CA2826522A1 - Genetic polymorphism in pnlpa3 associated with liver fibrosis methods of detection and uses thereof - Google Patents

Abstract

The present invention is based on the discovery of a genetic polymorphism in the PATATIN-LIKE PHOSPHOLIPASE DOMAIN CONTAINING 3 (PNPLA3) gene that is associated with liver fibrosis and related pathologies. In particular, the present disclosure relates to nucleic acid molecules containing the polymorphism, variant proteins encoded by such nucleic acid molecule, reagents for detecting the polymorphic nucleic acid molecules and proteins, and methods of using the nucleic acid and proteins as well as methods of using reagents for their detection.

Description

DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
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GENETIC POLYMORPHISMS ASSOCIATED WITH LIVER FIBROSIS
METHODS OF DETECTION AND USES THEREOF
FIELD OF 'I'HE INVENTION
The present invention is in the field of fibrosis diagnosis and therapy and in particular liver fibrosis diagnosis and therapy, and more particularly, liver fibrosis associated with hepatitis C virus (HCV) infection. More specifically, the present invention relates to specific single nucleotide polymorphisms (SNPs) in the human genome, and their association with liver fibrosis and related pathologies.
Based on differences in allele frequencies in the patient population with advanced or bridging fibrosis/cirrhosis relative to individuals with no or minimal fibrosis, 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 liver fibrosis and for early detection of the disease, for providing clinically important information for the prevention and/or treatment of liver fibrosis, and for screening and ,selecting therapeutic agents. The SNPs disclosed herein are also useful for human identification applications. Methods, assays, kits, and reagents for detecting the presence of these polymorphisms and their encoded products are provided. ' BACKGROUND OF THE INVENTION
Fibrosis Fibrosis is a quantitative and qualitative change in the extracellular matrix that surrounds cells as a response to tissue injury. The trauma that generates fibrosis is varied and includes radiological trauma (i.e., x-ray, gamma ray, etc.), chemical trauma (ie., radicals, ethanol, phenols, etc.) viral infection and physical -trauma.
Fibrosis encompasses pathological conditions in a variety of tissues such as pulmonary fibrosis, retroperitoneal fibrosis, epidural fibrosis, congenital fibrosis, focal fibrosis, muscle fibrosis, massive fibrosis, radiation fibrosis (e.g. radiation induced lung fibrosis), liver fibrosis and cardiac fibrosis.

Liver Fibrosis in HCV-Infected Subjects HCV affects about 4 million people in the United States and more than 170 million people worldwide. Approximately 85% of the infected individuals develop chronic hepatitis, and up to 20% progress to bridging fibrosis/cirrhosis, which is end-stage severe liver fibrosis and is generally = irreversible (Lauer et al. 2001, N Eng J Med 345: 41-52). HCV
infection is =
the major cause of cirrhosis and hepatocellular carcinoma (HCC), and accounts for one third of liver transplantations. The interval between infection and the development of Cirrhosis may exceed 30 years but varies widely among individuals. Based on fibrosis progression rate, chronic HCV
patients can be roughly divided into three groups (Poynard et al 1997, Lancet 349: 825-832): rapid, median, and slow fibrosers.
Previous studies have indicated that host factors may play a role in the progression of fibrosis, and these include age at infection, duration of infection, alcohol consumption, and gender. However, these host factors account for only 17%-29% of the variability in fibrosis progression (Poynard et al., 1997, Lancet 349: 825-832; Wright et al Gut. 2003, 52(4):574-9). Viral load or viral genotype has not shown significant correlation with fibrosis progression (Poynard et al., 1997, Lancet 349: 825-832). Thus, other factors, such as host genetic factors, are likely to play an important role in determining the rate of fibrosis progression.
Recent studies suggest that some genetic polymorphisms influence the progression of fibrosis in patients with HCV infection (Powell et al.
Hepatology 31(4): 828-33, 2000), autoimmune chronic cholestasis (Tanaka et al. J. Infec. Dis. 187:1822-5, 2003), alcohol induced liver diseases (Yamauchi et al., J. Hepatology 23(5):519-23, 1995), and nonalcoholic fatty liver diseases (Bernard et al. Diabetologia 2000, 43(8):995-9). However, none of these genetic polymorphisms have been integrated into clinical practice for various reasons (Bataller et at Hepatology. 2003, 37(3):493-503). For example, limitations in study design, such as small study populations, lack of replication sample sets, and lack of proper control groups have contributed to contradictory results; an example being the conflicting results reported on the role of mutations in the hemochromatosis gene (HFE) on fibrosis progression in HCV-infected patients (Smith et al., Hepatology. 1998, 27(6):1695-9; =
Thorburn et al., Gut. 2002, 50(2):248-52).
Currently, there is no diagnostic test that can identify patients who are predisposed to developing liver damage from chronic HCV infection, despite the large variability in fibrosis progression rate among HCV patients.
Furthermore, diagnosis of fibrosis stage (early, middle or late) and =
monitoring of fibrosis progression is currently accomplished by liver biopsy, which is invasive, painful, and costly, and generally must be performed multiple firnes to assess fibrosis status. The discovery of genetic markers which are=useful in identifying HCV-infected individuals who are at increased risk for advancing from early stage fibrosis to cirrhosis and/or HCC
may lead to, for example, better therapeutic strategies, economic models, and health care policy decisions.
SNPs .=
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. Biochern. 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.
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, site, SNP locus, SNP marker, or marker) 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 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 A synonymous codon change, or silent mutation/SNP (terms such as "SNP", 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 July 2001).
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. .
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.
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 liver fibrosis and related pathologies 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.
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 liver fibrosis, increased or decreased risk of developing bridging fibrosis/cirrhosis, and progression of liver fibrosis. 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).
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 "pharrnacogenomics").
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
The present invention relates to the identification of novel SNPs, unique combinations of such SNPs, and haplotypes of SNPs that are associated with liver fibrosis and in particular the increased or decreased risk of developing bridging fibrosis/cirrhosis, and the rate of progression of liver fibrosis. 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 liver fibrosis and related pathologies.
Based on the identification of SNPs associated with liver fibrosis, 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, for example, novel SNPs in genetic sequences involved in liver fibrosis and related pathologies, isolated nucleic acid molecules (including, for example, DNA and RNA
molecules) containing these SNPs, 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 liver fibrosis based on the presence or absence of one or more particular nucleotides (alleles) at one or more SNP sites disclosed herein or the detection of one or more encoded variant products (e.g., variant mRNA transcripts or variant proteins), methods of identifying individuals who are more or less likely to respond to a treatment (or more or less likely to experience undesirable side effects from a treatment, etc.), 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, methods of using the novel SNPs of the present invention for human identification, etc.
In Tables 1-2, the present invention provides gene information, transcript sequences (SEQ ID NOS:1-14), encoded amino acid sequences (SEQ ID NOS:15-28), genomic sequences (SEQ ID NOS:43-50), transcript-based context sequences (SEQ ID NOS:29-42) and genomic-based context sequences (SEQ ID NOS:51-58) 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:1-14), amino acid sequences (SEQ ID NOS:15-28), genomic sequences (SEQ ID NOS:43-50), transcript-based SNP
context sequences (SEQ ID NOS: 29-42), and genomic-based SNP context sequences (SEQ ID

NOS:51-58) are also provided in the Sequence Listing.
In a specific embodiment of the present invention, SNPs that occur naturally in the human genome are provided as isolated nucleic acid molecules. These SNPs are associated with liver fibrosis and related pathologies. In particular the SNPs are associated with either an increased or decreased risk of developing bridging fibrosis/cirrhosis and affect the rate of progression of liver fibrosis. As such, they can have a variety of uses in the diagnosis and/or treatment of liver fibrosis and related pathologies. 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 that is encoded by a nucleic acid molecule containing a SNP disclosed herein.
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 that 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.
Various embodiments of the invention also provide 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 liver fibrosis by detecting the presence or absence of one or more SNP alleles disclosed herein.

In another embodiment, a method for diagnosis of liver fibrosis and related pathologies by detecting the presence or absence of one or more SNP alleles disclosed herein is provided. =
- 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 liver fibrosis and related pathologies.
An aspect of this invention is a method for treating liver fibrosis in a human subject wherein said human subject harbors a SNP, 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.
Another aspect of this invention is a method for identifying an agent useful in therapeutically or prophylactically treating liver fibrosis and related pathologies in a human subject wherein said human subject harbors a SNP, 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.
Another aspect of this invention is a method for treating liver fibrosis and related pathologies in a human subject, which method comprises:
(i) determining that said human subject harbors a SNP, gene, transcript, and/or encoded protein identified in Tables 1-2, and (ii) administering to said subject a therapeutically or prophylactically effective amount of one or more agents counteracting the effects of the disease.
Various embodiments of the invention provide a method for determining whether a human has an increased risk for developing liver fibrosis, comprising: a) testing nucleic acid from said human to determine the presence or absence of a polymorphism in gene TLR4 at position 101 of the nucleotide sequence defined by SEQ ID NO:53 or its complement; and b) correlating the presence of C at position 101 of SEQ ID NO:53 or G at position 101 of its complement with said human having said increased risk for developing liver fibrosis. The human may be homozygous or heterozygous for said C or G. The method may be performed in an automated fashion and the correlating may be performed using computer software. The human may be a hepatitis C virus-infected human.
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.

The Sequence Listing provides the transcript sequences (SEQ ID NOS: 1-14) and protein sequences (SEQ ID NOS:15-28) as shown in Table 1, and genomic sequences (SEQ ID
NOS:43-50) as shown in Table 2, for each liver fibrosis-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:29-42) and genomic-based context sequences as shown in Table 2 (SEQ
ID NOS:51-58). The context sequences generally provide 100bp upstream (5') and 100b downstream (3') of each SNP, with the SNP in the middle of the context sequence, for a total of 200bp of context sequence surrounding each SNP.
10a 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 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 gene/transcript/protein information includes:
- a gene number (1 through n, where n = the total number of genes in the Table) - a Celera hCG and UID internal identification numbers for the gene - a Celera hCT and UID internal identification numbers for the transcript (Table 1 only) - a public Genbank accession number (e.g., RefSeq NM number) for the transcript (Table 1 only) - a Celera hCP and UID internal identification numbers for the protein encoded by the hCT transcript (Table 1 only) - a public Genbank accession number (e.g., RefSeq NP number) for the protein (Table 1 only) - an art-known gene symbol - an art-known gene/protein name - Celera genomic axis position (indicating start nucleotide position-stop nucleotide position) - the chromosome number of the chromosome on which the gene is located - 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 - alternative gene/protein name(s) and/or symbol(s) in the OMIM entry 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.
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:
- transcript sequence (Table 1 only) (corresponding to SEQ ID NOS:1-14 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 TUB codes within the transcript.) - the encoded protein sequence (Table 1 only) (corresponding to SEQ ID
NOS:15-28 of the Sequence Listing) - the genomic sequence of the gene (Table 2 only), including 6kb on each side of the gene boundaries (i.e., 6kb on the 5' side of the gene plus 6kb on the 3' side of the gene) (corresponding to SEQ ID NOS:43-50 of the Sequence Listing).

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).
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:1-14), protein sequence (SEQ
The SNP information includes:
- 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:15-28; the genomic-based SNP context sequences in Table 2 are provided in the - Celera hCV internal identification number for the SNP (in some instances, an `11DV"
number is given instead of an "hCV" number) - SNP position [position of the SNP within the given transcript sequence (Table 1) or within the given genomic sequence (Table 2)]
- 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 a disease, "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 (FIGMD) public database, "HapMap" = SNP observed in the International HapMap Project public database, "CSNP" = SNP observed in an.
internal =
Applied Biosystems (Foster City, CA) database of coding SNPS (cSNPs)) (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 beingzgfided) - Population/allele/allele count information in the format of [populationl(first_allele,countisecond allele,count)population2(first allele,countlsecond =
allele,count) total (first_allele,total countlsecond_allele,total count)].
Thednformation 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, "id" = Indian, "mex" = Mexican, "am" = "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 ("inder) 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 "I"); "-"in the count field indicates that allele count =
information is not available]. For certain SNPs from the public dbSNP
database, population/ethnic information is indicated as follows (this population information is publicly available in dbSNP): "IIISP1" = human individual DNA (anonymized samples) from 23 individuals of self-described HISPANIC heritage; "PAC" = human individual DNA (anonymized samples) from 24 individuals of self-described PACIFIC RIM
heritage; "CAUCl" =human individual DNA (anonymized samples) from 31 individuals of self-described CAUCASIAN heritage; "AFR1" = human individual DNA
(anonymized samples) from 24 individuals of self-described AFRICAN/AFRICAN
AMERICAN heritage; "Pl" = human individual DNA (anonymized samples) from 102 individuals of self-described heritage; "PA130299515"; "SC_12_A" = SANGER 12 DNAs of Asian origin from Corielle cell repositories, 6 of which are male and 6 female;
"SC_12_C" = SANGER 12 DNAs of Caucasian origin from Corielle cell repositories from the CEPH/UTAH library. Six male and 6 female; "SC_12_AA" = SANGER 12 DNAs of African-American origin from Corielle cell repositories 6 of which are male and 6 female; "SC_95_C" = SANGER 95 DNAs of Caucasian origin from Corielle cell repositories from the CEPH/UTAH library; and "SC_12 CA" = Caucasians - 12 DNAs-from Corielle cell repositories that are from the CEPH/UTAH library. Six male and 6 female.
NOTE: For SNPs of "Applera" SNP source, genes/regulatory regions of 39 . 10 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 ti-p to 78.
(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) - 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 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]
- Protein coding information (Table 1 only), where relevant, in the format of [protein SEQ ID NO:#, amino acid position, (amino acid-1, codonl) (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, s`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.

Table 3 provides sequences (SEQ ID NOS: 59-82) 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 4 and 5 during the course of association studies to verify the association of these SNPs with liver fibrosis.
Table 3 provides the following:
- the column labeled -Marker" provides an hCV identification number for each SNP
site - 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") [NOTE:
Alleles may be presented in Table 3 based on a different orientation (i.e., the reverse complement) relative to how the same alleles are presented in Tables 1, 2, 4, and 5].
- the column labeled "Sequence A (allele-specific primer)" provides an allele-specific primer that is specific for an allele designated in the "Alleles" column - the column labeled "Sequence B (allele-specific primer)" provides an allele-specific primer that is specific for the other allele designated in the "Alleles"
column - 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.
All primer sequences are given in the 5' to 3' direction.
Each of the nucleotides designated in the "Alleles" column matches or is the reverse complement of (depending on the orientation of the primer relative to the designated allele) the 3' nucleotide of the allele-specific primer (either "Sequence A" or "Sequence B") that is specific for that allele.

Table 4 provides results of statistical analyses for SNPs disclosed in Tables 1-2 (SNPs can be cross-referenced between tables based on their hCV identification numbers), and the association of these SNPs with early and late stages of fibrosis (minimal or moderate to severe fibrosis). The statistical results shown in Table 4 provide support for the association of a SNP
with minimal to severe fibrosis. Table 4 shows the association of this SNP
with fibrosis is supported by p-values <0.05 in a genotype association based on ordinal (ord) (major homozygotes, heterozygotes and minor homozygotes) or dominant/recessive (dom) modes (major homozygotes vs. heterozygotes and minor homozygotes) of inheritance.
Table 4 presents statistical associations of the SNP with the trial endpoint.
The column labeled -Marker" presents the SNP as identified by its unique identifier number and its mode of association with the fibrosis stage endpoint. The column labeled "Gene symbol"
presents the common gene name of the gene containing the SNP. The data obtained from the individual sample sets are presented in two groups of columns. The groups of columns labeled "Stanford Samples" means the samples were obtained from patients at Stanford. This sample set contains samples obtained from patients that had extreme cases of fibrosis.
62% of the patients had a minimum fibrosis stage (level 0-2) (controls) and 38% had a severe fibrosis stage (level 3-4) (cases). The groups of columns labeled "UCSF Samples" means the samples were obtained from a study performed at the University of California, San Francisco. These samples were obtained from patients that had a variety of stages of fibrosis including minimal, moderate and severe stages of fibrosis (46%, 26% and 28% respectively), which reflects the distribution of fibrosis patients in clinics. The column labeled "OR's indicates the Odds Ratio, an approximation of the relative risk for an individual for the defined endpoint associated with the SNP. ORs less than 1 indicate the risk allele is protective for the defined endpoint, and ORs greater than 1 indicate the risk allele increases the risk of having the defined endpoint. The columns labeled -LCL" and "UCL" give the lower and upper confidence levels of the ORs.
The column labeled "p val" indicates the results of either the chi-square test (Dom) or the Fisher Exact test (Ord) to determine if the qualitative phenotype is a function of the SNP
genotype.

io Table 5 provides results of statistical analyses for SNPs disclosed in Tables 1-2 (SNPs can be cross-referenced between tables based on their hCV identification numbers), and the association of these SNPs with mild or severe fibrosis stage. The statistical results shown in Table 5 provide support for the association of these SNPs with bridging fibrosis/cirrhosis. For example, the statistical results provided in Table 5 show that the association of these SNPs with is supported by p-values <0.1 in an allelic association test in the University of California (UCSF) and the Virginia Commonwealth University (VCU) sample sets in at least one of the following strata; all patients (A), Caucasian only (C), or other than Caucasian (0). Additional SNP association with bridging fibrosis/cirrhosis is seen in the sample sets obtained from the University of Illinois, Chicago (UIC) and Stanford University (Stanford).
Table 5 presents statistical associations of SNPs with trial endpoints. The column labeled "Marker" presents each SNP as identified by its unique identifier number. The column labeled -Risk allele" presents the risk allele for each of the identified SNPs. The risk allele may also be presented in the Tables 1-2 as the reverse complement of the allele presented in Table 4. The column labeled "Strata" indicates the group of individuals in which the association was observed. "A" indicates that the association was observed in all individuals, "C" indicates that the association was observed in Caucasians, "0" indicates the association was observed in other than Caucasians. The groups of columns labeled "UCSF"
means the samples were obtained from the University of California, San Francisco. Among the 537 patients from UCSF, the samples had minimal (stage 0-1, 52%), moderate (stage 2, 23%) or severe (stage 3-4, 25%) fibrosis. The groups of columns labeled "VCU" means the samples were obtained from the Virginia , Commonwealth University. These samples were obtained from 483 patients that had minimal (stage 0-1, 18%), moderate (stage 2, 34%) or severe (stage 3-4, 48%) fibrosis.
.. The groups of columns labeled "UIC" means the samples were obtained from the University of Minois, Chicago. These samples were obtained from 115 patients that had minimal (stage 0-1, 29%), moderate (stage 2, 30%) or severe (stage 3-4, 41%) fibrosis.
The groups of columns labeled "Stanford" means the samples were obtained from Stanford University. These samples were obtained from extreme cases, 62%
contained .. minimal (stage 0-1) fibrosis and 38% contained severe (stage 3-4) fibrosis.
The column =
labeled "CT AF" gives the control allele frequency of that SNP in that stratum. The column labeled "CASE AF" gives the case allele frequency of that SNP in that stratum.
The column labeled "OR" indicates an approximation of the relative risk for an individual for the defined endpoint associated with the SNP. ORs less than 1 indicate the .. risk allele is protective for the defined endpoint, and ORs greater than 1 indicate the risk - allele increases the risk of having the defined endpoint. The column labeled "p_2tail"
indicates the p-value generated by the Fisher Exact test (allelic association) to determine if the qualitative phenotype is a function of the SNP genotype and is either a protective or risk allele in the UCSF sample set. The column labeled "p_ltail" indicates the p-value .. generated by the Fisher Exact test to determine if the qualitative phenotype is a function of the SNP genotype in the VCU, UIC or Stanford samples and the OR is going in the same direction as the OR for that SNP in the UCSF sample.
DESCRIPTION OF THE FIGURE
Figure 1 provides a diagrammatic representation of a computer-based discovery .
system containing the SNP information of the present invention in computer readable form.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides SNPs associated with liver fibrosis and related pathologies, 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 liver fibrosis-associated SNPs disclosed herein are useful for diagnosing, screening for, and evaluating predisposition to liver fibrosis, including an increased or decreased risk of developing bridging fibrosis/cirrhosis, the rate of progression of fibrosis, and related pathologies in humans.
Furthermore, such SNPs and their encoded products are useful targets for the development of therapeutic agents.
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 o 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.
Thus, the present invention provides individual SNPs associated with liver fibrosis, as well as combinations of SNPs and haplotypes in genetic regions associated with liver fibrosis, polymorphic/variant transcript sequences (SEQ ID NOS:1-14) and genomic sequences (SEQ
ID NOS:43-50) containing SNPs, encoded amino acid sequences (SEQ ID NOS: 15-28), and both transcript-based SNP context sequences (SEQ ID NOS: 29-42) and genomic-based SNP
context sequences (SEQ ID NOS:51-58) (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 liver fibrosis, methods of screening for compounds useful for treating disorders associated with a variant gene/protein such as liver fibrosis, 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.
The present invention provides novel SNPs associated with liver fibrosis and related pathologies, as well as SNPs that were previously known in the art, but were not previously known to be associated with liver fibrosis. 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 liver fibrosis (e.g., for diagnosing liver fibrosis, 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 "FIGMD" = SNP observed in the Human Gene Mutation Database (HGMD).
Particular SNP alleles of the present invention can be associated with either an increased risk of having or developing liver fibrosis and related pathologies, or a decreased risk of having or developing liver fibrosis. SNP alleles that are associated with a decreased risk of having or developing liver fibrosis may be referred to as "protective"
alleles, and SNP alleles that are associated with an increased risk of having or developing liver fibrosis may be referred to as "susceptibility" alleles, "risk" 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 liver fibrosis (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 liver fibrosis (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).
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.
. = 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
Tables 1 and 2 provide a variety of information about each SNP of the present invention that is associated with liver fibrosis, including the transcript sequences (SEQ ID NOS:1-14), genomic sequences (SEQ ID NOS:43-50), and protein sequences (SEQ ID NOS:15-28) 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:29-42 correspond to transcript-based SNP context sequences disclosed in Table 1, and SEQ ID NOS:51-58 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.
Isolated Nucleic Acid Molecules The present invention provides isolated nucleic acid molecules that contain one or more SNPs disclosed Table 1 and/or Table 2. Isolated nucleic acid molecules containing one or more SNPs disclosed in at least one of Tables 1-2 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.
As used herein, an "isolated nucleic acid molecule" generally is one that contains a SNP of the present inyention 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.
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.
For full-length genes and entire protein-coding sequences, a SNP flanking sequence can be, for example, up to about 5KB, 4KB, 3KB, 2KB, 1KB 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.
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: 1-14), and polymorphic genomic sequences are provided in Table 2 and in the Sequence Listing (SEQ ID
NOS:43-50). 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.
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:1-14, genomic sequences are provided in Table 2 as SEQ ID NOS:43-50, transcript-based SNP context sequences are provided in Table 1 as SEQ ID NO:29-42, and genomic-based SNP
context sequences are provided in Table 2 as SEQ ID NO:51-58) 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, 80, 100, 150, 200, 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 nucleotid sequences provided in Table 1 and/or Table 2 for the synthesis of a polynucleotide probe. A
, labeled, robe 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.
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. Patent = Nos. 4,683,195; and 4,683,202; PCR Technology: Principles and Applications for DNA
Amplification, ed. H.A. Erlich, Freeman Press, NY, NY, 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. Patent Nos. 5,270,184;
and 5,422,252), transcription-mediated amplification (TmA) (U.S. Patent No.
5,399,491), linked linear amplification (LLA) (U.S. Patent 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.
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 genonaic DNA, but the precise amount of amplification needed for an assay depends on the 'sensitivity of the subsequent detection õ
method used.
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, 300, 400, or 500 nucleotides in length. While the total length of an amplified =polynucleotide of the invention can be as long as an ern, an intron or the entire gene =
where the SNP of interest resides, an amplified product is typically up to 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 600-700 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.
= 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). =
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.

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:1-14, genomic sequences are provided in Table 2 as SEQ
ID NOS:43-50, transcript-based SNP context sequences are provided in Table 1 as SEQ ID NO:15-42, and genomic-based SNP context sequences are provided in Table 2 as SEQ ID NO:51-58), or any nucleic acid molecule that encodes any of the variant proteins provided in Table 1 (SEQ ID
NOS:15-28). A nucleic acid molecule consists of a nucleotide sequence when the nucleotide sequence is the complete nucleotide sequence of the nucleic acid molecule.
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:1-14, genomic sequences are provided in Table 2 as SEQ ID
NOS:43-50, transcript-based SNP context sequences are provided in Table 1 as SEQ ID NO:29-42, and genomic-based SNP context sequences are provided in Table 2 as SEQ ID
NO:51-58), or any nucleic acid molecule that encodes any of the variant proteins provided in Table 1 (SEQ ID
NOS:15-28). 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.
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:1-14, genomic sequences are provided in Table 2 as SEQ ID NOS:43-50, transcript-based SNP context sequences are provided in Table 1 as SEQ ID NO:29-42, and genomic-based SNP context sequences are provided in Table

2 as SEQ ID NO:51-58), or any nucleic acid molecule that encodes any of the variant proteins provided in Table 1 (SEQ ID NOS:15-28). 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.pmvided 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).
The isolated nucleic acid molecules can encode mature proteins plus additional amino or carboxyl-tenninal 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.
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.
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. Patent 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 Jun;15(6):224-9, and Hyrup et al., "Peptide nucleic acids (PNA): synthesis, properties and potential applications", Bioorg Med Chem. 1996 Jan;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, CA) 3900 High-= Throughput DNA Synthesizer or Expedite 8909 Nucleic Acid Synthesis System, and the = sequence information provided herein.
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 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 at., Bioorganic & Medicinal Chemistry Letters, 4:
1081-1082 (1994), Petersen et at., Bioorganic & Medicinal Chemistry Letters, 6: 793-796 (1996), Kumar et at., Organic Letters 3(9): 1269-1272 (2001), W096/04000). 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:
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. Patent No. 4,835,263) and the =
minor groove binders (U.S. Patent 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).
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. =
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 Sls.TP 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, an aspect of the present invention that is specifically contemplated are isolated nucleic acid molecules 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.
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.
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 I, Griffin, A.M., and Griffin, H.G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von q, 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)All /53 (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.
= = 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 PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4.
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 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 Dec;20(12):1269-71). For further information regarding bioinformatics techniques, see Current Protocols in Bioinfbrmatics., John Wiley & Sons, Inc., N.Y.
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.
SNP Detection Reagents 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:1-14), genomic sequences (provided in Table 2 as SEQ ID NOS:43-50), and context sequences (transcript-based context sequences are provided in Table 1 as SEQ ID NOS:29-42; genomic-based context sequences are provided in Table 2 as SEQ ID NOS:51-58), 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 as SEQ ID NOS:29-42; genomic-based context sequences are provided in Table 2 as SEQ ID NOS:51-58). 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.
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.
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, 55, 60, 65, 70, 80, 90, 100, 120 (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.
Other preferred primer and probe sequences can readily be determined using the transcript sequences (SEQ ID NOS:1-14), genomic sequences (SEQ ID NOS:43-50), and SNP
context sequences (transcript-based context sequences are provided in Table 1 as SEQ ID NOS:
29-42; genomic-based context sequences are provided in Table 2 as SEQ ID
NOS:51-58) 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.
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.
A primer or probe of the present invention is typically at least about 8 nucleotides =
in length. In one embodiment of the invention, a primer or a probe is at least about 10 nucleotides in length. In a preferred embodiment, a prinier 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").
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 polymoiphisms 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, E2235,726; and Saiki, WO 89/11548.

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 5X standard saline phosphate EDTA (SSPE), 0.5% NaDodSO4 (SDS) at 55 C, and incubating probe with target nucleic acid molecules in the same.solution at-the same temperature, followed by washing with a sOlution containing 2X SSPE, and 0.1%SDS at =
55 C or room temperature. =
= Moderate stringency hybridization conditions may be used for allele-specific = primer extension reactions with a solution containing, e.g., about 50mM
KCI at about 46 C. Alternatively, the reaction may be carried out at an elevated temperature such as = 60 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 100mM
KC1 at a temperature of 46 C.
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.
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' .10 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. Patent No.

4,988,617), the 3'most nucleotide of the probe aligns witlythe SNP position in the target sequence.
Oligonucleotide probes and primers may be prepared by methods well known in the art. Chemical synthetic methods include, but are 'limited to, the phosphotriester 15. 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.
Patent No.
4,458,066.
20 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 25 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.
30 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 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 .
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.
= 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.
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-Fara, Tet, Joe, Hex, Oregon Green, RhodRmine, Rhodol Green, Tamra, Rox, and Texas Red.

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. Patent Nos. 5,210,015 and 5,538,848) or Molecular Beacon probe (U.S. Patent Nos. 5,118,801 and 5,312728), 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. Patent Nos. 5,866,336 and 6,117,635). =
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 =
1.0 oligonucleotide for binding to another complementary oligonucle,otide such as pairs of =
= zipcodes.
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 =
= 15 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 20 particular nucleotide (allele) is present at that target SNP site, and the primer extension product can be detected in order to determine which SNP
allele is present at the target SNP site. For example, particular ddl\TTPs are typically used in the primer extension reaction to terminate primer extension once a ddNTP is incorporated into the extension product (a primer extension 25 product which includes a ddNTP at the 3'-most end of the primer extension product, and in which the ddNTP is a nucleotide of a SNP disclosed herein, is a composition that is specifically contemplated by the present invention).
30 include the SNP site itself, are also contemplated by the present invention.

SNP Detection,Kits and Systems 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 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 - 15 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 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.
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 to 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-contairling 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 ) compartmentali7ed kits, including microfluidic/lab-on-a-chip systems.
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.
The terms "arrays", "microarrays", and "DNA chips" are used herein interchangeably to refer to an array of distinct polynucleotides __ ffixed 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. US.
Patent No. 5,837,832, Chee et at., POT application W095/11995 (Chee et al.), Lockhart, D. J. et at. (1996; Nat. Biotech. 14: 1675-1680) and Schena, M. et at.
(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. Patent No.

5,807,522.
Nucleic acid arrays are reviewed in the following references:
Zamraatteo et al., "New chips for molecular biology and diagnostics", Biotechnol Annu Rev. 2002;8:85-101; Sosnowski et at., "Active microelectronic array system for DNA hybridization, genotyping and pharmacogenoraic ' applications", Psychiatr Genet. 2002 Dec;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 genoraic variations using gel-based chips", Hum Mutat. 2002 Apr;19(4):343-60; and McGall et al., "High-density genechip oligonucleotide probe arrays", Adv Biochem Eng Biotechnol. 2002;77:21-42.
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 pol3mucleotide 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.
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 15-30 nucleotides M 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 chemilumMescent 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 L
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 . . 5 gene/transcript or genes/transcripts of interest. 0=
Hybridization assays based on. polynucleotide arrays rely on the differences in hybridization stability of the probes to perfectly matched and mismatched target sequence variants. or SNP genotyping, it is generally preferable that stringency conditions used in hybridization assays are high enough such that nucleic acid molecules that rli-Ffer 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.
= 20 In other embodiments, the arrays are used in conjunction with chemilurainescent 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 applications 10/620332 and 10/620333 describe chemiluminescent approaches for =
microarray detection; U.S. Patent Nos. -6124478,6107024, 5994073, 5981768, 5871938, 5843681, 5800999, and 5773628 describe methods and compositions of clioxetane for performing chemiluminescent detection; and U.S. published application US2002/0110828 discloses methods and compositions for microarray controls.

In one embodiment of the invention, a nucleic acid array can comprise an array of 1probes'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.
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 W095/251116 (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.
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.
= A SNP detection kit/system of the present invention may include components that are used to prepare nucleic acids from a test sampler 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' PRISMTm 6700 sample preparation system, and iRoche Molecular Systems' COBAS AmpliPrep System.
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 rabee 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 at., "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".
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. Patent No. 5,589,136, which describes the integration of POE 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 dxample, U.S. Patent Nos. 6,153,073, Dubrow et al., and 6,156,181, Parce et al.
For genotyping SNPs, an exemplary raicrofluidic 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.
USES OF NUCLEIC ACID MOLECULES
The nucleic acid molecules of the present invention have a variety of uses, especially in the diagnosis and treatment of liver fibrosis and related pathologies. 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-lengtb cDNA and genomic clones encoding the variant peptides disclosed in Table 1 as well as their orthologs.
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).
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 = Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, NY).
Probes can be used as part of a diagnostic test kit for identifying cells or tissues in .
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 developed early stage liver fibrosis. Detection of a SNP associated with a disease phenotype provides a diagnostic tool for an active disease and/or genetic predisposition to =
the disease.
Furthermore, the nucleic acid molecules of the invention are therefore useful for 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.
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. I. 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.
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 15- = substitution) caused by a SNP disclosed in Table 1 and/or Table 2. .
" 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.
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.
= 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 valiant peptides.
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.
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.

=
The nucleic acid molecules of the invention are also useful in gene therapy in Patientslvihose 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.
r4 SNP Genotvping Methods The process of determining which specific nucleotide (Le., 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 liver fibrosis or related pathologies, or determining predisposition thereto, or determining responsiveness to a form of .treatment, or in genome mapping or SNP association analysis, etc. }
Nucleic acid samples can be genotyped to determine which allele(s) is/are present : 15 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", Pharmacogenomica.
=
2003;3(2):77-96; Kwok et al., "Detection of single nucleotide polymorphisms", Curr Issues Mol Biol. 2003 Apr;5(2):43-60; Sin, "Technologies for individual genotyping:.
detection of genetic polymorphisms in drug targets and disease genes", Am J
Pharmacogenomics.
20022(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 Marnellos, "High-throughput SNP analysis for genetic association studies", Cum 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 (US.
Patent No.

4,988,167), multiplex ligation reaction sorted on genetic arrays, restriction-fragment length ' polyhaorphism, 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.
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. EnzyrnoL 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 Hayathi 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 (DOGE) (Myers et al., Nature 313:495 (1985)). =
Sequence variations at specific locations can also be assessed by nuclease protection assays .such as RNase and Si protection or chemical cleavage methods.
In a preferred embodiment, SNP genotyping is performed using the TaqMan assay, which is also known as the 5' nuclease assay (U.S. Patent 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.
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.
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, CA), 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 liver fibrosis 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.
Patent Nos. 5,118,801 and 5,312,728) and other variant formats (U.S. Patent Nos.
5,866,336 and 6,117,635).
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. Patent No.
4,988,617). lii.
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 complementarily 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 Cletected as indicators of the presence of a SNP.
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. Patent Nos. 6027889, 6268148, 5494810, 5830711, 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 60/427818, 60/445636, and 60/445494 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.
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.

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 tripbosphates (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 1 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.
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=
-'I 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 u.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 =
at., "A standard protocol for single nucleotide primer extension in the human genome = using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry", - 15 Rapid Commun Mass Spectrom. 2003;17(11):1195-202.
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", Bioinfornu2tics. 2003 Jul;19 Suppl 1:144-153; Storm et at., "MALDI-TOF mass spectrometry-based SNP
genotyping", Methods Mol Biol. 2003;212:241-62; Jurinke et at., "The use of Mass ARRAY technology for high throughput genotyping", Adv Biothem Eng Biotechnol.
2002;77:57-74; and Jurinke et at., "Automated genotyping using the DNA
MassArray technology", Methods Mol Biol. 2002;187:179-92.
SNPs can also be scored by direct DNA sequencing. A variety of automated =
sequencing procedures can he utilized ((1995) Biotechniques /9:448), including sequencing by mass spectrometry (see, e.g., PCT International Publication No. W094/16101;
Cohen et at., Adv. Chromatogr. 36:127-162 (1996); and Griffin et at., 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, CA), is commonly used in the art for automated sequencing.
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)). SSC? 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). = =
Sequence-specific ribozymes (U.S.Patent 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 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, raRNA 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.
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 ("phannacogenomics"), 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.
Analysis of Genetic AssociationEetween SNPs and Phenotypic Traits SNP genotyping for disease diagnosis, disease predisposition screening, disease prognosis, determining drug responsiveness (phamiacogenomics), 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.
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 poplation) 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.
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.
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.
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 (1.990)).
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 2x2 table (2 SNP alleles x 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 3x2 table (3 genotypes x 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%.
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 autoimraune 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,' l', 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.
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 R2, 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.
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 (Sebald 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 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 unadjustap-value <0.2 (a . 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 15 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, In replication studies using samples from different populations after statistically significant markers have been identified in the exploratory stage, meta-analyses can then 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.
=
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.
= 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, 65220-228) 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). =
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).
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 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)).
Disease Diagnosis and Predisposition Screening 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 individual may have an increased risk by virtue of having the susceptibility allele(s).
The SNPs of the invention may contribute to liver fibrosis and related pathologies 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.
As used herein, the terms "diagnose", "diagnosis", and "diagnostics" include, but are not limited to any of the following: detection of liver fibrosis that an individual may presently have, predisposition/susceptibility screening (i.e., determining the increased risk of an individual in developing liver fibrosis in the future, or determining whether an individual has a decreased risk of developing liver fibrosis in the future, determining the rate of progression of fibrosis to bridging fibrosis/cirrhosis), determining a particular type or subclass of liver fibrosis in an individual known to have liver fibrosis, confirming or reinforcing a previously made diagnosis of liver fibrosis, 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 liver fibrosis. Such diagnostic uses are based on the SNIPS
individually or in a unique combination or SNP haplotypes of the present invention.
= liaplotypes are particularly useful in that, for example, fewer SNPs can be genotyped to determine if a particular genornic region harbors a locus that influences a particular phenotype, such as in linkage disequilibrium-based SNP association analysis. = =
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.
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 Li) 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.
. For diagnostic purposes and similar uses, if. a particular SNP site is found to be =
useful for diagnosing liver fibrosis and related pathologies (e.g., has a significant = statistical association with the condition and/or is recognized as a causative = polymorphism for the condition), then the skilled artisan would recognize that other SNP
sites which are in ID with this SNP site would also be useful for diagnosing the = condition. Thus, polymorphisms (e.g., SNPs and/or haplotypes) that are not the actual disease-causing (causative) polymorphisms, but are in Li) 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., liver fibrosis) that is influenced by the causative SNP(s). Therefore, 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.
Examples of polymorphisms that can be in LD with one or more causative polymorphisms (and/or in LD with one or more polymorphisms that have a significant statistical association with a condition) and therefore. useful for diagnosing the same condition that the causative/associated SNP(s) is used to diagnose, include, for example, other SNPs in the same gene, protein-coding, or mRNA transcript-coding region as the causative/associated SNP, other SNPs in the same exon or same intron as the causative/associated SNP, other SNPs in the same haplotype block as the causative/associated SNP, other SNPs in the same intergenic region as the causative/associated SNP, SNPs that are outside but near a gene (e.g., within 6kb on either side, 5' or 3', of a gene boundary) that harbors a causative/associated SNP, etc.
, Such useful ID SNPs can be selected from among the SNPs disclosed in Tables 1-2, for example.
= 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 Aug;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 Jan;24(1):57-67; Ardlie et al., "Patterns of linkage disequilibrium in the human =
.genome", Nat Rev Genet. 2002 Apr;3(4):299-309 (erratum in Nat Rev Genet 2002 Jul;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 -Feb;6(1):24-30.
= The contribution or association of particular SNPs and/or SNP
haplotypes with disease phenotypes, such as liver fibrosis, 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 liver fibrosis, 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 .20 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 liver fibrosis might indicate a probability of 20% that an individual has or is at risk of developing liver fibrosis, whereas detection of five SNPs, each of which correlates with liver fibrosis, might indicate a probability of 80% that . an individual has or is at risk of developing liver fibrosis. 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 polyraorphisras or I. 0 other risk factors of liver fibrosis, such as disease symptoms, pathological characteristics, family history, diet, environmental factors or lifestyle factors. =
It will, of course, be understood by practitioners skilled in the treatment or diagnosis of liver fibrosis 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 liver fibrosis, and/or pathologies related to liver fibrosis, 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.
. 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 ,20 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 liver fibrosis.
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.
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 naRNA 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.
Pharmacogenomics and Therapeutics/Drug Development 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, Gun. Exp. Pharrnacol. 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 tbe 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. =
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 df the =
extensive metabolizer andin the phenotype of the poor metabolizer.
Accordingly, SNPs = 10 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 mocinlity. 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.
= 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.
Pharmacogenomic uses of the SNPs of the present invention provide several significant advantages for patient care, particularly in treating liver fibrosis.
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 hospitali7ation and death, as well as a significant economic burden on the healthcare system (Pfost et. al., Trends in Biotechnology, Aug.
2000.). Thus, pharmacogenomics based on the SNPs disclosed herein has the potential to both save lives and reduce healthcare costs substantially. .
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 andother .neuro degenerative 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 Phannacol. 2001 Feb 9;413(1):11-29, and Poirier, "Apolipoprotein E: a pharmacogenetic target for the treatment of Alzheimer's disease", Mol Diagn. 1999 Dec;4(4):335-41.
-Pharmacogenonaics as it relates to cardiovascular disorders is discussed in Siest et al., =
"Pharmacogenomics of drugs affecting the cardiovascular system", Clin Chem Lab Med.
2003 Apr;41(4):590-9, Muldierjee et al., "Pharmacogenomics in cardiovascular ' =diseases", Prog Cardiovasc Dis. 2002 May-Jun;44(6):479-98, and Mooser et al., "Cardiovascular pharmacogenetics in the SNP era", J Thromb Haemo,st. 2003 Jul:1(7):1398-402. Pharmacogenomics as it relates to cancer is discussed in McLeod et at., "Cancer pharmacogenomics: SNPs, chips, and the individual patient", Cancer Invest.
2003;21(4):630-40 and Waters et al., "Cancer pharmacogenomics: current and future applications", Biochim Biophys Acta. 2003 Mar 17;1603(2):99-111.
The SNPs of the present invention also can be used to identify novel therapeutic targets for liver fibrosis. 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 raimetics which modulate the functions or levels of the target genes or gene products.
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 Discoveiy 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).
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 Jul;6(4):561-9; Stephens et al., "Antisense oligonucleotide therapy in cancer", Curr Opin Mol Ther. 2003 Apr;5(2):118-22; Kurreck, "Antisense technologies..
Improvement through novel chemical modifications", Eur JBioche,n. 2003 Apr;270(8):1628-44;
Dias et al., "Antisense oligonucleotides: basic concepts and mechanisms", Mol Cancer Then 2002 Mar;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", Cun- Cancer Drug Targets.
2001.Nov;1(3):177-96; and Bennett, "Efficiency of antisense oligonucleotide drug discovery", Antisense Nucleic Acid Drug Dev. 2002 Jun;12(3):215-24. =
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). =
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 liver fibrosis, 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.
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, or 23 nucleotides 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)). Accordingly, an aspect of the present mvention specifically contemplates isolated nucleic acid molecules that are about 18-26 nucleotides in length, preferably 19-25 nucleotides in length, and more preferably 20, 21, 22, or 23 nucleotides in length, and the use of these nucleic acid molecules for RNAi.

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).
The following references provide a further review of RNAi: Reynolds et al., "Rational siRNA design for RNA interference", Nat Biotechnol. 2004 Mar;22(3):326-30. =
Epub 2004 Feb 01; Chi et at., "Geriomewide view of gene silencing by small interfering RNAs", PNAS 100(11):6343-6346, 2003; Vickers et at., "Efficient Reduction=of Target RNAs by Small Interfering RNA and RNase H-dependent Antisense Agents", T.
Biol.
Chem. 278: 7108-7118, 2003; Agami, "RNAi and related mechanisms and their potential use for therapy", Curr Opin Chem Biol. 2002 Dec;6(6):829-34; Lavery et al., `..Arrtisense and RNAi: powerful tools in drug target discovery and validation", Curr Opin Drug =
Discov Devel. 2003 Jul;6(4):561-9; Shi, "Mammalian RNAi for the masses", Trends Genet 2003 Jan;19(1):9-12), Shuey et at., "RNAi: gene-silencing in therapeutic intervention", Drug Discovery Today 2002 Oct;7(20):1040-1046; McManus et al., Nat Rev Genet 2002 Oct;3(10):737-47; Xia et at., Nat Biotechnol 2002 Oct;20(10):1006-10; =
Plasterk et al., OPT Opin Genet Dev 2000 Oct;10(5):562-7; Bosher et at., Nat Cell Biol 2000 Feb;2(2):E31-6; and Hunter, Curr Rio! 1999 Jun 17;9(12):R440-2).
A subject suffering from a pathological condition, such as liver fibrosis, ascribed to a SNP may be treated so as to correct the genetic defect (see Kren et at., Proc. Natl.
Acad. ScL 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 = la incorporation of the normal sequence into the subject's genome. Upon incorporation, the normal gene product is expressed, and the replacement is propagated, thereby 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-= pathological condition.
The invention further provides a method for identifying a compound or agent that =
can be used to treat liver fibrosis. 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.

Variant gene expression in a liver fibrosis 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):
Assays for variant gene expression can involve direct assays of nucleic acid levels.
= (e.g., naRNA 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.=
=
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 naRNA
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 liver fibrosis 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 roRNA 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.
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 naRNA 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 (Le., suppression or antagonization) of nucleic acid exiaression:
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. , .
The SNP-containing nucleic acid molecules of the present invention are also useful . 10 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 tcndcities. The gene expression pattern can also serve as a marker =
inclicative(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.
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.
The SNPs/haplotypes of the present invention are also usehil for improving many different aspects of the drug development process. For instance, an aspect of the present , invention includes selecting individuals for clinical trials based on their SNP genotype.
For example, individuals with SNP genotypes that indicate that they are likely to -positively respond to a drug can be included in the trials, whereas those individuals whose SNP genotypes indicate that they are less likely to or would not respond to the drug, or who are at risk for suffering toxic effects or other adverse reactions, can be excluded from the clinical trials. This not only can improve the safety of clinical trials, but also can 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 = 5 subset of the population that would benefit from a drug that had previously performed poorly in clinical trials, thereby "rescuing" previously developed drags, and enabling the = drug to be made available to a particular liver fibrosis patient population that can benefit from it. =
SNPs have many important uses in drug discovery, screening, and development.
r 10 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 Mar; S30-S36).
15 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 - 20 2001 Mar,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.
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 =
25 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 Mar; S30-S36).
Additionally, screening therapeutic candidates against all known variants of a 30 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 br drugnietabolizing genes, can be identified, and this information can be utilized during the drug development process to minimize variability in drag 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. =
= 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. =
Pharmaceutical Compositions and Administration Thereof Any of the liver fibrosis-associated proteins, and encoding nucleic acid molecules, disclosed herein can be used as therapeutic targets (or directly used themselves as therapeutic compounds) for treating liver fibrosis 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.
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 I
.compound used, the route and form of administration, and other factors. =
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;
= 5 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:
= 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 = , 10 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.
15 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 20 increasing the surface area, i.e., decreasing particle size. For example, U.S. Patent No.
4,107,288 describes a pharmaceutical formulation having particles in the size range from . . =
to 1,000 nm in which the active material is supported on a cross-linked matrix of macromolecules. U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle 25 size of 400 rim) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
Pharmaceutical compositions are comprised of, in general, a therapeutic =
compound in combination with at least one pharmaceutically acceptable dxcipient.
30 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.
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.
-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.
Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by B. W. Martin (Mack Publishing =

Company, le ed., 1990).
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 %. =
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 liver fibrosis-associated protein can be administered in combination with another agent that inhibits or stimulates the activity of the same or a different liver fibrosis-associated protein to thereby counteract the affects of liver fibrosis.
For further information regarding pharmacology, see Current Protocols in Pharmacology, John Wiley & Sons, Inc., N.Y.

Human Identification Applications in addition to their diagnostic and therapeutic uses in liver fibrosis 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", hit .1" 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 (L 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. =
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.
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, 11GBASE, and/or HOOD). The allele frequencies provided in Tables 1-2 enable these ' SNP i '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 .10 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. =
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.
20, 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(4Y:771-782. . .
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 - 10 . susceptible to artefacts 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 = 15 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. =
20 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, 25 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 30 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, referrato 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.
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 = 10 probes specific for certain known alleles. Furthermore, off-ladder alleles and microvariants encountered with STR analysis, even when correctly typed,Imay leadto 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.
= 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.
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
' allele's'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 .
= 5 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 computer readable medium (see the section of the present specification entitled =
"Computer-Related Embodiments").
The SNPs of the present invention can also be assayed for use in paternity testing.
-= 10 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 15 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 20 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 fatheris the true biological father of the child.
= In addition to paternity testing, SNPs are also useful for other types of kinship 25 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 30 nucleotide polymorphisms", Electrophoresis 1999 Jun;20(8):1676-81.

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 == õmilitary 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. Patent No. 6,119,096): _ =
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 real-lily 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.
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
Variant Proteins Encoded by SNP-Containing Nucleic Acid Molecules 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:15-28 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.
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.
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.
As used herein, "substantially free of cellular material" includes preparations of the variant protein having less than about 30% (by dry weight) other proteins (L 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 five of culture medium, i.e., culture medium represents less than about 20% of the volume of the protein preparation.
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 prectirsors or other chemicals, or less than about 5% chemical precursors or other chemicals.
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 .10 described in detail below (Sambrook and Russell, 2000, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY).
- 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.
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.
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.
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.
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 polpucleotide 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 psi' 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.
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 Jan;60(5):523-33. Epub 2002 Nov 07; Graddis et al., 'Designing proteins that work using recombinant technologies", Curr Phann Biotechnol.

=
2002 Dec;3(4):285-97; and Nilsson et al., "Affinity fusion strategies for detection;
purification, and immobilization of recombinant proteins", Protein Expr Punf.

Oct;11(1):1-16.
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 acidtechnology and protein biochemistry. It is understood, however, that variants exclude those known in =
the prior art before the present invention.
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, an aspect of the present invention that is specifically contemplated are 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. In other words, as long as a polypeptide contains a novel amino acid residue disclosed herein, other portions of die polypeptide that flank the novel amino acid residue can vary to some degree from the polypeptide sequences shown in Table 1.
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.
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.
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 exchange of the acidic residues Asp and Glu; substitution between the amide residues Asn and Gin; 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).
= -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 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.
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 photoaffmity labeling (Smith et al., J. Mot. Biol. 224:899-904(1992); de Vos et aL Science 255:306-312(1992)).
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 10.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.
Known protein modifications include, but are not limited to, acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of Ravin, 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, clemethylation, formation of covalent crosslinks, formation of cysiine, formation of pyroglutamate, formylation, gamma carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, rnyristoylation, oxidation; proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, saltation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination.
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).
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. =
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 = immtnogen. 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/substratehinding 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., PROS1TE analysis) (Current Protocols.in Protein Science, .
John Wiley & Sons, N.Y. (2002)).
Uses of Variant Proteins 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 = 95 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).
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: 15-28. 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.
In another specific aspect of the invention, the variant proteins of the present invention are used as targets for diagnosing liver fibrosis or for determining predisposition tq liver fibrosis 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.
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.
In vitro methods for detection of the variant proteins associated with liver fibrosis =
that are disclosed herein and fragments thereof include, but are not limited to; enzyme linked immunosorbent assays (ELISAs), radioimmunoassays (R1A), Western blots, immunoprecipitations, immunofluorescence, and protein arrays/chips (erg., 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.
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.

Alternatively, variant proteins can be detected in vivo in a subject by introducing I
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.
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. =- .
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) canhe developed that target the variant protein and modulate (e.g., up- or down-regulate) protein = function/activity.
=
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 polyworphic 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 raRNA molecules).

' 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-contsining nucleic acid fragment that encodes the variant protein.
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.
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.
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 antihodies as well as Fab, F(ab-)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).
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 forrn 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.
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. =
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.

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 I technology, 1992, Sept 10(9), 973-80).
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. 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/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., 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.
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.
=
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 liver fibrosis. 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.
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 = 15 disclosed herein or fragments thereof.
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 .
= Patent No. 5,283,317; Zervos et at. (1993) Cell 72:223-232; Madura et at.

(1993) J. Biol. Chem. 268:12046-12054; Bartel et al. (1993) Biotechniques 14:920-924; Iwabuchi et at. (1993) Oncogene 8:1693-1696; and Brent W094/10300) 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.
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. =
Antibodies Directed to Variant Proteins =
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).
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)'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. Patent 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.
Patent Nos. 5,693,762; 5,585,089; and 5,565,332), a single-chain Fv (U.S.
Patent 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.
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.
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., .I. Immunol., 169:595, 2002). Fd phage and Pd phagernid technologies may be used to generate and select recombinant antibodies in vitro (Hoogenboom and Chames, ImmunoL Today 21:371, 2000; Liu et al., .1. 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. Patent No. 5,637,677).

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 8-10 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, = 15 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.
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, P-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and aviciin/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 1251, 1311, "S or 311. =
Antibodies, particularly the use of antibodies as therapeutic agents, are reviewed in:
Morgan, "Antibody therapy for Alzheimer's disease", Expert Rev Vaccines. 2003 Feb;2(1):53-9; Ross et al., "Anticancer antibodies", Am J Clin Pathol. 2003 Apr;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 Feb;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 µ. cancer", Armu Rev Med. 2003;54:343-69. Epub 2001 Dec 03; Hudson et al., "Engineered antibodies", Nat Med. 2003 Jan;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 =
= . Jan;2(1):52-62 (Erratum in: Nat Rev Drug Discov. 2003 Mar;2(3):240);
Houdebine, ' "Antibody manufacture in transgenic animals and comparisons with other systems",,Curr = Opin Biotechnol. 2002 Dec;13(6):625-9; Andreakos et al., "Monoclonal antibodies in = immune and inflammatory diseases", Gun- Opin-Biotechnol. 2002 Dec;13(6):615-20;
. Kellermann et al., "Antibody discovery: the use of transgenic mice to generate human monoclonal antibodies for therapeutics", Gun- Opin Biotechnol..2002 Dec;13(6):593-7; Pini =
et at., "Phage display and colony filter screening for high-throughput selection of antibody libraries", Comb Chem High Throughput Screen. 2002 Nov;5(7):503-10; Batra et at., = "Pharmacokinetics= and biodistribution of genetically engineered antibodies", =Curr Opin - BiotechnoL 2002 Dec;13(6):603-8; and Tangri et at., "Rationally engineered proteins or antibodies with absent or reduced immunogenicity", Gun -Med Chem. 2002 - 20 Dec;9(24):2191-9.
= Uses of Antibodies .
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 liver fibrosis. Additionally, antibody detection of circulating fragments of the full-length variant protein can be used to identify turnover.
Antibodies to the variant proteins of the present invention are also useful in =
pharraacogenomic analysis. Thus, antibodies against variant proteins encoded by alternative SNP alleles can be used to identify individuals that require modified treatment modalities.
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 liver fibrosis.
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 liver fibrosis as indicated by the presence of the variant protein.
Antibodies are also useful as diagnostic tools for evaluating the variant proteins in = 1 = conjunction with analysis by electrophoretic mobility, isoelectric point, tryptic peptide digest, and other physical assays well known in the art. =
. 15. 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. =
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 modnlity. 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.
.25 , 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 valiant 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 sudh is a rclionuclide, an enzyme, an immunogenic epitope, or a cytptoxic agent. Suitable cytotmdc 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).
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. =
=
Vectors and Host Cells . 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.
A vector can be maintained in a host cell as an extra.chromosomal 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.
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).
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.
The regulatory sequences to which the SNP-containing nucleic acid molecules, =
described herein an be operably linked include promoters for directing mRNA =
transcription. These include, but are not limited to, the left promoter from bacteriophage X, 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.
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.
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, NY).
A variety of expression vectors can be used to express a SNP-containing nucleic acid molecule. Such vectors include chromosomal, episornal, 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, NY.
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. V=
= 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.
= =
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. coil, 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. =
V=
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 proteinby 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, MA) and pRIT5 (Pharmacia, Piscataway, NJ) 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. coil expression vectors include pTrc (Amann et al., Gene 69:301-315 (1988)) and pET .
lid (Studier et al., Gene Expression Technology: Methods in Enzymology 185:60-(1990)).
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, California (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.
coil (Wada et at., = Nucleic Acids Res. 20:2111-2118 (1992)). = =
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 pYepSecl (Baldari, et al., EMBO J. 6:229-234 (1987)), pMFa (Kurjan et al., Cell 30:933-943(1982)), pJRY88 (Schultz et al., Gene 54:113-123 (1987)), and pYES2 =
- . (lnvitrogen Corporation, San Diego, CA).
= The SNP-containing nucleic acid molecules can also be expressed in insect cells =
' 20 :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 (Lucldow et at., Virology 170:31-39 (1989)).
= 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 T. 6:187-195 (1987)).
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 WO 2005/111241 PCT/US2005/(J16051 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).
The invention also relates to recombinant host coils 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. =
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, NY).
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.
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.
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.
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.
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. -. .
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, . =
. 15 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. = =
It is also understood that, depending upon the host cell in which = 20 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.

For further information regarding vectors and host cells, see Current 25 Protocols in Molecular Biology, John Wiley & Sons, N.Y.
Uses of Vectors and Host Cells, and Transgenic Animals 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 30 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.
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.
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.
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.
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.

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. Patent Nos. 4,736,866 and 4,870,009, both by Leder et -al., U.S. Patent 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. =
=
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 (Lalcso 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.
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.
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).
For further information regarding transgenic animals, see Houdebine, "Antibody manufacture in transgenic animals and comparisons with other systems", Curr Opin Biotechnol. 2002 Dec;13(6):625-9; Petters et at., "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 Jun;50(6):567-74; Echelard, "Recombinant protein production in transgenic animals", Curr Opin Blotechnol. 1996 Oct;7(5):536-40; Houdebine, "Transgenic animal bioreactors", Transgenic Res. 2000;9(4-5):305-20; Pirity et at., "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' , The riogenology. 2003 Jan 1;59(1):107-13:.
-COMPUTER-RELATED EMBODIMENTS
The SNPs provided in the present invention may be "provided" in a variety of mediums to facilitate use thereof. As used in this section, "provided" refers to a manufacture, other than an isolated nucleic acid molecule, that contains SNP
information of the present invention. Such a manufacture provides the SNP information in a form that allows a skilled artisan to examine the manufacture using means not directly applicable to examining the SNPs or a subset thereof as they -exist in nature or in purified form. The SNP information that may be provided in such a form includes any of the SNP
information provided by the present invention such as, for example, polymorphic nucleic acid and/or amino acid sequence information such as SEQ ID NOS:1-14, SEQ ID NOS:15-28, SEQ
ID NOS:43-50, SEQ ID NOS:29-42, and SEQ ID NOS:51-58; information about observed SNP
or any other information provided by the present invention in Tables 1-2 and/or the Sequence Listing.
In one application of this embodiment, the SNPs of the present invention can be recorded on a computer readable medium. As used herein, "computer readable medium" refers 25 As used herein, "recorded" refers to a process for storing information on computer readable medium. A skilled artisan can readily adopt any of the presently known methods for recording information on computer readable medium to generate manufactures comprising the SNP information of the present invention.
A variety of data storage structures are available to a skilled artisan for creating a of the present invention. The choice of the data storage structure will generally be based on the means chosen to access the stored information. In addition, a variety of data =
processor programs and formats can be used to store the nucleotide/amino acid sequence information of the present invention on computer readable medium. For example, the sequence information can be represented in a word processing text file, formatted in = . commercially-available software such as WordPerfect and Microsoft Word, represented - in the form of an ASCII file, or stored in a database application, such as 0B2, Sybase, =.: Oracle, or the like. A skilled artisan can readily adapt any number of data processor . structuring formats (e.g., text file or database) in order to obtain computer readable ' medium having recorded thereon the SNP information of the present invention.
= By providing the SNPs of the present invention in computer readable form, a skilled artisan can routinely access the SNP information for a variety of purposes.
Computer software is publicly available which allows a skilled artisan to access sequence - information provided in a computer readable medium. Examples of publicly available computer software include BLAST (Altschul et al., J. Mol. Biol. 215:403-410 (1990)) and BLAZE (Brutlag et aL, Comp. Chem. 17:203-207 (1993)) search algorithms.
The present invention further provides systems, particularly computer-based . systems, which contain the SNP information described herein. Such systems may be designed to store and/or analyze information on, for example, a large number of SNP = ' positions, or information on SNP genotypes from a large number of individuals.
The SNP information of the present invention represents a valuable information source. The SNP information of the present invention stored/analyzed in a computer-based system may be used for such computer-intensive applications as determining or analyzing SNP
allele frequencies in a population, mapping disease genes, genotype-phenotype association studies, grouping SNPs into haplotypes, correlating SNP haplotypes with response to particular drugs, or for various other bioinformatic, pharmacogenomic, drug development, or human identification/forensic applications.
As used herein, "a computer-based system" refers to the hardware means, software means, and data storage means used to analyze the SNP information of the present invention. The minimum hardware means of the computer-based systems of the present invention typically comprises a central processing unit (CPU), input means, output means, and data storage means. A skilled artisan can readily appreciate that any one of the currently available computer-based systems are suitable for use in the present invention. Such a system can be changed into a system of the present invention by utilizing the SNP information provided on the CD-R, or a subset thereof, without any experimentation. =
As stated above, the computer-based systems of the present invention comprise a data storage means having stored therein SNPs of the present invention and the necessary = =
hardware means and software means for supporting and implementing a search means. =
As used herein, "data storage means" refers to memory which can store SNP
information of the present invention, or a memory access means which can access manufactures = having recorded thereon the SNP information of the present invention.
= As used herein, "search means" refers to one or more programs or algorithms that =
= are implemented on the computer-based system to identify or analyze SNPs in a target = = =
sequence based on the SNP information stored within the data storage means.
Search :
means can be used to determine which nucleotide is present at a particular SNP
position = in the target sequence. As used herein, a "target sequence" can be any DNA sequence .
- containing the SNP position(s) to be searched or queried.
= As used herein, "a target structural motif," or "target motif," refers to any rationally selected sequence or combination of sequences containing a SNP
position in which the sequence(s) is chosen based on a three-dimensional configuration that is formed upon the folding of the target motif. There are a variety of target motifs known in the art. Protein target motifs include, but are not limited to, enzymatic active sites and =
= = signal sequences. Nucleic acid target motifs include, but are not limited to, promoter =
sequences, hairpin structures, and inducible expression elements (protein binding = 25 sequences). =
A variety of structural formats for the input and output means can be used to input and output the information in the computer-based systems of the present invention. An exemplary format for an output means is a display that depicts the presence or absence of specified nucleotides (alleles) at particular SNP positions of interest. Such presentation can provide a rapid, binary scoring system for many SNPs simultaneously.

One exemplary embodiment of a computer-based system comprising SNP
µ1 information of the present invention is provided in Figure 1. Figure 1 provides a block diagram of a computer system 102 that can be used to implement the present invention.
The computer system 102 includes a processor 106 connected to a bus 104. Also connected to the bus 104 are a main memory 108 (preferably implemented as random access memory, RAM) and a variety of secondary storage devices 110, such as a hard drive 112 and a removable medium storage device 114. The removable medium storage =
device 114 may represent, for example, a floppy disk drive, a CD-ROM drive, a magnetic tapedrive, etc. A removable storage medium 116 (such as a floppy disk, a compact disk, a magnetic tape, etc.) containing control logic and/or data recorded therein may be inserted into the removable medium storage device 114. The computer system 102 includes appropriate software for reading the control logic and/or the data from the = removable storage medium 116 once inserted in the removable medium storage device = 114.
= The SNP information of the present invention may be stored in a well:known = manner in the main memory 108, any of the secondary storage devices 110, and/or a removable storage medium 116. Software for accessing and processing the SNP
information (such as SNP scoring tools, search tools, comparing tools, etc.) preferably resides in main memory 108 during execution.
EXAMPLES
The following examples are offered to illustrate, but not to limit the claimed invention.
STATISTICAL ANALYSIS OF SNP ASSOCIATION WITH LIVER
FIBROSIS IN =HCV-INFECTED INDIVIDUALS
Example 1:
A case-control genetic study was performed to determine the association of SNPs in the human genome with liver fibrosis and in particular the increased or decreased risk of developing bridging fibrosis/cirrhosis, and the rate of progression of fibrosis in HCV
infected patients. The study involved genotyping SNE's in DNA samples obtained from >500 HCV-infected patients. The study population came from 2 clinic sites, the University of California, San Francisco (UCSF) and Stanford University (Stanford). Among the 435 patients from UCSF, the percentage for minimal, moderate, and severe fibrosis was 46%, 26%, and 28%, respectively, which reflects the distribution of HCV patients in their clinics. The 100 samples obtained from Stanford were intentionally collected on extreme cases, and therefore comprised 62% minimal fibrosers and 38% severe fibrosers. Samples were divided into a case group or a control group. The cases comprised those samples obtained from individuals determined to have severe fibrosis (bridging fibrosis/cirrhosis) and the controls comprised those samples obtained from individuals with minimal and moderate fibrosis.
The stage of fibrosis in each individual was determined according to the system of Batts et al., Am J. Surg.
Pathol. 19:1409-1417 (1995) as reviewed by Brunt Hepatology 31:241-246 (2000).
All patients who donated samples had signed informed, written consent, and the study protocols were approved by the respective Institutional Review Boards (IRB).
DNA was extracted from individual blood samples using conventional DNA
extraction methods or by using commercially available kits according to manufacturer's suggested conditions, such as the Q1A-amp kit from Qiagen (Valencia, CA). SNP markers in the extracted DNA samples were analyzed by genotyping using primers such as those presented in Table 5. While some samples were individually genotyped, the same samples and any remaining samples were also used for pooling studies, in which DNA samples from about 50 individuals were pooled and allele frequencies were obtained using a PRISM

Sequence Detection System (Applied Biosystems, Foster City, CA) by kinetic allele-specific PCR similar to the method described by Germer et al., Genome Research 10:258-266 (2000).
The results of statistical analysis of association of a SNP with a decreased risk of developing bridging fibrosis/cirrhosis are presented in Table 4. For statistical analysis, the outcomes include only fibrosis stage (categorized into 0+1, 2, for controls and 3+4 for cases) (and identified as "stage" in Table 4). Genotypes were categorized into ordinal (three groups, including major homozygotes, heterozygotes, and minor homozygotes) as well as using a dominant model assumption (two groups, including major homozygotes versus heterozygotes +
minor homozygotes). Multiple logistic regression as well as proportional logistic regression analysis was used to generate age-adjusted odds ratios and 95% confidence intervals to assess the association between the genotypes and fibrosis stage. All reported p-values are two-sided. =
A marker having an odds ratio (OR) < 1.0 is protective (e.g., an individual is less likely to develop severe liver fibrosis), whereas a marker having an odds ratio (OR) > 1.0 is associated with an increased risk (e.g., an individual is more likely to develop severe liver fibrosis). =
Among the 120 SNPs tested in the two sample sets, hCV11638783 is a marker ,=that is associated with decreased risk for severe fibrosis. hCV11638783 is a replicated marker because it shows significant association with severe fibrosis in both the.UCSF
and Stanford sample sets(p-values of 0.0014 and 0.0175 respectively in the ordinal analyses and 0..0055 and 0.0071 respectively in the dominant analyses). The odds ratio in =
. both sample sets was less than 1.0 (in the UCSF sample set, for ordinal, the odds ratio -was 0.583 for fibrosis stage, and, for dominant, the odds ratio was 0.586 for fibrosis stage. In the Stanford sample set, for ordinal, the odds ratio was 0.408 for fibrosis stage;
in "Sample Set 2", for dominant, the odds ratio was 0.291 for fibrosis stage).
Thus, this SNP may be used to identify individuals with a decreased risk of developing fibrosis, = especially bridging fibrosis/cirrhosis.
Example 2 =
=
Sample Set Description =
= In a second case control study, DNA samples obtained from the University of =
California San Francisco (UCSF) were used as a discovery sample set to initially identify . SNPs in association with severe =fibrosis. Among the 537 patients in the discovery sample set, the percentage for minimal stage 0-1, moderate stage 2, and severe stage 3-4 fibrosers was 52%, 23%, and 25%, respectively, which reflects the typical distribution of HCV infected patients in clinics.
In addition sample sets were collected from 3 additional but different clinic sites for use in replication studies: Virginia Commonwealth University (VCU), University of Illinois, Chicago (UIC) and Stanford University (Stanford). Among the approximately 483 patients in the sample set from VCU, the percentage for minimal, moderate, and severe fibrosis was approximately 18%, 34%, and 48%, respectively. Among the patients in the sample set from ITIC, the percentage for minimal, moderate, and severe fibrosis was 29%, 30%, and 41%, respectively. Samples from the Stanford sample set were intentionally collected on extreme cases, which contained 62% minimal stage 0-1 fibrosers and 38% severe stage 3-4 fibrosers. The stage of fibrosis in each individual in tbeVCU sample set was determined according to the system of Knodell et al., Hepatology 1:431-435 (1981). The stage of fibrosis in individuals in the UCSF, UIC and Stanford sample sets was determined according to the system of Batts et al., Am J. Surg.
Pathol. 19:1409-1417 (1995). Both scoring systems are reviewed by Brunt Hepatology =
31:241-246 (2000). All patients who donated samples had signed informed, written consent, and the study protocols were approved by their respective IRBs. =
All patients in the sample sets met the inclusion/exclusion criteria in the study = .protocol as follows:
Inclusion criteria:
= Adults (Age 18 ¨ 75).
' = HCV positive patients who have undergone a full course (at least 24 weeks) of = Interferon (IFN) treatment (any formulation +/- ribavirin) and for whom six month follow-up viral load data was available/potentially available.
Exclusion criteria:
= Discontinuation of IFN treatment secondary to poor tolerance of side effects = Evidence of other chronic active viral hepatitis including positive hepatitis antigen, = Evidence of co-infection with human immunodeficiency virus (HIV), e.g.
Positive anti-antibody.
= Evidence of other serious liver disease: e.g. Wilson's Hemachromatosis, etc = Other serious medical conditions: Rheumatic/renal/lung diseases, cardiovascular disease, cancer Additional information used for data analysis:
= Age = Race = Gender = HCV genotype = Viral load = Ethanol use = Intravenous drug use = Other medications = Exact treatment regimen = Alanine amino transferase levels = Response to IFN treatment = Other medical history, including serious medical illness such as kidney disease, cardiovascular disease, autoimmune disease, and cancer Pooling and whole genome scan on discovery sample set Association of SNP alleles in the human genome with fibrosis stage in HCV
patients was tested in the discovery sample set. DNA was extracted from blood samples using a standard protocol or DNA extraction kits as described above. DNA
samples from patients were pooled based on similar clinical phenotypes of the patients.
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 in the pools were obtained using primers such as those presented in Table 5. =
Genotypes and pool allele frequencies were measured using a PRISM 79001fT
Sequence Detection PCR System (Applied Biosystems) by kinetic 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).
Data analysis on whole genome scan using pooled DNA
Approximately 21,470 SNPs throughout the genome were genotyped in the discovery sample set. Allele odds ratios and p-values were generated comparing the 201 advanced or high fibrosis stage group (case group) (also known as bridging fibrosis/cirrhosis) vs .medium and low groups (mild or no fibrosis) (control group).
Results were stratified by ethnicity (all ethnic groups (A) Caucasian (C) and other than Caucasian (0)) for the stage outcome to assess any confounding by these factors.
Data analysis of individual genotyping results on replication sample sets About 175 SNPs were selected from a study using the discovery sample set based on their association with severe fibrosis. These SNPs were then retested by individual =
genotyping in the UCSF sample set to confirm the initial results and in the VCU, UIC or Stanford sample sets. The data obtained from the VCU sample set was used to replicate =the results obtained from the UCSF sample set. The UIC and Stanford sample sets provided additional replication data. The Allelic Association, Fischer Exact Test was used to analyze the association of a SNP with fibrosis stage. In replication studies, a SNP

was considered a replicated marker only if it had a significant p-value <0.1 for a particular stage in the UCSF sample set and the VCU sample set, and the Odds Ratio (OR) had to go in the same direction ¨ that is, the regression coefficient had to have the same sign in each of the UCSF and VCU sample sets. 67 markers were replicated in these two sample sets in showing statistically significant association with severe fibrosis (Table 7). For example, marker hCV7450990 is a replicated marker when all patients as well as patients other than Caucasian populations (but not the Caucasian only population were analyzed, whereas marker hCV11935588, is a replicated marker when all patients as well as Caucasian-only population were analyzed. Both of these SNPs are protective.
alleles with ORs <1.
hCV7450990 a missense SNP in DDX5, which encodes a DEAD (Asp-Gin-Ala-Asp) box polypeptide 5, and it is shown to have an association with severe fibrosis in both the UCSF and VCU sample sets. Previous studies in the art have shown that this gene is expressed in multiple tissues including the liver. A recent report indicates that DDX5, an RNA helicase also known as p68, interacts with HCV NS5B (HCV RNA-dependent RNA polymerase), suggesting that DDX5 is a human cellular factor involved in HCV RNA replication (Goh et al., J Virol., 2004, 78: 5288-98). Therefore, SNPs in the DDX5 gene, particularly missense SNPs such as hCV7450990, might render a protective effect by affecting the ability of HCV to replicate.
SNP (hCV11935588), which is located in a gene on chromosome 16, is an example of a marker associated with severe fibrosis in Caucasians in all four sample sets:
In addition, hCV15851335 also showed association with severe fibrosis when all patients as well as a Caucasian-only population were analyzed in the UCSF and VCU
sample sets (Table 7). hCV15851335 is a missense SNP in CPT1A (camitine.
palmitoyltransferase 1A, liver). CPTIA is a key enzyme in carnitine-dependent transport across the mitochondria' inner membrane, and its deficiency results in a decreased rate of fatty acid beta-oxidation, which causes fatty liver diseases.
The SNPs disclosed herein could be used to identify other markers that are associated with and increased risk of developing bridging fibrosis/cirrhosis, and progression of fibrosis in HCV-infected individuals and other liver disease patients. For example, the markers listed in Tables 4-5 can be used to identify other mutations (preferably SNPs), such as those that exhibit similar or enhanced predictive value, in the identified genes or surrounding nucleotide sequence (e.g., 500 Kb upstream to 500 Kb downstream of the marker) through database searches or through sequencing of DNA samples. Specifically, marker hCV7450990 is an A480S change in DDX5, a DEAD-Box RNA helicase. DEAD-Box proteins are characterized by an Asp-Glu-Ala-Asp motif. DDX5 is located on the long arm of chromosome 17, 17q24.1. The sex-averaged recombination rate in the region is estimated to be 0.6 cM/Mb. The SNP appears to fall within a region of high linkage disequilibrium that extends roughly 20Kb centromeric of the SNP and extends roughly 244Kb telomeric to the SNP. Other SNPs in these two regions may be associated with fibrosis progression rate or inflammation. Given the high homology within the DEAD-Box protein family, all DEAD-box genes and SNPs in those genes are likely to play a role in advanced fibrosis stage.
Marker hCV11935588 is located in a gene on chromosome 16. The following genes are located in the region and may also play a role in advanced fibrosis stage: 1) (chymotrypsinogen B1) is located within roughly 10kb of marker hCV11935588.
CTRB1 is a zymogen secreted by the pancreas (highly expressed in the pancreas) and cleaved by trypsin to become a protease in the small intestine. It is also expressed in the liver.
2) BCAR1 (breast cancer antiestrogen resistance) is within 50kb of marker hCV11935588 and is involved in apoptosis. 3) LDHD (lactate dehydrogenase D) is roughly 100kb away from marker hCV11935588. LDHD is in the electron transport chain and highly expressed in the liver. It's also expressed in the kidneys. Two isoforms of LDHD exist. 4) KARS (lysyl-tRNA

synthetase) is within 400kb of marker hCV11935588. KARS is expressed in many immune cells (NK, T-cells, B cells, etc.), and is also expressed in BM tissue. A p-value of 0.01 was observed in Sample Set 1 at a SNP in the KARS gene. KARS has been shown to play a role in autoimmune diseases and is a target for autoantibodies in polymyositis and dermatomyositis.
The SNPs disclosed herein, alone, or in combination with other risk factors, such as age, gender, and alcohol consumption, can provide a non-invasive test that enables physicians to assess the fibrosis risk in HCV-infected individuals. Such a test offers several advantages, such as: 1) enabling better treatment strategies (for example, individuals with a higher fibrosis risk can be given higher priority for treatment, while =
treatment for individuals with a lower fibrosis risk can be delayed, thereby alleviating them from the side effects and high cost of treatment); and 2) reducing the need for repeated liver biopsies for all patients. =
Furthermore, the SNPs disclosed herein could be used in diagnostic kits to assess the increased or decreased risk of developing bridging fibrosis/cirrhosis and progression. =
of fibrosis for patients with other liver diseases, such as hepatitis B, any co-infection with = = =
other viruses (such as HIV, etc.), non-alcoholic fatty liver diseases (NAFLD), drug-induced liver diseases, alcoholic liver diseases (ALD), primary biliary cirrhosis (PBC), :, primary sclerosing cholangitis (PSC), autoimmune hepatitis (AM) and cryptogenic cirrhosis. Depending on the genotypes of one or multiple markers disclosedin any of -Tables 6-7, alone or in combination with other risk factors, physicians could categorize -these patients into slow, median, or rapid fibrosers.
15.
L
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 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. =
=

