcacaa caactgaaag 35040 ctaaattgga gttttttcac aaaagcattc agcttgactt ggagagatac agcgagcaga 35100 tgacgtatgg gatatgtaag tgtctgtgta atgtatttga aaggagcatc tggtttcttg 35160 aagccatctg ttattttgcc ttcttaactc agccagttgt tttacttacc ttcacattag 35220 aacaagagac aggacaactt aaattaacat aaaccatgtt tgttttgaat gttacctctt 35280 tttttaaatt tgcttagttg agcaatttag cttcacaatt gggctaaaat tatttagctc 35340 taaaaaaata caggtgcgat ttaataatct tgaatttcaa acctgatttt aaaataaata 35400 caaaatctgg acttcttagc cagtgctgtg gactgaatgt atccccccca aaatacatat 35460 gttgaaattc tgaccctgaa ggtgaaggtg ttggtaggtg gagcctttgg gaagtgatta 35520 ggtcatgaga gtagagcctt cctgtttggg attaatgctc ttacaaaaga gacctgaatg 35580 agatccctca tcccttctgc atgtgaggac agagcaagaa gatggtcatc taggaaccag 35640 aaagcaggcc ctcaaatctg ccttgttctt ggacttccca gcctccagaa ctataagaaa 35700 taaatttctg ttgtttttat ggcacttagt ctatggtatt ttgttatagt agtccaaatg 35760 gactaagaca accaggggag tcttaaactg cttacttttc tgtaaataat gacacaaata 35820 ttctaaggct atgttttttt caaaccatct actgtggagt cctactattt tttagtgtac 35880 acagtctcca aattttccat atttgactcc aagcttatct ccttcagatg tactaaggaa 35940 gtgtaaaaaa acagagttaa aatatgagta aattgaagga gtcatactac cagcatttct 36000 gttttctttt ataaaacaaa tcctttttag gaaacaaata cttgtttcct aaaaacatat 36060 acttgtcctg agcaaactct gtgtatctca gagtaaacaa tcaatagtgt ccagttgggt 36120 gaatgaattt actctccaga actggtttta ttaatattat tgatatttta tttctattta 36180 tatattattg atattttatt tctatttgta tattattgac attctggtga gtgataaaac 36240 attataatta tttcattaaa atatcttaga cttgtcaaag gcttattata caattgttaa 36300 agaaaaatga ggtagatcta tatgtgcttt tattaaaaga tcacctaagt ctttagttga 36360 cagttttaaa ttgtgggaaa aaataaagag tatacagatg ttttcacttg tgagggagca 36420 ggctatgtgt ctatgtaaca gataatcata gtaaggtccc ttgaggtgga tggtagaggg 36480 gtagaagaga gagtcttttc tgtttatatc cttttatagt atttaatttt taaaaatcat 36540 attcaagtat taaatttctt ttctggccag gtggtgactc acgcctgtaa tcccaacact 36600 ttgggaggcc aaagcaggtg gatcccttga gctcaggaat tcaagactaa cctgggcaac 36660 atggggtaga acgccatctc tacaaaaaat gtaaaaatta gccgggcatg gtggtgcaca 36720 cctcagctat tcaggaggct aaggtgggag gatcgcttga gccctggaga tagaggttgc 36780 ggtgagctga gatcatgcca ctgcactcca gcctgggtga cagagtgaga ctctacctca 36840 aaaaaaaatt ttttttgttg ttttttcctt tatccaccca tctgcacact ggtataaata 36900 tatatatttt taagaaaaaa gtcatctgta ttcatttcct aagggttcca taacaaaatc 36960 ccataaactg agtggcttaa gcaatggaaa cttactgtct cacagccctg gaggctaaaa 37020 gtccaaaatt gaggtgttgg cagggccatg ttttctctga aatctgtaga gaagaatctt 37080 tccttgtttc tctctagctt cttatggtct gctagccatc attggcattc cttggcttac 37140 agctgcagca cctcaatctg tctccattgt cacagagcat tctcccctgt gtatctgtat 37200 cctgtgtctc ttctaagtac actggtcgta ctggactaag ggcccagacc attccagtat 37260 gagtattaat ttatctgatt acttctgtaa tgaccttatt tccaaatagg tcacattctg 37320 aggtattagg ggttaggaat tccacatatc ttttggggga ccacaattca actcataaca 37380 catctttgat gttgatatgg caaggaggca ggcagccagt aattaaagat atggctattt 37440 ctgagataac caatttagac ttttctttta gcttcagaaa aaatgctaaa agcatggaaa 37500 gaaatggaag aaaaggccat ccactatgct gaggtaaaat cattgacgtc attctgtata 37560 cttattaatt cttgatgtct ccattagaaa ctatctttgg ttttgatata taaagagcat 37620 ttttcatgtc attcctgaaa ttcagacaaa attctagtag atgctttgta tataaagagg 37680 gatgtatcat agtgattaaa aacaagggct ttgggaaaat tacctagtgc ctcactgagc 37740 ttcagtttcc tttatttatt tattttttga aacagggtct cactctgttg cccaggttgg 37800 agtgtagtgg catgatcaaa gctcactgca gcctcgactt cccaggctca agcagtcctc 37860 ccatcttagc ctcctgtgta gctgggacaa gaggtgcacc accatgcctg gctaactttt 37920 acattttttg tagagacggg gtctcactat gttgtccagg cttgtatcaa actcctgggc 37980 ttaagcaatc ctcccacctc agcctcccat agagctggga ttataggcat gagccaccac 38040 atccagctag tttccatatt atagggacaa tttcttttct agtagggtta tgaagattaa 38100 atgggagtca gtaatggtag ttgtcactat tatttttgtg actggtttag ataggatggc 38160 tgcacatcct ggtttacctg ggactgtccc agtttatact taatgtcttg ccataattat 38220 cagtagtagt ccctttcact ctcaaaatta tgccggtttg gacaataaat tatatggtgt 38280 ccctaggtat agctcattct ctaggtggca gattttttcc ccttatcctg tacatttgtc 38340 cacggtccta agttattaca ctccttaatg tcagtactta ccctgaggat gtgggtgggg 38400 atacccatgg tgtcctgggg tgggaaatcc aagttcttta tctttttgtg tccctattca 38460 aggtagtggg gaccaggggg cagtcaaaat catagagcca agatacaagt aataccaatg 38520 gttttggtgg tcctttttct ttcttgttag ttgatacctg ttgtagcttt ttgcttctcc 38580 ggaggtaaaa gcaaatacta gtagtttact gttgtcagga gagaaaagag agaagactaa 38640 gactaagtat gttcttatgt gaaagattaa gtgtcagaat ctgaagaata gaaaggcttt 38700 aacaaaatca gtgtttcgta ttatattatt tagttctcta atgaagcagc aagtcattct 38760 gtatccttaa gatctgaatt ttgtttccta tgatgtagtg gtaagccttt catttccttt 38820 gtattttcat catattttag gttggtgtca ttggatacct ggaggatcag attatgtctt 38880 tgcatgctga aatcatggag ctacagaaga gcccctatgg aagacgtcag ggagacttga 38940 tggaatctct gtaaggatgc acttgtgttg ttggtcttga catctgtaat attttgtatt 39000 ctttctgctt acatctggca aattaaacct ctagtggttc ttttctatag ttttcctttc 39060 cccaaatata ttggcattat atttaaaatg gaagcttttt ctcagtcaca ggaaacttcg 39120 gaaataattc tttgggttgg ccttttttgg tttttaataa aagcatttat ttcataggag 39180 tgttaagaat tttccaagta taactaagtt acaaactatt tccctactca ttatacctct 39240 ggtccaaggt attgactctt aaatgcccta aaacttgaaa ttttttctga attaaagttc 39300 tggattaaaa acttcagata ttttctcgaa ttataggtca taatttttgt ctttttaagt 39360 gtctgtggtg cagagatgtc cccatgatag atcagaatag atatgaacta tattaaactt 39420 tgcattttaa gaacttgtat agttcttatt actcaataca atgctctgtg aaatacttgt 39480 tggcaatatg aacttgcttt aaaatgggtt cattattcaa ataaaatatt gtttcaagtt 39540 gtagattatt gaagtcatta aattaccttc acttatcaga gcgtgttttc tcttttatag 39600 ggaacagcgt gccattgatc tatataagca gttaaaacac agaccttcag gtaagacact 39660 tctaccacag tgcttgaagg cattttaggt aactatcact agcctaacaa atgtggggga 39720 tctaatattt ttaagttaaa aattttctta aagctgcaga ataaattcca gttttggtat 39780 tgccattgag acatggtata ataagcttta agattgtgag aatttaggag atgataaaga 39840 gaaagtaaca gagaacgtga ggtagaaaaa ttttagaagg ggacgtgaaa agaaagaatg 39900 gaagacagaa aaaaggaact cagagaggaa aaagcagcaa gaaaatgttt agaaagatgg 39960 aaaaaataag tgttgcttaa gattagagag gttgggccag ttgtggtggc tcatgcctgt 40020 aatcccagca ctttgggagg ccaaggtggg tggatcacct gaggtcagga gttcaaaacc 40080 agcttggcca acatggtgaa accccatctc tactaaaaat agaaaagtta gctgggcatg 40140 ttggcatgtg cctgtaatcc cagctacttg ggaggatgag gcaggagaat cgcttgaacc 40200 tgggaagagg aggttgcagt gagccaagat cacaccactg cactccagcc tgggtgacag 40260 agcgagattc tgtctcaaaa caaaacaaaa aaatattata gaggttggaa agaatttgag 40320 gcagtgggtt caggtatgga atggttagag ggaaggcctg tgctgttcta ggccaaagca 40380 gattgctttg aaaataatgc cttcatctgc actggtcact gatgacttgt tttgttggca 40440 aaataattcc agttgaacat ctgctaaata ctgagcaagg tctgctggaa agagtactgg 40500 atggggaatc agaggcttga attctagatt gagtaattta ctgaccgtta cctcaggcaa 40560 atctgcgttt cccatttcct ccttctgcaa aatggggttg aaacctaact ttcctactca 40620 gtgagtatat tgtgacagtg tatttaagag gatgtttgtg aaaatgcttt gaaaactata 40680 aactattatg tacttgcaag atattatcat ttagttaaaa atttgttttg aagggtaaca 40740 gaagaaataa agtctgtgcc ctaatgtgca ttatacttaa atgcatgtta aaaaaagata 40800 tacttttaca ctttaaaatt tgtagacaca tagcaacaca tgcaaattaa tatacatgtg 40860 aaattgtatt tcatatacta ttttcacatt taaaaaataa cattatctcc tcttatactg 40920 cttttatttt actgaaatgt attcagttta gtctgaccag cagttctcaa aatgtggcat 40980 atggacctgt gagaatcctt gaaactttgt cagagagtct gtgaggttag aaccattttc 41040 ataataagat gttatttgca tttttcacca tgttgacatt ttcattgatg gtgcaacata 41100 aaatggcttt caccttagta tgaatcaagg cactagcgcc aaactatgct agtagccgtt 41160 atatttttta ccaccatgca gtcacagttt ttaaaaaatg acagtttcac ttacaaatgt 41220 ccttgataaa gcagtaaaaa tattatttta tttaaatctc aacgcttgag tatgggtttt 41280 taatattttg tgtgatgaaa tgggaagtac tcataaagtg tttcttctat acagtgaagt 41340 atgatggttg tcttaaggaa aaccacttca gtaattgttt acgttgctag ttgtctggcc 41400 tctttcaggg aagataccat ttttacttgg aagagcaact gtcaggcaaa ctatgattat 41460 tcagatttgc atacgtgaga taatttctaa gaaattaaat gaaaataaaa agtatagcac 41520 acttattact ttaagggaaa aaagcagtat ttgttgtcaa tgataaaatt ccatgtttca 41580 agcaaaaaga attttagaaa acttgtattt accagctgga atgacagctt ctcagtactt 41640 aaaaactttt ctgatgagat tagtggtgat atcagaaagg tttgcaaaaa tgtaaaacag 41700 tgcaagtgtt ctcactcaaa tttttttgtt ttagaaaata tcgttttttg gtttttgttt 41760 ttagaggtgg gctcttgcta tgttgaccag gctggccttg gactccctgg gttcaagtga 41820 tccttccact tcaggcttcc aagtatctca agtagcagta accagtgaaa ggaggtggct 41880 ctcgtagata tgagtatact gtgtagacac atgtatgtat agcacttagc atgtctgagg 41940 aaatgcagta tgactggagt gtagagtttc aggagagaga aaacctaaat ataggagaga 42000 gagaaaacgt aaatataggt ttttttgttt gtttttaata aaaacatgtt aatgggcaat 42060 aggtttgtta tttttaaatg aattaagaca cgagtatttt taaatttctg tttaattcct 42120 gaaaaaccct ttggggttct caagaatttt ctagtgtaaa ggggtcctga gaccaaaaag 42180 tttgagaact gcttatctag actattctca gaagcttggc tgctcaggaa agaagagagg 42240 tgggtgagta gctaaaagtt gatgtagagt caagggaggt cacttctcag aaggaagact 42300 taaacatgag gtgccacatg atgatgtttt ggttaacaac aaattgtgta tactatggta 42360 gtcccataag attatactac tgtattttta ctatgtattt tctatgttta catgcacaaa 42420 tacttaccat tgtgttacag ttgcctacag tattcagtac agtcacttgc tgaacaggta 42480 tgtagcctat tgtcaaaagg ctataccata cagcttaagt gtatagcagg ctgtaccatc 42540 agggtttgta taagtattca cacagtgacg aaagtgccca atgatgcact tctcagaaca 42600 tatgctcagg gccaaaaaag cctgtggaga gggaggtccc tgaacaagtt gagagattgg 42660 ctccaaagaa cagtaggagg gattagcctt gatactattg atattggaaa gagaatgagt 42720 gtggatacag atactttttt gggagtagag gttggaagat cagggtctta ctgccttatg 42780 gcctcttatc ctgcagtggt aagtgaggtt aactgaaatg gaagaggtga cgacctcata 42840 gatttgaata gagtgctaaa gacttctaaa agccactgtg tgcagtggaa gatgttgttg 42900 acccaaaaca ttcattaaga atccaggcca ggtggctcat acctgtgata ctagcgcttt 42960 gggaggctga gacaggagga tcgtttgagg ccaacagttt gagaccagtc tgggcaacat 43020 agtgagaccc tgtctctaca aaaaaataaa tcaataaaat ttttaaaaag ctgggtgtgg 43080 tagtgtatgc ctgtagtccc agctactcag gaggctgaag tagcaggatc gcttgaggcc 43140 caggaggtcg aggctgcagt gagccaagat tacactactg cacttcagcc tgggttgaca 43200 gagcaagact ttcttaaaaa aaaaaaaaaa aaaaacccag agcagaaatg aaaaacctgt 43260 gaattagcag tgacaaatag tgaacagtaa tattaatttt ttgttgataa tttagtagct 43320 tggatacagg aactgataga gcagatggtt ggattaatcc aaggttagga ttttgctgat 43380 ggaataagag gataaaaagg ttgaagatgt taacaaatag tgatttaagt gatagaagtt 43440 gtagctagag taaaatatta aaatctaaga tttcaaatag agcaagtcca attctttttc 43500 tttaatcaat atttctgggc caggcgtcgt ggcacatgcc tgtaatccca gccactttgg 43560 aggctgaggc aggagaattg cttgaaccag ggaggcagag gttgcagtga accaagactg 43620 tgccactgca ctctagcctg ggtgacagag ctagactcca tttcaaaaaa aaaattctga 43680 ctcccagttt tctggctaat gaatcagata ccacagatac acagtgatag catttgttta 43740 ggttatattt tttaaaactt tgaggcagcc ctgtcaacat accatgaagc tcagaaataa 43800 actgctaccc aggtagcttc tttgagtgtc accttgagtg acaaactgta acaagattgt 43860 gtctgtcatt ggggcctatt atataatcac acttgatttg tggcctctat tgtcttttct 43920 agcttagagt tgacttgaat ctcttgttca tctgaaatgg ttaaaaccag ctttcttcat 43980 tatcctggag aaggctaaag ttctgagggc tttcactgtc ttaaggagct agttatatga 44040 gaaagctctt ggcttggtcc atggtattta ggaaggaatg ctgtttggag aagaaccttt 44100 ttggagcctt gcatttgatt gttggtgagg aggagacaac agagatgtgt ggggaataaa 44160 gttgggctat gggggaagta tttggagtga tagataacaa aggacacaac gttttttaaa 44220 cctcctttga tgctcatcat ttcctttttg gtaaaatggg ggtaacaaaa gtagtcttct 44280 cacatgactg ctgtgaggat taaatgggaa aattataagc agagagtagc aaatattatt 44340 attattgcat ttaggcttaa ttattgtcca aagaaaatac cagcatgatg cataagcaac 44400 tttcaactcc tttagccatt ttctgaaata taacaattaa tgattttttt ttaaaatcga 44460 ggtcacattt taaactgtag aacccattgt gaccaacagc catcccattt gagggtatct 44520 ggctgctgcc agttggcttt aagatgtcat actgccctca aatggaactt tcaggatgtc 44580 tacaggtccc tttactagtt ggtttcaatg agcttttttc aaagtttttc tgggttgtaa 44640 acagacggat aaacatgaaa ttccaagcaa cctagttcaa gggcctcctt cctttaggta 44700 atgaaagttt gatgaattgt cctactgttt ctaaatatgt ggttaatcat ccaagaaaaa 44760 ttgttccctt ggccagaggc tgcatttgtg tctagggctt gggttagtat gggttaaaga 44820 tagccaagac tattgttctc aagcacaggc aactaaggtc tcttactgat aaatttatat 44880 atacattata cacctgcaaa ctttattttt tatatataac tagattttat ttataggtaa 44940 tctttatatc ttttatctta acccaatttt taatttaaat ggagatgttt attaattaaa 45000 attagtttca gagtttcagg gatttttgag gaattttttg tttggaggct gatatgttac 45060 agaagaaagg ttatatccac tgactgatgt cttttataga tcactcctac agtgacagca 45120 cagagatggt gaaaatcatt gtgcacactg tgcagagtca ggaccgtgtg ctcaaggagc 45180 tgtttggtca tttgaggtag gaaaattgct tcatttccta ctgaaaaacc aggatacgtt 45240 tatcttgttc ctctcaaagt acaaaagccc tctttggtaa agtatactta cccaggaaga 45300 attctgaagg taccttgggt agcttggcca tagctatctg catttatgtg tccttttgta 45360 tgcattactt tggagataag tcattaaatc tgatgctgat tgtggttcat ttcctcagct 45420 gggttttggg aatatggtgt acagtcttgg ggcatgtgaa agtgtctgac actgatttaa 45480 tctctccagc aagttgttgg gctgtaagca gaagattatt gatctactcc ctaaggtgga 45540 agtggccctc agtaatatca aagaagctga caatactgtc atgttcatgc agggaaaaag 45600 gcagaaagaa atatggcatc tccttaaaat tgcctgtgta agtaattatt aatgaattat 45660 ttaatgtgac attgagttgc tattattcct tgcaaagggg atttttatca gcatgaggtg 45720 ggccctcttg aagacatgta tattttgcat tgggatgaca tccatgttcc ttgcttggtg 45780 tccagactag caattgagat gcaggactta ttatcatctc tcctttccaa tttctctgtt 45840 gttatactcc tcttagccct tgactactgt ggtattccaa cctaacttgg ggatagatgt 45900 acctgcctag ataatgaaat tgaccatcta ttcaactggg tttttttttt ctttcttcaa 45960 ctaaaatggt ataagatgag tggatatatt tggttttagt caatgaagaa agggtccaag 46020 gacaggttac taatggtgtg taaaggtggg aatagttttg tactgaaata ctctggttgt 46080 gcatataagt agtaacggaa atgtaagtct taggaatatg ataagaaatt gtgtgaatca 46140 acagagatgc ttgcctgtaa tcttttgatg tttttttctt ttccttcaga cacagagttc 46200 tgcccggtcc cttgtaggat ccagtctaga aggtgcagta acccctcaga catcagcatg 46260 gctgcccccg acttcagcag aacatgatca ttctctgtca tgtgtggtaa ctcctcaaga 46320 tgggtgggtt tactttgtaa caatagatag ctgtgttttc atagcagtgg tataggaatg 46380 aggcagtagt tgttaaggta gtcttctgtg ccttcagacc agggttgagt cctgactatc 46440 cctttgtaat aatcttaggc aacttacttg acttttttga tgttcatatt tcctcacctg 46500 taaaacagga atgtctcata gaactgctgt ggaaatttga ttagacaatg tatataaagt 46560 gcttgggaaa taaatgttca gcaaatgttg cgtattatta gctcaaatgt tgcttattat 46620 tagctaagtc caagttctaa gtcctttctt ttattggctt attactttct tttactcaaa 46680 ccttactcct tcattaacag tttatgagaa attatgctat cattttgcat ttatcatttt 46740 ggggatcctt gattaccctt ctaataaatt tttgagatct attttataac tttgtatttc 46800 taagattaga cttttttcag tgttttaaat cagttttgca agaactcaga ttccaagccc 46860 tatattttat taattcctac tcttttgcta aaagctgaat gactatccat ttctgttatt 46920 ttctcagctt aagatgtgcc gtatccaaag ccagtggctc tttgctagct tgtgtattgt 46980 cgcttttctc acaactcatg gagacctcta cagcaccagc atttcctgga agctctgccc 47040 ataattagtt ttgcagaagt gcagccatgt tacatcactg ctcaggaggt catgcagttg 47100 cacattctgt actctacttt tatgagagaa aagcacatgg caggaaggca agctgatatc 47160 aggtatttta tttttttaaa gaaagcaagt tccagggtat atatcttggg gtcattatac 47220 atgtggccca atgcagtaca cctacaactg tagcacaggc tataattaaa tatatagact 47280 ttacaaaata ctccagtaat cagagttgaa ggaagtaaaa tttaatactt tacttacttt 47340 tttgccttta ttaaaggcat ttaagttttt tagcggatgt taatgtttac aaatgtcacc 47400 acaatacagg taatttccaa tttgaagtgt agttgcttgc aaaagtatat ctgacagaca 47460 ttttcaatgt attttctaga aggaacacat tatattttgt tttgagacgg agtctcattc 47520 tgtcgcccag gctggagtgc agtggcacag tcttggctca ttgcaacctc cgcctcccag 47580 attcaagcag ttctcctgct tcagcttccc gagtagctgg gatttcaggt gcgtgccacc 47640 atacctggct aatttttgta ttttagtaaa gacggagttt caccatgttg gccaggctgg 47700 tctcgaactc ctgacctcaa gtaatccacc tgcctcggcc tccaaaagtg ctggaattac 47760 aggcatgagc caccatgtcc agccagaata cattgtataa gaaaattgat ttcaattata 47820 atgtacctgt ggtacttaac taccaaggat tgggaaccgt

