WO1999009164A1 - Coding sequence haplotypes of the human brca2 gene - Google Patents

Abstract

Five DNA and protein sequences have been determined for the BRCA2 gene, as have been ten polymorphic sites and their rates of occurrence in the normal alleles of BRCA2. The sequences BRCA2?(omi1-5)¿ and the ten polymorphic sites will provide accuracy and reliability for genetic testing. One skilled in the art will be able to avoid misinterpretations of changes in the gene and/or protein sequence, determine the presence of a normal sequence, and of mutations of BRCA2. This invention is also related to a method of performing gene therapy with BRCA2?(omi1-5)¿ coding sequences or fragments thereof. This invention is further related to protein therapy with BRCA2?(omi1-5)¿ proteins or their functional equivalents.

Description

CODING SEQUENCE HAPLOTYPES OF THE HUMAN BRCA2 GENE

This is an U.S. utility patent application based on U.S. Provisional Application Serial Nos. 60/055,784 filed on August 15, 1997, 60/064,926 filed on November 7, 1997, and 60/065,367 filed on November 12, 1997.

FIELD OF THE INVENTION

This invention relates to a gene which has been associated with breast cancer where the gene is found to be mutated. More specifically, this invention relates to five unique coding sequences of BRCA2 gene

BRCA2^(omι1), BRCA2^(omι2), BRCA2^(omι3), BRCA2^(omι4), and BRCA2^(om,5) identified in human subjects which define five novel haplotypes.

BACKGROUND OF THE INVENTION It has been estimated that about 5-10% of breast cancer is inherited

(Rowell, S., et al., American Journal of Human Genetics 55:861-865 (1994)). The first gene associated with both breast and ovarian cancer was cloned in 1994 from chromosome 17 by Miki, Y., et al., Science 266:66-71 (1994). A second high-risk breast cancer conferring gene was located on chromosome 13 in 1994 (Wooster, R., et al., Science 265:2088-2090) and subsequently cloned in 1995 (Wooster, R., et al., Nature 378:789-792). Mutations in this "tumor suppressor" gene are thought to account for roughly 35% of inherited breast cancer and 80-90% of families with male breast cancer.

Locating one or more mutations in the BRCA2 region of chromosome 13 provides a promising approach to reducing the high incidence and mortality associated with breast cancer through the early detection of women and men at high risk. These individuals, once identified, can be targeted for more aggressive prevention programs. Screening is carried out by a variety of methods which include karyotyping, probe binding and DNA sequencing. In DNA sequencing technology, genomic DNA is extracted from whole blood and the coding regions of the BRCA2 gene are amplified. Each of the coding regions may be sequenced completely and the results are compared to the normal DNA sequence of the gene. Alternatively, the coding sequence of the sample gene may be compared to a panel of known mutations or other screening procedure before completely sequencing the gene and comparing it to a normal sequence of the gene.

The BRCA2 gene is divided into 27 separate exons. Exon 1 is noncoding, in that it is not part of the final functional BRCA2 protein product. The BRCA2 coding region spans roughly 10433 base pairs (bp) over 70 kb. Each exon consists of 100-600 bp, except for exons 10, 11 and 27. The full length mRNA is 11-12 kb. To sequence the coding region of the BRCA2 gene, each exon is amplified separately and the resulting PCR products are sequenced in the forward and reverse directions. Because exons 10, 11 , and 27 are so large, we have divided them into three, twenty-one, and two overlapping PCR fragments (respectively) of approximately 250-625 bp each (segments "A" through "C" of exon 10, "A" through "U" of exon 11 , and "A" through "B" of exon 27).

Many mutations and normal polymorphisms have already been reported in the BRCA2 gene. A world wide web site has been built to facilitate the detection and characterization of alterations in breast cancer susceptibility genes. Such mutations in BRCA2 can be accessed through the Breast Cancer Information Core (BIC) at http://www.nhgri.nih.gov/lntramural_research/Lab_transfer/Bic. This data site became publicly available on November 1 , 1995. Friend, S. et al. Nature

Genetics 11 :238, (1995). The information on BRCA2 was added in February, 1996.

The genetics of Breast Cancer Syndrome is autosomal dominant with reduced penetrance. In simple terms, this means that the syndrome runs through families: (1 ) both sexes can be carriers (mostly women get the disease but men can both pass it on and occasionally get breast cancer); (2) most generations will likely have breast cancer; (3) occasionally women carriers either die young before they have the time to manifest disease (and yet have offspring who get it) or they never develop breast or ovarian cancer and die of old age (the latter people are said to have "reduced penetrance" because they never develop cancer). Pedigree analysis and genetic counseling is absolutely essential to the proper workup of a family prior to any lab work. Until now, the only sources of genomic sequence information for BRCA2 were GenBank (Accession Number U43746), or through the Breast Information Core (BIC) database on the Internet which requires membership in the BIC consortium. However, based upon the disclosure of this patent application, in neither GenBank nor BIC were the sequences identified and listed entirely accurate. There is a need in the art to correct these mistakes which otherwise may lead to misinterpretation of the sequence data from the patient as abnormal when it was not, or vice versa.

In addition, there is a need in the art to have available a functional allele profile which represents the most likely BRCA2 sequences to be found in the majority of the normal population. This functional allele profile is based upon frequent polymorphisms and the correct backbone sequence. The knowledge of several common normal haplotypes will make it possible for true mutations to be easily identified or differentiated from polymorphisms. Identification of mutations of the BRCA2 gene and protein would allow more widespread diagnostic screening for hereditary breast cancer than is currently possible.

The use of these common normal haplotypes, in addition to the previously published BRCA2 sequence, will reduce the likelihood of misinterpreting a "sequence variation" found in the normal population with a pathologic "mutation" (i.e. causes disease in the individual or puts the individual at a high risk of developing the disease). With large interest in breast cancer predisposition testing, misinterpretation is particularly worrisome. People who already have breast cancer are asking the clinical question: "is my disease caused by a heritable genetic mutation?" The relatives of the those with breast cancer are asking the question: "Am I also a carrier of the mutation my relative has? Thus, is my risk increased, and should I undergo a more aggressive surveillance program?"

SUMMARY OF THE INVENTION

The present invention is based on the discovery of the correct genomic BRCA2 sequence and five novel sequence haplotypes found in normal human subjects of the BRCA2 gene. It is an object of this invention to provide the correct intronic/exonic sequence of the BRCA2 gene.

It is another object of this invention to provide five unique haplotype sequences of the BRCA2 gene in normal individuals which do not correspond to increased cancer susceptibility.

It is another object of this invention to sequence a BRCA2 gene or a portion thereof and compare it to the five haplotype sequences to determine whether a sequence variation noted represents a polymorphism or a potentially harmful mutation. It is another object of this invention to provide a list of the pairs which occur at each of ten polymorphic points in the BRCA2 gene.

It is another object of this invention to provide the rates of occurrence for the polymorphisms at codons 289, 372, 455, 743, 894, 991 , 1132, 1269, 2414, and 2951 in the BRCA2 gene. It is another object of this invention to provide a method wherein all exons of BRCA2 gene or parts thereof, are amplified with one or more oligonucleotide primers.

It is another object of this invention to provide a method of identifying a individual who carries no mutation(s) of the BRCA2 gene and is therefore at no increased risk or susceptibility to breast or ovarian cancer based on a finding that the individual does not carry an abnormal BRCA2 genes.

It is another object of this invention to provide a method of identifying a mutation in BRCA2 gene leading to predisposition or higher susceptibility to breast or ovarian cancer. It is another object of this invention to provide five novel BRCA2 protein sequences derived from five BRCA2 haplotype sequences.

It is another object of the invention to encompass prokaryotic or eukaryotic host cells comprising an expression vector having a DNA sequence that encodes for all or a fragment of the five novel BRCA2 protein sequences, a BRCA2 polypeptide thereof, or a functional equivalent thereof.

It is another object of the invention to encompass an anti-BRCA2 protein antibody using all of fragments of the five novel BRCA2 protein sequences, a BRCA2 polypeptide thereof or a functional equivalent thereof as an immunogen.

There is a need in the art for cDNA sequences of the BRCA2 gene and for the protein sequences of BRCA2 gene from normal individuals who are not at risk for increased susceptibility for cancer. In order to determine whether a sample from a patient suspected of containing a BRCA2 mutation actually has the mutation, the patient's BRCA2 DNA and/or amino acid sequence need to be compared to all known normal BRCA2 sequences. Failure to compare the sequence obtained to all naturally occurring normal sequences may result in reporting a sample as containing a potentially harmful mutation when it is a polymorphism without clinical significance.

A person skilled in the art of genetic susceptibility testing will find the present invention useful for: a) identifying individuals having a normal BRCA2 gene with no coding sequence mutations, who therefore cannot be said to have an increased genetic susceptibility to breast or ovarian cancer from their BRCA2 genes; b) avoiding misinterpretation of normal polymorphisms found in the BRCA2 gene; c) determining the presence of a previously unknown mutation in the BRCA2 gene; d) identifying a mutation in exon 11 of BRCA2 which indicates a predisposition or higher susceptibility to ovarian cancer than breast cancer (i.e., resides in the putative "ovarian cancer cluster" region); e) probing a human sample of the BRCA2 gene by allele to determine the presence or absence of either polymorphic alleles or mutations; f) performing gene therapy with the correct BRCA2 gene sequence.

9) performing protein replacement therapy with the correct BRCA 2 protein sequence or a functional equivalent thereof. BRIEF DESCRIPTION OF THE FIGURES

FIGURE 1 shows the GenBank genomic sequence of BRCA2 (Accession Number U43746). The lower case letters denote intronic sequences and the upper case letters denote exonic sequences. Incorrect exonic sequences at exons 5 and 16 are shown with boldface type.

FIGURE 2 shows the corrected genomic sequence of BRCA2. The lower case letters denote intronic sequences and the upper case letters denote exonic sequences. Corrected intronic and exonic sequences at exons 5, 11 and 15 are shown with boldface type.

FIGURE 3 shows the alternative alleles at polymorphic sites along a chromosome which can be represented as a unit or "haplotype" within a gene such as BRCA2. The haplotype that is in GenBank (GB) is shown with light shading. Five additional haplotypes are shown in FIGURE 3 (encompassing the alternative alleles found at nucleotide sites 1093, 1342, 1593, 2457, 2908, 3199, 3624, 4035, 7470 and 9079). BRCA2 ^(om'-¹⁾, BRCA2 ^(om,-₂ ⁾ _{ι BRC}A2 ^(om|-³⁾, BRCA2 ^{om|-⁴⁾, and BRCA2 ^(om|-⁵⁾ are represented with mixed dark and light shading (numbers 2, 4, 6, 8 and 10 from left to right). In total, 5 of 10 haplotypes along the BRCA2 gene are unique.

DETAILED DESCRIPTION OF THE INVENTION

DEFINITIONS

The following definitions are provided for the purpose of understanding this invention. "Breast and Ovarian cancer" is understood by those skilled in the art to include breast, ovarian and pancreatic cancer in women and also breast, prostate and pancreatic cancer in men. BRCA2 is associated with genetic susceptibility to breast, ovarian and pancreatic cancer. Therefore, claims in this document which recite breast and/or ovarian cancer refer to breast, ovarian, prostate, and pancreatic cancers in men and women.

"Coding sequence" refers to those portions of a gene which, taken together, code for a peptide (protein), or which nucleic acid itself has function. "Protein" or "peptide" refers to a sequence of amino acids which has function.

"BRCA2^(omi)" refers to the genomic BRCA2 sequence disclosed in Genbank (Accession Number U43746) wherein, (1 ) a 10 bp stretch (5'-TTTATTTTAG-3') is intronic at 3' end of intron 4, rather than at the 5' end of exon 5; and

(2) a 16 bp stretch (5'-GTGTTCTCATAAACAG-3') is exonic at the 3' end of exon 15, rather than at the 5' end of exon.

"BRCA2^{(omi 1 5)}" refers to five unique DNA sequences of the BRCA2 gene and their introns (particularly the slice sites adjacent to the exons).

These sequences were found by end to end sequencing of the BRCA2 gene from 5 individuals randomly drawn from the population and who were documented to have no family history of breast or ovarian cancer. The sequenced exons were found not to contain any truncating mutations. In all cases the change of a nucleic acid at a polymorphic site lead to a codon change and a change of amino acid from the previously published standard in GenBank (see TABLE III). In some cases the frequency of occurrence of a nucleic acid change was found to differ from the published frequency or was newly determined. These sequence variations are believed to be alleles whose haplotypes do not indicate an increased risk for cancer.

"Normal DNA sequence" also called " normal gene sequence" refers to a nucleic acid sequence, the nucleic acid of which are known to occur at their respective positions with high frequency in a population of individuals who carry the gene which codes for a normally functioning protein, or which itself has normal function.

"Normal Protein Sequence" refers to the protein sequence, the amino acids of which are known to occur with high frequency in a population of individuals who carry the gene which codes for a normally functioning protein. "Normal Sequence" refers to the nucleic acid or protein sequence, the nucleic or amino acids of which are known to occur with high frequency in a population of individuals who carry the gene which codes for a normally functioning protein, or which nucleic acid itself has a normal function. "Haplotype" refers to a series of specific alleles within a gene along a chromosome.

"Functional allele profile" refers a list of those alleles in the normal population which have the funll function. "Mutation" refers to a base change or a gain or loss of base pair(s) in a

DNA sequence, which results in a DNA sequence coding for a non-functional protein or a protein with substantially reduced or altered function.

"Polymorphism" refers to a base change in a DNA sequence which is not associated with known pathology. "Primer" refers to a sequence comprising about 15 or more nucleotides having a sequence complementary to the BRCA2 gene. Other primers which can be used for primer hybridization will be known or readily ascertainable to those skilled in the art.

"Substantially complementary to" refers to primer sequences which hybridize to the sequences provided under stringent conditions and/or sequences having sufficient homology with BRCA2 sequences, such that the allele specific oligonucleotide primers hybridize to the BRCA2 sequences to which they are complimentary.

"Isolated nucleic acids" refers to nucleic acids substantially free of other nucleic acids, proteins, lipids, carbohydrates or other materials with which they may be associated. Such association is typically either in cellular material or in a synthesis medium.

"Biological sample" or "body sample" refers to a sample containing DNA oatained from a biological source. The sample may be from a living, dead or even archeological source from a variety of tissues and cells.

Examples include body fluid (e.g. blood (leukocytes), urine (epithelial cells), saliva, breast milk, menstrual flow, cervical and vaginal secretions, etc.), skin, hair roots/follicle, mucus membrane (e.g. buccal or tongue cell scrapings), cervicovaginal cells (from PAP smear, etc.), lymphatic tissue, internal tissue (normal or tumor).

"Vector" refers to any polynucleotide which is capable of self replication or inducing integration into a self-replicating polynucleotide. Examples include polynucleotides containing an origin or replication or an integration site. Vectors may be intergrated into the host cell's chromosome or form an autonomously replicating unit.

"A tumor growth inhibitor" refers to a molecule such as, all or a fragment of BRCA2 protein, a BRCA2 polypeptide, or a functional equivalent 5 thereof that is effective for preventing the formation of, reducing, or eliminating a transformed or malignant phenotype of breast or ovarian cancer cells.

"A BRCA2 polypeptide" refers to a BRCA2 polypeptide either directly derived from the BRCA2 protein, or homologous to the BRCA2 protein, or a o fusion protein consisting of all or fragments of the BRCA2 protein and polypeptides.

"A functional equivalent" refers to a molecule including an unnatural BRCA2 polypeptide, a drug or a natural product which retains substantial biological activity as the native BRCA2 protein. The activity and function of 5 BRCA2 protein may include transactivation, granin, DNA repair, among others.

"A target polynucleotide" refers to the nucleic acid sequence of interest, for example, the BRCA2 encoding polynucleotide. Other primers which can be used for primer hybridization will be known or readily o ascertainable to those of skill in the art.

The invention in several of its embodiments includes: an isolated DNA sequence of the BRCA2 coding sequence as set forth in SEQ ID NO:4, 6, 8, 10, and 12, a protein sequence of the BRCA2 protein as set forth in SEQ ID NO:5, 7, 9, 11 , 13, a method of identifying individuals having a normal 5 BRCA2 gene with no increased risk for breast and ovarian cancer, a method of detecting an increased genetic susceptibility to breast and ovarian cancer in an individual resulting from the presence of a mutation in the BRCA2 coding sequence, a method of performing gene therapy to prevent or treat a tumor, a method of protein replacement therapy to prevent or treat a tumor, a o diagnostic reagent comprising all or fragments of the disclosed BRCA2 cDNA and protein sequences.

SEQUENCING Any nucleic acid specimen, in purified or non-purified form, can be utilized as the starting nucleic acid, providing it contains, or is suspected of containing, the specific nucleic acid sequence containing a polymorphic or a mutant allele. Thus, the process may amplify, for example, DNA or RNA, including mRNA and cDNA, wherein DNA or RNA may be single stranded or double stranded. In the event that RNA is to be used as a template, enzymes and/or conditions optimal for reverse transcribing the template to DNA would be utilized. In addition, a DNA-RNA hybrid which contains one strand of each may be utilized. A mixture of nucleic acids may also be employed, or the nucleic acids produced in a previous method such as an amplification reaction using the same or different primers may be so utilized. The specific nucleic acid sequence to be amplified, i.e., the polymorphic and/or the mutant allele, may be a fraction of a larger molecule or can be present initially as a discrete molecule, so that the specific sequence constitutes the entire nucleic acid. A variety of amplification techniques may be used such as ligating the DNA sample or fragments thereof to a vector capable of replication or incorporation into a replicating system thereby increasing the number of copies of DNA suspected of containing at least a portion of the BRCA2 gene. Amplification techniques include so called "shot gun cloning". It is not necessary that the sequence to be amplified be present initially in a pure form; it may be a minor fraction of a complex mixture, such as contained in whole human DNA.

It should be noted that one need not sequence the entire coding region or even an entire DNA fragment in order to determine whether or not a mutation is present. For example, when a mutation is known in one family member, it is sufficient to determine the sequence at only the mutation site by sequencing or by other mutation detection systems such as ASO when testing other family members.

DNA utilized herein may be extracted from a body sample, such as blood, tissue material and other biological sample by a variety of techniques such as that described by Maniatis, et al. in Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, NY, p 280-281 , 1982). If the extracted sample is impure, it may be treated before amplification with an amount of a reagent effective to open the cells, and to expose and/or separate the strand(s) of the nucleic acid(s). This lysing and nucleic acid denaturing step to expose and separate the strands will allow amplification to occur much more readily. For amplification by cloning, the isolated DNA may be cleaved into fragments by a restriction endonuclease or by shearing by passing the DNA containing mixture through a 25 gauge needle from a syringe to prepare 1- 1.5 kb fragments. The fragments are then ligated to a cleaved vector (virus, plasmid, transposon, cosmid etc.) and then the recombinant vector so formed is then replicated in a manner typical for that vector. For a PCR amplification, the deoxyribonucleotide triphosphates dATP, dCTP, dGTP, and dTTP are added to the synthesis mixture, either separately or together with the primers, in adequate amounts and the resulting solution is heated to about 90°-100°C from about 1 to 10 minutes, preferably from 1 to 4 minutes. After this heating period, the solution is allowed to cool, which is preferable for the primer hybridization. To the cooled mixture is added an appropriate agent for effecting the primer extension reaction (called herein "agent for polymerization"), and the reaction is allowed to occur under conditions known in the art. The agent for polymerization may also be added together with the other reagents if it is heat stable. This synthesis (or amplification) reaction may occur at room temperature up to a temperature above which the agent for polymerization no longer functions. Thus, for example, if DNA polymerase is used as the agent, the temperature is generally no greater than about 40°C. Most conveniently the reaction occurs at room temperature. When using thermostable DNA polymerase such as Taq, higher temperature may be used.

The allele specific oligonucleotide primers are useful in determining whether a subject is at risk of having breast or ovarian cancer, and also useful for characterizing a tumor. Primers direct amplification of a target polynucleotide prior to sequencing. These unique BRCA2 oligonucleotide primers for exons 2-27 shown in TABLE II were designed and produced specifically to optimize amplification of portions of BRCA2 which are to be sequenced. The primers used to carry out this invention embrace oligonucleotides of sufficient length and appropriate sequence to provide initiation of polymerization. Environmental conditions conducive to synthesis include the presence of nucleoside triphosphates and an agent for polymerization, such as DNA polymerase, and a suitable temperature and pH. The primer is preferably single stranded for maximum efficiency in amplification, but may be double stranded. If double stranded, the primer is first treated to separate its strands before being used to prepare extension products. The primer must be sufficiently long to prime the synthesis of extension products in the presence of the inducing agent for polymerization. The exact length of primer will depend on many factors, including temperature, buffer, and nucleotide composition. The oligonucleotide primer typically contains 18-28 bp plus in some cases an M13 "tail" for convenience.

Primers used to carry out this invention are designed to be substantially complementary to each strand of the genomic locus to be amplified. This means that the primers must be sufficiently complementary to hybridize with their respective strands under conditions which allow the agent for polymerization to perform. In other words, the primers should have sufficient complementarity with the 5' and 3' sequences flanking the mutation to hybridize therewith and permit amplification of the genomic locus. Oligonucleotide primers of the invention are employed in the amplification process which is an enzymatic chain reaction that produces exponential quantities of polymorphic locus relative to the number of reaction steps involved. Typically, one primer is complementary to the negative (-) strand of the polymorphic locus and the other is complementary to the positive (+) strand. Annealing the primers to denatured nucleic acid followed by extension with an enzyme, such as the large fragment of DNA polymerase I (Klenow) and nucleotides, results in newly synthesized + and - strands containing the target polymorphic locus sequence. Because these newly synthesized sequences are also templates, repeated cycles of denaturing, primer annealing, and extension results in exponential production of the region (i.e., the target polymorphic locus sequence) defined by the primers. The product of the chain reaction is a discreet nucleic acid duplex with termini corresponding to the ends of the specific primers employed.

The oligonucleotide primers of the invention may be prepared using any suitable method, such as conventional phosphotriester and phosphodiester methods or automated embodiments thereof. In one such automated embodiment, diethylphosphoramidites are used as starting materials and may be synthesized as described by Beaucage, et al., Tetrahedron Letters, 22:1859-1862, 1981. One method for synthesizing oligonucleotides on a modified solid support is described in U.S. Patent No. 4,458,066.

The agent for polymerization may be any compound or system which will function to accomplish the synthesis of primer extension products, including enzymes. Suitable enzymes for this purpose include, for example, E. coli DNA polymerase I, Klenow fragment of E. coli DNA polymerase, polymerase muteins, reverse transcriptase, other enzymes, including heat- stable enzymes (i.e., those enzymes which perform primer extension after being subjected to temperatures sufficiently elevated to cause denaturation), such as Taq polymerase. Suitable enzymes will facilitate combination of the nucleotides in the proper manner to form the primer extension products which are complementary to each polymorphic locus nucleic acid strand.

Generally, the synthesis will be initiated at the 3' end of each primer and proceed in the 5' direction along the template strand, until synthesis terminates, producing molecules of different lengths.

The newly synthesized strand and its complementary nucleic acid strand will form a double-stranded molecule under hybridizing conditions described above and this hybrid is used in subsequent steps of the process. In the next step, the newly synthesized double-stranded molecule is subjected to denaturing conditions using any of the procedures described above to provide single-stranded molecules. The steps of denaturing, annealing, and extension product synthesis can be repeated as often as needed to amplify the target polymorphic locus nucleic acid sequence to the extent necessary for detection. The amount of the specific nucleic acid sequence produced will accumulate in an exponential fashion. Amplification is described in PCR. A Practical Approach, ILR Press, Eds. M. J. McPherson, P. Quirke, and G. R. Taylor, 1992.

The amplification products may be detected by Southern blots analysis, without using radioactive probes. In such a process, for example, a small sample of DNA containing a very low level of the nucleic acid sequence of the polymorphic locus is amplified, and analyzed via a Southern blotting technique or similarly, using dot blot analysis. The use of non- radioactive probes or labels is facilitated by the high level of the amplified signal. Alternatively, probes used to detect the amplified products can be directly or indirectly detectably labeled, for example, with a radioisotope, a fluorescent compound, a bioluminescent compound, a chemiluminescent compound, a metal chelator or an enzyme. Those of ordinary skill in the art will know of other suitable labels for binding to the probe, or will be able to ascertain such, using routine experimentation.

Sequences amplified by the methods of the invention can be further evaluated, detected, cloned, sequenced, and the like, either in solution or after binding to a solid support, by any method usually applied to the detection of a specific DNA sequence such as PCR, oligomer restriction (Saiki, etal., Bio/Technology, 3:1008-1012, 1985), allele-specific oligonucleotide (ASO) probe analysis (Conner, et al., Proc. Natl. Acad. Sci. U.S.A., 80:278, 1983), oligonucleotide ligation assays (OLAs) (Landgren, et al., Science, 241 :1007. 1988), and the like. Molecular techniques for DNA analysis have been reviewed (Landgren, et al., Science, 242:229-237, 1988).

Preferably, the method of amplifying is by PCR, as described herein and as is commonly used by those of ordinary skill in the art. Alternative methods of amplification have been described and can also be employed as long as the BRCA2 locus amplified by PCR using primers of the invention is similarly amplified by the alternative means. Such alternative amplification systems include but are not limited to self-sustained sequence replication, which begins with a short sequence of RNA of interest and a T7 promoter. Reverse transcriptase copies the RNA into cDNA and degrades the RNA, followed by reverse transcriptase polymerizing a second strand of DNA. Another nucleic acid amplification technique is nucleic acid sequence-based amplification (NASBA) which uses reverse transcription and T7 RNA polymerase and incorporates two primers to target its cycling scheme. NASBA can begin with either DNA or RNA and finish with either, and amplifies to 10°^* copies within 60 to 90 minutes. Alternatively, nucleic acid can be amplified by ligation activated transcription (LAT). LAT works from a single-stranded template with a single primer that is partially single-stranded and partially double-stranded. Amplification is initiated by ligating a cDNA to the promoter oligonucleotide and within a few hours, and amplification is 10^ to 10⁹ fold. Another amplification system useful in the method of the invention is the Qβ Replicase System. The Qβ replicase system can be utilized by attaching an RNA sequence called MDV-1 to RNA complementary to a DNA sequence of interest. Upon mixing with a sample, the hybrid RNA finds its complement among the specimen's mRNAs and binds, activating the replicase to copy the tag-along sequence of interest. Another nucleic acid amplification technique, ligase chain reaction (LCR), works by using two differently labeled halves of a sequence of interest which are covalently bonded by ligase in the presence of the contiguous sequence in a sample, forming a new target. The repair chain reaction (RCR) nucleic acid amplification technique uses two complementary and target-specific oligonucleotide probe pairs, thermostable polymerase and ligase, and DNA nucleotides to geometrically amplify targeted sequences. A 2-base gap separates the oligonucleotide probe pairs, and the RCR fills and joins the gap, mimicking normal DNA repair. Nucleic acid amplification by strand displacement activation (SDA) utilizes a short primer containing a recognition site for hincll with short overhang on the 5' end which binds to target DNA. A DNA polymerase fills in the part of the primer opposite the overhang with sulfur-containing adenine analogs. Hincll is added but only cuts the unmodified DNA strand. A DNA polymerase that lacks 5' exonuclease activity enters at the site of the nick and begins to polymerize, displacing the initial primer strand downstream and building a new one which serves as more primer. SDA produces greater than 10⁷-fold amplification in 2 hours at 37°C. Unlike PCR and LCR, SDA does not require instrumented Temperature cycling.

Another method is a process for amplifying nucleic acid sequences 5 from a DNA or RNA template which may be purified or may exist in a mixture of nucleic acids. The resulting nucleic acid sequences may be exact copies of the template, or may be modified. The process has advantages over PCR in that it increases the fidelity of copying a specific nucleic acid sequence, and it allows one to more efficiently detect a particular point mutation in a 0 single assay. A target nucleic acid is amplified enzymatically while avoiding strand displacement. Three primers are used. A first primer is complementary to the first end of the target. A second primer is complementary to the second end of the target. A third primer which is similar to the first end of the target and which is substantially complementary 5 to at least a portion of the first primer such that when the third primer is hybridized to the first primer, the position of the third primer complementary to the base at the 5' end of the first primer contains a modification which substantially avoids strand displacement. This method is detailed in U.S. Patent 5,593,840 to Bhatnagar et al. 1997, incorporated herein by reference. o Finally, recent application of DNA chips or microarray technology where DNA or oligonucleotides are immobilized on small solid support may also be used to rapidly sequence sample BRCA2 gene and analyze its expression. Typically, high density arrays of DNA fragment are fabricated on glass or nylon substrates by in situ light-directed combinatorial synthesis or by 5 conventional synthesis followed by immobilization (Fodor et al. U.S. patent

No. 5,445,934). Sample DNA or RNA may be amplified by PCR, labeled with a fluorescent tag, and hybridized to the microarray. Examples of this technology are provided in U.S. Patents 5,510, 270, U.S. 5,547,839, incorporated herein by reference. o All exonic and adjacent intronic sequences of the BRCA2 gene were obtained by end to end sequencing of five normal subjects in the manner described above followed by analysis of the data obtained. The data obtained provided us with the opportunity to establish the correct intronic/exonic structure of the BRCA2 gene. In addition, we evaluated six previously published normal polymorphisms (1342, 2457, 3199, 3624, 4035, and 7470) for correctness and frequency in the population, and to identify four additional polymorphisms not previously characterized (1093, 1593, 2908, and 9079).

GENE THERAPY

The polynucleotide(s) which result from either sense or antisense transcription of any exon or the entire coding sequence or fragments of BRCA2 gene may be used for gene therapy. A variety of methods are known for gene transfer, any of which might be available for use.

Direct injection of Recombinant DNA in vivo:

1. Direct injection of "naked" DNA directly with a syringe and needle into a specific tissue, infused through a vascular bed, or transferred through a catheter into endothelial cells.

2. Direct injection of DNA that is contained in artificially generated lipid vesicles or other encapsulating vehicles.

3. Direct injection of DNA conjugated to a target receptor structure, such as a diptheria toxin, an antibody or other suitable receptor. 4. Direct injection by particle bombardment. For example, the

DNA may be coated onto gold particles and shot into the cells.

Human Artificial Chromosomes The gene delivery approach involves the use of human chromosomes that have been stripped down to contain only the essential components for replication and the genes desired for transfer.

Receptor-Mediated Gene Transfer DNA is linked to a targeting molecule that will bind to specific cell- surface receptors, inducing endocytosis and transfer of the DNA into mammalian cells. One such technique uses poly-L-lysine to link asialoglycoprotein to DNA. An adenovirus is also added to the complex to disrupt the lysosomes and thus allow the DNA to avoid degradation and move to the nucleus. Infusion of these particles intravenously has resulted in gene transfer into hepatocytes. RECOMBINANT VIRUS VECTORS

Several vectors may be used in gene therapy. Among them are the Moloney Murine Leukemia Virus (MoMLV) Vectors, the adenovirus vectors, the Adeno-Associated Virus (AAV) vectors, the herpes simplex virus (HSV) vectors, the poxvirus vectors, the retrovirus vectors, and human immunodeficiency virus (HIV) vectors.

GENE REPLACEMENT AND REPAIR The ideal genetic manipulation for treatment of a genetic disease would be the actual replacement of the defective gene with a normal copy of the gene. Homologous recombination is the term used for switching out a section of DNA and replacing it with a new piece. By this technique, the defective gene may be replaced with a normal gene which expresses a functioning BRCA2 tumor growth inhibitor protein.

A complete description of gene therapy can also be found in "Gene Therapy A Primer For Physicians" 2d Ed. by Kenneth W. Culver, M.D. Publ. Mary Ann Liebert Inc. (1996). Two Gene Therapy Protocols for BRCA1 gene have been approved by the Recombinant DNA Advisory Committee for Jeffrey T. Holt et al. They are listed as 9602-148, and 9603-149 and are available from the NIH. Protocols for BRCA2 gene therapy may be similarly employed. The isolated BRCA2 gene may be synthesized or constructed from amplification products and inserted into a vector such as the LXSN vector.

A BRCA2 POLYPEPTIDE OR ITS FUNCTIONAL EQUIVALENT

The growth of breast and ovarian cancer may be arrested or prevented by directly increasing the BRCA2 protein level where inadequate functional BRCA2 activity is responsible for breast and ovarian cancer. The cDNA and amino acid sequences of five novel BRCA2 haplotypes are disclosed herein (SEQ ID No:4-13). All or a fragment of BRCA2 protein may be used in therapeutic or prophylactic treatment of breast and ovarian cancer. Such a fragment may have a similar biological function as the native BRCA2 protein or may have a desired biological function as specified below. BRCA2 polypeptides or their functional equivalents including homologous and modified polypeptide sequences are also within the scope of the present invention. Changes in the native sequence may be advantageous in producing or using the BRCA2 derived polypeptides or functional equivalents suitable for therapeutic or prophylactic treatment of breast and ovarian cancer. For example, these changes may be desirable for producing resistance against in vivo proteolytic cleavage, for facilitating transportation and delivery of therapeutic reagents, for localizing and compartmentalizing tumor suppressing agents, or for expression, isolating and purifying the target species.

There are a variety of methods to produce an active BRCA2 polypeptide or a functional equivalent as a tumor growth inhibitor. For example, one or more amino acids may be substituted, deleted, or inserted using methods well known in the art (Maniatis et al., 1982). Considerations of polarity, charge, solubility, hydrophobicity, hydrophilicity and/or the amphiphathic nature of the amino acids play an important role in designing homologous polypeptide changes suitable for the intended treatment. In particular, conservative amino acid substitution using amino acids that are related in side-chain structure and charge may be employed to preserve the chemical and biological property. A homologous polyeptide typically contains at least 70% homology to the native sequence. Unnatural forms of the polypeptide may also be incorporated so long as the modification retains substantial biological activity. These unnatural polypeptides typically include structural mimics and chemical medications, which have similar three- dimensional structures as the active regions of the native BRCA2 protein. For example, these modifications may include terminal D-amino acids, cyclic peptides, unnatural amino acids side chains, pseudopeptide bonds, N- terminal acetylation, glycosylation, and biotinylation, etc. These unnatural forms of polypeptide may have a desired biological function, for example, they may be particularly robust in the presence of cellular or serum proteases and exopeptidase. An effective BRCA2 polypeptide or a functional equivalent may also be recognized by the reduction of the native BRCA2 protein. Regions of the BRCA2 protein may be systematically deleted to identify which regions are essential for tumor growth inhibitor activity. These smaller fragments of BRCA2 protein may then be subjected to structural and functional modification to derive therapeutically or prophylactically effective regiments. Finally, drugs, natural products or small molecules may be screened or synthesized to mimic the function of the BRCA2 protein. Typically, the active species retain the essential three- dimensional shape and chemical reactivity, and therefore retain the desired aspects of the biological activity of the native BRCA2 protein. The activity and function of BRCA2 may include transactivation, granin, DNA repair among others. Functions of BRCA2 protein are also reviewed in Bertwistle and Ashworth, Curr. Opin. Genet. Dev. 8(1 ): 14-20 (1998) and Zhang et al., Cell 92:433-436 (1998). It will be apparent to one skilled in the art that a BRCA2 polypeptide or a functional equivalent may be selected because such polypeptide or functional equivalent possesses similar biological activity as the native BRCA2 protein.

EXPRESSION OF THE BRCA2 PROTEIN AND POLYPEPTIDE IN HOST CELLS All or fragments of the BRCA2 protein and polypeptide may be produced by host cells that are capable of directing the replication and the expression of foreign genes. Suitable host cells include prokaryotes, yeast cells, or higher eukaryotic cells, which contain an expression vector comprising all or a fragment of the BRCA2 cDNA sequence (SEQ. ID No: 4, 6, 8, 10, or 12) operatively linked to one or more regulatory sequences to produce the intended BRCA2 protein or polypeptide. Prokaryotes may include gram negative or gram positive organisms, for example E. coli or Bacillus strains. Suitable eukaryotic host cells may include yeast, virus, and mamalian systems. For example, Sf9 insect cells and human cell lines, such as COS, MCF7, HeLa, 293T, HBL100, SW480, and HCT116 cells.

A broad variety of suitable expression vectors are available in the art. An expression vector typically contains an origin of replication, a promoter, a phenotypic selection gene (antibiotic resistance or autotrophic requirement), and a DNA sequence coding for all or fragments of the BRCA2 protein. The expression vectors may also include other operatively linked regulatory DNA sequences known in the art, for example, stability leader sequences, secretory leader sequences, restriction enzyme cleavage sequences, 5 polyadenylation sequences, and termination sequences, among others. The essential and regulatory elements of the expression vector must be compatible with the intended host cell. Suitable expression vectors containing the desired coding and control regions may be constructed using standard recombinant DNA techniques known in the art, many of which are 0 described in Sambrook, et al., Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. (1989). For example, suitable origins of replication may include Col E1 , SV4O viral and M13 origins of replication. Suitable promoters may be constitutive or inducible, for example, tac promoter, lac Z promoter, SV40 5 promoter, MMTV promoter, and LXSN promoter. Examples of selectable markers include neomycin, ampicillin, and hygromycin resistance and the like. Many suitable prokaryotic, viral and mammalian expression vectors may be obtained commercially, for example, from Invitrogen Corp., San Diego, CA or from Clontech, Palo Alto, CA. It may be desirable that the BRCA2 protein or o polypeptide is produced as a fusion protein to enhance the expression in selected host cells, to detect the expression in transfected cells, or to simplify the purification process. Suitable fusion partners for the BRCA2 protein or polypeptide are well known in the art and may include β-galactosidase, glutathione-S-transferase, and poly-histidine tag. 5 Expression vectors may be introduced into host cells by various methods known in the art. The transformation procedure used depends upon the host to be transformed. Methods for introduction of vectors into host cells may include calcium phosphate precipitation, electrosporation, dextran- mediated transfection, liposome encapsulation, nucleus microinjection, and o viral or phage infection, among others.

Once an expression vector has been introduced into a suitable host cell, the host cell may be cultured under conditions permitting expression of large amounts of the BRCA2 protein or polypeptide. The expression product may be identified by many approaches well known in the art, for example, sequencing after PCR-based amplification, hybridization using probes complementary to the desired DNA sequence, the presence or absence of marker gene functions such as enzyme activity or antibiotic resistance, the level of mRNA production encoding the intended sequence, immunological detection of a gene product using monoclonal and polyclonal antibodies, such as Western blotting or ELISA. The BRCA2 protein or polypeptides produced in this manner may then be isolated following cell lysis and purified using various protein purification techniques known in the art, for example, ion exchange chromatography, gel filtration chromatography and immunoaffinity chromatography.

It is generally preferred that whenever possible, longer fragments of BRCA2 protein or polypeptide are used, particularly to include the desired functional domains of BRCA2 protein. Expression of shorter fragments of DNA may be useful in generating BRCA2 derived immunogen for the production of anti-BRCA2 antibodies. It should, of course, be understood that not all expression vectors, DNA regulatory sequences or host cells will function equally well to express the BRCA2 protein or polypeptides of the present invention. However, one of ordinary skill in the art may make a selection among expression vectors, DNA regulatory sequences, host cells, and codon usage in order to optimize expression using known technology in the art without undue experimentation. Studies of BRCA2 protein function and examples of genetic manipulation of BRCA2 protein are summarized in two recent review articles, Bertwistle and Ashworth, Curr. Opin. Genet. Dev. 8(1): 14-20 (1998) and Zhang et al., Cell 92:433-436 (1998).

IN VITRO SYNTHESIS AND CHEMICAL SYNTHESIS

Although it is preferred that fragments of the BRCA2 protein or polypeptides be obtained by overexpression in prokaryotic or eukaryotic host cells, the BRCA2 polypeptides or their functional equivalents may also be obtained by in vitro translation or synthetic means by methods known to those of ordinary skill in the art. For example, in vitro translation may employ an mRNA encoded by a DNA sequence coding for fragments of the BRCA2 protein or polypeptides. Chemical synthesis methodology such as solid phase synthesis may be used to synthesize a BRCA2 polypeptide structural mimic and chemically modified analogs thereof. The polypeptides or the modifications and mimic thereof produced in this manner may then be isolated and purified using various purification techniques, such as chromatographic procedures including ion exchange chromatography, gel filtration chromatography and immunoaffinity chromatography.

PROTEIN REPLACEMENT THERAPY The tumor suppressing function of BRCA2 suggests that various

BRCA2 protein targeted therapies may be utilized in treating and preventing tumors in breast and ovarian cancer. The present invention therefore includes therapeutic and prophylactic treatment of breast and ovarian cancer using therapeutic pharmaceutical compositions containing the BRCA2 protein, polypeptides, or their functional equivalents. For example, protein replacement therapy may involve directly administering the BRCA2 protein, a BRCA2 polypeptide, or a functional equivalent in a pharmaceutically effective carrier. Alternatively, protein replacement therapy may utilize tumor antigen specific antibody fused to fragments of the BRCA2 protein, a polypeptide, or a functional equivalent to deliver anti-cancer regiments specifically to the tumor cells.

To prepare the pharmaceutical compositions of the present invention, an active BRCA2 protein, a BRCA2 polypeptide, or its functional equivalent is combined with a pharmaceutical carrier selected and prepared according to conventional pharmaceutical compounding techniques. A suitable amount of the composition may be administered locally to the site of a tumor or systemically to arrest the proliferation of tumor cells. The methods for administration, may include parenteral, oral, or intravenous, among others according to established protocols in the art. Pharmaceutically acceptable solid or liquid carriers or components which may be added to enhance or stabilize the composition, or to facilitate preparation of the composition include, without limitation, syrup, water, isotonic solution, 5 % glucose in water or buffered sodium or ammonium acetate solution, oils, glycerin, alcohols, flavoring agents, preservatives, coloring agents, starches, sugars, diluents, granulating agents, lubricants, binders, and sustained release materials. The dosage at which the therapeutic compositions are administered may vary within a wide range and 5 depends on various factors, such as the stage of cancer progression, the age and condition of the patient, and may be individually adjusted.

DIAGNOSTIC REAGENTS

The BRCA2 protein, polypeptides, their functional equivalents, 0 antibodies, and polynucleotides may be used in a wide variety of ways in addition to gene therapy and protein replacement therapy. They may be useful as diagnostic reagents to measure normal or abnormal activity of BRCA2 at the DNA, RNA, and protein level. The present invention therefore encompasses the diagnostic reagents derived from the BRCA2 cDNA and 5 protein sequences as set forth in SEQ. ID. Nos: 4-13. These reagents may be utilized in methods for monitoring disease progression, for determining patients suited for gene and protein replacement therapy, or for detecting the presence or quantifying the amount of a tumor growth inhibitor following such therapy. Such methods may involve conventional histochemical o techniques, such as obtaining a tumor tissue from the patient, preparing an extract and testing this extract for tumor growth or metabolism. For example, the test for tumor growth may involve measuring abnormal BRCA2 activity using conventional diagnostic assays, such as Southern, Northern, and Western blotting, PCR, RT-PCR, and immunoprecipitation. In biopsies of 5 tumor tissues, the loss of BRCA2 expression in tumor tissue may be verified by RT-PCR and Northern blotting at the RNA level. A Southern blot analysis, genomic PCR, or fluorescence in situ hybridization (FISH) may also be performed to examine the mutations of BRCA2 at the DNA level. And, a Western blotting, protein truncation assay, or immunoprecipitation may be o utilized to analysis the effect at the protein level.

These diagnostic reagents are typically either covalently or non convalently attached to a detectable label. Such a label includes a radioactive label, a colorimetric enzyme label, a fluorescence label, or an epitope label. Frequently, a reporter gene downstream of the regulatory sequences is fused with the BRCA2 protein or polypeptide to facilitate the detection and purification of the target species. Commonly used reporter genes in BRCA2 fusion proteins include β-galactosidase and luciferase gene.

The BRCA2 protein, polypeptides, their functional equivalents, antibodies, and polynucleotides may also be useful in the study of the characteristics of BRCA2 proteins, such as structure and function of BRCA2 in oncogenesis or subcellular localization of BRCA2 protein in normal and cancerous cell. For example, yeast two-hybrid system has been used in the study of cellular function of BRCA2 to identify the regulator and effector of BRCA2 tumor suppressing function (Sharan et al., Nature 386:804-810 (1997) and Katagiri et al., Genes, Chromosomes & Cancer 21:217 ^'-222 (1988)). In addition, the BRCA2 protein, polypeptides, their functional equivalents, antibodies, and polynucleotides may also be used in in vivo cell based and in vitro cell free assays to screen natural products and synthetic compounds which may mimic, regulate or stimulate BRCA2 protein function.

ANTISENSE INHIBITION Antisense suppression of endogenous BRCA2 expression may assess the effect of BRCA2 protein on cell growth inhibition using known method in the art (Crooke, Annu. Rev. Pharmacol. Toxicol. 32:329-376 (1992) and Robinson-Benion and Holt, Methods Enzymol. 254:363-375 (1995)). Given the cDNA sequence as set forth in SEQ ID. NO: 4, 6, 8, 10, and 12, one of skill in the art can readily obtain anti-sense strand of DNA and RNA sequences to interfere with the production of wild-type BRCA2 protein or the mutated form of BRCA2 protein. Alternatively, antisense oligonucleotide may be designed to target the control sequences of BRCA2 gene to reduce or prevent the expression of the endogenous BRCA2 gene.

ANTIBODIES

The BRCA2 protein, polypeptides, or their functional equivalents may be used as immunogens to prepare polyclonal or monoclonal antibodies capable of binding the BRCA2 derived antigens in a known manner (Harlow & Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 1988). These antibodies may be used for the detection of the BRCA2 protein, polypeptides, or a functional equivalent in an immunoassay, such as ELISA, Western blot, radioimmunoassay, enzyme immunoassay, and immunocytochemistry. Typically, an anti-BRCA2 antibody is in solution or is attached to a solid surface such as a plate, a particle, a bead, or a tube. The antibody is allowed to contact a biological sample or a blot suspected of containing the BRCA2 protein or polypeptide to form a primary immunocomplex. After sufficient incubation period, the primary immunocomplex is washed to remove any non-specifically bound species. The amount of specifically bound BRCA2 protein or polypeptide may be determined using the detection of an attached label or a marker, such as a radioactive, a fluorescent, or an enzymatic label. Alternatively, the detection of BRCA2 derived antigen is allowed by forming a secondary immunocomplex using a second antibody which is attached with a such label or marker. The antibodies may also be used in affinity chromatography for isolating or purifying the BRCA2 protein, polypeptides or their functional equivalents.

EXAMPLE 1

Determination of the Coding Sequence Haplotypes of the BRCA2 Gene

From Normal Individuals

Approximately 150 volunteers were screened in order to identify individuals with no cancer history in their immediate family (i.e. first and second degree relatives). Each person was asked to fill out a hereditary cancer prescreening questionnaire (See TABLE I). Five of these were randomly chosen for end-to-end sequencing of their BRCA2 gene. A first degree relative is a parent, sibling, or offspring. A second degree relative is an aunt, uncle, grandparent, grandchild, niece, nephew, or half-sibling. Genomic DNA was isolated from white blood cells of five normal subjects selected from analysis of their answers to the questions above. Dideoxy sequence analysis was performed following polymerase chain reaction amplification.

All exons of the BRCA2 gene were subjected to direct dideoxy sequence analysis by asymmetric amplification using the polymerase chain reaction (PCR) to generate a single stranded product amplified from this DNA sample. Shuldiner, et al., Handbook of Techniques in Endocrine Research, p. 457-486, DePablo, F., Scanes, C, eds., Academic Press, Inc., 1993. Fluorescent dye was attached for automated sequencing using the

Taq Dye Terminator Kit (Perkin-Elmer® cat# 401628). DNA sequencing was performed in both forward and reverse directions on an Applied Biosystems, Inc. (ABI) automated sequencer (Model 377). The software used for analysis of the resulting data was "Sequence Navigator" purchased through ABI.

1. Polymerase Chain Reaction (PCR) Amplification

Genomic DNA (100 nanograms) extracted from white blood cells of five normal subjects. Each of the five samples was sequenced end to end. Each sample was amplified in a final volume of 25 microliters containing 1 microliter (100 nanograms) genomic DNA, 2.5 microliters 10X PCR buffer (100 mM Tris, pH 8.3, 500 mM KCI, 1.2 mM MgCI₂), 2.5 microliters 10X dNTP mix (2 mM each nucleotide), 2.5 microliters forward primer, 2.5 microliters reverse primer, and 1 microliter Taq polymerase (5 units), and 13 microliters of water.

The primers in TABLE II below were used to carry out amplification of the various sections of the BRCA2 gene samples. The primers were synthesized on an DNA/RNA Synthesizer Model 394®.

Thirty-five cycles were performed, each consisting of denaturing (95°C; 30 seconds), annealing (55^CC; 1 minute), and extension (72°C; 90 seconds), except during the first cycle in which the denaturing time was increased to 5 minutes, and during the last cycle in which the extension time was increased to 5 minutes. PCR products were purified using Qia-quick® PCR purification kits

(Qiagen®, cat# 28104; Chatsworth, CA). Yield and purity of the PCR product are determined spectrophotometrically at OD260 ^{on a} Beckman DU

650 spectrophotometer.

2. Dideoxy Sequence Analysis

Fluorescent dye was attached to PCR products for automated sequencing using the Taq Dye Terminator Kit (Perkin-Elmer® cat # 401628). DNA sequencing was performed in both forward and reverse directions on an Applied Biosystems, Inc. (ABI) Foster City, CA., automated sequencer (Model 377). The software used for analysis of the resulting data was "Sequence

Navigator®" purchased through ABI.

3. RESULTS Based upon the sequencing of the five normal individuals, it was determined that the standard sequence found in both GenBank and BIC were inaccurate. In Genbank, a 10 bp stretch (5'-TTTATTTTAG-3') was mistakenly listed as exonic at the 5' end of exon 5 while it should be intronic which would not be included in the cDNA and resultant protein. In addition, a more detrimental error that has the significant potential to lead to an incorrect diagnosis of breast cancer propensity exists in both Genbank and BIC: a sequence of 16 bp (5'-GTGTTCTCATAAACAG-3') should be at the end of exon 15, but instead is listed at the beginning of exon 16 in the database. The disclosure and listing of GenBank is shown in Figure 1. The correct intron/exon sequence of BRCA2 is presented in Figure 2, wherein,

(1 ) a 10 bp stretch (5'-TTTATTTTAG-3') is intronic at 3' end of intron 4, rather than at the 5' end of exon 5 (corrected exon 5 is listed as SEQ. ID. NO: 1 ) and

(2) a 16 bp stretch (5'-GTGTTCTCATAAACAG-3') is exonic at the 3' end of exon 15, rather than at the 5' end of exon 16 (corrected exons

15 and 16 are listed as SEQ. ID. No: 2 and 3 respectively) The BIC BRCA2 sequence also contains sequence errors in which a strech of nine nucleotides at positions 5554-5460 is listed as CGTTTGTGT (amino acids: Arg-Leu-Cys). The correct sequence at these positions is GTTTGTGTT (amino acids: Val-Cys-Val). In addition, the BIC BRCA2 nuclotides at positions 2024 (codon 599), 4553 (codon 1442), 4815 (codon 1529), 5841 (codon 1871 ), and 5972 (codon 1915) are T, T, A, C, and T respectively, wherein the correct nucleotides at these positions are C, C, G, T, and C respectively. Among them, the nuclotide errors at codon 599, 1442, 1915 result in amino acids changes. Additional differences in the nucleic acids of the five normal individuals were found in ten polymorphic locations. The changes and their positions are found in TABLE III. The individual haplotypes of each chromosome of BRCA2 are displayed in FIGURE 3. In each case, the initial haplotype reported in Genbank (accession number U43746) was subtracted to determine the new haplotypes OMI 1-5. Thus, the Genbank sequence only represents 50% of the haplotypes found; the five new BRCA2 ^{(omι 1 5)} DNA sequences are shown as SEQ. ID. NO: 4, 6, 8, 10, and 12, respectively (See FIGURE 3), and the corresponding polypeptides are listed as SEQ. ID. NO: 5, 7, 9, 11 , and 13 respectively. In combination, these seven haplotypes represent a functional allele profile for the BRCA2 gene.

The data show that for each of the samples, all exons of BRCA2 were identical except in the region of ten polymorphisms. Six of these polymorphisms were previously identified (Tartigan et al., Nature Genetics 12: 333-337 (1996); Phelan et al., Nature Genetics 13: 120-122 (1996); Couch et al., Nature Genetics _3: 123-125 (1996); Teng, et al., Nature Genetics _3: 241-244 (1996); Schubert et al 60: 1031-1040 (1997)), but four were unique to this work. Even though the individual polymorphisms may have been identified, none of these complete haplotypes has been previously determined. TABLE I Hereditary Cancer Pre-Screening Questionnaire

Part A: Answer the following questions about your family

1. To your knowledge, has anyone in your family been diagnosed with a very specific hereditary colon disease called Familial Adenomatous Polyposis (FAP)?

2. To your knowledge, have you or any aunt had breast cancer diagnosed before the age 35?

3. Have you had Inflammatory Bowel Disease, also called Crohn's Disease or Ulcerative Colitis, for more than 7 years? Part B: Refer to the list of cancers below for your responses only to questions in Part B

Bladder Cancer Lung Cancer Pancreatic Cancer Breast Cancer Gastric Cancer Prostate Cancer Colon Cancer Malignant Melanoma Renal Cancer Endometrial Cancer Ovarian Cancer Thyroid Cancer

Have your mother or father, your sisters or brothers or your children had any of the listed cancers?

Have there been diagnosed in your mother's brothers or sisters, or your mother's parents more than one of the cancers in the above list?

6. Have there been diagnosed in your father's brothers or sisters, or your father's parents more than one of the cancers in the above list?

Part C: Refer to the list of relatives below for responses only to questions in Part C

You Your mother

Your sisters or brothers Your mother's sisters or brothers (maternal aunts & uncles)

Your children Your mother's parents (maternal grandparents)

7. Have there been diagnosed in these relatives 2 or more identical types of cancer?

Do not count "simple" skin cancer, also called basal cell or squamous cell skin cancer.

8. Is there a total of 4 or more of any cancers in the list of relatives above other than

"simple" skin cancers?

Part D: Refer to the list of relatives below for responses only to questions in Part D.

You Your father

Your sisters or brothers Your father's sisters or brothers (paternal aunts and uncles)

Your children Your father's parents (paternal grandparents)

9. Have there been diagnosed in these relatives 2 or more identical types of cancer?

Do not count "simple" skin cancer, also called basal cell or squamous cell skin cancer.

10. Is there a total of 4 or more of any cancers in the list of relatives above other than "simple" skin cancers?

© Copyright 1996, OncorMed, Inc. NOT FURNISHED UPON FILING

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TABLE II BRCA2 PRIMER SEQUENCES

TABLE II BRCA2 PRIMER SEQUENCES

TABLE II BRCA2 PRIMER SEQUENCES

TABLE II BRCA2 PRIMER SEQUENCES

TABLE II BRCA2 PRIMER SEQUENCES

TABLE III NORMAL PANEL TYPING

TABLE III NORMAL PANEL TYPING

EXAMPLE 2

Determination Of A Normal Individual Using BRCA2^{(OM1 1 5)} and The Ten

Polymorphisms For Reference A person skilled in the art of genetic susceptibility testing will find the present invention useful for: a) identifying individuals having a normal BRCA2 gene; b) avoiding misinterpretation of normal polymorphisms found in the normal population. Sequencing was carried out as in EXAMPLE 1 using a blood sample from the

(omi1-5) patient in question. However, the BRCA2 sequences were used for reference and any polymorphic sites seen in the patient were compared to the nucleic acid sequences listed above for normal codons at each polymorphic site. A normal sample is one which is comparable to the BRCA2^{(omi 5)} sequences and contains only minor variations which occur at minor polymorphic sites. The allelic variations which occur at each of the polymorphic sites are paired here for reference.

AAT (Asn) and CAT (His) at position 1093 (codon 289) CAT (His) and AAT (Asn) at position 1342 (codon 372) • TCA (Ser) and TCG (Ser) at position 1593 (codon 455)

CAI (His) and CAC (His) at position 2457 (codon 743) GTA (Val) and ATA (lie) at position 2908 (codon 894) AAC (Asn) and GAC (Asp) at position 3199 (codon 991 ) AAA (Lys) and AAG (Lys) at position 3624 (codon 1132) • GTT (Val) and GTC (Val) at position 4035 (codon 1269) TCA (Ser) and TCG (Ser) at position 7470 (codon 2414) GCC (Ala) and ACC (Thr) at position 9079 (codon 2951 )

The availability of these polymorphic pairs provides added assurance that one skilled in the art can correctly interpret the polymorphic variations without mistaking a normal variation for a mutation.

All exons of the BRCA2 gene are subjected to direct dideoxy sequence analysis by asymmetric amplification using the polymerase chain reaction (PCR) to generate a single stranded product amplified from this DNA sample. Shuldiner, et al., Handbook of Techniques in Endocrine Research, p. 457-486, DePablo, F., Scanes, C, eds., Academic Press, Inc., 1993. Fluorescent dye is attached for automated sequencing using the Taq Dye Terminator Kit (Perkin-Elmer® cat# 5 401628). DNA sequencing is performed in both forward and reverse directions on an Applied Biosystems, Inc. (ABI) automated sequencer (Model 377). The software used for analysis of the resulting data is "Sequence Navigator" purchased through ABI.

0 1. Polymerase Chain Reaction (PCR) Amplification

The PCR primers used to amplify a patient's sample BRCA2 gene are listed in TABLE II. The primers were synthesized on a DNA/RNA Synthesizer Model

394®. Thirty-five cycles are of amplification are performed, each consisting of denaturing (95°C; 30 seconds), annealing (55°C; 1 minute), and extension (72°C; 90 5 seconds), except during the first cycle in which the denaturing time is increased to 5 minutes and during the last cycle in which the extension time is increased to 5 minutes.

PCR products are purified using Qia-quick® PCR purification kits (Qiagen®, cat# 28104; Chatsworth, CA). Yield and purity of the PCR product are determined o spectrophotometrically at OD260 on a Beckman DU 650 spectrophotometer.

2. Dideoxy Sequence Analysis

Fluorescent dye is attached to PCR products for automated sequencing using the Taq Dye Terminator Kit (Perkin-Elmer® cat# 401628). DNA sequencing is 5 performed in both forward and reverse directions on an Applied Biosystems, Inc. (ABI) Foster City, CA., automated sequencer (Model 377). The software used for analysis of the resulting data is "Sequence Navigator®" purchased through ABI. The BRCA2^{(o i 1 5)} sequences were entered sequentially into the Sequence Navigator software as the standards for comparison. The Sequence Navigator software 0 compares the patient sample sequence to each BRCA2 ^{(omi 1 5)} standard, base by base. The Sequence Navigator highlights all differences between the standards (omi 1-5) and the patient's sample sequence. A first technologist checks the computerized results by comparing visually the BRCA2 ^{(o i 1}-⁵' standards against the patient's sample, and again highlights any differences between the standard and the sample. The first primary technologist 5 then interprets the sequence variations at each position along the sequence. Chromatograms from each sequence variation are generated by the Sequence Navigator and printed on a color printer. The peaks are interpreted by the first primary technologist and a second primary technologist. A secondary technologist then reviews the chromatograms. The results are finally interpreted by a geneticist. 0 In each instance, a variation is compared to known normal polymorphisms for position and base change.

3. Results

The patient's BRCA2 sequence was found to be heterozygous at seven 5 nucleotide positions: 1093 (A/C), 1342 (A/C), 1593 (A/G), 2457 (C/T), 2908 (A/G), 3199 (A/G) and 9079 (A G). In addition, this changes five amino acids in the polypeptide product: Asn to His at codon 289, Asn to His at codon 372, Val to lie at codon 894, Asn to Asp at codon 991 , and Ala to Thr at codon 2951. The question arises whether any or all of these changes have significance to the patient. o Comparison of the patient's results to the BRCA ^{(omi 1"5)} haplotypes demonstrates that it matches one of the BRCA2 omi standards (#5), and thus the patient sample is interpreted as carrying a normal gene sequence without causing any elevation in their risk status for breast cancer.

5 EXAMPLE 3

DETERMINING THE PRESENCE OF A MUTATION IN EXON 11 OF THE BRCA2

GENE USING BRCA2(^omi1"⁵)

A person skilled in the art of genetic susceptibility testing will find the present invention useful for determining the presence of a known or previously unknown o mutation in the BRCA2 gene. A list of mutations of BRCA2 is publicly available in the Breast Cancer Information Core at http://www.nchgr.nih.gov/dir/lab_transfer/bic. This data site became publicly available on November 1 , 1995. Friend, S. et al. Nature Genetics 11:238, (1995). In this example, a mutation in exon 11 is characterized by amplifying the region of the mutation with a primer set which amplifies the region of the mutation. Sequencing was carried out as in Example 1 using a blood sample from the patient in question. Specifically, exon 11 of the BRCA2 gene is subjected to direct dideoxy sequence analysis by asymmetric amplification using the polymerase chain reaction (PCR) to generate a single stranded product amplified from this DNA sample. Shuldiner, et al., Handbook of Techniques in Endocrine Research, p. 457-486, DePablo, F., Scanes, C, eds., Academic Press, Inc., 1993. Fluorescent dye is attached for automated sequencing using the Taq Dye Terminator Kit (Perkin- Elmer® cat# 401628). DNA sequencing is performed in both forward and reverse directions on an Applied Biosystems, Inc. (ABI) automated sequencer (Model 377). The software used for analysis of the resulting data is "Sequence Navigator" purchased through ABI.

1. Polymerase Chain Reaction (PCR) Amplification

Genomic DNA (100 nanograms) extracted from white blood cells of the subject is amplified in a final volume of 25 microliters containing 1 microliter (100 nanograms) genomic DNA, 2.5 microliters 10X PCR buffer (100 mM Tris, pH 8.3, 500 mM KCI, 1.2 mM MgCI₂), 2.5 microliters 10X dNTP mix (2 mM each nucleotide),

2.5 microliters forward primer (BRCA2-11Q-F, 10 micromolar solution), 2.5 microliters reverse primer (BRCA2-11Q-R, 10 micromolar solution),and 1 microliter Taq polymerase (5 units), and 13 microliters of water.

The PCR primers used to amplify segment Q of exon 11 (where the mutation 6174delT is found) are as follows:

BRCA2-11Q-F: 5'-ACG' AAA' ATT ATG' GCA GGT TGT-3'

BRCA2-11Q-R: 5'- CTT' GTC TTG' CGT TTT' GTA ATG-3'

The primers are synthesized on an DNA/RNA Synthesizer Model 394®. Thirty-five cycles are performed, each consisting of denaturing (95°C; 30 seconds), annealing (55°C; 1 minute), and extension (72°C; 90 seconds), except during the first cycle in which the denaturing time is increased to 5 minutes, and during the last cycle in which the extension time is increased to 5 minutes.

PCR products are purified using Qia-quick® PCR purification kits (Qiagen®, cat# 28104; Chatsworth, CA). Yield and purity of the PCR product are determined spectrophotometrically at OD260 on a Beckman DU 650 spectrophotometer.

2. Dideoxy Sequence Analysis

Fluorescent dye is attached to PCR products for automated sequencing using the Taq Dye Terminator Kit (Perkin-Elmer® cat# 401628). DNA sequencing is performed in both forward and reverse directions on an Applied Biosystems, Inc. (ABI) Foster City, CA., automated sequencer (Model 377). The software used for analysis of the resulting data is "Sequence Navigator®" purchased through ABI.

The BRCA2^{(omi 1"5)} sequence is entered into the Sequence Navigator software as the Standard for comparison. The Sequence Navigator software compares the sample sequence to the BRCA2^{(o i)} standard, base by base. The Sequence Navigator highlights all differences between the BRCA2^(omi) normal DNA sequence and the patient's sample sequence.

A first technologist checks the computerized results by comparing visually the BRCA2^{(omi 1 5)} standard against the patient's sample, and again highlights any differences between the standard and the sample. The first primary technologist then interprets the sequence variations at each position along the sequence.

Chromatograms from each sequence variation are generated by the Sequence

Navigator and printed on a color printer. The peaks are interpreted by the first primary technologist and a second primary technologist. A secondary technologist then reviews the chromatograms. The results are finally interpreted by a geneticist.

In each instance, a sequence variation is compared to known normal polymorphisms for position and base change. The ten frequent polymorphisms which occur in

BRCA2 are:

AAT (Asn) and CAT (His) at position 1093 (codon 289) CAT (His) and AAT (Asn) at position 1342 (codon 372) TCA (Ser) and TCG (Ser) at position 1593 (codon 455) CAI (His) and CAC (His) at position 2457 (codon 743) GTA (Val) and ATA (He) at position 2908 (codon 894) AAC (Asn) and GAC (Asp) at position 3199 (codon 991) AAA (Lys) and AAG (Lys) at position 3624 (codon 1132) GTT (Val) and GTC (Val) at position 4035 (codon 1269) TCA (Ser) and TCG (Ser) at position 7470 (codon 2414) GCC (Ala) and ACC (Thr) at position 9079 (codon 2951)

3. Results

Using the above PCR amplification and standard fluorescent sequencing technology, the 6174delT mutation may be found. Mutations are noted by the length of non-matching sequence variation. Such a lengthy mismatch pattern occurs with deletions and insertions. This mutation is named in accordance with the suggested nomenclature for naming mutations, Beaudet, A et al., Human Mutation 2:245-248, (1993). The 6174delT mutation at codon 1982 of the BRCA2 gene lies in segment "Q" of exon 11. The DNA sequence results demonstrate the presence of a one base pair deletion of a T at nucleotide 6174 of the BRCA2^{(omM 5)} sequences. This mutation interrupts the normal reading frame of the BRCA2 transcript, resulting in the appearance of an in-frame terminator (TAG) at codon position 2003. This mutation is, therefore, predicted to result in a truncated, and most likely, nonfunctional protein.

EXAMPLE 4 GENERATION OF MONOCLONAL AND POLYCLONAL ANTIBODIES USING GST-BRCA2 FUSION PROTEIN AS AN IMMUNOGEN

DNA primers are used to amplify a fragment of BRCA2 using PCR technology. The product is then digested with suitable restriction enzymes and fused in frame with the gene encoding glutathione S-transferase (GST) in Eschehchia coli using GST expression vector pGEX (Pharmacia Biotech Inc.) The expression of the fusion protein is induced by the addition of isopropyl-β- thiogalactopyranoside. The bacteria are then lysed and the overexpressed fusion protein is purified with glutathione-sepharose beads. The fusion protein is then verified by SDS/PAGE gel and N-terminus protein sequencing. The purified protein is used to immunize rabbits according to standard procedures described in Harlow & Lane (1988). Polycolonal antibody is collected from the serum several weeks after and purified using known methods in the art. Monoclonal antibodies against all or fragments of BRCA2 protein, polypeptides, or functional equivalents are obtained using hybridoma technology, see also Harlow & Lane (1988). The BRCA2 protein or polypeptide is coupled to the carrier keyhole limpet hemocyanin in the presence of glutaraldehyde. The conjugated immunogen is mixed with an adjuvant and injected into rabbits. Spleens from antibody-containing rabbits are removed. The B-cells isolated from spleen are fused to myeloma cells using polyethylene glycol (PEG) to promote fusion. The hybrids between the myeloma and B-cells are selected and screened for the production of antibodies to immunogen BRCA2 protein or polypeptide. Positive cells are recloned to generate monoclonal antibodies.