Gene Number: 25 Celera Gene: hCG1810767 - 64000126973272 Celera Transcript: hCT1950036 - 64000126973273 Public Transcript Accession: NM 025225 Celera Protein: hCP1765925 - 197000069451968 Public Protein Accession: NP 079501 Gene Symbol: C22orf20 Protein Name: chromosome 22 open reading frame 20 Celera Genomic Axis: GA_x5YUV32VY8D(1403768..1440680) Chromosome: 22 OMIM NUMBER:
OMIM Information:
Transcript SEQ ID NO: 1 Protein SEQ ID NO: 15 SNP Information:
Context (SEQ ID NO: 29):
GCATCTCTCTTACCAGAGTGTCTGATGGGGAAAACGTTCTGGIGTCTGACTTTCGGTCCAAAGACGAAGTCCTG
GATGCCTTGGTATGTTCCTGCTTCAT
CCCTTCTACAGTGGCCTTATCCCICCTTCCTTCAGAGGCGTGCGATATGTGGATGGAGGACTGAGTGACAACGT
ACCCTTCATTGATGCCAAAACAACCA
Celera SNP ID: hCV7241 SNP Position Transcript: 617 SNP Source: dbSNP
Population(Allele,Count): no pop(C,71IG,21) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 15, 148,(I,ATC) (M,ATG) Gene Number: 51 Celera Gene: hCG27399 - 146000220312482 Celera Transcript: hCT18539 - 146000220312504 Public Transcript Accession: NM 003266 Celera Protein: hCP43686 - 197000064928737 Public Protein Accession: NP 003257 Gene Symbol: TLR4 Protein Name: toll-like receptor 4 Celera Genomic Axis: GA_x5YUV32W1V9(4596116..4621277) Chromosome: 9 OMIM NUMBER: 603030 OMIM Information: Endotoxin hyporesponsiveness (3) Transcript SEQ ID NO: 2 Protein SEQ ID NO: 16 SNP Information:
Context (SEQ ID NO: 30):
GCTTTTTCAGAAGTTGATCTACCAAGCCTTGAGTTTCTAGATCTCAGTAGAAATGGCTTGAGTTTCAAAGGTTG
CTGTTCTCAAAGTGATTTTGGGACAA
CAGCCTAAAGTATTTAGATCTGAGCTTCAATGGTGTTATTACCATGAGTTCAAACTTCTTGGGCTTAGAACAAC
TACAACATCTGGATTTCCAGCATTCC
Celera SNP ID: hCV11722237 SNP Position Transcript: 1429 SNP Source: Applera Population(Allele,Count): caucasian(C,37IT,3) african american(C,36IT,2) total(C,73IT,5) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 16, 399,(T,ACC) (I,ATC) SNP Source: HGMD; dbSNP; Nickerson Population(Allele,Count): no_pop(C,-IT,-) ; no_pop(C,-IT,-) ;
no_pop(C,436IT,26) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 16, 399,(T,ACC) (I,ATC) Gene Number: 51 Celera Gene: hCG27399 - 146000220312482 Celera Transcript: hCT1961394 - 146000220312489 Public Transcript Accession: NM 003266 Celera Protein: hCP1774277 - 197000064928735 Public Protein Accession: NP 003257 Gene Symbol: TLR4 Protein Name: toll-like receptor 4 Celera Genomic Axis: GA_x5YUV32W1V9(4596116..4621277) Chromosome: 9 OMIM NUMBER: 603030 OMIM Information: Endotoxin hyporesponsiveness (3) Transcript SEQ ID NO: 3 Protein SEQ ID NO: 17 SNP Information:
Context (SEQ ID NO: 31):
GCTTTTTCAGAAGTTGATCTACCAAGCCTTGAGTTTCTAGATCTCAGTAGAAATGGCTTGAGTTTCAAAGGTTG
CTGTTCTCAAAGTGATTTTGGGACAA
CAGCCTAAAGTATTTAGATCTGAGCTTCAATGGTGTTATTACCATGAGTTCAAACTTCTTGGGCTTAGAACAAC
TAGAACATCTGGATTTCCAGCATTCC
Celera SNP ID: hCV11722237 SNP Position Transcript: 1549 SNP Source: Applera Population(Allele,Count): caucasian(C,37IT,3) african american(C,36IT,2) total(C,73IT,5) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 17, 359,(T,ACC) (I,ATC) SNP Source: HGMD; dbSNP; Nickerson Population(Allele,Count): no_pop(C,-IT,-) ; no_pop(C,-IT,-) ;
no_pop(C,436IT,26) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 17, 359,(T,ACC) (I,ATC) Gene Number: 51 Celera Gene: hCG27399 - 146000220312482 Celera Transcript: hCT1961395 - 146000220312483 Public Transcript Accession: NM 138554 Celera Protein: hCP1774243 - 197000064928734 Public Protein Accession: NP 612564 Gene Symbol: TLR4 Protein Name: toll-like receptor 4 Celera Genomic Axis: GA_x5YUV32W1V9(4596116..4621277) Chromosome: 9 OMIM NUMBER: 603030 OMIM Information: Endotoxin hyporesponsiveness (3) Transcript SEQ ID NO: 4 Protein SEQ ID NO: 18 SNP Information:
Context (SEQ ID NO: 32):
GCTTTTTCAGAAGTTGATCTACCAAGCCTTGAGTTTCTAGATCTCAGTAGAAATGGCTTGAGTTTCAAAGGTTG
CIGTTCTCAAAGTGATTTTGGGACAA
CAGCCTAAAGTATTTAGATCTGAGCTTCAATGGTGTTATTACCATGAGTTCAAACTTCTTGGGCTTAGAACAAC
TAGAACATCTGGATTTCCAGCATTCC
Celera SNP ID: hCV11722237 SNP Position Transcript: 1262 SNP Source: Applera Population(Alle1e,Count): caucasian(C,37IT,3) african american(C,36IT,2) total(C,73IT,5) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 18, 199,(T,ACC) (I,ATC) SNP Source: HGMD; dbSNP; Nickerson Population(Allele,Count): no_pop(C,-IT,-) ; no_pop(C,-IT,-) ;
no_pop(C,436IT,26) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 18, 199,(T,ACC) (I,ATC) Gene Number: 51 Celera Gene: hCG27399 - 146000220312482 Celera Transcript: hCT2316295 - 146000220312497 Public Transcript Accession: NM 138554 Celera Protein: hCP1796095 - 197000064928736 Public Protein Accession: NP 612564 Gene Symbol: TLR4 Protein Name: toll-like receptor 4 Celera Genomic Axis: GA_x5YUV32W1V9(4596116..4621277) Chromosome: 9 OMIM NUMBER: 603030 OMIM Information: Endotoxin hyporesponsiveness (3) Transcript SEQ ID NO: 5 Protein SEQ ID NO: 19 SNP Information:
Context (SEQ ID NO: 33):
GCTTTTTCAGAAGTTGATCTACCAAGCCTTGAGTTTCTAGATCTCAGTAGAAATGGCTTGAGTTTCAAAGGTTG
CTGTTCTCAAAGTGATTTTGGGACAA
CAGCCTAAAGTATTTAGATCTGAGCTTCAATGGTGTTATTACCATGAGTTCAAACTTCTTGGGCTTAGAACAAC
TAGAACATCTGGATTTCCAGCATTCC
Celera SNP ID: hCV11722237 SNP Position Transcript: 1382 SNP Source: Applera Population(Allele,Count): caucasian(C,37IT,3) african american(C,36IT,2) total(C,73IT,5) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 19, 342,(T,ACC) (I,ATC) SNP Source: HGMD; dbSNP; Nickerson Population(Allele,Count): no_pop(C,-IT,-) ; no_pop(C,-IT,-) ;
no pop(C,436IT,26) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 19, 342,(T,ACC) (I,ATC) Gene Number: 53 Celera Gene: hCG27643 - 62000133384069 Celera Transcript: hCT18784 - 62000133384087 Public Transcript Accession: NM 004396 Celera Protein: hCP43680 - 197000064924833 Public Protein Accession: NP 004387 Gene Symbol: DDX5 Protein Name: DEAD (Asp-Glu-Ala-Asp) box polypeptide 5 Celera Genomic Axis: GA_x5YUV32W3KM(353933..374581) Chromosome: 17 OMIM NUMBER: 180630 OMIM Information:
Transcript SEQ ID NO: 6 Protein SEQ ID NO: 20 SNP Information:
Context (SEQ ID NO: 34):
ACCTAATAACATAAAGCAAGTGAGCGACCITATCTCTGTGOTTCGTGAAGCTAATCAAGCAATTAATCCCAAGT
TGCTTCAGTTGGTCGAAGACAGAGGT
CAGGTCGTTCCAGGGGTAGAGGAGGCATGAAGGATGACCGTCGGGACAGATACTCTGCGGGCAAAAGGGGTGGA
TTTAATACCTTTAGAGACAGGGAAAA
Celera SNP ID: hCV7450990 SNP Position Transcript: 1729 SNP Source: dbSNP; Nickerson; HapMap Population(Allele,Count): no_pop(T,172)G,12) ; no_pop(T,-)G,-) ;
no_pop(T,-IG,-) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 20, 480,(S,TCA) (A,GCA) Gene Number: 53 Celera Gene: hCG27643 - 62000133384069 Celera Transcript: hCT1971014 - 62000133384070 Public Transcript Accession: NM 004396 Celera Protein: hCP1783369 - 197000064924832 Public Protein Accession: NP 004387 Gene Symbol: DDX5 Protein Name: DEAD (Asp-Glu-Ala-Asp) box polypeptide 5 Celera Genomic Axis: GA_x5YUV32W3KM(353933..374581) Chromosome: 17 OMIM NUMBER: 180630 OMIM Information:
Transcript SEQ ID NO: 7 Protein SEQ ID NO: 21 SNP Information:
Context (SEQ ID NO: 35):
ACCTAATAACATAAAGCAAGTGAGCGACCTTATCTCTGTGCTTCGTGAAGCTAATCAAGCAATTAATCCCAAGT
TGCTTCAGTTGGTCGAAGACAGAGGT
CAGGICGTTCCAGGGGTAGAGGAGGCATGAAGGATGACCGTCGGGACAGATACTCTGCGGGCAAAAGGGGTGGA
TTTAATACCTTTAGAGACAGGGAAAA
Celera SNP ID: hCV7450990 SNP Position Transcript: 1690 SNP Source: dbSNP; Nickerson; HapMap Population(Allele,Count): no_pop(T,172IG,12) ; no_pop(T,-IG,-) ;
no_pop(T,-)G,-) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 21, 480,(S,TCA) (A,GCA) Gene Number: 67 Celera Gene: hCG37774 - 104000117648431 Celera Transcript: hCT29008 - 104000117648432 Public Transcript Accession: NM 000253 Celera Protein: hCP48619 - 197000069479734 Public Protein Accession: NP 000244 Gene Symbol: MT-g Protein Name: microsomal triglyceride transfer protein (large polypeptide, 88kDa) Celera Genomic Axis: GA_x5YUV32W7K2(47612373..47673550) Chromosome: 4 OMIM NUMBER: 157147 OMIM Information: Abetalipoproteinemia, 200100 (3) Transcript SEQ ID NO: 8 Protein SEQ ID NO: 22 SNP Information:
Context (SEQ ID NO: 36):
CAGAGAGGAGAGAAGAGCATCTTCAAAGGAAAAAGCCCATCTAAAATAATGGGAAAGGAAAACTTGGAAGCTCT
GCAAAGACCTACGCTCCTTCATCTAA
CCATGGAAAGGTCAAAGAGTTCTACTCATATCAAAATGAGGCAGTGGCCATAGAAAATATCAAGAGAGGCCTGG
CTAGCCTATTTCAGACACAGTTAAGC
Celera SNP ID: hCV22274307 SNP Position Transcript: 469 SNP Source: Applera Population(Allele,Count): caucasian(C,10IT,26) african american(C,16IT,22) total(C,26IT,48) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 22, 128,(I,ATC) (T,ACC) SNP Source: dbSNP; Nickerson Population(Allele,Count): no_pop(T,2502IC,490) ; no_pop(T,-IC,-) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 22, 128,(I,ATC) (T,ACC) Gene Number: 98 Celera Gene: hCG2039431 - 208000027149733 Celera Transcript: hCT2258512 - 208000027149752 Public Transcript Accession: NM 000120 Celera Protein: hC-51806343 - 208000027149691 Public Protein Accession: NP 000111 Gene Symbol: EP-H-X1 Protein Name: epoxide hydrolase 1, microsomal (xenobiotic) Celera Genomic Axis: GA_x5YUV32VWMC(1764047..1812133) Chromosome: 1 OMIM NUMBER: 132810 OMIM Information: ?Fetal hydantoin syndrome (1);
Diphenylhydantoin toxicity (1);/Hyperch olanemia, familial, 607748 (3) Transcript SEQ ID NO: 9 Protein SEQ ID NO: 23 SNP Information:
Context (SEQ ID NO: 37):

CAGGTGGAGATTCTCAACAGATACCCTCACTTCAAGACTAAGATTGAAGGGCTGGACATCCACTTCATCCACGT
GAAGCCCCCCCAGCTGCCCGCAGGCC
TACCCCGAAGCCCTTGCTGATGGTGCACGGCTGGCCCGGCTCTTTCTACGAGTTTTATAAGATCATCCCACTCC
TGACTGACCCCAAGAACCATGGCCTG
Celera SNP ID: hCV11638783 SNP Position Transcript: 917 SNP Source: HGMD; dbSNP; Nickerson; HapMap Population(Allele,Count): no_pop(A,-1G,-) ; no_pop(A,24881G,504) ;
no_pop(A,632,1904) ; no_pop (A,21761G,544) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 23, 139,(H,CAT) (R,CGT) Gene Number: 98 Celera Gene: hCG2039431 - 208000027149733 Celera Transcript: hCT2258514 - 208000027149726 Public Transcript Accession: NM 000120 Celera Protein: hCP1806345 - 208000027149688 Public Protein Accession: NP 000111 Gene Symbol: EPHX1 Protein Name: epoxide hydrolase 1, microsomal (xenobiotic) Celera Genomic Axis: GA_x5YUV32VWMC(1764047-1812133) Chromosome: 1 OMIM NUMBER: 132810 OMIM Information: ?Fetal hydantoin syndrome (1);
Diphenylhydantoin toxicity (1);/Hyperch olanemia, familial, 607748 (3) Transcript SEQ ID NO: 10 Protein SEQ ID NO: 24 SNP Information:
Context (SEQ ID NO: 38):
CAGGTGGAGATTCTCAACAGATACCCTCACTTCAAGACTAAGATTGAAGGGCTGGACATCCACTTCATCCACGT
GAAGCCCCCCCAGCTGCCCGCAGGCC
TACCCCGAAGCCCTTGCTGATGGTGCACGGCTGGCCCGGCTCTTTCTACGAGTTTTATAAGATCATCCCACTCC
TGACTGACCCCAAGAACCATGGCCTG
Celera SNP ID: hCV11638783 SNP Position Transcript: 438 SNP Source: HGMD; dbSNP; Nickerson; HapMap Population(Allele,Count): no_pop(A,-1G,-) ; no pop(A,24881G,504) ;
no_pop(A,632)G,1904) ; no_pop (A,2176IG,544) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 24, 139,(H,CAT) (R,CGT) Gene Number: 98 Celera Gene: hCG2039431 - 208000027149733 Celera Transcript: hCT2258516 - 208000027149772 Public Transcript Accession: NM 000120 Celera Protein: hCP1806342 - 208000027149690 Public Protein Accession: NP 000111 Gene Symbol: EPHX1 Protein Name: epoxide hydrolase 1, microsomal (xenobiotic) Celera Genomic Axis: GA_x5YUV32VWMC(1764047..1812133) Chromosome: 1 OMIM NUMBER: 132810 OMIM Information: ?Fetal hydantoin syndrome (1);
Diphenylhydantoin toxicity (1);/Hyperch olanemia, familial, 607748 (3) Transcript SEQ ID NO: 11 Protein SEQ ID NO: 25 SNP Information:
Context (SEQ ID NO: 39):
CAGGTGGAGATTCTCAACAGATACCCTCACTTCAAGACTAAGATTGAAGGGCTGGACATCCACTTCATCCACGT
GAAGCCCCCCCAGCTGCCCGCAGGCC
TACCCCGAAGCCCTTGCTGATGGTGCACGGCTGGCCCGGCTCTTTCTACGAGTTTTATAAGATCATCCCACTCC
TGACTGACCCCAAGAACCATGGCCTG
Celera SNP ID: hCV11638783 SNP Position Transcript: 691 SNP Source: HGMD; dbSNP; Nickerson; HapMap Population(Allele,Count): no_pop(A,-1G,-) ; no_pop(A,24881G,504) ;
no_pop(A,6321G,1904) ; no pop (A,21761G,544) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 25, 139,(H,CAT) (R,CGT) Gene Number: 98 Celera Gene: hCG2039431 - 208000027149733 Celera Transcript: hCT2344145 - 208000027149694 Public Transcript Accession: NM 000120 Celera Protein: hCP1909440 - 208000027149693 Public Protein Accession: NP 000111 Gene Symbol: EPHX1 Protein Name: epoxide hydrolase 1, microsomal (xenobiotic) Celera Genomic Axis: GA_x5YUV32VWMC(1764047..1812133) Chromosome: 1 OMIM NUMBER: 132810 OMIM Information: ?Fetal hydantoin syndrome (1);
Diphenylhydantoin toxicity (1);/Hyperch olanemia, familial, 607748 (3) Transcript SEQ ID NO: 12 Protein SEQ ID NO: 26 SNP Information:
Context (SEQ ID NO: 40):
CAGGTGGAGATTCTCAACAGATACCCTCACTTCAAGACTAAGATTGAAGGGCTGGACATCCACTTCATCCACGT
GAAGCCCCCCCAGCTGCCCGCAGGCC
TACCCCGAAGCCCTTGCTGATGGTGCACGGCTGGCCCGGCTOTTTCTACGAGTTTTATAAGATCATCCCACTCC
TGACTGACCCCAAGAACCATGGCCTG
Celera SNP ID: hCV11638783 SNP Position Transcript: 659 SNP Source: HGMD; dbSNP; Nickerson; HapMap Population(Allele,Count): no_pop(A,-IG,-) ; no_pop(A,24881G,504) ;
no_pop(A,6321G,1904) ; no_pop (A,21761G,544) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 26, 139,(H,CAT) (R,CGT) Gene Number: 99 Celera Gene: hCG2039450 - 208000027162714 Celera Transcript: hCT2309553 - 208000027162700 Public Transcript Accession: NM 001876 Celera Protein: hCi)-1901811 - 208000027162705 Public Protein Accession: NP 001867 Gene Symbol: CPT1A
Protein Name: carnitine palmitoyltransferase lA (liver) Celera Genomic Axis: GA_x5YUV32VYAU(14202585..14299809) Chromosome: 11 OMIM NUMBER: 600528 OMIM Information: CPT deficiency, hepatic, type IA, 255120 (3) Transcript SEQ ID NO: 13 Protein SEQ ID NO: 27 SNP Information:
Context (SEQ ID NO: 41):
CCTCCGAGGACGAGGGCCGCTCATGGTGAACAGCAACTATTATGCCATGGATCTGCTGTATATCCTTCCAACTC
ACATTCAGGCAGCAAGAGCCGGCAAC
CCATCCATGCCATCCTGCTTTACAGGCGCAAACTGGACCGGGAGGAAATCAAACCAATTCGTCTTTTGGGATCC
ACGATTCCACTCTGCTCCGCTCAGTG
Celera SNP ID: hCV15851335 SNP Position Transcript: 920 SNP Source: Applera Population(Allele,Count): caucasian(G,39)A,1) african american(G,36IA,0) total(G,75IA,1) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 27, 275,(A,GCC) (T,ACC) SNP Source: HGMD
Population(Allele,Count): no pop(G,-)A,-) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 27, 275,(A,GCC) (T,ACC) Gene Number: 99 Celera Gene: hCG2039450 - 208000027162714 Celera Transcript: hCT2309554 - 208000027162777 Public Transcript Accession: NM 001876 Celera Protein: hCP1901807 - 208000027162702 Public Protein Accession: NP 001867 Gene Symbol: CPT1A
Protein Name: carnitine palmitoyltransferase 1A (liver) Celera Genomic Axis: GA x5YUV32VYAU(14202585..14299809) Chromosome: 11 OMIM NUMBER: 600528 OMIM Information: CPT deficiency, hepatic, type IA, 255120 (3) Transcript SEQ ID NO: 14 Protein SEQ ID NO: 28 SNP Information:
Context (SEQ ID NO: 42):
CCTCCGAGGACGAGGGCCGCTCATGGTGAACAGCAACTATTATGCCATGGATCTGCTGTATATCCTTCCAACTC
ACATTCAGGCAGCAAGAGCCGGCAAC

CCATCCATGCCATCCTGCTITACAGGCGCAAACTGGACCGGGAGGAAATCAAACCAATTCGTCTTTTGGGATCC
ACGATTCCACTCTGCTCCGCTCAGTG
Celera SNP ID: hCV15851335 SNP Position Transcript: 977 SNP Source: Applera Population(Allele,Count): caucasian(G,39IA,1) african american(G,361A,O) total(G,751A,1) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 28, 275,(A,GCC) (T,ACC) SNP Source: HGMD
Population(Allele,Count): no_pop(G,-IA,-) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 28, 275,(A,GCC) (T,ACC) Gene Number: 25 Celera Gene: hCG1810767 - 64000126973272 Gene Symbol: C22orf20 Protein Name: chromosome 22 open reading frame 20 Celera Genomic Axis: GA_x5YUV32VY8D(1403768..1440680) Chromosome: 22 OMIM NUMBER:
OMIM Information:
Genomic SEQ ID NO: 43 SNP Information:
Context (SEQ ID NO: 51):
TGGAGAAAGCTTATGAAGGATCAGGAAAATTAAAAGGGTGCTCTCGCCTATAACTTCTCTCTCCTTTGCTTTCA
CAGGCCTTGGTATGTTCCTGCTTCAT
CCCTTCTACAGTGGCCTTATCCCTCCTTCCTTCAGAGGCGTGGTAAGTCGGCTTTCTCTGCTAGCGCTGAGTCC
TGGGGGCCTCTGAAGTGTGCTCACAC
Celera SNP ID: hCV7241 SNP Position Genomic: -1403769 SNP Source: dbSNP
Population(Allele,Count): no_pop(C,71IG,21) SNP Type: MISSENSE MUTATION;HUMAN-MOUSE SYNTENIC
REGION
Gene Number: 50 Celera Gene: hCG27192 - 104000117137572 Gene Symbol: LRP5 Protein Name: low density lipoprotein receptor-related protein 5 Celera Genomic Axis: GA_x5YUV32VYAU(13757051..13906097) Chromosome: 11 OMIM NUMBER: 603506 OMIM Information: Osteoporosis-pseudoglioma syndrome, 259770 (3); [Bone mineral density/
variability 1], 601884 (3); Osteopetrosis, autosomal dominant, type I, 607634 (3); Hyperostosis, end osteal, 144750 (3); van Buchem disease, type 2, 607636/(3):
{Osteoporosis}, 166710 (3); Exudative vi treoretinopathy, dominant, 133780 (3); Exudative vitreoretinopathy, recessive, 601813 (3) Genomic SEQ ID NO: 44 SNP Information:
Context (SEQ ID NO: 52):
GAGGCTIGCAAAGGTTAAGGGGCTGTTCGAGGCCCAGGCTGGCAGGAGATGGGCCTGGGCCAGAGTCTGGGACT
TCCCATGCCTGGGCTGTCTTTGGTCC
GTTGCTCACCATCCCTCCCTGGGGCCATGACCTTAGAGAGCCAAATGGAGGTGCAGGTAACCCACGGCAAGGAG
GGGTTGCCATGACTCAGAGTCCCCGT
Celera SNP ID: hCV8761599 SNP Position Genomic: -13757052 SNP Source: dhSNP; Celera; Nickerson; ABI_Val Population(Allele,Count): no_pop(T,516IC,92) ; no_pop(T,144IC,36) ;
no_pop(T,402IC,99) ; no pop) T,1041C,16) SNP Type: INTRON
Gene Number: 51 Celera Gene: hCG27399 - 146000220312482 Gene Symbol: TLR4 Protein Name: toll-like receptor 4 Celera Genomic Axis: GA_x5YUV32W1V9(4596116..4621277) Chromosome: 9 OMIM NUMBER: 603030 OMIM Information: Endotoxin hyporesponsiveness (3) Genomic SEQ ID NO: 45 SNP Information:
Context (SEQ ID NO: 53):
GCTTTTTCAGAAGTTGATCTACCAAGCCTTGAGTTTCTAGATCTCAGTAGAAATGGCTTGAGTTTCAAAGGTTG
CTGTTCTCAAAGTGATTTTGGGACAA
CAGCCTAAAGTATTTAGATCTGAGCTTCAATGGTGTTATTACCATGAGTTCAAACTTCTTGGGCTTAGAACAAC
TAGAACATCTGGATTTCCAGCATTCC
Celera SNP ID: hCV11722237 SNP Position Genomic: -4596117 SNP Source: Applera Population(Allele,Count): caucasian(C,37IT,3) african american(C,36IT,2) total(C,73IT,5) SNP Type: MISSENSE MUTATION;HUMAN-MOUSE SYNTENIC
REGION
SNP Source: HGMD; dbSNP; Nickerson Population(Allele,Count): no_pop(C,-IT,-) ; no_pop(C,-IT,-) ;
no_pop(C,436IT,26) SNP Type: MISSENSE MUTATION;HUMAN-MOUSE SYNTENIC
REGION
Gene Number: 53 Celera Gene: hCG27643 - 62000133384069 Gene Symbol: DDX5 Protein Name: DEAD (Asp-Glu-Ala-Asp) box polypeptide 5 Celera Genomic Axis: GA_x5Y0V32W3K4(353933..374581) Chromosome: 17 OMIM NUMBER: 180630 OMIM Information:
Genomic SEQ ID NO: 46 SNP Information:
Context (SEQ ID NO: 54):
CATTCAAGGTTTTACTCACCCTccAATACCATTTAAATGGATTTGTAGACAACGATGTGACTCGTAACTACCAA
CATTTCCTATCAGTCATCCTTACCTG
ACCTCTGTCTTCGACCAACTGAAGCAACTTGGGATTAATTGCTTGATTAGCTTCACGAAGCACAGAGATAAGGT
CGCTCACTTGCTTTATGTTATTAGGT
Celera SNP ID: hCV7450990 SNP Position Genomic: 374583 SNP Source: dbSNP; Nickerson; HapMap Population(Allele,Count): no_pop(A,172IC,12) ; no_pop(A,-1C,-) ;
no_pop(A,-IC,-) SNP Type: MISSENSE MUTATION;TRANSCRIPTION FACTOR
BINDING SITE;HUMAN-MOUSE SYNTEN
IC REGION
Gene Number: 67 Celera Gene: hCG37774 - 104000117648431 Gene Symbol: MTP
Protein Name: microsomal triglyceride transfer protein (large polypeptide, 88kDa) Celera Genomic Axis: GA_x5YUV32W7K2(47612373..47673550) Chromosome: 4 OMIM NUMBER: 157147 OMIM Information: Abetalipoproteinemia, 200100 (3) Genomic SEQ ID NO: 47 SNP Information:
Context (SEQ ID NO: 55):
CAGAGAGGAGAGAAGAGCATCTTCAAAGGAAAAAGCCCATCTAAAATAATGGGAAAGGAAAACTTGGAAGCTCT
GCAAAGACCTACGCTCCTTCATCTAA
CCATGGAAAGGTAAAGGGGCGTTTAGATTCCACAACTTTTTCTCCAACTTCATATTTTTCTTCCCTTCAGTAGA
TATTATTTTGAGGTAATCACATTGTA
Celera SNP ID: hCV22274307 SNP Position Genomic: -47612374 SNP Source: Applera Population(Allele,Count): caucasian(C,10IT,26) african american(C,16IT,22) total(C,26IT,48) SNP Type: MISSENSE MUTATION;HUMAN-MOUSE SYNTENIC
REGION
SNP Source: dbSNP; Nickerson Population(Allele,Count): no_pop(T,2502IC,490) ; no_pop(T,-IC,-) SNP Type: MISSENSE MUTATION;HUMAN-MOUSE SYNTENIC
REGION
Gene Number: 98 Celera Gene: hCG2039431 - 208000027149733 Gene Symbol: EPHX1 Protein Name: epoxide hydrolase 1, microsomal (xenobiotic) Celera Genomic Axis: GA_x5YUV32VWMC(1764047..1812133) Chromosome: 1 OMIM NUMBER: 132810 OMIM Information: ?Fetal hydantoin syndrome (1);
Diphenylhydantoin toxicity (1);/Hyperch olanemia, familial, 607748 (3) Genomic SEQ ID NO: 48 SNP Information:
Context (SEQ ID NO: 56):
TGCAGGGTCTTCTCTCTCCCTCCACCCTGACTGTGCTCTGTCCCCCCAGGGCTGGACATCCACTTCATCCACGT
GAAGCCCCCCCAGCTGCCCGCAGGCC
TACCCCGAAGCCCTTGCTGATGGTGCACGGCTGGCCCGGCTCTTTCTACGAGTTTTATAAGATCATCCCACTCC
TGACTGACCCCAAGAACCATGGCCTG
Celera SNP ID: hCV11638783 SNP Position Genomic: -1764048 SNP Source: HGMD; dbSNP; Nickerson; HapMap Population(Allele,Count): no_pop(A,-IG,-) ; no_pop(A,2488IG,504) ;
no_pop(A,632IG,1904) ; no pop (A,2176IG,544) SNP Type: MISSENSE MUTATION
Gene Number: 99 Celera Gene: hCG2039450 - 208000027162714 Gene Symbol: CPT1A
Protein Name: carnitine palmitoyltransferase íA (liver) Celera Genomic Axis: GA x5YUV32VYAU(14202585..14299809) Chromosome: 11 OMIM NUMBER: 600528 OMIM Information: CPT deficiency, hepatic, type IA, 255120 (3) Genomic SEQ ID NO: 49 SNP Information:
Context (SEQ ID NO: 57):
AAGCTGTTTGAAAATAATTTTTTTAAAGCAATTTGTTTGCCTACTGGTTTGATTTCCTCCCGGTCCAGTTTGCG
CCTGTAAAGCAGGATGGCATGGATGG
GTTGCCGGCTCTTGCTGCCTGAATGTGAGTTGGAAGGATATACAGCAGATCCTGAAAAGCGACAAAGGTGGAGA
GAATTTGCATAGGGAAAGATAAGCAA
Celera SNP ID: hCV15851335 SNP Position Genomic: -14202526 SNP Source: Applera Population(Allele,Count): caucasian(C,39IT,1) african american(C,361T,0) total(C,75)T,1) SNP Type: MISSENSE MUTATION;TRANSCRIPTION FACTOR
BINDING SITE;HUMAN-MOUSE SYNTEN
IC REGION
SNP Source: HGMD
Population(Allele,Count): no_pop(C,-IT,-) SNP Type: MISSENSE MUTATION;TRANSCRIPTION FACTOR
BINDING SITE;HUMAN-MOUSE SYNTEN
IC REGION
Gene Number: 112 Celera Gene: hCG1642252 -Gene Symbol:
Protein Name:
Celera Genomic Axis: GA x5YUV32W3V0(13011322..13024095) Chromosome: 16 OMIM NUMBER:
OMIM Information:
Genomic SEQ ID NO: 50 SNP Information:
Context (SEQ ID NO: 58):
GTTGGATTCCCTTCATCCCCATAGTCACCTTCCTCACTTTGCACAGGTTGTACTTTGCCTCTTCGACTGTAACG
CGATCAACAGCAACACAGCCCTTGGG
CACAGACCAGGCAGAAATGCTCACCTGTCTTGATGCCGATGACATCCGTGAATCCAGCAGGGTATGTGATAGCC
ACTCGAACCTTGCCATCAATTTTAAT
Celera SNP ID: hCV11935588 SNP Position Genomic: 13024097 SNP Source: dbSNP; Celera; Nickerson; HapMap Population(Allele,Count): no_pop(T,-IA,-) ; no_pop(T,7IA,1) ;
no_pop(T,-)A,-) ; no_pop(T,-IA,-) SNP Type: UTR5 Marker Alleles Sequence A (allele-specific primer) _Sequence B
(allele-specific primer) Sequence C (common primer) hCV11638783 A/G AAGGGCTTCGGGGTAC AAGGGCTTCGGGGTAT
ACCGTGCAGGGTCTTCT
(SEQ ID NO: 59) (SEQ ID NO: 60) (SEQ ID NO: 61) hCV11722237 C/T CAAAGTGATTTTGGGACAAC CAAAGTGATTTTGGGACAAT
GAATACTGAAAACTCACTCATTTGT
(SEQ ID NO: 62) (SEQ ID NO: 63) (SEQ ID NO: 64) hCV11935588 A/T ATTTCTGCCTGGTCTGTGT Err CTGCCTGGTCTGTGA
CTCACTTTGCACAGGTTGTACT
(SEQ ID NO: 65) (SEQ ID NO: 66) (SEQ ID NO: 67) hCV15851335 C/T GATGGCATGGATGGC GGATGGCATGGATGGT
GCAGGATGTGCTGTGATTAT
(SEQ ID NO: 68 (SEQ ID NO: 69) (SEQ ID NO: 70) hCV22274307 C/T GACCTACGCTCCTTCATCTAAC GACCTACGCTCCTTCATCTAAT
CAATGTGATTACCTCAAAATAATATCTAC
(NI (SEQ ID NO: 71) (SEQ ID NO: 72) (SEQ ID NO: 73) (NI
hCV7241 C/G TGGTATGTTCCTGCTTCATC TGGTATGTTCCTGCTTCATG CAGGCAGGAGATGTGTGAG
(SEQ ID NO: 74) (SEQ ID NO: 75) (SEQ ID NO: 76) hCV7450990 A/C TGGTCGAAGACAGAGGTG TTGGTCGAAGACAGAGGTT

0 (SEQ ID NO: 77) (SEQ ID NO: 78) (SEQ ID NO: 79) (NI
hCV8761599 C/T GGGATGGTGAGCAACG AGGGATGGTGAGCAACA
GAACTTGAGGCTTGCAAAGGTTAAG
(NI
(NI (SEQ ID NO: 80) (SEQ ID NO: 81) (SEQ ID NO: 82) Io co = TABLE 4 = MarIcers.re,p8bat9d bbtwoon "Sbinforci Simples" anti "UM Semliki": Stade ertaly14, :NI/nicer Gene symbol "Stamfdrd salmi/A. fstagl ''UC8F9amplis" tamp) OR LCL UCIL pia! ' OR LCL UCL p-vat 11838783 ord EPHX1 0.408 0.195 0.855 0.0175 10.588 0.419 0.811 0.0014 11838788 dam EPHX1 0.281 0.118 0.715 0.0071 = 0.580 0.402 0.855 9.0055 =
= =
=
=
=
= =
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Igµ gliONV 41 V
itstiosfatraimstot 1; 0111 s 5÷sootssssr:-A-631ssts =
.5! stsinsisuittitiiitig 2 :
11 011101ii St551.695573.3.11/535 =
a It = 1111ilililtIVIIM
= %I,ItiSIMS55SSiS55,3 StStaiSISIngliiitill = =
II" Wit t SEQUENCE LISTING
<110> Celera Corporation <120> Genetic Polymorphisms Associated with Fibrosis, Methods of Detection and Uses Thereof <130> 49984-4D
<140> CA 2,826,522 <141> 2005-05-09 <150> CA 2,566,256 <151> 2005-05-09 <150> PCT/US2005/016051 <151> 2005-05-09 <150> US 60/568,846 <151> 2004-05-07 <150> US 60/582,609 <151> 2004-06-25 <150> US 60/599,554 <151> 2004-08-09 <160> 82 <170> FastSEQ for Windows Version 4.0 <210> 1 <211> 2807 <212> DNA
<213> Homo Sapiens <400> 1 atggtccgag gggggcgggg ctgacgtcgc gctgggaatg ccctggccga gacactgagg 60 cagggtagag agcgcttgcg ggcgccgggc ggagctgctg cggatcagga cccgagccga 120 ttcccgatcc cgacccagat cctaacccgc gcccccgccc cgccgccgcc gccatgtacg 180 acgcagagcg cggctggagc ttgtccttcg cgggctgcgg cttcctgggc ttctaccacg 240 tcggggcgac ccgctgcctg agcgagcacg ccccgcacct cctccgcgac gcgcgcatgt 300 tgttcggcgc ttcggccggg gcgttgcact gcgtcggcgt cctctccggt atcccgctgg 360 agcagactct gcaggtcctc tcagatcttg tgcggaaggc caggagtcgg aacattggca 420 tcttccatcc atccttcaac ttaagcaagt tcctccgaca gggtctctgc aaatgcctcc 480 cggccaatgt ccaccagctc atctccggca aaataggcat ctctcttacc agagtgtctg 540 atggggaaaa cgttctggtg tctgactttc ggtccaaaga cgaagtcgtg gatgccttgg 600 tatgttcctg cttcatcccc ttctacagtg gccttatccc tccttccttc agaggcgtgc 660 gatatgtgga tggaggagtg agtgacaacg tacccttcat tgatgccaaa acaaccatca 720 ccgtgtcccc cttctatggg gagtacgaca tctgccctaa agtcaagtcc acgaactttc 780 ttcatgtgga catcaccaag ctcagtctac gcctctgcac agggaacctc taccttctct 840 cgagagcttt tgtccccccg gatctcaagg tgctgggaga gatatgcctt cgaggatatt 900 tggatgcatt caggttcttg gaagagaagg gcatctgcaa caggccccag ccaggcctga 960 agtcatcctc agaagggatg gatcctgagg tcgccatgcc cagctgggca aacatgagtc 1020 tggattcttc cccggagtcg gctgccttgg ctgtgaggct ggagggagat gagctgctag 1080 accacctgcg tctcagcatc ctgccctggg atgagagcat cctggacacc ctctcgccca 1140 ggctcgctac agcactgagt gaagaaatga aagacaaagg tggatacatg agcaagattt 1200 gcaacttgct acccattagg ataatgtctt atgtaatgct gccctgtacc ctgcctgtgg 1260 aatctgccat tgcgattgtc cagagactgg tgacatggct tccagatatg cccgacgatg 1320 tcctgtggtt gcagtgggtg acctcacagg tgttcactcg agtgctgatg tgtctgctcc 1380 ccgcctccag gtcccaaatg ccagtgagca gccaacaggc ctccccatgc acacctgagc 1440 aggactggcc ctgctggact ccctgctccc ccgagggctg tccagcagag accaaagcag 1500 aggccacccc gcggtccatc ctcaggtcca gcctgaactt cttcttgggc aataaagtac 1560 ctgctggtgc tgaggggctc tccacctttc ccagtttttc actagagaag agtctgtgag 1620 tcacttgagg aggcgagtct agcagattct ttcagaggtg ctaaagtttc ccatctttgt 1680 gcagctacct ccgcattgct gtgtagtgac ccctgcctgt gacgtggagg atcccagcct 1740 ctgagctgag ttggttttat gaaaagctag gaagcaacct ttcgcctgtg cagcggtcca 1800 gcacttaact ctaatacatc agcatgcgtt aattcagctg gttgggaaat gacaccagga 1860 agcccagtgc agagggtccc ttactgactg tttcgtggcc ctattaatgg tcagactgtt 1920 ccagcatgag gttcttagaa tgacaggtgt ttggatgggt gggggccttg tgatgggggg 1980 taggctggcc catgtgtgat cttgtggggt ggagggaaga gaatagcatg atcccacttc 2040 cccatgctgt gggaaggggt gcagttcgtc cccaagaacg acactgcctg tcaggtggtc 2100 tgcaaagatg ataaccttga ctactaaaaa cgtctccatg gcgggggtaa caagatgata 2160 atctacttaa ttttagaaca cctttttcac ctaactaaaa taatgtttaa agagttttgt 2220 ataaaaatgt aaggaagcgt tgttacctgt tgaattttgt attatgtgaa tcagtgagat 2280 gttagtagaa taagccttaa aaaaaaaaaa aaatcggttg ggtgcagcgg cacacggctg 2340 taatcccagc actttgggag gccaaggttg gcagatcacc tgaggtcagg agttcaagac 2400 cagtctggcc aacatagcaa aaccctgtct ctactaaaaa tacaaaaatt atctgggcat 2460 ggtggtgcat gcctgtaatc ccagctattc ggaaggctga ggcaggagaa tcacttgaac 2520 ccaggaggcg gaggttgcgg tgagctgaga ttgcaccatt tcattccagc ctgggcaaca 2580 tgagtgaaag tctgactcaa aaaaaaaaaa tttaaaaaac aaaataatct agtgtgcagg 2640 gcattcacct cagcccccca ggcaggagcc aagcacagca ggagcttccg cctcctctcc 2700 actggagcac acaacttgaa cctggcttat tttctgcagg gaccagcccc acatggtcag 2760 tgagtttctc cccatgtgtg gcgatgagag agtgtagaaa taaagac 2807 <210> 2 <211> 5506 <212> DNA
<213> Homo Sapiens <400> 2 ctgtgacaaa agagataact attagagaaa caaaagtcca gaatgctaag gttgccgctt 60 tcacttcctc tcacccttta gcccagaact gctttgaata caccaattgc tgtggggcgg 120 ctcgaggaag agaagacacc agtgcctcag aaactgctcg gtcagacggt gatagcgagc 180 cacgcattca cagggccact gctgctcaca gaagcagtga ggatgatgcc aggatgatgt 240 ctgcctcgcg cctggctggg actctgatcc cagccatggc cttcctctcc tgcgtgagac 300 cagaaagctg ggagccctgc gtggaggtgg ttcctaatat tacttatcaa tgcatggagc 360 tgaatttcta caaaatcccc gacaacctcc ccttctcaac caagaacctg gacctgagct 420 ttaatcccct gaggcattta ggcagctata gcttcttcag tttcccagaa ctgcaggtgc 480 tggatttatc caggtgtgaa atccagacaa ttgaagatgg ggcatatcag agcctaagcc 540 acctctctac cttaatattg acaggaaacc ccatccagag tttagccctg ggagcctttt 600 ctggactatc aagtttacag aagctggtgg ctgtggagac aaatctagca tctctagaga 660 acttccccat tggacatctc aaaactttga aagaacttaa tgtggctcac aatcttatcc 720 aatctttcaa attacctgag tatttttcta atctgaccaa tctagagcac ttggaccttt 780 ccagcaacaa gattcaaagt atttattgca cagacttgcg ggttctacat caaatgcccc 840 tactcaatct ctctttagac ctgtccctga accctatgaa ctttatccaa ccaggtgcat 900 ttaaagaaat taggcttcat aagctgactt taagaaataa ttttgatagt ttaaatgtaa 960 tgaaaacttg tattcaaggt ctggctggtt tagaagtcca tcgtttggtt ctgggagaat 1020 ttagaaatga aggaaacttg gaaaagtttg acaaatctgc tctagagggc ctgtgcaatt 1080 tgaccattga agaattccga ttagcatact tagactacta cctcgatgat attattgact 1140 tatttaattg tttgacaaat gtttcttcat tttccctggt gagtgtgact attgaaaggg 1200 taaaagactt ttcttataat ttcggatggc aacatttaga attagttaac tgtaaatttg 1260 gacagtttcc cacattgaaa ctcaaatctc tcaaaaggct tactttcact tccaacaaag 1320 gtgggaatgc tttttcagaa gttgatctac caagccttga gtttctagat ctcagtagaa 1380 atggcttgag tttcaaaggt tgctgttctc aaagtgattt tgggacaacc agcctaaagt 1440 atttagatct gagcttcaat ggtgttatta ccatgagttc aaacttcttg ggcttagaac 1500 aactagaaca tctggatttc cagcattcca atttgaaaca aatgagtgag ttttcagtat 1560 tcctatcact cagaaacctc atttaccttg acatttctca tactcacacc agagttgctt 1620 tcaatggcat cttcaatggc ttgtccagtc tcgaagtctt gaaaatggct ggcaattctt 1680 tccaggaaaa cttccttcca gatatcttca cagagctgag aaacttgacc ttcctggacc 1740 tctctcagtg tcaactggag cagttgtctc caacagcatt taactcactc tccagtcttc 1800 aggtactaaa tatgagccac aacaacttct tttcattgga tacgtttcct tataagtgtc 1860 tgaactccct ccaggttctt gattacagtc tcaatcacat aatgacttcc aaaaaacagg 1920 aactacagca ttttccaagt agtctagctt tcttaaatct tactcagaat gactttgctt 1980 gtacttgtga acaccagagt ttcctgcaat ggatcaagga ccagaggcag ctcttggtgg 2040 aagttgaacg aatggaatgt gcaacacctt cagataagca gggcatgcct gtgctgagtt 2100 tgaatatcac ctgtcagatg aataagacca tcattggtgt gtcggtcctc agtgtgcttg 2160 tagtatctgt tgtagcagtt ctggtctata agttctattt tcacctgatg cttcttgctg 2220 gctgcataaa gtatggtaga ggtgaaaaca tctatgatgc ctttgttatc tactcaagcc 2280 aggatgagga ctgggtaagg aatgagctag taaagaattt agaagaaggg gtgcctccat 2340 ttcagctctg ccttcactac agagacttta ttcccggtgt ggccattgct gccaacatca 2400 tccatgaagg tttccataaa agccgaaagg tgattgttgt ggtgtcccag cacttcatcc 2460 agagccgctg gtgtatcttt gaatatgaga ttgctcagac ctggcagttt ctgagcagtc 2520 gtgctggtat catcttcatt gtcctgcaga aggtggagaa gaccctgctc aggcagcagg 2580 tggagctgta ccgccttctc agcaggaaca cttacctgga gtgggaggac agtgtcctgg 2640 ggcggcacat cttctggaga cgactcagaa aagccctgct ggatggtaaa tcatggaatc 2700 cagaaggaac agtgggtaca ggatgcaatt ggcaggaagc aacatctatc tgaagaggaa 2760 aaataaaaac ctcctgaggc atttcttgcc cagctgggtc caacacttgt tcagttaata 2820 agtattaaat gctgccacat gtcaggcctt atgctaaggg tgagtaattc catggtgcac 2880 tagatatgca gggctgctaa tctcaaggag cttccagtgc agagggaata aatgctagac 2940 taaaatacag agtcttccag gtgggcattt caaccaactc agtcaaggaa cccatgacaa 3000 agaaagtcat ttcaactctt acctcatcaa gttgaataaa gacagagaaa acagaaagag 3060 acattgttct tttcctgagt cttttgaatg gaaattgtat tatgttatag ccatcataaa 3120 accattttgg tagttttgac tgaactgggt gttcactttt tcctttttga ttgaatacaa 3180 tttaaattct acttgatgac tgcagtcgtc aaggggctcc tgatgcaaga tgccccttcc 3240 attttaagtc tgtctcctta cagaggttaa agtctagtgg ctaattccta aggaaacctg 3300 attaacacat gctcacaacc atcctggtca ttctcgagca tgttctattt tttaactaat 3360 cacccctgat atatttttat ttttatatat ccagttttca tttttttacg tcttgcctat 3420 aagctaatat cataaataag gttgtttaag acgtgcttca aatatccata ttaaccacta 3480 tttttcaagg aagtatggaa aagtacactc tgtcactttg tcactcgatg tcattccaaa 3540 gttattgcct actaagtaat gactgtcatg aaagcagcat tgaaataatt tgtttaaagg 3600 gggcactctt ttaaacggga agaaaatttc cgcttcctgg tcttatcatg gacaatttgg 3660 gctagaggca ggaaggaagt gggatgacct caggaggtca ccttttcttg attccagaaa 3720 catatgggct gataaacccg gggtgacctc atgaaatgag ttgcagcaga agtttatttt 3780 tttcagaaca agtgatgttt gatggacctc tgaatctctt tagggagaca cagatggctg 3840 ggatccctcc cctgtaccct tctcactgcc aggagaacta cgtgtgaagg tattcaaggc 3900 agggagtata cattgctgtt tcctgttggg caatgctcct tgaccacatt ttgggaagag 3960 tggatgttat cattgagaaa acaatgtgtc tggaattaat ggggttctta taaagaaggt 4020 tcccagaaaa gaatgttcat ccagcctcct cagaaacaga acattcaaga aaaggacaat 4080 caggatgtca tcagggaaat gaaaataaaa accacaatga gatatcacct tataccaggt 4140 agaatggcta ctataaaaaa atgaagtgtc atcaaggata tagagaaatt ggaacccttc 4200 ttcactgctg gagggaatgg aaaatggtgt agccgttatg aaaaacagta cggaggtttc 4260 tcaaaaatta aaaatagaac tgctatatga tccagcaatc tcacttctgt atatataccc 4320 aaaataattg aaatcagaat ttcaagaaaa tatttacact cccatgttca ttgtggcact 4380 cttcacaatc actgtttcca aagttatgga aacaacccaa atttccattg aaaaataaat 4440 ggacaaagaa aatgtgcata tacgtacaat gggatattat tcagcctaaa aaaaggggga 4500 atcctgttat ttatgacaac atgaataaac ccggaggcca ttatgctatg taaaatgagc 4560 aagtaacaga aagacaaata ctgcctgatt tcatttatat gaggttctaa aatagtcaaa 4620 ctcatagaag cagagaatag aacagtggtt cctagggaaa aggaggaagg gagaaatgag 4680 gaaataggga gttgtctaat tggtataaaa ttatagtatg caagatgaat tagctctaaa 4740 gatcagctgt atagcagagt tcgtataatg aacaatactg tattatgcac ttaacatttt 4800 gttaagaggg tacctctcat gttaagtgtt cttaccatat acatatacac aaggaagctt 4860 ttggaggtga tggatatatt tattaccttg attgtggtga tggtttgaca ggtatgtgac 4920 tatgtctaaa ctcatcaaat tgtatacatt aaatatatgc agttttataa tatcaattat 4980 gtctgaatga agctataaaa aagaaaagac aacaaaattc agttgtcaaa actggaaata 5040 tgaccacagt cagaagtgtt tgttactgag tgtttcagag tgtgtttggt ttgagcaggt 5100 ctagggtgat tgaacatccc tgggtgtgtt tccatgtctc atgtactagt gaaagtagat 5160 gtgtgcattt gtgcacatat ccctatgtat ccctatcagg gctgtgtgta tttgaaagtg 5220 tgtgtgtccg catgatcata tctgtataga agagagtgtg attatatttc ttgaagaata 5280 catccatttg aaatggatgt ctatggctgt ttgagatgag ttctctactc ttgtgcttgt 5340 acagtagtct ccccttatcc cttatgcttg gtggatacgt tcttagaccc caagtggatc 5400 tctgagaccg cagatggtac caaacctcat atatgcaata ttttttccta tacataaata 5460 cctaagataa agttcatctt ctgaattagg cacagtaaga gattaa 5506 <210> 3 <211> 5626 <212> DNA
<213> Homo Sapiens <400> 3 ctgtgacaaa agagataact attagagaaa caaaagtcca gaatgctaag gttgccgctt 60 tcacttcctc tcacccttta gcccagaact gctttgaata caccaattgc tgtggggcgg 120 ctcgaggaag agaagacacc agtgcctcag aaactgctcg gtcagacggt gatagcgagc 180 cacgcattca cagggccact gctgctcaca gaagcagtga ggatgatgcc aggatgatgt 240 ctgcctcgcg cctggctggg actctgatcc cagccatggc cttcctctcc tgcgtgagac 300 cagaaagctg ggagccctgc gtggagactt ggccctaaac cacacagaag agctggcatg 360 aaacccagag ctttcagact ccggagcctc agcccttcac cccgattcca ttgcttcttg 420 ctaaatgctg ccgttttatc acggaggtgg ttcctaatat tacttatcaa tgcatggagc 480 tgaatttcta caaaatcccc gacaacctcc ccttctcaac caagaacctg gacctgagct 540 ttaatcccct gaggcattta ggcagctata gcttcttcag tttcccagaa ctgcaggtgc 600 tggatttatc caggtgtgaa atccagacaa ttgaagatgg ggcatatcag agcctaagcc 660 acctctctac cttaatattg acaggaaacc ccatccagag tttagccctg ggagcctttt 720 ctggactatc aagtttacag aagctggtgg ctgtggagac aaatctagca tctctagaga 780 acttccccat tggacatctc aaaactttga aagaacttaa tgtggctcac aatcttatcc 840 aatctttcaa attacctgag tatttttcta atctgaccaa tctagagcac ttggaccttt 900 ccagcaacaa gattcaaagt atttattgca cagacttgcg ggttctacat caaatgcccc 960 tactcaatct ctctttagac ctgtccctga accctatgaa ctttatccaa ccaggtgcat 1020 ttaaagaaat taggcttcat aagctgactt taagaaataa ttttgatagt ttaaatgtaa 1080 tgaaaacttg tattcaaggt ctggctggtt tagaagtcca tcgtttggtt ctgggagaat 1140 ttagaaatga aggaaacttg gaaaagtttg acaaatctgc tctagagggc ctgtgcaatt 1200 tgaccattga agaattccga ttagcatact tagactacta cctcgatgat attattgact 1260 tatttaattg tttgacaaat gtttcttcat tttccctggt gagtgtgact attgaaaggg 1320 taaaagactt ttcttataat ttcggatggc aacatttaga attagttaac tgtaaatttg 1380 gacagtttcc cacattgaaa ctcaaatctc tcaaaaggct tactttcact tccaacaaag 1440 gtgggaatgc tttttcagaa gttgatctac caagccttga gtttctagat ctcagtagaa 1500 atggcttgag tttcaaaggt tgctgttctc aaagtgattt tgggacaacc agcctaaagt 1560 atttagatct gagcttcaat ggtgttatta ccatgagttc aaacttcttg ggcttagaac 1620 aactagaaca tctggatttc cagcattcca atttgaaaca aatgagtgag ttttcagtat 1680 tcctatcact cagaaacctc atttaccttg acatttctca tactcacacc agagttgctt 1740 tcaatggcat cttcaatggc ttgtccagtc tcgaagtctt gaaaatggct ggcaattctt 1800 tccaggaaaa cttccttcca gatatcttca cagagctgag aaacttgacc ttcctggacc 1860 tctctcagtg tcaactggag cagttgtctc caacagcatt taactcactc tccagtcttc 1920 aggtactaaa tatgagccac aacaacttct tttcattgga tacgtttcct tataagtgtc 1980 tgaactccct ccaggttctt gattacagtc tcaatcacat aatgacttcc aaaaaacagg 2040 aactacagca ttttccaagt agtctagctt tcttaaatct tactcagaat gactttgctt 2100 gtacttgtga acaccagagt ttcctgcaat ggatcaagga ccagaggcag ctcttggtgg 2160 aagttgaacg aatggaatgt gcaacacctt cagataagca gggcatgcct gtgctgagtt 2220 tgaatatcac ctgtcagatg aataagacca tcattggtgt gtcggtcctc agtgtgcttg 2280 tagtatctgt tgtagcagtt ctggtctata agttctattt tcacctgatg cttcttgctg 2340 gctgcataaa gtatggtaga ggtgaaaaca tctatgatgc ctttgttatc tactcaagcc 2400 aggatgagga ctgggtaagg aatgagctag taaagaattt agaagaaggg gtgcctccat 2460 ttcagctctg ccttcactac agagacttta ttcccggtgt ggccattgct gccaacatca 2520 tccatgaagg tttccataaa agccgaaagg tgattgttgt ggtgtcccag cacttcatcc 2580 agagccgctg gtgtatcttt gaatatgaga ttgctcagac ctggcagttt ctgagcagtc 2640 gtgctggtat catcttcatt gtcctgcaga aggtggagaa gaccctgctc aggcagcagg 2700 tggagctgta ccgccttctc agcaggaaca cttacctgga gtgggaggac agtgtcctgg 2760 ggcggcacat cttctggaga cgactcagaa aagccctgct ggatggtaaa tcatggaatc 2820 cagaaggaac agtgggtaca ggatgcaatt ggcaggaagc aacatctatc tgaagaggaa 2880 aaataaaaac ctcctgaggc atttcttgcc cagctgggtc caacacttgt tcagttaata 2940 agtattaaat gctgccacat gtcaggcctt atgctaaggg tgagtaattc catggtgcac 3000 tagatatgca gggctgctaa tctcaaggag cttccagtgc agagggaata aatgctagac 3060 taaaatacag agtcttccag gtgggcattt caaccaactc agtcaaggaa cccatgacaa 3120 agaaagtcat ttcaactctt acctcatcaa gttgaataaa gacagagaaa acagaaagag 3180 acattgttct tttcctgagt cttttgaatg gaaattgtat tatgttatag ccatcataaa 3240 accattttgg tagttttgac tgaactgggt gttcactttt tcctttttga ttgaatacaa 3300 tttaaattct acttgatgac tgcagtcgtc aaggggctcc tgatgcaaga tgccccttcc 3360 attttaagtc tgtotcctta cagaggttaa agtctagtgg ctaattccta aggaaacctg 3420 attaacacat gctcacaacc atcctggtca ttctcgagca tgttctattt tttaactaat 3480 cacccctgat atatttttat ttttatatat ccagttttca tttttttacg tcttgcctat 3540 aagctaatat cataaataag gttgtttaag acgtgcttca aatatccata ttaaccacta 3600 tttttcaagg aagtatggaa aagtacactc tgtcactttg tcactcgatg tcattccaaa 3660 gttattgcct actaagtaat gactgtcatg aaagcagcat tgaaataatt tgtttaaagg 3720 gggcactctt ttaaacggga agaaaatttc cgcttcctgg tcttatcatg gacaatttgg 3780 gctagaggca ggaaggaagt gggatgacct caggaggtca ccttttcttg attccagaaa 3840 catatgggct gataaacccg gggtgacctc atgaaatgag ttgcagcaga agtttatttt 3900 tttcagaaca agtgatgttt gatggacctc tgaatctctt tagggagaca cagatggctg 3960 ggatccctcc cctgtaccct tctcactgcc aggagaacta cgtgtgaagg tattcaaggc 4020 agggagtata cattgctgtt tcctgttggg caatgctcct tgaccacatt ttgggaagag 4080 tggatgttat cattgagaaa acaatgtgtc tggaattaat ggggttctta taaagaaggt 4140 tcccagaaaa gaatgttcat ccagcctcct cagaaacaga acattcaaga aaaggacaat 4200 caggatgtca tcagggaaat gaaaataaaa accacaatga gatatcacct tataccaggt 4260 agaatggcta ctataaaaaa atgaagtgtc atcaaggata tagagaaatt ggaacccttc 4320 ttcactgctg gagggaatgg aaaatggtgt agccgttatg aaaaacagta cggaggtttc 4380 tcaaaaatta aaaatagaac tgctatatga tccagcaatc tcacttctgt atatataccc 4440 aaaataattg aaatcagaat ttcaagaaaa tatttacact cccatgttca ttgtggcact 4500 cttcacaatc actgtttcca aagttatgga aacaacccaa atttccattg aaaaataaat 4560 ggacaaagaa aatgtgcata tacgtacaat gggatattat tcagcctaaa aaaaggggga 4620 atcctgttat ttatgacaac atgaataaac ccggaggcca ttatgctatg taaaatgagc 4680 aagtaacaga aagacaaata ctgcctgatt tcatttatat gaggttctaa aatagtcaaa 4740 ctcatagaag cagagaatag aacagtggtt cctagggaaa aggaggaagg gagaaatgag 4800 gaaataggga gttgtctaat tggtataaaa ttatagtatg caagatgaat tagctctaaa 4860 gatcagctgt atagcagagt tcgtataatg aacaatactg tattatgcac ttaacatttt 4920 gttaagaggg tacctctcat gttaagtgtt cttaccatat acatatacac aaggaagctt 4980 ttggaggtga tggatatatt tattaccttg attgtggtga tggtttgaca ggtatgtgac 5040 tatgtctaaa ctcatcaaat tgtatacatt aaatatatgc agttttataa tatcaattat 5100 gtctgaatga agctataaaa aagaaaagac aacaaaattc agttgtcaaa actggaaata 5160 tgaccacagt cagaagtgtt tgttactgag tgtttcagag tgtgtttggt ttgagcaggt 5220 ctagggtgat tgaacatccc tgggtgtgtt tccatgtctc atgtactagt gaaagtagat 5280 gtgtgcattt gtgcacatat ccctatgtat ccctatcagg gctgtgtgta tttgaaagtg 5340 tgtgtgtccg catgatcata tctgtataga agagagtgtg attatatttc ttgaagaata 5400 catccatttg aaatggatgt ctatggctgt ttgagatgag ttctctactc ttgtgcttgt 5460 acagtagtct ccccttatcc cttatgcttg gtggatacgt tcttagaccc caagtggatc 5520 tctgagaccg cagatggtac caaacctcat atatgcaata ttttttccta tacataaata 5580 cctaagataa agttcatctt ctgaattagg cacagtaaga gattaa 5626 <210> 4 <211> 5339 <212> DNA
<213> Homo Sapiens <400> 4 ctgtgacaaa agagataact attagagaaa caaaagtcca gaatgctaag gttgccgctt 60 tcacttcctc tcacccttta gcccagaact gctttgaata caccaattgc tgtggggcgg 120 ctcgaggaag agaagacacc agtgcctcag aaactgctcg gtcagacggt gatagcgagc 180 cacgcattca cagggccact gctgctcaca gaagcagtga ggatgatgcc aggatgatgt 240 ctgcctcgcg cctggctggg actctgatcc cagccatggc cttcctctcc tgcgtgagac 300 cagaaagctg ggagccctgc gtggaggtgt gaaatccaga caattgaaga tggggcatat 360 cagagcctaa gccacctctc taccttaata ttgacaggaa accccatcca gagtttagcc 420 ctgggagcct tttctggact atcaagttta cagaagctgg tggctgtgga gacaaatcta 480 gcatctctag agaacttccc cattggacat ctcaaaactt tgaaagaact taatgtggct 540 cacaatctta tccaatcttt caaattacct gagtattttt ctaatctgac caatctagag 600 cacttggacc tttccagcaa caagattcaa agtatttatt gcacagactt gcgggttcta 660 catcaaatgc ccctactcaa tctctcttta gacctgtccc tgaaccctat gaactttatc 720 caaccaggtg catttaaaga aattaggctt cataagctga ctttaagaaa taattttgat 780 agtttaaatg taatgaaaac ttgtattcaa ggtctggctg gtttagaagt ccatcgtttg 840 gttctgggag aatttagaaa tgaaggaaac ttggaaaagt ttgacaaatc tgctctagag 900 ggcctgtgca atttgaccat tgaagaattc cgattagcat acttagacta ctacctcgat 960 gatattattg acttatttaa ttgtttgaca aatgtttctt cattttccct ggtgagtgtg 1020 actattgaaa gggtaaaaga cttttcttat aatttcggat ggcaacattt agaattagtt 1080 aactgtaaat ttggacagtt tcccacattg aaactcaaat ctctcaaaag gcttactttc 1140 acttccaaca aaggtgggaa tgctttttca gaagttgatc taccaagcct tgagtttcta 1200 gatctcagta gaaatggctt gagtttcaaa ggttgctgtt ctcaaagtga ttttgggaca 1260 accagcctaa agtatttaga tctgagcttc aatggtgtta ttaccatgag ttcaaacttc 1320 ttgggcttag aacaactaga acatctggat ttccagcatt ccaatttgaa acaaatgagt 1380 gagttttcag tattcctatc actcagaaac ctcatttacc ttgacatttc tcatactcac 1440 accagagttg ctttcaatgg catcttcaat ggcttgtcca gtctcgaagt cttgaaaatg 1500 gctggcaatt ctttccagga aaacttcctt ccagatatct tcacagagct gagaaacttg 1560 accttcctgg acctctctca gtgtcaactg gagcagttgt ctccaacagc atttaactca 1620 ctctccagtc ttcaggtact aaatatgagc cacaacaact tcttttcatt ggatacgttt 1680 ccttataagt gtctgaactc cctccaggtt cttgattaca gtctcaatca cataatgact 1740 tccaaaaaac aggaactaca gcattttcca agtagtctag ctttcttaaa tcttactcag 1800 aatgactttg cttgtacttg tgaacaccag agtttcctgc aatggatcaa ggaccagagg 1860 cagctcttgg tggaagttga acgaatggaa tgtgcaacac cttcagataa gcagggcatg 1920 cctgtgctga gtttgaatat cacctgtcag atgaataaga ccatcattgg tgtgtcggtc 1980 ctcagtgtgc ttgtagtatc tgttgtagca gttctggtct ataagttcta ttttcacctg 2040 atgcttcttg ctggctgcat aaagtatggt agaggtgaaa acatctatga tgcctttgtt 2100 atctactcaa gccaggatga ggactgggta aggaatgagc tagtaaagaa tttagaagaa 2160 ggggtgcctc catttcagct ctgccttcac tacagagact ttattcccgg tgtggccatt 2220 gctgccaaca tcatccatga aggtttccat aaaagccgaa aggtgattgt tgtggtgtcc 2280 cagcacttca tccagagccg ctggtgtatc tttgaatatg agattgctca gacctggcag 2340 tttctgagca gtcgtgctgg tatcatcttc attgtcctgc agaaggtgga gaagaccctg 2400 ctcaggcagc aggtggagct gtaccgcctt ctcagcagga acacttacct ggagtgggag 2460 gacagtgtcc tggggcggca catcttctgg agacgactca gaaaagccct gctggatggt 2520 aaatcatgga atccagaagg aacagtgggt acaggatgca attggcagga agcaacatct 2580 atctgaagag gaaaaataaa aacctcctga ggcatttctt gcccagctgg gtccaacact 2640 tgttcagtta ataagtatta aatgctgcca catgtcaggc cttatgctaa gggtgagtaa 2700 ttccatggtg cactagatat gcagggctgc taatctcaag gagcttccag tgcagaggga 2760 ataaatgcta gactaaaata cagagtcttc caggtgggca tttcaaccaa ctcagtcaag 2820 gaacccatga caaagaaagt catttcaact cttacctcat caagttgaat aaagacagag 2880 aaaacagaaa gagacattgt tcttttcctg agtcttttga atggaaattg tattatgtta 2940 tagccatcat aaaaccattt tggtagtttt gactgaactg ggtgttcact ttttcctttt 3000 tgattgaata caatttaaat tctacttgat gactgcagtc gtcaaggggc tcctgatgca 3060 agatgcccct tccattttaa gtctgtctcc ttacagaggt taaagtctag tggctaattc 3120 ctaaggaaac ctgattaaca catgctcaca accatcctgg tcattctcga gcatgttcta 3180 ttttttaact aatcacccct gatatatttt tatttttata tatccagttt tcattttttt 3240 acgtcttgcc tataagctaa tatcataaat aaggttgttt aagacgtgct tcaaatatcc 3300 atattaacca ctatttttca aggaagtatg gaaaagtaca ctctgtcact ttgtcactcg 3360 atgtcattcc aaagttattg cctactaagt aatgactgtc atgaaagcag cattgaaata 3420 atttgtttaa agggggcact cttttaaacg ggaagaaaat ttccgcttcc tggtcttatc 3480 atggacaatt tgggctagag gcaggaagga agtgggatga cctcaggagg tcaccttttc 3540 ttgattccag aaacatatgg gctgataaac ccggggtgac ctcatgaaat gagttgcagc 3600 agaagtttat ttttttcaga acaagtgatg tttgatggac ctctgaatct ctttagggag 3660 acacagatgg ctgggatccc tcccctgtac ccttctcact gccaggagaa ctacgtgtga 3720 aggtattcaa ggcagggagt atacattgct gtttcctgtt gggcaatgct ccttgaccac 3780 attttgggaa gagtggatgt tatcattgag aaaacaatgt gtctggaatt aatggggttc 3840 ttataaagaa ggttcccaga aaagaatgtt catccagcct cctcagaaac agaacattca 3900 agaaaaggac aatcaggatg tcatcaggga aatgaaaata aaaaccacaa tgagatatca 3960 ccttatacca ggtagaatgg ctactataaa aaaatgaagt gtcatcaagg atatagagaa 4020 attggaaccc ttcttcactg ctggagggaa tggaaaatgg tgtagccgtt atgaaaaaca 4080 gtacggaggt ttctcaaaaa ttaaaaatag aactgctata tgatccagca atctcacttc 4140 tgtatatata cccaaaataa ttgaaatcag aatttcaaga aaatatttac actcccatgt 4200 tcattgtggc actcttcaca atcactgttt ccaaagttat ggaaacaacc caaatttcca 4260 ttgaaaaata aatggacaaa gaaaatgtgc atatacgtac aatgggatat tattcagcct 4320 aaaaaaaggg ggaatcctgt tatttatgac aacatgaata aacccggagg ccattatgct 4380 atgtaaaatg agcaagtaac agaaagacaa atactgcctg atttcattta tatgaggttc 4440 taaaatagtc aaactcatag aagcagagaa tagaacagtg gttcctaggg aaaaggagga 4500 agggagaaat gaggaaatag ggagttgtct aattggtata aaattatagt atgcaagatg 4560 aattagctct aaagatcagc tgtatagcag agttcgtata atgaacaata ctgtattatg 4620 cacttaacat tttgttaaga gggtacctct catgttaagt gttcttacca tatacatata 4680 cacaaggaag cttttggagg tgatggatat atttattacc ttgattgtgg tgatggtttg 4740 acaggtatgt gactatgtct aaactcatca aattgtatac attaaatata tgcagtttta 4800 taatatcaat tatgtctgaa tgaagctata aaaaagaaaa gacaacaaaa ttcagttgtc 4860 aaaactggaa atatgaccac agtcagaagt gtttgttact gagtgtttca gagtgtgttt 4920 ggtttgagca ggtctagggt gattgaacat ccctgggtgt gtttccatgt ctcatgtact 4980 agtgaaagta gatgtgtgca tttgtgcaca tatccctatg tatccctatc agggctgtgt 5040 gtatttgaaa gtgtgtgtgt ccgcatgatc atatctgtat agaagagagt gtgattatat 5100 ttcttgaaga atacatccat ttgaaatgga tgtctatggc tgtttgagat gagttctcta 5160 ctcttgtgct tgtacagtag tctcccctta tcccttatgc ttggtggata cgttcttaga 5220 ccccaagtgg atctctgaga ccgcagatgg taccaaacct catatatgca atattttttc 5280 ctatacataa atacctaaga taaagttcat cttctgaatt aggcacagta agagattaa 5339 <210> 5 <211> 5459 <212> DNA
<213> Homo Sapiens <400> 5 ctgtgacaaa agagataact attagagaaa caaaagtcca gaatgctaag gttgccgctt 60 tcacttcctc tcacccttta gcccagaact gctttgaata caccaattgc tgtggggcgg 120 ctcgaggaag agaagacacc agtgcctcag aaactgctcg gtcagacggt gatagcgagc 180 cacgcattca cagggccact gctgctcaca gaagcagtga ggatgatgcc aggatgatgt 240