ttgaccataa tttttccatc 47880 tgttggataa gagctgaatc agaatgtcat tctaagctaa tagtggctat catccatgac 47940 ctaaaacgga ctcttgttag gggactgaag attggcaaag ggagaagcta gaggccatat 48000 agaagaggaa agcatgaagg tagaaaccac aatcaggact gccttcaaat atgaacttcc 48060 agggatactt cttggttctg ggtagctccc ccaccacact gttttctttt gctgtcctca 48120 ggaatcagct tgcttgtttc gtttcattgc tatcatctgt agtttctaat gagtttttca 48180 ctttctgtga tctctacaga acagatttta cttttctctc ttctccccta catttgtgtc 48240 tgtgaagtat gcatgctggt gtttttacta cttttaagga aagagaagta tttagaaaca 48300 aaaacgtatt tcatctgtct ttgccacaag gattttttcc tccctagtta cattttcacg 48360 ggaaaaacaa gttgtacata agtgcatctt acatttcaga ggaaagtcag actggagtta 48420 tagtggactt cttatcatta gttaggtaga ggtagaggca gcagcctggt cttaacagga 48480 ctctgcctct gtagggaggg atgaggaaac taaagactac aggagtcaac tgcactgggg 48540 tactgggtta caggaaggct agtgatcttg ctaacctaga agactagaaa gtagaggaaa 48600 ttcatatgcc cttttcctga gtttgaaaag gctttgttct ttcatctcac agggagactt 48660 cagcacaaat gatagaagaa aatttgaact gccttggcca tttaagcact attattcatg 48720 aggcaaatga ggaacagggc aatagtatga tggtaagttt tgtgtggata tgggtgcctg 48780 ctttggctat gttgggtgca aaaggtttaa ctttccatgc tagccttatc tggcatttgg 48840 gatgcatatg ggaaatagaa gaactcaaga ggaaagagca tttggggaat atcctcaacc 48900 ttaaatcctt atctgccgtt actcagggat atactaggat tatgtcatca attatcttca 48960 ataatagcat ttttggtcaa attaaatgag tggtaagctt cttcacaatg tgaccattga 49020 aattgaatgg tttgttctgt acctttttgc ttcagcaatc aattttctcc attaagatgg 49080 gacttgtact ttaattcaga tatggtacct cccgaataga aaataaatta tgttaatata 49140 gttgtaataa taagtgtgtg ttaagatttg gttactataa actactgatt tgttaaaact 49200 tgaggaaatt accataaaat gtctactgaa tcaatttttc ctgcatttag tcttaatgtc 49260 aattctgtac atttcctctt tcattaagaa aaatagcagt ggccaggcat ggtggctcac 49320 gcctgtaatc ctagcacttt gggaggccaa ggcaggtgga ttgcttgagc ccaggagttt 49380 gagactagcc tggccaacat gggaaaccct gtctttataa aaaatataaa aattggccag 49440 gtgtggtggc acacacctgt ggtcccagct acttgggagg ctgaggcagg aagatcgctt 49500 gagttcaaga gtttcaggct gcagtgagcc gtaatcctgc cattgcactc cagcctgtga 49560 cagagtgaga ctttgtctcg gggaaaaaaa aaaaaaaaaa ggataatggt ggccagccat 49620 atgacatgta cctgtagtcc gagttactag ggaggctgag gcagaaggat tgcatgagcc 49680 caggagttca aggctgcagt gcattatgat tggacttgtg aatagccact gtactccagc 49740 ttggcaacat agcaagatcc tgctctctta agaaaaaaaa aaaaaaagaa aagaaaagga 49800 aagaataatt gtttacttca aatatttatg aaaaaaactc tgaaattttt ttaaatcagg 49860 aaataaggta aatgaaatga tttttcaact tttgattatg aaatgtccaa acagaaaact 49920 tgcaaaaatg aacacccata tacttataac ttatagtcaa catctaattg taactttttc 49980 atgcctggtt ttagaatctt gattggagtt ggttaacaga atgagttgtc acttgttcac 50040 tgtccccaaa cctatggaag ttgttgctat acatgttgga aatgtgtttt tcccccatga 50100 aaccattctt cagacatcag tcaatggaag aaatggctat gaacagaaac tacatttcta 50160 ctatgatcag aagaacatga ttttacaagt ataacagttt tgagtaattc aagcctctaa 50220 acagacagga atttagaaaa agtcaatgta cttgtttgaa tatttgtttt aataccacag 50280 ctatttagaa gcatcatcac gacacatttg ccttcagtct tggtaaaaca ttacttattt 50340 aactgattaa aaataccttc tatgtattag tgtcaacttt taacttttgg gcgtaagacc 50400 aaatgtagtt ttgtatacag agaagaaaac ctcaagtaat aggcatttta agtaaaagtc 50460 tacctgtgtt tttttctaaa aaggctgctc acaagttcta tttcttgaag aataaattct 50520 acctccttgt gttgcactga acaggttctc ttcctggcat cataaggagt tggtgtaatc 50580 attttaaatt ccactgaaaa tttaacagta tccccttctc atcgaaggga ttgtgtatct 50640 gtgcttctaa tattagttgg ctttcataaa tcatgttgtt gtgtgtatat gtatttaaga 50700 tgtacattta ataatatcaa agagaagatg cctgttaatt tataatgtat ttgaaaatta 50760 catgtttttt catttgtaaa aatgagtcat ttgtttaaac aatctttcat gtcttgtcat 50820 acaaatttat aaaggtctgc actcctttat ctgtaattgt aattccaaaa tccaaaaagc 50880 tctgaaaaca aggtttccat aagcttggtg acaaaattca tttgcttgca atctaatctg 50940 aactgacctt gaatcttttt atcccattta gtgtgaatat tcctttattt tgctgcttga 51000 tgatgagagg gagggctgct gccacagact gtggtgaggg ctggttaatg tagtatggta 51060 tatgcacaaa actacttttc taaaatctaa aatttcataa ttctgaaaca acttgcccca 51120 agggtttcag agaaaggact gtggacctct atcatctgct aagtaattta gaagatatta 51180 tttgtcttaa aaaatgtgaa atgcttttat attctaatag tttttcactt tgtgtattaa 51240 atggttttta aattactttc ttgatctcta ttcattataa aaatcagatt ataataaaac 51300 agttgaatat ggcttaggaa aatatgaagg ttccatgaag tggaattaag agcatagaat 51360 aactgtactt tccttaggaa taataggact tatggtaaag gtagtattgg gcaacttctt 51420 taagagtgtt ttcctctgaa atgtcctatc accactatct acatctaaaa aacatgctcg 51480 attcttgccc tataaactga tgtcacagcc ccaccatccc catttttgct agtggtatca 51540 ttttcctagt caaccaaatt ttttagtcat cacatatcac tgttcgtcat ctattataat 51600 aggcagtctc tctcttgttt ccctggtttt agaagatttt agtaataaac atttattggg 51660 tacctgttac ttggagggta ttaagctaga tggcaagatc tgaaacaaca taggcagtat 51720 agtaaaagtg cttatctggg agtctgaaca ttacaagcca tccaagcatt gcaattattg 51780 ttaaggatta ttttcaatgg tcatgcattt tctaatattt taataattgg ttaaagattt 51840 gttatagcgt gggggccgct gctggtgtgt ggctggggtt atgtcagggc agcctgatct 51900 atataatttg ggcagatggt gtgagtcaga acagactatt atagtgggat ccccaaactt 51960 gcttttgatg catgagttgg accactattt tttggtgggt aacaactttt cagaggggaa 52020 tggcagttgt gaattgtata catttcattc tttaagcaat attatgaaaa acttcagaga 52080 atgtctacag aaaacagggt atggagcaag ttattttcca ttctttttgc tttttggaag 52140 ttaaaatagc taagctctgc aaatatcatt tatttggaac agataaggtc ccagacattc 52200 ctagataata aaaatcaaat gaatgataca ggtaagtgta tttattgaag ggtgtgggta 52260 gagtggtctg ggaagtcttg ctttaatgaa gacggattga ttctatttac ctcttcttac 52320 ttccactact aagtaaccct gggcctgcag tttcctaacc acttgacttc cttgccaaca 52380 gtctgtctcc actttcagcc gttttataga ttcattggcc ctaaagcact gctttcccat 52440 acttccctac ccaagagggc aggggtcccc aagccctggg ccgcggaccg gaaccagaca 52500 gtggcctgtt aggaaccaag ccggatagca ggaggtgagc ggcgggcgag tgagcattat 52560 cgccttgagc tctgcctgct gtcagattag cgagtggcat cagattctca taggcacgcg 52620 aaccctattg tgaactgcac atgtgaggtt tgccggctcc ctgtgagaat ctaatgcctg 52680 atgatctgaa gtggaacagt ttcatcccca acccacacac acccccaccc cgtccgctgg 52740 gttagaggac tttacaaccc tagtccacct tgtccagtta tagttccacc tctagccttt 52800 caaggcttaa accattaatg tccttaattt ctcttgtatt catctatctc ccaactatac 52860 ctttttcctt ccctttttta tttttggcaa tatgtgccca tggtttttta atttaaaacg 52920 aacagaatat gtagtgacgc ctaccatagc actccttccc atcacacaag ccttcaagga 52980 aactgaagta cttactttgg tctccctgga ggattccctc cgcctcccgc cccatgtgct 53040 tagcaattct gttcctgtag tctggatggc cttcataaag ccctcactgg accagcattc 53100 tggcacataa taggaacact taaaaaacga gagaatgatg ccgttatatc taatatcttc 53160 ctcttctgaa ctttcacagc actttatttg caacaagttt agttgctcct gaagggcagg 53220 atctctgccg gaagcaagtg cgtgccacac agtggggctc cgcatacact gcaaaaggac 53280 aaataaaccg aacagctacc gtttgagagt gagcgagtgg gttctctgca caagaacaaa 53340 ccaaccagtc ccttgtccga aagggcgtct ccttttctct gcttcgctgc tcactccaga 53400 ctgcgggctg tcctcttccg aagcagttaa ccagcagtgt acagaaagcg acttgcctcc 53460 aaaggagcct gcgcggcccg cggctaggag aattttgtcc catgcgctcc ccgtctcact 53520 agccgcgggc cggggctacg ccgtgtgcgt ccccgcgcag ccgcagtgct gggcgagtgg 53580 gcggggccgg ctgttggcgg cggttggctc ggcgcgggag tcggctgcac gtgcgggcgg 53640 gggcgatgcg tcactgatcg gtgaggcgcg gccgaggggt cggctttcct cgcgagcctg 53700 cggctgggct tcttctcagt tagtgccttc cacccgggag cgacccttgg gagagggagt 53760 ttcaggaagc tcaccgagca ggggcggccc actggcctcc gggggcggag gagttggcaa 53820 ggggtcagcg ggctcagcca gaagggaaga atgaggggac aggggtactg gactccccgg 53880 ctcagcctgc gagagagcgc caagtttccg gagggagagg gtagaaactg gagggggtgg 53940 acctgtcact cacgggactg agggtccttt tctcccgctc ccaggaggaa cgagaatgaa 54000 tatgactcaa gcccgggttc tggtggctgc agtggtgggg ttggtggctg tcctgctcta 54060 cgcctccatc cacaagattg aggagggcca tctggctgtg tactacaggt gagcggcatg 54120 tgcagtcagt tagggctcta gagcagatta aaagggtact ccagagtgga gtctgggaag 54180 ttgttccctc tgcaacgttc gggggcgcat gtcccatctc tagggagagc acgggggtcg 54240 aagcgggctt ttgcggagca ccctccagat gttggacagt tttagtgcta tgttcgtttt 54300 gttgcagaga ttaagtctcc ctacggttat tcctatacac agcaaactca attatttgta 54360 gaaaaatgaa gaaggaagaa aggaagtagt cactctacct ctaactgaag agatggataa 54420 attatagttc gttcaactgt acaggcttta gtttgccgct gtagatgctg tatgtttatg 54480 gttgtttctt agactttttc atttaaaagc ttccagtgtc tggttacgtc ttgtaacacc 54540 atgatgactg tgatggtgct tatgtccctg gacctccagg gacataagca caacactgat 54600 gggccatgct cctccctcct tactgttgct gttcaagttg gggacaggag tggtgtggga 54660 gctgttgctc tcttgttgag ctcgcttagc ttttccttca gcctaattac cacaagttcc 54720 ttttgataca gactagtaag agaggccagt ttgtggagaa attgggataa tggtgtattc 54780 aaaaagagcg tcaacttttt gcttgtttcc actatccctc aaaactgata tttctacttt 54840 caaatccatc ctgaatccta gaaaaagagc aattttaatg gtatatctta gcagatggag 54900 ctctacataa gaaattacag attagtccag atttccttcc agtttaaaag cattgtcttt 54960 ctgacagtaa aaccagagaa aggacatttc aaggaatgac tcaaagaatt agtaatgaac 55020 ctcaaacagt tcatctttcc ttgttattat gaccttgcaa atgtgtttat attttcaaga 55080 ccggtagcta agttctatga atttacaagg tgcaaaatag gactttgttt tctttgctcc 55140 ccaaatgcct cctttttata atttccaggg cttgctttca tagttttcac attccaggat 55200 ttggttaaca agcccttatg ctatttattt gtatagtctt gtcacccttc atcttttcat 55260 gctaattttt tgtttttata tagaaatttt atgttcccag tattttaatt accttgtaga 55320 tagatcgaaa gaattataag cctcagaaat tttctcttta cttcaaagtt tgcattgtct 55380 ttttttcaac ctggtgatta aatgtattat atattttgat ttggctcttg ttatgtacta 55440 ttaatgtacc tctactgaaa gccattagaa ttttttaaac aaatatttct cagaaggtta 55500 aagaccgagg agaatccttt gaaccttaga gcagtgctgg agacccagag gtacggttgg 55560 ttgagcttat gaaacaaggt gtaacattgg cagtttaatt tgatcttttt ccctttttag 55620 gtgtggaggt attttaagca gttgttcatt atgagcaatt catattagtg aggctttagt 55680 aggtcagcag catgagcaag agtgagtatt tattatagca ttttagattt ggaaagataa 55740 tttttctttt tataattttg tcaaattgaa acatcttttt gcaggggagg agctttacta 55800 actagcccca gtggaccagg ctatcatatc atgttgcctt tcattactac gttcagatct 55860 gtgcaggtga gtgattccta ggggaagcct ccataccaga tagacaggca tgacaggagt 55920 taccacactt gtgggtggag atagatttcc ttattgctta agcagatggt ggtatttact 55980 taaatgcaga agttaacgtt cagagtacag ttgttacaac acaagttatg atgttaaacc 56040 acctcactta cttgaaatga attaaaggta tgaaccagga agcttggaag gactgacttc 56100 taccatctat atcgtggtat atagcaaatt ttctgttgct gctgtcacaa taaaagtaag 56160 aattagaaac acaactagac atacaaacca gtgattatgt ggtttagaac agtgtttagt 56220 ttccatagag gcaggctcct gggctactgt taacatggag gatcaaaatt tttatacaca 56280 gcctttctgc ctcatgtttt tttgcctggt atattaagca caattttatg tggaacctta 56340 gtgaatgtta tattttgatg gcatcccggg atatttgaaa taagtgtcta atcctcgaaa 56400 agtgtcttgg ccatgggaga caataaaata agtatctttc aatgtaacaa gatgacaaaa 56460 ccaggattag gctgtgacca ctttcgcaag cccagtgtga tcataaatct ttggattcag 56520 aagtttgtct gccatctgct gctaattttt caggactcag gaaaattctg tgttatttaa 56580 tcttgtaatc ttatgtctag gcttcctgct aagtgagagt ttaattataa attcttaaat 56640 cccctaggtt ttcttcctgt ccccttttag atggcttagg gaaagaattg tgtctactga 56700 agtgaaatgt attcttcccc taatcagact gatttccata tgttgttcca tatttatttt 56760 acccattctt tccttagttc atgccatcac ttctttatct gccatctcac tctccattcc 56820 ttctctcctg tctaaatctt gccaggcttt taaaggctca tcccagattc ttcctcttct 56880 gatctatagc tcttaaagtc tatattgtaa attttggccc tttgtcttat tttctttaat 56940 attgttgtct tgcattgttt gctaagtttt tttatgtgtt ttctttccag aaaggctcca 57000 gttttcttaa aggcaggagt tgtaacacat ttatatttct ggctttctat ttatggtgga 57060 agttgttaaa ttgagctgat ttctcaggaa gcaatgtggt gtaatgaaca tggggaccca 57120 gcgttaccgc cagttggtgg catgactttg gaaaaattgc ttaactgtca tagacttcag 57180 ttagtcttct gtgaaaggag gaattttaat tacataacct catcaacagc cgaaacaatc 57240 tataataatg ttagcaatgg cagcattaga cccttaaaaa tcaagactct aaggcccggc 57300 gcagtggctc atgcctgtaa tccgagcact ttgggaggct gaagcaggtg gatcacttga 57360 gcctaggagt ttgagaccag cctgggcaac atggggaaac tccgtctctt aaaaaaaaaa 57420 aaaaaaaaaa atcaaggctc taacaaatag atcttgttca aaaccaggta gatctgtctc 57480 tgccttcatg cttagtatgt taagtcatac tgatgcaaaa atataaataa aggagatata 57540 gataatagta aacagatttt ggagtttaat tgtgtatata tataacaaat atagtgtgtg 57600 tatatattta ataataaact atcataagag atgtaaatga aattagtaca gagacttcag 57660 tgtaaactaa aatacttcgc atctacaaaa aagttttaca tgggctagag ccagccagtg 57720 tgactaaata ggaatgttct ttatgtgtaa aacggtaaca ttctaggaaa taattatatt 57780 aataaaacca tatttaaaaa gtgttcttgg ccgggcgtgg cggctcacgc ctgtaatccc 57840 agcactttgg gaggccgagg caggcagatc acttgaggtc aggagttcaa gaccagcctg 57900 gccaacctgg tcaaacgctg tgtctacaaa aatacaaaaa ttagctgggc gtggttgtgc 57960 gtgcctgtaa tcccagctat ttgggaggct gaggcaggag aatcgcttga acctgggaga 58020 ccgaggttgc agtgagccga gatcgtaccc ttgcactcca gcctgggcaa cagaggaaga 58080 ctccgtctca aaaaaaaaaa aaaaaaaaga gtgttcttaa gagagtaaga cataaattta 58140 tttttaggaa tttttggaac atattagaag acatagtcca gataaacaaa tggtttaaca 58200 aacttggcaa ttgaaaggaa tgtatataaa tgtgaaattc catatatgat gtaaaaagaa 58260 aaagcaatgg agaaattata tgaaaacctt cagccttcat aaagtaacca tagattcact 58320 ttttaaataa attttctgtc atactgggaa agtaattttt aagaggacat aaaagaaata 58380 taaaagtaca taaagatagg gtgttaaatg gaagatttaa catttgaacc ctttcctagt 58440 tcttctgagt ttgaaaattg gctagagaat atccttttgg tttaaatagg aacgtgtatt 58500 taaagttggt gtggaatatg gaaactgaat taatgttata aaggaaataa atataatttg 58560 tctcttcatc aatcccctta acctagaact gccaccaatg tttactgtca ttctaatgtc 58620 tcaacctaag agttattttt tattctttcc cctcctggaa ttttatatca accaagtatc 58680 agatacctcc tctattatgt ctggattgac agctttcatg gcctttactg aattaatcta 58740 aataaattaa ttatttagcc tcccagctgg ttttcttacc tccctataag atggagaatg 58800 agaactacat cacatgtgag aaaaggaatt aagtaaacat atttttgaat ggttcgtttt 58860 gtgactgtat ataaggtgaa ctagagagat cccaaactcc ccagccagca ttcagggccc 58920 tctgtctagt attaccatgg tctcttgtca gaatttcatc tttcatccaa attgtccctt 58980 ctgctccagg caagcctatc tactttcgtt cgcctataca catgttgtct tcaactgtgt 59040 gtatttcagt aggatattta ttgagcttaa gatgttcctc tgcctcatct gttcttattt 59100 ctcccactct agacctggct tataaatcct tcacctcaga gagcttttca aactactatt 59160 tttttcactt tctgtaattt accacttaac agttcagttt ataatttgtg tttttggttt 59220 tgttttgttt tgttttgtac ctgttgatgg attgattgca ttgtaacatt ttgtctcctg 59280 tgctggattg tgaactcttt ggaaacaggg actgtgattc ctttttcctt tgctttgtgc 59340 ttgataagat gcagtatgtc tagaatgtac tcattaggtg ctgacctatt tgaggcctta 59400 gagtacagca ggaagtcatt cattctggat ctgaacaaag gtgtgacaag ggcaaagcaa 59460 ttaagtacca gattgttggt tcaccaggag gaagcagtac tggtggtagc acttctatta 59520 aaaaggaaac tgaataggac atgtgagaga tcactaggta ttaaactaaa atgttgacca 59580 cagctttaga gaagaaaggt tgctgttgga ttcaagggca gctttgagtc ttagagtact 59640 tgtatgcata aaatctcttt tatcttcaac ataaatagta atattagcag tggaatcaaa 59700 gttcagagtg caagttgtag ccagagtatc tatgtgagca agctgtgttg tttacaaccc 59760 ctggccagct ccaggcaggt aagggactct ggaagagttt tctacttatt agcagactga 59820 acattgaacc tttcccagtg aatcttaatt caaacattcg ctgtaggcca ggcacagtgg 59880 ctcacgcctg taatcccagc actttgggag gccaaggtgg gtggatcact tgaggccagg 59940 agttcaagac cagcctggcc aacatggtga aacctcatct ttactaaaaa tacaaaaatt 60000 agctgagcgt agtggtgcat acctgtaatc ccagctactt gggaggctgg ggcacaagaa 60060 ccgcctgaac ccaggaggca gaggttgcag tgagccaaga ttgcaccact gcattccagc 60120 ctgggtgaca aagcaagact ctgtctccaa aaaaaaaaaa aaattgctgt aaaatatttt 60180 ctgtctcaag tctttcattt ctactagaat acaaaaagaa atgactgttc tgagagctaa 60240 tctttgggaa ctgaaattgt gatggatctc tgctgtactt actgtcagca gctttccaga 60300 gatttgcctc tggtaccagt agttttttga caatgtgtgt cttgagtgtt gatgagatat 60360 cttttcctcc ctagacaaca ctacaaactg atgaagttaa aaatgtgcct tgtggaacaa 60420 ggtaagcttt ctctttgcct acgagcctcc ctttagctca gacagagttt ctgttcctac 60480 agctatgatc acttagacat atctcaaata ggcatgatag ttaacccaag gggacttctg 60540 atctgagcat tgtttgagca aaggcctatc tccaaatagg agcttttcca tcttaagaac 60600 cattattgtt cttatggtat tattggaaaa aactggagtt ttagagcaag tagacctaac 60660 tgtgtattag cactgctgca tctgctttat tgactatttt ttaaagactt tattttttac 60720 agcagtttta ggttcatagt gaaattgacc aaaaagtaca gacagttttt atatacctct 60780 ttccccaaca cattccttta ttgacacttt aaagcttagt ttcctccttt ataaaggcag 60840 taaaatctac cttgcagagt tgttgtaagg attagaatta ctgtatatga agtgcctaac 60900 cagaacttgg cccagaatag gtgcttaata aaacatagtt taaaattaat catcccaccg 60960 tcttctcatc tgtagtgtta aatgccatct aatttagagt ttctgattca ataggtctgg 61020 ggtgaggccc gagaatttgc atttctaaca aaagttcctg ggtgatgctg atactgctgg 61080 tctgaagacc tcactttgag aattgctgtc ctaaagaggt ttagggaaag aaaggcaagc 61140 agggcccaaa ttatttctag ggtataatca ctgcattgaa ttgtatcaaa agaagaatgt 61200 gaagttcaag gtatttttta aattacttat tttaaatgac tattacaagt gtaaaaaaga 61260 cattgacatc tatagaggga cagaaatgct atgaaaaagg aagcgaactc tttctgtgtt 61320 ttaagtgaa 61329 39 31394 DNA Homo sapien misc_feature 5165, 5166, 5167, 5168, 5169, 5170, 5171, 5172, 5173, 5174, 5175, 5176, 5177, 5178, 5179, 5180, 5181, 5182, 5183, 5184, 5185, 5186, 5187, 5188, 5189, 5190, 5191, 5192, 5193, 5194, 5195, 5196, 5197, 5198, 5199, 5200, 5201, 5202, 5203 n = A,T,C or G misc_feature 5204, 5205, 5206, 5207, 5208, 5209, 5210, 5211, 5212, 5213, 5214, 5215, 5216, 5217, 5218, 5219, 5220, 5221, 5222, 5223, 5224, 5225, 5226, 5227, 5228, 5229, 5230, 5231, 5232, 5233, 5234, 5235, 5236, 5237, 5238, 5239, 5240, 5241, 5242 n = A,T,C or G misc_feature 5243, 5244, 5245, 5246, 5247, 5248, 5249, 5250, 5251, 5252, 5253, 5254, 5255, 5256, 5257, 5258, 5259, 5260, 5261, 5262, 5263, 5264, 5265, 5266, 5267, 5268, 5269, 5270, 5271, 5272, 5273, 5274, 5275, 5276, 5277, 5278, 5279, 5280, 5281 n = A,T,C or G misc_feature 5282, 5283, 5284, 5285, 5286, 5287, 5288, 5289, 5290, 5291, 5292, 5293, 5294, 5295, 5296, 5297, 5298, 5299, 5300, 5301, 5302, 5303, 5304, 5305, 5306, 5307 n = A,T,C or G 39 tgcacacaaa actctctaca ctgctagtct ttaattctca aaaacagttc cctgagagag 60 ggaacataat tgcctctatt ttacagatga caaaaccagg cttagaagtt acacaaattg 120 ccttgcacag tggctcacac ctataatccc acacattggg aggctgaggc aggaggattg 180 agttagaaac cagcctggtc aacatagcaa gacccccatc tctacaaaag aaaagataaa 240 tttgctgggc atagtggtgc acacctatac tcctgcttgg gaggctgagg caggaggatc 300 gcttgagccc aggaggtcga ggctacagtg atccatgatc gcaccattgc actccagcct 360 gggcgacaga gcgaggccct atcgcttaga aaacaaaaag ttacatgaag ttcccccaag 420 gtcccgtagc tagcatgtga tgtggcaggg agagagcctg tccgcttcac tctctcacat 480 gggaccagaa aggggtgatg ctgtgcgtgg acaggacatc tggcaagtgg tgtgtccagg 540 acacaggaag cagcgtagtg gccaagctgc ctccagctgt cacatctgtg tgtctctgca 600 gtaaggatga gtctgccttc atggtccacc cgctgacggc acagggagtg