EXAMPLE 5

DETECTION OF BRCA2 EXPRESSION IN HUMAN TISSUES AND CELL LINES

The expression of BRCA2 in human tissues is determined using Northern blot analysis. Human tissues include those from pancreas, testis, prostate, ovary, breast, small intestine, and colon are obtained from Clontech Laboratories, Inc., Palo Alto, CA. The poly(A)+ mRNA Northern blots from different human tissues is hybridized to BRCA2 cDNA probes according to manufacture protocol. The expression level is further conformed by RT-PCR using oligo-d(T) as a primer and other suitable primers.

For Northern Blot analysis of cancer cell lines, the human ovarian cancer cell line SKOV-3 and the human breast cancer cell line MCF-7 are obtained from the American Type Culture Collection. Total RNA is prepared by lysing cell in the presence of guanidinium isocyanate. Poly(A)⁺ mRNA is isolated using the PolyATract mRNA isolation system from Promega, Madison, Wl. The isolated RNA is then electrophoresed under denaturing conditions and transferred to Nylon membrane. The probe used for Northern blot is a fragment of BRCA2 sequence obtained by PCR amplification. The probes are labeled with [α-³²P] dCTP using a random-primed labeling kit (Amersham Life Science, Arlington Heights, IL). EXAMPLE 6

EXPRESSION OF THE BRCA2 PROTEIN

The whole-cell extracts of BRCA2 transfected cells are subjected to immunoprecipitation and immunoblotting to determine the BRCA2 protein level. The BRCA2 protein or polypeptide is immunoprecipitated using anti-BRCA2 antibodies prepared according to Example 4. Samples are then fractionated using SDS/PAGE gel and transferred to nitrocellulose. Western blot of the BRCA2 protein or polypeptide is performed with the indicated antibodies. Antibody reaction is revealed using enhanced chemiluminescence reagents (Dupont New England Nuclear, Boston, MA).

EXAMPLE 7

USE OF THE BRCA2^(omi15) GENE THERAPY The growth of ovarian or breast cancer may be arrested by increasing the expression of the BRCA2 gene where inadequate expression of that gene is responsible for hereditary ovarian or breast cancer. Gene therapy may be performed on a patient to reduce the size of a tumor. The LXSN vector may be transformed with a BRCA2^{(omι1 5)} coding sequence as presented SEQ ID NO:4, 6, 8, 10, or 12 or a fragment thereof.

Vector

The LXSN vector is transformed with a fragment of the wildtype BRCA2^(omι1-⁵⁾ coding sequence as set forth in SEQ ID NO:4, 6, 8, 10, or 12. The LXSN-BRCA2^(omι1-⁵⁾ retroviral expression vector is constructed by cloning a Sal I linkered BRCA2^{(omι1 5)} cDNA or fragments thereof into the Xho I site of the vector LXSN. Constructs are confirmed by DNA sequencing. See Holt et al., Nature Genetics 12: 298-302 (1996). Retroviral vectors are manufactured from viral producer cells using serum free and phenol-red free conditions and tested for sterility, absence of specific pathogens, and absence of replication-competent retrovirus by standard assays. Retrovirus is stored frozen in aliquots which have been tested.

Patients receive a complete physical exam, blood, and urine tests to determine overall health. They may also have a chest X-ray, electrocardiogram, and appropriate radiologic procedures to assess tumor stage. Patients with metastatic ovarian cancer are treated with retroviral gene therapy by infusion of recombinant LXSN-BRCA2^{(omι1 5)} retroviral vectors into peritoneal sites containing tumor, between 10⁹ and 10¹⁰ viral particles per dose. 5 Blood samples are drawn each day and tested for the presence of retroviral vector by sensitive polymerase chain reaction (PCR)-based assays. The fluid which is removed is analyzed to determine:

1. The percentage of cancer cells which are taking up the recombinant LXSN-BRCA2^(omι1-⁵⁾ retroviral vector combination. Successful transfer of BRCA1 0 gene into cancer cells has been shown by both RT-PCR analysis and in situ hybridization. RT-PCR is performed with by the method of Thompson et al., Nature Genetics 9: 444-450 (1995), using primers derived from a BRCA2^{(omι1 5)} coding sequence as in SEQ ID NO:4, 6, 8, 10, or 12 or fragments thereof. Cell lysates are prepared and immunoblotting is performed by the method of Jensen et al., Nature 5 Genetics 12: 303-308 (1996) and Jensen et al., Biochemistry 3 _.: 10887-10892 (1992).

2. Presence of programmed cell death using APOTAG^® in situ apoptosis detection kit (ONCOR, INC., Gaithersburg, Maryland) and DNA analysis.

3. Measurement of BRCA2 gene expression by slide immunofluorescence or o Western blot.

Patients with measurable disease are also evaluated for a clinical response to LXSN-BRCA2^{(omι1 5)} especially those that do not undergo a palliative intervention immediately after retroviral vector therapy. Fluid cytology, abdominal girth, CT scans of the abdomen, and local symptoms are followed. 5

For other sites of disease, conventional response criteria are used as follows:

1. Complete Response (CR), complete disappearance of all measurable lesions and of all signs and symptoms of disease for at least 4 weeks.

2. Partial Response (PR), decrease of at least 50% of the sum of the products of 0 the 2 largest perpendicular diameters of all measurable lesions as determined by 2 observations not less than 4 weeks apart. To be considered a PR, no new lesions should have appeared during this period and none should have increased in size.

3. Stable Disease, less than 25% change in tumor volume from previous evaluations. 4. Progressive Disease, greater than 25% increase in tumor measurements from prior evaluations. The number of doses depends upon the response to treatment.

5 EXAMPLE 8

PROTEIN REPLACEMENT THERAPY

Therapeutically elevated level of functional BRCA2 protein may alleviate the absence or reduced endogenous BRCA2 tumor suppressing activity. Breast or ovarian cancer is treated by the administration of a therapeutically effective amount 0 of the BRCA2 protein, a polypeptide, or its functional equivalent in a pharmaceutically acceptable carrier. Clinically effective delivery method is applied either locally at the site of the tumor or systemically to reach other metastasized locations with known protocols in the art. These protocols may employ the methods of direct injection into a tumor or diffusion using time release capsule. A 5 therapeutically effective dosage is determined by one of skill in the art.

Breast or ovarian cancer may be prevented by the administration of a prophylactically effective amount of the BRCA2 protein, polypeptide, or its functional equivalent in a pharmaceutically acceptable carrier. Individuals with known risk for breast or ovarian cancer are subjected to protein replacement therapy to prevent o tumorigenesis or to decrease the risk of cancer. Elevated risk for breast and ovarian cancer includes factors such as carriers of one or more known BRCA1 and BRCA2 mutations, late child bearing, early onset of menstrual period, late occurrence of menopause, and certain high risk dietary habits. Clinically effective delivery method is used with known protocols in the art, such as administration into peritoneal cavity, 5 or using an implantable time release capsule. A prophylactically effective dosage is determined by one of skill in the art.

TABLE OF REFERENCES 1. Sanger. F., et al., J. Mol. Biol. 42:1617, (1980). 0 2. Beaucage, ef a/., Tetrahedron Letters 22:1859-1862, (1981 ).

3. Maniatis, et al. in Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, NY, p 280-281 , (1982).

4. Conner, et al., Proc. Natl. Acad. Sci. U.S.A. 80:278, (1983)

5. Saiki, et.al.., Bio/Technology 3:1008-1012, (1985) 6. Landgren, et al., Science 241 :1007.(1988)

7. Landgren, et al., Science 242 :229-237, (1988).

8. PCR. A Practical Approach, ILR Press, Eds. M. J. McPherson, P. Quirke, and G. R. Taylor, (1992).

9. Easton et al., American Journal of Human Genetics 52:678-701 , (1993).

10. Patent No. 4,458,066.

H . Rowell, S., et al., American Journal of Human Genetics 55:861-865, (1994)

12. Miki, Y. et al., Science 266:66-71. (1994). 13. Wooster, R. et al., Science 265:2088-2090, (1994).

14. Wooster, R. et al., Nature 378:789-792. (1995).

15. Beaudet, A ef a/., Human Mutation 2:245-248, (1993).

16. Friend, S. et al. Nature Genetics 1_:238, (1995).

17. Teng et al, Nature Genetics 13: 241-244 (1996). 18. Couch et al, Nature Genetics 13: 123-125 (1996).

19.Tartigan et al, Nature Genetics 12: 333-337 (1996).

20. Phelan et al, Nature Genetics _3: 120-122 (1996).

21. Schubert et al, American Journal of Human Genetics QO: 1031-1040 (1996).

22. Sambrook, et al., Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. (1989).

23. Bertwistle and Ashworth, Curr. Opin. Genet. Dev. 8(1 ): 14-20 (1998).

24. Zhang et al., Cell 92:433-436 (1998).

25. Sharan et al., Nature 386:804-810 (1997).

26. Katagiri et al., Genes, Chromosomes & Cancer 21 :217 -222 (1988). 27. Crooke, Annu. Rev. Pharmacol. Toxicol. 32:329-376 (1992)

28. Robinson-Benion and Holt, Methods Enzymol. 254:363-375 (1995). 29. Harlow & Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor

Laboratory, Cold Spring Harbor, NY, 1988. 30. Shuldiner, et al., Handbook of Techniques in Endocrine Research, p. 457-486, DePablo, F., Scanes, C, eds., Academic Press, Inc., 1993.

31. Holt et al., Nature Genetics _2: 298-302 (1996). 32. Thompson et al., Nature Genetics 9: 444-450 (1995). 33. Jensen et al., Nature Genetics _2: 303-308 (1996) 34. Jensen et al., Biochemistry 3J_: 10887-10892 (1992). Although the invention has been described with reference to the presently preferred embodiments, it should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.

SEQUENCE LISTING

( 1 ) GENERAL INFORMATION

( i ) APPLICANT : Murphy , Patricia

White , Marga Rabin , Mark

Ol son , Sheri

Yoshikawa, Matthew

Jackson, Geoffrey

Eskanderi, Tara Schryer, Brenda

Park, Michael

(ii) TITLE OF THE INVEN ION: NOVEL CODING SEQUENCE HAPLOTYPES OF THE HUMAN BRCA2 GENE

(iii) NUMBER OF SEQUENCES: 111

(iv) CORRESPONDENCE ADDRESS:

(A) ADDRESSEE: Howrey & Simon (B) STREET: 1299 Pennsylvania Avenue N.W.

(C) CITY: Washington

(D) STATE: DC

(E) COUNTRY: USA

(F) ZIP: 20004

(v) COMPUTER READABLE FORM:

(A) MEDIUM TYPE: Diskette

(B) COMPUTER: IBM Compatible

(C) OPERATING SYSTEM: DOS (D) SOFTWARE: FastSEQ for Windows Version 2.

(vi) CURRENT APPLICATION DATA:

(A) APPLICATION NUMBER:

(B) FILING DATE: (C) CLASSIFICATION:

(vii) PRIOR APPLICATION DATA:

(A) APPLICATION NUMBER:

(B) FILING DATE:

(viii) ATTORNEY/AGENT INFORMATION: (A) NAME: Halluin, Albert P (B) REGISTRATION NUMBER: 25,227

(C) REFERENCE/DOCKET NUMBER: 5371.31.US02

(ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: 650-463-8109 (B) TELEFAX: 650-463-8400

(C) TELEX:

(2) INFORMATION FOR SEQ ID NO : 1 :

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 50 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: double

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: Genomic DNA (ix) FEATURE:

(A) NAME/KEY: exon (B) LOCATION: 1...50

(D) OTHER INFORMATION: Exon 5

(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 1 : TCCTGTTGTT CTACAATGTA CACATGTAAC ACCACAAAGA GATAAGTCAG 50

(2) INFORMATION FOR SEQ ID NO : 2 :

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 182 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: Genomic DNA

(ix) FEATURE:

(A) NAME/KEY: exon

(B) LOCATION: 1...182 (D) OTHER INFORMATION: Exon 15

(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 2 :

ATTTAATTAC AAGTCTTCAG AATGCCAGAG ATATACAGGA TATGCGAATT AAGAAGAAAC 60 AAAGGCAACG CGTCTTTCCA CAGCCAGGCA GTCTGTATCT TGCAAAAACA TCCACTCTGC 120

CTCGAATCTC TCTGAAAGCA GCAGTAGGAG GCCAAGTTCC CTCTGCGTGT TCTCATAAAC 180

AG 182

(2) INFORMATION FOR SEQ ID NO : 3 :

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 188 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: Genomic DNA (ix) FEATURE: (A) NAME/KEY: exon

(B) LOCATION: 1...188

(D) OTHER INFORMATION: Exon 16

(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 3 :

CTGTATACGT ATGGCGTTTC TAAACATTGC ATAAAAATTA ACAGCAAAAA TGCAGAGTCT 60

TTTCAGTTTC ACACTGAAGA TTATTTTGGT AAGGAAAGTT TATGGACTGG AAAAGGAATA 120

CAGTTGGCTG ATGGTGGATG GCTCATACCC TCCAATGATG GAAAGGCTGG AAAAGAAGAA 180

TTTTATAG 188

(2) INFORMATION FOR SEQ ID NO : 4 : (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 10485 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA (ix) FEATURE:

(A) NAME/KEY: Coding Sequence

(B) LOCATION: 229...10482

(D) OTHER INFORMATION: BRCA2 (OMI1) (xi) SEQUENCE DESCRIPTION: SEQ ID NO : 4 :

GGTGGCGCGA GCTTCTGAAA CTAGGCGGCA GAGGCGGAGC CGCTGTGGCA CTGCTGCGCC 60

TCTGCTGCGC CTCGGGTGTC TTTTGCGGCG GTGGGTCGCC GCCGGGAGAA GCGTGAGGGG 120

ACAGATTTGT GACCGGCGCG GTTTTTGTCA GCTTACTCCG GCCAAAAAAG AACTGCACCT 180 CTGGAGCGGA CTTATTTACC AAGCATTGGA GGAATATCGT AGGTAAAA ATG CCT ATT 237

Met Pro lie 1

GGA TCC AAA GAG AGG CCA ACA TTT TTT GAA ATT TTT AAG ACA CGC TGC 285 Gly Ser Lys Glu Arg Pro Thr Phe Phe Glu lie Phe Lys Thr Arg Cys 5 10 15

AAC AAA GCA GAT TTA GGA CCA ATA AGT CTT AAT TGG TTT GAA GAA CTT 333 Asn Lys Ala Asp Leu Gly Pro lie Ser Leu Asn Trp Phe Glu Glu Leu 20 25 30 35

TCT TCA GAA GCT CCA CCC TAT AAT TCT GAA CCT GCA GAA GAA TCT GAA 381 Ser Ser Glu Ala Pro Pro Tyr Asn Ser Glu Pro Ala Glu Glu Ser Glu 40 45 50

CAT AAA AAC AAC AAT TAC GAA CCA AAC CTA TTT AAA ACT CCA CAA AGG 429 His Lys Asn Asn Asn Tyr Glu Pro Asn Leu Phe Lys Thr Pro Gin Arg 55 60 65 AAA CCA TCT TAT AAT CAG CTG GCT TCA ACT CCA ATA ATA TTC AAA GAG 477 Lys Pro Ser Tyr Asn Gin Leu Ala Ser Thr Pro lie lie Phe Lys Glu 70 75 80

CAA GGG CTG ACT CTG CCG CTG TAC CAA TCT CCT GTA AAA GAA TTA GAT 525 Gin Gly Leu Thr Leu Pro Leu Tyr Gin Ser Pro Val Lys Glu Leu Asp 85 90 95

AAA TTC AAA TTA GAC TTA GGA AGG AAT GTT CCC AAT AGT AGA CAT AAA 573 Lys Phe Lys Leu Asp Leu Gly Arg Asn Val Pro Asn Ser Arg His Lys 100 105 110 115

AGT CTT CGC ACA GTG AAA ACT AAA ATG GAT CAA GCA GAT GAT GTT TCC 621

Ser Leu Arg Thr Val Lys Thr Lys Met Asp Gin Ala Asp Asp Val Ser 120 125 130

TGT CCA CTT CTA AAT TCT TGT CTT AGT GAA AGT CCT GTT GTT CTA CAA 669

Cys Pro Leu Leu Asn Ser Cys Leu Ser Glu Ser Pro Val Val Leu Gin 135 140 145 TGT ACA CAT GTA ACA CCA CAA AGA GAT AAG TCA GTG GTA TGT GGG AGT 717 Cys Thr His Val Thr Pro Gin Arg Asp Lys Ser Val Val Cys Gly Ser 150 155 160 TTG TTT CAT ACA CCA AAG TTT GTG AAG GGT CGT CAG ACA CCA AAA CAT 765 Leu Phe His Thr Pro Lys Phe Val Lys Gly Arg Gin Thr Pro Lys His 165 170 175

ATT TCT GAA AGT CTA GGA GCT GAG GTG GAT CCT GAT ATG TCT TGG TCA 813 lie Ser Glu Ser Leu Gly Ala Glu Val Asp Pro Asp Met Ser Trp Ser 180 185 190 195

AGT TCT TTA GCT ACA CCA CCC ACC CTT AGT TCT ACT GTG CTC ATA GTC 861 Ser Ser Leu Ala Thr Pro Pro Thr Leu Ser Ser Thr Val Leu lie Val 200 205 210 AGA AAT GAA GAA GCA TCT GAA ACT GTA TTT CCT CAT GAT ACT ACT GCT 909 Arg Asn Glu Glu Ala Ser Glu Thr Val Phe Pro His Asp Thr Thr Ala 215 220 225

AAT GTG AAA AGC TAT TTT TCC AAT CAT GAT GAA AGT CTG AAG AAA AAT 957 Asn Val Lys Ser Tyr Phe Ser Asn His Asp Glu Ser Leu Lys Lys Asn

230 235 240

GAT AGA TTT ATC GCT TCT GTG ACA GAC AGT GAA AAC ACA AAT CAA AGA 1005 Asp Arg Phe lie Ala Ser Val Thr Asp Ser Glu Asn Thr Asn Gin Arg 245 250 255

GAA GCT GCA AGT CAT GGA TTT GGA AAA ACA TCA GGG AAT TCA TTT AAA 1053

Glu Ala Ala Ser His Gly Phe Gly Lys Thr Ser Gly Asn Ser Phe Lys

260 265 270 275

GTA AAT AGC TGC AAA GAC CAC ATT GGA AAG TCA ATG CCA AAT GTC CTA 1101

Val Asn Ser Cys Lys Asp His lie Gly Lys Ser Met Pro Asn Val Leu 280 285 290 GAA GAT GAA GTA TAT GAA ACA GTT GTA GAT ACC TCT GAA GAA GAT AGT 1149

Glu Asp Glu Val Tyr Glu Thr Val Val Asp Thr Ser Glu Glu Asp Ser 295 300 305

TTT TCA TTA TGT TTT TCT AAA TGT AGA ACA AAA AAT CTA CAA AAA GTA 1197 Phe Ser Leu Cys Phe Ser Lys Cys Arg Thr Lys Asn Leu Gin Lys Val

310 315 320

AGA ACT AGC AAG ACT AGG AAA AAA ATT TTC CAT GAA GCA AAC GCT GAT 1245 Arg Thr Ser Lys Thr Arg Lys Lys lie Phe His Glu Ala Asn Ala Asp 325 330 335

GAA TGT GAA AAA TCT AAA AAC CAA GTG AAA GAA AAA TAC TCA TTT GTA 1293 Glu Cys Glu Lys Ser Lys Asn Gin Val Lys Glu Lys Tyr Ser Phe Val 340 345 350 355

TCT GAA GTG GAA CCA AAT GAT ACT GAT CCA TTA GAT TCA AAT GTA GCA 1341 Ser Glu Val Glu Pro Asn Asp Thr Asp Pro Leu Asp Ser Asn Val Ala 360 365 370 CAT CAG AAG CCC TTT GAG AGT GGA AGT GAC AAA ATC TCC AAG GAA GTT 1389 His Gin Lys Pro Phe Glu Ser Gly Ser Asp Lys lie Ser Lys Glu Val 375 380 385

GTA CCG TCT TTG GCC TGT GAA TGG TCT CAA CTA ACC CTT TCA GGT CTA 1437 Val Pro Ser Leu Ala Cys Glu Trp Ser Gin Leu Thr Leu Ser Gly Leu 390 395 400 AAT GGA GCC CAG ATG GAG AAA ATA CCC CTA TTG CAT ATT TCT TCA TGT 1485

Asn Gly Ala Gin Met Glu Lys lie Pro Leu Leu His lie Ser Ser Cys

405 410 415

GAC CAA AAT ATT TCA GAA AAA GAC CTA TTA GAC ACA GAG AAC AAA AGA 1533

Asp Gin Asn lie Ser Glu Lys Asp Leu Leu Asp Thr Glu Asn Lys Arg

420 425 430 435 AAG AAA GAT TTT CTT ACT TCA GAG AAT TCT TTG CCA CGT ATT TCT AGC 1581 Lys Lys Asp Phe Leu Thr Ser Glu Asn Ser Leu Pro Arg lie Ser Ser 440 445 450

CTA CCA AAA TCA GAG AAG CCA TTA AAT GAG GAA ACA GTG GTA AAT AAG 1629 Leu Pro Lys Ser Glu Lys Pro Leu Asn Glu Glu Thr Val Val Asn Lys

455 460 465

AGA GAT GAA GAG CAG CAT CTT GAA TCT CAT ACA GAC TGC ATT CTT GCA 1677 Arg Asp Glu Glu Gin His Leu Glu Ser His Thr Asp Cys lie Leu Ala 470 475 480

GTA AAG CAG GCA ATA TCT GGA ACT TCT CCA GTG GCT TCT TCA TTT CAG 1725 Val Lys Gin Ala lie Ser Gly Thr Ser Pro Val Ala Ser Ser Phe Gin 485 490 495

GGT ATC AAA AAG TCT ATA TTC AGA ATA AGA GAA TCA CCT AAA GAG ACT 1773 Gly lie Lys Lys Ser lie Phe Arg lie Arg Glu Ser Pro Lys Glu Thr 500 505 510 515 TTC AAT GCA AGT TTT TCA GGT CAT ATG ACT GAT CCA AAC TTT AAA AAA 1821 Phe Asn Ala Ser Phe Ser Gly His Met Thr Asp Pro Asn Phe Lys Lys 520 525 530

GAA ACT GAA GCC TCT GAA AGT GGA CTG GAA ATA CAT ACT GTT TGC TCA 1869 Glu Thr Glu Ala Ser Glu Ser Gly Leu Glu lie His Thr Val Cys Ser

535 540 545

CAG AAG GAG GAC TCC TTA TGT CCA AAT TTA ATT GAT AAT GGA AGC TGG 1917 Gin Lys Glu Asp Ser Leu Cys Pro Asn Leu lie Asp Asn Gly Ser Trp 550 555 560

CCA GCC ACC ACC ACA CAG AAT TCT GTA GCT TTG AAG AAT GCA GGT TTA 1965

Pro Ala Thr Thr Thr Gin Asn Ser Val Ala Leu Lys Asn Ala Gly Leu 565 570 575

ATA TCC ACT TTG AAA AAG AAA ACA AAT AAG TTT ATT TAT GCT ATA CAT 2013 lie Ser Thr Leu Lys Lys Lys Thr Asn Lys Phe lie Tyr Ala lie His

580 585 590 595 GAT GAA ACA TCT TAT AAA GGA AAA AAA ATA CCG AAA GAC CAA AAA TCA 2061 Asp Glu Thr Ser Tyr Lys Gly Lys Lys lie Pro Lys Asp Gin Lys Ser 600 605 610

GAA CTA ATT AAC TGT TCA GCC CAG TTT GAA GCA AAT GCT TTT GAA GCA 2109 Glu Leu lie Asn Cys Ser Ala Gin Phe Glu Ala Asn Ala Phe Glu Ala

615 620 625

CCA CTT ACA TTT GCA AAT GCT GAT TCA GGT TTA TTG CAT TCT TCT GTG 2157 Pro Leu Thr Phe Ala Asn Ala Asp Ser Gly Leu Leu His Ser Ser Val 630 635 640

AAA AGA AGC TGT TCA CAG AAT GAT TCT GAA GAA CCA ACT TTG TCC TTA 2205 Lys Arg Ser Cys Ser Gin Asn Asp Ser Glu Glu Pro Thr Leu Ser Leu 645 650 655 ACT AGC TCT TTT GGG ACA ATT CTG AGG AAA TGT TCT AGA AAT GAA ACA 2253 Thr Ser Ser Phe Gly Thr lie Leu Arg Lys Cys Ser Arg Asn Glu Thr 660 665 670 675

TGT TCT AAT AAT ACA GTA ATC TCT CAG GAT CTT GAT TAT AAA GAA GCA 2301 Cys Ser Asn Asn Thr Val lie Ser Gin Asp Leu Asp Tyr Lys Glu Ala

680 685 690

AAA TGT AAT AAG GAA AAA CTA CAG TTA TTT ATT ACC CCA GAA GCT GAT 2349

Lys Cys Asn Lys Glu Lys Leu Gin Leu Phe lie Thr Pro Glu Ala Asp 695 700 705

TCT CTG TCA TGC CTG CAG GAA GGA CAG TGT GAA AAT GAT CCA AAA AGC 2397

Ser Leu Ser Cys Leu Gin Glu Gly Gin Cys Glu Asn Asp Pro Lys Ser 710 715 720

AAA AAA GTT TCA GAT ATA AAA GAA GAG GTC TTG GCT GCA GCA TGT CAC 2445

Lys Lys Val Ser Asp lie Lys Glu Glu Val Leu Ala Ala Ala Cys His 725 730 735 CCA GTA CAA CAT TCA AAA GTG GAA TAC AGT GAT ACT GAC TTT CAA TCC 2493

Pro Val Gin His Ser Lys Val Glu Tyr Ser Asp Thr Asp Phe Gin Ser 740 745 750 755

CAG AAA AGT CTT TTA TAT GAT CAT GAA AAT GCC AGC ACT CTT ATT TTA 2541 Gin Lys Ser Leu Leu Tyr Asp His Glu Asn Ala Ser Thr Leu lie Leu

760 765 770

ACT CCT ACT TCC AAG GAT GTT CTG TCA AAC CTA GTC ATG ATT TCT AGA 2589

Thr Pro Thr Ser Lys Asp Val Leu Ser Asn Leu Val Met lie Ser Arg 775 780 785

GGC AAA GAA TCA TAC AAA ATG TCA GAC AAG CTC AAA GGT AAC AAT TAT 2637

Gly Lys Glu Ser Tyr Lys Met Ser Asp Lys Leu Lys Gly Asn Asn Tyr 790 795 800

GAA TCT GAT GTT GAA TTA ACC AAA AAT ATT CCC ATG GAA AAG AAT CAA 2685

Glu Ser Asp Val Glu Leu Thr Lys Asn lie Pro Met Glu Lys Asn Gin 805 810 815 GAT GTA TGT GCT TTA AAT GAA AAT TAT AAA AAC GTT GAG CTG TTG CCA 2733

Asp Val Cys Ala Leu Asn Glu Asn Tyr Lys Asn Val Glu Leu Leu Pro 820 825 830 835

CCT GAA AAA TAC ATG AGA GTA GCA TCA CCT TCA AGA AAG GTA CAA TTC 2781 Pro Glu Lys Tyr Met Arg Val Ala Ser Pro Ser Arg Lys Val Gin Phe

840 845 850

AAC CAA AAC ACA AAT CTA AGA GTA ATC CAA AAA AAT CAA GAA GAA ACT 2829

Asn Gin Asn Thr Asn Leu Arg Val lie Gin Lys Asn Gin Glu Glu Thr 855 860 865

ACT TCA ATT TCA AAA ATA ACT GTC AAT CCA GAC TCT GAA GAA CTT TTC 2877

Thr Ser lie Ser Lys lie Thr Val Asn Pro Asp Ser Glu Glu Leu Phe 870 875 880

TCA GAC AAT GAG AAT AAT TTT GTC TTC CAA GTA GCT AAT GAA AGG AAT 2925 Ser Asp Asn Glu Asn Asn Phe Val Phe Gin Val Ala Asn Glu Arg Asn 885 890 895

AAT CTT GCT TTA GGA AAT ACT AAG GAA CTT CAT GAA ACA GAC TTG ACT 2973 Asn Leu Ala Leu Gly Asn Thr Lys Glu Leu His Glu Thr Asp Leu Thr 900 905 910 915

TGT GTA AAC GAA CCC ATT TTC AAG AAC TCT ACC ATG GTT TTA TAT GGA 3021 Cys Val Asn Glu Pro lie Phe Lys Asn Ser Thr Met Val Leu Tyr Gly 920 925 930

GAC ACA GGT GAT AAA CAA GCA ACC CAA GTG TCA ATT AAA AAA GAT TTG 3069 Asp Thr Gly Asp Lys Gin Ala Thr Gin Val Ser lie Lys Lys Asp Leu 935 940 945

GTT TAT GTT CTT GCA GAG GAG AAC AAA AAT AGT GTA AAG CAG CAT ATA 3117 Val Tyr Val Leu Ala Glu Glu Asn Lys Asn Ser Val Lys Gin His lie 950 955 960 AAA ATG ACT CTA GGT CAA GAT TTA AAA TCG GAC ATC TCC TTG AAT ATA 3165 Lys Met Thr Leu Gly Gin Asp Leu Lys Ser Asp lie Ser Leu Asn lie 965 970 975

GAT AAA ATA CCA GAA AAA AAT AAT GAT TAC ATG AAC AAA TGG GCA GGA 3213 Asp Lys lie Pro Glu Lys Asn Asn Asp Tyr Met Asn Lys Trp Ala Gly 980 985 990 995

CTC TTA GGT CCA ATT TCA AAT CAC AGT TTT GGA GGT AGC TTC AGA ACA 3261 Leu Leu Gly Pro lie Ser Asn His Ser Phe Gly Gly Ser Phe Arg Thr 1000 1005 1010

GCT TCA AAT AAG GAA ATC AAG CTC TCT GAA CAT AAC ATT AAG AAG AGC 3309 Ala Ser Asn Lys Glu lie Lys Leu Ser Glu His Asn lie Lys Lys Ser 1015 1020 1025

AAA ATG TTC TTC AAA GAT ATT GAA GAA CAA TAT CCT ACT AGT TTA GCT 3357 Lys Met Phe Phe Lys Asp lie Glu Glu Gin Tyr Pro Thr Ser Leu Ala 1030 1035 1040 TGT GTT GAA ATT GTA AAT ACC TTG GCA TTA GAT AAT CAA AAG AAA CTG 3405 Cys Val Glu lie Val Asn Thr Leu Ala Leu Asp Asn Gin Lys Lys Leu 1045 1050 1055

AGC AAG CCT CAG TCA ATT AAT ACT GTA TCT GCA CAT TTA CAG AGT AGT 3453 Ser Lys Pro Gin Ser lie Asn Thr Val Ser Ala His Leu Gin Ser Ser 1060 1065 1070 1075

GTA GTT GTT TCT GAT TGT AAA AAT AGT CAT ATA ACC CCT CAG ATG TTA 3501 Val Val Val Ser Asp Cys Lys Asn Ser His lie Thr Pro Gin Met Leu 1080 1085 1090

TTT TCC AAG CAG GAT TTT AAT TCA AAC CAT AAT TTA ACA CCT AGC CAA 3549 Phe Ser Lys Gin Asp Phe Asn Ser Asn His Asn Leu Thr Pro Ser Gin 1095 1100 1105

AAG GCA GAA ATT ACA GAA CTT TCT ACT ATA TTA GAA GAA TCA GGA AGT 3597 Lys Ala Glu lie Thr Glu Leu Ser Thr lie Leu Glu Glu Ser Gly Ser 1110 1115 1120 CAG TTT GAA TTT ACT CAG TTT AGA AAA CCA AGC TAC ATA TTG CAG AAG 3645 Gin Phe Glu Phe Thr Gin Phe Arg Lys Pro Ser Tyr lie Leu Gin Lys 1125 1130 1135 AGT ACA TTT GAA GTG CCT GAA AAC CAG ATG ACT ATC TTA AAG ACC ACT 3693 Ser Thr Phe Glu Val Pro Glu Asn Gin Met Thr lie Leu Lys Thr Thr 1140 1145 1150 1155

TCT GAG GAA TGC AGA GAT GCT GAT CTT CAT GTC ATA ATG AAT GCC CCA 3741 Ser Glu Glu Cys Arg Asp Ala Asp Leu His Val lie Met Asn Ala Pro 1160 1165 1170

TCG ATT GGT CAG GTA GAC AGC AGC AAG CAA TTT GAA GGT ACA GTT GAA 3789 Ser lie Gly Gin Val Asp Ser Ser Lys Gin Phe Glu Gly Thr Val Glu 1175 1180 1185 ATT AAA CGG AAG TTT GCT GGC CTG TTG AAA AAT GAC TGT AAC AAA AGT 3837 lie Lys Arg Lys Phe Ala Gly Leu Leu Lys Asn Asp Cys Asn Lys Ser 1190 1195 1200

GCT TCT GGT TAT TTA ACA GAT GAA AAT GAA GTG GGG TTT AGG GGC TTT 3885 Ala Ser Gly Tyr Leu Thr Asp Glu Asn Glu Val Gly Phe Arg Gly Phe 1205 1210 1215

TAT TCT GCT CAT GGC ACA AAA CTG AAT GTT TCT ACT GAA GCT CTG CAA 3933 Tyr Ser Ala His Gly Thr Lys Leu Asn Val Ser Thr Glu Ala Leu Gin 1220 1225 1230 1235

AAA GCT GTG AAA CTG TTT AGT GAT ATT GAG AAT ATT AGT GAG GAA ACT 3981 Lys Ala Val Lys Leu Phe Ser Asp lie Glu Asn lie Ser Glu Glu Thr 1240 1245 1250

TCT GCA GAG GTA CAT CCA ATA AGT TTA TCT TCA AGT AAA TGT CAT GAT 4029 Ser Ala Glu Val His Pro lie Ser Leu Ser Ser Ser Lys Cys His Asp 1255 1260 1265 TCT GTT GTT TCA ATG TTT AAG ATA GAA AAT CAT AAT GAT AAA ACT GTA 4077 Ser Val Val Ser Met Phe Lys lie Glu Asn His Asn Asp Lys Thr Val 1270 1275 1280

AGT GAA AAA AAT AAT AAA TGC CAA CTG ATA TTA CAA AAT AAT ATT GAA 4125 Ser Glu Lys Asn Asn Lys Cys Gin Leu lie Leu Gin Asn Asn lie Glu 1285 1290 1295

ATG ACT ACT GGC ACT TTT GTT GAA GAA ATT ACT GAA AAT TAC AAG AGA 4173 Met Thr Thr Gly Thr Phe Val Glu Glu lie Thr Glu Asn Tyr Lys Arg 1300 1305 1310 1315

AAT ACT GAA AAT GAA GAT AAC AAA TAT ACT GCT GCC AGT AGA AAT TCT 4221 Asn Thr Glu Asn Glu Asp Asn Lys Tyr Thr Ala Ala Ser Arg Asn Ser 1320 1325 1330

CAT AAC TTA GAA TTT GAT GGC AGT GAT TCA AGT AAA AAT GAT ACT GTT 4269 His Asn Leu Glu Phe Asp Gly Ser Asp Ser Ser Lys Asn Asp Thr Val 1335 1340 1345 TGT ATT CAT AAA GAT GAA ACG GAC TTG CTA TTT ACT GAT CAG CAC AAC 4317 Cys lie His Lys Asp Glu Thr Asp Leu Leu Phe Thr Asp Gin His Asn 1350 1355 1360

ATA TGT CTT AAA TTA TCT GGC CAG TTT ATG AAG GAG GGA AAC ACT CAG 4365 lie Cys Leu Lys Leu Ser Gly Gin Phe Met Lys Glu Gly Asn Thr Gin 1365 1370 1375 ATT AAA GAA GAT TTG TCA GAT TTA ACT TTT TTG GAA GTT GCG AAA GCT 4413 lie Lys Glu Asp Leu Ser Asp Leu Thr Phe Leu Glu Val Ala Lys Ala 1380 1385 1390 1395

CAA GAA GCA TGT CAT GGT AAT ACT TCA AAT AAA GAA CAG TTA ACT GCT 4461

Gin Glu Ala Cys His Gly Asn Thr Ser Asn Lys Glu Gin Leu Thr Ala 1400 1405 1410 ACT AAA ACG GAG CAA AAT ATA AAA GAT TTT GAG ACT TCT GAT ACA TTT 4509 Thr Lys Thr Glu Gin Asn lie Lys Asp Phe Glu Thr Ser Asp Thr Phe 1415 1420 1425

TTT CAG ACT GCA AGT GGG AAA AAT ATT AGT GTC GCC AAA GAG TCA TTT 4557 Phe Gin Thr Ala Ser Gly Lys Asn lie Ser Val Ala Lys Glu Ser Phe 1430 1435 1440

AAT AAA ATT GTA AAT TTC TTT GAT CAG AAA CCA GAA GAA TTG CAT AAC 4605 Asn Lys lie Val Asn Phe Phe Asp Gin Lys Pro Glu Glu Leu His Asn 1445 1450 1455

TTT TCC TTA AAT TCT GAA TTA CAT TCT GAC ATA AGA AAG AAC AAA ATG 4653

Phe Ser Leu Asn Ser Glu Leu His Ser Asp lie Arg Lys Asn Lys Met 1460 1465 1470 1475

GAC ATT CTA AGT TAT GAG GAA ACA GAC ATA GTT AAA CAC AAA ATA CTG 4701

Asp lie Leu Ser Tyr Glu Glu Thr Asp lie Val Lys His Lys lie Leu 1480 1485 1490 AAA GAA AGT GTC CCA GTT GGT ACT GGA AAT CAA CTA GTG ACC TTC CAG 4749 Lys Glu Ser Val Pro Val Gly Thr Gly Asn Gin Leu Val Thr Phe Gin 1495 1500 1505

GGA CAA CCC GAA CGT GAT GAA AAG ATC AAA GAA CCT ACT CTG TTG GGT 4797 Gly Gin Pro Glu Arg Asp Glu Lys lie Lys Glu Pro Thr Leu Leu Gly 1510 1515 1520

TTT CAT ACA GCT AGC GGG AAA AAA GTT AAA ATT GCA AAG GAA TCT TTG 4845 Phe His Thr Ala Ser Gly Lys Lys Val Lys lie Ala Lys Glu Ser Leu 1525 1530 1535

GAC AAA GTG AAA AAC CTT TTT GAT GAA AAA GAG CAA GGT ACT AGT GAA 4893

Asp Lys Val Lys Asn Leu Phe Asp Glu Lys Glu Gin Gly Thr Ser Glu 1540 1545 1550 1555

ATC ACC AGT TTT AGC CAT CAA TGG GCA AAG ACC CTA AAG TAC AGA GAG 4941 lie Thr Ser Phe Ser His Gin Trp Ala Lys Thr Leu Lys Tyr Arg Glu 1560 1565 1570 GCC TGT AAA GAC CTT GAA TTA GCA TGT GAG ACC ATT GAG ATC ACA GCT 4989 Ala Cys Lys Asp Leu Glu Leu Ala Cys Glu Thr lie Glu lie Thr Ala 1575 1580 1585

GCC CCA AAG TGT AAA GAA ATG CAG AAT TCT CTC AAT AAT GAT AAA AAC 5037 Ala Pro Lys Cys Lys Glu Met Gin Asn Ser Leu Asn Asn Asp Lys Asn 1590 1595 1600

CTT GTT TCT ATT GAG ACT GTG GTG CCA CCT AAG CTC TTA AGT GAT AAT 5085 Leu Val Ser lie Glu Thr Val Val Pro Pro Lys Leu Leu Ser Asp Asn 1605 1610 1615

TTA TGT AGA CAA ACT GAA AAT CTC AAA ACA TCA AAA AGT ATC TTT TTG 5133 Leu Cys Arg Gin Thr Glu Asn Leu Lys Thr Ser Lys Ser lie Phe Leu 1620 1625 1630 1635 AAA GTT AAA GTA CAT GAA AAT GTA GAA AAA GAA ACA GCA AAA AGT CCT 5181 Lys Val Lys Val His Glu Asn Val Glu Lys Glu Thr Ala Lys Ser Pro 1640 1645 1650

GCA ACT TGT TAC ACA AAT CAG TCC CCT TAT TCA GTC ATT GAA AAT TCA 5229 Ala Thr Cys Tyr Thr Asn Gin Ser Pro Tyr Ser Val lie Glu Asn Ser 1655 1660 1665

GCC TTA GCT TTT TAC ACA AGT TGT AGT AGA AAA ACT TCT GTG AGT CAG 5277 Ala Leu Ala Phe Tyr Thr Ser Cys Ser Arg Lys Thr Ser Val Ser Gin 1670 1675 1680

ACT TCA TTA CTT GAA GCA AAA AAA TGG CTT AGA GAA GGA ATA TTT GAT 5325

Thr Ser Leu Leu Glu Ala Lys Lys Trp Leu Arg Glu Gly lie Phe Asp 1685 1690 1695

GGT CAA CCA GAA AGA ATA AAT ACT GCA GAT TAT GTA GGA AAT TAT TTG 5373

Gly Gin Pro Glu Arg lie Asn Thr Ala Asp Tyr Val Gly Asn Tyr Leu 1700 1705 1710 1715 TAT GAA AAT AAT TCA AAC AGT ACT ATA GCT GAA AAT GAC AAA AAT CAT 5421

Tyr Glu Asn Asn Ser Asn Ser Thr lie Ala Glu Asn Asp Lys Asn His 1720 1725 1730

CTC TCC GAA AAA CAA GAT ACT TAT TTA AGT AAC AGT AGC ATG TCT AAC 5469 Leu Ser Glu Lys Gin Asp Thr Tyr Leu Ser Asn Ser Ser Met Ser Asn

1735 1740 1745

AGC TAT TCC TAC CAT TCT GAT GAG GTA TAT AAT GAT TCA GGA TAT CTC 5517 Ser Tyr Ser Tyr His Ser Asp Glu Val Tyr Asn Asp Ser Gly Tyr Leu 1750 1755 1760

TCA AAA AAT AAA CTT GAT TCT GGT ATT GAG CCA GTA TTG AAG AAT GTT 5565 Ser Lys Asn Lys Leu Asp Ser Gly lie Glu Pro Val Leu Lys Asn Val 1765 1770 1775

GAA GAT CAA AAA AAC ACT AGT TTT TCC AAA GTA ATA TCC AAT GTA AAA 5613 Glu Asp Gin Lys Asn Thr Ser Phe Ser Lys Val lie Ser Asn Val Lys 1780 1785 1790 1795 GAT GCA AAT GCA TAC CCA CAA ACT GTA AAT GAA GAT ATT TGC GTT GAG 5661

Asp Ala Asn Ala Tyr Pro Gin Thr Val Asn Glu Asp lie Cys Val Glu 1800 1805 1810

GAA CTT GTG ACT AGC TCT TCA CCC TGC AAA AAT AAA AAT GCA GCC ATT 5709 Glu Leu Val Thr Ser Ser Ser Pro Cys Lys Asn Lys Asn Ala Ala lie

1815 1820 1825

AAA TTG TCC ATA TCT AAT AGT AAT AAT TTT GAG GTA GGG CCA CCT GCA 5757 Lys Leu Ser lie Ser Asn Ser Asn Asn Phe Glu Val Gly Pro Pro Ala 1830 1835 1840

TTT AGG ATA GCC AGT GGT AAA ATC GTT TGT GTT TCA CAT GAA ACA ATT 5805 Phe Arg lie Ala Ser Gly Lys lie Val Cys Val Ser His Glu Thr lie 1845 1850 1855

AAA AAA GTG AAA GAC ATA TTT ACA GAC AGT TTC AGT AAA GTA ATT AAG 5853 Lys Lys Val Lys Asp lie Phe Thr Asp Ser Phe Ser Lys Val lie Lys 1860 1865 1870 1875

GAA AAC AAC GAG AAT AAA TCA AAA ATT TGC CAA ACG AAA ATT ATG GCA 5901 Glu Asn Asn Glu Asn Lys Ser Lys lie Cys Gin Thr Lys lie Met Ala

1880 1885 1890

GGT TGT TAC GAG GCA TTG GAT GAT TCA GAG GAT ATT CTT CAT AAC TCT 5949 Gly Cys Tyr Glu Ala Leu Asp Asp Ser Glu Asp lie Leu His Asn Ser 1895 1900 1905

CTA GAT AAT GAT GAA TGT AGC ACG CAT TCA CAT AAG GTT TTT GCT GAC 5997 Leu Asp Asn Asp Glu Cys Ser Thr His Ser His Lys Val Phe Ala Asp 1910 1915 1920

ATT CAG AGT GAA GAA ATT TTA CAA CAT AAC CAA AAT ATG TCT GGA TTG 6045 lie Gin Ser Glu Glu lie Leu Gin His Asn Gin Asn Met Ser Gly Leu 1925 1930 1935 GAG AAA GTT TCT AAA ATA TCA CCT TGT GAT GTT AGT TTG GAA ACT TCA 6093 Glu Lys Val Ser Lys lie Ser Pro Cys Asp Val Ser Leu Glu Thr Ser 1940 1945 1950 1955

GAT ATA TGT AAA TGT AGT ATA GGG AAG CTT CAT AAG TCA GTC TCA TCT 6141 Asp lie Cys Lys Cys Ser lie Gly Lys Leu His Lys Ser Val Ser Ser

1960 1965 1970

GCA AAT ACT TGT GGG ATT TTT AGC ACA GCA AGT GGA AAA TCT GTC CAG 6189 Ala Asn Thr Cys Gly lie Phe Ser Thr Ala Ser Gly Lys Ser Val Gin 1975 1980 1985

GTA TCA GAT GCT TCA TTA CAA AAC GCA AGA CAA GTG TTT TCT GAA ATA 6237 Val Ser Asp Ala Ser Leu Gin Asn Ala Arg Gin Val Phe Ser Glu lie 1990 1995 2000

GAA GAT AGT ACC AAG CAA GTC TTT TCC AAA GTA TTG TTT AAA AGT AAC 6285 Glu Asp Ser Thr Lys Gin Val Phe Ser Lys Val Leu Phe Lys Ser Asn 2005 2010 2015 GAA CAT TCA GAC CAG CTC ACA AGA GAA GAA AAT ACT GCT ATA CGT ACT 6333 Glu His Ser Asp Gin Leu Thr Arg Glu Glu Asn Thr Ala lie Arg Thr 2020 2025 2030 2035

CCA GAA CAT TTA ATA TCC CAA AAA GGC TTT TCA TAT AAT GTG GTA AAT 6381 Pro Glu His Leu lie Ser Gin Lys Gly Phe Ser Tyr Asn Val Val Asn

2040 2045 2050

TCA TCT GCT TTC TCT GGA TTT AGT ACA GCA AGT GGA AAG CAA GTT TCC 6429 Ser Ser Ala Phe Ser Gly Phe Ser Thr Ala Ser Gly Lys Gin Val Ser 2055 2060 2065

ATT TTA GAA AGT TCC TTA CAC AAA GTT AAG GGA GTG TTA GAG GAA TTT 6477 lie Leu Glu Ser Ser Leu His Lys Val Lys Gly Val Leu Glu Glu Phe 2070 2075 2080

GAT TTA ATC AGA ACT GAG CAT AGT CTT CAC TAT TCA CCT ACG TCT AGA 6525 Asp Leu lie Arg Thr Glu His Ser Leu His Tyr Ser Pro Thr Ser Arg 2085 2090 2095 CAA AAT GTA TCA AAA ATA CTT CCT CGT GTT GAT AAG AGA AAC CCA GAG 6573 Gin Asn Val Ser Lys lie Leu Pro Arg Val Asp Lys Arg Asn Pro Glu 2100 2105 2110 2115 CAC TGT GTA AAC TCA GAA ATG GAA AAA ACC TGC AGT AAA GAA TTT AAA 6621 His Cys Val Asn Ser Glu Met Glu Lys Thr Cys Ser Lys Glu Phe Lys 2120 2125 2130

TTA TCA AAT AAC TTA AAT GTT GAA GGT GGT TCT TCA GAA AAT AAT CAC 6669 Leu Ser Asn Asn Leu Asn Val Glu Gly Gly Ser Ser Glu Asn Asn His 2135 2140 2145

TCT ATT AAA GTT TCT CCA TAT CTC TCT CAA TTT CAA CAA GAC AAA CAA 6717 Ser lie Lys Val Ser Pro Tyr Leu Ser Gin Phe Gin Gin Asp Lys Gin 2150 2155 2160 CAG TTG GTA TTA GGA ACC AAA GTC TCA CTT GTT GAG AAC ATT CAT GTT 6765 Gin Leu Val Leu Gly Thr Lys Val Ser Leu Val Glu Asn lie His Val 2165 2170 2175

TTG GGA AAA GAA CAG GCT TCA CCT AAA AAC GTA AAA ATG GAA ATT GGT 6813 Leu Gly Lys Glu Gin Ala Ser Pro Lys Asn Val Lys Met Glu lie Gly

2180 2185 2190 2195

AAA ACT GAA ACT TTT TCT GAT GTT CCT GTG AAA ACA AAT ATA GAA GTT 6861 Lys Thr Glu Thr Phe Ser Asp Val Pro Val Lys Thr Asn lie Glu Val 2200 2205 2210

TGT TCT ACT TAC TCC AAA GAT TCA GAA AAC TAC TTT GAA ACA GAA GCA 6909 Cys Ser Thr Tyr Ser Lys Asp Ser Glu Asn Tyr Phe Glu Thr Glu Ala 2215 2220 2225

GTA GAA ATT GCT AAA GCT TTT ATG GAA GAT GAT GAA CTG ACA GAT TCT 6957 Val Glu lie Ala Lys Ala Phe Met Glu Asp Asp Glu Leu Thr Asp Ser 2230 2235 2240 AAA CTG CCA AGT CAT GCC ACA CAT TCT CTT TTT ACA TGT CCC GAA AAT 7005

Lys Leu Pro Ser His Ala Thr His Ser Leu Phe Thr Cys Pro Glu Asn 2245 2250 2255

GAG GAA ATG GTT TTG TCA AAT TCA AGA ATT GGA AAA AGA AGA GGA GAG 7053 Glu Glu Met Val Leu Ser Asn Ser Arg lie Gly Lys Arg Arg Gly Glu

2260 2265 2270 2275

CCC CTT ATC TTA GTG GGA GAA CCC TCA ATC AAA AGA AAC TTA TTA AAT 7101 Pro Leu lie Leu Val Gly Glu Pro Ser lie Lys Arg Asn Leu Leu Asn 2280 2285 2290

GAA TTT GAC AGG ATA ATA GAA AAT CAA GAA AAA TCC TTA AAG GCT TCA 7149 Glu Phe Asp Arg lie lie Glu Asn Gin Glu Lys Ser Leu Lys Ala Ser 2295 2300 2305

AAA AGC ACT CCA GAT GGC ACA ATA AAA GAT CGA AGA TTG TTT ATG CAT 7197 Lys Ser Thr Pro Asp Gly Thr lie Lys Asp Arg Arg Leu Phe Met His 2310 2315 2320 CAT GTT TCT TTA GAG CCG ATT ACC TGT GTA CCC TTT CGC ACA ACT AAG 7245 His Val Ser Leu Glu Pro lie Thr Cys Val Pro Phe Arg Thr Thr Lys 2325 2330 2335

GAA CGT CAA GAG ATA CAG AAT CCA AAT TTT ACC GCA CCT GGT CAA GAA 7293 Glu Arg Gin Glu lie Gin Asn Pro Asn Phe Thr Ala Pro Gly Gin Glu 2340 2345 2350 2355 TTT CTG TCT AAA TCT CAT TTG TAT GAA CAT CTG ACT TTG GAA AAA TCT 7341 Phe Leu Ser Lys Ser His Leu Tyr Glu His Leu Thr Leu Glu Lys Ser 2360 2365 2370

TCA AGC AAT TTA GCA GTT TCA GGA CAT CCA TTT TAT CAA GTT TCT GCT 7389 Ser Ser Asn Leu Ala Val Ser Gly His Pro Phe Tyr Gin Val Ser Ala 2375 2380 2385 ACA AGA AAT GAA AAA ATG AGA CAC TTG ATT ACT ACA GGC AGA CCA ACC 7437 Thr Arg Asn Glu Lys Met Arg His Leu lie Thr Thr Gly Arg Pro Thr 2390 2395 2400

AAA GTC TTT GTT CCA CCT TTT AAA ACT AAA TCA CAT TTT CAC AGA GTT 7485 Lys Val Phe Val Pro Pro Phe Lys Thr Lys Ser His Phe His Arg Val 2405 2410 2415

GAA CAG TGT GTT AGG AAT ATT AAC TTG GAG GAA AAC AGA CAA AAG CAA 7533 Glu Gin Cys Val Arg Asn lie Asn Leu Glu Glu Asn Arg Gin Lys Gin 2420 2425 2430 2435

AAC ATT GAT GGA CAT GGC TCT GAT GAT AGT AAA AAT AAG ATT AAT GAC 7581 Asn lie Asp Gly His Gly Ser Asp Asp Ser Lys Asn Lys lie Asn Asp 2440 2445 2450

AAT GAG ATT CAT CAG TTT AAC AAA AAC AAC TCC AAT CAA GCA GCA GCT 7629 Asn Glu lie His Gin Phe Asn Lys Asn Asn Ser Asn Gin Ala Ala Ala 2455 2460 2465 GTA ACT TTC ACA AAG TGT GAA GAA GAA CCT TTA GAT TTA ATT ACA AGT 7677 Val Thr Phe Thr Lys Cys Glu Glu Glu Pro Leu Asp Leu lie Thr Ser 2470 2475 2480

CTT CAG AAT GCC AGA GAT ATA CAG GAT ATG CGA ATT AAG AAG AAA CAA 7725 Leu Gin Asn Ala Arg Asp lie Gin Asp Met Arg lie Lys Lys Lys Gin 2485 2490 2495

AGG CAA CGC GTC TTT CCA CAG CCA GGC AGT CTG TAT CTT GCA AAA ACA 7773 Arg Gin Arg Val Phe Pro Gin Pro Gly Ser Leu Tyr Leu Ala Lys Thr 2500 2505 2510 2515

TCC ACT CTG CCT CGA ATC TCT CTG AAA GCA GCA GTA GGA GGC CAA GTT 7821 Ser Thr Leu Pro Arg lie Ser Leu Lys Ala Ala Val Gly Gly Gin Val 2520 2525 2530

CCC TCT GCG TGT TCT CAT AAA CAG CTG TAT ACG TAT GGC GTT TCT AAA 7869 Pro Ser Ala Cys Ser His Lys Gin Leu Tyr Thr Tyr Gly Val Ser Lys 2535 2540 2545 CAT TGC ATA AAA ATT AAC AGC AAA AAT GCA GAG TCT TTT CAG TTT CAC 7917 His Cys lie Lys lie Asn Ser Lys Asn Ala Glu Ser Phe Gin Phe His 2550 2555 2560

ACT GAA GAT TAT TTT GGT AAG GAA AGT TTA TGG ACT GGA AAA GGA ATA 7965 Thr Glu Asp Tyr Phe Gly Lys Glu Ser Leu Trp Thr Gly Lys Gly lie 2565 2570 2575

CAG TTG GCT GAT GGT GGA TGG CTC ATA CCC TCC AAT GAT GGA AAG GCT 8013 Gin Leu Ala Asp Gly Gly Trp Leu lie Pro Ser Asn Asp Gly Lys Ala 2580 2585 2590 2595

GGA AAA GAA GAA TTT TAT AGG GCT CTG TGT GAC ACT CCA GGT GTG GAT 8061 Gly Lys Glu Glu Phe Tyr Arg Ala Leu Cys Asp Thr Pro Gly Val Asp 2600 2605 2610 CCA AAG CTT ATT TCT AGA ATT TGG GTT TAT AAT CAC TAT AGA TGG ATC 8109 Pro Lys Leu lie Ser Arg lie Trp Val Tyr Asn His Tyr Arg Trp lie 2615 2620 2625

ATA TGG AAA CTG GCA GCT ATG GAA TGT GCC TTT CCT AAG GAA TTT GCT 8157 lie Trp Lys Leu Ala Ala Met Glu Cys Ala Phe Pro Lys Glu Phe Ala 2630 2635 2640

AAT AGA TGC CTA AGC CCA GAA AGG GTG CTT CTT CAA CTA AAA TAC AGA 8205 Asn Arg Cys Leu Ser Pro Glu Arg Val Leu Leu Gin Leu Lys Tyr Arg 2645 2650 2655

TAT GAT ACG GAA ATT GAT AGA AGC AGA AGA TCG GCT ATA AAA AAG ATA 8253

Tyr Asp Thr Glu lie Asp Arg Ser Arg Arg Ser Ala lie Lys Lys lie 2660 2665 2670 2675

ATG GAA AGG GAT GAC ACA GCT GCA AAA ACA CTT GTT CTC TGT GTT TCT 8301

Met Glu Arg Asp Asp Thr Ala Ala Lys Thr Leu Val Leu Cys Val Ser 2680 2685 2690 GAC ATA ATT TCA TTG AGC GCA AAT ATA TCT GAA ACT TCT AGC AAT AAA 8349 Asp lie lie Ser Leu Ser Ala Asn lie Ser Glu Thr Ser Ser Asn Lys 2695 2700 2705

ACT AGT AGT GCA GAT ACC CAA AAA GTG GCC ATT ATT GAA CTT ACA GAT 8397 Thr Ser Ser Ala Asp Thr Gin Lys Val Ala lie lie Glu Leu Thr Asp 2710 2715 2720

GGG TGG TAT GCT GTT AAG GCC CAG TTA GAT CCT CCC CTC TTA GCT GTC 8445 Gly Trp Tyr Ala Val Lys Ala Gin Leu Asp Pro Pro Leu Leu Ala Val 2725 2730 2735

TTA AAG AAT GGC AGA CTG ACA GTT GGT CAG AAG ATT ATT CTT CAT GGA 8493

Leu Lys Asn Gly Arg Leu Thr Val Gly Gin Lys lie lie Leu His Gly 2740 2745 2750 2755

GCA GAA CTG GTG GGC TCT CCT GAT GCC TGT ACA CCT CTT GAA GCC CCA 8541

Ala Glu Leu Val Gly Ser Pro Asp Ala Cys Thr Pro Leu Glu Ala Pro 2760 2765 2770 GAA TCT CTT ATG TTA AAG ATT TCT GCT AAC AGT ACT CGG CCT GCT CGC 8589 Glu Ser Leu Met Leu Lys lie Ser Ala Asn Ser Thr Arg Pro Ala Arg 2775 2780 2785

TGG TAT ACC AAA CTT GGA TTC TTT CCT GAC CCT AGA CCT TTT CCT CTG 8637 Trp Tyr Thr Lys Leu Gly Phe Phe Pro Asp Pro Arg Pro Phe Pro Leu 2790 2795 2800

CCC TTA TCA TCG CTT TTC AGT GAT GGA GGA AAT GTT GGT TGT GTT GAT 8685 Pro Leu Ser Ser Leu Phe Ser Asp Gly Gly Asn Val Gly Cys Val Asp 2805 2810 2815

GTA ATT ATT CAA AGA GCA TAC CCT ATA CAG TGG ATG GAG AAG ACA TCA 8733 Val lie lie Gin Arg Ala Tyr Pro lie Gin Trp Met Glu Lys Thr Ser 2820 2825 2830 2835

TCT GGA TTA TAC ATA TTT CGC AAT GAA AGA GAG GAA GAA AAG GAA GCA 8781 Ser Gly Leu Tyr lie Phe Arg Asn Glu Arg Glu Glu Glu Lys Glu Ala 2840 2845 2850

GCA AAA TAT GTG GAG GCC CAA CAA AAG AGA CTA GAA GCC TTA TTC ACT 8829 Ala Lys Tyr Val Glu Ala Gin Gin Lys Arg Leu Glu Ala Leu Phe Thr 2855 2860 2865

AAA ATT CAG GAG GAA TTT GAA GAA CAT GAA GAA AAC ACA ACA AAA CCA 8877 Lys lie Gin Glu Glu Phe Glu Glu His Glu Glu Asn Thr Thr Lys Pro 2870 2875 2880

TAT TTA CCA TCA CGT GCA CTA ACA AGA CAG CAA GTT CGT GCT TTG CAA 8925

Tyr Leu Pro Ser Arg Ala Leu Thr Arg Gin Gin Val Arg Ala Leu Gin

2885 2890 2895

GAT GGT GCA GAG CTT TAT GAA GCA GTG AAG AAT GCA GCA GAC CCA GCT 8973

Asp Gly Ala Glu Leu Tyr Glu Ala Val Lys Asn Ala Ala Asp Pro Ala

2900 2905 2910 2915 TAC CTT GAG GGT TAT TTC AGT GAA GAG CAG TTA AGA GCC TTG AAT AAT 9021 Tyr Leu Glu Gly Tyr Phe Ser Glu Glu Gin Leu Arg Ala Leu Asn Asn 2920 2925 2930

CAC AGG CAA ATG TTG AAT GAT AAG AAA CAA GCT CAG ATC CAG TTG GAA 9069 His Arg Gin Met Leu Asn Asp Lys Lys Gin Ala Gin lie Gin Leu Glu 2935 2940 2945

ATT AGG AAG GCC ATG GAA TCT GCT GAA CAA AAG GAA CAA GGT TTA TCA 9117 lie Arg Lys Ala Met Glu Ser Ala Glu Gin Lys Glu Gin Gly Leu Ser 2950 2955 2960

AGG GAT GTC ACA ACC GTG TGG AAG TTG CGT ATT GTA AGC TAT TCA AAA 9165

Arg Asp Val Thr Thr Val Trp Lys Leu Arg lie Val Ser Tyr Ser Lys 2965 2970 2975

AAA GAA AAA GAT TCA GTT ATA CTG AGT ATT TGG CGT CCA TCA TCA GAT 9213

Lys Glu Lys Asp Ser Val lie Leu Ser lie Trp Arg Pro Ser Ser Asp 2980 2985 2990 2995 TTA TAT TCT CTG TTA ACA GAA GGA AAG AGA TAC AGA ATT TAT CAT CTT 9261 Leu Tyr Ser Leu Leu Thr Glu Gly Lys Arg Tyr Arg lie Tyr His Leu 3000 3005 3010

GCA ACT TCA AAA TCT AAA AGT AAA TCT GAA AGA GCT AAC ATA CAG TTA 9309 Ala Thr Ser Lys Ser Lys Ser Lys Ser Glu Arg Ala Asn lie Gin Leu 3015 3020 3025

GCA GCG ACA AAA AAA ACT CAG TAT CAA CAA CTA CCG GTT TCA GAT GAA 9357 Ala Ala Thr Lys Lys Thr Gin Tyr Gin Gin Leu Pro Val Ser Asp Glu 3030 3035 3040

ATT TTA TTT CAG ATT TAC CAG CCA CGG GAG CCC CTT CAC TTC AGC AAA 9405 lie Leu Phe Gin lie Tyr Gin Pro Arg Glu Pro Leu His Phe Ser Lys 3045 3050 3055

TTT TTA GAT CCA GAC TTT CAG CCA TCT TGT TCT GAG GTG GAC CTA ATA 9453

Phe Leu Asp Pro Asp Phe Gin Pro Ser Cys Ser Glu Val Asp Leu lie 3060 3065 3070 3075 GGA TTT GTC GTT TCT GTT GTG AAA AAA ACA GGA CTT GCC CCT TTC GTC 9501 Gly Phe Val Val Ser Val Val Lys Lys Thr Gly Leu Ala Pro Phe Val 3080 3085 3090 TAT TTG TCA GAC GAA TGT TAC AAT TTA CTG GCA ATA AAG TTT TGG ATA 9549 Tyr Leu Ser Asp Glu Cys Tyr Asn Leu Leu Ala lie Lys Phe Trp lie 3095 3100 3105

GAC CTT AAT GAG GAC ATT ATT AAG CCT CAT ATG TTA ATT GCT GCA AGC 9597 Asp Leu Asn Glu Asp lie lie Lys Pro His Met Leu lie Ala Ala Ser 3110 3115 3120

AAC CTC CAG TGG CGA CCA GAA TCC AAA TCA GGC CTT CTT ACT TTA TTT 9645 Asn Leu Gin Trp Arg Pro Glu Ser Lys Ser Gly Leu Leu Thr Leu Phe 3125 3130 3135 GCT GGA GAT TTT TCT GTG TTT TCT GCT AGT CCA AAA GAG GGC CAC TTT 9693 Ala Gly Asp Phe Ser Val Phe Ser Ala Ser Pro Lys Glu Gly His Phe 3140 3145 3150 3155

CAA GAG ACA TTC AAC AAA ATG AAA AAT ACT GTT GAG AAT ATT GAC ATA 9741 Gin Glu Thr Phe Asn Lys Met Lys Asn Thr Val Glu Asn lie Asp He

3160 3165 3170

CTT TGC AAT GAA GCA GAA AAC AAG CTT ATG CAT ATA CTG CAT GCA AAT 9789 Leu Cys Asn Glu Ala Glu Asn Lys Leu Met His He Leu His Ala Asn 3175 3180 3185

GAT CCC AAG TGG TCC ACC CCA ACT AAA GAC TGT ACT TCA GGG CCG TAC 9837 Asp Pro Lys Trp Ser Thr Pro Thr Lys Asp Cys Thr Ser Gly Pro Tyr 3190 3195 3200

ACT GCT CAA ATC ATT CCT GGT ACA GGA AAC AAG CTT CTG ATG TCT TCT 9885 Thr Ala Gin He He Pro Gly Thr Gly Asn Lys Leu Leu Met Ser Ser 3205 3210 3215 CCT AAT TGT GAG ATA TAT TAT CAA AGT CCT TTA TCA CTT TGT ATG GCC 9933

Pro Asn Cys Glu He Tyr Tyr Gin Ser Pro Leu Ser Leu Cys Met Ala 3220 3225 3230 3235

AAA AGG AAG TCT GTT TCC ACA CCT GTC TCA GCC CAG ATG ACT TCA AAG 9981 Lys Arg Lys Ser Val Ser Thr Pro Val Ser Ala Gin Met Thr Ser Lys

3240 3245 3250

TCT TGT AAA GGG GAG AAA GAG ATT GAT GAC CAA AAG AAC TGC AAA AAG 10029 Ser Cys Lys Gly Glu Lys Glu He Asp Asp Gin Lys Asn Cys Lys Lys 3255 3260 3265

AGA AGA GCC TTG GAT TTC TTG AGT AGA CTG CCT TTA CCT CCA CCT GTT 10077 Arg Arg Ala Leu Asp Phe Leu Ser Arg Leu Pro Leu Pro Pro Pro Val 3270 3275 3280

AGT CCC ATT TGT ACA TTT GTT TCT CCG GCT GCA CAG AAG GCA TTT CAG 10125 Ser Pro He Cys Thr Phe Val Ser Pro Ala Ala Gin Lys Ala Phe Gin 3285 3290 3295 CCA CCA AGG AGT TGT GGC ACC AAA TAC GAA ACA CCC ATA AAG AAA AAA 10173 Pro Pro Arg Ser Cys Gly Thr Lys Tyr Glu Thr Pro He Lys Lys Lys 3300 3305 3310 3315

GAA CTG AAT TCT CCT CAG ATG ACT CCA TTT AAA AAA TTC AAT GAA ATT 10221 Glu Leu Asn Ser Pro Gin Met Thr Pro Phe Lys Lys Phe Asn Glu He

3320 3325 3330 TCT CTT TTG GAA AGT AAT TCA ATA GCT GAC GAA GAA CTT GCA TTG ATA 10269 Ser Leu Leu Glu Ser Asn Ser He Ala Asp Glu Glu Leu Ala Leu He 3335 3340 3345