7 ctgcctcgcg cctggctggg actctgatcc cagccatggc cttcctctcc tgcgtgagac 300 cagaaagctg ggagccctgc gtggagactt ggccctaaac cacacagaag agctggcatg 360 aaacccagag ctttcagact ccggagcctc agcccttcac cccgattcca ttgcttcttg 420 ctaaatgctg ccgttttatc acggaggtgt gaaatccaga caattgaaga tggggcatat 480 cagagcctaa gccacctctc taccttaata ttgacaggaa accccatcca gagtttagcc 540 ctgggagcct tttctggact atcaagttta cagaagctgg tggctgtgga gacaaatcta 600 gcatctctag agaacttccc cattggacat ctcaaaactt tgaaagaact taatgtggct 660 cacaatctta tccaatcttt caaattacct gagtattttt ctaatctgac caatctagag 720 cacttggacc tttccagcaa caagattcaa agtatttatt gcacagactt gcgggttcta 780 catcaaatgc ccctactcaa tctctcttta gacctgtccc tgaaccctat gaactttatc 840 caaccaggtg catttaaaga aattaggctt cataagctga ctttaagaaa taattttgat 900 agtttaaatg taatgaaaac ttgtattcaa ggtctggctg gtttagaagt ccatcgtttg 960 gttctgggag aatttagaaa tgaaggaaac ttggaaaagt ttgacaaatc tgctctagag 1020 ggcctgtgca atttgaccat tgaagaattc cgattagcat acttagacta ctacctcgat 1080 gatattattg acttatttaa ttgtttgaca aatgtttctt cattttccct ggtgagtgtg 1140 actattgaaa gggtaaaaga cttttcttat aatttcggat ggcaacattt agaattagtt 1200 aactgtaaat ttggacagtt tcccacattg aaactcaaat ctctcaaaag gcttactttc 1260 acttccaaca aaggtgggaa tgctttttca gaagttgatc taccaagcct tgagtttcta 1320 gatctcagta gaaatggctt gagtttcaaa ggttgctgtt ctcaaagtga ttttgggaca 1380 accagcctaa agtatttaga tctgagcttc aatggtgtta ttaccatgag ttcaaacttc 1440 ttgggcttag aacaactaga acatctggat ttccagcatt ccaatttgaa acaaatgagt 1500 gagttttcag tattcctatc actcagaaac ctcatttacc ttgacatttc tcatactcac 1560 accagagttg ctttcaatgg catcttcaat ggcttgtcca gtctcgaagt cttgaaaatg 1620 gctggcaatt ctttccagga aaacttcctt ccagatatct tcacagagct gagaaacttg 1680 accttcctgg acctctctca gtgtcaactg gagcagttgt ctccaacagc atttaactca 1740 ctctccagtc ttcaggtact aaatatgagc cacaacaact tcttttcatt ggatacgttt 1800 ccttataagt gtctgaactc cctccaggtt cttgattaca gtctcaatca cataatgact 1860 tccaaaaaac aggaactaca gcattttcca agtagtctag ctttcttaaa tcttactcag 1920 aatgactttg cttgtacttg tgaacaccag agtttcctgc aatggatcaa ggaccagagg 1980 cagctcttgg tggaagttga acgaatggaa tgtgcaacac cttcagataa gcagggcatg 2040 cctgtgctga gtttgaatat cacctgtcag atgaataaga ccatcattgg tgtgtcggtc 2100 ctcagtgtgc ttgtagtatc tgttgtagca gttctggtct ataagttcta ttttcacctg 2160 atgcttcttg ctggctgcat aaagtatggt agaggtgaaa acatctatga tgcctttgtt 2220 atctactcaa gccaggatga ggactgggta aggaatgagc tagtaaagaa tttagaagaa 2280 ggggtgcctc catttcagct ctgccttcac tacagagact ttattcccgg tgtggccatt 2340 gctgccaaca tcatccatga aggtttccat aaaagccgaa aggtgattgt tgtggtgtcc 2400 cagcacttca tccagagccg ctggtgtatc tttgaatatg agattgctca gacctggcag 2460 tttctgagca gtcgtgctgg tatcatcttc attgtcctgc agaaggtgga gaagaccctg 2520 ctcaggcagc aggtggagct gtaccgcctt ctcagcagga acacttacct ggagtgggag 2580 gacagtgtcc tggggcggca catcttctgg agacgactca gaaaagccct gctggatggt 2640 aaatcatgga atccagaagg aacagtgggt acaggatgca attggcagga agcaacatct 2700 atctgaagag gaaaaataaa aacctcctga ggcatttctt gcccagctgg gtccaacact 2760 tgttcagtta ataagtatta aatgctgcca catgtcaggc cttatgctaa gggtgagtaa 2820 ttccatggtg cactagatat gcagggctgc taatctcaag gagcttccag tgcagaggga 2880 ataaatgcta gactaaaata cagagtcttc caggtgggca tttcaaccaa ctcagtcaag 2940 gaacccatga caaagaaagt catttcaact cttacctcat caagttgaat aaagacagag 3000 aaaacagaaa gagacattgt tcttttcctg agtcttttga atggaaattg tattatgtta 3060 tagccatcat aaaaccattt tggtagtttt gactgaactg ggtgttcact ttttcctttt 3120 tgattgaata caatttaaat tctacttgat gactgcagtc gtcaaggggc tcctgatgca 3180 agatgcccct tccattttaa gtctgtctcc ttacagaggt taaagtctag tggctaattc 3240 ctaaggaaac ctgattaaca catgctcaca accatcctgg tcattctcga gcatgttcta 3300 ttttttaact aatcacccct gatatatttt tatttttata tatccagttt tcattttttt 3360 acgtcttgcc tataagctaa tatcataaat aaggttgttt aagacgtgct tcaaatatcc 3420 atattaacca ctatttttca aggaagtatg gaaaagtaca ctctgtcact ttgtcactcg 3480 atgtcattcc aaagttattg cctactaagt aatgactgtc atgaaagcag cattgaaata 3540 atttgtttaa agggggcact cttttaaacg ggaagaaaat ttccgcttcc tggtcttatc 3600 atggacaatt tgggctagag gcaggaagga agtgggatga cctcaggagg tcaccttttc 3660

8 ttgattccag aaacatatgg gctgataaac ccggggtgac ctcatgaaat gagttgcagc 3720 agaagtttat ttttttcaga acaagtgatg tttgatggac ctctgaatct ctttagggag 3780 acacagatgg ctgggatccc tcccctgtac ccttctcact gccaggagaa ctacgtgtga 3840 aggtattcaa ggcagggagt atacattgct gtttcctgtt gggcaatgct ccttgaccac 3900 attttgggaa gagtggatgt tatcattgag aaaacaatgt gtctggaatt aatggggttc 3960 ttataaagaa ggttcccaga aaagaatgtt catccagcct cctcagaaac agaacattca 4020 agaaaaggac aatcaggatg tcatcaggga aatgaaaata aaaaccacaa tgagatatca 4080 ccttatacca ggtagaatgg ctactataaa aaaatgaagt gtcatcaagg atatagagaa 4140 attggaaccc ttcttcactg ctggagggaa tggaaaatgg tgtagccgtt atgaaaaaca 4200 gtacggaggt ttctcaaaaa ttaaaaatag aactgctata tgatccagca atctcacttc 4260 tgtatatata cccaaaataa ttgaaatcag aatttcaaga aaatatttac actcccatgt 4320 tcattgtggc actcttcaca atcactgttt ccaaagttat ggaaacaacc caaatttcca 4380 ttgaaaaata aatggacaaa gaaaatgtgc atatacgtac aatgggatat tattcagcct 4440 aaaaaaaggg ggaatcctgt tatttatgac aacatgaata aacccggagg ccattatgct 4500 atgtaaaatg agcaagtaac agaaagacaa atactgcctg atttcattta tatgaggttc 4560 taaaatagtc aaactcatag aagcagagaa tagaacagtg gttcctaggg aaaaggagga 4620 agggagaaat gaggaaatag ggagttgtct aattggtata aaattatagt atgcaagatg 4680 aattagctct aaagatcagc tgtatagcag agttcgtata atgaacaata ctgtattatg 4740 cacttaacat tttgttaaga gggtacctct catgttaagt qttcttacca tatacatata 4800 cacaaggaag cttttggagg tgatggatat atttattacc ttgattgtgg tgatggtttg 4860 acaggtatgt gactatgtct aaactcatca aattgtatac attaaatata tgcagtttta 4920 taatatcaat tatgtctgaa tgaagctata aaaaagaaaa gacaacaaaa ttcagttgtc 4980 aaaactggaa atatgaccac agtcagaagt gtttgttact gagtgtttca gagtgtgttt 5040 ggtttgagca ggtctagggt gattgaacat ccctgggtgt gtttccatgt ctcatgtact 5100 agtgaaagta gatgtgtgca tttgtgcaca tatccctatg tatccctatc agggctgtgt 5160 gtatttgaaa gtgtgtgtgt ccgcatgatc atatctgtat agaagagagt gtgattatat 5220 ttcttgaaga atacatccat ttgaaatgga tgtctatggc tgtttgagat gagttctcta 5280 ctcttgtgct tgtacagtag tctcccctta tcccttatgc ttggtggata cgttcttaga 5340 ccccaagtgg atctctgaga ccgcagatgg taccaaacct catatatgca atattttttc 5400 ctatacataa atacctaaga taaagttcat cttctgaatt aggcacagta agagattaa 5459 <210> 6 <211> 3557 <212> DNA
<213> Homo Sapiens <400> 6 caggacgtga aacgggggcg gtttgggaag tttagagacc attctccgcc gaccaaaacc 60 cgtcaaagga ttatcagaca cgcgggtcgg acggtccaca tcagccggca gcccgggcgg 120 gtcccggggt gcgagcagcg cacttccgta gtgcagcttc ggctggtgtc atcggtgtcc 180 ttcctccgct gccgcccccg caaggcttcg ccgtcatcga ggccatttcc agcgacttgt 240 cgcacgcttt tctatatact tcgttccccg ccaaccgcaa ccattgacgc catgtcgggt 300 tattcgagtg accgagaccg cggccgggac cgagggtttg gtgcacctcg atttggagga 360 agtagggcag ggcccttatc tggaaagaag tttggaaacc ctggggagaa attagttaaa 420 aagaagtgga atcttgatga gctgcctaaa tttgagaaga atttttatca agagcaccct 480 gatttggcta ggcgcacagc acaagaggtg gaaacataca gaagaagcaa ggaaattaca 540 gttagaggtc acaactgccc gaagccagtt ctaaattttt atgaagccaa tttccctgca 600 aatgtcatgg atgttattgc aagacagaat ttcactgaac ccactgctat tcaagctcag 660 ggatggccag ttgctctaag tggattggat atggttggag tggcacagac tggatctggg 720 aaaacattgt cttatttgct tcctgccatt gtccacatca atcatcagcc attcctagag 780 agaggcgatg ggcctatttg tttggtgctg gcaccaactc gggaactggc ccaacaggtg 840 cagcaagtag ctgctgaata ttgtagagca tgtcgcttga agtctacttg tatctacggt 900 ggtgctccta agggaccaca aatacgtgat ttggagagag gtgtggaaat ctgtattgca 960 acacctggaa gactgattga ctttttagag tgtggaaaaa ccaatctgag aagaacaacc 1020 taccttgtcc ttgatgaagc agatagaatg cttgatatgg gctttgaacc ccaaataagg 1080

9 aagattgtgg atcaaataag acctgatagg caaactctaa tgtggagtgc gacttggcca 1140 aaagaagtaa gacagcttgc tgaagatttc ctgaaagact atattcatat aaacattggt 1200 gcacttgaac tgagtgcaaa ccacaacatt cttcagattg tggatgtgtg tcatgacgta 1260 gaaaaggatg aaaaacttat tcgtctaatg gaagagatca tgagtgagaa ggagaataaa 1320 accattgttt ttgtggaaac caaaagaaga tgtgatgagc ttaccagaaa aatgaggaga 1380 gatgggtggc ctgccatggg tatccatggt gacaagagtc aacaagagcg tgactgggtt 1440 ctaaatgaat tcaaacatgg aaaagctcct attctgattg ctacagatgt ggcctccaga 1500 gggctagatg tggaagatgt gaaatttgtc atcaattatg actaccctaa ctcctcagag 1560 gattatattc atcgaattgg aagaactgct cgcagtacca aaacaggcac agcatacact 1620 ttctttacac ctaataacat aaagcaagtg agcgacctta tctctgtgct tcgtgaagct 1680 aatcaagcaa ttaatcccaa gttgcttcag ttggtcgaag acagaggttc aggtcgttcc 1740 aggggtagag gaggcatgaa ggatgaccgt cgggacagat actctgcggg caaaaggggt 1800 ggatttaata cctttagaga cagggaaaat tatgacagag gttactctag cctgcttaaa 1860 agagattttg gggcaaaaac tcagaatggt gtttacagtg ctgcaaatta caccaatggg 1920 agctttggaa gtaattttgt gtctgctggt atacagacca gttttaggac tggtaatcca 1980 acagggactt accagaatgg ttatgatagc actcagcaat acggaagtaa tgttccaaat 2040 atgcacaatg gtatgaacca acaggcatat gcatatcctg ctactgcagc tgcacctatg 2100 attggttatc caatgccaac aggatattcc caataagact ttagaagtat atgtaaatgt 2160 ctgtttttca taattgctct ttatattgtg tgttatctga caagatagtt atttaagaaa 2220 catgggaatt gcagaaatga ctgcagtgca gcagtaatta tggtgcactt tttcgctatt 2280 taagttggat atttctctac attcctgaaa caatttttag gttttttttg tactagaaaa 2340 tgcaggcagt gttttcacaa aagtaaatgt acagtgattt gaaatacaat aaatgaaggc 2400 aatgcatggc cttccaataa aaaatatttg aagactgaat taagtggaaa ttgtacttta 2460 ttttatataa tgtcatgtaa aactttgcta gtatggttaa atgagaaaat agtaaaatag 2520 atacaaagtc atctatatag tgtgagaacg tgggtgactt tttcaaagtt tataatttaa 2580 aaagctccaa ataactggct ttttcaagag acttatactc atgctcttgg ctatactgtg 2640 aattactgaa atgttgaaca aacctgtgaa agacatacat tagcccttta agatggccag 2700 gagctaagct tgagtctcct ttactgaatt tcgttcttag tgcaggttac ttgtagattc 2760 tagtcttcac aggctccctg gggctcttaa ctagtcacac tgggagtcat gaatgtcttt 2820 ccaataattc agggaattct agagatcctc aaactgtaag gtctattcat actcaacaca 2880 aggaaaaaac ctcattaaaa ttaatgacta atcaggaggc aacgtaacca aaagcacagt 2940 gaatgaaagt tttcatggta ggttcaacat gggtttattg ctagaaagat ccaggggata 3000 gctttaggtt taacttcggc tcaccaacgt aactttctaa tcatttattt cagtaatagc 3060 tagaagtggg tctgaatgtt ttcccagagt ctgatacgtg tttttttttg ccagaagaga 3120 ggtcttcagg agacttcatt taaattctga ttattaaact gaggctttaa ttgatgttaa 3180 tgccttatgt caaatgtaaa gttagaattt gctagggctg ggatagggag tgatatttct 3240 aggacttaga cattgaaaac taattcagcc tgtagtaacc tggatggttt tcaatggcat 3300 ggttagtcaa attcatggtt ttaaacttag aagcagcttt cgggggagag ggtaggttgg 3360 agcatttatt acatatttta ctgtttaatg tcttaaccgt gggcctttta atttgtaaac 3420 actgaaatga ttgttgggct gtggaaaaca tttacctatt taccttggaa gttttaaaag 3480 acagtccact ttttagcatg tgtgttgtgt ccagcctgtg gtcgtcttaa ctaataaatg 3540 tgatttttct ccccatt 3557 <210> 7 <211> 3038 <212> DNA
<213> Homo Sapiens <400> 7 aggtcataga gcggctccca gcgttccctg cggcgtagga ggcggtccag actacaaaag 60 cggctgccgg aaagcggccg gcacctcatt catttctacc ggtctctagt agtgcagctt 120 cggctggtgt catcggtgtc cttcctccgc tgccgccccc gcaaggcttc gccgtcatcg 180 aggccatttc cagcgacttg tcgcacgctt ttctatatac ttcgttcccc gccaaccgca 240 accattgacg ccatgtcggg ttattcgagt gaccgagacc gcggccggga ccgagggttt 300 ggtgcacctc gatttggagg aagtagggca gggcccttat ctggaaagaa gtttggaaac 360 cctggggaga aattagttaa aaagaagtgg aatcttgatg agctgcctaa atttgagaag 420 aatttttatc aagagcaccc tgatttggct aggcgcacag cacaagaggt ggaaacatac 480 agaagaagca aggaaattac agttagaggt cacaactgcc cgaagccagt tctaaatttt 540 tatgaagcca atttccctgc aaatgtcatg gatgttattg caagacagaa tttcactgaa 600 cccactgcta ttcaagctca gggatggcca gttgctctaa gtggattgga tatggttgga 660 gtggcacaga ctggatctgg gaaaacattg tcttatttgc ttcctgccat tgtccacatc 720 aatcatcagc cattcctaga gagaggcgat gggcctattt gtttggtgct ggcaccaact 780 cgggaactgg cccaacaggt gcagcaagta gctgctgaat attgtagagc atgtcgcttg 840 aagtctactt gtatctacgg tggtgctcct aagggaccac aaatacgtga tttggagaga 900 ggtgtggaaa tctgtattgc aacacctgga agactgattg actttttaga gtgtggaaaa 960 accaatctga gaagaacaac ctaccttgtc cttgatgaag cagatagaat gcttgatatg 1020 ggctttgaac cccaaataag gaagattgtg gatcaaataa gacctgatag gcaaactcta 1080 atgtggagtg cgacttggcc aaaagaagta agacagcttg ctgaagattt cctgaaagac 1140 tatattcata taaacattgg tgcacttgaa ctgagtgcaa accacaacat tcttcagatt 1200 gtggatgtgt gtcatgacgt agaaaaggat gaaaaactta ttcgtctaat ggaagagatc 1260 atgagtgaga aggagaataa aaccattgtt tttgtggaaa ccaaaagaag atgtgatgag 1320 cttaccagaa aaatgaggag agatgggtgg cctgccatgg gtatccatgg tgacaagagt 1380 caacaagagc gtgactgggt tctaaatgaa ttcaaacatg gaaaagctcc tattctgatt 1440 gctacagatg tggcctccag agggctagat gtggaagatg tgaaatttgt catcaattat 1500 gactacccta actcctcaga ggattatatt catcgaattg gaagaactgc tcgcagtacc 1560 aaaacaggca cagcatacac tttctttaca cctaataaca taaagcaagt gagcgacctt 1620 atctctgtgc ttcgtgaagc taatcaagca attaatccca agttgcttca gttggtcgaa 1680 gacagaggtt caggtcgttc caggggtaga ggaggcatga aggatgaccg tcgggacaga 1740 tactctgcgg gcaaaagggg tggatttaat acctttagag acagggaaaa ttatgacaga 1800 ggttactcta gcctgcttaa aagagatttt ggggcaaaaa ctcagaatgg tgtttacagt 1860 gctgcaaatt acaccaatgg gagctttgga agtaattttg tgtctgctgg tatacagacc 1920 agttttagga ctggtaatcc aacagggact taccagaatg gttatgatag cactcagcaa 1980 tacggaagta atgttccaaa tatgcacaat ggtatgaacc aacaggcata tgcatatcct 2040 gctactgcag ctgcacctat gattggttat ccaatgccaa caggatattc ccaataagac 2100 tttagaagta tatgtaaatg tctgtttttc ataattgctc tttatattgt gtgttatctg 2160 acaagatagt tatttaagaa acatgggaat tgcagaaatg actgcagtgc agcagtaatt 2220 atggtgcact ttttcgctat ttaagttgga tatttctcta cattcctgaa acaattttta 2280 ggtttttttt gtactagaaa atgcaggcag tgttttcaca aaagtaaatg tacagtgatt 2340 tgaaatacaa taaatgaagg caatgcatgg ccttccaata aaaaatattt gaagactgaa 2400 ttaagtggaa attgtacttt attttatata atgtcatgta aaactttgct taagatggtc 2460 tggttttttt tttgtttttg tttggttttt tttttccatg aaaacaaatg actgttcctt 2520 tttatttaat ttgggaggca gggggaatca gaaggccctt ctttataatg agctattcat 2580 attgcaggag tcagaatgaa ttgatacagg tgaattttta gttacaggct aaattgcata 2640 aaagctttgt cagcttccag catcagggga gtcatttaat agcctttttc cttatttgct 2700 agtatggtta aatgagaaaa tagtaaaata gatacaaagt catctatata gtgtgagaac 2760 gtgggtgact ttttcaaagt ttataattta aaaagctcca aataactggc tttttcaaga 2820 gacttatact catgctcttg gctatactgt gaattactga aatgttgaac aaacctgtga 2880 aagacataca ttagcccttt aagatggcca ggagctaagc ttgagtctcc tttactgaat 2940 ttcgttctta gtgcaggtta cttgtagatt ctagtcttca caggctccct ggggctctta 3000 actagtcaca ctgggagtca tgaatgtctt tccaataa 3038 <210> 8 <211> 3919 <212> DNA
<213> Homo Sapiens <400> 8 actccctcac tggctgccat tgaaagagtc cacttctcag tgactcctag ctgggcactg 60 gatgcagttg aggattgctg gtcaatatga ttcttcttgc tgtgcttttt ctctgcttca 120 tttcctcata ttcagcttct gttaaaggtc acacaactgg tctctcatta aataatgacc 180 ggctgtacaa gctcacgtac tccactgaag ttcttcttga tcggggcaaa ggaaaactgc 240 aagacagcgt gggctaccgc atttcctcca acgtggatgt ggccttacta tggaggaatc 300 ctgatggtga tgatgaccag ttgatccaaa taacgatgaa ggatgtaaat gttgaaaatg 360 tgaatcagca gagaggagag aagagcatct tcaaaggaaa aagcccatct aaaataatgg 420 gaaaggaaaa cttggaagct ctgcaaagac ctacgctcct tcatctaatc catggaaagg 480 tcaaagagtt ctactcatat caaaatgagg cagtggccat agaaaatatc aagagaggcc 540 tggctagcct atttcagaca cagttaagct ctggaaccac caatgaggta gatatctctg 600 gaaattgtaa agtgacctac caggctcatc aagacaaagt gatcaaaatt aaggccttgg 660 attcatgcaa aatagcgagg tctggattta cgaccccaaa tcaggtcttg ggtgtcagtt 720 caaaagctac atctgtcacc acctataaga tagaagacag ctttgttata gctgtgcttg 780 ctgaagaaac acacaatttt ggactgaatt tcctacaaac cattaagggg aaaatagtat 840 cgaagcagaa attagagctg aagacaaccg aagcaggccc aagattgatg tctggaaaqc 900 aggctgcagc cataatcaaa gcagttgatt caaagtacac ggccattccc attgtggggc 960 aggtcttcca gagccagtgt aaaggatgtc cttctctctc ggagctctgg cggtccacca 1020 ggaaatacct gcagcctgac aacctttcca aggctgaggc tgtcagaaac ttcctggcct 1080 tcattcagca cctcaggact gcgaagaaag aagagatcct tcaaatacta aagatggaaa 1140 ataaggaagt attacctcag ctggtggatg ctgtcacctc tgctcagacc tcagactcat 1200 tagaagccat tttggacttt ttggatttca aaagtgacag cagcattatc ctccaggaga 1260 ggtttctcta tgcctgtgga tttgcttctc atcccaatga agaactcctg agagccctca 1320 ttagtaagtt caaaggttct attggtagca gtgacatcag agaaactgtt atgatcatca 1380 ctgggacact tgtcagaaag ttgtgtcaga atgaaggctg caaactcaaa gcagtagtgg 1440 aagctaagaa gttaatcctg ggaggacttg aaaaagcaga gaaaaaagag gacaccagga 1500 tgtatctgct ggctttgaag aatgccctgc ttccagaagg catcccaagt cttctgaagt 1560 atgcagaagc aggagaaggg cccatcagcc acctggctac cactgctctc cagagatatg 1620 atctcccttt cataactgat gaggtgaaga agaccttaaa cagaatatac caccaaaacc 1680 gtaaagttca tgaaaagact gtgcgcactg ctgcagctgc tatcatttta aataacaatc 1740 catcctacat ggacgtcaag aacatcctgc tgtctattgg ggagcttccc caagaaatga 1800 ataaatacat gctcgccatt gttcaagaca tcctacgttt tgaaatgcct gcaagcaaaa 1860 ttgtccgtcg agttctgaag gaaatggtcg ctcacaatta tgaccgtttc tccaggagtg 1920 gatcttcttc tgcctacact ggctacatag aacgtagtcc ccgttcggca tctacttaca 1980 gcctagacat tctctactcg ggttctggca ttctaaggag aagtaacctg aacatctttc 2040 agtacattgg gaaggctggt cttcacggta gccaggtggt tattgaagcc caaggactgg 2100 aagccttaat cgcagccacc cctgacgagg gggaggagaa ccttgactcc tatgctggta 2160 tgtcagccat cctctttgat gttcagctca gacctgtcac ctttttcaac ggatacagtg 2220 atttgatgtc caaaatgctg tcagcatctg gcgaccctat cagtgtggtg aaaggactta 2280 ttctgctaat agatcattct caggaacttc agttacaatc tggactaaaa gccaatatag 2340 aggtccaggg tggtctagct attgatattt caggtgcaat ggagtttagc ttgtggtatc 2400 gtgagtctaa aacccgagtg aaaaataggg tgactgtggt aataaccact gacatcacag 2460 tggactcctc ttttgtgaaa gctggcctgg aaaccagtac agaaacagaa gcaggcttgg 2520 agtttatctc cacagtgcag ttttctcagt acccattctt agtttgcatg cagatggaca 2580 aggatgaagc tccattcagg caatttgaga aaaagtacga aaggctgtcc acaggcagag 2640 gttatgtctc tcagaaaaga aaagaaagcg tattagcagg atgtgaattc ccgctccatc 2700 aagagaactc agagatgtgc aaagtggtgt ttgcccctca gccggatagt acttccagcg 2760 gatggttttg aaactgacct gtgatatttt acttgaattt gtctccccga aagggacaca 2820 atgtggcatg actaagtact tgctctctga gagcacagcg tttacatatt tacctgtatt 2880 taagattttt gtaaaaagct acaaaaaact gcagtttgat caaatttggg tatatgcagt 2940 atgctaccca cagcgtcatt ttgaatcatc atgtgacgct ttcaacaacg ttcttagttt 3000 acttatacct ctctcaaatc tcatttggta cagtcagaat agttattctc taagaggaaa 3060 ctagtgtttg ttaaaaacaa aaataaaaac aaaaccacac aaggagaacc caattttgtt 3120 tcaacaattt ttgatcaatg tatatgaagc tcttgatagg acttccttaa gcatgacggg 3180 aaaaccaaac acgttcccta atcaggaaaa aaaaaaaaaa aaaaagtaag acacaaacaa 3240 accatttttt ttctcttttt ttggagttgg gggcccaggg agaagggaca agacttttaa 3300 aagacttgtt agccaacttc aagaattaat atttatgtct ctgttattgt tagttttaag 3360 ccttaaggta gaaggcacat agaaataaca tctcatcttt ctgctgacca ttttagtgag 3420 gttgttccaa agacattcag gtctctacct ccagccctgc aaaaatattg gacctagcac 3480 agaggaatca ggaaaattaa tttcagaaac tccatttgat ttttcttttg ctgtgtcttt 3540 ttgagactgt aatatggtac actgtcctct aagggacatc ctcattttat ctcacctttt 3600 tgggggtgag agctctagtt catttaactg tactctgcac aatagctagg atgactaaga 3660 gaacattgct tcaagaaact ggtggatttg gatttccaaa atatgaaata aggaaaaaaa 3720 tgtttttatt tgtatgaatt aaaagatcca tgttgaacat ttgcaaatat ttattaataa 3780 acagatgtgg tgataaaccc aaaacaaatg acaggtgctt attttccact aaacacagac 3840 ET
OT <OTZ>
TZLZ o oeouop000s 3 3643E36e OOLZ b4p3obbPbb eb334366,44 433454364E. 3o-26335464 343344opo3 2465p000bp 0f79 333236;33o 5642666452 366.6p2o43.6 eoPoo5.262o 354334433; 3333643656 08s 4266626225 2E66'2562o oo4-2Pb2333 344.p000gpo .5446p-2443g Beu52o6beo 0n. 134.4356.256 pbbbp36-235 bPb5q33333 646644,3364 644o6bpoep 6.4op4opoof) 0917z 0004-20000D Pou3344.343 6433.256433 5266-243545 445.23356pp 33365-2233E
OHZ 45bebeop43 3666.236623 pobbeoebbo bPpobbeoop 333b6p3336 -224p623336 HU bp-26254625 4333qbeb-eb -2234536po2, bp.2366555o 5432333o5 643.2352355 08ZZ pbsob2b544. obeobbbbeo bobeo33403 3323333363 323554p-23o 2523323643 OZ 6;2436552o obbqpepobb 26T2566643 643366-2666 3-2366-26236 643544334.3 09-T 3336633E64. 36E623622o 5454333335 6664-2o-233o opb436354.5 3625;pp-264 00-H bpoloes5bl obbobp2224 3432444026 pep-425426 444.36.6423e eobeelbbqb 0170z 4.603q3PPD 3OPP0330q opo4362-epo 4330323.4 o 33323435o2 3336'25664o 0861 .64-epoobqoo 304_6334335 44_45.264.peb 5.2643444.4o 30321.2.6226 bb64.4o4.4qq 0Z61 3552334333 64.52-232333 3334.332335 4.33boop000 '4343333-Poo 3-P6'4P-0981 6-2E64.05456 3464.334:46p pobooleop5 bp000_63436 qob-255336-2 66-2.544400f 0081 b054443Pop 5666646344 664p324334 4e433434p3 43bepeo33-2 4.62po44bbE, 0f7Li 5456645.222 P64_3363232 364424.o625 4.444330443 35434344o5 54op00054E
0891 4.p43456225 425536254u 352-2623332 566-43.556 -23266E433p 2bp652eoe;
0Z91 3443b3bpo3 34.33434:234 233Pobbpop 23-26643-243 43.64p34.63e po3e643b43 09s1 op6o2664Do 34.3445-22E5 ppp56qoo55 u5bbpbb qoop4Pboo4 gee65324-2P
OOST 00e6b43323 344q4bee6e 62434424e4 3354366434 6664643343 goe64-22643 0-E 4354.343562 450023254.c 3522032364 6e3o4232o6 4po24356o6 262.6.65p642 08E1 6,43ob233 4424.56226p 562234.533o 3-24543.5gob -2664.54pb66 -2626432oqo OZET o55443444.6 5266634.446 obepPbb643 34334.opoeb 43opp43434 go2p36ee44.
09Z1 ;;5bq44366 4popp544.oe 33356-2.2e 64E3E336E3 3364.554.36e 0005542TeP
0OZT 40236434e6 4333466_666 4326566-266 Pso4423p43 442E652334 4obb543663 0f7T1 64361-26436 ee3244-44.34 -255s3o533.2 33554_663.4o upo445bbbp ufrePooqop4 0801 235626234o 44.36.5q2435 64=42334. -43oo.643.4-eo 41u2b4.44.44 63236254.26 OZOT 36pb4o36b4 epouPbeeop 332b4o2.64o 343-20334E3 4Pbue4p4.4_4 4626324344.
096 43.436633 6 54ob5opobq 654:2E43544. 33362E633o oe4e0366-eo 633354_36-2o 006 333333.6p2b 4632334_234 4.3233423-26 64.obbb-epbq 4-ebee432be 2344323433 0f/8 3.2q26232-23 434.4:262664 662362e522 654o-26444e p.642-2E6366 4.o243o434.2 08L 045-2226.225 4o3243-2233 43223440.55 4p4opoo44o 543_63p55-2 5544;33233 OZL oppo4445oo 44bep4pbo4 2bbpbe3opo 244oeboppo gp52.6.5p64p buo45o2upb 099 64bbpeo4,4. 33353342 6 2326o-8652b 66Poobeo6o 34.56-ebopo5 623365666;
009 6.646664p6p Pbqq3P3364 44_3peeb6p6 pp-23-256633 3434e344_66 4.0u-434.2336 (,s- 4443665436 qbp344opoq o3433-42-2,26 2.43561542o 362546444.o 662opeepoe 08f7 332625.2254 5463346053 642344.442.6 43eoup55ol 5re2333346 4.4.42Pqqoeo OZp b4peeb4.5bo 5531353435 64533666.23 D44364.3436 .e5o6,5540o6 6433334536 09s Do-23536.252 .53333-26obo 4o55.25662.6 55 booboo 55obb54643 2623334.635 00E 03442e55b2 obo4344325 6363326356 23.64o36Pbb pPbbbbb4oP 4335336.453 0f7 53.64.3p5p66 Poo653o3o5 400;o6popo 336004.5644 624.6443266 626.236q655 081 6-235333E63 4663643665 634_55Ebe5o 3636666336 6535635564 6666336035 0?' 6343566363 5334356634 46636o-25e boebb0000q oPob000bb6 3366336666 09 303536es-45 poebeboo6? 6364335e56 3353363354 pobo5obo4-2 625.256005p 6 <OH.>
silo-pies 01110H <ETZ>
VNG <zTZ>
TZLZ <TTZ>
6 <OTZ>

3422.25245 4.24.2224eep 006E P4'26454.622 6322p-2644P 2P45445444 243poo3524 352444622p blee.26423P

ti ofi, opgeobepe6 oebbebbbeo obeo5epq55 eboeobbeoo bb5bb4554.6 Ugebeebqq 09E peooL4qqoe eebbebeeeo ebbb000qoq upqqbbqoe4 o4eDob;q4o bbb4obqbeo coo 5e435 bqbqeaabeb beoe.456e5q obq6qpooqo qqobqbeobe 0D, oebobeebbb ebe4doqeqe 4q4e3eDb44 beeebbbbee ebeoec.544 44o4e.5554o 081 eobeee6466 ece65-qbbo obetlilboee befyqb8be6e o4eeqbebbe eDooqqqDqo OZT gobeopoogo bebeob45be opbo4epbeb eq4Doobbeo epqo4o400b l000bqoobe 09 ob4do645eo 06665_54beb bEtqboobbe etec.45qqee o54bqoebbe Da6qqoebqo IT <00t'>
suaTdes owoH <10>
VNU <-E>
860 <TTZ>
TT <OTZ>
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<213> Homo Sapiens <400> 13 ctcacctgcc tcacctggct gctgtctgtt tccaggaaga gggcatcagt gggcgaaaac 60 aggaaaatca tcctgtgctt ccaggtactc tctgaagatg gcagaagctc accaagctgt 120 ggcctttcag ttcacggtca ctccggacgg gattgacctg cggctgagcc atgaagctct 180 tagacaaatc tatctctctg gacttcattc ctggaaaaag aagttcatca gattcaagaa 240 cggcatcatc actggcgtgt acccggcaag cccctccagt tggcttatcg tggtggtggg 300 cgtgatgaca acgatgtacg ccaagatcga cccctcgtta ggaataattg caaaaatcaa 360 tcggactctg gaaacggcca actgcatgtc cagccagacg aagaacgtgg tcagcggcgt 420 gctgtttggc accggcctgt gggtggccct catcgtcacc atgcgctact ccctgaaagt 480 gctgctctcc taccacgggt ggatgttcac tgagcacggc aagatgagtc gtgccaccaa 540 gatctggatg ggtatggtca agatcttttc aggccgaaaa cccatgttgt acagcttcca 600 gacatcgctg cctcgcctgc cggtcccggc tgtcaaagac actgtgaaca ggtatctaca 660 gtcggtgagg cctcttatga aggaagaaga cttcaaacgg atgacagcac ttgctcaaga 720 ttttgctgtc ggtcttggac caagattaca gtggtatttg aagttaaaat cctggtgggc 780 tacaaattac gtgagcgact ggtgggagga gtacatctac ctccgaggac gagggccgct 840 catggtgaac agcaactatt atgccatgga tctgctgtat atccttccaa ctcacattca 900 ggcagcaaga gccggcaacg ccatccatgc catcctgctt tacaggcgca aactggaccg 960 ggaggaaatc aaaccaattc gtcttttggg atccacgatt ccactctgct ccgctcagtg 1020 ggagcggatg tttaatactt cccggatccc aggagaggag acagacacca tccagcacat 1080 gagagacagc aagcacatcg tcgtgtacca tcgaggacgc tacttcaagg tctggctcta 1140 ccatgatggg oggctgctga agccccggga gatggagcag cagatgcaga ggatcctgga 1200 caatacctcg gagcctcagc ccggggaggc caggctggca gccctcaccg caggagacag 1260 agttccctgg gccaggtgtc gtcaggccta ttttggacgt gggaaaaata agcagtctct 1320 tgatgctgtg gagaaagcag cgttcttcgt gacgttagat gaaactgaag aaggatacag 1380 aagtgaagac ccggatacgt caatggacag ctacgccaaa tctctactac acggccgatg 1440 ttacgacagg tggtttgaca agtcgttcac gtttgttgtc ttcaaaaacg ggaagatggg 1500 cctcaacgct gaacactcct gggcagatgc gccgatcgtg gcccaccttt gggagtacgt 1560 catgtccatt gacagcctcc agctgggcta tgcggaggat gggcactgca aaggcgacat 1620 caatccgaac attccgtacc ccaccaggct gcagtgggac atcccggggg aatgtcaaga 1680 ggttatagag acctccctga acaccgcaaa tcttctggca aacgacgtgg atttccattc 1740 cttcccattc gtagcctttg gtaaaggaat catcaagaaa tgtcgcacga gcccagacgc 1800 ctttgtgcag ctggccctcc agctggcgca ctacaaggac atgggcaagt tttgcctcac 1860 atacgaggcc tccatgaccc ggctcttccg agaggggagg acggagaccg tgcgctcctg 1920 caccactgag tcatgcgact tcgtgcgggc catggtggac ccggcccaga cggtggaaca 1980 gaggctgaag ttgttcaagt tggcgtctga gaagcatcag catatgtatc gcctcgccat 2040 gaccggctct gggatcgatc gtcacctctt ctgcctttac gtggtgtcta aatatctcgc 2100 tgtggagtcc cctttcctta aggaagtttt atctgagcct tggagattat caacaagcca 2160 gacccctcag cagcaagtgg agctgtttga cttggagaat aacccagagt acgtgtccag 2220 cggagggggc tttggaccgg ttgctgatga cggctatggt gtgtcgtaca tccttgtggg 2280 agagaacctc atcaatttcc acatttcttc caagttctct tgccctgaga cggattctca 2340 tcgctttgga aggcacctga aagaagcaat gactgacatc atcactttgt ttggtctcag 2400 ttctaattcc aaaaagtaat tccactggag ctgctgggaa ggaaaacgag ctcttctgat 2460 gcaaaccaaa tgaaaaatag gcattaatcc tgaccttagc tcgggatgaa acactgctct 2520 taaaaaaact cagttttcct tccagaaaat gtgggtgttt ttttttccta gaacagtatc 2580 tctcccctgt gaagcataac cccactactt ccagacttgc cctcccttgg gggacatctg 2640 ataaagtctc ccctgatgtc tccgcatcgg cttggattta ttaagggatg caaatcttgt 2700 tgagttaatg aaggaattag tagggttgtg gcttcacaca cagtggaatg gaaatggtgt 2760 gctttctcag tggcaaccga aggcctagtg cttaagggca tttagcatca tccaagcagg 2820 gtaaactttt gttttgttaa aagaaaaatg tgttattcaa gttggtgtcc ccagttgtag 2880 ctaacacatc tggaatgcac taaccaaaat gctgtgcttt ggagacctgc ttttgtcacc 2940 gtgggtaacc gttcccgtct ggtccagtag cctgtgtttg cctctccaca tttgaagcaa 3000 gcaggatgca aggtcttcag ttttactgac cttgtatgtc ttcaagtctt cacaacccag 3060 tgccttaaaa atgaaaggcc ctaaatgtaa gggagatgga gagaaagatt tattttgtag 3120 agtctttggg tggaattgtg ggtatactgt tcccttcaca attgactgag tatggataac 3180 cgtacataag catttgctac accccaccag ccccctcccc ctcagaaaca ccagttc 3237 <210> 14 <211> 3294 <212> DNA
<213> Homo Sapiens <400> 14 aatccgctgc tgccggcgtc gggtgcgctc ggcctcgccc gcggccctcc ttccccggct 60 tccgctcgcc gctcgttcac tccacgcgcc gctgccgccg ccgccgccgt cgtgccgtgc 120 cgcacctccg tagctgactc ggtactctct gaagatggca gaagctcacc aagctgtggc 180 ctttcagttc acggtcactc cggacgggat tgacctgcgg ctgagccatg aagctcttag 240 acaaatctat ctctctggac ttcattcctg gaaaaagaag ttcatcagat tcaagaacgg 300 catcatcact ggcgtgtacc cggcaagccc ctccagttgg cttatcgtgg tggtgggcgt 360 gatgacaacg atgtacgcca agatcgaccc ctcgttagga ataattgcaa aaatcaatcg 420 gactctggaa acggccaact gcatgtccag ccagacgaag aacgtggtca gcggcgtgct 480 gtttggcacc ggcctgtggg tggccctcat cgtcaccatg cgctactccc tgaaagtgct 540 gctctcctac cacgggtgga tgttcactga gcacggcaag atgagtcgtg ccaccaagat 600 ctggatgggt atggtcaaga tcttttcagg ccgaaaaccc atgttgtaca gcttccagac 660 atcgctgcct cgcctgccgg tcccggctgt caaagacact gtgaacaggt atctacagtc 720 ggtgaggcct cttatgaagg aagaagactt caaacggatg acagcacttg ctcaagattt 780 tgctgtcggt cttggaccaa gattacagtg gtatttgaag ttaaaatcct ggtgggctac 840 aaattacgtg agcgactggt gggaggagta catctacctc cgaggacgag ggccgctcat 900 ggtgaacagc aactattatg ccatggatct gctgtatatc cttccaactc acattcaggc 960 agcaagagcc ggcaacgcca tccatgccat cctgctttac aggcgcaaac tggaccggga 1020 ggaaatcaaa ccaattcgtc ttttgggatc cacgattcca ctctgctccg ctcagtggga 1080 gcggatgttt aatacttccc ggatcccagg agaggagaca gacaccatcc agcacatgag 1140 agacagcaag cacatcgtcg tgtaccatcg aggacgctac ttcaaggtct ggctctacca 1200 tgatgggcgg ctgctgaagc cccgggagat ggagcagcag atgcagagga tcctggacaa 1260 tacctcggag cctcagcccg gggaggccag gctggcagcc ctcaccgcag gagacagagt 1320 tccctgggcc aggtgtcgtc aggcctattt tggacgtggg aaaaataagc agtctcttga 1380 tgctgtggag aaagcagcgt tcttcgtgac gttagatgaa actgaagaag gatacagaag 1440 tgaagacccg gatacgtcaa tggacagcta cgccaaatct ctactacacg gccgatgtta 1500 cgacaggtgg tttgacaagt cgttcacgtt tgttgtcttc aaaaacggga agatgggcct 1560 caacgctgaa cactcctggg cagatgcgcc gatcgtggcc cacctttggg agtacgtcat 1620 gtccattgac agcctccagc tgggctatgc ggaggatggg cactgcaaag gcgacatcaa 1680 tccgaacatt ccgtacccca ccaggctgca gtgggacatc ccgggggaat gtcaagaggt 1740 tatagagacc tccctgaaca ccgcaaatct tctggcaaac gacgtggatt tccattcctt 1800 cccattcgta gcctttggta aaggaatcat caagaaatgt cgcacgagcc cagacgcctt 1860 tgtgcagctg gccctccagc tggcgcacta caaggacatg ggcaagtttt gcctcacata 1920 cgaggcctcc atgacccggc tcttccgaga ggggaggacg gagaccgtgc gctcctgcac 1980 cactgagtca tgcgacttcg tgcgggccat ggtggacccg gcccagacgg tggaacagag 2040 gctgaagttg ttcaagttgg cgtctgagaa gcatcagcat atgtatcgcc tcgccatgac 2100 cggctctggg atcgatcgtc acctcttctg cctttacgtg gtgtctaaat atctcgctgt 2160 ggagtcccct ttccttaagg aagttttatc tgagccttgg agattatcaa caagccagac 2220 ccctcagcag caagtggagc tgtttgactt ggagaataac ccagagtacg tgtccagcgg 2280 agggggcttt ggaccggttg ctgatgacgg ctatggtgtg tcgtacatcc ttgtgggaga 2340 gaacctcatc aatttccaca tttcttccaa gttctcttgc cctgagacgg attctcatcg 2400 ctttggaagg cacctgaaag aagcaatgac tgacatcatc actttgtttg gtctcagttc 2460 taattccaaa aagtaattcc actggagctg ctgggaagga aaacgagctc ttctgatgca 2520 aaccaaatga aaaataggca ttaatcctga ccttagctcg ggatgaaaca ctgctcttaa 2580 aaaaactcag ttttccttcc agaaaatgtg ggtgtttttt tttcctagaa cagtatctct 2640 cccctgtgaa gcataacccc actacttcca gacttgccct cccttggggg acatctgata 2700 aagtctcccc tgatgtctcc gcatcggctt ggatttatta agggatgcaa atcttgttga 2760 gttaatgaag gaattagtag ggttgtggct tcacacacag tggaatggaa atggtgtgct 2820 ttctcagtgg caaccgaagg cctagtgctt aagggcattt agcatcatcc aagcagggta 2880 aacttttgtt ttgttaaaag aaaaatgtgt tattcaagtt ggtgtcccca gttgtagcta 2940 acacatctgg aatgcactaa ccaaaatgct gtgctttgga gacctgcttt tgtcaccgtg 3000 ggtaaccgtt cccgtctggt ccagtagcct gtgtttgcct ctccacattt gaagcaagca 3060 ggatgcaagg tcttcagttt tactgacctt gtatgtcttc aagtcttcac aacccagtgc 3120 cttaaaaatg aaaggcccta aatgtaaggg agatggagag aaagatttat tttgtagagt 3180 ctttgggtgg aattgtgggt atactgttcc cttcacaatt gactgagtat ggataaccgt 3240 acataagcat ttgctacacc ccaccagccc cctccccctc agaaacacca gttc 3294 <210> 15 <211> 481 <212> PRT
<213> Homo sapiens <400> 15 Net Tyr Asp Ala Glu Arg Gly Trp Ser Leu Ser Phe Ala Gly Cys Gly Phe Leu Gly Phe Tyr His Val Gly Ala Thr Arg Cys Leu Ser Glu His Ala Pro His Leu Leu Arg Asp Ala Arg Met Leu Phe Gly Ala Ser Ala Gly Ala Leu His Cys Val Gly Val Leu Ser Gly Ile Pro Leu Glu Gln Thr Leu Gin Val Leu Ser Asp Leu Val Arg Lys Ala Arg Ser Arg Asn Ile Gly Ile Phe His Pro Ser Phe Asn Leu Ser Lys Phe Leu Arg Gin Gly Leu Cys Lys Cys Leu Pro Ala Asn Val His Gin Leu Ile Ser Gly Lys Ile Gly Ile Ser Leu Thr Arg Val Ser Asp Gly Glu Asn Val Leu Val Ser Asp Phe Arg Ser Lys Asp Glu Val Val Asp Ala Leu Val Cys Ser Cys Phe Ile Pro Phe Tyr Ser Gly Leu Ile Pro Pro Ser Phe Arg Gly Val Arg Tyr Val Asp Gly Gly Val Ser Asp Asn Val Pro Phe Ile Asp Ala Lys Thr Thr Ile Thr Val Ser Pro Phe Tyr Gly Glu Tyr Asp Ile Cys Pro Lys Val Lys Ser Thr Asn Phe Leu His Val Asp Ile Thr Lys Leu Ser Leu Arg Leu Cys Thr Gly Asn Leu Tyr Leu Leu Ser Arg Ala Phe Val Pro Pro Asp Leu Lys Val Leu Gly Glu Ile Cys Leu Arg Gly Tyr Leu Asp Ala Phe Arg Phe Leu Glu Glu Lys Gly Ile Cys Asn Arg Pro Gin Pro Gly Leu Lys Ser Ser Ser Glu Gly Met Asp Pro Glu Val Ala Met Pro Ser Trp Ala Asn Met Ser Leu Asp Ser Ser Pro Glu Ser Ala Ala Leu Ala Val Arg Leu Glu Gly Asp Glu Leu Leu Asp His Leu Arg Leu Ser Ile Leu Pro Trp Asp Glu Ser Ile Lou Asp Thr Leu Ser Pro Arg Leu Ala Thr Ala Leu Ser Glu Glu Met Lys Asp Lys Gly Gly Tyr Met Ser Lys Ile Cys Asn Leu Leu Pro Ile Arg Ile Met Ser Tyr Val Met Lou Pro Cys Thr Leu Pro Val Glu Ser Ala Ile Ala Ile Val Gin Arg Leu Val Thr Trp Lou Pro Asp Met Pro Asp Asp Val Leu Trp Lou Gin Trp Val Thr Ser Gin Val Phe Thr Arg Val Leu Met Cys Leu Leu Pro Ala Ser Arg Ser Gin Met Pro Val Ser Ser Gin Gin Ala Ser Pro Cys Thr Pro Glu Gin Asp Trp Pro Cys Trp Thr Pro Cys Ser Pro Glu Gly Cys Pro Ala Glu Thr Lys Ala Glu Ala Thr Pro Arg Ser Ile Leu Arg Ser Ser Lou Asn Phe Phe Leu Gly Asn Lys Val Pro Ala Gly Ala Glu Gly Lou Ser Thr Phe Pro Ser Phe Ser Leu Glu Lys Ser Leu <210> 16 <211> 839 <212> PRT
<213> Homo sapiens <400> 16 Met Met Ser Ala Ser Arg Leu Ala Gly Thr Leu Ile Pro Ala Met Ala Phe Lou Ser Cys Val Arg Pro Glu Ser Trp Glu Pro Cys Val Glu Val Val Pro Asn Ile Thr Tyr Gin Cys Met Glu Lou Asn Phe Tyr Lys Ile Pro Asp Asn Leu Pro Phe Ser Thr Lys Asn Leu Asp Leu Ser Phe Asn Pro Leu Arg His Leu Gly Ser Tyr Ser Phe Phe Ser Phe Pro Glu Leu Gln Val Leu Asp Leu Ser Arg Cys Glu Ile Gin Thr Ile Glu Asp Gly Ala Tyr Gin Ser Leu Ser His Leu Ser Thr Leu Ile Leu Thr Gly Asn Pro Ile Gln Ser Leu Ala Leu Gly Ala Phe Ser Gly Leu Ser Ser Leu Gln Lys Leu Val Ala Val Glu Thr Asn Leu Ala Ser Leu Glu Asn Phe Pro Ile Gly His Leu Lys Thr Leu Lys Glu Leu Asn Val Ala His Asn Leu Ile Gln Ser Phe Lys Leu Pro Glu Tyr Phe Ser Asn Leu Thr Asn Leu Glu His Leu Asp Leu Ser Ser Asn Lys Ile Gln Ser Ile Tyr Cys Thr Asp Lou Arg Val Leu His Gln Met Pro Leu Leu Asn Leu Ser Leu Asp Leu Ser Leu Asn Pro Met Asn Phe Ile Gln Pro Gly Ala Phe Lys Glu Ile Arg Leu His Lys Leu Thr Leu Arg Asn Asn Phe Asp Ser Leu Asn Val Met Lys Thr Cys Ile Gln Gly Leu Ala Gly Leu Glu Val His Arg Lou Val Leu Gly Glu Phe Arg Asn Glu Gly Asn Leu Glu Lys Phe Asp Lys Ser Ala Leu Glu Gly Leu Cys Asn Leu Thr Ile Glu Glu Phe Arg Leu Ala Tyr Lou Asp Tyr Tyr Lou Asp Asp Ile Ile Asp Leu Phe Asn Cys Leu Thr Asn Val Ser Ser Phe Ser Leu Val Ser Val Thr Ile Glu Arg Val Lys Asp Phe Ser Tyr Asn Phe Gly Trp Gin His Leu Glu Lou Val Asn Cys Lys Phe Gly Gln Phe Pro Thr Leu Lys Leu Lys Ser Lou Lys Arg Leu Thr Phe Thr Ser Asn Lys Gly Gly Asn Ala Phe Ser Glu Val Asp Lou Pro Ser Lou Glu Phe Leu Asp Leu Ser Arg Asn Gly Leu Ser Phe Lys Gly Cys Cys Ser Gln Ser Asp Phe Gly Thr Thr Ser Lou Lys Tyr Leu Asp Leu Ser Phe Asn Gly Val Ile Thr Met Ser Ser Asn Phe Leu Gly Leu Glu Gln Leu Glu His Leu Asp Phe Gln His Ser Asn Lou Lys Gln Met Ser Glu Phe Ser Val Phe Lou Ser Leu Arg Asn Leu Ile Tyr Leu Asp Ile Ser His Thr His Thr Arg Val Ala Phe Asn Gly Ile Phe Asn Gly Leu Ser Ser Leu Glu Val Leu Lys Met Ala Gly Asn Ser Phe Gln Glu Asn Phe Lou Pro Asp Ile Phe Thr Glu Leu Arg Asn Lou Thr Phe Leu Asp Lou Ser Gln Cys Gln Leu Glu Gln Leu Ser Pro Thr Ala Phe Asn Ser Leu Ser Ser Lou Gln Val Leu Asn Met Ser His Asn Asn Phe Phe Ser Lou Asp Thr Phe Pro Tyr Lys Cys Leu Asn Ser Leu Gin Val Leu Asp Tyr Ser Leu Asn His Ile Met Thr Ser Lys Lys Gin Glu Leu Gin His Phe Pro Ser Ser Leu Ala Phe Leu Asn Leu Thr Gin Asn Asp Phe Ala Cys Thr Cys Glu His Gin Ser Phe Leu Gin Trp Ile Lys Asp Gin Arg Gin Leu Leu Val Glu Val Glu Arg Met Glu Cys Ala Thr Pro Ser Asp Lys Gin Gly Met Pro Val Leu Ser Leu Asn Ile Thr Cys Gin Met Asn Lys Thr Ile Ile Gly Val Ser Val Leu Ser Val Leu Val Val Ser Val Val Ala Val Leu Val Tyr Lys Phe Tyr Phe His Leu Met Leu Leu Ala Gly Cys Ile Lys Tyr Gly Arg Gly Glu Asn Ile Tyr Asp Ala Phe Val Ile Tyr Ser Ser Gin Asp Glu Asp Trp Val Arg Asn Glu Leu Vol Lys Asn Leu Glu Glu Gly Val Pro Pro Phe Gin Leu Cys Leu His Tyr Arg Asp Phe Ile Pro Gly Val Ala Ile Ala Ala Asn Ile Ile His Glu Gly Phe His Lys Ser Arg Lys Val Ile Vol Val Vol Ser Gin His Phe Ile Gin Ser Arg Trp Cys Ile Phe Glu Tyr Glu Ile Ala Gin Thr Trp Gin Phe Leu Ser Ser Arg Ala Gly Ile Ile Phe Ile Val Leu Gin Lys Val Glu Lys Thr Leu Leu Arg Gin Gin Val Glu Leu Tyr Arg Leu Leu Ser Arg Asn Thr Tyr Leu Glu Trp Glu Asp Ser Val Leu Gly Arg His Ile Phe Trp Arg Arg Leu Arg Lys Ala Lou Leu Asp Gly Lys Ser Trp Asn Pro Glu Gly Thr Val Gly Thr Gly Cys Asn Trp Gin Glu Ala Thr Ser Ile <210> 17 <211> 799 <212> PRT
<213> Homo sapiens <400> 17 Met Glu Leu Asn Phe Tyr Lys Ile Pro Asp Asn Leu Pro Phe Ser Thr Lys Asn Leu Asp Lou Ser Phe Asn Pro Leu Arg His Leu Gly Ser Tyr Ser Phe Phe Ser Phe Pro Glu Leu Gin Val Leu Asp Leu Ser Arg Cys Glu Ile Gin Thr Ile Glu Asp Gly Ala Tyr Gin Ser Leu Ser His Leu Ser Thr Leu Ile Leu Thr Gly Asn Pro Ile Gin Ser Leu Ala Leu Gly Ala Phe Ser Gly Leu Ser Ser Leu Gin Lys Leu Val Ala Val Glu Thr Asn Leu Ala Ser Leu Glu Asn Phe Pro Ile Gly His Leu Lys Thr Leu Lys Glu Leu Asn Val Ala His Asn Leu Ile Gin Ser Phe Lys Leu Pro Glu Tyr Phe Ser Asn Leu Thr Asn Leu Glu His Leu Asp Leu Ser Ser Asn Lys Ile Gin Ser Ile Tyr Cys Thr Asp Leu Arg Val Leu His Gin Met Pro Leu Leu Asn Leu Ser Leu Asp Leu Ser Leu Asn Pro Met Asn Phe Ile Gin Pro Gly Ala Phe Lys Glu Ile Arg Leu His Lys Leu Thr Leu Arg Asn Asn Phe Asp Ser Leu Asn Val Met Lys Thr Cys Ile Gin Gly Leu Ala Gly Leu Glu Val His Arg Leu Val Leu Gly Glu Phe Arg Asn Glu Gly Asn Leu Glu Lys Phe Asp Lys Ser Ala Leu Glu Gly Leu Cys Asn Leu Thr Ile Glu Glu Phe Arg Leu Ala Tyr Leu Asp Tyr Tyr Leu Asp Asp Ile Ile Asp Leu Phe Asn Cys Leu Thr Asn Val Ser Ser Phe Ser Leu Val Ser Val Thr Ile Glu Arg Val Lys Asp Phe Ser Tyr Asn Phe Gly Trp Gin His Leu Giu Leu Val Asn Cys Lys Phe Gly Gin Phe Pro Thr Leu Lys Leu Lys Ser Leu Lys Arg Leu Thr Phe Thr Ser Asn Lys Gly Gly Asn Ala Phe Ser Glu Val Asp Leu Pro Ser Leu Glu Phe Leu Asp Leu Ser Arg Asn Gly Leu Ser Phe Lys Gly Cys Cys Ser Gin Ser Asp Phe Gly Thr Thr Ser Leu Lys Tyr Leu Asp Leu Ser Phe Asn Gly Val Ile Thr Met Ser Ser Asn Phe Leu Gly Leu Glu Gin Leu Glu His Leu Asp Phe Gin His Ser Asn Leu Lys Gin Met Ser Glu Phe Ser Val Phe Leu Ser Leu Arg Asn Leu Ile Tyr Leu Asp Ile Ser His Thr His Thr Arg Val Ala Phe Asn Gly Ile Phe Asn Gly Leu Ser Ser Leu Glu Val Leu Lys Met Ala Gly Asn Ser Phe Gin Glu Asn Phe Leu Pro Asp Ile Phe Thr Glu Leu Arg Asn Leu Thr Phe Leu Asp Leu Ser Gin Cys Gin Leu Glu Gin Leu Ser Pro Thr Ala Phe Asn Ser Leu Ser Ser Leu Gin Val Leu Asn Met Ser His Asn Asn Phe Phe Ser Leu Asp Thr Phe Pro Tyr Lys Cys Leu Asn Ser Leu Gin Val Leu Asp Tyr Ser Leu Asn His Ile Met Thr Ser Lys Lys Gin Glu Leu Gin His Phe Pro Ser Ser Leu Ala She Leu Asn Leu Thr Gin Asn Asp She Ala Cys Thr Cys Glu His Gin Ser Phe Leu Gin Trp Ile Lys Asp Gin Arg Gin Leu Leu Val Glu Val Glu Arg Met Glu Cys Ala Thr Pro Ser Asp Lys Gin Gly Met Pro Val Leu Ser Leu Asn Ile Thr Cys Gin Met Asn Lys Thr Ile Ile Gly Val Ser Val Leu Ser Val Leu Val Val Ser Val Val Ala Val Leu Val Tyr Lys Phe Tyr Phe His Leu Met Leu Leu Ala Gly Cys Ile Lys Tyr Gly Arg Gly Glu Asn Ile Tyr Asp Ala Phe Val Ile Tyr Ser Ser Gin Asp Glu Asp Trp Val Arg Asn Glu Leu Val Lys Asn Leu Glu Glu Gly Val Pro Pro Phe Gin Leu Cys Leu His Tyr Arg Asp Phe Ile Pro Gly Val Ala Ile Ala Ala Asn Ile Ile His Glu Gly Phe His Lys Ser Arg Lys Val Ile Val Val Val Ser Gin His Phe Ile Gin Ser Arg Trp Cys Ile Phe Glu Tyr Glu Ile Ala Gin Thr Trp Gin Phe Leu Ser Ser Arg Ala Gly Ile Ile Phe Ile Val Leu Gin Lys Val Glu Lys Thr Leu Leu Arg Gin Gin Val Glu Leu Tyr Arg Leu Leu Ser Arg Asn Thr Tyr Leu Glu Trp Glu Asp Ser Val Leu Gly Arg His Ile Phe Trp Arg Arg Leu Arg Lys Ala Leu Leu Asp Gly Lys Ser Trp Asn Pro Glu Gly Thr Val Gly Thr Gly Cys Asn Trp Gin Glu Ala Thr Ser Ile <210> 18 <211> 639 <212> PRT
<213> Homo sapiens <400> 18 Met Pro Leu Leu Asn Leu Ser Leu Asp Leu Ser Leu Asn Pro Met Asn Phe Ile Gin Pro Gly Ala Phe Lys Glu Ile Arg Leu His Lys Leu Thr Leu Arg Asn Asn Phe Asp Ser Leu Asn Val Met Lys Thr Cys Ile Gin Gly Leu Ala Gly Leu Glu Val His Arg Leu Val Leu Gly Glu Phe Arg Asn Glu Gly Asn Leu Glu Lys Phe Asp Lys Ser Ala Leu Glu Gly Leu Cys Asn Leu Thr Ile Glu Glu Phe Arg Leu Ala Tyr Leu Asp Tyr Tyr Leu Asp Asp Ile Ile Asp Leu Phe Asn Cys Leu Thr Asn Val Ser Ser Phe Ser Leu Val Ser Val Thr Ile Glu Arg Val Lys Asp Phe Ser Tyr Asn Phe Gly Trp Gin His Leu Glu Leu Val Asn Cys Lys Phe Gly Gin Phe Pro Thr Leu Lys Leu Lys Ser Leu Lys Arg Leu Thr Phe Thr Ser Asn Lys Gly Gly Asn Ala Phe Ser Glu Val Asp Leu Pro Ser Leu Glu Phe Leu Asp Leu Ser Arg Asn Gly Leu Ser Phe Lys Gly Cys Cys Ser Gin Ser Asp Phe Gly Thr Thr Ser Leu Lys Tyr Leu Asp Leu Ser Phe Asn Gly Val Ile Thr Met Ser Ser Asn Phe Leu Gly Leu Glu Gin Leu Glu His Leu Asp Phe Gin His Ser Asn Leu Lys Gin Met Ser Glu Phe Ser Val Phe Leu Ser Leu Arg Asn Leu Ile Tyr Leu Asp Ile Ser His Thr His Thr Arg Val Ala Phe Asn Gly Ile Phe Asn Gly Leu Ser Ser Leu Glu Val Leu Lys Met Ala Gly Asn Ser She Gin Glu Asn She Leu Pro Asp Ile She Thr Glu Leu Arg Asn Leu Thr Phe Leu Asp Leu Ser Gin Cys Gin Leu Glu Gin Leu Ser Pro Thr Ala Phe Asn Ser Leu Ser Ser Leu Gin Val Leu Asn Met Ser His Asn Asn Phe Phe Ser Leu Asp Thr She Pro Tyr Lys Cys Leu Asn Ser Leu Gin Val Leu Asp Tyr Ser Leu Asn His Ile Met Thr Ser Lys Lys Gin Glu Leu Gin His She Pro Ser Ser Leu Ala Phe Leu Asn Leu Thr Gin Asn Asp Phe Ala Cys Thr Cys Glu His Gin Ser Phe Leu Gin Trp Ile Lys Asp Gin Arg Gin Leu Leu Val Glu Val Glu Arg Met Glu Cys Ala Thr Pro Ser Asp Lys Gin Gly Met Pro Val Leu Ser Leu Asn Ile Thr Cys Gin Met Asn Lys Thr Ile Ile Gly Val Ser Val Leu Ser Val Leu Val Val Ser Val Val Ala Val Leu Val Tyr Lys Phe Tyr Phe His Leu Met Leu Leu Ala Gly Cys Ile Lys Tyr Gly Arg Gly Glu Asn Ile Tyr Asp Ala She Val Ile Tyr Ser Ser Gin Asp Glu Asp Trp Val Arg Asn Glu Leu Val Lys Asn Leu Glu Glu Gly Val Pro Pro Phe Gin Leu Cys Leu His Tyr Arg Asp Phe Ile Pro Gly Val Ala Ile Ala Ala Asn Ile Ile His Glu Gly She His Lys Ser Arg Lys Val Ile Val Val Val Ser Gin His She Ile Gin Ser Arg Trp Cys Ile Phe Glu Tyr Glu Ile Ala Gin Thr Trp Gin Phe Leu Ser Ser Arg Ala Gly Ile Ile Phe Ile Val Leu Gin Lys Val Glu Lys Thr Leu Leu Arg Gin Gin Val Glu Leu Tyr Arg Leu Leu Ser Arg Asn Thr Tyr Leu Glu Trp Glu Asp Ser Val Leu Gly Arg His Ile Phe Trp Arg Arg Leu Arg Lys Ala Leu Leu Asp Gly Lys Ser Trp Asn Pro Glu Gly Thr Val Gly Thr Gly Cys Asn Trp Gln Glu Ala Thr Ser Ile <210> 19 <211> 782 <212> PRT
<213> Homo sapiens <400> 19 Met Lys Pro Arg Ala Phe Arg Leu Arg Ser Leu Ser Pro Ser Pro Arg Phe His Cys Phe Leu Leu Asn Ala Ala Val Leu Ser Arg Arg Cys Glu Ile Gln Thr Ile Glu Asp Gly Ala Tyr Gln Ser Leu Ser His Leu Ser Thr Leu Ile Leu Thr Gly Asn Pro Ile Gln Ser Leu Ala Leu Gly Ala Phe Ser Gly Leu Ser Ser Leu Gln Lys Leu Val Ala Val Glu Thr Asn Leu Ala Ser Leu Glu Asn Phe Pro Ile Gly His Leu Lys Thr Leu Lys Glu Leu Asn Val Ala His Asn Leu Ile Gln Ser Phe Lys Leu Pro Glu Tyr Phe Ser Asn Leu Thr Asn Leu Glu His Leu Asp Leu Ser Ser Asn Lys Ile Gln Ser Ile Tyr Cys Thr Asp Leu Arg Val Leu His Gln Met Pro Leu Leu Asn Leu Ser Leu Asp Leu Ser Leu Asn Pro Met Asn Phe Ile Gln Pro Gly Ala Phe Lys Glu Ile Arg Leu His Lys Leu Thr Leu Arg Asn Asn Phe Asp Ser Leu Asn Val Met Lys Thr Cys Ile Gln Gly Leu Ala Gly Leu Glu Val His Arg Leu Val Leu Gly Glu Phe Arg Asn Glu Gly Asn Leu Glu Lys Phe Asp Lys Ser Ala Leu Glu Gly Leu Cys Asn Leu Thr Ile Glu Glu Phe Arg Leu Ala Tyr Leu Asp Tyr Tyr Leu Asp Asp Ile Ile Asp Leu Phe Asn Cys Leu Thr Asn Val Ser Ser Phe Ser Leu Val Ser Val Thr Ile Glu Arg Val Lys Asp Phe Ser Tyr Asn Phe Gly Trp Gln His Leu Glu Leu Val Asn Cys Lys Phe Gly Gln Phe Pro Thr Leu Lys Leu Lys Ser Leu Lys Arg Leu Thr Phe Thr Ser Asn Lys Gly Gly Asn Ala Phe Ser Glu Val Asp Leu Pro Ser Leu Glu Phe Leu Asp Leu Ser Arg Asn Gly Leu Ser Phe Lys Gly Cys Cys Ser Gln Ser Asp Phe Gly Thr Thr Ser Leu Lys Tyr Leu Asp Leu Ser Phe Asn Gly Val Ile Thr Met Ser Ser Asn Phe Leu Gly Leu Glu Gln Leu Glu His Leu Asp Phe Gin His Ser Asn Leu Lys Gin Met Ser Glu Phe Ser Val Phe Leu Ser Leu Arg Asn Leu Ile Tyr Leu Asp Ile Ser His Thr His Thr Arg Val Ala Phe Asn Gly Ile Phe Asn Gly Leu Ser Ser Leu Glu Val Leu Lys Met Ala Gly Asn Ser Phe Gin Glu Asn Phe Leu Pro Asp Ile Phe Thr Glu Leu Arg Asn Leu Thr Phe Leu Asp Leu Ser Gin Cys Gin Leu Glu Gin Leu Ser Pro Thr Ala Phe Asn Ser Leu Ser Ser Leu Gin Val Leu Asn Met Ser His Asn Asn Phe Phe Ser Leu Asp Thr Phe Pro Tyr Lys Cys Leu Asn Ser Leu Gin Val Leu Asp Tyr Ser Leu Asn His Ile Met Thr Ser Lys Lys Gin Glu Leu Gin His Phe Pro Ser Ser Leu Ala Phe Leu Asn Leu Thr Gin Asn Asp Phe Ala Cys Thr Cys Glu His Gin Ser She Leu Gin Trp Ile Lys Asp Gin Arg Gin Leu Leu Val Glu Val Glu Arg Met Glu Cys Ala Thr Pro Ser Asp Lys Gin Gly Met Pro Val Leu Ser Leu Asn Ile Thr Cys Gin Met Asn Lys Thr Ile Ile Gly Val Ser Val Leu Ser Val Leu Val Val Ser Val Val Ala Val Leu Val Tyr Lys Phe Tyr Phe His Leu Met Leu Leu Ala Gly Cys Ile Lys Tyr Gly Arg Gly Glu Asn Ile Tyr Asp Ala Phe Val Ile Tyr Ser Ser Gin Asp Glu Asp Trp Val Arg Asn Glu Leu Val Lys Asn Leu Glu Glu Gly Val Pro Pro Phe Gin Leu Cys Leu His Tyr Arg Asp Phe Ile Pro Gly Val Ala Ile Ala Ala Asn Ile Ile His Glu Gly Phe His Lys Ser Arg Lys Val Ile Val Val Val Ser Gin His Phe Ile Gin Ser Arg Trp Cys Ile She Glu Tyr Glu Ile Ala Gin Thr Trp Gin She Leu Ser Ser Arg Ala Gly Ile Ile Phe Ile Val Leu Gin Lys Val Glu Lys Thr Leu Leu Arg Gin Gin Val Glu Leu Tyr Arg Leu Leu Ser Arg Asn Thr Tyr Leu Glu Trp Glu Asp Ser Val Lou Gly Arg His Ile She Trp Arg Arg Leu Arg Lys Ala Leu Leu Asp Gly Lys Ser Trp Asn Pro Glu Gly Thr Val Gly Thr Gly Cys Asn Trp Gin Glu Ala Thr Ser Ile <210> 20 <211> 614 <212> PRT