gccgtggtaa 660 tagtggctta cggcatcgcc cccaaaggta ataggagtgg ttgctgcagg tccgagggcc 720 ggtgggcttt aggaggaagt gcatccctga cccagctcat gctctctgtg caggcaccct 780 ggaccacatg gtagaccagg tgacccgcag cgttgcgttt gtccagaagc ggtatccaag 840 caacaagtgg gtgttgccag tagattttct tcctgttgga cctcagtggg tgggaggaca 900 gtgcaatcag tacctaggat acagccaagc tgcccctctg gcctgtggag cagaaagcaa 960 attgggactc ttcgaagggg gcctgatgtt gtggggaaac tgcgtgcaaa tccagctctc 1020 tgctctgacc cctcccaggg gaatttacct gtgtggacac tcagccgggg cccacctggc 1080 tgccatgatg ctcctggccg actggaccaa gcatggggtc acgcccaacc tcagaggttt 1140 ccatgggagc tacagcctgg ctgggcaacc ttcatctccc catgagcctt ggggtttggg 1200 ccaactgctt gaaatcctcc cggccatgag tggcttgacc gcagggcttc gagccctctg 1260 agcaaggcct tctctgcctc ctctgtgccc cttcccctgg tcctgcccct ctggcggtgg 1320 gggtgggctg gccctgcctt gctccgcctg gagcctggcc ctgtgacaat tctgtacctt 1380 cacaggcttt ttcctggtga gtggggtctt tgacctggag cccatcgtgt atacttcaca 1440 gaacgttgct ctccagctga ccctgtgagt tacttggcca ccacctcccc tggctcacca 1500 ggagcctggc tcctctctgt cctgacccct gtccactccc caccccaggg aggacgctca 1560 gaggaatagc ccccagctga aggtggccca ggcacagccg gtggacccca cctgccgtgt 1620 gctggtggtc gtgggccagt tcgactcccc cgaattccac cgacagtcct gggagtttta 1680 ccaggtactc ccagtgcagg tttgtggcca gaggtcgagg gtcatgtggg ctcattattt 1740 tcctctttct tttacccaag tggacaagac cctccatcat ttatttaaca cgtactgagt 1800 gaaccctgac ctgtgccagg catggcccca tgtcctgccc cacctcccct cccactgctc 1860 aggcccctct tcccatgtct cccctgccca gaccctgtgt caaggagagt ggaaagcctc 1920 atttgaagag ctccacgatg tggaccactt tgaaattgtt gagaatctga cccagaagga 1980 caacgtgctc acccaggtgg ggcctcatcc ctggcagccc tttcatggta gacagcacag 2040 gtcctgtcgc agccccttag atgtgcaaac caggagttca agaccagcct ggccaacatg 2100 gagaaactcc gtgtctacta aaaatacaaa acaaattagc cagatgtgat ggtacgtgcc 2160 tgtaatccca gctactcagg aggctgaggc atgagaattg ctttaaccca ggaggcagag 2220 attgcagtga gccaagattg caccactgca ctccggcctg agcgacagag tataagactc 2280 tgtctcaaaa aaaaaaagac ctgagaacct aggaaagaaa gaacctaaga aagaccatct 2340 tgtttctttc tttttttttt tctttagaga cagggtctcc tctcttgcac ccaggctgga 2400 gtatagtggc aaaatcttag ctctctgctg cctcctgggc tcaagtggtt atcctgcccc 2460 agcctcttga gtagctggga ctacaaaggc gtgccactgt gccctgctaa ttattcaatg 2520 tttttgtaga gatggggtct ctctatgttc cccaggctgg tcgtcgtcgt cttccttctt 2580 cttcctcctt cctccttcat cttctttctt ctcctcctcc ccctaccccc ccttcttctt 2640 cttcttcctt catctcagca tattatacct ctaaccagac tgtcttcaac tcctgagttc 2700 aagtgatctt cccacctcag cctcccgaag ggttggggtt gcagacgtga gccactgcat 2760 ccagccctgt ctcatttcct taatcaaatt cctgcaaaga gctgctctga ttctggggct 2820 tttgtgtctt ctcttcctgt tccagattat cttgaaaaca atcttccagt agttctgacg 2880 atacttggag cctggtccac gtgcatccca ccttgggaag cctctccaaa gagctttcgg 2940 agctgacact gacagcttca gtttccccca gcacccagga gagccttgct gtgtctgtct 3000 gcccggcaag agtccattct cactgctggg acactcatga aaatctccac gtcctccctc 3060 ttcccagcct ggatggagct ccagggctgg ggaacgtccg caagtcaatg ctcagagatg 3120 cccggagctg cctcttagac tcgtctggcc catctacctg ctgacagagc atgacaaaga 3180 tgacgctcaa aagtaatgcc attacttctt tttttttttt tttttttttt ttttttgaga 3240 aggagtctta ctctgtcacc caggctggag tgcaggggcg tgatcttggc tcactgcaac 3300 ctccacctcc cggggtcaag ctattctcct tcttcagcct cctgagcctt tgggactggg 3360 ggcgcctgcc atcatgcctg gctaattttt gtttttttag gggagacggg ggttcaacct 3420 attggccagg ctggtctcaa actcctaacc ttgtgattcg cccgccttgg cctcccaaag 3480 tgctgggatt ccaggcgtga gccactgcgc ccggccagaa tggcattata tttaaatagt 3540 tcataaagaa gcacaaaaga atattatttc ataacatgta aaaattatat aaaacgtaaa 3600 tttccatgtt gataaataaa gttgtattgg aacacggccc tgctcgttca tttacgtatt 3660 gtctagggca gctttcaagc tgcagggtgg agctgagtgg tggtgacagt gacctcctgg 3720 cccgtagtgc ctgaagcatt tcctatctgg cccttttcag gaaaagtttg cggacccctg 3780 ggtaagggct tccccaagcc agctaccctc tgccttctgc ttcagtctcc tgtctgctct 3840 gtcctccatc tccctgacat ttgggtctgt ccctgaatgc cccggggtct cagcgttggg 3900 gccaacacct tgaccttgac aggacaatgc tacccacatg taggacaagc ttcctctgca 3960 cccgagagtg gtgtgcatgt cccaagaagc cagctatatc catccaccac ccaccccacc 4020 acaccgcctc tttctctcac accgaatagc attcaagaat ttccactgtg ggctgggcgc 4080 aggggctagt gcctgtaatc ccagcacttt aggaggccga ggtgggcgaa tcacctgagg 4140 tcaggagttc aagaccagcc tggccaacat ggcaaaaccc tgtctctact aaaaatacaa 4200 aaattagcca ggcgtggtgg ctggcgcctg taatcctaga tacgtgggag gctgagttag 4260 gagaatctct tgaatccggg aggcagaggt tgcagtgagc tgagattgtg cccctgcact 4320 ccagcctggg tgacaaagcc agactccatc tcaaagaaaa aaaaaaaaat tccactgtat 4380 gtgtgcagca aaccatcatg acacacattt acctgtgtaa caaacctgca catcctacac 4440 atataccctg gaacttaaag taaaagttgg gggggggggt aaaaaagaat ttccaccgtg 4500 acattattga gtatagcaaa aaaaaaaaaa acaagaaaca gcctagtgtt cattagggaa 4560 taaacgcatt caagcagcat caaaccctgc agccattaca aagagatcta tgttgaccat 4620 gtggaatatc tccaagagcc acagtagcct cccttatctg taggattcac tccaagaccc 4680 tctgaaacca tggataatac tgaaccctat atacactatg ttttttcttg tatatacata 4740 cctacgataa agtttaattt ataaattggc aaagggtata taaatattcc ttctaagaga 4800 ttaacaataa ctaataaagt agaacgatta aaacaatata ctgtgatcaa agttatgtga 4860 agccaggtgc tgtggctcat gcctgtaatc ccagcacttt gggaggctga gacaggtgga 4920 tcacctgagg tcaggagttg gagaccagcc tggccaacat gacaaaaccc cgtctctact 4980 aaagataaaa aaaattagcc gggcatggtg acacatgcct gtaatcccag ctacttggga 5040 ggctgaggca ggagaatcgc ttgaacctgg gaggcggagg ttgcagtgag ctaagatcac 5100 accattgcac tccagcctgg gcaacaagag tgaaactctg tctcaaaaca aaacaaaaca 5160 aaacnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 5220 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 5280 nnnnnnnnnn nnnnnnnnnn nnnnnnnact tcatctcaaa aaaaaaaaaa gaaaaaagaa 5340 gtccagaaac ccgcggagac actatcacac tatccccccc aggctggtag tgcagtggcc 5400 caatcatggc tcactgcagc ctcgacctcc caggatcaag tgatccttcc acctcagcct 5460 cccgagtagc tggaagtata ggtgcacgcc cgactgattt tttttttttt tttttagacg 5520 gagtctcact cttgttgctc tggctggagt gcaatggcag gatctcggct cactgcaacc 5580 tctgcctctt agattcaagc gattctcgtg cctcagcctc ccgagtagct gggattacag 5640 gtgcccacca ccatgcccgg ataatttttt gtatttttaa tagagacagg gtttcaccat 5700 attggtcagg ctggtctcaa actcctgacc tcaggtgatc cacctgcctc agcctcccaa 5760 actgctggga ttacaggcgt gagccaccgg gcatggcctt tcctggctaa ttttttaaat 5820 ttttgataga gatggggtct cagtgttgcc caggctgatc ttgaactcct agattcaagt 5880 gatcctccct ccttggtctc ccaaagtgct gagattacag gcgtgagcca ccgccccggg 5940 ctggaaaata cttttttaaa cgagggcaat gtgaatctga aatgccattt gaggaaagat 6000 ctgttcgcct gacatcctgt ttgagcctgg gtggacagga cagcacctgc cagcatcggg 6060 aagcactgca gatgggaaga ggcttggtca ctctccaaag gtggcaggag ttggaggggg 6120 tgagctgaag gtaaggagaa aggaggtggg gacccaggag acaggggctg cgcagcgggc 6180 tcggggctga cacccccacg gatacagttc actggggctc aaacataaaa ggaacccaac 6240 tattgtggga ggaaaagact cttctgcctt tctgcctttt ctttttttct ttttctttct 6300 ttcttttttt tttttttttt ttgagacaga gtcttgctct atcgcccagg ctggagtgca 6360 gtggcgtgat ctcggctcac tgcaagctct gcctcccggg atcacgccat tctcctgcct 6420 caacctcccg agcagctggg actacaggcg cctgccacca cacccggcta tttttttgta 6480 ttttttagta gagatggggt ttcaccatgt tagccaggac ggtctcgatc tcctgacctt 6540 gtgatccgcc cgcctcggcc tcccaaagtg ctgggattac aggcgtgagc caccgcgcct 6600 ggctcttttt tctttctttt tttttttccg agacagagtt tcactcttgt tgcccaggct 6660 ggagtgcagt ggcgcgatct tggctcactg caacctccac ctccagggtt caagcgattc 6720 tcctgcctca gcctcctgag tagctgggac tgcaggcgcg caccaccacg cctggctaat 6780 ttttgtattt ttagtagaga cagggtttca ccatattggc caggctggtc tcgaactcct 6840 gaccttgtga tctgcccacc tcagcctccc aaagtcctgg gattacaggc gtgagccacc 6900 gtgcccagcc tgacccctct gccctttcaa aaactatgtt cgttctctca cagccttctc 6960 ttgtcatatt aagtccacac cgcaggccta atttgtccag tgaatgctat gcaaatattt 7020 catgcacctg ctgatcgcag gaatgatatg tacttggtac gcactgatcg tacctcgggg 7080 tgggagaaga gagggcaagg aagcaaagaa tagccccctc ctttcctggt gcaccttcag 7140 atgtgccgat ggggcccagg ctcgctgcag atggccccct tcccagagac aggggaggat 7200 cctccaccca ctccccagcc tccaggacca tcctgactcc tgccttcagg cactcaagtt 7260 atgcgtctag acatgcggat atattcaagc tgggcacagc acagcagccc caccccaggc 7320 agcttgaaat cagagctggg gtccaaaggg accacacccc gagggactgt gtgggggtcg 7380 gggcacacag gccactgctt ccccccgtct ttctcagcca ttcctgaagt cagcctcact 7440 ctgcttctca gggatttcaa atgtgcagag actctggcac ttttgtagaa gccccttctg 7500 gtcctaactt acacctggat gctgtggggc tgcagctgct gctcgggctc gggaggatgc 7560 tgggggcccg gtgcccatga gcttttgaag ctcctggaac tcggttttga gggtgttcag 7620 gtccaggtgg acacctgggc tgtccttgtc catgcatttg atgacattgt gtgcagaagt 7680 gaaaaggagt taggccgggc atgctggctt atgcctgtaa tcccagcact ttgggaggct 7740 gaggcgggtg gatcacgagg tcaggagttc aataccagcc tggccaagat ggtgaaaccc 7800 cgtctctact aaaaatacaa aaaaattagc cgggcatggt ggcgggcgca tgtaatccca 7860 gctactgggg gggctgaggc agagaattgc tggaacccag gagatggagg ttgcagtgag 7920 ccaagattgt gccactgcac tgcactccag cctggcgaca gagcaagact ctgtctcaaa 7980 aaaaaaaaaa aaaagtgaaa aggagttgtt cctttcctcc ctcctgaggg caggcaactg 8040 ctgcggttgc cagtggaggt ggtgcgtcct tggtctgtgc ctgggggcca ccccagcaga 8100 ggccatggtg gtgccagggc ccggttagcg agccaatcag caggacccag gggcgacctg 8160 ccaaagtcaa ctggatttga taactgcagc gaagttaagt ttcctgattt tgatgattgt 8220 gttgtggttg tgtaagagaa tgaagtattt cggggtagta tggtaatgcc ttcaacttac 8280 aaacggttca ggtaaaccac ccatatacat acatatacat gcatgtgata tatacacata 8340 cagggatgtg tgtgtgttca catatatgag gggagagaga ctaggggaga gaaagtaggt 8400 tggggagagg gagagagaaa ggaaaacagg agacagcgag agagcgggga gtagagagag 8460 ggaaggggta agagagggag aggaggagag aaagggagga agaagcagag agtgaatgtt 8520 aaaggaaata ggcaaaacat aaacagaaaa tctgggtgaa gggtatatga gtattctttg 8580 tactattctt gcaattatct tttatttaaa ttgacatcgg gccgggcgca gtggctcaca 8640 tctgtaatcc cagcactttg ggaggccgag gcaggcagat cacttgaggt caggagtttg 8700 agaccagcct ggcaaacatg gtgaaacccc atctctacta aaaatacaaa aattagcctg 8760 gtgtggtggt gcatgccttt aatctcagct actcgggagg ctgaggcagg agaatcgctt 8820 gaacccgtgg cggggaggag gttgcagtga gctgagatca tgccactgca ctccagcctg 8880 ggcgatagag cgagactcag tttcaaataa ataaataaac atcaaaataa aaagttactg 8940 tattaaagaa tgggggcggg gtgggagggg tggggagagg ttgcaaaaat aaataaataa 9000 ataaataaac cccaaaatga aaaagacagt ggaggcacca ggcctgcgtg gggctggagg 9060 gctaataagg ccaggcctct tatctctggc catagaacca gagaagtgag tggatgtgat 9120 gcccagctcc agaagtgact ccagaacacc ctgttccaaa gcagaggaca cactgatttt 9180 ttttttaata ggctgcagga cttactgttg gtgggacgcc ctgctttgcg aagggaaagg 9240 aggagtttgc cctgagcaca ggcccccacc ctccactggg ctttccccag ctcccttgtc 9300 ttcttatcac ggtagtggcc cagtccctgg cccctgactc cagaaggtgg ccctcctgga 9360 aacccaggtc gtgcagtcaa cgatgtactc gccgggacag cgatgtctgc tgcactccat 9420 ccctcccctg ttcatttgtc cttcatgccc gtctggagta gatgcttttt gcagaggtgg 9480 caccctgtaa agctctcctg tctgactttt tttttttttt tagactgagt tttgctcttg 9540 ttgcctaggc tggagtgcaa tggcacaatc tcagctcact gcaccctctg cctcccgggt 9600 tcaagcgatt ctcctgcctc agcctcccga gtagttggga ttacaggcat gcaccaccac 9660 gcccagctaa tttttgtatt tttagtagag acaaggtttc accgtgatgg ccaggctggt 9720 cttgaactcc aggactcaag tgatgctcct gcctaggcct ctcaaagtgt tgggattaca 9780 ggcgtgagcc actgcacccg gcctgcacgc gttctttgaa agcagtcgag ggggcgctag 9840 gtgtgggcag ggacgagctg gcgcggcgtc gctgggtgca ccgcgaccac gggcagagcc 9900 acgcggcggg aggactacaa ctcccggcac accccgcgcc gccccgcctc tactcccaga 9960 aggccgcggg gggtggaccg cctaagaggg cgtgcgctcc cgacatgccc cgcggcgcgc 10020 cattaaccgc cagatttgaa tcgcgggacc cgttggcaga ggtggcggcg gcggcatggg 10080 tgccccgacg ttgccccctg cctggcagcc ctttctcaag gaccaccgca tctctacatt 10140 caagaactgg cccttcttgg agggctgcgc ctgcaccccg gagcgggtga gactgcccgg 10200 cctcctgggg tcccccacgc ccgccttgcc ctgtccctag cgaggccact gtgactgggc 10260 ctcgggggta caagccgccc tcccctcccc gtcctgtccc cagcgaggcc actgtggctg 10320 ggccccttgg gtccaggccg gcctcccctc cctgctttgt ccccatcgag gcctttgtgg 10380 ctgggcctcg gggttccggg ctgccacgtc cactcacgag ctgtgctgtc ccttgcagat 10440 ggccgaggct ggcttcatcc actgccccac tgagaacgag ccagacttgg cccagtgttt 10500 cttctgcttc aaggagctgg aaggctggga gccagatgac gaccccatgt aagtcttctc 10560 tggccagcct cgatgggctt tgttttgaac tgagttgtca aaagatttga gttgcaaaga 10620 cacttagtat gggagggttg ctttccaccc tcattgcttc ttaaacagct gttgtgaacg 10680 gatacctctc tatatgctgg tgccttggtg atgcttacaa cctaattaaa tctcatttga 10740 ccaaaatgcc ttggggtgga cgtaagatgc ctgatgcctt tcatgttcaa cagaatacat 10800 cagcagaccc tgttgttgtg aactcccagg aacgtccaag tgcttttttt gagatttttt 10860 aaaaaacagt ttaattgaaa tataacctac acagcacaaa aattaccctt tgaaagtgtg 10920 cacttcacac tttcggaggc tgaggcgggc ggatcacctg aggtcaggag ttcaagacct 10980 gcctggccaa cttggcgaaa ccccgtctct actaaaaata caaaaattag ccgggcatgg 11040 tagcgcacgc ccgtaatccc agctactcgg gaggctaagg caggagaatc gcttgaacct 11100 gggaggcgga ggttgcagtg agccgagatt gtgccaatgc actccagcct cggcgacaga 11160 gcgagactcc gtcataaaaa taaaaaattg aaaaaaaaaa aagaaagaaa gcatatactt 11220 cagtgttgtt ctggattttt ttcttcaaga tgcctagtta atgacaatga aattctgtac 11280 tcggatggta tctgtctttc cacactgtaa tgccatattc ttttctcacc tttttttctg 11340 tcggattcag ttgcttccac agctttaatt tttttcccct ggagaatcac cccagttgtt 11400 tttctttttg gccagaagag agtagctgtt ttttttctta gtatgtttgc tatggtggtt 11460 atactgcatc cccgtaatca ctgggaaaag atcagtggta ttcttcttga aaatgaataa 11520 gtgttatgat attttcagat tagagttaca actggctgtc tttttggact ttgtgtggcc 11580 atgttttcat tgtaatgcag ttctggtaac ggtgatagtc agttatacag ggagactccc 11640 ctagcagaaa atgagagtgt gagctagggg gtcccttggg gaacccgggg caataatgcc 11700 cttctctgcc cttaatcctt acagtgggcc gggcacggtg gcttacgcct gtaataccag 11760 cactttggga ggccgaggcg ggcggatcac gaggtcagga gatcgagacc atcttggcta 11820 atacggtgaa accccgtctc cactaaaaat acaaaaaatt agccgggcgt ggtggtgggc 11880 gcctgtagtc ccagctactc gggaggctga ggcaggagaa tggcgtgaac ccaggaggcg 11940 gagcttgcag tgagccgaga ttgcaccact gcactccagc ctgggcgaca gaatgagact 12000 ccgtctcaaa aaaaaaaaaa aaagaaaaaa atctttacag tggattacat aacaattcca 12060 gtgaaatgaa attacttcaa acagttcctt gagaatgttg gagggatttg acatgtaatt 12120 cctttggaca tataccatgt aacacttttc caactaattg ctaaggaagt ccagataaaa 12180 tagatacatt agccacacag atgtgggggg agatgtccac agggagagag aaggtgctaa 12240 gaggtgccat atgggaatgt ggcttgggca aagcactgat gccatcaact tcagacttga 12300 cgtcttactc ctgaggcaga gcagggtgtg cctgtggagg gcgtggggag gtggcccgtg 12360 gggagtggac tgccgcttta atcccttcag ctgcctttcc gctgttgttt tgatttttct 12420 agagaggaac ataaaaagca ttcgtccggt tgcgctttcc tttctgtcaa gaagcagttt 12480 gaagaattaa cccttggtga atttttgaaa ctggacagag aaagagccaa gaacaaaatt 12540 gtatgtattg ggaataagaa ctgctcaaac cctgttcaat gtctttagca ctaaactacc 12600 tagtccctca aagggactct gtgttttcct caggaagcat tttttttttt tttctgagat 12660 agagtttcac tcttgttgcc caggctggag tgcaatggtg caatcttggc tcactgcaac 12720 ctctgcctct cgggttcaag tgattctcct gcctcagcct cccaagtaac tgggattaca 12780 gggaagtgcc accacaccca gctaattttt gtatttttag tagagatggg gtttcaccac 12840 attgcccagg ctggtcttga actcctgacc tcgtgattcg cccaccttgg cctcccaaag 12900 tgctgggatt acaggcgtga accaccacgc ctggcttttt tttttttgtt ctgagacaca 12960 gtttcactct gttacccagg ctggagtggg gtggcctgat ctcggatcac tgcaacctcc 13020 gcctcctggg ctcaagtgat ttgcctgctt cagcctccca agtagccgag attacaggca 13080 tgtgccacca cacccaggta atttttgtat ttttggtaga gacgaggttt caccatgttg 13140 gccaggctgg tcttgaactc ctgacctcag gtgatccacc cgcctcagcc tcccaaagtg 13200 ctgagattat aggtgtgagc caccacacct ggcctcagga agtattttta tttttaaatt 13260 tatttattta tttgagatgg agtcttgctc tgtcgcccag gctagagtgc agcgacggga 13320 tctcggctca ctgcaagctc cgccccccag gttcaagcca ttctcctgcc tcagcctccc 13380 gagtagctgg gactacaggc gcccgccacc acacccggct aatttttttg tatttttagt 13440 agagacgggt tttcaccgtg ttagccagga gggtctcgat ctcctgacct cgtgatctgc 13500 ctgcctcggc ctcccaaagt gctgggatta caggtgtgag ccaccacacc cggctatttt 13560 tatttttttg agacagggac tcactctgtc acctgggctg cagtgcagtg gtacaccata 13620 gctcactgca gcctcgaact cctgagctca agtgatcctc ccacctcatc ctcccaagta 13680 attgggacta caggcgcacc ccaccatgcc caccttattt atttatttat ttatttattt 13740 atttattttc atagagatga gggttccctg tgttgtccag gctggtcttg aactcctgag 13800 ctcaagggat ccttttgcct gggcctccca aagtgctgag attacaggca tgagccaccg 13860 tgcccagcta ggaatcattt ttaaagcccc taggatgtct gtgtgatttt aaagctcctg 13920 gagtgtggcc ggtataagta tataccggta taagtaaatc ccacattttg tgtcagtatt 13980 tactagaaac ttagtcattt atctgaagtt gaaatgtaac tgggctttat ttatttattt 14040 atttatttat ttatttttaa tttttttttt tgagacgagt ctcactttgt cacccaggct 14100 ggagtgcagt ggcacgatct cggctcactg caacctctgc ctcccggggt caagcgattc 14160 tcctgcctta gcctcccgag tagctgggac tacaggcacg caccaccatg cctggctaat 14220 ttttgtattt ttagtagacg gggtttcacc atgctggcca agctggtctc aaactcctga 14280 ccttgtgatc tgcccgcttt agcctcccag agtgctggga ttacaggcat gagccaccat 14340 gcgtggtctt tttaaaattt tttgattttt tttttttttg agacagagcc ttgctctgtc 14400 gcccaggctg gagtgcagtg gcacgatctc agctcactac aagctccgcc tcccgggttc 14460 acgccattct tctgcctcag cctcctgagt agctgggact acaggtgccc accaccacgc 14520 ctggctaatt ttttttggta tttttattag agacaaggtt tcatcatgtt ggccaggctg 14580 gtctcaaact cctgacctca agtgatctgc ctgcctcggc ctcccaaagc gctgagatta 14640 caggtgtgat ctactgcacc aggcctgggc gtcatatatt cttatttgct aagtctggca 14700 gccccacaca gaataagtac tgggggattc catatccttg tagcaaagcc ctgggtggag 14760 agtcaggaga tgttgtagtt ctgtctctgc cacttgcaga ctttgagttt aagccagtcg 14820 tgctcatgct ttccttgcta aatagaggtt agacccccta tcccatggtt tctcaggttg 14880 cttttcagct tgaaaattgt attcctttgt agagatcagc gtaaaataat tctgtcctta 14940 tatgtggctt tattttaatt tgagacagag tgtcactcag tcgcccaggc tggagtgtgg 15000 tggtgcgatc ttggctcact gcgacctcca cctcccaggt tcaagcgatt ctcgtgcctc 15060 aggctcccaa gtagctgaga ttataggtgt gtgccaccag gcccagctaa cttttgtatt 15120 tttagtagag acagggtttt gccatgttgg ctaagctggt ctcgaactcc tggcctcaag 15180 tgatctgccc gccttggcat cccaaagtgc tgggattaca ggtgtgaacc accacacctg 15240 gcctcaatat agtggctttt aagtgctaag gactgagatt gtgttttgtc aggaagaggc 15300 cagttgtggg tgaagcatgc tgtgagagag cttgtcacct ggttgaggtt gtgggagctg 15360 cagcgtggga actggaaagt gggctgggga tcatcttttt ccaggtcagg ggtcagccag 15420 cttttctgca gcgtgccata gaccatctct tagccctcgt gggtcagagt ctctgttgca 15480 tattgtcttt tgttgttttt cacaaccttt tagaaacata aaaagcattc ttagcccgtg 15540 ggctggacaa aaaaaggcca tgacgggctg tatggatttg gcccagcagg cccttgcttg 15600 ccaagccctg ttttagacaa ggagcagctt gtgtgcctgg aaccatcatg ggcacagggg 15660 aggagcagag tggatgtgga ggtgtgagct ggaaaccagg tcccagagcg

