CA2500521A1 - Novel nucleic acids and polypeptides - Google Patents

Abstract

The present invention provides novel nucleic acids, novel polypeptide sequences encoded by these nucleic acids and uses thereof.

Description

DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME
NOTE POUR LE TOME / VOLUME NOTE:

NOVEL NUCLEIC ACIDS AND POLYPEPTIDES
1. CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the priority benefit of U.S. Provisional Application Serial No.
60/416,186 filed October 2, 2002 entitled "Novel Nucleic Acids and Polypeptides" , which contains material previously disclosed in the following applications: U.S.
Application Serial No. 10/084,643 filed February 26, 2002 entitled "Novel Nucleic Acids and Polypeptides", Attorney Docket No. 21272-502; PCT Application Serial No. PCT/US00/35017 filed December 22, 2000 entitled "Novel Contigs Obtained from Various Libraries", Attorney Docket No. 784CIP3A/PCT; PCT Application Serial No. PCT/LTSO1/02623 filed January 25, 2001 entitled "Novel Contigs Obtained from Various Libraries", Attorney Docket No.
785CIP3/PCT; PCT Application Serial No. PCT/LTSO1/03800 filed February 5, 2001 entitled "Novel Contigs Obtained from Various Libraries", Attorney Docket No.
787CIP3/PCT; PCT
Application Serial No. PCT/USO1/04927 filed February 26, 2001 entitled "Novel Contigs Obtained from Various Libraries", Attorney Docket No. 788CIP3/PCT; PCT
Application Serial No. PCT/USO1/04941 filed March 5, 2001 entitled "Novel Contigs Obtained from Various Libraries", Attorney Docket No. 789CIP3/PCT; PCT Application Serial No.
PCT/LTSO1/08631 filed March 30, 2001 entitled "Novel Contigs Obtained from Various Libraries", Attorney Docket No. 790CIP3/PCT; PCT Application Serial No.
PCT/LTSO1/08656 filed April 18, 2001 entitled "Novel Contigs Obtained from Various Libraries", Attorney Docket No. 791 CIP3/PCT; all of which are incorporated herein by reference in their entirety.

2. DACKGROUND OF THE INVENTION
2.1 TECHNICAL FIELD
The present invention provides novel polynucleotides and proteins encoded by such polynucleotides, along with uses for these polynucleotides and proteins, for example in therapeutic, diagnostic and research methods.
2.2 BACKGROUND
Technology aimed at the discovery of protein factors (including e.g., cytokines, such as lymphokines, interferons, circulating soluble factors, chemokines, and interleukins) has matured rapidly over the past decade. The now routine hybridization cloning and expression cloning techniques clone novel polynucleotides "directly" in the sense that they rely on information directly related to the discovered protein (i.e., partial DNA/amino acid sequence of the protein in the case of hybridization cloning; activity of the protein in the case of expression cloning). More recent "indirect" cloning techniques such as signal sequence cloning, which isolates DNA sequences based on the presence of a now well-recognized secretory leader sequence motif, as well as various PCR-based or low stringency hybridization-based cloning techniques, have advanced the state of the art by making available large numbers of DNA/amino acid sequences for proteins that are known to have biological activity, for example, by virtue of their secreted nature in the case of leader sequence cloning, by virtue of their cell or tissue source in the case of PCR-based techniques, or by virtue of structural similarity to other genes of known biological activity.
Identified polynucleotide and polypeptide sequences have numerous applications in, for example, diagnostics, forensics, gene mapping; identification of mutations responsible for genetic disorders or other traits, to assess biodiversity, and to produce many other types of data and products dependent on DNA and amino acid sequences.

3. SU ~Y ~F" TIIE I1~TVE1~TTIOIV
The compositions of the present invention include novel isolated polypeptides, novel isolated polynucleotides encoding such polypeptides, including recombinant DNA
molecules, cloned genes or degenerate variants thereof, especially naturally occurring variants such as allelic variants, antisense polynucleotide molecules, and antibodies that specifically recognize one or more epitopes present on such polypeptides, as well as hybridomas producing such antibodies.
The compositions of the present invention additionally include vectors, including expression vectors, containing the polynucleotides of the invention, cells genetically engineered to contain such polynucleotides and cells genetically engineered to express such polynucleotides.
The present invention relates to a collection or library of at least one novel nucleic acid sequence assembled from expressed sequence tags (ESTs) isolated mainly by sequencing by hybridization (SBH), and in some cases, sequences obtained from one or more public databases. 'The invention relates also to the proteins encoded by such polynucleotides, along with therapeutic, diagnostic and research utilities for these polynucleotides and proteins. These nucleic acid sequences are designated as SEQ ID NO: 1-684, or 1369-1966 and are provided in the Sequence Listing. In the nucleic acids provided in the Sequence Listing, A
is adenine; C is cytosine; G is guanine; T is thymine; and N is any of the four bases or unknown. In the amino acids provided in the Sequence Listing, an asterisk (*) corresponds to the stop codon.
The nucleic acid sequences of the present invention also include, nucleic acid sequences that hybridize to the complement of SEQ ID NO: 1-684, or 1369-1966 under stringent hybridization conditions; nucleic acid sequences which are allelic variants or species homologues of any of the nucleic acid sequences recited above, or nucleic acid sequences that encode a peptide comprising a specific domain or truncation of the peptides encoded by SEQ
ZD NO: 1-684, or 1369-1966. A polynucleotide comprising a nucleotide sequence having at least 90°!o identity to an identifying sequence of SEQ ID NO: 1-684, or 1369-1966 or a degenerate variant or fragment thereof. The identifying sequence can be 100 base pairs in length.
The nucleic acid sequences of the present invention also include the sequence information from the nucleic acid sequences of SEQ Ilk NO: 1-684, or 1369-1966. The sequence information can be a segment of any one of SEQ 11? NO: 1-684, or 1369-1966 that uniquely identifies or represents the sequence information of SEQ 11? NO: 1-684, or 1369-1966.
A collection as used in this application can be a collection of only one polynucleotide.
The collection of sequence information or identifying information of each sequence can be provided on a nucleic acid array. In one embodiment, segments of sequence information are provided on a nucleic acid array to detect the polynucleotide that contains the segment. The array can be designed to detect full-match or mismatch to the polynucleotide that contains the segment. 'The collection can also be provided in a computer-readable format.
This invention also includes the reverse or direct complement of any of the nucleic acid sequences recited above; cloning or expression vectors containing the nucleic acid sequences;
and host cells or organisms transformed with these expression vectors. Nucleic acid sequences (or their reverse or direct complements) according to the invention have numerous applications in a variety of techniques known to those skilled in the art of molecular biology, such as use as hybridization probes, use as primers for PCR, use in an array, use in computer-readable media, use in sequencing full-length genes, use for chromosome and gene mapping, use in the recombinant production of protein, and use in the generation of anti-sense DNA
or RNA, their chemical analogs and the like.

In a preferred embodiment, the nucleic acid sequences of SEQ ID NO: 1-684, or 1966 or novel segments or parts of the nucleic acids of the invention are used as primers in expression assays that are well known in the art. In a particularly preferred embodiment, the nucleic acid sequences of SEQ ff~ NO: 1-684, or 1369-1966 or novel segments or parts of the nucleic acids provided herein are used in diagnostics for identifying expressed genes or, as well known in the art and exemplified by Vollrath et al., Science 258:52-59 (1992), as expressed sequence tags for physical mapping of the human genome.
The isolated polynucleotides of the invention include, but are not limited to, a polynucleotide comprising any one of the nucleotide sequences set forth in SEQ
ZD NO: 1-684, or 1369-1966; a polynucleotide comprising any of the full length protein coding sequences of SEQ ~ NO: 1-684, or 1369-1966; and a polynucleotide comprising any of the nucleotide sequences of the mature protein coding sequences of SEQ ID NO: 1-684, or 1369-1966. The polynucleotides of the present invention also include, but are not limited to, a polynucleotide that hybridizes under stringent hybridization conditions to (a) the complement of any one of the nucleotide sequences set forth in SEQ ID NO: 1-684, or 1369-1966; (b) a nucleotide sequence encoding any one of the amino acid sequences set forth in SEQ 11? NO: 1-684, or 1369-1966;
(c) a polynuclcotidc which is an allelic variant of any polynuclcotides recited above; (d) a polynucleotide which encodes a species homologue (e.g. orthologs) of any of the proteins recited above; or (e) a polynucleotide that encodes a polypeptide comprising a specific domain or truncation of any of the polypeptides comprising an amino acid sequence set forth in SEQ ID
NO: 685-1368, or 1967-2564, or Tables 3A., 3B, 5, 7, or 8.
'1 he isolated polypeptides of the invention include, but are not limited to, a polypeptide comprising any of the amino acid sequences set forth in the Sequence Listing;
or the corresponding full length or mature protein. Polypeptides of the invention also include polypeptides with biological activity that are encoded by (a) any of the polynucleotides having a nucleotide sequence set forth in SEQ 11? NO: 1-684, or 1369-1966; or (b) polynucleotides that hybridize to the complement of the polynucleotides of (a) under stringent hybridization conditions. Biologically active variants of any ofthe polypeptide sequences in the Sequence Listing, and "substantial equivalents" thereof (e.g., with at least about 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% amino acid sequence identity) that preferably retain biological activity are also contemplated. The polypeptides of the invention may be wholly or partially chemically synthesized but are preferably produced by recombinant means using the genetically engineered cells (e.g. host cells) of the invention.

The invention also provides compositions comprising a polypeptide of the invention.
Polypeptide compositions of the invention may further comprise an acceptable carrier, such as a hydrophilic, e.g., pharmaceutically acceptable, carrier.
The invention also provides host cells transformed or transfected with a polynucleotide of the invention.
The invention also relates to methods for producing a polypeptide of the invention comprising growing a culture of the host cells of the invention in a suitable culture medium under conditions permitting expression of the desired polypeptide, and purifying the polypeptide from the culture or from the host cells. Preferred embodiments include those in which the protein produced by such processes is a mature form of the protein.
Polynucleotides according to the invention have numerous applications in a variety of techniques known to those skilled in the art of molecular biology. These techniques include use as hybridization probes, use as oligomers, or primers, for PCR, use for chromosome and gene mapping, use in the recombinant production of protein, and use in generation of anti-sense DNA or RNA, their chemical analogs and the like. For example, when the expression of an mRNA is largely restricted to a particular cell or tissue type9 polynucleotides of the invention can be used as hybridization probes to detect the presence of the particular cell or tissue mRNA in a sample using, e.~., in. situ hybridization.
In other exemplary embodiments, the polynucleotides are used in diagnostics as expressed sequence tags for identifying expressed genes or, as well known in the art and ey~emplif'md by ~ollrath et al., Science 258:52-5~ ~1~~2), as expressed sequence tags for physical mapping of the human genome.
The polypeptides according to the invention can be used in a variety of conventional procedures and methods that are currently applied to other proteins. For example, a polypeptide of the invention can be used to generate an antibody that specifically binds the polypeptide. Such antibodies, particularly monoclonal antibodies, are useful for detecting or quantitating the polypeptide in tissue. The polypeptides of the invention can also be used as molecular weight markers, and as a food supplement.
Methods are also provided for preventing, treating, or ameliorating a medical condition which comprises the step of administering to a mammalian subject a therapeutically effective amount of a composition comprising a polypeptide of the present invention and a pharmaceutically acceptable Garner.

In particular, the polypeptides and polynucleotides of the invention can be utilized, for example, in methods for the prevention and/or treatment of disorders involving aberrant protein expression or biological activity.
The present invention further relates to methods for detecting the presence of the polynucleotides or polypeptides of the invention in a sample. Such methods can, for example, be utilized as part of prognostic and diagnostic evaluation of disorders as recited herein and for the identification of subjects exhibiting a predisposition to such conditions.
The invention provides a method for detecting the polynucleotides of the invention in a sample, comprising contacting the sample with a compound that binds to and forms a complex with the polynucleotide of interest for a period sufficient to form the complex and under conditions sufficient to form a complex and detecting the complex such that if a complex is detected, the polynucleotide of interest is detected. The invention also provides a method for detecting the polypeptides of the invention in a sample comprising contacting the sample with a compound that binds to and forms a complex with the polypeptide under conditions and for a period sufficient to form the complex and detecting the formation of the complex such that if a complex is formed, the polypeptide is detected.
The invention also provides kits comprising polynucleotide probes and/or monoclonal antibodies, and optionally quantitative standards, for carrying out methods of the invention. Furthermore, the invention provides methods for evaluating the efficacy of drugs, and monitoring the progress of patients, involved in clinical trials for the treatment of disorders as recited above.
The invention also provides methods for the identification of compounds that modulate (i.e., increase or decrease) the expression or activity of the polynucleotides andJor polypeptides of the invention. Such methods can be utilized, for example, for the identification of compounds that can ameliorate symptoms of disorders as recited herein.
Such methods can include, but are not limited to, assays for identifying compounds and other substances that interact with (e.g., bind to) the polypeptides of the invention. The invention provides a method for identifying a compound that binds to the polypeptides of the invention comprising contacting the compound with a polypeptide of the invention in a cell for a time sufficient to form a polypeptide/compound complex, wherein the complex drives expression of a reporter gene sequence in the cell; and detecting the complex by detecting the reporter gene sequence expression such that if expression of the reporter gene is detected the compound that binds to a polypeptide of the invention is identified.