<213> Homo sapiens <400> 20 Met Ser Gly Tyr Ser Ser Asp Arg Asp Arg Gly Arg Asp Arg Gly Phe Gly Ala Pro Arg Phe Gly Gly Ser Arg Ala Gly Pro Leu Ser Gly Lys Lys Phe Gly Asn Pro Gly Glu Lys Leu Val Lys Lys Lys Trp Asn Leu Asp Glu Leu Pro Lys Phe Glu Lys Asn Phe Tyr Gin Glu His Pro Asp Leu Ala Arg Arg Thr Ala Gin Glu Val Glu Thr Tyr Arg Arg Ser Lys Glu Ile Thr Val Arg Gly His Asn Cys Pro Lys Pro Val Leu Asn Phe Tyr Glu Ala Asn Phe Pro Ala Asn Val Met Asp Val Ile Ala Arg Gin Asn Phe Thr Glu Pro Thr Ala Ile Gin Ala Gin Gly Trp Pro Val Ala Leu Ser Gly Leu Asp Met Val Gly Val Ala Gin Thr Gly Ser Gly Lys Thr Leu Ser Tyr Leu Leu Pro Ala Ile Val His Ile Asn His Gin Pro Phe Leu Glu Arg Gly Asp Gly Pro Ile Cys Leu Val Leu Ala Pro Thr Arg Glu Leu Ala Gin Gin Val Gin Gin Val Ala Ala Glu Tyr Cys Arg Ala Cys Arg Leu Lys Ser Thr Cys Ile Tyr Gly Gly Ala Pro Lys Gly Pro Gin Ile Arg Asp Leu Glu Arg Gly Val Glu Ile Cys Ile Ala Thr Pro Gly Arg Lou Ile Asp Phe Lou Glu Cys Gly Lys Thr Asn Leu Arg Arg Thr Thr Tyr Leu Val Leu Asp Glu Ala Asp Arg Met Leu Asp Met Gly Phe Glu Pro Gin Ile Arg Lys Ile Val Asp Gin Ile Arg Pro Asp Arg Gin Thr Leu Met Trp Ser Ala Thr Trp Pro Lys Glu Val Arg Gin Lou Ala Glu Asp Phe Leu Lys Asp Tyr Ile His Ile Asn Ile Gly Ala Leu Glu Leu Ser Ala Asn His Asn Ile Leu Gin Ile Val Asp Val Cys His Asp Val Glu Lys Asp Glu Lys Leu Ile Arg Leu Met Glu Glu Ile Met Ser Glu Lys Glu Asn Lys Thr Ile Val Phe Val Glu Thr Lys Arg Arg Cys Asp Glu Leu Thr Arg Lys Met Arg Arg Asp Gly Trp Pro Ala Met Gly Ile His Gly Asp Lys Ser Gin Gin Glu Arg Asp Trp Val Leu Asn Glu Phe Lys His Gly Lys Ala Pro Ile Leu Ile Ala Thr Asp Val Ala Ser Arg Gly Leu Asp Val Glu Asp Val Lys Phe Val Ile Asn Tyr Asp Tyr Pro Asn Ser Ser Glu Asp Tyr Ile His Arg Ile Gly Arg Thr Ala Arg Ser Thr Lys Thr Gly Thr Ala Tyr Thr Phe Phe Thr Pro Asn Asn Ile Lys Gln Val Ser Asp Leu Ile Ser Val Leu Arg Glu Ala Asn Gln Ala Ile Asn Pro Lys Leu Leu Gln Leu Val Glu Asp Arg Gly Ser Gly Arg Ser Arg Gly Arg Gly Gly Met Lys Asp Asp Arg Arg Asp Arg Tyr Ser Ala Gly Lys Arg Gly Gly Phe Asn Thr Phe Arg Asp Arg Glu Asn Tyr Asp Arg Gly Tyr Ser Ser Leu Leu Lys Arg Asp Phe Gly Ala Lys Thr Gln Asn Gly Val Tyr Ser Ala Ala Asn Tyr Thr Asn Gly Ser Phe Gly Ser Asn Phe Val Ser Ala Gly Ile Gln Thr Ser Phe Arg Thr Gly Asn Pro Thr Gly Thr Tyr Gln Asn Gly Tyr Asp Ser Thr Gln Gin Tyr Gly Ser Asn Val Pro Asn Met His Asn Gly Met Asn Gln Gln Ala Tyr Ala Tyr Pro Ala Thr Ala Ala Ala Pro Met Ile Gly Tyr Pro Met Pro Thr Gly Tyr Ser Gin <210> 21 <211> 614 <212> PRT
<213> Homo sapiens <400> 21 Met Ser Gly Tyr Ser Ser Asp Arg Asp Arg Gly Arg Asp Arg Gly Phe Gly Ala Pro Arg Phe Gly Gly Ser Arg Ala Gly Pro Leu Ser Gly Lys Lys Phe Gly Asn Pro Gly Glu Lys Leu Val Lys Lys Lys Trp Asn Leu Asp Glu Leu Pro Lys Phe Glu Lys Asn Phe Tyr Gln Glu His Pro Asp Leu Ala Arg Arg Thr Ala Gln Glu Val Glu Thr Tyr Arg Arg Ser Lys Glu Ile Thr Val Arg Gly His Asn Cys Pro Lys Pro Val Leu Asn Phe Tyr Glu Ala Asn Phe Pro Ala Asn Val Met Asp Val Ile Ala Arg Gln Asn Phe Thr Glu Pro Thr Ala Ile Gln Ala Gln Gly Trp Pro Val Ala Leu Ser Gly Leu Asp Met Val Gly Val Ala Gin Thr Gly Ser Gly Lys Thr Leu Ser Tyr Leu Leu Pro Ala Ile Val His Ile Asn His Gln Pro Phe Leu Glu Arg Gly Asp Gly Pro Ile Cys Leu Val Leu Ala Pro Thr Arg Glu Leu Ala Gln Gln Val Gln Gln Val Ala Ala Glu Tyr Cys Arg Ala Cys Arg Leu Lys Ser Thr Cys Ile Tyr Gly Gly Ala Pro Lys Gly Pro Gin Ile Arg Asp Leu Glu Arg Gly Val Glu Ile Cys Ile Ala Thr Pro Gly Arg Leu Ile Asp Phe Leu Glu Cys Gly Lys Thr Asn Leu Arg Arg Thr Thr Tyr Leu Val Leu Asp Glu Ala Asp Arg Met Leu Asp Met Gly Phe Glu Pro Gin Ile Arg Lys Ile Val Asp Gin Ile Arg Pro Asp Arg Gin Thr Leu Met Trp Ser Ala Thr Trp Pro Lys Glu Val Arg Gin Leu Ala Glu Asp Phe Leu Lys Asp Tyr Ile His Ile Asn Ile Gly Ala Leu Glu Leu Ser Ala Asn His Asn Ile Leu Gin Ile Val Asp Val Cys His Asp Val Glu Lys Asp Glu Lys Leu Ile Arg Leu Met Glu Glu Ile Met Ser Glu Lys Glu Asn Lys Thr Ile Val Phe Val Glu Thr Lys Arg Arg Cys Asp Glu Leu Thr Arg Lys Met Arg Arg Asp Gly Trp Pro Ala Met Gly Ile His Gly Asp Lys Ser Gin Gin Glu Arg Asp Trp Val Leu Asn Glu Phe Lys His Gly Lys Ala Pro Ile Leu Ile Ala Thr Asp Val Ala Ser Arg Gly Leu Asp Val Glu Asp Val Lys Phe Val Ile Asn Tyr Asp Tyr Pro Asn Ser Ser Glu Asp Tyr Ile His Arg Ile Gly Arg Thr Ala Arg Ser Thr Lys Thr Gly Thr Ala Tyr Thr Phe Phe Thr Pro Asn Asn Ile Lys Gin Val Ser Asp Leu Ile Ser Val Leu Arg Glu Ala Asn Gin Ala Ile Asn Pro Lys Leu Leu Gin Lou Val Glu Asp Arg Gly Ser Gly Arg Ser Arg Gly Arg Gly Gly Met Lys Asp Asp Arg Arg Asp Arg Tyr Ser Ala Gly Lys Arg Gly Gly Phe Asn Thr Phe Arg Asp Arg Glu Asn Tyr Asp Arg Gly Tyr Ser Ser Leu Leu Lys Arg Asp Phe Gly Ala Lys Thr Gin Asn Gly Val Tyr Ser Ala Ala Asn Tyr Thr Asn Gly Ser Phe Gly Ser Asn Phe Val Ser Ala Gly Ile Gin Thr Ser Phe Arg Thr Gly Asn Pro Thr Gly Thr Tyr Gin Asn Gly Tyr Asp Ser Thr Gin Gin Tyr Gly Ser Asn Val Pro Asn Met His Asn Gly Met Asn Gin Gin Ala Tyr Ala Tyr Pro Ala Thr Ala Ala Ala Pro Met Ile Gly Tyr Pro Met Pro Thr Gly Tyr Ser Gin <210> 22 <211> 894 <212> PRT
<213> Homo sapiens <400> 22 Met Ile Leu Leu Ala Val Leu Phe Leu Cys Phe Ile Ser Ser Tyr Ser Ala Ser Val Lys Gly His Thr Thr Gly Leu Ser Leu Asn Asn Asp Arg Leu Tyr Lys Leu Thr Tyr Ser Thr Glu Val Lou Leu Asp Arg Gly Lys Gly Lys Leu Gin Asp Ser Val Gly Tyr Arg Ile Ser Ser Asn Val Asp Val Ala Leu Leu Trp Arg Asn Pro Asp Gly Asp Asp Asp Gin Leu Ile Gin Ile Thr Met Lys Asp Val Asn Val Glu Asn Val Asn Gin Gin Arg Gly Glu Lys Ser Ile Phe Lys Gly Lys Ser Pro Ser Lys Ile Met Gly Lys Glu Asn Leu Glu Ala Leu Gin Arg Pro Thr Leu Leu His Leu Ile His Gly Lys Val Lys Glu Phe Tyr Ser Tyr Gin Asn Glu Ala Val Ala Ile Glu Asn Ile Lys Arg Gly Leu Ala Ser Leu Phe Gin Thr Gin Leu Ser Ser Gly Thr Thr Asn Glu Val Asp Ile Ser Gly Asn Cys Lys Val Thr Tyr Gin Ala His Gin Asp Lys Val Ile Lys Ile Lys Ala Leu Asp Ser Cys Lys Ile Ala Arg Ser Gly Phe Thr Thr Pro Asn Gin Val Lou Gly Val Ser Ser Lys Ala Thr Ser Val Thr Thr Tyr Lys Ile Glu Asp Ser Phe Val Ile Ala Val Leu Ala Glu Glu Thr His Asn Phe Gly Leu Asn Phe Lou Gin Thr Ile Lys Gly Lys Ile Val Ser Lys Gin Lys Lou Glu Leu Lys Thr Thr Glu Ala Gly Pro Arg Lou Met Ser Gly Lys Gin Ala Ala Ala Ile Ile Lys Ala Val Asp Ser Lys Tyr Thr Ala Ile Pro Ile Val Gly Gin Val Phe Gin Ser Gin Cys Lys Gly Cys Pro Ser Lou Ser Glu Leu Trp Arg Ser Thr Arg Lys Tyr Leu Gin Pro Asp Asn Leu Ser Lys Ala Glu Ala Val Arg Asn Phe Leu Ala Phe Ile Gin His Leu Arg Thr Ala Lys Lys Glu Glu Ile Leu Gin Ile Leu Lys Met Glu Asn Lys Glu Val Lou Pro Gin Leu Val Asp Ala Val Thr Ser Ala Gin Thr Ser Asp Ser Leu Glu Ala Ile Leu Asp Phe Leu Asp Phe Lys Ser Asp Ser Ser Ile Ile Lou Gin Glu Arg Phe Leu Tyr Ala Cys Gly Phe Ala Ser His Pro Asn Glu Glu Lou Leu Arg Ala Leu Ile Ser Lys Phe Lys Gly Ser Ile Gly Ser Ser Asp Ile Arg Glu Thr Val Met Ile Ile Thr Gly Thr Leu Val Arg Lys Leu Cys Gin Asn Glu Gly Cys Lys Leu Lys Ala Val Val Glu Ala Lys Lys Leu Ile Leu Gly Gly Leu Glu Lys Ala Glu Lys Lys Glu Asp Thr Arg Met Tyr Leu Leu Ala Leu Lys Asn Ala Leu Leu Pro Glu Gly Ile Pro Ser Leu Leu Lys Tyr Ala Glu Ala Gly Glu Gly Pro Ile Ser His Leu Ala Thr Thr Ala Leu Gln Arg Tyr Asp Leu Pro Phe Ile Thr Asp Glu Val Lys Lys Thr Leu Asn Arg Ile Tyr His Gin Asn Arg Lys Val His Glu Lys Thr Val Arg Thr Ala Ala Ala Ala Ile Ile Leu Asn Asn Asn Pro Ser Tyr Met Asp Val Lys Asn Ile Leu Leu Ser Ile Gly Glu Leu Pro Gln Glu Met Asn Lys Tyr Met Leu Ala Ile Val Gin Asp Ile Leu Arg Phe Glu Met Pro Ala Ser Lys Ile Val Arg Arg Val Leu Lys Glu Met Val Ala His Asn Tyr Asp Arg Phe Ser Arg Ser Gly Ser Ser Ser Ala Tyr Thr Gly Tyr Ile Glu Arg Ser Pro Arg Ser Ala Ser Thr Tyr Ser Leu Asp Ile Leu Tyr Ser Gly Ser Gly Ile Leu Arg Arg Ser Asn Leu Asn Ile Phe Gln Tyr Ile Gly Lys Ala Gly Leu His Gly Ser Gln Val Val Ile Glu Ala Gln Gly Leu Glu Ala Leu Ile Ala Ala Thr Pro Asp Glu Gly Glu Glu Asn Leu Asp Ser Tyr Ala Gly Met Ser Ala Ile Leu Phe Asp Val Gln Leu Arg Pro Val Thr Phe Phe Asn Gly Tyr Ser Asp Leu Met Ser Lys Met Leu Ser Ala Ser Gly Asp Pro Ile Ser Val Val Lys Gly Leu Ile Leu Leu Ile Asp His Ser Gln Glu Leu Gln Leu Gln Ser Gly Leu Lys Ala Asn Ile Glu Val Gin Gly Gly Lou Ala Ile Asp Ile Ser Gly Ala Met Glu Phe Ser Leu Trp Tyr Arg Glu Ser Lys Thr Arg Val Lys Asn Arg Val Thr Val Val Ile Thr Thr Asp Ile Thr Val Asp Ser Ser Phe Val Lys Ala Gly Leu Glu Thr Ser Thr Glu Thr Glu Ala Gly Leu Glu Phe Ile Ser Thr Val Gln Phe Ser Gln Tyr Pro Phe Leu Val Cys Met Gln Met Asp Lys Asp Glu Ala Pro Phe Arg Gln Phe Glu Lys Lys Tyr Glu Arg Leu Ser Thr Gly Arg Gly Tyr Val Ser Gln Lys Arg Lys Glu Ser Val Leu Ala Gly Cys Glu Phe Pro Leu His Gln Glu Asn Ser Glu Met Cys Lys Val Val Phe Ala Pro Gln Pro Asp Ser Thr Ser Ser Gly Trp Phe <210> 23 <211> 455 <212> PRT
<213> Homo sapiens <400> 23 Met Trp Leu Glu Ile Leu Leu Thr Ser Val Leu Gly Phe Ala Ile Tyr Trp Phe Ile Ser Arg Asp Lys Glu Glu Thr Leu Pro Leu Glu Asp Gly Trp Trp Gly Pro Gly Thr Arg Ser Ala Ala Arg Glu Asp Asp Ser Ile Arg Pro Phe Lys Val Glu Thr Ser Asp Glu Glu Ile His Asp Leu His Gin Arg Ile Asp Lys Phe Arg Phe Thr Pro Pro Leu Glu Asp Ser Cys Phe His Tyr Gly Phe Asn Ser Asn Tyr Leu Lys Lys Val Ile Ser Tyr Trp Arg Asn Glu Phe Asp Trp Lys Lys Gin Val Glu Ile Leu Asn Arg Tyr Pro His Phe Lys Thr Lys Ile Glu Gly Leu Asp Ile His Phe Ile His Val Lys Pro Pro Gin Leu Pro Ala Gly His Thr Pro Lys Pro Leu Leu Met Val His Gly Trp Pro Gly Ser Phe Tyr Glu Phe Tyr Lys Ile Ile Pro Leu Leu Thr Asp Pro Lys Asn His Gly Leu Ser Asp Glu His Val Phe Glu Val Ile Cys Pro Ser Ile Pro Gly Tyr Gly Phe Ser Glu Ala Ser Ser Lys Lys Gly Phe Asn Ser Val Ala Thr Ala Arg Ile Phe Tyr Lys Leu Met Leu Arg Leu Gly Phe Gin Glu Phe Tyr Ile Gin Gly Gly Asp Trp Gly Ser Leu Ile Cys Thr Asn Met Ala Gin Leu Val Pro Ser His Val Lys Gly Leu His Leu Asn Met Ala Leu Val Leu Ser Asn Phe Ser Thr Leu Thr Leu Leu Leu Gly Gin Arg Phe Gly Arg Phe Leu Gly Leu Thr Glu Arg Asp Val Glu Leu Leu Tyr Pro Val Lys Glu Lys Val Phe Tyr Ser Leu Met Arg Glu Ser Gly Tyr Met His Ile Gin Cys Thr Lys Pro Asp Thr Val Gly Ser Ala Leu Asn Asp Ser Pro Val Gly Leu Ala Ala Tyr Ile Leu Glu Lys Phe Ser Thr Trp Thr Asn Thr Glu Phe Arg Tyr Leu Glu Asp Gly Gly Leu Glu Arg Lys Phe Ser Leu Asp Asp Leu Leu Thr Asn Val Met Leu Tyr Trp Thr Thr Gly Thr Ile Ile Ser Ser Gin Arg Phe Tyr Lys Glu Asn Leu Gly Gin Gly Trp Met Thr Gin Lys His Glu Arg Met Lys Val Tyr Val Pro Thr Gly Phe Ser Ala Phe Pro Phe Glu Leu Leu His Thr Pro Glu Lys Trp Val Arg Phe Lys Tyr Pro Lys Leu Ile Ser Tyr Ser Tyr Met Val Arg Gly Gly His Phe Ala Ala Phe Glu Glu Pro Glu Leu Leu Ala Gln Asp Ile Arg Lys Phe Leu Ser Val Leu Glu Arg Gln <210> 24 <211> 455 <212> PRT
<213> Homo sapiens <400> 24 Met Trp Leu Glu Ile Leu Leu Thr Ser Val Leu Gly Phe Ala Ile Tyr Trp Phe Ile Ser Arg Asp Lys Glu Glu Thr Leu Pro Leu Glu Asp Gly Trp Trp Gly Pro Gly Thr Arg Ser Ala Ala Arg Glu Asp Asp Ser Ile Arg Pro Phe Lys Val Glu Thr Ser Asp Glu Glu Ile His Asp Leu His Gln Arg Ile Asp Lys Phe Arg Phe Thr Pro Pro Leu Glu Asp Ser Cys Phe His Tyr Gly Phe Asn Ser Asn Tyr Leu Lys Lys Val Ile Ser Tyr Trp Arg Asn Glu Phe Asp Trp Lys Lys Gln Val Glu Ile Leu Asn Arg Tyr Pro His Phe Lys Thr Lys Ile Glu Gly Leu Asp Ile His Phe Ile His Val Lys Pro Pro Gln Leu Pro Ala Gly His Thr Pro Lys Pro Leu Leu Met Val His Gly Trp Pro Gly Ser Phe Tyr Glu Phe Tyr Lys Ile Ile Pro Leu Leu Thr Asp Pro Lys Asn His Gly Leu Ser Asp Glu His Val Phe Glu Val Ile Cys Pro Ser Ile Pro Gly Tyr Gly Phe Ser Glu Ala Ser Ser Lys Lys Gly Phe Asn Ser Val Ala Thr Ala Arg Ile Phe Tyr Lys Leu Met Leu Arg Leu Gly Phe Gln Glu Phe Tyr Ile Gln Gly Gly Asp Trp Gly Ser Leu Ile Cys Thr Asn Met Ala Gln Leu Val Pro Ser His Val Lys Gly Leu His Leu Asn Met Ala Leu Val Leu Ser Asn Phe Ser Thr Leu Thr Leu Leu Leu Gly Gln Arg Phe Gly Arg Phe Leu Gly Leu Thr Glu Arg Asp Val Glu Leu Leu Tyr Pro Val Lys Glu Lys Val Phe Tyr Ser Leu Met Arg Glu Ser Gly Tyr Met His Ile Gln Cys Thr Lys Pro Asp Thr Val Gly Ser Ala Leu Asn Asp Ser Pro Val Gly Leu Ala Ala Tyr Ile Leu Glu Lys Phe Ser Thr Trp Thr Asn Thr Glu Phe Arg Tyr Leu Glu Asp Gly Gly Leu Glu Arg Lys Phe Ser Leu Asp Asp Leu Leu Thr Asn Val Met Leu Tyr Trp Thr Thr Gly Thr Ile Ile Ser Ser Gin Arg Phe Tyr Lys Glu Asn Leu Gly Gin Gly Trp Met Thr Gin Lys His Glu Arg Met Lys Val Tyr Val Pro Thr Gly Phe Ser Ala Phe Pro Phe Glu Leu Leu His Thr Pro Glu Lys Trp Val Arg Phe Lys Tyr Pro Lys Leu Ile Ser Tyr Ser Tyr Met Val Arg Gly Gly His The Ala Ala Phe Glu Glu Pro Glu Leu Leu Ala Gin Asp Ile Arg Lys Phe Leu Ser Val Leu Glu Arg Gin <210> 25 <211> 455 <212> PRT
<213> Homo sapiens <400> 25 Met Trp Leu Glu Ile Leu Lou Thr Ser Val Leu Gly Phe Ala Ile Tyr Trp Phe Ile Ser Arg Asp Lys Glu Glu Thr Leu Pro Leu Glu Asp Gly Trp Trp Gly Pro Gly Thr Arg Ser Ala Ala Arg Glu Asp Asp Ser Ile Arg Pro Phe Lys Val Glu Thr Ser Asp Glu Glu Ile His Asp Leu His Gin Arg Ile Asp Lys Phe Arg Phe Thr Pro Pro Leu Glu Asp Ser Cys Phe His Tyr Gly Phe Asn Ser Asn Tyr Leu Lys Lys Val Ile Ser Tyr Trp Arg Asn Glu Phe Asp Trp Lys Lys Gin Val Glu Ile Leu Asn Arg Tyr Pro His Phe Lys Thr Lys Ile Glu Gly Leu Asp Ile His Phe Ile His Val Lys Pro Pro Gin Leu Pro Ala Gly His Thr Pro Lys Pro Lou Leu Met Val His Gly Trp Pro Gly Per Phe Tyr Glu Phe Tyr Lys Ile Ile Pro Leu Leu Thr Asp Pro Lys Asn His Gly Leu Ser Asp Glu His Val Phe Glu Val Ile Cys Pro Ser Ile Pro Gly Tyr Gly Phe Ser Glu Ala Ser Ser Lys Lys Gly Phe Asn Ser Val Ala Thr Ala Arg Ile Phe Tyr Lys Leu Met Lou Arg Leu Gly Phe Gin Glu Phe Tyr Ile Gin Gly Gly Asp Trp Gly Ser Leu Ile Cys Thr Asn Met Ala Gin Leu Val Pro Ser His Val Lys Gly Leu His Leu Asn Met Ala Leu Val Leu Ser Asn Phe Ser Thr Leu Thr Leu Leu Lou Gly Gin Arg Phe Gly Arg Phe Leu Gly Leu Thr Glu Arg Asp Val Glu Leu Leu Tyr Pro Val Lys Glu Lys Val Phe Tyr Ser Leu Met Arg Glu Ser Gly Tyr Met His Ile Gin Cys Thr Lys Pro Asp Thr Val Gly Ser Ala Leu Asn Asp Ser Pro Val Gly Leu Ala Ala Tyr Tie Leu Glu Lys Phe Ser Thr Trp Thr Asn Thr Glu Phe Arg Tyr Leu Glu Asp Gly Gly Leu Glu Arg Lys Phe Ser Leu Asp Asp Leu Leu Thr Asn Val Met Leu Tyr Trp Thr Thr Gly Thr Ile Ile Ser Ser Gin Arg Phe Tyr Lys Glu Asn Leu Gly Gin Gly Trp Met Thr Gin Lys His Glu Arg Met Lys Vol Tyr Val Pro Thr Gly Phe Ser Ala Phe Pro Phe Glu Leu Leu His Thr Pro Glu Lys Trp Val Arg Phe Lys Tyr Pro Lys Leu Ile Ser Tyr Ser Tyr Met Val Arg Gly Gly His Phe Ala Ala Phe Glu Glu Pro Glu Leu Leu Ala Gin Asp Ile Arg Lys Phe Leu Ser Vol Leu Glu Arg Gin <210> 26 <211> 455 <212> PRT
<213> Homo sapiens <400> 26 Met Trp Leu Glu Ile Leu Leu Thr Ser Vol Leu Gly Phe Ala Ile Tyr Trp Phe Ile Ser Arg Asp Lys Glu Glu Thr Leu Pro Leu Glu Asp Gly Trp Trp Gly Pro Gly Thr Arg Ser Ala Ala Arg Glu Asp Asp Ser Ile Arg Pro Phe Lys Vol Glu Thr Ser Asp Glu Glu Ile His Asp Leu His Gin Arg Ile Asp Lys Phe Arg Phe Thr Pro Pro Leu Glu Asp Ser Cys Phe His Tyr Gly Phe Asn Ser Asn Tyr Leu Lys Lys Vol Ile Ser Tyr Trp Arg Asn Glu Phe Asp Trp Lys Lys Gin Val Glu Ile Leu Asn Arg Tyr Pro His Phe Lys Thr Lys Ile Glu Gly Leu Asp Ile His Phe Ile His Vol Lys Pro Pro Gin Leu Pro Ala Gly His Thr Pro Lys Pro Leu Leu Met Vol His Gly Trp Pro Gly Ser Phe Tyr Glu Phe Tyr Lys Ile Ile Pro Leu Leu Thr Asp Pro Lys Asn His Gly Leu Ser Asp Glu His Val Phe Glu Vol Ile Cys Pro Ser Ile Pro Gly Tyr Gly Phe Ser Glu Ala Ser Ser Lys Lys Gly Phe Asn Ser Vol Ala Thr Ala Arg Ile Phe Tyr Lys Leu Met Leu Arg Leu Gly Phe Gin Glu Phe Tyr Ile Gin Gly Gly Asp Trp Gly Ser Leu Ile Cys Thr Asn Met Ala Gin Leu Val Pro Ser His Val Lys Gly Leu His Leu Asn Met Ala Leu Val Leu Ser Asn Phe Ser Thr Leu Thr Leu Leu Leu Gly Gin Arg Phe Gly Arg Phe Leu Gly Leu Thr Glu Arg Asp Val Glu Leu Leu Tyr Pro Val Lys Glu Lys Val Phe Tyr Ser Leu Met Arg Glu Ser Gly Tyr Met His Ile Gin Cys Thr Lys Pro Asp Thr Val Gly Ser Ala Leu Asn Asp Ser Pro Val Gly Leu Ala Ala Tyr Ile Leu Glu Lys Phe Ser Thr Trp Thr Asn Thr Glu Phe Arg Tyr Leu Glu Asp Gly Gly Leu Glu Arg Lys Phe Ser Leu Asp Asp Leu Leu Thr Asn Val Met Leu Tyr Trp Thr Thr Gly Thr Ile Ile Ser Ser Gin Arg Phe Tyr Lys Glu Asn Leu Gly Gin Gly Trp Met Thr Gin Lys His Glu Arg Met Lys Val Tyr Val Pro Thr Gly Phe Ser Ala Phe Pro Phe Glu Leu Leu His Thr Pro Glu Lys Trp Val Arg Phe Lys Tyr Pro Lys Leu Ile Ser Tyr Ser Tyr Met Val Arg Gly Gly His Phe Ala Ala Phe Glu Glu Pro Glu Leu Leu Ala Gin Asp Ile Arg Lys Phe Leu Ser Val Leu Glu Arg Gin <210> 27 <211> 773 <212> PRT
<213> Homo sapiens <400> 27 Met Ala Glu Ala His Gin Ala Val Ala Phe Gin Phe Thr Val Thr Pro Asp Gly Ile Asp Leu Arg Leu Ser His Glu Ala Leu Arg Gin Ile Tyr Leu Ser Gly Leu His Ser Trp Lys Lys Lys Phe Ile Arg Phe Lys Asn Gly Ile Ile Thr Gly Val Tyr Pro Ala Ser Pro Ser Ser Trp Leu Ile Val Val Val Gly Val Met Thr Thr Met Tyr Ala Lys Ile Asp Pro Ser Leu Gly Ile Ile Ala Lys Ile Asn Arg Thr Leu Glu Thr Ala Asn Cys Met Ser Ser Gin Thr Lys Asn Val Val Ser Gly Val Leu Phe Gly Thr Gly Leu Trp Val Ala Leu Ile Val Thr Met Arg Tyr Ser Leu Lys Val Leu Leu Ser Tyr His Gly Trp Met Phe Thr Glu His Gly Lys Met Ser Arg Ala Thr Lys Ile Trp Met Gly Met Val Lys Ile Phe Ser Gly Arg Lys Pro Met Leu Tyr Ser Phe Gln Thr Ser Leu Pro Arg Leu Pro Val Pro Ala Val Lys Asp Thr Val Asn Arg Tyr Leu Gln Ser Val Arg Pro Leu Met Lys Glu Glu Asp Phe Lys Arg Met Thr Ala Leu Ala Gln Asp Phe Ala Val Gly Leu Gly Pro Arg Leu Gin Trp Tyr Leu Lys Leu Lys Ser Trp Trp Ala Thr Asn Tyr Val Ser Asp Trp Trp Glu Glu Tyr Ile Tyr Leu Arg Gly Arg Gly Pro Leu Met Val Asn Ser Asn Tyr Tyr Ala Met Asp Leu Leu Tyr Ile Leu Pro Thr His Ile Gln Ala Ala Arg Ala Gly Asn Ala Ile His Ala Ile Leu Leu Tyr Arg Arg Lys Leu Asp Arg Glu Glu Ile Lys Pro Ile Arg Leu Leu Gly Ser Thr Ile Pro Leu Cys Ser Ala Gln Trp Glu Arg Met Phe Asn Thr Ser Arg Ile Pro Gly Glu Glu Thr Asp Thr Ile Gln His Met Arg Asp Ser Lys His Ile Val Val Tyr His Arg Gly Arg Tyr Phe Lys Val Trp Leu Tyr His Asp Gly Arg Leu Leu Lys Pro Arg Giu Met Glu Gln Gln Met Gln Arg Ile Leu Asp Asn Thr Ser Glu Pro Gln Pro Gly Glu Ala Arg Leu Ala Ala Leu Thr Ala Gly Asp Arg Val Pro Trp Ala Arg Cys Arg Gln Ala Tyr Phe Gly Arg Gly Lys Asn Lys Gln Ser Leu Asp Ala Val Glu Lys Ala Ala Phe Phe Val Thr Leu Asp Glu Thr Glu Glu Gly Tyr Arg Ser Glu Asp Pro Asp Thr Ser Met Asp Ser Tyr Ala Lys Ser Leu Leu His Gly Arg Cys Tyr Asp Arg Trp Phe Asp Lys Ser Phe Thr Phe Val Val Phe Lys Asn Gly Lys Met Gly Leu Asn Ala Glu His Ser Trp Ala Asp Ala Pro Ile Val Ala His Leu Trp Glu Tyr Val Met Ser Ile Asp Ser Leu Gin Leu Gly Tyr Ala Glu Asp Gly His Cys Lys Gly Asp Ile Asn Pro Asn Ile Pro Tyr Pro Thr Arg Leu Gln Trp Asp Ile Pro Gly Glu Cys Gln Glu Val Ile Glu Thr Ser Leu Asn Thr Ala Asn Leu Leu Ala Asn Asp Val Asp Phe His Ser Phe Pro Phe Val Ala Phe Gly Lys Gly Ile Ile Lys Lys Cys Arg Thr Ser Pro Asp Ala Phe Val Gln Leu Ala Leu Gln Leu Ala His Tyr Lys Asp Met Gly Lys Phe Cys Leu Thr Tyr Glu Ala Ser Met Thr Arg Leu Phe Arg Glu Gly Arg Thr Glu Thr Val Arg Ser Cys Thr Thr Glu Ser Cys Asp Phe Val Arg Ala Met Val Asp Pro Ala Gin Thr Val Glu Gin Arg Leu Lys Lou Phe Lys Leu Ala Ser Glu Lys His Gin His Met Tyr Arg Leu Ala Met Thr Gly Ser Gly Ile Asp Arg His Leu Phe Cys Leu Tyr Val Val Ser Lys Tyr Leu Ala Val Glu Ser Pro Phe Leu Lys Glu Val Leu Ser Giu Pro Trp Arg Leu Ser Thr Ser Gin Thr Pro Gin Gin Gin Val Glu Leu Phe Asp Lou Glu Asn Asn Pro Glu Tyr Val Ser Ser Gly Gly Gly Phe Gly Pro Val Ala Asp Asp Gly Tyr Gly Val Ser Tyr Ile Leu Val Gly Glu Asn Leu Ile Asn Phe His Ile Ser Ser Lys Phe Ser Cys Pro Glu Thr Asp Ser His Arg Phe Gly Arg His Leu Lys Glu Ala Met Thr Asp Ile Ile Thr Leu Phe Gly Leu Ser Ser Asn Ser Lys Lys <210> 28 <211> 773 <212> PRT
<213> Homo sapiens <400> 28 Met Ala Glu Ala His Gin Ala Val Ala Phe Gin Phe Thr Val Thr Pro Asp Gly Ile Asp Lou Arg Lou Ser His Glu Ala Leu Arg Gin Ile Tyr Leu Ser Gly Leu His Ser Trp Lys Lys Lys Phe Ile Arg Phe Lys Asn Gly Ile Ile Thr Gly Val Tyr Pro Ala Ser Pro Ser Ser Trp Lou Ile Val Val Val Gly Val Met Thr Thr Met Tyr Ala Lys Ile Asp Pro Ser Leu Gly Ile Ile Ala Lys Ile Asn Arg Thr Leu Glu Thr Ala Asn Cys Met Ser Ser Gin Thr Lys Asn Val Vol Ser Gly Val Leu Phe Gly Thr Gly Leu Trp Val Ala Lou Ile Val Thr Met Arg Tyr Ser Lou Lys Val Lou Leu Ser Tyr His Gly Trp Met Phe Thr Glu His Gly Lys Met Ser Arg Ala Thr Lys Ile Trp Met Gly Met Val Lys Ile Phe Ser Gly Arg Lys Pro Met Leu Tyr Ser Phe Gin Thr Ser Leu Pro Arg Lou Pro Val Pro Ala Val Lys Asp Thr Val Asn Arg Tyr Lou Gin Ser Val Arg Pro Lou Met Lys Glu Glu Asp Phe Lys Arg Met Thr Ala Lou Ala Gin Asp Phe Ala Val Gly Lou Gly Pro Arg Lou Gin Trp Tyr Leu Lys Lou Lys Ser Trp Trp Ala Thr Asn Tyr Val Ser Asp Trp Trp Glu Glu Tyr Ile Tyr Leu Arg Gly Arg Gly Pro Leu Met Val Asn Ser Asn Tyr Tyr Ala Met Asp Leu Leu Tyr Ile Leu Pro Thr His Ile Gln Ala Ala Arg Ala Gly Asn Ala Ile His Ala Ile Leu Leu Tyr Arg Arg Lys Leu Asp Arg Glu Glu Ile Lys Pro Ile Arg Leu Leu Gly Ser Thr Ile Pro Leu Cys Ser Ala Gln Trp Glu Arg Met Phe Asn Thr Ser Arg Ile Pro Gly Glu Glu Thr Asp Thr Ile Gln His Met Arg Asp Ser Lys His Ile Val Val Tyr His Arg Gly Arg Tyr Phe Lys Val Trp Leu Tyr His Asp Gly Arg Leu Leu Lys Pro Arg Glu Met Glu Gln Gln Met Gln Arg Ile Leu Asp Asn Thr Ser Glu Pro Gln Pro Gly Glu Ala Arg Leu Ala Ala Leu Thr Ala Gly Asp Arg Val Pro Trp Ala Arg Cys Arg Gln Ala Tyr Phe Gly Arg Gly Lys Asn Lys Gln Ser Leu Asp Ala Val Glu Lys Ala Ala Phe Phe Val Thr Leu Asp Glu Thr Glu Glu Gly Tyr Arg Ser Glu Asp Pro Asp Thr Ser Met Asp Ser Tyr Ala Lys Ser Leu Leu His Gly Arg Cys Tyr Asp Arg Trp Phe Asp Lys Ser Phe Thr Phe Val Val Phe Lys Asn Gly Lys Met Gly Leu Asn Ala Glu His Ser Trp Ala Asp Ala Pro Ile Val Ala His Leu Trp Glu Tyr Val Met Ser Ile Asp Ser Leu Gln Leu Gly Tyr Ala Glu Asp Gly His Cys Lys Gly Asp Ile Asn Pro Asn Ile Pro Tyr Pro Thr Arg Leu Gln Trp Asp Ile Pro Gly Glu Cys Gln Glu Val Ile Giu Thr Ser Leu Asn Thr Ala Asn Leu Leu Ala Asn Asp Val Asp Phe His Ser Phe Pro Phe Val Ala Phe Gly Lys Gly Ile Ile Lys Lys Cys Arg Thr Ser Pro Asp Ala Phe Val Gln Leu Ala Leu Gln Leu Ala His Tyr Lys Asp Met Gly Lys Phe Cys Leu Thr Tyr Glu Ala Ser Met Thr Arg Leu Phe Arg Glu Gly Arg Thr Glu Thr Val Arg Ser Cys Thr Thr Glu Ser Cys Asp Phe Val Arg Ala Met Val Asp Pro Ala Gin Thr Val Glu Gln Arg Leu Lys Leu Phe Lys Leu Ala Ser Glu Lys His Gln His Met Tyr Arg Leu Ala Met Thr Gly Ser Gly Ile Asp Arg His Leu Phe Cys Leu Tyr Val Val Ser Lys Tyr Leu Ala Val Glu Ser Pro Phe Leu Lys Glu Val Leu Ser Glu Pro Trp Arg Leu Ser Thr Ser Gin Thr Pro Gin Gin Gin Val Glu Leu Phe Asp Leu Glu Asn Asn Pro Glu Tyr Val Ser Ser Gly Gly Gly Phe Gly Pro Val Ala Asp Asp Gly Tyr Gly Val Ser Tyr Ile Leu Val Gly Glu Asn Leu Ile Asn Phe His Ile Ser Ser Lys Phe Ser Cys Pro Glu Thr Asp Ser His Arg Phe Gly Arg His Leu Lys Glu Ala Met Thr Asp Ile Ile Thr Leu Phe Gly Leu Ser Ser Asn Ser Lys Lys <210> 29 <211> 201 <212> DNA
<213> Homo sapiens <400> 29 gcatctctct taccagagtg tctgatgggg aaaacgttct ggtgtctgac tttcggtcca 60 aagacgaagt cgtggatgcc ttggtatgtt cctgcttcat scccttctac agtggcctta 120 tccctccttc cttcagaggc gtgcgatatg tggatggagg agtgagtgac aacgtaccct 180 tcattgatgc caaaacaacc a 201 <210> 30 <211> 201 <212> DNA
<213> Homo sapiens <400> 30 gotttttcag aagttgatct accaagcctt gagtttctag atctcagtag aaatggcttg 60 agtttcaaag gttgctgttc tcaaagtgat tttgggacaa ycagcctaaa gtatttagat 120 ctgagcttca atggtgttat taccatgagt tcaaacttct tgggcttaga acaactagaa 180 catctggatt tccagcattc c 201 <210> 31 <211> 201 <212> DNA
<213> Homo sapiens <400> 31 gctttttcag aagttgatct accaagcctt gagtttctag atctcagtag aaatggcttg 60 agtttcaaag gttgctgttc tcaaagtgat tttgggacaa ycagcctaaa gtatttagat 120 ctgagcttca atggtgttat taccatgagt tcaaacttct tgggcttaga acaactagaa 180 catctggatt tccagcattc c 201 <210> 32 <211> 201 <212> DNA
<213> Homo sapiens <400> 32 gctttttcag aagttgatct accaagcctt gagtttctag atctcagtag aaatggcttg 60 agtttcaaag gttgctgttc tcaaagtgat tttgggacaa ycagcctaaa gtatttagat 120 ctgagcttca atggtgttat taccatgagt tcaaacttct tgggcttaga acaactagaa 180 catctggatt tccagcattc c 201 <210> 33 <211> 201 <212> DNA
<213> Homo sapiens <400> 33 gctttttcag aagttgatct accaagcctt gagtttctag atctcagtag aaatggcttg 60 agtttcaaag gttgctgttc tcaaagtgat tttgggacaa ycagcctaaa gtatttagat 120 ctgagcttca atggtgttat taccatgagt tcaaacttct tgggcttaga acaactagaa 180 catctggatt tccagcattc c 201 <210> 34 <211> 201 <212> DNA
<213> Homo sapiens <400> 34 acctaataac ataaagcaag tgagcgacct tatctctgtg cttcgtgaag ctaatcaagc 60 aattaatccc aagttgcttc agttggtcga agacagaggt kcaggtcgtt ccaggggtag 120 aggaggcatg aaggatgacc gtcgggacag atactctgcg ggcaaaaggg gtggatttaa 180 tacctttaga gacagggaaa a 201 <210> 35 <211> 201 <212> DNA
<213> Homo sapiens <400> 35 acctaataac ataaagcaag tgagcgacct tatctctgtg cttcgtgaag ctaatcaagc 60 aattaatccc aagttgcttc agttggtcga agacagaggt kcaggtcgtt ccaggggtag 120 aggaggcatg aaggatgacc gtcgggacag atactctgcg ggcaaaaggg gtggatttaa 180 tacctttaga gacagggaaa a 201 <210> 36 <211> 201 <212> DNA
<213> Homo sapiens <400> 36 cagagaggag agaagagcat cttcaaagga aaaagcccat ctaaaataat gggaaaggaa 60 aacttggaag ctctgcaaag acctacgctc cttcatctaa yccatggaaa ggtcaaagag 120 ttctactcat atcaaaatga ggcagtggcc atagaaaata tcaagagagg cctggctagc 180 ctatttcaga cacagttaag c 201 <210> 37 <211> 201 <212> DNA

<213> Homo sapiens <400> 37 caggtggaga ttctcaacag ataccctcac ttcaagacta agattgaagg gctggacatc 60 cacttcatcc acgtgaagcc cccccagctg cccgcaggcc rtaccccgaa gcccttgctg 120 atggtgcacg gctggcccgg ctctttctac gagttttata agatcatccc actcctgact 180 gaccccaaga accatggcct g 201 <210> 38 <211> 201 <212> DNA
<213> Homo sapiens <400> 38 caggtggaga ttctcaacag ataccctcac ttcaagacta agattgaagg gctggacatc 60 cacttcatcc acgtgaagcc cccccagctg cccgcaggcc rtaccccgaa gcccttgctg 120 atggtgcacg gctggcccgg ctctttctac gagttttata agatcatccc actcctgact 180 gaccccaaga accatggcct g 201 <210> 39 <211> 201 <212> DNA
<213> Homo sapiens <400> 39 caggtggaga ttctcaacag ataccctcac ttcaagacta agattgaagg gctggacatc 60 cacttcatcc acgtgaagcc cccccagctg cccgcaggcc rtaccccgaa gcccttgctg 120 atggtgcacg gctggcccgg ctctttctac gagttttata agatcatccc actcctgact 180 gaccccaaga accatggcct g 201 <210> 40 <211> 201 <212> DNA
<213> Homo sapiens <400> 40 caggtggaga ttctcaacag ataccctcac ttcaagacta agattgaagg gctggacatc 60 cacttcatcc acgtgaagcc cccccagctg cccgcaggcc rtaccccgaa gcccttgctg 120 atggtgcacg gctggcccgg ctctttctac gagttttata agatcatccc actcctgact 180 gaccccaaga accatggcct g 201 <210> 41 <211> 201 <212> DNA
<213> Homo sapiens <400> 41 cctccgagga cgagggccgc tcatggtgaa cagcaactat tatgccatgg atctgctgta 60 tatccttcca actcacattc aggcagcaag agccggcaac rccatccatg ccatcctgct 120 ttacaggcgc aaactggacc gggaggaaat caaaccaatt cgtcttttgg gatccacgat 180 tccactctgc tccgctcagt g 201 Et (:)61 3;opeobe5o qqbebbq=c ebeqeeebbe Eceeqqqobeo oqq.qe15qoq pboepabbqb 0981 55b b6 obbqobsbeo sceocobq..5-4 boboP56-4D4 5-43.2oe.5q5 beoq.555pp 0081 5-eb6bpqbqb bqbpDoo4q4 qeDqqqp6e3 bqpb5bpb15 5.5q.peeqb5q qqa5q3.5q5 0f7L' .5quo;oo4.5.2 345ebeopoo oq.opebe5q.6 pp5pbpob5g qbfreobbqoq.
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Zig <OIZ>

cttgctcccc ttcgtgaatg ttggggtacg taccatcaat tcttgtgatt catggtggtt 1980 acatttataa agtctccaca tacactgatc agccaagact gagtcattgc tcctagggga 2040 cggatggggt taggttccat ccaggtctgg gcacattttt gacaaatgat cgatacataa 2100 ccttgtttta tgtgtgttcc tggtaaagac accgtaatcg ataacttgtt tttttttttt 2160 gttttgagac agagtgtaac tcttcgccca ggctggagta caatggtggg atctctgctc 2220 actgcaaact ccacttcccg ggtcaagtgg ttctctcacc ccagcctccc aagtagctgg 2280 gattacgggc atcatgccca gcattttttg ttattttgta gagatggggt ttcaccatgt 2340 tggccaggct ggtctcgaac cctggcctca ggtgatccac ccaccttggc ctcccaaaac 2400 gctggaattc caggcgtgac cactccgccc agcggataac ctgtatattg ttgattcatt 2460 aaccttgaac ccacagcaac agcactagaa ctcatgccta aggagcttct ctaatgcatg 2520 gactttttgt ttttatcgag acagggtctc ccaaagtctg atattgaaaa gtggtcctgg 2580 acaggcgagg tggctccgcc tgtaatccta tcactttggg aggctgaggc gggcagatca 2640 cctgaggtca ggggtcgaga ccagcctggc caacgtggtg aaaccccatc tctactaaaa 2700 atacaaaatt agccgacatg gtggcacatg cctgtaatcc cagctactgg ggaggctgag 2760 gcaggagaat cactgaaccc aagagatggg ggttgcagtg agctgagatc gcaccactgt 2820 actccagcct ggtgacagtg agactccatc taaaaaaaaa aaaaaaagga aagtggtcct 2880 tagcgttcac tatagacgtt gccaatcagt cccacatcat atcacaagta ctgggaactg 2940 aaatttgaag ccgcaaggaa atgaacattt acgactcctg gaaaatagca cttccttatg 3000 caagcatcct gccatctgat gatgttttga cacatgaatt cacttttcct ccttcccaag 3060 tgcctcagca ccagtcctct ccattcttcc aagtagtgtc tgtgtctgat gtgagcaggg 3120 cacagcccaa ctctttgtac catgggcaag gcagtaactt ctcttttgag agaattgttc 3180 aagagaacaa agaagtctcc ctggggcctg aacactgagt tcaagataag aaatgtttat 3240 aactcgtgct ggcagccaag agctggatcc cagttgcaga tggggctatg cgtagcagtg 3300 agaggggaga cacagagaca gggactgaga gagagagaga gagagatggg atcagggata 3360 aggcagtact gccaggcact gggctgggtg ctttctgttc atcacattta acttcacaat 3420 gccctcacac aactgttttc toccccatgg tacagatata aaaagtgaag ctctgagaga 3480 taaatgatgc ttgcgagtct tgtgcactgg ctgtctgatg ccaaagcttg cagtctcaac 3540 atgatatcat gtgcctgtcc cactggaggc tggatggggg gctgagagag ctggaccata 3600 aacccttgcc cagctgggtc ctctctttgt ctctggaaag tggggagggc ccccagctct 3660 gtctacatgc agtgacgaag agggggtgag tcctcagccc tgctcctgtc ctgcccaatc 3720 tgggtcacac tggggatgac agatgtccag tgtggctggc caagaatgaa tgccggggac 3780 aggaagagaa tatgaatgcc tqtggctggt ggcagggtga ctcatctcgg gccttggtca 3840 cagcctcaaa ttcctgtgcc agagcctggc cctcctgtca ttagtcctaa gactgtcatg 3900 caatgcagga gggatggatg ggtacaggag gctagaggtt ctgaccccag ctgcccctcc 3960 agaagcctca gttccgccgc agccctgagc gtgaggtggg ggtggagggc agtagggcag 4020 gactgtaggt aatgcccctc tccagcaaag ccaacacgtc aggaatagat ggaccccctg 4080 tctgcttctc agctctcctg accttccccg ggacttagga cctgaccctg cttgctctgg 4140 gcctccatct acaaagtgtc tatgtgatga ggcagtcagc ccaggtatta ctaaggcctg 4200 aagctcccat gccctgggat tcctgcccag agaaaggagg cagccctgtc ccagctcccc 4260 tacccctcca ggcaaggcaa aagcaaggac tgcagcagaa tggggaactc agttgaacat 4320 gaaccaccca accaatccag gtgcttctca ggtgacattt ggaatctgac agcaatgtca 4380 cctgttttac aacaccacca gtcattctgc agttgaggac actgaccaca aagagggcag 4440 aggcctgacc ccaaagctca catactctgc attcctccag gtctacggag aagggggagg 4500 gcttcctggt ccactccagc tgggggcgct atggcccggc agacagggtc ctccagtgag 4560 gagctctgga ccaaggtcta acttggctcc atgtactgct gtggcttgct ccacccagtg 4620 ccaggggtag gtcaaggtca aggggcctct taggcatctc caagggcatg ctactatcca 4680 aatgtttgtg tccccactaa aggtcatctg ttgaaatcct caccttaagg tgatgatctt 4740 tggaggcggg ggcctttgga aggtgatttg atgagagggg gcacccttat gaatgggatt 4800 ggtgccctta tcaaagaggc ccagaggtga ggatgtggaa gatggcacct tctacgagcc 4860 atacctctca ccagggacca aatctgctgg tatcttgact tgggctttcc agcctccaga 4920 actgtgagac agagaaataa gccaggcgaa gtggctaccc ctgtaatccc agcattttgg 4980 gaggctgagg tgggtgatga cttgaggtca ggagtctaga ctagcctggc caacatggtg 5040 aaaccccatc tctactaaaa atacaaaaaa ttagcaggca tggtggcgca tgcttgtaat 5100 cccagctact cgtgaggctg aggcaggaga atccttgaac ccgggaggaa gaggctgcag 5160 tgggccaaga tcgtgccatt gcactccagc ctgggggaaa aagatagaaa taaatctctt 5220 gtttgtaagc ccctccgctt taaggtgttt tttttcgcac ctgaacggac taagggacta 5280 agggaccagg aatcatccag gcctcagctt ccaaagcact ccccactccc cagttcctac 5340 St 09L8 qq4p-eqqee5 -2455pouDeb peee4beuqe -254T2o-epab pebeqog.-4;q upb-4.544soq 00L8 54254epobs ebb4opouge ebbeqbb645 4obqbpobp3 ugoobbpb4o bbqbqoogge OP98 o4oebebbbq bePbbqoq4o bbbqopoqab qopbbebqbb Pbb4pobb6b qb6e6EqPob 0808 bab4.64-24pq opb6qopq4b 42.4p6o64.2p goq3bePpoo PoP;oTeoa5 bee4geobe4 0s.8 pbqpoppbqo oqp.425poqb Be5qee6yeo obbepobbeb Pbqopbe3-4.2 beo545p5pb 09178 beo3bTeob4 qol5b4bbbb PE6qobb544 bbbbpoobbq obb4eqqqpb peopoTeobq 00178 bqoop45430 bqopbbbbqo bboebbe345 bb4.44pbpoq ebspoqbpb4 b4obebPbbu 0178 ebbbeo4peo 3.65;Dg0000 epqqe-eob45 DepobpoDb4 Dowebeobb Debbbp.65eo 0878 .55413eegob b-eb;o6e5qo so545eoqop poLpopopbb qopgeob4o5 bebe000q64 OZZ8 pobpbqob43 bb66544o26 454obbbpbp opoqp4bqoo 3poppqq4ob go3l4bbso3 09T8 qobbbeopqg bbb4opoqeo ob.ebbeobb4 qbobbebb4o qbEci.bbeb bqoopqbepo 0018 pepoeebbpo qob5p.abeou oubbppabeo poqqq35555 goobeoblbb poebbpbeob (:)08 b5qDeqq3pq Tebeyepbege qb5434oupq oeougbeeeq po6s5bpopo .46b-ebeo5qp 086L eepqq-epbeo pbbb4Pop4q qbqeepoebb 4P02000POP bfq.bqopbbq bbepoop4p4 0Z6L b4444440be o4bppe4epo peobeq44bb bb4opo2opo bqqqeolpbq poepaboDeb 098L eqebbebbe ooq055m64e eeboPob55.2 Peobp55.2be b5555-eoo5e 43pooqqo 00EL bqD15q3.5.5q. Dobeoebegq .ebbblq.ebb bbqbbPbbbl opbqo66513 000beobbbq OVLL bP0E,PbbP4b bq4eopbqoo obepbbebpo bbbobppbbp b466-46e344 bqoebqbebb 089L 5eo5poo6p6 opbqoabqoo 3.6444343pb blppoepqqo oqqobbbloq .24414oppoo (:)9L bpqqeoopob 4e4q25p5be o5buDoop.4.6 oebeopopap bgge4352-25 4544-2 6p-45 09SL peobbbbgbb 552055p-45e opbubmbqq.5 bbbbebbpbo bbp554poqb uppoofq.bgb 000L 444e-ebb433 1.4ob4pqbbq b4bbbbqoe4 peebb43be4 peo4044464 4q6bLre6boe OL be3b4Ebbb4 b.64.54.64bqb qbqope4bbb 4b4poo4b44 qe4eeeb1ee 4334b44pqp 080L e5444oeorbo 34q..babquu 56qoo4oeq 52o4obbooq og000pqppo popobbp;Do 07L 25q0004445 p4o4ogq3qo o4eopoqeo oppoopoebb lopoqeobqb pbbqoabbbb 090L 400.4003eE6 bqq4bqbeo3 4op4opqooq 034D343344 4.5.44bppebb utuppbqqop 000L Pqbbbebbbb qbe4ogbpbb 4oee4obbpo bbbpop4pol eobbbqopop pobbbpbeo 017IL Dqop6p45b5 qa6665bqpi. qoofre000fre ofc456.64D4 34o6opqop.6 gobqopogob 080E_ oppobeb.45o bbpoeq4bbb 6gobgeeb23 oDqoabbpqp osopobqp;e b4boqopPbo OZOL ogo4abogo4 bbqebbeoob P446qboop3 444b5b6oab ebpqbpqm .44Eqb44q44 0969 peqabboopb eepoeoobeo Dbobbpop43 pbbbgobeqb eb000qoobp p400b4p4o4 0069 gpoobaeoqg bbeopo400e opqabpeobq oeDqoepoqo -T26.635545 pob45-2.5.405 0P89 bepoobo;6p 040634445e abopbe.644; 44q44qqqq4 044;444404 444044405o 08L9 6qopboboop peoEtPeolo PbbbPb44P6 bbb.43400p4 433.4obbb4b boeoopo4b6 00L9 opbbqq4D56 bb4tcebuee3 -ebboobbbqo pabrnebDo bbbbeboob4 obe4ob5boe 0999 55.43.5666e5 bbo4oqop4b qbqopDp-45.5 boogoebb3b 43opobbi.o5 451b6b2bbo 0099 bbbb000pbb bo5-255begb pElbbboubob ubbogogbob ub5045-25e5 4abboogooe Of7S9 ogoopebebb bee64P3b4b 3pobobbpo4 epopope4o3 poPpoop4bo qbo4oqoPbb 089 54Dobeeboo bbboo46bob eb0000Pebb qqba6586be Pb65000bbq 3344b4o5ob 0179 bbbbobqoog qobTebED55 pbooqoopoo bbbeboopqe o545555o5o poebbo5o2b 0909 boD,eobbbob e65p5b4000 ab5boboq55 bob bbb5o5eb155 3356-2;333o 00E9 obqbbbqbeb bob4bopoo4 Dbbboop640 boPbbbb.434 bob4bbqobo po4p3bb3o4 OVZ9 04Doqb3b53 lbob43Pobq 4bobbbboo8 boq43bobbo 445444e0b0 Boboeboboo 0819 qooqoopobo poo5opobub obpbqDobqo b000ebobbb 5345e3oeqo 44o555qpoq 0019 40Eb0600bb boboqq0346 qqabebbqa6 bDbobebeob opbe-454Poo boobooboob 0909 popobooppo boboopePqo oqpbppooPb 3po4eb000q qsoobeboop pbbeo4e5bo 0009 60,Dbqobp6b obbboDbobb bob44obobe bpbe45bbeo beb4oeoebs, boobb4003b 06s ;putbbqobo bo4bo-2b4pb 5.65Dbbb6.65 eboo455423 qggeo-4355D ab000qoobb 0880 54420435pp ob4opqb366 Ece5EZD3obo opobeeop4o opoge0000p Poppozboqb ONS opbpooboop op4epopoob oopoqbbooD pbppoogoop o4pe00000b opopobpoop 09L0 goopboqPpo booqop4bbe oPoboopopo 3ebb4o6epo p4obeb5bbo b4obo4b-ebo OOLS 2,04D44405q PPeee5544q qb-ebbqDbqo 4bqbeoquoe b5epo4o4oq 10boobee.65 0v90 pebeo8eep6 beeoqbTebe oppqqaeboo D003e0Dq0D op;oebobqo E.-800E05554 0800 5ePo4eb6pp qqborebqbeu -244b4bpppq pbgbpb5bep Peogbbboao 3404a66qob OZSS bP444obqop bqbb4b6qbb po44D4oebP qbeeEpoboe poPPob4o5 epa6popTeo 09f/0 4PPDEbee.54 qoeobep000 Teeeepepbq ppi.qoq4qD -84454004;o popbbqpeeb 0000 qqq32-2-2.55p ppouqgoe-44 qqqlepeoqg p4E,Doouabp popobpoopo pb0000bbbp cattgagccc aatatatcca aaataatatc atttcacatc tattcaatat aaaaatttac 8820 taatgagata tttcatacta agccactgaa tccagtttgt atcttacaca tctcagtttt 8880 gacgagccac atttcaaggg cgtgatagca catgtggctc ccatagtaga cagtactggt 8940 ctagagaaat gttggtggca tccttgcttc tggtttctgg ccttgccaaa agtattacca 9000 tcccagtgtg gtacattctt tcatgtattg tctcctgtcc ccagagcaga ctctgcaggt 9060 cctctcagat cttgtgcgga aggccagagt cggaacattg gcatcttcca tccatccttc 9120 aacttaagca agttcctccg acaggtctct gcaaatgcct cccggccaat gtccaccagc 9180 tcatctccgg caaaataggc atcttcttac cagagtgtct gatggggaaa acgttctggt 9240 gtctgacttt cggtccaaag acgagtcgtg gatgtaagca gtttgcttat ctggacgttg 9300 tcaagttaga aaagctgttt tggatgggtg tggtggctca tgcctgtcat cccggcactt 9360 tgggaggccg aagcgggtgg gtgcttgagc ccaggagctc gagaccaaca tgatgaaacc 9420 cagtctctac aaaaattaca agaaattagc taggcatggt gttgtgggcc catagtccca 9480 gctactaggg aggctgagga ggagaattgc ttgagcctgg gaggtggagg ttgcagtaag 9540 tcatgatcat gccactgtct ccagcccggg tgacagtgag atgctgtctg gaaaaaaaaa 9600 aaaaagaaag actgtttgtt ttggaagcaa cacaggcagt tgtaggcccc ctgtgccaga 9660 gtgacataaa ctctgtcacc tccagtgatt tggtccatgt ttgtaaaccc tgaatgttcc 9720 agggcagttt cttttttcac tttttatctc ttttttttgg gtgggggggc ggggtacaga 9780 gtcttgctct gtctccaggc tggagtgcag tggcgcaatc tcaacctccc gaggagctgg 9840 gactacaggc acagccatca caccttgcta atgtttgtac tttttgtaga gacggggttt 9900 tgccctgttg ccaggctggt cccaaactcc tgcacccaag taatctgccc acctctgcct 9960 ggcagttaca attcaaataa ttcctccctt tccttcaaca cttggctcat gaccgtccag 10020 tccaaggaac tgtcctgcag gtgtgcctct cccgagcttc ctctatgcat cttccataat 10080 gaagatgcct ctcactggaa accctacaag ggtgggaacg tgccttattt gcctgtatcc 10140 tcagggtcag cagagagaag ataatctgta ataccaaaac accattaaat tcagctgatg 10200 ctttcatagc gctccttgga ggaaggactc catttacttg acagatctgt gcaagacagc 10260 agcctgcgcg tctaacctgc agccagttgc atcctctgtt taaccttgtt tgcggaagct 10320 ttctcaaaca gccagcactt gtctgttccc acatgggtcc gttctcccag tgaatcaccg 10380 tggtcctgct gactgctctg tagcacagtg cttcgcaaag tgtgatcctg ggaccagcag 10440 agcgcagctc ctttgagctt attggaatgg cagaccctca ggtcccacct ctgacctgct 10500 gctgggaatt ctggggaggg acgcagaatc tctggttcca caggctctcc ggtgatgcta 10560 agaataccgg catttgaaca gcaccgatct agcccctttc agtccatgag ccaacaaccc 10620 tggtcctgtc tgtggtgacc cagtgtgact ctcatgggga gcaaggagag gaagttgaat 10680 tcactgacag ggttgttaag gggattatgc aatagatgag acccatgggc ctgaagtcga 10740 gggtgtatgt tagttccccg ttcttttgac ccatggatta acctactctg tgcaaaggca 10800 ttttcaagtt tgttgccctg ctcacttgga gaaagcttat gaaggatcag gaaaataaaa 10860 gggtgctctc gcctataact tctctctcct ttgctttcac aggccttggt atgttctgct 10920 tcatcccctt ctacagtggc cttatccctc cttccttcag aggcgtggta agtcgctttc 10980 tctgctagcg ctgagtcctg ggggcctctg aagtgtgctc acacatctcc tgctgcaggg 11040 cactggtgtc gggcacctca gggtctgtcc catggtggag ccccatgcct catgcctttc 11100 agacagagta gccacagctg gccctatttc caggctaccc gggcagcaaa attactgcat 11160 gtgtaattaa ttatttggct atctgtaagg taaactggct ggttcactta tctgcacctt 11220 aagcatcaga tagcttctca gtgatctagt taaactatat gatgttggca ggcgcggtgg 11280 ctcatgtctg taatcccagc actttgggag cctgaagcag gcagatcatt gaggtcagga 11340 gttcgagacc agcctggcca acagtgtgaa actctgtctc tcctaaaata nnnnnnnnnn 11400 nnnnnnnnnn gtgtaaaagt gttcctattt ctccgcatcc tctccacacc tgttgtttcc 11460 tgacttttta atgattgcca ttctaactgg tgtgagatga tatctatagt ggttttgatt 11520 tgcatttctc tgatggccag tgatgatgag catttcttca tgtgtttttg gctgcataaa 11580 tgtcttcttt tgagaagtgt ctgttcatgt ccttcgccca cttttgatgg ggttgtttgt 11640 ttttttcttg taaatttgtt tgagttcatt gtagattctg gaattagccc tttgtcagat 11700 gagtaggttg caaaaatttt ctcccatgtt gtaggttgcc tttcactctg atggtagttt 11760 cttttgctgt gcagaagctc tttagtttaa ttagatccca ttgtcaattt tgtcttttgt 11820 tgccattgct tttggtgttt tggacatgaa gtccttgcaa gggcattttc aagtttgttg 11880 ccctgctcac ttggagaaag cttatgaagg atcaggaaat taaaagggtg ctctcgcctg 11940 taacttctct ctcctttgct ttcacaggcc ttggtatttc ctgcttcatc cccttctaca 12000 gtggccttat ccctccttcc ttcagaggcg tggtaatcgg ctttctctgc tagcgctgag 12060 tcctgggggc ctctgaagtg tgctcacaca tctccgcctg cagggcactg gtgtcgggca 12120 cctcagggtc tgtcccatgg tggagoccca tgcccactgc ctttcagaca gagtagccac 12180 agctggccct atttccaggc tacccgggca gcaaacttac tgcatgtgta attaattatt 12240 tggctatctg taaggtaaac tggctggttc actaatctgc accttaagca tcagatagct 12300 tctcagtgat ctagttaaac tatatgatgt tgccaggcgc ggtggctcat gtctgtaatc 12360 ccagcacttt gggagcctga agcaggcaga cacttgaggt caggagttcg agaccagcct 12420 ggccaacagt gtgaaactct gtctctccta aaatacaaaa attagctggg catggtggtg 12480 tqcacctgta atcccagctg ctcgggagct gaggcaggag aattgcttga acttgggagg 12540 cggaagttgc agtgagccaa gatcgcacac tgcactccat cctgggtgac agagcgagac 12600 tctatctcaa aaagaaaaaa aaaaaaaggt aaataaagta tatgacactg aagaatctgt 12660 tacccctgga aggtggagct ttactttagg gggaactata acagtcatat atatatattt 12720 ttttcttttc tttttttttt ttttagatgg agtctggctc tgtcgcccag gctggagtgc 12780 agtggtgcaa tctcggctca ctgaacctcc acttcacagg ttcaggcaat tctcctgcct 12840 caacctcccg agtagctggg atacaggtgc ctgccgttac gccaagctaa tttttgtatt 12900 tttagtagag acagggtttc acatattggc caggctggtc tccaactcct gacctcaggt 12960 gatccgcccg ccttggcctc caaagtgctg agattacagg cgtgagccat ggtgcccggc 13020 caacaatcac atgtgttgta acaacaacaa aaatctgtca gcctggtcta acctagattt 13080 gtgctttgtt ttgttttgca ctttgtgatg cacaggagga agtttaggct gtaaaatact 13140 agccttttag ggtaattttg aactcacaag agcagcagcg gaacctttga tgcaatcctg 13200 tatgtagcac cagcaggcca cgtggcagag ggactcgcat taggagcctc ccattacaga 13260 ctacgtgctc ctgtggttat cttatagggt ccccacaacc aaggggagat gtgattattc 13320 atcctgtgtg gctgggggaa cttgagagtc atacttgccc aaagagcacg gccagcgagc 13380 ttgcacccag gtcctctctg ctcctctgtc agaacagggc atgtcttggt tcactgcagg 13440 gcggctcttc tcttctctgt agtttggggt ccaggatagt ggtccacgga gccactggag 13500 tgcccagcta cgagtgacca aagcatattt tggatttccg acattgccac agcatggttg 13560 ggcatcagca gaccccaacc ccttgttatg ctggtggctt tatgtggtta tttgatcttc 13620 cccagaacta gcaggagtgc acccagcagc accgtagtga tgctctctgg ctccccagtg 13680 cacggttcgg ctttccttcc tggtcgagag tttcaagccc tctgggtcct actctgtcct 13740 tttcagccat agctttgttc aaaagctgct ggcagtgttc agatttggct gagttcagtg 13800 aatatggcat tggctgattt ctgagccatg ccagggggat ggagaagccg aagcaggagt 13860 gtttgtctgc aggctctgga gtaggcattg ggtctgtgcc ggctcacttg ctagtcttgc 13920 atcctcccta accccctctg gggatgtctg gccacatcag aagacagttt gggttgtcag 13980 aacgggggag taccaggccg aggtgggtgg atcatgaggt caggagatcg agaccatcct 14040 ggtaacacag tgaaacctca tctctactaa acatacgaaa aaaattagct gggcgtggtg 14100 ggggcgcctg tagtcccagc tactcgggag gctgaggcag gagaatggtg tgaacccggg 14160 ggcggagctt gcagtgagct gagatcctgc cactgcactc cagcctgggc aacaaagcgg 14220 actccgtctc acaaaaaaaa caaaacaaaa caaaacaaaa tctgggggag tgccactgca 14280 tctgatgtat agaggcccga gatgctgtgt catcacccgt tgagtgcgct cataggctct 14340 tcctgacaat tagaacccat tattcttcaa attcaatgca agcaaattca aagcatactg 14400 tgtacatacc gcatgctaat caattgcacc actggagctc ctaaattcaa aacatactat 14460 aaaaaagttc aaaatgcatg gaaaagttgt acatggcagg agaatatttg ggctctgact 14520 accccttgaa tgaagatgat ccaccagccg ccttcctcct tggtcttcac tccgattcct 14580 agcatttcat tctgtgtctc tttatgcagt gaggtttttg tttgtttttt gaacagagtc 14640 tcactgtatc acctaggcct ggagtgcagt ggcgcgatct cagctcactg caccctcggc 14700 tcctgggttt aagcgattct cctgcctcag cctcccgagc agctgagatt caagcacaca 14760 tccccatgcc cagctaattt ttgtattttt agcagagaca gggtttcaca tgttgcccag 14820 gctggtctcg aactcctggc ctcaagtgat ccatgtgcct cagccttcaa agtgctggga 14880 ttacaggcgt gagccaccat gcccagctcc tagtgaggtt tttgatgctt gctacatctg 14940 ccctagaaat tgtgtgacta cgattttgga aatgttgctg tgtaaattgt gatcatttct 15000 ggactccagg caagaatctt gatggctaag gtgtggctga acatgctgat tctctcctgg 15060 acctgtttta ggccaaactc tgctctgaaa ttcctccgtg tggagggcgg gctggggaga 15120 gcctcccagc tggaatcttt tggatgcctt tctctgtggg tattgatggc tggctctgat 15180 ggctggctct gatggctgtg gctggaaatc attgttgaca tggtttcaca gatgcaggct 15240 ctgtccaaat tgtagcaaaa gctgcctgcc ccagccgagc ttgggcaata aggtggttta 15300 aggatataga tgaaggaaaa ctcaccctta gaataattta ccaaaatgct gctgtgttgt 15360 gggttagagg acattttctg aggtcccagg ttcattgttc atttaagtct caaaagtccc 15420 tccaggtgtt ggttctaatt 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acatctcgga 19260 gggtgaggag ggcatctgat agggcctgga aaggccgggg caagcatgaa tgtgaggtta 19320 tcttgggggg caaggctcag gcgttgagga gcgcccctgg tctcttcagc ctgaagttgg 19380 aagccagagt tgggccaggt gcagctgtgg tgtctgaagt ccccctcccc cagcccagtg 19440 tgccaatgct gtaagagcaa gggccgctca tggtgctggt ggctgagtcc cagcacccag 19500 gacagggcct ggcacatact ggtgcccaac ctcccttctg ggtgottctt ccaaggcctt 19560 gtgatggaag tgagtaccct cttcgacaca gacccagctt caaatcctgg ctctgctatg 19620 tattggctgc gtggctttag acaagtcttt aaccttgctg tgcttctgat ttctcagctg 19680 aaaaatggag atgatgatag tggttttgta aggccttatg gtgaagcacc tagctcaggg 19740 cctggaaggc aggtgtaacc agtggtcagt tgttataaac caacactaac cctcgccttt 19800 gcacctcatg aatccagata tgtaatggag cccacaaagc tagcaggagc caagctcacg 19860 tgtgtcctgc tttaaagccc catccccttt ctccgggtga caaacacctg tgctcgttct 19920 cttcccttcc cctcttcccc ttcatttggc taataacagg ccagctgcct gcctccctgc 19980 agtttggtag atgggtgggt acgaccacca ctcccacgtt cgcctgatgg gcttgttttc 20040 cgtgcccttc acaggcatct caacaggccc cagccaggcc tgaagtcatc ctcagaaggg 20100 atggatcctg aggtcgccag cccagctggg caaacatgag tctggattct tccccggagt 20160 cggctgcctt ggctgtgagc tggagggaga tgagctgcta gaccacctgc gtctcagcat 20220 cctgccctgg gatgagacat cctggacacc ctctcgccca ggctcgctac aggtacccac 20280 tcctcggggt gagcacggca gcaccttgtt ttctttcttg tgcattatgg aggaagatgg 20340 tactgccaca tgggacgata gggtgaggca accatgacag qtggttggga acatctcctt 20400 ccatgtgtac agccgggctg ctgccatcac tcccagcaca gcccccaacc cccccaatcc 20460 tggaaccttg ccagtctccc ttcccatggg gtcatgacca ggaggaaaac aaactccagc 20520 tgagcccctt gggttcccca tataggctcc tgcctgtggc agctgggccc tctgtacccc 20580 tttccaactc ttctccctaa catggcacct gagctcctgc catcctggat ttcatggacc 20640 ccaaggatgg ggtcctgcat ctgggacttg gcctattact cggagctcct tttcagccgc 20700 ctccctccac tgtccaccca cctcaaggct cctttcttga gacctctcct aatttctccc 20760 ttcccctaac ccacaatttt gaacctccat cgaatggtgc tgtattttat aatgtcatca 20820 aatatcaatg gagacagtgc tatggtccaa atgattgtgt accccccaga atttgtcttt 20880 tgaaatctaa cccccaacat gatggtctta ggaggtgggg cctttgqgag gagattaggt 20940 catgagaaag ggctgtcatg aatgggattg gtgcccttat taaacagacc caagagaggt 21000 ccctgtccct tctactgtgt gaggactcag aaggtggtgt ctatgaagaa gcaggccctc 21060 accgacacca acatgtctgc tgccccttga tctgggacct tgcagcctct agaactctga 21120 aaatcgatgt ttgttgtttt ataagccact cagttggtgg cattttgtta gagtagcctg 21180 acacggacta agtcaaacag aagaacccac aaaccagcta cagagttggg catttggaga 21240 attcaaaaat gagtcagaca taactcctta ttcttgaggt gccctaagag atgggacacg 21300 cagctgccca ggtgcattag tttgttctca cattgctata aagaaatacc tgagactggt 21360 aactcataaa gaaagaggtt gaattggctc acagttgcac aggctggaca ggaagcaggt 21420 gctggcatct gctcagcttc tggggaggcc tcaggaaact tacaatcatg gcagaagtga 21480 acgggaagca tgcacatccc atgactggag caggagtgag agagagaggg aaataaggga 21540 aggtgccata cacttttaaa caaccagatc tcatgagaac acattcacta tcaaagaaca 21600 gcaccagtgg ggaaatccgc ccccatgatc caatcacctc ccatcaggct ccgctccaac 21660 actgggaatt acaatttgac atgagatgtg ggcagggaca cagatccaaa cctatgacca 21720 gattaatacg atttgaggca tcacgaggtc attaaagaga gggaataaaa gctggggctc 21780 caggaagaag gctctggaat ccagcagagg gtcaaggacc agcttgtaaa ctggtggtgc 21840 ctgagaagta cctaggagaa catagatgct gtgacgtttg atgtagctgt ttttgttttg 21900 tgttttggtt tttgagacag agtctcactc tgttgcccag gctggagttg cagtggcgtg 21960 atcttggctc actggagcct ccatctccca ggttcaaatg atcctcagcc tcagcctcct 22020 gagttgctgg gattacaggt gcacaccacc acgcctggct aattttgtgt tttcagtaga 22080 gacagggttt caccatgttg gccaggctgg tcttgaactc ctgactcaag tgatccaaca 22140 acttcagcct cccaaagtgc tgggatgaca ggcatgagcc accagcccag cctgatgtag 22200 ctgtttctgt gcacattatt tgctgtgggg tatattcaga tttttaatac aagatgattc 22260 tttgcctcat gacttacaca ccattttcta tttaatttca gcatgatatt ggaaatggac 22320 atgtcttttc aaggaaaata aaagcaggct ttctggaatg ggacttccaa acatatttgt 22380 caatttaaag gagctgggag tggggaccct atgctccgta gcactctctt agctgttctt 22440 ggctgtgctc cccgcttcag cttcacactg cccttgctgg aagggagcag cctgggccgg 22500 gcgcggtggc ttacacctgt aatcctagca ctttgggagc cgaggtgggt ggatcacctg 22560 aggtcaggag ttcaagacca gcctggccaa catggtgaac tccatctcta ctaaaaatac 22620 aaaaaattag ctgggcatgg tggcaggtgc ctgtaaccca gctacttggg aggctgaggc 22680 agaagaatcg cttgaaccca ggaggcggag gttgcgtgag ccgagattgc gccattgcac 22740 tccagcctgg gggcaacaag agcaaaactc tgtcggaaaa aaaagaaagg agcagcttgg 22800 caaaccccac cttgtcgctt ttgtgagtgc ctcgaccctt tggctgccag gacgggcgta 22860 ttttatggaa atgctaagca ccaacagagt aagtggtttg gtttttcaca gtggtgggag 22920 ataatagctc caaattgtct ttttcagcac tagtgaagaa atgaaagaca aaggtggata 22980 catgagcaag atttgcaact tgctacccat aggataatgt cttatgtaat gctgccctgt 23040 accctgcctg tggaatctgc cattgcgatg tccagaggtg agcattttag gtggctccgt 23100 gtcttcctca cagggttgat atgaggataa acaagatgat agatcatggt ggcatgtagt 23160 ctgggacctg gattgtcgtg ccacagacac agctcacagt ctatgtgcaa tgcccctgaa 23220 tgttgcccac ctgtcctcaa gccacaatgc acctgtaact cagtgcaagc ccagaaactc 23280 cccgtgggga ctcctagagc tgtcatggcc tcacatagca gctggtccag tctcttgtga 23340 ttgcccaagg aaactgaggc ctgggagctt ggggtcgctg ctctgaggcc atagagatgc 23400 ctagtagaag ggccaggcct agagcaggat ccttgctgcc cctctgagct gtttccattt 23460 aaaatcacat gaaggccggc gcgtggctca cggctgtaat cccagcattt tgggaggcca 23520 aggtgggtgg atcatgtgag gcaggagttt gagaccagct tggccaacat ggtgaaatgc 23580 catctgtact aaaaatacaa aattagtgga gcatggtggc acgtgcctgt actcccagct 23640 acttggaagg ctggggcaga gaatcgcttg agcctgggag gcagaggttg tagtgagcca 23700 agattgtacc actgcactca gcctgggtga caggagagaa accctatctc aaaataaaat 23760 gaaaggtaat gaaatgataa aataataaat caagtcacgg ccgggcacgg tggctcacac 23820 ctgtaatccc agcgcttggg aggccgaggt gggtggataa tgaggtcagg agttcaagac 23880 cagcctggcc aacatgtgaa accatgtctc tactaaaaat acaaaaatta gctgggcatg 23940 gtggtgcatg cctgaatccc agctactccg gaggctaagg caggagaatt gattgaagca 24000 ggacctagga ggcgaggttg gttgcagtga gccgagatca tgccactgca ctctagcctg 24060 ggctacagag cgaactccga ctcaaaaaaa aaaaaaaaaa aaaatcaaat cacatgaaag 24120 tagaacatag gaattccatc tttcgttcta ggcatagttt gttaatatga ttcagagcca 24180 gcagttagga aacacagtgt gactctccta gaacttcttg attgggcttc ctctgattgg 24240 gtttcctcta ttgggcttcc tctgaaagtg ggggggatgg ggggtgggga gcagaatggt 24300 cagagcttgc tcagcagtca gactgctctt cttcaaatcc tggctgcatt gcttactaca 24360 gctgtgtact ccagatgact gaatccacct ctctgtgctg cagcttcccg tctagagaga 24420 tcacctgagc agagggtggt caggagactc aatctggtta ctgactcaca gtgcaggagt 24480 actcacccat agtaagcatc cagctagaga tgttgatttc tattttcagg taataatgat 24540 gatctaaaat tagagacaga taaaaggtat gggcattagg ccagggcact gcaatttcta 24600 agcgtgtgac ctcaggcaag ttactcgact tctctgagcc tcagcggttt catccgcaat 24660 attggatagg aaaaccgacc tcagtgggtt gtctgacagt ggagggcact tgattaaaaa 24720 aaaaaaatta ccctggtctg aatattaccc tggactgaaa gaaaaatatt gagctaatac 24780 ggcatcagga atggggctgc agggagtcca gggaagggag aacgaagagc ctgaaggtgg 24840 aggaggtgcg agtgctgatc tgtctgctac aaagaggctg ctgagcctcc tgtggatggg 24900 ccctggactt ggcagtttaa tacctgagct gttaaaataa cctcagatgc tgtgttctta 24960 aggggtagga ttcagattcc tgctgaaatg cttctgaaag ggagggaatg agccagccat 25020 ccccagttgc tttttaagat cattgggaag ttctggtctt gccatttgtc cctggccact 25080 cttaggtcct cctgccccac ttccatctgg gtgtgtgccc tgggctgtcc accaacagct 25140 acatcctgcc atcttccctc ctggagccac tgtgccatgc atggatctgt agctcatttt 25200 tcttggcttt tccctggttt ttctggagca gagtctctag taaactccca agaagaaaac 25260 gtttgacttt atgtgtgttg ggaaacgtgc tttttttcta ttacatctca ggataggttg 25320 gccatgtcta gaattgcagg ttgaaaatca tttcctctca gtatattggt agtgagaagc 25380 ctgggactga gacagtcaca ttctcacttc tttgcaggtg agtgctcttg gactgtcttt 25440 ttatccctta tactctgaaa tgtcatatgt cttggtgtaa gtccttattc agttattgag 25500 ctggacaagt actggagacc ccttcagtca aagccttctg tcattctcag ctctaggaaa 25560 ttatcttcta ttgttatttc tgttattcct tcccttccat tttctttttc tttttttttt 25620 tttttttttg agacagggtc ttactctggt gcccaggctg gaatgagtga cctgatcatg 25680 gtacactgca gcctgaacct cccagactca agtgatcctc ccactcaacc tcctaagtag 25740 ctgggactgc aagcacacat caccacaccc aacaaatatt tttaaaaatt ttgtaagatg 25800 ggatcttact atgttgccca gactttttct tcctcttcct gggctcttat taggaagatg 25860 lc O8Z6Z oqq4beeeqo 54bbpboqq4 pq;abeobeg plEyebbb.e.5 bebqqaeog6 ebqb;345e5 esbebe4oeo 44q44Poopq 4400poo4o4 obbbbpbqab T684obqoae qbeee4peob 09T6 op-eboobeoo 4.66-2o-4304e 3o;.55ob000 peoob&ebeo bee2opebu6 00-E6 -2o5e33q543 .66.6.6op000q obqoo3qo-eb 5.4o6qcoobb qoebb.eobp5 4Doeosabq-e 01706z opooloobbe 3Po0bPobpb qbpoobTes-e. 000qbbeoq4 4bqb4poo43 0443ppoobe 0868 pqo4o355op uabobeo5po b;opoeo6qo ubpoDbeqb ooepo4565.4 6T2E,obboo5 OZ68Z 540-2434003 D,554.5.1.5q1) beb.eqpoceo bboPb4b4a5 b4oqoqbqbq abebse5E.4 0988Z obbbpbgoeb poopErep4eo Eb4b6gbbp4 opebpebb4; obbPopoobb babbbqobp4 0088 55eopq5q5e 6.65.4beopqb qpb;6qDoso peoe5b455.4 qboggebbbe opqopoobbe 017L83 4PB4D-epa66 b6.45.454qqb buqbeeo6.5-2 obbq3oouo.e, bbe4564555 455065poo6 0898Z 4554bPqbb4 bbqoeb4b54 oopbpobbb6 qbebBee433 beepp44bbo 4b4bbebbe6 c)98z 6poebqqp4o 55upq3oqqo .55e5ebooe6 7qbqoqeboe bafteobbeoD obb6poo5;D
09S8 5555bpobe 355EDbeabb gobbqpoobb 5Toogebb45 bbebPqb-ePo obb;fre4.5.e3 ooggz bbbbPabbbE, qp5q44Pboo 4P5pueob4p ebbbbp4bep epqq4pbbee bepe3ebe4b 0ez 5geqqbqq.6q Tegobllogp loobbqeq5b ebbpoTeobb bqobqeoeab blq3e4b6Te Hee? opqboDo6pE, P5qoclobeb lboollq5b6 epoq000pq e0000Teblb 55bpos2qob OZUZ 140Polooql 1BEITloobbe leoqpe2ebq ooleq4b368 b44bbbeooe lleopolob4 cl9z8 op5bbp3415 e66DDbe6qo Pepbbqoqqe Pbqp4qpub4 oolqop4obo obqebbbboo 00z8 opbbpoe5.4-4 bob4o4bpob eqopbe-2645 bb600qoq5.2 opo;beb4os 4b4-45qopo3 Of/T8Z epo4opq.bqp D000beepb4 eeqbb4pobq bbegobb4b4 bobebbo43o 4obebeb243 0808Z bbbpobbbbe bbqpooebbb qbbbbEpbb Ppeobbqppo peobblog35 ebbppobeb4 ozo8 oqbqbobb4o bofreqebpog bqfrebbbfygo 2b6-2542655 4o55q5e5pc pbpoqpbqbb e4ebeopo35 bebebeobeb ee.5b4bbqet q4eabeobbb ebqgogoqbE
006LZ 64Pbbqqboo 3.443utppbb bqpobet_boo eab400peoo bbepoppoo6 qouteb4obq (8L ocepeo6.6D 32,b5-ebeoqb Poq5-254obp obbpbbbTeo goqbgpoo-eb Ebqb;ELbqq 08LLZ 033.544o5pb beabeepoe o2.543bLqD bepeeet-ego 44epeboeoe qo36b.ebqe6 OZLLZ 404P040404 00PDbb63ab boobbb4b45 4b6b4bq3bb qqqopqpeeb bepogooboo 54.e.b.Db4.6e boqaeoqqbq bbeoeolope 6-45.554bebq 4654.6;oom6 009LZ ;aboeboopb 4p4pbuDD4q obb4eDubqf bq3pEpobqo 434poqabbq q324_6;b441 017SLZ bqbqb4bqpq pobqpi.borbq -464obpe4bq qb4beqbbbP epopPpb444 4obpobb44b 08,L b6p5fq.
qpbe34eoqb ee58543q4D peopqpbpoo Dqeobooq5 qqoo454106 OZfiLZ bbqbbeogq4 ebebp444ob 44qqeo4o55 b46ppbeoop pbqqq.44obe bqgpoombep 097.2 qb4beoq44-2 444o4o3344 q4.44-4446qb bepoobeeep bqoobebeeb f&qabeopq 00EL oqooqobepq oc5Ebqecob 4obpD6po5q 4opobebe5; eo-e5q13-455 Teb5bbeDb6 GvZLpbqeD3e-epo 5Pouobeepo pbqbTepoq. ob5.54ob4c; obqbbqpooq oqoaeteDgq 08-CLz bobelupbb a6p4D4bpbe bbqebbbbbq oqb4bqe444 oqb55.66T65 pbqoopebeb OIL Z Po4Pqqqp35 bp045b4.640 qbqe5556bb Da540PDOP3 00P0000400 qoo;pcbeoq 090L op4obbo obepppoqqo 00OLZ 0404046Poo 3bqpe14440 4PelTeb400 ob5430-ePop P005Pb4b45 be3e44Ebbb 069Z 4054beee3o oqopbbi.qo b4pobqDoeb looqoobqop 4peeepq345 bqoo5Popb6 0989z -44.54p355q4 q6556gbbpb -24.5sqqqq;e qbqqqleeqo bbqop.eoeop eo36;5;u3b OZ89Z bP0P44Pbbb qobegbPbqo 34o4bpoq4o Eqopo44ebp bpeo4obbb4 oDq3opoogo 09L9 oppobqpPoq abeoqq.2.6.3 boqbqe-eobq be5qobbeco 4Do;bqb4o4 oqoqb.256Te OOL9Z bEq44444b 44444T4440 0;e6444004 b13454315P 44EIPPq6P44 11454440P;
01799Z 4454665q6b qqqPbeeboe oemoqeop opPo4qq-e44 aeobb4004 Eceob4ob4e3 08g9 5q4b5-4bbbe leo.22-2b654 aeoppabqbq 4o4;;Tebbb oqqopqbqqo ED5405beeq 0s9z bo.444osoq -eqqqebeabq 4 43.5445pp ogooqobqo pqabebqbbq luo;o544oq 09D'9Z P4PqP1PPPEI lqbqpqaegb pooqbbbboo bqo44o3oo4 000pabpoop p4p04411,43 oof/9 obg.o4D5.4.53 o33.4Db543.6 oPPElqbbbbq 0005qq44.55 .5445qDpebq qbbqobebbq of/E9z oopqqqopoe ppbp4pogqi. o600eqb;b5 DabqqDeqpq bTabbeebbb oblobbeobb 08Z9Z P3'e54bpoeb poop4obp6e 3bbqopo4so bq55PqbbbP uPutPbbb-eo qobPbbqqoP
ozz9z Hebeoepab Pqp4E-Dooqq -44qqa6465-4 -4o44.5q6a5b 6q34.4-eqqae qobqpqqqq3 09I9 40;q43q=4 40444-54044 444E'405554 43440-444Po 34044004.2 04ebe4D430 00T9 4b4Db444P4 eP5b443404 4PPP4b4Pbb qP44qq-bq40 q4b40qTeD5 e440q4-4444 01709z oqq.bqqogoq opmEyebeepo 44seqqmepq pquppobpoq 4qopqm44-48 poe400me4o 086SZ 0q5e-404q34 b4;q4PePO4 04q;PEoPb 40;0b40450 b44441-34b; ;5040'204PD
OZ6SZ 44444e4e04 b4440;0434 40eb494645 0040454004 4Pbb44E6.64 00440Pb;14 ccatctttgt gcagctacct ccgcattgct gtgtagtgac cccgcctgtg acgtggagga 29340 tcccagcctc tgagctgagt tggttttatg aaaagctagg aacaaccttt cgcctgtgca 29400 gcggtccagc acttaactct aatacatcag catgcgttaa tcagctggtt gggaaatgac 29460 accaggaagc ccagtgcaga gggtccctta ctgactgttt gtggccctat taatggtcag 29520 actgttccag catgaggttc ttagaatgac aggtgtttga tgggtggggg ccttgtgatg 29580 gggggtaggc tggcccatgt gtgatcttgt ggggtggagg aagagaatag catgatccca 29640 cttccccatg ctgtgggaag gggtgcagtt cgtccccaga acgacactgc ctgtcaggtg 29700 gtctgcaaag atgataacct tgactactaa aaacgttcca tggcgggggt aacaagatga 29760 taatctactt aattttagaa cacctttttc acctactaaa ataatgttta aagagttttg 29820 tataaaaatg taaggaagcg ttgttacctg ttgattttgt attatgtgaa tcagtgagat 29880 gttagtagaa taagccttaa aaaaaaaaaa aaacggttgg gtgcagcggc acacggctgt 29940 aatcccagca ctttgggagg ccaaggttgg caatcacctg aggtcaggag ttcaagacca 30000 gtctggccaa catagcaaaa ccctgtctct ataaaaatac aaaaattatc tgggcatggt 30060 ggtgcatgcc tgtaatccca gctattcgga ggctgaggca ggagaatcac ttgaacccag 30120 gaggcggagg ttgcggtgag ctgagattga ccatttcatt ccagcctggg caacatgagt 30180 gaaagtctga ctcaaaaaaa aaaaatttaa aaacaaaata atctagtgtg cagggcattc 30240 acctcagccc cccaggcagg agccaagaca gcaggagctt ccgcctcctc tccactggag 30300 cacacaactt gaacctggct tatttttgca gggaccagcc ccacatggtc agtgagtttc 30360 tccccatgtg tggcgatgag agagttagaa ataaagacac aagacaaaga gataaaagaa 30420 aagacagctg ggcccggggg accataccac caatgcgcgg agaccggtag tggccctgaa 30480 tgtctggctg cgctgttatt tatggataca aagcaaaagg ggcagggtaa agagtgtgac 30540 tcatctccaa tgataggtaa ggcacgtggg tcacgtgtcc actggacagg ggtcccttcc 30600 ctgcctggca gctgaggcag aagagagagg agacaaagag aaagacagct tacgccatta 30660 tttctgcata tcagagactt tagtactttc aataatttac tactgctatc tagaaggcag 30720 agccaggtgt acaggatgga catgaaggtg gactaggagc gtgaccactg aagcacagca 30780 tcacagggag acagttagcc tccagataac tgtgggcgag cctgactgat gccaggccct 30840 ccacaagagg tggaagacag agtcttctct aaactccccc agggaaaggg agactctctt 30900 tcctcgtctg ctaagtgcgg gtgttgttcc ttgacacttt ttgctaccgc tagaccacgg 30960 tccgcctggc aatggcgtct tcccagatgt tggtgtcacc gctagaccaa ggagccctct 31020 gatggccctg tccagcataa cagaaggctc gcactcctgt cttctggtca cttctcgcta 31080 cgtcccctca gctctatctc tgtatggcct ggtttttcct aggttatgat tgtagagtga 31140 ggattattat aaattggaat aaagagtaat tgctacaaat aatgattaat gatattcata 31200 tataatcata ttaagatcta tatctggtat aactattctt gttttatatt ttattatact 31260 ggaacagctc tgtcctcagt ctcttgcctc agcacctggg tggtttgcca cccacaattt 31320 tccacatgct ctggtctgcg ttcttttttt ctccttgcat cttctcattc tctgatcacc 31380 ccaacctcct ctgtcttccc tactctgcca gccttgatgg agacaagccc ttgagaccag 31440 aactcacttt tccccaggtg tgataatcta ttagcaaggt cagtgtaata tgactgacgg 31500 tgaaactgta tttttttcta tttatgcatt tgagtacagt acgtacaaga aaaataatgg 31560 tgtgccaaac tgttaaatgt tggaaaagaa agatacaacc cttacccata ttgtgtaagt 31620 gcccggagta gaagaaccag caagctcaga caaagcactt gactgagaag acagaccctt 31680 taaggaaacg ggttctaggg acaaactcta cgtgggcctg ttctcttgat aagaccgtga 31740 acctttgaga aaagaggcta cttgtgaaaa taatgagccc ccttcggggc aggagttccg 31800 ggtttgaacc tgccttctta catcttgagg gctaagtgag ttcccaaggc ctctgttcag 31860 ggttgctccg tcagtgagct caggtctggt gagtggcagg gtcttccacc cccaaccccc 31920 cgggtgtcag agcaagacac tgtcccccat ggagctggaa tggggtggag gagcccactc 31980 tggcacccac gtggcctcct tgtgacggac ccacccttgc aatgttggaa aggaaagtac 32040 aagtttcttt tcccaagttt cccagtaggc tttgttctgt tagcttcacg ccttcgtcat 32100 tagcagacat aaataaactt taaccattgt tttttatctt tttttttttt ttttggatgg 32160 agtttcactc ttgttgccca ggctggagta caatggcaca atctcggctc accaaacctc 32220 cgcctcccgg gttcaaacgt ttctcctgcc tcagcctccc aagtagatgc caacctccca 32280 agtagataca ggcatgtgcc accacgccca gctaattttt tgtattttta gtgagatggg 32340 gtttctccag gttggtcagg ctgatctcga attcccgacc tcagatgatc ccccgcctcg 32400 gtctcccaaa gtgttgggat tccaggtgtg agccaccacg cccggccaac gtattttcta 32460 ataaccagta tatttccata tacatgtgta catgggtatt gtgattgttt caggaaaaaa 32520 tatattaaat ggctgatagg agaccatggg acgtattttc tttctgcttt aaaaattatt 32580 caggccgggt goggtggctc atgcctgtaa tcccagccct ttgggagcca acgtggacag 32640 atcacctgag gtcaggagtt cgggacaagc ctggccaaca tggtgaaccc tgtctctact 32700 aaaaacacaa aaattagcca ggtgtggtgg caggcgcctg taatccaatt agtgggttgq 32760 ctgaggcagg agaatcactt gaacccagga ggtggtggtt gcaggagctg agatcgtgcc 32820 actgcacccc agcccgggtg acagagtgag actccatctc aaaaaataaa aaataaaaaa 32880 taaaaaataa attattcaat cttctttatt tttattgttt tatgactaaa gttattttta 32940 gtagaaacag ggtcttgcta tgttacccac gctagtcttg actcattggc ttaagcagtc 33000 ttcctgcctt agcctcccaa agtgctggga ttacaggcat cctggctcct ccaccttctt 33060 aaaataagca tttgttttat aattttttcc aagtgtgtac aagataagga aatcaggaag 33120 tgtaatattc ttatagaaat ggccaaggcc tcccccttac ctgtgcctca gatgctaccc 33180 aatcccgcct tctctgtccc tccagaaggc accctttctt aggcctccct ctcttcctga 33240 accacctctg gaagtttctt attggcctat gaatgcttct tatttcttct tatcaaataa 33300 agccttccct ttaatttatg gcacatttat gctttgaatc cactctcagg aataatcagt 33360 atgtagcata ttacacgtca ggcggcaaca ttcttttttt tttttttttt tttgaggcag 33420 ggtcccgctc tgtcatccag gctagagtac ggtgtgcaat catagttcac tgcagcctca 33480 acttcctggg gtcaagccat cttcccacct catctcccaa gtagctggaa ccacatgtgt 33540 gcactaccac acccagctag tttttttttg tgagacaggg ccttgccttg ttgcccaggc 33600 tggtctccaa gtcctgggct caagtgatgc cctgccttgg ccttccaaag tgctaggatt 33660 acaggtgtga gctaccatgc ctggtccaaa ttcttcattt ggtaaatggc taaacttagt 33720 gcagagtatg agcctgattt tgtttaaaaa aaaatgtgtg tgggtgtgta tatgtatctt 33780 tgagtgtata taaaaagact gaaagaggct gggcacggtg gctcatgcct gtaatcccag 33840 cactttggga ggctgaggga ggcggacact taagtcagga gtttgagacc agactgggtg 33900 aaaccccatc tctactaaaa aatgcaaaat tagctgggca tggtggcggg cacctgtaat 33960 cccagcaacc agggaggctg aggcggagaa tcacttgaac ccaggaggtg gaggttgcag 34020 tgacccgaga tgcagtgaga ctcacctcaa aaaaaaaaaa aaaaaaaaaa aaaaagacta 34080 aggatatata tcaaaaccct taggcagact gttatttgta attgtatttt atttgtcgtg 34140 cttatatgtg ttgcccaagt tctatggtga acggtatgca tcactttcag catgagaaaa 34200 taactcctaa taaacgtgat cttaaaggac tctccctgtg tacatccttt ccaaggagcc 34260 ccgatgtacc ctgcttcccc acagccaagc tcctctagga cagtcctccc tagggggtta 34320 cggccttgct cctttgatgc cctgccacag cccaggggct ctttcctggg cactgtggac 34380 cagaccctcc tagaatcctc tccttcctca accccagact ctcaggcacc ccatctctat 34440 cctggacacc gagctttcac caaggcccag ctgcagctgc tgtgctgagt gtgcacagcc 34500 acctctggga aggcttgctc cccctgagga cctgggtcct cagtctctga ctctgggggg 34560 attcggggcc acctcccacc ttctggctct actcaacacc agcagcccct caacatcaag 34620 ccctccagct cacgcacctc agctctgcag ctccaaagcc accccagcct ggaactgggg 34680 actcagggag acccctcgct ccaactccag ctggtcccag cactgcctct gctgtcatct 34740 ctggaatctg gctcttgtcc ccagcccact gctgccaggg tcagccctgg tactttctac 34800 ctgggttgct caacagcttc cctctggggg ccgcctgttt tcagccttgg gcccatctgc 34860 cctccacgtg ctgctgggca agctgaggcc ccaccacacc cccagcacct tcctgtgcct 34920 ccaggcctcc ctgccagtac accccctcca gcccctgaag ccctgtcagc agctcagagc 34980 ctttcccgga gtcaccctgc ttcccgaggg gacccacgtt gctgctgggc aagctgaggc 35040 cccgcccaac cccagcgcct tcctctgcct ccagactccc tcctagcaca ccctctccag 35100 ctcctcagtc ccaccagcag ctcagagcct cttccctgag tcaccctgct tcccgagggg 35160 acctcaccca gggaatgccc ttccaggctc ctctcactga ttcaccttca ctcctcagag 35220 gtcggtgctg gctgatagag gcaatgaggt gagcccctca cctcagggcg ctcagcccct 35280 ggaaggtgat gaaaaagggc accccaaggg gtgtcccaaa ctaataggtg gatgactccc 35340 ggggaagatc cagtctcccc tccccatggc caattaaatt tggggtgttt ttctttactt 35400 tttgaggcaa ggtcttgctt tgttgctcag gctggagtgc agtggcacaa tcacagctcc 35460 tgcagccttg acctcctggg ctcaagcaat cctcctcctt cagcttcctg aggaggttta 35520 attaaataaa ttaaaagcta attaaaaaca tttttttttt tttttggtag agatgggtct 35580 cactgttttc caggctgatc ttgaactcct ggactcaagc aatcctcttg cttcagctct 35640 ggagtagctg ggactacagg tgcatgctac tatgcccagc tatttttttt atttttattt 35700 ttattttgta gtgatggggt gtgtttccta ggctgatctt gaactcctgg gctcagcaat 35760 cctcctgcct cggcctccca aagtgctgag attataggta tgagccattg caccagcctg 35820 gattgtatta aggaaactag cttagtcact aaactgcact tctacttctg atggacaaga 35880 ttggcacttt gtaaaccagg ttttctggga tgctggtttc cttgaagatg ttctagctgg 35940 tattatcata taggataggc tgagttatgc tgcattaaca agcaaaaccc aaaggtttat 36000 ttctcattcg tgctgtatgt ccagcaaatg tggctgggct tcattttaat cgtcctcact 36060 cccagaccca gcctgtaggt gccccaccac tgggggatcg ctgattgcat ggcatggtta 36120 gagaaatatg gttcttaaag gttctcatcc agagtggcac atctctctct gctcacaatg 36180 tgttgaccaa agcaagtcac atggatqgga gcagggagat gcaatctctc ttgtgcccaa 36240 aagaggagca caagaaatac tgttgaatag cattgccaga ggccaagaaa aatctcc 36297 <210> 44 <211> 100000 <212> DNA
<213> Homo sapiens <400> 44 gcctgaatgt caactccttc atctgcagtg aaaaaataag actgctctgt ggaccagaca 60 cttagtttta tttttcactg cagattattt ttcactactc atgtgggcct gcccagggat 120 tctttcccag gaggcaagtt atgtggcaag caaaatgatc aggagagtca aacaaacgct 180 gcagaaacgg atggacgatg actgtcagaa ggaggagaga agtggagggt gacagcgagg 240 tgagtgcctg gctcattcat cctcactccc tctcttgaat ccatgttaat cacaattaca 300 tgaatgcagt gctttaaaat taaggtatat agagaaaccc catctctact aaaatacaaa 360 attagccggg tgtggtggcg catgcctgta atcccagcta ctcgggaggc tgagcaggag 420 aattgcttga acccgggagg tggaggttgc agtgagccaa gatcttgcca ttcactccag 480 cctgagcaac aagaacaaaa ctgcaactca aaaaaaaaag gtaaggtaag gttatgctta 540 taatcccaac actttgggag gccaggccag gaggatggct tgatcctagg gttcaagacc 600 agcctgggca acacagtgag accacagctg tcccccatct ctataaaaat ttagaaaaat 660 tttttaaagt gctaaaatta caggcttttt taaagtggta ggattatagc cggggggtgg 720 ctcataccta taatcctagc actttggcag gctgaggaag gtagattctt aagccctgga 780 gttcaagacc agcctgggca atatagtgaa accccatcct tcaaaatatt agctgggtgt 840 actggcacat acctgtagtc ccagctactt gggagactga agtgtaggat cacctaagcc 900 cagggaggtt gaggctgcag tgagccaaga gtgcaccact gcacccagcc tgggcaacag 960 agtgaaacct tgtctcaaaa gaaaaaatta tccaggtgcg gtgtgcatgc ctgtagttcc 1020 agctacttgg gaggctgtgg taggaggatc acttgagcct ggaggttaag gctgtagtga 1080 gccgtaatca caccactgca ctccagcctg ggtgagacag cagacattat cttaaaataa 1140 atgaaaaata aaagtaaggt agaaagagta tttttaaaag cttattggag gttcacatca 1200 gcactgagag ataagaaata gagcagatat catgattcca ctttttgaat gcagaaactg 1260 aggcccagag aggtgaatcc agcctgtgtc cttcacaccc agctggctca tagaaaccat 1320 ggcctgttac caaccaagcc ctccagagcc cagcacttag gccgatggcg gccttccctg 1380 gcctgctcct ggggcaggtt gctgagaagc attgccgttt tggggagagg cctgcggcag 1440 cctgaggaat gagcctggca gtgggcactc tcactgggcc tcctccggcg ctgccctcag 1500 gaagattctg tggctcccaa agccccaggg gcgctctgac cacagcagtc agtcctgccg 1560 ggttgggggg ggctcttgtg cccagcgtaa cttacagagc cagcacgttc cagcctggga 1620 gggaaaccaa aaggcacttt gcccaagtgt cacgggctga aacgacatcc tcatgggccc 1680 ctgtccccgg aagcaatgag attggacagg tctgagcccc tgttacttca ttgggatgga 1740 cttgcatcta aggaacgaac tgagagtgaa atttccaaat ttgaggccta agaaaagttt 1800 gttggcctga tgagctgtga caggcaacct ctggggaagt ggaagctcag cacatcctcc 1860 ggttacttat tacgttactg aagggtctaa aatgactgtc cttggggtgc tggaatcctg 1920 cagaataaaa tagtgctgaa ttttaatcat tctttgcaaa tgaatgttct caaggctccg 1980 gttggagtca ggcaccctgg gaccttcagt agtgtgcttt gggtcccagg ccacagcaca 2040 gcccctttct tttttttttt ctttttgaga tggagtcttg ctctgtcgcc caggctggag 2100 tgtagtggcg tgatatcggc tcatgcaacc tctgcctccc gggttcaagt gattctcccg 2160 cctcagcctc ccgagtagtt gggttacagg cgcccgccac caagcccaac taatcagcta 2220 attttttttt tttttttttt ttttgagacg gagtctaact ctgtcgccca ggctggatgg 2280 agtgcagtgg cgcaatctcg gtcactgcaa gctccgcctc ccaggttcac gccattctcc 2340 tgcctcagcc tcccaagtag tgggactaca ggtgcccgcc accacgcccg gctaattttt 2400 tgtattttaa gtagagatga gtttcaccat gttagccagg atggtctcga tctcctgacc 2460 tcgtgatcca cccacctcgc ctcccaaagt gctgggatta caggcatgag ccacctcatc 2520 tggccttttt tttctttttt tagagacgga gtcttgctct gtcgcccaag ctggagcata 2580 gtggctcaat ctcggccact gcaacctctg cctcctgggt tctagcaact ctcctgcctc 2640 CC
0909 boobboobbe o5ob5b4bbe qbbboboobo 330088=06 4o6ob45405 abbqobq384 0009 ob4oblab4o b4ob4ob4ob oobb4boobo abbb000boo bbeo5bebb4 eoeeoebboo 06c boabboo4bo oobbbobobb obobebqbeb opobebbleo bobooboobo oboobebbeb 0880 oboboobebb boobobbebb obbebbbbbb eb000bobbb 3345543o-4B o4b0000400 ong 430343bpo3 obobab0004 oboo44obbo bobbobeeeb babbbbbbob bobbobb4bb 09L0 babobbbbbb 384E633663 bobbbebbbo booabobbbb boo4obboob booboobb4o 00Lq o5oobb654o boobobqooe bbbboboobb bbeb5babob ebbbbobbbe obbbeoo430 0179g eobbebb000 400beeoobo b0000eeebb abbbbb0000 bbbooboobb oqeb0000bb 0800 boalobb400 eae3eb465e aeooqobbeb P4POOPOOOD 444bpoqpob 483o4ob400 0zss DBOODOPPOb bbqg000bqb 4b;aboq3o5 qoeebq000b opobqobbeo 0005bbb4bo 09f7s opoboobbbb oo4b4beeoe ebeb4bbeop oopoob4o4o 443poq4b4o oo4o4o44op 00f7c oobboobeoo oqopoo400e oopeeeoqoo epe4beoe44 qbp44qeopo eqbbbebe46 (pEg beeqope4po 44es4eoqo4 b4bol4o4be 53444_84.345 qb4bebbebe 4444oeobbe 08g be400beo4b 430043444o ebbbabb4ob ebbb434bob b46beeea4o ebbee84484 pen- lobbbabb4o oobbebePob bb4bboopP6 4abeb4abbq be344bbbeb bia34434l3 0910 qbopobecoe qopqoqo.44. -28-2618813o b4.64.abbeco 14=335154 3440 336Pb 00Tc boo44bbqob lqobbbqqop pooqlbbbbq opbeobelbe pebelo4lbo lbeoeobbbe 0f700 poob000pbe 44op4344bb ebebbbob4b ebePPbbebb Peeoe441oe oo3o4b4ob4 086f7 qpoob6D,55e eobqooesbq 34o400beeo 640.2455-854 b4a44beo4o eobbbaeo44 0z6p boeopaeoee bbebb4o4pe eop4b4obee eabb4opbeo ogoebqoobe 344bobbebe 098f, 0bbbeb4s3o D3PPP4P4SP beoo41245b 44.6444q4b4 4344o-45334 444Pe44445 008v 4454T44obb 564e2o054o ob4e344344 eobb4e34o4 -4423443305 oppoeobeob 0f7L, 43epee200o 344.4beDobe 433 44.3344 334814beeo4 o5eobe4554 qoo4ob4obb 08917 oebboop000 4opob4aPP4 oo44oqo54o 4b4p5b4boo 4004005o5e opoob4o400 09D, ob4obbeope babeooTebo opoo400448 5454eb400b bqeo4obeoo 4abeopeooe 09gf7 434433e4b4 3o4o40064o bb4opobb4o b454eoeb4o 4bbe54005o opo44o4004 00S 4-P534344Po 64885b5ogo bq4p000440 bb4005e400 4Pee44384o b44444e4ee N,f717 uebbbeebee bbqbbeobge 884obebe4b 643548,4.355 p0000pebe4 euee54-434e 08E17 40443404bb b4o4ebbb4o bebeebee4b 4beebe4be4 beobb4bbeo eb4bbb4beb on-p 4eoboebbbb qbeoblabbe bo45bbbbee bb4bbpoqp5 eb4poob4ob 5qopo4lobp 09D, 5540006ebo eopoobeobb qebebloo44 4344084444 obbeeboob4 bbeo5400p6 00EP beo5e5b44b bb4beebee6 beeo4bbebe b4abuebbee 4obb4bebbb pebbb484eb ()PIP 2b4bbbeo5e b4abbqb4oe oopoebebeo p000pebe54 44b4546540 oeob4bebbe 080t, ob5eb4opob eeepeobeeo beopebebeo be000qbebe eeeeeeeeee eeeeeeeeeo OZH' 404bqopobe bqbebepeoo bbb400buoo 43e3e43eao eo2o4eboe4 obeb4peob4 096E 4bbeb446eb beopobeb44 ob44ebbebb bqbbeb4obb ebeb44oe4o ee4obeepeo 0060 eepeepopee ea4ogeopo4 ebe54be6eo eeobbb400b eoogoeabqo epooabgqeb 080 epoobbq554 b44bbebeob bebbbqoobe b443b44.ee5 ebbeobbebq o5bebbb44o 08LE P4ob333gee 4b40054poe obbgbb4bob 6540.62P4PP PPPOP4PPPP egoe4o434b OZLE 40ceeeb4bb qeopeooebe oobeoaebee 344bebbeop 5beb4o4poq ebb4.6beobb 0990 ebobbebbb4 44oeo5eopo 4e34b400b4 eo4obbeoeb ebegoe4oep 4034be4b4o 009E 4403o3554e 84Pobbeope ogebbebbb4 bbeeeebeob ubb44bebee e54bbbb4be ovoE 4obbeboeoo bebqbebebe e458e5ee54 obeb5e6qoe b4005beo4o o4bbbbeopo 080 4444223844 4bb4b4bbbb b645b4bb4b 54bbb45e4e eobbqabgbe eebe45e54p oz'oeebebeobee e4bpeeebeb bepeoe4beb 4e814bb4bbe ombeb4ee4b qeoppe4oe4 0900 ebeeebeebe bebb45e4ob 4epo44obeb biao434o54 o4o4peoego eeee4ebbbe 00EE 34epeopee5 beoeobbboe 4b54000bbe 43b4bqb4oe 433eo5eb4o 2444223232 0pn- Poo4poq4b4 44e4b4opo4 lloogebeo4 ebp4b4eee4 eq.-44011305 4beboo5eo5 081E eogoeopoo4 ea4c4beoeb qoo400444o 4o3bbbbeoe 00000bbeoo bb4b4opeop 0210 op4b44epoe 4ob4obb400 4o4o4000bb ebeepo4beb 44apooqeoo oobeobebqo 090E pobebboobb m643344644 g000440000 obb5400leo obbeoeb4e4 poo4b4b4ep 00n 4.544beoobb 6444pee544 oeb400eee5 eqq4eep000 lqopo4e484 444446e4.44 0D'60 348Pb245eo o4bqopb4oe e4ee3444eo 4ee4b42434 444eoe4bb4 o44pe44444 088Z 4444444444 4440b4pe4e 344opoobb4 bb4o4o4bpb 8Z-4o-434044 400045elpo 0Z80 po5eoo4e0b opeom6eb4b qbbeqeq4e5 bb;obqbeee ooaqooboqo oqoopeooqs b4boqapeb4 oo4o2eb44o 4bb4o5be4o ab4454eope 4444bb55oe eebeq5e444 OOLZ 44P4b44444 Tee4abe000 b4poob4ob4 paeo5beoe4 lebbbobe4b ebo3o400be ZZ-TO-VTOZ ZZg9Z8Z0 VD