ctgagaaaga 15720 cagagggttt ttgcccttgc aaatagagca actgaaatct gacaccatcc agttccagaa 15780 agccctgaag tgctggtgga cgctgcgggg tgctccgctc tagggttaca gggatgaaga 15840 tgcagtctgg tagggggagt ccactcacct gttggaagat gtgattaaga aaagtagact 15900 ttcagggccg ggcatggtgg ctcacgcctg taatcccagc actttgggag gccgaggcgg 15960 gtggatcacg aggtcaggag atcgagacca tcctggctaa catggtgaaa ccccgtcttt 16020 actaaaaata caaaaaatta gctgggcgtg gtggcgggcg cctgtagtcc cagctactcg 16080 ggaggctgag gcaggagaat ggcgtgaacc tgggaggtgg agcttgcagt gagccgagat 16140 cgcgccactg cactccagcc tgggcgacag agcgagactc cgtctcaaaa aaaaaaaaaa 16200 aagtaggctt tcatgatgtg tgagctgaag gcgcagtagg cagaagtaga ggcctcagtc 16260 cctgcaggag acctctcggt ctctatctcc tgatagtcag acccagccac actggaaaga 16320 ggggagacat tacagcctgc aagaaaagta gggagattta aaaactgctt ggcttttatt 16380 ttgaactgtt ttttttgttt gtttgttttc cccaattcag aatacagaat acttttatgg 16440 atttgttttt attactttaa ttttgaaaca atataatctt ttttttgttg tttttttgag 16500 acggggtctt actctgtcac ccaggctgag tgcagtggtg tgatcttggc tcacctcagc 16560 ctcgaccccc tgggctcaaa tgattctccc acctcagctt cccaagtagc tgggaccaca 16620 ggtgcgtgtg ttgcgctata caaatcctga agacaaggat gctgttgctg gtgatgctgg 16680 ggattcccaa gatcccagat ttgatggcag gatgcccctg tctgctgcct tgccagggtg 16740 ccaggagggc gctgctgtgg aagctgaggc ccggccatcc agggcgatgc attgggcgct 16800 gattcttgtt cctgctgctg cctcggtgct tagcttttga aacaatgaaa taaattagaa 16860 ccagtgtgaa aatcgatcag gaaataaatt taatgtggaa ataaactgaa caacttagtt 16920 cttcataaga gtttacttgg taaatacttg tgatgaggac aaaacgaagc actagaagga 16980 gaggcgagtt gtagacctgg gtggcaggag tgttttgttt gttttctttg gcagggtctt 17040 gctctgttgc tcaggctgga gtacagtggc gcaatcacag ctcactatag cctcgacctc 17100 ctggactcaa gcaatcctcc tgcctcagcc tcccagtagc tgggactaca ggcgcatgcc 17160 accatgcctg gctaatttta aatttttttt tttctctttt ttgagatgga atctcactct 17220 gtcgcccagg ctggagtgca gtggcgtgat ctcggctgac ggcaagctcc gcctcccagg 17280 ttcactccat tcgcctgcct cagcctccca agtagctggg actacaggcg ctgggattac 17340 aaacccaaac ccaaagtgct gggattacag gcgtgagcca ccgcacccgg cctgttttgt 17400 ctttcaatag caagagttgt gtttgcttcg cccctacctt tagtggaaaa atgtataaaa 17460 tggagatatt gacctccaca ttggggtggt taaattatag catgtatgca aaggagcttc 17520 gctaatttaa ggcttttttg aaagagaaga aactgaataa tccatgtgtg tatatatatt 17580 ttaaaagcca tggtcatctt tccatatcag taaagctgag gctccctggg actgcagagt 17640 tgtccatcac agtccattat aagtgcgctg ctgggccagg tgcagtggct tgtgcctgaa 17700 tcccagcact ttgggaggcc aaggcaggag gattcattga gcccaggagt tttgaggcga 17760 gcctgggcaa tgtggccaga cctcatctct tcaaaaaata cacaaaaaat tagccaggca 17820 tggtggcacg tgcctgtagt ctcagctact caggaggctg aggtgggagg atcactttga 17880 gccttgcagg tcaaagctgc agtaagccat gatcttgcca ctgcattcca gcctggatga 17940 cagagcgaga ccctgtctct aaaaaaaaaa aaaccaaacg gtgcactgtt ttcttttttc 18000 ttatcaattt attattttta aattaaattt tcttttaata atttataaat tataaattta 18060 tattaaaaaa tgacaaattt ttattactta tacatgaggt aaaacttagg atatataaag 18120 tacatattga aaagtaattt tttggctggc acagtggctc acacctgtaa tcccagcact 18180 ttgggaggcc gtggcgggca gatcacatga gatcatgagt tcgagaccaa cctgaccaac 18240 atggagagac cccatctcta ctaaaaatac aaaattagcc ggggtggtgg cgcatgcctg 18300 taatcccagc tactcgggag gctgaggcag gagaatctct tgaacccggg aggcagaggt 18360 tgcggtgagc caagatcgtg cctttgcaca ccagccaagg caacaagagc gaaagtccgt 18420 ctcaaaaaaa aagtaatttt ttttaagtta acctctgtca gcaaacaaat ttaacccaat 18480 aaaggtcttt gttttttaat gtagtagagg agttagggtt tataaaaaat atggtaggga 18540 agggggtccc tggatttgct aatgtgattg tcatttgccc cttaggagag agctctgtta 18600 gcagaatgaa aaaattggaa gccagattca gggagggact ggaagcaaaa gaatttctgt 18660 tcgaggaaga gcctgatgtt tgccagggtc tgtttaactg gacatgaaga ggaaggctct 18720 ggactttcct ccaggagttt caggagaaag gtagggcagt ggttaagagc agagctctgc 18780 ctagactagc tggggtgcct agactagctg gggtgcccag actagctggg gtgcctagac 18840 tagctgggta ctttgagtgg ctccttcagc ctggacctcg gtttcctcac ctgtatagta 18900 gagatatggg agcacccagc gcaggatcac tgtgaacata aatcagttaa tggaggaagc 18960 aggtagagtg gtgctgggtg cataccaagc actccgtcag tgtttcctgt tattcgatga 19020 ttaggaggca gcttaaacta gagggagttg agctgaatca ggatgtttgt cccaggtagc 19080 tgggaatctg cctagcccag tgcccagttt atttaggtgc tctctcagtg ttccctgatt 19140 gttttttcct ttgtcatctt atctacagga tgtgactggg aagctctggt ttcagtgtca 19200 tgtgtctatt ctttatttcc aggcaaagga aaccaacaat aagaagaaag aatttgagga 19260 aactgcgaag aaagtgcgcc gtgccatcga gcagctggct gccatggatt gaggcctctg 19320 gccggagctg cctggtccca gagtggctgc accacttcca gggtttattc cctggtgcca 19380 ccagccttcc tgtgggcccc ttagcaatgt cttaggaaag gagatcaaca ttttcaaatt 19440 agatgtttca actgtgctct tgttttgtct tgaaagtggc accagaggtg cttctgcctg 19500 tgcagcgggt gctgctggta acagtggctg cttctctctc tctctctctt ttttgggggc 19560 tcatttttgc tgttttgatt cccgggctta ccaggtgaga agtgagggag gaagaaggca 19620 gtgtcccttt tgctagagct gacagctttg ttcgcgtggg cagagccttc cacagtgaat 19680 gtgtctggac ctcatgttgt tgaggctgtc acagtcctga gtgtggactt ggcaggtgcc 19740 tgttgaatct gagctgcagg ttccttatct gtcacacctg tgcctcctca gaggacagtt 19800 tttttgttgt tgtgtttttt tgtttttttt tttttggtag atgcatgact tgtgtgtgat 19860 gagagaatgg agacagagtc cctggctcct ctactgttta acaacatggc tttcttattt 19920 tgtttgaatt gttaattcac agaatagcac aaactacaat taaaactaag cacaaagcca 19980 ttctaagtca ttggggaaac ggggtgaact tcaggtggat gaggagacag aatagagtga 20040 taggaagcgt ctggcagata ctccttttgc cactgctgtg tgattagaca ggcccagtga 20100 gccgcggggc acatgctggc cgctcctccc tcagaaaaag gcagtggcct aaatcctttt 20160 taaatgactt ggctcgatgc tgtgggggac tggctgggct gctgcaggcc gtgtgtctgt 20220 cagcccaacc ttcacatctg tcacgttctc cacacggggg agagacgcag tccgcccagg 20280 tccccgcttt ctttggaggc agcagctccc gcagggctga agtctggcgt aagatgatgg 20340 atttgattcg ccctcctccc tgtcatagag ctgcagggtg gattgttaca gcttcgctgg 20400 aaacctctgg aggtcatctc ggctgttcct gagaaataaa aagcctgtca tttcaaacac 20460 tgctgtggac cctactgggt ttttaaaata ttgtcagttt ttcatcgtcg tccctagcct 20520 gccaacagcc atctgcccag acagccgcag tgaggatgag cgtcctggca gagacgcagt 20580 tgtctctggg cgcttgccag agccacgaac cccagacctg tttgtatcat ccgggctcct 20640 tccgggcaga aacaactgaa aatgcacttc agacccactt atttctgcca catctgagtc 20700 ggcctgagat agacttttcc ctctaaactg ggagaatatc acagtggttt ttgttagcag 20760 aaaatgcact ccagcctctg tactcatcta agctgcttat ttttgatatt tgtgtcagtc 20820 tgtaaatgga tacttcactt taataactgt tgcttagtaa ttggctttgt agagaagctg 20880 gaaaaaaatg gttttgtctt caactccttt gcatgccagg cggtgatgtg gatctcggct 20940 tctgtgagcc tgtgctgtgg gcagggctga gctggagccg cccctctcag cccgcctgcc 21000 acggcctttc cttaaaggcc atccttaaaa ccagaccctc atggctacca gcacctgaaa 21060 gcttcctcga catctgttaa taaagccgta ggcccttgtc taagtgcaac cgcctagact 21120 ttctttcaga tacatgtcca catgtccatt tttcaggttc tctaagttgg agtggagtct 21180 gggaagggtt gtgaatgagg cttctgggct atgggtgagg ttccaatggc aggttagagc 21240 ccctcgggcc aactgccatc ctggaaagta gagacagcag tgcccgctgc ccagaagaga 21300 ccagcaagcc aaactggagc ccccattgca ggctgtcgcc atgtggaaag agtaactcac 21360 aattgccaat aaagtctcat gtggttttat ctactttttt tttctttttc tttttttttg 21420 agacaaggcc ttgccctccc aggctggagt gcagtggaat gaccacagct caccgcaacc 21480 tcaaattctt gcgttcaagt gaacctccca ctttagcctc ccaagtagct gggactacag 21540 gcgcacgcca tcacacccgg ctaattgaaa aatttttttt tttgtttaga tggaatctca 21600 ctttgttgcc caggctggtc tcaaactcct gggctcaagt gatcatcctg cttcagcgtc 21660 cgacttgttg gtattatagg cgtgagccac tgggcctgac ctagctacca ttttttaatg 21720 cagaaatgaa gacttgtaga aatgaaataa cttgtccagg atagtcgaat aagtaacttt 21780 tagagctggg atttgaaccc aggcaatctg gctccagagc tgggccctca ctgctgaagg 21840 acactgtcag cttgggaggg tggctatggt cggctgtctg attctaggga gtgagggctg 21900 tctttaaagc accccattcc attttcagac agctttgtca gaaaggctgt catatggagc 21960 tgacacctgc ctccccaagg ctttcataga tcctctctgt acattgtaac cttttatttt 22020 gaaatgaaaa ttcacaggaa gttgtaaggc tagtacaggg gatcccgcat accgttctcc 22080 tccttttccc cgttgtgagg acagtgcact gtattcactt tcaacatcca aggtctgtgt 22140 tgagagggtg agttgtgcgg cccagcttgc cccaagcccg tcttgccatc acgaaggatt 22200 tcctgactca gctgaatcta gctcaacaaa gcaaaggact aactaagctg cagattttct 22260 ctccgctggg cttagcctac attatttaca cctgttttca gctggatggg accaaactgg 22320 ggccttgact tctggggttt ccacgtgatc cccaaagagg agacatccat tcattcactc 22380 aggtatttgc ttgtgcacct actgtgcgcc aggtgccaga tccaggaatt gaagcccagg 22440 aacaactctt gcagtgagct ccccgggttt ttgttttctg aacggtggga agacaggtca 22500 gcaaatagcc atgcacgtct gcacatgtgt ggctggtgtc tgcaggagta ccgagaagac 22560 ggtgagctct gccctggatg gcaacaggaa agggcatccc tgtgcagctg tttgtcctgg 22620 cacaggtggc aggctgccag cgggaccagg aagggaaggg gaggatgcac aggtcggagg 22680 gaacggaacg ggcactgcag gtgcgctctg cgatgtgagg aaggaagcaa aggctggttc 22740 cgggatgatg tcggagaagc cttgcagcct agggcactgc ccattccacg ttacccagtg 22800 agtcaaagcc tcccagaaag acatttagtc actcaaagcc agtgcaggtc tcagctttgt 22860 ccggggagga actttcactc tagaaaacac gaactcattt ccctttgagg aagttgtttc 22920 tccaggatat catttccagc caccatccag gatgctgggc aggtgctgca gtgcccaagg 22980 cacggctgcc gaagaagctt gtcccttaga aaccccttgt ggcctcggag gcgcctgcct 23040 gcctccctga gaatggaacc ctgttgggcc gccaggctcg ctgggcaggt gctggggaag 23100 gctgggtcac cgtgctgagc ccctcacagg cctgggagtt gtgcttgggg aggagagctc 23160 ccagctcttt ggctgcctcc caatcatggc cacatctcac aaacaatacc actgtccacg 23220 aaaaatgaaa aggtgcctgg