The methods of the invention also provide methods for treatment which involve the administration of the polynucleotides or polypeptides of the invention to individuals exhibiting symptoms or tendencies. In addition, the invention encompasses methods for treating diseases or disorders as recited herein comprising administering compounds and other substances that modulate the overall activity of the target gene products. Compounds and other substances can affect such modulation either on the level of target gene/protein expression or target protein activity.
The polypeptides of the present invention and the polynucleotides encoding them are also useful for the same functions known to one of skill in the art as the polypeptides and polynucleotides to which they have homology (set forth in Tables 2A and 2B);
for which they have a signature region (as set forth in Tables 3A and 3B); or for which they have homology to a gene family (as set forth in Tables 4A and 4B). If no homology is set forth for a sequence, then the polypeptides and polynucleotides of the present invention are useful for a variety of applications, as described herein, including use in arrays for detection.
4. DETAIIdEII I)E~CI~I~TI~I~T ~~ TII~TI~TTI~l~
4.1 DEFIIVITI~l~S
It must be noted that as used herein and in the appended claims, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise.
The term "active" refers t~ th~se f~rms of the polypept~ade which retain the biol~gic and/~r immunologic activities of any naturally occurriaig polypeptide.
According t~ the inventi~n, the terms "biologically active" or "biological activity" refer t~ a protein or peptide having structural, regulatory or biochemical functions of a naturally occurring molecule.
Likewise "immunologically active" or "immunological activity" refers t~ the capability of the natural, recombinant or synthetic polypeptide to induce a specific immune response in appropriate animals or cells and to bind with specific antibodies.
The term "activated cells" as used in this application are those cells which are engaged in extracellular or intracellular membrane trafficking, including the export of secretory or enzymatic molecules as part of a normal or disease process.
The terms "complementary" or "complementarity" refer to the natural binding of polynucleotides by base pairing. For example, the sequence 5'-AGT-3' binds to the complementary sequence 3'-TCA-5'. Complementarity between two single-stranded molecules may be "partial" such that only certain portions) of the nucleic acids bind or it may be "complete" such that total complementarity exists between the single stranded molecules. The degree of complementarity between the nucleic acid strands has significant effects on the efficiency and strength of the hybridization between the nucleic acid strands.
The term "embryonic stem cells (ES)" refers to a cell that can give rise to many differentiated cell types in an embryo or an adult, including the germ cells.
The term "germ line stem cells (GSCs)" refers to stem cells derived from primordial stem cells that provide a steady and continuous source of germ cells for the production of gametes. The term "primordial germ cells (PGCs)" refers to a small population of cells set aside from other cell lineages particularly from the yolk sac, mesenteries, or gonadal ridges during embryogenesis that have the potential to differentiate into germ cells and other cells. PGCs are the source from which GSCs and ES cells are derived. The PGCs, the GSCs and the ES cells are capable of self renewal. Thus these cells not only populate the germ line and give rise to a plurality of terminally differentiated cells that comprise the adult specialized organs, but are able to regenerate themselves.
The term "expression modulating fragment," EMF, means a series of nucleotides which modulates the expression ~f an operably linked ~RF or another EMF.
As used herein, a sequence is said to "modulate the expression of an operably linked sequence" when the expression of the sequence is altered by the presence of the EMF.
EMFs include, but are not limited to, promoters, and promoter modulating sequences (inducible elements). ~ne class of EMFs are nucleic acid fragments which induce the expression of an operably linked ~RF in response to a specific regulatory factor or physiological event.
The terms "nucleotide sequence" or "nucleic acid" or "polynucleotide" or "oligonucleotide" are used interchangeably and refer t~ a heteropolymer of nucleotides or the sequence of these nucleotides. These phrases also refer to I~NA or RNA of genomic or synthetic origin which may be single-stranded or double-stranded and may represent the sense or the antisense strand, to peptide nucleic acid (PNA) or to any DNA-like or RNA-like material. In the sequences herein A is adenine, C is cytosine, T is thymine, G
is guanine and N is A, C, G, or T (CT) or unknown. It is contemplated that where the polynucleotide is RNA, the T (thymine) in the sequences provided herein is substituted with U
(uracil).
Generally, nucleic acid segments provided by this invention may be assembled from fragments of the genome and short oligonucleotide linkers, or from a series of oligonucleotides, or from individual nucleotides, to provide a synthetic nucleic acid which is capable of being expressed in a recombinant transcriptional unit comprising regulatory elements derived from a microbial or viral operon, or a eukaryotic gene.
The teens "oligonucleotide fragment" or a "polynucleotide fragment", "portion," or "segment" or "probe" or "primer" are used interchangeably and refer to a sequence of nucleotide residues which are at least about 5 nucleotides, more preferably at least about 7 nucleotides, more preferably at least about 9 nucleotides, more preferably at least about 11 nucleotides and most preferably at least about 17 nucleotides. The fragment is preferably less than about 500 nucleotides, preferably less than about 200 nucleotides, more preferably less than about 100 nucleotides, more preferably less than about 50 nucleotides and most preferably less than 30 nucleotides. Preferably the probe is from about 6 nucleotides to about 200 nucleotides, preferably from about 15 to about 50 nucleotides, more preferably from about 17 to 30 nucleotides and most preferably from about 20 to 25 nucleotides.
Preferably the fragments can be used in polymerase chain reaction (PCR), various hybridisation procedures or microarray procedures to identify or amplify identical or related parts of mRNA or DNA molecules. A fragment or segment may uniquely identify each polynucleotide sequence of the present invention. Preferably the fragment comprises a sequence substantially similar to any one of SEQ ID NO: 1-684, or 1369-1966.
Probes may, for example, be used to determine whether specific mRNA molecules are present in a cell or tissue or to isolate similar nucleic acid sequences from chromosomal DNA as described by -SfJalsh et alo (~alsh~ P.S. et al., 1992, PCR Methods Appl 1:241-250).
They may be labeled by nick translation, I~lenow fill-in reaction, PCR, or other methods well knoWll lIl the art. Probes of the present invention, their preparation and/or labeling are elaborated in Sambrook, J. et al., 1989, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, NY; or Ausubel, F.M. et al., 1989, Current Protocols in Molecular Biology, John Wiley & Sons, New York NY, both of which are incorporated herein by reference in their entirety.
The nucleic acid sequences of the present invention also include the sequence information from the nucleic acid sequences of SEQ ID NO: 1-684, or 1369-1966.
The sequence information can be a segment of any one of SEQ ID NO: 1-684, or 1369-1966 that uniquely identifies or represents the sequence information of that sequence of SEQ ID NO:
1-684, or 1369-1966, or those segments identified in Tables 3A, 3B, 5, 7, or 8. One such segment can be a twenty-mer nucleic acid sequence because the probability that a twenty-mer is fully matched in the human genome is 1 in 300. In the human genome, there are three billion base pairs in one set of chromosomes. Because 42° possible twenty-mers exist, there are 300 times more twenty-mers than there are base pairs in a set of human chromosomes.
Using the same analysis, the probability for a seventeen-mer to be fully matched in the 5 human genome is approximately 1 in 5. When these segments are used in arrays for expression studies, fifteen-mer segments can be used. The probability that the fifteen-mer is fully matched in the expressed sequences is also approximately one in five because expressed sequences comprise less than approximately 5% of the entire genome sequence.
Similarly, when using sequence information for detecting a single mismatch, a segment 10 can be a twenty-five mer. The probability that the twenty-five mer would appear in a human genome with a single mismatch is calculated by multiplying the probability for a full match (1-4z5) times the increased probability for mismatch at each nucleotide position (3 x 25). 'The probability that an eighteen mer with a single mismatch can be detected in an array for expression studies is approximately one in five. The probability that a twenty-mer with a single mismatch can be detected in a human genome is approximately one in five.
The term "open reading frame," ~12F, means a series of nucleotide triplets coding for amino acids without any termination codons and is a sequence translatable into protein.
The terms "operably linked" or "operably associated" refer to functionally related nucleic acid sequences. For example, a promoter is operably associated or operably linked with a coding sequence if the promoter controls the transcription of the coding sequence.
While operably linked nucleic acid sequences can be contiguous and in the same reading frame, certain genetic elements e.g. repressor genes are not contiguously linked to the coding sequence but still control transcription/translation of the coding sequence.
The term "pluripotent" refers to the capability of a cell to differentiate into a number of differentiated cell types that are present in an adult organism. A
pluripotent cell is restricted in its differentiation capability in comparison to a totipotent cell.
The terms "polypeptide" or "peptide" or "amino acid sequence" refer to an oligopeptide, peptide, polypeptide or protein sequence or fragment thereof and to naturally occurring or synthetic molecules. A polypeptide "fragment," "portion," or "segment" is a stretch of amino acid residues of at least about 5 amino acids, preferably at least about 7 amino acids, more preferably at least about 9 amino acids and most preferably at least about 17 or more amino acids. The peptide preferably is not greater than about 200 amino acids, more preferably less than 150 amino acids and most preferably less than 100 amino acids.

Preferably the peptide is from about 5 to about 200 amino acids. To be active, any polypeptide must have sufficient length to display biological and/or immunological activity.
The term "naturally occurring polypeptide" refers to polypeptides produced by cells that have not been genetically engineered and specifically contemplates various polypeptides arising from post-translational modifications of the polypeptide including, but not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation and acylation.
The term "translated protein coding portion" means a sequence which encodes for the full-length protein which may include any leader sequence or any processing sequence.
The term "mature protein coding sequence" means a sequence which encodes a peptide or protein without a signal or leader sequence. The "mature protein portion" means that portion of the protein which does not include a signal or leader sequence. The peptide may have been produced by processing in the cell which removes any leader/signal sequence. The mature protein portion may or may not include the initial methionine residue.
The methionine residue may be removed from the protein during processing in the cell. The peptide may be produced synthetically or the protein may have been produced using a polynucleotide only encoding for the mature protein coding sequence.
The term "derivative" refers to polypeptides chemically modified by such techniques as ubiquitination, labeling (e.g., with radionuclides or various enzymes), covalent polymer attachment such as pegylation (derivatization with polyethylene glycol) and insertion or substitution by chemical synthesis of amino acids such as ornithine, which do not normally occur in human proteins.
The terns "variant"(or "analog") refers to any polypeptide differing from naturally occurring polypeptides by amino acid insertions, deletions, and substitutions, created using, a g~., recombinant DNA techniques. Guidance in deterniining which amino acid residues may be replaced, added or deleted without abolishing activities of interest, may be found by comparing the sequence of the particular polypeptide with that of homologous peptides and minimizing the number of amino acid sequence changes made in regions of high homology (conserved regions) or by replacing amino acids with consensus sequence.
Alternatively, recombinant variants encoding these same or similar polypeptides may be synthesized or selected by making use of the "redundancy" in the genetic code. Various codon substitutions, such as the silent changes which produce various restriction sites, may be introduced to optimize cloning into a plasmid or viral vector or expression in a particular prokaryotic or eukaryotic system. Mutations in the polynucleotide sequence may be reflected in the polypeptide or domains of other peptides added to the polypeptide to modify the properties of any part of the polypeptide, to change characteristics such as ligand-binding affinities, interchain affinities, or degradation/turnover rate.
Preferably, amino acid "substitutions" are the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, i.e., conservative amino acid replacements. "Conservative" amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues involved. For example, nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine; polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine; positively charged (basic) amino acids include arginine, lysine, and histidine; and negatively charged (acidic) amino acids include aspartic acid and glutamic acid. "Insertions" or "deletions" are preferably in the range of about 1 to 20 amino acids, more preferably 1 to 10 amino acids. The variation allowed may be experimentally determined by systematically making insertions, deletions, or substitutions of amino acids in a polypeptide molecule using recombinant DI~~ techniques and assaying the resulting recombinant variants for activity.
Alternatively, where alteration of function is desired, insertions, deletions or non-conservative alterations can be engineered to produce altered polypeptides. Such alterations can, for example, alter one or more of the biological functions or biochemical characteristics of the polypeptides of the invention. For ea~ample, such alterations may change polypeptide characteristics such as ligand-binding affinities, interchain affinities, or degradation/turnover rate. Further, such alterations can be selected so as to generate polypeptides that are better suited for expression, scale up and the like in the host cells chosen for expression. For example, cysteine residues can be deleted or substituted with another amino acid residue in order to eliminate disulfide bridges.
The terms "purified" or "substantially purified" as used herein denotes that the indicated nucleic acid or polypeptide is present in the substantial absence of other biological macromolecules, e.g., polynucleotides, proteins, and the like. In one embodiment, the polynucleotide or polypeptide is purified such that it constitutes at least 95% by weight, more preferably at least 99% by weight, of the indicated biological macromolecules present (but water, buffers, and other small molecules, especially molecules having a molecular weight of less than 1000 daltons, can be present).