AAT ACC CAA GCT CTT TTG TCT GGT TCA ACA GGA GAA AAA CAA TTT ATA 10317 Asn Thr Gin Ala Leu Leu Ser Gly Ser Thr Gly Glu Lys Gin Phe He 3350 3355 3360 TCT GTC AGT GAA TCC ACT AGG ACT GCT CCC ACC AGT TCA GAA GAT TAT 10365 Ser Val Ser Glu Ser Thr Arg Thr Ala Pro Thr Ser Ser Glu Asp Tyr 3365 3370 3375

CTC AGA CTG AAA CGA CGT TGT ACT ACA TCT CTG ATC AAA GAA CAG GAG 10413 Leu Arg Leu Lys Arg Arg Cys Thr Thr Ser Leu He Lys Glu Gin Glu 3380 3385 3390 3395

AGT TCC CAG GCC AGT ACG GAA GAA TGT GAG AAA AAT AAG CAG GAC ACA 10461 Ser Ser Gin Ala Ser Thr Glu Glu Cys Glu Lys Asn Lys Gin Asp Thr 3400 3405 3410

ATT ACA ACT AAA AAA TAT ATC TAA 10485

He Thr Thr Lys Lys Tyr He 3415

(2) INFORMATION FOR SEQ ID NO : 5 :

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 3418 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein

(v) FRAGMENT TYPE: internal

(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 5 : Met Pro He Gly Ser Lys Glu Arg Pro Thr Phe Phe Glu He Phe Lys

1 5 10 15

Thr Arg Cys Asn Lys Ala Asp Leu Gly Pro He Ser Leu Asn Trp Phe

20 25 30

Glu Glu Leu Ser Ser Glu Ala Pro Pro Tyr Asn Ser Glu Pro Ala Glu 35 40 45

Glu Ser Glu His Lys Asn Asn Asn Tyr Glu Pro Asn Leu Phe Lys Thr

50 55 60

Pro Gin Arg Lys Pro Ser Tyr Asn Gin Leu Ala Ser Thr Pro He He 65 70 75 80 Phe Lys Glu Gin Gly Leu Thr Leu Pro Leu Tyr Gin Ser Pro Val Lys

85 90 95

Glu Leu Asp Lys Phe Lys Leu Asp Leu Gly Arg Asn Val Pro Asn Ser

100 105 110

Arg His Lys Ser Leu Arg Thr Val Lys Thr Lys Met Asp Gin Ala Asp 115 120 125

Asp Val Ser Cys Pro Leu Leu Asn Ser Cys Leu Ser Glu Ser Pro Val

130 135 140

Val Leu Gin Cys Thr His Val Thr Pro Gin Arg Asp Lys Ser Val Val 145 150 155 160 Cys Gly Ser Leu Phe His Thr Pro Lys Phe Val Lys Gly Arg Gin Thr

165 170 175

Pro Lys His He Ser Glu Ser Leu Gly Ala Glu Val Asp Pro Asp Met 180 185 190

Ser Trp Ser Ser Ser Leu Ala Thr Pro Pro Thr Leu Ser Ser Thr Val 195 200 205 Leu He Val Arg Asn Glu Glu Ala Ser Glu Thr Val Phe Pro His Asp 210 215 220

Thr Thr Ala Asn Val Lys Ser Tyr Phe Ser Asn His Asp Glu Ser Leu 225 230 235 240

Lys Lys Asn Asp Arg Phe He Ala Ser Val Thr Asp Ser Glu Asn Thr 245 250 255

Asn Gin Arg Glu Ala Ala Ser His Gly Phe Gly Lys Thr Ser Gly Asn

260 265 270

Ser Phe Lys Val Asn Ser Cys Lys Asp His He Gly Lys Ser Met Pro 275 280 285 Asn Val Leu Glu Asp Glu Val Tyr Glu Thr Val Val Asp Thr Ser Glu 290 295 300

Glu Asp Ser Phe Ser Leu Cys Phe Ser Lys Cys Arg Thr Lys Asn Leu 305 310 315 320

Gin Lys Val Arg Thr Ser Lys Thr Arg Lys Lys He Phe His Glu Ala 325 330 335

Asn Ala Asp Glu Cys Glu Lys Ser Lys Asn Gin Val Lys Glu Lys Tyr

340 345 350

Ser Phe Val Ser Glu Val Glu Pro Asn Asp Thr Asp Pro Leu Asp Ser 355 360 365 Asn Val Ala His Gin Lys Pro Phe Glu Ser Gly Ser Asp Lys He Ser

370 375 380

Lys Glu Val Val Pro Ser Leu Ala Cys Glu Trp Ser Gin Leu Thr Leu 385 390 395 400

Ser Gly Leu Asn Gly Ala Gin Met Glu Lys He Pro Leu Leu His He 405 410 415

Ser Ser Cys Asp Gin Asn He Ser Glu Lys Asp Leu Leu Asp Thr Glu

420 425 430

Asn Lys Arg Lys Lys Asp Phe Leu Thr Ser Glu Asn Ser Leu Pro Arg 435 440 445 He Ser Ser Leu Pro Lys Ser Glu Lys Pro Leu Asn Glu Glu Thr Val

450 455 460

Val Asn Lys Arg Asp Glu Glu Gin His Leu Glu Ser His Thr Asp Cys 465 470 475 480

He Leu Ala Val Lys Gin Ala He Ser Gly Thr Ser Pro Val Ala Ser 485 490 495

Ser Phe Gin Gly He Lys Lys Ser He Phe Arg He Arg Glu Ser Pro

500 505 510

Lys Glu Thr Phe Asn Ala Ser Phe Ser Gly His Met Thr Asp Pro Asn 515 520 525 Phe Lys Lys Glu Thr Glu Ala Ser Glu Ser Gly Leu Glu He His Thr

530 535 540

Val Cys Ser Gin Lys Glu Asp Ser Leu Cys Pro Asn Leu He Asp Asn 545 550 555 560

Gly Ser Trp Pro Ala Thr Thr Thr Gin Asn Ser Val Ala Leu Lys Asn 565 570 575

Ala Gly Leu He Ser Thr Leu Lys Lys Lys Thr Asn Lys Phe He Tyr

580 585 590

Ala He His Asp Glu Thr Ser Tyr Lys Gly Lys Lys He Pro Lys Asp 595 600 605 Gin Lys Ser Glu Leu He Asn Cys Ser Ala Gin Phe Glu Ala Asn Ala 610 615 620

Phe Glu Ala Pro Leu Thr Phe Ala Asn Ala Asp Ser Gly Leu Leu His 625 630 635 640

Ser Ser Val Lys Arg Ser Cys Ser Gin Asn Asp Ser Glu Glu Pro Thr 645 650 655

Leu Ser Leu Thr Ser Ser Phe Gly Thr He Leu Arg Lys Cys Ser Arg 660 665 670 Asn Glu Thr Cys Ser Asn Asn Thr Val He Ser Gin Asp Leu Asp Tyr

675 680 685

Lys Glu Ala Lys Cys Asn Lys Glu Lys Leu Gin Leu Phe He Thr Pro 690 695 700

Glu Ala Asp Ser Leu Ser Cys Leu Gin Glu Gly Gin Cys Glu Asn Asp

705 710 715 720

Pro Lys Ser Lys Lys Val Ser Asp He Lys Glu Glu Val Leu Ala Ala

725 730 735 Ala Cys His Pro Val Gin His Ser Lys Val Glu Tyr Ser Asp Thr Asp

740 745 750

Phe Gin Ser Gin Lys Ser Leu Leu Tyr Asp His Glu Asn Ala Ser Thr

755 760 765

Leu He Leu Thr Pro Thr Ser Lys Asp Val Leu Ser Asn Leu Val Met 770 775 780

He Ser Arg Gly Lys Glu Ser Tyr Lys Met Ser Asp Lys Leu Lys Gly 785 790 795 800

Asn Asn Tyr Glu Ser Asp Val Glu Leu Thr Lys Asn He Pro Met Glu 805 810 815 Lys Asn Gin Asp Val Cys Ala Leu Asn Glu Asn Tyr Lys Asn Val Glu

820 825 830

Leu Leu Pro Pro Glu Lys Tyr Met Arg Val Ala Ser Pro Ser Arg Lys

835 840 845

Val Gin Phe Asn Gin Asn Thr Asn Leu Arg Val He Gin Lys Asn Gin 850 855 860

Glu Glu Thr Thr Ser He Ser Lys He Thr Val Asn Pro Asp Ser Glu 865 870 875 880

Glu Leu Phe Ser Asp Asn Glu Asn Asn Phe Val Phe Gin Val Ala Asn 885 890 895 Glu Arg Asn Asn Leu Ala Leu Gly Asn Thr Lys Glu Leu His Glu Thr

900 905 910

Asp Leu Thr Cys Val Asn Glu Pro He Phe Lys Asn Ser Thr Met Val

915 920 925

Leu Tyr Gly Asp Thr Gly Asp Lys Gin Ala Thr Gin Val Ser He Lys 930 935 940

Lys Asp Leu Val Tyr Val Leu Ala Glu Glu Asn Lys Asn Ser Val Lys 945 950 955 960

Gin His He Lys Met Thr Leu Gly Gin Asp Leu Lys Ser Asp He Ser 965 970 975 Leu Asn He Asp Lys He Pro Glu Lys Asn Asn Asp Tyr Met Asn Lys

980 985 990

Trp Ala Gly Leu Leu Gly Pro He Ser Asn His Ser Phe Gly Gly Ser

995 1000 1005

Phe Arg Thr Ala Ser Asn Lys Glu He Lys Leu Ser Glu His Asn He 1010 1015 1020

Lys Lys Ser Lys Met Phe Phe Lys Asp He Glu Glu Gin Tyr Pro Thr

1025 1030 1035 104

Ser Leu Ala Cys Val Glu He Val Asn Thr Leu Ala Leu Asp Asn Gin

1045 1050 1055 Lys Lys Leu Ser Lys Pro Gin Ser He Asn Thr Val Ser Ala His Leu

1060 1065 1070

Gin Ser Ser Val Val Val Ser Asp Cys Lys Asn Ser His He Thr Pro

1075 1080 1085

Gin Met Leu Phe Ser Lys Gin Asp Phe Asn Ser Asn His Asn Leu Thr 1090 1095 1100

Pro Ser Gin Lys Ala Glu He Thr Glu Leu Ser Thr He Leu Glu Glu

1105 1110 1115 112

Ser Gly Ser Gin Phe Glu Phe Thr Gin Phe Arg Lys Pro Ser Tyr He

1125 1130 1135 Leu Gin Lys Ser Thr Phe Glu Val Pro Glu Asn Gin Met Thr He Leu

1140 1145 1150

Lys Thr Thr Ser Glu Glu Cys Arg Asp Ala Asp Leu His Val He Met 1155 1160 1165

Asn Ala Pro Ser He Gly Gin Val Asp Ser Ser Lys Gin Phe Glu Gly

1170 1175 1180 Thr Val Glu He Lys Arg Lys Phe Ala Gly Leu Leu Lys Asn Asp Cys

1185 1190 1195 120

Asn Lys Ser Ala Ser Gly Tyr Leu Thr Asp Glu Asn Glu Val Gly Phe

1205 1210 1215

Arg Gly Phe Tyr Ser Ala His Gly Thr Lys Leu Asn Val Ser Thr Glu 1220 1225 1230

Ala Leu Gin Lys Ala Val Lys Leu Phe Ser Asp He Glu Asn He Ser

1235 1240 1245

Glu Glu Thr Ser Ala Glu Val His Pro He Ser Leu Ser Ser Ser Lys

1250 1255 1260 Cys His Asp Ser Val Val Ser Met Phe Lys He Glu Asn His Asn Asp

1265 1270 1275 128

Lys Thr Val Ser Glu Lys Asn Asn Lys Cys Gin Leu He Leu Gin Asn

1285 1290 1295

Asn He Glu Met Thr Thr Gly Thr Phe Val Glu Glu He Thr Glu Asn 1300 1305 1310

Tyr Lys Arg Asn Thr Glu Asn Glu Asp Asn Lys Tyr Thr Ala Ala Ser

1315 1320 1325

Arg Asn Ser His Asn Leu Glu Phe Asp Gly Ser Asp Ser Ser Lys Asn 1330 1335 1340 Asp Thr Val Cys He His Lys Asp Glu Thr Asp Leu Leu Phe Thr Asp

1345 1350 1355 136

Gin His Asn He Cys Leu Lys Leu Ser Gly Gin Phe Met Lys Glu Gly

1365 1370 1375

Asn Thr Gin He Lys Glu Asp Leu Ser Asp Leu Thr Phe Leu Glu Val 1380 1385 1390

Ala Lys Ala Gin Glu Ala Cys His Gly Asn Thr Ser Asn Lys Glu Gin

1395 1400 1405

Leu Thr Ala Thr Lys Thr Glu Gin Asn He Lys Asp Phe Glu Thr Ser 1410 1415 1420 Asp Thr Phe Phe Gin Thr Ala Ser Gly Lys Asn He Ser Val Ala Lys

1425 1430 1435 144

Glu Ser Phe Asn Lys He Val Asn Phe Phe Asp Gin Lys Pro Glu Glu

1445 1450 1455

Leu His Asn Phe Ser Leu Asn Ser Glu Leu His Ser Asp He Arg Lys 1460 1465 1470

Asn Lys Met Asp He Leu Ser Tyr Glu Glu Thr Asp He Val Lys His

1475 1480 1485

Lys He Leu Lys Glu Ser Val Pro Val Gly Thr Gly Asn Gin Leu Val

1490 1495 1500 Thr Phe Gin Gly Gin Pro Glu Arg Asp Glu Lys He Lys Glu Pro Thr

1505 1510 1515 152

Leu Leu Gly Phe His Thr Ala Ser Gly Lys Lys Val Lys He Ala Lys

1525 1530 1535

Glu Ser Leu Asp Lys Val Lys Asn Leu Phe Asp Glu Lys Glu Gin Gly 1540 1545 1550

Thr Ser Glu He Thr Ser Phe Ser His Gin Trp Ala Lys Thr Leu Lys

1555 1560 1565

Tyr Arg Glu Ala Cys Lys Asp Leu Glu Leu Ala Cys Glu Thr He Glu

1570 1575 1580 He Thr Ala Ala Pro Lys Cys Lys Glu Met Gin Asn Ser Leu Asn Asn

1585 1590 1595 160

Asp Lys Asn Leu Val Ser He Glu Thr Val Val Pro Pro Lys Leu Leu

1605 1610 1615

Ser Asp Asn Leu Cys Arg Gin Thr Glu Asn Leu Lys Thr Ser Lys Ser 1620 1625 1630

He Phe Leu Lys Val Lys Val His Glu Asn Val Glu Lys Glu Thr Ala 1635 1640 1645 Lys Ser Pro Ala Thr Cys Tyr Thr Asn Gin Ser Pro Tyr Ser Val He

1650 1655 1660

Glu Asn Ser Ala Leu Ala Phe Tyr Thr Ser Cys Ser Arg Lys Thr Ser 1665 1670 1675 168

Val Ser Gin Thr Ser Leu Leu Glu Ala Lys Lys Trp Leu Arg Glu Gly

1685 1690 1695

He Phe Asp Gly Gin Pro Glu Arg He Asn Thr Ala Asp Tyr Val Gly 1700 1705 1710 Asn Tyr Leu Tyr Glu Asn Asn Ser Asn Ser Thr He Ala Glu Asn Asp 1715 1720 1725

Lys Asn His Leu Ser Glu Lys Gin Asp Thr Tyr Leu Ser Asn Ser Ser

1730 1735 1740

Met Ser Asn Ser Tyr Ser Tyr His Ser Asp Glu Val Tyr Asn Asp Ser 1745 1750 1755 176

Gly Tyr Leu Ser Lys Asn Lys Leu Asp Ser Gly He Glu Pro Val Leu

1765 1770 1775

Lys Asn Val Glu Asp Gin Lys Asn Thr Ser Phe Ser Lys Val He Ser 1780 1785 1790 Asn Val Lys Asp Ala Asn Ala Tyr Pro Gin Thr Val Asn Glu Asp He

1795 1800 1805

Cys Val Glu Glu Leu Val Thr Ser Ser Ser Pro Cys Lys Asn Lys Asn

1810 1815 1820

Ala Ala He Lys Leu Ser He Ser Asn Ser Asn Asn Phe Glu Val Gly 1825 1830 1835 184

Pro Pro Ala Phe Arg He Ala Ser Gly Lys He Val Cys Val Ser His

1845 1850 1855

Glu Thr He Lys Lys Val Lys Asp He Phe Thr Asp Ser Phe Ser Lys 1860 1865 1870 Val He Lys Glu Asn Asn Glu Asn Lys Ser Lys He Cys Gin Thr Lys

1875 1880 1885

He Met Ala Gly Cys Tyr Glu Ala Leu Asp Asp Ser Glu Asp He Leu

1890 1895 1900

His Asn Ser Leu Asp Asn Asp Glu Cys Ser Thr His Ser His Lys Val 1905 1910 1915 192

Phe Ala Asp He Gin Ser Glu Glu He Leu Gin His Asn Gin Asn Met

1925 1930 1935

Ser Gly Leu Glu Lys Val Ser Lys He Ser Pro Cys Asp Val Ser Leu 1940 1945 1950 Glu Thr Ser Asp He Cys Lys Cys Ser He Gly Lys Leu His Lys Ser

1955 1960 1965

Val Ser Ser Ala Asn Thr Cys Gly He Phe Ser Thr Ala Ser Gly Lys

1970 1975 1980

Ser Val Gin Val Ser Asp Ala Ser Leu Gin Asn Ala Arg Gin Val Phe 1985 1990 1995 200

Ser Glu He Glu Asp Ser Thr Lys Gin Val Phe Ser Lys Val Leu Phe

2005 2010 2015

Lys Ser Asn Glu His Ser Asp Gin Leu Thr Arg Glu Glu Asn Thr Ala 2020 2025 2030 He Arg Thr Pro Glu His Leu He Ser Gin Lys Gly Phe Ser Tyr Asn

2035 2040 2045

Val Val Asn Ser Ser Ala Phe Ser Gly Phe Ser Thr Ala Ser Gly Lys

2050 2055 2060

Gin Val Ser He Leu Glu Ser Ser Leu His Lys Val Lys Gly Val Leu 2065 2070 2075 208

Glu Glu Phe Asp Leu He Arg Thr Glu His Ser Leu His Tyr Ser Pro

2085 2090 2095

Thr Ser Arg Gin Asn Val Ser Lys He Leu Pro Arg Val Asp Lys Arg 2100 2105 2110 Asn Pro Glu His Cys Val Asn Ser Glu Met Glu Lys Thr Cys Ser Lys 2115 2120 2125

Glu Phe Lys Leu Ser Asn Asn Leu Asn Val Glu Gly Gly Ser Ser Glu 2130 2135 2140

Asn Asn His Ser He Lys Val Ser Pro Tyr Leu Ser Gin Phe Gin Gin 2145 2150 2155 216 Asp Lys Gin Gin Leu Val Leu Gly Thr Lys Val Ser Leu Val Glu Asn

2165 2170 2175

He His Val Leu Gly Lys Glu Gin Ala Ser Pro Lys Asn Val Lys Met

2180 2185 2190

Glu He Gly Lys Thr Glu Thr Phe Ser Asp Val Pro Val Lys Thr Asn 2195 2200 2205

He Glu Val Cys Ser Thr Tyr Ser Lys Asp Ser Glu Asn Tyr Phe Glu

2210 2215 2220

Thr Glu Ala Val Glu He Ala Lys Ala Phe Met Glu Asp Asp Glu Leu 2225 2230 2235 224 Thr Asp Ser Lys Leu Pro Ser His Ala Thr His Ser Leu Phe Thr Cys

2245 2250 2255

Pro Glu Asn Glu Glu Met Val Leu Ser Asn Ser Arg He Gly Lys Arg

2260 2265 2270

Arg Gly Glu Pro Leu He Leu Val Gly Glu Pro Ser He Lys Arg Asn 2275 2280 2285

Leu Leu Asn Glu Phe Asp Arg He He Glu Asn Gin Glu Lys Ser Leu

2290 2295 2300

Lys Ala Ser Lys Ser Thr Pro Asp Gly Thr He Lys Asp Arg Arg Leu 2305 2310 2315 232 Phe Met His His Val Ser Leu Glu Pro He Thr Cys Val Pro Phe Arg

2325 2330 2335

Thr Thr Lys Glu Arg Gin Glu He Gin Asn Pro Asn Phe Thr Ala Pro

2340 2345 2350

Gly Gin Glu Phe Leu Ser Lys Ser His Leu Tyr Glu His Leu Thr Leu 2355 2360 2365

Glu Lys Ser Ser Ser Asn Leu Ala Val Ser Gly His Pro Phe Tyr Gin

2370 2375 2380

Val Ser Ala Thr Arg Asn Glu Lys Met Arg His Leu He Thr Thr Gly 2385 2390 2395 240 Arg Pro Thr Lys Val Phe Val Pro Pro Phe Lys Thr Lys Ser His Phe

2405 2410 2415

His Arg Val Glu Gin Cys Val Arg Asn He Asn Leu Glu Glu Asn Arg

2420 2425 2430

Gin Lys Gin Asn He Asp Gly His Gly Ser Asp Asp Ser Lys Asn Lys 2435 2440 2445

He Asn Asp Asn Glu He His Gin Phe Asn Lys Asn Asn Ser Asn Gin

2450 2455 2460

Ala Ala Ala Val Thr Phe Thr Lys Cys Glu Glu Glu Pro Leu Asp Leu 2465 2470 2475 248 He Thr Ser Leu Gin Asn Ala Arg Asp He Gin Asp Met Arg He Lys

2485 2490 2495

Lys Lys Gin Arg Gin Arg Val Phe Pro Gin Pro Gly Ser Leu Tyr Leu

2500 2505 2510

Ala Lys Thr Ser Thr Leu Pro Arg He Ser Leu Lys Ala Ala Val Gly 2515 2520 2525

Gly Gin Val Pro Ser Ala Cys Ser His Lys Gin Leu Tyr Thr Tyr Gly

2530 2535 2540

Val Ser Lys His Cys He Lys He Asn Ser Lys Asn Ala Glu Ser Phe 2545 2550 2555 256 Gin Phe His Thr Glu Asp Tyr Phe Gly Lys Glu Ser Leu Trp Thr Gly

2565 2570 2575

Lys Gly He Gin Leu Ala Asp Gly Gly Trp Leu He Pro Ser Asn Asp

2580 2585 2590

Gly Lys Ala Gly Lys Glu Glu Phe Tyr Arg Ala Leu Cys Asp Thr Pro 2595 2600 2605

Gly Val Asp Pro Lys Leu He Ser Arg He Trp Val Tyr Asn His Tyr 2610 2615 2620 Arg Trp He He Trp Lys Leu Ala Ala Met Glu Cys Ala Phe Pro Lys 2625 2630 2635 264

Glu Phe Ala Asn Arg Cys Leu Ser Pro Glu Arg Val Leu Leu Gin Leu 2645 2650 2655

Lys Tyr Arg Tyr Asp Thr Glu He Asp Arg Ser Arg Arg Ser Ala He

2660 2665 2670

Lys Lys He Met Glu Arg Asp Asp Thr Ala Ala Lys Thr Leu Val Leu 2675 2680 2685 Cys Val Ser Asp He He Ser Leu Ser Ala Asn He Ser Glu Thr Ser 2690 2695 2700

Ser Asn Lys Thr Ser Ser Ala Asp Thr Gin Lys Val Ala He He Glu 2705 2710 2715 272

Leu Thr Asp Gly Trp Tyr Ala Val Lys Ala Gin Leu Asp Pro Pro Leu 2725 2730 2735

Leu Ala Val Leu Lys Asn Gly Arg Leu Thr Val Gly Gin Lys He He

2740 2745 2750

Leu His Gly Ala Glu Leu Val Gly Ser Pro Asp Ala Cys Thr Pro Leu 2755 2760 2765 Glu Ala Pro Glu Ser Leu Met Leu Lys He Ser Ala Asn Ser Thr Arg

2770 2775 2780

Pro Ala Arg Trp Tyr Thr Lys Leu Gly Phe Phe Pro Asp Pro Arg Pro 2785 2790 2795 280

Phe Pro Leu Pro Leu Ser Ser Leu Phe Ser Asp Gly Gly Asn Val Gly 2805 2810 2815

Cys Val Asp Val He He Gin Arg Ala Tyr Pro He Gin Trp Met Glu

2820 2825 2830

Lys Thr Ser Ser Gly Leu Tyr He Phe Arg Asn Glu Arg Glu Glu Glu 2835 2840 2845 Lys Glu Ala Ala Lys Tyr Val Glu Ala Gin Gin Lys Arg Leu Glu Ala

2850 2855 2860

Leu Phe Thr Lys He Gin Glu Glu Phe Glu Glu His Glu Glu Asn Thr 2865 2870 2875 288

Thr Lys Pro Tyr Leu Pro Ser Arg Ala Leu Thr Arg Gin Gin Val Arg 2885 2890 2895

Ala Leu Gin Asp Gly Ala Glu Leu Tyr Glu Ala Val Lys Asn Ala Ala

2900 2905 2910

Asp Pro Ala Tyr Leu Glu Gly Tyr Phe Ser Glu Glu Gin Leu Arg Ala 2915 2920 2925 Leu Asn Asn His Arg Gin Met Leu Asn Asp Lys Lys Gin Ala Gin He 2930 2935 2940

Gin Leu Glu He Arg Lys Ala Met Glu Ser Ala Glu Gin Lys Glu Gin 2945 2950 2955 296

Gly Leu Ser Arg Asp Val Thr Thr Val Trp Lys Leu Arg He Val Ser 2965 2970 2975

Tyr Ser Lys Lys Glu Lys Asp Ser Val He Leu Ser He Trp Arg Pro

2980 2985 2990

Ser Ser Asp Leu Tyr Ser Leu Leu Thr Glu Gly Lys Arg Tyr Arg He 2995 3000 3005 Tyr His Leu Ala Thr Ser Lys Ser Lys Ser Lys Ser Glu Arg Ala Asn 3010 3015 3020

He Gin Leu Ala Ala Thr Lys Lys Thr Gin Tyr Gin Gin Leu Pro Val 3025 3030 3035 304

Ser Asp Glu He Leu Phe Gin He Tyr Gin Pro Arg Glu Pro Leu His 3045 3050 3055

Phe Ser Lys Phe Leu Asp Pro Asp Phe Gin Pro Ser Cys Ser Glu Val

3060 3065 3070

Asp Leu He Gly Phe Val Val Ser Val Val Lys Lys Thr Gly Leu Ala 3075 3080 3085 Pro Phe Val Tyr Leu Ser Asp Glu Cys Tyr Asn Leu Leu Ala He Lys 3090 3095 3100

Phe Trp He Asp Leu Asn Glu Asp He He Lys Pro His Met Leu He 3105 3110 3115 312

Ala Ala Ser Asn Leu Gin Trp Arg Pro Glu Ser Lys Ser Gly Leu Leu

3125 3130 3135 Thr Leu Phe Ala Gly Asp Phe Ser Val Phe Ser Ala Ser Pro Lys Glu

3140 3145 3150

Gly His Phe Gin Glu Thr Phe Asn Lys Met Lys Asn Thr Val Glu Asn

3155 3160 3165

He Asp He Leu Cys Asn Glu Ala Glu Asn Lys Leu Met His He Leu 3170 3175 3180

His Ala Asn Asp Pro Lys Trp Ser Thr Pro Thr Lys Asp Cys Thr Ser

3185 3190 3195 320

Gly Pro Tyr Thr Ala Gin He He Pro Gly Thr Gly Asn Lys Leu Leu

3205 3210 3215 Met Ser Ser Pro Asn Cys Glu He Tyr Tyr Gin Ser Pro Leu Ser Leu

3220 3225 3230

Cys Met Ala Lys Arg Lys Ser Val Ser Thr Pro Val Ser Ala Gin Met

3235 3240 3245

Thr Ser Lys Ser Cys Lys Gly Glu Lys Glu He Asp Asp Gin Lys Asn 3250 3255 3260

Cys Lys Lys Arg Arg Ala Leu Asp Phe Leu Ser Arg Leu Pro Leu Pro 3265 3270 3275 328

Pro Pro Val Ser Pro He Cys Thr Phe Val Ser Pro Ala Ala Gin Lys 3285 3290 3295 Ala Phe Gin Pro Pro Arg Ser Cys Gly Thr Lys Tyr Glu Thr Pro He

3300 3305 3310

Lys Lys Lys Glu Leu Asn Ser Pro Gin Met Thr Pro Phe Lys Lys Phe

3315 3320 3325

Asn Glu He Ser Leu Leu Glu Ser Asn Ser He Ala Asp Glu Glu Leu 3330 3335 3340

Ala Leu He Asn Thr Gin Ala Leu Leu Ser Gly Ser Thr Gly Glu Lys 3345 3350 3355 336

Gin Phe He Ser Val Ser Glu Ser Thr Arg Thr Ala Pro Thr Ser Ser 3365 3370 3375 Glu Asp Tyr Leu Arg Leu Lys Arg Arg Cys Thr Thr Ser Leu He Lys

3380 3385 3390

Glu Gin Glu Ser Ser Gin Ala Ser Thr Glu Glu Cys Glu Lys Asn Lys

3395 3400 3405

Gin Asp Thr He Thr Thr Lys Lys Tyr He 3410 3415

(2) INFORMATION FOR SEQ ID NO : 6 :

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 10485 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA

(ix) FEATURE:

(A) NAME/KEY: Coding Sequence

(B) LOCATION: 229...10482 (D) OTHER INFORMATION: BRCA2 (OMI2)

(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 6 :

GGTGGCGCGA GCTTCTGAAA CTAGGCGGCA GAGGCGGAGC CGCTGTGGCA CTGCTGCGCC 60 TCTGCTGCGC CTCGGGTGTC TTTTGCGGCG GTGGGTCGCC GCCGGGAGAA GCGTGAGGGG 120

ACAGATTTGT GACCGGCGCG GTTTTTGTCA GCTTACTCCG GCCAAAAAAG AACTGCACCT 180

CTGGAGCGGA CTTATTTACC AAGCATTGGA GGAATATCGT AGGTAAAA ATG CCT ATT 237 Met Pro He 1 GGA TCC AAA GAG AGG CCA ACA TTT TTT GAA ATT TTT AAG ACA CGC TGC 285 Gly Ser Lys Glu Arg Pro Thr Phe Phe Glu He Phe Lys Thr Arg Cys 5 10 15

AAC AAA GCA GAT TTA GGA CCA ATA AGT CTT AAT TGG TTT GAA GAA CTT 333 Asn Lys Ala Asp Leu Gly Pro He Ser Leu Asn Trp Phe Glu Glu Leu 20 25 30 35

TCT TCA GAA GCT CCA CCC TAT AAT TCT GAA CCT GCA GAA GAA TCT GAA 381 Ser Ser Glu Ala Pro Pro Tyr Asn Ser Glu Pro Ala Glu Glu Ser Glu 40 45 50

CAT AAA AAC AAC AAT TAC GAA CCA AAC CTA TTT AAA ACT CCA CAA AGG 429 His Lys Asn Asn Asn Tyr Glu Pro Asn Leu Phe Lys Thr Pro Gin Arg 55 60 65

AAA CCA TCT TAT AAT CAG CTG GCT TCA ACT CCA ATA ATA TTC AAA GAG 477 Lys Pro Ser Tyr Asn Gin Leu Ala Ser Thr Pro He He Phe Lys Glu 70 75 80 CAA GGG CTG ACT CTG CCG CTG TAC CAA TCT CCT GTA AAA GAA TTA GAT 525

Gin Gly Leu Thr Leu Pro Leu Tyr Gin Ser Pro Val Lys Glu Leu Asp 85 90 95

AAA TTC AAA TTA GAC TTA GGA AGG AAT GTT CCC AAT AGT AGA CAT AAA 573 Lys Phe Lys Leu Asp Leu Gly Arg Asn Val Pro Asn Ser Arg His Lys

100 105 110 115

AGT CTT CGC ACA GTG AAA ACT AAA ATG GAT CAA GCA GAT GAT GTT TCC 621 Ser Leu Arg Thr Val Lys Thr Lys Met Asp Gin Ala Asp Asp Val Ser 120 125 130

TGT CCA CTT CTA AAT TCT TGT CTT AGT GAA AGT CCT GTT GTT CTA CAA 669 Cys Pro Leu Leu Asn Ser Cys Leu Ser Glu Ser Pro Val Val Leu Gin 135 140 145

TGT ACA CAT GTA ACA CCA CAA AGA GAT AAG TCA GTG GTA TGT GGG AGT 717 Cys Thr His Val Thr Pro Gin Arg Asp Lys Ser Val Val Cys Gly Ser 150 155 160 TTG TTT CAT ACA CCA AAG TTT GTG AAG GGT CGT CAG ACA CCA AAA CAT 765

Leu Phe His Thr Pro Lys Phe Val Lys Gly Arg Gin Thr Pro Lys His 165 170 175

ATT TCT GAA AGT CTA GGA GCT GAG GTG GAT CCT GAT ATG TCT TGG TCA 813 He Ser Glu Ser Leu Gly Ala Glu Val Asp Pro Asp Met Ser Trp Ser 180 185 190 195

AGT TCT TTA GCT ACA CCA CCC ACC CTT AGT TCT ACT GTG CTC ATA GTC 861 Ser Ser Leu Ala Thr Pro Pro Thr Leu Ser Ser Thr Val Leu He Val 200 205 210

AGA AAT GAA GAA GCA TCT GAA ACT GTA TTT CCT CAT GAT ACT ACT GCT 909 Arg Asn Glu Glu Ala Ser Glu Thr Val Phe Pro His Asp Thr Thr Ala 215 220 225

AAT GTG AAA AGC TAT TTT TCC AAT CAT GAT GAA AGT CTG AAG AAA AAT 957 Asn Val Lys Ser Tyr Phe Ser Asn His Asp Glu Ser Leu Lys Lys Asn 230 235 240

GAT AGA TTT ATC GCT TCT GTG ACA GAC AGT GAA AAC ACA AAT CAA AGA 1005 Asp Arg Phe He Ala Ser Val Thr Asp Ser Glu Asn Thr Asn Gin Arg 245 250 255

GAA GCT GCA AGT CAT GGA TTT GGA AAA ACA TCA GGG AAT TCA TTT AAA 1053 Glu Ala Ala Ser His Gly Phe Gly Lys Thr Ser Gly Asn Ser Phe Lys 260 265 270 275

GTA AAT AGC TGC AAA GAC CAC ATT GGA AAG TCA ATG CCA AAT GTC CTA 1101

Val Asn Ser Cys Lys Asp His He Gly Lys Ser Met Pro Asn Val Leu 280 285 290

GAA GAT GAA GTA TAT GAA ACA GTT GTA GAT ACC TCT GAA GAA GAT AGT 1149

Glu Asp Glu Val Tyr Glu Thr Val Val Asp Thr Ser Glu Glu Asp Ser 295 300 305 TTT TCA TTA TGT TTT TCT AAA TGT AGA ACA AAA AAT CTA CAA AAA GTA 1197 Phe Ser Leu Cys Phe Ser Lys Cys Arg Thr Lys Asn Leu Gin Lys Val 310 315 320

AGA ACT AGC AAG ACT AGG AAA AAA ATT TTC CAT GAA GCA AAC GCT GAT 1245 Arg Thr Ser Lys Thr Arg Lys Lys He Phe His Glu Ala Asn Ala Asp 325 330 335

GAA TGT GAA AAA TCT AAA AAC CAA GTG AAA GAA AAA TAC TCA TTT GTA 1293 Glu Cys Glu Lys Ser Lys Asn Gin Val Lys Glu Lys Tyr Ser Phe Val 340 345 350 355

TCT GAA GTG GAA CCA AAT GAT ACT GAT CCA TTA GAT TCA AAT GTA GCA 1341

Ser Glu Val Glu Pro Asn Asp Thr Asp Pro Leu Asp Ser Asn Val Ala 360 365 370

CAT CAG AAG CCC TTT GAG AGT GGA AGT GAC AAA ATC TCC AAG GAA GTT 1389

His Gin Lys Pro Phe Glu Ser Gly Ser Asp Lys He Ser Lys Glu Val 375 380 385 GTA CCG TCT TTG GCC TGT GAA TGG TCT CAA CTA ACC CTT TCA GGT CTA 1437 Val Pro Ser Leu Ala Cys Glu Trp Ser Gin Leu Thr Leu Ser Gly Leu 390 395 400

AAT GGA GCC CAG ATG GAG AAA ATA CCC CTA TTG CAT ATT TCT TCA TGT 1485 Asn Gly Ala Gin Met Glu Lys He Pro Leu Leu His He Ser Ser Cys 405 410 415

GAC CAA AAT ATT TCA GAA AAA GAC CTA TTA GAC ACA GAG AAC AAA AGA 1533 Asp Gin Asn He Ser Glu Lys Asp Leu Leu Asp Thr Glu Asn Lys Arg 420 425 430 435

AAG AAA GAT TTT CTT ACT TCA GAG AAT TCT TTG CCA CGT ATT TCT AGC 1581 Lys Lys Asp Phe Leu Thr Ser Glu Asn Ser Leu Pro Arg He Ser Ser 440 445 450

CTA CCA AAA TCA GAG AAG CCA TTA AAT GAG GAA ACA GTG GTA AAT AAG 1629 Leu Pro Lys Ser Glu Lys Pro Leu Asn Glu Glu Thr Val Val Asn Lys 455 460 465 AGA GAT GAA GAG CAG CAT CTT GAA TCT CAT ACA GAC TGC ATT CTT GCA 1677 Arg Asp Glu Glu Gin His Leu Glu Ser His Thr Asp Cys He Leu Ala 470 475 480 GTA AAG CAG GCA ATA TCT GGA ACT TCT CCA GTG GCT TCT TCA TTT CAG 1725 Val Lys Gin Ala He Ser Gly Thr Ser Pro Val Ala Ser Ser Phe Gin 485 490 495

GGT ATC AAA AAG TCT ATA TTC AGA ATA AGA GAA TCA CCT AAA GAG ACT 1773 Gly He Lys Lys Ser He Phe Arg He Arg Glu Ser Pro Lys Glu Thr 500 505 510 515

TTC AAT GCA AGT TTT TCA GGT CAT ATG ACT GAT CCA AAC TTT AAA AAA 1821 Phe Asn Ala Ser Phe Ser Gly His Met Thr Asp Pro Asn Phe Lys Lys 520 525 530 GAA ACT GAA GCC TCT GAA AGT GGA CTG GAA ATA CAT ACT GTT TGC TCA 1869 Glu Thr Glu Ala Ser Glu Ser Gly Leu Glu He His Thr Val Cys Ser 535 540 545

CAG AAG GAG GAC TCC TTA TGT CCA AAT TTA ATT GAT AAT GGA AGC TGG 1917 Gin Lys Glu Asp Ser Leu Cys Pro Asn Leu He Asp Asn Gly Ser Trp 550 555 560

CCA GCC ACC ACC ACA CAG AAT TCT GTA GCT TTG AAG AAT GCA GGT TTA 1965 Pro Ala Thr Thr Thr Gin Asn Ser Val Ala Leu Lys Asn Ala Gly Leu 565 570 575

ATA TCC ACT TTG AAA AAG AAA ACA AAT AAG TTT ATT TAT GCT ATA CAT 2013 He Ser Thr Leu Lys Lys Lys Thr Asn Lys Phe He Tyr Ala He His 580 585 590 595

GAT GAA ACA TCT TAT AAA GGA AAA AAA ATA CCG AAA GAC CAA AAA TCA 2061 Asp Glu Thr Ser Tyr Lys Gly Lys Lys He Pro Lys Asp Gin Lys Ser 600 605 610 GAA CTA ATT AAC TGT TCA GCC CAG TTT GAA GCA AAT GCT TTT GAA GCA 2109 Glu Leu He Asn Cys Ser Ala Gin Phe Glu Ala Asn Ala Phe Glu Ala 615 620 625

CCA CTT ACA TTT GCA AAT GCT GAT TCA GGT TTA TTG CAT TCT TCT GTG 2157 Pro Leu Thr Phe Ala Asn Ala Asp Ser Gly Leu Leu His Ser Ser Val 630 635 640

AAA AGA AGC TGT TCA CAG AAT GAT TCT GAA GAA CCA ACT TTG TCC TTA 2205 Lys Arg Ser Cys Ser Gin Asn Asp Ser Glu Glu Pro Thr Leu Ser Leu 645 650 655

ACT AGC TCT TTT GGG ACA ATT CTG AGG AAA TGT TCT AGA AAT GAA ACA 2253 Thr Ser Ser Phe Gly Thr He Leu Arg Lys Cys Ser Arg Asn Glu Thr 660 665 670 675

TGT TCT AAT AAT ACA GTA ATC TCT CAG GAT CTT GAT TAT AAA GAA GCA 2301 Cys Ser Asn Asn Thr Val He Ser Gin Asp Leu Asp Tyr Lys Glu Ala 680 685 690 AAA TGT AAT AAG GAA AAA CTA CAG TTA TTT ATT ACC CCA GAA GCT GAT 2349 Lys Cys Asn Lys Glu Lys Leu Gin Leu Phe He Thr Pro Glu Ala Asp 695 700 705

TCT CTG TCA TGC CTG CAG GAA GGA CAG TGT GAA AAT GAT CCA AAA AGC 2397 Ser Leu Ser Cys Leu Gin Glu Gly Gin Cys Glu Asn Asp Pro Lys Ser 710 715 720 AAA AAA GTT TCA GAT ATA AAA GAA GAG GTC TTG GCT GCA GCA TGT CAC 2445

Lys Lys Val Ser Asp He Lys Glu Glu Val Leu Ala Ala Ala Cys His 725 730 735

CCA GTA CAA CAT TCA AAA GTG GAA TAC AGT GAT ACT GAC TTT CAA TCC 2493

Pro Val Gin His Ser Lys Val Glu Tyr Ser Asp Thr Asp Phe Gin Ser

740 745 750 755 CAG AAA AGT CTT TTA TAT GAT CAT GAA AAT GCC AGC ACT CTT ATT TTA 2541 Gin Lys Ser Leu Leu Tyr Asp His Glu Asn Ala Ser Thr Leu He Leu 760 765 770

ACT CCT ACT TCC AAG GAT GTT CTG TCA AAC CTA GTC ATG ATT TCT AGA 2589 Thr Pro Thr Ser Lys Asp Val Leu Ser Asn Leu Val Met He Ser Arg

775 780 785

GGC AAA GAA TCA TAC AAA ATG TCA GAC AAG CTC AAA GGT AAC AAT TAT 2637 Gly Lys Glu Ser Tyr Lys Met Ser Asp Lys Leu Lys Gly Asn Asn Tyr 790 795 800

GAA TCT GAT GTT GAA TTA ACC AAA AAT ATT CCC ATG GAA AAG AAT CAA 2685

Glu Ser Asp Val Glu Leu Thr Lys Asn He Pro Met Glu Lys Asn Gin 805 810 815

GAT GTA TGT GCT TTA AAT GAA AAT TAT AAA AAC GTT GAG CTG TTG CCA 2733

Asp Val Cys Ala Leu Asn Glu Asn Tyr Lys Asn Val Glu Leu Leu Pro

820 825 830 835 CCT GAA AAA TAC ATG AGA GTA GCA TCA CCT TCA AGA AAG GTA CAA TTC 2781 Pro Glu Lys Tyr Met Arg Val Ala Ser Pro Ser Arg Lys Val Gin Phe 840 845 850

AAC CAA AAC ACA AAT CTA AGA GTA ATC CAA AAA AAT CAA GAA GAA ACT 2829 Asn Gin Asn Thr Asn Leu Arg Val He Gin Lys Asn Gin Glu Glu Thr

855 860 865

ACT TCA ATT TCA AAA ATA ACT GTC AAT CCA GAC TCT GAA GAA CTT TTC 2877 Thr Ser He Ser Lys He Thr Val Asn Pro Asp Ser Glu Glu Leu Phe 870 875 880

TCA GAC AAT GAG AAT AAT TTT GTC TTC CAA GTA GCT AAT GAA AGG AAT 2925

Ser Asp Asn Glu Asn Asn Phe Val Phe Gin Val Ala Asn Glu Arg Asn 885 890 895

AAT CTT GCT TTA GGA AAT ACT AAG GAA CTT CAT GAA ACA GAC TTG ACT 2973

Asn Leu Ala Leu Gly Asn Thr Lys Glu Leu His Glu Thr Asp Leu Thr 900 905 910 915 TGT GTA AAC GAA CCC ATT TTC AAG AAC TCT ACC ATG GTT TTA TAT GGA 3021 Cys Val Asn Glu Pro He Phe Lys Asn Ser Thr Met Val Leu Tyr Gly 920 925 930

GAC ACA GGT GAT AAA CAA GCA ACC CAA GTG TCA ATT AAA AAA GAT TTG 3069 Asp Thr Gly Asp Lys Gin Ala Thr Gin Val Ser He Lys Lys Asp Leu

935 940 945

GTT TAT GTT CTT GCA GAG GAG AAC AAA AAT AGT GTA AAG CAG CAT ATA 3117 Val Tyr Val Leu Ala Glu Glu Asn Lys Asn Ser Val Lys Gin His He 950 955 960

AAA ATG ACT CTA GGT CAA GAT TTA AAA TCG GAC ATC TCC TTG AAT ATA 3165 Lys Met Thr Leu Gly Gin Asp Leu Lys Ser Asp He Ser Leu Asn He 965 970 975 GAT AAA ATA CCA GAA AAA AAT AAT GAT TAC ATG AAC AAA TGG GCA GGA 3213 Asp Lys He Pro Glu Lys Asn Asn Asp Tyr Met Asn Lys Trp Ala Gly 980 985 990 995

CTC TTA GGT CCA ATT TCA AAT CAC AGT TTT GGA GGT AGC TTC AGA ACA 3261 Leu Leu Gly Pro He Ser Asn His Ser Phe Gly Gly Ser Phe Arg Thr

1000 1005 1010

GCT TCA AAT AAG GAA ATC AAG CTC TCT GAA CAT AAC ATT AAG AAG AGC 3309 Ala Ser Asn Lys Glu He Lys Leu Ser Glu His Asn He Lys Lys Ser 1015 1020 1025

AAA ATG TTC TTC AAA GAT ATT GAA GAA CAA TAT CCT ACT AGT TTA GCT 3357

Lys Met Phe Phe Lys Asp He Glu Glu Gin Tyr Pro Thr Ser Leu Ala 1030 1035 1040

TGT GTT GAA ATT GTA AAT ACC TTG GCA TTA GAT AAT CAA AAG AAA CTG 3405

Cys Val Glu He Val Asn Thr Leu Ala Leu Asp Asn Gin Lys Lys Leu 1045 1050 1055 AGC AAG CCT CAG TCA ATT AAT ACT GTA TCT GCA CAT TTA CAG AGT AGT 3453

Ser Lys Pro Gin Ser He Asn Thr Val Ser Ala His Leu Gin Ser Ser 1060 1065 1070 1075

GTA GTT GTT TCT GAT TGT AAA AAT AGT CAT ATA ACC CCT CAG ATG TTA 3501 Val Val Val Ser Asp Cys Lys Asn Ser His He Thr Pro Gin Met Leu

1080 1085 1090

TTT TCC AAG CAG GAT TTT AAT TCA AAC CAT AAT TTA ACA CCT AGC CAA 3549 Phe Ser Lys Gin Asp Phe Asn Ser Asn His Asn Leu Thr Pro Ser Gin 1095 1100 1105

AAG GCA GAA ATT ACA GAA CTT TCT ACT ATA TTA GAA GAA TCA GGA AGT 3597 Lys Ala Glu He Thr Glu Leu Ser Thr He Leu Glu Glu Ser Gly Ser 1110 1115 1120

CAG TTT GAA TTT ACT CAG TTT AGA AAR CCA AGC TAC ATA TTG CAG AAG 3645 Gin Phe Glu Phe Thr Gin Phe Arg Xaa Pro Ser Tyr He Leu Gin Lys 1125 1130 1135 AGT ACA TTT GAA GTG CCT GAA AAC CAG ATG ACT ATC TTA AAG ACC ACT 3693 Ser Thr Phe Glu Val Pro Glu Asn Gin Met Thr He Leu Lys Thr Thr 1140 1145 1150 1155

TCT GAG GAA TGC AGA GAT GCT GAT CTT CAT GTC ATA ATG AAT GCC CCA 3741 Ser Glu Glu Cys Arg Asp Ala Asp Leu His Val He Met Asn Ala Pro

1160 1165 1170

TCG ATT GGT CAG GTA GAC AGC AGC AAG CAA TTT GAA GGT ACA GTT GAA 3789 Ser He Gly Gin Val Asp Ser Ser Lys Gin Phe Glu Gly Thr Val Glu 1175 1180 1185

ATT AAA CGG AAG TTT GCT GGC CTG TTG AAA AAT GAC TGT AAC AAA AGT 3837 He Lys Arg Lys Phe Ala Gly Leu Leu Lys Asn Asp Cys Asn Lys Ser 1190 1195 1200

GCT TCT GGT TAT TTA ACA GAT GAA AAT GAA GTG GGG TTT AGG GGC TTT 3885 Ala Ser Gly Tyr Leu Thr Asp Glu Asn Glu Val Gly Phe Arg Gly Phe 1205 1210 1215

TAT TCT GCT CAT GGC ACA AAA CTG AAT GTT TCT ACT GAA GCT CTG CAA 3933 Tyr Ser Ala His Gly Thr Lys Leu Asn Val Ser Thr Glu Ala Leu Gin 1220 1225 1230 1235

AAA GCT GTG AAA CTG TTT AGT GAT ATT GAG AAT ATT AGT GAG GAA ACT 3981 Lys Ala Val Lys Leu Phe Ser Asp He Glu Asn He Ser Glu Glu Thr 1240 1245 1250

TCT GCA GAG GTA CAT CCA ATA AGT TTA TCT TCA AGT AAA TGT CAT GAT 4029

Ser Ala Glu Val His Pro He Ser Leu Ser Ser Ser Lys Cys His Asp 1255 1260 1265

TCT GTC GTT TCA ATG TTT AAG ATA GAA AAT CAT AAT GAT AAA ACT GTA 4077

Ser Val Val Ser Met Phe Lys He Glu Asn His Asn Asp Lys Thr Val 1270 1275 1280 AGT GAA AAA AAT AAT AAA TGC CAA CTG ATA TTA CAA AAT AAT ATT GAA 4125 Ser Glu Lys Asn Asn Lys Cys Gin Leu He Leu Gin Asn Asn He Glu 1285 1290 1295

ATG ACT ACT GGC ACT TTT GTT GAA GAA ATT ACT GAA AAT TAC AAG AGA 4173 Met Thr Thr Gly Thr Phe Val Glu Glu He Thr Glu Asn Tyr Lys Arg 1300 1305 1310 1315

AAT ACT GAA AAT GAA GAT AAC AAA TAT ACT GCT GCC AGT AGA AAT TCT 4221 Asn Thr Glu Asn Glu Asp Asn Lys Tyr Thr Ala Ala Ser Arg Asn Ser 1320 1325 1330

CAT AAC TTA GAA TTT GAT GGC AGT GAT TCA AGT AAA AAT GAT ACT GTT 4269 His Asn Leu Glu Phe Asp Gly Ser Asp Ser Ser Lys Asn Asp Thr Val 1335 1340 1345

TGT ATT CAT AAA GAT GAA ACG GAC TTG CTA TTT ACT GAT CAG CAC AAC 4317 Cys He His Lys Asp Glu Thr Asp Leu Leu Phe Thr Asp Gin His Asn 1350 1355 1360 ATA TGT CTT AAA TTA TCT GGC CAG TTT ATG AAG GAG GGA AAC ACT CAG 4365 He Cys Leu Lys Leu Ser Gly Gin Phe Met Lys Glu Gly Asn Thr Gin 1365 1370 1375

ATT AAA GAA GAT TTG TCA GAT TTA ACT TTT TTG GAA GTT GCG AAA GCT 4413 He Lys Glu Asp Leu Ser Asp Leu Thr Phe Leu Glu Val Ala Lys Ala 1380 1385 1390 1395

CAA GAA GCA TGT CAT GGT AAT ACT TCA AAT AAA GAA CAG TTA ACT GCT 4461 Gin Glu Ala Cys His Gly Asn Thr Ser Asn Lys Glu Gin Leu Thr Ala 1400 1405 1410

ACT AAA ACG GAG CAA AAT ATA AAA GAT TTT GAG ACT TCT GAT ACA TTT 4509 Thr Lys Thr Glu Gin Asn He Lys Asp Phe Glu Thr Ser Asp Thr Phe 1415 1420 1425

TTT CAG ACT GCA AGT GGG AAA AAT ATT AGT GTC GCC AAA GAG TCA TTT 4557 Phe Gin Thr Ala Ser Gly Lys Asn He Ser Val Ala Lys Glu Ser Phe 1430 1435 1440 AAT AAA ATT GTA AAT TTC TTT GAT CAG AAA CCA GAA GAA TTG CAT AAC 4605 Asn Lys He Val Asn Phe Phe Asp Gin Lys Pro Glu Glu Leu His Asn 1445 1450 1455 TTT TCC TTA AAT TCT GAA TTA CAT TCT GAC ATA AGA AAG AAC AAA ATG 4653 Phe Ser Leu Asn Ser Glu Leu His Ser Asp He Arg Lys Asn Lys Met 1460 1465 1470 1475

GAC ATT CTA AGT TAT GAG GAA ACA GAC ATA GTT AAA CAC AAA ATA CTG 4701 Asp He Leu Ser Tyr Glu Glu Thr Asp He Val Lys His Lys He Leu 1480 1485 1490

AAA GAA AGT GTC CCA GTT GGT ACT GGA AAT CAA CTA GTG ACC TTC CAG 4749 Lys Glu Ser Val Pro Val Gly Thr Gly Asn Gin Leu Val Thr Phe Gin 1495 1500 1505 GGA CAA CCC GAA CGT GAT GAA AAG ATC AAA GAA CCT ACT CTG TTG GGT 4797 Gly Gin Pro Glu Arg Asp Glu Lys He Lys Glu Pro Thr Leu Leu Gly 1510 1515 1520

TTT CAT ACA GCT AGC GGG AAA AAA GTT AAA ATT GCA AAG GAA TCT TTG 4845 Phe His Thr Ala Ser Gly Lys Lys Val Lys He Ala Lys Glu Ser Leu

1525 1530 1535

GAC AAA GTG AAA AAC CTT TTT GAT GAA AAA GAG CAA GGT ACT AGT GAA 4893 Asp Lys Val Lys Asn Leu Phe Asp Glu Lys Glu Gin Gly Thr Ser Glu 1540 1545 1550 1555

ATC ACC AGT TTT AGC CAT CAA TGG GCA AAG ACC CTA AAG TAC AGA GAG 4941 He Thr Ser Phe Ser His Gin Trp Ala Lys Thr Leu Lys Tyr Arg Glu 1560 1565 1570

GCC TGT AAA GAC CTT GAA TTA GCA TGT GAG ACC ATT GAG ATC ACA GCT 4989 Ala Cys Lys Asp Leu Glu Leu Ala Cys Glu Thr He Glu He Thr Ala 1575 1580 1585 GCC CCA AAG TGT AAA GAA ATG CAG AAT TCT CTC AAT AAT GAT AAA AAC 5037

Ala Pro Lys Cys Lys Glu Met Gin Asn Ser Leu Asn Asn Asp Lys Asn 1590 1595 1600

CTT GTT TCT ATT GAG ACT GTG GTG CCA CCT AAG CTC TTA AGT GAT AAT 5085 Leu Val Ser He Glu Thr Val Val Pro Pro Lys Leu Leu Ser Asp Asn

1605 1610 1615

TTA TGT AGA CAA ACT GAA AAT CTC AAA ACA TCA AAA AGT ATC TTT TTG 5133 Leu Cys Arg Gin Thr Glu Asn Leu Lys Thr Ser Lys Ser He Phe Leu 1620 1625 1630 1635

AAA GTT AAA GTA CAT GAA AAT GTA GAA AAA GAA ACA GCA AAA AGT CCT 5181 Lys Val Lys Val His Glu Asn Val Glu Lys Glu Thr Ala Lys Ser Pro 1640 1645 1650

GCA ACT TGT TAC ACA AAT CAG TCC CCT TAT TCA GTC ATT GAA AAT TCA 5229 Ala Thr Cys Tyr Thr Asn Gin Ser Pro Tyr Ser Val He Glu Asn Ser 1655 1660 1665 GCC TTA GCT TTT TAC ACA AGT TGT AGT AGA AAA ACT TCT GTG AGT CAG 5277 Ala Leu Ala Phe Tyr Thr Ser Cys Ser Arg Lys Thr Ser Val Ser Gin 1670 1675 1680

ACT TCA TTA CTT GAA GCA AAA AAA TGG CTT AGA GAA GGA ATA TTT GAT 5325 Thr Ser Leu Leu Glu Ala Lys Lys Trp Leu Arg Glu Gly He Phe Asp 1685 1690 1695 GGT CAA CCA GAA AGA ATA AAT ACT GCA GAT TAT GTA GGA AAT TAT TTG 5373

Gly Gin Pro Glu Arg He Asn Thr Ala Asp Tyr Val Gly Asn Tyr Leu 1700 1705 1710 1715

TAT GAA AAT AAT TCA AAC AGT ACT ATA GCT GAA AAT GAC AAA AAT CAT 5421

Tyr Glu Asn Asn Ser Asn Ser Thr He Ala Glu Asn Asp Lys Asn His 1720 1725 1730 CTC TCC GAA AAA CAA GAT ACT TAT TTA AGT AAC AGT AGC ATG TCT AAC 5469 Leu Ser Glu Lys Gin Asp Thr Tyr Leu Ser Asn Ser Ser Met Ser Asn 1735 1740 1745

AGC TAT TCC TAC CAT TCT GAT GAG GTA TAT AAT GAT TCA GGA TAT CTC 5517 Ser Tyr Ser Tyr His Ser Asp Glu Val Tyr Asn Asp Ser Gly Tyr Leu 1750 1755 1760

TCA AAA AAT AAA CTT GAT TCT GGT ATT GAG CCA GTA TTG AAG AAT GTT 5565 Ser Lys Asn Lys Leu Asp Ser Gly He Glu Pro Val Leu Lys Asn Val 1765 1770 1775

GAA GAT CAA AAA AAC ACT AGT TTT TCC AAA GTA ATA TCC AAT GTA AAA 5613

Glu Asp Gin Lys Asn Thr Ser Phe Ser Lys Val He Ser Asn Val Lys 1780 1785 1790 1795

GAT GCA AAT GCA TAC CCA CAA ACT GTA AAT GAA GAT ATT TGC GTT GAG 5661

Asp Ala Asn Ala Tyr Pro Gin Thr Val Asn Glu Asp He Cys Val Glu 1800 1805 1810 GAA CTT GTG ACT AGC TCT TCA CCC TGC AAA AAT AAA AAT GCA GCC ATT 5709 Glu Leu Val Thr Ser Ser Ser Pro Cys Lys Asn Lys Asn Ala Ala He 1815 1820 1825

AAA TTG TCC ATA TCT AAT AGT AAT AAT TTT GAG GTA GGG CCA CCT GCA 5757 Lys Leu Ser He Ser Asn Ser Asn Asn Phe Glu Val Gly Pro Pro Ala 1830 1835 1840

TTT AGG ATA GCC AGT GGT AAA ATC GTT TGT GTT TCA CAT GAA ACA ATT 5805 Phe Arg He Ala Ser Gly Lys He Val Cys Val Ser His Glu Thr He 1845 1850 1855

AAA AAA GTG AAA GAC ATA TTT ACA GAC AGT TTC AGT AAA GTA ATT AAG 5853 Lys Lys Val Lys Asp He Phe Thr Asp Ser Phe Ser Lys Val He Lys 1860 1865 1870 1875

GAA AAC AAC GAG AAT AAA TCA AAA ATT TGC CAA ACG AAA ATT ATG GCA 5901 Glu Asn Asn Glu Asn Lys Ser Lys He Cys Gin Thr Lys He Met Ala 1880 1885 1890 GGT TGT TAC GAG GCA TTG GAT GAT TCA GAG GAT ATT CTT CAT AAC TCT 5949 Gly Cys Tyr Glu Ala Leu Asp Asp Ser Glu Asp He Leu His Asn Ser 1895 1900 1905

CTA GAT AAT GAT GAA TGT AGC ACG CAT TCA CAT AAG GTT TTT GCT GAC 5997 Leu Asp Asn Asp Glu Cys Ser Thr His Ser His Lys Val Phe Ala Asp 1910 1915 1920

ATT CAG AGT GAA GAA ATT TTA CAA CAT AAC CAA AAT ATG TCT GGA TTG 6045 He Gin Ser Glu Glu He Leu Gin His Asn Gin Asn Met Ser Gly Leu 1925 1930 1935

GAG AAA GTT TCT AAA ATA TCA CCT TGT GAT GTT AGT TTG GAA ACT TCA 6093 Glu Lys Val Ser Lys He Ser Pro Cys Asp Val Ser Leu Glu Thr Ser 1940 1945 1950 1955 GAT ATA TGT AAA TGT AGT ATA GGG AAG CTT CAT AAG TCA GTC TCA TCT 6141 Asp He Cys Lys Cys Ser He Gly Lys Leu His Lys Ser Val Ser Ser 1960 1965 1970

GCA AAT ACT TGT GGG ATT TTT AGC ACA GCA AGT GGA AAA TCT GTC CAG 6189 Ala Asn Thr Cys Gly He Phe Ser Thr Ala Ser Gly Lys Ser Val Gin 1975 1980 1985

GTA TCA GAT GCT TCA TTA CAA AAC GCA AGA CAA GTG TTT TCT GAA ATA 6237 Val Ser Asp Ala Ser Leu Gin Asn Ala Arg Gin Val Phe Ser Glu He 1990 1995 2000

GAA GAT AGT ACC AAG CAA GTC TTT TCC AAA GTA TTG TTT AAA AGT AAC 6285

Glu Asp Ser Thr Lys Gin Val Phe Ser Lys Val Leu Phe Lys Ser Asn 2005 2010 2015

GAA CAT TCA GAC CAG CTC ACA AGA GAA GAA AAT ACT GCT ATA CGT ACT 6333

Glu His Ser Asp Gin Leu Thr Arg Glu Glu Asn Thr Ala He Arg Thr 2020 2025 2030 2035 CCA GAA CAT TTA ATA TCC CAA AAA GGC TTT TCA TAT AAT GTG GTA AAT 6381

Pro Glu His Leu He Ser Gin Lys Gly Phe Ser Tyr Asn Val Val Asn 2040 2045 2050

TCA TCT GCT TTC TCT GGA TTT AGT ACA GCA AGT GGA AAG CAA GTT TCC 6429 Ser Ser Ala Phe Ser Gly Phe Ser Thr Ala Ser Gly Lys Gin Val Ser

2055 2060 2065

ATT TTA GAA AGT TCC TTA CAC AAA GTT AAG GGA GTG TTA GAG GAA TTT 6477 He Leu Glu Ser Ser Leu His Lys Val Lys Gly Val Leu Glu Glu Phe 2070 2075 2080

GAT TTA ATC AGA ACT GAG CAT AGT CTT CAC TAT TCA CCT ACG TCT AGA 6525

Asp Leu He Arg Thr Glu His Ser Leu His Tyr Ser Pro Thr Ser Arg 2085 2090 2095

CAA AAT GTA TCA AAA ATA CTT CCT CGT GTT GAT AAG AGA AAC CCA GAG 6573

Gin Asn Val Ser Lys He Leu Pro Arg Val Asp Lys Arg Asn Pro Glu 2100 2105 2110 2115 CAC TGT GTA AAC TCA GAA ATG GAA AAA ACC TGC AGT AAA GAA TTT AAA 6621

His Cys Val Asn Ser Glu Met Glu Lys Thr Cys Ser Lys Glu Phe Lys 2120 2125 2130

TTA TCA AAT AAC TTA AAT GTT GAA GGT GGT TCT TCA GAA AAT AAT CAC 6669 Leu Ser Asn Asn Leu Asn Val Glu Gly Gly Ser Ser Glu Asn Asn His 2135 2140 2145

TCT ATT AAA GTT TCT CCA TAT CTC TCT CAA TTT CAA CAA GAC AAA CAA 6717 Ser He Lys Val Ser Pro Tyr Leu Ser Gin Phe Gin Gin Asp Lys Gin 2150 2155 2160

CAG TTG GTA TTA GGA ACC AAA GTC TCA CTT GTT GAG AAC ATT CAT GTT 6765 Gin Leu Val Leu Gly Thr Lys Val Ser Leu Val Glu Asn He His Val 2165 2170 2175

TTG GGA AAA GAA CAG GCT TCA CCT AAA AAC GTA AAA ATG GAA ATT GGT 6813 Leu Gly Lys Glu Gin Ala Ser Pro Lys Asn Val Lys Met Glu He Gly 2180 2185 2190 2195

AAA ACT GAA ACT TTT TCT GAT GTT CCT GTG AAA ACA AAT ATA GAA GTT 6861 Lys Thr Glu Thr Phe Ser Asp Val Pro Val Lys Thr Asn He Glu Val

2200 2205 2210

TGT TCT ACT TAC TCC AAA GAT TCA GAA AAC TAC TTT GAA ACA GAA GCA 6909 Cys Ser Thr Tyr Ser Lys Asp Ser Glu Asn Tyr Phe Glu Thr Glu Ala 2215 2220 2225

GTA GAA ATT GCT AAA GCT TTT ATG GAA GAT GAT GAA CTG ACA GAT TCT 6957

Val Glu He Ala Lys Ala Phe Met Glu Asp Asp Glu Leu Thr Asp Ser 2230 2235 2240

AAA CTG CCA AGT CAT GCC ACA CAT TCT CTT TTT ACA TGT CCC GAA AAT 7005

Lys Leu Pro Ser His Ala Thr His Ser Leu Phe Thr Cys Pro Glu Asn 2245 2250 2255 GAG GAA ATG GTT TTG TCA AAT TCA AGA ATT GGA AAA AGA AGA GGA GAG 7053 Glu Glu Met Val Leu Ser Asn Ser Arg He Gly Lys Arg Arg Gly Glu 2260 2265 2270 2275

CCC CTT ATC TTA GTG GGA GAA CCC TCA ATC AAA AGA AAC TTA TTA AAT 7101 Pro Leu He Leu Val Gly Glu Pro Ser He Lys Arg Asn Leu Leu Asn

2280 2285 2290

GAA TTT GAC AGG ATA ATA GAA AAT CAA GAA AAA TCC TTA AAG GCT TCA 7149 Glu Phe Asp Arg He He Glu Asn Gin Glu Lys Ser Leu Lys Ala Ser 2295 2300 2305

AAA AGC ACT CCA GAT GGC ACA ATA AAA GAT CGA AGA TTG TTT ATG CAT 7197 Lys Ser Thr Pro Asp Gly Thr He Lys Asp Arg Arg Leu Phe Met His 2310 2315 2320

CAT GTT TCT TTA GAG CCG ATT ACC TGT GTA CCC TTT CGC ACA ACT AAG 7245 His Val Ser Leu Glu Pro He Thr Cys Val Pro Phe Arg Thr Thr Lys 2325 2330 2335 GAA CGT CAA GAG ATA CAG AAT CCA AAT TTT ACC GCA CCT GGT CAA GAA 7293 Glu Arg Gin Glu He Gin Asn Pro Asn Phe Thr Ala Pro Gly Gin Glu 2340 2345 2350 2355