ttctaaccca tggccccaac catgaaagag cccttagaat 23280 gtgggggttt gactcgaaca gtggctttga gtctcccagg ggggattagt gtcctaatgc 23340 cctgagttaa tgaattgact tgttggacag ggaaactcag tgaggttcat tttctgtggg 23400 gggacgtttg tcaaatgctg tgaaatcagt tgtagcatac gcgacgctca gctgctccga 23460 cagtgactca gccacggctc cagctgcttc cccagccctg tagtggaggt ggcagatggt 23520 gtcatcagcc tggcgcagag ggctgtgccc actggcatca caagggccag gcctgctggt 23580 cctccagcca ctggatccag gtagttacat atgggtttaa aagaagagag gcagggccag 23640 ttgcggtggc tcatgcctgt aatcccagca ctttgggaag ccgaggtggg tgatcatttg 23700 aggttaggag ttcaagatca gcctgaccaa catggcgaaa cccagcctcc actaaaaata 23760 caaaaaaatt agctgggcat agtgctgggt gcctgtagtc ccagctactc aggaggctga 23820 ggcaggagaa ttgcttgaac ccggaaggca gaggttgcaa tgagtcagga tcatgccact 23880 gcactccagc ctgggcaaca gaacgagact ctaaaaaaaa aagatcaata aataaaataa 23940 aaataagaga ggcagggtgg gagtattact tgaggccagg agtttgagac cagcctgggt 24000 aacaaagcaa gaccctgtct ctaccaaaat aataatttaa aaaattaccc gggaatggtg 24060 tgacatgcct gtggtcccag ctactctgga ggctgaggtg ggaggaacac tcgcacatag 24120 gaagttgagg ctgcagtgag ccgtgatcac accactgcac cactctagcc tgggtgacag 24180 agcaagacct catctctggg gaaaaaaaaa aaaagaagag gcttggaagc cacattgttt 24240 tttgtcactt ataactagag tttcgtccat caaaagccca ttctgcactg atttcagtga 24300 taggggtctg atgctggctt ggaagagggc ctgacagctt agagacaggc ttggagttcc 24360 aagttgatga aagaacgatg aataatgaaa aataatgtgt tgttctaaag tagtgccttt 24420 tcatactgag ctagggtata atttgggtcc atttcaaggg aaatatacta gcagaattca 24480 tcaaagtagc ccctcgaaga ctggtgcctg ctgcctacgg gacaatttaa tcagtggttc 24540 cagctgcaca tctagagttg ggaacactga acccaggctt tctcatgcag atggggtgtg 24600 gattgctaag gtggctgtct cctagcgctg cagcatgagt gaaacacgtg tccattctac 24660 agagacgcgg ctccgtgatg ctgaaacctc cttctttttt tttttttttg agacggagtc 24720 ttgctctgtc gcccaggctg gagtgcagtg gcgatatctt ggctcactgc aacctccgcc 24780 tcctgggttc atgcaattct cctccctcag cctcctgagt agctgggact acaggcgcgt 24840 gccaccatgc ctggctaatt tttgtatttt tagtagagac agggtttcac cgtgttagcc 24900 aggatggtct cgatctcctg acctcgtgat ctgcctgcct cggcctccca aagtgccggg 24960 attacaggcg tgagccactg caccccgctg aaacctcctt ctagataaca gcggcgttaa 25020 gcattttttt ttttttttga gatagagtgt tgctctgttg cccaggctgg agtgcagtga 25080 tgcgatctcg gctcactgca acctccacct cccaggttca agcaattctt ctgcctcagc 25140 ctcccgagta gctgggacta caggcacacg ccaccaggcc cagctaattt ttgtattttt 25200 agtagagacg gggtttcagt atattggcca ggctggtctc gaactcctga cctcatgatc 25260 cacccgtctc agcctcccaa agtgctggga ttacaggcgt gagccactgc acctggccaa 25320 aacctcctcc tagataacag tggcgttaag catttttttt ttttttgaga tggagtcttg 25380 ctctgttgcc caggctggag tgcagtggtg tgatctcagt tcactgcaac ctctgcctcc 25440 cgggttcaag tgattcttct gcctcaggct cctgagtagc tgggataaca ggcatgagcc 25500 accactccca gctaattttt gtatttttag tagagacagg gttttgccat gttggccagg 25560 ctggtctgga actcctgacc tcaagtgatc ctcccacctc ggcctcccaa agtgctgaga 25620 ttacaggcgt gagccactgc acctggcctt tttttgtttt ttaagacagg gtctcactct 25680 gttgatcaca gccacagctc actgcagcct caacctcctg cctgggttca agcaatcctc 25740 ccaccttggc ctcccaggta gctgagacca caggcacaag ccaccatatc tggccctacg 25800 taagctttat gtgggtgcaa taacagatct caaaccagct ctcagctcaa gagaagggga 25860 agctgggcac agtggctcac gcctataatc ccagcacttt gggaagccga ggcaggagga 25920 tcacttgaac ccaggagttc gagaccagcc tgggcaacat agggagaccc ctgccctccc 25980 tgtctctgaa aaaaaaaaaa aaaaaaaaag aaaggagagg ctgggcttgg tggctcacac 26040 ctgtaatccc agcactttgg gaagcccagg caggaggatc acttgaaccc tggagtttga 26100 gtccagcctg ggcaacatag ggagaccttg tctctaaaaa aataaataga gtgagagaga 26160 gaaggggaag tcaccgggag gacacacatg gagcacgcag cccaaatggg gctcctctgt 26220 tctccctgca gagtcagttc gtacctttca catgcacaaa ggtgttgatc caaccgaagc 26280 aatattgatt cttgttatat tgctttattg tggggtcagt gtcagagtac cacgagtttt 26340 catcacgcac cgttctttcc ccagctgcag tgtgtttagg gggggaacga ggccccaccc 26400 cctatcccta tcgcctctgc ctttataacg gctgctactc tctgagcacc tgttgagttc 26460 tttcaccttc cagatctaat gtgctatccc cacccctaga gaacagggct gctggatgcc 26520 acatggctcc cagagagggg ctgtggtcag ggaagcccca gctccaaggg ggctggaaaa 26580 ccccagagct gcccacgtgc ggcaacacag tctggtgctg caggtgtgag gacggctaca 26640 aaatacctga gccattctgt cactctgtct gaactctgtt tgaaatattg tttcaataac 26700 tgctaggctg gtttttcctt cctgactata ttcctcaaac caacaagagc ctagcagagg 26760 aaagcatggc caaaacgccc caagaagaga gccttggctt cacctccaag ggccaccatc 26820 cgggaggatg tcctcagacc tctgatcccc tctctgcagg ctctgcccag ccctgtgtgg 26880 caacccagag gaagcctccc cttcgtttga gatttaaccc cagaccttag gcgatggctg 26940 cccagcctgt cccttccgcc tgtgtggctg cccacgcggg cgttgctcat ggggctagtc 27000 ctgggtggat gggtgggggc ctctcgccgg ctcctctgcc tcccaccccc actggcaccc 27060 cacgcctgtc ctagaaggtt ctttctgcct gttttctccg tgagtgactg gacaggcaga 27120 ggccggcctt gctggagggg gcatttgtaa ttatgagtga atccaaaaca aggttttttc 27180 cttccgcagc cccccgcccg gctgtggggc ccagccactg cacttcaccg gatgccgtct 27240 ggttggtcct caggactgat acagaccagg accccagggc cagcccgtgc caggctccta 27300 tgcttccagg agcacgggtg ggtggtcctg ctgcctggcc ggccatcctc ctggggtcgg 27360 tctctggccg atcctccctc ctcctctcaa gccctgcaca gcccggccag gcaggtgcat 27420 cttgtttggc tgctgaggag ccgggggttc agggaaatta aggaacgtgc ccagggaccc 27480 ggggccagcc cgtggggacg ctgggattgg agcccaagcc ccaggttcgc cgcgcggctc 27540 tcgacttcct ctcctttccc ccaggggcga gctcagcgac cgcagagagg tggggtcgat 27600 ctccctgcga ccccaggggg cccgcgaggc cagtgcgcgg gcaggagcgg ggacgtgctc 27660 agaagagccg ggcgccgccg cgcccgcccg ccccccgtcc cccggctccc ggctccgcgc 27720 gccccccgcc gcccccgggg ccctgctacc cccgacccgt ccccacccgc cggccgcccc 27780 catggcccgg ctgggcgcgc tgctcctggc cgccgccctg ggtgcactgc tcagcttcgc 27840 gctcctggcc gccgcggtcg ccagcgacta ctggtacatc ctggaggtgg cggacgccgg 27900 caatggcagc gcctggcccg ggcgcgcaga gctgctctcc tcgcactcgg ggctctggcg 27960 catctgcgaa ggtaaccggc caccgcgccg gccctcctcc ctccgcgacc tcgtccctcc 28020 gacaccccct taaccccgcc ctgctcgtgt tgccccgcca gacccccttc caggacccct 28080 ctcttgcatc ccgctctgcc ccagggtgtc tctccgctcc ctccccatca ccctccgtct 28140 tcccccaaaa ctgacagccc aagggctaca ggagggaggg agcccagttc ggggcccctc 28200 acagccggag gagggggctg tggggcgaca gtgggggagg gaagcctaga ggtgtgtagt 28260 tggggggcct catccaagtc accaggggtt gtttcttgat cacgctcccc ggggtttggg 28320 cctggcagcc ccttgtcccc gtccctgtca ggcactgtca gagctgttca ccccacacct 28380 cctgatgccg cgggggcagg ggttccaaat gtgtacagag gcttcagagt ccggggagag 28440 agaaggggat cccagcaggc tggagggtcc acagggcccc ctccgttccc cccagctccc 28500 tcctccggag ctggggccag cctggggagc ttccccttca cagcgcgagg gctggcaggg 28560 caggggtgtg tgtgtgagtg agcatgtgtg tgcatctgaa tatgtgtgca tgtgctgaac 28620 atgaacatgt gtgagcacct ggctgtgtat gtaaatatga atatgtgagt gtgagtgtat 28680 gtagttgtgt gtgcatgtga atatgagtgt gtgagcatgt cagtgtgcat gtgtgtgcat 28740 gtgagagtgt gtgggcatgt atatgagtga gtgcatgtgt gggtggtgca catgtgctgg 28800 tggcttcctc agtgcaactg gggaggagtt aggagccttg tgttcatcca acagactgcc 28860 taactgtgct ccaaagacct cctgacatgc acctgtgtgc acgtgtgcac acgcctgtgc 28920 ctatgcaggt ggctctgcac gcgtgtgaga accagagagt atgtatgccc acatgacacg 28980 agtcaggaag attccagagc gaggcttccc aggagcccgt tttgtacacc ctttttcctt 29040 tcaggcaaag cctgagttcc acacacaaac gcattacaag gacccctgcc tgagggactc 29100 tgagggggcc tccatggagc gtttgaaagt ttaaacatgc acctgtgcag gcataacttg 29160 cacgtgaaaa taaacaaggt gaaggctggg cccggtggcc cacgcctgta atcccagcac 29220 tttgggaggc cgaggcgggt ggatcacgag gtcaggagat cgagaccaca gtgaaacccc 29280 gtctctacta aaaatacaaa aaattagccg ggcacggtgg cgggtgcctg tagtcccagc 29340 tacttgggag gctgaggcag gagaatggcg cgaaaccggg aggcggagct tgcagtgaac 29400 cgagatcgcg ccactgcact ccagcctggg gtgacagagc gagactccat ctcaaaaaaa 29460 aaaaaaagaa aaagaaaata aacaaggcta aaggtcttgg gccttttcat cccacttgga 29520 gtcccagccc tgagtttcag cagaagagaa gctggcaggg ccctgtggtg ccagggggtc 29580 ccctgggctc gggtaggctg ctgggtgcac cacagcgtcc aggccccagg cttcgaggcc 29640 tatgtttccc agggcagaac ggctgcatcc cgctggtcga cccttttgcc agtgagagcc 29700 tggacgtctc cacctcggtg cagcacctca tctgtgagtc ctgggtgggg ccacctcccc 29760 atcctttcca aatattcagg caaggcagat cccagccatc cccatcccca tcccgcagca 29820 ctgcttccac tgcccctgcg tttccaagag gacgtttcca cgcagacctg tcccagtgct 29880 gtgctgctgt ccctaaccac aggtgcccag ctcccagcct atcctgtttt cccctgtctc 29940 agtttccctc tcagtggtga tggctcatcc ctttgttatt ggggaagcca ggcagctccc 30000 agcttggctg gatcctgcgg gccttgcaga ctcctggctc cccatttagg actcgattct 30060 tccagatggc ctgctgtcta cctggctggc accttccacc tggcgggttg ggggacatgt 30120 gaggcctggg gatgggggct gggagtgttc tggggacgcc tcccctcctg gccttaggaa 30180 gcccctgcca gagtcagagg gggccactgg gagggtccag tggtgtccac agagatgggc 30240 gtcagccgct tttcctgaga agacgaagca ccacgtcact gtcctccggc agacaagtgc 30300 tgaagggccc acctggacca gaattctcac ctgagccccc tttcctgcag tgctgcaccg 30360 tgcagtcatt gtggtcctgc ccctgagcct ggtccttctc gtgtgtggct ggatctgcgg 30420 cctgctcagc tccctggccc agagcgtgtc tctgctgctt ttcaccggct gctacttcct 30480 gctggggagt gagtctgggg ccctggggga atggctccaa agatgggagc tgggccacag 30540 gtcccgggag tggggtgctg cctctcctgt tgccctcgtc ccctgctccc ttctgggcgg 30600 gtgctgagtc tggcgatgga gccgtggcag gcagctccct gtggttccag aaggtaccca 30660 tgtatatttg ttctcacgtt gctataaaga aatgcctgag actgcgtaat ttataaagaa 30720 aagaggttta ggccgggagc agtggctcat gcctgtgatc ccagcacttt