The term "isolated" as used herein refers to a nucleic acid or polypeptide separated from at least one other component (e.g., nucleic acid or polypeptide) present with the nucleic acid or polypeptide in its natural source. In one embodiment, the nucleic acid or polypeptide is found in the presence of (if anything) only a solvent, buffer, ion, or other component normally present in a solution of the same. The terms "isolated" and "purified" do not encompass nucleic acids or polypeptides present in their natural source.
The term "recombinant," when used herein to refer to a polypeptide or protein, means that a polypeptide or protein is derived from recombinant (e.g., microbial, insect, or mammalian) expression systems. "Microbial" refers to recombinant polypeptides or proteins made in bacterial or fungal (e.g., yeast) expression systems. As a product, "recombinant microbial" defines a polypeptide or protein essentially free of native endogenous substances and unaccompanied by associated native glycosylation. Polypeptides or proteins expressed in most bacterial cultures, e.g., E. coli, will be free of glycosylation modifications;
polypeptides or proteins expressed in yeast will have a glycosylation pattern in general different from those expressed in mammalian cells.
The term "recombinant expression vehicle or vector" refers to a plasmid or phage or virus or vector, fox expressing a polypeptide from a DNA (RNA) sequence. An expression vehicle can comprise a transcriptional unit comprising an assembly of (1) a genetic element or elements having a regulatory role in gene expression, for example, promoters or enhancers, (2) a structural or coding sequence which is transcribed into mRNA
and translated into protein, and (3) appropriate transcription initiation and termination sequences.
Structural units intended for use in yeast or eukaryotic expression systems preferably include a leader sequence enabling extracellular secretion of translated protein by a host cell.
Alternatively, where recombinant protein is expressed without a leader or transport sequence, it may include an amino terminal methionine residue. This residue may or may not be subsequently cleaved from the expressed recombinant protein to provide a anal product.
The term "recombinant expression system" means host cells which have stably integrated a recombinant transcriptional unit into chromosomal DNA or carry the recombinant transcriptional unit extrachromosomally. Recombinant expression systems as defined herein will express heterologous polypeptides or proteins upon induction of the regulatory elements linked to the DNA segment or synthetic gene to be expressed. This term also means host cells which have stably integrated a recombinant genetic element or elements having a regulatory role in gene expression, for example, promoters or enhancers.
Recombinant expression systems as defined herein will express polypeptides or proteins endogenous to the cell upon induction of the regulatory elements linked to the endogenous DNA segment or gene to be expressed. The cells can be prokaryotic or eukaryotic.
The term "secreted" includes a protein that is transported across or through a membrane, including transport as a result of signal sequences in its amino acid sequence when it is expressed in a suitable host cell. "Secreted" proteins include without limitation proteins secreted wholly (e.g., soluble proteins) or partially (e.g., receptors) from the cell in which they are expressed. "Secreted" proteins also include without limitation proteins that are transported across the membrane of the endoplasmic reticulum. "Secreted"
proteins are also intended to include proteins containing non-typical signal sequences (e.g. Interleukin-1 Beta, see I~rasney, P.A. and Young, P.R. (1992) Cytokine 4(2): 134 -143) and factors released from damaged cells (e.g. Interleukin-1 Receptor Antagonist, see Arend, W.P. et. al.
(1990 Annu. Rev. Immunol. 16:27-55) Where desired, an expression vector may be designed to contain a "signal or leader sequence" which will direct the polypeptide through the membrane of a cell.
Such a sequence may be naturally present on the polypeptides of the present invention or provided from heterologous protein sources by recombinant DNA techniques.
The term "stringent" is used to refer to conditions that are commonly understood in the art as stringent. Stringent conditions can include highly stringent conditions (i.e., hybridization to alter-bound DNA in 0.5 l~Jl NaIiP~4.~ 7% sodium dodecyl sulfate (SDS), 1 mI~ EDTA at 65°C, and washing in 0.1~ SSC/0.1% SDS at 6S°C), and moderately stringent conditions (i.e., washing in 0.2X SSC/0.1% SDS at 42°C). ~ther exemplary hybridization conditions are described herein in the examples.
In instances of hybridization of deoxyoligonucleotides, additional exemplary stringent hybridization conditions include washing in 6~ SSC/0.05% sodium pyrophosphate at 37°C (for 14-base oligonucleotides), 4~°C (for 17-base oligonucleotides), 55°C (for 20-base oligonucleotides), and 60°C (for 23-base oligonucleotides).
As used herein, "substantially equivalent" or "substantially similar" can refer both to nucleotide and amino acid sequences, for example a mutant sequence, that varies from a reference sequence by one or more substitutions, deletions, or additions, the net effect of which does not result in an adverse functional dissimilarity between the reference and subject sequences. Typically, such a substantially equivalent sequence varies from one of those listed herein by no more than about 35% (i.e., the number of individual residue substitutions, additions, and/or deletions in a substantially equivalent sequence, as compared to the corresponding reference sequence, divided by the total number of residues in the substantially equivalent sequence is about 0.35 or less). Such a sequence is said to have 5 65% sequence identity to the listed sequence. In one embodiment, a substantially equivalent, e.g., mutant, sequence of the invention varies from a listed sequence by no more than 30% (70% sequence identity); in a variation of this embodiment, by no more than 25%
(75% sequence identity); and in a further variation of this embodiment, by no more than 20% (80% sequence identity) and in a further variation of this embodiment, by no more than 10 10% (90% sequence identity) and in a further variation of this embodiment, by no more that 5% (95% sequence identity). Substantially equivalent, e.g., mutant, amino acid sequences according to the invention preferably have at least 80% sequence identity with a listed amino acid sequence, more preferably at least 85% sequence identity, more preferably at least 90°/~
sequence identity, more preferably at least 95% sequence identity, more preferably at least 15 98% sequence identity, and most preferably at least 99°/~ sequence identity. Substantially equivalent nucleotide sequence of the invention can have lower percent sequence identities, taking into account, for example, the redundancy or degeneracy of the genetic code.
Preferably, the nucleotide sequence has at least about 65% identity, more preferably at least about 75% identity, more preferably at least about 80% sequence identity, more preferably at least 85% sequence identity, more preferably at least 90% sequence identity, more preferably at least about 95% sequence identity9 more preferably at least 98% sequence identity, and most preferably at least 99% sequence identity. For the purposes of the present invention, sequences having substantially equivalent biological activity and substantially equivalent expression characteristics are considered substantially equivalent. For the purposes of determining equivalence, truncation of the mature sequence (e.g., via a mutation which creates a new stop codon) should be disregarded. Sequence identity may be determined, e.g., using the Jotun Hein method (Hero, J. (1990) Methods Enzymol. 183:626-645).
Identity between sequences can also be determined by other methods known in the art, e.g.
by varying hybridization conditions.
The term "totipotent" refers to the capability of a cell to differentiate into all of the cell types of an adult organism.
The term "transformation" means introducing DNA into a suitable host cell so that the DNA is replicable, either as an extrachromosomal element, or by chromosomal integration. The term "transfection" refers to the taking up of an expression vector by a suitable host cell, whether or not any coding sequences are in fact expressed.
The term "infection" refers to the introduction of nucleic acids into a suitable host cell by use of a virus or viral vector.
As used herein, an "uptake modulating fragment," UMF, means a series of nucleotides which mediate the uptake of a linked DNA fragment into a cell.
UMFs can be readily identified using known UMFs as a target sequence or target motif with the computer-based systems described below. The presence and activity of a UMF can be confirmed by attaching the suspected UMF to a marker sequence. The resulting nucleic acid molecule is then incubated with an appropriate host under appropriate conditions and the uptake of the marker sequence is determined. As described above, a UMF will increase the frequency of uptake of a linked marker sequence.
Each of the above terms is meant to encompass all that is described for each, unless the context dictates otherwise.
4.2 T'~iJCI~EIC ALIDS OF TIC IN~EI~'I"I~1~
Nucleotide sequences of the invention are set forth in the Sequence Listing.
The isolated polynucleotides of the invention include a polynucleotide comprising the nucleotide sequences of SEQ ID NO: 1-684, or 1369-1966; a polynucleotide encoding any one of the peptide sequences of SEQ ID NO: 1-684, or 1369-1966; and a polynucleotide comprising the nucleotide sequence encoding the mature protein coding sequence of the polynucleotides of any one of SEQ ID NO: 1-684, or 1369-1966. The polynucleotides of the present invention also include, but are not limited to, a polynucleotide that hybridises under stringent conditions to (a) the complement of any of the nucleotides sequences of SEQ ID
NO: 1-684, or 1369-1966; (b) nucleotide sequences encoding any one of the amino acid sequences set forth in the Sequence Listing, or Table 7; (c) a polynucleotide which is an allelic variant of any polynucleotide recited above; (d) a polynucleotide which encodes a species homologue of any of the proteins recited above; or (e) a polynucleotide that encodes a polypeptide comprising a specific domain or truncation of the polypeptides of SEQ ID NO:
685-1368, or 1967-2564 (for example, as set forth in Tables 3A, 3B, 5, 7, or 8). Domains of interest may depend on the nature of the encoded polypeptide; e.g., domains in receptor-like polypeptides include ligand-binding, extracellular, transmembrane, or cytoplasmic domains, or combinations thereof; domains in immunoglobulin-like proteins include the variable immunoglobulin-like domains; domains in enzyme-like polypeptides include catalytic and substrate binding domains; and domains in ligand polypeptides include receptor-binding domains.
The polynucleotides of the invention include naturally occurring or wholly or partially synthetic DNA, e.g., cDNA and genomic DNA, and RNA, e.g., mRNA. The polynucleotides may include entire coding region of the cDNA or may represent a portion of the coding region of the cDNA.
The present invention also provides genes corresponding to the cDNA sequences disclosed herein. The corresponding genes can be isolated in accordance with known methods using the sequence information disclosed herein. Such methods include the preparation of probes or primers from the disclosed sequence information for identification and/or amplification of genes in appropriate genomic libraries or other sources of genomic materials.
Further 5' and 3' sequence can be obtained using methods known in the art. For example, full length cDNA or genomic DNA that corresponds to any of the polynucleotides of SEQ ~ NO:
1-684, or 1369-1966 can be obtained by screening appropriate cDNA or genomic DNA
libraries under suitable hybridization conditions using any of the polynucleotides of SEQ ff~
NO: 1-684, or 1369-1966 or a portion thereof as a probe. Alternatively, the polynucleotides of SEQ ~ NO: 1-684, or 1369-1966 may be used as the basis for suitable primers) that allow identification and/or amplification of genes in appropriate genomic DNA or cDNA libraries.
The nucleic acid sequences of the invention can be assembled from ESTs and sequences (including cDNA and genomic sequences) obtained from one er more public databases, such as dbEST, gbpri, and LTniGene. The EST sequences can provide identifying sequence information, representative fragment ~r segment information, or novel segment information for the full-length gene.
The polynucleotides of the invention also provide polynucleotides including nucleotide sequences that are substantially equivalent to the polynucleotides recited above.
Polynucleotides according to the invention can have, e.~., at least about 65%, at least about 70%, at least about 75%, at least about 80%, 81%, 82%, 83%, 84°/~, more typically at least about 85%, 86%, 87%, 88%, 89%, more typically at least about 90%, 91%, 92%, 93%, 94%, and even more typically at least about 95%, 96%, 97%, 98%, 99% sequence identity to a polynucleotide recited above.
Included within the scope of the nucleic acid sequences of the invention are nucleic acid sequence fragments that hybridize under stringent conditions to any of the nucleotide sequences of SEQ ID NO: 1-684, or 1369-1966, or complements thereof, which fragment is greater than about 5 nucleotides, preferably 7 nucleotides, more preferably greater than 9 nucleotides and most preferably greater than 17 nucleotides. Fragments of, e.g. 15, 17, or 20 nucleotides or more that are selective for (i.e. specifically hybridize to) any one of the polynucleotides of the invention are contemplated. Probes capable of specifically hybridizing to a polynucleotide can differentiate polynucleotide sequences of the invention from other polynucleotide sequences in the same family of genes or can differentiate human genes from genes of other species, and are preferably based on unique nucleotide sequences.
The sequences falling within the scope of the present invention are not limited to these specific sequences, but also include allelic and species variations thereof.
Allelic and species variations can be routinely determined by comparing the sequence provided in SEQ ID NO: 1-684, or 1369-1966, a representative fragment thereof, or a nucleotide sequence at least 90%
identical, preferably 95°!° identical, to SEQ ID NO: 1-684, or 1369-1966 with a sequence from another isolate of the same species. Furthermore, to accommodate colon variability, the invention includes nucleic acid molecules coding for the same amino acid sequences as do the specific OIZFs disclosed herein. In other words, in the coding region of an OIZF, substitution of one colon for another colon that encodes the same amin~ acid is expressly contemplated.
The nearest neighbor or homology results for the nucleic acids ~f the present invention, including SEQ ID NO: 1-684, or 1369-1966 can be obtained by searching a database using an algorithm or a program. Preferably, a BLAST (Basic Local Alignment Search Tool) program is used t~ search for local sequence alignments (Altshul, S.F. J I~IoI. Evol. 36 290-300 (1993) and Altschul S.F. et al. J. I~IoI. Biol. 21:403-410 (1990)). Alternatively a PASTA
versi~n 3 search against Genpept, using FAST' algorithm may be performed.
Species homologs (or orthologs) of the disclosed polynucleotides and proteins are also provided by the present invention. Species homologs may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source from the desired species.
The invention also encompasses allelic variants of the disclosed polynucleotides or proteins; that is, naturally-occurring alternative forms of the isolated polynucleotide which also encode proteins which are identical, homologous or related to that encoded by the polynucleotides.
The nucleic acid sequences of the invention are further directed to sequences which encode variants of the described nucleic acids. These amino acid sequence variants may be prepared by methods known in the art by introducing appropriate nucleotide changes into a native or variant polynucleotide. There are two variables in the construction of amino acid sequence variants: the location of the mutation and the nature of the mutation. Nucleic acids encoding the amino acid sequence variants are preferably constructed by mutating the polynucleotide to encode an amino acid sequence that does not occur in nature.
These nucleic acid alterations can be made at sites that differ in the nucleic acids from different species (variable positions) or in highly conserved regions (constant regions). Sites at such locations will typically be modified in series, e.g., by substituting first with conservative choices (e.g., hydrophobic amino acid to a different hydrophobic amino acid) and then with more distant choices (e.g., hydrophobic amino acid to a charged amino acid), and then deletions or insertions may be made at the target site. Amino acid sequence deletions generally range from about 1 to 30 residues, preferably about 1 to 10 residues, and are typically contiguous. Amino acid insertions include amino- and/or carboxyl-terminal fusions ranging in length from one t~ one hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Intrasequence insertions may range generally from about 1 to 10 amino residues, preferably from 1 to 5 residues.
Examples of terminal insertions include the heterologous signal sequences necessary for secretion or for intracellular targeting in different host cells and sequences such as FLAG or poly-histidine sequences useful for purifying the expressed protein.
In a preferred method, polynucleotides encoding the novel amino acid sequences are changed via site-directed muta.genesis. This method uses oligonucle~tide sequences to alter a polynucleotide to encode the desired amino acid variant, as well as sufficient adjacent nucle~tides on both sides of the changed amino acid to form a stable duplex on either side of the site of being changed. In general, the techniques of site-directed mutagenesis are well known to those of skill in the art and this technique is exemplified by publications such as, Edelman et al., I~NA 2:183 (1983). A versatile and efficient method for producing site-specific changes in a polynucleotide sequence was published by Zoller and Smith, Nucleic Acids Res. 10:6487-6500 (1982). PCR may also be used to create amino acid sequence variants of the novel nucleic acids. When small amounts of template DNA are used as starting material, primers) that differs slightly in sequence from the corresponding region in the template DNA can generate the desired amino acid variant. PCR
amplification results in a population of product DNA fragments that differ from the polynucleotide template encoding the polypeptide at the position specified by the primer. The product DNA