TTT CTG TCT AAA TCT CAT TTG TAT GAA CAT CTG ACT TTG GAA AAA TCT 7341 Phe Leu Ser Lys Ser His Leu Tyr Glu His Leu Thr Leu Glu Lys Ser

2360 2365 2370

TCA AGC AAT TTA GCA GTT TCA GGA CAT CCA TTT TAT CAA GTT TCT GCT 7389 Ser Ser Asn Leu Ala Val Ser Gly His Pro Phe Tyr Gin Val Ser Ala 2375 2380 2385

ACA AGA AAT GAA AAA ATG AGA CAC TTG ATT ACT ACA GGC AGA CCA ACC 7437 Thr Arg Asn Glu Lys Met Arg His Leu He Thr Thr Gly Arg Pro Thr 2390 2395 2400

AAA GTC TTT GTT CCA CCT TTT AAA ACT AAA TCA CAT TTT CAC AGA GTT 7485 Lys Val Phe Val Pro Pro Phe Lys Thr Lys Ser His Phe His Arg Val 2405 2410 2415 GAA CAG TGT GTT AGG AAT ATT AAC TTG GAG GAA AAC AGA CAA AAG CAA 7533 Glu Gin Cys Val Arg Asn He Asn Leu Glu Glu Asn Arg Gin Lys Gin 2420 2425 2430 2435 AAC ATT GAT GGA CAT GGC TCT GAT GAT AGT AAA AAT AAG ATT AAT GAC 7581 Asn He Asp Gly His Gly Ser Asp Asp Ser Lys Asn Lys He Asn Asp 2440 2445 2450

AAT GAG ATT CAT CAG TTT AAC AAA AAC AAC TCC AAT CAA GCA GCA GCT 7629 Asn Glu He His Gin Phe Asn Lys Asn Asn Ser Asn Gin Ala Ala Ala 2455 2460 2465

GTA ACT TTC ACA AAG TGT GAA GAA GAA CCT TTA GAT TTA ATT ACA AGT 7677 Val Thr Phe Thr Lys Cys Glu Glu Glu Pro Leu Asp Leu He Thr Ser 2470 2475 2480 CTT CAG AAT GCC AGA GAT ATA CAG GAT ATG CGA ATT AAG AAG AAA CAA 7725 Leu Gin Asn Ala Arg Asp He Gin Asp Met Arg He Lys Lys Lys Gin 2485 2490 2495

AGG CAA CGC GTC TTT CCA CAG CCA GGC AGT CTG TAT CTT GCA AAA ACA 7773 Arg Gin Arg Val Phe Pro Gin Pro Gly Ser Leu Tyr Leu Ala Lys Thr

2500 2505 2510 2515

TCC ACT CTG CCT CGA ATC TCT CTG AAA GCA GCA GTA GGA GGC CAA GTT 7821 Ser Thr Leu Pro Arg He Ser Leu Lys Ala Ala Val Gly Gly Gin Val 2520 2525 2530

CCC TCT GCG TGT TCT CAT AAA CAG CTG TAT ACG TAT GGC GTT TCT AAA 7869 Pro Ser Ala Cys Ser His Lys Gin Leu Tyr Thr Tyr Gly Val Ser Lys 2535 2540 2545

CAT TGC ATA AAA ATT AAC AGC AAA AAT GCA GAG TCT TTT CAG TTT CAC 7917 His Cys He Lys He Asn Ser Lys Asn Ala Glu Ser Phe Gin Phe His 2550 2555 2560 ACT GAA GAT TAT TTT GGT AAG GAA AGT TTA TGG ACT GGA AAA GGA ATA 7965

Thr Glu Asp Tyr Phe Gly Lys Glu Ser Leu Trp Thr Gly Lys Gly He 2565 2570 2575

CAG TTG GCT GAT GGT GGA TGG CTC ATA CCC TCC AAT GAT GGA AAG GCT 8013 Gin Leu Ala Asp Gly Gly Trp Leu He Pro Ser Asn Asp Gly Lys Ala

2580 2585 2590 2595

GGA AAA GAA GAA TTT TAT AGG GCT CTG TGT GAC ACT CCA GGT GTG GAT 8061 Gly Lys Glu Glu Phe Tyr Arg Ala Leu Cys Asp Thr Pro Gly Val Asp 2600 2605 2610

CCA AAG CTT ATT TCT AGA ATT TGG GTT TAT AAT CAC TAT AGA TGG ATC 8109 Pro Lys Leu He Ser Arg He Trp Val Tyr Asn His Tyr Arg Trp He 2615 2620 2625

ATA TGG AAA CTG GCA GCT ATG GAA TGT GCC TTT CCT AAG GAA TTT GCT 8157 He Trp Lys Leu Ala Ala Met Glu Cys Ala Phe Pro Lys Glu Phe Ala 2630 2635 2640 AAT AGA TGC CTA AGC CCA GAA AGG GTG CTT CTT CAA CTA AAA TAC AGA 8205 Asn Arg Cys Leu Ser Pro Glu Arg Val Leu Leu Gin Leu Lys Tyr Arg 2645 2650 2655

TAT GAT ACG GAA ATT GAT AGA AGC AGA AGA TCG GCT ATA AAA AAG ATA 8253 Tyr Asp Thr Glu He Asp Arg Ser Arg Arg Ser Ala He Lys Lys He 2660 2665 2670 2675 ATG GAA AGG GAT GAC ACA GCT GCA AAA ACA CTT GTT CTC TGT GTT TCT 8301 Met Glu Arg Asp Asp Thr Ala Ala Lys Thr Leu Val Leu Cys Val Ser 2680 2685 2690

GAC ATA ATT TCA TTG AGC GCA AAT ATA TCT GAA ACT TCT AGC AAT AAA 8349 Asp He He Ser Leu Ser Ala Asn He Ser Glu Thr Ser Ser Asn Lys 2695 2700 2705 ACT AGT AGT GCA GAT ACC CAA AAA GTG GCC ATT ATT GAA CTT ACA GAT 8397 Thr Ser Ser Ala Asp Thr Gin Lys Val Ala He He Glu Leu Thr Asp 2710 2715 2720

GGG TGG TAT GCT GTT AAG GCC CAG TTA GAT CCT CCC CTC TTA GCT GTC 8445 Gly Trp Tyr Ala Val Lys Ala Gin Leu Asp Pro Pro Leu Leu Ala Val 2725 2730 2735

TTA AAG AAT GGC AGA CTG ACA GTT GGT CAG AAG ATT ATT CTT CAT GGA 8493 Leu Lys Asn Gly Arg Leu Thr Val Gly Gin Lys He He Leu His Gly 2740 2745 2750 2755

GCA GAA CTG GTG GGC TCT CCT GAT GCC TGT ACA CCT CTT GAA GCC CCA 8541

Ala Glu Leu Val Gly Ser Pro Asp Ala Cys Thr Pro Leu Glu Ala Pro 2760 2765 2770

GAA TCT CTT ATG TTA AAG ATT TCT GCT AAC AGT ACT CGG CCT GCT CGC 8589

Glu Ser Leu Met Leu Lys He Ser Ala Asn Ser Thr Arg Pro Ala Arg 2775 2780 2785 TGG TAT ACC AAA CTT GGA TTC TTT CCT GAC CCT AGA CCT TTT CCT CTG 8637 Trp Tyr Thr Lys Leu Gly Phe Phe Pro Asp Pro Arg Pro Phe Pro Leu 2790 2795 2800

CCC TTA TCA TCG CTT TTC AGT GAT GGA GGA AAT GTT GGT TGT GTT GAT 8685 Pro Leu Ser Ser Leu Phe Ser Asp Gly Gly Asn Val Gly Cys Val Asp 2805 2810 2815

GTA ATT ATT CAA AGA GCA TAC CCT ATA CAG TGG ATG GAG AAG ACA TCA 8733 Val He He Gin Arg Ala Tyr Pro He Gin Trp Met Glu Lys Thr Ser 2820 2825 2830 2835

TCT GGA TTA TAC ATA TTT CGC AAT GAA AGA GAG GAA GAA AAG GAA GCA 8781 Ser Gly Leu Tyr He Phe Arg Asn Glu Arg Glu Glu Glu Lys Glu Ala 2840 2845 2850

GCA AAA TAT GTG GAG GCC CAA CAA AAG AGA CTA GAA GCC TTA TTC ACT 8829 Ala Lys Tyr Val Glu Ala Gin Gin Lys Arg Leu Glu Ala Leu Phe Thr 2855 2860 2865 AAA ATT CAG GAG GAA TTT GAA GAA CAT GAA GAA AAC ACA ACA AAA CCA 8877 Lys He Gin Glu Glu Phe Glu Glu His Glu Glu Asn Thr Thr Lys Pro 2870 2875 2880

TAT TTA CCA TCA CGT GCA CTA ACA AGA CAG CAA GTT CGT GCT TTG CAA 8925 Tyr Leu Pro Ser Arg Ala Leu Thr Arg Gin Gin Val Arg Ala Leu Gin 2885 2890 2895

GAT GGT GCA GAG CTT TAT GAA GCA GTG AAG AAT GCA GCA GAC CCA GCT 8973 Asp Gly Ala Glu Leu Tyr Glu Ala Val Lys Asn Ala Ala Asp Pro Ala 2900 2905 2910 2915

TAC CTT GAG GGT TAT TTC AGT GAA GAG CAG TTA AGA GCC TTG AAT AAT 9021 Tyr Leu Glu Gly Tyr Phe Ser Glu Glu Gin Leu Arg Ala Leu Asn Asn 2920 2925 2930 CAC AGG CAA ATG TTG AAT GAT AAG AAA CAA GCT CAG ATC CAG TTG GAA 9069 His Arg Gin Met Leu Asn Asp Lys Lys Gin Ala Gin He Gin Leu Glu 2935 2940 2945

ATT AGG AAG GCC ATG GAA TCT GCT GAA CAA AAG GAA CAA GGT TTA TCA 9117 He Arg Lys Ala Met Glu Ser Ala Glu Gin Lys Glu Gin Gly Leu Ser 2950 2955 2960

AGG GAT GTC ACA ACC GTG TGG AAG TTG CGT ATT GTA AGC TAT TCA AAA 9165 Arg Asp Val Thr Thr Val Trp Lys Leu Arg He Val Ser Tyr Ser Lys 2965 2970 2975

AAA GAA AAA GAT TCA GTT ATA CTG AGT ATT TGG CGT CCA TCA TCA GAT 9213

Lys Glu Lys Asp Ser Val He Leu Ser He Trp Arg Pro Ser Ser Asp 2980 2985 2990 2995

TTA TAT TCT CTG TTA ACA GAA GGA AAG AGA TAC AGA ATT TAT CAT CTT 9261

Leu Tyr Ser Leu Leu Thr Glu Gly Lys Arg Tyr Arg He Tyr His Leu 3000 3005 3010 GCA ACT TCA AAA TCT AAA AGT AAA TCT GAA AGA GCT AAC ATA CAG TTA 9309 Ala Thr Ser Lys Ser Lys Ser Lys Ser Glu Arg Ala Asn He Gin Leu 3015 3020 3025

GCA GCG ACA AAA AAA ACT CAG TAT CAA CAA CTA CCG GTT TCA GAT GAA 9357 Ala Ala Thr Lys Lys Thr Gin Tyr Gin Gin Leu Pro Val Ser Asp Glu 3030 3035 3040

ATT TTA TTT CAG ATT TAC CAG CCA CGG GAG CCC CTT CAC TTC AGC AAA 9405 He Leu Phe Gin He Tyr Gin Pro Arg Glu Pro Leu His Phe Ser Lys 3045 3050 3055

TTT TTA GAT CCA GAC TTT CAG CCA TCT TGT TCT GAG GTG GAC CTA ATA 9453

Phe Leu Asp Pro Asp Phe Gin Pro Ser Cys Ser Glu Val Asp Leu He 3060 3065 3070 3075

GGA TTT GTC GTT TCT GTT GTG AAA AAA ACA GGA CTT GCC CCT TTC GTC 9501

Gly Phe Val Val Ser Val Val Lys Lys Thr Gly Leu Ala Pro Phe Val 3080 3085 3090 TAT TTG TCA GAC GAA TGT TAC AAT TTA CTG GCA ATA AAG TTT TGG ATA 9549 Tyr Leu Ser Asp Glu Cys Tyr Asn Leu Leu Ala He Lys Phe Trp He 3095 3100 3105

GAC CTT AAT GAG GAC ATT ATT AAG CCT CAT ATG TTA ATT GCT GCA AGC 9597 Asp Leu Asn Glu Asp He He Lys Pro His Met Leu He Ala Ala Ser 3110 3115 3120

AAC CTC CAG TGG CGA CCA GAA TCC AAA TCA GGC CTT CTT ACT TTA TTT 9645 Asn Leu Gin Trp Arg Pro Glu Ser Lys Ser Gly Leu Leu Thr Leu Phe 3125 3130 3135

GCT GGA GAT TTT TCT GTG TTT TCT GCT AGT CCA AAA GAG GGC CAC TTT 9693 Ala Gly Asp Phe Ser Val Phe Ser Ala Ser Pro Lys Glu Gly His Phe 3140 3145 3150 3155

CAA GAG ACA TTC AAC AAA ATG AAA AAT ACT GTT GAG AAT ATT GAC ATA 9741 Gin Glu Thr Phe Asn Lys Met Lys Asn Thr Val Glu Asn He Asp He 3160 3165 3170

CTT TGC AAT GAA GCA GAA AAC AAG CTT ATG CAT ATA CTG CAT GCA AAT 9789 Leu Cys Asn Glu Ala Glu Asn Lys Leu Met His He Leu His Ala Asn 3175 3180 3185

GAT CCC AAG TGG TCC ACC CCA ACT AAA GAC TGT ACT TCA GGG CCG TAC 9837 Asp Pro Lys Trp Ser Thr Pro Thr Lys Asp Cys Thr Ser Gly Pro Tyr 3190 3195 3200

ACT GCT CAA ATC ATT CCT GGT ACA GGA AAC AAG CTT CTG ATG TCT TCT 9885 Thr Ala Gin He He Pro Gly Thr Gly Asn Lys Leu Leu Met Ser Ser 3205 3210 3215

CCT AAT TGT GAG ATA TAT TAT CAA AGT CCT TTA TCA CTT TGT ATG GCC 9933 Pro Asn Cys Glu He Tyr Tyr Gin Ser Pro Leu Ser Leu Cys Met Ala 3220 3225 3230 3235 AAA AGG AAG TCT GTT TCC ACA CCT GTC TCA GCC CAG ATG ACT TCA AAG 9981 Lys Arg Lys Ser Val Ser Thr Pro Val Ser Ala Gin Met Thr Ser Lys 3240 3245 3250

TCT TGT AAA GGG GAG AAA GAG ATT GAT GAC CAA AAG AAC TGC AAA AAG 10029 Ser Cys Lys Gly Glu Lys Glu He Asp Asp Gin Lys Asn Cys Lys Lys 3255 3260 3265

AGA AGA GCC TTG GAT TTC TTG AGT AGA CTG CCT TTA CCT CCA CCT GTT 10077 Arg Arg Ala Leu Asp Phe Leu Ser Arg Leu Pro Leu Pro Pro Pro Val 3270 3275 3280

AGT CCC ATT TGT ACA TTT GTT TCT CCG GCT GCA CAG AAG GCA TTT CAG 10125 Ser Pro He Cys Thr Phe Val Ser Pro Ala Ala Gin Lys Ala Phe Gin 3285 3290 3295

CCA CCA AGG AGT TGT GGC ACC AAA TAC GAA ACA CCC ATA AAG AAA AAA 10173 Pro Pro Arg Ser Cys Gly Thr Lys Tyr Glu Thr Pro He Lys Lys Lys 3300 3305 3310 3315 GAA CTG AAT TCT CCT CAG ATG ACT CCA TTT AAA AAA TTC AAT GAA ATT 10221 Glu Leu Asn Ser Pro Gin Met Thr Pro Phe Lys Lys Phe Asn Glu He 3320 3325 3330

TCT CTT TTG GAA AGT AAT TCA ATA GCT GAC GAA GAA CTT GCA TTG ATA 10 69 Ser Leu Leu Glu Ser Asn Ser He Ala Asp Glu Glu Leu Ala Leu He 3335 3340 3345

AAT ACC CAA GCT CTT TTG TCT GGT TCA ACA GGA GAA AAA CAA TTT ATA 10317 Asn Thr Gin Ala Leu Leu Ser Gly Ser Thr Gly Glu Lys Gin Phe He 3350 3355 3360

TCT GTC AGT GAA TCC ACT AGG ACT GCT CCC ACC AGT TCA GAA GAT TAT 10365 Ser Val Ser Glu Ser Thr Arg Thr Ala Pro Thr Ser Ser Glu Asp Tyr 3365 3370 3375

CTC AGA CTG AAA CGA CGT TGT ACT ACA TCT CTG ATC AAA GAA CAG GAG 10413 Leu Arg Leu Lys Arg Arg Cys Thr Thr Ser Leu He Lys Glu Gin Glu 3380 3385 3390 3395 AGT TCC CAG GCC AGT ACG GAA GAA TGT GAG AAA AAT AAG CAG GAC ACA 10461 Ser Ser Gin Ala Ser Thr Glu Glu Cys Glu Lys Asn Lys Gin Asp Thr 3400 3405 3410 ATT ACA ACT AAA AAA TAT ATC TAA 10485

He Thr Thr Lys Lys Tyr He 3415

(2) INFORMATION FOR SEQ ID NO : 7 : (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 3418 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein (v) FRAGMENT TYPE: internal

(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 7 :

Met Pro He Gly Ser Lys Glu Arg Pro Thr Phe Phe Glu He Phe Lys

1 5 10 15

Thr Arg Cys Asn Lys Ala Asp Leu Gly Pro He Ser Leu Asn Trp Phe 20 25 30 Glu Glu Leu Ser Ser Glu Ala Pro Pro Tyr Asn Ser Glu Pro Ala Glu

35 40 45

Glu Ser Glu His Lys Asn Asn Asn Tyr Glu Pro Asn Leu Phe Lys Thr

50 55 60

Pro Gin Arg Lys Pro Ser Tyr Asn Gin Leu Ala Ser Thr Pro He He 65 70 75 80

Phe Lys Glu Gin Gly Leu Thr Leu Pro Leu Tyr Gin Ser Pro Val Lys

85 90 95

Glu Leu Asp Lys Phe Lys Leu Asp Leu Gly Arg Asn Val Pro Asn Ser 100 105 110 Arg His Lys Ser Leu Arg Thr Val Lys Thr Lys Met Asp Gin Ala Asp

115 120 125

Asp Val Ser Cys Pro Leu Leu Asn Ser Cys Leu Ser Glu Ser Pro Val

130 135 140

Val Leu Gin Cys Thr His Val Thr Pro Gin Arg Asp Lys Ser Val Val 145 150 155 160

Cys Gly Ser Leu Phe His Thr Pro Lys Phe Val Lys Gly Arg Gin Thr

165 170 175

Pro Lys His He Ser Glu Ser Leu Gly Ala Glu Val Asp Pro Asp Met 180 185 190 Ser Trp Ser Ser Ser Leu Ala Thr Pro Pro Thr Leu Ser Ser Thr Val

195 200 205

Leu He Val Arg Asn Glu Glu Ala Ser Glu Thr Val Phe Pro His Asp

210 215 220

Thr Thr Ala Asn Val Lys Ser Tyr Phe Ser Asn His Asp Glu Ser Leu 225 230 235 240

Lys Lys Asn Asp Arg Phe He Ala Ser Val Thr Asp Ser Glu Asn Thr

245 250 255

Asn Gin Arg Glu Ala Ala Ser His Gly Phe Gly Lys Thr Ser Gly Asn 260 265 270 Ser Phe Lys Val Asn Ser Cys Lys Asp His He Gly Lys Ser Met Pro 275 280 285

Asn Val Leu Glu Asp Glu Val Tyr Glu Thr Val Val Asp Thr Ser Glu

290 295 300

Glu Asp Ser Phe Ser Leu Cys Phe Ser Lys Cys Arg Thr Lys Asn Leu 305 310 315 320

Gin Lys Val Arg Thr Ser Lys Thr Arg Lys Lys He Phe His Glu Ala 325 330 335 Asn Ala Asp Glu Cys Glu Lys Ser Lys Asn Gin Val Lys Glu Lys Tyr

340 345 350

Ser Phe Val Ser Glu Val Glu Pro Asn Asp Thr Asp Pro Leu Asp Ser 355 360 365

Asn Val Ala His Gin Lys Pro Phe Glu Ser Gly Ser Asp Lys He Ser

370 375 380

Lys Glu Val Val Pro Ser Leu Ala Cys Glu Trp Ser Gin Leu Thr Leu 385 390 395 400 Ser Gly Leu Asn Gly Ala Gin Met Glu Lys He Pro Leu Leu His He

405 410 415

Ser Ser Cys Asp Gin Asn He Ser Glu Lys Asp Leu Leu Asp Thr Glu

420 425 430

Asn Lys Arg Lys Lys Asp Phe Leu Thr Ser Glu Asn Ser Leu Pro Arg 435 440 445

He Ser Ser Leu Pro Lys Ser Glu Lys Pro Leu Asn Glu Glu Thr Val

450 455 460

Val Asn Lys Arg Asp Glu Glu Gin His Leu Glu Ser His Thr Asp Cys 465 470 475 480 He Leu Ala Val Lys Gin Ala He Ser Gly Thr Ser Pro Val Ala Ser

485 490 495

Ser Phe Gin Gly He Lys Lys Ser He Phe Arg He Arg Glu Ser Pro

500 505 510

Lys Glu Thr Phe Asn Ala Ser Phe Ser Gly His Met Thr Asp Pro Asn 515 520 525

Phe Lys Lys Glu Thr Glu Ala Ser Glu Ser Gly Leu Glu He His Thr

530 535 540

Val Cys Ser Gin Lys Glu Asp Ser Leu Cys Pro Asn Leu He Asp Asn 545 550 555 560 Gly Ser Trp Pro Ala Thr Thr Thr Gin Asn Ser Val Ala Leu Lys Asn

565 570 575

Ala Gly Leu He Ser Thr Leu Lys Lys Lys Thr Asn Lys Phe He Tyr

580 585 590

Ala He His Asp Glu Thr Ser Tyr Lys Gly Lys Lys He Pro Lys Asp 595 600 605

Gin Lys Ser Glu Leu He Asn Cys Ser Ala Gin Phe Glu Ala Asn Ala

610 615 620

Phe Glu Ala Pro Leu Thr Phe Ala Asn Ala Asp Ser Gly Leu Leu His 625 630 635 640 Ser Ser Val Lys Arg Ser Cys Ser Gin Asn Asp Ser Glu Glu Pro Thr

645 650 655

Leu Ser Leu Thr Ser Ser Phe Gly Thr He Leu Arg Lys Cys Ser Arg

660 665 670

Asn Glu Thr Cys Ser Asn Asn Thr Val He Ser Gin Asp Leu Asp Tyr 675 680 685

Lys Glu Ala Lys Cys Asn Lys Glu Lys Leu Gin Leu Phe He Thr Pro

690 695 700

Glu Ala Asp Ser Leu Ser Cys Leu Gin Glu Gly Gin Cys Glu Asn Asp 705 710 715 720 Pro Lys Ser Lys Lys Val Ser Asp He Lys Glu Glu Val Leu Ala Ala

725 730 735

Ala Cys His Pro Val Gin His Ser Lys Val Glu Tyr Ser Asp Thr Asp

740 745 750

Phe Gin Ser Gin Lys Ser Leu Leu Tyr Asp His Glu Asn Ala Ser Thr 755 760 765

Leu He Leu Thr Pro Thr Ser Lys Asp Val Leu Ser Asn Leu Val Met

770 775 780

He Ser Arg Gly Lys Glu Ser Tyr Lys Met Ser Asp Lys Leu Lys Gly 785 790 795 800 Asn Asn Tyr Glu Ser Asp Val Glu Leu Thr Lys Asn He Pro Met Glu

805 810 815

Lys Asn Gin Asp Val Cys Ala Leu Asn Glu Asn Tyr Lys Asn Val Glu 820 825 830

Leu Leu Pro Pro Glu Lys Tyr Met Arg Val Ala Ser Pro Ser Arg Lys 835 840 845 Val Gin Phe Asn Gin Asn Thr Asn Leu Arg Val He Gin Lys Asn Gin 850 855 860

Glu Glu Thr Thr Ser He Ser Lys He Thr Val Asn Pro Asp Ser Glu 865 870 875 880

Glu Leu Phe Ser Asp Asn Glu Asn Asn Phe Val Phe Gin Val Ala Asn 885 890 895

Glu Arg Asn Asn Leu Ala Leu Gly Asn Thr Lys Glu Leu His Glu Thr

900 905 910

Asp Leu Thr Cys Val Asn Glu Pro He Phe Lys Asn Ser Thr Met Val 915 920 925 Leu Tyr Gly Asp Thr Gly Asp Lys Gin Ala Thr Gin Val Ser He Lys 930 935 940

Lys Asp Leu Val Tyr Val Leu Ala Glu Glu Asn Lys Asn Ser Val Lys 945 950 955 960

Gin His He Lys Met Thr Leu Gly Gin Asp Leu Lys Ser Asp He Ser 965 970 975

Leu Asn He Asp Lys He Pro Glu Lys Asn Asn Asp Tyr Met Asn Lys

980 985 990

Trp Ala Gly Leu Leu Gly Pro He Ser Asn His Ser Phe Gly Gly Ser 995 1000 1005 Phe Arg Thr Ala Ser Asn Lys Glu He Lys Leu Ser Glu His Asn He 1010 1015 1020

Lys Lys Ser Lys Met Phe Phe Lys Asp He Glu Glu Gin Tyr Pro Thr 1025 1030 1035 104

Ser Leu Ala Cys Val Glu He Val Asn Thr Leu Ala Leu Asp Asn Gin 1045 1050 1055

Lys Lys Leu Ser Lys Pro Gin Ser He Asn Thr Val Ser Ala His Leu

1060 1065 1070

Gin Ser Ser Val Val Val Ser Asp Cys Lys Asn Ser His He Thr Pro 1075 1080 1085 Gin Met Leu Phe Ser Lys Gin Asp Phe Asn Ser Asn His Asn Leu Thr 1090 1095 1100

Pro Ser Gin Lys Ala Glu He Thr Glu Leu Ser Thr He Leu Glu Glu 1105 1110 1115 112

Ser Gly Ser Gin Phe Glu Phe Thr Gin Phe Arg Xaa Pro Ser Tyr He 1125 1130 1135

Leu Gin Lys Ser Thr Phe Glu Val Pro Glu Asn Gin Met Thr He Leu

1140 1145 1150

Lys Thr Thr Ser Glu Glu Cys Arg Asp Ala Asp Leu His Val He Met 1155 1160 1165 Asn Ala Pro Ser He Gly Gin Val Asp Ser Ser Lys Gin Phe Glu Gly

1170 1175 1180

Thr Val Glu He Lys Arg Lys Phe Ala Gly Leu Leu Lys Asn Asp Cys 1185 1190 1195 120

Asn Lys Ser Ala Ser Gly Tyr Leu Thr Asp Glu Asn Glu Val Gly Phe 1205 1210 1215

Arg Gly Phe Tyr Ser Ala His Gly Thr Lys Leu Asn Val Ser Thr Glu

1220 1225 1230

Ala Leu Gin Lys Ala Val Lys Leu Phe Ser Asp He Glu Asn He Ser 1235 1240 1245 Glu Glu Thr Ser Ala Glu Val His Pro He Ser Leu Ser Ser Ser Lys

1250 1255 1260

Cys His Asp Ser Val Val Ser Met Phe Lys He Glu Asn His Asn Asp

1265 1270 1275 128

Lys Thr Val Ser Glu Lys Asn Asn Lys Cys Gin Leu He Leu Gin Asn 1285 1290 1295

Asn He Glu Met Thr Thr Gly Thr Phe Val Glu Glu He Thr Glu Asn

1300 1305 1310 Tyr Lys Arg Asn Thr Glu Asn Glu Asp Asn Lys Tyr Thr Ala Ala Ser

1315 1320 1325

Arg Asn Ser His Asn Leu Glu Phe Asp Gly Ser Asp Ser Ser Lys Asn 1330 1335 1340

Asp Thr Val Cys He His Lys Asp Glu Thr Asp Leu Leu Phe Thr Asp

1345 1350 1355 136

Gin His Asn He Cys Leu Lys Leu Ser Gly Gin Phe Met Lys Glu Gly

1365 1370 1375 Asn Thr Gin He Lys Glu Asp Leu Ser Asp Leu Thr Phe Leu Glu Val

1380 1385 1390

Ala Lys Ala Gin Glu Ala Cys His Gly Asn Thr Ser Asn Lys Glu Gin

1395 1400 1405

Leu Thr Ala Thr Lys Thr Glu Gin Asn He Lys Asp Phe Glu Thr Ser 1410 1415 1420

Asp Thr Phe Phe Gin Thr Ala Ser Gly Lys Asn He Ser Val Ala Lys 1425 1430 1435 144

Glu Ser Phe Asn Lys He Val Asn Phe Phe Asp Gin Lys Pro Glu Glu 1445 1450 1455 Leu His Asn Phe Ser Leu Asn Ser Glu Leu His Ser Asp He Arg Lys

1460 1465 1470

Asn Lys Met Asp He Leu Ser Tyr Glu Glu Thr Asp He Val Lys His

1475 1480 1485

Lys He Leu Lys Glu Ser Val Pro Val Gly Thr Gly Asn Gin Leu Val 1490 1495 1500

Thr Phe Gin Gly Gin Pro Glu Arg Asp Glu Lys He Lys Glu Pro Thr 1505 1510 1515 152

Leu Leu Gly Phe His Thr Ala Ser Gly Lys Lys Val Lys He Ala Lys 1525 1530 1535 Glu Ser Leu Asp Lys Val Lys Asn Leu Phe Asp Glu Lys Glu Gin Gly

1540 1545 1550

Thr Ser Glu He Thr Ser Phe Ser His Gin Trp Ala Lys Thr Leu Lys

1555 1560 1565

Tyr Arg Glu Ala Cys Lys Asp Leu Glu Leu Ala Cys Glu Thr He Glu 1570 1575 1580

He Thr Ala Ala Pro Lys Cys Lys Glu Met Gin Asn Ser Leu Asn Asn 1585 1590 1595 160

Asp Lys Asn Leu Val Ser He Glu Thr Val Val Pro Pro Lys Leu Leu 1605 1610 1615 Ser Asp Asn Leu Cys Arg Gin Thr Glu Asn Leu Lys Thr Ser Lys Ser

1620 1625 1630

He Phe Leu Lys Val Lys Val His Glu Asn Val Glu Lys Glu Thr Ala

1635 1640 1645

Lys Ser Pro Ala Thr Cys Tyr Thr Asn Gin Ser Pro Tyr Ser Val He 1650 1655 1660

Glu Asn Ser Ala Leu Ala Phe Tyr Thr Ser Cys Ser Arg Lys Thr Ser

1665 1670 1675 168

Val Ser Gin Thr Ser Leu Leu Glu Ala Lys Lys Trp Leu Arg Glu Gly

1685 1690 1695 He Phe Asp Gly Gin Pro Glu Arg He Asn Thr Ala Asp Tyr Val Gly

1700 1705 1710

Asn Tyr Leu Tyr Glu Asn Asn Ser Asn Ser Thr He Ala Glu Asn Asp

1715 1720 1725

Lys Asn His Leu Ser Glu Lys Gin Asp Thr Tyr Leu Ser Asn Ser Ser 1730 1735 1740

Met Ser Asn Ser Tyr Ser Tyr His Ser Asp Glu Val Tyr Asn Asp Ser

1745 1750 1755 176

Gly Tyr Leu Ser Lys Asn Lys Leu Asp Ser Gly He Glu Pro Val Leu

1765 1770 1775 Lys Asn Val Glu Asp Gin Lys Asn Thr Ser Phe Ser Lys Val He Ser

1780 1785 1790

Asn Val Lys Asp Ala Asn Ala Tyr Pro Gin Thr Val Asn Glu Asp He 1795 1800 1805

Cys Val Glu Glu Leu Val Thr Ser Ser Ser Pro Cys Lys Asn Lys Asn

1810 1815 1820 Ala Ala He Lys Leu Ser He Ser Asn Ser Asn Asn Phe Glu Val Gly

1825 1830 1835 184

Pro Pro Ala Phe Arg He Ala Ser Gly Lys He Val Cys Val Ser His

1845 1850 1855

Glu Thr He Lys Lys Val Lys Asp He Phe Thr Asp Ser Phe Ser Lys 1860 1865 1870

Val He Lys Glu Asn Asn Glu Asn Lys Ser Lys He Cys Gin Thr Lys

1875 1880 1885

He Met Ala Gly Cys Tyr Glu Ala Leu Asp Asp Ser Glu Asp He Leu

1890 1895 1900 His Asn Ser Leu Asp Asn Asp Glu Cys Ser Thr His Ser His Lys Val

1905 1910 1915 192

Phe Ala Asp He Gin Ser Glu Glu He Leu Gin His Asn Gin Asn Met

1925 1930 1935

Ser Gly Leu Glu Lys Val Ser Lys He Ser Pro Cys Asp Val Ser Leu 1940 1945 1950

Glu Thr Ser Asp He Cys Lys Cys Ser He Gly Lys Leu His Lys Ser

1955 1960 1965

Val Ser Ser Ala Asn Thr Cys Gly He Phe Ser Thr Ala Ser Gly Lys

1970 1975 1980 Ser Val Gin Val Ser Asp Ala Ser Leu Gin Asn Ala Arg Gin Val Phe

1985 1990 1995 200

Ser Glu He Glu Asp Ser Thr Lys Gin Val Phe Ser Lys Val Leu Phe

2005 2010 2015

Lys Ser Asn Glu His Ser Asp Gin Leu Thr Arg Glu Glu Asn Thr Ala 2020 2025 2030

He Arg Thr Pro Glu His Leu He Ser Gin Lys Gly Phe Ser Tyr Asn

2035 2040 2045

Val Val Asn Ser Ser Ala Phe Ser Gly Phe Ser Thr Ala Ser Gly Lys

2050 2055 2060 Gin Val Ser He Leu Glu Ser Ser Leu His Lys Val Lys Gly Val Leu

2065 2070 2075 208

Glu Glu Phe Asp Leu He Arg Thr Glu His Ser Leu His Tyr Ser Pro

2085 2090 2095

Thr Ser Arg Gin Asn Val Ser Lys He Leu Pro Arg Val Asp Lys Arg 2100 2105 2110

Asn Pro Glu His Cys Val Asn Ser Glu Met Glu Lys Thr Cys Ser Lys

2115 2120 2125

Glu Phe Lys Leu Ser Asn Asn Leu Asn Val Glu Gly Gly Ser Ser Glu

2130 2135 2140 Asn Asn His Ser He Lys Val Ser Pro Tyr Leu Ser Gin Phe Gin Gin

2145 2150 2155 216

Asp Lys Gin Gin Leu Val Leu Gly Thr Lys Val Ser Leu Val Glu Asn

2165 2170 2175

He His Val Leu Gly Lys Glu Gin Ala Ser Pro Lys Asn Val Lys Met 2180 2185 2190

Glu He Gly Lys Thr Glu Thr Phe Ser Asp Val Pro Val Lys Thr Asn

2195 2200 2205

He Glu Val Cys Ser Thr Tyr Ser Lys Asp Ser Glu Asn Tyr Phe Glu

2210 2215 2220 Thr Glu Ala Val Glu He Ala Lys Ala Phe Met Glu Asp Asp Glu Leu

2225 2230 2235 224

Thr Asp Ser Lys Leu Pro Ser His Ala Thr His Ser Leu Phe Thr Cys

2245 2250 2255

Pro Glu Asn Glu Glu Met Val Leu Ser Asn Ser Arg He Gly Lys Arg 2260 2265 2270

Arg Gly Glu Pro Leu He Leu Val Gly Glu Pro Ser He Lys Arg Asn 2275 2280 2285 Leu Leu Asn Glu Phe Asp Arg He He Glu Asn Gin Glu Lys Ser Leu

2290 2295 2300

Lys Ala Ser Lys Ser Thr Pro Asp Gly Thr He Lys Asp Arg Arg Leu 2305 2310 2315 232

Phe Met His His Val Ser Leu Glu Pro He Thr Cys Val Pro Phe Arg

2325 2330 2335

Thr Thr Lys Glu Arg Gin Glu He Gin Asn Pro Asn Phe Thr Ala Pro 2340 2345 2350 Gly Gin Glu Phe Leu Ser Lys Ser His Leu Tyr Glu His Leu Thr Leu 2355 2360 2365

Glu Lys Ser Ser Ser Asn Leu Ala Val Ser Gly His Pro Phe Tyr Gin

2370 2375 2380

Val Ser Ala Thr Arg Asn Glu Lys Met Arg His Leu He Thr Thr Gly 2385 2390 2395 240

Arg Pro Thr Lys Val Phe Val Pro Pro Phe Lys Thr Lys Ser His Phe

2405 2410 2415

His Arg Val Glu Gin Cys Val Arg Asn He Asn Leu Glu Glu Asn Arg 2420 2425 2430 Gin Lys Gin Asn He Asp Gly His Gly Ser Asp Asp Ser Lys Asn Lys

2435 2440 2445

He Asn Asp Asn Glu He His Gin Phe Asn Lys Asn Asn Ser Asn Gin

2450 2455 2460

Ala Ala Ala Val Thr Phe Thr Lys Cys Glu Glu Glu Pro Leu Asp Leu 2465 2470 2475 248

He Thr Ser Leu Gin Asn Ala Arg Asp He Gin Asp Met Arg He Lys

2485 2490 2495

Lys Lys Gin Arg Gin Arg Val Phe Pro Gin Pro Gly Ser Leu Tyr Leu 2500 2505 2510 Ala Lys Thr Ser Thr Leu Pro Arg He Ser Leu Lys Ala Ala Val Gly

2515 2520 2525

Gly Gin Val Pro Ser Ala Cys Ser His Lys Gin Leu Tyr Thr Tyr Gly

2530 2535 2540

Val Ser Lys His Cys He Lys He Asn Ser Lys Asn Ala Glu Ser Phe 2545 2550 2555 256

Gin Phe His Thr Glu Asp Tyr Phe Gly Lys Glu Ser Leu Trp Thr Gly

2565 2570 2575

Lys Gly He Gin Leu Ala Asp Gly Gly Trp Leu He Pro Ser Asn Asp 2580 2585 2590 Gly Lys Ala Gly Lys Glu Glu Phe Tyr Arg Ala Leu Cys Asp Thr Pro

2595 2600 2605

Gly Val Asp Pro Lys Leu He Ser Arg He Trp Val Tyr Asn His Tyr

2610 2615 2620

Arg Trp He He Trp Lys Leu Ala Ala Met Glu Cys Ala Phe Pro Lys 2625 2630 2635 264

Glu Phe Ala Asn Arg Cys Leu Ser Pro Glu Arg Val Leu Leu Gin Leu

2645 2650 2655

Lys Tyr Arg Tyr Asp Thr Glu He Asp Arg Ser Arg Arg Ser Ala He 2660 2665 2670 Lys Lys He Met Glu Arg Asp Asp Thr Ala Ala Lys Thr Leu Val Leu 2675 2680 2685

Cys Val Ser Asp He He Ser Leu Ser Ala Asn He Ser Glu Thr Ser

2690 2695 2700

Ser Asn Lys Thr Ser Ser Ala Asp Thr Gin Lys Val Ala He He Glu 2705 2710 2715 272

Leu Thr Asp Gly Trp Tyr Ala Val Lys Ala Gin Leu Asp Pro Pro Leu

2725 2730 2735

Leu Ala Val Leu Lys Asn Gly Arg Leu Thr Val Gly Gin Lys He He 2740 2745 2750 Leu His Gly Ala Glu Leu Val Gly Ser Pro Asp Ala Cys Thr Pro Leu 2755 2760 2765

Glu Ala Pro Glu Ser Leu Met Leu Lys He Ser Ala Asn Ser Thr Arg 2770 2775 2780

Pro Ala Arg Trp Tyr Thr Lys Leu Gly Phe Phe Pro Asp Pro Arg Pro 2785 2790 2795 280 Phe Pro Leu Pro Leu Ser Ser Leu Phe Ser Asp Gly Gly Asn Val Gly

2805 2810 2815

Cys Val Asp Val He He Gin Arg Ala Tyr Pro He Gin Trp Met Glu

2820 2825 2830

Lys Thr Ser Ser Gly Leu Tyr He Phe Arg Asn Glu Arg Glu Glu Glu 2835 2840 2845

Lys Glu Ala Ala Lys Tyr Val Glu Ala Gin Gin Lys Arg Leu Glu Ala

2850 2855 2860

Leu Phe Thr Lys He Gin Glu Glu Phe Glu Glu His Glu Glu Asn Thr 2865 2870 2875 288 Thr Lys Pro Tyr Leu Pro Ser Arg Ala Leu Thr Arg Gin Gin Val Arg

2885 2890 2895

Ala Leu Gin Asp Gly Ala Glu Leu Tyr Glu Ala Val Lys Asn Ala Ala

2900 2905 2910

Asp Pro Ala Tyr Leu Glu Gly Tyr Phe Ser Glu Glu Gin Leu Arg Ala 2915 2920 2925

Leu Asn Asn His Arg Gin Met Leu Asn Asp Lys Lys Gin Ala Gin He

2930 2935 2940

Gin Leu Glu He Arg Lys Ala Met Glu Ser Ala Glu Gin Lys Glu Gin 2945 2950 2955 296 Gly Leu Ser Arg Asp Val Thr Thr Val Trp Lys Leu Arg He Val Ser

2965 2970 2975

Tyr Ser Lys Lys Glu Lys Asp Ser Val He Leu Ser He Trp Arg Pro

2980 2985 2990

Ser Ser Asp Leu Tyr Ser Leu Leu Thr Glu Gly Lys Arg Tyr Arg He 2995 3000 3005

Tyr His Leu Ala Thr Ser Lys Ser Lys Ser Lys Ser Glu Arg Ala Asn

3010 3015 3020

He Gin Leu Ala Ala Thr Lys Lys Thr Gin Tyr Gin Gin Leu Pro Val 3025 3030 3035 304 Ser Asp Glu He Leu Phe Gin He Tyr Gin Pro Arg Glu Pro Leu His

3045 3050 3055

Phe Ser Lys Phe Leu Asp Pro Asp Phe Gin Pro Ser Cys Ser Glu Val

3060 3065 3070

Asp Leu He Gly Phe Val Val Ser Val Val Lys Lys Thr Gly Leu Ala 3075 3080 3085

Pro Phe Val Tyr Leu Ser Asp Glu Cys Tyr Asn Leu Leu Ala He Lys

3090 3095 3100

Phe Trp He Asp Leu Asn Glu Asp He He Lys Pro His Met Leu He 3105 3110 3115 312 Ala Ala Ser Asn Leu Gin Trp Arg Pro Glu Ser Lys Ser Gly Leu Leu

3125 3130 3135

Thr Leu Phe Ala Gly Asp Phe Ser Val Phe Ser Ala Ser Pro Lys Glu

3140 3145 3150

Gly His Phe Gin Glu Thr Phe Asn Lys Met Lys Asn Thr Val Glu Asn 3155 3160 3165

He Asp He Leu Cys Asn Glu Ala Glu Asn Lys Leu Met His He Leu

3170 3175 3180

His Ala Asn Asp Pro Lys Trp Ser Thr Pro Thr Lys Asp Cys Thr Ser 3185 3190 3195 320 Gly Pro Tyr Thr Ala Gin He He Pro Gly Thr Gly Asn Lys Leu Leu

3205 3210 3215

Met Ser Ser Pro Asn Cys Glu He Tyr Tyr Gin Ser Pro Leu Ser Leu

3220 3225 3230

Cys Met Ala Lys Arg Lys Ser Val Ser Thr Pro Val Ser Ala Gin Met 3235 3240 3245

Thr Ser Lys Ser Cys Lys Gly Glu Lys Glu He Asp Asp Gin Lys Asn

3250 3255 3260 Cys Lys Lys Arg Arg Ala Leu Asp Phe Leu Ser Arg Leu Pro Leu Pro 3265 3270 3275 328

Pro Pro Val Ser Pro He Cys Thr Phe Val Ser Pro Ala Ala Gin Lys 3285 3290 3295

Ala Phe Gin Pro Pro Arg Ser Cys Gly Thr Lys Tyr Glu Thr Pro He

3300 3305 3310

Lys Lys Lys Glu Leu Asn Ser Pro Gin Met Thr Pro Phe Lys Lys Phe 3315 3320 3325 Asn Glu He Ser Leu Leu Glu Ser Asn Ser He Ala Asp Glu Glu Leu 3330 3335 3340

Ala Leu He Asn Thr Gin Ala Leu Leu Ser Gly Ser Thr Gly Glu Lys 3345 3350 3355 336

Gin Phe He Ser Val Ser Glu Ser Thr Arg Thr Ala Pro Thr Ser Ser 3365 3370 3375

Glu Asp Tyr Leu Arg Leu Lys Arg Arg Cys Thr Thr Ser Leu He Lys

3380 3385 3390

Glu Gin Glu Ser Ser Gin Ala Ser Thr Glu Glu Cys Glu Lys Asn Lys 3395 3400 3405 Gin Asp Thr He Thr Thr Lys Lys Tyr He 3410 3415

(2) INFORMATION FOR SEQ ID NO : 8 : (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 10485 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA (ix) FEATURE:

(A) NAME/KEY: Coding Sequence (B) LOCATION: 229...10482

(D) OTHER INFORMATION: BRCA2 (OMI3)

(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 8 : GGTGGCGCGA GCTTCTGAAA CTAGGCGGCA GAGGCGGAGC CGCTGTGGCA CTGCTGCGCC 60

TCTGCTGCGC CTCGGGTGTC TTTTGCGGCG GTGGGTCGCC GCCGGGAGAA GCGTGAGGGG 120

ACAGATTTGT GACCGGCGCG GTTTTTGTCA GCTTACTCCG GCCAAAAAAG AACTGCACCT 180

CTGGAGCGGA CTTATTTACC AAGCATTGGA GGAATATCGT AGGTAAAA ATG CCT ATT 237

Met Pro He 1

GGA TCC AAA GAG AGG CCA ACA TTT TTT GAA ATT TTT AAG ACA CGC TGC 285

Gly Ser Lys Glu Arg Pro Thr Phe Phe Glu He Phe Lys Thr Arg Cys 5 10 15

AAC AAA GCA GAT TTA GGA CCA ATA AGT CTT AAT TGG TTT GAA GAA CTT 333

Asn Lys Ala Asp Leu Gly Pro He Ser Leu Asn Trp Phe Glu Glu Leu

20 25 30 35 TCT TCA GAA GCT CCA CCC TAT AAT TCT GAA CCT GCA GAA GAA TCT GAA 381 Ser Ser Glu Ala Pro Pro Tyr Asn Ser Glu Pro Ala Glu Glu Ser Glu 40 45 50

CAT AAA AAC AAC AAT TAC GAA CCA AAC CTA TTT AAA ACT CCA CAA AGG 429 His Lys Asn Asn Asn Tyr Glu Pro Asn Leu Phe Lys Thr Pro Gin Arg

55 60 65 AAA CCA TCT TAT AAT CAG CTG GCT TCA ACT CCA ATA ATA TTC AAA GAG 477

Lys Pro Ser Tyr Asn Gin Leu Ala Ser Thr Pro He He Phe Lys Glu 70 75 ■ 80

CAA GGG CTG ACT CTG CCG CTG TAC CAA TCT CCT GTA AAA GAA TTA GAT 525

Gin Gly Leu Thr Leu Pro Leu Tyr Gin Ser Pro Val Lys Glu Leu Asp 85 90 95 AAA TTC AAA TTA GAC TTA GGA AGG AAT GTT CCC AAT AGT AGA CAT AAA 573 Lys Phe Lys Leu Asp Leu Gly Arg Asn Val Pro Asn Ser Arg His Lys 100 105 110 115

AGT CTT CGC ACA GTG AAA ACT AAA ATG GAT CAA GCA GAT GAT GTT TCC 621 Ser Leu Arg Thr Val Lys Thr Lys Met Asp Gin Ala Asp Asp Val Ser

120 125 130

TGT CCA CTT CTA AAT TCT TGT CTT AGT GAA AGT CCT GTT GTT CTA CAA 669 Cys Pro Leu Leu Asn Ser Cys Leu Ser Glu Ser Pro Val Val Leu Gin 135 140 145

TGT ACA CAT GTA ACA CCA CAA AGA GAT AAG TCA GTG GTA TGT GGG AGT 717 Cys Thr His Val Thr Pro Gin Arg Asp Lys Ser Val Val Cys Gly Ser 150 155 160

TTG TTT CAT ACA CCA AAG TTT GTG AAG GGT CGT CAG ACA CCA AAA CAT 765 Leu Phe His Thr Pro Lys Phe Val Lys Gly Arg Gin Thr Pro Lys His 165 170 175 ATT TCT GAA AGT CTA GGA GCT GAG GTG GAT CCT GAT ATG TCT TGG TCA 813 He Ser Glu Ser Leu Gly Ala Glu Val Asp Pro Asp Met Ser Trp Ser 180 185 190 195

AGT TCT TTA GCT ACA CCA CCC ACC CTT AGT TCT ACT GTG CTC ATA GTC 861 Ser Ser Leu Ala Thr Pro Pro Thr Leu Ser Ser Thr Val Leu He Val

200 205 210

AGA AAT GAA GAA GCA TCT GAA ACT GTA TTT CCT CAT GAT ACT ACT GCT 909 Arg Asn Glu Glu Ala Ser Glu Thr Val Phe Pro His Asp Thr Thr Ala 215 220 225

AAT GTG AAA AGC TAT TTT TCC AAT CAT GAT GAA AGT CTG AAG AAA AAT 957 Asn Val Lys Ser Tyr Phe Ser Asn His Asp Glu Ser Leu Lys Lys Asn 230 235 240

GAT AGA TTT ATC GCT TCT GTG ACA GAC AGT GAA AAC ACA AAT CAA AGA 1005 Asp Arg Phe He Ala Ser Val Thr Asp Ser Glu Asn Thr Asn Gin Arg 245 250 255 GAA GCT GCA AGT CAT GGA TTT GGA AAA ACA TCA GGG AAT TCA TTT AAA 1053 Glu Ala Ala Ser His Gly Phe Gly Lys Thr Ser Gly Asn Ser Phe Lys 260 265 270 275

GTA AAT AGC TGC AAA GAC CAC ATT GGA AAG TCA ATG CCA CAT GTC CTA 1101 Val Asn Ser Cys Lys Asp His He Gly Lys Ser Met Pro His Val Leu

280 285 290

GAA GAT GAA GTA TAT GAA ACA GTT GTA GAT ACC TCT GAA GAA GAT AGT 1149 Glu Asp Glu Val Tyr Glu Thr Val Val Asp Thr Ser Glu Glu Asp Ser 295 300 305

TTT TCA TTA TGT TTT TCT AAA TGT AGA ACA AAA AAT CTA CAA AAA GTA 1197 Phe Ser Leu Cys Phe Ser Lys Cys Arg Thr Lys Asn Leu Gin Lys Val 310 315 320 AGA ACT AGC AAG ACT AGG AAA AAA ATT TTC CAT GAA GCA AAC GCT GAT 1245 Arg Thr Ser Lys Thr Arg Lys Lys He Phe His Glu Ala Asn Ala Asp 325 330 335

GAA TGT GAA AAA TCT AAA AAC CAA GTG AAA GAA AAA TAC TCA TTT GTA 1293 Glu Cys Glu Lys Ser Lys Asn Gin Val Lys Glu Lys Tyr Ser Phe Val 340 345 350 355

TCT GAA GTG GAA CCA AAT GAT ACT GAT CCA TTA GAT TCA AAT GTA GCA 1341 Ser Glu Val Glu Pro Asn Asp Thr Asp Pro Leu Asp Ser Asn Val Ala 360 365 370

AAT CAG AAG CCC TTT GAG AGT GGA AGT GAC AAA ATC TCC AAG GAA GTT 1389 Asn Gin Lys Pro Phe Glu Ser Gly Ser Asp Lys He Ser Lys Glu Val 375 380 385

GTA CCG TCT TTG GCC TGT GAA TGG TCT CAA CTA ACC CTT TCA GGT CTA 1437 Val Pro Ser Leu Ala Cys Glu Trp Ser Gin Leu Thr Leu Ser Gly Leu 390 395 400 AAT GGA GCC CAG ATG GAG AAA ATA CCC CTA TTG CAT ATT TCT TCA TGT 1485 Asn Gly Ala Gin Met Glu Lys He Pro Leu Leu His He Ser Ser Cys 405 410 415

GAC CAA AAT ATT TCA GAA AAA GAC CTA TTA GAC ACA GAG AAC AAA AGA 1533 Asp Gin Asn He Ser Glu Lys Asp Leu Leu Asp Thr Glu Asn Lys Arg

420 425 430 435

AAG AAA GAT TTT CTT ACT TCA GAG AAT TCT TTG CCA CGT ATT TCT AGC 1581 Lys Lys Asp Phe Leu Thr Ser Glu Asn Ser Leu Pro Arg He Ser Ser 440 445 450

CTA CCA AAA TCA GAG AAG CCA TTA AAT GAG GAA ACA GTG GTA AAT AAG 1629 Leu Pro Lys Ser Glu Lys Pro Leu Asn Glu Glu Thr Val Val Asn Lys 455 460 465

AGA GAT GAA GAG CAG CAT CTT GAA TCT CAT ACA GAC TGC ATT CTT GCA 1677 Arg Asp Glu Glu Gin His Leu Glu Ser His Thr Asp Cys He Leu Ala 470 475 480 GTA AAG CAG GCA ATA TCT GGA ACT TCT CCA GTG GCT TCT TCA TTT CAG 1725

Val Lys Gin Ala He Ser Gly Thr Ser Pro Val Ala Ser Ser Phe Gin 485 490 495

GGT ATC AAA AAG TCT ATA TTC AGA ATA AGA GAA TCA CCT AAA GAG ACT 1773 Gly He Lys Lys Ser He Phe Arg He Arg Glu Ser Pro Lys Glu Thr

500 505 510 515

TTC AAT GCA AGT TTT TCA GGT CAT ATG ACT GAT CCA AAC TTT AAA AAA 1821 Phe Asn Ala Ser Phe Ser Gly His Met Thr Asp Pro Asn Phe Lys Lys 520 525 530

GAA ACT GAA GCC TCT GAA AGT GGA CTG GAA ATA CAT ACT GTT TGC TCA 1869 Glu Thr Glu Ala Ser Glu Ser Gly Leu Glu He His Thr Val Cys Ser 535 540 545

CAG AAG GAG GAC TCC TTA TGT CCA AAT TTA ATT GAT AAT GGA AGC TGG 1917 Gin Lys Glu Asp Ser Leu Cys Pro Asn Leu He Asp Asn Gly Ser Trp 550 555 560

CCA GCC ACC ACC ACA CAG AAT TCT GTA GCT TTG AAG AAT GCA GGT TTA 1965 Pro Ala Thr Thr Thr Gin Asn Ser Val Ala Leu Lys Asn Ala Gly Leu 565 570 575

ATA TCC ACT TTG AAA AAG AAA ACA AAT AAG TTT ATT TAT GCT ATA CAT 2013 He Ser Thr Leu Lys Lys Lys Thr Asn Lys Phe He Tyr Ala He His 580 585 590 595

GAT GAA ACA TCT TAT AAA GGA AAA AAA ATA CCG AAA GAC CAA AAA TCA 2061 Asp Glu Thr Ser Tyr Lys Gly Lys Lys He Pro Lys Asp Gin Lys Ser 600 605 610

GAA CTA ATT AAC TGT TCA GCC CAG TTT GAA GCA AAT GCT TTT GAA GCA 2109 Glu Leu He Asn Cys Ser Ala Gin Phe Glu Ala Asn Ala Phe Glu Ala 615 620 625 CCA CTT ACA TTT GCA AAT GCT GAT TCA GGT TTA TTG CAT TCT TCT GTG 2157 Pro Leu Thr Phe Ala Asn Ala Asp Ser Gly Leu Leu His Ser Ser Val 630 635 640

AAA AGA AGC TGT TCA CAG AAT GAT TCT GAA GAA CCA ACT TTG TCC TTA 2205 Lys Arg Ser Cys Ser Gin Asn Asp Ser Glu Glu Pro Thr Leu Ser Leu 645 650 655

ACT AGC TCT TTT GGG ACA ATT CTG AGG AAA TGT TCT AGA AAT GAA ACA 2253 Thr Ser Ser Phe Gly Thr He Leu Arg Lys Cys Ser Arg Asn Glu Thr 660 665 670 675

TGT TCT AAT AAT ACA GTA ATC TCT CAG GAT CTT GAT TAT AAA GAA GCA 2301 Cys Ser Asn Asn Thr Val He Ser Gin Asp Leu Asp Tyr Lys Glu Ala 680 685 690

AAA TGT AAT AAG GAA AAA CTA CAG TTA TTT ATT ACC CCA GAA GCT GAT 2349 Lys Cys Asn Lys Glu Lys Leu Gin Leu Phe He Thr Pro Glu Ala Asp 695 700 705 TCT CTG TCA TGC CTG CAG GAA GGA CAG TGT GAA AAT GAT CCA AAA AGC 2397 Ser Leu Ser Cys Leu Gin Glu Gly Gin Cys Glu Asn Asp Pro Lys Ser 710 715 720

AAA AAA GTT TCA GAT ATA AAA GAA GAG GTC TTG GCT GCA GCA TGT CAC 2445 Lys Lys Val Ser Asp He Lys Glu Glu Val Leu Ala Ala Ala Cys His 725 730 735

CCA GTA CAA CAC TCA AAA GTG GAA TAC AGT GAT ACT GAC TTT CAA TCC 2493 Pro Val Gin His Ser Lys Val Glu Tyr Ser Asp Thr Asp Phe Gin Ser 740 745 750 755

CAG AAA AGT CTT TTA TAT GAT CAT GAA AAT GCC AGC ACT CTT ATT TTA 2541 Gin Lys Ser Leu Leu Tyr Asp His Glu Asn Ala Ser Thr Leu He Leu 760 765 770

ACT CCT ACT TCC AAG GAT GTT CTG TCA AAC CTA GTC ATG ATT TCT AGA 2589 Thr Pro Thr Ser Lys Asp Val Leu Ser Asn Leu Val Met He Ser Arg 775 780 785 GGC AAA GAA TCA TAC AAA ATG TCA GAC AAG CTC AAA GGT AAC AAT TAT 2637 Gly Lys Glu Ser Tyr Lys Met Ser Asp Lys Leu Lys Gly Asn Asn Tyr 790 795 800 GAA TCT GAT GTT GAA TTA ACC AAA AAT ATT CCC ATG GAA AAG AAT CAA 2685 Glu Ser Asp Val Glu Leu Thr Lys Asn He Pro Met Glu Lys Asn Gin 805 810 815

GAT GTA TGT GCT TTA AAT GAA AAT TAT AAA AAC GTT GAG CTG TTG CCA 2733 Asp Val Cys Ala Leu Asn Glu Asn Tyr Lys Asn Val Glu Leu Leu Pro 820 825 830 835

CCT GAA AAA TAC ATG AGA GTA GCA TCA CCT TCA AGA AAG GTA CAA TTC 2781 Pro Glu Lys Tyr Met Arg Val Ala Ser Pro Ser Arg Lys Val Gin Phe 840 845 850 AAC CAA AAC ACA AAT CTA AGA GTA ATC CAA AAA AAT CAA GAA GAA ACT 2829 Asn Gin Asn Thr Asn Leu Arg Val He Gin Lys Asn Gin Glu Glu Thr 855 860 865

ACT TCA ATT TCA AAA ATA ACT GTC AAT CCA GAC TCT GAA GAA CTT TTC 2877 Thr Ser He Ser Lys He Thr Val Asn Pro Asp Ser Glu Glu Leu Phe

870 875 880

TCA GAC AAT GAG AAT AAT TTT GTC TTC CAA GTA GCT AAT GAA AGG AAT 2925 Ser Asp Asn Glu Asn Asn Phe Val Phe Gin Val Ala Asn Glu Arg Asn 885 890 895

AAT CTT GCT TTA GGA AAT ACT AAG GAA CTT CAT GAA ACA GAC TTG ACT 2973

Asn Leu Ala Leu Gly Asn Thr Lys Glu Leu His Glu Thr Asp Leu Thr 900 905 910 915

TGT GTA AAC GAA CCC ATT TTC AAG AAC TCT ACC ATG GTT TTA TAT GGA 3021

Cys Val Asn Glu Pro He Phe Lys Asn Ser Thr Met Val Leu Tyr Gly 920 925 930 GAC ACA GGT GAT AAA CAA GCA ACC CAA GTG TCA ATT AAA AAA GAT TTG 3069

Asp Thr Gly Asp Lys Gin Ala Thr Gin Val Ser He Lys Lys Asp Leu 935 940 945

GTT TAT GTT CTT GCA GAG GAG AAC AAA AAT AGT GTA AAG CAG CAT ATA 3117 Val Tyr Val Leu Ala Glu Glu Asn Lys Asn Ser Val Lys Gin His He

950 955 960

AAA ATG ACT CTA GGT CAA GAT TTA AAA TCG GAC ATC TCC TTG AAT ATA 3165 Lys Met Thr Leu Gly Gin Asp Leu Lys Ser Asp He Ser Leu Asn He 965 970 975

GAT AAA ATA CCA GAA AAA AAT AAT GAT TAC ATG GAC AAA TGG GCA GGA 3213 Asp Lys He Pro Glu Lys Asn Asn Asp Tyr Met Asp Lys Trp Ala Gly 980 985 990 995

CTC TTA GGT CCA ATT TCA AAT CAC AGT TTT GGA GGT AGC TTC AGA ACA 3261 Leu Leu Gly Pro He Ser Asn His Ser Phe Gly Gly Ser Phe Arg Thr 1000 1005 1010 GCT TCA AAT AAG GAA ATC AAG CTC TCT GAA CAT AAC ATT AAG AAG AGC 3309 Ala Ser Asn Lys Glu He Lys Leu Ser Glu His Asn He Lys Lys Ser 1015 1020 1025

AAA ATG TTC TTC AAA GAT ATT GAA GAA CAA TAT CCT ACT AGT TTA GCT 3357 Lys Met Phe Phe Lys Asp He Glu Glu Gin Tyr Pro Thr Ser Leu Ala 1030 1035 1040 TGT GTT GAA ATT GTA AAT ACC TTG GCA TTA GAT AAT CAA AAG AAA CTG 3405 Cys Val Glu He Val Asn Thr Leu Ala Leu Asp Asn Gin Lys Lys Leu 1045 1050 1055

AGC AAG CCT CAG TCA ATT AAT ACT GTA TCT GCA CAT TTA CAG AGT AGT 3453 Ser Lys Pro Gin Ser He Asn Thr Val Ser Ala His Leu Gin Ser Ser 1060 1065 1070 1075 GTA GTT GTT TCT GAT TGT AAA AAT AGT CAT ATA ACC CCT CAG ATG TTA 3501 Val Val Val Ser Asp Cys Lys Asn Ser His He Thr Pro Gin Met Leu 1080 1085 1090

TTT TCC AAG CAG GAT TTT AAT TCA AAC CAT AAT TTA ACA CCT AGC CAA 3549 Phe Ser Lys Gin Asp Phe Asn Ser Asn His Asn Leu Thr Pro Ser Gin 1095 1100 1105

AAG GCA GAA ATT ACA GAA CTT TCT ACT ATA TTA GAA GAA TCA GGA AGT 3597 Lys Ala Glu He Thr Glu Leu Ser Thr He Leu Glu Glu Ser Gly Ser 1110 1115 1120

CAG TTT GAA TTT ACT CAG TTT AGA AAG CCA AGC TAC ATA TTG CAG AAG 3645 Gin Phe Glu Phe Thr Gin Phe Arg Lys Pro Ser Tyr He Leu Gin Lys 1125 1130 1135

AGT ACA TTT GAA GTG CCT GAA AAC CAG ATG ACT ATC TTA AAG ACC ACT 3693 Ser Thr Phe Glu Val Pro Glu Asn Gin Met Thr He Leu Lys Thr Thr 1140 1145 1150 1155 TCT GAG GAA TGC AGA GAT GCT GAT CTT CAT GTC ATA ATG AAT GCC CCA 3741 Ser Glu Glu Cys Arg Asp Ala Asp Leu His Val He Met Asn Ala Pro 1160 1165 1170

TCG ATT GGT CAG GTA GAC AGC AGC AAG CAA TTT GAA GGT ACA GTT GAA 3789 Ser He Gly Gin Val Asp Ser Ser Lys Gin Phe Glu Gly Thr Val Glu 1175 1180 1185

ATT AAA CGG AAG TTT GCT GGC CTG TTG AAA AAT GAC TGT AAC AAA AGT 3837 He Lys Arg Lys Phe Ala Gly Leu Leu Lys Asn Asp Cys Asn Lys Ser 1190 1195 1200

GCT TCT GGT TAT TTA ACA GAT GAA AAT GAA GTG GGG TTT AGG GGC TTT 3885

Ala Ser Gly Tyr Leu Thr Asp Glu Asn Glu Val Gly Phe Arg Gly Phe 1205 1210 1215

TAT TCT GCT CAT GGC ACA AAA CTG AAT GTT TCT ACT GAA GCT CTG CAA 3933

Tyr Ser Ala His Gly Thr Lys Leu Asn Val Ser Thr Glu Ala Leu Gin 1220 1225 1230 1235 AAA GCT GTG AAA CTG TTT AGT GAT ATT GAG AAT ATT AGT GAG GAA ACT 3981 Lys Ala Val Lys Leu Phe Ser Asp He Glu Asn He Ser Glu Glu Thr 1240 1245 1250

TCT GCA GAG GTA CAT CCA ATA AGT TTA TCT TCA AGT AAA TGT CAT GAT 4029 Ser Ala Glu Val His Pro He Ser Leu Ser Ser Ser Lys Cys His Asp 1255 1260 1265

TCT GTT GTT TCA ATG TTT AAG ATA GAA AAT CAT AAT GAT AAA ACT GTA 4077 Ser Val Val Ser Met Phe Lys He Glu Asn His Asn Asp Lys Thr Val 1270 1275 1280

AGT GAA AAA AAT AAT AAA TGC CAA CTG ATA TTA CAA AAT AAT ATT GAA 4125 Ser Glu Lys Asn Asn Lys Cys Gin Leu He Leu Gin Asn Asn He Glu 1285 1290 1295 ATG ACT ACT GGC ACT TTT GTT GAA GAA ATT ACT GAA AAT TAC AAG AGA 4173 Met Thr Thr Gly Thr Phe Val Glu Glu He Thr Glu Asn Tyr Lys Arg 1300 1305 1310 1315

AAT ACT GAA AAT GAA GAT AAC AAA TAT ACT GCT GCC AGT AGA AAT TCT 4221 Asn Thr Glu Asn Glu Asp Asn Lys Tyr Thr Ala Ala Ser Arg Asn Ser

1320 1325 1330

CAT AAC TTA GAA TTT GAT GGC AGT GAT TCA AGT AAA AAT GAT ACT GTT 4269 His Asn Leu Glu Phe Asp Gly Ser Asp Ser Ser Lys Asn Asp Thr Val 1335 1340 1345