gggaggctga 30780 ggtgggtgga tcatctgagg tcaggagttc aagaccagcc tgaccaacat ggtaaaaccc 30840 catctttact aaaaacacaa aaattagctg ggcttataaa gaaaagaggt ttaattggct 30900 catggttctg catgctgtag aggaagcatg atgcttggct tctggggagg cctcaggaaa 30960 atgacaatca caggcggaag gccaaggcag ggagccagca tttcacatgg ctgggacagg 31020 aggaagagag tagggaggtg ttacacactt tttttttttt ttgagatgga gtttcgctct 31080 tgttgcccag gctggagtgc aatcgcatga tctcgactca ctgcaacctc cgcatcctgg 31140 gttcgagcaa ttctcctgcc tcagcctcct gagtagctgg gattacaggc atgcgccacc 31200 acacccagct aattttgtat ttttggtaga gacggggtct ctccatgctg gtgaggctgg 31260 tcttgaactc ctgacctcag gtaatccacc tgcctcagcc tccctaagtg ctgggattat 31320 aggtgtgagg caccgttccc agctgggtgc tacatagttt tttttttttt ttttttgaga 31380 cggagtctcg ctct 31394 40 24915 DNA Homo sapien 40 ttggttcttt gaaaagatga accaaattgg caaaccttta gctacaggaa gaaaaaggtg 60 agaagacaca aataactaaa atcataaagg aaagtgtaca tattaccacc aaacttacag 120 aaataaaaag gattataata ctgtgaacaa ttgtatgtca acaaattaga taacttagat 180 gaatagaaaa gctgaacaga cctataacaa gtaaagagat tcaatcagta atcaaaacat 240 tccaacaaag aaaagtccag gagtagatca cttctctggt gaataatatc caacatttaa 300 agaattaaca ctgttccttt tcaaactctc aataaataga cctgagagaa cactctctaa 360 ctcattctat taagctagta ctctgatacc aaggcagata atgacatcac aagaaaagca 420 aattacagat attgcacacc catgtttata gcagcacttt tcacaatagc caagaggtgg 480 aagcaaccca aatatctatc aacaggtgaa tggataaaaa aaatgtgtta tctacataca 540 atggaatatc attcagcctt aagaggaagg aaatcctgtc aaatgctaca atgtggatga 600 accttgaggt cattatccta aatgaaataa gccagtgaca gacaaatact gtatgattcc 660 acttacatga ggtatattaa ggagtcaaat tcctagaaac agaaagtaga gtggtgttta 720 ccaggggctg gggacagagg gaaaaggcca attgtttaat gggcatagag ttatagtttt 780 gcaaggtgaa aacgttttgg agatctgttt cacaactatt tgaatatgtt tcacactact 840 aaactgtact tttgaaaatg gttaatatgg taagttttat gttatatgct tttaccacta 900 taaaaaaatt gcagaccagt atcccttacg aatatagata caaaagttct caaaaagggc 960 cgggcaccgt gactcatgcc tgtaatccca gcactttggg aggccgaggt gggtggatca 1020 tgaggtcagg agttcaagac catcctggcc cagatggtga aaccccgtct ctactaaaac 1080 tacaaaaatt agccaggtgc agtggcaggc atctgtaatc ccagctactt gggaggctga 1140 ggcaagataa ttgcctgagc tggggtagca gagtttgcag tgaattgaga tcatgcaact 1200 gcactccagc ctgggtgaca aagtgacact ccatctcaaa aaaaaagaat ccgtctcaaa 1260 aaaaaaaatt ctcaaaaact actagtaaac ccaaaccaac agcatattaa aaggattata 1320 taccattacc acatgaggtt tatcccagga atgcaagggt agctcaacat aagaaagtca 1380 attagtataa tatgccacat tagtaaaaca agggaaaaag acaaacattt catttcaatt 1440 gagcagaata ggcattttat tccctaataa aaaccagcag aaaactggga atagaaggga 1500 acttcctcaa cttgataaag ggtataatga aaaacccaca gctaacatca agcaacaaca 1560 acaaaataga taaattggat ttcatcaaaa ttaaaaactt ttgggcatca aagaacattg 1620 taaagaaagt aaaaagacaa tttacagaat ggaagaaaat atttgtaaat catatatctg 1680 ataaagattt aacatacaga atatataaag aacttctaca accccacaac aaaaagaacc 1740 cagttaaaaa aagtactgat caaaggactt gaacagacat ttctcaaaag aagatataca 1800 aatagccaac atgcagttga aaatatgctc tacaccatta gttattaggg aaatgcaaat 1860 caaaatcaca atgagatacc atttcacatc tactaggatg gcaataataa tataataata 1920 atacagaaaa taacaagtgt tggcaaggat atggaaaaac ttaaatcctt taacattgct 1980 agtgggaatg taaaataatg gagccattat ggaaggtagt ttagagattc ctcaaaaagt 2040 taaagaagaa ccatatgacc tagcaatcct gcttctaggt atatatccca aataatttaa 2100 agactcagat acttgtacac caagtataca ccaagtgtgc tgtttcatcg tagcgctatt 2160 aaccatagcc aaaaagtaga aacaactcaa ttgtccataa atggataaac aaaatgtagt 2220 tatacatatc tttaattatt actcagctat gaaaaggaat gaagttctga tatgtgctac 2280 aacatgatga ttcttgaaat aatgctaagt gttttaaaat aatgtttgaa aaaacactaa 2340 atgaaataag ccagacacaa gtaaaaagac aatctataga atgggagaaa atatttgatt 2400 tttcaggggc ttgggagatg ggggaattag gtgttactgc ttaatggaaa gtttctgatt 2460 gtggttatga aaaagttttg gaaatagatg gtagtgatga ttacacaata ttgtgaatat 2520 aattaatagt cactgaattg tatatataac atagttaaaa tggcaaattg tatattatat 2580 gtatcttaac caccttaaaa gaacccccct caaaaagaat attaatactt gacagtcttc 2640 accttcccca caacaaaaag tcacattggt cttcattagg ggactaaatc tgtagaataa 2700 attacagata attcctgtag tttattaagt tggactctct ggaagcaatc agggtagcag 2760 ttcttaagta aataattctc tttatgtatt tttatgtata gagagaggga gagacagagt 2820 ctcactgttg cccaggctgg tctcaaactc ttggcctcat gtgatccttt cacctggcct 2880 cccaaagcac tgggatttca ggtgtgagcc accacacctg gcccttgcct ttatgtctta 2940 agtggggctc tttaaggtct taaaaggtga atttttcaag tgctgagaaa attaaagtag 3000 aaaagcttag aagacactgg gtctgtgagg tagaggacac ctaagccctt ttggccccca 3060 tgttccagct gatagccaaa aggtagcgat agatgtgaaa ggaggaggtt ctgctgccag 3120 ctaaacccca atattccagg acctatggta agactttgag gacaccatct agtccagtac 3180 tttgttctca gatctgattg aacaagtcca ggtgcttcag ataatcgctt cttgtgacaa 3240 cttcaggttg tgccattctt tactccctga aaggaatatt aaagtggaaa acctcaagta 3300 gtattgcatt aagaatgagc tagtgtaccc tcttctaggt gcagaaagta gagttgacag 3360 tgtaggcatt gttaggcttc catgaggatt tcttttgaaa agatgttccc tgcttaaaaa 3420 ataaatgaca aatttagagt attctcagag ttcaaaagaa aaagtttatt ttccccctat 3480 tttctatgtt ggcaaatggg ccacataaag gtgcagttct gttcatttaa gcttttggag 3540 tattgcaaca ggtacctcaa agttggggaa atgttacttg attttgaaaa gcatgaggca 3600 taggaggtaa aagatgacac caaaaagcta acctaaatca acttaagagg gatacaggct 3660 catggtttgt tagtggtcag agttatagaa tgtaggcata gtgcagctgt ggtgtttctc 3720 tctgtttctt catcattccc aggcacacta aatttcataa acaactttat tttcatagag 3780 tgactcttgc ctggggatta agggtactcc ctaggaacct aagggaatga gtaaaatgac 3840 ccccacagga agacagggct actctccctg gtgtgagaat gacttcatca atttgtaacc 3900 caggccgact aaatatatca atcatgtgtt gtttttataa cagctagaaa ctgggaagaa 3960 tagagttcat aaggttttca gtattgttac ctcacaaaat aatccttcag aaattccaat 4020 tcaaaacata gaaggagtct attgtttgtt tcatattgct tattttgtta cattactctg 4080 ttcttcctta gctagcaact ttgagccccc ataggctatg ctaattaggc tctttattta 4140 tttttttgag acacagtctc ttccagcctg gagtgcagtg gcgtgatcat ggctcactgc 4200 agccttgacc tcctgggctc aagggatcct cctgcctcaa cctcctgagt agctgggatt 4260 gcaggtgtga gctactgtat ccagccctag gctcactata ttacagagcc cagaaacact 4320 cagtgtaatt ccaaggctct ttaagactgt cactggctca aggatccaaa tccaggcctc 4380 tgactaaaac atacttagaa tggctcattc tctcactccc ttcaagtgtt gctcaaatgt 4440 tacctattca gtgctatctt actccctatt taaaactgca cccatgatct cacctctgac 4500 actccacatc cctctttctg gttttatttt tctcaatagc gcttatatca tctaatgtac 4560 tatatatttt acttcattct cttgtttatt atctgtatcc cttccatgat gacagggatt 4620 tttgtctgtc ttgttctttg ttgtagctgt aacacctaga tcagcacctg gcacatagtg 4680 cctgcatata agacatgctt aatatatatt ttgatggacg atatttcgaa tgaaaattta 4740 cctacataac cacatcaagt aaaattgaat ttggactcta ggacaactgc ttgggtccaa 4800 atcctggttc agcgacttat ggctgttgac cttgggcaag ttatataacc tctctctgcc 4860 tcagttttct catgtgtaaa atgagactaa taataattgt tcttattata tagactttgt 4920 tgtgatgatg aacatgaatt ggtattataa agcactttga aaaatacctg gcacattgga 4980 aacaccatgt attaataaat gttaacttgt agtggtagaa ggagttgcat ttaactgtat 5040 ctgagttagt gctatgtttt ataaataaag catttattta gattttatga tatccccctt 5100 gtgtgtagga gccaatttgt atgaaaataa ggatgacagg agtctgatgt gtgagttagg 5160 ccctttaata attcaagaaa gtctgtacaa ttaagcatct tatgaaaaat agttcaatgg 5220 aaagtataat tcaagatcgc atatatttct atgaaagcct accgttactc ctttataata 5280 cttatcacaa taatttttac ttattcaata tgtcttctat gtctagattc taagctaagc 5340 agattcaaag ttccatggga acaaaataga tttgtcttgt tcaccactaa aactcatgtc 5400 atatttagca catggtaggt gcttggttca tatttggtta aaggaatatg tattcttggc 5460 tactcagaat acgaggagcc tatactgaac aagttatctt tttatccacc agaagcaaga 5520 attcattact tccacatcta aaaatgttat ctcacccctc ttttcttcta tccggttttt 5580 gtttactaga actcatcatg actgctttta cctcatggca tctgttgttt gcttttccat 5640 ctgtatctta acttttgccc atcattacta gctaatgact ttctctgtgt attgaagtca 5700 aattctcaac agagacccta cctggtttta attaatgaga attattggtc ttggacagag 5760 ttctcctatc attggctgct ctcaagtata gaaattgact gcccttgggt caggtggcca 5820 tttttgacct aatcagatat ggctagggtg atctggttca gaataagttt atctgtttgt 5880 aaagaacaac aaggacttat tccctcagta gatcttctgg gtttaagaaa gaatggggaa 5940 agctggcttt ctgaggctgg ggctgcccag catgccccaa attacaatca ttaatatttg 6000 ctatgtgtta gagggataca gtgtggggta tagatataag accctatcct tgccctcata 6060 tagctcacaa actagaggag gcaggcaagc agattgaata tagagtaatg gtattgctgg 6120 agttgaacac tttgtgccat gggaacatgc aggacaaaca ctcagtctgg actgggattg 6180 tgaaataacc tccatcttta ctgaggtttc tctgttccaa gtatatgtta aagagaggaa 6240 gttctgtgtc acaatgatgc ccttcagtat ccttttttta aaaaaaatct tgtttaaaag 6300 tttctaaatt aaaacccagt gaaggcattg agcatatact cctttaccta aaagacattt 6360 tgttttcaag tttaggaaga gtactgttct ttgactttca ggtgttttct ccagtgaata 6420 tagtgagtgt gccagaatca tttgataaga acagttacac tacctgtaat ctgagagatg 6480 tggctttgaa actgggctga catttaggga gcacttcctt gcctgtcctc cttcagagtt 6540 ctactactcc ttcatttcac agcagtccta actactaatt gtttaagctc cctctttcat 6600 tcctggaaat cttgattaca tggcagggag gacttctcgc aatccatcat tctaatggaa 6660 tcttcaatga ggatatatat ggatgagaga agccctctgg aacactatgc tttatccatg 6720 actattgatt tccaccattt gcttcaaact ttcatcttct gccactgtct tgcatactct 6780 tcttttccag tcaattctcc agtaaaatct gttccagaca atagcttgaa ggttggtcat 6840 cgggcctgaa ggcaatatac accaccctgc atattagcac ccactgagtg agagtataac 6900 cctactctag atgaccatcc aatgctgaag atgatgatgc tattcttggt atttcgattc 6960 agacccaaga tgagcctgag agtttgtatc catttgagga aattcttaat cacctaaata 7020 tctctaccaa tagtgttcat cattaaatac ttgctgtctg gcacatagtg cttttttaaa 7080 attatttttt gttcaataaa tgaaagcagt tttagtggat cggttcaaga ggagtctttg 7140 tattagcttt gtttagtgtg gagtttggaa ctgaagaagc atttaataat taacatttta 7200 aagtgtagac tacggtatat cagacctttc tggaacactc cctagacact gaaatgcggc 7260 aaagacactg cattggaaac ctccgaaaga gtctgtatcc ttggccagca gatggcattc 7320 ttatactata gtttagagaa agcaagtagc aaaaggtaaa gaagcacttc ttaatgatga 7380 agtgaccatc tacctccttt ttcccttccc catcaccaca taaccttatc tcacttccat 7440 tttatcccag gcaactatct tttccatcca tccattcacc cttctttagg tgcctagaga 7500 tgtcttgcta ccattctctc tagttgctca taggaaaata tcttttgtac ttattaatag 7560 tcaatccata gaaataggac aagccacata attttcaggg ccctgtgtaa aatgaaaatg 7620 cagaagttgt tcaaaaagta ttgagaattt taggacagta agaaaagagc attaaaccaa 7680 gcacagggcc ctctgagcct gcacaagcca tacacccatg aaaccagcca tactttataa 7740 tgtaaatatt tccctcttcc catcctacct tccattgttc taatgtcctg tcccctgtga 7800 cccacaccaa aaaggctgct taagaaagga aggaatcact aaatgtcatt cagacatcat 7860 agaatcttag cactgaaaga aaatttggag atctagttca atcctctcat tttaaagatg 7920 attaaactac attccaaaga gatgaagaga ctctcccaaa gtccccagct agttatgtca 7980 cagactggac tggaactaag tattctcatc taccaggcca aggctcactc tctcacgcag 8040 actccatgag aggtatttta agaaaatagt tttcccatct actcaggata tactttgccc 8100 cattttctct agaggagaag ggtacatgtt tatgttacat ttgagtacca ggtatatgcc 8160 aggcattaca ctcgatgttt tatacataat acctcaattg caacaagctc agaaaatcat 8220 tacattttcc ccatttttca aatgagaaaa atagagaatc agaacttgaa ttttagtcag 8280 taaatgggca gacaagaatt tgggcaagtc tgtgattcta aaacccattc tttttcacca 8340 catcattcct aaattttagg aaagctgagt cagcctgtgt ttcctgaaca ttggtcttgt 8400 ttttggtcag ctctgggtga tttggggact ctttccaggc tatgttcttc aaatttacca 8460 ggtttgctac tgccttggtg tctttgctcc agggtgtttc ctctgcttga aacactcttc 8520 ccccagatat ttcatgaaaa acaggaccac gtgttggaga ggtaacaggg catctgatca 8580 tatagggtct tacaggtcat tgtaagaaca ttggcttttt cctctgagtg aaaatggaag 8640 ccattgcagc agtttgagca gataagcgat gtgatcagat ttagattttt aaaggatcct 8700 tctggctgct gtgtagaaaa agagactaaa ggggtggagt agggaaggta gaagttcttg 8760 ggctttttag agagttgtaa cagtaatcca ggaaaaagat aatggtggct catactaagg 8820 tgatagcagt ggaagtgatg ggaagtggtt ggattctgga gttatatgtg tatgtaagta 8880 ctatattttt aacttcttgt tatggaaaat ctcaaataca tacagaagta cagagatgaa 8940 tataatgaat tcctgtgttc ctattcagtg aacctatcat atgttattat gtgtcaggca 9000 ctttgcaaca gctgcaagaa ttgccaactt gtatcaatct tcctccccaa ccctagattg 9060 gggagaaagc aatttgaagc aaatcccaga taccatattg catgtgtaaa tatttcagct 9120 tctactactc caactgcttc tgactgcccc gacattctgc tatctaccct atggttactg 9180 cttgttcata gtttcaggta ctcatgactt ctacttattg tctgctctat ttgtcctctt 9240 taagcctttt tccttgctat caactactaa ctgtgtactt ctcaaattca aactccctag 9300 aaagaggttc ttgcaggttc agttagttgt catttttcct tctacacaga gctcatgatc 9360 tggccaaatt gtggtagatt ggctgctctt gggtcaggga ccctcttttg gccaagcagg 9420 gtggtgtaat gacaaggttg gttttcccga aaaacggttg ttgaaatgga agtcacttaa 9480 caaataatag gctgttctcc aatactaata aatagtggaa atttaattct agaaaggata 9540 taaatggtga aaaaagtcag cctgcaatga gactagaaat agataagtgt ctaatcactc 9600 aacaccatta ttttacagtc tgacctgact catttagagt gctattcttg ggtgccactg 9660 aggaattaag gacatttttt ttcttaatat atttttgttt ataacaggct gagtaatagc 9720 atagatcata atgatctagg ctgaaagtca agacctacat ttaattcttc tgttcatcat 9780 ggactttgta caatattaga caagctaata aacttctttg tgcctttgtc tctctcagtt 9840 tttgtattga gattaatacc tgccttttcc tgattcatat atggtagaca cataagatta 9900 gagggataaa aatacattga gcttttatga agagaagcat gtgaaaatct aaataattac 9960 tatttcctat gtgaagattt ttatgaaatt ataaaatgaa catagattta aggtattttt 10020 atataaattt aaggagtaca agtatagttt tgttacattg atatattgca tagtggtaaa 10080 gtctgggctg taaccatcac cccctgaata atgtacattg tacccattaa gtaaattatc 10140 atcgccccct gccaaccctc caactcttcc aagtctccag tgtctattat tctacactct 10200 ggtgtgtcca tgtgtataca ttatttagct cccacttata agtgagaaca cgcagtattc 10260 agctttcaaa gattacatac tctctattca ttttcatcag gtactcaaac atttttcttc 10320 ctacatttta atatatatgt catatgtata taccacttag aacagtgtgt ggcaagtagt 10380 aagaactatg taaatgttaa gctgttatct acatcagtgt gaaaaagaat ttgtcaaaag 10440 tctatagagt tgcagctgca aatgcttaaa aattgtaccc cctctccatc ccctaatatg 10500 taccctgcta aaatacaatt atgtgaagca cataaaattt tacgtcatgt gaaaatatga 10560 ataaaaggaa actttttgag ccctggaaaa ttggcaatgt atgtgtttat gtgaaaaaac 10620 ccacaacaac aaaaaagaag ggggtggtta aaaataacat tgataactga tatctccatt 10680 gttctcaaag acaagttagt ggacaggctg catcagaatc accaggaaat tttctagaat 10740 tcttggttct attagcgatt ctgatataat agaataacag tggagattaa gaatgcagaa 10800 attgtttaag tttctcagat gatcctgatt ttcagccaag cgtgggaatg actgatgtgt 10860 acaaaaatgt aatacaataa tttaatttaa tgtagtacat catttatttc ctatcatcct 10920 attcaaagtg gtatgtattg ggaaatatct gcccccaggg aagagagctg agaggatatc 10980 tatcaaaatc agaatggcaa ttatctctgg attatgagtt atggaaatac ttattttaca 11040 tttgtgtttc ttatttctaa gttttctggt tgagcatata ttatttttat aataatagat 11100 attacttaca accagtgcca gaaaattatt cacaaccagt tcaagatgtt aaagactcat 11160 atgcagccta tgcttttagt ttatcaaatg taaagaaaaa aaacaacttg agaggctgag 11220 gcaggaggat tgcttgaggc caggggttca agaccagcct gggcaatata gcaagacccc 11280 atctctaaaa aaaataaaaa gaaaacaaaa caaaaattag ctgggcactg tggaatgtac 11340 ccatagtcct agctactcag aagcctgagg caggaagatt gcatgagtcc aggagtttga 11400 ggttacagtg agctatgatc tctccactac attccagcct gagtgaaaga gtaagaccct 11460 ctctctacga aaacagtctg tcaattcata ttcacatact ttttctttta aaaggcaagg 11520 ctacatataa agcaacatgg acgcaatatt tatttttgtt ttttaaaatg tcacaaattc 11580 ttttagtaaa tatatatctt agagaatata aaacaaatta aatcctaatt agcttttact 11640 tcttttgctt tggcatgaat ggaaatatac caatgtttat aaaaggacca atcaatcagt 11700 aaccttatac ttgatggggt gaaataaata gttctggtac aatatagatc ttctgtccaa 11760 tttgtatttt ggactgtgcg ccaagaataa tgctcaatcc tttttaaaga tccttttggc 11820 ttctactcct tcatacacat aagtctgaaa ggtgttaaca aacagaagaa tttatcttta 11880 aggtttacat ctaagttaag aaaaagtagt attatagttt tatactatat gagtttatac 11940 tatttttata ttatatattc atatatatta tatgagtatg agtttataca attttttctt 12000 gtacttgata gcaagattta tacagatatg ggatacagcc attttaaaac acatgttggt 12060 ttgtagtcat ttatattttc agttaaaata ggcattgatt atttgacata tataagttgt 12120 ctttagtaaa taggcatcag aaaatagcta tacaatattt ttaaaatcag taagatttat 12180 gagaaaagaa gtagtcagtt tactgaagat ctggctcagc agtgacaaaa attattgttt 12240 tgtagtaatt tttgcctttt gaaaatagct ataaatttga caactcacct ggactagttc 12300 atcacctata atttctcgga cagtattcag ttcgtttcca ttgtctgtcc gtttgaattt 12360 tccaataagt ttatttccct caaggctcca ggtcccctac ataataataa taataataat 12420 aataataata ataatggcat ttattagggt cttacacatg tcaggcactg ttctgagttc 12480 tgtagacaca ctttttcatt taatcttcat ggtgacccta tgaaactgat actattatct 12540 ctactttgca gaagaggaga ctgtaaaatg gcacagtgat tcacctaaag tcacagagtg 12600 aggattgaac ctaggccatt gggctacaga gtatgtgttg ataaccatta tgcttgttct 12660 cttcaataat ttccatacgc tgaattttaa ggcagatgag cagcacttct ttctgaatct 12720 ttcatgttac gtgtccagaa atatagtcat ggttaaaatt agtttcatgg agatgttaac 12780 aactctgtgc ttgttttaat ttgtgtgatt gtggtactaa ttaaagaaag acataactta 12840 tgataaaaca ttcagtagtt aaattgtcat tacaaacatg taatttaaat agaaaaatgt 12900 tgaggctaaa aaaagttttt aaaaaatttg ttgaaaatga tgacttccta aaatgtgtta 12960 tcttaaacat gaaaaggtac actcccaatg acctacaata catcaaatct ttccatttgg 13020 taactcactc atttgttcat ctattcattt cttttattat ttcaacatgt taaacattac 13080 agttaagtta catattaact ctaaaggctt cttttgctgt actgtttaaa aacacagttt 13140 taaatttctt tatgaatagg tctatattca gtcattcaaa agatagtttt ctaattctta 13200 ctgttcaatt cagattcttc acagatgcgt ataaaaataa aaacatattt aaatatcctg 13260 ccaatttgtg caatatataa tgtagacaaa cttcattggc ttcttcagtt agtgaaggag 13320 acctgcatta attaaaccat ccaatgaaat agagcagaaa tcattttaat attgggtaga 13380 aaaatcaaga atgcattgct cataaaaaaa aaaattctta ccctgagttc agttccgtct 13440 gctagattgt aattaaaggt gacaccaagt tcaaaaacaa cttcaatgtt tcgaaaagcg 13500 cttgattctt tgactgtgaa tttatttcct tcttgtgtaa ttgtcagctt caaattgtca 13560 tgagctgcaa gcttcctttt cactatatta acacctgtaa aaggtaagac aatggagaaa 13620 ataaagtcaa atcccatagg aagtgtttat ttttccaagt tatgttttgt ttgtttattt 13680 tgagggtggg aagaaaactc ggtagcattg cctttgcaca agaacattca gattgcttct 13740 acagaagttc aggttcaatc cgatcaagag aactgattaa agttgttttt ccataacttg 13800 agaaaaatta agtagagtac agaattatag aatcttagag ctgagcaacc ttaataagat 13860 taacaaactg ttcatttcag tgttaagtaa atcaaattct agaaatatca aatgaaggat 13920 taaaatgtat attcatatat ttataaggaa gcacatcttt aattccacat atacagtatt 13980 cttttttctt aaatgcccct ttgtttttct tagtggcttt aacattttga actttatagt 14040 tctatttgct tcttgtggca tttctttctg acacaaaaat gagaaaatta gcaaatatta 14100 agccaaaatc actataagaa tctacaactt ttataaattt aaacttagag ttcctaaact 14160 gtaagctata attgatgcag atttttcttt taggggaatg acacaaattt gtttgcctat 14220 cttgtatagt atatgggctg ccagagtatt ggtatcaaat tataaatcag ttaaattaaa 14280 cgccctggag aaaactacac agcttctcaa gattattcca aaactttttt aagttagaag 14340 aaatcagaat taaatctaac