ggggccgcgg gttgctcgac aatggcccgg gcggccccgc ggccaagtgc gcgggcgccg 6120 ccgccgtctc ggaagcactt ggcgagttgg gagcgagttg gggcgcgcgc ccgggatccc 6180 cctgccgtcc ccggctcccc gccacgcgcg ggccctttgt ctccccaccc gggccctccc 6240 cggggacgct gcgtccgggc tggcgaggag ggcgcccgct ccgccaggtg cggcgcgggc 6300 gggtcctcac ctgccgagcc cgcgggaagc cgggagccga gccgagcccg cgctgggccc 6360 gtgtggcccg ggcgggcacc gagcggggac ttggggcgcg gaggcgggcc tggcccgggg 6420 agccggttcg cagcctgttt ccagcggccg cgcggccgcc ccgcgtgctc cgaggacggg 6480 ctgaagttgc gcgagaaagt tctgagcccg ggcgcggggc ggcctggccg gtggcgctgc 6540 tcctgtgagc gcgtggctgt gggtttccaa gcggactgac acctgccagg tgcccgggcg 6600 acccgaatcc ccgtgtggcc gccgggtccc cagatagtgt ccatccccgg gtcggctacg 6660 cggaggtacg tggtcccaga tcgcggggca gtgggggagg caggcttgtg cctcagttgt 6720 acactccgtg gggagaggta gggcggggga actttctctc caacttttgg tgtttcccag 6780 ggggtgagtt gaggtcagga ggactcagga aacttaagca gtcgtgaaac gctacacatg 6840 ttctttaatt tggagattgc catgtggttt ttcaagcaag cctcttgcta cctaaatcat 6900 tctttcggat gtgcgtgttt tgtttttctg gagtatggct ggccaagtgg cacggccgca 6960 aggcctgtgc acgccgcggc tcctgttctg tttgtggcag tttagcgggg aggacctcgg 7020 gccctttgtc tgggcctcct taaggcaaac agctgtctcc ctgaatattt ccagtgtgaa 7080 ggtgcagcgg ggtggccctg tagtcagatc ccccaggctg cagcctctgc ttggaggtgg 7140 ggggacagcg gggaacagga ggagcttgga gtttgtttca cgtcctcctg cctctgacca 7200 agcctagaga ttctatggac agtttcaccc caaatctgcc tctttcagga gcgtgttaca 7260 ttgtggggcc ttgtctggag ctagcaaaac aaggtgaaga caaaacagcg acagtactgg 7320 ggagtacagg ccagcgccgc tcctttttcc ggaaatgcct gggtcaagga ggcaaagggg 7380 ttttggggaa actgtttgtt ttaaaggggg ggtttctagg ccgaccgcgt tgccttcacc 7440 tcattgcagt tttgggtttt gtgcacgttt tggggtgatg ttgctggagt caatgcctgt 7500 cgtccatgtg gttcgagccc ctgaggagaa agaattatag ctgtagagtt cattgtgtgt 7560 gaggcaaaaa tagagttgat tattttaaca ttaggcagca aggcctggga gcccagtgaa 7620 tgtggtgatc caggcctaaa atggaaggaa agggaggaat ctttctgcag acggttttga 7680 tgttatatcc ctggttttac tgtgtgaaat acatgcctcg gacctcagca agccagtaag 7740 tgggccgcta attatttttc ctgattgctt cctgttgcaa ttggaagcgt gaacgcacgg 7800 aaatggcttt gttctagtgg tcccagtgct gagaacttcc ccagctccaa gccctagtcc 7860 tctctcctcg gggcccaagt gcttgttcca gggccggcct gtccagcacc ccctctcccc 7920 ctggaggttc ctcctgtaga tgcccaaggc caaggccggg ccctcgggag agcccagaag 7980 ggctgagtgg ggttaaccaa gtgctgtgtg gagcaccctg agaggtcccc tccaaagcag 8040 ggccccgtgt gtttagctcc cctcttcagt tccaagaaat tcgcggtgaa cccgatccag 8100 catttgttca gcactttcct ggggagattc acctcgtgct tctgtcgttt ttggaacccg 8160 tttaatttca gccgtgctgt gtcactgctc aggcatttag tgaactcaca cacacgggtg 8220 ggggatgtag gcaggtgagg cctctgagtt gctttctccc tgcagcgacg ggttgcaggg 8280 ctgatggggg tggaggggtt tggggtcaga cccacctggt ttacatgctc agtggctgtt 8340 tgacttcggg caccatacct agtttctgtt atctcacccg ttcctctccc aggctatggg 8400 gagccctaac tgccctgtgt gagaccttta gccccatcct ggcagagctg cagtgagcgc 8460 agttgtgtgt cagcgtcctc gatctttctg gccccaccgg tctagaggct gttattacaa 8520 tagtctggat ttttcctgta tgaccttgga catccgtcca ctgacaaact cactcactca 8580 ccgctgcagc cctcgggggc aggagtagtt agttgcactg tggacagagc ccctgcgccc 8640 agggtctgat tccagcctgg ccgcttcctg tgcgggaggc ttaggaagct gatgctacct 8700 ttgtgtgcct cagttttctc acctgtaaaa tggaatagaa tccttcctac catgaattca 8760 gtgagttaac gtgcacctgg cccggtataa tctgttgctg ttttgctttg gtgtctgcta 8820 ccgagtgaag tgctagggtt gagtgcgata aatggcagat aaggccccgc ccctgcgggc 8880 agagcttccc atgtagaggg gaggacagga aagaagcttt gcagctatgc agaggtgggc 8940 ccacgggtgc tccttcaccc tcggggtgcc tgcgagaggc ccttagaggc cagatcatgc 9000 tgtggagtct ggttgtgatc cacaaggagc ggaagcttct ggaaggcttt aggcaggagt 9060 tacaggaaat gcaagctaaa gccagacttt cctaggtgaa aggtgtcgag ttgttttttt 9120 tttaaattga ggtgaaactt atatatataa aatattaaag tatagaaggc aggcatttgg 9180 tacattcaca gtgtttacaa cccttcttct atcaagttat aagagatttc catcacccca 9240 aaataaaacc catacccatt acaggtgact tcccgttccc tctccccgga tcccctggtg 9300 aacaccagtc gactttctgc cttgtggttc tgcctgttct gggcattttg catgaaggga 9360 atcttacaat gcgtcttcgt gctgacttcc ttggttactg taacgttttc aggagtcatc 9420 caagtagtac cacgtatggg gtttcagcct tttatttttt ttttgaaatg gagtcttgct 9480 ctgttgccca ggttggagtc ggtggtgcga tcttggctca ctgcaacttc tgcctcctgg 9540 gtttaagtga ttctcctgct caggctccca agtagcttgc attacaggtg cccgccacca 9600 cgcccagcta atttttgatt tttagtagag acgggatttc accatgttgg ccaggctggt 9660 cttgaactcc tgacctaagt gagctgccgg cctcggcctc ccaaagtgct gggattacag 9720 gtgtgagcca tcacgccggc ctatttcagc cctttttgtg gctgaataat attccattgt 9780 gtggagggac cacatatatt tgtcagttca tccgctgatt ggattgatct tggttggttg 9840 catctcccag ccgcacgagc aggtctcatg cctcctgcat cctggtggag gtggctggtg 9900 ggaggatctg gctgagactc tcctgccgag gttcaggaac gagccaggtg atggggacaa 9960 gttggggagt cgtgctggca tctcagagga ggggcctggg ccctgagagg agtgctggga 10020 gggcagagtg gggccaagtt caggttacag aagccgtgag acagccggac atctgtggtt 10080 tgtgaggctt ggaaacactt aatgcgctct ccaaatgggg agtctgttgg ggaggccctg 10140 gcgggagcgg ggctacatcc aggtcctcgg cttggtggcc ttgttcactt atttgttcag 10200 gaagcagagg gtgtgggctc tgtgccaggc cgccctggag ggctgtcctg gggccagtga 10260 ggtccagtgt gatgggcgga ggcagctgtg gcttgctacg agccggcctc agggacccac 10320 cggctgctcc ggctgctctc tgcattctct tcagctctgg agagccgtgt gccagccctc 10380 agcccagttt cctcatctgc aaaatcggga cgatggtgtc caccttgccc atgctggtgg 10440 ggtccaagag ctggtgtctg gggtgaggga gctgggggcc aaaagctcct gccctggggc 10500 atcagctgtc ctttgaagag taccccgagg gtgtgactga gagccagtcc ccagcaccct 10560 ttccagatgg ggaccaggag gtgggtgaag atatttgggg tctgagctct gtgctggttg 10620 ccccgagggg gcctggagcc ctgagttagg agcagaacgg ggtgctggtc ctatccgttc 10680 ctacctgggt agtgggggct gccttcctgg gttgggggtg gggggagctc cctgtgtcct 10740 aagccatgca gaggcatgcg catacgcgct gctcttaggc atgtgggtgg cgctctgggt 10800 ccctgcccat tccccagccc catgtggtgg tccctgtgct ccaggtccag cctctgtttc 10860 cagtttgtcc tagtttgtca ccttgtaggg ggcagttgac actttgctgg cctgatcgtg 10920 gtgtgccaga gcccgtggct gctgggcgac tgtgcctctt tctctcagtg gcaaagcctt 10980 attttctaat agagcctgat gggccagagg ttccgccaca gggacactgt tcttgtctct 11040 cgtgcttggg gtctcttgct gtggaccocc tgggaggttg tcctgggggt gcgggattgt 11100 gttttctggg tattttctta tttgctctat tggagtgtat ttaatttaat aatatatttt 11160 aaacatcttt tagtttgcct taatgtaatt ttttttgaga tttaattttt tttttttgag 11220 atggagtctt gctctgtcgc ccaggctgga gtgcagcggt gtgatctcac tcactgcaag 11280 ctccacctcc cagggtcacg cctttctcct gcctcagcct cctgagtact ggaactacag 11340 gcacccgcca ccacgcccgg ctaatttttt gcatttttag tagagacggg tttcaccgtg 11400 ttagccagga tggtctccat ctcctgatcc tcccgctcgg cctcccaggt gctgggatta 11460 caggcgtgag ccaccacacc cggcctgctt tttttttttt ttttggtctt gctctgttgc 11520 tgaggctgga gtgcagtgat tcagtcaccg cttactgcag cctcacctcc tgggctgaag 11580 caatcctctc acctcagccc gcaagtagtt gggacctcag gtggcaccac cacgcccagc 11640 tgattttgtt gttttttgta gagacagggt ttcactatgt tgccaggctg gtcttgaact 11700 cctgggctca agcgatccac ccacctcagc ctcccaaagt gtgggattac agacatgagc 11760 cactgcgctg ggccttaatg tagtttttct tgtggttaaa tgaggtgaag gttcactcaa 11820 ggaggaaagt ggtttttagc cttttgaggg gctcaaggac ccttcaagga tatgacaacg 11880 gctcctctcc tgagaaggtg cctggtgggg gcggcacagc tccactccac cccattgcaa 11940 gaatccaggg ccctgcaggg ctcagagccc tctccctcct ccctgtgggg cattgagagg 12000 cactcacctt ctgagggcct cagtttcctt tttttgaaaa tagaaccagc tgattccaat 12060 ctctatggtc tcttctagca cggagcttca cgtttttctc ccttcaggat cctgaggcct 12120 ctggatcgct agagattggg ggtgccccca gaagggcgct gcttctgtgc cctccctcac 12180 cccaccgtgc ctggctcctt gttttttttt tttttttttt ttgagacagg agtctcactc 12240 acgcccagga tggagtgcgg tggcacgatc tcgctcactg taacttctgc caccctggtt 12300 caagcgattc ttgtgcctca gtagctggga cacaggcatc tgccaccatg cccagctaat 12360 ttttgtattt ttagtagaga cagggttttg cacgttggcc aggctggtct cgaactcctg 12420 acctcaagtg atctgcctgc ctcggcctcc aaagtgctgg gattacaggc gtgagccacc 12480 atgcccagcc tgcctggctg attttttaaa tttgtcgttg agatgggtgt cttgctttgc 12540 tgcccaggct ggccttgaac tcctgggtca agcgatcctc ccacctcagc ctcccaaagt 12600 gttgggatta caggcatgag ccgctggccc agcctatttt attattatta ttatttaatt 12660 ttattttttc tcactattgc ccagccctgg cctccaactc ctgggctcaa aggatcttcc 12720 tgcctcagcc tcctgagtag ctggactgca ggcatgtgcc atcacaccct actttgtact 12780 tttgcttttc tgtctttgct cttttaaaag ccaagtgcca tttcatagta cacaggtgca 12840 cttgacagca tttacctgat tgggagtttt tccagccttc attgctatta caaagcatgc 12900 ttgctcgtgt gtctctgcat ggtataagtg tttttatagg atacattcct agtcaaagag 12960 tgtgtccatt tctgttttta agatattgag gccgggcaca gtggctcatc caggtaatcc 13020 cagcactttg ggaggttgag caggaggatc acttgagtcc aggagttcga gaccagcctg 13080 ggcaaaattg ggagaccccc atgtctacaa aaaatttaaa aaattagctg agtatgattg 13140 cacactcctg tagtctcgct acttgaaagg ctgaggtggg aaaatctatt gagctcagga 13200 ggtcaaggct gcagtagcca tgatcacagc actgcaacag atctagcctg ggcaacagag 13260 cgagaccctg tctcaataca tacatacaag catacataca tacataactc ctaaaaggct 13320 gtagcagttc atactgcaag catctacgag aacacacact ttcctatatc ctctctgatg 13380 ctggcaatta caaattttgg tttttggtgt tttctttggt ccagtttggt taaaaattat 13440 aacacctttt gattgcacaa ccctcatttc tggtttattg gtatttactt ttctgcaaat 13500 tgcctacact ttccttggcc catttttctg ttgtcttttt cttttctttt ttcttcttct 13560 tctttttttt tttttttgag acagagtctc gctgtgtcct ccaggctgga gtgcagtggc 13620 gcgattgcct cttggttcac tgcaacctct gcctcccggg ttccagctgt tctcctggct 13680 cagcctccaa gtagctggga ctacaggcat gcgccaccac gcctggctaa tttttgtatt 13740 tttggtaaga cagggtttca ccatgttggc caggctggtc tcgaactcct gacctcaagt 13800 gacctaccat ctccgcctcc caaagtgctg ggattacaga cataagccac ggtgccagcc 13860 tgttttcttt ttcttataga tttgtgggag gtctttattt ggtatggact ttaattcttt 13920 gttcgtttgt ttcaggtttc actgctggtc tgtagctagt ccttcatcct tgtttctggt 13980 ggtcattatc ataaagatat taagaagctt catataatca taactctact ttttccctat 14040 ggttttttcc tatcccttgt tactccatct ccagattata aatatatcct ccattatttt 14100 ctccaggact gttactgttt tatgttttac attcagacat tattctgtct gggttttttt 14160 tttttttttt ttttgtatat ggtatgaggt aggggtctgg ccagtgaata gggagttgtc 14220 aacaccttgg tgggatggtc catcctatcc attcattgta aatgctgctc ttttatgtta 14280 gtgtccacag acacctgggt cctgattcca gacccttcac tgtgctccac tgcctgtagt 14340 gtctttgtgt accggaatgc tgctgtctcc atctctgaag catcagaaca tattttagat 14400 cagttatgta aattcccacc tcattgtcct tttcaaaaga cgtattggct ctgctgcacg 14460 tttatgcttt tgtggtgaac ttcagagccg tcctatcagg ttccaccctt tgattcttga 14520 tctggggacg gtaaatggtg atatccagca ggtgtcagag ggctggattt taatggcctc 14580 cgatgagctg gcggtctcag gctgtggaag tgaattcatc tgctgggtgc agggagccgg 14640 ccttgacatt tgtgggtttt gctgacattt gtggaaggct ctggaggtgc ctttgtgccg 14700 acttgcccga gccactcctg ctgcccaact cactccggtg tctgctcagg aagaaattct 14760 aatgcacact aattttagca ttagcccgat ggcaaatata attactgagt aattatcact 14820 cccctcccta gttaatccca gagcaaaatg tgggcacctt tcatttctcc ttgggatgta 14880 cccctgtatt agttcagatg gggaggcggt acctgcctgg caaagcttca ggaaattgct 14940 caacggggca ttaatagcta tctgagcgtg tggcctgggc tggaaccacc agcctgggtg 15000 ctgggtgcct tccaggctct ggccaccttg ggttctgccc caggaggagc agactgtctc 15060 ctctagggga cctgaagctt aacgtcctca ctgtacgaga tagtttggag caagatatgt 15120 tctggggctt gcttctgcgg gtaaaggcca tttctccaaa cttcccccag agcgaacttg 15180 cttcccaaaa ggagtctgga tccgggcgtg gccgtgctgc ccggccgcct cctcacttca 15240 gctggagcct ccgagctgac gtccatgcct attcctcctg acactgtaga cacaggcccc 15300 agctctgtcc cctgccctct cctccactca gactccctgg ctctgaggct ttacctacag 15360 gccctgcggt gcatattcag tgaaagccta gattcagagc aatgacatca gcttttactt 15420 ggtctccttg ctttctggaa cctccccttt gcccattttc ttatgctctg gccagattaa 15480 tttttctcca agtagttttc atcacatcct tcccttttca gacagtcgtg cccattctcc 15540 agcatctgaa gttggaactt tttggcctgg caggcctgcc gccctgagca gacctgccca 15600 tcttctgccc ctggtgtggg cacttctctt gccagtctgt ctggaacctt ccatggtcca 15660 cccaacctgg gagggccttg aggacagggg ctgtttcgtc tgcgcccctc tgcctotagt 15720 gtgatgtctg gtagatgatc agtaactgtt ctgggccaag gcctcatctg tccagggagc 15780 agatcttacc catcttttac ctcctctggc tcaattctgc tggagcatga gctccctcta 15840 gcctaggttg tagaacacct gtctggctat ggacagcttc tgggccaagt gtgaggaccc 15900 ccatggtcct gcagtaagag cccatatttc ggggtgtggg aaacccagtg taccccaaag 15960 ggacttgact gtgaagtccc gggtccacgg gtacccacca gcctcctagg gcccagactc 16020 cgtgagatgc cacggtgggg gcttgggctt tgcagccttc acttggcatt cttaccattt 16080 tcaggaaact ttatataaac atttttatca tgcaaaaaag gaattatgga ataataaatg 16140 tttatattaa aaagtcttgg tggtttgatt gatttattta ttttttgaga tggagtctcg 16200 ttctgtctcc caggcttgag tgcagagcac agtcttggct cactgcaacc tctgcctcct 16260 gggttcaagc agttctcctg cctcgcttcc tgagtagctg ggattacagg cacccgccac 16320 OVL6T ubgbgabuoo qopo56gooq obpbqqopbp pbobooppEce abebebqp&E) bogooboqe 08961 opooq365q6 qo5loob2a6 qco-43qoqop oppobb6.6ft bbqbpubqo4 oobbaq.pbp 03961 opb55T5434 5Pooqoqobq bqebubebqo bqbb4booqD babbTlleob obqbqpoobb 09g6T pooboebqo 4o6opooEq4 qopbqbeo.48 bebqboo56-4 poobogopoq 436poo2oo 00S6T obqopoqbbp poopfiqogoo poo4qoqq65 oopobbbqoo beopbbbeoe. b2ebqobwe 0÷6-C oqqp5roqDp opoogoobob Poqpob4opo obbqoqqqoo p6Pobeopeb qobB000loo 08E61 gobbbbbb45 qogooqqa6; obbi.oBbboq bcbqogeop5 wooebbbbe 6q454.4opb 03E61 bPbeoqqqqD oqogoob000 o15705peop eoTbqbb245 qqqeqoqpqo abqabbbebq 09361 ob6bbteobb geqbeebepq bqqqoboqop 6.65654opoo 4035054bbb oggpopq5be 00361 obqbbepetb bbbgo.48258 243155455 upq5bb6qpb 554b5g33ob pbbgabulbq 0P161 q4qP qqq_pob bogoo&E.gob 433-4go3qb obqfqbeboo 245b3gbpoq gewobpbbq 08061 boer=l5quo gobobqq555 qbqobbqbbq opabgbgbyq Pob4ogoEcep qgpooppeb 03061 opb54-40.5qo bbe6p5qobe oqbeoqqbqq op654Dq3e5 EbbooppooP bopbqbeq-23 09681 ogoeqqb4TE, eoboq=501 epeqq&bbeg qbqabp4gbb oubqbpoqa6 Egoobbbpoq 00681 obPq3o2q.bp pee544bobe bbe.babeDbq abbpbqD345 oqDbbuoupo oqobi.-244q3 0f7881 Teb1ee66be TebqbcoqpD Doqqqbeoqo bebeoqqobq oeegmbopob pPoubbb4o;
09L9T 66o5qoqobe qopqobqoqb 2,bqqbqp8qo oebqooboo qTb000Polo popoobbeob 03L81 42000buebu beoogpoupb obgegbgbob 4gbbbbbgpo qbbbbp4b5b pobqbbuobq 09981 obebobegbe 3bbbb5Bqop pqbeHgobq qq5beboopo Eqoppoqqoo wobepooqq 00981 eqbbebopoe oebboqqbqo bqobeebeob eepogoobbl beobs,354-eq qeopppobeo 0f7S81 55543bg5g6 Ebblobbqbb eoeobbiLbe peopeogffe pbbqbgeob bepopeogb6 08V81 440bsoo5be uqpeabuDeD 0054056q10 TTeqoqqbqo oDbbfq.Ebbb Ebbp5peblb 03D'81 4freqq5.4bgq qoqgogoobo opbqbeebog bPogo?ob4e bbbube4Dbp Eqqopobbeb 09E81 qbpolebqbq popp5goopb qq34pbbbqg pebeobgeeb b6Debeo652 2P5qe55eD6 00E81 pftobb4qbq bgabbqoppq po5poopoqb leBE,Bpoq45 bpoeepfrebq bbeoqq-45q5 0f7381 1P6qp455qe ooqbb_66.4ob Obebboopqo qoobbbeqqE b6bpoqbPop oppo4pqpbq 08181 oqebqbuoee 4qopqbbbqo 44=6622o Debqoopobe bbqopopeop popoeoqepo 0318I Dboppopopq ebbbDbefieo ooEcegeqopb bqbb6pogeo oqoogoopfie opopengoqq.
09081 bboopboeob qoDobqb433 lobbbqp400 oqb5bbbqoq obebgbbeop uop-ebebPoq 00081 D6qpoopfibb pbqqbbbebq pqoqqqqobq b4o5qqo3qo abb3bbbgog ob6bi.o5o56 06L1 24o5b6bqop ooboeobbqo qbbRobbeoo qebbeopqpq ebebEtTebq 555-2,554qoe 089LI 5435-4Pobbb qqbbbqopoq bbbqbqobbb 4boopobboe 3gqop2o23b poloebbqqo 038L1 44obbeebog 546epoogg3 bb44oeopbq Mebbuopuo Poogobqopb 3o4q.ET)bb4b 09LLT 5066p6roft buDE5q3ppo obqbqobepo 46oqeogobq D4qopoof.Po Pepbeeqqe;
ooLLT qboebqeeub free-443qopq rqqqqbbeep bi.44q6goTe ooqqqeePpp pe2-eqlee-44 OD'9LT 4beooep3bb q440401e00 qqqp5q5555 eepeobbeff bebbbqabae oqbb5qebp5 08SL1 e05454L5eb qqoeyeo-ebo bpobbfqopp pubebbpoqo obqbpoppoo b33ppoqq4P
OZSLT 66oe3gob56 pboobb;Dbb oPoobebebe poqobebpob 666q33b6qe 6qopo66gb3 09f7L1 650036;565 epoopobbgb qbwoobqo 066bqD6uoo oebqabqbqb qopobqbqbP
0017L1 000fqb;6qq. pabubPoqpb bebbbbeoeo qbobqp5p6 ebq62q-2.556 -4_655qbP400 0f7EL1 eobbooDoq? bpop556.464 poppoTeqeo Eceopfy46qoq 66qbpqbbqD qoblpoofthp 083L1 obuousbbob bbobqp55qo oploPbmbbp obebbqbqoo 34543o5415 obobgbepoo (:)3LI opobeobebe 6006-4=45 pqoqobpbbq obqpbebqob 55-2.55pD4oq 434pqq626b 091L1 4Pobeftqlo qop6qpiimb qoBoo4boob ;664-4-4o55-4 Mq544obbb boopobbbeo 001L1 54epo6goo-e, 5go3goe6E6 eoqbbqbpbo babePeopqq. .65404o5poq pe333e5e;
()VOLT boqopbqqop qbppeopobo obqoepobbq 6qabqq423 ooebb qqopoq354o 08691 oboobpaboo poqoobqbqo b5oop.4.5554 3oq3255Pbb op6q5eolo5 qqq&ebbbeo 03691 Do66665u0q p64D6Dq66q ooepobqloe ofiqeoqqbeb 6.600p064e; qbbeopoqop 09891 opoqbqbpbe beebouoPeb qqleebeecl oqq.bobTeeq 4qq4eebqbe b4oeSq.657], 00891 6e6P424o-2e. P-2446P6qq4 qp-eqbbqqqo e4o55400bD 63ouDEce6g6 055eq4e5 017L91 bbqoelbeer poo4qa5p3i. Dabqqoqoog e6-46pegga6 66qDqDep66 Tqleoqqbbe 08991 poobqqb;po oqopoqbbbb Tepubegbqq. -44qq4Deoue uuq4-414-2-eq bbeopobbpo 03991 OPOOPOPOPO 65poE,4pubb bob?-4b-e54 33qopbeoqo opooq34455 4.54-epq4b5b 09891 43330.403pq owo6uo5qo p400bpaeoq -2o35455q5P bqbeftqobb pooppgqb4o 00S91 43E.643q6et egebpbqqq; egggp2.24.44 qq35455445 5qoa6ePoor, po5e5454bb 0÷91 PoeqqeMbq obqfvebqoDo qoo52pqoof) lqopooTe4,5 Eceoqoebqpq qoe2boqoqE.
08891 5q3bbbqabb qqbquoaeoq qqbebb.4-25e b6qbeqqq42 ;644;q4-2-24 abbqopboep ZZ-TO-VTOZ ZZg9Z8Z0 VD