TGT ATT CAT AAA GAT GAA ACG GAC TTG CTA TTT ACT GAT CAG CAC AAC 4317 Cys He His Lys Asp Glu Thr Asp Leu Leu Phe Thr Asp Gin His Asn 1350 1355 1360

ATA TGT CTT AAA TTA TCT GGC CAG TTT ATG AAG GAG GGA AAC ACT CAG 4365 He Cys Leu Lys Leu Ser Gly Gin Phe Met Lys Glu Gly Asn Thr Gin 1365 1370 1375 ATT AAA GAA GAT TTG TCA GAT TTA ACT TTT TTG GAA GTT GCG AAA GCT 4413 He Lys Glu Asp Leu Ser Asp Leu Thr Phe Leu Glu Val Ala Lys Ala 1380 1385 1390 1395

CAA GAA GCA TGT CAT GGT AAT ACT TCA AAT AAA GAA CAG TTA ACT GCT 4461 Gin Glu Ala Cys His Gly Asn Thr Ser Asn Lys Glu Gin Leu Thr Ala

1400 1405 1410

ACT AAA ACG GAG CAA AAT ATA AAA GAT TTT GAG ACT TCT GAT ACA TTT 4509 Thr Lys Thr Glu Gin Asn He Lys Asp Phe Glu Thr Ser Asp Thr Phe 1415 1420 1425

TTT CAG ACT GCA AGT GGG AAA AAT ATT AGT GTC GCC AAA GAG TCA TTT 4557

Phe Gin Thr Ala Ser Gly Lys Asn He Ser Val Ala Lys Glu Ser Phe 1430 1435 1440

AAT AAA ATT GTA AAT TTC TTT GAT CAG AAA CCA GAA GAA TTG CAT AAC 4605

Asn Lys He Val Asn Phe Phe Asp Gin Lys Pro Glu Glu Leu His Asn 1445 1450 1455 TTT TCC TTA AAT TCT GAA TTA CAT TCT GAC ATA AGA AAG AAC AAA ATG 4653 Phe Ser Leu Asn Ser Glu Leu His Ser Asp He Arg Lys Asn Lys Met 1460 1465 1470 1475

GAC ATT CTA AGT TAT GAG GAA ACA GAC ATA GTT AAA CAC AAA ATA CTG 4701 Asp He Leu Ser Tyr Glu Glu Thr Asp He Val Lys His Lys He Leu

1480 1485 1490

AAA GAA AGT GTC CCA GTT GGT ACT GGA AAT CAA CTA GTG ACC TTC CAG 4749 Lys Glu Ser Val Pro Val Gly Thr Gly Asn Gin Leu Val Thr Phe Gin 1495 1500 1505

GGA CAA CCC GAA CGT GAT GAA AAG ATC AAA GAA CCT ACT CTG TTG GGT 4797 Gly Gin Pro Glu Arg Asp Glu Lys He Lys Glu Pro Thr Leu Leu Gly 1510 1515 1520

TTT CAT ACA GCT AGC GGG AAA AAA GTT AAA ATT GCA AAG GAA TCT TTG 4845 Phe His Thr Ala Ser Gly Lys Lys Val Lys He Ala Lys Glu Ser Leu 1525 1530 1535

GAC AAA GTG AAA AAC CTT TTT GAT GAA AAA GAG CAA GGT ACT AGT GAA 4893 Asp Lys Val Lys Asn Leu Phe Asp Glu Lys Glu Gin Gly Thr Ser Glu 1540 1545 1550 1555

ATC ACC AGT TTT AGC CAT CAA TGG GCA AAG ACC CTA AAG TAC AGA GAG 4941 He Thr Ser Phe Ser His Gin Trp Ala Lys Thr Leu Lys Tyr Arg Glu 1560 1565 1570

GCC TGT AAA GAC CTT GAA TTA GCA TGT GAG ACC ATT GAG ATC ACA GCT 4989

Ala Cys Lys Asp Leu Glu Leu Ala Cys Glu Thr He Glu He Thr Ala 1575 1580 1585

GCC CCA AAG TGT AAA GAA ATG CAG AAT TCT CTC AAT AAT GAT AAA AAC 5037

Ala Pro Lys Cys Lys Glu Met Gin Asn Ser Leu Asn Asn Asp Lys Asn 1590 1595 1600 CTT GTT TCT ATT GAG ACT GTG GTG CCA CCT AAG CTC TTA AGT GAT AAT 5085 Leu Val Ser He Glu Thr Val Val Pro Pro Lys Leu Leu Ser Asp Asn 1605 1610 1615

TTA TGT AGA CAA ACT GAA AAT CTC AAA ACA TCA AAA AGT ATC TTT TTG 5133 Leu Cys Arg Gin Thr Glu Asn Leu Lys Thr Ser Lys Ser He Phe Leu 1620 1625 1630 1635

AAA GTT AAA GTA CAT GAA AAT GTA GAA AAA GAA ACA GCA AAA AGT CCT 5181 Lys Val Lys Val His Glu Asn Val Glu Lys Glu Thr Ala Lys Ser Pro 1640 1645 1650

GCA ACT TGT TAC ACA AAT CAG TCC CCT TAT TCA GTC ATT GAA AAT TCA 5229 Ala Thr Cys Tyr Thr Asn Gin Ser Pro Tyr Ser Val He Glu Asn Ser 1655 1660 1665

GCC TTA GCT TTT TAC ACA AGT TGT AGT AGA AAA ACT TCT GTG AGT CAG 5277 Ala Leu Ala Phe Tyr Thr Ser Cys Ser Arg Lys Thr Ser Val Ser Gin 1670 1675 1680 ACT TCA TTA CTT GAA GCA AAA AAA TGG CTT AGA GAA GGA ATA TTT GAT 5325 Thr Ser Leu Leu Glu Ala Lys Lys Trp Leu Arg Glu Gly He Phe Asp 1685 1690 1695

GGT CAA CCA GAA AGA ATA AAT ACT GCA GAT TAT GTA GGA AAT TAT TTG 5373 Gly Gin Pro Glu Arg He Asn Thr Ala Asp Tyr Val Gly Asn Tyr Leu 1700 1705 1710 1715

TAT GAA AAT AAT TCA AAC AGT ACT ATA GCT GAA AAT GAC AAA AAT CAT 5421 Tyr Glu Asn Asn Ser Asn Ser Thr He Ala Glu Asn Asp Lys Asn His 1720 1725 1730

CTC TCC GAA AAA CAA GAT ACT TAT TTA AGT AAC AGT AGC ATG TCT AAC 5469 Leu Ser Glu Lys Gin Asp Thr Tyr Leu Ser Asn Ser Ser Met Ser Asn 1735 1740 1745

AGC TAT TCC TAC CAT TCT GAT GAG GTA TAT AAT GAT TCA GGA TAT CTC 5517 Ser Tyr Ser Tyr His Ser Asp Glu Val Tyr Asn Asp Ser Gly Tyr Leu 1750 1755 1760 TCA AAA AAT AAA CTT GAT TCT GGT ATT GAG CCA GTA TTG AAG AAT GTT 5565 Ser Lys Asn Lys Leu Asp Ser Gly He Glu Pro Val Leu Lys Asn Val 1765 1770 1775 GAA GAT CAA AAA AAC ACT AGT TTT TCC AAA GTA ATA TCC AAT GTA AAA 5613 Glu Asp Gin Lys Asn Thr Ser Phe Ser Lys Val He Ser Asn Val Lys 1780 1785 1790 1795

GAT GCA AAT GCA TAC CCA CAA ACT GTA AAT GAA GAT ATT TGC GTT GAG 5661 Asp Ala Asn Ala Tyr Pro Gin Thr Val Asn Glu Asp He Cys Val Glu 1800 1805 1810

GAA CTT GTG ACT AGC TCT TCA CCC TGC AAA AAT AAA AAT GCA GCC ATT 5709 Glu Leu Val Thr Ser Ser Ser Pro Cys Lys Asn Lys Asn Ala Ala He 1815 1820 1825 AAA TTG TCC ATA TCT AAT AGT AAT AAT TTT GAG GTA GGG CCA CCT GCA 5757 Lys Leu Ser He Ser Asn Ser Asn Asn Phe Glu Val Gly Pro Pro Ala 1830 1835 1840

TTT AGG ATA GCC AGT GGT AAA ATC GTT TGT GTT TCA CAT GAA ACA ATT 5805 Phe Arg He Ala Ser Gly Lys He Val Cys Val Ser His Glu Thr He

1845 1850 1855

AAA AAA GTG AAA GAC ATA TTT ACA GAC AGT TTC AGT AAA GTA ATT AAG 5853 Lys Lys Val Lys Asp He Phe Thr Asp Ser Phe Ser Lys Val He Lys 1860 1865 1870 1875

GAA AAC AAC GAG AAT AAA TCA AAA ATT TGC CAA ACG AAA ATT ATG GCA 5901

Glu Asn Asn Glu Asn Lys Ser Lys He Cys Gin Thr Lys He Met Ala 1880 1885 1890

GGT TGT TAC GAG GCA TTG GAT GAT TCA GAG GAT ATT CTT CAT AAC TCT 5949

Gly Cys Tyr Glu Ala Leu Asp Asp Ser Glu Asp He Leu His Asn Ser 1895 1900 1905 CTA GAT AAT GAT GAA TGT AGC ACG CAT TCA CAT AAG GTT TTT GCT GAC 5997

Leu Asp Asn Asp Glu Cys Ser Thr His Ser His Lys Val Phe Ala Asp 1910 1915 1920

ATT CAG AGT GAA GAA ATT TTA CAA CAT AAC CAA AAT ATG TCT GGA TTG 6045 He Gin Ser Glu Glu He Leu Gin His Asn Gin Asn Met Ser Gly Leu

1925 1930 1935

GAG AAA GTT TCT AAA ATA TCA CCT TGT GAT GTT AGT TTG GAA ACT TCA 6093 Glu Lys Val Ser Lys He Ser Pro Cys Asp Val Ser Leu Glu Thr Ser 1940 1945 1950 1955

GAT ATA TGT AAA TGT AGT ATA GGG AAG CTT CAT AAG TCA GTC TCA TCT 6141 Asp He Cys Lys Cys Ser He Gly Lys Leu His Lys Ser Val Ser Ser 1960 1965 1970

GCA AAT ACT TGT GGG ATT TTT AGC ACA GCA AGT GGA AAA TCT GTC CAG 6189 Ala Asn Thr Cys Gly He Phe Ser Thr Ala Ser Gly Lys Ser Val Gin 1975 1980 1985 GTA TCA GAT GCT TCA TTA CAA AAC GCA AGA CAA GTG TTT TCT GAA ATA 6237 Val Ser Asp Ala Ser Leu Gin Asn Ala Arg Gin Val Phe Ser Glu He 1990 1995 2000

GAA GAT AGT ACC AAG CAA GTC TTT TCC AAA GTA TTG TTT AAA AGT AAC 6285 Glu Asp Ser Thr Lys Gin Val Phe Ser Lys Val Leu Phe Lys Ser Asn 2005 2010 2015 GAA CAT TCA GAC CAG CTC ACA AGA GAA GAA AAT ACT GCT ATA CGT ACT 6333

Glu His Ser Asp Gin Leu Thr Arg Glu Glu Asn Thr Ala He Arg Thr

2020 2025 2030 2035

CCA GAA CAT TTA ATA TCC CAA AAA GGC TTT TCA TAT AAT GTG GTA AAT 6381

Pro Glu His Leu He Ser Gin Lys Gly Phe Ser Tyr Asn Val Val Asn

2040 2045 2050 TCA TCT GCT TTC TCT GGA TTT AGT ACA GCA AGT GGA AAG CAA GTT TCC 6429 Ser Ser Ala Phe Ser Gly Phe Ser Thr Ala Ser Gly Lys Gin Val Ser 2055 2060 2065

ATT TTA GAA AGT TCC TTA CAC AAA GTT AAG GGA GTG TTA GAG GAA TTT 6477 He Leu Glu Ser Ser Leu His Lys Val Lys Gly Val Leu Glu Glu Phe 2070 2075 2080

GAT TTA ATC AGA ACT GAG CAT AGT CTT CAC TAT TCA CCT ACG TCT AGA 6525 Asp Leu He Arg Thr Glu His Ser Leu His Tyr Ser Pro Thr Ser Arg 2085 2090 2095

CAA AAT GTA TCA AAA ATA CTT CCT CGT GTT GAT AAG AGA AAC CCA GAG 6573

Gin Asn Val Ser Lys He Leu Pro Arg Val Asp Lys Arg Asn Pro Glu 2100 2105 2110 2115

CAC TGT GTA AAC TCA GAA ATG GAA AAA ACC TGC AGT AAA GAA TTT AAA 6621

His Cys Val Asn Ser Glu Met Glu Lys Thr Cys Ser Lys Glu Phe Lys 2120 2125 2130 TTA TCA AAT AAC TTA AAT GTT GAA GGT GGT TCT TCA GAA AAT AAT CAC 6669 Leu Ser Asn Asn Leu Asn Val Glu Gly Gly Ser Ser Glu Asn Asn His 2135 2140 2145

TCT ATT AAA GTT TCT CCA TAT CTC TCT CAA TTT CAA CAA GAC AAA CAA 6717 Ser He Lys Val Ser Pro Tyr Leu Ser Gin Phe Gin Gin Asp Lys Gin 2150 2155 2160

CAG TTG GTA TTA GGA ACC AAA GTC TCA CTT GTT GAG AAC ATT CAT GTT 6765 Gin Leu Val Leu Gly Thr Lys Val Ser Leu Val Glu Asn He His Val 2165 2170 2175

TTG GGA AAA GAA CAG GCT TCA CCT AAA AAC GTA AAA ATG GAA ATT GGT 6813

Leu Gly Lys Glu Gin Ala Ser Pro Lys Asn Val Lys Met Glu He Gly 2180 2185 2190 2195

AAA ACT GAA ACT TTT TCT GAT GTT CCT GTG AAA ACA AAT ATA GAA GTT 6861

Lys Thr Glu Thr Phe Ser Asp Val Pro Val Lys Thr Asn He Glu Val 2200 2205 2210 TGT TCT ACT TAC TCC AAA GAT TCA GAA AAC TAC TTT GAA ACA GAA GCA 6909 Cys Ser Thr Tyr Ser Lys Asp Ser Glu Asn Tyr Phe Glu Thr Glu Ala 2215 2220 2225

GTA GAA ATT GCT AAA GCT TTT ATG GAA GAT GAT GAA CTG ACA GAT TCT 6957 Val Glu He Ala Lys Ala Phe Met Glu Asp Asp Glu Leu Thr Asp Ser 2230 2235 2240

AAA CTG CCA AGT CAT GCC ACA CAT TCT CTT TTT ACA TGT CCC GAA AAT 7005 Lys Leu Pro Ser His Ala Thr His Ser Leu Phe Thr Cys Pro Glu Asn 2245 2250 2255

GAG GAA ATG GTT TTG TCA AAT TCA AGA ATT GGA AAA AGA AGA GGA GAG 7053 Glu Glu Met Val Leu Ser Asn Ser Arg He Gly Lys Arg Arg Gly Glu 2260 2265 2270 2275 CCC CTT ATC TTA GTG GGA GAA CCC TCA ATC AAA AGA AAC TTA TTA AAT 7101 Pro Leu He Leu Val Gly Glu Pro Ser He Lys Arg Asn Leu Leu Asn 2280 2285 2290

GAA TTT GAC AGG ATA ATA GAA AAT CAA GAA AAA TCC TTA AAG GCT TCA 7149 Glu Phe Asp Arg He He Glu Asn Gin Glu Lys Ser Leu Lys Ala Ser 2295 2300 2305

AAA AGC ACT CCA GAT GGC ACA ATA AAA GAT CGA AGA TTG TTT ATG CAT 7197 Lys Ser Thr Pro Asp Gly Thr He Lys Asp Arg Arg Leu Phe Met His 2310 2315 2320

CAT GTT TCT TTA GAG CCG ATT ACC TGT GTA CCC TTT CGC ACA ACT AAG 7245

His Val Ser Leu Glu Pro He Thr Cys Val Pro Phe Arg Thr Thr Lys 2325 2330 2335

GAA CGT CAA GAG ATA CAG AAT CCA AAT TTT ACC GCA CCT GGT CAA GAA 7293

Glu Arg Gin Glu He Gin Asn Pro Asn Phe Thr Ala Pro Gly Gin Glu 2340 2345 2350 2355 TTT CTG TCT AAA TCT CAT TTG TAT GAA CAT CTG ACT TTG GAA AAA TCT 7341

Phe Leu Ser Lys Ser His Leu Tyr Glu His Leu Thr Leu Glu Lys Ser 2360 2365 2370

TCA AGC AAT TTA GCA GTT TCA GGA CAT CCA TTT TAT CAA GTT TCT GCT 7389 Ser Ser Asn Leu Ala Val Ser Gly His Pro Phe Tyr Gin Val Ser Ala

2375 2380 2385

ACA AGA AAT GAA AAA ATG AGA CAC TTG ATT ACT ACA GGC AGA CCA ACC 7437 Thr Arg Asn Glu Lys Met Arg His Leu He Thr Thr Gly Arg Pro Thr 2390 2395 2400

AAA GTC TTT GTT CCA CCT TTT AAA ACT AAA TCG CAT TTT CAC AGA GTT 7485

Lys Val Phe Val Pro Pro Phe Lys Thr Lys Ser His Phe His Arg Val 2405 2410 2415

GAA CAG TGT GTT AGG AAT ATT AAC TTG GAG GAA AAC AGA CAA AAG CAA 7533

Glu Gin Cys Val Arg Asn He Asn Leu Glu Glu Asn Arg Gin Lys Gin 2420 2425 2430 2435 AAC ATT GAT GGA CAT GGC TCT GAT GAT AGT AAA AAT AAG ATT AAT GAC 7581 Asn He Asp Gly His Gly Ser Asp Asp Ser Lys Asn Lys He Asn Asp 2440 2445 2450

AAT GAG ATT CAT CAG TTT AAC AAA AAC AAC TCC AAT CAA GCA GCA GCT 7629 Asn Glu He His Gin Phe Asn Lys Asn Asn Ser Asn Gin Ala Ala Ala 2455 2460 2465

GTA ACT TTC ACA AAG TGT GAA GAA GAA CCT TTA GAT TTA ATT ACA AGT 7677 Val Thr Phe Thr Lys Cys Glu Glu Glu Pro Leu Asp Leu He Thr Ser 2470 2475 2480

CTT CAG AAT GCC AGA GAT ATA CAG GAT ATG CGA ATT AAG AAG AAA CAA 7725 Leu Gin Asn Ala Arg Asp He Gin Asp Met Arg He Lys Lys Lys Gin 2485 2490 2495

AGG CAA CGC GTC TTT CCA CAG CCA GGC AGT CTG TAT CTT GCA AAA ACA 7773 Arg Gin Arg Val Phe Pro Gin Pro Gly Ser Leu Tyr Leu Ala Lys Thr 2500 2505 2510 2515

TCC ACT CTG CCT CGA ATC TCT CTG AAA GCA GCA GTA GGA GGC CAA GTT 7821 Ser Thr Leu Pro Arg He Ser Leu Lys Ala Ala Val Gly Gly Gin Val

2520 2525 2530

CCC TCT GCG TGT TCT CAT AAA CAG CTG TAT ACG TAT GGC GTT TCT AAA 7869 Pro Ser Ala Cys Ser His Lys Gin Leu Tyr Thr Tyr Gly Val Ser Lys 2535 2540 2545

CAT TGC ATA AAA ATT AAC AGC AAA AAT GCA GAG TCT TTT CAG TTT CAC 7917 His Cys He Lys He Asn Ser Lys Asn Ala Glu Ser Phe Gin Phe His 2550 2555 2560

ACT GAA GAT TAT TTT GGT AAG GAA AGT TTA TGG ACT GGA AAA GGA ATA 7965 Thr Glu Asp Tyr Phe Gly Lys Glu Ser Leu Trp Thr Gly Lys Gly He 2565 2570 2575 CAG TTG GCT GAT GGT GGA TGG CTC ATA CCC TCC AAT GAT GGA AAG GCT 8013 Gin Leu Ala Asp Gly Gly Trp Leu He Pro Ser Asn Asp Gly Lys Ala 2580 2585 2590 2595

GGA AAA GAA GAA TTT TAT AGG GCT CTG TGT GAC ACT CCA GGT GTG GAT 8061 Gly Lys Glu Glu Phe Tyr Arg Ala Leu Cys Asp Thr Pro Gly Val Asp

2600 2605 2610

CCA AAG CTT ATT TCT AGA ATT TGG GTT TAT AAT CAC TAT AGA TGG ATC 8109 Pro Lys Leu He Ser Arg He Trp Val Tyr Asn His Tyr Arg Trp He 2615 2620 2625

ATA TGG AAA CTG GCA GCT ATG GAA TGT GCC TTT CCT AAG GAA TTT GCT 8157

He Trp Lys Leu Ala Ala Met Glu Cys Ala Phe Pro Lys Glu Phe Ala 2630 2635 2640

AAT AGA TGC CTA AGC CCA GAA AGG GTG CTT CTT CAA CTA AAA TAC AGA 8205

Asn Arg Cys Leu Ser Pro Glu Arg Val Leu Leu Gin Leu Lys Tyr Arg 2645 2650 2655 TAT GAT ACG GAA ATT GAT AGA AGC AGA AGA TCG GCT ATA AAA AAG ATA 8253 Tyr Asp Thr Glu He Asp Arg Ser Arg Arg Ser Ala He Lys Lys He 2660 2665 2670 2675

ATG GAA AGG GAT GAC ACA GCT GCA AAA ACA CTT GTT CTC TGT GTT TCT 8301 Met Glu Arg Asp Asp Thr Ala Ala Lys Thr Leu Val Leu Cys Val Ser

2680 2685 2690

GAC ATA ATT TCA TTG AGC GCA AAT ATA TCT GAA ACT TCT AGC AAT AAA 8349 Asp He He Ser Leu Ser Ala Asn He Ser Glu Thr Ser Ser Asn Lys 2695 2700 2705

ACT AGT AGT GCA GAT ACC CAA AAA GTG GCC ATT ATT GAA CTT ACA GAT 8397 Thr Ser Ser Ala Asp Thr Gin Lys Val Ala He He Glu Leu Thr Asp 2710 2715 2720

GGG TGG TAT GCT GTT AAG GCC CAG TTA GAT CCT CCC CTC TTA GCT GTC 8445 Gly Trp Tyr Ala Val Lys Ala Gin Leu Asp Pro Pro Leu Leu Ala Val 2725 2730 2735 TTA AAG AAT GGC AGA CTG ACA GTT GGT CAG AAG ATT ATT CTT CAT GGA 8493 Leu Lys Asn Gly Arg Leu Thr Val Gly Gin Lys He He Leu His Gly 2740 2745 2750 2755 GCA GAA CTG GTG GGC TCT CCT GAT GCC TGT ACA CCT CTT GAA GCC CCA 8541 Ala Glu Leu Val Gly Ser Pro Asp Ala Cys Thr Pro Leu Glu Ala Pro 2760 2765 2770

GAA TCT CTT ATG TTA AAG ATT TCT GCT AAC AGT ACT CGG CCT GCT CGC 8589 Glu Ser Leu Met Leu Lys He Ser Ala Asn Ser Thr Arg Pro Ala Arg 2775 2780 2785

TGG TAT ACC AAA CTT GGA TTC TTT CCT GAC CCT AGA CCT TTT CCT CTG 8637 Trp Tyr Thr Lys Leu Gly Phe Phe Pro Asp Pro Arg Pro Phe Pro Leu 2790 2795 2800 CCC TTA TCA TCG CTT TTC AGT GAT GGA GGA AAT GTT GGT TGT GTT GAT 8685 Pro Leu Ser Ser Leu Phe Ser Asp Gly Gly Asn Val Gly Cys Val Asp 2805 2810 2815

GTA ATT ATT CAA AGA GCA TAC CCT ATA CAG TGG ATG GAG AAG ACA TCA 8733 Val He He Gin Arg Ala Tyr Pro He Gin Trp Met Glu Lys Thr Ser 2820 2825 2830 2835

TCT GGA TTA TAC ATA TTT CGC AAT GAA AGA GAG GAA GAA AAG GAA GCA 8781 Ser Gly Leu Tyr He Phe Arg Asn Glu Arg Glu Glu Glu Lys Glu Ala 2840 2845 2850

GCA AAA TAT GTG GAG GCC CAA CAA AAG AGA CTA GAA GCC TTA TTC ACT 8829 Ala Lys Tyr Val Glu Ala Gin Gin Lys Arg Leu Glu Ala Leu Phe Thr 2855 2860 2865

AAA ATT CAG GAG GAA TTT GAA GAA CAT GAA GAA AAC ACA ACA AAA CCA 8877 Lys He Gin Glu Glu Phe Glu Glu His Glu Glu Asn Thr Thr Lys Pro 2870 2875 2880 TAT TTA CCA TCA CGT GCA CTA ACA AGA CAG CAA GTT CGT GCT TTG CAA 8925 Tyr Leu Pro Ser Arg Ala Leu Thr Arg Gin Gin Val Arg Ala Leu Gin 2885 2890 2895

GAT GGT GCA GAG CTT TAT GAA GCA GTG AAG AAT GCA GCA GAC CCA GCT 8973 Asp Gly Ala Glu Leu Tyr Glu Ala Val Lys Asn Ala Ala Asp Pro Ala 2900 2905 2910 2915

TAC CTT GAG GGT TAT TTC AGT GAA GAG CAG TTA AGA GCC TTG AAT AAT 9021 Tyr Leu Glu Gly Tyr Phe Ser Glu Glu Gin Leu Arg Ala Leu Asn Asn 2920 2925 2930

CAC AGG CAA ATG TTG AAT GAT AAG AAA CAA GCT CAG ATC CAG TTG GAA 9069

His Arg Gin Met Leu Asn Asp Lys Lys Gin Ala Gin He Gin Leu Glu 2935 2940 2945

ATT AGG AAG GCC ATG GAA TCT GCT GAA CAA AAG GAA CAA GGT TTA TCA 9117

He Arg Lys Ala Met Glu Ser Ala Glu Gin Lys Glu Gin Gly Leu Ser 2950 2955 2960 AGG GAT GTC ACA ACC GTG TGG AAG TTG CGT ATT GTA AGC TAT TCA AAA 9165 Arg Asp Val Thr Thr Val Trp Lys Leu Arg He Val Ser Tyr Ser Lys 2965 2970 2975

AAA GAA AAA GAT TCA GTT ATA CTG AGT ATT TGG CGT CCA TCA TCA GAT 9213 Lys Glu Lys Asp Ser Val He Leu Ser He Trp Arg Pro Ser Ser Asp 2980 2985 2990 2995 TTA TAT TCT CTG TTA ACA GAA GGA AAG AGA TAC AGA ATT TAT CAT CTT 9261 Leu Tyr Ser Leu Leu Thr Glu Gly Lys Arg Tyr Arg He Tyr His Leu 3000 3005 3010

GCA ACT TCA AAA TCT AAA AGT AAA TCT GAA AGA GCT AAC ATA CAG TTA 9309 Ala Thr Ser Lys Ser Lys Ser Lys Ser Glu Arg Ala Asn He Gin Leu 3015 3020 3025 GCA GCG ACA AAA AAA ACT CAG TAT CAA CAA CTA CCG GTT TCA GAT GAA 9357 Ala Ala Thr Lys Lys Thr Gin Tyr Gin Gin Leu Pro Val Ser Asp Glu 3030 3035 3040

ATT TTA TTT CAG ATT TAC CAG CCA CGG GAG CCC CTT CAC TTC AGC AAA 9405 He Leu Phe Gin He Tyr Gin Pro Arg Glu Pro Leu His Phe Ser Lys 3045 3050 3055

TTT TTA GAT CCA GAC TTT CAG CCA TCT TGT TCT GAG GTG GAC CTA ATA 9453 Phe Leu Asp Pro Asp Phe Gin Pro Ser Cys Ser Glu Val Asp Leu He 3060 3065 3070 3075

GGA TTT GTC GTT TCT GTT GTG AAA AAA ACA GGA CTT GCC CCT TTC GTC 9501 Gly Phe Val Val Ser Val Val Lys Lys Thr Gly Leu Ala Pro Phe Val 3080 3085 3090

TAT TTG TCA GAC GAA TGT TAC AAT TTA CTG GCA ATA AAG TTT TGG ATA 9549 Tyr Leu Ser Asp Glu Cys Tyr Asn Leu Leu Ala He Lys Phe Trp He 3095 3100 3105 GAC CTT AAT GAG GAC ATT ATT AAG CCT CAT ATG TTA ATT GCT GCA AGC 9597 Asp Leu Asn Glu Asp He He Lys Pro His Met Leu He Ala Ala Ser 3110 3115 3120

AAC CTC CAG TGG CGA CCA GAA TCC AAA TCA GGC CTT CTT ACT TTA TTT 9645 Asn Leu Gin Trp Arg Pro Glu Ser Lys Ser Gly Leu Leu Thr Leu Phe 3125 3130 3135

GCT GGA GAT TTT TCT GTG TTT TCT GCT AGT CCA AAA GAG GGC CAC TTT 9693 Ala Gly Asp Phe Ser Val Phe Ser Ala Ser Pro Lys Glu Gly His Phe 3140 3145 3150 3155

CAA GAG ACA TTC AAC AAA ATG AAA AAT ACT GTT GAG AAT ATT GAC ATA 9741

Gin Glu Thr Phe Asn Lys Met Lys Asn Thr Val Glu Asn He Asp He 3160 3165 3170

CTT TGC AAT GAA GCA GAA AAC AAG CTT ATG CAT ATA CTG CAT GCA AAT 9789

Leu Cys Asn Glu Ala Glu Asn Lys Leu Met His He Leu His Ala Asn 3175 3180 3185 GAT CCC AAG TGG TCC ACC CCA ACT AAA GAC TGT ACT TCA GGG CCG TAC 9837 Asp Pro Lys Trp Ser Thr Pro Thr Lys Asp Cys Thr Ser Gly Pro Tyr 3190 3195 3200

ACT GCT CAA ATC ATT CCT GGT ACA GGA AAC AAG CTT CTG ATG TCT TCT 9885 Thr Ala Gin He He Pro Gly Thr Gly Asn Lys Leu Leu Met Ser Ser 3205 3210 3215

CCT AAT TGT GAG ATA TAT TAT CAA AGT CCT TTA TCA CTT TGT ATG GCC 9933 Pro Asn Cys Glu He Tyr Tyr Gin Ser Pro Leu Ser Leu Cys Met Ala 3220 3225 3230 3235

AAA AGG AAG TCT GTT TCC ACA CCT GTC TCA GCC CAG ATG ACT TCA AAG 9981 Lys Arg Lys Ser Val Ser Thr Pro Val Ser Ala Gin Met Thr Ser Lys 3240 3245 3250 TCT TGT AAA GGG GAG AAA GAG ATT GAT GAC CAA AAG AAC TGC AAA AAG 10029 Ser Cys Lys Gly Glu Lys Glu He Asp Asp Gin Lys Asn Cys Lys Lys 3255 3260 3265

AGA AGA GCC TTG GAT TTC TTG AGT AGA CTG CCT TTA CCT CCA CCT GTT 10077 Arg Arg Ala Leu Asp Phe Leu Ser Arg Leu Pro Leu Pro Pro Pro Val 3270 3275 3280

AGT CCC ATT TGT ACA TTT GTT TCT CCG GCT GCA CAG AAG GCA TTT CAG 10125 Ser Pro He Cys Thr Phe Val Ser Pro Ala Ala Gin Lys Ala Phe Gin 3285 3290 3295

CCA CCA AGG AGT TGT GGC ACC AAA TAC GAA ACA CCC ATA AAG AAA AAA 10173

Pro Pro Arg Ser Cys Gly Thr Lys Tyr Glu Thr Pro He Lys Lys Lys 3300 3305 3310 3315

GAA CTG AAT TCT CCT CAG ATG ACT CCA TTT AAA AAA TTC AAT GAA ATT 10221

Glu Leu Asn Ser Pro Gin Met Thr Pro Phe Lys Lys Phe Asn Glu He 3320 3325 3330 TCT CTT TTG GAA AGT AAT TCA ATA GCT GAC GAA GAA CTT GCA TTG ATA 10269 Ser Leu Leu Glu Ser Asn Ser He Ala Asp Glu Glu Leu Ala Leu He 3335 3340 3345

AAT ACC CAA GCT CTT TTG TCT GGT TCA ACA GGA GAA AAA CAA TTT ATA 10317 Asn Thr Gin Ala Leu Leu Ser Gly Ser Thr Gly Glu Lys Gin Phe He

3350 3355 3360

TCT GTC AGT GAA TCC ACT AGG ACT GCT CCC ACC AGT TCA GAA GAT TAT 10365 Ser Val Ser Glu Ser Thr Arg Thr Ala Pro Thr Ser Ser Glu Asp Tyr 3365 3370 3375

CTC AGA CTG AAA CGA CGT TGT ACT ACA TCT CTG ATC AAA GAA CAG GAG 10413 Leu Arg Leu Lys Arg Arg Cys Thr Thr Ser Leu He Lys Glu Gin Glu 3380 3385 3390 3395

AGT TCC CAG GCC AGT ACG GAA GAA TGT GAG AAA AAT AAG CAG GAC ACA 10461 Ser Ser Gin Ala Ser Thr Glu Glu Cys Glu Lys Asn Lys Gin Asp Thr 3400 3405 3410 ATT ACA ACT AAA AAA TAT ATC TAA 10485

He Thr Thr Lys Lys Tyr He 3415

(2) INFORMATION FOR SEQ ID NO : 9 :

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 3418 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein (v) FRAGMENT TYPE: internal

(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 9 : Met Pro He Gly Ser Lys Glu Arg Pro Thr Phe Phe Glu He Phe Lys

1 5 10 15

Thr Arg Cys Asn Lys Ala Asp Leu Gly Pro He Ser Leu Asn Trp Phe 20 25 30

Glu Glu Leu Ser Ser Glu Ala Pro Pro Tyr Asn Ser Glu Pro Ala Glu

35 40 45

Glu Ser Glu His Lys Asn Asn Asn Tyr Glu Pro Asn Leu Phe Lys Thr 50 55 60 Pro Gin Arg Lys Pro Ser Tyr Asn Gin Leu Ala Ser Thr Pro He He 65 70 75 80

Phe Lys Glu Gin Gly Leu Thr Leu Pro Leu Tyr Gin Ser Pro Val Lys

85 90 95

Glu Leu Asp Lys Phe Lys Leu Asp Leu Gly Arg Asn Val Pro Asn Ser 100 105 110

Arg His Lys Ser Leu Arg Thr Val Lys Thr Lys Met Asp Gin Ala Asp

115 120 125

Asp Val Ser Cys Pro Leu Leu Asn Ser Cys Leu Ser Glu Ser Pro Val 130 135 140 Val Leu Gin Cys Thr His Val Thr Pro Gin Arg Asp Lys Ser Val Val

145 150 155 160

Cys Gly Ser Leu Phe His Thr Pro Lys Phe Val Lys Gly Arg Gin Thr

165 170 175

Pro Lys His He Ser Glu Ser Leu Gly Ala Glu Val Asp Pro Asp Met 180 185 190

Ser Trp Ser Ser Ser Leu Ala Thr Pro Pro Thr Leu Ser Ser Thr Val

195 200 205

Leu He Val Arg Asn Glu Glu Ala Ser Glu Thr Val Phe Pro His Asp 210 215 220 Thr Thr Ala Asn Val Lys Ser Tyr Phe Ser Asn His Asp Glu Ser Leu

225 230 235 240

Lys Lys Asn Asp Arg Phe He Ala Ser Val Thr Asp Ser Glu Asn Thr

245 250 255

Asn Gin Arg Glu Ala Ala Ser His Gly Phe Gly Lys Thr Ser Gly Asn 260 265 270

Ser Phe Lys Val Asn Ser Cys Lys Asp His He Gly Lys Ser Met Pro

275 280 285

His Val Leu Glu Asp Glu Val Tyr Glu Thr Val Val Asp Thr Ser Glu 290 295 300 Glu Asp Ser Phe Ser Leu Cys Phe Ser Lys Cys Arg Thr Lys Asn Leu

305 310 315 320

Gin Lys Val Arg Thr Ser Lys Thr Arg Lys Lys He Phe His Glu Ala

325 330 335

Asn Ala Asp Glu Cys Glu Lys Ser Lys Asn Gin Val Lys Glu Lys Tyr 340 345 350

Ser Phe Val Ser Glu Val Glu Pro Asn Asp Thr Asp Pro Leu Asp Ser

355 360 365

Asn Val Ala Asn Gin Lys Pro Phe Glu Ser Gly Ser Asp Lys He Ser

370 375 380 Lys Glu Val Val Pro Ser Leu Ala Cys Glu Trp Ser Gin Leu Thr Leu

385 390 395 400

Ser Gly Leu Asn Gly Ala Gin Met Glu Lys He Pro Leu Leu His He

405 410 415

Ser Ser Cys Asp Gin Asn He Ser Glu Lys Asp Leu Leu Asp Thr Glu 420 425 430

Asn Lys Arg Lys Lys Asp Phe Leu Thr Ser Glu Asn Ser Leu Pro Arg

435 440 445

He Ser Ser Leu Pro Lys Ser Glu Lys Pro Leu Asn Glu Glu Thr Val

450 455 460 Val Asn Lys Arg Asp Glu Glu Gin His Leu Glu Ser His Thr Asp Cys

465 470 475 480

He Leu Ala Val Lys Gin Ala He Ser Gly Thr Ser Pro Val Ala Ser 485 490 495

Ser Phe Gin Gly He Lys Lys Ser He Phe Arg He Arg Glu Ser Pro 500 505 510 Lys Glu Thr Phe Asn Ala Ser Phe Ser Gly His Met Thr Asp Pro Asn 515 520 525

Phe Lys Lys Glu Thr Glu Ala Ser Glu Ser Gly Leu Glu He His Thr

530 535 540

Val Cys Ser Gin Lys Glu Asp Ser Leu Cys Pro Asn Leu He Asp Asn 545 550 555 560

Gly Ser Trp Pro Ala Thr Thr Thr Gin Asn Ser Val Ala Leu Lys Asn

565 570 575

Ala Gly Leu He Ser Thr Leu Lys Lys Lys Thr Asn Lys Phe He Tyr 580 585 590 Ala He His Asp Glu Thr Ser Tyr Lys Gly Lys Lys He Pro Lys Asp 595 600 605

Gin Lys Ser Glu Leu He Asn Cys Ser Ala Gin Phe Glu Ala Asn Ala

610 615 620

Phe Glu Ala Pro Leu Thr Phe Ala Asn Ala Asp Ser Gly Leu Leu His 625 630 635 640

Ser Ser Val Lys Arg Ser Cys Ser Gin Asn Asp Ser Glu Glu Pro Thr

645 650 655

Leu Ser Leu Thr Ser Ser Phe Gly Thr He Leu Arg Lys Cys Ser Arg 660 665 670 Asn Glu Thr Cys Ser Asn Asn Thr Val He Ser Gin Asp Leu Asp Tyr 675 680 685

Lys Glu Ala Lys Cys Asn Lys Glu Lys Leu Gin Leu Phe He Thr Pro

690 695 700

Glu Ala Asp Ser Leu Ser Cys Leu Gin Glu Gly Gin Cys Glu Asn Asp 705 710 715 720

Pro Lys Ser Lys Lys Val Ser Asp He Lys Glu Glu Val Leu Ala Ala

725 730 735

Ala Cys His Pro Val Gin His Ser Lys Val Glu Tyr Ser Asp Thr Asp 740 745 750 Phe Gin Ser Gin Lys Ser Leu Leu Tyr Asp His Glu Asn Ala Ser Thr 755 760 765

Leu He Leu Thr Pro Thr Ser Lys Asp Val Leu Ser Asn Leu Val Met

770 775 780

He Ser Arg Gly Lys Glu Ser Tyr Lys Met Ser Asp Lys Leu Lys Gly 785 790 795 800

Asn Asn Tyr Glu Ser Asp Val Glu Leu Thr Lys Asn He Pro Met Glu

805 810 815

Lys Asn Gin Asp Val Cys Ala Leu Asn Glu Asn Tyr Lys Asn Val Glu 820 825 830 Leu Leu Pro Pro Glu Lys Tyr Met Arg Val Ala Ser Pro Ser Arg Lys 835 840 845

Val Gin Phe Asn Gin Asn Thr Asn Leu Arg Val He Gin Lys Asn Gin

850 855 860

Glu Glu Thr Thr Ser He Ser Lys He Thr Val Asn Pro Asp Ser Glu 865 870 875 880

Glu Leu Phe Ser Asp Asn Glu Asn Asn Phe Val Phe Gin Val Ala Asn

885 890 895

Glu Arg Asn Asn Leu Ala Leu Gly Asn Thr Lys Glu Leu His Glu Thr 900 905 910 Asp Leu Thr Cys Val Asn Glu Pro He Phe Lys Asn Ser Thr Met Val 915 920 925

Leu Tyr Gly Asp Thr Gly Asp Lys Gin Ala Thr Gin Val Ser He Lys

930 935 940

Lys Asp Leu Val Tyr Val Leu Ala Glu Glu Asn Lys Asn Ser Val Lys 945 950 955 960

Gin His He Lys Met Thr Leu Gly Gin Asp Leu Lys Ser Asp He Ser 965 970 975 Leu Asn He Asp Lys He Pro Glu Lys Asn Asn Asp Tyr Met Asp Lys

980 985 990

Trp Ala Gly Leu Leu Gly Pro He Ser Asn His Ser Phe Gly Gly Ser 995 1000 1005

Phe Arg Thr Ala Ser Asn Lys Glu He Lys Leu Ser Glu His Asn He

1010 1015 1020

Lys Lys Ser Lys Met Phe Phe Lys Asp He Glu Glu Gin Tyr Pro Thr 1025 1030 1035 104 Ser Leu Ala Cys Val Glu He Val Asn Thr Leu Ala Leu Asp Asn Gin

1045 1050 1055

Lys Lys Leu Ser Lys Pro Gin Ser He Asn Thr Val Ser Ala His Leu

1060 1065 1070

Gin Ser Ser Val Val Val Ser Asp Cys Lys Asn Ser His He Thr Pro 1075 1080 1085

Gin Met Leu Phe Ser Lys Gin Asp Phe Asn Ser Asn His Asn Leu Thr

1090 1095 1100

Pro Ser Gin Lys Ala Glu He Thr Glu Leu Ser Thr He Leu Glu Glu 1105 1110 1115 112 Ser Gly Ser Gin Phe Glu Phe Thr Gin Phe Arg Lys Pro Ser Tyr He

1125 1130 1135

Leu Gin Lys Ser Thr Phe Glu Val Pro Glu Asn Gin Met Thr He Leu

1140 1145 1150

Lys Thr Thr Ser Glu Glu Cys Arg Asp Ala Asp Leu His Val He Met 1155 1160 1165

Asn Ala Pro Ser He Gly Gin Val Asp Ser Ser Lys Gin Phe Glu Gly

1170 1175 1180

Thr Val Glu He Lys Arg Lys Phe Ala Gly Leu Leu Lys Asn Asp Cys 1185 1190 1195 120 Asn Lys Ser Ala Ser Gly Tyr Leu Thr Asp Glu Asn Glu Val Gly Phe

1205 1210 1215

Arg Gly Phe Tyr Ser Ala His Gly Thr Lys Leu Asn Val Ser Thr Glu

1220 1225 1230

Ala Leu Gin Lys Ala Val Lys Leu Phe Ser Asp He Glu Asn He Ser 1235 1240 1245

Glu Glu Thr Ser Ala Glu Val His Pro He Ser Leu Ser Ser Ser Lys

1250 1255 1260

Cys His Asp Ser Val Val Ser Met Phe Lys He Glu Asn His Asn Asp 1265 1270 1275 128 Lys Thr Val Ser Glu Lys Asn Asn Lys Cys Gin Leu He Leu Gin Asn

1285 1290 1295

Asn He Glu Met Thr Thr Gly Thr Phe Val Glu Glu He Thr Glu Asn

1300 1305 1310

Tyr Lys Arg Asn Thr Glu Asn Glu Asp Asn Lys Tyr Thr Ala Ala Ser 1315 1320 1325

Arg Asn Ser His Asn Leu Glu Phe Asp Gly Ser Asp Ser Ser Lys Asn

1330 1335 1340

Asp Thr Val Cys He His Lys Asp Glu Thr Asp Leu Leu Phe Thr Asp 1345 1350 1355 136 Gin His Asn He Cys Leu Lys Leu Ser Gly Gin Phe Met Lys Glu Gly

1365 1370 1375

Asn Thr Gin He Lys Glu Asp Leu Ser Asp Leu Thr Phe Leu Glu Val

1380 1385 1390

Ala Lys Ala Gin Glu Ala Cys His Gly Asn Thr Ser Asn Lys Glu Gin 1395 1400 1405

Leu Thr Ala Thr Lys Thr Glu Gin Asn He Lys Asp Phe Glu Thr Ser

1410 1415 1420

Asp Thr Phe Phe Gin Thr Ala Ser Gly Lys Asn He Ser Val Ala Lys 1425 1430 1435 144 Glu Ser Phe Asn Lys He Val Asn Phe Phe Asp Gin Lys Pro Glu Glu

1445 1450 1455

Leu His Asn Phe Ser Leu Asn Ser Glu Leu His Ser Asp He Arg Lys 1460 1465 1470

Asn Lys Met Asp He Leu Ser Tyr Glu Glu Thr Asp He Val Lys His 1475 1480 1485 Lys He Leu Lys Glu Ser Val Pro Val Gly Thr Gly Asn Gin Leu Val 1490 1495 1500

Thr Phe Gin Gly Gin Pro Glu Arg Asp Glu Lys He Lys Glu Pro Thr 1505 1510 1515 152

Leu Leu Gly Phe His Thr Ala Ser Gly Lys Lys Val Lys He Ala Lys 1525 1530 1535

Glu Ser Leu Asp Lys Val Lys Asn Leu Phe Asp Glu Lys Glu Gin Gly

1540 1545 1550

Thr Ser Glu He Thr Ser Phe Ser His Gin Trp Ala Lys Thr Leu Lys 1555 1560 1565 Tyr Arg Glu Ala Cys Lys Asp Leu Glu Leu Ala Cys Glu Thr He Glu 1570 1575 1580

He Thr Ala Ala Pro Lys Cys Lys Glu Met Gin Asn Ser Leu Asn Asn 1585 1590 1595 160

Asp Lys Asn Leu Val Ser He Glu Thr Val Val Pro Pro Lys Leu Leu 1605 1610 1615

Ser Asp Asn Leu Cys Arg Gin Thr Glu Asn Leu Lys Thr Ser Lys Ser

1620 1625 1630

He Phe Leu Lys Val Lys Val His Glu Asn Val Glu Lys Glu Thr Ala 1635 1640 1645 Lys Ser Pro Ala Thr Cys Tyr Thr Asn Gin Ser Pro Tyr Ser Val He

1650 1655 1660

Glu Asn Ser Ala Leu Ala Phe Tyr Thr Ser Cys Ser Arg Lys Thr Ser 1665 1670 1675 168

Val Ser Gin Thr Ser Leu Leu Glu Ala Lys Lys Trp Leu Arg Glu Gly 1685 1690 1695

He Phe Asp Gly Gin Pro Glu Arg He Asn Thr Ala Asp Tyr Val Gly

1700 1705 1710

Asn Tyr Leu Tyr Glu Asn Asn Ser Asn Ser Thr He Ala Glu Asn Asp 1715 1720 1725 Lys Asn His Leu Ser Glu Lys Gin Asp Thr Tyr Leu Ser Asn Ser Ser

1730 1735 1740

Met Ser Asn Ser Tyr Ser Tyr His Ser Asp Glu Val Tyr Asn Asp Ser 1745 1750 1755 176

Gly Tyr Leu Ser Lys Asn Lys Leu Asp Ser Gly He Glu Pro Val Leu 1765 1770 1775

Lys Asn Val Glu Asp Gin Lys Asn Thr Ser Phe Ser Lys Val He Ser

1780 1785 1790

Asn Val Lys Asp Ala Asn Ala Tyr Pro Gin Thr Val Asn Glu Asp He 1795 1800 1805 Cys Val Glu Glu Leu Val Thr Ser Ser Ser Pro Cys Lys Asn Lys Asn

1810 1815 1820

Ala Ala He Lys Leu Ser He Ser Asn Ser Asn Asn Phe Glu Val Gly 1825 1830 1835 184

Pro Pro Ala Phe Arg He Ala Ser Gly Lys He Val Cys Val Ser His 1845 1850 1855

Glu Thr He Lys Lys Val Lys Asp He Phe Thr Asp Ser Phe Ser Lys

1860 1865 1870

Val He Lys Glu Asn Asn Glu Asn Lys Ser Lys He Cys Gin Thr Lys 1875 1880 1885 He Met Ala Gly Cys Tyr Glu Ala Leu Asp Asp Ser Glu Asp He Leu 1890 1895 1900

His Asn Ser Leu Asp Asn Asp Glu Cys Ser Thr His Ser His Lys Val 1905 1910 1915 192

Phe Ala Asp He Gin Ser Glu Glu He Leu Gin His Asn Gin Asn Met 1925 1930 1935

Ser Gly Leu Glu Lys Val Ser Lys He Ser Pro Cys Asp Val Ser Leu 1940 1945 1950 Glu Thr Ser Asp He Cys Lys Cys Ser He Gly Lys Leu His Lys Ser

1955 1960 1965

Val Ser Ser Ala Asn Thr Cys Gly He Phe Ser Thr Ala Ser Gly Lys 1970 1975 1980

Ser Val Gin Val Ser Asp Ala Ser Leu Gin Asn Ala Arg Gin Val Phe

1985 1990 1995 200

Ser Glu He Glu Asp Ser Thr Lys Gin Val Phe Ser Lys Val Leu Phe

2005 2010 2015 Lys Ser Asn Glu His Ser Asp Gin Leu Thr Arg Glu Glu Asn Thr Ala

2020 2025 2030

He Arg Thr Pro Glu His Leu He Ser Gin Lys Gly Phe Ser Tyr Asn

2035 2040 2045

Val Val Asn Ser Ser Ala Phe Ser Gly Phe Ser Thr Ala Ser Gly Lys 2050 2055 2060

Gin Val Ser He Leu Glu Ser Ser Leu His Lys Val Lys Gly Val Leu 2065 2070 2075 208

Glu Glu Phe Asp Leu He Arg Thr Glu His Ser Leu His Tyr Ser Pro 2085 2090 2095 Thr Ser Arg Gin Asn Val Ser Lys He Leu Pro Arg Val Asp Lys Arg

2100 2105 2110

Asn Pro Glu His Cys Val Asn Ser Glu Met Glu Lys Thr Cys Ser Lys

2115 2120 2125

Glu Phe Lys Leu Ser Asn Asn Leu Asn Val Glu Gly Gly Ser Ser Glu 2130 2135 2140

Asn Asn His Ser He Lys Val Ser Pro Tyr Leu Ser Gin Phe Gin Gin 2145 2150 2155 216

Asp Lys Gin Gin Leu Val Leu Gly Thr Lys Val Ser Leu Val Glu Asn 2165 2170 2175 He His Val Leu Gly Lys Glu Gin Ala Ser Pro Lys Asn Val Lys Met

2180 2185 2190

Glu He Gly Lys Thr Glu Thr Phe Ser Asp Val Pro Val Lys Thr Asn

2195 2200 2205

He Glu Val Cys Ser Thr Tyr Ser Lys Asp Ser Glu Asn Tyr Phe Glu 2210 2215 2220

Thr Glu Ala Val Glu He Ala Lys Ala Phe Met Glu Asp Asp Glu Leu 2225 2230 2235 224

Thr Asp Ser Lys Leu Pro Ser His Ala Thr His Ser Leu Phe Thr Cys 2245 2250 2255 Pro Glu Asn Glu Glu Met Val Leu Ser Asn Ser Arg He Gly Lys Arg

2260 2265 2270

Arg Gly Glu Pro Leu He Leu Val Gly Glu Pro Ser He Lys Arg Asn

2275 2280 2285

Leu Leu Asn Glu Phe Asp Arg He He Glu Asn Gin Glu Lys Ser Leu 2290 2295 2300

Lys Ala Ser Lys Ser Thr Pro Asp Gly Thr He Lys Asp Arg Arg Leu

2305 2310 2315 232

Phe Met His His Val Ser Leu Glu Pro He Thr Cys Val Pro Phe Arg

2325 2330 2335 Thr Thr Lys Glu Arg Gin Glu He Gin Asn Pro Asn Phe Thr Ala Pro

2340 2345 2350

Gly Gin Glu Phe Leu Ser Lys Ser His Leu Tyr Glu His Leu Thr Leu

2355 2360 2365

Glu Lys Ser Ser Ser Asn Leu Ala Val Ser Gly His Pro Phe Tyr Gin 2370 2375 2380

Val Ser Ala Thr Arg Asn Glu Lys Met Arg His Leu He Thr Thr Gly

2385 2390 2395 240

Arg Pro Thr Lys Val Phe Val Pro Pro Phe Lys Thr Lys Ser His Phe

2405 2410 2415 His Arg Val Glu Gin Cys Val Arg Asn He Asn Leu Glu Glu Asn Arg

2420 2425 2430

Gin Lys Gin Asn He Asp Gly His Gly Ser Asp Asp Ser Lys Asn Lys 2435 2440 2445

He Asn Asp Asn Glu He His Gin Phe Asn Lys Asn Asn Ser Asn Gin

2450 2455 2460 Ala Ala Ala Val Thr Phe Thr Lys Cys Glu Glu Glu Pro Leu Asp Leu

2465 2470 2475 248

He Thr Ser Leu Gin Asn Ala Arg Asp He Gin Asp Met Arg He Lys

2485 2490 2495

Lys Lys Gin Arg Gin Arg Val Phe Pro Gin Pro Gly Ser Leu Tyr Leu 2500 2505 2510

Ala Lys Thr Ser Thr Leu Pro Arg He Ser Leu Lys Ala Ala Val Gly

2515 2520 2525

Gly Gin Val Pro Ser Ala Cys Ser His Lys Gin Leu Tyr Thr Tyr Gly

2530 2535 2540 Val Ser Lys His Cys He Lys He Asn Ser Lys Asn Ala Glu Ser Phe

2545 2550 2555 256

Gin Phe His Thr Glu Asp Tyr Phe Gly Lys Glu Ser Leu Trp Thr Gly

2565 2570 2575

Lys Gly He Gin Leu Ala Asp Gly Gly Trp Leu He Pro Ser Asn Asp 2580 2585 2590

Gly Lys Ala Gly Lys Glu Glu Phe Tyr Arg Ala Leu Cys Asp Thr Pro

2595 2600 2605

Gly Val Asp Pro Lys Leu He Ser Arg He Trp Val Tyr Asn His Tyr 2610 2615 2620 Arg Trp He He Trp Lys Leu Ala Ala Met Glu Cys Ala Phe Pro Lys

2625 2630 2635 264

Glu Phe Ala Asn Arg Cys Leu Ser Pro Glu Arg Val Leu Leu Gin Leu

2645 2650 2655

Lys Tyr Arg Tyr Asp Thr Glu He Asp Arg Ser Arg Arg Ser Ala He 2660 2665 2670

Lys Lys He Met Glu Arg Asp Asp Thr Ala Ala Lys Thr Leu Val Leu

2675 2680 2685

Cys Val Ser Asp He He Ser Leu Ser Ala Asn He Ser Glu Thr Ser 2690 2695 2700 Ser Asn Lys Thr Ser Ser Ala Asp Thr Gin Lys Val Ala He He Glu

2705 2710 2715 272

Leu Thr Asp Gly Trp Tyr Ala Val Lys Ala Gin Leu Asp Pro Pro Leu

2725 2730 2735

Leu Ala Val Leu Lys Asn Gly Arg Leu Thr Val Gly Gin Lys He He 2740 2745 2750

Leu His Gly Ala Glu Leu Val Gly Ser Pro Asp Ala Cys Thr Pro Leu

2755 2760 2765

Glu Ala Pro Glu Ser Leu Met Leu Lys He Ser Ala Asn Ser Thr Arg 2770 2775 2780 Pro Ala Arg Trp Tyr Thr Lys Leu Gly Phe Phe Pro Asp Pro Arg Pro

2785 2790 2795 280

Phe Pro Leu Pro Leu Ser Ser Leu Phe Ser Asp Gly Gly Asn Val Gly

2805 2810 2815

Cys Val Asp Val He He Gin Arg Ala Tyr Pro He Gin Trp Met Glu 2820 2825 2830

Lys Thr Ser Ser Gly Leu Tyr He Phe Arg Asn Glu Arg Glu Glu Glu

2835 2840 2845

Lys Glu Ala Ala Lys Tyr Val Glu Ala Gin Gin Lys Arg Leu Glu Ala

2850 2855 2860 Leu Phe Thr Lys He Gin Glu Glu Phe Glu Glu His Glu Glu Asn Thr

2865 2870 2875 288

Thr Lys Pro Tyr Leu Pro Ser Arg Ala Leu Thr Arg Gin Gin Val Arg

2885 2890 2895

Ala Leu Gin Asp Gly Ala Glu Leu Tyr Glu Ala Val Lys Asn Ala Ala 2900 2905 2910

Asp Pro Ala Tyr Leu Glu Gly Tyr Phe Ser Glu Glu Gin Leu Arg Ala 2915 2920 2925 Leu Asn Asn His Arg Gin Met Leu Asn Asp Lys Lys Gin Ala Gin He

2930 2935 2940

Gin Leu Glu He Arg Lys Ala Met Glu Ser Ala Glu Gin Lys Glu Gin 2945 2950 2955 296

Gly Leu Ser Arg Asp Val Thr Thr Val Trp Lys Leu Arg He Val Ser

2965 2970 2975

Tyr Ser Lys Lys Glu Lys Asp Ser Val He Leu Ser He Trp Arg Pro 2980 2985 2990 Ser Ser Asp Leu Tyr Ser Leu Leu Thr Glu Gly Lys Arg Tyr Arg He 2995 3000 3005

Tyr His Leu Ala Thr Ser Lys Ser Lys Ser Lys Ser Glu Arg Ala Asn

3010 3015 3020

He Gin Leu Ala Ala Thr Lys Lys Thr Gin Tyr Gin Gin Leu Pro Val 3025 3030 3035 304

Ser Asp Glu He Leu Phe Gin He Tyr Gin Pro Arg Glu Pro Leu His

3045 3050 3055

Phe Ser Lys Phe Leu Asp Pro Asp Phe Gin Pro Ser Cys Ser Glu Val 3060 3065 3070 Asp Leu He Gly Phe Val Val Ser Val Val Lys Lys Thr Gly Leu Ala

3075 3080 3085

Pro Phe Val Tyr Leu Ser Asp Glu Cys Tyr Asn Leu Leu Ala He Lys

3090 3095 3100

Phe Trp He Asp Leu Asn Glu Asp He He Lys Pro His Met Leu He 3105 3110 3115 312

Ala Ala Ser Asn Leu Gin Trp Arg Pro Glu Ser Lys Ser Gly Leu Leu

3125 3130 3135

Thr Leu Phe Ala Gly Asp Phe Ser Val Phe Ser Ala Ser Pro Lys Glu 3140 3145 3150 Gly His Phe Gin Glu Thr Phe Asn Lys Met Lys Asn Thr Val Glu Asn

3155 3160 3165

He Asp He Leu Cys Asn Glu Ala Glu Asn Lys Leu Met His He Leu

3170 3175 3180

His Ala Asn Asp Pro Lys Trp Ser Thr Pro Thr Lys Asp Cys Thr Ser 3185 3190 3195 320

Gly Pro Tyr Thr Ala Gin He He Pro Gly Thr Gly Asn Lys Leu Leu

3205 3210 3215

Met Ser Ser Pro Asn Cys Glu He Tyr Tyr Gin Ser Pro Leu Ser Leu 3220 3225 3230 Cys Met Ala Lys Arg Lys Ser Val Ser Thr Pro Val Ser Ala Gin Met

3235 3240 3245

Thr Ser Lys Ser Cys Lys Gly Glu Lys Glu He Asp Asp Gin Lys Asn

3250 3255 3260

Cys Lys Lys Arg Arg Ala Leu Asp Phe Leu Ser Arg Leu Pro Leu Pro 3265 3270 3275 328

Pro Pro Val Ser Pro He Cys Thr Phe Val Ser Pro Ala Ala Gin Lys

3285 3290 3295

Ala Phe Gin Pro Pro Arg Ser Cys Gly Thr Lys Tyr Glu Thr Pro He 3300 3305 3310 Lys Lys Lys Glu Leu Asn Ser Pro Gin Met Thr Pro Phe Lys Lys Phe 3315 3320 3325

Asn Glu He Ser Leu Leu Glu Ser Asn Ser He Ala Asp Glu Glu Leu

3330 3335 3340

Ala Leu He Asn Thr Gin Ala Leu Leu Ser Gly Ser Thr Gly Glu Lys 3345 3350 3355 336

Gin Phe He Ser Val Ser Glu Ser Thr Arg Thr Ala Pro Thr Ser Ser

3365 3370 3375

Glu Asp Tyr Leu Arg Leu Lys Arg Arg Cys Thr Thr Ser Leu He Lys 3380 3385 3390 Glu Gin Glu Ser Ser Gin Ala Ser Thr Glu Glu Cys Glu Lys Asn Lys 3395 3400 3405

Gin Asp Thr He Thr Thr Lys Lys Tyr He 3410 3415

(2) INFORMATION FOR SEQ ID NO: 10:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 10485 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA (ix) FEATURE: (A) NAME/KEY: Coding Sequence

(B) LOCATION: 229...10482 (D) OTHER INFORMATION: BRCA2 (OMI4)

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10:

GGTGGCGCGA GCTTCTGAAA CTAGGCGGCA GAGGCGGAGC CGCTGTGGCA CTGCTGCGCC 60

TCTGCTGCGC CTCGGGTGTC TTTTGCGGCG GTGGGTCGCC GCCGGGAGAA GCGTGAGGGG 120

ACAGATTTGT GACCGGCGCG GTTTTTGTCA GCTTACTCCG GCCAAAAAAG AACTGCACCT 180

CTGGAGCGGA CTTATTTACC AAGCATTGGA GGAATATCGT AGGTAAAA ATG CCT ATT 237 Met Pro He

1

GGA TCC AAA GAG AGG CCA ACA TTT TTT GAA ATT TTT AAG ACA CGC TGC 285 Gly Ser Lys Glu Arg Pro Thr Phe Phe Glu He Phe Lys Thr Arg Cys 5 10 15

AAC AAA GCA GAT TTA GGA CCA ATA AGT CTT AAT TGG TTT GAA GAA CTT 333 Asn Lys Ala Asp Leu Gly Pro He Ser Leu Asn Trp Phe Glu Glu Leu 20 25 30 35

TCT TCA GAA GCT CCA CCC TAT AAT TCT GAA CCT GCA GAA GAA TCT GAA 381 Ser Ser Glu Ala Pro Pro Tyr Asn Ser Glu Pro Ala Glu Glu Ser Glu 40 45 50 CAT AAA AAC AAC AAT TAC GAA CCA AAC CTA TTT AAA ACT CCA CAA AGG 429 His Lys Asn Asn Asn Tyr Glu Pro Asn Leu Phe Lys Thr Pro Gin Arg 55 60 65

AAA CCA TCT TAT AAT CAG CTG GCT TCA ACT CCA ATA ATA TTC AAA GAG 477 Lys Pro Ser Tyr Asn Gin Leu Ala Ser Thr Pro He He Phe Lys Glu 70 75 80

CAA GGG CTG ACT CTG CCG CTG TAC CAA TCT CCT GTA AAA GAA TTA GAT 525 Gin Gly Leu Thr Leu Pro Leu Tyr Gin Ser Pro Val Lys Glu Leu Asp 85 90 95

AAA TTC AAA TTA GAC TTA GGA AGG AAT GTT CCC AAT AGT AGA CAT AAA 573

Lys Phe Lys Leu Asp Leu Gly Arg Asn Val Pro Asn Ser Arg His Lys

100 105 110 115

AGT CTT CGC ACA GTG AAA ACT AAA ATG GAT CAA GCA GAT GAT GTT TCC 621

Ser Leu Arg Thr Val Lys Thr Lys Met Asp Gin Ala Asp Asp Val Ser 120 125 130 TGT CCA CTT CTA AAT TCT TGT CTT AGT GAA AGT CCT GTT GTT CTA CAA 669 Cys Pro Leu Leu Asn Ser Cys Leu Ser Glu Ser Pro Val Val Leu Gin 135 140 145 TGT ACA CAT GTA ACA CCA CAA AGA GAT AAG TCA GTG GTA TGT GGG AGT 717 Cys Thr His Val Thr Pro Gin Arg Asp Lys Ser Val Val Cys Gly Ser 150 155 160

TTG TTT CAT ACA CCA AAG TTT GTG AAG GGT CGT CAG ACA CCA AAA CAT 765 Leu Phe His Thr Pro Lys Phe Val Lys Gly Arg Gin Thr Pro Lys His 165 170 175

ATT TCT GAA AGT CTA GGA GCT GAG GTG GAT CCT GAT ATG TCT TGG TCA 813 He Ser Glu Ser Leu Gly Ala Glu Val Asp Pro Asp Met Ser Trp Ser 180 185 190 195 AGT TCT TTA GCT ACA CCA CCC ACC CTT AGT TCT ACT GTG CTC ATA GTC 861 Ser Ser Leu Ala Thr Pro Pro Thr Leu Ser Ser Thr Val Leu He Val 200 205 210

AGA AAT GAA GAA GCA TCT GAA ACT GTA TTT CCT CAT GAT ACT ACT GCT 909 Arg Asn Glu Glu Ala Ser Glu Thr Val Phe Pro His Asp Thr Thr Ala

215 220 225

AAT GTG AAA AGC TAT TTT TCC AAT CAT GAT GAA AGT CTG AAG AAA AAT 957 Asn Val Lys Ser Tyr Phe Ser Asn His Asp Glu Ser Leu Lys Lys Asn 230 235 240

GAT AGA TTT ATC GCT TCT GTG ACA GAC AGT GAA AAC ACA AAT CAA AGA 1005 Asp Arg Phe He Ala Ser Val Thr Asp Ser Glu Asn Thr Asn Gin Arg 245 250 255

GAA GCT GCA AGT CAT GGA TTT GGA AAA ACA TCA GGG AAT TCA TTT AAA 1053 Glu Ala Ala Ser His Gly Phe Gly Lys Thr Ser Gly Asn Ser Phe Lys 260 265 270 275 GTA AAT AGC TGC AAA GAC CAC ATT GGA AAG TCA ATG CCA AAT GTC CTA 1101 Val Asn Ser Cys Lys Asp His He Gly Lys Ser Met Pro Asn Val Leu 280 285 290

GAA GAT GAA GTA TAT GAA ACA GTT GTA GAT ACC TCT GAA GAA GAT AGT 1149 Glu Asp Glu Val Tyr Glu Thr Val Val Asp Thr Ser Glu Glu Asp Ser

295 300 305

TTT TCA TTA TGT TTT TCT AAA TGT AGA ACA AAA AAT CTA CAA AAA GTA 1197 Phe Ser Leu Cys Phe Ser Lys Cys Arg Thr Lys Asn Leu Gin Lys Val 310 315 320