fragments replace the corresponding region in the plasmid and this gives a polynucleotide encoding the desired amino acid variant.
A further technique for generating amino acid variants is the cassette mutagenesis technique described in Wells et al., Gene 34:315 (1985); and other mutagenesis techniques 5 well known in the art, such as, for example, the techniques in Sambrook et al., supra, and Currefat Protocols in Molecular Biology, Ausubel et al. Due to the inherent degeneracy of the genetic code, other DNA sequences which encode substantially the same or a functionally equivalent amino acid sequence may be used in the practice of the invention for the cloning and expression of these novel nucleic acids. Such DNA sequences include those 10 which are capable of hybridizing to the appropriate novel nucleic acid sequence under stringent conditions.
Polynucleotides encoding preferred polypeptide truncations of the invention could be used to generate polynucleotides encoding chimeric or fusion proteins comprising one or more domains of the invention and heterologous protein sequences.
15 The polynucleotides of the invention additionally include the complement of any of the polynucleotides recited above. The polynucleotide can be DNA (genomic, cDNA, amplified, or synthetic) or RNA. Methods and algorithms for obtaining such polynucleotides are well known to those of skill in the art and can include, for example, methods for determining hybridization conditions that can routinely isolate polynucleotides 20 of the desired sequence identities.
In accordance vJith the invention, polynucleotide sequences comprising the mature protein coding sequences corresponding to any one of SEQ ID N~: 1-684, or 1369-1966, or functional equivalents thereof, may be used to generate recombinant DNA
molecules that direct the expression of that nucleic acid, or a functional equivalent thereof, in appropriate host cells. Also included are the cDNA inserts of any of the clones identified herein.
A polynucleotide according to the invention can be joined to any of a variety of other nucleotide sequences by well-established recombinant DNA techniques (see Sambrook J et al. (1989) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, NY).
Useful nucleotide sequences for joining to polynucleotides include an assortment of vectors, e.g., plasmids, cosmids, lambda phage derivatives, phagemids, and the like, that are well known in the art. Accordingly, the invention also provides a vector including a polynucleotide of the invention and a host cell containing the polynucleotide.
In general, the vector contains an origin of replication functional in at least one organism, convenient restriction endonuclease sites, and a selectable marker for the host cell.
Vectors according to the invention include expression vectors, replication vectors, probe generation vectors, and sequencing vectors. A host cell according to the invention can be a prokaryotic or eukaryotic cell and can be a unicellular organism or part of a multicellular organism.
The present invention further provides recombinant constructs comprising a nucleic acid having any of the nucleotide sequences of SEQ ID NO: 1-684, or 1369-1966 or a fragment thereof or any other polynucleotides of the invention. In one embodiment, the recombinant constructs of the present invention comprise a vector, such as a plasmid or viral vector, into which a nucleic acid having any of the nucleotide sequences of SEQ ID NO: 1-684, or 1369-1966 or a fragment thereof is inserted, in a forward or reverse orientation. In the case of a vector comprising one of the ORFs of the present invention, the vector may further comprise regulatory sequences, including for example, a promoter, operably linked to the ORF. Large numbers of suitable vectors and promoters are known to those of skill in the art and are commercially available for generating the recombinant constructs of the present invention. The following vectors are provided by way of example: Bacterial:
pBs, phagescript, PsiX174, pFluescript SIB, pBs IBS, pNI38a, pNHl6a, pNI318a, pNII46a (Stratagene), pTrc99A, p 23-3, pI~233-3, pDR540, pRITS (Pharmacia);
Eukaryotic:
pWLneo, pSV2cat, pOG44, PXTI, pSG (Stratagene) pSVI~3, pBPV, pMSG, pSVL
(Pharmacia).
The isolated polynucleotide of the invention may be operably linked to an expression c~ntr~1 sequence such as the pMT2 or pED expression vectors disclosed in I~aufman et al., Naceleic Acids yes. 19, 4485-4490 (1991), in order to produce the protein recombinantly.
Many suitable expression control sequences are kn~wn in the art. General methods of expressing recombinant proteins are also known and are exemplified in R.
I~aufman, Methods in EaZZymol~gy 185, 537-566 (1990). As defined herein "operably linked" means that the isolated polynucleotide of the invention and an expression control sequence are situated within a vector or cell in such a way that the protein is expressed by a host cell which has been transformed (transfected) with the ligated polynucleotide/expression control sequence.
Promoter regions can be selected from any desired gene using CAT
(chloramphenicol transferase) vectors or other vectors with selectable markers. Two appropriate vectors are pKI~232-8 and pCM7. Particular named bacterial promoters include lacI, lac2, T3, T7, gpt, lambda PR, and trc. Eukaryotic promoters include CMV
immediate early, HSV thymidine kinase, early and late SV40, LTRs from retrovirus, and mouse metallothionein-I. Selection of the appropriate vector and promoter is well within the level of ordinary skill in the art. Generally, recombinant expression vectors will include origins of replication and selectable markers permitting transformation of the host cell, e.g., the ampicillin resistance gene of E. coli and S. ce~evisiae TRP 1 gene, and a promoter derived from a highly expressed gene to direct transcription of a downstream structural sequence.
Such promoters can be derived from operons encoding glycolytic enzymes such as phosphoglycerate kinase (PGK), a-factor, acid phosphatase, or heat shock proteins, among others. The heterologous structural sequence is assembled in appropriate phase with translation initiation and termination sequences, and preferably, a leader sequence capable of directing secretion of translated protein into the periplasmic space or extracellular medium.
Optionally, the heterologous sequence can encode a fusion protein including an amino terminal identification peptide imparting desired characteristics, e.g., stabilization or simplified purification of expressed recombinant product. Useful expression vectors for bacterial use are c~nstructed by inserting a structural DNA sequence encoding a desired protein t~gether with suitable translation initiation and termination signals in operable reading phase with a functional promoter. 'The vector will comprise one ~r more phenotypic selectable markers and an origin of replication to ensure maintenance of the vector and to, if desirable, provide amplification within the host. Suitable prokaryotic hosts for transformation include E. coli, Bacillus subtilis, Salmofaella t~phir~aurium and various species within the genera Pseac~~araacyaas, Sta°e~at~anyces, and Sta~alayl~c~ccus, although others may also be employed as a matter of choice.
As a representative but n~n-limiting example, useful expression vectors for bacterial use can comprise a selectable marker and bacterial origin of replication derived from commercially available plasmids comprising genetic elements of the well known cloning vector pBR32,2 (ATCC 37017). Such commercial vectors include, for example, pKK223-3 (Pharmacia Fine Chemicals, Uppsala, Sweden) and GEM 1 (Promega Biotech, Madison, WI, USA). These pBR322 "backbone" sections are combined with an appropriate promoter and the structural sequence to be expressed. Following transformation of a suitable host strain and growth of the host strain to an appropriate cell density, the selected promoter is induced or derepressed by appropriate means (e.g., temperature shift or chemical induction) and cells are cultured for an additional period. Cells are typically harvested by centrifugation, disrupted by physical or chemical means, and the resulting crude extract retained for further purification.
Polynucleotides of the invention can also be used to induce immune responses.
For example, as described in Fan et al., Nat. Biotech 17, 870-872 (1999), incorporated herein by reference, nucleic acid sequences encoding a polypeptide may be used to generate antibodies against the encoded polypeptide following topical administration of naked plasmid DNA or following injection, and preferably infra-muscular injection of the DNA. The nucleic acid sequences are preferably inserted in a recombinant expression vector and may be in the form of naked DNA.
4.3 ANTISENSE
Another aspect of the invention pertains to isolated antisense nucleic acid molecules that are hybridizable to or complementary to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 1-684, or 1369-1966, or fragments, analogs or derivatives thereof. An "antisense" nucleic acid comprises a nucleotide sequence that is complementary to a "sense" nucleic acid encoding a protein, e.g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to an mRNA
sequence. In specific aspects, antisense nucleic acid molecules are provided that c~mprise a sequence complementary to at least about 10, 25, 50, 100, 250 or 500 nucleotides or an entire coding strand, or to only a portion thereof. Nucleic acid molecules encoding fragments, homologs, derivatives and analogs of a protein of any of SEQ ID NO:
1-684, or 1369-1966 or antisense nucleic acids complementary to a nucleic acid sequence of SEQ ID
NO: 1-684, or 1369-1966 are additionally provided.
In one embodiment, an antisense nucleic acid molecule is antisense to a "coding region" of the coding strand of a nucleotide sequence of the invention. The ternz "coding region" refers to the region of the nucleotide sequence comprising colons which are translated into amino acid residues. In another embodiment, the antisense nucleic acid molecule is antisense to a "noncoding region" of the coding strand of a nucleotide sequence of the invention. The term "noncoding region" refers to 5' and 3' sequences that flank the coding region that are not translated into amino acids (i.e., also referred to as 5' and 3' untranslated regions).
Given the coding strand sequences encoding a nucleic acid disclosed herein (e.g., SEQ ID NO: 1-684, or 1369-1966, antisense nucleic acids of the invention can be designed according to the rules of Watson and Crick or Hoogsteen base pairing. The antisense nucleic acid molecule can be complementary to the entire coding region of an mRNA, but more preferably is an oligonucleotide that is antisense to only a portion of the coding or noncoding region of an mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of an mRNA. An antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 nucleotides in length. An antisense nucleic acid of the invention can be constructed using chemical synthesis or enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally occurnng nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used.
Examples of modified nucleotides that can be used to generate the antisense nucleic acid include: 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxyhxaethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection).
The antisense nucleic acid molecules of the invention are typically administered to a subject or generated ira situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a protein according to the invention to thereby inhibit expression of the protein, e.g., by inhibiting transcription andlor translation. The hybridization can be by conventional nucleotide complementarity to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix. An example of a route of 5 administration of antisense nucleic acid molecules of the invention includes direct injection at a tissue site. Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then administered systemically. For example, for systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface, e.g., by linking the antisense nucleic acid molecules to 10 peptides or antibodies that bind to cell surface receptors or antigens. The antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. To achieve sufficient intracellular concentrations of antisense molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II
or pol III
promoter are preferred.
15 In yet another embodiment, the antisensc nucleic acid molecule of the invention is an ce-anomeric nucleic acid molecule. An ~,-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual oc-units, the strands run parallel to each other (Gaultier et al. (1987) Nucleic Acids lees 15:
6625-6641). The antisense nucleic acid molecule can also comprise a 20 2'-o-methylribonucleotide (moue et al. (1987) Nucleic Acids Res 15: 6131-6148) or a chimeric RNA -DNA analogue (Inoue et al. (1987) ~R"R~'Lett 215: 32?-330).
4.4 I~I~~~S AND PNA 1~IOIETyES
In still another embodiment, an antisense nucleic acid of the invention is a ribozyme.
25 Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes (described in Haselhoff and Gerlach (1988) Nature 334:585-591)) can be used to catalytically cleave mRNA transcripts to thereby inhibit translation of an mRNA. A ribozyme having specificity for a nucleic acid of the invention can be designed based upon the nucleotide sequence of a DNA disclosed herein (i.e., SEQ ID NO: 1-684, or 1369-1966). For example, a derivative of Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in a mRNA. See, e.g., Cech et al. U.S. Pat. No. 4,987,071; and Cech et al. U.S. Pat. No. 5,116,742.
Alternatively, mRNA of the invention can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et al., (1993) Sciezzce 261:1411-1418.
Alternatively, gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region (e.g., promoter and/or enhancers) to form triple helical structures that prevent transcription of the gene in target cells. See generally, Helens.
(1991) Anticancer Dz-ug Des. 6: 569-84; Helens. et al. (1992) Arz>z. N. Y.
Acad. Sci.
660:27-36; and Maher (1992) Bioassays 14: 807-15.
In various embodiments, the nucleic acids of the invention can be modified at the base moiety, sugar moiety or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids (see Hyrup et al. (1996) Bioorg Med C'laezzz 4: 5-23). As used herein, the terms "peptide nucleic acids"
or "PNAs" refer to nucleic acid mimics, e.g., DNA mimics, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength.
The synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols as described in Hyrup et al. (1996) above; Perry-O'I~eefe et al.
(1996) PNAS' 93:
14670-67~.
PNAs of the invention can be used in therapeutic and diagnostic applications.
For example, PNAs can be used as antisense or antigens agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication. PNAs of the invention can also be used, e.g., in the analysis of single base pair mutations in a gene by, e.g., PNA directed PCR clamping; as artificial restriction enzymes when used in combination with other enzymes, e.g., Sl nucleases (Hyrup B.
(1996) above);
or as probes or primers for DNA sequence and hybridization (Hyrup et al.
(1996), above;
Perry-O'Keefe (1996), above).
In another embodiment, PNAs of the invention can be modified, e.g., to enhance their stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art. For example, PNA-DNA chimeras can be generated that may combine the advantageous properties of PNA and DNA. Such chimeras allow DNA
recognition enzymes, e.g., RNase H and DNA polymerases, to interact with the DNA
portion while the PNA portion would provide high binding affinity and specificity.
PNA-DNA chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleobases, and orientation (Hyrup (1996) above). The synthesis of PNA-DNA chimeras can be performed as described in Hyrup (1996) above and Finn et al. (1996) Nucl Acids Res 24: 3357-63. For example, a DNA chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry, and modified nucleoside analogs, e.g., 5'-(4-methoxytrityl)amino-5'-deoxy-thymidine phosphoramidite, can be used between the PNA and the 5' end of DNA (Mag et al.
(1989) Nucl Acid Res 17: 5973-88). PNA monomers are then coupled in a stepwise manner to produce a chimeric molecule with a 5' PNA segment and a 3' DNA segment (Finn et al.
(1996) above). Alternatively, chimeric molecules can be synthesized with a 5' DNA
segment and a 3' PNA segment. See, Petersen et al. (1975) Bioorg Med Claezn Lett 5:
1119-11124.
In other embodiments, the oligonucleotide may include other appended groups such as peptides (e.g., for targeting host cell receptors in viv~), or agents facilitating transport across the cell membrane (see, e.g., Letsinger et al., 1989, Proc. Natl. Acad.
~'ci. ZJ:S.A.
86:6553-6556; Lemaitre et al., 1987, Proc. Natl. Acad. Sci. 84:648-652; PCT
Publication No. W088/09810) or the blood-brain barrier (see, e.g., PCT Publication No.
W089/10134).
In addition, oligonucleotides can be modified with hybridization triggered cleavage agents (See, e.g., I~rol et al., 1988, Bi~T'eclzzziques 6:958-976) or intercalating agents. (See e.g., ion, 1988, Pharnz. Res. 5: 539-549). To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, a hybridization triggered cross-linking agent, a transport agent, a hybridization-triggered cleavage agent, etc.
4.5 I3~STS
The present invention further provides host cells genetically engineered to contain the polynucleotides of the invention. For example, such host cells may contain nucleic acids of the invention introduced into the host cell using known transformation, transfection or infection methods. The present invention still further provides host cells genetically engineered to express the polynucleotides of the invention, wherein such polynucleotides are in operative association with a regulatory sequence heterologous to the host cell which drives expression of the polynucleotides in the cell.
Knowledge of nucleic acid sequences allows for modification of cells to permit, or increase, expression of endogenous polypeptide. Cells can be modified (e.g., by homologous recombination) to provide increased polypeptide expression by replacing, ~in whole or in part, the naturally occurring promoter with all or part of a heterologous promoter so that the cells express the polypeptide at higher levels. The heterologous promoter is inserted in such a manner that it is operatively linked to the encoding sequences. See, for example, PCT International Publication No. W094/12650, PCT International Publication No. W092/20808, and PCT International Publication No. W091/09955. It is also contemplated that, in addition to heterologous promoter DNA, amplifiable marker DNA
(e.g., ada, dhfr, and the multifunctional CAD gene which encodes carbamyl phosphate synthase, aspartate transcarbamylase, and dihydroorotase) and/or intron DNA
may be inserted along with the heterologous promoter DNA. If linked to the coding sequence, amplification of the marker DNA by standard selection methods results in co-amplification of the desired protein coding sequences in the cells.
The host cell can be a higher eukaryotic host cell, such as a mammalian cell, a lower eukaryotic host cell, such as a yeast cell, or the host cell can be a prokaryotic cell, such as a bacterial cell. Introduction of the recombinant construct into the host cell can be effected by calcium ph~sphate transfection, DEAF, dextran mediated transfection, or electroporation (Davis, L. et al., B~asie 111rIletla~ds ifi. ll~l~leeulcz,- Bi~l~,~~ (1986)).
The host cells containing one of the polynucleotides of the inventi~n, can be used in conventional manners to produce the gene product encoded by the isolated fragment (in the case of an OI2F) or can be used to produce a heterologous protein under the control of the EMF.
Any host/vector system can be used to express one or more of the ORFs of the present invention. These include, but are not limited to, eukaryotic hosts such as HeLa cells, Cv-1 cell, COS cells, 293 cells, and Sf~ cells, as well as prokaryotic host such as E. coli and B. subtilis. The most preferred cells are those which d~ not normally express the particular polypeptide or protein or which expresses the polypeptide or protein at low natural level.
Mature proteins can be expressed in mammalian cells, yeast, bacteria, or other cells under the control of appropriate promoters. Cell-free translation systems can also be employed to produce such proteins using RNAs derived from the DNA constructs of the present invention. Appropriate cloning and expression vectors for use with prokaryotic and eukaryotic hosts are described by Sambrook, et al., in Molecular Cloning: A
Laboratory Manual, Second Edition, Cold Spring Harbor, New York (1989), the disclosure of which is hereby incorporated by reference.
Various mammalian cell culture systems can also be employed to express recombinant protein. Examples of mammalian expression systems include the COS-7 lines of monkey kidney fibroblasts, described by Gluzman, Cell 23:175 (1981). Other cell lines capable of expressing a compatible vector are, for example, the C127, monkey COS cells, Chinese Hamster Ovary (CHO) cells, human kidney 293 cells, human epidermal A431 cells, human Co1o205 cells, 3T3 cells, CV-1 cells, other transformed primate cell lines, normal diploid cells, cell strains derived from in vitro culture of primary tissue, primary explants, HeLa cells, mouse L cells, BHK, HL-60, U937, HaK or Jurkat cells. Mammalian expression vectors will comprise an origin of replication, a suitable promoter and also any necessary ribosome binding sites, polyadenylation site, splice donor and acceptor sites, transcriptional termination sequences, and 5 ° flanking nontranscribed sequences. DNA
sequences derived from the SV40 viral genome, for example, SV40 origin, early promoter, enhancer, splice, and polyadenylation sites may be used to provide the required nontranscribed genetic elements. Recombinant polypeptides and proteins produced in bacterial culture are usually isolated by initial extraction fiom cell pellets, followed by one or more saltinb out, aqueous ion exchange or size exclusion chromatography steps. Protein refolding steps can be used, as necessary, in completing configuration of the mature protein. Finally, high performance liquid chr~matography (HPLC) can be employed for final purification steps.
Micr~bial cells empl~yed in expression of proteins can be disrupted by any convenient method, including freeze-thaw cycling, sonication, mechanical disruption, or use of cell lysing agents.
Alternatively, it may be possible to produce the protein in lower eukaryotes such as yeast or insects or in prokaryotes such as bacteria. Potentially suitable yeast strains include Sczeclzai~~nayces cerevisiae, Selziz~sacchaYOrnyces ponabe, Kluyveromyces strains, Candida, or any yeast strain capable of expressing heterologous proteins. Potentially suitable bacterial strains include Escher~ichia coli, Bacillus subtilis, S'alm~nella yphinaur~ium, or any bacterial strain capable of expressing heterologous proteins. If the protein is made in yeast or bacteria, it may be necessary to modify the protein produced therein, for example by phosphorylation or glycosylation of the appropriate sites, in order to obtain the functional protein. Such covalent attachments may be accomplished using known chemical or enzymatic methods.