gcccaggtgg gaccacccag ttacagagcg ttaggcctgg ctgtgtagga gacgtgtgtc 19800 tccacaccag agtccttgcg gcactgggaa gccttcatgg tcctcatggt ggggaggggt 19860 ccccggggag gcatggagtc tcgtcctagg ttgctgtgtg gcttcagcgc tctgtacctc 19920 catgcccctg tcctgcagat gtaacaccca gttgaggaga acgtggactt tgcccagtgt 19980 tgtgcaggga tggtggggcc agctggagcc cacgtgtcct gccttcgccc tggccaaggt 20040 gggggttatc tgccctggcc agctgtgccg cccgtccctg cccgccccag caggtggggg 20100 cctgcggtgg gatcccacca tgagcagtag aggcttgttg acttactggc ctcccaggct 20160 ccccctccaa agccaagtct ccaggacggt tcttgcccct gagaaggggc agtgtgggtg 20220 ctgggctgca gcgagccctc ttcgttccat ttcctcacag tcttggggac ggagggcttg 20280 tcctggagca caggacggga ttgtgctgag gtcctgggag gccacggtca tgaggggacc 20340 cagtgaaggc caggagggac aagcatccct ccaggtatgg ggagggtcac cccagcgcct 20400 ctgcggatct gaccactggc tgcggctcct gtgcttgacc cttttggcaa agatatgcag 20460 tggtctttca gttccccccc ttaggcagca tgaaaacaat ttaactcttg cagaaagaac 20520 ctgggaattg attcccctgt cactgatccc acaagtgtga ctttgcattg gtttcttggt 20580 ccccttgtgc cagtctcccc atctgtaaaa tggggtgaca gtagttccac ctcctatgag 20640 gactgagtga gtcaggaacc agaagcagct cccacatgag actcagaaag tgtgacaggc 20700 gtggagggtg ggacccatga agctaggccc ggcaccttag gaagaagagg gagctttcct 20760 gcaggtttcc ccggacggaa tgtgtttcgt cctgtgcacc tgcctgcaga gcccctcgca 20820 cgctgtcgtc cacaatgaat gcttggtgga agagttcacc cagggcctgc aacaccatag 20880 tgctcacttc tccaaattct tcttaacttc cagactcgac acgtaaactt gattccaagg 20940 aaatcaagct gatcgtcaac actggacttt gcaggcagct cccaaaccca catgcatatt 21000 tacactaaga aatgccagtt cctcaaagaa tgttagcctc tgagatgcat caggagacca 21060 ggagcaaggg gttaaaggca aaccgtggca ttccccaaat ctgtccagtt ccctggcatg 21120 gtcagtgtcg cggagcccga ggtggcatct tttgtttggc tgctgatggc ggccttcggg 21180 cttggcatcc acgttgctgc aattttccag gaacagtaat catttgaaag tagagctgcc 21240 cgttttgctc aataaaggga ttttgtagag cgatgataaa tttggcatgt ctttattata 21300 ttattttttc aacacttaaa gaaaataaaa gctggtacaa aggtatgttt gtttctgaat 21360 gtgtttcctt ccccagatgt tcttttctgc cagttctaaa atgcgttctg agctcggcct 21420 ccagtttcct ccctgtgagg aagaacaatg agacctttgt aaccacacag gggaaaggcc 21480 gcttccctct gcagtgggca tgggggaggg gctgggacgt cccacctcct cccactcgat 21540 ggaaaccacg agtctgtgcc agcccagccg actgtcgggg ggtttggcag cctctttccc 21600 atggtggtaa tttgcagggt catggctcag gggcaccgca gtctgcacct ccgccctgga 21660 tccgtgcgtt tgctgtgtgg cctcgcagta aatgcttcca tctgcgtggc attatggacc 21720 ctggggcttg gtactgtctg tgttatctgg agtcgaactt gcccttttcc tttctgtctg 21780 cctttcttgc atcaaatgct ggtccccacc caaagggtag cccagtctgc ggacacggcg 21840 cagaggtaga gttggtggct tcacgagggt ccagtggggc acagaccttc tcggctgctc 21900 tgtcgctttg tgacttgaga ctgcgtgggt ggggtacctg agggatcctg agcccgccct 21960 tcccacacgt gtgcatgcac acacacatgt gcacagtgct tcagaagacc accttagttg 22020 gatttgaagg acagccaaga gacctgtata aagcttgtag ttagagcgtt tcgatactgg 22080 cctgaattaa gagcagtctc catggggttg ctgtctgtgg ggtactgttt aatgaaaatc 22140 cttgttttta aataaatgta tcctgcttta gaacacccaa gataaaaatc tagacttcat 22200 agacaaaaat agctaacatt tgttgtgtat cacagtgtgc cagtgggctc taagagatgt 22260 ttgatttctt taatccttcc agctgccctg tgggctgggg gcatccctac cctcatttta 22320 cagacgaaga aactgaggct gggagaggtc aattaacttg ccaaatttgg tataggcaaa 22380 actaggaatt ggcagacggt ggttccagtg cctgcctttt attggtactt gaattatacg 22440 agtgttttct tccatcaata aaagaaatcg gcgaacagct cccatgggtt tcagtaagtg 22500 caagccctcc ttgtcatccc agacctcagc ctgcccatta atggatgaag acactgaggc 22560 ctggagggaa cagtgacttc ggagccactc tcctggatct gccactcctc tcgcctccca 22620 tatgaacctg agtggccaca tgaccctggg ggagagtact caactgtccc aaggagaggg 22680 tgatgactgc tggcctccca ccggccatca gcgcccactg actgacaccc ctgagtcagt 22740 ctccaccctg gaactgtttc tctcactatt tgcctggcct tgggccgctt ccgggggctt 22800 ggcaaggcag gaggcgtgga accaagatgg tattaatcag aatgctatat tttgttgaaa 22860 ataagaatgt tagtaatggg ctggtttctg gcggtcaaac tgggactctg aaatacatat 22920 ttttctctgc tctgccctaa accttctaat tgtgaaaacg cacatttgca gacatcaatc 22980 aaatgtcata ttccctagca gcttgtcctg gatcactgag ctggtcacat tccacagttg 23040 ctaactcagg gcttgcagag tatgtgtgcc gtgtgtgtgc atgcgtgtgt ttgtgagaga 23100 gatacatgcc ttctggggag ccctggtgcc tgtttccttc cctcccaggc ccctgagctt 23160 ctgctcccca ccccgccccc agcccctgtc agcacatgcg cggccactgc aatgagatac 23220 agacgttcgc ccaattaaaa cacagtagtg gaggacacat ggctttcagg gaaaactgct 23280 ttctctcagg aagatctctg ctgtgagtat tccatagcta gaccccagct ccactcaaca 23340 gtggactcca ttaatagcct gggtttggaa gaggcgattt gcttctggta actggctccg 23400 gtgcatggat gttccctcct cttctggaat ctctgcccga cccagacagt gcttgtgaac 23460 cagccctggt gggctccatg ggttctgggt ctgggaggca aggacttgcc tggggtcatt 23520 ctcattctgc acggcactag catgctggct gcatgaagcc gtatcacaga gacctgtggg 23580 tcctttacat ctgatcatcc gtcatttgta tctgtatctg gggtggttag ttgcaaacaa 23640 ttccacagta gccaaatcag aaagtcactg gctctcgcag gagcgcgatt ggtgtggggc 23700 gagcctgggg gtgtagccag gcaagccott caccctgatg cgcattagcc ttcttatcca 23760 ggaaatgggg ggaggcgtct gggcccaggg aggggagcat gccaagctgg ggatctccac 23820 cggtccagga ttcaggcgcc tctgaccgtt ctctgcccag tgcctcctgt tcagttttac 23880 ttttgtgttt tccattcact tctgcctcta ggccagtgtt tttcaaaata tgtttcctga 23940 gtggaaatga aaaatgttct gtgatcaggc gcagttggga aatcctaggg gagagaaagt 24000 gaactaggct tcccaccgca ggacttctca gagcctttaa aatggtaatt atgctccagg 24060 ccttgtgccc cttacctagg catcctttac tggttgggaa gagacggcag gttacgggtg 24120 agtccgggta atggagttgt gcctaagctg ataacctgac gtcaccaaca ctgttctgtc 24180 accttgcttt gtgtggcttc ttcacagttg tcacatctgg gccgtttgga gtgacctagc 24240 aagtcctttc ttgtctccca ggactttccg gagtagccaa gcagagcctt cggccagttc 24300 ccttgtgggc caggccctgc ccgggagcac aggcaggaga acagctgcct ccccgcctgc 24360 cccagggctt ggtgtcaggg ccatagcccc cagctctgcg gtggagcagc agggacctgc 24420 ctggccatct ccctgttgag ggaagacccg gaggcgcctg tcctgttctg tgtgctccga 24480 ggtgttgaaa ccagctacct cattttcttt ttatcttttg caagtgattt cttatttcct 24540 gctcaccccc aaacgtgccc cctgtatgtt tcctgttcgc ctgcttccct gacctttgaa 24600 atgggtccct gctcgggaaa cttgcctgga cctcagtcaa ttatggtttt cctctgggct 24660 gttgtgtgtg tgtgtgtgtg tgtgtttgag tgtgcaagtg tgtgcattag gattagagag 24720 attcgatggg gggccagggg ccaacaggaa tgggggtggc tgagctgaga ggccaagggc 24780 ggttccaggt tgcattgaga gccgaagctg gtgagtgtga ggcgggcaga tgtgaggtgg 24840 tgtggggagt ggggtgctgt ctgggtgact gggctgggag agggcaggtg ggggccaact 24900 ggaagaggtg gtgttattct gtagcacctg atgtacacag accttggggg tgcagctcag 24960 gctttctctc tccccacccg cccctgaagg ccccactctc ccgccttctg cagccacctt 25020 ccttttgtct gcccctgagc tcctccgctc ttgtggtcgt taagaaaagc ttttttaatc 25080 caagttggtt tgggaagagg caaactgtcc tttcccaaca gtcatatgcc aacctggcca 25140 catctattct ggatttgaag caaaatatgg tatttattca ttattgtcat gcaatgtcag 25200 cagctcgctc attcttgatg gagacagcac ctggaatggg agggatgggt cccggccagc 25260 attggaggtg ctcggcccca gcacccgggc cttgctctgc aggcagccct gtctgcaccg 25320 ggccctgctc tgcaccaggt tccactgggt ggcatcagcc atgcctgccc gaggaggtga 25380 agtgcgggct ctctccagtg aaggtgcaga ggcagggtga gctggcgggt tacggaggac 25440 gtgggcttca cctgggtcca ggaggccagg tcacattcag ccaagtatca tcagctgggt 25500 gtagagacca gggagggttt ttaggggtgg gaatggctgg aggcatgagg tggtcagggt 25560 ggagtctacg ggagacttgg tctactctgg tgcggtggga ttcatgagag agagcccttg 25620 tgggctgagg ccaggctgtg gggtagatgg gagagacctc ctggctagca ggtccttggg 25680 tggatggatg gacggatgga gggatgttgg gggaattggt gggaatagat ggttcagcca 25740 aggtggaaat gggggagtag agctattcct ggggtgcttg aagtgtcagc aagtatccca 25800 ctccagcttg agtttgcaga gctttctcta aaaggcagaa cagtgcttgg ttaaaggaaa 25860 cccaagattt tattattgtt gtaaatgtca agtccctcat ttgaatcttt agacaactgc 25920 agaattgtgt cactgacttg ggtaaaagcc caaggaaaaa atgaaattat gttgccaaaa 25980 ttgcggtcat cgtagctgca tgagggtttg agtggccacg ccaccccagt aggagagacg 26040 cgtagatgtt gaatacactg tgagctgcgt gcaggtaatg aaacgtggat gtggggaagg 26100 tccctggctt catggaactg tctacataaa agcgagctgg gtgtttcctg tttcttctac 26160 cttaagaaat ttccacgaga agctaaggta tggtttgcca agaatgttgt taatggccca 26220 gcaatgaata ttttcagcca cttgtagaca cctgacttca ttcttggcaa acaggtgtat 26280 gattcttgga cttggagaga ctgaactttg ctgtctcaga atggaggaga ccagctcact 26340 tgtactttga tttctccctg gtocctgtca tttagcctga tcagtgcttt ttcaagcatt 26400 tccccttgaa ggggagatag gactttctgg ctagggatgg ggaggcttcc aggcagcctt 26460 aaacattgtc cctgccccac cctaagtatc ttgaagtttc atgttttatc ataaagtctg 26520 tgagaatgtt gcagactccg ttatagtcat ctagttttat ttttttaaat gtggtttgaa 26580 ttttatataa agtatatgga ttatatctgg aactaatatg caaggcctgt atgcaaaaca 26640 taatacaact ttacagaagg acattggaag gactgcagta gatgttcacg gataggaaga 26700 caggagatgg agatggcagt tgcccccgat tgatcagtgg attcagtgca ggggccggca 26760 gtgcgctctc ctccctgttc tttcctccac cccattgcac aaatgttggt gcctggcatt 26820 taaagaagca gaccaggcgc ggtggtcaca cctgtaatcc cagcactttg agaggccaag 26880 gtggatcact tgaggtcagg agttgagacc agcctggcca acatggtgaa accccatctc 26940 tactaaaaat acaaaaatta gctggcgtgg tggtgggcac ctgtaatccc agctatttga 27000 gaagctgagg caggagaatc actgaaccca ggaggcggac gttgcagtga gcctggatcg 27060 tgccactgca ctccagcctg gcaacagagt aagactccat ctcaaacaaa taaataagaa 27120 ataaagaagc agcatgtcga ggtggtgcta tgtagaggtg tcgggggtga ttggcatcca 27180 gcatccggaa gcaaggtggg tagggtgcag aggtgactga cagcagaggc tactggagca 27240 gatgggaagc tggttatgag ctaataagta aattgattga gcaaataagt aaacatatgg 27300 atagtaacac aagccagctt tgcactttgg agaaggtgct tacaaacttg gacgagacag 27360 tacccagaca catagcgaaa ctgtaggtac tgccacgcac acatgcacag aaatagagaa 27420 atagtcatag atgcagtgtg tataaaagtg tatgtaggct aggcacggca gctcatgcct 27480 gtaattccag cacttgggag gctgaggtgg gtggatcact tgaggttagg agtttgagac 27540 cagcgtggcc aattggcgaa actccgtctc tactaaaaat acagaaatta gccggttgtg 27600 ggggcacacc tgaatcccag ctacttggga ggctgagaat cacttgaacc tgggaggcgg 27660 aggttgcagt ggtcgagatc acgccatttt actccagcct gggtgacaga gtgagactct 27720 gtctcaaaaa taaaataaaa taaaataaaa gtgtgagtat acatacacac gtacagttgg 27780 ttcttgttat cttgaaagtt atgctccata aagtcactgg gaaccctgaa ttattgaata 27840 ctgaaccatg ctcctagggg aaacatcggg ctaggttcct gtgagcctca ggtcacaacg 27900 tttttgcaac tgttcgatac ctgacctggc tttttttttt ttttttttaa gacagcgtct 27960 tgctgttcac cccaggctgg aatgcagtgg tacaatcatg ggtcactgca gccttgacct 28020 cctggctcag gccattttcc tgcctcagcc tctccagtag ctgggactat aggcatgcac 28080 cacccacctg tctgatttaa aaaaatatac agatgaggtc ttgccatgtt gcccaggcta 28140 gtccaaactt ctggcctcaa gtgaacctcc caccttggcc tcccaaagtg ttgggattac 28200 agcatgagcc accgcactca gcccataacc ttgtcttatg tgtgtttcta agacacctta 28260 ttaggctgag tgcagtagct cacgcctgta atcccaacag tttgggaggc tgaggtggga 28320 gatcacttga gcccaggagg ttgaggcggc agtgagccaa ggtcacacca ctggactcta 28380 agcctgggtg acagagtgag accctgtctc taaaaagcac cttatttact gtatattgtg 28440 attcattaac attgaattca tggccaacta cgctataact catacctgaa taaagccctc 28500 atgcatattc tctctgtaag gcgtggggca gcctcatgca cctaggagca ctacacgcag 28560 catatgtgca ggggacattt tatacagcaa aattgcccac aaaaagcaca gtgattggaa 28620 agcatggcac tagctagacc gagagaagga cacttgctta catctcgaca gccgagcaag 28680 aagatggggc gttgtggcct cagttgacct cagtttggaa cgtgtgatgg tgatcagttt 28740 tttcacactc tgcaagtcag tgagtgattg cagaagtgct gtgaggttta attgggggat 28800 ataaataaat gttagcaagt aggcgagctc aagtacggaa tctgggaaga ggaagactgt 28860 acgtgtatat cctacctcca tcagcagaga ggcctagaag caatgacccc agtagcagtg 28920 agcacaccag agcccaggtc tgggtttctg aataccattc tccacccaag gagtcagagc 28980 ttgtccacga agaagctggt tctagggctg gggcaaggaa aggtacaacc gagcatgggg 29040 catcttattg tgtaagaaag caaagaagtt ctggaggact ggtggggcct ctgggacaga 29100 agagccagct tagaggggtg ctcactgtcc aaatctagga atatttaacg tcaaaatgtt 29160 gtgtacatgc cttagcgacc aacccacatt taaaacaaat tcctgatgag ggctgtaact 29220 gtagtcccaa gtcattcttt tttgtagctc ataatagccc ataaattact ataccatatg 29280 tttgcattta cctattttta ttttatttta tttttttgag acaagttttg cttttgtcac 29340 ccaggctgga gtgcaatggt acaatctcag ctcatggcaa ccctgcctcc cggtttcaag 29400 ctattttcct gcctcagcct cctgagaagc tgggattaca gcatgcacca ccacatctgg 29460 ctaatttttg tatttttaat agagacagag tttcaccgtg tggcgagact ggtctcgaac 29520 ccctgacctc aggtgatctg cctgccttgg cctcccaaat gctgagatta cagtcgtgag 29580 ccaccgtgcc cggcctgcat ttacctgttt ttaattgtgt aaaatacata taacacttat 29640 cgtcgtaacc atttgtaagt gtgaagttca gtggcataag aacattcatg ttgctggtaa 29700 ccactgccac catccatctc ccaccacaat ttaataatca ttgaaaacag actttcttga 29760 ccacaaacaa tggtgcagca gaagcatcat agatcctgtc tgtcctgctg gctgagctgt 29820 ggcatccttc cttttttata ttgtaaaaac tgtaataaaa tgccataaaa acgccagcgt 29880 tgatctttgt ggaacttgcg gagctgactg tagatgtgtt gggggtataa caggaccagg 29940 gcagcccagg tgtttctgaa ggagacgaat cggagggact cgctccgcca ggcatcaggg 30000 cagattgcaa agccttgttt ttgcacatca tccgatgcgg ggtggacagt tagaccaaga 30060 ggagcccgga agcagaccca ggctttggca caggagcttt ggcatctggc agaactcctg 30120 tccctggggt tggggtgtga ggaggtgtga gggtagtagc gtgaataact gctttgagga 30180 gctgaagcta gaaggtgccc agagctgttt aggtgtcaga gaagttgttt gtgaggcatt 30240 gtgagtagaa ttaagtaact tgagtgctaa ttgcctctgg ggatcaggcc tgggcatgct 30300 caacattcac caagtcatgt ttgttttcaa tgctccagct cttcctcctc caggaagcct 30360 gcccagtcta cccacagcca ggtctcccac agtcagccct tcctcttctt agaagcctgc 30420 ccactctaac cgcagccaga tcttctctgt ctaggaagcc tgcctggttc acccacagcc 30480 gtgtcttctt cctctaggaa gccgcctggt ccacccatag tcaggtctac ctcctccaag 30540 aagcctgcct gatccaccca caccagatct tcctcctcca agaagcctgc ctggtccacc 30600 aacagccagg tgtacccata gcagctcttc ctcctctcgg aaacctgcca actccaccca 30660 cagccagatc ttccccatct gaaagcctgc ctaccccacc tacagccagg tcttcttcct 30720 ccaggaagcc tgcctgggca cctgcagtca gcttatccat ccccaggctc caggcattac 30780 ctgtccatgc attcatccac cttttcttct tgggtggttt tgtgtgtgcg tgtgtgtgtg 30840 tatgtgtgta tatcctgcca actaacctgc aggctccttg actctggagc cctgatgtct 30900 tctgtttctc tgtctctcca tcatgctggc actggacgca ggatcattcc tgactgatta 30960 atctctagct tgtgtcaggc tgcagcttgc tccgatgagc agttggaggc ctagtgtaat 31020 gcttggtgaa tataataagg catggactga aaatgttgct tattttggta tagtagcaaa 31080 ggattgggtt acctgaattg agtcttgttt ggtgtaacca tgtaaataaa cagtgtaaaa 31140 tataggctat tgaatggaag cccagacatc tgttatgaat tctatatata aatattggat 31200 atgcttacat ggttaaaatg agattgttgg cacttgggtt ttcaaactcc tgattctgct 31260 ccgggtagga tgatcacggg tcctgggact caaggcagga ggggccacga gctggccttt 31320 ctctgacacg acttgccaga agtgggcgtt cctgggagtg gcagacatgc acccactaga 31380 gatagatcga atcaccccct cacattctcc taatagtgcc aagaacccac agcagagtgc 31440 ggggtgtctg agtttgtgct gagcaggggt gcctgaatcc cggattgaag aaagtgttct 31500 acgcccatta aaccaactgg gaatccaggc aaaagaagac gttcccaggg gaagccagcc 31560 tgcccgtgtg catggtgcct tttaaacaaa ttatctgcat tcccattggg atgaagttca 31620 cttgcaacat tactcattgg tttttttgct tttgtttagt tttttttttt tttttttttt 31680 tttgagacag aatctcactc tgtcacccag gctggagtat aatggtgcaa tgtcggctca 31740 ctcaacctcc gcttcctggg ttcaagcgat tctcctgcct cagcctoccg agtagctggg 31800 atacaggcat gtgccaccac acctggctaa tttctgtatt tttagtagag atggggtttc 31860 ccgtgttgcc caggctgctc tcaaactcct gacctcagat gatctgcctg ccttggcttc 31920 caaagtgttg gcattacagg tgtaagacac cgcgtcgggc cttttttgtt tttgtttttt 31980 gagacagagt ctccttctgt cacacaggct ggagcgcagt ggcacaatct cagctcacgc 32040 aacctccacc tcccgggttc aagtggttct cctgcctcag tatcccaagt agagctggat 32100 tacagggacc cacccgccac cacacctggc taattttttc ttttttttcc gaaacgaatt 32160 ttggtctgtc gcccaggctg gagtgcagtg gtgcaatctc agctcactgc aaccctgttt 32220 cccaggttca agggattctc ttgcctcagc ctccggagta gctggtatta cagcgccctc 32280 caccatgccc agctaatttg tgtattttta gtagagatgg ggtttcaccg tgtggccagg 32340 ctggtctcga actccttacc tcgtgatccg cccgcctcag cctcccaaag tctgggatta 32400 caggcgtgag ccaccatacc tggccataat attcgttttt atgcatcatt ctttttatgg 32460 cccctctcac ctccgtcagg tggtgaatag actacgtttc atttatccgt catcggttat 32520 ggacatttga gctgtttcca tgttttggct ttgtgaacac tgctgttaca tgcgtgtacc 32580 tgtatgtgta catacatgag tagaggggtt cagttctttt gggtataatg taggagtgga 32640 attactggtc ataggatcat tctatgtgta actttttgag gcactacagg ctgttttcca 32700 cagcagccag aggtgtcttt aaaagcagtt gtcaactggg cttggggctc acacctgtaa 32760 tcccagcact ttgggatgcc aaggcgggcg gatcacctga ggtcggagtt cgagaccagc 32820 ctgaccaaca tggcaaaacc ccgtctctac taaaaataca aaatagctgg gcgtggtggc 32880 gtgtgcctgt aatcccagct actcaggaga ctgaggtggg agatcgcttg aaactgggag 32940 gccgaggttg cagtgagctg agattgcgcc atcatactcc acctgggcaa ctagagtgaa 33000 actccgtctc aaaataaaaa taaaaataaa aataaaagga tgatcacttc ctgtttcatg 33060 aatgaggaaa ctgaggctct gggagatggg aaatcctgcc ggaatctcac agctggaggc 33120 caggccgggc tttgaatcca ggcaactgag tctgagtgat ggtgtgtgct ttgtgttgga 33180 gctggcccag ggctggatga aggcaacatt taattaagaa aaccactacc ccctcccggc 33240 tgttacctct tgagcgcttt tctatgaagc atcctgttaa gcctcgcact ctgtgatgtg 33300 gaggtgcagt aattatcccc atttcacaga caggagttga ggtcagaggg gttgagtgat 33360 tgtcatgggc caggtctcag ccaggcttgc taacctggag tctgccgtct gctctgaagt 33420 ggtcactctc agctggagag ctgacctggc cctttgcctt tgtgatgtac ggtcctgaaa 33480 aaaatatttg cagaaatagc ttcataggaa caatatggaa tttggaatta aaaaatatat 33540 taaaaactat atatttacca gtattacaat aattacccag agacttgtct ccctaatgag 33600 gccaccttta ctttttcaat ctttgtctcc ctggtgcttt ctcataactg ccattcattc 33660 tagtagaaat catggttcac ggttatgctg gtgtgtggtt tttggtgttg acatgtcgaa 33720 cgttttgttg ttaccgcagt cattttgtac tagttaattg gtgctacctt tccacggaga 33780 caatagtcta gttacccctg ccgctgggat tgttcttttt tttttttttt tttttttttt 33840 tttttttgct attacaaata aggcctagca aatattgtga ctcagacgtt ttccttcttt 33900 ctggtgtttc ttgggacaga ctcctcaggg gtgatccctg gggagagggc gtaattattt 33960 tatgttcatg atgcggcagt caccccgtgt ttctgaaagg tttgttctgc actctgggct 34020 gccagttgac attcggtttt tcaggtgatc tggtgggtcc tggggtgtga tggtggccgg 34080 gcccagctgc ttcagccctc agctgtccat cccccaccca cacccagaac tgaggctcca 34140 aggtgcagcc tcaggtgtct gcaccctgtg catccctcat cgccccaggt ctgttgccct 34200 cccttctcct ccttctcaaa tacgctgccc agaggtcagg ctagaggtca gcaggtccat 34260 cactggatgg aatgacctgg gcaggccaag gtatctgggg gctgtgtagc tgtgacccct 34320 gagcttcagg gggctgtgaa cgagagacct tgggcacatg ggcacatgac gtggtgggaa 34380 ggcgcccaga ggaccagacc cgccatgcta cccccacact ctgctccagt gtgctcccac 34440 cccaggacct ttgcccggcc tgccggctcc ttctttccca gcaaggcctg ctctgtctca 34500 ggtagcatgc agccgccgac ccacttctca tgtagcatgc agccccccga cccacttcac 34560 cctgcaccat ttcctgatct gcagcgttta tgatgtaaca ttactaaggt gtccttattg 34620 gctatgtgta ttgttgttta ttaccaccca cgtgaatacg gagccattca ggccgtgtcc 34680 tgggtgtctg gggggccagc tggtgctggg cactcgcctg ctggaggagt gagtgcccat 34740 ggccagcccc tctggtgcct gggctgcgtc tcctccttag tgtgctgcct ctacaggctt 34800 ttctcctgaa tgtcctcttt gctttttttt ttttttttaa gctttaaaag aagtttttgt 34860 agagatgcgt cttgctgtgt tgcccaggct ggtcttgaac tcctggcctg agatgatcct 34920 ctctcctcga aagtgctggg attataggtg tgagctacgg agccggccct tcccttctac 34980 tctgctatct gctgttctct ctccctcccg tcgggttctg ctcctgccac gttctcccct 35040 ctccccccaa aggctgggtt ttctttgtca gggctccttt cccctttgga gaagaggggg 35100 ctgtaggcct tggtgcgagg ccctccagtg acaggatccc ccatcaccca gagttccaca 35160 ggcctggtag ggaggagggg gagcagaaga ggaggtgcca tctttgcctg ctggggaagg 35220 gcagggccac ccacacagag ctctcccatt tgctgtggac cctggggcca ctgccagttc 35280 ctccaaagga aagccagctc cccaggtggt gggagagtga tgtggcttcc tcttaaactt 35340 agaattgagt gtgtggttgc ttctaagtgc cttagaagcc ggagcggctc ctggaaagag 35400 ctgcctgcca cagcgggcct taccctggct gtgcccacag atgtccctgg ggcctgccgt 35460 cctgcccggc tctcctggcc tcccccggtg tgggttggga aaagcacagc aaattaaaaa 35520 cacctccatc tctggccttt gaagaatgca tctgaacagc cgagagtgta aaccgtgtga 35580 aatgtggtct ttccagtttg gggagaagca gggcagagct ggggcttttg tacccaggtt 35640 tccaagagct cctgcctccc tcggctgggc tggccagggc cccccgctgg gacctcagct 35700 gtaataggga aggttttact gggttgctgg ccactgtgga ctgcccctaa gggcggtatg 35760 cctgccttta cccgggttcc cctcctgcct ggaagataca gcccatggga ggctgttgtc 35820 tgtgggatcc tccagcatca gagacactgg ggccagcgtc tgcctggtga gggcaggcct 35880 ggcaggcccg gtcccccacc tgcttgagca cccacggtgg tgggggctcg cgcctcccga 35940 gacaatctat gtcattgttg tccaaggaag ctaatttaga gtagaaagtt cgtgtccagt 36000 cccactctgt gcgtgtgtta gcaggggact ctcgggccgg agctgggtca ccctggtagg 36060 gggacttcat ggggcctggg cgacagcact gtgtatttgt gtgtgtgttg tttgtgtgtg 36120 tgtgtgtctg aggaggtgga ccagtttctc aaaaggcctg tgaccccaga accaaggaat 36180 ttcagcctgg gtggatcaca ccttcactgg tgagtgggac aagctggggc cctcgccaca 36240 ggagcagcca gggcatgggg cacagttggc ctcattcaca aaatggagta taagtgatcc 36300 ctgctctggc ggccaggacg atgagtggga acacaccgtg tggggctgcc tggcctgggt 36360 gtgccgcggg tgtccttgtt ggtgatggtt ccacctgctt gtgcaccagt gccctctggg 36420 tctcacacac aactctcttc ccagcgaagg cccctcctgc cccaggcctc agtgctgctt 36480 ccgtctcgga aggccccagg agctcctgca tcctgggcgt gttcctgtgt gcctgcagac 36540 cccctcgcgg ctgccatctc atcctttggt gcacctgttg ccagacctcc tggtagcggg 36600 tgctgcactc ccctgaatgt gccggggcct gggggcagga cctgggctcc tccctcactg 36660 agtggaggga actcagtgtc ttggagttgg ggtgcctgag gctgggtggt gcaggtgaaa 36720 tgcagacctc tcagctggtg ttccagagca gctgcctccc ccgcccgagg gacttcaccc 36780 gcagcccagt caggggtggc gcctgggtgc atcgccgcag gctgggtagg ggtggagcct 36840 gggtggccct gcctgtgagc tgcatagttg tcgccttgac cctgagtttt cttcgttatc 36900 tgtttggacc tgtttggggc aggcagggga tgagtctgaa gataaatgcc ttagctgtga 36960 ccatctcctt ttgtgagagg tcaatgtcca gttcgctgca gttataacat cccatttttt 37020 gatttctttt tattttttcc tttttctttt tggatggagt ctcgctctgt cacccaggct 37080 ggagtgcaat ggggtgacct cagctcactg cacctccact tctcgggttc aagtgattct 37140 cctgcctcag cctcctgact agcaggggtt caggcgtgag ccaccacgcc cagctaattt 37200 ttgtattttt agtagaggca aggtttcgta tgttggccag gctggtctca aactcctggc 37260 cttaagtgat ctgcccgcct cggcctccaa agtgctgaga tgacaggtgt gagccaccgt 37320 gcccggccca gaactcttta attcccactg aaacttgccg ccttaagcag gtccccagtc 37380 tccctcccct agtccctggt cccaccttct gotttctgtc tcaatgaatt tgcctaccgt 37440 aagtacctca tataaattga atcataagta tttgtctttt tatatctggc ttatttcact 37500 tagcataaca ttcttaagtt tcatcatgtt gtagcatgtg tcagaatctc tctctttttt 37560 tttttttttt tttttttttt tttcagacag agtctcgctc tgtcatctag actggagttc 37620 agtggcacga tctcggttca ctcaacatct gcctcctggg tccaagcaat tctcctgcct 37680 cagcctcctt agcagctgga atacaggcgc gtgccaccat gccttgctaa tttttgtatt 37740 ttttgtggag gcagggtttc ccatcttggc caggctggtc ttgaattcct gacttcaggt 37800 gatccacccg cctcagcctc ccaagtgctg ggattacagg catgagccac cgtgcctgac 37860 cagaatcttt ttccttttga gactgaatag tactccattg tgtggatgga gcagattttg 37920 ccccgctatt catccctagt agagggacgc ttgggttgct tccatgtttg tttgtttttt 37980 tgtttttgtt ttgctgtttt tgagacagag tctcgctgtg tcacccaggc tggaatgcag 38040 tggcgcaatc ttggccactg caacctccac ctccagggtt caagtgattc tcctgcctca 38100 gacttgtgag tagcgggatt acaggtgccc gtcactacgc ccagctaatt tttgtatttt 38160 agtagagacg gggttcacca tgttggccag gctggtctcg aactcctgac ctcaggtgat 38220 ccacccgcct cacctcccaa agtgctggga ttacaggcgt gagccaccat gcctggctgc 38280 ctccatgttt tgctgttggg aaggatgctg ctgtgatcca aggtgtatgc atatctgatt 38340 gtgtccctgt ttcagttctt ttgggtatat aacccaaagc gaaattgctg ggtcatatgg 38400 taattctgtt ttaagttttt ggggaactgc catgctgttt tccatagtag ctgcaccatt 38460 tcacattttg ccagtggtgc acaagggttc cagttgctcc agatcctcac caacacttgc 38520 tattttgttt tttgatagta gccgtcctaa ttggtgcaag atggtatctt attgtagttt 38580 tgatttcatt tccctgatga ttagggatat attaagcctg ttttgatgtg tttattggcc 38640 atttaatgtc atctttggag aaatgtctgt tcaagttgtt tgcccatttt tgagttggct 38700 tagtgttttc tcattgttga gttttaggag ttctctgtat ttcatggata ttaatctctt 38760 agtgatctat gatttggaaa tattttctct cattctgtgg gttgcctttt tactctctcg 38820 atgtgtcttt tgatgcacaa aatctttagc ttcccatgaa gtcccgtttg tctttatttg 38880 tgcctatgcc ttcctgttgt ttgactttca cagtgtccct cgttgccaca aagaactgta 38940 acctaagatg atgacagcac gggtggggcg gcggaggcgc cgctgtcatt ttcctggccc 39000 aggtcctctg tgtgtcctcc catcctgtgg agcatgtctc ctgggaatgg gaggggccgg 39060 atttgagcca gtgcttgtct tggcagggag gcctgtgctc ggaaccatct accccacgcg 39120 ctggggtctc ctgggccatg ctctggccct ttgtgttccc agctaccctc atagagctgc 39180 aaatctttcc cctgctgaaa tgaaaccaac tgaactaact acaggattca gttcttgatt 39240 gtcattggct gagttgagtt tgttttggct ttctctttct tggtgaaggt gggatgtggg 39300 gttggctggg ctcccccatc tgcgcaggag gacccagggg tctgcagttt tcagaggaat 39360 gtcagctgtt tcaagccaag gcttcagatg ttttttgggg gtgtttgtgg ccgcccagcc 39420 tagccctgct gacagcagac acggactgat ggagctccct ggaggccctt acctcctcct 39480 gtccacatct tgtgttcact cctcatgtgg cttcttagtc cctctgagtc gtgttggggg 39540 ttgctggacc ctcctggtcc gacgtctgag gtgtctggtg gggtgatggc tgaaggcctc 39600 tcctgatttc tcattgagcc cgttgtggga atgagaccgt tgtctgtgga tgaggcttct 39660 tgcacaggca gaaggggctg agggctgcgg tgcagaggga ggtgaggagc cagcctggcc 39720 gcaggcagat caggaatgct tggggtgggg tggtggagag aagtgtggtg aggccagagg 39780 ccaaggcctt ggaggccagg ctagggggtc tgaccttgtt ctgcaggcac tggcacaggg 39840 agctgtggaa ggtgtctgag ccaaggggtg gcattccaga gtgaccttta aatgtaggaa 39900 tgtccagaag cagggtggga gaaacatgga atacaggggt ggagggaagc tgatgccacg 39960 gccaaggaaa cgggcctgag cttggacagt ggtcaaagac tttaagggaa tcttgaggct 40020 ctgtctggcc tgggctctga acccctcaaa aaatgtggcc cgtggctggg tctgtagcga 40080 gcagcatggc cagtgctgtg cctgcatgtc cccgtcccct tgtcaggcca acaaagggga 40140 tgtggcttct ctgcagaaca ggacagggcc cctgtagccc tggaggacga tgtgggaggt 40200 tttgggcatg gcaggaaggg tcacccatat ctgggggaca gacgtaacag ttggtaaaca 40260 aacaggtgct gtcaccgaat gtgggaagaa ggctgttgct gcgctgcagg agcctctgaa 40320 tgatgcgggc cggggctgcc caggcaactt cctgacacgc cttaggggtg ggaggaagga 40380 actggaggtc ttgggcatgg gcagggcagt accagagtgc tctgggcata gtgctccatc 40440 ccagggctgt gtatcttgct ggcttagcca gtggcctcac ggtttgcttc tgccccacag 40500 cctcgccgct cctgctattt gccaaccgcc gggcgtacgg ctggtggacg ccggcggagt 40560 caagctggag tccaccatcg tggtcagcgg ccggaggatg cggccgcagt ggacttccag 40620 ttttccaagg gagccgtgta ctggacagac ggagcgagga ggccatcaag cagacctacc 40680 tgaaccagac gggggccgcc gtgcagaacg ggtcatctcc ggcctggtct ctcccgacgg 40740 cctcgcctgc gactgggtgg gcaagaagcg tactggacgg actcagagac caaccgcatc 40800 gaggtggcca acctcaatgg cacatcccga aggtgctctt ctggcaggac cttgaccagc 40860 cgagggccat cgccttggac cccgctccgg gtaaaccctg ctgcgactcc acctgggtcc 40920 agggggcggg gagtgtcacc atctcttctc gaatttgcat gagcccaagt tgtttttcag 40980 aaaaagggtg tgactctgaa aatgacccgt gggggggttg gctcaggcct gtaaccccag 41040 cactcggtgt gactctgaaa atgacccgtg ggggtgttgg ctcaggcctg taaccccagc 41100 actcggtgtc actcttaaaa tgacccgtgg gggggttggc tcaggcctgt aaccccagca 41160 ctcggtgcga ctctgaaaat gactcgtggg ggggttggtt caggcctgta accccagcac 41220 tcggtgtcac tcttaaaatg acccgtgggg gggttggctc aggcctgtaa ccccagcact 41280 cggtgcgact ctgaaaatga cccgtggggg tgttggctca ggcctgtaat cccagcactc 41340 tgggaggcca aggcgggcaa tcacctgagt ccaggaattc aagaccacac tgggcaacat 41400 ggtgagaccc catttctaaa agtatacaaa aatgaatcgg gtgtgatggt atgcacctgt 41460 aatcccagct tcttgggggc tgaggtagga ggatcatttg agcctgggag atcgaggctg 41520 cagtgagctg tgatccacca ctgcactcca gcctgggcga caaagtgagg agatcctgtc 41580 tcaaaaaaaa aaaaggctca gctttcaaga tttgttattg ttgaaggaat tacttcccct 41640 tgagattcca tagtatgttc cttttttttt tttttttttt taattgagat ggagtctccc 41700 ttgttgccca ggcggagtgc agtggcacaa tctcggctca ctgcaacctt cgcctcccgg 41760 gttcaagtga tttcctqcct cagcttccca agtagctggg attacaggcg cccaccacca 41820 cgcccagcta attttgtagt tttggtacag atggggtttc accatggtgt ctaggctggt 41880 ctcgaactcc gacctcaggt gatccaccca cctcggcctc ccaaagtgct gggattacag 41940 acgtgaaccc cgtgcctggc ccatagttat gttccttttt aaaacttgca tgtctgaggc 42000 aaccgatggg ttggccatgg gtttgaatgg ttaaacacat ctttgctgtg tgtatggtgg 42060 gcggcctgga agtgcggacg ctcaggcagg tggaatttgc accttctcct ggctttctaa 42120 ttgcatggct gaaaaagtgc agctccttgt 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popowobbo 008CP oppobqbes,b -e6qopeqopo oppEq.boqop beob2b2po6 beoq55b-qo opq5P544;4 of,Lep eqbeeepobo qeq4q2bbl. boepeb.6.6q5 bbbeobeope q5E5b4-2q6P pq545-45.43-4 taaagcaagg cgtctgccgc aggcacgcgg gagccttccc tggctggctg ccagcacctt 47160 ggagtcccag gctgccagga aaagttcacc cacacccggg tttgctggcg aagggtgagt 47220 catatgatgg ccgggctcgg gccctcagca gacaccaagg tgttcccaga gcagccgctc 47280 agcgcctgta acctggaaca ggccagcctt tcggggccca gttttctcat ctgcctaatg 47340 ggaatagcaa ttcccacctt ccctttgttg gttgggtctc actagatgca caggagacag 47400 cagcttgaga gggactgttt ggagagctgt tccatggaca cccctcttac cctgtcccca 47460 cggggccgga ggagcagggg cttggtgata gcagcgggcg cagtcagcct ctgcagggaa 47520 gagggcatgt ttggttcgag gctcctatgc cctcttcttg ttgatcttgt cacagcccct 47580 ctggaaggtg gagatggtac tcgctcagga acgtaccact caaggaagca tggccccctg 47640 gatggggtgg cccttggtgc acctgaggct ccgaggctgc agagcaccat ggtgggggag 47700 gaggcggctg tgtgtctgtc atttgcctct ttgctgaatg gagaccccca gagggcaaag 47760 cggggcttgt tctccctgtg tcccgggatc ctctcatgcc tggcttgggc gagctgcctg 47820 tttctaaatc acttgctaag gctgagggga tggggtttgc cgcccacccc aggaagaagg 47880 gagcaaggga gtcagcacca ttttacaaga ccaagagtgg gaggaggctc ctcagaggac 47940 attctgggca ctgtcccctt tctctgcgtg aagggtggac aaaacacaat aggtctgcca 48000 gcccttgtgt cctgtggctc atcccactgg ctgggatggg aactgagtcc tccaagctgg 48060 tgtggttccc ctctggtctc cgctggagtc acgcccagcc tctgggcaca caccctgtgg 48120 tcacctccaa acagggcaca ctggcactgg tgggggtggg acctgccatc ccagacctgg 48180 tgtctgctca ctttgtcttg gttattggcc agagatcacg taagggcgcc ctgaggatgt 48240 gcttgtttct catggatggg tgtgcttgtc tcttgggaac atggagaagc aaagccacgt 48300 cgcccacaga cctacccagg acagctgcag ctgcaggttc agggtccatc ccagccatgg 48360 gttttattct tttttttttg gacggagtgt tgctgtctcc caggctgaga gtgcagtggt 48420 gtgatcttgg ctcactgcag ctccgcctcc cgggttcacg ccattctcct gcctcagcct 48480 cccgagtagc tgtgactaag gtgtccgcca ccatgcccgg ctaatttttt tttttgtact 48540 tttagtagag acggggttca ccgtgttagc caggatggtc tcgatctcct gacctcgtga 48600 tccgcccatc tcggccccca aagcgctgga attacaggca tgagccaccg cacccagcct 48660 tttttttttt tttttaggca gggtctcact ctgtcatcca ggctggagtg cagtggtaca 48720 gtcacagctc actgagcctc gacctcccag ggctgaaggg atcctcccac gtcagcctcc 48780 caagtagctg ggatacaaga gtgtgccacc atgcccagct aacttttttt taatttttat 48840 tttttgtaga gggggatttt gccatgttgc ccagggtggc tcaagtgacc cacccacctc 48900 agcctcccga atactggaat tacaggtgca agccatcgtg cctggccatg ttttgttgtt 48960 tttaaataga ttaatttttt caaacagttg taggttcaca gcaaaattga tgagcagcag 49020 gtactgagtc ctatacatcc ctgtcctcac acccacacag ccttcccaac tgtcagcatc 49080 ctgtgcaggt ggtacatttg ttacaactga tgaaagctgg ctgacgcacc atcacccaaa 49140 atccacgtta cacgagggtt cgcccttgat ttgtacattc ttggtttaga cagatgagta 49200 aggacagcac ccaccattcc atgtcataca ggatagttcc actgccctga ttttctgtgc 49260 tccaccattc atccctctcc tctccaactc ctggcaacca ctgatgcttt actgtctctg 49320 tgtattgctt tttccagagt gtttagaact ggactcatac agattggctc tttcacctac 49380 taaatgcatt taagtttcct ccatgtcttt tcatggcttg atagatcatt tcttttcttt 49440 tctttttttt tttttgagat ggagtctcgc tctgtcgccc aggatggagt gcaatggtgc 49500 gtttctgctc actgcaacct ccccctcccg ggttcaaatg attctcctgc ctcagcctcc 49560 aagtagctgg gactacaggt gctcactacc acgcctggct aatgttttgt atttttagtg 49620 ggacggggtt tcactgtgtt agccaggatg gtcttgatct cccgacctcg tgatccaccg 49680 ccttggcctc ccaaagtgct gggattagag gtgtgagcca ctgggcccag ccgatagtca 49740 tttctttata ccactaaata atattccatc ctgagtgttt tgaattgcct tttagagttc 49800 atttacagca ttttcatggt agcaaaaaaa tcagaaataa cctgaagttc tttaaaaact 49860 tacagcagag tacactaggc aatcatcaaa agaacaagga atctttctat ccacagaagg 49920 gaaggtgccc agaatttact gttaactgag aacaagttgg aaatagtata tttgattgcc 49980 cagcttaagg caggaatacc tgaaaccata cctgttggtt atttccgatg gggagatttt 50040 agggcaagtt cactgtctgt tgtttcatgt ctgcatctat gcagacaaaa aaaaaaacag 50100 atctgtgtta gctgcttctc ttgccctgcc cccgtcacag gtacatgtac ggacagactg 50160 gggtgagacg ccccggattg agcgggcagg gatggatggc agcacccgga gatcattgtg 50220 gactcggaca tttactggcc caatggactg accatcgacc tggaggagag aagctctact 50280 gggctgacgc 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tgctctccct ccccagttcc gtgtgccctg gggtcagtga tagaagacac ggccctggac 67680 cccaagtctg ctgagctgac acctcgggct gccgctcacc tgcagagaga catagaaggc 67740 tccgactccc ttcctggccc ccactctgtt tttctacctt ttaccgccta tccaatggaa 67800 atgcacgatt tgtttctccc tgtgcacatc tgagtgtgga cctccctgcc ctgctcgtgc 67860 tgtgcccacc acctggagca cccttcccct gccccctgcc cccggccacg cgcccctcca 67920 tccagacccc actcctgcac acggctcctc cgcccgtgcg cagccctcga gagtgtggca 67980 ggtgcaccag gctctgctct agggagcttc ttcctcttcc tgtgtccacg ggaccaacat 68040 cgggacccag gaaacaggct gggagagttc ggtaacacct tcaagaggtt tgagagctga 68100 ggttctttgg tcttcagtgg agctggcagt gactttcttg acttttcaag agaagccgcc 68160 cgtctctgtg ccacctctgg ggatgtgatt gaacggaaat cagacatccg agttccagcc 68220 tcagccctct gctgtgtggc tgtgaaatgt aggccctgtg tgcttgctga cctgggaggg 68280 tcgaaaggac ggtgtctggg gaaggatgca taagttgtag aggccctgca cttgtgatag 68340 gtggggccgc gtgaactgct gatagccatc ttctgtcagt tgggcagtgg cattgtcaca 68400 tggttccatt ctaatccgtt attttggcta ctgccactga gcggggtggg tgacaaaagt 68460 aacgtttctt gggggccact gcagcggtca tggtcctgac cctataccca ggcacgcgtc 68520 ctgggagctg tgtgaggggt cgtccgtggc tggccctgtt cttttttttt tttttttttt 68580 ttttaattga gacagagtct ctctctgtca cctaggcgga gtgcaatggc gcgatctccg 68640 ctaactgcaa cctctgcctg ctgagctcaa gcgatttcct gcctcagcct cccgagtagc 68700 ttggactata ggcacccgcc accacactcg gcttattttt gtatttttag tagagatggg 68760 gtttcaccgt gttagccagg atggtctcga tctctgacca tctcgtgatc cacccacctt 68820 ggcctcccaa agtgctggga ttacaggcat gagcaccatg cctggccggc cctacttctt 68880 aaatgggcct gaggcacatg gtgccgagag ctgctgaggt ctatggagga agggcgcaga 68940 tgggatctgg gcctggcgtc ctggccggcc ccaaggcctt ctccacagag tttccatgta 69000 taccggggtg gccttgcgga ggggcgcagc atgcgtcagg ctggagccag ctgcagaggc 69060 cacagacagg gtgtcatgag cagtacaaga accgctgctg tccattgaac acctactgtg 69120 tgcctgggtt cagaaaggca ccctgtgcgg cttttaaaga attaggccgc ctgcctaaag 69180 gggggagtgt ggccttcttt ttcatttagt caccaactgt tttatacatc cacgccccta 69240 aattcttcag ttttaggcaa agatgaaggg ctgcccaggc gtcatttgct caacaaaacc 69300 acacttcact tgtgaggctg tgttcctcac cagggtcccc agcaaggggg tgtgagtgtt 69360 tagtaccaca gggagggctg gcgcgtggct cacgcctgta atcccagcac tttaggaact 69420 cctcacctga ggtcaggagt tcggaccagc ctggccaaca tggtgaaatc ccatccccac 69480 tgcctgcctg gggagtggcc atcagccatg ggcctgaggt tgtggtgggg catgggggca 69540 gaggcaggca gtggggggcc aaggaggggc tggctggcac cgagggatgg gagaggaagg 69600 gacccgcctg caggtccctt ctgaggccgg cactgacttg gtcactctct ggctgccctg 69660 accccaggca gagcagcgat ttcctgtttt agagctgagc agacagagcc cctgactgca 69720 ggccaaggtg cctgccagtg ctcctggagg gccatagcct ctctgtgctt gctggaaggt 69780 cccaggcacc gtgcagggac agtggccggc ctcaggttcc agcagagcca gcatcgggcc 69840 cagccacttc ccttgtcttt gtgaccctat ggtcacttgg cacaggatcc cgggtcaaat 69900 gctgcggttg cggcattgcc ccaccactta cccctggggg cagcggagaa acttaatcaa 69960 ttgctaaaca acaaaataat ctggccgcct gccagctggg aagccactgt ggccaggctg 70020 tttatggcct tggatctgcg cagtggacag tggcctgcac cgtgaccccg ttcatcctgc 70080 gtgccccagg ccaggaggtg gctcaagccc tctgcctcct gtaagggcac ctgagaagga 70140 ggccctggag cgggagcaga gctgggggtg ggcgtccggg cagcagaggc cgattctcag 70200 ctttccctgg tctcagcttt ccccggatct cagctttctg ctacccgtgt gaaaagaagc 70260 caggagaacc agctatcctg ggttggtgcc ggctgtggtg ggaggcctgc ggtgggagcc 70320 tccgggggca ctggaccttt cctgggtggc ctgtggcctg ggagctgcac ttggttcggt 70380 gcagggagtt gtgacatcca ctctgtctgc agggatggcc ggggccctgc ggctgggtga 70440 tgaggtggat ggaggtgtcc ggggctgccc tgcctccttt tgccaaaata acaaaaatta 70500 tcttgttgtt gtgaaaaaac ctgttttccc acattggggc atggagggta ttaactgtga 70560 tgacttctga gttcctgcac actggtgacc cattggcagg gtctcctcct ggctctggca 70620 gggtggctca ggccgctqgg tgacggtgtg ctggccagat agttcctggg gctgcaggtg 70680 gctctttcgc cccatccctc ccatcccctt tcattcttcc tgtcaacaca tctcagaccc 70740 tgacaccgaa tgagccgtcg gtacccacac cccagggcaa ttcagtggag gggtaggtgg 70800 tcgttccccc acgttgcccc aggaagagga ccctgtcccc ggcatcctga cccacctcct 70860 tagagaccga gagcctctaa ggataaaccc attcacccgt gtttcagagg ctttttttcc 70920 tcttataaaa taacatttat acgttcgctg tagcaaggaa aacattataa aaaataggaa 70980 gaaaatagaa attacccata attttgccac acagacttag ttgtgtccat gtatctgtgc 71040 accttttttc tgtttacgga tcaaaatcga cttttagggt caggcgcggt ggctccacct 71100 gtaatcccaa cactttggga ggctggagtt ggggttgggg ggtggatcac tgaaatcagg 71160 agtttgagac cagcctggcc aacatggcga aactccatct ctactaaaaa taaagattag 71220 ccaggcgtgg tggtgggtgc ctctaatccc agctactccg gaggctgagg cagagaatcg 71280 cttgaaccca ggagacagag gttgcagtga gccaggatca cgccactgca cccagcctgg 71340 caacagagcg agactctgtc tcaaaaaaaa aaataaaaat aaaataaata atacataaat 71400 tgacttttag gagattggtt caaacaatgt gtgtaatgtt gtgtctgagg tttttcattt 71460 atcgttcatg caaattccga catcattcac tcttctccag agtgtgcttt ttcctgcctg 71520 tgtcatcacc cgtcaccttg aatgccctcg tttaggtaaa ataagtaatt ttattcaaaa 71580 atatttgagg acatttgggt tgtctccagg ttcttggtct tgagtttgct gttcttgtgg 71640 agccatggtg gtgtctggtt gcaggaacct ccatgcgttc cagctctgct tctgcctgtg 71700 ttcttagaga ggaaatgctg gggtccgcgg ttcccgggct gctgccagga agcctgcggt 71760 gctttacggc ccttccagaa gcgggagatg cccccactta agttcagaca ggcctttcca 71820 cctcactggc agctctgagc ggctcccttc tatttgcaga tgctgagaag ttaccaattt 71880 ccacgtttac tgactgctgt ttctcctgtt aatttgtatt ttagtcttcg ctaatttatt 71940 gctagggttt tggtgttgtc cctattgact tgtatgcctt taatttttta aacaacatta 72000 atagacttca tttttttaga gcagttttaa gtttacagga aattaaggga caagtacaga 72060 gagttccttc cacctgctgt cctcctctcc tcctcccccc ttccctcctt cccctattgt 72120 aactttcttt ctgatattat aaaagtcact catggctggc gtggtggctc acgcctgtaa 72180 tcccagcacg ttgggaggca gaggcaggca gatcactgag gtcaggagtt ccagaccagc 72240 ctggccaaca tggtgaaacc ccgtctctac taaaacacaa aaagttagcc aggcgtggtg 72300 gcgggcacct gtaatcccag ctactcagga ggctaggcag gagaatggcg tgaacctggg 72360 aggcagaggt tacagtgagt cgagatcgcg ccatgcactc cagcctgggc aataagagtg 72420 aagcttcgtc tcaaaaacaa agtcacacac gctcttgtac gagggtcatt tggccgaggg 72480 gccagatggc tcaccatcta gttgggacag gcatgagctc ggaatgcttt ttacatattt 72540 acatggttga gaagaaaatc aggagaataa gttttgggac atgggaaaat gacatggaat 72600 ttgcatttta gtgtccataa atgaagtttg tttgctccca gctgtgttga ctgaggcagg 72660 ctggcttcct acagctgcgg cagagctggg aggcgggaag gagaccgtgc aggccgcagc 72720 accgaaaata tttgctctct ggcccttcca gagtgcttgc cgacctctgt ccgacagcta 72780 gaaggaagga taggacccgt ccgacgtaac cactgttgac atttgagcgc gtttccttcc 72840 cggcttttgt gtgagagtgg cagtcgtttg cttttgtggt cgggatctgc tgcacgcacg 72900 gcgggctgtt tgcatgaggc ttccggagga tagggctggg ctcggagctg cacgcagtgg 72960 ggcgtgtcct gcatgcagtg gggctcagaa gagagctgtg gtgggcgggg cagtgccaac 73020 gctggtgggt gccaggcctc cagctcagat cagccccggc gacaggtttg ggccaccctc 73080 tctctggcct ctgtgcagtg gccaggccgt ctgctctgcc tggcacactt gcctctgtcc 73140 ttccactgaa gcgctcctct accctctgct cccggctggg tacgttgaat tgtgtccctc 73200 aaggagatat gctaaaggtt aaccccagga acctgtgtat gtgatctaat ttggaaacag 73260 ggtcttggct gatgtaataa gcgaggatga ggtcacccta gagtaggggg cctatatcca 73320 cggtgctggt gtcctcagag agcaggtgag cagacactga cactcagggg tgaaggctgc 73380 atggagtcag aacaggctta gtgcgatggc ggccacaagc caaggaactc caagtatttc 73440 ctgcaacacc agaagtggaa gatgccagga aggatcctgc cctggagcct tcggagggag 73500 tctgtccctg cagagtcttg acttttgatt gcagggatgc atgtcttagg gtgtgtgggg 73560 gggtgcattt ctgtgttaga agccacctgg ttggtggcga tgtgtcacgg gagccctctg 73620 caggttctgc gttccatgtg gtcggggaca gaggtgggca gggagggagg gtgtcgagct 73680 ggacatgtcc agacgtcggc catcccttgg gatggctttt ttgttttgag gataaggctg 73740 cctgccagga gctgtgccct gcctggccct tgccccaagc ccctggcctg tgcttggcct 73800 cgcggaagga tgtcgccctt ctctcctgca tgcgtgcagg gaggaagggg agaggtcagc 73860 agcccgccgg aggaggctcg ggcgagggga aggtttcact ttcaggcaat gttgtggggc 73920 tgtttaacaa ccccaaagaa aaccatttgg ccaaactgtt agtttccaaa cattttactt 73980 ccttgggttt aaataaattc ctaccaagac tctgtagctg gtcccaggga aggagttggc 74040 ctctctcttt atagcccggc acagtcagtc ccctgcacct gcccctccca accccaggcc 74100 tgctccccgt ggccatggct gctgcccgga cctctctaca cacagaacct cctggaggcc 74160 agcgtgggca ccagccttgg cagggctgtg gcggagccca ggctgctggt actctctctg 74220 cactgctccc tgctggcctg gctggacaga gtccccacca ccactggggt cacctctgtg 74280 cggtcacagc tcactcagac cttcaggcaa atgggttgga tcctgcctct ctcccaggtg 74340 ctcagtctct gcaaaactca aaaacctcag aggccttgca gcctgagggg tgtcagagaa 74400 cctccttcga atcagtaaac acctacagat tcaccccagc agtgaaagga ctgcttcgca 74460 cagaggtttg atttactcct aagtaattgg aagggatgcc gagaataggt tcctcatgtg 74520 ggactagagg ccctctgctg acctagttaa cagagggcta gggctgggtg tgctcacccc 74580 tgaaggttct aggcccattt gggacacccc gccagaacct gccacaacct gccattggtg 74640 acagctacct aaatcccaga ggctcttgag ctggagagca gacctctcaa tctcgcaggc 74700 cccccacaca gaccccataa ccctagtctg ccttcacagt acagttcgtg gcttgtgttc 74760 acggatggtg ttgttcacct aaggtctctg ccctgtgacc ccaagggcgt ccgagggcag 74820 attccaagtc tgtttcgtcc acccctcctt ccctagcagc gggtccaggg ctggcctgaa 74880 ctagcttccc acagagatac tggtgggatg atgaaggcag ccaggcggca gtgaaaaacg 74940 cacttcctgc atgtgctggc tcctgggatt gaagtgtttg aggaagcaag tgaagtgagc 75000 tttcctcttg cggctgtgtg tccttgggcc gggagcctac cctctctggc gttggggtcc 75060 ttgtcagtag aatggggcat cctcatagct caaggggtgg tgtgtgaaat tgtgctattg 75120 tgttacttta atgatttttt ttttttcgag acaaagtctc accccacgcg caggctggag 75180 tgcagtggcg cgatctcagc tcattgcaac ctctgcctcc tgggtcaagt gattctcctg 75240 cctcagcctc ccaagtagct ggaattacag gagtgcgcca ccagcccggc atatttttct 75300 atttttagta gagagggggt tttaccatgt tggctaggct ggtttgaact cctgacctca 75360 ggtgatccac ctgcctcggc ctcccaaagt gctgggatta cagcatgagc caccgcgccc 75420 ggcctacttt agtgatttct taggaggaca gagggaacgg gtggcaagac aggcttggaa 75480 tgtgttttgg gatcaagtgc cggtttctgt ctggcactgg gttctctgtg gggccatgat 75540 ggacacactg ctgaggtcaa gcgtgattcg tcttgcgctt gcctggcagt ctcattggaa 75600 agttctgtag acatcgtgtg gatggggctc ttcccggcaa gcccttgggg accttccagg 75660 actgtgatct ccccacagtg gctgttaagc agggaccttc gtgaagtgga gtctctggtc 75720 ccctccaagt catagctaga cagggactcg ggcatcccaa gcctggctga ttattcactg 75780 gatgaggaga caggcccaga gaggggcagg aacctcccga ggtcacccag caggccccag 75840 aggtttcggt ctcggattct ccctgctcat ccctgatgta gtgctgctgt ggatgtggtt 75900 ctgtgctggg ggctgtggag agcagggggc ttggccagga ccccagtgag ggtggcgccc 75960 tcgccatgag gccgactgtt ggtatggggc ggcatccact ggggtgtggg gaggaacagc 76020 tttcctgagg aggaggtggc gggaggaaca gttccctgag gaggaggtgg cggtgctgtg 76080 tgacctgggc cttgaaggac aggtccattg caacagaaca ttttgggagt ggagcctaga 76140 gggagaaaat ttgttgaaat tcagattccc tccccctacc aatacacacc aaatcagatg 76200 cccctgacca gatctaaatt tggctctcga gatttccatt gtagctgggc acttggggaa 76260 ccttctaagt gctgcctctg cctctcccag cctgcctgcc tcagtttccc cagccctggg 76320 cccgtgtcgc tgttgccatc acgtggcgcc ctctagtgga ggaatcagat tatgcactcc 76380 ggggcttgga gcaggagtca ggagggctcc tgtctttcct tgaaacgttg gatgccggga 76440 tcctggaaca gtctctgcat tcctctggcg agaaccagag cctgggcaca ggggaccatc 76500 tgttgtttga aggctgcagc ctgcagggca ctcaggagat ctggcagttg gctgcagggc 76560 caggtctagg ggccagggca tcgggaggct ctgggctggt tcagccccgg gcccctttgc 76620 agattgtgac ctgggcccct ggcaggggca tggccacagg atgctgggag gggtctctga 76680 ccctgacctt cttggctctg gcatccttga gaccagaaag gtctggaaca aatgagtaga 76740 cgatgcccta acctggggag gagccacatc ctgatcccag caacctcggg aaggatctgt 76800 caggattatg gggcacccgg gggccccaag tctgcatggg tctccacttg caatttctgt 76860 aggaagctct gataaatcaa actgggggtc ctaggacaca gtcagaaatg ctgataccgt 76920 tgtgtgtgga gcctcggccc tgggggtcag gagcatgtgg agggtgggcc acgggggttc 76980 agaagagaat cctgtacccc ccacccccca aactgaagcc cacttgaggg ccatggctga 77040 aaggttgggg ggtcccgtgc gtcctgtgga gtgggtggtg aggagtcctt gggtttgcac 77100 gcctctgggc ctggcggcgg gaccccgtcc acagcggatc cctgggccct gttgctcaga 77160 tgctctcaga gtttgctgtg gccacggagg gagcctgagt taagcttctc ttgtgccggt 77220 tgtacgctgt cggtcacact ggtgagttag gcagggcaca gatgcccaga gcagagggaa 77280 ctttccttgg gattcaacac gtgcaagtct taggggctgg caaatcctgc cctcagctag 77340 agagggggct ttatttgaga ccagaatcac ctgagcatcc tcctgtcccc agctgtgtcc 77400 agcctgtcgc agggacatcc tgagaggacc aggctctccc ctcatccacc tgcctaagtg 77460 ccactctaac cctgtccacc tgtgccgtgg aggggcgtga cctcaagctg ctcagccagc 77520 agcaggttgg ccctgggggg cagcagagac ccaggtggct gtggggtggg tgcttcgtgg 77580 cgtggtctga aacttcgttg gaagtgtgtg gacagtgcct tgcctgttct ctgtgggacc 77640 ctattagaaa cgaggtctga gttactgggg gtcatcactg tgttctgatg gcccagctgt 77700 gtgaggccgc ggtgcagccc catccaagga gccagggccc tgggtctagc cgtgaccaga 77760 atcatgcccc ggaggtgttt ctcatctcgc acctgtgttg cctggtgtgt caagtggtcg 77820 taaactctgt gttagctctt ggtgttcctg aaagtgcccc cgggtctcag gcctcagaac 77880 LL
00E18 4oeou-eoo-eq. qq-eoPopeo eboDeqq4eo epooeoppoo pqaTeabbqi. poeb4opoqe 0f7zIe 3-25qopoepo opqqqPqDPo ueoae4qq2o -25qDposbDo Pgqqeo-abqo sopecoqoTe 08u8 of&qpeoebq ouq34Poubq puospopegq 46qopoPPoo eqq4eoeb43 eoeboe444e oziTe op6opeop6o pe54q325o oeoppeDE,gq qeoepopeDe 5qoelcqeob s3ouebgaeq 09018 40eobpooqo oqb2oqabTe obbgoboo51 qobbbqo-epq 55qDwebbb poDpo6ebb5 00018 bpoo3454o3 oquobbbqbp ubbgbbbeou ab000PPPbq bb4b465435 Bbeopqbebe 0{7608 bqDDoo654q pqobP.Eqebe Ebbqp5554q qoopb4oPpo qBqoqqq2o4 5.5pDb6bloo 08808 oebepoopb4 3bbeb4b4e5 ea4be4oepo Dbeop4poqD beo4obqbbe oqoDo4D344 0808 pooDbqoqob qoqq55EEEce cbqbqeqbe oq4poo5e.66 ElreqeDbqqD oqbqpDepqb 09L08 esoe-2555-23 poo6.555b5.4 qDoqopoqq.5 bbqoq-eabo oco-2335qbp bqopoo-eoqq 00L08 opepbpoqoo 6bbbqqop64 Bq3b5ebeo5 ppb4obpopo pbpoq.65-4ob Boob54obbb 0f/908 Bpbppabebb bobppbb4ob pb3oe355.5b -255bPoombb 55mbo.45254 5goop.6qoq5 08008 pobh44obbh 4eDpbbbeop o42b.bebqo4 bpEqeog44E, bqoDoeqopq oopobbppoo 0Z008 40eb4obpeb bbbqebbbep bbepPpabgb goqeoqooqb 4bb000bbb4 Ppegoqb4DP
0908 oqbePoq554 .4352552o45 bubgooabbo eopt65.2.25 qb2-2qobeoo bqqbbqoeub 00t,08 .6-eo336babb PbePohpqqq. oftEbP3333 lelbbblbPPb PPbbbPbleb blbbb?bbab of7008 o3op66ThEl 6.6.666pp6 lo56.46235.6 .1coqp5qpb 6PEcebbbgbq eobtcebboo 0808 55bbqopoeb 54boogpoob ea5.2b3qabb bbobbbpfceD bPobepeobe bbbob?obbe 0zz08 35p3bgbpbb bobeobbeob pobbpoqbqu obepobpbbq oqbqbb4opb b4bepobqoo 09108 qq1435-ebbb 5D3654o545 -45-eb.4b-44.6b b6b400p5o3 06.6q5oq354 .64op5ebbqb 00108 q3bbbgb444 ebbebeobbb obbDbeDbbb D4boopeabb PoDabqqoee qbeebqbbeE
0N008 fle-q05.2Pbq oDpbb.6qDoo bbqeoqq6bp opqqqbbqbb popeobbbqb pqqoPobubb 08660 qbqowoobq obqbbabe-4.5 uoq5be6554 o5EbbbeoD3 gbupfabqp.6 pa64.655-4bq 0Z66L obebblbeob obbubbPbbq pb4pooPep bbbqpb4pe3 epbeopopuq poqobbbbbq 0986L 004430666f) .23a6p;beq5 EftebeoTobb o6p3oobooD abubloq44o pbeb55,6pqb 0086L bo4bboqbq4 qbeqebeofye eabqbqoqeu p5qeobeop4 qqob-eop4ob 54bobeobbq 0f7L6L 00bbb43bbb 54b4bbeobb qb4-26bebe poep-455bpo 335443.655 .34obficebEt 0896L p0006pp.54o soebbsbqqb poeq5qmbeo 4.654655.55 beooqpoqqq. qombbb4poo 0Z96L PDPobqqqoe pepbqq4qp4 oabbPpobbo qbboopEcp3 oPpobpb4p3 bbeoPqmebb 0906L 5qobqbeeeo 304305-2o-4o abqopeDoef) -455poqoc-2.6 400qaePPD6 oqbfigabbeo 0006L obb443qbDo pp4-44656bq ubp5e464.44 44-24b44.454 ppqobb.44ob ;Eqoppob4o 0f7D'6L 0.64bbeoelq pbbbqobeqb Pb4op4obe3 4oablo3qpi. 4ebqbppoqo bbbqop43ob 08E6L ;o400es-De4 3eoqa6pow qe5.4b554.6p o5qbp554Db eyeDooboqbq 343-eowqbe 0ZE6L 5154ebeb444 4444444444 D444444343 obbDD-O6e3 e46e3e03eb 4DeDe54540 09Z6L 4pobeobbbe pqbeDpbqbe qbeebqebbu Dqq.q.ebqbb bqpqeopqbb opebbqeebe 00z6L 45-40qpoloo 44mbpoq4o5 bloop4454q qopabebbbe 55q33-25e55 40335pp-ebp 0t.16L 4b054P334b bb bob bbboo4bb46 Pooppeobpe pee43qq4bb Bq4oebeeb4 0806L obbbbobbbe oo4o5ebbo Te545636a6 P000poepoo obbbqc5.e3b 53DPOPPPP4 OZO6L 4-54405bbeb bebb000-2-2-2 olpobqq34b 4oepebElb4o 44eo454DDp 55qpoeb44e 0968L bbbbebpbo bEcepobpop bbPoobbbeo o5ebb400bb 564obbbbbp Bbbo-ebpem6 0068L HE,TeflgEoD c3pob4o3bo qpoofyeb000 o5eboP55qo opbbpbboqb qbbqooqebe 0V88L P06000q3DP 3bbOPP4036 oboebqbbeb oTeoboopbb oeobbbopoe boopbbqoeq 08L8L oqoDeeeboo 3b6-45bqDp5 Dqb5obo4Po 55qpboo3pe 6o.epoq-2.626 opeoeepqb5 0zL8L goboebeobo bbbbogbbbo p&blgooe450 555eo5o3qe po556a5qb5 pboet4u6po 0998L P.5_64pe4o46 qpqbbbpbP; ob000eboeq opEcleopbq 4po3b3pobb opmeopboPb 00980 bqbbeobob qb4Pos5ooe oqqopbboo5 o2cpbb4abo qoqpbbubbo '2.4o3p56oe.5 0S8L bobb000bb4 oqDb4abq55 ebbeEpobeb beoeDo404.6 gooeobqqeo opoeb4Doop 08f78L P5440oobbe .64a6qpob48 qqoebeqopf) bPODDOPODO 55=544= 34T4eq5e54 ozveL o.554po555b 4Doo5rebe55 eeobqqqoab POOPD4EOUP gooeo45.4.60 bqbbbqDbbb 09E8L 4PDbe4bq3p pbqbeboeeb 4ebbpbqeo4 64b6ubeopo goobpoob4b POPPPOPPPb oosn 5e64epeqbq qqeogoqoqq beoq4o54bu DgogDoeqp DE4bo5qobe ogowbbqbq 0f,z8L E4DE.643b6q peDoobeebq ab20.62000P oppqabpabb Etqb4opbbb 55eeop5e.6.6 0818L Po66T6565e fiebbeopbbq 64445blo55 65 66b oebbbobboo peqb6q3Dbp 0z18L obqab564ob sobepobbqe 05235e543b pubbbbgabq -eo555-4.65ep obqoopobub 0908L 45bupftpob 6643.6e5345 obbqbppbqp boSpbbbebb pbebbqbbqb bbo4pooblo 0008L .5-264D36565 qcb-4553eab b0003op5p5 524pobqpoo 55qoqbqbqe bbeebqqpeo 0f76LL qpbob552be puobpb44bp 3bb5.4o4p35 p66b4335.6q b5o4Dqppqq poo4qqbbbe gaatttaccg acaccgacat ttaccgacac cgtttaccaa caccgacgtt taccgacacc 81360 gcatttaccg acactgatat ttaccaacac tgacatctac tgacgctggc atctactgac 81420 ccgatgccag catctaccaa caccgacatt taccaacact gacatttacc aacactgact 81480 ttaccgacat tgacatttac tgacactgac atctactgac actggcatct actgacacga 81540 cgtttaccga cactagcatc tactgacact gacatttacc aacaccagca tctaccacac 81600 cgacatttac caacactgac atttactgac actgatatct actgacactg gcatctctga 81660 caccaacatt taccaacacc agcatctacc aacaccgaca tttaccaaca ccagctttac 81720 caacaccgat gtttaccaac gccgacgttt accgacgcca gcatctacca acacgacatt 81780 taccgacacc gacatttacc gacactgaca tttactgaca ctgacatcta ctgtactggc 81840 atctaccgac actgatattt accaacgcca gcatctactg acactgatgt ttccaacacc 81900 gacatttacg agcaccgaca tttactgaca ccaatattta ctgacatcaa ctttagccat 81960 gtgatggggg ccggcttggg ggcaggcctt gctcttggca ctggggatgc gcagagacca 82020 gacagactca tggggtcatg gacttctgct tcttctccag cctcatgtat ggacagactg 82080 gggagagaac cctaaaatcg agtgtgccaa cttggatggg caggagcgcg tgtgctggtc 82140 aatgcctccc tcgggtggcc caacggcctg gccctggacc tgcaggaggg aagctctact 82200 ggggagacgc caagacagac aagatcgagg tgaggctcct gtggactgtt tgatccagga 82260 ggccaggccc agccaccccc tgcagccaga tgtacgtatt ggcgagcacc gatgggtgcc 82320 tgtgctctgc tatttggcca catggaatgc ttgagaaaat agttcaatac tttctgacaa 82380 aaacgccttg agagggtagc gctatacaac gtcctgtggt tactaagatg ttatcattcg 82440 gccaggtgcc tgtagacaca gctacttgga gactgaggtg ggggatcgct ggagtccaag 82500 agtttgaggc cagcccgggc aaaggggaca caggaatcct cgcactgctt ttgccactta 82560 ctgtgagatt taaattattt cacaatacaa aattaagaca aaagttaatc acatatccac 82620 tgccctgctt aagacagaaa acatgggtgt tgttgaagca gaggcagctg ctggcctgag 82680 tttggtgatt ggttcctaag cagttgaagg cagttttgtt ttccatagat gtctgttctc 82740 cctttgctgg gtgcagcctc gccctgctgc tgtggtcggt ttcagtggcc tcgtcccgtg 82800 gacgcagcct cgccctgccg ctgtggtogg gtttcatggc ctcgtcccgt ggacgcagcc 82860 tcgccctgcc gctgtggtcg ggtttcagtg gcctctcccg tggacgcagc ctcgccctgc 82920 cgctgtggtc gggtttcagt ggcctcgtcc cgtgacgcag cctcgccctg ccgctgtggt 82980 cgggtttcag tggcctcgtc ctgtggacgc agctcgccct gccgctgtgg tcgggtttca 83040 gtggcctcgt cccatgggcg tgctttggca gcttttgctc acctgtggag cctctcttga 83100 gcttttttgt ttgttgtttg tttttgtttg atttgtttga ttgtttgttt ttgttgtcgt 83160 tgttgttgcc caggctggag tgcagtggcg gatctcagct cactgaaacc tctgcctcct 83220 tgggttcatg ccattctcct gcctcagccc ccacatagct gggattacaa gtgcccgcca 83280 ccacgcctgg ctaaattttg tatttttata gacagggggt ttcaccatgt tggtcaggct 83340 ggtctggaac tcctggtctc acatgatcac ctgcctcggc ctcccaaagt gttgggatta 83400 caggcgtgag ccaccgcgcc cagccttgtt gagcatattt tgaggttctc ttggtgccag 83460 tgatatgtac atgtgtcccc atcgcccatc gtcacccatt gaggtgacat tggtgcctct 83520 cctcggggtg gatgcctccc tctgttccag caacttctga aggattttcc tgagctgcat 83580 cagtccttgt tgacgtcacc atcgggtcac ctttgctctc ctcagggctc ccaggggagg 83640 cccgaatcag gcagcttgca ggcagggcag gatggagaac acgagtgtgt gtctgtgttg 83700 caggatttca gaccctgctt cgagcgggag gagtctcagc accttcaggg tggggaaccc 83760 agggatgggg gaggctgagt gacgcccttc ccacgaaaac cctaggagct gcaggtgtgg 83820 ccatttcctg ctggagctct tgtaaatgtt ttgtttttgg caaggcccat gtttgcgggc 83880 cgctgaggat gatttgcctc acgcatcccc gctacccgtg ggagcaggtc agggactcgc 83940 gtgtctgtgg cacaccagcc tgtgacaggc gttgttccat gtactgtctc agcagtggtt 84000 ttcttgagac agggtccgct cgctcaccca ggcgagagtg cagtggcgca atcacggctc 84060 gctgtagcct caatcccctg ggctcaggtg atcctcctgc ctcaccctct gagtagctgg 84120 gactacagac acatccacca cacccagcta gtttttgtgt attttttgtg gggggagatg 84180 gggtttcgct gtgtgcccaa gctgatctca aactcctgag gcacaagcga tccacctgcc 84240 tcggcctccc aagtgctggg atgacaggca tcagccgtca cacgcagctc aatgatttta 84300 ttgtggtaaa aaaacatagc acaaaattga tgattttaac cattttaaag tgaacagttc 84360 aggctgggcg ggtggcttat gcttgtaatc ccagtacttt gagaggctga ggtgggcaga 84420 tcacctgagt caggagtttg agaccagcct ggccaacatg atgaaatcca gtctctacta 84480 aaaatacaaa attagccggg catggtggca ggtgcctgta atcccagcta ctcgggaggc 84540 tgaggcagag aatcgcttga gcccgggagg tggaggttgc agtgatctga gatcatgcca 84600 ctgcacccaa tctgtgtgac agagcaagac tctgtcttga aaaataaata aataaaaaaa 84660 attttaaaag tgaacaattc agggcattta gtatgaggac aatgtggtgc aggtatctct 84720 gctatatcta cttctagaac actttcttct gccctgaagg aaaccccatg cccaccggca 84780 ctccgcccat tctcccctct ctcccagcct ctgtcaacca ctaatctact ttctgtctct 84840 ggggttcact tcttctggac gttttgtgtg actggaatcc tgcaatatgt ggtccctgcg 84900 ttggcttctt tccatagcat tgtgttttcc agattcaccc acacattgtc gcacgttatc 84960 gaatctcatt cctgactggg tgcagtgggt taggcctgta atcctaacat tctgggaggc 85020 aaggcgggac gatcacttga ggcaggagtt tgagaccagc ctggccagcc tagcaagacc 85080 cagctaccaa aaaattttaa aagttaactg aacgtggtgg tggtgggcac ttgtggtccc 85140 agctacctgg gaggctgagg tgggaggatc gcttaagccc aggaggtcaa ggctgcgtga 85200 gctatgatcg caccactgca ctccagcctg gacaacagag caagaccctg tctgaaaaaa 85260 aaacaaaaaa aaaagttcct ttctttttgt ggctggatga catcccattg tatgccacag 85320 cacattttgt ttgtctgttt atcgggtggt gggcagtggt ttccaccttt tgttcctgtg 85380 aataatgctg ctgtgaacat ttgaattcaa gtttttgttt gaacacctgt tggaattatt 85440 tggatatatg tgtaggggta ggattgctga gtcctatggt aatgttaggt tgacttactg 85500 aggaaccatt aaactgtttt caacagtggc tgcgccgttc tgcatcccca cggcagtgtg 85560 tgagggttct gactttacct cctcacaaac gcttcttttc catttaaaaa atattcagcc 85620 aggtgctctg gctcacgcct gtaatcccag cactttggga ggccgtgggg gcggatcacc 85680 tgaggtcagg agttcgagac gagcctggcc aacatggtgt aaccccactc taccaaaaat 85740 ataaaaatta gccgggtgtg gcagcgggcg cctgtaatcc cagctattgg gaggctgagg 85800 caggagaatc acttgaaccc gggaggcaga ggttgcagtg agccagatcg cgccactaca 85860 ctccagcctg ggtgacaaga gtgaaactcc atctaaaata aaacaaaata aaaataaata 85920 aaaatttatt aaaacattca tcacagccag cctagtgggt gtccatgtgg ctttgcctcg 85980 catttccctg ataactagga tgctgagcgt cttgtcccag gctgccacac ctcagcactt 86040 tgagatacgt cgcacagtcc ccatttgcga acgagaaatg agtttaggga acagcagctg 86100 tgtcatgtca cacagcgagc agggggtctc tgagccgtct accccacagc cgaccaagct 86160 ccaatcctta ccgcctccta gtgttgtgga tgtagcccag gtgctcccac atttttcaga 86220 tgagaacacc gaagctcaaa acaggagcgt tttgtccaat tggatacacg atgtctgtgg 86280 tttggtcctg aagtcacttt atatctcagt ggtccagctg gagtaggaca gggggttctg 86340 gggaatgggg aaggtgtctc aggtgaaagg aaggaatcca gattctccat actgtccttg 86400 ggaagttaga agactcagag ggtctggcaa agtcaacaaa gcaagagaaa tgcagtcagg 86460 aggaagcgga gctgtccagg aacagggggg tcgcggagct cacccccagg aactacactt 86520 gctggggcct tcgtgtcaca atgacgtgag cacgcgtgtt gattacccac tttttttttt 86580 tttttgaggt ggagtctcgc tctcttgccc agctggagtg cagtggcacg atctcggctc 86640 actgcaagct ctgcctcccg ggttcatgcc atctcctgcc tcagcctccc gcgtagctgg 86700 gactacaggc gcctgccacc gcgcccggct atttttgtat ttttagtaga gatgggattt 86760 cactacatta gccaggatgg tctcgatctc tgacctcatg atccgcccgt ctcggcctcc 86820 caaagtgctg ggattacagg cgtgagcccc gcgcccggcc cgatttccca ctttaagaat 86880 ctgtctgtac atcctcaaag ccctataaca gtgctgggtt gctataggga atatgaggct 86940 tacaggccat ggtgctggac acacagaggg acggaggtca ggaggtagaa gggcggagag.87000 agggaacagg cggaggtcac atcctggctt tcaaaatggg ccagggagag acaccctctg 87060 agcatggtag gacaggaaag caagttggaa cacattgaga gcaaccgagg tggctgggcg 87120 tggtggctta cgcctgtaat cccacacttt ggaaagctga ggtgggtgga ttgcttgagg 87180 ccaggagttc aagaccagcc tgccaacatg gtgagacccc gtctctacta aatatacaaa 87240 aattagccag gcgtgatggt gatacctgta atcccagctg cttgggaggc tgaggcagga 87300 gaattgctta aacctgggag cggaggttgc agtgagccga gatcccgcca ctgcactcca 87360 gcctgggcca cagagtgagc tccatctcaa aaaaaaaaaa aaaaaagata aaaagaccaa 87420 ccgaggaatt gaagtggggg gcgtcacagt agcagaaggg ggatcgtgga gcaggccacc 87480 ctgtggtcat gcactggagc tcattacctg acgatttgga gctcatcact gggggcctaa 87540 ggagaataga tactgaggat gaggagtgat ggcgcggggc acgggtgtct ttggtggcca 87600 gaacttgggg actgcggggt gcctcactgc aggccttctc agcgcccttt atatgcttac 87660 acaggctgtt tctagagggg gatacattgc ataagcgttt tcagactacc tcatcatggg 87720 tccctttctt tacctctgtg gccctggtgg cgcactctct gggaaggtgc aggtggatgc 87780 ccagacccgc ccgccatcca cctgcacgtc cagagctgac ttagcctcga gattgctgct 87840 ggcacctcct gcccgggaca cctcggatgt gcccgtggag atgctggctc tgtgttttct 87900 gctggagttt gtgcgtottt tcctcctgca agtggccacc gctcttgggt atgtcctcag 87960 gcttctgcgg tcatggctgc ttctcaggtc cttgcccagc gccaggagca aaccctcctg 88020 gcactttgtc aggggtggat gcgccagtgt tcctgctgtg gacccccatc tcacatgagg 88080 gtcttggcct gcaggctcgt tcaggaaaca cccgctgagt atgcagtgtg tgccagctgt 88140 gtcccagcaa tggcggggac agtggctgct gctggggttg tggtggcttc tggggactct 88200 ggggaagctg aggtgcaagg agccacggct ccttgaggat gcagttggac tccaggtgga 88260 agggtggttg ggggaggtat aaatggggtc agggaggaga cacatttgga acaatgggaa 88320 cattttaaga tgctatgtcg ggaggcaaca aggtggccaa cccaggtgct gaggagccca 88380 cacagccctg gacgtgtttt gccgctcacc tttgctgggg agtggtggga gagaggattc 88440 cttccacgtg gtggtgtgcg cagctgggct gtgtggagct gggcgctagg aggaaggtgc 88500 ttctgcgggg ctagccgggc tctgcctttg aacacaatca ggctccaggt tttcagcatc 88560 agtgcatgag aggacttcac gggcagctgt ggctgatccc ttgatgaatt gggagaagac 88620 aaaggtctat gaaatgaggt ttcatgtaga tggcattaga gacgcccaca acagattaca 88680 gagtggagcg gagacggcgg atgggtctgg gaggccoctc ctgctggcct tgactggaca 88740 gctgtcctgg gaatcagctt ccaggccgcc ccagcagcct gactgacaca cacagggttt 88800 tagccccatc ctgcgaccag ctgttgccat catcagtgac agctgggagt ggcgtggttc 88860 cagccctggg caccctcccc acctgctggg gcccacccag ggcagtcctg acactacagg 88920 ttgcttggag ccgcatccga gtcctgcccc accacgtgtg aagcccgagt ggcgtgggct 88980 gaggtcccct gattgcatcc ccacttccct tctgcttcac atagctgcct ctctcaccgt 89040 ttttccagcc tcctgggcta ggaattccag tgttgtgctg gctttgcccc ggacacctcc 89100 ttagccctct tcctgagtct agagccccgg gggttggaag ttctggccct gggacacctg 89160 cagccacact cagcttctcc tgtgagcctc cagcatgtcc cctcaggaca agccctcacg 89220 ttcttgcctc cccgcccacc tgggctcagc caggggaagg cctggctgga gcgtctcccc 89280 tctgccctgc ccttctcccc tctaccctgc ccttctctcc tctgcccgcc atggctttta 89340 tatcctgtgc cacaagacat ggctgtgtgt gaaagtggca gggtcggcat ctctgtgggt 89400 ctctgaggcc cacgctccag tgccactctt cccacccgct ggcctgccct catgctggag 89460 ggacagccca gccctctccc gaaccccagc cccatgtgcc cagtgccccc ggccctctcc 89520 cctggaagcc ggggtcactc cagccgtatg ccatggtggg gaatcctgct tccttggcct 89580 tccagggaag gtcctctttc caaatggcga cacctggtcc cgcctggagg ctggaagctg 89640 tggcccttgt atgcccctcc agggtctgtg cgctcggttg cccgagttcc catcaccgtc 89700 gtcatcatca ccatcatcat tgtcatttcg cttgtctgta gccggcctgg tctcccagag 89760 cagagaccct ctgaggtcca gcctgagttg gggtctcctg ctgacccctg acggggactc 89820 aggacgtacc aggtctgggt caggagtgac ccccaaactc gtgccctttg acaggcaccc 89880 ctgacttttg ctaagtgggt ggaggtgaca tcacttcagc gggagtgatg ggacagggtc 89940 tgttggctgc actgtgctcc cagggatctg gggagggcta tatccctggg ctttggcact 90000 gcagagctgt gtgtgtttgt gtqtgtgtgt gtgttgtgtg tgtgtgtgtg tgtgtgtgtg 90060 tgtttgcgtg cgcgcacatg tgtataagat cttttttatt acatgaagca agataactgt 90120 tgctgtttcc ttttgggttt tgtgttcaac aggtggggta cttcttccct cagacaacag 90180 aactctcccc tttaaacacg tgctgtcaga ggtgggtctt gggctcatgt ctgtttgcac 90240 agccgagtca gaggaaacac agggttcttc taaaaacact gcacagcaqg cgactqtcca 90300 gagtcagcct gcaggacggc agcagccctc ccctcagagc acagctaggg tgggctgctt 90360 tgggatctcc cgtcattccc tcccagctgc agccggcggc cggcccattc cttggtgtgc 90420 tggtcagggg ggcgtgcgcc tgctctgtca ccctgggaat gggacagaag ctggcagctc 90480 ggagaggaca gggctggacc cttgggggcc tctggctgga ccatctcatt gtcctcagac 90540 acagcctctc gggtctagtt tcattcctga aaaacaagtg cacagaacta gagcaggagt 90600 cgagagctac ggcccccggg ccagtccagc cctgccacct gttttcacac catgctcaag 90660 ctgagtgggt tttacatttt ttattacttg aaaaaaaaaa agccaaagga ggtttcatga 90720 cccatgaaaa ttatatggaa ttaaaaaaaa aaaattatat ggaattcaaa tttcagtgtc 90780 cataaataat ttcttgagac aggtctcgct ctgtcaccca ggctggagtg cagtgctatg 90840 gcatggctcg ctgtaccctt acctcccagg ctcaagcgat cctcctgtct cagcctcctg 90900 agtagctggg actacgggtt gtgccaccaa gcccggctaa ttttttttta attttagtaa 90960 agacagggtc tttctatgtg cccaggcttt tctggaactc catcttggcc tcccaaagtg 91020 ctgggattac aggctcggcc acggagccca gcctgttttt gttttttcac tgataaagtt 91080 ttgccgggtg tggtaggtgt gcctctagcg atttgggagg ctgaggtggg aggatcgctt 91140 aagcccagga gtttgggctg ggctcaagtg atcaggaggt gaactatgat catgtcattg 91200 cattccagcc tggggacaga gcaagaacct atctcttaaa aatatatatt taaaaagtat 91260 tgggtgtggt ggccacgcct gtggtcccag ctacttaggc atctgaggtg ggaggatggc 91320 ttgagcccag gatttgaggt tgcagcgagc caagatcgtg tcactacact ctagcctggg 91380 tgacagagcc cgaccctgcc tctttaaaaa aaaaaaccaa aaaacatgta ttggaacaca 91440 gccatgcctg tcagtcacgt gctctccatg ctgctttctg ctccagagac ccttatggcc 91500 tgaaagctga aatattttct atcctttaca aaaaagtttg ctgacctctg tcctggaaaa 91560 ttcatctcca agttctcttc cggcactggc gttcctgggt gtcctaaatt tggcccctgt 91620 tatttctaac tctgttttgg ctctgttccc tcccaggagc caggacaggc acgttctctg 91680 catctttccc ctgacgccca gaggcttggc tcggctcagg cattcttgga aatatctggc 91740 tccagaaagg cagaggcctc ctgagtcggc ccagagggaa cctgccccag gtctggggga 91800 ggccgaccca gcagagtggc ttttgccgat gggttgggcc ggtcaagatg tgctgaaagt 91860 tgtctcagaa ggccactttg ggattccttc ctccagtatt agagcaactg agagctgctc 91920 atgcaagcct gatgttttcc cagttggccg ggtccaccgg gtgccctggg attctgggat 91980 cgggtggaaa gtagggggct tgggggagtg tcctgggttc tggaatccag gtggcaagtg 92040 tgaggttcag ggagtggctt ctgagccacc ataggggtct ctgtgggagg ctctgcccac 92100 caggagattc cgcaggccct gccggcccag agccagcgtc ttgcgcttgc cgaggctaag 92160 ccagccccag ccgggtggaa cagcccgtcg cctcctctca ctttgttttg gggccactgg 92220 gagtgtggag caagggtaga gagggaggaa gtggctgccg gccgctgccc agcaccttgt 92280 ttgccttggg ccctctgtgg gctccttttt attgctcttc aatgaagcca gggaatggac 92340 ttccttgcct cacttcagtt caacatgtct ggaagtttgg tattaaaatt aagaagtgtg 92400 gaaatagagc aagaagagaa aaatctctcc aagagataat agtgacctct gagtgggcgc 92460 ggtggctcac gcctgtaaat cccagtactt tgggaggctg aggcgggcag atacctgagg 92520 tcgggagttt gtgaccggcc tgaccaagat ggagaaaccc cgtctctact aaaataaata 92580 aataaataaa taaataaata caaaattagc caggcatggt ggcgcctgcc ataatcccag 92640 ctaaggcagg agaatcgctt gaacctggga ggcaaaggtt gcagtgagca agatcacgcc 92700 attgcactct agtctgggca acaagagtga aactccgtct caaaaaaata aataaataaa 92760 aaataaaaat agtgacctct ggccaggtgt ggcagctcat acccgtatcc cagcactttg 92820 gaaggaaggc cgagatgggc agattgcttt agcacaggag tttgagccag cctggccaac 92880 atggtggaac cccatctcta caaaaataga ataaaattta agaggaatag tgaccttttg 92940 gtagatcgaa acctggattg ctttcttttt ctaaatgctg attctttctt tgtggtgttt 93000 gtgttctgtg ccgatgtccc tcccccagcc ctgttattgt gagggaagaa ggggaaaggg 93060 ttcgcccgct actgtgagcc cctcctctca cgctgggtgt cctggagaag cctgcacttc 93120 ttcattgtac gccagggctg ggtccctccc tggagtggtt cgtgctgctg ggatggggcc 93180 aacccctcag atgttttctg agtgtcacac acaggtgtgt cattcatggc ctttgcgtgt 93240 cttcctgttg tggaggcaaa aatgtgaaga accctagata ttttgggacc agggctccat 93300 cacctgctgt tcattgcaca ccggagcatc caggcatggt ggagagctca gacttccagg 93360 cacggtcgca ggggctggtc taaccatgtt cccgccccct gctcgtcaga accgcctgtt 93420 gggagctgtt atcatgatac catacctggg ccctggctat ccgattctga cttaattgct 93480 ccaggttggg gccaggccgt tgtttgctgt tttgtgtttc ttctgtgacg ttagccactg 93540 ggctaatctg agcccctcag ttacaggtgg agaactgaga cccatggggg tgcaaggact 93600 tgccgaggac ccagagcccc ttgggggcag agcgaggcgg ggcctggctt tgggtcccag 93660 agcttccagt ccccttcccg ctctcctaac agtttttttt ttgagacaag atctcaccct 93720 gtcacccagg ctggagtgca atggcatgat ccggctcact gcaatcttcg ctagctgcgt 93780 tccagcgatt ctcctgcctc agcctcccga cagctgggat tacaggtgtg tgccgccatg 93840 cccagctcgt ttttttttgt acttttagtg agatagggtt tcaccatgtt ggccaggctg 93900 atctcgaact cctgacctca aatgatcccc tgcctcggcc tcccaaagtg ctaggattac 93960 aggctgggat cacactgtgc ctggcccagc agctttgtcc tgtgccatcc aacaacagat 94020 gaccgaagtc tttgtttctt aacatgattc catctgcctt acagttttgc cacctgcaaa 94080 acagaggact tgtcgctttt ctggtagctg gaaatgtaat ctggtagcag gaggcctgtg 94140 gaagcttgcc tttaatggcc ttgttctctt tcatcctgtc ctgagagccg gagaacttgg 94200 atgttgcacc taactcaacc ttctgttaac atacagttct gcaggctcat ggatcatcag 94260 aaccacgtcc tatctcacgc ggtgtatgct tccgttggtt caggtgtttt taccttgaca 94320 gtattttctc ctcggtggct ttgcggtggt tgcttttaat cagcattgac tcttcaagaa 94380 aaatatttag ctgctacatc cagaggagac agggtggaaa gcatctgaga cctgcaggct 94440 cagacttaga accagaagtc cctcagagtt catccggccc tgacccagcg ggaaatgagt 94500 tcacagagaa gcgggagact ttgccccagg ccctgccgtt gctcataact gccccaggtg 94560 cttacatttg ctccaggcct gccccaggcc ctgcagttgc tcataactgc cccaggtcct 94620 tatatttgct ccaggtctgc cccaggtcct gcagttgctc tgtgtggtgg gtgtgatctg 94680 gagccctccg cccatgctgc acctggggca ggcattgcta attgatccca ggactccttc 94740 ctgcggagca cgcctggttc tccaggcagc cgctgcctgt cagcctgcag tggttcggga 94800 gaggacacct gctgcctggt ctgttccaaa tcttgcttct catcccagca caggtagggg 94860 gtgctatggg aagggatcct cagttggccc tgtcactgct ctatcagctg gggacgtggc 94920 atcctagtga aacatcatgg ccgggcgcgg tggctcacgc ctggaatccc agcactttgg 94980 00m6 bbbqobq000 qqqopopeob Dobbqqobbq bqbqq.poge obeobbooqo bbqbqbqobe Of7E86 bqopoopobb oqobebqool beb4bbbbbq o3ub400ebb oqbbebeoob p000ePoobb 08786 qoobeq4qbb bebq44bqbq b4bobqbbpp ebqbbpoqqq obbqoqeopo bbqqqqobeb 0zz86 bqqpoeobqb qabeeeleeb b5obbqbqb4 eb4qqbqcoo qbqpq=000 poeooecooq 09186 oq4bqbbsoo bqqpoobqqb bqqopebebb bbeoopqbqo bbg000eqpb 4peqqbqobl 00186 peob000bpb eoqbpooqbb ppoebqoobo bbgoobqbeo opbbq000qo ebqbbeopbb 0f7086 Dqqbebqbpb bqepb4bbee oogooeqooq obeppbebq pbbbqueepp bgeebqqooq 086L6 qqbeqq;oPo bqobqgoobe obpoqqqooq obmeoosbqo ;qopb4000g 3b4Dbpboob 076L6 qgo3oe365q ob65qopope bbqobbebbo oobbeoPoqb eoobbb400q 4oqqqo6g3e 098L6 o4.4b3b5e54 poobqopoqb bqooblqopp obbbbe64o3 bbppoobebb poqoqoebbb 00eL6 qobegoobbb eebbebboqp pbqbqoqbqe ebbbqobqbb bpoqqqqbpb qbqeeoobbb 017LL6 gob0eoo5b4 qqobpobbeb pepeebqbge qoeqbqqbbo PP5OUPP4Pe pppoDbbqce 08906 bpoppqq-epp bqb-2.6q26q4 bbq4q-e.a6 oepqqq.seoD b-epsqq-eupg peoeu;;Te4 0Z9L6 pPeb4o5bql qqqqqoqqeb bppeeebbbq ebebppegob 44gbbqboo3 opog34o3po 096L6 W000044oq qobbbqgeee bpbqobeepq qmpqbqbbbb bqpooloobq bbbeepeopb 000L6 2.24e6-252o3 opeee;e2ep peopebeepo -2,p6;beb .bq.00eblop beb455e-ebb 0u/L6 Teooepo.
op4qqeobe peeeee-epp eeppppvoqo 0543ooeb25 poef=e5-45 08EL6 bbgoobpoo; oeobqopoob geo4pbebq3 ebmbppbqlb bebeobbebb 4o4bubwoe 0ZEL6 o4ebbeobbq boeb4ob6bb belloe4obo oo4bb4bloo o4equobb4b bquobb000b 09L6pqmeeepppe peepbpooeq oqp4eoqopb ebebe;eoee 0.65.543ooqq. oqb45.25.254 00L6 ;.4-eeP.boop bpbqqceo4e b5pbbpo5p.6 q3pbpe5bi.i. qoes.Ece3ooq pep5q0054E
0P1L6 ogobbq5b4b lbbpoobqe4 44POPPEPPe eeeepppeeb peppeowqb 4ol3ebebob 080L6 Pbe4eeobbb qoppooqopo bqopoeqbo4 eqb000beb4 bp4bqqbbpb pqbbebbpoo 0ZOL6 opebqqobqq eebebbobbe b;obebeboq op4DepqDqp pTegD3bobo pDqeqbbqbq 09696 55; PUPeePPPPP pesegbepee PPPPS'ec2PPP ppoqoqbooq 3ebubobpbe 00696 oebobbbgoo bbooqbeobo ogeobqoeop bobqqebebo 3bebqbeo54 qobebbobee 0f7896 bbb000sebq bobbgeubeb bob6eb4obb ebbboqopqo bp0004begb 400bo6bbob 08L96 bqbb3.5q5bb pobe;;peee eoeqepe-epq opq3.434.6po poppubqbbp u.Deeob6TD
0ZL96 0'4-B33-2.5.25o qebebbeoqb ebqeoqebbq bbbDbfre.boo bbebbbqq;o eoopoopqe 09996 pbqoleopoq obbgbpobbe obbbboobbb bq364poqqb 3bopeepe44 qooqopbeoo 00996 044445Pq44 eebqpoopoo bqpbbbbsqb geoqoogbeo figoopeoboq poqqopb5q2 017096 0q4D34-40bq bebqbebebb qoppoebo55 bqbqbeone bqp6pbb43o be-ebb4b3oo 08096 obuo-eobeeu beo55544bb eobebbbebq Teebbbgobe Eneboeqee ueqqqoaboo eb4bebb4bb boqb000bqo b4oqop6q4b bb000b4ebe blbbbqooqb 09E96 Pob400b4qp 35454o5440 bqpbgbopbb ebeopbbebe bqebbeebqe bqobq4qoqe 00E96 poqbeoqoeo bbbeoqb4qo bqoaeo.643.2 oeopoqbbbb opbqoo4bqb 4owebbbeo 00096 bbboboqobb bwobbeoeb bbeobb3b4.6 beoo;pobeo be5.25-ebbqo uoeqq5pbeo 08196 pbqbbeppeb op-443;046g 44eb4eeopo bb4ogbqgbo qbbebbeboo oogobopbbe 00196 oq4o4e65po beepbqooeo oqqooeo54b qeobop000b b4bqopoo6q 4bqlobqb4o 09096 b554355boo b43q5bbloo qopp4oebbP oqobeeoobq bb?oo4oes, ofy4boobp.be 00096 oboebbebeb bbbqoeoboq pegoo3bqqo oqq5e;b4ee eobqoq5Doo pe.646.23E,D3 00606 ob4b34005e bbboobbwo obb000bqbq bqob400eob e6-44644qeo peloub4bee 08806 ebeq4bqPeo ee4bboqble ebbuqoebbq eqqb64bebb beqqebqobp bbbeepoebb 0806 beebbqpbpo ebbepoobbq 34eqbeob; bbeePbbuop bbeonbeeb bbbqooeboD
09006 Dobbbeoqob a6T4546eeq eobbb40052, uDD4b653e5 45esbbeb6e 64eDbqqoab 00L06 Poqeoobeog obbgpoobee poombbbbbb ooqbebqbbo qbo4bbeepo bbqbqeebqb 0D'906 4beepogobb bbqpbqopeb opobqobpoo ubqqeoqeoq boebbboobe pobbeeoqbb 08006 p3uobqbbec beboqp3be3 boobabeo55 4oebqoebbq opqo4poqqo ubbb_654o,53 (:)666 bopp4466bo 44-4geopobo pogpbeepe5 bebbqc3q3D opbboabebe Pbebbbgbi.
09006 4bleeoqpbq bbeobqoolb pobqoq44e4 eqooebeooq epoobbwoo bb4b4bb4bo 00006 404Dbblq56 booqbbbeob bp0000bbeo qobeobbbbq 6q64434600 opub4qobbb 0006 qqo6ob6pb4 qbe25455-83 5455peo0.6.4 Doe4.5b4.244 44.6455loop qobqeoePbb 08766 bbq0000pob eooqpq4qeo qbobeeuoee poeesoe22e ppceppoe-2.2 opeppepoqo 00066 4eeeeoqp46 43boebeb4b ebeoeeobb8 400beoo4oe ob4oepob4q oTeeboobet 09166 qbeobq4o6p bbqbbebbb4 opeebqqobo quebebbeob bebqobbebb b3De4obPbo 00106 oq-eeqbqooP 666505.66bb q6qbbecobo qTePeeeop4 eepepqopqo qqeD3opeeb 00006 456qp3E,po6 bbqop5eopu beboqqbe.6 eo6b5ebg4o eogsbbqbbb bbebqobbpb ctgttgatgt ttgactggag cctctgtgtt cgcttccagg aaccaacccg tgtgcggaca 98460 ggaacggggg ggcagccacc tgtgcttctt cacaccccac gcaacccggt gtggctgccc 98520 catcggcctg agctgctgag tgacatgaag acctgcatcg tgcctgaggc cttcttggtc 98580 ttcaccagcg agccgccatc cacaggatct ccctcgagac caataacaac gacgtggcca 98640 tcccgctccg ggcgtcaagg aggcctcagc cctggacttt gatgtgtcca acaaccacat 98700 ctactggcag acgtcagcct gaaggtagcg tgggccagaa cgtgcacaca ggcagccttt 98760 atgggaaacc ttgcctctgt tcctgcctca aaggcttcag acacttttct taaagcacta 98820 tcgtattatt gtaacgcagt tcaagctaat caaatatgag caagcctatt taaaaaaaaa 98880 aaagtgatta taatgagcaa gtccggtaga cacacataag ggcttttgtg aaatgcttgt 98940 gtgatgtgaa atatttgttg tccgttgagc ttgacttcag acaccccacc cactcccttg 99000 tcgtgcccgt ttgctcagca gactctttct tcatttatag tgcaaatgta aacatccagg 99060 aaaatacagg aagacttttt tttttttttt ttgagacaga gtcttactct gttgcccagg 99120 tggagtaccg tagcgtgagc tcagctcact gcaacctccg cctcccaggt tcaagcgatc 99180 ttctgcctca gcctcctgag tagctgggac tacagacatg caccaccaca cccagctatt 99240 ttttttatat ttttagtaga gacagggttt catcatgttg gccaggctgg tcttgaatcc 99300 tgacctcagg tgatctgccc gcctcggcac tcccaaagtg ctgagataac aggtgtagcc 99360 accgttcccg gcactaggaa aacttttgcc ttctaaagaa gagtttagca aactatctgt 99420 gggctggcct tctgattctg taaagaaagt ttgattggtg gctgggtgcg gtggtcacac 99480 ctgtaatccc agcactttgg gaggccgagg tgggcagatc acctgaggtc ggggttcgag 99540 accagcctca cccacgtgga gaaaccccgt ctctactaaa aataccaaaa aaaaattaac 99600 cgggcatggc ggcgcctgcc tgtaatcgca gctactcagg aggctgaagc agagaattgc 99660 ttgaacctgg gaggcggagg ttgtggtgag ctgagatggc accattgcac ccagcctggg 99720 caacaaaagt gaaactccgt ctcagaaaaa aaaaagtttg attggtgtac caaagcgcat 99780 ttgtttatgg attgtctgtg gcagcttttg ttctgccgag atgagttgga cagatctgta 99840 tgggctctaa agcctaaaac atgtgccatc cgccccttta cagaaaagtg tgctgacctc 99900 tgttctaaag tattggacaa ctacaatgtt tgctcattta ttattcatga tttgttttct 99960 gctttttgtt gttgttgttg ttgttgagat agggtttccc <210> 45 <211> 24742 <212> DNA