AGA ACT AGC AAG ACT AGG AAA AAA ATT TTC CAT GAA GCA AAC GCT GAT 1245 Arg Thr Ser Lys Thr Arg Lys Lys He Phe His Glu Ala Asn Ala Asp 325 330 335

GAA TGT GAA AAA TCT AAA AAC CAA GTG AAA GAA AAA TAC TCA TTT GTA 1293 Glu Cys Glu Lys Ser Lys Asn Gin Val Lys Glu Lys Tyr Ser Phe Val 340 345 350 355 TCT GAA GTG GAA CCA AAT GAT ACT GAT CCA TTA GAT TCA AAT GTA GCA 1341 Ser Glu Val Glu Pro Asn Asp Thr Asp Pro Leu Asp Ser Asn Val Ala 360 365 370

CAT CAG AAG CCC TTT GAG AGT GGA AGT GAC AAA ATC TCC AAG GAA GTT 1389 His Gin Lys Pro Phe Glu Ser Gly Ser Asp Lys He Ser Lys Glu Val

375 380 385 GTA CCG TCT TTG GCC TGT GAA TGG TCT CAA CTA ACC CTT TCA GGT CTA 1437 Val Pro Ser Leu Ala Cys Glu Trp Ser Gin Leu Thr Leu Ser Gly Leu 390 395 400

AAT GGA GCC CAG ATG GAG AAA ATA CCC CTA TTG CAT ATT TCT TCA TGT 1485 Asn Gly Ala Gin Met Glu Lys He Pro Leu Leu His He Ser Ser Cys 405 410 415 GAC CAA AAT ATT TCA GAA AAA GAC CTA TTA GAC ACA GAG AAC AAA AGA 1533 Asp Gin Asn He Ser Glu Lys Asp Leu Leu Asp Thr Glu Asn Lys Arg 420 425 430 435

AAG AAA GAT TTT CTT ACT TCA GAG AAT TCT TTG CCA CGT ATT TCT AGC 1581 Lys Lys Asp Phe Leu Thr Ser Glu Asn Ser Leu Pro Arg He Ser Ser

440 445 450

CTA CCA AAA TCA GAG AAG CCA TTA AAT GAG GAA ACA GTG GTA AAT AAG 1629 Leu Pro Lys Ser Glu Lys Pro Leu Asn Glu Glu Thr Val Val Asn Lys 455 460 465

AGA GAT GAA GAG CAG CAT CTT GAA TCT CAT ACA GAC TGC ATT CTT GCA 1677 Arg Asp Glu Glu Gin His Leu Glu Ser His Thr Asp Cys He Leu Ala 470 475 480

GTA AAG CAG GCA ATA TCT GGA ACT TCT CCA GTG GCT TCT TCA TTT CAG 1725 Val Lys Gin Ala He Ser Gly Thr Ser Pro Val Ala Ser Ser Phe Gin 485 490 495 GGT ATC AAA AAG TCT ATA TTC AGA ATA AGA GAA TCA CCT AAA GAG ACT 1773 Gly He Lys Lys Ser He Phe Arg He Arg Glu Ser Pro Lys Glu Thr 500 505 510 515

TTC AAT GCA AGT TTT TCA GGT CAT ATG ACT GAT CCA AAC TTT AAA AAA 1821 Phe Asn Ala Ser Phe Ser Gly His Met Thr Asp Pro Asn Phe Lys Lys

520 525 530

GAA ACT GAA GCC TCT GAA AGT GGA CTG GAA ATA CAT ACT GTT TGC TCA 1869 Glu Thr Glu Ala Ser Glu Ser Gly Leu Glu He His Thr Val Cys Ser 535 540 545

CAG AAG GAG GAC TCC TTA TGT CCA AAT TTA ATT GAT AAT GGA AGC TGG 1917 Gin Lys Glu Asp Ser Leu Cys Pro Asn Leu He Asp Asn Gly Ser Trp 550 555 560

CCA GCC ACC ACC ACA CAG AAT TCT GTA GCT TTG AAG AAT GCA GGT TTA 1965 Pro Ala Thr Thr Thr Gin Asn Ser Val Ala Leu Lys Asn Ala Gly Leu 565 570 575 ATA TCC ACT TTG AAA AAG AAA ACA AAT AAG TTT ATT TAT GCT ATA CAT 2013 He Ser Thr Leu Lys Lys Lys Thr Asn Lys Phe He Tyr Ala He His 580 585 590 595

GAT GAA ACA TCT TAT AAA GGA AAA AAA ATA CCG AAA GAC CAA AAA TCA 2061 Asp Glu Thr Ser Tyr Lys Gly Lys Lys He Pro Lys Asp Gin Lys Ser

600 605 610

GAA CTA ATT AAC TGT TCA GCC CAG TTT GAA GCA AAT GCT TTT GAA GCA 2109 Glu Leu He Asn Cys Ser Ala Gin Phe Glu Ala Asn Ala Phe Glu Ala 615 620 625

CCA CTT ACA TTT GCA AAT GCT GAT TCA GGT TTA TTG CAT TCT TCT GTG 2157 Pro Leu Thr Phe Ala Asn Ala Asp Ser Gly Leu Leu His Ser Ser Val 630 635 640 AAA AGA AGC TGT TCA CAG AAT GAT TCT GAA GAA CCA ACT TTG TCC TTA 2205 Lys Arg Ser Cys Ser Gin Asn Asp Ser Glu Glu Pro Thr Leu Ser Leu 645 650 655

ACT AGC TCT TTT GGG ACA ATT CTG AGG AAA TGT TCT AGA AAT GAA ACA 2253 Thr Ser Ser Phe Gly Thr He Leu Arg Lys Cys Ser Arg Asn Glu Thr 660 665 670 675

TGT TCT AAT AAT ACA GTA ATC TCT CAG GAT CTT GAT TAT AAA GAA GCA 2301 Cys Ser Asn Asn Thr Val He Ser Gin Asp Leu Asp Tyr Lys Glu Ala 680 685 690

AAA TGT AAT AAG GAA AAA CTA CAG TTA TTT ATT ACC CCA GAA GCT GAT 2349 Lys Cys Asn Lys Glu Lys Leu Gin Leu Phe He Thr Pro Glu Ala Asp 695 700 705

TCT CTG TCA TGC CTG CAG GAA GGA CAG TGT GAA AAT GAT CCA AAA AGC 2397 Ser Leu Ser Cys Leu Gin Glu Gly Gin Cys Glu Asn Asp Pro Lys Ser 710 715 720 AAA AAA GTT TCA GAT ATA AAA GAA GAG GTC TTG GCT GCA GCA TGT CAC 2445 Lys Lys Val Ser Asp He Lys Glu Glu Val Leu Ala Ala Ala Cys His 725 730 735

CCA GTA CAA CAT TCA AAA GTG GAA TAC AGT GAT ACT GAC TTT CAA TCC 2493 Pro Val Gin His Ser Lys Val Glu Tyr Ser Asp Thr Asp Phe Gin Ser 740 745 750 755

CAG AAA AGT CTT TTA TAT GAT CAT GAA AAT GCC AGC ACT CTT ATT TTA 2541 Gin Lys Ser Leu Leu Tyr Asp His Glu Asn Ala Ser Thr Leu He Leu 760 765 770

ACT CCT ACT TCC AAG GAT GTT CTG TCA AAC CTA GTC ATG ATT TCT AGA 2589 Thr Pro Thr Ser Lys Asp Val Leu Ser Asn Leu Val Met He Ser Arg 775 780 785

GGC AAA GAA TCA TAC AAA ATG TCA GAC AAG CTC AAA GGT AAC AAT TAT 2637 Gly Lys Glu Ser Tyr Lys Met Ser Asp Lys Leu Lys Gly Asn Asn Tyr 790 795 800 GAA TCT GAT GTT GAA TTA ACC AAA AAT ATT CCC ATG GAA AAG AAT CAA 2685 Glu Ser Asp Val Glu Leu Thr Lys Asn He Pro Met Glu Lys Asn Gin 805 810 815

GAT GTA TGT GCT TTA AAT GAA AAT TAT AAA AAC GTT GAG CTG TTG CCA 2733 Asp Val Cys Ala Leu Asn Glu Asn Tyr Lys Asn Val Glu Leu Leu Pro 820 825 830 835

CCT GAA AAA TAC ATG AGA GTA GCA TCA CCT TCA AGA AAG GTA CAA TTC 2781 Pro Glu Lys Tyr Met Arg Val Ala Ser Pro Ser Arg Lys Val Gin Phe 840 845 850

AAC CAA AAC ACA AAT CTA AGA GTA ATC CAA AAA AAT CAA GAA GAA ACT 2829 Asn Gin Asn Thr Asn Leu Arg Val He Gin Lys Asn Gin Glu Glu Thr 855 860 865

ACT TCA ATT TCA AAA ATA ACT GTC AAT CCA GAC TCT GAA GAA CTT TTC 2877 Thr Ser He Ser Lys He Thr Val Asn Pro Asp Ser Glu Glu Leu Phe 870 875 880

TCA GAC AAT GAG AAT AAT TTT GTC TTC CAA GTA GCT AAT GAA AGG AAT 2925 Ser Asp Asn Glu Asn Asn Phe Val Phe Gin Val Ala Asn Glu Arg Asn 885 890 895

AAT CTT GCT TTA GGA AAT ACT AAG GAA CTT CAT GAA ACA GAC TTG ACT 2973 Asn Leu Ala Leu Gly Asn Thr Lys Glu Leu His Glu Thr Asp Leu Thr 900 905 910 915

TGT GTA AAC GAA CCC ATT TTC AAG AAC TCT ACC ATG GTT TTA TAT GGA 3021

Cys Val Asn Glu Pro He Phe Lys Asn Ser Thr Met Val Leu Tyr Gly 920 925 930

GAC ACA GGT GAT AAA CAA GCA ACC CAA GTG TCA ATT AAA AAA GAT TTG 3069

Asp Thr Gly Asp Lys Gin Ala Thr Gin Val Ser He Lys Lys Asp Leu 935 940 945 GTT TAT GTT CTT GCA GAG GAG AAC AAA AAT AGT GTA AAG CAG CAT ATA 3117 Val Tyr Val Leu Ala Glu Glu Asn Lys Asn Ser Val Lys Gin His He 950 955 960

AAA ATG ACT CTA GGT CAA GAT TTA AAA TCG GAC ATC TCC TTG AAT ATA 3165 Lys Met Thr Leu Gly Gin Asp Leu Lys Ser Asp He Ser Leu Asn He 965 970 975

GAT AAA ATA CCA GAA AAA AAT AAT GAT TAC ATG AAC AAA TGG GCA GGA 3213 Asp Lys He Pro Glu Lys Asn Asn Asp Tyr Met Asn Lys Trp Ala Gly 980 985 990 995

CTC TTA GGT CCA ATT TCA AAT CAC AGT TTT GGA GGT AGC TTC AGA ACA 3261 Leu Leu Gly Pro He Ser Asn His Ser Phe Gly Gly Ser Phe Arg Thr 1000 1005 1010

GCT TCA AAT AAG GAA ATC AAG CTC TCT GAA CAT AAC ATT AAG AAG AGC 3309 Ala Ser Asn Lys Glu He Lys Leu Ser Glu His Asn He Lys Lys Ser 1015 1020 1025 AAA ATG TTC TTC AAA GAT ATT GAA GAA CAA TAT CCT ACT AGT TTA GCT 3357 Lys Met Phe Phe Lys Asp He Glu Glu Gin Tyr Pro Thr Ser Leu Ala 1030 1035 1040

TGT GTT GAA ATT GTA AAT ACC TTG GCA TTA GAT AAT CAA AAG AAA CTG 3405 Cys Val Glu He Val Asn Thr Leu Ala Leu Asp Asn Gin Lys Lys Leu 1045 1050 1055

AGC AAG CCT CAG TCA ATT AAT ACT GTA TCT GCA CAT TTA CAG AGT AGT 3453 Ser Lys Pro Gin Ser He Asn Thr Val Ser Ala His Leu Gin Ser Ser 1060 1065 1070 1075

GTA GTT GTT TCT GAT TGT AAA AAT AGT CAT ATA ACC CCT CAG ATG TTA 3501 Val Val Val Ser Asp Cys Lys Asn Ser His He Thr Pro Gin Met Leu 1080 1085 1090

TTT TCC AAG CAG GAT TTT AAT TCA AAC CAT AAT TTA ACA CCT AGC CAA 3549 Phe Ser Lys Gin Asp Phe Asn Ser Asn His Asn Leu Thr Pro Ser Gin 1095 1100 1105 AAG GCA GAA ATT ACA GAA CTT TCT ACT ATA TTA GAA GAA TCA GGA AGT 3597 Lys Ala Glu He Thr Glu Leu Ser Thr He Leu Glu Glu Ser Gly Ser 1110 1115 1120 CAG TTT GAA TTT ACT CAG TTT AGA AAG CCA AGC TAC ATA TTG CAG AAG 3645 Gin Phe Glu Phe Thr Gin Phe Arg Lys Pro Ser Tyr He Leu Gin Lys 1125 1130 1135

AGT ACA TTT GAA GTG CCT GAA AAC CAG ATG ACT ATC TTA AAG ACC ACT 3693 Ser Thr Phe Glu Val Pro Glu Asn Gin Met Thr He Leu Lys Thr Thr 1140 1145 1150 1155

TCT GAG GAA TGC AGA GAT GCT GAT CTT CAT GTC ATA ATG AAT GCC CCA 3741 Ser Glu Glu Cys Arg Asp Ala Asp Leu His Val He Met Asn Ala Pro 1160 1165 1170 TCG ATT GGT CAG GTA GAC AGC AGC AAG CAA TTT GAA GGT ACA GTT GAA 3789 Ser He Gly Gin Val Asp Ser Ser Lys Gin Phe Glu Gly Thr Val Glu 1175 1180 1185

ATT AAA CGG AAG TTT GCT GGC CTG TTG AAA AAT GAC TGT AAC AAA AGT 3837 He Lys Arg Lys Phe Ala Gly Leu Leu Lys Asn Asp Cys Asn Lys Ser

1190 1195 1200

GCT TCT GGT TAT TTA ACA GAT GAA AAT GAA GTG GGG TTT AGG GGC TTT 3885 Ala Ser Gly Tyr Leu Thr Asp Glu Asn Glu Val Gly Phe Arg Gly Phe 1205 1210 1215

TAT TCT GCT CAT GGC ACA AAA CTG AAT GTT TCT ACT GAA GCT CTG CAA 3933

Tyr Ser Ala His Gly Thr Lys Leu Asn Val Ser Thr Glu Ala Leu Gin 1220 1225 1230 1235

AAA GCT GTG AAA CTG TTT AGT GAT ATT GAG AAT ATT AGT GAG GAA ACT 3981

Lys Ala Val Lys Leu Phe Ser Asp He Glu Asn He Ser Glu Glu Thr 1240 1245 1250 TCT GCA GAG GTA CAT CCA ATA AGT TTA TCT TCA AGT AAA TGT CAT GAT 4029

Ser Ala Glu Val His Pro He Ser Leu Ser Ser Ser Lys Cys His Asp 1255 1260 1265

TCT GTT GTT TCA ATG TTT AAG ATA GAA AAT CAT AAT GAT AAA ACT GTA 4077 Ser Val Val Ser Met Phe Lys He Glu Asn His Asn Asp Lys Thr Val

1270 1275 1280

AGT GAA AAA AAT AAT AAA TGC CAA CTG ATA TTA CAA AAT AAT ATT GAA 4125 Ser Glu Lys Asn Asn Lys Cys Gin Leu He Leu Gin Asn Asn He Glu 1285 1290 1295

ATG ACT ACT GGC ACT TTT GTT GAA GAA ATT ACT GAA AAT TAC AAG AGA 4173 Met Thr Thr Gly Thr Phe Val Glu Glu He Thr Glu Asn Tyr Lys Arg 1300 1305 1310 1315

AAT ACT GAA AAT GAA GAT AAC AAA TAT ACT GCT GCC AGT AGA AAT TCT 4221 Asn Thr Glu Asn Glu Asp Asn Lys Tyr Thr Ala Ala Ser Arg Asn Ser 1320 1325 1330 CAT AAC TTA GAA TTT GAT GGC AGT GAT TCA AGT AAA AAT GAT ACT GTT 4269 His Asn Leu Glu Phe Asp Gly Ser Asp Ser Ser Lys Asn Asp Thr Val 1335 1340 1345

TGT ATT CAT AAA GAT GAA ACG GAC TTG CTA TTT ACT GAT CAG CAC AAC 4317 Cys He His Lys Asp Glu Thr Asp Leu Leu Phe Thr Asp Gin His Asn 1350 1355 1360 ATA TGT CTT AAA TTA TCT GGC CAG TTT ATG AAG GAG GGA AAC ACT CAG 4365

He Cys Leu Lys Leu Ser Gly Gin Phe Met Lys Glu Gly Asn Thr Gin 1365 1370 1375

ATT AAA GAA GAT TTG TCA GAT TTA ACT TTT TTG GAA GTT GCG AAA GCT 4413

He Lys Glu Asp Leu Ser Asp Leu Thr Phe Leu Glu Val Ala Lys Ala 1380 1385 1390 1395 CAA GAA GCA TGT CAT GGT AAT ACT TCA AAT AAA GAA CAG TTA ACT GCT 4461 Gin Glu Ala Cys His Gly Asn Thr Ser Asn Lys Glu Gin Leu Thr Ala 1400 1405 1410

ACT AAA ACG GAG CAA AAT ATA AAA GAT TTT GAG ACT TCT GAT ACA TTT 4509 Thr Lys Thr Glu Gin Asn He Lys Asp Phe Glu Thr Ser Asp Thr Phe 1415 1420 1425

TTT CAG ACT GCA AGT GGG AAA AAT ATT AGT GTC GCC AAA GAG TCA TTT 4557 Phe Gin Thr Ala Ser Gly Lys Asn He Ser Val Ala Lys Glu Ser Phe 1430 1435 1440

AAT AAA ATT GTA AAT TTC TTT GAT CAG AAA CCA GAA GAA TTG CAT AAC 4605

Asn Lys He Val Asn Phe Phe Asp Gin Lys Pro Glu Glu Leu His Asn 1445 1450 1455

TTT TCC TTA AAT TCT GAA TTA CAT TCT GAC ATA AGA AAG AAC AAA ATG 4653

Phe Ser Leu Asn Ser Glu Leu His Ser Asp He Arg Lys Asn Lys Met 1460 1465 1470 1475 GAC ATT CTA AGT TAT GAG GAA ACA GAC ATA GTT AAA CAC AAA ATA CTG 4701 Asp He Leu Ser Tyr Glu Glu Thr Asp He Val Lys His Lys He Leu 1480 1485 1490

AAA GAA AGT GTC CCA GTT GGT ACT GGA AAT CAA CTA GTG ACC TTC CAG 4749 Lys Glu Ser Val Pro Val Gly Thr Gly Asn Gin Leu Val Thr Phe Gin 1495 1500 1505

GGA CAA CCC GAA CGT GAT GAA AAG ATC AAA GAA CCT ACT CTG TTG GGT 4797 Gly Gin Pro Glu Arg Asp Glu Lys He Lys Glu Pro Thr Leu Leu Gly 1510 1515 1520

TTT CAT ACA GCT AGC GGG AAA AAA GTT AAA ATT GCA AAG GAA TCT TTG 4845

Phe His Thr Ala Ser Gly Lys Lys Val Lys He Ala Lys Glu Ser Leu 1525 1530 1535

GAC AAA GTG AAA AAC CTT TTT GAT GAA AAA GAG CAA GGT ACT AGT GAA 4893

Asp Lys Val Lys Asn Leu Phe Asp Glu Lys Glu Gin Gly Thr Ser Glu 1540 1545 1550 1555 ATC ACC AGT TTT AGC CAT CAA TGG GCA AAG ACC CTA AAG TAC AGA GAG 4941 He Thr Ser Phe Ser His Gin Trp Ala Lys Thr Leu Lys Tyr Arg Glu 1560 1565 1570

GCC TGT AAA GAC CTT GAA TTA GCA TGT GAG ACC ATT GAG ATC ACA GCT 4989 Ala Cys Lys Asp Leu Glu Leu Ala Cys Glu Thr He Glu He Thr Ala 1575 1580 1585

GCC CCA AAG TGT AAA GAA ATG CAG AAT TCT CTC AAT AAT GAT AAA AAC 5037 Ala Pro Lys Cys Lys Glu Met Gin Asn Ser Leu Asn Asn Asp Lys Asn 1590 1595 1600

CTT GTT TCT ATT GAG ACT GTG GTG CCA CCT AAG CTC TTA AGT GAT AAT 5085 Leu Val Ser He Glu Thr Val Val Pro Pro Lys Leu Leu Ser Asp Asn 1605 1610 1615 TTA TGT AGA CAA ACT GAA AAT CTC AAA ACA TCA AAA AGT ATC TTT TTG 5133 Leu Cys Arg Gin Thr Glu Asn Leu Lys Thr Ser Lys Ser He Phe Leu 1620 1625 1630 1635

AAA GTT AAA GTA CAT GAA AAT GTA GAA AAA GAA ACA GCA AAA AGT CCT 5181 Lys Val Lys Val His Glu Asn Val Glu Lys Glu Thr Ala Lys Ser Pro

1640 1645 1650

GCA ACT TGT TAC ACA AAT CAG TCC CCT TAT TCA GTC ATT GAA AAT TCA 5229 Ala Thr Cys Tyr Thr Asn Gin Ser Pro Tyr Ser Val He Glu Asn Ser 1655 1660 1665

GCC TTA GCT TTT TAC ACA AGT TGT AGT AGA AAA ACT TCT GTG AGT CAG 5277 Ala Leu Ala Phe Tyr Thr Ser Cys Ser Arg Lys Thr Ser Val Ser Gin 1670 1675 1680

ACT TCA TTA CTT GAA GCA AAA AAA TGG CTT AGA GAA GGA ATA TTT GAT 5325 Thr Ser Leu Leu Glu Ala Lys Lys Trp Leu Arg Glu Gly He Phe Asp 1685 1690 1695 GGT CAA CCA GAA AGA ATA AAT ACT GCA GAT TAT GTA GGA AAT TAT TTG 5373

Gly Gin Pro Glu Arg He Asn Thr Ala Asp Tyr Val Gly Asn Tyr Leu 1700 1705 1710 1715

TAT GAA AAT AAT TCA AAC AGT ACT ATA GCT GAA AAT GAC AAA AAT CAT 5421 Tyr Glu Asn Asn Ser Asn Ser Thr He Ala Glu Asn Asp Lys Asn His

1720 1725 1730

CTC TCC GAA AAA CAA GAT ACT TAT TTA AGT AAC AGT AGC ATG TCT AAC 5469 Leu Ser Glu Lys Gin Asp Thr Tyr Leu Ser Asn Ser Ser Met Ser Asn 1735 1740 1745

AGC TAT TCC TAC CAT TCT GAT GAG GTA TAT AAT GAT TCA GGA TAT CTC 5517 Ser Tyr Ser Tyr His Ser Asp Glu Val Tyr Asn Asp Ser Gly Tyr Leu 1750 1755 1760

TCA AAA AAT AAA CTT GAT TCT GGT ATT GAG CCA GTA TTG AAG AAT GTT 5565 Ser Lys Asn Lys Leu Asp Ser Gly He Glu Pro Val Leu Lys Asn Val 1765 1770 1775 GAA GAT CAA AAA AAC ACT AGT TTT TCC AAA GTA ATA TCC AAT GTA AAA 5613 Glu Asp Gin Lys Asn Thr Ser Phe Ser Lys Val He Ser Asn Val Lys 1780 1785 1790 1795

GAT GCA AAT GCA TAC CCA CAA ACT GTA AAT GAA GAT ATT TGC GTT GAG 5661 Asp Ala Asn Ala Tyr Pro Gin Thr Val Asn Glu Asp He Cys Val Glu

1800 1805 1810

GAA CTT GTG ACT AGC TCT TCA CCC TGC AAA AAT AAA AAT GCA GCC ATT 5709 Glu Leu Val Thr Ser Ser Ser Pro Cys Lys Asn Lys Asn Ala Ala He 1815 1820 1825

AAA TTG TCC ATA TCT AAT AGT AAT AAT TTT GAG GTA GGG CCA CCT GCA 5757 Lys Leu Ser He Ser Asn Ser Asn Asn Phe Glu Val Gly Pro Pro Ala 1830 1835 1840

TTT AGG ATA GCC AGT GGT AAA ATC GTT TGT GTT TCA CAT GAA ACA ATT 5805 Phe Arg He Ala Ser Gly Lys He Val Cys Val Ser His Glu Thr He 1845 1850 1855

AAA AAA GTG AAA GAC ATA TTT ACA GAC AGT TTC AGT AAA GTA ATT AAG 5853 Lys Lys Val Lys Asp He Phe Thr Asp Ser Phe Ser Lys Val He Lys 1860 1865 1870 1875

GAA AAC AAC GAG AAT AAA TCA AAA ATT TGC CAA ACG AAA ATT ATG GCA 5901 Glu Asn Asn Glu Asn Lys Ser Lys He Cys Gin Thr Lys He Met Ala 1880 1885 1890

GGT TGT TAC GAG GCA TTG GAT GAT TCA GAG GAT ATT CTT CAT AAC TCT 5949

Gly Cys Tyr Glu Ala Leu Asp Asp Ser Glu Asp He Leu His Asn Ser 1895 1900 1905

CTA GAT AAT GAT GAA TGT AGC ACG CAT TCA CAT AAG GTT TTT GCT GAC 5997

Leu Asp Asn Asp Glu Cys Ser Thr His Ser His Lys Val Phe Ala Asp 1910 1915 1920 ATT CAG AGT GAA GAA ATT TTA CAA CAT AAC CAA AAT ATG TCT GGA TTG 6045 He Gin Ser Glu Glu He Leu Gin His Asn Gin Asn Met Ser Gly Leu 1925 1930 1935

GAG AAA GTT TCT AAA ATA TCA CCT TGT GAT GTT AGT TTG GAA ACT TCA 6093 Glu Lys Val Ser Lys He Ser Pro Cys Asp Val Ser Leu Glu Thr Ser 1940 1945 1950 1955

GAT ATA TGT AAA TGT AGT ATA GGG AAG CTT CAT AAG TCA GTC TCA TCT 6141 Asp He Cys Lys Cys Ser He Gly Lys Leu His Lys Ser Val Ser Ser 1960 1965 1970

GCA AAT ACT TGT GGG ATT TTT AGC ACA GCA AGT GGA AAA TCT GTC CAG 6189 Ala Asn Thr Cys Gly He Phe Ser Thr Ala Ser Gly Lys Ser Val Gin 1975 1980 1985

GTA TCA GAT GCT TCA TTA CAA AAC GCA AGA CAA GTG TTT TCT GAA ATA 6237 Val Ser Asp Ala Ser Leu Gin Asn Ala Arg Gin Val Phe Ser Glu He 1990 1995 2000 GAA GAT AGT ACC AAG CAA GTC TTT TCC AAA GTA TTG TTT AAA AGT AAC 6285 Glu Asp Ser Thr Lys Gin Val Phe Ser Lys Val Leu Phe Lys Ser Asn 2005 2010 2015

GAA CAT TCA GAC CAG CTC ACA AGA GAA GAA AAT ACT GCT ATA CGT ACT 6333 Glu His Ser Asp Gin Leu Thr Arg Glu Glu Asn Thr Ala He Arg Thr 2020 2025 2030 2035

CCA GAA CAT TTA ATA TCC CAA AAA GGC TTT TCA TAT AAT GTG GTA AAT 6381 Pro Glu His Leu He Ser Gin Lys Gly Phe Ser Tyr Asn Val Val Asn 2040 2045 2050

TCA TCT GCT TTC TCT GGA TTT AGT ACA GCA AGT GGA AAG CAA GTT TCC 6429 Ser Ser Ala Phe Ser Gly Phe Ser Thr Ala Ser Gly Lys Gin Val Ser 2055 2060 2065

ATT TTA GAA AGT TCC TTA CAC AAA GTT AAG GGA GTG TTA GAG GAA TTT 6477 He Leu Glu Ser Ser Leu His Lys Val Lys Gly Val Leu Glu Glu Phe 2070 2075 2080 GAT TTA ATC AGA ACT GAG CAT AGT CTT CAC TAT TCA CCT ACG TCT AGA 6525 Asp Leu He Arg Thr Glu His Ser Leu His Tyr Ser Pro Thr Ser Arg 2085 2090 2095 CAA AAT GTA TCA AAA ATA CTT CCT CGT GTT GAT AAG AGA AAC CCA GAG 6573 Gin Asn Val Ser Lys He Leu Pro Arg Val Asp Lys Arg Asn Pro Glu 2100 2105 2110 2115

CAC TGT GTA AAC TCA GAA ATG GAA AAA ACC TGC AGT AAA GAA TTT AAA 6621 His Cys Val Asn Ser Glu Met Glu Lys Thr Cys Ser Lys Glu Phe Lys 2120 2125 2130

TTA TCA AAT AAC TTA AAT GTT GAA GGT GGT TCT TCA GAA AAT AAT CAC 6669 Leu Ser Asn Asn Leu Asn Val Glu Gly Gly Ser Ser Glu Asn Asn His 2135 2140 2145 TCT ATT AAA GTT TCT CCA TAT CTC TCT CAA TTT CAA CAA GAC AAA CAA 6717 Ser He Lys Val Ser Pro Tyr Leu Ser Gin Phe Gin Gin Asp Lys Gin 2150 2155 2160

CAG TTG GTA TTA GGA ACC AAA GTC TCA CTT GTT GAG AAC ATT CAT GTT 6765 Gin Leu Val Leu Gly Thr Lys Val Ser Leu Val Glu Asn He His Val 2165 2170 2175

TTG GGA AAA GAA CAG GCT TCA CCT AAA AAC GTA AAA ATG GAA ATT GGT 6813 Leu Gly Lys Glu Gin Ala Ser Pro Lys Asn Val Lys Met Glu He Gly 2180 2185 2190 2195

AAA ACT GAA ACT TTT TCT GAT GTT CCT GTG AAA ACA AAT ATA GAA GTT 6861 Lys Thr Glu Thr Phe Ser Asp Val Pro Val Lys Thr Asn He Glu Val 2200 2205 2210

TGT TCT ACT TAC TCC AAA GAT TCA GAA AAC TAC TTT GAA ACA GAA GCA 6909 Cys Ser Thr Tyr Ser Lys Asp Ser Glu Asn Tyr Phe Glu Thr Glu Ala 2215 2220 2225 GTA GAA ATT GCT AAA GCT TTT ATG GAA GAT GAT GAA CTG ACA GAT TCT 6957 Val Glu He Ala Lys Ala Phe Met Glu Asp Asp Glu Leu Thr Asp Ser 2230 2235 2240

AAA CTG CCA AGT CAT GCC ACA CAT TCT CTT TTT ACA TGT CCC GAA AAT 7005 Lys Leu Pro Ser His Ala Thr His Ser Leu Phe Thr Cys Pro Glu Asn 2245 2250 2255

GAG GAA ATG GTT TTG TCA AAT TCA AGA ATT GGA AAA AGA AGA GGA GAG 7053 Glu Glu Met Val Leu Ser Asn Ser Arg He Gly Lys Arg Arg Gly Glu 2260 2265 2270 2275

CCC CTT ATC TTA GTG GGA GAA CCC TCA ATC AAA AGA AAC TTA TTA AAT 7101 Pro Leu He Leu Val Gly Glu Pro Ser He Lys Arg Asn Leu Leu Asn 2280 2285 2290

GAA TTT GAC AGG ATA ATA GAA AAT CAA GAA AAA TCC TTA AAG GCT TCA 7149 Glu Phe Asp Arg He He Glu Asn Gin Glu Lys Ser Leu Lys Ala Ser 2295 2300 2305 AAA AGC ACT CCA GAT GGC ACA ATA AAA GAT CGA AGA TTG TTT ATG CAT 7197 Lys Ser Thr Pro Asp Gly Thr He Lys Asp Arg Arg Leu Phe Met His 2310 2315 2320

CAT GTT TCT TTA GAG CCG ATT ACC TGT GTA CCC TTT CGC ACA ACT AAG 7245 His Val Ser Leu Glu Pro He Thr Cys Val Pro Phe Arg Thr Thr Lys 2325 2330 2335 GAA CGT CAA GAG ATA CAG AAT CCA AAT TTT ACC GCA CCT GGT CAA GAA 7293 Glu Arg Gin Glu He Gin Asn Pro Asn Phe Thr Ala Pro Gly Gin Glu 2340 2345 2350 2355

TTT CTG TCT AAA TCT CAT TTG TAT GAA CAT CTG ACT TTG GAA AAA TCT 7341 Phe Leu Ser Lys Ser His Leu Tyr Glu His Leu Thr Leu Glu Lys Ser 2360 2365 2370 TCA AGC AAT TTA GCA GTT TCA GGA CAT CCA TTT TAT CAA GTT TCT GCT 7389 Ser Ser Asn Leu Ala Val Ser Gly His Pro Phe Tyr Gin Val Ser Ala 2375 2380 2385

ACA AGA AAT GAA AAA ATG AGA CAC TTG ATT ACT ACA GGC AGA CCA ACC 7437 Thr Arg Asn Glu Lys Met Arg His Leu He Thr Thr Gly Arg Pro Thr 2390 2395 2400

AAA GTC TTT GTT CCA CCT TTT AAA ACT AAA TCG CAT TTT CAC AGA GTT 7485 Lys Val Phe Val Pro Pro Phe Lys Thr Lys Ser His Phe His Arg Val 2405 2410 2415

GAA CAG TGT GTT AGG AAT ATT AAC TTG GAG GAA AAC AGA CAA AAG CAA 7533 Glu Gin Cys Val Arg Asn He Asn Leu Glu Glu Asn Arg Gin Lys Gin 2420 2425 2430 2435

AAC ATT GAT GGA CAT GGC TCT GAT GAT AGT AAA AAT AAG ATT AAT GAC 7581 Asn He Asp Gly His Gly Ser Asp Asp Ser Lys Asn Lys He Asn Asp 2440 2445 2450 AAT GAG ATT CAT CAG TTT AAC AAA AAC AAC TCC AAT CAA GCA GCA GCT 7629 Asn Glu He His Gin Phe Asn Lys Asn Asn Ser Asn Gin Ala Ala Ala 2455 2460 2465

GTA ACT TTC ACA AAG TGT GAA GAA GAA CCT TTA GAT TTA ATT ACA AGT 7677 Val Thr Phe Thr Lys Cys Glu Glu Glu Pro Leu Asp Leu He Thr Ser 2470 2475 2480

CTT CAG AAT GCC AGA GAT ATA CAG GAT ATG CGA ATT AAG AAG AAA CAA 7725 Leu Gin Asn Ala Arg Asp He Gin Asp Met Arg He Lys Lys Lys Gin 2485 2490 2495

AGG CAA CGC GTC TTT CCA CAG CCA GGC AGT CTG TAT CTT GCA AAA ACA 7773

Arg Gin Arg Val Phe Pro Gin Pro Gly Ser Leu Tyr Leu Ala Lys Thr 2500 2505 2510 2515

TCC ACT CTG CCT CGA ATC TCT CTG AAA GCA GCA GTA GGA GGC CAA GTT 7821

Ser Thr Leu Pro Arg He Ser Leu Lys Ala Ala Val Gly Gly Gin Val 2520 2525 2530 CCC TCT GCG TGT TCT CAT AAA CAG CTG TAT ACG TAT GGC GTT TCT AAA 7869 Pro Ser Ala Cys Ser His Lys Gin Leu Tyr Thr Tyr Gly Val Ser Lys 2535 2540 2545

CAT TGC ATA AAA ATT AAC AGC AAA AAT GCA GAG TCT TTT CAG TTT CAC 7917 His Cys He Lys He Asn Ser Lys Asn Ala Glu Ser Phe Gin Phe His 2550 2555 2560

ACT GAA GAT TAT TTT GGT AAG GAA AGT TTA TGG ACT GGA AAA GGA ATA 7965 Thr Glu Asp Tyr Phe Gly Lys Glu Ser Leu Trp Thr Gly Lys Gly He 2565 2570 2575

CAG TTG GCT GAT GGT GGA TGG CTC ATA CCC TCC AAT GAT GGA AAG GCT 8013 Gin Leu Ala Asp Gly Gly Trp Leu He Pro Ser Asn Asp Gly Lys Ala 2580 2585 2590 2595 GGA AAA GAA GAA TTT TAT AGG GCT CTG TGT GAC ACT CCA GGT GTG GAT 8061 Gly Lys Glu Glu Phe Tyr Arg Ala Leu Cys Asp Thr Pro Gly Val Asp 2600 2605 2610

CCA AAG CTT ATT TCT AGA ATT TGG GTT TAT AAT CAC TAT AGA TGG ATC 8109 Pro Lys Leu He Ser Arg He Trp Val Tyr Asn His Tyr Arg Trp He 2615 2620 2625

ATA TGG AAA CTG GCA GCT ATG GAA TGT GCC TTT CCT AAG GAA TTT GCT 8157 He Trp Lys Leu Ala Ala Met Glu Cys Ala Phe Pro Lys Glu Phe Ala 2630 2635 2640

AAT AGA TGC CTA AGC CCA GAA AGG GTG CTT CTT CAA CTA AAA TAC AGA 8205

Asn Arg Cys Leu Ser Pro Glu Arg Val Leu Leu Gin Leu Lys Tyr Arg 2645 2650 2655

TAT GAT ACG GAA ATT GAT AGA AGC AGA AGA TCG GCT ATA AAA AAG ATA 8253

Tyr Asp Thr Glu He Asp Arg Ser Arg Arg Ser Ala He Lys Lys He 2660 2665 2670 2675 ATG GAA AGG GAT GAC ACA GCT GCA AAA ACA CTT GTT CTC TGT GTT TCT 8301

Met Glu Arg Asp Asp Thr Ala Ala Lys Thr Leu Val Leu Cys Val Ser 2680 2685 2690

GAC ATA ATT TCA TTG AGC GCA AAT ATA TCT GAA ACT TCT AGC AAT AAA 8349 Asp He He Ser Leu Ser Ala Asn He Ser Glu Thr Ser Ser Asn Lys

2695 2700 2705

ACT AGT AGT GCA GAT ACC CAA AAA GTG GCC ATT ATT GAA CTT ACA GAT 8397 Thr Ser Ser Ala Asp Thr Gin Lys Val Ala He He Glu Leu Thr Asp 2710 2715 2720

GGG TGG TAT GCT GTT AAG GCC CAG TTA GAT CCT CCC CTC TTA GCT GTC 8445

Gly Trp Tyr Ala Val Lys Ala Gin Leu Asp Pro Pro Leu Leu Ala Val 2725 2730 2735

TTA AAG AAT GGC AGA CTG ACA GTT GGT CAG AAG ATT ATT CTT CAT GGA 8493

Leu Lys Asn Gly Arg Leu Thr Val Gly Gin Lys He He Leu His Gly 2740 2745 2750 2755 GCA GAA CTG GTG GGC TCT CCT GAT GCC TGT ACA CCT CTT GAA GCC CCA 8541 Ala Glu Leu Val Gly Ser Pro Asp Ala Cys Thr Pro Leu Glu Ala Pro 2760 2765 2770

GAA TCT CTT ATG TTA AAG ATT TCT GCT AAC AGT ACT CGG CCT GCT CGC 8589 Glu Ser Leu Met Leu Lys He Ser Ala Asn Ser Thr Arg Pro Ala Arg 2775 2780 2785

TGG TAT ACC AAA CTT GGA TTC TTT CCT GAC CCT AGA CCT TTT CCT CTG 8637 Trp Tyr Thr Lys Leu Gly Phe Phe Pro Asp Pro Arg Pro Phe Pro Leu 2790 2795 2800

CCC TTA TCA TCG CTT TTC AGT GAT GGA GGA AAT GTT GGT TGT GTT GAT 8685 Pro Leu Ser Ser Leu Phe Ser Asp Gly Gly Asn Val Gly Cys Val Asp 2805 2810 2815

GTA ATT ATT CAA AGA GCA TAC CCT ATA CAG TGG ATG GAG AAG ACA TCA 8733 Val He He Gin Arg Ala Tyr Pro He Gin Trp Met Glu Lys Thr Ser 2820 2825 2830 2835

TCT GGA TTA TAC ATA TTT CGC AAT GAA AGA GAG GAA GAA AAG GAA GCA 8781 Ser Gly Leu Tyr He Phe Arg Asn Glu Arg Glu Glu Glu Lys Glu Ala

2840 2845 2850

GCA AAA TAT GTG GAG GCC CAA CAA AAG AGA CTA GAA GCC TTA TTC ACT 8829 Ala Lys Tyr Val Glu Ala Gin Gin Lys Arg Leu Glu Ala Leu Phe Thr 2855 2860 2865

AAA ATT CAG GAG GAA TTT GAA GAA CAT GAA GAA AAC ACA ACA AAA CCA 8877 Lys He Gin Glu Glu Phe Glu Glu His Glu Glu Asn Thr Thr Lys Pro 2870 2875 2880

TAT TTA CCA TCA CGT GCA CTA ACA AGA CAG CAA GTT CGT GCT TTG CAA 8925 Tyr Leu Pro Ser Arg Ala Leu Thr Arg Gin Gin Val Arg Ala Leu Gin 2885 2890 2895 GAT GGT GCA GAG CTT TAT GAA GCA GTG AAG AAT GCA GCA GAC CCA GCT 8973 Asp Gly Ala Glu Leu Tyr Glu Ala Val Lys Asn Ala Ala Asp Pro Ala 2900 2905 2910 2915

TAC CTT GAG GGT TAT TTC AGT GAA GAG CAG TTA AGA GCC TTG AAT AAT 9021 Tyr Leu Glu Gly Tyr Phe Ser Glu Glu Gin Leu Arg Ala Leu Asn Asn

2920 2925 2930

CAC AGG CAA ATG TTG AAT GAT AAG AAA CAA GCT CAG ATC CAG TTG GAA 9069 His Arg Gin Met Leu Asn Asp Lys Lys Gin Ala Gin He Gin Leu Glu 2935 2940 2945

ATT AGG AAG GCC ATG GAA TCT GCT GAA CAA AAG GAA CAA GGT TTA TCA 9117 He Arg Lys Ala Met Glu Ser Ala Glu Gin Lys Glu Gin Gly Leu Ser 2950 2955 2960

AGG GAT GTC ACA ACC GTG TGG AAG TTG CGT ATT GTA AGC TAT TCA AAA 9165 Arg Asp Val Thr Thr Val Trp Lys Leu Arg He Val Ser Tyr Ser Lys 2965 2970 2975 AAA GAA AAA GAT TCA GTT ATA CTG AGT ATT TGG CGT CCA TCA TCA GAT 9213 Lys Glu Lys Asp Ser Val He Leu Ser He Trp Arg Pro Ser Ser Asp 2980 2985 2990 2995

TTA TAT TCT CTG TTA ACA GAA GGA AAG AGA TAC AGA ATT TAT CAT CTT 9261 Leu Tyr Ser Leu Leu Thr Glu Gly Lys Arg Tyr Arg He Tyr His Leu

3000 3005 3010

GCA ACT TCA AAA TCT AAA AGT AAA TCT GAA AGA GCT AAC ATA CAG TTA 9309 Ala Thr Ser Lys Ser Lys Ser Lys Ser Glu Arg Ala Asn He Gin Leu 3015 3020 3025

GCA GCG ACA AAA AAA ACT CAG TAT CAA CAA CTA CCG GTT TCA GAT GAA 9357 Ala Ala Thr Lys Lys Thr Gin Tyr Gin Gin Leu Pro Val Ser Asp Glu 3030 3035 3040

ATT TTA TTT CAG ATT TAC CAG CCA CGG GAG CCC CTT CAC TTC AGC AAA 9405 He Leu Phe Gin He Tyr Gin Pro Arg Glu Pro Leu His Phe Ser Lys 3045 3050 3055 TTT TTA GAT CCA GAC TTT CAG CCA TCT TGT TCT GAG GTG GAC CTA ATA 9453 Phe Leu Asp Pro Asp Phe Gin Pro Ser Cys Ser Glu Val Asp Leu He 3060 3065 3070 3075 GGA TTT GTC GTT TCT GTT GTG AAA AAA ACA GGA CTT GCC CCT TTC GTC 9501 Gly Phe Val Val Ser Val Val Lys Lys Thr Gly Leu Ala Pro Phe Val 3080 3085 30.90

TAT TTG TCA GAC GAA TGT TAC AAT TTA CTG GCA ATA AAG TTT TGG ATA 9549 Tyr Leu Ser Asp Glu Cys Tyr Asn Leu Leu Ala He Lys Phe Trp He 3095 3100 3105

GAC CTT AAT GAG GAC ATT ATT AAG CCT CAT ATG TTA ATT GCT GCA AGC 9597 Asp Leu Asn Glu Asp He He Lys Pro His Met Leu He Ala Ala Ser 3110 3115 3120 AAC CTC CAG TGG CGA CCA GAA TCC AAA TCA GGC CTT CTT ACT TTA TTT 9645 Asn Leu Gin Trp Arg Pro Glu Ser Lys Ser Gly Leu Leu Thr Leu Phe 3125 3130 3135

GCT GGA GAT TTT TCT GTG TTT TCT GCT AGT CCA AAA GAG GGC CAC TTT 9693 Ala Gly Asp Phe Ser Val Phe Ser Ala Ser Pro Lys Glu Gly His Phe 3140 3145 3150 3155

CAA GAG ACA TTC AAC AAA ATG AAA AAT ACT GTT GAG AAT ATT GAC ATA 9741 Gin Glu Thr Phe Asn Lys Met Lys Asn Thr Val Glu Asn He Asp He 3160 3165 3170

CTT TGC AAT GAA GCA GAA AAC AAG CTT ATG CAT ATA CTG CAT GCA AAT 9789 Leu Cys Asn Glu Ala Glu Asn Lys Leu Met His He Leu His Ala Asn 3175 3180 3185

GAT CCC AAG TGG TCC ACC CCA ACT AAA GAC TGT ACT TCA GGG CCG TAC 9837 Asp Pro Lys Trp Ser Thr Pro Thr Lys Asp Cys Thr Ser Gly Pro Tyr 3190 3195 3200 ACT GCT CAA ATC ATT CCT GGT ACA GGA AAC AAG CTT CTG ATG TCT TCT 9885 Thr Ala Gin He He Pro Gly Thr Gly Asn Lys Leu Leu Met Ser Ser 3205 3210 3215

CCT AAT TGT GAG ATA TAT TAT CAA AGT CCT TTA TCA CTT TGT ATG GCC 9933 Pro Asn Cys Glu He Tyr Tyr Gin Ser Pro Leu Ser Leu Cys Met Ala 3220 3225 3230 3235

AAA AGG AAG TCT GTT TCC ACA CCT GTC TCA GCC CAG ATG ACT TCA AAG 9981 Lys Arg Lys Ser Val Ser Thr Pro Val Ser Ala Gin Met Thr Ser Lys 3240 3245 3250

TCT TGT AAA GGG GAG AAA GAG ATT GAT GAC CAA AAG AAC TGC AAA AAG 10029 Ser Cys Lys Gly Glu Lys Glu He Asp Asp Gin Lys Asn Cys Lys Lys 3255 3260 3265

AGA AGA GCC TTG GAT TTC TTG AGT AGA CTG CCT TTA CCT CCA CCT GTT 10077 Arg Arg Ala Leu Asp Phe Leu Ser Arg Leu Pro Leu Pro Pro Pro Val 3270 3275 3280 AGT CCC ATT TGT ACA TTT GTT TCT CCG GCT GCA CAG AAG GCA TTT CAG 10125 Ser Pro He Cys Thr Phe Val Ser Pro Ala Ala Gin Lys Ala Phe Gin 3285 3290 3295

CCA CCA AGG AGT TGT GGC ACC AAA TAC GAA ACA CCC ATA AAG AAA AAA 10173 Pro Pro Arg Ser Cys Gly Thr Lys Tyr Glu Thr Pro He Lys Lys Lys 3300 3305 3310 3315 GAA CTG AAT TCT CCT CAG ATG ACT CCA TTT AAA AAA TTC AAT GAA ATT 10221 Glu Leu Asn Ser Pro Gin Met Thr Pro Phe Lys Lys Phe Asn Glu He 3320 3325 3330

TCT CTT TTG GAA AGT AAT TCA ATA GCT GAC GAA GAA CTT GCA TTG ATA 10269 Ser Leu Leu Glu Ser Asn Ser He Ala Asp Glu Glu Leu Ala Leu He 3335 3340 3345 AAT ACC CAA GCT CTT TTG TCT GGT TCA ACA GGA GAA AAA CAA TTT ATA 10317 Asn Thr Gin Ala Leu Leu Ser Gly Ser Thr Gly Glu Lys Gin Phe He 3350 3355 3360

TCT GTC AGT GAA TCC ACT AGG ACT GCT CCC ACC AGT TCA GAA GAT TAT 10365 Ser Val Ser Glu Ser Thr Arg Thr Ala Pro Thr Ser Ser Glu Asp Tyr 3365 3370 3375

CTC AGA CTG AAA CGA CGT TGT ACT ACA TCT CTG ATC AAA GAA CAG GAG 10413 Leu Arg Leu Lys Arg Arg Cys Thr Thr Ser Leu He Lys Glu Gin Glu 3380 3385 3390 3395

AGT TCC CAG GCC AGT ACG GAA GAA TGT GAG AAA AAT AAG CAG GAC ACA 10461 Ser Ser Gin Ala Ser Thr Glu Glu Cys Glu Lys Asn Lys Gin Asp Thr 3400 3405 3410

ATT ACA ACT AAA AAA TAT ATC TAA 10485

He Thr Thr Lys Lys Tyr He 3415

(2) INFORMATION FOR SEQ ID NO: 11:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 3418 amino acids (B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein (v) FRAGMENT TYPE: internal

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 11:

Met Pro He Gly Ser Lys Glu Arg Pro Thr Phe Phe Glu He Phe Lys 1 5 10 15

Thr Arg Cys Asn Lys Ala Asp Leu Gly Pro He Ser Leu Asn Trp Phe

20 25 30

Glu Glu Leu Ser Ser Glu Ala Pro Pro Tyr Asn Ser Glu Pro Ala Glu 35 40 45 Glu Ser Glu His Lys Asn Asn Asn Tyr Glu Pro Asn Leu Phe Lys Thr 50 55 60

Pro Gin Arg Lys Pro Ser Tyr Asn Gin Leu Ala Ser Thr Pro He He 65 70 75 80

Phe Lys Glu Gin Gly Leu Thr Leu Pro Leu Tyr Gin Ser Pro Val Lys 85 90 95

Glu Leu Asp Lys Phe Lys Leu Asp Leu Gly Arg Asn Val Pro Asn Ser

100 105 110

Arg His Lys Ser Leu Arg Thr Val Lys Thr Lys Met Asp Gin Ala Asp 115 120 125 Asp Val Ser Cys Pro Leu Leu Asn Ser Cys Leu Ser Glu Ser Pro Val 130 135 140

Val Leu Gin Cys Thr His Val Thr Pro Gin Arg Asp Lys Ser Val Val 145 150 155 160

Cys Gly Ser Leu Phe His Thr Pro Lys Phe Val Lys Gly Arg Gin Thr

165 170 175 Pro Lys His He Ser Glu Ser Leu Gly Ala Glu Val Asp Pro Asp Met

180 185 190

Ser Trp Ser Ser Ser Leu Ala Thr Pro Pro Thr Leu Ser Ser Thr Val

195 200 205

Leu He Val Arg Asn Glu Glu Ala Ser Glu Thr Val Phe Pro His Asp 210 215 220

Thr Thr Ala Asn Val Lys Ser Tyr Phe Ser Asn His Asp Glu Ser Leu

225 230 235 240

Lys Lys Asn Asp Arg Phe He Ala Ser Val Thr Asp Ser Glu Asn Thr

245 250 255 Asn Gin Arg Glu Ala Ala Ser His Gly Phe Gly Lys Thr Ser Gly Asn

260 265 270

Ser Phe Lys Val Asn Ser Cys Lys Asp His He Gly Lys Ser Met Pro

275 280 285

Asn Val Leu Glu Asp Glu Val Tyr Glu Thr Val Val Asp Thr Ser Glu 290 295 300

Glu Asp Ser Phe Ser Leu Cys Phe Ser Lys Cys Arg Thr Lys Asn Leu

305 310 315 320

Gin Lys Val Arg Thr Ser Lys Thr Arg Lys Lys He Phe His Glu Ala

325 330 335 Asn Ala Asp Glu Cys Glu Lys Ser Lys Asn Gin Val Lys Glu Lys Tyr

340 345 350

Ser Phe Val Ser Glu Val Glu Pro Asn Asp Thr Asp Pro Leu Asp Ser

355 360 365

Asn Val Ala His Gin Lys Pro Phe Glu Ser Gly Ser Asp Lys He Ser 370 375 380

Lys Glu Val Val Pro Ser Leu Ala Cys Glu Trp Ser Gin Leu Thr Leu

385 390 395 400

Ser Gly Leu Asn Gly Ala Gin Met Glu Lys He Pro Leu Leu His He

405 410 415 Ser Ser Cys Asp Gin Asn He Ser Glu Lys Asp Leu Leu Asp Thr Glu

420 425 430

Asn Lys Arg Lys Lys Asp Phe Leu Thr Ser Glu Asn Ser Leu Pro Arg

435 440 445

He Ser Ser Leu Pro Lys Ser Glu Lys Pro Leu Asn Glu Glu Thr Val 450 455 460

Val Asn Lys Arg Asp Glu Glu Gin His Leu Glu Ser His Thr Asp Cys

465 470 475 480

He Leu Ala Val Lys Gin Ala He Ser Gly Thr Ser Pro Val Ala Ser

485 490 495 Ser Phe Gin Gly He Lys Lys Ser He Phe Arg He Arg Glu Ser Pro

500 505 510

Lys Glu Thr Phe Asn Ala Ser Phe Ser Gly His Met Thr Asp Pro Asn

515 520 525

Phe Lys Lys Glu Thr Glu Ala Ser Glu Ser Gly Leu Glu He His Thr 530 535 540

Val Cys Ser Gin Lys Glu Asp Ser Leu Cys Pro Asn Leu He Asp Asn

545 550 555 560

Gly Ser Trp Pro Ala Thr Thr Thr Gin Asn Ser Val Ala Leu Lys Asn

565 570 575 Ala Gly Leu He Ser Thr Leu Lys Lys Lys Thr Asn Lys Phe He Tyr

580 585 590

Ala He His Asp Glu Thr Ser Tyr Lys Gly Lys Lys He Pro Lys Asp

595 600 605

Gin Lys Ser Glu Leu He Asn Cys Ser Ala Gin Phe Glu Ala Asn Ala 610 615 620

Phe Glu Ala Pro Leu Thr Phe Ala Asn Ala Asp Ser Gly Leu Leu His 625 630 635 640 Ser Ser Val Lys Arg Ser Cys Ser Gin Asn Asp Ser Glu Glu Pro Thr

645 650 655

Leu Ser Leu Thr Ser Ser Phe Gly Thr He Leu Arg Lys Cys Ser Arg 660 665 670

Asn Glu Thr Cys Ser Asn Asn Thr Val He Ser Gin Asp Leu Asp Tyr

675 680 685

Lys Glu Ala Lys Cys Asn Lys Glu Lys Leu Gin Leu Phe He Thr Pro

690 695 700 Glu Ala Asp Ser Leu Ser Cys Leu Gin Glu Gly Gin Cys Glu Asn Asp

705 710 715 720

Pro Lys Ser Lys Lys Val Ser Asp He Lys Glu Glu Val Leu Ala Ala

725 730 735

Ala Cys His Pro Val Gin His Ser Lys Val Glu Tyr Ser Asp Thr Asp 740 745 750

Phe Gin Ser Gin Lys Ser Leu Leu Tyr Asp His Glu Asn Ala Ser Thr

755 760 765

Leu He Leu Thr Pro Thr Ser Lys Asp Val Leu Ser Asn Leu Val Met 770 775 780 He Ser Arg Gly Lys Glu Ser Tyr Lys Met Ser Asp Lys Leu Lys Gly

785 790 795 800

Asn Asn Tyr Glu Ser Asp Val Glu Leu Thr Lys Asn He Pro Met Glu

805 810 815

Lys Asn Gin Asp Val Cys Ala Leu Asn Glu Asn Tyr Lys Asn Val Glu 820 825 830

Leu Leu Pro Pro Glu Lys Tyr Met Arg Val Ala Ser Pro Ser Arg Lys

835 840 845

Val Gin Phe Asn Gin Asn Thr Asn Leu Arg Val He Gin Lys Asn Gin 850 855 860 Glu Glu Thr Thr Ser He Ser Lys He Thr Val Asn Pro Asp Ser Glu

865 870 875 880

Glu Leu Phe Ser Asp Asn Glu Asn Asn Phe Val Phe Gin Val Ala Asn

885 890 895

Glu Arg Asn Asn Leu Ala Leu Gly Asn Thr Lys Glu Leu His Glu Thr 900 905 910

Asp Leu Thr Cys Val Asn Glu Pro He Phe Lys Asn Ser Thr Met Val

915 920 925

Leu Tyr Gly Asp Thr Gly Asp Lys Gin Ala Thr Gin Val Ser He Lys 930 935 940 Lys Asp Leu Val Tyr Val Leu Ala Glu Glu Asn Lys Asn Ser Val Lys

945 950 955 960

Gin His He Lys Met Thr Leu Gly Gin Asp Leu Lys Ser Asp He Ser

965 970 975

Leu Asn He Asp Lys He Pro Glu Lys Asn Asn Asp Tyr Met Asn Lys 980 985 990

Trp Ala Gly Leu Leu Gly Pro He Ser Asn His Ser Phe Gly Gly Ser

995 1000 1005

Phe Arg Thr Ala Ser Asn Lys Glu He Lys Leu Ser Glu His Asn He

1010 1015 1020 Lys Lys Ser Lys Met Phe Phe Lys Asp He Glu Glu Gin Tyr Pro Thr

1025 1030 1035 104

Ser Leu Ala Cys Val Glu He Val Asn Thr Leu Ala Leu Asp Asn Gin

1045 1050 1055

Lys Lys Leu Ser Lys Pro Gin Ser He Asn Thr Val Ser Ala His Leu 1060 1065 1070

Gin Ser Ser Val Val Val Ser Asp Cys Lys Asn Ser His He Thr Pro

1075 1080 1085

Gin Met Leu Phe Ser Lys Gin Asp Phe Asn Ser Asn His Asn Leu Thr

1090 1095 1100 Pro Ser Gin Lys Ala Glu He Thr Glu Leu Ser Thr He Leu Glu Glu

1105 1110 1115 112

Ser Gly Ser Gin Phe Glu Phe Thr Gin Phe Arg Lys Pro Ser Tyr He 1125 1130 1135

Leu Gin Lys Ser Thr Phe Glu Val Pro Glu Asn Gin Met Thr He Leu 1140 1145 1150 Lys Thr Thr Ser Glu Glu Cys Arg Asp Ala Asp Leu His Val He Met 1155 1160 1165

Asn Ala Pro Ser He Gly Gin Val Asp Ser Ser Lys Gin Phe Glu Gly

1170 1175 1180

Thr Val Glu He Lys Arg Lys Phe Ala Gly Leu Leu Lys Asn Asp Cys 1185 1190 1195 120

Asn Lys Ser Ala Ser Gly Tyr Leu Thr Asp Glu Asn Glu Val Gly Phe

1205 1210 1215

Arg Gly Phe Tyr Ser Ala His Gly Thr Lys Leu Asn Val Ser Thr Glu 1220 1225 1230 Ala Leu Gin Lys Ala Val Lys Leu Phe Ser Asp He Glu Asn He Ser 1235 1240 1245

Glu Glu Thr Ser Ala Glu Val His Pro He Ser Leu Ser Ser Ser Lys

1250 1255 1260

Cys His Asp Ser Val Val Ser Met Phe Lys He Glu Asn His Asn Asp 1265 1270 1275 128

Lys Thr Val Ser Glu Lys Asn Asn Lys Cys Gin Leu He Leu Gin Asn

1285 1290 1295

Asn He Glu Met Thr Thr Gly Thr Phe Val Glu Glu He Thr Glu Asn 1300 1305 1310 Tyr Lys Arg Asn Thr Glu Asn Glu Asp Asn Lys Tyr Thr Ala Ala Ser

1315 1320 1325

Arg Asn Ser His Asn Leu Glu Phe Asp Gly Ser Asp Ser Ser Lys Asn

1330 1335 1340

Asp Thr Val Cys He His Lys Asp Glu Thr Asp Leu Leu Phe Thr Asp 1345 1350 1355 136

Gin His Asn He Cys Leu Lys Leu Ser Gly Gin Phe Met Lys Glu Gly

1365 1370 1375

Asn Thr Gin He Lys Glu Asp Leu Ser Asp Leu Thr Phe Leu Glu Val

1380 1385 1390 Ala Lys Ala Gin Glu Ala Cys His Gly Asn Thr Ser Asn Lys Glu Gin

1395 1400 1405

Leu Thr Ala Thr Lys Thr Glu Gin Asn He Lys Asp Phe Glu Thr Ser

1410 1415 1420

Asp Thr Phe Phe Gin Thr Ala Ser Gly Lys Asn He Ser Val Ala Lys 1425 1430 1435 144

Glu Ser Phe Asn Lys He Val Asn Phe Phe Asp Gin Lys Pro Glu Glu

1445 1450 1455

Leu His Asn Phe Ser Leu Asn Ser Glu Leu His Ser Asp He Arg Lys

1460 1465 1470 Asn Lys Met Asp He Leu Ser Tyr Glu Glu Thr Asp He Val Lys His

1475 1480 1485

Lys He Leu Lys Glu Ser Val Pro Val Gly Thr Gly Asn Gin Leu Val

1490 1495 1500

Thr Phe Gin Gly Gin Pro Glu Arg Asp Glu Lys He Lys Glu Pro Thr 1505 1510 1515 152

Leu Leu Gly Phe His Thr Ala Ser Gly Lys Lys Val Lys He Ala Lys

1525 1530 1535

Glu Ser Leu Asp Lys Val Lys Asn Leu Phe Asp Glu Lys Glu Gin Gly 1540 1545 1550 Thr Ser Glu He Thr Ser Phe Ser His Gin Trp Ala Lys Thr Leu Lys 1555 1560 1565

Tyr Arg Glu Ala Cys Lys Asp Leu Glu Leu Ala Cys Glu Thr He Glu

1570 1575 1580

He Thr Ala Ala Pro Lys Cys Lys Glu Met Gin Asn Ser Leu Asn Asn 1585 1590 1595 160

Asp Lys Asn Leu Val Ser He Glu Thr Val Val Pro Pro Lys Leu Leu 1605 1610 1615 Ser Asp Asn Leu Cys Arg Gin Thr Glu Asn Leu Lys Thr Ser Lys Ser

1620 1625 1630

He Phe Leu Lys Val Lys Val His Glu Asn Val Glu Lys Glu Thr Ala 1635 1640 1645

Lys Ser Pro Ala Thr Cys Tyr Thr Asn Gin Ser Pro Tyr Ser Val He

1650 1655 1660

Glu Asn Ser Ala Leu Ala Phe Tyr Thr Ser Cys Ser Arg Lys Thr Ser 1665 1670 1675 168 Val Ser Gin Thr Ser Leu Leu Glu Ala Lys Lys Trp Leu Arg Glu Gly

1685 1690 1695

He Phe Asp Gly Gin Pro Glu Arg He Asn Thr Ala Asp Tyr Val Gly

1700 1705 1710

Asn Tyr Leu Tyr Glu Asn Asn Ser Asn Ser Thr He Ala Glu Asn Asp 1715 1720 1725

Lys Asn His Leu Ser Glu Lys Gin Asp Thr Tyr Leu Ser Asn Ser Ser

1730 1735 1740

Met Ser Asn Ser Tyr Ser Tyr His Ser Asp Glu Val Tyr Asn Asp Ser 1745 1750 1755 176 Gly Tyr Leu Ser Lys Asn Lys Leu Asp Ser Gly He Glu Pro Val Leu

1765 1770 1775

Lys Asn Val Glu Asp Gin Lys Asn Thr Ser Phe Ser Lys Val He Ser

1780 1785 1790

Asn Val Lys Asp Ala Asn Ala Tyr Pro Gin Thr Val Asn Glu Asp He 1795 1800 1805

Cys Val Glu Glu Leu Val Thr Ser Ser Ser Pro Cys Lys Asn Lys Asn

1810 1815 1820

Ala Ala He Lys Leu Ser He Ser Asn Ser Asn Asn Phe Glu Val Gly 1825 1830 1835 184 Pro Pro Ala Phe Arg He Ala Ser Gly Lys He Val Cys Val Ser His

1845 1850 1855

Glu Thr He Lys Lys Val Lys Asp He Phe Thr Asp Ser Phe Ser Lys

1860 1865 1870

Val He Lys Glu Asn Asn Glu Asn Lys Ser Lys He Cys Gin Thr Lys 1875 1880 1885

He Met Ala Gly Cys Tyr Glu Ala Leu Asp Asp Ser Glu Asp He Leu

1890 1895 1900

His Asn Ser Leu Asp Asn Asp Glu Cys Ser Thr His Ser His Lys Val 1905 1910 1915 192 Phe Ala Asp He Gin Ser Glu Glu He Leu Gin His Asn Gin Asn Met

1925 1930 1935

Ser Gly Leu Glu Lys Val Ser Lys He Ser Pro Cys Asp Val Ser Leu

1940 1945 1950

Glu Thr Ser Asp He Cys Lys Cys Ser He Gly Lys Leu His Lys Ser 1955 1960 1965

Val Ser Ser Ala Asn Thr Cys Gly He Phe Ser Thr Ala Ser Gly Lys

1970 1975 1980

Ser Val Gin Val Ser Asp Ala Ser Leu Gin Asn Ala Arg Gin Val Phe 1985 1990 1995 200 Ser Glu He Glu Asp Ser Thr Lys Gin Val Phe Ser Lys Val Leu Phe

2005 2010 2015

Lys Ser Asn Glu His Ser Asp Gin Leu Thr Arg Glu Glu Asn Thr Ala

2020 2025 2030

He Arg Thr Pro Glu His Leu He Ser Gin Lys Gly Phe Ser Tyr Asn 2035 2040 2045

Val Val Asn Ser Ser Ala Phe Ser Gly Phe Ser Thr Ala Ser Gly Lys

2050 2055 2060

Gin Val Ser He Leu Glu Ser Ser Leu His Lys Val Lys Gly Val Leu 2065 2070 2075 208 Glu Glu Phe Asp Leu He Arg Thr Glu His Ser Leu His Tyr Ser Pro

2085 2090 2095

Thr Ser Arg Gin Asn Val Ser Lys He Leu Pro Arg Val Asp Lys Arg 2100 2105 2110

Asn Pro Glu His Cys Val Asn Ser Glu Met Glu Lys Thr Cys Ser Lys 2115 2120 2125 Glu Phe Lys Leu Ser Asn Asn Leu Asn Val Glu Gly Gly Ser Ser Glu 2130 2135 2140

Asn Asn His Ser He Lys Val Ser Pro Tyr Leu Ser Gin Phe Gin Gin 2145 2150 2155 216