In another embodiment of the present invention, cells and tissues may be engineered to express an endogenous gene comprising the polynucleotides of the invention under the control of inducible regulatory elements, in which case the regulatory sequences of the endogenous gene may be replaced by homologous recombination. As described herein, gene 5 targeting can be used to replace a gene's existing regulatory region with a regulatory sequence isolated from a different gene or a novel regulatory sequence synthesized by genetic engineering methods. Such regulatory sequences may be comprised of promoters, enhancers, scaffold-attachment regions, negative regulatory elements, transcriptional initiation sites, and regulatory protein binding sites or combinations of said sequences.
10 Alternatively, sequences which affect the structure or stability of the RNA
or protein produced may be replaced, removed, added, or otherwise modified by targeting.
These sequence include polyadenylation signals, mRNA stability elements, splice sites, leader sequences for enhancing or modifying transport or secretion properties of the protein, or other sequences which alter or improve the function or stability of protein or RNA
15 molecules.
The targeting event may be a simple insertion of the regulatory sequence, placing the gene under the contr~1 of the new regulatory sequence, e.g., inserting a new promoter or enhances or both upstream of a gene. Alternatively, the targeting event may be a simple deletion of a regulatory element, such as the deletion of a tissue-specific negative regulatory 20 element. Alternatively, the targeting event may replace an existing element; for example, a tissue-specific enhances can be replaced by an enhances that has broader or different cell-type speci~acity than the naturally occurring elements. Here, the naturally occurring sequences are deleted and new sequences are added. In all cases, the identification of the targeting event may be facilitated by the use of one or more selectable marker genes that are 25 contiguous with the targeting DNA, allowing for the selection of cells in which the exogenous DNA has integrated into the host cell genome. The identification of the targeting event may also be facilitated by the use of one or more marker genes exhibiting the property of negative selection, such that the negatively selectable marker is linked to the exogenous DNA, but configured such that the negatively selectable marker flanks the targeting 30 sequence, and such that a correct homologous recombination event with sequences in the host cell genome does not result in the stable integration of the negatively selectable marker.
Markers useful for this purpose include the Herpes Simplex Virus thymidine kinase (TK) gene or the bacterial xanthine-guanine phosphoribosyl-transferase (gpt) gene.