<213> Homo sapiens <400> 45 gcagttaccc ccatgctgct gttctcatta ttgtgagtga gttctcatga gatctgatgt 60 tttataagtg ccaggcattt cctctgcttg cacctctcct tcctgctacc atgtgaagag 120 gacatgtctg cttccccttc caccatgatt gtaagtttcc tgaggcctcc ccagcctgca 180 gaacagtgag tcaattaaac ctcttttttg ttgttgttgt tgttttgttt tgtttttttt 240 taaataaact accaagtctt gggtatttct tcattgaggt gtgagaatgg gctagacacc 300 ttttctatat tacaccatgc tcttccacgg tatgaatgaa taagcttgga ttcatggcca 360 aactgggagt cagaacaaag agggaaaacc ctcttgcctg caatgaacca tccttgccta 420 tttattcatg aataaataga caaaaaggat ttttctacct caggaaaaaa caagtgttta 480 ctgcaacaag acttcctttc aaatccactt gctatgactc tgtccttctc tttgcttgaa 540 ctagggtaca tgaatctcaa tgtaatatag ggatgtagaa aagtataaga aagccccaga 600 ataatcaata gacctctagt aagatagtca cattgctcaa tatgcaaagt gacaaatact 660 ctaagatact cactacatgt taaaaataaa tacagatata ttgttcagga tgtattcatc 720 aactacttaa ctatgtatct acccatgcat ttaataactg tgagcatata ccaggcctcc 780 attctcatgg agtttgtatt ctactggtag aggcagataa taaagaatga gaaattcaaa 840 gtaatttaaa aaataacaca ggaaaggtca tagacatttt ggtctgggag gagatggcac 900 tatgtaggct gattacctgt gagggtgcac tcactcacct cttgacttgt gaagaacata 960 ctgaaatgta cagggtgttt gggaggaaaa taatgagatg cacgggcagt acttaatgtg 1020 aagacctcac catagagaca ggaattaagt cacctggagc cagagaatac cctttatgcc 1080 tttgcttaaa agcaccattt tctgtactat ataccacaag acattggtcc atggcacatt 1140 aatggattct ggactggtaa tgggtgtcca aggataaaag gggttgaatg ggtcaaaaag 1200 ttgggaaaca ttgagtactc tatctccttt catagatgca aataaacatt agtctaatac 1260 atgttctaag gagtccttag aaaataaatc tgtttttcct gtttaactat ttgtttcttt 1320 tacttacctg aacagagctt ttttttcttc ctagtaaaaa ctgttgttgt atataaggta 1380 ccactgatta taaggtgtac cattacttta tttgccctaa gaaagaaaaa aaactctgcc 1440 aattataatt gtactatatt gtcaattata tgagaccatt ctgctttgag aggtgttgac 1500 atgaaaaaaa catgaaactt aaaaacttga gatgttggat ggaatgaggt ttggttttta 1560 gatatgtcag gttaatggga ccttttttaa aatactatgc aatggaaatt ataggattct 1620 aaggttgtgg cataaataca acctgctgat cacagaattt tgtgttcctc ttccacagta 1680 tagtattggt gctgtgaagt ggtgctcacc ataagtgtgt gtgtgtgttt aagttttggg 1740 tagggggaag agccttgaag cttagaagat gagatccctt gcaacttggt attgtgttgg 1800 gtctagtttt ggtcaaatgc aatgagagcg agataatgca tgtcacttct gagcagaggt 1860 agttaaatac atgatatcat cccctacttc ttcacattct gcagtaaact tggaggctgc 1920 atgttgaata tgaaagtata atgaaataaa gaagcctaga accaggaatc atacctgggg 1980 taatccaatc agaaatatcc tcattggtgt ttcatgagcc aggaaaactt ttattaagtc 2040 acaataaaat ctggaagttt atacacaatt agcttagtct aacacttgtc agttttgtgc 2100 atatttctta cagcatatgc attactgcca aataaaagca aacacttcta ggtccctggc 2160 gaatatggga ttcctccatt gacgactgat tatgggtcct gagttgaact tgctctgcat 2220 gaaggatgta ggcgatcaag tgcttgtttt gcctctggcc aaatctctac cactatgctt 2280 aagatgcgat taattatgta cacaaacccc catgacacac gtttacctat gtaacaaacc 2340 tgctcatcct gcacatgtac tctgaatgta aaaataaaag taaaaaaaaa gaaaacaaga 2400 ggtggttatt attctactgg ggagaaatta taggcccata atggtaacta atcaccacgg 2460 tcttacctca ttataatatg catcggtaag ttcatcaaca taagcaagtt agatctgata 2520 accaaggggc ttacagttct aatttgtatt tgacacatgg tctgccttct ggaagagcag 2580 catagaacct agatgttttg attaaggtca gtaaatgatt gagtgttaat cccattcatt 2640 tcccaggaaa aggaacctct ttacaagtca ccaccaggga ttctccaatc acacatagga 2700 aaaatttcca ggaaacttct ataaaacaca tgtattaaca tctccgaaaa catagttgaa 2760 aggacttccc tggccctttt ccttagttcc tcatctagac tatcaagcgg tttcctctcc 2820 aaatgatggg aaaaagtgca tttgtctatt acacacttgt attactctat tcacttaagc 2880 actgtgtccc ataatggggt ctagttatgt ctggcttgaa atgacccaca tatttgtttc 2940 tcattcttag aagtggagtg tttctgtatg tgtatatgtg atgggggtag gccaggagat 3000 tttttatctg gcaataccca gcctgaaatc attattagca tgacatgagt taaacgtatt 3060 tctattttga aagatgtttt caacagcagg atgaagaatc aattggaaga gctggtacat 3120 tgaaagagtg aatctagact ttgggaggct tcttaaagta tattgaacta gtctaggccg 3180 tgggattgtt caatagtaat ggtagtagaa atggcgactg acattttgga attattttac 3240 agataaattt ctacaacttg gtggaacatt ttttaaaatg taggttttat tattcggcta 3300 tggtaaaaca acagatcaga agatgatgcc actggaaata tagtttgttg tttacagttc 3360 ctagaagcgg gggcatgcca caccatgcag ggccacattg gtagcaccag agtccgtcag 3420 gagcagaggg agcaagagga aattataggc acaagctttt attgttgtta ctgcagaaaa 3480 gcaaggcaag gcagggtaag cagggatagg actggctagt ttgaataacc tcagtgggct 3540 tggggtagag ggtctgtctc tagttgtctg gtacctggac ctgtgatgat tagggctgat 3600 aacagtgtct acttgggtgt aaaagccagg tagaggaggt ggttcagagg aagggctcgg 3660 attgcttagt gtgcataagg catgctccag agcaaatctt ttgctatttt ttagaacaac 3720 tagccctggt aagtgcagtc tcttcccaga tgccagaaca tcaagaacac agaaaaaaga 3780 caattgggtt aatacatgtt tagcatgaga aatgaggaag taagggaaat aaagtaaaga 3840 gatttccacc ttggatgact atgtcaaagt gaaacaccat taactttcca gggactaaac 3900 tttattgagc acctactctg tgtcaggcac tgctctaaaa tctttacatg aatatctcaa 3960 tactcagagc aaagctttga catggaggtt gtttttatct taactctact gggtgttgat 4020 ggagtctaca agagtttgtg cccagtccac cacaaaatgg tccctcacag ctggtttttg 4080 acacgttgga ttggaagtgc ttggaggata ttacagtaga actatctagg cttagcatac 4140 ataatattcc tgttttaaat caggttctta tttaacagaa acttacattc acttgctact 4200 ttccagacac tgtcctaaaa gctttacaaa tgccagttca tttaatccaa tacaatactt 4260 tgagatacat attatcatct tcattctatc cacattttca atcctcacat agctctcatt 4320 tatggaatgt aatgatgatg ctctagacta gacgttttac gtaagtagct taattcagta 4380 attcaaaaca catgcgatta tcttcgtttt aaagaccaga aaactaaggt tggtaggttt 4440 gtataatttg actaccattg cgtatcttta ttttaataca tttttaaatg caagcttctg 4500 ctatgattaa aagtgattac cacattttac agaccagaaa gtataataag tgttggtgaa 4560 gatgtgaaaa aatgagaact cctgtacacc atttgtggga attaaaatgg tacagatgct 4620 gtggagaatc atatggtggg tgctcaaaaa attaaaaata gtttaccaca tgatccagca 4680 atctcacttc tgagtacgta tccaaaagaa ttgaaaacag gactttaaga gatatttgta 4740 caaccatgtt tatggcagca ttattcacaa tagctaacgg tggcaacaat gcaagtgtcc 4800 atgaacagac aaatggataa gcaaaatgtg gtctatacta caatggaata ttgttcagct 4860 ttaaaaagga aggaggcttt gatctatact acacagaaag aaccttgagg acattatgca 4920 aagtgaaata agccagtgac aaaaagatac atactgatga ttccacttct aagagctgcc 4980 tagagtagtc aagattatag agacaaaagt agtgctagat tcaagggcct agggaaaggg 5040 gaaatgggga gttatttatt aatgaatagt ggtgtgattg tacaaaaata tgaacataat 5100 taatgccact aaattgtaca catacaaatg gtcagataat aaattttatg ttatgtcatg 5160 ttatgttatg tgattttacc ataatacaga aatgaaaaaa gaaaagaaag aaagtaaagc 5220 ttagcggttt acatgacttg accaatgcct caagccatga gtcacccagc tgagatctga 5280 acttcagtat attccattct gaaatcccag cttttcccaa tcttcttgta cttttcaaac 5340 tgtgtttcag ttgaggttta ttttcagttt gtatgtgagt ttcttcacaa gaaggggcgg 5400 gccaaattgt gtcctgcaaa aacctacaat cgaagtccta acccctctac ctcagactat 5460 gactgtatat ggagagagag ccttgaagag gtatgtaagg tagaatgagg tcattatggt 5520 gggccctaat ccaacataac tggtgtctta taagaagggg agattagaat tcagacacac 5580 ttgctgacac cttgagttca gactgaagcc tctagaattg tgagaaaatg aatgtctgtt 5640 gtttaagcca cccagtctgt ggtattcctt atggcagccc cagcaaacta atacaaatag 5700 tgtttccaca gctgaaacaa aatggaaaat caccgtcatc ctagagagtt acaagggcta 5760 ttttaataga acctgattgt ttcctaaatt caccaagccc aggcagaggt cagatgacta 5820 attgggataa aagccaacta gttcctcttg ctgtttcttt agccactggt ctgcaggcgt 5880 tttcttcttc taacttcctc cctgtgacaa aagagataac tattagagaa acaaaagtcc 5940 agaatgctaa ggttgccgct tcacttcctc tcacccttta gcccagaact gctttgaata 6000 caccaattgc tgtggggcgc tcgaggaaga gaagacacca gtgcctcaga aactgctcgg 6060 tcagacggtg atagcgacca cgcattcaca gggccactgc tgctcacaga agcagtgagg 6120 atgatgccag gatgattctg cctcgcgcct ggctgggact ctgatcccag ccatggcctt 6180 cctctcctgc gtgagccaga aagctgggag ccctgcgtgg aggtatgtgg ctggagtcag 6240 ctcctctgaa ctttcctcac ttctgcccag aacttctcac tgtgtgccct ggtttgttta 6300 tttttgcaaa aaaaaaagag ttaaattacc ttaaagactc aagaagccac agagatcaaa 6360 taattcattg ttcagggcac tagaggcagc cattgggggt ttgttccatt tggaaatttt 6420 gagtgctaac agggcatgag ataacataga tctgcttaag gtccctgctc tgctaccttg 6480 tggctctgtg agaaattatc aaacctgtct gagactagtt ttcgcatctg taagagaatt 6540 ataatacctc ttcactagag agtaagcaga ctgcttcagt gtcatttctt cccactggtg 6600 gtctttacct cagcttcaag cagtcaccct gctcctttca atctcaggaa aaagatggct 6660 tttgtgttgt gtctctagag aaagaacttt ctaagtgggt gtcagacttc tgtatgcagt 6720 aatatattta gtccagagga tgaaaaaaat aagagaatga aaaaggaaaa gagagagaga 6780 gagaaaaaaa agcaagaggg aaatatgtat aatgtcagct aatgcaacag tttctttctt 6840 agtgaatacc aatcagctgg ttggtaatct tattcatgat ggatctcttt tgtttttccc 6900 ctggcagact tcacagttgc tttagaaacc catagtagag ccgaacagct aagaaaatga 6960 ttacagtgag gcagggtcag aaactcaaga gagaaaaagc cagctgcagt cctgaagttg 7020 agatatagga gaaaatcaag taatatttag caaagactaa ttcattatct tgaagccatc 7080 cttccctcaa ttccctgccc atagtcctcc tccttgtcct cttctctgta tccctctgcg 7140 ttaggttaat ggagatagat tttctaatta ggctcactgc gagataaaac cacagccaac 7200 ttgacttctt ttccccatgt accttttcct gtcagtccct gaagcctgtc catccctccc 7260 atccccttag ttccactgta aggcaggccc tcatttcccc tggcattgac tcttaccact 7320 aactgctttc ctgattccag tcttcttcct ttaactcatt ctgcacgttc ttgttgttat 7380 gtacttgcat ttgttgttat tatttttcct taggcttcaa tctaacaaat tacttcctta 7440 aaaactttta ataactctcc attgccatta gaacagcttt ctaccacagg gccttgcact 7500 ggctatttct tctacctaga atgctagatc agtgctatcc attggcaata tttgtgagcc 7560 acatatgtac ttttaaagtt tttagtagcc tcattaaaaa aagaaacaag taatttaatt 7620 tcgataatag ttttatttaa cttagcgtat ttaaaataat gtttaaaatt taatatatat 7680 ttacctatta ttgatatttt tacattcctt gtttggtact aagtctggat ttagtatata 7740 ttttacattt accacacttc tcaatttaca ctattcacat ttcttgtgtt gataactgtg 7800 tatggctagt gactaccgta ttggtcagtg cagcccaagt ccttttctgc tttaatcact 7860 ccattcagat ctctgattaa atgtcccctc ctcagggcag tcttcctgat tgccccatgt 7920 agagctctcc agcctcactt atttgcctca aatcccctta tactgttaat attttttttt 7980 ctagagcaca acattttata tttttgtttg tttattttct ctcttccctt tgtaatggaa 8040 tcggtaagga ggcaggatca ttgctggttt tatttaccac tattttccag tggccagcac 8100 acagtagccg ctagatgtgt aagtgataaa tgattgaaat aatgctgcag gacaaagtct 8160 gaggccctcc tgatctggct tgccctctta cttagatttc acactcccac cactcaccag 8220 ctaatctgag tttgttttcc actctttacg tgctcacgtt tcctctcctt aggacatgtt 8280 tttcttcccc tttccacata tctaaacctt actcatcttc aagacccact ttaaaatctt 8340 ccttttctgg gaagcctttc ctgaatccag acttgatcct gctttctctg aaccacaggg 8400 catattttct aagcctattt tatggcccct tgagatatgt tagctttgct cctatctaaa 8460 ctcttactct agactgtgag tccattgaag tctggactgc atcatatttt tctttgtaat 8520 gcccacagca cttggcagga aatgcctaca atttgactta agtaaacctt catttaatca 8580 gttattcaat cagttagtga ttcagcaaat atttttgagc accaaccatt tgccagacac 8640 cattctgagt gctggagaca aagcagtggg caacccatca aacttgcaat ggaatacagg 8700 agatgaacaa tacgatgaga acaatcagat agcaacataa tgttagatgg ttgtgcttcc 8760 tgtgaaaggg aataaaagag ggcaaagaaa ggtgcctggc actgtttcta ttagacaata 8820 ttgtctttga ggctccatgg cttgcaacat taagcagaca tacgaatgaa gatctgcatg 8880 tttgaactct gactttgcgc atattactta tttctttgaa tttccatttt cctcatcttt 8940 aaatgcttat ttgaagatta agtgaaagat ataacaaaca agaactatgc aggcgtatgg 9000 taagggatta atgatagatg ataataataa tgttgacatc tattgatcac ttatactgta 9060 gcgggctttt aaataaactc tttaaaacct tatctcattt aatccttcaa acattctatt 9120 ggtttcaaac aacagaaaac tacaatagct ggcttctgca aggaattttg ttggaggaaa 9180 tgagagcatt cagaaattag atggagcgtt agagaattag gcttacaaag aatgtgggaa 9240 agtaggctag aaagcagtgt aaaacaaaga cagcataaag cacttgacct tatttactag 9300 gttccaccat gggaatccat gcctctaaag atttccccct atttctacat cactttgctc 9360 aagggtcaat gagccaagga aagaatgcag ttgtcaaaat ctgggccatg actaaggaag 9420 gtctggacat cttgactgcc gacagtctcc ccaatgatat ggagtattta gaatgatact 9480 ggatatttta tttatttttg tattttcaac ttttaagttc agaggcacat gtgcagagca 9540 tgcaggttta ttacataata aatgtgtgcc atggtgattt gctgcataga tcatgaaaat 9600 atggaacgca tcatggattg tgtgtcatcc ttgtgcaggg gccatgctca tcttctctgt 9660 atccttccaa ttttagatat gtgctactgc agcaagcacg atattggata ttttattacc 9720 tacattttac atatgtaaaa tgaggctcac tgaggttttt cttttgttcg ttttattttg 9780 ttttgttttt aaagcttggc cctaaaccac acagaagagc tggcatgaaa cccagagctt 9840 tcagactccg gagctcagcc cttcaccccg attccattgc ttcttgctaa atgctgccgt 9900 tttatcacgg agttagaatg ctgagcacgt agtaggtgct ctttactttc taatctagag 9960 taagacaatt ttaagcatga attgagtgaa tggatggatg gatatatgga tggaaggatg 10020 gacagatgga gaaaggttga ctgaattttg tgcttgcaca aaaagaggcc cctctccacc 10080 atctctggtt aggagagggg agttgggaga ccatgcagta aagatacttc atgtcatgtg 10140 taatcattca ggtggttcct aatattactt atcaatgcat ggagctgaat ttctacaaaa 10200 tocccgaaac ctccccttct caaccaagaa cctggacctg agctttaatc ccctgaggca 10260 tttaggagct atagcttctt cagtttccca gaactgcagg tgctggattt atccaggtaa 10320 tgaatcactt ttacatactg cacaaggtga ggtgttcatt gtcctatcat ttcattattg 10380 gactgaaagc ttggtttgtg gagtctcatc ttcattcact tattcattca tacaacagat 10440 gtctattaac tatataacct tgagcaagct acctctattc tccaggtctc agttttctaa 10500 tcgtgaagta ggcagttggc tgagacagct tctaagggca attctaattt taggttttct 10560 ttaagacagg agagaaaatt agcttaaatt ctttcataag cagctattta ttgactactt 10620 ctatatgttg tacactctgc aagaagacag gcatatattg atatataaca cacagccccg 10680 ttgttaagga ggcatatctt cttgaaagag ttaatacctt aaagtcctgg gtatggtctg 10740 ggtacatagt atatagtcaa cacattttaa ttatgatttt ttggatctgg aaactgaata 10800 aagatagcga catataacag taggtgataa attatgttta aactaaaggt aactaatgta 10860 tttttcagaa gaggggcctt ctctgtggtg ggtagtcaag aaagatttca tgaacgcata 10920 agattcaaac aatgtctaga atattaaaac tagtgtacag gatagggaat taggaaagac 10980 aagtaaccca aggagaaaga tgtcaagatt aaaggaaaac atctgctgtg ggcgggaata 11040 atggctaaga ttttcttttc tgatgcaggg aagtatatcg tttgttgtgg cagtgaaatg 11100 tcatcttgat attttagggg aaccaaattc taaaagggtt ttcatcatcg ggccttattt 11160 gcaaatcgaa ctagataatg gatcatgttc tctgcaatgg tttgtaaaac tttcaaaaca 11220 ttttacatat tttttattat agaaattatt gataaagact aaggtcacat ataaaaatcc 11280 tttttagagc agacatttct gtagaagagt gaacatatga cctattatct ctaatttgga 11340 tatagatagg atgtaacaaa ggagtaatgg aacaattcaa aggcagtgta tagtgcatag 11400 agtcctgttg gggtcagaag acctgagcca agtttacccc caacattata accatgtaac 11460 cttaggcata ttacttcatc tcccttaatc ttagttttca tatctatcaa tggaaatgat 11520 gaaacttatt ctgctggatt aaatgtgata ataaatatta atatctgtat atatttaaat 11580 ttttataaaa tatattttat aagcataaag tattcttaca gaattcatta ggtttttaaa 11640 ataatttcaa cttttatttt tgattcaggg atttacatgg tttattgcgt aatgctgagg 11700 tgtagggtac aatcgatacc atcactcagg tagtgagcat atacccaata gttagttttt 11760 caacccttgc tgctttctct ctatcccctc tctagtaatc ccagggtcta tttttgtcat 11820 ctttatgtcc atgtgtactc catgtttgga tcctacttaa aagtgagaac tcatggtatt 11880 tggctttctg ttcctttgtt aatttgctta ggataatgct actagctgca tctatgccat 11940 tatgttctaa atttcagttt cctgcatgaa aattttgcaa gtactctatt aaggtagacc 12000 acctctccct tttttttttt ttcaaacaag aagtagtttt caccaaacaa tgtctcttat 12060 gtaattcatc ttcaatccac tggataccca ataaattgcc ccagaaacct taaatctgtg 12120 cttacagaga ggccagcttc ccttcttgtt aaccatagga gattctgaat tagggcaagc 12180 acaaaagata gcacaataga catcctttgc ctttcgtaca gtgttcacat acagtaactc 12240 aactagtctt gtaagaatgc tttgtgatag acaggcagcc ttctttcccc tatagaaata 12300 tatatatatt tctttttata ggtgaggaaa cgaagcttga ataatttaaa tgacttatat 12360 acattatcat tgcttgttag ccacagacca agatttaagt tcacatctcc agaatccaac 12420 ttaaatgttt tctttgtctt aatactctat tctctaaagt gattatcacc aatgtaatga 12480 tatagagaca cagcaagacc ctttcctttc acctaatgta tagagcaatg cagagataga 12540 atgatgggct ataacaatca tataattaaa gaaagaactt caaaaataat caagttcagc 12600 tgtttgattt ataaatgtga taactaaacc tagagaggaa aagaggtact caagatcaca 12660 cagtaggaga ggactgcaga aacacaaacc caagctcttt tgtccactct tccagcgttc 12720 tttctactat actgcctatc cttttctagt taccaataaa taacaaaagc ttggaccaca 12780 atgcttttat tgtctaggaa actctgaaga agctaaataa aatgggtggg gaatattgta 12840 aatgtaattc aggctggatt aaaaagaact tatttgtaca ttgtaactga caagcacctg 12900 caatgctgaa aggaattttt cttggcttgc tgtttgctgg ctgcatcaaa gccctgtctc 12960 taggacatgt ctctgaacat gtgtgtagca tggctttcat ttcttttagg ataaaattca 13020 aaacccttta tctggttgga aacctctgcc taattgggaa ccttctttct ccacaactcc 13080 atattgtaca ctccaattca tctctgttct ccaaccatgg aagctatttg tcatgattcc 13140 tccttgtgtc atttttttct gtcaaccttg gggcttttgt gtttgctgtt cacttcacct 13200 ccttttattg ttaactctac tcatctttca attttcaact taagtgttct cagagaaacc 13260 tactttgatt ttcttgtcca caacggttct ctggatgtga actcttatag cacataattt 13320 tcactttttt ccacaaactc gctcctatca cctgttacaa gcatttacct ctgataacaa 13380 gaactttcaa atactagctg tcatgtaagc acttttcata aacattaaga gtatctgtga 13440 cacttatgtg tatgtttcgt atctctgaaa ttgatattta ccagtcattt atcttggcta 13500 ccaactaaca atatccatat tatctgtacc aatcagatgt ataatcacaa ttttgtgtga 13560 cagaaaatgg taaacttgat ccaaggctat tacatgcttt atcaactgca caatctttat 13620 atatgtcaat attgatcttt aactgatttc cttcttatgg attttctcct ctgcttatca 13680 tgtatgccaa catgacaaaa aagagcctat cattgcagcc agtatgataa tactcagtct 13740 gtggggctct tatttgctta ttccatcatc atctgtcctg cttgatgtct ttgcctatgc 13800 acaatctatg acccatcaca tctgtatgaa gagctggatg actaggatta atattctatt 13860 ttaggtctta ttcagcagaa atattagata atcaatgtct ttttattcct gtaggtgtga 13920 aatcagacaa ttgaagatgg ggcatatcag agcctaagcc acctctctac cttaatattg 13980 acagaaaccc catccagagt ttagccctgg gagccttttc tggactatca agtttacaga 14040 agtggtggct gtggagacaa atctagcatc tctagagaac ttccccattg gacatctcaa 14100 actttgaaag aacttaatgt ggctcacaat cttatccaat ctttcaaatt acctgagtat 14160 tttctaatct gaccaatcta gagcacttgg acctttccag caacaagatt caaagtatta 14220 ttgcacagac ttgcgggttc tacatcaaat gcccctactc aatctctctt tagacctgcc 14280 ctgaacccta tgaactttat ccaaccaggt gcatttaaag aaattaggct tcataagtga 14340 ctttaagaaa taattttgat agtttaaatg taatgaaaac ttgtattcaa ggtctgctgg 14400 tttagaagtc catcgtttgg ttctgggaga atttagaaat gaaggaaact tggaaagttt 14460 gacaaatctg ctctagaggg cctgtgcaat ttgaccattg aagaattccg attacatact 14520 tagactacta cctcgatgat attattgact tatttaattg tttgacaaat gttcttcatt 14580 ttccctggtg agtgtgacta ttgaaagggt aaaagacttt tcttataatt tcgatggcaa 14640 catttagaat tagttaactg taaatttgga cagtttccca cattgaaact caatctctca 14700 aaaggcttac tttcacttcc aacaaaggtg ggaatgcttt ttcagaagtt atctaccaag 14760 ccttgagttt ctagatctca gtagaaatgg cttgagtttc aaaggttgcg ttctcaaagt 14820 gattttggga caaccagcct aaagtattta gatctgagct tcaatggttt attaccatga 14880 gttcaaactt cttgggctta gaacaactag aacatctgga tttccagatt ccaatttgaa 14940 acaaatgagt gagttttcag tattcctatc actcagaaac ctcattacct tgacatttct 15000 catactcaca ccagagttgc tttcaatggc atcttcaatg gcttgccagt ctcgaagtct 15060 tgaaaatggc tggcaattct ttccaggaaa acttccttcc agattcttca cagagctgag 15120 aaacttgacc ttcctggacc tctctcagtg tcaactggag cagtgtctcc aacagcattt 15180 aactcactct ccagtcttca ggtactaaat atgagccaca acacttcttt tcattggata 15240 cgtttcctta taagtgtctg aactccctcc aggttcttga tacagtctca atcacataat 15300 gacttccaaa aaacaggaac tacagcattt tccaagtagt tagctttctt aaatcttact 15360 cagaatgact ttgcttgtac ttgtgaacac cagagtttct gcaatggatc aaggaccaga 15420 ggcagctctt ggtggaagtt gaacgaatgg aatgtgcaca ccttcagata agcagggcat 15480 gcctgtgctg agtttgaata tcacctgtca gatgaataga ccatcattgg tgtgtcggtc 15540 ctcagtgtgc ttgtagtatc tgttgtagca gttctgtcta taagttctat tttcacctga 15600 tgcttcttgc tggctgcata aagtatggta gaggtaaaac atctatgatg cctttgttat 15660 ctactcaagc caggatgagg actgggtaag gaatagctag taaagaattt agaagaaggg 15720 gtgcctccat ttcagctctg ccttcactac agaactttat tcccggtgtg gccattgctg 15780 ccaacatcat ccatgaaggt ttccataaaa gcgaaaggtg attgttgtgg tgtcccagca 15840 cttcatccag agccgctggt gtatctttga aatgagattg ctcagacctg gcagtttctg 15900 agcagtcgtg ctggtatcat cttcattgtc tgcagaaggt ggagaagacc ctgctcaggc 15960 agcaggtgga gctgtaccgc cttctcagcg gaacacttac ctggagtggg aggacagtgt 16020 cctggggcgg cacatcttct ggagacgatc agaaaagccc tgctggatgg taaatcatgg 16080 aatccagaag gaacagtggg tacaggagca attggcagga agcaacatct atctgaagag 16140 gaaaaataaa aacctcctga ggcattcttg cccagctggg tccaacactt gttcagttaa 16200 taagtattaa atgctgccac atgtcggcct tatgctaagg gtgagtaatt ccatggtgca 16260 ctagatatgc agggctgcta atctaaggag cttccagtgc agagggaata aatgctagac 16320 taaaatacag agtcttccag gtggcatttc aaccaactca gtcaaggaac ccatgacaaa 16380 gaaagtcatt tcaactctta cccatcaagt tgaataaaga cagagaaaac agaaagagac 16440 attgttcttt tcctgagtct ttgaatggaa attgtattat gttatagcca tcataaaacc 16500 attttggtag ttttgactga ctgggtgttc actttttcct ttttgattga atacaattta 16560 aattctactt gatgactgcg tcgtcaaggg gctcctgatg caagatgccc cttccatttt 16620 aagtctgtct ccttacaggg ttaaagtcta gtggctaatt cctaaggaaa cctgattaac 16680 acatgctcac aaccatctgg tcattctcga gcatgttcta ttttttaact aatcacccct 16740 gatatatttt tattttatat atccagtttt cattttttta cgtcttgcct ataagctaat 16800 atcataaata aggtttttaa gacgtgcttc aaatatccat attaaccact atttttcaag 16860 gaagtatgga aaagacactc tgtcactttg tcactcgatg tcattccaaa gttattgcct 16920 actaagtaat gacgtcatga aaggagcatt gaaataattt gtttaaaggg ggcactcttt 16980 taaacgggaa gaaatttccg cttcctggtc ttatcatgga caatttgggc tagaggcagg 17040 aaggaagtgg gtgacctcag gaggtcacct tttcttgatt ccagaaacat atgggctgat 17100 aaacccgggg gacctcatga aatgagttgc agcagaagtt tatttttttc agaacaagtg 17160 atgtttgatg acctctgaat ctctttaggg agacacagat ggctgggatc cctcccctgt 17220 acccttctac tgccaggaga actacgtgtg aaggtattca aggcagggag tatacattgc 17280 tgtttccgtt gggcaatgct ccttgaccac attttgggaa gagtggatgt tatcattgag 17340 aaaacatgtg tctggaatta atggggttct tataaagaag gttcccagaa aagaatgttc 17400 atccacctcc tcagaaacag aacattcaag aaaaggacaa tcaggatgtc atcagggaaa 17460 tgaaataaaa accacaatga gatatcacct tataccaggt agaatggcta ctataaaaaa 17520 atgagtgtca tcaaggatat agagaaattg gaacccttct tcactgctgg agggaatgga 17580 aatggtgtag ccgttatgaa aaacagtacg gaggtttctc aaaaattaaa aatagaactg 17640 catatgatcc agcaatctca cttctgtata tatacccaaa ataattgaaa tcagaatttc 17700 agaaaatatt tacactccca tgttcattgt ggcactottc acaatcactg tttccaaagt 17760 atggaaacaa cccaaatttc cattgaaaaa taaatggaca aagaaaatgt gcatatacta 17820 caatgggata ttattcagcc taaaaaaagg gggaatcctg ttatttatga caacatgata 17880 aacccggagg ccattatgct atgtaaaatg agcaagtaac agaaagacaa atactgctga 17940 tttcatttat atgaggttct aaaatagtca aactcataga agcagagaat agaacgtggt 18000 tcctagggaa aaggaggaag ggagaaatga ggaaataggg agttgtctaa ttggataaaa 18060 ttatagtatg caagatgaat tagctctaaa gatcagctgt atagcagagt tcgataatga 18120 acaatactgt attatgcact taacattttg ttaagagggt acctctcatg ttagtgttct 18180 taccatatac atatacacaa ggaagctttt ggaggtgatg gatatattta taccttgatt 18240 gtggtgatgg tttgacaggt atgtgactat gtctaaactc atcaaattgt tacattaaat 18300 atatgcagtt ttataatatc aattatgtct gaatgaagct ataaaaaaga aagacaacaa 18360 aattcagttg tcaaaactgg aaatatgacc acagtcagaa gtgtttgtac tgagtgtttc 18420 agagtgtgtt tggtttgagc aggtctaggg tgattgaaca tccctggtgt gtttccatgt 18480 ctcatgtact agtgaaagta gatgtgtgca tttgtgcaca tatcccatgt atccctatca 18540 gggctgtgtg tatttgaaag tgtgtgtgtc cgcatgatca tatcttatag aagagagtgt 18600 gattatattt cttgaagaat acatccattt gaaatggatg tctaggctgt ttgagatgag 16660 ttctctactc ttgtgcttgt acagtagtct ccccttatcc ctttgcttgg tggatacgtt 18720 cttagacccc aagtggatct ctgagaccgc agatggtacc aacctcatat atgcaatatt 18780 ttttcctata cataaatacc taagataaag ttcatcttct gattaggcac agtaagagat 18840 taacaataac taacaataaa attgaatagt tataataata attgtaataa aagttatgtg 18900 aatgtgatct ctttctttct ctctctcaaa atatcttacg tactgtactc acctattttc 18960 agaccataac tgaccatgaa acctgggaaa gtgaaacttg gataagtgag gaactaacat 19020 acatacatga ttgtttatct acagatgtat gcctcagttc ttagtatgct tgaaaatgta 19080 tgattttgtg tatatccgtg ctacatgtaa gtgtggtcta ttcatatttg aatatgaatt 19140 ctgcataagt gtgtttattc aagcaaatgt acaagctctg agaaggaaga tcaacataca 19200 acttggaata tttcaaggcc gaaatattca aggcgacatt ggcctccttc ctatcagttc 19260 cctctcccag atggaaattc tagaaatggc agggaggtgg acaagcaggg aaagaaatta 19320 tatgcataga acagaaggag aagaaagagt aagtcaggcc tcagccagcc tctttttagc 19380 tctttaaatc ctctggattt aagagggata agggtggaat aaggataaat taatgccaat 19440 tgtaatgcct taaatttgtg tgatacctta aacttgaaac atattcacaa aactatatat 19500 ttgaatatct cattagctga gtaaggtaga aatcataatt aactttttcc attttattga 19560 tgggaaagct gaagttcaat gaagtaaatt ttcaatagcc cacagagtag gaaagtgaca 19620 aaacctgagc ctgggcctcc aggtcaccaa ggacactttc tttcttccac acccaattgc 19680 ttcatgctta aagttggcaa aacaggagtg aaactcctgc agttttctgt gtggttgaca 19740 ctagcaaggg tttctcagtt gaagcatgaa tcattaagcc aatacatatg catatatgtt 19800 atacatacca aatgatttat ttatacccta tctttccata aaggacttga aggagcttca 19860 aacaaaggat atgtgaacaa taggttaatc aataataagt agaaaatctg gacatagaat 19920 aaaaagagga gagaaagaca ccagaatgag cgttaataca gtgctttcca tttttctggt 19980 gttttgagta gcgtggcttt tgagaaagcc aaaactcaaa ttcactcctt atcaactgtg 20040 tgccttgggc tccatttctc gagagtctac ttagctccaa tgtaaaataa gaatagaact 20100 atgactttgt aaggttgctt aaggattgaa aatcatgtat tatgttcaat acggggacac 20160 tgtccttatg ggtgagtatc ccctaagact ttattaagag ggcactagga gaagcactgg 20220 gaggtcttct cagtaacaca ctaaagtaat tgctattttt ccagcctgtg gaaccacaga 20280 agtgactgta actaaattag acatttcttt ctgattcatt ctctactcac gggattgtca 20340 gaccccagtc ttctttggac tctataaact ttttagaaat catcagcagg ctcctggaga 20400 agcttaaatg aactacacaa tatgtgacag tgaactccct gggagagtga aaaccaaagt 20460 ctaagccagt gtcccattta cttgtgtgat tgtgggcaag tcattcaagt gctttgaggc 20520 tcaggtctta atcatgaaat ggaggtaata ataccttgtt ggcagacctc acttggttaa 20580 aatgataatg tgatagttac aatagttaca tttaattgat caattgtttt atgcaagggc 20640 tttatttgtg tatctcagtt tgtcacatca atgaattaga aagatacgaa agtatttcca 20700 atttacaaag aggagtctga gtctgggagt cattctgtca tgtgtccact gtcacctgct 20760 cattggtgca gcactgagat taggatctaa gtccacttca ccgcagaagc agggcttcta 20820 aatactgtct atggcaagag caccctgctc tcacaaaatg cataaaactt cctatctcac 20880 cattatattt tgactgatat taaacaaaga gaagtattat tattattact tgtttttatt 20940 tatatacagc tgtaagagcc aggaaaaatg tgatctaagt tatgtgatca aagatttttt 21000 aacatgaaca aatcaggccc actagatgat ggcctttctt tgaacaacat gcctagggtt 21060 gcttatcatg tctacagttg gtctgacttc ctgacgggca tcacagactt gtgattaaac 21120 acgaggttat gggggaagtt ccaaaagctt aggactttcc agatggttgg aataagatca 21180 ccactctggc tgcccttatg gagatcaccg aacttttcaa ctcaaagtaa aatctgtgga 21240 taaatggtcg atcaaaagga accaactata ttgagcacca tgcgtgatca tctgatcgta 21300 ctgctacctt gtgagttaaa ggctactctt ctcattttag aaatgagaaa agagatgcca 21360 gagaggacga gtaacttgcc ttaggtcaca cagcttatat taatcacaat aacatttccg 21420 caccttctgt atttttttta agttgctaag cttttggtgc atgtctggca ccgtttagtt 21480 gtatattatt tcatttaatt gttaaaatga ccttctgatg caggtatttg tagcttgcca 21540 ttccacagat gaagaaacag atgaaaggac tgaattgttc aataggaagg agcaaatcag 21600 gatatgaact tgggttggcc tgattcttgg ggctgcattc tttccataac atattgcttg 21660 ctgtgatgtc ctgggctact ctgccagggg tggttagtgg agtgaatgga gataatttag 21720 acaaggtcag taactcccat gccatctaga aattaaaagt ttaaaaggca ggtctgcaac 21780 tctccttgat ttctacagaa ataaagatga tccctcctgt gacagtgcta gtgacaattc 21840 tgagtgtaaa tgcgcttttt ggcacaaatt gtcctgtcct aatagtctta ttataattat 21900 aaaataatgg gtttctgaaa ggctgcaagc agttctggga atggcaataa ggtttagaaa 21960 tgacgtgatg tttatgagag aagtgttttg ttgaaaatta aactcacttt aggagaaagg 22020 attgtgttgt atgctcctag gaaactatct cactatgtaa ttaaataaaa ccagccagtt 22080 accaatttga gctcttgact catactaaca acaccccatt tcccagggcc aagcaaggca 22140 ggactgacct gaaataaccc agcctgactc tatccacagc cacccaggac cttgcccctc 22200 cgtcttccta gggctcggcc gtgagatgct agtgcatgac cctcctcttc ctgggactgt 22260 ccttgtcttt ccctttggac tctgggaggt ctgttctcct cccagaaagg aataaacact 22320 ctttctattt gtgggattcc ctaggagaca ctatataaaa aatagagtta aaaaaactat 22380 ttaaaaaaaa gacaacttca tgtctctact ctgacttcat ctttttaaga tgggtaacaa 22440 agactctctt caaggttaga aaattttatt ttaatttttt agatttagag agtgcaaatg 22500 cagttttgtt acatgaatat attgcataat ggtttagttg ggctgttagc gtaaccatca 22560 actgaacagt gtactttgta cctattaggt actttctatc ccttaacccc ttcccacctt 22620 tctgagtcct caatgtctgt tatttcattc tccatgccat gtctacaaat tatttagttt 22680 ccactcataa gtgagagcat ggatggaact ggagagagta ttttctatcc caagatcggt 22740 tccttgatct tgtgtctcca aatcacttgc tctcctctta catcttttct atcttcttct 22800 agcctctttt tgcaaacttc attttgacaa agattccagg cagtctacag ctgattttat 22860 ttcaatacaa cgattaaaat ggaaaccata tagaagatga caaagttgag caggtcccaa 22920 actctcactt ttaaacaaat gcttggctta aaatcactta atgactttca ttctgctatc 22980 tatgtgtctg tgtatctagg tactaattat tatctttatg atctttattg ctagaaattc 23040 tggttcaata tcagaggtta gtcctaagga tttatatttt aaaatattct cccagttttc 23100 gtgcacagac agatttggga attactgtat aatggaaaat ggagaataac cacccacatt 23160 taatatggtt attggttttg ttcttgaatt tattgctaag attcatgata gcccaggcaa 23220 ggtcagataa tgtattttta ttttacctgt atagttgatt cttctcaatc ccactagatc 23280 agactctttg ggatactagg attggctatt tgatggtgag ctcactacat ccatttagat 23340 gttgtgtcca tgcaatcatt ttagtctcct agtttctacc tatcacgttg tcattttccc 23400 ttctttatca tcctgggtag ctggacccca cataaatata taccagaaaa atgttgtggt 23460 cttttctaaa ctctctgagg cactgttgtc aatgtgatgt tgttttttgt ttccagtcca 23520 aaatatatca aagtaaaatt tactccactt ttgctaagta ttcatcttgc cttgagtact 23580 aagattccaa aaatgacttt ccctctgaaa aacacaggat ttccttgcga aaacttgctg 23640 ggccactgcc aatcttcccg aaactccttt ttccttatcg ttgaggggaa ttggggaagt 23700 gatcactgac ggttgaaatc agtagttttg gtctttaagc tgagaccctg agtcttctga 23760 ggagtctact gctccccgtg ggaaacacct gctgtcaaaa ttttcctgct tgcaaagagc 23820 acttttgaaa ttaatgcagg ggatgaatat ctggctagtg ctgtgctcag ctgagttatt 23880 aatagggcct tctgatcctc tctacacatc atctttggct gaattagctg tggtttcagc 23940 acctgagagt ctagaccact aaaggcaggg aatacctttg ccagtttctg gcatattaac 24000 agctgagatc agaaagtgaa cagcgataga ggtagtgagg tttaggattc aggtctgcca 24060 ccgggagcgc actctgggct caggtctctc atttgtaaaa tgggacattt aggtcagatc 24120 agcattttca aagtgtgaca tgttagtaaa taagatgatt ttatgtggtt gacagatgaa 24180 tgtattacct tagtggttat atgtttattt tcatggttac ttttatttat aataaatttt 24240 gtgactagca agaatcaatt atctctttaa aatatattta agtttaaaat gtgggccaac 24300 ttaggaaaaa acgggatgaa atgaattata taaaaggtat gcagatttgg aaaaattttg 24360 aaggtgtaca agaaagattg gcagtcagaa aggaatgaac caaacggctg ctgagggtca 24420 ggccagtctc tgacattcta gcatgttcac atctccaggg ctgtttcctt acctataaat 24480 tgtggaattg gagtaaatgt ccattccagg aattctattc tatgattaga ggtgtaactt 24540 catctccaga ttttccagca tccttaacat gtggttttag cgttctaaac ctgatgatgc 24600 tattcaaaac gggagactca ttcgtcaagt catgatgtat ccatgtattt ataatatttc 24660 cctgttccct catttctgaa aaggattaag ctatcaaccc cattgagtta taggtgaaag 24720 gtgtggaaac aagacattga ta 24742 <210> 46 <211> 20304 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <222> 18801, 18802, 18803, 18804, 18805, 18806, 18807, 18808, 18809, 18810, 18811, 18812, 18813, 18814, 18815, 18816, 18817, 18818, 18819, 18820 <223> n = A,T,C or G
<400> 46 tatgtttata accctgctat agtatgttta acaagcacaa ataccagaac ttgtcctact 60 gggtgataaa gcaattacaa attgcaaaaa aaagagggaa actatgggag tagccctcaa 120 ttatctccga actgatttac ccattcactc acctagaact gcattaaaaa acttaagcag 180 aagagtattt tattctcttc gcaaaaattt gttcttgtca gtatcaaatt aagagagtaa 240 atcaggactt atcctgatta acatttatct ccttttacaa ctatcaaaga ataaacaaca 300 gtataaatcc tctttttgtg attatagttt cacattgtca atattccctc tattataagc 360 ttgaaataac ttactggaat aatcattcat ttctaaacat aaatgaaata cactaataca 420 gtgatttata aatatatttg gtatgcttag ttttagaata cagtatagta tatttatttt 480 ggagatttaa ttacagaaaa aaacttctga atagataaca tggttcaaaa tcagcaagtg 540 caaaaagtat acactgaaag ttcttgtccc tttgtcctgc aaccctgagg tccctttgtt 600 ggaagcaatc agtattacga gtttcttgta tatgcttcta gagagttctc cgattgcaaa 660 caactgcaaa tacttctgca cacctttgtt tttacaaaca ctagcatata ctctgcacat 720 taccattata attgtactac atttttctcg catcacatat gctagagttg ttcccaacac 780 ggaacattgt gcacaaagag catattcagt catcttttac agccacgagc agtccactgt 840 atgcagctat catgatttat ctaaccaatc cctactaatg gacattaggt gtttctaatt 900 tttagctatc acaaacaagt agcattagta tgctttaaaa taaacaatac ggccaggtgt 960 tgcgagaagt cagggacccc aaacagaggg accggctgaa gcctggcaga agaacgtgga 1020 ttgtgaagat ttcatggaca tttattagtt ccccaaatta atcttttata acttcttatg 1080 cctgtcttta ctgcaatctc tgaacatgaa ttgtaaagat tcatggacac ttatcacttc 1140 cccaatcaat acccttgtga tttcctaggc ctgtcttcac ttaatctctt aatcctgtca 1200 tcttgtaaac cgaggaggat gtatgtagcc tcaggaccag tgataattgc gttaactgca 1260 caaaattgta gagcatgtgt gtttgaacaa tatgaaattg ggcaccttga aaaaaagaac 1320 aggataacag caattgttca gggaataaga cagataactt aaactctgtc cgttggtgag 1380 ccgggcggaa cagagccata tttcttttct ttcaaagcaa atgggagaaa tatcgctgaa 1440 ttctttttct cagcaaggaa catccctggg aaagaaatac acgcctgggg gcaggtctac 1500 agacggtccc ccgggcgtgg ccatctttta tggttgtaga ctgtagggct gaaatagacc 1560 tcagtctccc atatcgctcc caggcttatt aggagaagaa attcccgcct aataaatttt 1620 ggtcagacag gttgctctca aaaccctgtc tctgataaga tgttatcaat gacaatggtg 1680 cccaaaactt cattagcaat tttaatttca cccagtcagg tggtcctgtg atctcgccct 1740 gcctccattt gccttgtgat attctattac ttgtgaagta cttgatgtct gtgacccaca 1800 acctattcgt atactccctc cccttttgaa atccctaata aaaacttgct ggtttttgca 1860 gcttgtgggg catcacggaa cctacagaat gtgatgtctc ccccagacgc ccagctttaa 1920 aatttctctc ttttgtactc tgtcccttat ttctcaaacc tgccgatgct tagataaaat 1980 agaaaagaac ctacgtgact atcgggcagg ttccccgaag gccaggcaca gtggtccagg 2040 cctgtaatcc cagcaatttc acgagggagc caggtggatc agctgagccc aggagttcca 2100 gaccagcctg ggcaaatggc gaaatcttgt ctttacaaaa aatagaaaaa attagccagg 2160 catggtggtg cacacctgta gcccggctac ccgggaggct gaggtgagag gatcacctga 2220 gcttgggagg ttgaggctgc aggagctgtg attgcaccac tgcactccag cctgggcaac 2280 agagactctg aatcaaaaaa taaaataaat aaaacaacat aacataaaaa caaaaaacac 2340 acctcaaatt accagctagg tatttacgtt tcagacccag atcaattgca aaatcaatgt 2400 tcagctctcc tggaaaagtc tcatgtatgg acctgacctc tatcagttga ttgtcttagc 2460 tcaatcttac aatttggtta ctccataagc tcactcattt ggttaagtaa acaatgtcta 2520 cagttctaac aattatttta ctaaaatgca taattatgtg atagttatac atataccaac 2580 ctgttatgtg agacaactga cctgcaagta gtccaaggcc agtgaatcaa ttactgcttg 2640 tacattgtgt gcatctcttc ttgactccta ggaataacta tgaggtctgg ggggggaaaa 2700 aatcacataa tttttatcca tgagaggcca agttttcatc tcattgtctc tgactaggct 2760 actgaatatg ctcactgcta taaaggctct gcccaaacag aacatgctgt aaagtacaga 2820 taaagttaat aaccctgaac tctacacagc agaatcttta ctggttgagt atttattgat 2880 tgaaccgatt ttcaatatta gactggttga atacggttga atatttatta caccatatat 2940 atatatatag tatatagata tacatgaata tgctttacaa gaagcaccat gttaaggaag 3000 ataaagtggc cctaaattca aagacagcta atagtctaat aagggagcca agacatgata 3060 ctttaaccat aactatgggc tactttctac gaagaaaaaa aaaacacagc aggcattcaa 3120 ggagcgtctt atatatacac atatgtatgt ttatttatta tttattgaga cagggtctcg 3180 ctctatgccc aggctggaat gcagtggcgt gatcttggct cactacaacc tccactttcc 3240 cggctaagca attctcttgc ctcagcctcc caagtagctg ggtttatagg cgtgcaccac 3300 tatgctggct aatttttgta tttttagcag agatggcatt ttgccatatt ggccaggctg 3360 gtatgaactc ctggcctcag gtgatccacc tgcctcaagt gatgagcctc ccaaggtaat 3420 ggattagagg tgtgagccac cgcgcctggc ccttatatgt ccttttgaat agccaactag 3480 attattggta taaagattta aaaggtcagc acaggctgga cgtggtggct catgcctgta 3540 tcctatcact ttgggaggta gacgggagga tcacttaagc tgagttggta ccaccctggc 3600 ttgaacatag tgagatggtg agcaagatga aaggacatat gcgcttatta actgtcttgt 3660 aaatgaggtt catcatctac aagcatcaat tcttatccct agcactggtt aagtaacgaa 3720 tccaataaat tcccaagctc cactcaattt tacaaccttt gaaggtacat ttacagaaag 3780 atgcaacttt cacaaggcag tagccatgat taggttaagc cgtgattatc aggagcctca 3840 aactgatctg ctcaaggccg ttattatgag tgggttccac agggtattcc ttaagaatac 3900 aatattataa ttatacaata tgtgatatta aatacaattt aatatacaat attattttaa 3960 tattgtatat taatatagaa tttaatatgc aatattaaaa aaagaaacaa gcaagagaaa 4020 atgaaatttt ataaatatca aagaatctaa ctaaaggact aaaaactttt gcctaagata 4080 taggcaaaat tactcctgct tttagtattc ttacctggta ccttttctcc aaaatagact 4140 gataaagagc aataaaaaca ttagcatcac agtcttgaag ttcatgtatc tcagatgtat 4200 atgacactta aaaagaaggt tattggcaat ggttacccac tctgttggaa aaagggggaa 4260 agatcagtct taaaaaccac cagaaaaaaa tcacacagac atttaaaaat ccaacaacct 4320 cccccccaac aaaaacagac actgaacttt gcagaagata aggaattgat tgttagagaa 4380 tttcaaagac cctttaggca tggtttttaa aaagatgtat ttaattcttg ggatgatttc 4440 cagagtgctg taatttctac atagtcaaaa ctatactgca aattaattga tactgttgca 4500 gcctaaaatc ttaagttact tatataagcc ttacatgggt gttttagtta aaacatattt 4560 acaagtaaac aggaatatta tgtcataaac aacagtttaa tgtaatccga ggttaccaga 4620 aactcattaa tggaggctgc ttcgcacttg caatagtatt gtcttgtgtt tacccaatta 4680 tcttgtgcaa gtcagggttt ctctggtgcc ggaaaaagtg tgattaaact taggctgtta 4740 agaactggta taataacaac atcaacggta atgcatttgt agtttttctt ttttattata 4800 tcgatctata tgaaagaaaa tatgggaagt acatgaagtc agaattatca atactgttga 4860 cgtttcctgc gtaccacatt ctcctctccc ctagatatgc tgggatttgc aaagtttaac 4920 ggtttctgta ccaaaagtaa cttagcttaa aatactgttc cttgaaatgc ctgggaattg 4980 gtaggaaagc actttcaatc ggtattagaa acaaaatctc cactatgttc tggacacgta 5040 acgttctgga aacgaatgag agtgtatttt ccatcacata atccccctcc ccacgcccat 5100 ttctcacagc tggccaaacc atgacaactg gttgtacgca gtccttgtga aaaggatgaa 5160 agcgtcctag acaaccaaat taattcgctc ttaaaagcgg tgctagacaa agcccatgac 5220 tctagagggc actgaagaga aaaaagcaca atattctaca ggggcatatt ctactattct 5280 gcaggggcat aataaatctt aagaatgctg tcctttaaag accaatacaa aagcaggtac 5340 gacctcaggg cccatagtgc aagggcggag gcacacggac agcggctaga cgccccacag 5400 aaagacaagt ccggggacga cccttctgcc gctcttttta cagccaggac ccaagtgtcc 5460 taccggcctc gccccagtgc ctctctcctc ccacagcata ctgctgttcc acggcctcga 5520 agcgaagagg tggtgaagct gagagaccta tccagggaac ccgccagcgc gacgcggcgt 5580 ctgaaggtca cgagccccgc cgacacccag acccagtccg ggctagcccg aggcctccct 5640 ggaggtggac ggtttcagtc cacaatactg ggaccccagg gagacactca ccagcatccg 5700 agcctgccat gtttcagagg cagtcgccgc cggactccga cgcggccggg aaggcgacgg 5760 tgtcctggaa ggaccgatcc accagacccg acactggggc gcggacgcac gaaccaaagc 5820 gcggggaagg aggcgtgaaa gaggacggac gttaaaagag cttctcgccg ctgattggtc 5880 atcagaggag cacttccttt acaggacgtg aaacgggggc ggtttgggaa gtttagagac 5940 cattctccgc cgaccaaaac cgtcaaagga ttatcagaca cgcgggtcgg acggtccaca 6000 tcagccggca gcccgggcgg tcccggggtg cgagcagcgc acttccggtg agctatttcg 6060 ttttgtatcc ctccgccacg tcaacgggaa agtagtgcgg accgctctct cggtggtccg 6120 gggtggtaca gccacggaca acgccaggcc ccgccttccc cctcttttgg ttacagacgt 6180 gagggctctt tggagcgtaa acatctccga gtggcgaggg tgggcggggc tgggcttggg 6240 aaagggcggg gtggttgctt gaggtgtgga aagaccagaa gaaggtgagg tcaagagagt 6300 gcagaatgag gcatccaatg gtgggtgggc cctgacctga gagagtggcg cggggagggg 6360 tgaaagcgcg gcatcctgga acgccagcgg gcgttgcggc ctatgcgcga ggggcggggc 6420 gattaggtca tgagcggctc ccagcgttcc ctgcggcgta ggaggcggtc cagactacaa 6480 aagcggctgc ggaaagcggc cggcacctca ttcatttcta ccggtctcta gtagtgcagc 6540 ttcggctggg tcatcggtgt ccttcctccg ctgccgcccc cgcaaggctt cgccgtcatc 6600 gaggccattc cagcgacttg tcgcacgctt ttctatatac ttcgttcccc gccaaccgca 6660 accattgcgc catgtcgggt tattcgagtg accgagaccg cggccgggac cgagggtgag 6720 tttggggccg agctgtcagg cctggcgggt ggggggatgg gagggcgggt cagggtggcg 6780 gccggggggg ctttgcggct tggacttggc ctttccgggc tatcttggga cttcctttcc 6840 cgaagcttgc gccattttga tattcacgtc acagtgattg gaagagattt gacggtgtag 6900 tgtttcaagc ttgctttttg tgtggggatt ggggagctgt cggggcggct gccatttggt 6960 agtgttgagg gagttgagag ggagcgtatt gtgcggatga aagcgggacg cttcgaggca 7020 gcgaaggaac atctgttagg tgcggcgttt cgggaggtgt ttttggggtg gccgggcatt 7080 tgtgggagcg aggggaccac ttccaaagcc ctggtgctgt tggggtagga gggcggccgc 7140 atcagccatg tggctgagtc gcgagtacaa aatgccggcc tcggacatgg cggcggcgct 7200 ttgttacccc gcccggcgga ggagctcaaa atggcagcgt cgagaaaatg tggcgcaaga 7260 gaaatgcgag acaaaggggg aagcgccgcc ccagcgggaa cgccgcccgg ccgactcgcc 7320 cgggccggga ctcctccccc ggtagtcgcc ggctcctcct tttctttttt cctgcttata 7380 taattttgat tcgttgatcc ggagctctac cgcggcgttc ccccagctgg gtttctagca 7440 gaagtgtttc tgagaaaacc cttgttctgt tatcgctgac tgtactgttt aggtcttacc 7500 actaaagctg tttggttcca aaacggccat atgagtaaca tcgtcgtgat gccttcggtt 7560 catgtagcct tgttattgct gatagtgaat tgctaggctg gtggggaaga tacagtaacc 7620 acaagaagtg gtgtgtgcca gaatcccaaa ttctggcatg tgggtgacaa tttccgacat 7680 gataaatccc cggcttccga catgataaat cccaggctgt ttacatgact aagtaatgtg 7740 tacttgggac tacgggaaat gttaactgtg gctgttgaga gagagagaat tttcacgaag 7800 gacagtgcta ggtttacctc tcgaagtctg ttttcagtgg tttttagttg tgccaatgga 7860 tgacaaatct atacagaaac ctgggtatag ccatttgaaa atgtgataac gttttttttc 7920 attccaggtt tggtgcacct cgatttggag gaagtagggc agggccttat ctggaaagaa 7980 gtttggaaac cctggggaga aattagttaa aaagaagtgg aatctgatga gctgcctaaa 8040 tttgagaaga atttttatca agagcaccct gatttggcta ggccacagca gtgagtaaat 8100 tcatgtggct tcatcaggct gtaactcgat cgtggattct agaaatgaaa ttctgacagg 8160 tgttttgcaa ataactcaat tttggtagag ttacatgttc tacttcataa ttgggaaagg 8220 tgtgactcac ttttggatat aggtggcttt gggattttta ttaaattagg ttgagtataa 8280 caataaattt tttttttcat aatagggtgt tcataggtgg tccagattaa aatgaaggct 8340 actttaaact agttactaaa ttatgaagtt aggggctttc aattacgtat ttagctaggg 8400 gtggtgtcat gaattttaag actgttataa tttgtttgca gcaagaggtg gaaacataca 8460 gaagaagcaa ggaaattaca gttagaggtc acaactcccg aagccagttc taaattttta 8520 tgaagccaat ttccctggta agtgctactt ttcagtctac ctacccgtgt ttttgtttcc 8580 acctaccccc tctttttctt ggcatcacta attttactaa atatctgtta ctaattatag 8640 caaatgtcat ggatgttatt gcaagacaga attcactgaa cccactgcta ttcaagctca 8700 gggatggcca gttgctctaa gtggattgga taggttggag tggcacagac tggatctggg 8760 aaaacattgt ctgtaagttt gggagaactc tgagttgatc tgatatatgc aagaaaatgt 8820 aatggtaatt taaaaacgag tattttaatg gatttctgtt tgtccccact ttcaccctaa 8880 atagtatttg cttcctgcca ttgtccacac aatcatcagc cattcctaga gagaggcgat 8940 gggcctattg taagtatata tttttacttt attagaagca taatgtgtag attttagact 9000 acatagctaa agatgtaatc atttgtgtgg ttttatatag aggttagctc atcctattca 9060 gctggagctg ttttgggtat tggacacaca tgaagaaagg atctgctagt ataataagtt 9120 agcagtttaa aactagtatc caggttgtgc tgaaagctgt ttctctttcc ttagtgtttg 9180 gtgctggcac caactcggga actgcccaac aggtgcagca agtagctgct gaatattgta 9240 gagcatgtcg cttgaagtct actgtatcta cggtggtgct cctaagggac cacaaatacg 9300 tgatttggag agaggtatgt aagaaaaggg ttttatttgt cattggtgct aaatatccta 9360 ggtattgtag ttacacttac gatttaatta aaggtgtgga aatctgtatt gcaacacctg 9420 gaagactgat tgacttttta agtgtggaaa aaccaatctg agaagaacaa cctaccttgt 9480 ccttgatgaa gcagatagat gcttgatatg ggctttgaac cccaaataag gaagattgtg 9540 gatcaaataa gagtaagttc ctttgaaata tgtgatcaaa ctgaattgtg ttttcactct 9600 taagagtctg atactaattt tccgcccaaa atccattagc ctgataggca aactctaatg 9660 tggagtgcga cttggcaaaa gaagtaagac agcttgctga agatttcctg aaagactata 9720 ttcatataaa cattgtgcac ttgaactgag tgcaaaccac aacattcttc agattgtgga 9780 tgtgtgtcat gacgagaaaa ggatgaaaag taagttttat taactctgtt atatttgctt 9840 cctaacaact ttgtgtaaaa ttgagggatc attgtttggt gagttgtttt aggttatttc 9900 agttggtgtg attcatttag ttagcctact aatcctgaaa atttcttgaa tccttcaaat 9960 aatggctgtc acatttatag ctttcctata gaaggaattc atgtgtcccc tggttgactt 10020 aaggaccaag gtcgaactgc tcgataagtg gattagcagg cgtttcctct ttgacttcca 10080 gccatgtaat tgaacttaat gttttgctga ccataaatgt gtggccctag caatggtctt 10140 ttaaaactag gatttttcct ttctctctcc tattattaga cttattcgtc taatggaaga 10200 gatcatggtg agaaggagaa taaaaccatt gtttttgtgg aaaccaaaag aagatgtgat 10260 gagcttccag aaaaatgagg agagatgggt atgtgtgagc tcctccattg aagcagattg 10320 attaaacagc ttaggaaagg gcaaacttgg atcacgagca gtggattttt ttcatatctg 10380 ataggaattt aactttttca tttctggcga aattaaagag atctgtgacc aaaagtggtc 10440 aagactggag tctgaggttt tcaatgtgag tttaataaca caacttgtct tttaacttag 10500 gtgcctgcca tgggtatcca tggtgacaag agtcaacaag agcgtgactg ggttctaaat 10560 gtaaatattt caaatgaagt atttttcccc cttacttaac ctagctagaa ttctgctcag 10620 taattgatca tgtatatgcc ttcctttgta gaattcaaac atggaaaagc tcctattcta 10680 ttgctacaga tgtggcctcc agagggctag gttagtacaa actcgcattc atggcttgtt 10740 tcccagaaga tctccattta acttttttaa agaaagttta ttgctttctt taacctgatt 10800 ttttctaagt tttttttcac ataaaggtgc tgtctttgtg gcaaggccta ggcatgcaat 10860 cggaggactc gagggggatg gaggactagt gatcggctgg ctgcttccag tcgatagaga 10920 ggtgaaaaag ctgaacgtgt gccagtaatc ttcaaaaggc agaacatatc accttgcccc 10980 gtaaactgtt ctctccgagg gaaaaaatgg aagttatcct cacagttcac tgcgtggtat 11040 ttcttctgtc ccatgctttg catgactgcc atggtacagc cttgtttcaa acgttcactg 11100 tgatctgtgg gtctttgagt ttcagtgagt ttgctgaaat gtcgaagaag tgttccaaac 11160 ttcaatgttc aatgaaattt ttgttcaagt ttgaaatgga gagagcagct taaaaggtac 11220 taagcctttt acaaattggt gagtactggc acatgagatc tagagcaggg caacttctca 11280 cacatagtaa gtgggaaaag aaagtgcttt gaaagttcct ccctcaccac acagtagtcg 11340 tcatgtcgag acctgccaga gagagacaca ttctcaagtg aatcctgctt cttggaagcg 11400 cttgcctaga cgagacacag tgcataaaaa caacttttgg gggacagtat gttttcttgc 11460 agctgcggtt gtaaggtctt ggcaagacaa gcagtgtggc cagaatttga acttctgatg 11520 aatgtgtaat gcaaaggacc ttgtacattt ttttgtttca aggtctcaaa atgagcacat 11580 gaagaggttg ctgtgaaact ttaagtggcc ctactgcgca gaacattcag atgtcacttg 11640 atgatctgta agggaacttg ctgatttggg aatgtgctta ggaacacaca ttccttttga 11700 cagggtctgt cactgggtgg gtgatgaatt atacagatga ctgtgctttt ttttcttttt 11760 tcaacctcaa tggtattcct acaggaaatg gataaccatt taactgtatt ttttgcagcc 11820 cgtaccttct tgggaataca attgtctaac tttttatttt ggtctggctg ttgtggtgtg 11880 caaaactccg tacattgcta ttttgccaca ctgcaacact tacagatgtg gaagatgtga 11940 aatttgtcat caattatgac taccctaact cctcagagat tatattcatc gaattggaag 12000 aactgctcgc agtaccaaaa caggcacagc atacacttct ttacacctaa taacataaag 12060 caagtgagcg accttatctc tgtgcttcgt gaagcaatca agcaattaat cccaagttgc 12120 ttcagttggt cgaagacaga ggttcaggta aggagactga taggaaatgt tggtagttac 12180 gagtcacatc gttgtctaca aatccattta aatgtattgg agggtgagta aaaccttgaa 12240 tgtgaaaact taagctgaaa aattgtaaaa actttcacgc ctaccatgaa tagatctgtt 12300 tctttctgtc cacaatgatt tgtgtcatag aataattgat caatttgcaa ttgttttctt 12360 gacaggtcgt tccaggggta gaggaggcat aaggatgacc gtcgggacag atactctgcg 12420 ggcaaaaggg gtggatttaa tacctttagg acagggaaaa ttatgacaga ggttactcta 12480 gcctgcttaa aagagatttt ggggcaaaac tcagaatggt gtttacagtg ctgcaaatta 12540 caccaatggg agctttggaa gtaatttgtg tctgctggta tacagaccag ttttaggact 12600 ggtaatccaa cagggactta ccagaaggtt atgatagcac tcagcaatac ggaagtaatg 12660 ttccaaatat gcacaatggt atgaacaaca ggcatatgca tatcctgcta ctgcagctgc 12720 acctatgatt ggttatccaa tgccacagga tattcccaat aagactttag aagtatatgt 12780 aaatgtctgt ttttcataat tgcctttata ttgtgtgtta tctgacaaga tagttattta 12840 agaaacatgg gaattgcaga aagactgcag tgcagcagta attatggtgc actttttcgc 12900 tatttaagtt ggatatttct cacattcctg aaacaatttt taggtttttt ttgtactaga 12960 aaatgcaggc agtgttttca aaaagtaaat gtacagtgat ttgaaataca ataaatgaag 13020 gcaatgcatg gccttccaaa aaaaatattt gaagactgaa ttaagtggaa attgtacttt 13080 attttatata atgtcatgaa aactttgctt aagatggtct ggtttttttt ttgtttttgt 13140 ttggtttttt ttttccagaa aacaaatgac tgttcctttt tatttaattt gggaggcagg 13200 gggaatcaga aggccctctt tataatgagc tattcatatt gcaggagtca gaatgaattg 13260 atacaggtga attttagtta caggctaaat tgcataaaag ctttgtcagc ttccagcatc 13320 aggggagtca tttatagcct ttttccttat ttgctagtat ggttaaatga gaaaatagta 13380 aaatagatac aaatcatcta tatagtgtga gaacgtgggt gactttttca aagtttataa 13440 tttaaaaagc tcaaataact ggctttttca agagacttat actcatgctc ttggctatac 13500 tgtgaattac taaatgttga acaaacctgt gaaagacata cattagccct ttaagatggc 13560 caggagctaa cttgagtetc ctttactgaa tttcgttctt agtgcaggtt acttgtagat 13620 tctagtctta caggctccct ggggctctta actagtcaca ctgggagtca tgaatgtctt 13680 tccaataatc agggaattct agagatcctc aaactgtaag gtctattcat actcaacaca 13740 aggaaaaacc tcattaaaat taatgactaa tcaggaggca acgtaaccaa aagcacagtg 13800 aatgaagttt tcatggtagg ttcaacatgg gtttattgct agaaagatcc aggggatagc 13860 tttagtttaa cttcggctca ccaacgtaac tttctaatca tttatttcag taatagctag 13920 aagtggtctg aatgttttcc cagagtctga tacgtgtttt tttttgccag aagagaggtc 13980 ttcggagact tcatttaaat tctgattatt aaactgaggc tttaattgat gttaatgcct 14040 tagtcaaatg taaagttaga atttgctagg gctgggatag ggagtgatat ttctaggact 14100 tgacattgaa aactaattca gcctgtagta acctggatgg ttttcaatgg catggttagt 14160 aaattcatgg ttttaaactt agaagcagct ttcgggggag agggtaggtt ggagcatttt 14220 tacatatttt actgtttaat gtcttaaccg tgggcctttt aatttgtaaa cactgaaaga 14280 ttgttgggct gtggaaaaca tttacctatt taccttggaa gttttaaaag acagtccctt 14340 tttagcatgt gtgttgtgtc cagcctgtgg tcgtcttaac taataaatgt gattttctcc 14400 ccattctctc tttttattta tttgcgtata ggccttttac ctggtgtgag ttcctaatgt 14460 ggaaaacacc tggcagtagt acccagcttt gcagttaatt actatctagc tggctttttt 14520 taaacccttg tatacacttg taaagaagaa ctatttcctg aacctggtac agcctttact 14580 aatgataaaa ctttactcct gaattacatt aactcaattg ctaagctgtt accctcttaa 14640 tcaggtagta gtttggtagt ctcacagtga aatgtagatt gttccttttt cctgaacctc 14700 tttaaaggtt ttcgtaactg aggctggtat aagaaatcat ggactttgga tcaaacttcc 14760 tcagtctggg tataccactt ttccactttc tgggtaggtc ttaaggtctg acctatttaa 14820 atagaaactg caaaatcaga aacctgcaat ttaatcatga gtctcttata ataacagtca 14880 caagtctcat tgttttgatg aacccataga aggggcccct ggaagaattg cacgtacgtg 14940 gttttctctg acaccaggag ggtttaagac atgtcagggc cccttgttta tttctagtgc 15000 attcccaggt gaggcagatg ctgctggctg gggactgccc tttggagcca ctgcaatatt 15060 taaagtgacc ataccactac cctagtcacg aagcctatcg ccccctcccc ggaagcttaa 15120 gcgtcaagac aacggctctg gggttaggcc taggccacct ggcgcagcat ttgcctagtt 15180 aagaaggcct gggcttacaa atcaccgtaa aggactaaaa cttttaaagg gaaaccaaat 15240 gccaaattta gtccaagtgc ttgattgagg tgtatataga agtgatttgg ataatactga 15300 agtattttaa ttttctggac tgcaaaacag tggcagaagg agtgactcaa gtggctacac 15360 cacggttata aataggtggg aataaccttt actggtgcta cgaggaaaga aaaaagtcaa 15420 tctgaaggga ggggcgcgac gcgaacggca agctagcaag aaccatccga gccggcgtcc 15480 gccatggtgg gcgggggacg gctgcggccg gaacgcaaca tgcgcttccg gggtggggcc 15540 tgccgcccgc aagcacgctc acctccgttg cgcctggccg tggcctctcc ggattctgtt 15600 aacggtagtg gtggcttgtt gggatccgtt gagtgtggga gagtgtgctc tttaacttcg 15660 gagagagatg cgctctcgtg tagccgtcag ggccgccata aggtctgcag gtgcctgttg 15720 tctgggtttg ggggtcgagt agatgcgggg cagcggagct gttgacggaa aggagtagcc 15780 ccaaaggagg gcatgtgaag tcgcacgcgg agtcgagggg aacggcgagc acccagaagc 15840 ccccgggtct ggagagggaa gcgaggcgct gtagagatct gtcagagaag gcatttccta 15900 agtggaagca agcagcagct tagccgggat ctcttctgag tgggtgccac cccggcttcg 15960 gacccttggg cgtagagttg cggaagaact ggccgcagaa tggtggacct cggtggtggt 16020 gttcagggag caggtattcc cggtggaccc ctccaccaca aaccaggccc tttgctaccc 16080 ggggacagtg ccttcaggtt agtttctcag aaactctacg cgaaatcttg caagacaaag 16140 agctgagtaa ggaacagcta gtagcattct tgagaacgta ttaaaaactt ctgggaaact 16200 acgggagaac cttcttcacg gtatgttcac gatttcatgc ttcaaaacag gtgtcgggtg 16260 gaaaggcgag gcagtcttgc tggacttggg gattgcaact ggccctgtat tcccatgcaa 16320 ggaagttagt tagttctcat cttttgaagt agtcggatat attaacagtg ctctaccctg 16380 gagaaaactg gtccatggaa tcttgctgtt ccttaaacaa tctgtccgaa ggacctggga 16440 acgctctcaa tttcacgggg cacttctgaa cacagtgctg tcatttagtg caatgtagtc 16500 taagtgcata aggaactaca agacattttg aacttttctt agatttattc taagtaaaaa 16560 tgttgaaatt ataattctga actatttcat gtatatcata ggataaatca aggccaggcg 16620 cagtggctca cgcctgtatc ccagcatttt gcaaggcaga ggcgggtgga tcacctgagg 16680 tcaggagttc gagactacct ggccaacatg gtgaaacccc gtctctacta aaaagacaaa 16740 aattagccgg ccgtgaggcg agcgcctgta atcccagcta cttgggaggc tgaggcagga 16800 gaatcgcttg aacccggagg cagaggttgc agtgagccga gatcacgcca ctgcactcca 16860 gcttgggtga caaggcaaaa ctccgtctta aaaaaaaaaa attcaaatag ttgggttagt 16920 tgttattagg aacaagatat tcattgtaaa agaagagata atatgtaaaa gaaggtacgt 16980 ataaactaat gtaaatatgg attggtaaat taaatatgaa ttggtaaatt aaaattgaat 17040 atgggtctca cctgtcaccc agactcgagt gcagtggtgt gatcatggct cactgcagcc 17100 tcgacctcgg ctcaagtgaa cctcccacct cagcctccca agtagctgga ctacaggcac 17160 atgccaccaa cccagctaat ttttgtgttt tttgtagaga tgaggttttg ccatgttgtc 17220 caggctggct tgaactcctg agcttaagca atccgcccat cttggccccc caaagtgctg 17280 ggattacggt gtgagccaca gtgcccagcc tcatgatttt taaaaatata tttcctaact 17340 ttcttcttta aagttcctag aagcaatgac cctcagtagc aatgagcaca cctagtgccc 17400 agatctggtt cctttttttt tttttttttg agacagagtc tcgctctgcc gcccaggctg 17460 gagtcagtgg cacaatctcg gctcactgca agctccatct cccaggttca cgccattctc 17520 ctgctcagcc tcccgagtag ctgggactag actacaggca cttgccacca cgcctggcta 17580 atttttgtat ttttagtaga gacggggttt caccttgtta gccaggatgg tctctatctc 17640 cgaccttgtg atccgcccgc ctcggcctcc caaagtgctg ggattacagg cgtgagccac 17700 gcgcccggcc tccagatctt ggtttctaag atgaaccagt actgggagaa atggctgatc 17760 cgggtctggg gttagggaaa gtacaaggtg agtttgaaac actttatggt gctaaaaaca 17820 aagaattgct tgaagactaa tgggtcatat aaaaaggtca cagatgctgg cttgaggggg 17880 ttgtcactgg ccacatctag gacaaattga acattaagat acatattaat ggtaatgatc 17940 ataacacatt gactaaaatc taagagtcaa tagtattaat caaaaacaaa taattaccct 18000 agaggtcggg ggcgggggga agaggtagag aaagcttatg tttttacaga agcttggaat 18060 aaatgtagaa ggaaagatac attagaaaat tcaccatttc atgatattgc aaacccgata 18120 tcattgattc aagcaacagt catcaatgga ttctaaaata ctgggtgaaa tatgttgggg 18180 agcaggatat tattggggag tggatattta ctaccttaac caagtaatca atttggtgtc 18240 ttcagtagtg gaataatttg ataacatgtt cctcatgtta tgatgcaata gatacacaca 18300 tctactatgt agtattttgc taaaaatgat tagccgaaat taaatcatag gaaacaatca 18360 gacaaatccc aaatgtgaga caatctatga ctaacctgga ctcacatcaa agtcagtgtc 18420 attaatagca aaattaaggg ggaaaggagg caagggaaat gttctagttc aaatggatga 18480 aagaaaccta ctcagaatgc agtacatgaa tcttaactgg aaagagacag taaaagatat 18540 ttggggtgaa aattggaaca actaaaatat caccatatgt tagatatatt gtggtattat 18600 ggttaacttt ttatggtgtt ataatggtat ataggaaata ttttattttt agaagatgta 18660 tgcggcagta tttgggagtg aacaagaaaa aaatgtggca aaagttgata attgatgaat 18720 ctaggtaaag ggtatacaag tgttcattgt atatggatgt ttttattttt tcaactttct 18780 tatagatttg aaaatctttg nnnnnnnnnn nnnnnnnnnn gaaatgatac cactctcttc 18840 ttcagataac atgttattct ccataagttt cttcctgttg ccttttgatg caaaccaggc 18900 ttcccatagc tgtcttaggc agcaactagt tggctgatta atacttcctg acagttcatg 18960 taaacaacag gtccagttgt ctcagacaaa ttaaccaata agattcaaca gtaatatttt 19020 taattaagtt atggtgttga ggcaatcaga cccttacatc tttaaagtgt ctttttttgt 19080 tcaattttaa aactatgagg ccgggtgcag tggctcctcc tgtaatccca gcactttggg 19140 aggccgagtt gggcggatca cgaggtcagg agatccgacc aacctggcta acacggtgaa 19200 accccgtctc tactaaaaat acagaaaaaa ttagcgggcg tggtggcggg cgcctgtagt 19260 cccagctact cgggagggtg aggcaggaga atgcatgaac ccgggaggcg gaggttgcaa 19320 tgagccgaga ccctgccact gcactccagc ctggcgacag agcgagactc catctcaaaa 19380 aaaaaagaaa atcttcaaac taaaaactca ggtgaaacta cctagaatta agtggtgatc 19440 tgtctttttt tgtttttttt taagacaggg ttcactctgt tgcccaggct ggagcacagt 19500 ggcaccatcc cagctcactg caaccttggc tcccagacta aagtgatcca cctcccagct 19560 ttccaagtag ctgggactac aaggcacaac caccatgcct ggcttatttt tgtatatttt 19620 tagagatggg gttttgctgt gttgcccgtc tggtctcaga actcctgagc tcaagcaatc 19680 tgcccacctc gacctcccaa agtgctggat tataggcgtg agccaccaag cttagccaac 19740 atctgtcttt atgctgtgtt aacgtattac tactattaat gtgtctattg acaaaaatga 19800 tttgggtttg tggactagat gtatcaatga ttgatttatc ttttgacagg tgccttggaa 19860 cactatgtta attgcctgga tctgtaaaca agaggctacc ttatggcctt gctcagattg 19920 gagtgtgttt tcatcctgtt ttgacactaa gcagatacga aatggtgtta aaaggtataa 19980 aaagtggcaa ataacttggc ctgtatttaa atagtcaaaa accagtcatt tccacttggg 20040 ataaattata taattttcag taagctaact tcctgatacg ttttatatct aaagtattgg 20100 tgagaagact gaagcttcgt agtatggttt actcctccga gaacttcaaa ccagtggctt 20160 gatttctggt tacgtcatga ctccagtggt ggagaaaggt actgcaataa ttacctttaa 20220 tttaatagtt aatacataat tgtcttaatg tgtcagtggt aattcttctg acatacaaga 20280 aattatattt gatgtagtag ctat 20304 <210> 47 <211> 60158 <212> DNA
<213> Homo sapiens <400> 47 ggattcaacc ttaacccaaa gtataaatta aatatccaca agtccttatt gatatagtgt 60 taaataaatc aattggaaat taaagacaaa tttcccatgt ggaggaattc aaataattac 120 gtagctactc caccctcaag gaggaggaac ataactcctc actccataaa tgtgggagta 180 catagcattt ccttccaaag agtgcactat gaaaaaaagg gtgaagaaaa acaattactt 240 tacaatggag aaatctgaca acactgctga gccaggtgat caaagtcaat gtaaaagaga 300 taaatcatgt tgatattatg tacctctgat gtaatgtggt atcaagaaaa tagcctttac 360 ctctgtggta ttcctcctcc aaacttaaca acctcagtca aatcatgaga aaataccaca 420 aaaattcact agaggaatat cttgcgaagt atctgaccat ttctcctcag agtattacag 480 ccaagaggag cctaaagata cttgagaact aaatgtaatg taccctggat ggagattgga 540 aaagaaaaaa agaattaggt aaaaacaaaa gtaacctaaa taaagtatga ttttagttaa 600 taatatatta atattggttt attaataata acaaatcaac tacactaatt aagttattaa 660 cagaagtaac tgtgcaggct atatgagaaa tctttgtgtt attttagcat ttttctgtaa 720 atctaaaact gttataaaca ataaacctat tttaaagtaa catatactta tacaatgtga 780 gaaaatataa tggcaaaaaa agaaaatgca agcacaaact atattcgtct ctcagggata 840 ataattatta aggtgttcag tgaatattgt tctaatcctt tttcttgctc atatgtatgt 900 atattgttta aacaagaaat ctcaaaccat atctacatct gctgttacca gactgcttcc 960 tttacttact aagatatggt aaatatacta tatttacaag tttcatattt acatatacca 1020 aactatacaa aatacacact tttatagtat tattttaaaa tgcttcatgg aattctgttg 1080 aattgatacg ccataattta ttgaactatt tttgtcatta acaaacatgg tatccaaatt 1140 ttcactatac cacaaagttc cttgtgacac catttttaat tttttttttt gtgcacttta 1200 tgcctaactc cacaagacac tgttattaag agccagtgtt ttctccacca tactttcttt 1260 gctcttcatc ccttcttgca tctcagattt tatctgggtc aatttttttc taattgaagc 1320 agatttttaa agatgtcatt tggaggagtc ctttactgta aattttcagt tttagttttt 1380 ctggaaaatc tctatttcaa gtttatactt aaaagaatct ttacagaata tatatagaat 1440 acttaattca caagtatttt ctctcagcac attgagacaa cattctaatg tctcctaatt 1500 ttcattgata ctgttaataa tttagtagtt gtctcttctc tttcttcttg aaaataatct 1560 gtcctctcta tctagttcct ttaaatatct tcttctctct ctgatattct gcagtttaat 1620 tatgatgtat ctacttgtgt gtatgtgtgt ttaaaaatta tcctgcttaa gacttattga 1680 gcctcgtgaa tctgtggatt ggtatctgtg aaggcagaca atggctcccc aaagatctta 1740 aatgtcttaa tctccagaac ctgtgatagt taagttaagg ttgtagatga aattaaagtt 1800 accaatccac agacctcagg gtaaaaagat atcctggatt atttaggcag gcccagtata 1860 atcacaagga ttcataaaac ggaagaggag acagaagaga tggtcagagt gatatgaagt 1920 aaaaaggatt cagottactc ttgctggttt gtaaatgcag gaagggacca cgagtcaagg 1980 aatgcaggta gcttctagaa gctagaaagg taagaaacaa attctcccct aaagcctcca 2040 gaaagggata cacctgccaa tacttcattt tatccctgtg agaccagtgt tagacttctg 2100 acctccaaga gtataagaca ataatctgct gttttaagcc actaagtttt gtggtaattt 2160 gttatggtag ctatggagaa ctgtacagtg cctttcaata gttcttggaa attcttcaaa 2220 tatattcccc aaatattgcc ttgcaccact cactctatcc tctatatctc ttgacctctc 2280 tttaacattt tttattttct tttttggtaa ttatttaaaa caattggctt cttgttccac 2340 ttcaaataaa ttcatatttt atatctacat attaagaatt agttcataaa tgtaattgtt 2400 gtatcgtata tactttaaag gaaaattgca tttatacttg gatattatta tattttaggt 2460 tttgaaattt ctttttttaa tgtctgataa atttattctg atcaaaatta aaatcttatt 2520 gtatttacag tagtctataa aagagtttac atcaattctc tcctttaaat gctagcaatt 2580 cagttttgtg tggtcaagat aatttagaat ccttttatgg taactgatat gatacaaagg 2640 atttttttgg ttgtttcaaa tttgtatgtg cgtatatatg tatagggggt agaaaatttg 2700 gttagtgact ctatttggaa aaatgaatgt tctttttgga gttttagatt cccagtgttt 2760 caaaccaagt ttgttttgat aaggaattca gtgaatcttt attttctcgt agagaatttt 2820 taaacaatac cttcaaaata ttgtatgtat tcctatataa ttttgccttg gaataaaaaa 2880 agtcatcaca taagaatatt tttaacttaa gaaatttttt caagattctt tcaaaatgct 2940 aactccctca tgatttgaaa atacttttag agtttaaact attatgacca tgtagggata 3000 acttaaagtt ccttctaaat ttttttttca ttaatgtcat gcttctttct aagaacaaag 3060 tgtttcaagt tataaacaga ctgttttttc acatagcttt catacatcct gactttctat 3120 atctagtggg taatacattt ccttccaacc tttagtgggg tgaagttcat ttgtcttcta 3180 atctaaaaaa tacgttaact cctgacaacc tctgacactc aacagaaaca caactgtact 3240 ttggattaat catccatctt tatttcatag tctccttatt tatcaatgca aatggaagta 3300 tagcaatatt tcacagtgtc atgtactacc taaggaattt cattgcaata gcattgtttt 3360 gaatgtatca tttgattttg atctaactat catagatcag ttttacccct gtatgttcag 3420 ccgaatgtct aaccacaatt tcacaaaaat caagggctct gttagttttc atacaaaatt 3480 ggatgactta ttatgaagac agtcccaatt aacaattgca tgtcatctgt aagaaatcaa 3540 ttttttctca ctccccacct gtaatttttt ttaagcaaag aagaatactt gggtctaggt 3600 tcaaggttta tttttctgta gtcctaatat cacttcagta aattaatctg agactcattt 3660 tctaatatgt caaatgactg ttgtaaggat tattataaaa acgtaaggtg attaacaagt 3720 atgtaattgt tccatagatg gcagctcttg tttttttact gtgctttgct tctgcctgct 3780 tcacatatta tgtaaaatag ctggtgagtt ttaggaggta gtgctcacat gtttgacagt 3840 gtttgctgtg gacgatcaac agtaacagaa gagcatactt cttcgataca cagatttact 3900 gaatttggaa aggctttggc attcttatgt catctgtaat gaaacaatct ccaaagtctt 3960 ttctaaaatg tccttgtaaa aagaaaaaag ttatgtttat attttataaa agatgatgtt 4020 atttataacc agcagaagca gccttatttg aacatcttat gttgaaattg cacttaatac 4080 agtgactcat aggagctttc tagtggaaat caaatgctca aatgaaatag atttagtttg 4140 ttaggcaata gtgatatgtc ttttattggt tggactctgg aaaacactta caacgaatag 4200 tactttaccc gaagggcacg tatcatgcac cacatagcct aaccacaaca ttaaaggtct 4260 tgtaactgtg agcctcaaat gaaaatacat aaggacagct ctcatacatc aaatacaata 4320 caaactagct tttaatttaa ataaatatgt aagtaaagtt caagtgctat aatgatttta 4380 tatccctatg tatgtatcac agaaattgtg gcaaactgta gaaattattc aaatggaaag 4440 taacaaagca ctttcacatt gccttgtatt caaaatccct actctcataa aaacttatat 4500 ttctttaaca aagctacttt tctgtttaac tcccggaaaa cttgtattta taacttaagg 4560 gggtttctcc aaccaaacaa tttatttttg ctaggtacta tactatattt tttatacaaa 4620 atttgtgaca gcaaatgaaa ttctaatccc aatagaagaa caacaatttt catgtttcga 4680 tcttcatata tataattcaa gaggaaatat gcttaacttt tagattttta cattttaaat 4740 tgcattgtgt ctgtatcaag tctactatct tttacctagt tgtctggaag atttaagctc 4800 aaggttacgg tttgagaaaa gggttttgag agtgaccaga tagatttaag aattcatttt 4860 atactaaaat atggccataa atatttttaa atacattaaa tagccctttg ctggcacatt 4920 ttttcccttc tttgccaaaa cattcccaca ggcggctaag tcacctcatt ttataggttt 4980 agtaggttta gcaggcttta tgtgctctag tagggtagta ggttttgttc atatcaggtc 5040 tctctcatgg gagtttccag ggacaaggat tgctcagtta gtatggcctt agccatacta 5100 gggtatttgc tttaattcta cagaagtttt ctattaatat tctgtagcaa aagaactaag 5160 atctggaatt ccccctctta atctcttcct agaatgagat tcagaaagga caggactgca 5220 tccagcctgt ttgggaactc agacaaatgt ggttgtcaca gacacaaata gaggtctact 5280 atgaaataat tggcttgcta gtgtgctaat acagacaatg ctgatttgct ccaacctcat 5340 acagtttcac acataaggac aatcatctag tttcatgaaa gttctatcta ctttaacatt 5400 attttgaagt gattggtggt ggtatgaata acagtttaaa tttaaatcct aaaattcagt 5460 gtgaattttt tataatagca taaaaatcaa agatgtccat acaagaaaaa ttaaaatttg 5520 gttaggttta gcagagtttg agaatcttac taccctccca catagtattg taatgtgaat 5580 ataggcagtt actattacag gcatatgatg attatgtatt aagcagaaag aagtatcacc 5640 accagttttt ttctttgaat gccctcagta cttctgcatt tataggatgg tagactggtt 5700 tggtttagct ctcaaaagtg aaacatttaa agtttcctca ttgggtgaaa aaaattaaaa 5760 agagtgagag actgaaaact gcgcccacct acgtttaatc attaatagtg agcccttcag 5820 tgaacttagg tcctgatttt gagtttggag tctgaccttt ccccaaagat aaacatgatt 5880 gttgcaggtt ctgaagaggg cactccctca ctggctgcca ttgaaagagt ccacttctca 5940 gtgactccta gctgggcacg gatgcagttg aggattgctg gtcaatatga ttcttcttgc 6000 tgtgcttttt ctctgcttat ttcctcatat tcagcttctg ttaaaggtaa gtttgtgttg 6060 ccttttgcta aactttattt ccatctttgg agttggaggc agatacgtgc gtgtgtgtgt 6120 gtttgtgtga gtgaatgtga aagagtttct gactaaacta tcttcaaaac catgtaactt 6180 tggaatgttt gtgaagcatg gctgagttga aatgaaaacc aaattcaaat ccctacaaac 6240 attaagaaaa cagaatttct tttagtttca gttcctcaga ccagtgtgtt cttgcttcaa 6300 tttctcattc atgtctgttt ttaaaagaag gaaaaaagat acccactatt gttacctgct 6360 gttgttggtc acttgaatgc agctccttca tttgaattgt aaatgaggat tttttttaaa 6420 aaccgagttc taaattttct tttagttgct tagcaatgtg acctcaagaa gaattagacc 6480 caatgaaaaa gcatttgatt tgccaaagaa ttatgaatga aatggcacaa catatattta 6540 attccgttaa attaaaaaat gatagaattc atagtgaatt aaagaaaatt aaatttcctg 6600 atacagatta agaaataaga cattatcttt ggaaaaataa tgttgctact tacagtttct 6660 attttaaatg aaattaattt taaaaataca tatgaattaa taccattgaa aaggcaagtg 6720 aaaaaaattt tatgaggaat ggtttcataa aactgttgtg aagtgtatta atatagaatc 6780 atgttcagat cagctacatt ataaacatcg gttttccaaa tgctgcattg tgtaaaatga 6840 tcacttttag tttcttagga agacacactg ttaaaaacca attgatataa caacatagcg 6900 ttaagggacc aattttaaaa ccatgtactc taagtaattg atagaaaaca attcacttat 6960 aacttataaa acctgttagg gataaatgtg gcttttgata ttaaagtaaa gtttgcctca 7020 gattttttgt gtagaaaatt tccacatgag gaaaaaaacc taatcttcat tattggagca 7080 tagagggtta aatttaaacc aattcacctc agcaaatcac actgtaggtt cttgaactaa 7140 gaaaatattt tcaccaattt ctaaatattt actatttaaa catacagttc ttacttggca 7200 aaagaaattt tttaatgaga agaagattta taaattatat ctgactgaga gtgttattag 7260 aggacttact atttcatctg ccaaataaac tgttgagtag tcaaaatatg tgtgattaaa 7320 taccatagta tcaaacctaa taccataagt attttgagaa aaataattga gacatgtact 7380 tatcatgagc ttctcctgtt ttcccatttt ataaactaga acattgggtg acctatgttt 7440 tcaaatatac ttataaaaaa tttaaggccg ggcgtggtgg ctcacgcctg taacccagca 7500 ctttgggagg ccgaggcggg cggatcacga ggtcaggaga tcgagaccat ccggctaaaa 7560 cggtgaaacc ccgtctctac taaaaataca aaaaattagc cgggcgtagt gcgggcgcct 7620 gtagtcccag ctacttggga ggctgcggca ggagaatggc gtgaacccgg aggcggagct 7680 tgcagtgagc cgagatcccg ccactgcact ccagcctggg cgacagagca gactccgtct 7740 caaaaaaaaa aaaaaaaaaa aaaaaattta aatatacaca tacactagca atggcataat 7800 tgggaaatgg cataaatgag aaaatgtggt ttagaatatt ataggtacta cagtttattg 7860 taaacaagct tagtagtaaa tctagatttt taaagcttga aacataataa tttaggggcc 7920 acttttgaga aaagattaca aaaatatctt actattgcaa aggttctgaa aaagatatgg 7980 catgtggata cattgctagg gtccacttct ggagtctttg gaagatcctg ggcaagagag 8040 cttaagcttc atcagcatca tggtacgttg cttatgctga tatataaatt aaaagtgtac 8100 aacttgagag cttctttacc tagatggaat aactttttgc atatggtacc atgatttaat 8160 tatagattct ttgcccttgt aacaactgac attaattagc aacaacttgt gaagagttta 8220 ccttaaaatc agtccattta aaatttgggg atcccatgcc cattgcctca aaactcatct 8280 ctaaattacc aatgcaactg tttggtaaat cctcagatcg ggtggatgtt gaagggcagg 8340 ttagaatcta aagaaaattg aggctgggtg tggtggctat gcctgtaatc ccagcgcttt 8400 gggaggccaa ggtgggtaga tcacttgagg ttgggagtcg agaccagtct gaccaacgtg 8460 gagaaacccc atctctgcta aaaacacaaa attagcaggc atggtagcgc atgcctgtaa 8520 tcccagctac tcaggaggct gaggcaggag aattggtgaa actgggaggt ggaggttgca 8580 gtgagctgag atcacaccat tgcactccag cctggcaata agagcgaaac tctgtttcaa 8640 aaaaaaaaaa aaaagaaaga aaagaaagaa aggaggaaga aaagaaaaag gaaaattgaa 8700 tggcagattg gaatctgaag agggtattag gataggataa aagagcacat ctatatgatt 8760 tgctgtgtga actttctaaa gactcaagtt tccctacttt ttcttaatta tactttgtca 8820 tggttggact attttcagcg ccttctctgt ttttccttat atagtatttt taccttctat 8880 ttaattttgt cacctttaaa cctgtacact ccttcatttc cagtctttct ctcaatccct 8940 caccccaccc ttacttttta gtcaatttta ttaatcatct tccagttctt ttttcttctt 9000 acccttcatc ttctttttta acttctgccc tttagttttc tgttgggttc ataaatgcca 9060 ttacctatca cccttatcat cactgctgtc tcttcaaacc tcaccaataa ctcagctctg 9120 ctttgtcttc ttgactaagc cagtttcagt gattgtactc atataaatct gacaaaggag 9180 tatttaaaaa atatttcttg aagatcaaaa ctaacagttt tgttgctttt aagtcactta 9240 aaaattctaa atgcacttga aggcaaatga aagagattct gacttttttg gctaatatta 9300 ctttctgttt tggttttatc tacaacagtt atcaaaaaat attactatac atactctgaa 9360 gagcactatc ctacaaaagg attaagtcaa caatataaat gggacatgcc ccaatgccca 9420 gtgttgccag atctctgcaa gcataaacag agaaatactt atcaaaaagg aaagtataag 9480 aggatgacac tctagcacat ccaccttatt tgaaccgttt taggctttat ctcctgttga 9540 aagaggtagg aaacagttgg aggaataaag ggcccattct tttctgtgct ttaacatttc 9600 ctactcatag tcaaaaatga tttattatat ggccagtaaa gtagaggtaa gaaaagaagt 9660 gaataacata atagttggaa agctttggaa tttaagaaag gttaccttcc tacaaatgtt 9720 tcgtagttat tttaacagag gacaccttaa tatagtccac agaacttgga ttttggtaaa 9780 tttaaacatc aaattgcatt atatttgcta tgttgggttg aacttggggt cagcttctat 9840 ctgctgtcac acatgcttac ttttcagaat tgctctgagg attagataag acaacatgta 9900 tttcctttat gcctatgtgg aatttgatag gtgtcataaa aagaaggcct cctgaccgaa 9960 atatttttcc taccagaaag ccagtatttg aacccgctat agagtcccca attacaatgc 10020 agaagacata agataagagg gaatcccagt cttcatcccc ttcaaggttt ttcctgactc 10080 tctttgcctc tgtgtctcac acctcagttt ctgcctgact tggtgcttgg acacagcttg 10140 gttttgtgat acacatagat cctttcatac ttccttctcc tggctcttct tgattcctat 10200 gaaaatgttg tcccttttct ttgaaggttc gacagattat gtgacttcac tacccaaaat 10260 tctatgcagc gtcccatctc actcaaactc cccaaatctt cctgccaccc ataggtacct 10320 cctttccttg tctccttcac tgtgtctttt acttatttat ttccagcctc tttggtctcc 10380 ctgccttcct ccattacacc tgcaggagcc ctcctcgggg cctttgcact tgctgtttcc 10440 tcttgagggg aaggggtaga aagggtagga gttgggggag ggggatgccc ttcccacaga 10500 taccatgtag ctcaccgaaa acctttgtcc aaaatgtcac ctttccacag aggtttttct 10560 ccagcatctc cattcccttt cctgcttcag ttttctttat gagcacttct atcatactat 10620 taacttgctt atgtactcat ttttttattg cccttctcca tcgcatttaa atgtaccttc 10680 aatttacatt tacaaagggt agaaaattta caaagggtat taaatttaca aaaggtagaa 10740 ctttgtctgc tggttgggtg cggtggctca cacctgtaat cccagcactt tgggaggtga 10800 ggtgggtgga ttgcttgagc tcaggagttc aggaccagcc tggccaacaa ggcaaaccct 10860 atctctacaa aaatataaaa attaactggg cttagtggcg tgagtgtgtg gtcccactac 10920 tcagaaggct gaggtgggag gatcacttga gcctggagat gaaggttgca gtgaccgaga 10980 tcgcatgact gcactccagc ctgggtgaca gagtgagacc ctgtctcaaa aaaaaaaaaa 11040 aaaaaaagta aagaaagaag aagaaacttt ctctgccttt ctctgcttgt tactggtgta 11100 gtcccagagc cttaaaaagt acttactatt caacaggtac tcactatatt cagttgaatg 11160 aatgaataaa tttctagctc actgcctagg aatggaaaat aattcaacct tagttttaga 11220 gatatatagt atagataaga gcatcatctt tagagacaga cagcctggat aaaatcatat 11280 ctccagccag acgtggtagc tcacatctat aatcactttg ggaggccggg tgggtggatt 11340 acctgaggtt aggagttcaa gaccagcctg gctaacatgg tgaaacccgt ctctactaaa 11400 aatacaaaaa ttagccaggc gtggtggcac acacctgtat tactagtact caggaggctg 11460 aggcaggaga attgcttgag cctgggagat ggaggttgca gtgaatgaaa tcgtgtcact 11520 gcactccagc ctggccgaca gagtgagact ctgtctcaaa aaaaaaaaaa aaaaaaaaaa 11580 aagaatcatg tctctatgat gaattacctg ggtgacctta ggtaattata tagtttctgt 11640 gtcccctcag tctcttcatc tataaaatga gactaataat aggcctacct cattagattt 11700 ttgtgaggat taaataagtt aatacatgta acatgcagat gtggattttt gaccaccatt 11760 tcctctgggc aagtacgtgc tgtcatatgt agaggagaca tgaacagatt gttactgtgt 11820 aggtgggtaa ggccttttca ggcattgcaa agtaattttg ctatcacctt tctcagctgc 11880 tttgcttctt gtctagtcac cccaaacccc ttttctgtcc tctccccata tgtatatttc 11940 ctgagagaaa aaaagattat ggttgcgtgt catagtaact gggcaatgca accccattag 12000 cattgaggaa taaggtaaac tgaagtcttt tttaacatct cctgagagcc atacatagaa 12060 aatatacaaa agaaaaaaga tttatgtgac catactttta agtcatctct gggaaagact 12120 tgctccttgg catttctttg ggctaggtaa actgattgga tactgtgtga actcattcat 12180 acatcagttt tcttggctca cagtacagat ttgatactat ttgatctttt taaattaccc 12240 catgccaact ttaagcctgt actaagattt caatagtaaa acattatttt attcgggcac 12300 agctaattta aagttacata tgtgcaacgc taaatgtacc tttgtactaa aagtttgata 12360 attacattaa tagagtaaat tacactgaag gatgtttctt aaatatcaaa aatgtccaaa 12420 ttaaagaact tccttctaac cactaaaaca ccttggcatt gatctgcttg catttaaata 12480 atacgttaat tacgaatggc tcatattaat ttatcaacca attcctggtg ggtcctctac 12540 ttgaaatcat gttcatataa ttaagagaat acaatggcat ttaaacaaaa aaaaacccaa 12600 aatatctata gttcaaccat ggcacttcgg ataagtgatt aggaatacaa actaaggttc 12660 tctgaaatgg gagtttattt gtttgttttt gtttgtttat ctatgttttt caagtcaatg 12720 atttcagcag atgaagtagc accagtttca atcagcgaat atttaccaag cttcctgagc 12780 cccactgtgg tagagagatg cacgatggtg agacagcatg ttcccttaca atgaaaactg 12840 gatatgtgtc attatcttta tgaggtcaca caactggtct ctcattaaat aatgaccggc 12900 tgtacaagct cacgtactcc atgaagttct tcttgatcgg ggcaaaggaa aactgcaaga 12960 cagcgtgggc taccgcattt ctccaacgtg gatgtggcct tactatggag gaatcctgat 13020 ggtgatgatg accagttgac caaataacgg tgggcatttt ctaccagata aatgcaaaga 13080 ttagatatca gaagttttga gaagtgtacc attggacagc acttgtattg ggttcccgtt 13140 tataaatcca tttagttctt atctatcact aaaacaagca gttctatgta tttaaaggtt 13200 ttgctgatga aaagtgactg atctttccaa gttattgcaa cagacaatag aaggtatata 13260 ctggtaaacg accaggtatg gtgttcaatt ctatagatca tgttaatagg gaagttatac 13320 tagagtcttt tcaaatgttc tgggagagaa gggtcaataa tccatgttgt atgaaaaaca 13380 atttagacca ctcaactcaa gaggagatca gttaggaggt tcctgcattc cttgatacaa 13440 caggtggaat tatgaagaga gagtaaacct agtctgtgtt cttcctgagg aaggaaccaa 13500 gtactcccct gataacagtg tttggtcagt taaaatggtt tagatttatg tgctgagaag 13560 ggaggccaaa tagttggtct ctggggactt ttccaattgt aatatatggt gattccctta 13620 tttgcttcta agaacctaaa gataatagat tccttgagta aagtcagtta ttcttctaca 13680 tcttggtgga aacaggtaca caggacaaag tacttggaac aagtagttgc tggtgtcctt 13740 tatattgggt gtcatagcaa tacatttaca agtgatattt gcttctttgg gtgtctctaa 13800 ttgctctgtg ttttccaagt tagatctaag catcatcatc catctctctg agccatttct 13860 caataaacag taaactgttc tccagaaaac attatattcc tccttattca gtaattagac 13920 tttattttat ttacacagat aaggtagaat agggcagggg tcctttccaa caagtggtaa 13980 agaagtgaag tgatcaggta gacagcaacc acaaaaaaca aatgaagagt ggcaatgata 14040 ggaagaatca cactcaagtc acaattattt taagcctaaa gtcacagagt tctttaagta 14100 tgctattttt gccttattaa aaaacctagt ttttaaatac cttctccatt cttttaaagt 14160 agtggcaagg tcctataaat catgaattga aaaatgacag aagaaattgt ggccaactct 14220 tctgtttctt tatcatttta ttttcagaga tactctgatg aagacagata taggaagttt 14280 ttttaacagc tttctttctg ttactccaga tgaaggatgt aaatgttgaa aatgtgatca 14340 gcagagagga gagaagagca tottcaaagg aaaaagccca tctaaaataa tgggaaggaa 14400 aacttggaag ctctgcaaag acctacgctc cttcatctaa tccatggaaa ggtaaggggc 14460 gtttagattc cacaactttt tctccaactt catatttttc ttcccttcag tagaattatt 14520 ttgaggtaat cacattgtaa ctacttttat ggtaaatgga atttcttcaa gaataaagaa 14580 cagaggttgt aaattaaatg tttccaaact gaatcaatgc cctgagttcc ctacatttac 14640 tagccaattt gtttcctatt tttctggaaa tctttatagt ggaatgaagt attatttatt 14700 gatgaaaggc attattaaaa ggtaaatttc tcatcaaatt ataagggatt caaacataat 14760 gtaacaaagc aagtcatcaa agcatgattg gatgaattca ggaaaggagc aaattatgag 14820 actgaaatga tccaactgag attagtaata ttgatttgtt atgagatttc gatatctggc 14880 taaagtacaa ggttaaagat tttaaaaggg tatgacaagt ctaaagtgag tttttttaaa 14940 gcctttagaa attattttaa aactatgaca tggaaaagcc ttttattatt aaaataatga 15000 ttgaacactt tataatatat atttgaaaat ctgttttaaa aattcatgtg tgcattactt 15060 atggcttgat tctagtcaat tgaaatggtc taaataaatt tggattgaga aacaattgtg 15120 atcagttgat tattaggcat tacatatttg tgtttatgaa aatacagata gtgtgttgac 15180 atacataaaa atgtgtctaa agatgagagc tcaattttag gacaaaagca ggaaaacaga 15240 aagggaacat tgagttataa ttccatacgt ctctgaaatt tactttctaa attcaaaata 15300 aagaaaaact gatctttata tactgataaa gtaatacttt tttattttca actgaagtat 15360 ttgaaaacaa atactttgga catttcatat atgtatattc taatcatgat gcacattttt 15420 atatgaagtt ctaaaaagga actcacaaga agaaatctgt gttttcacct cgcctacaac 15480 caaatatgaa tcactatctt caagaatgct ttctcttctt ctttacttgt caaaatactt 15540 gccatgtttc tgactgctca catgccattt ctgtcaaaag ttcataccct tccagccagc 15600 tggaaataac catcactctt tagaatgctc ttagcctttg cagctcactc atgaccctta 15660 tcactttgtt tttggtcatt tgtgttcatt gctaattatg ggtgttggat agaaaaaaat 15720 ccaattcctc tttgtatttc agcctctccc cttacctcca tgcccttcca ctccctcctt 15780 ccccaaagca cccagaatta tgccttgcac tgatatttta tgaagccttc tccgacatct 15840 ttccaaaccc ctgggcctat ttctgtcaaa ggtttatcac agtgtattgt cactctcctt 15900 ttatgtcttg gctctccaca ttcagaataa tttctcatgg gcagagttgt atctgtctat 15960 tcagcacctt gctcataggg gatactgaaa tagatgcttc taaaataaag gataaacaaa 16020 taagattata tggggctcaa ctgagttgac tttgataaag gttttactta ttgtttactt 16080 aataatagct aaaatgaact aagcactact gtgtgctagg tgctgactaa aggcattaca 16140 cgaactgtct cttttattct tgtaatgccc tgagcagtaa gggctgcctt atcaacctct 16200 tgtgatagat gaggaaccaa agttagaaaa gttaggaaat ttgcctatgg tcatacaact 16260 ggcaggtggt ggagttggga cttgaataga gtctatgctc aaacttctat gcctactgtc 16320 ttccagctgg aaagtatttg gagaatgcct gcctctttgg ttgacttgta gtgttcctta 16380 tttacatcat gagatcagtt gattatttga ttttcttatg gctcaacttt gttaacaaca 16440 agaaatattg ttattttctt cctgagcttc caatgtggca agacacttga gttcatagat 16500 attatttgca tttataatct actgacaacc aatcatttta tagctccttt ggtagcagct 16560 gagtacaaag tcttctgctc acacatgaaa ggactcagta ccctcactgt tcaaaggctg 16620 ggatggaact gccacatctt attttaataa ctgcaatggg ccaattctag aggagctatg 16680 atttgcgatg atttacttaa ccacaggtta aagtacatca ttgtatcttt caagtatata 16740 ataaaatatt tgttggaaaa acttaacaat gaggactaag aagccaacag gaagttttgg 16800 ccatgtcact gtcagaagat cattacttaa attatcattt cagtttacta tgagagaaat 16860 tatggacagg cagataaggc tatggacagg ctattttctt agagagcatt ttctaccaca 16920 ggctcaaatt aagtgtgctc ctgaagtttc tgggatttca aggatgctca tcagcatgta 16980 atttttgtcc ttcagacctc cccctgtctc cctttcccat ctgaggctct catatttaca 17040 ttttaaaaga ggtccattaa aatacttaga tacatattca ttgcacatct tcttttttcc 17100 atgcccactc tcttccctac ataagtgggc ataactctag ttttgtctac aaatcattaa 17160 gttgtaaact gacagttatc tgattacgtt gattaatgct gacgagtgaa agatgcctca 17220 agttatacat ggattctttt ttaggcctga aatgctgctc caattaactg gataattacc 17280 agatttcatt tctggttttg gctttgtgtt gattaaatta accacgtggc tgctgagtca 17340 gaccttattt tgtattgttt ccgggcattg atttgctctc taaatcagca tggctcttgt 17400 acacaactga actgccacaa gaaatgtgac accttgaaag tccttctgaa atttgttgta 17460 tattctttac ttgtttgttc tccagtgtgt catttcctag ccatgctctg tcttagatag 17520 atacaaagat aaaattacta atctttgttt gctgggattc tttttattat ttttattgtt 17580 tgccacttaa tggaatttag tctcctctta ttcttaaaat aaatataaag gaaggtgtgg 17640 aaaaggcatc ttottcctaa ggaaaaaaca atatgaatga tgcctaccta tttcaagagg 17700 aactggcccc tcatatttgg ctggaagagg cactgtacca ccttcccagc cattttacca 17760 gtctccctct agctgtggtt tccttgggtt aaagacttcg tttgtaacca ggtcatactg 17820 ctgctgctct ttggaagctc tgagtactgt aaatttagat aagaacctgt gctcttgatg 17880 ttcagaacta atttcattgc tgaatgaagt aatcaacttt atggcctgag tataataaac 17940 ttactcagtt cctgttgtga aataataaat ttaagattat tgctgtgaca gccattggct 18000 tgaaatgcaa aattctgatt tcagattatt attttttaaa tgattacaag gcagtcaatt 18060 ctaacagttt tgacatttag ctggtatgga tatcagtact atcttcactt tggtctcatc 18120 agtctacact aaagaaacag aatttaggcc ctagaagtag cagtcatata aagaaaaaga 18180 gatgtgttca tttttctagt tctggggaag caataaaaac taatagaaag gttaaaaaaa 18240 cttttttcat tgtgtttcac agtttatatc tatcattcag cctgccagga ggaaaaaagg 18300 ctctaacacc attttctaag ggatccagag gtcaagatca aaacttgatc attgcagtgg 18360 gtcagtaaca gataagcact gaaccttatg cacagtccaa agattaaacc aagaactggg 18420 tttccttacc ttttaggtaa aactttaaaa atagctcaga tacatttgta gcctggaagg 18480 aaagtgacat agtggtgaca atactggtat ttttcccact taggagtctt gctttctaaa 18540 gtatttaagg ttcataccaa aaagacatgg gccatataga catgttgcat tgccactgag 18600 tgaacacttc tgactatttt ggggcaatct agttatgaac ttctatggtc atgatacctg 18660 gagatacact tccaaatatt tgaaaaggaa attacactgt gatattagag gaaggagata 18720 tagtttacaa aatagaactt cagaaactca ggcttgggtc tggatattgc cagtgatttg 18780 tttgagaata tgatactgtg aattttcaga cactgaggtc atattccagt tcctttctaa 18840 gtcggacaaa cactattcca acatttatag gttagtccag ctaatgacta aaactgattg 18900 ccagataaag tacctagtaa atccatcact aggcagagtt atgtaggaag taaaaataga 18960 gatttgagac acttgtttgg ataattcagg aaaagtatct cttcttctaa ggcacaagat 19020 aattttcatg tagactaaat tactgagctt ggtattattg gattcattgc atagctattg 19080 agctttatgt tttactttag aagctatggt tggtttaaag agtactagga aggcattcag 19140 gatatttctg gtagaaatgc tcagctataa ttatctagac cttgggaatt tttacaggga 19200 acatgtatct atcctctatt tctaaattgt gtgagcatat caagtctaca gggtgaaaac 19260 caacaagctg attttcatta aattcacttt gtattttatc cttgtttctt aaacattagt 19320 taaattatca aaatggcaaa agacacttat cactctgtgc ctataaatat caaagatgat 19380 aaaacaaaac taagtggctt actattcctg caaatcatag tcaccctcct catttcaacc 19440 tcctttctct gccttctgat ggtaacctca agcagtgcct ggggcaggtt atgcagcagt 19500 agcaatctca acctcaaatt ttccagcctc tgaatatata tatacacaca tatatatata 19560 tgttcatata tatacacaca tatatatagt tcatatatat acacacatat atatatgttc 19620 atatatatac acacatatat atatgttata tatatacaca catatatata tgttcatata 19680 tatacacaca tatatatatg ttcataatat acacacatat atatatgttc atatatatac 19740 acacatatat atatgttcat atataacaca catatatata tgttcatata tatacacaca 19800 tatatatgtt catatatata cacaatatat atatgttcat atatatacac acatatatat 19860 gttcatatat atacacacat ataatgttca tatatatatt catatatata tatatttttt 19920 ttttacccaa taccaatata aagctctgga gggtggaaaa cattgcccct gtgaaatgtt 19980 gaccatgggt attatggcca tcctggggcc ttgcaatagc ccataaaggc tgtgccatct 20040 caggaatctc aaaggtagtg ttgccatttt cgtccaagaa cttttttatt tgctattatt 20100 ttaaacctta gttatttttg tttcaagtac agttacaggt agagaacatg ctgacatgtt 20160 caaacagaat tttcatcatt ctcttccctg ggccatcctt gttttcatga ggctcccagc 20220 ctatatcagt gctctctcca atgctgtgcc catcatgcaa gagccttcat tatcggtctc 20280 cctaaacttc atattcgatg gtctcagaga tttaaatagc ttcttttcac aaaaaggaaa 20340 ttccagattt ggagttcaga tctctttctc ccaggattaa tacaggtaag aatctgacct 20400 tgcctgacac ttattaaatc tgataaatga tgcatttttg cttcatttgt gttctgttcc 20460 cctctcccca ccagtcaaag agttctactc atatcaaaat gaggcagtgg ccatagaaaa 20520 tatcaagaga ggctggctag cctatttcag acacagttaa gctctggaac caccaatgag 20580 gtacttacca aattaataag gattcagcat ctcaataaaa tttgtaagga tttctactta 20640 tacaatttca tagaagagtt actactaagg taatgctcag aaaaggtgac ttgtgtagtg 20700 aagtcgcatt gcctatgaaa caattgccat ttatcccaat gttttgttaa ttaattacaa 20760 ggtagagaga ttagaaatat ttatactaaa ggagcttcgt ggggatcatt ccagtggttc 20820 ccagatacac tgtgcaccac tgtaccatgg aggggcttgt tacaaatata gattccctat 20880 attcatccag agattctgat tcagtagatc ggggaggacc cgaacgtctt tttttttgag 20940 atggatctca ctctgtggcc caggctggag tgcaatggcg caatctcggc tcactgcaac 21000 ctctcctccc aggttcaagc gattctcctg cctcagcctc ccaagtagct gggattacag 21060 gcggtgccac catgcccggc ttgtattttt agtagagaca gggtttcacc atgttggcca 21120 ggtggtcttg aactcctgac ctcagatgat ccacccgcct tggcctccca aagtgctggg 21180 atacaagcat gagccaccgc gcttggtcaa acatctgtat tttaacagtc tttgtggatt 21240 tttggatgca ttgtcaatgt agggaaccac tggtctatac caacactgtt cattttgcaa 21300 agaagaaact agagaagtta ggtggatctt ccagtatcat acctggagtc aaggctgggt 21360 ccaagtttct tagactgaat tcaaccagcc catgagtggg tgaaaaatct gatggtaggt 21420 tggaccaaaa gaatgttggt tagcttgcta gaaaagagac ctctgcttct gtgatgtggc 21480 agaggcccca ggaaaaagct cagagaagct agacagagtc tgtattggga tacattgcct 21540 aaactcaaac tgatgatgta gctaatgatg atttgagtta atcccagtgg atttaattaa 21600 tcccacagga ttttaagaat ttctaatcat gttcagctag ttgaagttac acaacacaca 21660 cacacacaca cacaccacac acacacagaa tctagataca gcattaacaa tcactccctt 21720 gccacagaat tacccattta tccaaagttt caattattac caggccattt gctaatttta 21780 attggatttc gagagaagta ggaaatccca cattatttgt gaaaaaaaat agaaggcgct 21840 attaagacac tcaaccaaag agaatgggag ggaatcaatg agctaccaga accttgttct 21900 tgtctttgta tcttatcatc ctgggggaga aaaaaagtcc cctatggcta ttagagacct 21960 caattttcaa gccacttctc actagaattc aaatggccca caaggaaccc aagcattatg 22020 cccttgcctt tctttttagg tagatatctc tggaaattgt aaagtgccta ccaggctcat 22080 caagacaaag tgatcaaaat taaggccttg gattcatgca aaatacgagg tctggattta 22140 cgaccccaaa tcaggtatga tagatgtcac tttctttgag gcataaaata attacatttt 22200 gtagagacta atttaatgta atagaaaaat aaagtagaaa tagattttga aacatttgta 22260 atttttagtt taggctacaa attcacacat atgtaatgaa taacccattt caattgttgt 22320 aggtgttagt aatgagggat gggtgtaatg gggaagctgt tgtagactga aagacagttt 22380 gctatttgac ttgattcaat aatttaaacg atgattactt ttataaagat ggctatttat 22440 ttatttaggt cttgggtgtc agttcaaaag ctacatctgc accacctata agatagaaga 22500 cagctttgtt atagctgtgc ttgctgaaga aacacacatt ttggactgaa tttcctacaa 22560 accattaagg ggaaaatagt atcgaagtaa gataatgtaa aatttttatt ttctttgcta 22620 ttctttgtta tattattata cttgatttgt aaatagtctg tgtttgtgtg tgtgtgtgtg 22680 tgcgcgtgta gtcatgcatt gcttaacaat gggaaaagtt ctgagaaaag cattgttagg 22740 caatttcatc actgtgcaaa catcatagag tataatacac aaacctagat ggcatagcct 22800 acactacatt atatggtata gcctattgct cctggctaca aacctgtata gcatgttgct 22860 gtactgcata ctgtagacaa ttaaacacaa tgtaagtttt tgtgtatcta gacatagaaa 22920 aagtcagcag aaaaatacag tataaaagat atatgtaggt gtacctttat tcataaaagg 22980 tacataagtg aaatttgcag ggctgaaagt gctctggatg aatcaccaaa tgagcactga 23040 gtgaatgtca tagactagga cgttactgtc actactgtag actttataaa cactgtacac 23100 ttatgctacg ctgaatttct aaaaaacttt ttcctccatc ataaattaac cttagcttac 23160 tgtaatattt ttacgttaaa aacttttaat ttttgttaac ttttgaagta ctctgtaata 23220 acacatagtt taaaacacat tgtatagtgt acaaaaaata ttttttcttt aaatctttat 23280 aagctttttt ctatttttaa atttttattt ttattttttt cttttaaaaa tttctggtta 23340 aaaattaaga cataagcata tatatagcct cggcctacac aaggtcagga tcatcaatat 23400 cactgtcttc ctccagtgga aggacttaca acctccaaat gttgtctcac tgaaaggtct 23460 tcaggtgcaa taacatacat agactgtcac ttcctctgat aacaatgcct tcttctggaa 23520 tacctcctga agaacctgcc taggctgtct tacagttaat ttttttaata agtagaagaa 23580 gtacactgta aaataataat aaatgtgtgg tataataaac acagaaatca gtaataatca 23640 tttgtcacca ttatcaagtt tatgtattgt acgtaactgc acgtgctata cttttatata 23700 acagtagcac agtaggtggt taaccaccag catcgacaaa aacacgtgag taatgctttg 23760 cactgtgatg ataggacgct atgatgtcac taggcaagag gaatgtttca gcttcataat 23820 tttatgggac caccttgtac atgggtccat cattgaccaa aatgtccttg tgcagcacat 23880 gactgtattt attgtcttcc tcatttcaac tgtgagctcc ttgaaaatag tgattatatc 23940 ttgttcatct ttatttttac atcatctaca acaattcacg gcacatggta aataattact 24000 ttttaaataa aatgtattaa aaatcaatta tttattgaac aggttttaag ttttaaaaag 24060 acaaactact tgttcattct agttcatttt ctaatttctc tgtcaaatgt ttttaatatt 24120 aaggtaaaaa atggtagcat ttgtaatttt taagagtttt taaaaaaaat tgttgttaaa 24180 aaacataaaa gttccgtagt gaagagatgt gacaaaattt ttgatatgac ttatgcaact 24240 taaatatttg gcctgtttat catttgaaga ccattctctg gacagaattg ttctaacagg 24300 attaagaata gaatgttaaa tcttagagtt tctgttattt tcagatttta attcagaaaa 24360 caatgtttct agcagtgaat gtgttatacc ttatgccatt gcttctcaaa aaatttctct 24420 ggagtactgt aatattagca ccaaatagat gcaaaatagt agtaaaaatg cctgattaaa 24480 atgctgaaat tttatagaag tctcatctgg aatagaattt tgcattctac ttcatatact 24540 actgtatatc tatagtgttt tattatattt tcatataaaa taaatatttt aaataactta 24600 tcagcctatg agatttccat tgctatgtaa caaccccaga tttagtggta taaaatgcaa 24660 catcactgta ctgttctctg tcataattta caggcttgcc ttggccttgc taggcatcta 24720 tatgtagttt cagacagtca aactattcaa aggtggttcc cccatgtatc tggtgcatgg 24780 ctggaaagac tcaaacatct gaggctoctc atgcaactat ctttatttcc ctgtcgcctt 24840 cagcattgca gcttcatgtc agacttctta tgtagtagct caaggctccg aagcacatta 24900 ctgatagtgt gccagagaaa agctgaattc tcttttaaga catagcctta gagatcaaca 24960 gtgttacttt cagtctcctc tattagttga ggcagtcaca gagtcctacc caggttaagg 25020 agagggatgt agaccctacc ttttgatgac agacaggttc tggaagagca tgtcaacaaa 25080 aatagagttg agactatttt tggaaaataa gattttctag ctgtcttggt taatagtaac 25140 acgtggttgt attgacgata tcattttcag aaagctgggc taaattcaaa agactgacat 25200 tgcatatctt attcatcatc caggcaattt ttcttccctg tatactgttg aataatattt 25260 tgaaaatgca aacttaaatt ttcaaatctt ttaatataat tgttgctcca gaagacttca 25320 taatgagctt tcagttacct ctggagatat cacagtttga aagacatggc atatacaact 25380 tgaataaatt actatcttgt ttgccaaaag aatggcaatt agtatcttgt cactcaaaag 25440 aatgattata atatagcatt tccctttggt attatgcagg cagaaattga gctgaagaca 25500 accgaagcag gcccaagatt gatgtctgga aagcaggctg cagccatatc aaagcagttg 25560 attcaaagta cacggccatt cccattgtgg ggcaggtctt ccagagcagt gtaaaggatg 25620 tccttctgta agtgcagaca aatatgggaa taatcatgac atcagctctg ttttcatttt 25680 gtctccagtg aaagcatcaa ctcattcaat gaagacagtt tctaagaact accagctacc 25740 acagagttgt gatgacagca gtctcacaat atgcacctga catgtgcatg acacatcaat 25800 aattaacaaa tagttaccat tcattcctct caaaaagtgt taaactcaag ggcagccttt 25860 aataagtcac atctagaatt cagggaggat agagggctta agaagttagg gggaagcata 25920 tggtgtcaag aatgtggaca acggctgaac cttgaaagtt tgtcacataa tagttatttg 25980 tccacaggtg acatacttta ctggcctcag tgttctgata ttgctgcaag gactgaaaaa 26040 ggataccagg atctttgcct aaattaggaa acatttatta ccccagtttc ccctacaatt 26100 cctgtcagaa atgcgatatc tcatccccag ggcaaaggta gatcattgta acatttttaa 26160 tccaacaaag aaaattttcc ttttattgca tgaatcgtta tgatatacat tcagagaaat 26220 DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.

NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des Brevets.
JUMBO APPLICATIONS / PATENTS
THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE
THAN ONE VOLUME.

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Claims (34)

What Is Claimed Is:

1. A method for identifying an individual who has an altered risk for developing liver fibrosis, comprising detecting a single nucleotide polymorphism (SNP) in any one of the nucleotide sequences of SEQ ID NOS: 1-261, 523-18973, and 18974-34256 in said individual's nucleic acids, wherein the presence of the SNP is correlated with an altered risk for liver fibrosis in said individual.

2. The method of claim 1 in which the altered risk is an increased risk.

3. The method of claim 1 in which the altered risk is a decreased risk.

4. The method of claim 1, wherein the SNP is selected from the group consisting of the SNPs set forth in Tables 6 and 7.

5. The method of claim 1 in which detection 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.

6. An isolated nucleic acid molecule comprising at least 8 contiguous nucleotides wherein one of the nucleotides is a single nucleotide polymorphism (SNP) selected from any one of the nucleotide sequences in SEQ ID NOS: 1-261, 523-18973, and 18974-34256, or a complement thereof.

7. The isolated nucleic acid molecule of claim 6, wherein the SNP is selected from the group consisting of the SNPs set forth in Tables 3 and 4.

8. An isolated nucleic acid molecule that encodes any one of the amino acid sequences in SEQ ID NOS:262-522.

9. An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:262-522.

10. An antibody that specifically binds to a polypeptide of claim 9, or an antigen-binding fragment thereof.

11. An amplified polynucleotide containing a single nucleotide polymorphism (SNP) selected from any one of the nucleotide sequences of SEQ ID NOS: 1-261, 523-18973, and 18974-34256 , or a complement thereof, wherein the amplified polynucleotide is between about 16 and about 1,000 nucleotides in length.

12. An isolated polynucleotide which specifically hybridizes to a nucleic acid molecule containing a single nucleotide polymorphism (SNP) in any one of the nucleotide sequences in SEQ ID NOS: 1-261, 523-18973, and 18974-34256.

13. The polynucleotide of claim 12, which is an allele-specific probe.

14. The polynucleotide of claim 12, which is an allele-specific primer.

15. The polynucleotide of claim 12, wherein the polynucleotide comprises a nucleotide sequence selected from the group consisting of the primer sequences set forth in Table 5 (SEQ
ID NOS:34257-34458).

16. A kit for detecting a single nucleotide polymorphism (SNP) in a nucleic acid, comprising the polynucleotide of claim 12, a buffer, and an enzyme.

17. A method for identifying an agent useful in therapeutically or prophylactically treating liver fibrosis, comprising contacting the polypeptide of claim 9 with a candidate agent under conditions suitable to allow formation of a binding complex between the polypeptide and the candidate agent, and detecting the formation of the binding complex, wherein the presence of the complex identifies said agent.

18. A method for identifying an individual who has a risk for progressing rapidly from minimal fibrosis to bridging fibrosis/cirrhosis, comprising detecting a single nucleotide polymorphism (SNP) in any one of the nucleotide sequences of SEQ ID NOS: 1-261 and 523-34256 in said individual's nucleic acids, wherein the presence of the SNP is correlated with a risk for a rapid rate of progression to bridging fibrosis/cirrhosis in said individual.

19. A method for determining whether a hepatitis C virus-infected human has an increased risk for developing liver fibrosis, comprising:
a) testing nucleic acid from said human to determine the presence or absence of a polymorphism in gene PNPLA3 at position 101 of the nucleotide sequence defined by SEQ ID
NO:8938 or its complement; and b) correlating the presence of G at position 101 of SEQ ID NO:8938 or C at position 101 of its complement with said human having said increased risk for developing liver fibrosis.

20. A method for determining whether a hepatitis C virus-infected human has an increased risk for developing liver fibrosis, comprising:
a) testing nucleic acid from said human to determine the presence or absence of a polymorphism in gene LRP5 at position 101 of the nucleotide sequence defined by SEQ ID
NO:18900 or its complement; and b) correlating the presence of C at position 101 of SEQ ID NO:18900 or G at position 101 of its complement with said human having said increased risk for developing liver fibrosis.

21. A method for determining whether a human has an altered risk for developing liver fibrosis, comprising:

a) testing nucleic acid from said human to determine the presence or absence of a polymorphism in gene DDX5 at position 101 of the nucleotide sequence defined by SEQ ID
NO:19179 or its complement; and b) correlating the presence of the polymorphism at position 101 of SEQ ID
NO:19179 or its complement with said human having said altered risk for developing liver fibrosis.

22. A method for determining whether a human has an altered risk for developing liver fibrosis, comprising:
a) testing nucleic acid from said human to determine the presence or absence of a polymorphism in gene MTP at position 101 of the nucleotide sequence defined by SEQ ID
NO:22070 or its complement; and b) correlating the presence of the polymorphism at position 101 of SEQ ID
NO:22070 or its complement with said human having said altered risk for developing liver fibrosis.

23. The method of any one of claims 19 to 22, wherein said nucleic acid is a nucleic acid extract from a biological sample from said human.

24. The method of claim 23, wherein said biological sample is blood, saliva, or buccal cells.

25. The method of claim 23 or 24, further comprising preparing said nucleic acid extract from said biological sample prior to said testing.

26. The method of any one of claims 19 to 25, wherein said testing comprises nucleic acid amplification.

27. The method of claim 26, wherein said nucleic acid amplification is carried out by polymerase chain reaction.

28. The method of any one of claims 19 to 27, wherein said testing is performed using sequencing, 5' nuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, single-stranded conformation polymorphism analysis, or denaturing gradient gel electrophoresis (DGGE).

29. The method of any one of claims 19 to 27, wherein said testing is performed using an allele-specific method.

30. The method of claim 29, wherein said allele-specific method is allele-specific probe hybridization, allele-specific primer extension, or allele-specific amplification.

31. The method of claim 19 or 20, wherein said human is homozygous for said C or said G.

32. The method of claim 19 or 20, wherein said human is heterozygous for said C or said G.

33. The method of any one of claims 19 to 32, wherein said correlating is performed using computer software.

34. The method of any one of claims 19 to 33, which is an automated method.