Asp Lys Gin Gin Leu Val Leu Gly Thr Lys Val Ser Leu Val Glu Asn 2165 2170 2175

He His Val Leu Gly Lys Glu Gin Ala Ser Pro Lys Asn Val Lys Met

2180 2185 2190

Glu He Gly Lys Thr Glu Thr Phe Ser Asp Val Pro Val Lys Thr Asn 2195 2200 2205 He Glu Val Cys Ser Thr Tyr Ser Lys Asp Ser Glu Asn Tyr Phe Glu 2210 2215 2220

Thr Glu Ala Val Glu He Ala Lys Ala Phe Met Glu Asp Asp Glu Leu 2225 2230 2235 224

Thr Asp Ser Lys Leu Pro Ser His Ala Thr His Ser Leu Phe Thr Cys 2245 2250 2255

Pro Glu Asn Glu Glu Met Val Leu Ser Asn Ser Arg He Gly Lys Arg

2260 2265 2270

Arg Gly Glu Pro Leu He Leu Val Gly Glu Pro Ser He Lys Arg Asn 2275 2280 2285 Leu Leu Asn Glu Phe Asp Arg He He Glu Asn Gin Glu Lys Ser Leu 2290 2295 2300

Lys Ala Ser Lys Ser Thr Pro Asp Gly Thr He Lys Asp Arg Arg Leu 2305 2310 2315 232

Phe Met His His Val Ser Leu Glu Pro He Thr Cys Val Pro Phe Arg 2325 2330 2335

Thr Thr Lys Glu Arg Gin Glu He Gin Asn Pro Asn Phe Thr Ala Pro

2340 2345 2350

Gly Gin Glu Phe Leu Ser Lys Ser His Leu Tyr Glu His Leu Thr Leu 2355 2360 2365 Glu Lys Ser Ser Ser Asn Leu Ala Val Ser Gly His Pro Phe Tyr Gin 2370 2375 2380

Val Ser Ala Thr Arg Asn Glu Lys Met Arg His Leu He Thr Thr Gly 2385 2390 2395 240

Arg Pro Thr Lys Val Phe Val Pro Pro Phe Lys Thr Lys Ser His Phe 2405 2410 2415

His Arg Val Glu Gin Cys Val Arg Asn He Asn Leu Glu Glu Asn Arg

2420 2425 2430

Gin Lys Gin Asn He Asp Gly His Gly Ser Asp Asp Ser Lys Asn Lys 2435 2440 2445 He Asn Asp Asn Glu He His Gin Phe Asn Lys Asn Asn Ser Asn Gin 2450 2455 2460

Ala Ala Ala Val Thr Phe Thr Lys Cys Glu Glu Glu Pro Leu Asp Leu 2465 2470 2475 248

He Thr Ser Leu Gin Asn Ala Arg Asp He Gin Asp Met Arg He Lys 2485 2490 2495

Lys Lys Gin Arg Gin Arg Val Phe Pro Gin Pro Gly Ser Leu Tyr Leu

2500 2505 2510

Ala Lys Thr Ser Thr Leu Pro Arg He Ser Leu Lys Ala Ala Val Gly 2515 2520 2525 Gly Gin Val Pro Ser Ala Cys Ser His Lys Gin Leu Tyr Thr Tyr Gly 2530 2535 2540

Val Ser Lys His Cys He Lys He Asn Ser Lys Asn Ala Glu Ser Phe 2545 2550 2555 256

Gin Phe His Thr Glu Asp Tyr Phe Gly Lys Glu Ser Leu Trp Thr Gly 2565 2570 2575

Lys Gly He Gin Leu Ala Asp Gly Gly Trp Leu He Pro Ser Asn Asp 2580 2585 2590 Gly Lys Ala Gly Lys Glu Glu Phe Tyr Arg Ala Leu Cys Asp Thr Pro

2595 2600 2605

Gly Val Asp Pro Lys Leu He Ser Arg He Trp Val Tyr Asn His Tyr 2610 2615 2620

Arg Trp He He Trp Lys Leu Ala Ala Met Glu Cys Ala Phe Pro Lys

2625 2630 2635 264

Glu Phe Ala Asn Arg Cys Leu Ser Pro Glu Arg Val Leu Leu Gin Leu

2645 2650 2655 Lys Tyr Arg Tyr Asp Thr Glu He Asp Arg Ser Arg Arg Ser Ala He

2660 2665 2670

Lys Lys He Met Glu Arg Asp Asp Thr Ala Ala Lys Thr Leu Val Leu

2675 2680 2685

Cys Val Ser Asp He He Ser Leu Ser Ala Asn He Ser Glu Thr Ser 2690 2695 2700

Ser Asn Lys Thr Ser Ser Ala Asp Thr Gin Lys Val Ala He He Glu 2705 2710 2715 272

Leu Thr Asp Gly Trp Tyr Ala Val Lys Ala Gin Leu Asp Pro Pro Leu 2725 2730 2735 Leu Ala Val Leu Lys Asn Gly Arg Leu Thr Val Gly Gin Lys He He

2740 2745 2750

Leu His Gly Ala Glu Leu Val Gly Ser Pro Asp Ala Cys Thr Pro Leu

2755 2760 2765

Glu Ala Pro Glu Ser Leu Met Leu Lys He Ser Ala Asn Ser Thr Arg 2770 2775 2780

Pro Ala Arg Trp Tyr Thr Lys Leu Gly Phe Phe Pro Asp Pro Arg Pro 2785 2790 2795 280

Phe Pro Leu Pro Leu Ser Ser Leu Phe Ser Asp Gly Gly Asn Val Gly 2805 2810 2815 Cys Val Asp Val He He Gin Arg Ala Tyr Pro He Gin Trp Met Glu

2820 2825 2830

Lys Thr Ser Ser Gly Leu Tyr He Phe Arg Asn Glu Arg Glu Glu Glu

2835 2840 2845

Lys Glu Ala Ala Lys Tyr Val Glu Ala Gin Gin Lys Arg Leu Glu Ala 2850 2855 2860

Leu Phe Thr Lys He Gin Glu Glu Phe Glu Glu His Glu Glu Asn Thr 2865 2870 2875 288

Thr Lys Pro Tyr Leu Pro Ser Arg Ala Leu Thr Arg Gin Gin Val Arg 2885 2890 2895 Ala Leu Gin Asp Gly Ala Glu Leu Tyr Glu Ala Val Lys Asn Ala Ala

2900 2905 2910

Asp Pro Ala Tyr Leu Glu Gly Tyr Phe Ser Glu Glu Gin Leu Arg Ala

2915 2920 2925

Leu Asn Asn His Arg Gin Met Leu Asn Asp Lys Lys Gin Ala Gin He 2930 2935 2940

Gin Leu Glu He Arg Lys Ala Met Glu Ser Ala Glu Gin Lys Glu Gin

2945 2950 2955 296

Gly Leu Ser Arg Asp Val Thr Thr Val Trp Lys Leu Arg He Val Ser

2965 2970 2975 Tyr Ser Lys Lys Glu Lys Asp Ser Val He Leu Ser He Trp Arg Pro

2980 2985 2990

Ser Ser Asp Leu Tyr Ser Leu Leu Thr Glu Gly Lys Arg Tyr Arg He

2995 3000 3005

Tyr His Leu Ala Thr Ser Lys Ser Lys Ser Lys Ser Glu Arg Ala Asn 3010 3015 3020

He Gin Leu Ala Ala Thr Lys Lys Thr Gin Tyr Gin Gin Leu Pro Val

3025 3030 3035 304

Ser Asp Glu He Leu Phe Gin He Tyr Gin Pro Arg Glu Pro Leu His

3045 3050 3055 Phe Ser Lys Phe Leu Asp Pro Asp Phe Gin Pro Ser Cys Ser Glu Val

3060 3065 3070

Asp Leu He Gly Phe Val Val Ser Val Val Lys Lys Thr Gly Leu Ala 3075 3080 3085

Pro Phe Val Tyr Leu Ser Asp Glu Cys Tyr Asn Leu Leu Ala He Lys

3090 3095 3100 Phe Trp He Asp Leu Asn Glu Asp He He Lys Pro His Met Leu He

3105 3110 3115 312

Ala Ala Ser Asn Leu Gin Trp Arg Pro Glu Ser Lys Ser Gly Leu Leu

3125 3130 3135

Thr Leu Phe Ala Gly Asp Phe Ser Val Phe Ser Ala Ser Pro Lys Glu 3140 3145 3150

Gly His Phe Gin Glu Thr Phe Asn Lys Met Lys Asn Thr Val Glu Asn

3155 3160 3165

He Asp He Leu Cys Asn Glu Ala Glu Asn Lys Leu Met His He Leu

3170 3175 3180 His Ala Asn Asp Pro Lys Trp Ser Thr Pro Thr Lys Asp Cys Thr Ser

3185 3190 3195 320

Gly Pro Tyr Thr Ala Gin He He Pro Gly Thr Gly Asn Lys Leu Leu

3205 3210 3215

Met Ser Ser Pro Asn Cys Glu He Tyr Tyr Gin Ser Pro Leu Ser Leu 3220 3225 3230

Cys Met Ala Lys Arg Lys Ser Val Ser Thr Pro Val Ser Ala Gin Met

3235 3240 3245

Thr Ser Lys Ser Cys Lys Gly Glu Lys Glu He Asp Asp Gin Lys Asn

3250 3255 3260 Cys Lys Lys Arg Arg Ala Leu Asp Phe Leu Ser Arg Leu Pro Leu Pro

3265 3270 3275 328

Pro Pro Val Ser Pro He Cys Thr Phe Val Ser Pro Ala Ala Gin Lys

3285 3290 3295

Ala Phe Gin Pro Pro Arg Ser Cys Gly Thr Lys Tyr Glu Thr Pro He 3300 3305 3310

Lys Lys Lys Glu Leu Asn Ser Pro Gin Met Thr Pro Phe Lys Lys Phe

3315 3320 3325

Asn Glu He Ser Leu Leu Glu Ser Asn Ser He Ala Asp Glu Glu Leu

3330 3335 3340 Ala Leu He Asn Thr Gin Ala Leu Leu Ser Gly Ser Thr Gly Glu Lys

3345 3350 3355 336

Gin Phe He Ser Val Ser Glu Ser Thr Arg Thr Ala Pro Thr Ser Ser

3365 3370 3375

Glu Asp Tyr Leu Arg Leu Lys Arg Arg Cys Thr Thr Ser Leu He Lys 3380 3385 3390

Glu Gin Glu Ser Ser Gin Ala Ser Thr Glu Glu Cys Glu Lys Asn Lys

3395 3400 3405

Gin Asp Thr He Thr Thr Lys Lys Tyr He 3410 3415

(2) INFORMATION FOR SEQ ID NO : 12 :

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 10485 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: double

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA (ix) FEATURE:

(A) NAME/KEY: Coding Sequence

(B) LOCATION: 229...10482

(D) OTHER INFORMATION: BRCA2 (0MI5)

(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 12 : GGTGGCGCGA GCTTCTGAAA CTAGGCGGCA GAGGCGGAGC CGCTGTGGCA CTGCTGCGCC 60

TCTGCTGCGC CTCGGGTGTC TTTTGCGGCG GTGGGTCGCC GCCGGGAGAA GCGTGAGGGG 120

ACAGATTTGT GACCGGCGCG GTTTTTGTCA GCTTACTCCG GCCAAAAAAG AACTGCACCT 180 CTGGAGCGGA CTTATTTACC AAGCATTGGA GGAATATCGT AGGTAAAA ATG CCT ATT 237

Met Pro He 1

GGA TCC AAA GAG AGG CCA ACA TTT TTT GAA ATT TTT AAG ACA CGC TGC 285 Gly Ser Lys Glu Arg Pro Thr Phe Phe Glu He Phe Lys Thr Arg Cys 5 10 15

AAC AAA GCA GAT TTA GGA CCA ATA AGT CTT AAT TGG TTT GAA GAA CTT 333 Asn Lys Ala Asp Leu Gly Pro He Ser Leu Asn Trp Phe Glu Glu Leu 20 25 30 35

TCT TCA GAA GCT CCA CCC TAT AAT TCT GAA CCT GCA GAA GAA TCT GAA 381 Ser Ser Glu Ala Pro Pro Tyr Asn Ser Glu Pro Ala Glu Glu Ser Glu 40 45 50

CAT AAA AAC AAC AAT TAC GAA CCA AAC CTA TTT AAA ACT CCA CAA AGG 429 His Lys Asn Asn Asn Tyr Glu Pro Asn Leu Phe Lys Thr Pro Gin Arg 55 60 65 AAA CCA TCT TAT AAT CAG CTG GCT TCA ACT CCA ATA ATA TTC AAA GAG 477

Lys Pro Ser Tyr Asn Gin Leu Ala Ser Thr Pro He He Phe Lys Glu 70 75 80

CAA GGG CTG ACT CTG CCG CTG TAC CAA TCT CCT GTA AAA GAA TTA GAT 525 Gin Gly Leu Thr Leu Pro Leu Tyr Gin Ser Pro Val Lys Glu Leu Asp

85 90 95

AAA TTC AAA TTA GAC TTA GGA AGG AAT GTT CCC AAT AGT AGA CAT AAA 573 Lys Phe Lys Leu Asp Leu Gly Arg Asn Val Pro Asn Ser Arg His Lys 100 105 110 115

AGT CTT CGC ACA GTG AAA ACT AAA ATG GAT CAA GCA GAT GAT GTT TCC 621

Ser Leu Arg Thr Val Lys Thr Lys Met Asp Gin Ala Asp Asp Val Ser 120 125 130

TGT CCA CTT CTA AAT TCT TGT CTT AGT GAA AGT CCT GTT GTT CTA CAA 669

Cys Pro Leu Leu Asn Ser Cys Leu Ser Glu Ser Pro Val Val Leu Gin 135 140 145 TGT ACA CAT GTA ACA CCA CAA AGA GAT AAG TCA GTG GTA TGT GGG AGT 717 Cys Thr His Val Thr Pro Gin Arg Asp Lys Ser Val Val Cys Gly Ser 150 155 160

TTG TTT CAT ACA CCA AAG TTT GTG AAG GGT CGT CAG ACA CCA AAA CAT 765 Leu Phe His Thr Pro Lys Phe Val Lys Gly Arg Gin Thr Pro Lys His 165 170 175

ATT TCT GAA AGT CTA GGA GCT GAG GTG GAT CCT GAT ATG TCT TGG TCA 813 He Ser Glu Ser Leu Gly Ala Glu Val Asp Pro Asp Met Ser Trp Ser 180 185 190 195

AGT TCT TTA GCT ACA CCA CCC ACC CTT AGT TCT ACT GTG CTC ATA GTC 861 Ser Ser Leu Ala Thr Pro Pro Thr Leu Ser Ser Thr Val Leu He Val 200 205 210

AGA AAT GAA GAA GCA TCT GAA ACT GTA TTT CCT CAT GAT ACT ACT GCT 909 Arg Asn Glu Glu Ala Ser Glu Thr Val Phe Pro His Asp Thr Thr Ala 215 220 225

AAT GTG AAA AGC TAT TTT TCC AAT CAT GAT GAA AGT CTG AAG AAA AAT 957 Asn Val Lys Ser Tyr Phe Ser Asn His Asp Glu Ser Leu Lys Lys Asn 230 235 240

GAT AGA TTT ATC GCT TCT GTG ACA GAC AGT GAA AAC ACA AAT CAA AGA 1005 Asp Arg Phe He Ala Ser Val Thr Asp Ser Glu Asn Thr Asn Gin Arg 245 250 255

GAA GCT GCA AGT CAT GGA TTT GGA AAA ACA TCA GGG AAT TCA TTT AAA 1053

Glu Ala Ala Ser His Gly Phe Gly Lys Thr Ser Gly Asn Ser Phe Lys

260 265 270 275

GTA AAT AGC TGC AAA GAC CAC ATT GGA AAG TCA ATG CCA CAT GTC CTA 1101

Val Asn Ser Cys Lys Asp His He Gly Lys Ser Met Pro His Val Leu 280 285 290 GAA GAT GAA GTA TAT GAA ACA GTT GTA GAT ACC TCT GAA GAA GAT AGT 1149 Glu Asp Glu Val Tyr Glu Thr Val Val Asp Thr Ser Glu Glu Asp Ser 295 300 305

TTT TCA TTA TGT TTT TCT AAA TGT AGA ACA AAA AAT CTA CAA AAA GTA 1197 Phe Ser Leu Cys Phe Ser Lys Cys Arg Thr Lys Asn Leu Gin Lys Val 310 315 320

AGA ACT AGC AAG ACT AGG AAA AAA ATT TTC CAT GAA GCA AAC GCT GAT 1245 Arg Thr Ser Lys Thr Arg Lys Lys He Phe His Glu Ala Asn Ala Asp 325 330 335

GAA TGT GAA AAA TCT AAA AAC CAA GTG AAA GAA AAA TAC TCA TTT GTA 1293

Glu Cys Glu Lys Ser Lys Asn Gin Val Lys Glu Lys Tyr Ser Phe Val 340 345 350 355

TCT GAA GTG GAA CCA AAT GAT ACT GAT CCA TTA GAT TCA AAT GTA GCA 1341

Ser Glu Val Glu Pro Asn Asp Thr Asp Pro Leu Asp Ser Asn Val Ala

360 365 370 CAT CAG AAG CCC TTT GAG AGT GGA AGT GAC AAA ATC TCC AAG GAA GTT 1389 His Gin Lys Pro Phe Glu Ser Gly Ser Asp Lys He Ser Lys Glu Val 375 380 385

GTA CCG TCT TTG GCC TGT GAA TGG TCT CAA CTA ACC CTT TCA GGT CTA 1437 Val Pro Ser Leu Ala Cys Glu Trp Ser Gin Leu Thr Leu Ser Gly Leu 390 395 400

AAT GGA GCC CAG ATG GAG AAA ATA CCC CTA TTG CAT ATT TCT TCA TGT 1485 Asn Gly Ala Gin Met Glu Lys He Pro Leu Leu His He Ser Ser Cys 405 410 415

GAC CAA AAT ATT TCA GAA AAA GAC CTA TTA GAC ACA GAG AAC AAA AGA 1533 Asp Gin Asn He Ser Glu Lys Asp Leu Leu Asp Thr Glu Asn Lys Arg 420 425 430 435

AAG AAA GAT TTT CTT ACT TCA GAG AAT TCT TTG CCA CGT ATT TCT AGC 1581 Lys Lys Asp Phe Leu Thr Ser Glu Asn Ser Leu Pro Arg He Ser Ser 440 445 450 CTA CCA AAA TCG GAG AAG CCA TTA AAT GAG GAA ACA GTG GTA AAT AAG 1629 Leu Pro Lys Ser Glu Lys Pro Leu Asn Glu Glu Thr Val Val Asn Lys 455 460 465 AGA GAT GAA GAG CAG CAT CTT GAA TCT CAT ACA GAC TGC ATT CTT GCA 1677 Arg Asp Glu Glu Gin His Leu Glu Ser His Thr Asp Cys He Leu Ala 470 475 480

GTA AAG CAG GCA ATA TCT GGA ACT TCT CCA GTG GCT TCT TCA TTT CAG 1725 Val Lys Gin Ala He Ser Gly Thr Ser Pro Val Ala Ser Ser Phe Gin 485 490 495

GGT ATC AAA AAG TCT ATA TTC AGA ATA AGA GAA TCA CCT AAA GAG ACT 1773 Gly He Lys Lys Ser He Phe Arg He Arg Glu Ser Pro Lys Glu Thr 500 505 510 515 TTC AAT GCA AGT TTT TCA GGT CAT ATG ACT GAT CCA AAC TTT AAA AAA 1821 Phe Asn Ala Ser Phe Ser Gly His Met Thr Asp Pro Asn Phe Lys Lys 520 525 530

GAA ACT GAA GCC TCT GAA AGT GGA CTG GAA ATA CAT ACT GTT TGC TCA 1869 Glu Thr Glu Ala Ser Glu Ser Gly Leu Glu He His Thr Val Cys Ser

535 540 545

CAG AAG GAG GAC TCC TTA TGT CCA AAT TTA ATT GAT AAT GGA AGC TGG 1917 Gin Lys Glu Asp Ser Leu Cys Pro Asn Leu He Asp Asn Gly Ser Trp 550 555 560

CCA GCC ACC ACC ACA CAG AAT TCT GTA GCT TTG AAG AAT GCA GGT TTA 1965 Pro Ala Thr Thr Thr Gin Asn Ser Val Ala Leu Lys Asn Ala Gly Leu 565 570 575

ATA TCC ACT TTG AAA AAG AAA ACA AAT AAG TTT ATT TAT GCT ATA CAT 2013 He Ser Thr Leu Lys Lys Lys Thr Asn Lys Phe He Tyr Ala He His 580 585 590 595 GAT GAA ACA TCT TAT AAA GGA AAA AAA ATA CCG AAA GAC CAA AAA TCA 2061

Asp Glu Thr Ser Tyr Lys Gly Lys Lys He Pro Lys Asp Gin Lys Ser 600 605 610

GAA CTA ATT AAC TGT TCA GCC CAG TTT GAA GCA AAT GCT TTT GAA GCA 2109 Glu Leu He Asn Cys Ser Ala Gin Phe Glu Ala Asn Ala Phe Glu Ala

615 620 625

CCA CTT ACA TTT GCA AAT GCT GAT TCA GGT TTA TTG CAT TCT TCT GTG 2157 Pro Leu Thr Phe Ala Asn Ala Asp Ser Gly Leu Leu His Ser Ser Val 630 635 640

AAA AGA AGC TGT TCA CAG AAT GAT TCT GAA GAA CCA ACT TTG TCC TTA 2205 Lys Arg Ser Cys Ser Gin Asn Asp Ser Glu Glu Pro Thr Leu Ser Leu 645 650 655

ACT AGC TCT TTT GGG ACA ATT CTG AGG AAA TGT TCT AGA AAT GAA ACA 2253 Thr Ser Ser Phe Gly Thr He Leu Arg Lys Cys Ser Arg Asn Glu Thr 660 665 670 675 TGT TCT AAT AAT ACA GTA ATC TCT CAG GAT CTT GAT TAT AAA GAA GCA 2301 Cys Ser Asn Asn Thr Val He Ser Gin Asp Leu Asp Tyr Lys Glu Ala 680 685 690

AAA TGT AAT AAG GAA AAA CTA CAG TTA TTT ATT ACC CCA GAA GCT GAT 2349 Lys Cys Asn Lys Glu Lys Leu Gin Leu Phe He Thr Pro Glu Ala Asp

695 700 705 TCT CTG TCA TGC CTG CAG GAA GGA CAG TGT GAA AAT GAT CCA AAA AGC 2397 Ser Leu Ser Cys Leu Gin Glu Gly Gin Cys Glu Asn Asp Pro Lys Ser 710 715 720

AAA AAA GTT TCA GAT ATA AAA GAA GAG GTC TTG GCT GCA GCA TGT CAC 2445 Lys Lys Val Ser Asp He Lys Glu Glu Val Leu Ala Ala Ala Cys His 725 730 735 CCA GTA CAA CAC TCA AAA GTG GAA TAC AGT GAT ACT GAC TTT CAA TCC 2493 Pro Val Gin His Ser Lys Val Glu Tyr Ser Asp Thr Asp Phe Gin Ser 740 745 750 755

CAG AAA AGT CTT TTA TAT GAT CAT GAA AAT GCC AGC ACT CTT ATT TTA 2541 Gin Lys Ser Leu Leu Tyr Asp His Glu Asn Ala Ser Thr Leu He Leu

760 765 770

ACT CCT ACT TCC AAG GAT GTT CTG TCA AAC CTA GTC ATG ATT TCT AGA 2589 Thr Pro Thr Ser Lys Asp Val Leu Ser Asn Leu Val Met He Ser Arg 775 780 785

GGC AAA GAA TCA TAC AAA ATG TCA GAC AAG CTC AAA GGT AAC AAT TAT 2637 Gly Lys Glu Ser Tyr Lys Met Ser Asp Lys Leu Lys Gly Asn Asn Tyr 790 795 800

GAA TCT GAT GTT GAA TTA ACC AAA AAT ATT CCC ATG GAA AAG AAT CAA 2685 Glu Ser Asp Val Glu Leu Thr Lys Asn He Pro Met Glu Lys Asn Gin 805 810 815 GAT GTA TGT GCT TTA AAT GAA AAT TAT AAA AAC GTT GAG CTG TTG CCA 2733 Asp Val Cys Ala Leu Asn Glu Asn Tyr Lys Asn Val Glu Leu Leu Pro 820 825 830 835

CCT GAA AAA TAC ATG AGA GTA GCA TCA CCT TCA AGA AAG GTA CAA TTC 2781 Pro Glu Lys Tyr Met Arg Val Ala Ser Pro Ser Arg Lys Val Gin Phe

840 845 850

AAC CAA AAC ACA AAT CTA AGA GTA ATC CAA AAA AAT CAA GAA GAA ACT 2829 Asn Gin Asn Thr Asn Leu Arg Val He Gin Lys Asn Gin Glu Glu Thr 855 860 865

ACT TCA ATT TCA AAA ATA ACT GTC AAT CCA GAC TCT GAA GAA CTT TTC 2877 Thr Ser He Ser Lys He Thr Val Asn Pro Asp Ser Glu Glu Leu Phe 870 875 880

TCA GAC AAT GAG AAT AAT TTT GTC TTC CAA ATA GCT AAT GAA AGG AAT 2925 Ser Asp Asn Glu Asn Asn Phe Val Phe Gin He Ala Asn Glu Arg Asn 885 890 895 AAT CTT GCT TTA GGA AAT ACT AAG GAA CTT CAT GAA ACA GAC TTG ACT 2973 Asn Leu Ala Leu Gly Asn Thr Lys Glu Leu His Glu Thr Asp Leu Thr 900 905 910 915

TGT GTA AAC GAA CCC ATT TTC AAG AAC TCT ACC ATG GTT TTA TAT GGA 3021 Cys Val Asn Glu Pro He Phe Lys Asn Ser Thr Met Val Leu Tyr Gly

920 925 930

GAC ACA GGT GAT AAA CAA GCA ACC CAA GTG TCA ATT AAA AAA GAT TTG 3069 Asp Thr Gly Asp Lys Gin Ala Thr Gin Val Ser He Lys Lys Asp Leu 935 940 945

GTT TAT GTT CTT GCA GAG GAG AAC AAA AAT AGT GTA AAG CAG CAT ATA 3117 Val Tyr Val Leu Ala Glu Glu Asn Lys Asn Ser Val Lys Gin His He 950 955 960 AAA ATG ACT CTA GGT CAA GAT TTA AAA TCG GAC ATC TCC TTG AAT ATA 3165 Lys Met Thr Leu Gly Gin Asp Leu Lys Ser Asp He Ser Leu Asn He 965 970 975

GAT AAA ATA CCA GAA AAA AAT AAT GAT TAC ATG GAC AAA TGG GCA GGA 3213 Asp Lys He Pro Glu Lys Asn Asn Asp Tyr Met Asp Lys Trp Ala Gly 980 985 990 995

CTC TTA GGT CCA ATT TCA AAT CAC AGT TTT GGA GGT AGC TTC AGA ACA 3261 Leu Leu Gly Pro He Ser Asn His Ser Phe Gly Gly Ser Phe Arg Thr 1000 1005 1010

GCT TCA AAT AAG GAA ATC AAG CTC TCT GAA CAT AAC ATT AAG AAG AGC 3309 Ala Ser Asn Lys Glu He Lys Leu Ser Glu His Asn He Lys Lys Ser 1015 1020 1025

AAA ATG TTC TTC AAA GAT ATT GAA GAA CAA TAT CCT ACT AGT TTA GCT 3357 Lys Met Phe Phe Lys Asp He Glu Glu Gin Tyr Pro Thr Ser Leu Ala 1030 1035 1040 TGT GTT GAA ATT GTA AAT ACC TTG GCA TTA GAT AAT CAA AAG AAA CTG 3405 Cys Val Glu He Val Asn Thr Leu Ala Leu Asp Asn Gin Lys Lys Leu 1045 1050 1055

AGC AAG CCT CAG TCA ATT AAT ACT GTA TCT GCA CAT TTA CAG AGT AGT 3453 Ser Lys Pro Gin Ser He Asn Thr Val Ser Ala His Leu Gin Ser Ser

1060 1065 1070 1075

GTA GTT GTT TCT GAT TGT AAA AAT AGT CAT ATA ACC CCT CAG ATG TTA 3501 Val Val Val Ser Asp Cys Lys Asn Ser His He Thr Pro Gin Met Leu 1080 ^• 1085 1090

TTT TCC AAG CAG GAT TTT AAT TCA AAC CAT AAT TTA ACA CCT AGC CAA 3549 Phe Ser Lys Gin Asp Phe Asn Ser Asn His Asn Leu Thr Pro Ser Gin 1095 1100 1105

AAG GCA GAA ATT ACA GAA CTT TCT ACT ATA TTA GAA GAA TCA GGA AGT 3597 Lys Ala Glu He Thr Glu Leu Ser Thr He Leu Glu Glu Ser Gly Ser 1110 1115 1120 CAG TTT GAA TTT ACT CAG TTT AGA AAA CCA AGC TAC ATA TTG CAG AAG 3645

Gin Phe Glu Phe Thr Gin Phe Arg Lys Pro Ser Tyr He Leu Gin Lys 1125 1130 1135

AGT ACA TTT GAA GTG CCT GAA AAC CAG ATG ACT ATC TTA AAG ACC ACT 3693 Ser Thr Phe Glu Val Pro Glu Asn Gin Met Thr He Leu Lys Thr Thr 1140 1145 1150 1155

TCT GAG GAA TGC AGA GAT GCT GAT CTT CAT GTC ATA ATG AAT GCC CCA 3741 Ser Glu Glu Cys Arg Asp Ala Asp Leu His Val He Met Asn Ala Pro 1160 1165 1170

TCG ATT GGT CAG GTA GAC AGC AGC AAG CAA TTT GAA GGT ACA GTT GAA 3789 Ser He Gly Gin Val Asp Ser Ser Lys Gin Phe Glu Gly Thr Val Glu 1175 1180 1185

ATT AAA CGG AAG TTT GCT GGC CTG TTG AAA AAT GAC TGT AAC AAA AGT 3837 He Lys Arg Lys Phe Ala Gly Leu Leu Lys Asn Asp Cys Asn Lys Ser 1190 1195 1200

GCT TCT GGT TAT TTA ACA GAT GAA AAT GAA GTG GGG TTT AGG GGC TTT 3885 Ala Ser Gly Tyr Leu Thr Asp Glu Asn Glu Val Gly Phe Arg Gly Phe 1205 1210 1215

TAT TCT GCT CAT GGC ACA AAA CTG AAT GTT TCT ACT GAA GCT CTG CAA 3933 Tyr Ser Ala His Gly Thr Lys Leu Asn Val Ser Thr Glu Ala Leu Gin 1220 1225 1230 1235

AAA GCT GTG AAA CTG TTT AGT GAT ATT GAG AAT ATT AGT GAG GAA ACT 3981

Lys Ala Val Lys Leu Phe Ser Asp He Glu Asn He Ser Glu Glu Thr 1240 1245 1250

TCT GCA GAG GTA CAT CCA ATA AGT TTA TCT TCA AGT AAA TGT CAT GAT 4029

Ser Ala Glu Val His Pro He Ser Leu Ser Ser Ser Lys Cys His Asp 1255 1260 1265 TCT GTT GTT TCA ATG TTT AAG ATA GAA AAT CAT AAT GAT AAA ACT GTA 4077 Ser Val Val Ser Met Phe Lys He Glu Asn His Asn Asp Lys Thr Val 1270 1275 1280

AGT GAA AAA AAT AAT AAA TGC CAA CTG ATA TTA CAA AAT AAT ATT GAA 4125 Ser Glu Lys Asn Asn Lys Cys Gin Leu He Leu Gin Asn Asn He Glu 1285 1290 1295

ATG ACT ACT GGC ACT TTT GTT GAA GAA ATT ACT GAA AAT TAC AAG AGA 4173 Met Thr Thr Gly Thr Phe Val Glu Glu He Thr Glu Asn Tyr Lys Arg 1300 1305 1310 1315

AAT ACT GAA AAT GAA GAT AAC AAA TAT ACT GCT GCC AGT AGA AAT TCT 4221 Asn Thr Glu Asn Glu Asp Asn Lys Tyr Thr Ala Ala Ser Arg Asn Ser 1320 1325 1330

CAT AAC TTA GAA TTT GAT GGC AGT GAT TCA AGT AAA AAT GAT ACT GTT 4269 His Asn Leu Glu Phe Asp Gly Ser Asp Ser Ser Lys Asn Asp Thr Val 1335 1340 1345 TGT ATT CAT AAA GAT GAA ACG GAC TTG CTA TTT ACT GAT CAG CAC AAC 4317 Cys He His Lys Asp Glu Thr Asp Leu Leu Phe Thr Asp Gin His Asn 1350 1355 1360

ATA TGT CTT AAA TTA TCT GGC CAG TTT ATG AAG GAG GGA AAC ACT CAG 4365 He Cys Leu Lys Leu Ser Gly Gin Phe Met Lys Glu Gly Asn Thr Gin 1365 1370 1375

ATT AAA GAA GAT TTG TCA GAT TTA ACT TTT TTG GAA GTT GCG AAA GCT 4413 He Lys Glu Asp Leu Ser Asp Leu Thr Phe Leu Glu Val Ala Lys Ala 1380 1385 1390 1395

CAA GAA GCA TGT CAT GGT AAT ACT TCA AAT AAA GAA CAG TTA ACT GCT 4461 Gin Glu Ala Cys His Gly Asn Thr Ser Asn Lys Glu Gin Leu Thr Ala 1400 1405 1410

ACT AAA ACG GAG CAA AAT ATA AAA GAT TTT GAG ACT TCT GAT ACA TTT 4509 Thr Lys Thr Glu Gin Asn He Lys Asp Phe Glu Thr Ser Asp Thr Phe 1415 1420 1425 TTT CAG ACT GCA AGT GGG AAA AAT ATT AGT GTC GCC AAA GAG TCA TTT 4557 Phe Gin Thr Ala Ser Gly Lys Asn He Ser Val Ala Lys Glu Ser Phe 1430 1435 1440 AAT AAA ATT GTA AAT TTC TTT GAT CAG AAA CCA GAA GAA TTG CAT AAC 4605 Asn Lys He Val Asn Phe Phe Asp Gin Lys Pro Glu Glu Leu His Asn 1445 1450 1455

TTT TCC TTA AAT TCT GAA TTA CAT TCT GAC ATA AGA AAG AAC AAA ATG 4653 Phe Ser Leu Asn Ser Glu Leu His Ser Asp He Arg Lys Asn Lys Met 1460 1465 1470 1475

GAC ATT CTA AGT TAT GAG GAA ACA GAC ATA GTT AAA CAC AAA ATA CTG 4701 Asp He Leu Ser Tyr Glu Glu Thr Asp He Val Lys His Lys He Leu 1480 1485 1490 AAA GAA AGT GTC CCA GTT GGT ACT GGA AAT CAA CTA GTG ACC TTC CAG 4749 Lys Glu Ser Val Pro Val Gly Thr Gly Asn Gin Leu Val Thr Phe Gin 1495 1500 1505

GGA CAA CCC GAA CGT GAT GAA AAG ATC AAA GAA CCT ACT CTG TTG GGT 4797 Gly Gin Pro Glu Arg Asp Glu Lys He Lys Glu Pro Thr Leu Leu Gly

1510 1515 1520

TTT CAT ACA GCT AGC GGG AAA AAA GTT AAA ATT GCA AAG GAA TCT TTG 4845 Phe His Thr Ala Ser Gly Lys Lys Val Lys He Ala Lys Glu Ser Leu 1525 1530 1535

GAC AAA GTG AAA AAC CTT TTT GAT GAA AAA GAG CAA GGT ACT AGT GAA 4893

Asp Lys Val Lys Asn Leu Phe Asp Glu Lys Glu Gin Gly Thr Ser Glu 1540 1545 1550 1555

ATC ACC AGT TTT AGC CAT CAA TGG GCA AAG ACC CTA AAG TAC AGA GAG 4941

He Thr Ser Phe Ser His Gin Trp Ala Lys Thr Leu Lys Tyr Arg Glu 1560 1565 1570 GCC TGT AAA GAC CTT GAA TTA GCA TGT GAG ACC ATT GAG ATC ACA GCT 4989

Ala Cys Lys Asp Leu Glu Leu Ala Cys Glu Thr He Glu He Thr Ala 1575 1580 1585

GCC CCA AAG TGT AAA GAA ATG CAG AAT TCT CTC AAT AAT GAT AAA AAC 5037 Ala Pro Lys Cys Lys Glu Met Gin Asn Ser Leu Asn Asn Asp Lys Asn

1590 1595 1600

CTT GTT TCT ATT GAG ACT GTG GTG CCA CCT AAG CTC TTA AGT GAT AAT 5085 Leu Val Ser He Glu Thr Val Val Pro Pro Lys Leu Leu Ser Asp Asn 1605 1610 1615

TTA TGT AGA CAA ACT GAA AAT CTC AAA ACA TCA AAA AGT ATC TTT TTG 5133

Leu Cys Arg Gin Thr Glu Asn Leu Lys Thr Ser Lys Ser He Phe Leu 1620 1625 1630 • 1635

AAA GTT AAA GTA CAT GAA AAT GTA GAA AAA GAA ACA GCA AAA AGT CCT 5181

Lys Val Lys Val His Glu Asn Val Glu Lys Glu Thr Ala Lys Ser Pro 1640 1645 1650 GCA ACT TGT TAC ACA AAT CAG TCC CCT TAT TCA GTC ATT GAA AAT TCA 5229 Ala Thr Cys Tyr Thr Asn Gin Ser Pro Tyr Ser Val He Glu Asn Ser 1655 1660 1665

GCC TTA GCT TTT TAC ACA AGT TGT AGT AGA AAA ACT TCT GTG AGT CAG 5277 Ala Leu Ala Phe Tyr Thr Ser Cys Ser Arg Lys Thr Ser Val Ser Gin 1670 1675 1680 ACT TCA TTA CTT GAA GCA AAA AAA TGG CTT AGA GAA GGA ATA TTT GAT 5325

Thr Ser Leu Leu Glu Ala Lys Lys Trp Leu Arg Glu Gly He Phe Asp 1685 1690 1695

GGT CAA CCA GAA AGA ATA AAT ACT GCA GAT TAT GTA GGA AAT TAT TTG 5373

Gly Gin Pro Glu Arg He Asn Thr Ala Asp Tyr Val Gly Asn Tyr Leu 1700 1705 1710 1715 TAT GAA AAT AAT TCA AAC AGT ACT ATA GCT GAA AAT GAC AAA AAT CAT 5421 Tyr Glu Asn Asn Ser Asn Ser Thr He Ala Glu Asn Asp Lys Asn His 1720 1725 1730

CTC TCC GAA AAA CAA GAT ACT TAT TTA AGT AAC AGT AGC ATG TCT AAC 5469 Leu Ser Glu Lys Gin Asp Thr Tyr Leu Ser Asn Ser Ser Met Ser Asn 1735 1740 1745

AGC TAT TCC TAC CAT TCT GAT GAG GTA TAT AAT GAT TCA GGA TAT CTC 5517 Ser Tyr Ser Tyr His Ser Asp Glu Val Tyr Asn Asp Ser Gly Tyr Leu 1750 1755 1760

TCA AAA AAT AAA CTT GAT TCT GGT ATT GAG CCA GTA TTG AAG AAT GTT 5565 Ser Lys Asn Lys Leu Asp Ser Gly He Glu Pro Val Leu Lys Asn Val 1765 1770 1775

GAA GAT CAA AAA AAC ACT AGT TTT TCC AAA GTA ATA TCC AAT GTA AAA 5613 Glu Asp Gin Lys Asn Thr Ser Phe Ser Lys Val He Ser Asn Val Lys 1780 1785 1790 1795 GAT GCA AAT GCA TAC CCA CAA ACT GTA AAT GAA GAT ATT TGC GTT GAG 5661 Asp Ala Asn Ala Tyr Pro Gin Thr Val Asn Glu Asp He Cys Val Glu 1800 1805 1810

GAA CTT GTG ACT AGC TCT TCA CCC TGC AAA AAT AAA AAT GCA GCC ATT 5709 Glu Leu Val Thr Ser Ser Ser Pro Cys Lys Asn Lys Asn Ala Ala He 1815 1820 1825

AAA TTG TCC ATA TCT AAT AGT AAT AAT TTT GAG GTA GGG CCA CCT GCA 5757 Lys Leu Ser He Ser Asn Ser Asn Asn Phe Glu Val Gly Pro Pro Ala 1830 1835 1840

TTT AGG ATA GCC AGT GGT AAA ATC GTT TGT GTT TCA CAT GAA ACA ATT 5805 Phe Arg He Ala Ser Gly Lys He Val Cys Val Ser His Glu Thr He 1845 1850 1855

AAA AAA GTG AAA GAC ATA TTT ACA GAC AGT TTC AGT AAA GTA ATT AAG 5853 Lys Lys Val Lys Asp He Phe Thr Asp Ser Phe Ser Lys Val He Lys 1860 1865 1870 1875 GAA AAC AAC GAG AAT AAA TCA AAA ATT TGC CAA ACG AAA ATT ATG GCA 5901 Glu Asn Asn Glu Asn Lys Ser Lys He Cys Gin Thr Lys He Met Ala 1880 1885 1890

GGT TGT TAC GAG GCA TTG GAT GAT TCA GAG GAT ATT CTT CAT AAC TCT 5949 Gly Cys Tyr Glu Ala Leu Asp Asp Ser Glu Asp He Leu His Asn Ser 1895 1900 1905

CTA GAT AAT GAT GAA TGT AGC ACG CAT TCA CAT AAG GTT TTT GCT GAC 5997 Leu Asp Asn Asp Glu Cys Ser Thr His Ser His Lys Val Phe Ala Asp 1910 1915 1920

ATT CAG AGT GAA GAA ATT TTA CAA CAT AAC CAA AAT ATG TCT GGA TTG 6045 He Gin Ser Glu Glu He Leu Gin His Asn Gin Asn Met Ser Gly Leu 1925 1930 1935 GAG AAA GTT TCT AAA ATA TCA CCT TGT GAT GTT AGT TTG GAA ACT TCA 6093 Glu Lys Val Ser Lys He Ser Pro Cys Asp Val Ser Leu Glu Thr Ser 1940 1945 1950 1955

GAT ATA TGT AAA TGT AGT ATA GGG AAG CTT CAT AAG TCA GTC TCA TCT 6141 Asp He Cys Lys Cys Ser He Gly Lys Leu His Lys Ser Val Ser Ser

1960 1965 1970

GCA AAT ACT TGT GGG ATT TTT AGC ACA GCA AGT GGA AAA TCT GTC CAG 6189 Ala Asn Thr Cys Gly He Phe Ser Thr Ala Ser Gly Lys Ser Val Gin 1975 1980 1985

GTA TCA GAT GCT TCA TTA CAA AAC GCA AGA CAA GTG TTT TCT GAA ATA 6237 Val Ser Asp Ala Ser Leu Gin Asn Ala Arg Gin Val Phe Ser Glu He 1990 1995 2000

GAA GAT AGT ACC AAG CAA GTC TTT TCC AAA GTA TTG TTT AAA AGT AAC 6285 Glu Asp Ser Thr Lys Gin Val Phe Ser Lys Val Leu Phe Lys Ser Asn 2005 2010 2015 GAA CAT TCA GAC CAG CTC ACA AGA GAA GAA AAT ACT GCT ATA CGT ACT 6333

Glu His Ser Asp Gin Leu Thr Arg Glu Glu Asn Thr Ala He Arg Thr 2020 2025 2030 2035

CCA GAA CAT TTA ATA TCC CAA AAA GGC TTT TCA TAT AAT GTG GTA AAT 6381 Pro Glu His Leu He Ser Gin Lys Gly Phe Ser Tyr Asn Val Val Asn

2040 2045 2050

TCA TCT GCT TTC TCT GGA TTT AGT ACA GCA AGT GGA AAG CAA GTT TCC 6429 Ser Ser Ala Phe Ser Gly Phe Ser Thr Ala Ser Gly Lys Gin Val Ser 2055 2060 2065

ATT TTA GAA AGT TCC TTA CAC AAA GTT AAG GGA GTG TTA GAG GAA TTT 6477 He Leu Glu Ser Ser Leu His Lys Val Lys Gly Val Leu Glu Glu Phe 2070 2075 2080

GAT TTA ATC AGA ACT GAG CAT AGT CTT CAC TAT TCA CCT ACG TCT AGA 6525 Asp Leu He Arg Thr Glu His Ser Leu His Tyr Ser Pro Thr Ser Arg 2085 2090 2095 CAA AAT GTA TCA AAA ATA CTT CCT CGT GTT GAT AAG AGA AAC CCA GAG 6573 Gin Asn Val Ser Lys He Leu Pro Arg Val Asp Lys Arg Asn Pro Glu 2100 2105 2110 2115

CAC TGT GTA AAC TCA GAA ATG GAA AAA ACC TGC AGT AAA GAA TTT AAA 6621 His Cys Val Asn Ser Glu Met Glu Lys Thr Cys Ser Lys Glu Phe Lys

2120 2125 2130

TTA TCA AAT AAC TTA AAT GTT GAA GGT GGT TCT TCA GAA AAT AAT CAC 6669 Leu Ser Asn Asn Leu Asn Val Glu Gly Gly Ser Ser Glu Asn Asn His 2135 2140 2145

TCT ATT AAA GTT TCT CCA TAT CTC TCT CAA TTT CAA CAA GAC AAA CAA 6717 Ser He Lys Val Ser Pro Tyr Leu Ser Gin Phe Gin Gin Asp Lys Gin 2150 2155 2160

CAG TTG GTA TTA GGA ACC AAA GTC TCA CTT GTT GAG AAC ATT CAT GTT 6765 Gin Leu Val Leu Gly Thr Lys Val Ser Leu Val Glu Asn He His Val 2165 2170 2175

TTG GGA AAA GAA CAG GCT TCA CCT AAA AAC GTA AAA ATG GAA ATT GGT 6813 Leu Gly Lys Glu Gin Ala Ser Pro Lys Asn Val Lys Met Glu He Gly 2180 2185 2190 2195

AAA ACT GAA ACT TTT TCT GAT GTT CCT GTG AAA ACA AAT ATA GAA GTT 6861 Lys Thr Glu Thr Phe Ser Asp Val Pro Val Lys Thr Asn He Glu Val 2200 2205 2210

TGT TCT ACT TAC TCC AAA GAT TCA GAA AAC TAC TTT GAA ACA GAA GCA 6909 Cys Ser Thr Tyr Ser Lys Asp Ser Glu Asn Tyr Phe Glu Thr Glu Ala 2215 2220 2225

GTA GAA ATT GCT AAA GCT TTT ATG GAA GAT GAT GAA CTG ACA GAT TCT 6957 Val Glu He Ala Lys Ala Phe Met Glu Asp Asp Glu Leu Thr Asp Ser 2230 2235 2240 AAA CTG CCA AGT CAT GCC ACA CAT TCT CTT TTT ACA TGT CCC GAA AAT 7005 Lys Leu Pro Ser His Ala Thr His Ser Leu Phe Thr Cys Pro Glu Asn 2245 2250 2255

GAG GAA ATG GTT TTG TCA AAT TCA AGA ATT GGA AAA AGA AGA GGA GAG 7053 Glu Glu Met Val Leu Ser Asn Ser Arg He Gly Lys Arg Arg Gly Glu 2260 2265 2270 2275

CCC CTT ATC TTA GTG GGA GAA CCC TCA ATC AAA AGA AAC TTA TTA AAT 7101 Pro Leu He Leu Val Gly Glu Pro Ser He Lys Arg Asn Leu Leu Asn 2280 2285 2290

GAA TTT GAC AGG ATA ATA GAA AAT CAA GAA AAA TCC TTA AAG GCT TCA 7149 Glu Phe Asp Arg He He Glu Asn Gin Glu Lys Ser Leu Lys Ala Ser 2295 2300 2305

AAA AGC ACT CCA GAT GGC ACA ATA AAA GAT CGA AGA TTG TTT ATG CAT 7197 Lys Ser Thr Pro Asp Gly Thr He Lys Asp Arg Arg Leu Phe Met His 2310 2315 2320 CAT GTT TCT TTA GAG CCG ATT ACC TGT GTA CCC TTT CGC ACA ACT AAG 7245 His Val Ser Leu Glu Pro He Thr Cys Val Pro Phe Arg Thr Thr Lys 2325 2330 2335

GAA CGT CAA GAG ATA CAG AAT CCA AAT TTT ACC GCA CCT GGT CAA GAA 7293 Glu Arg Gin Glu He Gin Asn Pro Asn Phe Thr Ala Pro Gly Gin Glu 2340 2345 2350 2355

TTT CTG TCT AAA TCT CAT TTG TAT GAA CAT CTG ACT TTG GAA AAA TCT 7341 Phe Leu Ser Lys Ser His Leu Tyr Glu His Leu Thr Leu Glu Lys Ser 2360 2365 2370

TCA AGC AAT TTA GCA GTT TCA GGA CAT CCA TTT TAT CAA GTT TCT GCT 7389 Ser Ser Asn Leu Ala Val Ser Gly His Pro Phe Tyr Gin Val Ser Ala 2375 2380 2385

ACA AGA AAT GAA AAA ATG AGA CAC TTG ATT ACT ACA GGC AGA CCA ACC 7437 Thr Arg Asn Glu Lys Met Arg His Leu He Thr Thr Gly Arg Pro Thr 2390 2395 2400 AAA GTC TTT GTT CCA CCT TTT AAA ACT AAA TCA CAT TTT CAC AGA GTT 7485 Lys Val Phe Val Pro Pro Phe Lys Thr Lys Ser His Phe His Arg Val 2405 2410 2415 GAA CAG TGT GTT AGG AAT ATT AAC TTG GAG GAA AAC AGA CAA AAG CAA 7533 Glu Gin Cys Val Arg Asn He Asn Leu Glu Glu Asn Arg Gin Lys Gin 2420 2425 2430 2435

AAC ATT GAT GGA CAT GGC TCT GAT GAT AGT AAA AAT AAG ATT AAT GAC 7581 Asn He Asp Gly His Gly Ser Asp Asp Ser Lys Asn Lys He Asn Asp 2440 2445 2450

AAT GAG ATT CAT CAG TTT AAC AAA AAC AAC TCC AAT CAA GCA GCA GCT 7629 Asn Glu He His Gin Phe Asn Lys Asn Asn Ser Asn Gin Ala Ala Ala 2455 2460 2465 GTA ACT TTC ACA AAG TGT GAA GAA GAA CCT TTA GAT TTA ATT ACA AGT 7677 Val Thr Phe Thr Lys Cys Glu Glu Glu Pro Leu Asp Leu He Thr Ser 2470 2475 2480

CTT CAG AAT GCC AGA GAT ATA CAG GAT ATG CGA ATT AAG AAG AAA CAA 7725 Leu Gin Asn Ala Arg Asp He Gin Asp Met Arg He Lys Lys Lys Gin

2485 2490 2495

AGG CAA CGC GTC TTT CCA CAG CCA GGC AGT CTG TAT CTT GCA AAA ACA 7773 Arg Gin Arg Val Phe Pro Gin Pro Gly Ser Leu Tyr Leu Ala Lys Thr 2500 2505 2510 2515

TCC ACT CTG CCT CGA ATC TCT CTG AAA GCA GCA GTA GGA GGC CAA GTT 7821 Ser Thr Leu Pro Arg He Ser Leu Lys Ala Ala Val Gly Gly Gin Val 2520 2525 2530

CCC TCT GCG TGT TCT CAT AAA CAG CTG TAT ACG TAT GGC GTT TCT AAA 7869 Pro Ser Ala Cys Ser His Lys Gin Leu Tyr Thr Tyr Gly Val Ser Lys 2535 2540 2545 CAT TGC ATA AAA ATT AAC AGC AAA AAT GCA GAG TCT TTT CAG TTT CAC 7917

His Cys He Lys He Asn Ser Lys Asn Ala Glu Ser Phe Gin Phe His 2550 2555 2560

ACT GAA GAT TAT TTT GGT AAG GAA AGT TTA TGG ACT GGA AAA GGA ATA 7965 Thr Glu Asp Tyr Phe Gly Lys Glu Ser Leu Trp Thr Gly Lys Gly He

2565 2570 2575

CAG TTG GCT GAT GGT GGA TGG CTC ATA CCC TCC AAT GAT GGA AAG GCT 8013 Gin Leu Ala Asp Gly Gly Trp Leu He Pro Ser Asn Asp Gly Lys Ala 2580 2585 2590 2595

GGA AAA GAA GAA TTT TAT AGG GCT CTG TGT GAC ACT CCA GGT GTG GAT 8061

Gly Lys Glu Glu Phe Tyr Arg Ala Leu Cys Asp Thr Pro Gly Val Asp 2600 2605 2610

CCA AAG CTT ATT TCT AGA ATT TGG GTT TAT AAT CAC TAT AGA TGG ATC 8109

Pro Lys Leu He Ser Arg He Trp Val Tyr Asn His Tyr Arg Trp He 2615 2620 2625 ATA TGG AAA CTG GCA GCT ATG GAA TGT GCC TTT CCT AAG GAA TTT GCT 8157 He Trp Lys Leu Ala Ala Met Glu Cys Ala Phe Pro Lys Glu Phe Ala 2630 2635 2640

AAT AGA TGC CTA AGC CCA GAA AGG GTG CTT CTT CAA CTA AAA TAC AGA 8205 Asn Arg Cys Leu Ser Pro Glu Arg Val Leu Leu Gin Leu Lys Tyr Arg 2645 2650 2655 TAT GAT ACG GAA ATT GAT AGA AGC AGA AGA TCG GCT ATA AAA AAG ATA 8253

Tyr Asp Thr Glu He Asp Arg Ser Arg Arg Ser Ala He Lys Lys He 2660 2665 2670 2675

ATG GAA AGG GAT GAC ACA GCT GCA AAA ACA CTT GTT CTC TGT GTT TCT 8301

Met Glu Arg Asp Asp Thr Ala Ala Lys Thr Leu Val Leu Cys Val Ser 2680 2685 2690 GAC ATA ATT TCA TTG AGC GCA AAT ATA TCT GAA ACT TCT AGC AAT AAA 8349 Asp He He Ser Leu Ser Ala Asn He Ser Glu Thr Ser Ser Asn Lys 2695 2700 2705

ACT AGT AGT GCA GAT ACC CAA AAA GTG GCC ATT ATT GAA CTT ACA GAT 8397 Thr Ser Ser Ala Asp Thr Gin Lys Val Ala He He Glu Leu Thr Asp 2710 2715 2720

GGG TGG TAT GCT GTT AAG GCC CAG TTA GAT CCT CCC CTC TTA GCT GTC 8445 Gly Trp Tyr Ala Val Lys Ala Gin Leu Asp Pro Pro Leu Leu Ala Val 2725 2730 2735

TTA AAG AAT GGC AGA CTG ACA GTT GGT CAG AAG ATT ATT CTT CAT GGA 8493

Leu Lys Asn Gly Arg Leu Thr Val Gly Gin Lys He He Leu His Gly 2740 2745 2750 2755

GCA GAA CTG GTG GGC TCT CCT GAT GCC TGT ACA CCT CTT GAA GCC CCA 8541

Ala Glu Leu Val Gly Ser Pro Asp Ala Cys Thr Pro Leu Glu Ala Pro 2760 2765 2770 GAA TCT CTT ATG TTA AAG ATT TCT GCT AAC AGT ACT CGG CCT GCT CGC 8589 Glu Ser Leu Met Leu Lys He Ser Ala Asn Ser Thr Arg Pro Ala Arg 2775 2780 2785

TGG TAT ACC AAA CTT GGA TTC TTT CCT GAC CCT AGA CCT TTT CCT CTG 8637 Trp Tyr Thr Lys Leu Gly Phe Phe Pro Asp Pro Arg Pro Phe Pro Leu 2790 2795 2800

CCC TTA TCA TCG CTT TTC AGT GAT GGA GGA AAT GTT GGT TGT GTT GAT 8685 Pro Leu Ser Ser Leu Phe Ser Asp Gly Gly Asn Val Gly Cys Val Asp 2805 2810 2815

GTA ATT ATT CAA AGA GCA TAC CCT ATA CAG TGG ATG GAG AAG ACA TCA 8733

Val He He Gin Arg Ala Tyr Pro He Gin Trp Met Glu Lys Thr Ser 2820 2825 2830 2835

TCT GGA TTA TAC ATA TTT CGC AAT GAA AGA GAG GAA GAA AAG GAA GCA 8781

Ser Gly Leu Tyr He Phe Arg Asn Glu Arg Glu Glu Glu Lys Glu Ala 2840 2845 2850 GCA AAA TAT GTG GAG GCC CAA CAA AAG AGA CTA GAA GCC TTA TTC ACT 8829 Ala Lys Tyr Val Glu Ala Gin Gin Lys Arg Leu Glu Ala Leu Phe Thr 2855 2860 2865

AAA ATT CAG GAG GAA TTT GAA GAA CAT GAA GAA AAC ACA ACA AAA CCA 8877 Lys He Gin Glu Glu Phe Glu Glu His Glu Glu Asn Thr Thr Lys Pro 2870 2875 2880

TAT TTA CCA TCA CGT GCA CTA ACA AGA CAG CAA GTT CGT GCT TTG CAA 8925 Tyr Leu Pro Ser Arg Ala Leu Thr Arg Gin Gin Val Arg Ala Leu Gin 2885 2890 2895

GAT GGT GCA GAG CTT TAT GAA GCA GTG AAG AAT GCA GCA GAC CCA GCT 8973 Asp Gly Ala Glu Leu Tyr Glu Ala Val Lys Asn Ala Ala Asp Pro Ala 2900 2905 2910 2915 TAC CTT GAG GGT TAT TTC AGT GAA GAG CAG TTA AGA GCC TTG AAT AAT 9021 Tyr Leu Glu Gly Tyr Phe Ser Glu Glu Gin Leu Arg Ala Leu Asn Asn 2920 2925 2930

CAC AGG CAA ATG TTG AAT GAT AAG AAA CAA GCT CAG ATC CAG TTG GAA 9069 His Arg Gin Met Leu Asn Asp Lys Lys Gin Ala Gin He Gin Leu Glu 2935 2940 2945

ATT AGG AAG ACC ATG GAA TCT GCT GAA CAA AAG GAA CAA GGT TTA TCA 9117 He Arg Lys Thr Met Glu Ser Ala Glu Gin Lys Glu Gin Gly Leu Ser 2950 2955 2960

AGG GAT GTC ACA ACC GTG TGG AAG TTG CGT ATT GTA AGC TAT TCA AAA 9165

Arg Asp Val Thr Thr Val Trp Lys Leu Arg He Val Ser Tyr Ser Lys 2965 2970 2975

AAA GAA AAA GAT TCA GTT ATA CTG AGT ATT TGG CGT CCA TCA TCA GAT 9213

Lys Glu Lys Asp Ser Val He Leu Ser He Trp Arg Pro Ser Ser Asp 2980 2985 2990 2995 TTA TAT TCT CTG TTA ACA GAA GGA AAG AGA TAC AGA ATT TAT CAT CTT 9261

Leu Tyr Ser Leu Leu Thr Glu Gly Lys Arg Tyr Arg He Tyr His Leu 3000 3005 3010

GCA ACT TCA AAA TCT AAA AGT AAA TCT GAA AGA GCT AAC ATA CAG TTA 9309 Ala Thr Ser Lys Ser Lys Ser Lys Ser Glu Arg Ala Asn He Gin Leu

3015 3020 3025

GCA GCG ACA AAA AAA ACT CAG TAT CAA CAA CTA CCG GTT TCA GAT GAA 9357 Ala Ala Thr Lys Lys Thr Gin Tyr Gin Gin Leu Pro Val Ser Asp Glu 3030 3035 3040

ATT TTA TTT CAG ATT TAC CAG CCA CGG GAG CCC CTT CAC TTC AGC AAA 9405

He Leu Phe Gin He Tyr Gin Pro Arg Glu Pro Leu His Phe Ser Lys

3045 3050 3055

TTT TTA GAT CCA GAC TTT CAG CCA TCT TGT TCT GAG GTG GAC CTA ATA 9453

Phe Leu Asp Pro Asp Phe Gin Pro Ser Cys Ser Glu Val Asp Leu He

3060 3065 3070 3075 GGA TTT GTC GTT TCT GTT GTG AAA AAA ACA GGA CTT GCC CCT TTC GTC 9501

Gly Phe Val Val Ser Val Val Lys Lys Thr Gly Leu Ala Pro Phe Val 3080 3085 3090

TAT TTG TCA GAC GAA TGT TAC AAT TTA CTG GCA ATA AAG TTT TGG ATA 9549 Tyr Leu Ser Asp Glu Cys Tyr Asn Leu Leu Ala He Lys Phe Trp He 3095 3100 3105

GAC CTT AAT GAG GAC ATT ATT AAG CCT CAT ATG TTA ATT GCT GCA AGC 9597 Asp Leu Asn Glu Asp He He Lys Pro His Met Leu He Ala Ala Ser 3110 3115 3120

AAC CTC CAG TGG CGA CCA GAA TCC AAA TCA GGC CTT CTT ACT TTA TTT 9645 Asn Leu Gin Trp Arg Pro Glu Ser Lys Ser Gly Leu Leu Thr Leu Phe 3125 3130 3135

GCT GGA GAT TTT TCT GTG TTT TCT GCT AGT CCA AAA GAG GGC CAC TTT 9693 Ala Gly Asp Phe Ser Val Phe Ser Ala Ser Pro Lys Glu Gly His Phe 3140 3145 3150 3155

CAA GAG ACA TTC AAC AAA ATG AAA AAT ACT GTT GAG AAT ATT GAC ATA 9741 Gin Glu Thr Phe Asn Lys Met Lys Asn Thr Val Glu Asn He Asp He

3160 3165 3170

CTT TGC AAT GAA GCA GAA AAC AAG CTT ATG CAT ATA CTG CAT GCA AAT 9789 Leu Cys Asn Glu Ala Glu Asn Lys Leu Met His He Leu His Ala Asn 3175 3180 3185

GAT CCC AAG TGG TCC ACC CCA ACT AAA GAC TGT ACT TCA GGG CCG TAC 9837 Asp Pro Lys Trp Ser Thr Pro Thr Lys Asp Cys Thr Ser Gly Pro Tyr 3190 3195 3200

ACT GCT CAA ATC ATT CCT GGT ACA GGA AAC AAG CTT CTG ATG TCT TCT 9885 Thr Ala Gin He He Pro Gly Thr Gly Asn Lys Leu Leu Met Ser Ser 3205 3210 3215 CCT AAT TGT GAG ATA TAT TAT CAA AGT CCT TTA TCA CTT TGT ATG GCC 9933 Pro Asn Cys Glu He Tyr Tyr Gin Ser Pro Leu Ser Leu Cys Met Ala 3220 3225 3230 3235

AAA AGG AAG TCT GTT TCC ACA CCT GTC TCA GCC CAG ATG ACT TCA AAG 9981 Lys Arg Lys Ser Val Ser Thr Pro Val Ser Ala Gin Met Thr Ser Lys

3240 3245 3250

TCT TGT AAA GGG GAG AAA GAG ATT GAT GAC CAA AAG AAC TGC AAA AAG 10029 Ser Cys Lys Gly Glu Lys Glu He Asp Asp Gin Lys Asn Cys Lys Lys 3255 3260 3265

AGA AGA GCC TTG GAT TTC TTG AGT AGA CTG CCT TTA CCT CCA CCT GTT 10077 Arg Arg Ala Leu Asp Phe Leu Ser Arg Leu Pro Leu Pro Pro Pro Val 3270 3275 3280

AGT CCC ATT TGT ACA TTT GTT TCT CCG GCT GCA CAG AAG GCA TTT CAG 10125 Ser Pro He Cys Thr Phe Val Ser Pro Ala Ala Gin Lys Ala Phe Gin 3285 3290 3295 CCA CCA AGG AGT TGT GGC ACC AAA TAC GAA ACA CCC ATA AAG AAA AAA 10173 Pro Pro Arg Ser Cys Gly Thr Lys Tyr Glu Thr Pro He Lys Lys Lys 3300 3305 3310 3315

GAA CTG AAT TCT CCT CAG ATG ACT CCA TTT AAA AAA TTC AAT GAA ATT 10221 Glu Leu Asn Ser Pro Gin Met Thr Pro Phe Lys Lys Phe Asn Glu He

3320 3325 3330

TCT CTT TTG GAA AGT AAT TCA ATA GCT GAC GAA GAA CTT GCA TTG ATA 10269 Ser Leu Leu Glu Ser Asn Ser He Ala Asp Glu Glu Leu Ala Leu He 3335 3340 3345

AAT ACC CAA GCT CTT TTG TCT GGT TCA ACA GGA GAA AAA CAA TTT ATA 10317 Asn Thr Gin Ala Leu Leu Ser Gly Ser Thr Gly Glu Lys Gin Phe He 3350 3355 3360

TCT GTC AGT GAA TCC ACT AGG ACT GCT CCC ACC AGT TCA GAA GAT TAT 10365 Ser Val Ser Glu Ser Thr Arg Thr Ala Pro Thr Ser Ser Glu Asp Tyr 3365 3370 3375 CTC AGA CTG AAA CGA CGT TGT ACT ACA TCT CTG ATC AAA GAA CAG GAG 10413 Leu Arg Leu Lys Arg Arg Cys Thr Thr Ser Leu He Lys Glu Gin Glu 3380 3385 3390 3395 AGT TCC CAG GCC AGT ACG GAA GAA TGT GAG AAA AAT AAG CAG GAC ACA 10461 Ser Ser Gin Ala Ser Thr Glu Glu Cys Glu Lys Asn Lys Gin Asp Thr 3400 3405 3410

ATT ACA ACT AAA AAA TAT ATC TAA 10485

He Thr Thr Lys Lys Tyr He 3415

(2) INFORMATION FOR SEQ ID NO: 13;

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 3418 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein

(v) FRAGMENT TYPE: internal

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 13: Met Pro He Gly Ser Lys Glu Arg Pro Thr Phe Phe Glu He Phe Lys 1 5 10 15

Thr Arg Cys Asn Lys Ala Asp Leu Gly Pro He Ser Leu Asn Trp Phe

20 25 30

Glu Glu Leu Ser Ser Glu Ala Pro Pro Tyr Asn Ser Glu Pro Ala Glu 35 40 45

Glu Ser Glu His Lys Asn Asn Asn Tyr Glu Pro Asn Leu Phe Lys Thr

50 55 60

Pro Gin Arg Lys Pro Ser Tyr Asn Gin Leu Ala Ser Thr Pro He He 65 70 75 80 Phe Lys Glu Gin Gly Leu Thr Leu Pro Leu Tyr Gin Ser Pro Val Lys

85 90 95

Glu Leu Asp Lys Phe Lys Leu Asp Leu Gly Arg Asn Val Pro Asn Ser

100 105 110

Arg His Lys Ser Leu Arg Thr Val Lys Thr Lys Met Asp Gin Ala Asp 115 120 125

Asp Val Ser Cys Pro Leu Leu Asn Ser Cys Leu Ser Glu Ser Pro Val

130 135 140

Val Leu Gin Cys Thr His Val Thr Pro Gin Arg Asp Lys Ser Val Val 145 150 155 160 Cys Gly Ser Leu Phe His Thr Pro Lys Phe Val Lys Gly Arg Gin Thr