The gene targeting or gene activation techniques which can be used in accordance with this aspect of the invention are more particularly described in U.S.
Patent No. 5,272,071 to Chappel; U.S. Patent No. 5,578,461 to Sherwin et al.; International Application No.
PCT/LTS92/09627 (W093/09222) by Selden et al.; and International Application No.
PCT/US90/06436 (W091/06667) by Skoultchi et al., each of which is incorporated by reference herein in its entirety.
4.6 POLYPEPTIDES OF THE INVENTION
The isolated polypeptides of the invention include, but are not limited to, a polypeptide comprising: the amino acid sequences set forth as any one of SEQ
ID NO: 685-1368, or 1967-2564 or an amino acid sequence encoded by any one of the nucleotide sequences SEQ ID NO: 1-684, or 1369-1966 or the corresponding full length or mature protein. Polypeptides of the invention also include polypeptides preferably with biological or immunological activity that are encoded by: (a) a polynucleotide having any one of the nucleotide sequences set forth in SEQ ID NO: 1-684, or 1369-1966 or (b) polynucleotides encoding any one of the amino acid sequences set forth as SEQ ID NO: 685-1368, or 1967-2564 or (c) polynucleotides that hybridize to the complement of the polynucleotides of either (a) or (b) under stringent hybridization conditions. The invention also provides biologically active or immunologically active variants of any of the amino acid sequences set forth as SEQ ID NO: 685-1368, or 1967-2564 or the corresponding full length or mature protein; and "substantial equivalents" thereof (e.g., with at least about 65°A°, at least about 70°/~, at least about 75°/~, at least about 80%, at least about 85°/~, 86°/~, 87°!~, 88°d°, 89°/~, at least about 90%, 91%, 92%, 93°f°, 94°~°, typically at least about 95°f°, 96%, 97°J°, more typically at least about 98%, or most typically at least about 99% amino acid identity) that retain biological activity. Polypeptides encoded by allelic variants may have a similar, increased, or decreased activity compared to polypeptides comprising SEQ ID NO: 685-1368, or 2564.
Fragments of the proteins of the present invention which are capable of exhibiting biological activity are also encompassed by the present invention. Fragments of the protein may be in linear form or they may be cyclized using known methods, for example, as described in H. U. Saragovi, et al., Bio/Technology 10, 773-778 (1992) and in R. S.
McDowell, et al., J. Amer. Chem. Soc. 114, 9245-925'3 (1992), both of which are incorporated herein by reference. Such fragments may be fused to carrier molecules such as immunoglobulins for many purposes, including increasing the valency of protein binding sites. Fragments are also identified in Tables 3A, 3B, 5, 7, or 8.
The present invention also provides both full-length and mature forms (for example, without a signal sequence or precursor sequence) of the disclosed proteins.
The protein coding sequence is identified in the sequence listing by translation of the disclosed nucleotide sequences. The predicted signal sequence is set forth in Table 5.
The mature form of such protein may be obtained and confirmed by expression of a full-length polynucleotide in a suitable mammalian cell or other host cell and sequencing of the cleaved product. One of skill in the art will recognize that the actual cleavage site may be different than that predicted in Table 5. The sequence of the mature form of the protein is also determinable from the amino acid sequence of the full-length form. Where proteins of the present invention are membrane bound, soluble forms of the proteins are also provided. In such forms, part or all of the regions causing the proteins to be membrane bound are deleted so that the proteins are fully secreted from the cell in which they are expressed (See, e.g., Sakal et al., Prep. Biochem. Biotechnol. (2000), 30(2), pp. 107-23, incorporated herein by reference).
Protein compositions of the present invention may further comprise an acceptable carrier, such as a hydrophilic, e.g., pharmaceutically acceptable, carrier.
The present invention further provides isolated polypeptides encoded by the nucleic acid fragments of the present invention or by degenerate variants of the nucleic acid fragments of the present invention. By "degenerate variant" is intended nucleotide fragments which differ from a nucleic acid fragment of the present invention (e.g., an OHF) by nucleotide sequence but, due to the degeneracy of the genetic code, encode an identical polypeptide sequence. Preferred nucleic acid fragments of the present invention are the ORFs that encode proteins.
A variety of methodologies known in the art can be utilized to obtain any one of the isolated polypeptides or proteins of the present invention. At the simplest level, the amino acid sequence can be synthesized using commercially available peptide synthesizers. The synthetically-constructed protein sequences, by virtue of sharing primary, secondary or tertiary structural and/or conformational characteristics with proteins may possess biological properties in common therewith, including protein activity. This technique is particularly useful in producing small peptides and fragments of larger polypeptides.
Fragments are useful, for example, in generating antibodies against the native polypeptide.
Thus, they may be employed as biologically active or immunological substitutes for natural, purified proteins in screening of therapeutic compounds and in immunological processes for the development of antibodies. .
The polypeptides and proteins of the present invention can alternatively be purred from cells which have been altered to express the desired polypeptide or protein. As used herein, a cell is said to be altered to express a desired polypeptide or protein when the cell, through genetic manipulation, is made to produce a polypeptide or protein which it normally does not produce or which the cell normally produces at a lower level. One skilled in the art can readily adapt procedures for introducing and expressing either recombinant or synthetic sequences into eukaryotic or prokaryotic cells in order to generate a cell which produces one of the polypeptides or proteins of the present invention.
The invention also relates to methods for producing a polypeptide comprising growing a culture of host cells of the invention in a suitable culture medium, and purifying the protein from the cells or the culture in which the cells are grown. For example, the methods of the invention include a process for producing a polypeptide in which a host cell containing a suitable expression vector that includes a polynucleotide of the invention is cultured under conditions that allow expression of the encoded polypeptide.
The polypeptide can be recovered from the culture, conveniently from the culture medium, or from a lysate prepared from the host cells and further purified. Preferred embodiments include those in which the protein produced by such process is a full length or mature form of the protein.
In an alternative method, the polypeptide or protein is purified from bacterial cells which naturally produce the polypeptide or protein. One skilled in the art can readily follow known methods for isolating polypeptides and proteins in order to obtain one of the isolated polypeptides or proteins of the present invention. These include, but are not limited to, immunochromatography, HPLC, size-exclusion chromatography, ion-exchange chromatography, and immuno-affinity chromatography. See, e.g~., Scopes, Proteifa Purification: Principles arad Pf°actice, Springer-Verlag (1994);
Sambrook, et al., in Molecular Cloning: A Labof°ato~y Manual; Ausubel et al., Current Pi°otocols in Molecular Biology. Polypeptide fragments that retain biological/immunological activity include fragments comprising greater than about 100 amino acids, or greater than about 200 amino acids, and fragments that encode specific protein domains.

The purified polypeptides can be used in in vitro binding assays which are well known in the art to identify molecules which bind to the polypeptides. These molecules include but are not limited to, for e.g., small molecules, molecules from combinatorial libraries, antibodies or other proteins. The molecules identified in the binding assay are then tested for antagonist or agonist activity in ira vivo tissue culture or animal models that are well known in the art. In brief, the molecules are titrated into a plurality of cell cultures or animals and then tested for either cell/animal death or prolonged survival of the animal/cells.
In addition, the peptides of the invention or molecules capable of binding to the peptides may be complexed with toxins, e.g., ricin or cholera, or with other compounds that are toxic to cells. The toxin-binding molecule complex is then targeted to a tumor or other cell by the specificity of the binding molecule for SEQ ID NO: 685-1368, or 1967-2564.
The protein of the invention may also be expressed as a product of transgenic animals, e.g., as a component of the milk of transgenic cows, goats, pigs, or sheep which are characterized by somatic or germ cells containing a nucleotide sequence encoding the protein.
The proteins provided herein also include proteins characterized by amino acid sequences similar to those of purified proteins but lllto which modification are naturally provided or deliberately engineered. For example, modifications, in the peptide or DNA
sequence, can be made by those skilled in the art using laiown techniques.
Modifications of interest in the protein sequences may include the alteration, substitution, replacement, insertion or deletion of a selected amino acid residue in the coding sequence.
For example, one or more of the cysteine residues may be deleted or replaced with another amino acid to alter the conformation of the molecule. Techniques for such alteration, substitution, replacement, insertion or deletion are well known to those skilled in the art (see, e.g., U.S.
Pat. No. 4,518,584). Preferably, such alteration, substitution, replacement, insertion or deletion retains the desired activity of the protein. Regions of the protein that are important for the protein function can be determined by various methods known in the art including the alanine-scanning method which involved systematic substitution of single or strings of amino acids with alanine, followed by testing the resulting alanine-containing variant for biological activity. This type of analysis determines the importance of the substituted amino acids) in biological activity. Regions of the protein that are important for protein function may be determined by the eMATRIX program.

Other fragments and derivatives of the sequences of proteins which would be expected to retain protein activity in whole or in part and are useful for screening or other imrnunological methodologies may also be easily made by those skilled in the art given the disclosures herein. Such modifications are encompassed by the present invention.
The protein may also be produced by operably linking the isolated polynucleotide of the invention to suitable control sequences in one or more insect expression vectors, and employing an insect expression system. Materials and methods for baculovirus/insect cell expression systems are commercially available in kit form from, e.g., Invitrogen, San Diego, Cali~, U.S.A. (the MaxBatTM kit), and such methods are well known in the art, as described 10 in Summers and Smith, Texas Agricultural Experiment Station Bulletin No.
1555 (1987), incorporated herein by reference. As used herein, an insect cell capable of expressing a polynucleotide of the present invention is "transformed."
The protein of the invention may be prepared by culturing transformed host cells under culture conditions suitable to express the recombinant protein. The resulting 15 expressed protein may then be purified from such culture (i.e., from culture medium or cell extracts) using known purification processes, such as gel filtration and ion exchange chromatography. The purification of the protein may also include an affinity column containing agents which will bind to the protein, one or more column steps over such affinity resins as concanavalin A-agarose, heparin-toyopearlTM or Cibacrom blue 3GA
SepharoseTM;
20 one or more steps involving hydrophobic interaction chromatography using such resins as phenyl ether, butyl ether, or propyl ethers or nnmunoafBmtg, chromatography.
Altea-natively, the protein of the invention may also be expressed in a form which will facilitate purification. For example, it may be expressed as a fusion protein, such as those of maltose binding protein (MBP), glutathione-S-transferase (GST) or thioredoxin (TRX), or as 25 a His tag. Kits for expression and purification of such fusion proteins are commercially available from New England BioLab (Beverly, Mass.), Pharmacia (Piscataway, N.J.) and Invitrogen, respectively. The protein can also be tagged with an epitope and subsequently purred by using a specific antibody directed to such epitope. One such epitope ("FLAGO") is commercially available from Kodak (New Haven, Conn.).
30 Finally, one or more reverse-phase high performance liquid chromatography (RP-HPLC) steps employing hydrophobic RP-HPLC media, e.g., silica gel having pendant methyl or other aliphatic groups, can be employed to further purify the protein. Some or all of the foregoing purification steps, in various combinations, can also be employed to provide a substantially homogeneous isolated recombinant protein. The protein thus purified is substantially free of other mammalian proteins and is defined in accordance with the present invention as an "isolated protein."
The polypeptides of the invention include analogs (variants). This embraces fragments, as well as peptides in which one or more amino acids has been deleted, inserted, or substituted. Also, analogs of the polypeptides of the invention embrace fusions of the polypeptides or modifications of the polypeptides of the invention, wherein the polypeptide or analog is fused to another moiety or moieties, e.g., targeting moiety or another therapeutic agent. Such analogs may exhibit improved properties such as activity and/or stability.
Examples of moieties which may be fused to the polypeptide or an analog include, for example, targeting moieties which provide for the delivery of polypeptide to pancreatic cells, e.g., antibodies to pancreatic cells, antibodies to immune cells such as T-cells, monocytes, dendritic cells, granulocytes, etc., as well as receptor and ligands expressed on pancreatic or immune cells. Other moieties which may be fused to the polypeptide include therapeutic agents which are used for treatment, for example, immunosuppressive drugs such as cyclosporin, SI~506, a~athioprine, CD3 antibodies and steroids. Also, polypeptides may be fused to immune modulators, and other cytokines such as alpha or beta interferon.
4.6.1 DETERMINING POLYPEPT~E AND POLYNiJCLEOTIDE
IDENTITY AND SIMILARITY
Preferred identity and/or similarity are designed to give the largest match between the sequences tested. Methods to determine identity and similarity are codified in computer programs including, but are not limited to, the GCG program package, including GAP
(Devereux, J., et al., Nucleic Acids Research 12(1):387 (1984); Genetics Computer Group, University of Wisconsin, Madison, WI), BLASTP, BLASTN, BLASTX, FASTA
(Altschul, S.F. et al., J. Molec. Biol. 215:403-410 (1990), PSI-BLAST (Altschul S.F. et al., Nucleic Acids Res. vol. 25, pp. 3389-3402, herein incorporated by reference), eMatrix software (Wu et al., J. Comp. Biol., Vol. 6, pp. 219-235 (1999), herein incorporated by reference), eMotif software (Nevill-Manning et al, ISMB-97, Vol. 4, pp. 202-209, herein incorporated by reference), Pfam software (Sonnhammer et al., Nucleic Acids Res., Vol. 26(1), pp. 320-322 (1998), herein incorporated by reference) and the I~yte-Doolittle hydrophobocity prediction algoritlnn (J. Mol Biol, 157, pp. 105-31 (1982), the GeneAtlas software (Molecular Simulations Inc. (MSI), San Diego, CA) (Sanchez and Sali (1998) Proc. Natl.
Acad. Sci., 95, 13597-13602; Kitson DH et al, (2000) "Remote homology detection using structural modeling - an evaluation" Submitted; Fischer and Eisenberg (1996) Protein Sci.
5, 947-955), Neural Network SignalP V1.1 program (from Center for Biological Sequence Analysis, The Technical University of Denmark) incorporated herein by reference).
Polypeptide sequences were examined by a proprietary algorithm, SeqLoc that separates the proteins into three sets of locales: intracellular, membrane, or secreted.
This prediction is based upon three characteristics of each polypeptide, including percentage of cysteine residues, Kyte-Doolittle scores for the first 20 amino acids of each protein, and Kyte-Doolittle scores to calculate the longest hydrophobic stretch of the said protein. Values of predicted proteins are compared against the values from a set of 592 proteins of known cellular localization from the Swissprot database (http://www.expasy.ch/sprot). Predictions are based upon the maximum likelihood estimation.
Pesence of transmembrane regions) was detected using the TMpred program (http~//www ch embnet.or~/software/TMPRED form.htinl).
The BLAST programs are publicly available from the National Center for Biotechnology Information (IVCBI) and other sources (BLAST Manual, Altschul, S., et al.
NCBI NLM NIH Bethesda, MD 20894; Altschul, S., et al., J. Mol. Biol. 215:403-( 1990).
4.7 CHIMERIC AND FUSION PROTEINS
The invention also provides chimeric or fusion proteins. As used herein, a "chimeric protein" or "fusion protein" comprises a polypeptide of the invention operatively linked to another polypeptide. within a fusion protein the polypeptide according to the invention can correspond to all or a portion of a protein according to the invention. In one embodiment, a fusion protein comprises at least one biologically active portion of a protein according to the invention. In another embodiment, a fusion protein comprises at least two biologically active portions of a protein according to the invention. Within the fusion protein, the term "operatively linked" is intended to indicate that the polypeptide according to the invention and the other polypeptide are fused in-frame to each other. The polypeptide can be fused to the N-terminus or C-terminus, or to the middle.
For example, in one embodiment a fusion protein comprises a polypeptide according to the invention operably linked to the extracellular domain of a second protein.