ttattcagcg ctataaattt taagagaacc ttttccatta 14400 ctttcttata tggtctttgt ttttccatct cctagaattt aacattttca gatctggaag 14460 ttatcattac acgctgccat tttcttactg taaacaacaa aaaaagtcat ttttcagtta 14520 aagagtgaag gaaacatttc tggatctttt tggtgtgttt cagagaacag cactcaaaga 14580 atcttttctt ccattagtga gatagtggat tcttcctaat gtaagaaggg agaatatggt 14640 ttccctcctc tgaacatctt ctggatcctc tctaccacat caggagctat ctgtaagcta 14700 tctgtaatct cctagagatt taggagttag aaagaaaaat gtttgtaaga aagcaaagaa 14760 tgagccacaa agaaataaag tctttaccca ttttttccat gaacttgtca tagttttcac 14820 tccggtctac cttccaagtg ctgtcaaacg ccatgatttc agttgagtca gcctctaggc 14880 agctagagat tcaggtctgt ccttgggcga gaatttatta tatttcttat cttgaaccaa 14940 cttcatactg tgatgtggaa gcttaaagtt caggaaatca cctaactact ctatgtcaag 15000 caattaatta attcttattc ttattaattc ttaattctcg ttctgtacat tcctgagatc 15060 ttctgaaatt caactgaatt aaaacatgag aagcatacct attctgtctt aaattacagt 15120 ttgtgggcat acttatttca agaattagaa tgcatgccgt ctgaagattg tttttctaag 15180 ttcaaagtgc agactatgtt ggaggtaata taatttatag catatatcaa ataacatctg 15240 ggaaatgaga ccatgacctt tccctttttc acaacagcaa ttatcttgta aagtaagact 15300 ttatgatgaa atacagttga aaagttaaag ttaataagat tcgttttcta atatgtcttt 15360 ttgcattgtg tttagcattg ccaggagttt ggataaatat cctggcactt tgtagggtgc 15420 atgacacaca ataagtgctc attgattttt gtcttgatcc tgaatggtga taggccactg 15480 agcaaaaatt caagaggtac aaatgaggct ggatggtgta aaaacttgca taaaagaaag 15540 aatgagcttt aaacatctgc catgtgcaga gagaacaaaa tccagtttta gctgtgccat 15600 taattaaaac cactccttca ttttactctc aatgcctctc atccccaaac ccagtagagt 15660 cagaagccac agctcaatta tgtatgtggg gtcagggtat agagggtagc tagaaaggta 15720 caaagaaaag gtcaccatat ctctcctttc cctacttcag gctgccagcc aggaacaggc 15780 caagcttggg gaggaaactt ggtgtgaagt aaagagtttt aattactagt cttaagatgt 15840 ttattactaa aatgagtcta ttattgtgac tgaatgtgac cagataacat cttattaact 15900 aagggtcagg aaagaagctc tagggcttgc ccaagatatt acttagggtc aagggaagat 15960 aaatctaaca gatttgaaca gaactttggg gaacagaatc ccagttttta aattttgata 16020 ttattttata ttttgatttt taaaaatctt ttaaacatgt tagatattgt ttgatttttt 16080 atttcgagtt gcccactttt tattttatta agtaagcact ttaaaaagca aactattttc 16140 tactagctct attatttcat taaaaaagaa aaagaggccg ggcgcggtgg ctcgcgcctg 16200 taatcccagc actttgggag gccgaggcgg gcggatcacg aggtcaggag atcgagacca 16260 tcctggctaa cacggtgaaa ccccgtctct actaaaaatg caaaaaaaat tagccgggcg 16320 tggtggtggg cgcctgtagt cccagctgct cgggaggctg aggcaggaga atggcgtgaa 16380 cccgggaggc ggagcttgca gtgagccgag atcgtgccac tgcactccag cctgggcgac 16440 agagcgagac tccgtctcaa aaaacaaaaa aacaaaaaaa caaaaaaaca aaaaacaaaa 16500 aaaaacaaaa aagaaaaaga gttgcctggt gcagtggttc ttgcctgtaa tcccagctat 16560 tagagaggct gaggcaggag aatcacttca ggccaggagt tcgaaaccag cagtttgagg 16620 ccagcctaag caacataggg agagcctggc tgtaacaatt ataataaaat aaattagcca 16680 ggtgtaatgg cacatgcctg tagtcccagc tacttgggag gctaaggcgg gaagatctct 16740 tgatcccagg agttggagat tgcaatgagt tgtgatcatg ccagtacact ccagcctggg 16800 caacagagag atcccatctc taaaaaataa ataatttttt aaatgtcaaa aaaggaaaga 16860 aaacacatat acacactcat gagttgggga caaaggtcat aatgggaagt cctttacatt 16920 cataatttag ctttactttc aaaattaggt acattgtgat tttttaatct tttttcaaag 16980 aattaaaact gtatcacttg ggagctatca acctaataca ctttctttct ttttttatta 17040 cactttaagt tttagggcac atgtgcacaa cgtgcaggtt tgttacatat gtacacatgt 17100 gccatgttgg tgtgctgcac ccattaactc gtcatttaac attaggtata cctcctaatg 17160 ctatccctac cccctccccc caccccataa caggccccgg tgtgtgatgt tccccttcct 17220 gtgtctaagt gttctcattg ttcaattccc acctataagt gagaacatgc ggtctttggt 17280 tttttgtcct tgcgatagtt tgctgagaat gatggcttcc agcttcatcc atgtccctac 17340 aaaggacatg aactcatcat tttttatggc tgcatagtat tccatggtgt atatgtgcca 17400 cattttctta atccagtcta tcattgttgg acatttgggt tggttccaag tctttgctat 17460 tgtgaatagt gcccctataa acatatgtgt gcatgtgtct ttatagcagc atgttttata 17520 atcctttggt tatataccca gtaatgggat ggctgggtca aatggtattt ctagttctag 17580 atccctgagg aatcgccaca ctgacttcca caagggttga actagtttac agtcccctca 17640 acagtgtaaa agtgttccta tttctccaca tcctctccag cacctgttgt ttcctgactt 17700 tttaatgatt gccattctaa ctggtgtgag atggtatctc attgtggttt tgatttgcat 17760 ttctctgatg gccagtgatg atgagcattt tttcatgtgt cttttggctg cataaatgtc 17820 ttcttttgag aagtgtctgt tcatatcctt cgcccacttg ttgatgtggt tgtttatttt 17880 tttcctgtaa atttgtttga gttcattgta gattctggat attagccctt tgtcagatga 17940 gtagattgca aaaattttcg cccattctgt aggttgcctg ttcaccctga tggtagtttc 18000 ttttgctgtg cagaagctct ttagtttaat tagatctcat ttgtcaattt tggcttttgt 18060 tgccattgct tttggtgttt ttagtcatga agtacttgcc catgcctatg tcctgaatgg 18120 tattgcctag gttttcttct agggtttttg tggttttagg tctaacattt aagtctttaa 18180 tctatcttga attaattttt gtataaggtg taaggaaggg atccagtttc agctttctac 18240 atatggctag ccagttttcc cagcaccatt tattaaacag ggaatccttt ctccatttct 18300 tgtttttgtc aggtttgtca aagatcagat cgttgtagat aagcagcatt atttctgagg 18360 gctctgttct gttccattgg tctatatctc tattttggta ccagtactat gctgttttgg 18420 ttactgtagc cttgtagtat agtttgaagt caggtagcgt gatgcctcca gctttgttct 18480 tttggcttag gattgacttg gcaatgtggg cttttttggt tccatatgaa ctttcaagta 18540 gttttttcca attctgtgaa gaaagtcatt ggtagcttga tggggatggc attgaatcta 18600 taaattactt tgggaggatg gccattttca cgatattgat tcttcctacc catgagcatg 18660 gaatgttctt ccatttgttt gtatcctctt ttatttcatt gagcagtggt ttgtagttct 18720 ccttgaagac gtccttcata tcccatgtaa gttggatttc tgggtatttt attctctttg 18780 aagcaattgt gaatgggact tcactcatga tttggctctc tgtttgtctg ttattggtgt 18840 ataagaatgt ttgtgatttt tgcacattga ttttgtatcc tgagactttg ctgaagttgc 18900 ctatcagctt aaggagattt tgggctgaga caatggggtt ttctagatat acaatcatgt 18960 catctgcaaa cagggacaat ttggcttcct cttttcctaa ttgaatgtcc tttatttcct 19020 tctcctgcct gattgccctg gccagaactt ccaacactat gttgaatagg agtggtgaga 19080 gagggcatcc ctgtcttgtg ccagttttca aagggaatgc ttccagtttt tgcccattca 19140 gtatgatatt ggctgtgggt ttatcataga tagctcttat tattttgaga tacgtcccat 19200 caatacctaa tatattgaga gtttttagca tgaaggttgt tgaattttgt caaaggcctt 19260 ttctgcatct attgagataa tcatgtggtt tttgttgttg gttctgttta tatgctggat 19320 tacatttatt gatttgtgta tgttgaacca gccttgcatc ccagggatga agcccacttg 19380 atcatggtgg ataaactttt tgatgtgctg ctggagttgg tttgccagta ttttattgag 19440 gatttttgca tcgatgttca tcagggatat tggtctaaaa tctctttttt tgttgtgtct 19500 ctgacaggct ttggtatcag gatgatgctg gcctcatgaa atgagttagg gaggattccc 19560 tctttttcta ttgtttggaa tagtttcaga aggaatggta ccagctcctc cttgtacctc 19620 tggtagaatt tggctgtgaa tccatctggt cctggacttt ttttggttgg taagctatta 19680 attattgcct caatttagga gcctgttact ggtctattca gagattcaac ttcttcctgg 19740 tttagtcttg ggaggatgca tgtgccgagg aatttatcca tttcttctag attttctagt 19800 ttatttgcgt agaggtgttt atagtattct ctgatggtag tttgtatttc tgtgggattg 19860 gtggtggtat cccctttatc attttttatt gcatccattt gattcttctc tcttttcttc 19920 tttattagtc ttgctagtgg tccatcaatt ttgttgatct tttcaaaaaa ccagctccag 19980 aattcattga ttttttgaag ggttttttat gtctctatta cactttcaac ttggagggaa 20040 gtagaaaact ttgtttaaag ctgaggactc aacagtctct caggtagttg actggctgtg 20100 gtgatttgtg aactcagaag cctatggata atgaatccaa tctttatttc taggtcagaa 20160 aactacatgt atctggtcac tgaaataaac gtatggtaga gtgaaaagaa catgtgtttt 20220 agaaacaaga cccattgact tgggtttcag tgctgactaa acatacatta ctctgcagaa 20280 tcttcgtcac attacttact caatctctct gagcctcagt tttctcatca ataaaatgaa 20340 gacaataata atacctgata tgtatatttt atgaacaaat tacataaagc acccacctga 20400 aacaacttat agataacagg tcctcaacaa acctttgttt ctctcctaat tctctgagaa 20460 aggaaatctg ggagcaataa caatgtttta gaagcatcct aggtctcaaa ccagtgatat 20520 tttgttaaga aaacccatgt cattctggtg tttatgagaa agtcacctaa aagttactta 20580 ggtattttat gatttgcact agtgatcaac ttgggactgg ctatgccttg gatttgcctg 20640 ttaaggatag tattgcactg tatcaccctc tgggaataca tgtttccact atgtgatctc 20700 atagcaattg aaattaaagt gtctgattca agaaggaagg ttggcaggaa gaaactaaag 20760 tggcttctta ccattttcac catgacctaa cccgtgtctc atggccattt taagcttcgc 20820 agaaggatcc aaataggatc aatataaagc aaatagccct tgggctcaca gaaggctggt 20880 aacaaaataa gcatgttaaa ctttcagtct taaatttatc agtggcagtg acctaattta 20940 accttaggta ggacatcctg ttatctctgt taagtagcat cattagtttt tttttttatt 21000 aatgctcaga ttacattttt aacattacac ttttccttct ccagctaccc aattctgtag 21060 cccctcggtt tttatcactt atctgtagtc catctagaaa ataatatacg gaacttaggg 21120 accaatttct ctacagacct tttctactga tgatatgatt gagccaacca gctaagggca 21180 gacccagccc tttcttttcc attttgataa tattaaaaga cttgagtatt gcagtttggg 21240 ggtcgtgagt ggactaagta tatgtgtgca tgtggatgca gatgctatgg aggtagagct 21300 atagctgtac cctctctctc tgggctctac agtcaacatc acccacggag tggtctggaa 21360 gaagtggaaa tcagcagaaa ctcctgtgga tccctattcc attcctccaa gggaaagtac 21420 aaaccacaat ccttagcatg gtttacaaag ccactactta aatctccagt tgatttttcc 21480 attccctact gtgtactgca agatctagat ctattaaact tcttgcagtc cccaatcccc 21540 tgaatgtcca tgcctctgtt gcttcaggtc tcagcttgga tgctgattgc tcaaagattc 21600 ttgcctcgaa ctatcaagag tgagtcaggc aacccttctt ctcccaggtg taatgacctt 21660 ctaaaggtct cagagtagct cataaaagac aagaacagct gattcatgat aaccaaagga 21720 atattgttat catgaagccc agcgacatca ttagcaaggg caataggatg ttaaaatctc 21780 atctcaaagg aataatgttt tagagatcac aaaaatcctt ttaccccatt gtataataga 21840 agggagtgtt tttgtagagt attattcttt atatatcctt attgtgaaat agcattttaa 21900 ggcatattct aatcatctca gaatttatgt atcctatttt ttgatcttaa gttgtttagc 21960 tttttatatg tcaaaaaata gaggtctcta tcagaaatat atgagagaag gatttgaggg 22020 acagatagaa ggagtaacag gaaagtctta aggttactgt caaatcccta gcagtgaatg 22080 gggaatgaga gagaattctg aagtttgccg acaaagctta tttcattctg ttttaatgat 22140 tagcctctaa attttagaaa tattatgacc tatttaatta ggttttagat tttgtatctg 22200 ggatgactgg ttggttttct ttcaaagaga ttataaatgt acagcagtgt gcaggagaat 22260 gtctaccata gagtggtgag tgtggcttgc taattctcat taataacaaa acagcctaag 22320 aaaacagcca ttttagaaga ttaatgtgtc cattgaatga tcttgcatga agaatttatg 22380 actccttctt agtctgggtt tatcccagaa atgatgagcc actttcaagc aatgtagata 22440 agaggttgtt catctcctat gcccctcata ccacaggtag aaaaagatgg atttgcatta 22500 tcacagctcc ctactgccac aaccaaacca ttatgtttct gcctttttca aaacaaaata 22560 ttgttttctg agaccactcc catttggctg tggtccagcc tacttcatca ttgttatcta 22620 ccatccactc cctctagcat tatcatctac catctatcac tgaaaatctt ggtacttggc 22680 tcaccatcat ctgtgtcctg ccatcatcct gggtgacctc aaagtccatg tggataagcc 22740 acttgtcagt ctggcttcac agctccttaa ccccctcata tctaatgacc tttacttctt 22800 ttatgcttta tctacttaca tccagggctg tgtcctgtga tctgtcatca ttaaagctgc 22860 tccttctgtt gtatttaaca tgccactctg accacaactt tccatgctct cagctccttt 22920 attttattct gcacattagt tattggctgg gagagaaatt ttcttagttg ttgcctctat 22980 ttcctctcaa gttaaagccc cctcctgttt gtttaaattc tttattcaat tgatatcctg 23040 tttccaattt taaaactctc tcactttttc ctgcactgac ctaggtgcta ttaggcatgc 23100 atggtttcta gtcttagagt aattatcagc actccctgga atgacttctg tgtatttcaa 23160 tcagcttcct ccacatttgc gacaatggct gtgcctttag tcaccctcct gtagcctttt 23220 acctttgccc tcagcagaca acctgcacat tacttcacag aggaaagaaa ccatcaaaca 23280 attccctcaa tttatgcctt ctcaattaca aagttaccta ctattacttt ctttactcct 23340 attaattgtt acactcacgt atgaggttgt ttttgcattg ctataaagaa atacctgaga 23400 ctgggtaatt tataaagaaa agaggtttaa tttgctcatg attatgcagg ctatacagga 23460 agcatggtgg catgtgcttc tggggaggcc tcaggaagct tccgatcatg gtggaaggca 23520 aagggggagc tggcacatca catggcaaaa gcaagcgaga gggggaaggt gccacatact 23580 tttaaatgac cagatctcgt gaaaactcac cattgcgagt acagtaccaa cggaatggta 23640 aaccattcat gagaaatctg cccccttgag ccaatcacct cccaccaggc ccaacctcca 23700 acattgggga ttacatttca acatgagatt tgggtgggga caacatcaaa ccatgtcaac 23760 ccacttactc tttcaatgtg tattttaatt cctcctatgg tctaggcact gtgccacatt 23820 ataaacagaa aaatagacac agtttcagtc aagggaaagc aaggcttgaa attgcaatag 23880 tgtgtcacat gtaaagtttt ttttttttct ccctgtttct tcctatcacc ctctctttct 23940 tttttattta tttgcttatt tggatgaggt gggatgtgaa gacgatcaag tctctcccat 24000 tataagacat aaagatacct aaattctgtt gacatttcta gaacctactc aatctttctc 24060 cttctctttg tagccaggct tcttgaaaaa ataatttgta ctttttgtct tcacatgctt 24120 atccttcatt aatacctcaa tctactgcaa catggctttc atattcacca gtccactgaa 24180 actactcact aaggtcatag atgaattttt agttgccaaa cccagtgcac atcttggccc 24240 ttattttatg tcattgtagc attgcatacc attgactctt cttcttcttc ttcttctttt 24300 taatttctcc ttttcttttg ctgacttttt tctttcttga cattcctctt ctctggatac 24360 ttcttttcag gctcttccat aagcaacttt tccttaactg acagatacct taaatgttgg 24420 aattgcatct ttaaatcact ttttattcca tacaatctac ctcgatcatc tttttcattc 24480 tcatgtctta atgttcaaac catatgtctc taaaatttag agatccagcc cagacatctt 24540 tcctactggg taggaaaagt gctgtaatcc cagcactttg ggaggccgaa gtgggcagat 24600 cacctgaggt tgcaagttca agaccagcct ggccaacatg gcgaaatccc gtctctacta 24660 caaatacaaa aattagctag gcatggtgtg cctgtaatcc tagctacttg ggaggctgtg 24720 gcttctcatt cagaagcaga acagaaaatg atgcataatg tctaaaacta tagatgtgag 24780 atatatatac atatatatta ggaataacta gttaagtgag aggtaaaggt ttggggtttg 24840 cttaatttta gaggttatat tcatgttgag tacctgtttc atggcttcat gtaccatcca 24900 tgtaaccagt gattc 24915 41 201 DNA Homo sapien 41 catataggtc gatggatact cactgtcaca tgtgatccag gtctcctccg aggggctggc 60 cagtctcttc tcccatggag atgatgggca ctgccacagc rtgtcaggtc cttttggaca 120 ctgaacattg tccacccaca tgggaatgga catggccttg tctaaagatg cagggttgat 180 tttccctttg tctgcacagc c 201 42 201 DNA Homo sapien 42 aaacatcttg gctgcttcaa agtaaggtca acaggtcctc ctctctgctg agggtcccaa 60 ttcaacatca actgtagcca gttttccatg ggttctacta ytaaactaga aaacatacaa 120 aatagggtga aaatcaaatc attatgttcc aatttccctt tatactgtta gaaaggtaat 180 tttgcaggtt gtccattttc t 201 43 201 DNA Homo sapien 43 ggatgtgact gggaagctct ggtttcagtg tcatgtgtct attctttatt tccaggcaaa 60 ggaaaccaac aataagaaga aagaatttga ggaaactgcg ragaaagtgc gccgtgccat 120 cgagcagctg gctgccatgg attgaggcct ctggccggag ctgcctggtc ccagagtggc 180 tgcaccactt ccagggttta t 201 44 201 DNA Homo sapien 44 ctcataaaaa aaaaaattct taccctgagt tcagttccgt ctgctagatt gtaattaaag 60 gtgacaccaa gttcaaaaac aacttcaatg tttcgaaaag ygcttgattc tttgactgtg 120 aatttatttc cttcttgtgt aattgtcagc ttcaaattgt catgagctgc aagcttcctt 180 ttcactatat taacacctgt a 201 45 23 DNA Homo sapien 45 cagttttcca tgggttctac tac 23 46 23 DNA Homo sapien 46 cagttttcca tgggttctac tat 23 47 25 DNA Homo sapien 47 ttatgaaatg gtacagacaa gtgat 25 48 16 DNA Homo sapien 48 cacggcgcac tttctt 16 49 16 DNA Homo sapien 49 cacggcgcac tttctc 16 50 26 DNA Homo sapien 50 tgttttttcc tttgtcatct tatcta 26 51 18 DNA Homo sapien 51 tccaaaagga cctgacat 18 52 18 DNA Homo sapien 52 tccaaaagga cctgacac 18 53 18 DNA Homo sapien 53 ggctgcagaa tggaattt 18 54 20 DNA Homo sapien 54 cacagtcaaa gaatcaagcg 20 55 21 DNA Homo sapien 55 tcacagtcaa agaatcaagc a 21 56 24 DNA Homo sapien 56 aaattcttac cctgagttca gttc 24