165 170 175

Pro Lys His He Ser Glu Ser Leu Gly Ala Glu Val Asp Pro Asp Met

180 185 190

Ser Trp Ser Ser Ser Leu Ala Thr Pro Pro Thr Leu Ser Ser Thr Val 195 200 205

Leu He Val Arg Asn Glu Glu Ala Ser Glu Thr Val Phe Pro His Asp

210 215 220

Thr Thr Ala Asn Val Lys Ser Tyr Phe Ser Asn His Asp Glu Ser Leu 225 230 235 240 Lys Lys Asn Asp Arg Phe He Ala Ser Val Thr Asp Ser Glu Asn Thr

245 250 255

Asn Gin Arg Glu Ala Ala Ser His Gly Phe Gly Lys Thr Ser Gly Asn

260 265 270

Ser Phe Lys Val Asn Ser Cys Lys Asp His He Gly Lys Ser Met Pro 275 280 285

His Val Leu Glu Asp Glu Val Tyr Glu Thr Val Val Asp Thr Ser Glu 290 295 300 Glu Asp Ser Phe Ser Leu Cys Phe Ser Lys Cys Arg Thr Lys Asn Leu 305 310 315 320

Gin Lys Val Arg Thr Ser Lys Thr Arg Lys Lys He Phe His Glu Ala 325 330 335

Asn Ala Asp Glu Cys Glu Lys Ser Lys Asn Gin Val Lys Glu Lys Tyr

340 345 350

Ser Phe Val Ser Glu Val Glu Pro Asn Asp Thr Asp Pro Leu Asp Ser 355 360 365 Asn Val Ala His Gin Lys Pro Phe Glu Ser Gly Ser Asp Lys He Ser 370 375 380

Lys Glu Val Val Pro Ser Leu Ala Cys Glu Trp Ser Gin Leu Thr Leu 385 390 395 400

Ser Gly Leu Asn Gly Ala Gin Met Glu Lys He Pro Leu Leu His He 405 410 415

Ser Ser Cys Asp Gin Asn He Ser Glu Lys Asp Leu Leu Asp Thr Glu

420 425 430

Asn Lys Arg Lys Lys Asp Phe Leu Thr Ser Glu Asn Ser Leu Pro Arg 435 440 445 He Ser Ser Leu Pro Lys Ser Glu Lys Pro Leu Asn Glu Glu Thr Val

450 455 460

Val Asn Lys Arg Asp Glu Glu Gin His Leu Glu Ser His Thr Asp Cys 465 470 475 480

He Leu Ala Val Lys Gin Ala He Ser Gly Thr Ser Pro Val Ala Ser 485 490 495

Ser Phe Gin Gly He Lys Lys Ser He Phe Arg He Arg Glu Ser Pro

500 505 510

Lys Glu Thr Phe Asn Ala Ser Phe Ser Gly His Met Thr Asp Pro Asn 515 520 525 Phe Lys Lys Glu Thr Glu Ala Ser Glu Ser Gly Leu Glu He His Thr

530 535 540

Val Cys Ser Gin Lys Glu Asp Ser Leu Cys Pro Asn Leu He Asp Asn 545 550 555 560

Gly Ser Trp Pro Ala Thr Thr Thr Gin Asn Ser Val Ala Leu Lys Asn 565 570 575

Ala Gly Leu He Ser Thr Leu Lys Lys Lys Thr Asn Lys Phe He Tyr

580 585 590

Ala He His Asp Glu Thr Ser Tyr Lys Gly Lys Lys He Pro Lys Asp 595 600 605 Gin Lys Ser Glu Leu He Asn Cys Ser Ala Gin Phe Glu Ala Asn Ala

610 615 620

Phe Glu Ala Pro Leu Thr Phe Ala Asn Ala Asp Ser Gly Leu Leu His 625 630 635 640

Ser Ser Val Lys Arg Ser Cys Ser Gin Asn Asp Ser Glu Glu Pro Thr 645 650 655

Leu Ser Leu Thr Ser Ser Phe Gly Thr He Leu Arg Lys Cys Ser Arg

660 665 670

Asn Glu Thr Cys Ser Asn Asn Thr Val He Ser Gin Asp Leu Asp Tyr 675 680 685 Lys Glu Ala Lys Cys Asn Lys Glu Lys Leu Gin Leu Phe He Thr Pro 690 695 700

Glu Ala Asp Ser Leu Ser Cys Leu Gin Glu Gly Gin Cys Glu Asn Asp 705 710 715 720

Pro Lys Ser Lys Lys Val Ser Asp He Lys Glu Glu Val Leu Ala Ala 725 730 735

Ala Cys His Pro Val Gin His Ser Lys Val Glu Tyr Ser Asp Thr Asp

740 745 750

Phe Gin Ser Gin Lys Ser Leu Leu Tyr Asp His Glu Asn Ala Ser Thr 755 760 765 Leu He Leu Thr Pro Thr Ser Lys Asp Val Leu Ser Asn Leu Val Met 770 775 780

He Ser Arg Gly Lys Glu Ser Tyr Lys Met Ser Asp Lys Leu Lys Gly 785 790 795 800

Asn Asn Tyr Glu Ser Asp Val Glu Leu Thr Lys Asn He Pro Met Glu

805 810 815 Lys Asn Gin Asp Val Cys Ala Leu Asn Glu Asn Tyr Lys Asn Val Glu

820 825 830

Leu Leu Pro Pro Glu Lys Tyr Met Arg Val Ala Ser Pro Ser Arg Lys

835 840 845

Val Gin Phe Asn Gin Asn Thr Asn Leu Arg Val He Gin Lys Asn Gin 850 855 860

Glu Glu Thr Thr Ser He Ser Lys He Thr Val Asn Pro Asp Ser Glu

865 870 875 880

Glu Leu Phe Ser Asp Asn Glu Asn Asn Phe Val Phe Gin He Ala Asn

885 890 895 Glu Arg Asn Asn Leu Ala Leu Gly Asn Thr Lys Glu Leu His Glu Thr

900 905 910

Asp Leu Thr Cys Val Asn Glu Pro He Phe Lys Asn Ser Thr Met Val

915 920 925

Leu Tyr Gly Asp Thr Gly Asp Lys Gin Ala Thr Gin Val Ser He Lys 930 935 940

Lys Asp Leu Val Tyr Val Leu Ala Glu Glu Asn Lys Asn Ser Val Lys

945 950 955 960

Gin His He Lys Met Thr Leu Gly Gin Asp Leu Lys Ser Asp He Ser

965 970 975 Leu Asn He Asp Lys He Pro Glu Lys Asn Asn Asp Tyr Met Asp Lys

980 985 990

Trp Ala Gly Leu Leu Gly Pro He Ser Asn His Ser Phe Gly Gly Ser

995 1000 1005

Phe Arg Thr Ala Ser Asn Lys Glu He Lys Leu Ser Glu His Asn He 1010 1015 1020

Lys Lys Ser Lys Met Phe Phe Lys Asp He Glu Glu Gin Tyr Pro Thr 1025 1030 1035 104

Ser Leu Ala Cys Val Glu He Val Asn Thr Leu Ala Leu Asp Asn Gin 1045 1050 1055 Lys Lys Leu Ser Lys Pro Gin Ser He Asn Thr Val Ser Ala His Leu

1060 1065 1070

Gin Ser Ser Val Val Val Ser Asp Cys Lys Asn Ser His He Thr Pro

1075 1080 1085

Gin Met Leu Phe Ser Lys Gin Asp Phe Asn Ser Asn His Asn Leu Thr 1090 1095 1100

Pro Ser Gin Lys Ala Glu He Thr Glu Leu Ser Thr He Leu Glu Glu 1105 1110 1115 112

Ser Gly Ser Gin Phe Glu Phe Thr Gin Phe Arg Lys Pro Ser Tyr He 1125 1130 1135 Leu Gin Lys Ser Thr Phe Glu Val Pro Glu Asn Gin Met Thr He Leu

1140 1145 1150

Lys Thr Thr Ser Glu Glu Cys Arg Asp Ala Asp Leu His Val He Met

1155 1160 1165

Asn Ala Pro Ser He Gly Gin Val Asp Ser Ser Lys Gin Phe Glu Gly 1170 1175 1180

Thr Val Glu He Lys Arg Lys Phe Ala Gly Leu Leu Lys Asn Asp Cys

1185 1190 1195 120

Asn Lys Ser Ala Ser Gly Tyr Leu Thr Asp Glu Asn Glu Val Gly Phe

1205 1210 1215 Arg Gly Phe Tyr Ser Ala His Gly Thr Lys Leu Asn Val Ser Thr Glu

1220 1225 1230

Ala Leu Gin Lys Ala Val Lys Leu Phe Ser Asp He Glu Asn He Ser

1235 1240 1245

Glu Glu Thr Ser Ala Glu Val His Pro He Ser Leu Ser Ser Ser Lys 1250 1255 1260

Cys His Asp Ser Val Val Ser Met Phe Lys He Glu Asn His Asn Asp 1265 1270 1275 128 Lys Thr Val Ser Glu Lys Asn Asn Lys Cys Gin Leu He Leu Gin Asn

1285 1290 1295

Asn He Glu Met Thr Thr Gly Thr Phe Val Glu Glu He Thr Glu Asn 1300 1305 1310

Tyr Lys Arg Asn Thr Glu Asn Glu Asp Asn Lys Tyr Thr Ala Ala Ser

1315 1320 1325

Arg Asn Ser His Asn Leu Glu Phe Asp Gly Ser Asp Ser Ser Lys Asn

1330 1335 1340 Asp Thr Val Cys He His Lys Asp Glu Thr Asp Leu Leu Phe Thr Asp

1345 1350 1355 136

Gin His Asn He Cys Leu Lys Leu Ser Gly Gin Phe Met Lys Glu Gly

1365 1370 1375

Asn Thr Gin He Lys Glu Asp Leu Ser Asp Leu Thr Phe Leu Glu Val 1380 1385 1390

Ala Lys Ala Gin Glu Ala Cys His Gly Asn Thr Ser Asn Lys Glu Gin

1395 1400 1405

Leu Thr Ala Thr Lys Thr Glu Gin Asn He Lys Asp Phe Glu Thr Ser 1410 1415 1420 Asp Thr Phe Phe Gin Thr Ala Ser Gly Lys Asn He Ser Val Ala Lys

1425 1430 1435 144

Glu Ser Phe Asn Lys He Val Asn Phe Phe Asp Gin Lys Pro Glu Glu

1445 1450 1455

Leu His Asn Phe Ser Leu Asn Ser Glu Leu His Ser Asp He Arg Lys 1460 1465 1470

Asn Lys Met Asp He Leu Ser Tyr Glu Glu Thr Asp He Val Lys His

1475 1480 1485

Lys He Leu Lys Glu Ser Val Pro Val Gly Thr Gly Asn Gin Leu Val 1490 1495 1500 Thr Phe Gin Gly Gin Pro Glu Arg Asp Glu Lys He Lys Glu Pro Thr

1505 1510 1515 152

Leu Leu Gly Phe His Thr Ala Ser Gly Lys Lys Val Lys He Ala Lys

1525 1530 1535

Glu Ser Leu Asp Lys Val Lys Asn Leu Phe Asp Glu Lys Glu Gin Gly 1540 1545 1550

Thr Ser Glu He Thr Ser Phe Ser His Gin Trp Ala Lys Thr Leu Lys

1555 1560 1565

Tyr Arg Glu Ala Cys Lys Asp Leu Glu Leu Ala Cys Glu Thr He Glu 1570 1575 1580 He Thr Ala Ala Pro Lys Cys Lys Glu Met Gin Asn Ser Leu Asn Asn

1585 1590 1595 160

Asp Lys Asn Leu Val Ser He Glu Thr Val Val Pro Pro Lys Leu Leu

1605 1610 1615

Ser Asp Asn Leu Cys Arg Gin Thr Glu Asn Leu Lys Thr Ser Lys Ser 1620 1625 1630

He Phe Leu Lys Val Lys Val His Glu Asn Val Glu Lys Glu Thr Ala

1635 1640 1645

Lys Ser Pro Ala Thr Cys Tyr Thr Asn Gin Ser Pro Tyr Ser Val He 1650 1655 1660 Glu Asn Ser Ala Leu Ala Phe Tyr Thr Ser Cys Ser Arg Lys Thr Ser

1665 1670 1675 168

Val Ser Gin Thr Ser Leu Leu Glu Ala Lys Lys Trp Leu Arg Glu Gly

1685 1690 1695

He Phe Asp Gly Gin Pro Glu Arg He Asn Thr Ala Asp Tyr Val Gly 1700 1705 1710

Asn Tyr Leu Tyr Glu Asn Asn Ser Asn Ser Thr He Ala Glu Asn Asp

1715 1720 1725

Lys Asn His Leu Ser Glu Lys Gin Asp Thr Tyr Leu Ser Asn Ser Ser

1730 1735 1740 Met Ser Asn Ser Tyr Ser Tyr His Ser Asp Glu Val Tyr Asn Asp Ser

1745 1750 1755 176

Gly Tyr Leu Ser Lys Asn Lys Leu Asp Ser Gly He Glu Pro Val Leu 1765 1770 1775

Lys Asn Val Glu Asp Gin Lys Asn Thr Ser Phe Ser Lys Val He Ser 1780 1785 1790 Asn Val Lys Asp Ala Asn Ala Tyr Pro Gin Thr Val Asn Glu Asp He 1795 1800 1805

Cys Val Glu Glu Leu Val Thr Ser Ser Ser Pro Cys Lys Asn Lys Asn

1810 1815 1820

Ala Ala He Lys Leu Ser He Ser Asn Ser Asn Asn Phe Glu Val Gly 1825 1830 1835 184

Pro Pro Ala Phe Arg He Ala Ser Gly Lys He Val Cys Val Ser His

1845 1850 1855

Glu Thr He Lys Lys Val Lys Asp He Phe Thr Asp Ser Phe Ser Lys 1860 1865 1870 Val He Lys Glu Asn Asn Glu Asn Lys Ser Lys He Cys Gin Thr Lys 1875 1880 1885

He Met Ala Gly Cys Tyr Glu Ala Leu Asp Asp Ser Glu Asp He Leu

1890 1895 1900

His Asn Ser Leu Asp Asn Asp Glu Cys Ser Thr His Ser His Lys Val 1905 1910 1915 192

Phe Ala Asp He Gin Ser Glu Glu He Leu Gin His Asn Gin Asn Met

1925 1930 1935

Ser Gly Leu Glu Lys Val Ser Lys He Ser Pro Cys Asp Val Ser Leu 1940 1945 1950 Glu Thr Ser Asp He Cys Lys Cys Ser He Gly Lys Leu His Lys Ser

1955 1960 1965

Val Ser Ser Ala Asn Thr Cys Gly He Phe Ser Thr Ala Ser Gly Lys

1970 1975 1980

Ser Val Gin Val Ser Asp Ala Ser Leu Gin Asn Ala Arg Gin Val Phe 1985 1990 1995 200

Ser Glu He Glu Asp Ser Thr Lys Gin Val Phe Ser Lys Val Leu Phe

2005 2010 2015

Lys Ser Asn Glu His Ser Asp Gin Leu Thr Arg Glu Glu Asn Thr Ala 2020 2025 2030 He Arg Thr Pro Glu His Leu He Ser Gin Lys Gly Phe Ser Tyr Asn

2035 2040 2045

Val Val Asn Ser Ser Ala Phe Ser Gly Phe Ser Thr Ala Ser Gly Lys

2050 2055 2060

Gin Val Ser He Leu Glu Ser Ser Leu His Lys Val Lys Gly Val Leu 2065 2070 2075 208

Glu Glu Phe Asp Leu He Arg Thr Glu His Ser Leu His Tyr Ser Pro

2085 2090 2095

Thr Ser Arg Gin Asn Val Ser Lys He Leu Pro Arg Val Asp Lys Arg 2100 2105 2110 Asn Pro Glu His Cys Val Asn Ser Glu Met Glu Lys Thr Cys Ser Lys

2115 2120 2125

Glu Phe Lys Leu Ser Asn Asn Leu Asn Val Glu Gly Gly Ser Ser Glu

2130 2135 2140

Asn Asn His Ser He Lys Val Ser Pro Tyr Leu Ser Gin Phe Gin Gin 2145 2150 2155 216

Asp Lys Gin Gin Leu Val Leu Gly Thr Lys Val Ser Leu Val Glu Asn

2165 2170 2175

He His Val Leu Gly Lys Glu Gin Ala Ser Pro Lys Asn Val Lys Met 2180 2185 2190 Glu He Gly Lys Thr Glu Thr Phe Ser Asp Val Pro Val Lys Thr Asn 2195 2200 2205

He Glu Val Cys Ser Thr Tyr Ser Lys Asp Ser Glu Asn Tyr Phe Glu

2210 2215 2220

Thr Glu Ala Val Glu He Ala Lys Ala Phe Met Glu Asp Asp Glu Leu 2225 2230 2235 224

Thr Asp Ser Lys Leu Pro Ser His Ala Thr His Ser Leu Phe Thr Cys 2245 2250 2255 Pro Glu Asn Glu Glu Met Val Leu Ser Asn Ser Arg He Gly Lys Arg

2260 2265 2270

Arg Gly Glu Pro Leu He Leu Val Gly Glu Pro Ser He Lys Arg Asn 2275 2280 2285

Leu Leu Asn Glu Phe Asp Arg He He Glu Asn Gin Glu Lys Ser Leu

2290 2295 2300

Lys Ala Ser Lys Ser Thr Pro Asp Gly Thr He Lys Asp Arg Arg Leu 2305 2310 2315 232 Phe Met His His Val Ser Leu Glu Pro He Thr Cys Val Pro Phe Arg

2325 2330 2335

Thr Thr Lys Glu Arg Gin Glu He Gin Asn Pro Asn Phe Thr Ala Pro

2340 2345 2350

Gly Gin Glu Phe Leu Ser Lys Ser His Leu Tyr Glu His Leu Thr Leu 2355 2360 2365

Glu Lys Ser Ser Ser Asn Leu Ala Val Ser Gly His Pro Phe Tyr Gin

2370 2375 2380

Val Ser Ala Thr Arg Asn Glu Lys Met Arg His Leu He Thr Thr Gly 2385 2390 2395 240 Arg Pro Thr Lys Val Phe Val Pro Pro Phe Lys Thr Lys Ser His Phe

2405 2410 2415

His Arg Val Glu Gin Cys Val Arg Asn He Asn Leu Glu Glu Asn Arg

2420 2425 2430

Gin Lys Gin Asn He Asp Gly His Gly Ser Asp Asp Ser Lys Asn Lys 2435 2440 2445

He Asn Asp Asn Glu He His Gin Phe Asn Lys Asn Asn Ser Asn Gin

2450 2455 2460

Ala Ala Ala Val Thr Phe Thr Lys Cys Glu Glu Glu Pro Leu Asp Leu 2465 2470 2475 248 He Thr Ser Leu Gin Asn Ala Arg Asp He Gin Asp Met Arg He Lys

2485 2490 2495

Lys Lys Gin Arg Gin Arg Val Phe Pro Gin Pro Gly Ser Leu Tyr Leu

2500 2505 2510

Ala Lys Thr Ser Thr Leu Pro Arg He Ser Leu Lys Ala Ala Val Gly 2515 2520 2525

Gly Gin Val Pro Ser Ala Cys Ser His Lys Gin Leu Tyr Thr Tyr Gly

2530 2535 2540

Val Ser Lys His Cys He Lys He Asn Ser Lys Asn Ala Glu Ser Phe

2545 2550 2555 256 Gin Phe His Thr Glu Asp Tyr Phe Gly Lys Glu Ser Leu Trp Thr Gly

2565 2570 2575

Lys Gly He Gin Leu Ala Asp Gly Gly Trp Leu He Pro Ser Asn Asp

2580 2585 2590

Gly Lys Ala Gly Lys Glu Glu Phe Tyr Arg Ala Leu Cys Asp Thr Pro 2595 2600 2605

Gly Val Asp Pro Lys Leu He Ser Arg He Trp Val Tyr Asn His Tyr

2610 2615 2620

Arg Trp He He Trp Lys Leu Ala Ala Met Glu Cys Ala Phe Pro Lys 2625 2630 2635 264 Glu Phe Ala Asn Arg Cys Leu Ser Pro Glu Arg Val Leu Leu Gin Leu

2645 2650 2655

Lys Tyr Arg Tyr Asp Thr Glu He Asp Arg Ser Arg Arg Ser Ala He

2660 2665 2670

Lys Lys He Met Glu Arg Asp Asp Thr Ala Ala Lys Thr Leu Val Leu 2675 2680 2685

Cys Val Ser Asp He He Ser Leu Ser Ala Asn He Ser Glu Thr Ser

2690 2695 2700

Ser Asn Lys Thr Ser Ser Ala Asp Thr Gin Lys Val Ala He He Glu 2705 2710 2715 272 Leu Thr Asp Gly Trp Tyr Ala Val Lys Ala Gin Leu Asp Pro Pro Leu

2725 2730 2735

Leu Ala Val Leu Lys Asn Gly Arg Leu Thr Val Gly Gin Lys He He 2740 2745 2750

Leu His Gly Ala Glu Leu Val Gly Ser Pro Asp Ala Cys Thr Pro Leu 2755 2760 2765 Glu Ala Pro Glu Ser Leu Met Leu Lys He Ser Ala Asn Ser Thr Arg 2770 2775 2780

Pro Ala Arg Trp Tyr Thr Lys Leu Gly Phe Phe Pro Asp Pro Arg Pro 2785 2790 2795 280

Phe Pro Leu Pro Leu Ser Ser Leu Phe Ser Asp Gly Gly Asn Val Gly 2805 2810 2815

Cys Val Asp Val He He Gin Arg Ala Tyr Pro He Gin Trp Met Glu

2820 2825 2830

Lys Thr Ser Ser Gly Leu Tyr He Phe Arg Asn Glu Arg Glu Glu Glu 2835 2840 2845 Lys Glu Ala Ala Lys Tyr Val Glu Ala Gin Gin Lys Arg Leu Glu Ala 2850 2855 2860

Leu Phe Thr Lys He Gin Glu Glu Phe Glu Glu His Glu Glu Asn Thr 2865 2870 2875 288

Thr Lys Pro Tyr Leu Pro Ser Arg Ala Leu Thr Arg Gin Gin Val Arg 2885 2890 2895

Ala Leu Gin Asp Gly Ala Glu Leu Tyr Glu Ala Val Lys Asn Ala Ala

2900 2905 2910

Asp Pro Ala Tyr Leu Glu Gly Tyr Phe Ser Glu Glu Gin Leu Arg Ala 2915 2920 2925 Leu Asn Asn His Arg Gin Met Leu Asn Asp Lys Lys Gin Ala Gin He 2930 2935 2940

Gin Leu Glu He Arg Lys Thr Met Glu Ser Ala Glu Gin Lys Glu Gin 2945 2950 2955 296

Gly Leu Ser Arg Asp Val Thr Thr Val Trp Lys Leu Arg He Val Ser 2965 2970 2975

Tyr Ser Lys Lys Glu Lys Asp Ser Val He Leu Ser He Trp Arg Pro

2980 2985 2990

Ser Ser Asp Leu Tyr Ser Leu Leu Thr Glu Gly Lys Arg Tyr Arg He 2995 3000 3005 Tyr His Leu Ala Thr Ser Lys Ser Lys Ser Lys Ser Glu Arg Ala Asn 3010 3015 3020

He Gin Leu Ala Ala Thr Lys Lys Thr Gin Tyr Gin Gin Leu Pro Val 3025 3030 3035 304

Ser Asp Glu He Leu Phe Gin He Tyr Gin Pro Arg Glu Pro Leu His 3045 3050 3055

Phe Ser Lys Phe Leu Asp Pro Asp Phe Gin Pro Ser Cys Ser Glu Val

3060 3065 3070

Asp Leu He Gly Phe Val Val Ser Val Val Lys Lys Thr Gly Leu Ala 3075 3080 3085 Pro Phe Val Tyr Leu Ser Asp Glu Cys Tyr Asn Leu Leu Ala He Lys 3090 3095 3100

Phe Trp He Asp Leu Asn Glu Asp He He Lys Pro His Met Leu He 3105 3110 3115 312

Ala Ala Ser Asn Leu Gin Trp Arg Pro Glu Ser Lys Ser Gly Leu Leu 3125 3130 3135

Thr Leu Phe Ala Gly Asp Phe Ser Val Phe Ser Ala Ser Pro Lys Glu

3140 3145 3150

Gly His Phe Gin Glu Thr Phe Asn Lys Met Lys Asn Thr Val Glu Asn 3155 3160 3165 He Asp He Leu Cys Asn Glu Ala Glu Asn Lys Leu Met His He Leu 3170 3175 3180

His Ala Asn Asp Pro Lys Trp Ser Thr Pro Thr Lys Asp Cys Thr Ser 3185 3190 3195 320

Gly Pro Tyr Thr Ala Gin He He Pro Gly Thr Gly Asn Lys Leu Leu 3205 3210 3215

Met Ser Ser Pro Asn Cys Glu He Tyr Tyr Gin Ser Pro Leu Ser Leu 3220 3225 3230 Cys Met Ala Lys Arg Lys Ser Val Ser Thr Pro Val Ser Ala Gin Met

3235 3240 3245

Thr Ser Lys Ser Cys Lys Gly Glu Lys Glu He Asp Asp Gin Lys Asn 3250 3255 3260

Cys Lys Lys Arg Arg Ala Leu Asp Phe Leu Ser Arg Leu Pro Leu Pro

3265 3270 3275 328

Pro Pro Val Ser Pro He Cys Thr Phe Val Ser Pro Ala Ala Gin Lys

3285 3290 3295 Ala Phe Gin Pro Pro Arg Ser Cys Gly Thr Lys Tyr Glu Thr Pro He

3300 3305 3310

Lys Lys Lys Glu Leu Asn Ser Pro Gin Met Thr Pro Phe Lys Lys Phe

3315 3320 3325

Asn Glu He Ser Leu Leu Glu Ser Asn Ser He Ala Asp Glu Glu Leu 3330 3335 3340

Ala Leu He Asn Thr Gin Ala Leu Leu Ser Gly Ser Thr Gly Glu Lys 3345 3350 3355 336

Gin Phe He Ser Val Ser Glu Ser Thr Arg Thr Ala Pro Thr Ser Ser 3365 3370 3375 Glu Asp Tyr Leu Arg Leu Lys Arg Arg Cys Thr Thr Ser Leu He Lys

3380 3385 3390

Glu Gin Glu Ser Ser Gin Ala Ser Thr Glu Glu Cys Glu Lys Asn Lys

3395 3400 3405

Gin Asp Thr He Thr Thr Lys Lys Tyr He 3410 3415

(2) INFORMATION FOR SEQ ID NO : 14 :

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 2F primer (xi) SEQUENCE DESCRIPTION: SEQ ID NO : 14 :

TGAGTTTTAC CTCAGTCACA 20

(2) INFORMATION FOR SEQ ID NO: 16:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 41 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS : single (D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16: CAGGAAACAG CTATGACCCT GTGACGTACT GGGTTTTTAG C 41

(2) INFORMATION FOR SEQ ID NO: 17:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 24 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 3FII primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17:

GATCTTTAAC TGTTCTGGGT CACA 24

(2) INFORMATION FOR SEQ ID NO: 18: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 22 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 3RII primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 18:

CCCAGCATGA CACAATTAAT GA 22 (2) INFORMATION FOR SEQ ID NO: 19:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 44 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: 4F/M 13F primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 19: TGTAAAACGA CGGCCAGTAG AATGCAAATT TATAATCCAG AGTA 44

(2) INFORMATION FOR SEQ ID NO: 20:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 4R-1A primer (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 20:

ATCAGATTCA TCTTTATAGA AC 22 (2) INFORMATION FOR SEQ ID NO: 21:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 40 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 5+6F/M13F primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 21: TGTAAAACGA CGGCCAGTTG TGTTGGCATT TTAAACATCA 40 (2) INFORMATION FOR SEQ ID NO: 22:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 38 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: 5+6R/M13R primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:22: CAGGAAACAG CTATGACCCA GGGCAAAGGT ATAACGCT 38

(2) INFORMATION FOR SEQ ID NO: 23:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 38 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 7F/M13F primer (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:

TGTAAAACGA CGGCCAGTTA AGTGAAATAA AGAGTGAA 38

(2) INFORMATION FOR SEQ ID NO:24:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 36 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear (A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 7R/M13R primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:

CAGGAAACAG CTATGACCAG AAGTATTAGA GATGAC 36 (2) INFORMATION FOR SEQ ID NO: 25:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 40 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: 8F/M13F primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 25: TGTAAAACGA CGGCCAGTGC CATATCTTAC CACCTTGTGA 40

(2) INFORMATION FOR SEQ ID NO: 26:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (ix) FEATURE:

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 8FIA primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 26:

TTGCATTCTA GTGATAATAT AC 22 (2) INFORMATION FOR SEQ ID NO: 27:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 19 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: 8RIA primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:27: AATTGTTAGC AATTTCAAC 19

(2) INFORMATION FOR SEQ ID NO: 28: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 40 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 9F/M13F primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 28: TGTAAAACGA CGGCCAGTTG GACCTAGGTT GATTGCAGAT 40

(2) INFORMATION FOR SEQ ID NO: 29: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 40 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 9R/M13R primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 29: CAGGAAACAG CTATGACCTA AACTGAGATC ACGGGTGACA 40 (2) INFORMATION FOR SEQ ID NO: 30:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 24 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: 10AF primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 30: GAATAATATA AATTATATGG CTTA 24

(2) INFORMATION FOR SEQ ID NO: 31:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 37 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 10AR/M13R primer (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 31: CAGGAAACAG CTATGACCCC TAGTCTTGCT AGTTCTT 37

(2) INFORMATION FOR SEQ ID NO: 32: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 42 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 10BF/M13F primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:32: TGTAAAACGA CGGCCAGTAR CTGAAGTGGA ACCAAATGAT AC 42 (2) INFORMATION FOR SEQ ID NO: 33:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 44 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: 10BR/M13R primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:33: CAGGAAACAG CTATGACCAC GTGGCAAAGA ATTCTCTGAA GTAA 44

(2) INFORMATION FOR SEQ ID NO:34:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 40 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (ix) FEATURE:

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 10CF/M13F primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:34: TGTAAAACGA CGGCCAGTCA GCATCTTGAA TCTCATACAG 40 (2) INFORMATION FOR SEQ ID NO: 35:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH : 19 base pairs

(B ) TYPE : nucleic acid

(C) STRANDEDNESS : single (D) TOPOLOGY : l inear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 10CRII primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 35: AGACAGAGGT ACCTGAATC 19

(2) INFORMATION FOR SEQ ID NO: 36:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 40 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 11AF-M13 primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 36: TGTAAAACGA CGGCCAGTTG GTACTTTAAT TTTGTCACTT 40

(2) INFORMATION FOR SEQ ID NO: 37: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 37 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 11AR-M13 primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:37: CAGGAAACAG CTATGACCTG CAGGCATGAC AGAGAAT 37 (2) INFORMATION FOR SEQ ID NO: 38:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 22 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: 11BF primer (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 38:

AAGAAGCAAA ATGTAATAAG GA 22

(2) INFORMATION FOR SEQ ID NO: 39:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 11BR primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 39: CATTTAAAGC ACATACATCT TG 22

(2) INFORMATION FOR SEQ ID NO: 40: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 11CF primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:40: TCTAGAGGCA AAGAATCATA C 21 (2) INFORMATION FOR SEQ ID NO: 41:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 22 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: 11CR primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 41: CAAGATTATT CCTTTCATTA GC 22

(2) INFORMATION FOR SEQ ID NO:42:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 11DF primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:

AACCAAAACA CAAATCTAAG AG 22

(2) INFORMATION FOR SEQ ID NO:43: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 23 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 11DR primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 43: GTCATTTTTA TATGCTGCTT TAC 23 (2) INFORMATION FOR SEQ ID NO:44:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: 11EF primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 44: GGTTTTATAT GGAGACACAG G 21

(2) INFORMATION FOR SEQ ID NO: 45:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 23 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: HER primer (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 45:

GTATTTACAA TTTCAACACA AGC 23 (2) INFORMATION FOR SEQ ID NO: 46:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 11FF primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 46: ATCACAGTTT TGGAGGTAGC 20 (2) INFORMATION FOR SEQ ID NO: 47:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: 11FR primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 47: CTGACTTCCT GATTCTTCTA A 21

(2) INFORMATION FOR SEQ ID NO: 48:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 21 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 11GF primer (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 48:

CTCAGATGTT ATTTTCCAAG C 21

(2) INFORMATION FOR SEQ ID NO: 49:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear (A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 11GR primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 49:

CTGTTAAATA ACCAGAAGCA C 21 (2) INFORMATION FOR SEQ ID NO: 50:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 18 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: 11HF primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 50: AGGTAGACAG CAGCAAGC 18

(2) INFORMATION FOR SEQ ID NO: 51:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (ix) FEATURE:

(A) NAME/KEY: None

(B) LOCATION:

(D) OTHER INFORMATION: 11HR primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 51:

GTAATATCAG TTGGCATTTA TT 22 (2) INFORMATION FOR SEQ ID NO:52:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: 11IF primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:52: TGCAGAGGTA CATCCAATAA G 21

(2) INFORMATION FOR SEQ ID NO:53: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 11IR primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:53: GATCAGTAAA TAGCAAGTCC G 21

(2) INFORMATION FOR SEQ ID NO : 54 : (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 23 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 11JF primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 54 : TACTGAAAAT GAAGATAACA AAT 23 (2) INFORMATION FOR SEQ ID NO: 55:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 22 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: ! ! JR primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:55: ATTTTGTTCT TTCTTATGTC AG 22

(2) INFORMATION FOR SEQ ID NO: 56:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 35 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 11KF-M13 primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 56:

TGTAAAACGA CGGCCAGTCT ACTAAAACGG AGCAA 35

(2) INFORMATION FOR SEQ ID NO:57: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 35 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 11KR-M13 primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 57: CAGGAAACAG CTATGACCGT ATGAAAACCC AACAG 35 (2) INFORMATION FOR SEQ ID NO: 58:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 22 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: 11LF primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 58: CACAAAATAC TGAAAGAAAG TG 22

(2) INFORMATION FOR SEQ ID NO: 59:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 19 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 11LR primer (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 59:

GGCACCACAG TCTCAATAG 19

(2) INFORMATION FOR SEQ ID NO: 60:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 11MF primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 60: GCAAAGACCC TAAAGTACAG 20 (2) INFORMATION FOR SEQ ID NO: 61:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 22 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: 11MR primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 61: CATCAAATAT TCCTTCTCTA AG 22

(2) INFORMATION FOR SEQ ID NO:62:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 35 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 11NF-M13 primer (xi) SEQUENCE DESCRIPTION: SEQ ID NO : 62 :

TGTAAAACGA CGGCCAGTGA AAATTCAGCC TTAGC 35

(2) INFORMATION FOR SEQ ID NO: 63:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 35 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 11NR-M13 primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 63: CAGGAAACAG CTATGACCAT CAGAATGGTA GGAAT 35 (2) INFORMATION FOR SEQ ID NO: 64:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 22 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: 110F primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 64 : GTACTATAGC TGAAAATGAC AA 22

(2) INFORMATION FOR SEQ ID NO: 65:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 110R primer (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 65:

ACCACTGGCT ATCCTAAATG 20

(2) INFORMATION FOR SEQ ID NO: 66:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 11PF primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 66: TGAAGATATT TGCGTTGAGG 20

(2) INFORMATION FOR SEQ ID NO: 67:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear (A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: 11PR primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 67: GTCAGCAAAA ACCTTATGTG 20

(2) INFORMATION FOR SEQ ID NO: 68:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 21 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 11QF primer (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 68:

ACGAAAATTA TGGCAGGTTG T 21

(2) INFORMATION FOR SEQ ID NO: 69:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 11QR primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 69: CTTGTCTTGC GTTTTGTAAT G 21

(2) INFORMATION FOR SEQ ID NO: 70:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 11RF primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:70: GCTTCATAAG TCAGTCTCAT 20 (2) INFORMATION FOR SEQ ID NO: 71:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 11RR primer (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 71:

TCAAATTCCT CTAACACTCC 20

(2) INFORMATION FOR SEQ ID NO: 72:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 35 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 11SF-M13 primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 72: TGTAAAACGA CGGCCAGTTA CAGCAAGTGG AAAGC 35

(2) INFORMATION FOR SEQ ID NO: 73:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 37 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 11SR-M13 primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 73: CAGGAAACAG CTATGACCAA GTTTCAGTTT TACCAAT 37

(2) INFORMATION FOR SEQ ID NO: 74: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 22 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

17i (B) LOCATION:

(D) OTHER INFORMATION: 11TF primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:74:

GTTCTTCAGA AAATAATCAC TC 22

(2) INFORMATION FOR SEQ ID NO: 75:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 11TR primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 75: TGTAAAAAGA GAATGTGTGG C 21

(2) INFORMATION FOR SEQ ID NO: 76:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 39 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 11UF-M13 primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 76: TGTAAAACGA CGGCCAGTAC TTTTTCTGAT GTTCCTGTG 39

(2) INFORMATION FOR SEQ ID NO: 77: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 39 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 11UR-M13 primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 77: CAGGAAACAG CTATGACCTA AAAATAGTGA TTGGCAACA 39 (2) INFORMATION FOR SEQ ID NO: 78:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 42 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 12F/M13F primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 78: TGTAAAACGA CGGCCAGTAG TGGTGTTTTA AAGTGGTCAA AA 42

(2) INFORMATION FOR SEQ ID NO: 79:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 40 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 12R/M13R primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 79: CAGGAAACAG CTATGACCGG ATCCACCTGA GGTCAGAATA 40

(2) INFORMATION FOR SEQ ID NO: 80: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 13-2F primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 80: TAACATTTAA GCATCCGTTA C 21 (2) INFORMATION FOR SEQ ID NO: 81:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 28 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: 13-2R primer (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 81:

AAACGAGACT TTTCTCATAC TGTATTAG 28

(2) INFORMATION FOR SEQ ID NO: 82:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 14F primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 82: ACCATGTAGC AAATGAGGGT CT 22

(2) INFORMATION FOR SEQ ID NO:83: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 22 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 14AR primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:83: GCTTTTGTCT GTTTTCCTCC AA 22 (2) INFORMATION FOR SEQ ID NO: 84:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: 15-2F primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 84: CCAGGGGTTG TGCTTTTTAA A 21

(2) INFORMATION FOR SEQ ID NO: 85:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 38 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 15FUT/M13-R primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 85:

CAGGAAACAG CTATGACCAC TCTGTCATAA AAGCCATC 38

(2) INFORMATION FOR SEQ ID NO: 86: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 24 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 16AF primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 86: TTTGGTTTGT TATAATTGTT TTTA 24 (2) INFORMATION FOR SEQ ID NO: 87:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: 16AR primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:87: CCAACTTTTT AGTTCGAGAG 20

(2) INFORMATION FOR SEQ ID NO: 88:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 19 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 17F primer (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 88:

TTCAGTATCA TCCTATGTG 19 (2) INFORMATION FOR SEQ ID NO: 89:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 17AR primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 89: AGAAACCTTA ACCCATACTG 20 (2) INFORMATION FOR SEQ ID NO: 90:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 39 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: 18FUT/M13-AF primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:90: TGTAAAACGA CGGCCAGTGA ATTCTAGAGT CACACTTCC 39

(2) INFORMATION FOR SEQ ID NO: 91:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 38 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 18R/M13R primer (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 91:

CAGGAAACAG CTATGACCTT TAACTGAATC AATGACTG 38

(2) INFORMATION FOR SEQ ID NO : 92 :

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 41 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear (A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 19F/M13F primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 92 :

TGTAAAACGA CGGCCAGTAA GTGAATATTT TTAAGGCAGT T 41 (2) INFORMATION FOR SEQ ID NO:93:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 39 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: 19FUT/M13-R primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 93: CAGGAAACAG CTATGACCAA GAGACCGAAA CTCCATCTC 39

(2) INFORMATION FOR SEQ ID NO: 94:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 38 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 20F/M13F primer (xi) SEQUENCE DESCRIPTION: SEQ ID NO : 94 :

TGTAAAACGA CGGCCAGTCA CTGTGCCTGG CCTGATAC 38

(2) INFORMATION FOR SEQ ID NO: 95:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 39 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 20R/M13R primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 95 :

CAGGAAACAG CTATGACCAT GTTAAATTCA AAGTCTCTA 39

(2) INFORMATION FOR SEQ ID NO: 96: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 39 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY: (B) LOCATION:

(D) OTHER INFORMATION: 21F/M13F primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 96: TGTAAAACGA CGGCCAGTGG GTGTTTTATG CTTGGTTCT 39

(2) INFORMATION FOR SEQ ID NO:97:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 40 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 21R/M13R primer (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 97:

CAGGAAACAG CTATGACCCA TTTCAACATA TTCCTTCCTG 40

(2) INFORMATION FOR SEQ ID NO: 98:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 19 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 22F-1A primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 98: AACCACACCC TTAAGATGA 19

(2) INFORMATION FOR SEQ ID NO: 99:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 22R-1A primer (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 99: GCATTAGTAG TGGATTTTGC 20

(2) INFORMATION FOR SEQ ID NO: 100:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 16 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 23FII primer (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 100:

TCACTTCCAT TGCATC 16

(2) INFORMATION FOR SEQ ID NO: 101:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 17 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 23RII primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 101: TGCCAACTGG TAGCTCC 17

(2) INFORMATION FOR SEQ ID NO:102:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 24 2F primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 102: TACAGTTAGC AGCGACAAAA 20

(2) INFORMATION FOR SEQ ID NO:103: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 38 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 24R/M13R primer (xi) SEQUENCE DESCRIPTION: SEQ ID NO:103:

CAGGAAACAG CTATGACCAT TTGCCAACTG GTAGCTCC 38

(2) INFORMATION FOR SEQ ID NO: 104:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 25F-7/23 primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 104: GCTTTCGCCA AATTCAGCTA 20

(2) INFORMATION FOR SEQ ID NO: 105:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 25R-7/23 primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 105: TACCAAAATG TGTGGTGATG 20

(2) INFORMATION FOR SEQ ID NO: 106: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 26-2F primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 106: AATCACTGAT ACTGGTTTTG 20

(2) INFORMATION FOR SEQ ID NO: 107:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single (D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 26-2R primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 107: TATACTTACA GGAGCCACAT 20

(2) INFORMATION FOR SEQ ID NO: 108:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 18 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 27AF-1A primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 108: CTGTGTGTAA TATTTGCG 18

(2) INFORMATION FOR SEQ ID NO: 109: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 40 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 27AR/M13R primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 109: CAGGAAACAG CTATGACGGC AAGTTCTTCG TCAGCTATTG 40 (2) INFORMATION FOR SEQ ID NO: 110:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 40 base pairs

(B) TYPE: nucleic acid (C) STRANDEDNESS: single

(D) TOPOLOGY: linear (A) NAME/KEY:

(B) LOCATION:

(D) OTHER INFORMATION: 27BF/M13F primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 110: TGTAAAACGA CGGCCAGTGA ATTCTCCTCA GATGACTCCA 40

(2) INFORMATION FOR SEQ ID NO: 111:

(i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 38 base pairs (B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(A) NAME/KEY:

(B) LOCATION: (D) OTHER INFORMATION: 27BR/M13R primer

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 111: CAGGAAACAG CTATGACCTC TTTGCTCATT GTGCAACA

Claims

WE CLAIM:

1. A genomic DNA containing a BRCA2 gene, wherein the first twelve nucleotides beginning exon 5 are 5'- TCCTGTTGTTCT-3' as set forth in SEQ. ID. NO: 1 , wherein nucleotides numbers 5782-5790 are GTTTGTGTT as set forth in SEQ. ID. NO: 4, and wherein the last 20 nucleotides ending exon 15 are 5'-

CTGCGTGTTCTCATAAACAG-3' as set forth in SEQ. ID. NO: 2 and the first 20 nucleotides beginning exon 16 are 5'-CTGTATACGTATGGCGTTTC-3' as set forth in SEQ. ID. NO: 3.

2. The genomic DNA according to claim 1 wherein the coding sequence nucleotides are as follows:

1093 A 1342 A 1593 A 2457 T

2908 G 3199 A 3624 A 4035 T 7470 A

9079 G.

3. The genomic DNA according to claim 1 wherein the coding sequence nucleotides are as follows:

1093 A 1342 C 1593 A 2457 T 2908 G

3199 A 3624 A 4035 T 7470 A 9079 G.

4. The genomic DNA according to claim 1 wherein the coding sequence nucleotides are as follows: 1093 A 1342 C 1593 A 2457 T 2908 G 3199 A 3624 A 0 4035 C 7470 A 9079 G.

5 5. The genomic DNA according to claim 1 wherein the coding sequence nucleotides are as follows:

1093 C 1342 A 0 1593 A

2457 C 2908 G 3199 G 3624 G 5 4035 T

7470 G 9079 G.

6. The genomic DNA according to claim 1 wherein the coding sequence o nucleotides are as follows:

1093 A 1342 C 1593 A 5 2457 T

2908 G 3199 A 3624 G 4035 T 0 7470 G

9079 G.

7. The genomic DNA according to claim 1 wherein the coding sequence nucleotides are as follows: 5

1093 C 1342 C 1593G 2457 C 0 2908 A 3199 G 3624 A

4035 T

7470 A 9079 A.

8. The genomic DNA according to claim 1 wherein the coding sequence nucleotides are as follows: 2024 C

4553 C

4815 G

5841 T

5972 C.

9. A DNA comprising a BRCA2 coding sequence, wherein nucleotide numbers 643-666 are

CTTAGTGAAAGTCCTGTTGTTCTA and wherein nucleotides numbers 5782-5790 are GTTTGTGTT.

10. The DNA according to claim 9 wherein the coding sequence nucleotides are as follows:

1093 A

1342 A

1593 A

2457 T

2908 G

3199 A

3624 A

4035 T

7470 A

9079 G

11. The DNA according to claim 9 wherein the coding sequence nucleotides are as follows:

1093 A

1342 C

1593 A

2457 T

2908 G

3199 A

3624 A

4035 T

7470 A

9079 G as set forth in SEQ. ID. NO: 4

12. The DNA according to claim 9 wherein the coding sequence nucleotides are as follows: 1093 A

1342 C 1593 A

2457 T

2908 G

3199 A

3624 A 4035 C

7470 A

9079 G as set forth in SEQ. ID. NO: 6.

13. The DNA according to claim 9 wherein the coding sequence nucleotides are as follows:

1093 C

1342 A 1593 A

2457 C

2908 G

3199 G

3624 G 4035 T

7470 G

9079 G as set forth in SEQ. ID. NO: 8.

14. The DNA according to claim 9 wherein the coding sequence nucleotides are as follows:

1093 A

1342 C 1593 A

2457 T

2908 G

3199 A

3624 G 4035 T

7470 G

9079 G as set forth in SEQ. ID. NO: 10.

15. The DNA according to claim 9 wherein the coding sequence nucleotides are as follows:

1093 C

1342 C 1593 G

2457 C 2908 A

3199 G

3624 A 4035 T

7470 A

9079 A as set forth in SEQ. ID. NO: 12.

16. The DNA according to claim 9 wherein the coding sequence nucleotides are as follows:

2024 C

4553 C 4815 G

5841 T

5972 C.

17. A BRCA2 protein having the following amino acids at the following peptide numbers:

289 asparagine

372 histidine

894 valine 991 asparagine

1852 valine

1853 cysteine

1854 valine 2951 alanine as set forth in SEQ. ID. NO: 5.

18. The BRCA2 protein having the following amino acids at the following peptide numbers: 289 asparagine

372 asparagine

599 serine

894 valine

991 asparagine 2951 alanine.

19. The BRCA2 protein having the following amino acids at the following peptide numbers: 289 histidine

372 histidine

894 valine

991 asparatic acid

2951 alanine as set forth in SEQ. ID. NO: 9.

20. The BRCA2 protein having the following amino acids at the following peptide numbers:

5 289 histidine

372 asparagine 894 isoleucine 991 aspartic acid 2951 threonine 0 as set forth in SEQ. ID. NO: 13.

21. The BRCA2 protein according to claims 17-20 having the following amino acids at the following peptide numbers: 5 599 serine

1442 serine 1915 threonine.

22. A haplotype of BRCA2 coding sequence (BRCA2^{om╬╣ 1}) as set forth in SEQ. ID. o NO: 4 or a sequence complementary thereto.

23. A BRCA2 protein comprising an amino acid sequence derived from BRCA2^{om 1} as set forth in SEQ. ID. NO: 5.

5 24. A haplotype of BRCA2 coding sequence (BRCA2^{om╬╣ 2}) as set forth in SEQ. ID. NO: 6 or a sequence complementary thereto.

25. A BRCA2 protein comprising an amino acid sequence derived from BRCA2┬░^{m 2} as set forth in SEQ. ID. NO: 7. 0

26. A haplotype of BRCA2 coding sequence (BRCA2^om'³) as set forth in SEQ. ID. NO: 8 or a sequence complementary thereto.

27. A BRCA2 protein comprising an amino acid sequence derived from BRCA2^om 5 ³ as set forth in SEQ. ID. NO: 9.

28. A haplotype of BRCA2 coding sequence (BRCA2^{om╬╣ 4}) as set forth in SEQ. ID. NO: 10 or a sequence complementary thereto.

5 29. A BRCA2 protein comprising an amino acid sequence derived from BRCA2^{om 4} as set forth in SEQ. ID. NO: 11.

30. A haplotype of BRCA2 coding sequence (BRCA2^{om╬╣ 5}) as set forth in SEQ. ID. NO: 12 or a sequence complementary thereto. 0

31. A BRCA2 protein comprising an amino acid sequence derived from BRCA2^{om╬╣ 5} as set forth in SEQ. ID. NO: 13.

32. A method of identifying individuals having a BRCA2 gene with a BRCA2 5 coding sequence not associated with disease, comprising:

(a) amplifying a DNA or a fragment thereof of an individual's BRCA2 coding sequence;

(b) sequencing said amplified DNA fragment;

(c) if necessary, repeating steps (a) and (b) until said individual's BRCA2 0 coding sequence is sufficiently sequenced to determine whether a mutation is present;

(d) comparing the sequence of said amplified DNA fragment to a BRCA2^(om╬╣) DNA sequence selecting from the group consisting of SEQ. ID. NO: 4, SEQ. ID. NO: 6, SEQ. ID. NO: 8, SEQ. ID. NO: 10, SEQ. ID. 5 NO: 12, and their respective complementary sequences;

(e) determining the presence of absence of each of the following polymorphic variations in said individual's BRCA2 coding sequence:

(i) AAT and CAT at position 1093, (ii) CAT and AAT at position 1342, o (iii) TCA and TCG at position 1593, (iv) CAT and CAC at position 2457,

(v) GTA and ATA at position 2908,

(vi) AAC and GAC at position 3199,

5 (vii) AAA and AAG at position 3624,

(viii) GTT and GTC at position 4035, (ix) TCA and TCG at position 7470, and (x) GCC and ACC at position 9079; and (f) determining any sequence differences between said individual's 0 BRCA2 coding sequences and a BRCA2^(omi) DNA sequence selected from the group consisting of SEQ. ID. NO: 4, SEQ. ID. NO: 6, SEQ. ID. NO: 8, SEQ. ID. NO: 10, SEQ. ID. NO: 12, and their respective complementary sequences, wherein the presence of said polymorphic variations and the absence of a variation outside of positions 1093, 5 1342, 1593, 2457, 2908, 3199, 3624, 4035, 7470, and 9079 is correlated with an absence of increased genetic susceptibility to breast or ovarian cancer resulting from a BRCA2 mutation in the BRCA2 coding sequence.

33. A method of identifying individuals having a BRCA2 gene with a BRCA2 0 coding sequence not associated with disease, comprising:

(a) amplifying a DNA or a fragment thereof of an individual's BRCA2 coding sequence;

(b) sequencing said amplified DNA fragment;

(c) if necessary, repeating steps (a) and (b) until said individual's BRCA2 5 coding sequence is sufficiently sequenced to determine whether a mutation is present;

(d) comparing the sequence of said amplified DNA fragment to a BRCA2^{(o i)} DNA sequence selecting from the group consisting of SEQ. ID. NO: 4, SEQ. ID. NO: 6, SEQ. ID. NO: 8, SEQ. ID. NO: 10, SEQ. ID. o NO: 12, and their respective complementary sequences; (e) determining the presence of absence of each of the following polymorphic variations in said individual's BRCA2 coding sequence:

(i) AAT and CAT at position 1093, (ii) CAT and AAT at position 1342,

(iii) TCA and TCG at position 1593, (iv) CAT and CAC at position 2457, (v) GTA and ATA at position 2908, (vi) AAC and GAC at position 3199, (vii) AAA and AAG at position 3624,

(viii) GTT and GTC at position 4035, (ix) TCA and TCG at position 7470, and (x) GCC and ACC at position 9079; and

(f) determining any sequence differences between said individual's BRCA2 coding sequences and a BRCA2^(omi) DNA sequence selected from the group consisting of SEQ. ID. NO: 4, SEQ. ID. NO: 6, SEQ. ID. NO: 8, SEQ. ID. NO: 10, SEQ. ID. NO: 12, and their respective complementary sequences, wherein the presence of said polymorphic variations and the absence of a variation outside of positions 1093, 1342, 1593, 2457, 2908, 3199, 3624, 4035, 7470, and 9079 is correlated with an absence of increased genetic susceptibility to breast or ovarian cancer resulting from a BRCA2 mutation in the BRCA2 coding sequence; wherein, codon variations occur at the following frequencies, respectively, in a Caucasian population of individuals free of disease: (i) at position 1093, AAT and CAT occur at frequencies from about 75-85%, and from about 15-25%, respectively, (ii) at position 1342, CAT and AAT occur at frequencies from about 35-45%, and from about 55-65%, respectively, (iii) at position 1593, TCA and TCG occur at frequencies from about 85-95%, and from about 5-15%, respectively, (iv) at position 2457, CAT and CAC occur at frequencies from about 75-85%, and from about 15-25%, respectively, (v) at position 2908, GTA and ATA occur at frequencies from about 85-95%, and from about 5-15%, respectively,

(vi) at position 3199, AAC and GAC occur at frequencies from about 75-85%, and from about 15-25%, respectively, (vii) at position 3624, AAA and AAG occur at frequencies from about 75-85%, and from about 15-25%, respectively, (viii) at position 4035, GTT and GTC occur at frequencies from about 85-95%, and from about 5-15%, respectively, (ix) at position 7470, TCA and TCG occur at frequencies from about 75-85%, and from about 15-25%, respectively, and

(x) at position 9079, GCC and ACC occur at frequencies from about 85-95%, and from about 5-15%, respectively.

34. A method of detecting an increased genetic susceptibility to breast and ovarian cancer in an individual resulting from the presence of a mutation in the BRCA2 coding sequence, comprising:

(a) amplifying a DNA or a fragment thereof of an individual's BRCA2 coding sequence;

(b) sequencing said amplified DNA fragment; (c) if necessary, repeating steps (a) and (b) until said individual's BRCA2 coding sequence is sufficiently sequenced to determine whether a mutation is present; (d) comparing the sequence of said amplified DNA fragment to a

BRCA2^{(o i)} DNA sequence selected from the group consisting of SEQ. ID. NO: 4, SEQ. ID. NO: 6, SEQ. ID. NO: 8, SEQ. ID. NO: 10, SEQ. ID. NO: 12, and their respective complementary sequences; (e) determining any sequence differences between said individual's BRCA2 coding sequences and a BRCA2^(om╬╣) DNA sequence selected from the group consisting of SEQ. ID. NO: 4, SEQ. ID. NO: 6, SEQ. ID. NO: 8, SEQ. ID. NO: 10, SEQ. ID. NO: 12, and their respective complementary sequences in order to determine the presence or absence of base changes in said individual's BRCA2 coding sequence wherein a base change which is not any one of the following:

(i) AAT and CAT at position 1093, (ii) CAT and AAT at position 1342, (iii) TCA and TCG at position 1593, (iv) CAT and CAC at position 2457, (v) GTA and ATA at position 2908,

(vi) AAC and GAC at position 3199, (vii) AAA and AAG at position 3624, (viii) GTT and GTC at position 4035, (ix) TCA and TCG at position 7470, and (x) GCC and ACC at position 9079, is correlated with the potential of increased genetic susceptibility to breast or ovarian cancer resulting from a BRCA2 mutation in the BRCA2 coding sequence.

35. A method of detecting an increased genetic susceptibility to breast and ovarian cancer in an individual resulting from the presence of a mutation in the BRCA2 coding sequence, comprising:

(a) amplifying a DNA or a fragment thereof of an individual's BRCA2 coding sequence;

(b) sequencing said amplified DNA fragment; (c) if necessary, repeating steps (a) and (b) until said individual's BRCA2 coding sequence is sufficiently sequenced to determine whether a mutation is present; (d) comparing the sequence of said amplified DNA fragment to a

BRCA2^(om╬╣) DNA sequence selected from the group consisting of: SEQ. ID. NO: 4, SEQ. ID. NO: 6, SEQ. ID. NO: 8, SEQ. ID. NO: 10, SEQ. ID. NO: 12, and their respective complementary sequences; (e) determining any sequence differences between said individual's BRCA2 coding sequences and a BRCA2^(om╬╣) DNA sequence selected from the group consisting of: SEQ. ID. NO: 4, SEQ. ID. NO: 6, SEQ. ID. NO: 8, SEQ. ID. NO: 10, SEQ. ID. NO: 12, and their respective complementary sequences in order to determine the presence or absence of base changes in said individual's BRCA2 coding sequence wherein a base change which is not any one of the following:

(i) AAT and CAT at position 1093, (ii) CAT and AAT at position 1342, (iii) TCA and TCG at position 1593, (iv) CAT and CAC at position 2457, (v) GTA and ATA at position 2908,

(vi) AAC and GAC at position 3199, (vii) AAA and AAG at position 3624, (viii) GTT and GTC at position 4035, (ix) TCA and TCG at position 7470, and (x) GCC and ACC at position 9079, is correlated with the potential of increased genetic susceptibility to breast or ovarian cancer resulting from a BRCA2 mutation in the BRCA2 coding sequence, wherein, codon variations occur at the following frequencies, respectively, in a Caucasian population of individuals free of disease: (i) at position 1093, AAT and CAT occur at frequencies from about 75-85%, and from about 15-25%, respectively, (ii) at position 1342, CAT and AAT occur at frequencies from about 35-45%, and from about 55-65%, respectively,

(iii) at position 1593, TCA and TCG occur at frequencies from about 85-95%, and from about 5-15%, respectively, (iv) at position 2457, CAT and CAC occur at frequencies from about 75-85%, and from about 15-25%, respectively, (v) at position 2908, GTA and ATA occur at frequencies from about 85-95%, and from about 5-15%, respectively, (vi) at position 3199, AAC and GAC occur at frequencies from about 75-85%, and from about 15-25%, respectively, (vii) at position 3624, AAA and AAG occur at frequencies from about 75-85%, and from about 15-25%, respectively, (viii) at position 4035, GTT and GTC occur at frequencies from about 85-95%, and from about 5-15%, respectively, (ix) at position 7470, TCA and TCG occur at frequencies from about 75-85%, and from about 15-25%, respectively, and (x) at position 9079, GCC and ACC occur at frequencies from about 85-95%, and from about 5-15%, respectively.

36. A method according to any of the claims 32-35 wherein the said amplifying is performed by annealing at least one oligonucleotide primer to said DNA fragment and extending the oligonucleotide primer by an agent for polymerization.

37. A method according to claim 36 wherein said oligonucleotide primer is directly or indirectly labeled with a radioactive label, a fluorescent label, a bioluminescent label, a chemiluminescent label, a metal chelator, or an enzyme label.

5

38. A BRCA2 coding sequence according to claims 32, wherein the codon pairs occur at the following frequencies:

(i) at position 1093, AAT and CAT occur at frequencies from about 75-85%, and from about 15-25%, respectively, 0 (ii) at position 1342, CAT and AAT occur at frequencies from about 35-45%, and from about 55-65%, respectively, (iii) at position 1593, TCA and TCG occur at frequencies from about 85-95%, and from about 5-15%, respectively, (iv) at position 2457, CAT and CAC occur at frequencies from 5 about 75-85%, and from about 15-25%, respectively,

(v) at position 2908, GTA and ATA occur at frequencies from about 85-95%, and from about 5-15%, respectively, (vi) at position 3199, AAC and GAC occur at frequencies from about 75-85%, and from about 15-25%, o respectively,

(vii) at position 3624, AAA and AAG occur at frequencies from about 75-85%, and from about 15-25%, respectively, (viii) at position 4035, GTT and GTC occur at frequencies from 5 about 85-95%, and from about 5-15%, respectively,

(ix) at position 7470, TCA and TCG occur at frequencies from about 75-85%, and from about 15-25%, respectively, and (x) at position 9079, GCC and ACC occur at frequencies from about 85-95%, and from about 5-15%, respectively. 0

39. An oligonucleotide primer capable of hybridizing to a sample of BRCA2 gene, or its respective complementary sequences selected from the group consisting of SEQ. ID. NO: 14, 19, 22, 23, 25, 26, 29-76, 83, 85-88, 90, 91 , 97, 98, 101 , and 104- 107.

40. A chip array having "n" elements for performing allele specific sequence- based techniques comprising a solid phase chip and oligonucleotides having "n" different nucleotide sequences, wherein "n" is an interger greater than or equal to ten, wherein said oligonucleotides are bound to said solid phase chip in a manner which permits said oligonucleotides to effectively hybridize to complementary oligonucleotides or polynucleotides, wherein oligonucleotides having different nucleotide sequence are bound to said solid phase chip at different locations so that a particular location on said solid phase chip exclusively binds oligonucleotides having a specific nucleotide sequence, and wherein at least ten oligonucleotides are capable of specifically hybridizing to the BRCA2 DNA having the sequence as set forth in SEQ. ID. NO: 4, SEQ. ID. NO: 6, SEQ. ID. NO: 8, SEQ. ID. NO: 10, SEQ. ID. NO: 12 or their respective complementary sequences, at least one oligonucleotide being capable of specifically hybridizing at each of the nucleotide positions 1093, 1342, 1593, 2457, 2908, 3199, 3624, 4035, 7470, 9079, or complementary thereto.

41. A method of performing gene therapy on a patient, comprising: a) contacting cancer cells in vivo with an effective amount of a vector comprising DNA containing at least a portion of BRCA2 sequence selected from the group consisting of SEQ. ID. NO: 4, SEQ. ID. NO: 6, SEQ. ID. NO: 8, SEQ. ID. NO: 10, SEQ. ID. NO: 12, or their respective complementary sequences b) allowing the vector to enter the cancer cells, and c) measuring a reduction in tumor growth.

42. The method according to claim 41 wherein said cancer cells have a mutation in the BRCA2 gene.

43. The method according to claim 41 wherein said patient has a mutation in the BRCA2 gene of non-cancer cells.

44. A method of performing gene therapy on a patient or a sample, comprising: a) contacting cells in vivo or in vitro with an effective amount of a vector comprising DNA containing at least a portion of BRCA2 sequence selected from the group consisting of SEQ. ID. NO: 4, SEQ. ID. NO: 6, SEQ. ID. NO: 8, SEQ. ID. NO: 10, SEQ. ID. NO: 12, or their respective complementary sequences, and b) allowing the vector to enter the cells, wherein said patient has a reduced susceptibility for developing a cancer associated with a mutation in the BRCA2 gene.

45. A method according to claim 44 wherein said cells include healthy breast, ovarian or pancreatic tissues.

46. A method according to claim 44 wherein a patient has an inherited mutation in the BRCA2 gene.*

47. A method of treating a patient suspected of having a tumor, comprising: a) administering to a patient an effective amount of BRCA2 tumor growth inhibitor having an amino acid sequence selected from the group consisting of SEQ. ID. NO: 5, SEQ. ID. NO: 7, SEQ. ID. NO: 9, SEQ. ID. NO: 11 , SEQ. ID. NO: 13, any fragments thereto, and any functional equivalent thereof; b) allowing the patient's cells to take up the protein, and c) measuring a reduction in tumor growth.

48. The method according to claim 47 wherein said tumor is a breast cancer, an ovarian cancer or a pancreatic cancer.

49. The method according to claim 47 wherein said patient has an inherited mutation in the BRCA2 gene.

50. A method of preventing the formation or growth of a tumor, comprising: a) adminstering to a patient an effective amount of BRCA2 tumor growth inhibiting protein having an amino acid sequence selected from the group consisting

5 of SEQ. ID. NO: 5, SEQ. ID. NO: 7, SEQ. ID. NO: 9, SEQ. ID. NO: 11 , SEQ. ID. NO: 13, any fragments thereto, and any functional equivalent thereof; and b) allowing the patient cells to take up the protein.

51. The method according to claim 31 wherein the protein is administered 0 parenternally, by buccal adsorption or inhalation.

52. A cloning vector comprising:

(a) a DNA sequence as set forth in SEQ. ID. NO: 4, SEQ. ID. NO: 6, SEQ. ID. NO: 8, SEQ. ID. NO: 10, SEQ. ID. NO: 12, or any fragments thereof; and 5 (b) one or more suitable regulatory sequences to induce replication and/or integration in a host cell.

53. An expression vector comprising a DNA sequence as set forth in SEQ. ID. NO: 4, SEQ. ID. NO: 6, SEQ. ID. NO: 8, SEQ. ID. NO: 10, SEQ. ID. NO: 12, or any o fragments thereof operatively linked to one or more promoter sequences capable of directing expression of said sequence in a host cell.

54. A host cell transformed with the vector according to claim 52 or 53.

5 55. A BRCA2 polypeptide which is selected from the group consisting of:

(a) a fragment of BRCA2 protein sequence as set forth in SEQ. ID. NO: 5, SEQ. ID. NO: 7, SEQ. ID. NO: 9, SEQ. ID. NO: 11 , or SEQ. ID. NO:13;

(b) an amino acid sequence which is substantially homologous to the BRCA2 protein sequence as set forth in SEQ. ID. NO: 5, SEQ. ID. NO: 7, SEQ. ID. 0 NO: 9, SEQ. ID. NO: 11 , or SEQ. ID. NO: 13;

(c) a molecule which has similar function to the BRCA2 protein; and

(d) a fusion protein of (a), (b), or (c).

56. An anti-BRCA2 antibody wherein a molecule according to claims 17-21 , 23, 25, 27, 29, 31 , or 55 is used as an immunogen.

57. A diagnostic reagent comprising a molecule selected from the group consisting of:

(a) a DNA sequence as set forth in SEQ. ID. NO: 4, SEQ. ID. NO: 6, SEQ. ID. NO: 8, SEQ. ID. NO: 10, SEQ. ID. NO: 12, or their complementary sequences;

(b) a nucleic acid fragment of (a) comprising at least 10 nucleotide in length; (c) a sequence which hybridizes to (a) or (b);

(d) a polypeptide according to claim 17-21 , 23, 25, 27, 29, 31 , or 55; and

(e) an antibody which specifically binds to the polypeptide of (d).

58. A pharmaceutical composition comprising a molecule according to any one of the claims 17-21 , 23, 25, 27, 29, 31 , 55 in a pharmaceutically acceptable carrier.

59. A pharmaceutical composition comprising a molecule according claim 56 in a pharmaceutically acceptable carrier.

60. A pharmaceutical composition comprising a molecule according to claim 57 in a pharmaceutically acceptable carrier.