In another embodiment, the fusion protein is a GST-fusion protein in which the polypeptide sequences of the invention are fused to the C-terminus of the GST
(i.e., glutathione S-transferase) sequences.
In another embodiment, the fusion protein is an irnrnunoglobulin fusion protein in which the polypeptide sequences according to the invention comprise one or more domains fused to sequences derived from a member of the immunoglobulin protein family.
The immunoglobulin fusion proteins of the invention can be incorporated into pharmaceutical compositions and administered to a subject to inhibit an interaction between a ligand and a protein of the invention on the surface of a cell, to thereby suppress signal transduction in vivo. The immunoglobulin fusion proteins can be used to affect the bioavailability of a cognate ligand. Inhibition of the ligand/protein interaction may be useful therapeutically for b~th the treatment of proliferative and differentiative disorders, e.g., cancer as well as modulating (e.g., promoting or inhibiting) cell survival. Moreover, the immunoglobulin fusion proteins of the invention can be used as irnmunogens to produce antibodies in a subject, to purify ligands, and in screening assays to identify molecules that inhibit the interacti~n of a polypeptide of the invention with a ligand.
A chimeric or fusion protein of the inventi~n can be produced by standard recombinant DNA techniques. F'or example, DNA fragments coding for the different polypeptide sequences are ligated together in-frame in accordance with conventional techniques, e.g., by employing blunt-ended or stagger-ended termini for ligation, restriction enzyme digestion to provide for appra~priate termini, filling-in ~f cohesive ends as appropriate, alkaline phosphatase treatment t~ avoid undesirable joining, and enzymatic ligation. In another emb~diment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR
amplification of gene fragments can be carried out using anchor primers that give rise to complementary overhangs between two consecutive gene fragments that can subsequently be annealed and reamplified t~ generate a chimeric gene sequence (see, for example, Ausubel et al. (eds.) CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, Tohn Wiley & Sons, 1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide). A nucleic acid encoding a polypeptide of the invention can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the protein of the invention.

4.8 GENE THERAPY
Mutations in the polynucleotides of the invention gene may result in loss of normal function of the encoded protein. The invention thus provides gene therapy to restore normal activity of the polypeptides of the invention; or to treat disease states involving polypeptides of the invention. Delivery of a functional gene encoding polypeptides of the invention to appropriate cells is effected ex vivo, in situ, or in vivo by use of vectors, and more particularly viral vectors (e.g., adenovirus, adeno-associated virus, or a retrovirus), or ex vivo by use of physical DNA transfer methods (e.g., liposomes or chemical treatments). See, for example, Anderson, Nature, supplement to vol. 392, no. 6679, pp.25-20 (1998).
For additional reviews of gene therapy technology see Friedmann, Science, 244:

(1989); Verma, Scientific American: 68-84 (1990); and Miller, Nature, 357: 455-460 (1992).
Introduction of any one of the nucleotides of the present invention or a gene encoding the polypeptides of the present invention can also be accomplished with extrachromosomal substrates (transient expression) or artificial chromosomes (stable expression). Cells may also be cultured ~ vivo in the presence of proteins of the present invention in order to proliferate or to produce a desired effect on or activity in such cells.
Treated cells can then be introduced in viv~ for therapeutic puaposes. Alternatively, it is contemplated that in other human disease states, preventing the expression of or inhibiting the activity of polypeptides of the invention will be useful in treating the disease states. It is contemplated that antisense therapy or gene therapy could be applied to negatively regulate the expression of polypeptides of the invention.
~ther methods inhibiting expression of a protein include the introduction of antisense molecules to the nucleic acids of the present invention, their complements, or their translated RNA sequences, by methods lrnown in the art. Further, the polypeptides of the present invention can be inhibited by using targeted deletion methods, or the insertion of a negative regulatory element such as a silencer, which is tissue specific.
The present invention still further provides cells genetically engineered in vivo to express the polynucleotides of the invention, wherein such polynucleotides are in operative association with a regulatory sequence heterologous to the host cell which drives expression of the polynucleotides in the cell. These methods can be used to increase or decrease the expression of the polynucleotides of the present invention.
Knowledge of DNA sequences provided by the invention allows for modification of cells to permit, increase, or decrease, expression of endogenous polypeptide.
Cells can be modified (e.g., by homologous recombination) to provide increased polypeptide expression by replacing, in whole or in part, the naturally occurring promoter with all or part of a heterologous promoter so that the cells express the protein at higher levels. The heterologous promoter is inserted in such a manner that it is operatively linked to the desired protein encoding sequences.
5 See, for example, PCT International Publication No. WO 94/12650, PCT
International Publication No. WO 92/20808, and PCT International Publication No. WO
91/09955. It is also contemplated that, in addition to heterologous promoter DNA, amplifiable marker DNA (e.g., ada, dhfr, and the multifunctional CAD gene which encodes carbamyl phosphate synthase, aspartate transcarbamylase, and dihydroorotase) and/or intron DNA may be inserted along with 10 the heterologous promoter DNA. If linked to the desired protein coding sequence, amplification of the marker DNA by standard selection methods results in co-amplification of the desired protein coding sequences in the cells.
In another embodiment of the present invention, cells and tissues may be engineered to express an endogenous gene comprising the polynucleotides of the invention under the control 15 of inducible regulatory elements, in which case the regulatory sequences of the endogenous gene may be replaced by homologous recombination. As described herein, gene targeting can be used to replace a gene's existing regulatory region with a regulatory sequence isolated from a different gene or a n~vel regulatory sequence synthesized by genetic engineering methods.
Such regulatory sequences may be comprised of promoters, enhancers, scaffold-attachment 20 regions, negative regulatory elements, transcriptional initiation sites, regulatory protein binding sites or combinations of said sequences. Alternatively, sequences which affect the structure or stability of the RNA or protein produced may be replaced, removed9 added9 or otherwise modified by targeting. These sequences include polyadenylation signals, mRNA
stability elements, splice sites, leader sequences for enhancing or modifying transport or secretion 25 properties of the protein, or other sequences which alter or improve the function or stability of protein or RNA molecules.
The targeting event may be a simple insertion of the regulatory sequence, placing the gene under the control of the new regulatory sequence, e.g., inserting a new promoter or enhancer or both upstream of a gene. Alternatively, the targeting event may be a simple 30 deletion of a regulatory element, such as the deletion of a tissue-specific negative regulatory element. Alternatively, the targeting event may replace an existing element;
for example, a tissue-specific enhancer can be replaced by an enhancer that has broader or different cell-type specificity than the naturally occurnng elements. Here, the naturally occurring sequences are deleted and new sequences are added. In all cases, the identification of the targeting event may be facilitated by the use of one or more selectable marker genes that are contiguous with the targeting DNA, allowing for the selection of cells in which the exogenous DNA
has integrated into the cell genome. The identification of the targeting event may also be facilitated by the use of one or more marker genes exhibiting the property of negative selection, such that the negatively selectable marker is linked to the exogenous DNA, but configured such that the negatively selectable marker flanks the targeting sequence, and such that a correct homologous recombination event with sequences in the host cell genome does not result in the stable integration of the negatively selectable marker. Markers useful for this purpose include the Herpes Simplex Virus thymidine kinase (TK) gene or the bacterial xanthine-guanine phosphoribosyl-transferase (gpt) gene.
The gene targeting or gene activation techniques which can be used in accordance with this aspect of the invention are more particularly described in U.S. Patent No. 5,272,071 to Chappel; U.S. Patent No. 5,578,461 to Sherwin et al.; International Application No.
PCT/LTS92/09627 (WO93/09222) by Selden et al.; and International Application No.
PCT/LTS90/06436 (WO91/06667) by Skoultchi et al., each of which is incorporated by reference herein in its entirety.
4.9 TRA1VSGE1VIC ANI1V1ALS
In preferred methods to determine biological functions of the polypeptides of the invention in vivo, one or more genes provided by the invention are either over expressed or inactivated in the germ line of animals using homologous recombination [Capecchi, Science 244:1288-1292 (1989)]. Animals in which the gene is over expressed, under the regulatory control of exogenous or endogenous promoter elements, are known as transgenic animals.
Animals in which an endogenous gene has been inactivated by homologous recombination are referred to as "knockout" animals. Knockout animals, preferably non-human mammals, can be prepared as described in U.S. Patent No. 5,557,032, incorporated herein by reference.
Transgenic animals are useful to determine the roles polypeptides of the invention play in biological processes, and preferably in disease states. Transgenic animals are useful as model systems to identify compounds that modulate lipid metabolism. Transgenic animals, preferably non-human mammals, are produced using methods as described in U.S.
Patent No 5,489,743 and PCT Publication No. W094/28122, incorporated herein by reference.

Transgenic animals can be prepared wherein all or part of a promoter of the polynucleotides of the invention is either activated or inactivated to alter the level of expression of the polypeptides of the invention. Inactivation can be carried out using homologous recombination methods described above. Activation can be achieved by supplementing or even replacing the homologous promoter to provide for increased protein expression. The homologous promoter can be supplemented by insertion of one or more heterologous enhancer elements known to confer promoter activation in a particular tissue.
The polynucleotides of the present invention also make possible the development, through, e.g., homologous recombination or knock out strategies, of animals that fail to express polypeptides of the invention or that express a variant polypeptide.
Such animals are useful as models for studying the iia vivo activities of polypeptide as well as for studying modulators of the polypeptides of the invention.
In preferred methods to determine biological functions of the polypeptides of the invention ift. vivo, one or more genes provided by the invention are either over expressed or inactivated in the germ line of animals using homologous recombination [Capecchi, Science 244:1288-1292 (1989)x. Animals in which the gene is over expressed, under the regulatory control of exogenous or endogenous promoter elements, are known as transgenic animals.
Animals in which an endogenous gene has been inactivated by homologous recombination are referred to as "knockout" animals. IW ockout animals, preferably non-human mammals, can be prepared as described in U.S. Patent No. 5,557,032, incorporated herein by reference.
Transgenic animals are useful to determine the roles polypeptides of the invention play in biological processes, and preferably in disease states. Transgenic animals are useful as model systems to identify compounds that modulate lipid metabolism. Transgenic animals, preferably non-human mammals, are produced using methods as described in U.S.
Patent No 5,489,743 and PCT Publication No. W094/28122, incorporated herein by reference.
Transgenic animals can be prepared wherein all or part of the polynucleotides of the invention promoter is either activated or inactivated to alter the level of expression of the polypeptides of the invention. Inactivation can be carried out using homologous recombination methods described above. Activation can be achieved by supplementing or even replacing the homologous promoter to provide for increased protein expression. The homologous promoter can be supplemented by insertion of one or more heterologous enhancer elements known to confer promoter activation in a particular tissue.

4.10 USES AND BIOLOGICAL ACTIVITY
The polynucleotides and proteins of the present invention are expected to exhibit one or more of the uses or biological activities (including those associated with assays cited herein) identified herein. Uses or activities described for proteins of the present invention may be provided by administration or use of such proteins or of polynucleotides encoding such proteins (such as, for example, in gene therapies or vectors suitable for introduction of DNA). The mechanism underlying the particular condition or pathology will dictate whether the polypeptides of the invention, the polynucleotides of the invention or modulators (activators or inhibitors) thereof would be beneficial to the subject in need of treatment.
Thus, "therapeutic compositions of the invention" include compositions comprising isolated polynucleotides (including recombinant DNA molecules, cloned genes and degenerate variants thereof) or polypeptides of the invention (including full length protein, mature protein and truncations or domains thereof), or compounds and other substances that modulate the overall activity of the target gene products, either at the level of target gene/protein expression or target protein activity. Such modulators include polypeptides, analogs, (variants), including fragments and fusion proteins, antibodies and other binding proteins; chemical compounds that directly or indirectly activate or inhibit the polypeptides of the invention (identified, e.g., via drug screening assays as described herein); antisense polynucleotides and polynucleotides suitable for triple helix formation; and in particular antibodies or other binding partners that specifically recognize one or more epitopes of the polypeptides of the invention.
The polypeptides of the present invention may likewise be involved in cellular activation or in one of the other physiological pathways described herein.
4.10.1 RESEARCH USES AND UTILITIES
The polynucleotides provided by the present invention can be used by the research conununity for various purposes. The polynucleotides can be used to express recombinant protein for analysis, characterization or therapeutic use; as markers for tissues in which the corresponding protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in disease states); as molecular weight markers on gels; as chromosome markers or tags (when labeled) to identify chromosomes or to map related gene positions; to compare with endogenous DNA sequences in patients to identify potential genetic disorders; as probes to hybridize and thus discover novel, related DNA