Claims

1. A method of identifying a human having an altered risk for coronary stenosis, comprising detecting the presence of a single nucleotide polymorphism (SNP) at position 101 of SEQ ID NO: 41 or its complement thereof in said human's nucleic acids, wherein the presence of G at position 101 of SEQ ID NO: 41 is indicative of an increased risk for coronary stenosis, or the presence of A at position 101 of SEQ ID NO: 41 is indicative of a decreased risk for coronary stenosis.

2. The method of claim 1 wherein SEQ ID NO: 41 is a segment within the genomic sequence of CD163 gene as represented by SEQ ID NO: 37.

3. The method of claim 1 wherein the SNP is located at position 24287 of SEQ ID NO: 37.

4. The method of claim 1 wherein said human's nucleic acids are extracted from a biological sample therefrom.

5. The method of claim 1 wherein said human's nucleic acids are amplified before being detected.

6. The method of claim 1 wherein the detecting is carried out by using detection reagents comprising the nucleotide sequences of SEQ ID NO: 51, SEQ ID NO: 52, and SEQ ID NO: 53.

7. The method of claim 1 in which the detecting is carried out by a process selected from the group consisting of: allele-specific probe hybridization, allele-specific primer extension, allele-specific amplification, sequencing, 5' nuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, and single-stranded conformation polymorphism.

8. A method of identifying a human having an increased risk for coronary stenosis, comprising detecting the presence of a single nucleotide polymorphism (SNP) at position 101 of SEQ ID NO: 41 or its complement thereof in said human's nucleic acids, wherein the presence of G at position 101 of SEQ ID NO: 41 is indicative of an increased risk for coronary stenosis.

9. The method of claim 8 wherein SEQ ID NO: 41 is a segment within the genomic sequence of CD163 gene as represented by SEQ ID NO: 37.

10. The method of claim 8 wherein the SNP is located at position 24287 of SEQ ID NO: 37.

11. The method of claim 8 wherein said human's nucleic acids are extracted from a biological sample therefrom.

12. The method of claim 8 wherein said human's nucleic acids are amplified before being detected.

13. The method of claim 8 wherein the detecting is carried out by using detection reagents comprising the nucleotide sequences of SEQ ID NO: 51, SEQ ID NO: 52, and SEQ ID NO: 53.

14. The method of claim 8 in which the detecting is carried out by a process selected from the group consisting of: allele-specific probe hybridization, allele-specific primer extension, allele-specific amplification, sequencing, 5' nuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, and single-stranded conformation polymorphism.

15. A method of identifying a human having a decreased risk for coronary stenosis, comprising detecting the presence of a single nucleotide polymorphism (SNP) at position 101 of SEQ ID NO: 41 or its complement thereof in said human's nucleic acids, wherein the presence of A at position 101 of SEQ ID NO: 41 is indicative of a decreased risk for coronary stenosis.

16. The method of claim 15 wherein SEQ ID NO: 41 is a segment within the genomic sequence of CD163 gene as represented by SEQ ID NO: 37.

17. The method of claim 15 wherein the SNP is located at position 24287 of SEQ ID NO: 37.

18. The method of claim 15 wherein said human's nucleic acids are extracted from a biological sample therefrom.

19. The method of claim 15 wherein said human's nucleic acids are amplified before being detected.

20. The method of claim 15 wherein the detecting is carried out by using detection reagents comprising the nucleotide sequences of SEQ ID NO: 51, SEQ ID NO: 52, and SEQ ID NO: 53.

21. The method of claim 15 in which the detecting is carried out by a process selected from the group consisting of: allele-specific probe hybridization, allele-specific primer extension, allele-specific amplification, sequencing, 5' nuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, and single-stranded conformation polymorphism.

22. A method of determining a human's risk for developing coronary stenosis, comprising detecting the presence of a single nucleotide polymorphism (SNP) at position 101 of SEQ ID NO: 41 or its complement thereof in said human's nucleic acids, wherein the presence of G at position 101 of SEQ ID NO: 41 is indicative of an increased risk for developing coronary stenosis in said human, or the presence of A at position 101 of SEQ ID NO: 41 is indicative of a decreased risk for developing coronary stenosis in said human.

23. The method of claim 22 wherein said human's nucleic acids are amplified before being detected.

24. The method of claim 22 wherein the detecting is carried out by using detection reagents comprising the nucleotide sequences of SEQ ID NO: 51, SEQ ID NO: 52, and SEQ ID NO: 53.

25. The method of claim 22 in which the detecting is carried out by a process selected from the group consisting of: allele-specific probe hybridization, allele-specific primer extension, allele-specific amplification, sequencing, 5' nuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, and single-stranded conformation polymorphism.