sequences; as a source of information to derive PCR primers for genetic fingerprinting; as a probe to "subtract-out" known sequences in the process of discovering other novel polynucleotides; for selecting and making oligomers for attachment to a "gene chip" or other support, including for examination of expression patterns; to raise anti-protein antibodies using DNA immunization techniques; and as an antigen to raise anti-DNA
antibodies or elicit another immune response. Where the polynucleotide encodes a protein which binds or potentially binds to another protein (such as, for example, in a receptor-ligand interaction), the polynucleotide can also be used in interaction trap assays (such as, for example, that described in Gyuris et al., Cell 75:791-803 (1993)) to identify polynucleotides encoding the other protein with which binding occurs or to identify inhibitors of the binding interaction.
The polypeptides provided by the present invention can similarly be used in assays to determine biological activity, including in a panel of multiple proteins for high-throughput screening; to raise antibodies or to elicit another immune response; as a reagent (including the labeled reagent) in assays designed to quantitatively determine levels of the protein (or its receptor) in biological fluids; as markers for tissues in which the corresponding polypeptide is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in a disease state); and, of course, to isolate correlative receptors or ligands. Proteins involved in these binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction.
Any or all of these research utilities are capable of being developed into reagent grade or kit format for coanmercialization as research products.
Methods for performing the uses listed above are well knov~m to those skilled in the art. References disclosing such methods include without limitation "Molecular Cloning: A
Laboratory Manual", 2d ed., Cold Spring Harbor Laboratory Press, Sambrook, J., E. F.
Fritsch and T. Maniatis eds., 1989, and "Methods in Enzymology: Guide to Molecular Cloning Techniques", Academic Press, Bergen S. L. and A. R. I~immel eds., 1987.
4.10.2 NUTRITIONAL USES
Polynucleotides and polypeptides of the present invention can also be used as nutritional sources or supplements. Such uses include without limitation use as a protein or amino acid supplement, use as a carbon source, use as a nitrogen source and use as a source of carbohydrate. In such cases the polypeptide or polynucleotide of the invention can be added to the feed of a particular organism or can be administered as a separate solid or liquid preparation, such as in the form of powder, pills, solutions, suspensions or capsules. In the case of microorganisms, the polypeptide or polynucleotide of the invention can be added to the medium in or on which the microorganism is cultured.
4.10.3 CYTOKINE AND CELL PROLIFERATION/DIFFERENTIATION
ACTIVITY
A polypeptide of the present invention may exhibit activity relating to cytokine, cell proliferation (either inducing or inhibiting) or cell differentiation (either inducing or inhibiting) activity or may induce production of other cytokines in certain cell populations.
10 A polynucleotide of the invention can encode a polypeptide exhibiting such attributes.
Many protein factors discovered to date, including all known cytokines, have exhibited activity in one or more factor-dependent cell proliferation assays, and hence the assays serve as a convenient confirmation of cytokine activity. The activity of therapeutic compositions of the present invention is evidenced by any one of a number of routine factor dependent cell 15 proliferation assays for cell lines including, without limitation, 32D, DA2, DA1G, T10, B9, B9/11, BaF3, MC9lG, M+(preB M+), 2E8, RBS, DA1, 123, T1165, HT2, CTLL2, TF-1, Mo7e, CMI~, HUVEC, and Cac~. Therapeutic compositi~ns of the invention can be used in the following:
Assays for T-cell or thymocyte proliferation include without limitation those 20 described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M.
I~ruisbeek, D. H.
Margulies, E. M. Shevach, W. Strobes, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, Iya T~a~a~~ assays for Mouse Lymphocyte Function 3.1-3.19;
Chapter 7, Immunol~gic studies in Humans); Takai et al., J. Immunol. 137:3494-3500, 1986;
Bertagnolli et al., J. Immunol. 145:1706-1712, 1990; Bertagnolli et al., Cellular Immunology 25 133:327-341, 1991; Bertagnolli, et al., I. Immunol. 149:3778-3783, 1992;
Bowman et al., I.
Immunol. 152:1756-1761, 1994.
Assays for cytokine production and/or proliferation of spleen cells, lymph node cells or thymocytes include, without limitation, those described in: Polyclonal T
cell stimulation, Kruisbeek, A. M. and Shevach, E. M. In Current Protocols in Immunology. J. E.
e.a. Coligan 30 eds. Vol 1 pp. 3.12.1-3.12.14, John Wiley and Sons, Toronto. 1994; and Measurement of mouse and human interleukin-y, Schreiber, R. D. In Current Protocols in Immunology. J. E.
e.a. Coligan eds. Vol 1 pp. 6.8.1-6.8.8, Jolm Wiley and Sons, Toronto. 1994.

Assays for proliferation and differentiation of hematopoietic and lyrnphopoietic cells include, without limitation, those described in: Measurement of Human and Murine Interleukin 2 and Interleukin 4, Bottomly, K., Davis, L. S. and Lipsky, P. E.
In Current Protocols in Immunology. J. E. e.a. Coligan eds. Vol 1 pp. 6.3.1-6.3.12, John Wiley and Sons, Toronto. 1991; deVries et al., J. Exp. Med. 173:1205-1211, 1991; Moreau et al., Nature 336:690-692, 1988; Greenberger et al., Proc. Natl. Acad. Sci. U.S.A.
80:2931-2938, 1983; Measurement of mouse and human interleukin 6--Nordan, R. In Current Protocols in Immunology. J. E. Coligan eds. Vol 1 pp. 6.6.1-6.6.5, John Wiley and Sons, Toronto. 1991;
Smith et al., Proc. Natl. Aced. Sci. U.S.A. 83:1857-1861, 1986; Measurement of human Interleukin 11--Bennett, F., Giannotti, J., Clark, S. C. and Turner, K. J. In Current Protocols in Immunology. J. E. Coligan eds. Vol 1 pp. 6.15.1 John Wiley and Sons, Toronto. 1991;
Measurement of mouse and human Interleukin 9--Ciarletta, A., Giannotti, J., Clark, S. C.
and Turner, K. J. In Current Protocols in Immunology. J. E. Coligan eds. Vol 1 pp. 6.13.1, John Wiley and Sons, Toronto. 1991.
Assays for T-cell clone responses to antigens (which will identify, among others, proteins that affect APC-T cell interactions as well as direct T-cell effects by measuring proliferation and cytokine production) include, without limitation, those described in:
Current Protocols in Immunology, Ed by J. E. Coligan, A. M. Krnisbeek, D. H.
Margulies, E. M. Shevach, W Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function; Chapter 6, Cytokines and their cellular receptors; Chapter 7, Immunologic studies in humans); Weinberger et al., Proc.
Natl. Acad. Sci. USA 77:6091-6095, 1980; Weinberger et al., Eur. J. Immun.
11:405-411, 1981; Takai et al., J. Immunol. 137:3494-3500, 1986; Takai et al., J. Immunol.
140:508-512, 1988.
4.10.4 STEM CELL GROWTH FACTOR ACTIVITY
A polypeptide of the present invention may exhibit stem cell growth factor activity and be involved in the proliferation, differentiation and survival of pluripotent and totipotent stem cells including primordial germ cells, embryonic stem cells, hematopoietic stem cells andlor germ line stem cells. Administration of the polypeptide of the invention to stem cells ira vivo or ex vivo is expected to maintain and expand cell populations in a totipotential or pluripotential state which would be useful for re-engineering damaged or diseased tissues, transplantation, manufacture of bio-pharmaceuticals and the development of bio-sensors.

The ability to produce large quantities of human cells has important working applications for the production of human proteins which currently must be obtained from non-human sources or donors, implantation of cells to treat diseases such as Parkinson's, Alzheimer's and other neurodegenerative diseases; tissues for grafting such as bone marrow, skin, cartilage, tendons, bone, muscle (including cardiac muscle), blood vessels, cornea, neural cells, gastrointestinal cells and others; and organs for transplantation such as kidney, liver, pancreas (including islet cells), heart and lung.
It is contemplated that multiple different exogenous growth factors and/or cytokines may be administered in combination with the polypeptide of the invention to achieve the desired effect, including any of the growth factors listed herein, other stem cell maintenance factors, and specifically including stem cell factor (SCF), leukemia inhibitory factor (LIF), Flt-3 ligand (Flt-3L), any of the interleukins, recombinant soluble IL-6 receptor fused to IL-6, macrophage inflammatory protein 1-alpha (MIP-1-alpha), G-CSF, GM-CSF, thrombopoietin (TPQ), platelet factor 4 (PF-4), platelet-derived growth factor (PDGF), neural growth factors and basic fibroblast growth factor (bFGF).
Since totipotent stem cells can give rise to virtually any mature cell type, expansion of these cells in culture will facilitate the production of large quantities of mature cells.
Techniques for culturing stem cells are known in the art and administration of polypeptides of the invention, optionally with other growth factors and/or cytokines, is expected to enhance the survival and proliferation of the stem cell populations. This can be accomplished by direct administration of the polypeptide of the invention to the culture medium. Alternatively, stroma cells transfected with a polynucleotide that encodes for the polypeptide of the invention can be used as a feeder layer for the stem cell populations in culture or in vivo. Stromal support cells for feeder layers rnay include embryonic bone marrow fibroblasts, bone marrow stromal cells, fetal liver cells, or cultured embryonic fibroblasts (see U.S. Patent No. 5,690,926).
Stem cells themselves can be transfected with a polynucleotide of the invention to induce autocrine expression of the polypeptide of the invention. This will allow for generation of undifferentiated totipotential/pluripotential stem cell lines that are useful as is or that can then be differentiated into the desired mature cell types. These stable cell lines can also serve as a source of undifferentiated totipotential/pluripotential mRNA to create cDNA libraries and templates for polymerase chain reaction experiments. These studies would allow for the isolation and identification of differentially expressed genes in stem cell populations that regulate stem cell proliferation and/or maintenance.
Expansion and maintenance of totipotent stem cell populations will be useful in the treatment of many pathological conditions. For example, polypeptides of the present invention may be used to manipulate stem cells in culture to give rise to neuroepithelial cells that can be used to augment or replace cells damaged by illness, autoimmune disease, accidental damage or genetic disorders. The polypeptide of the invention may be useful for inducing the proliferation of neural cells and for the regeneration of nerve and brain tissue, i.e. for the treatment of central and peripheral nervous system diseases and neuropathies, as well as mechanical and traumatic disorders which involve degeneration, death or trauma to neural cells or nerve tissue. In addition, the expanded stem cell populations can also be genetically altered for gene therapy purposes and to decrease host rejection of replacement tissues after grafting or implantation.
Expression of the polypeptide of the invention and its effect on stem cells can also be manipulated to achieve controlled differentiation of the stem cells into more differentiated cell types. A broadly applicable method of obtaining pure populations of a specific differentiated cell type from undifferentiated stem cell populations involves the use of a cell-type specific promoter driving a selectable marker. The selectable marker allows only cells of the desired type to survive. For example, stem cells can be induced to differentiate into cardiomyocytes (Wobus et al., Differentiation, 48: 173-182, (1991); Klug et al., J. Clin.
Invest., 98(1): 216-224, (1998)) or skeletal muscle cells (Erowder, L. V~. In:
Pa-t~eipl~s ~f Tissue E~z~iraeeF°i~ag- eds. Lanza et al., Academic Press (1997)).
Alternatively, directed differentiation of stem cells can be accomplished by culturing t1]e stem cells in the presence of a differentiation factor such as retinoic acid and an antagonist of the polypeptide of the invention which would inhibit the effects of endogenous stem cell factor activity and allow differentiation to proceed.
Irr vitro cultures of stem cells can be used to determine if the polypeptide of the invention exhibits stem cell growth factor activity. Stem cells are isolated from any one of various cell sources (including hematopoietic stem cells and embryonic stem cells) and cultured on a feeder layer, as described by Thompson et al. Proc. Natl. Acad.
Sci, U.S.A., 92: 7844-7848 (1995), in the presence of the polypeptide of the invention alone or in combination with other growth factors or cytokines. The ability of the polypeptide of the invention to induce stem cells proliferation is determined by colony formation on semi-solid support e.g. as described by Bernstein et al., Blood, 77: 2316-2321 (1991).
4.10.5 HEMATOPOIESIS REGULATING ACTIVITY
A polypeptide of the present invention may be involved in regulation of hematopoiesis and, consequently, in the treatment of myeloid or lymphoid cell~disorders.
Even marginal biological activity in support of colony forming cells or of factor-dependent cell lines indicates involvement in regulating hematopoiesis, e.g. in supporting the growth and proliferation of erythroid progenitor cells alone or in combination with other cytokines, thereby indicating utility, for example, in treating various anemias or for use in conjunction with irradiatioi~/chemotherapy to stimulate the production of erythroid precursors and/or erythroid cells; in supporting the growth and proliferation of myeloid cells such as granulocytes and monocytes/macrophages (i.e., traditional CSF activity) useful, for example, in conjunction with chemotherapy to prevent or treat consequent myelo-suppression; in supporting the growth and proliferation of megakaryocytes and consequently of platelets thereby allowing prevention or treatment of various platelet disorders such as thxombocytopenia, and generally for use in place of or complimentary to platelet transfusions; and/or in supporting the growth and proliferation of hematopoietic stem cells which are capable of maturing to any and all of the above-mentioned hematopoietic cells and therefore find therapeutic utility in various stem cell disorders (such as those usually treated with transplantation, including, without limitation, aplastic anemia and paroxysmal nocturnal hemoglobinuria), as well as in repopulating the stem cell compartment post irradiationchemotherapy, either ifa-viv~ or ex-viv~ (i.e., in conjunction with bone marrow transplantation or with peripheral progenitor cell transplantation (homologous or heterologous)) as normal cells or genetically manipulated for gene therapy.
Therapeutic compositions of the invention can be used in the following:
Suitable assays for proliferation and differentiation of various hematopoietic lines are cited above.
Assays for embryonic stem cell differentiation (which will identify, among others, proteins that influence embryonic differentiation hematopoiesis) include, without limitation, those described in: Johansson et al. Cellular Biology 15:141-151, 1995; Keller et al., Molecular and Cellular Biology 13:473-486, 1993; McClanahan et al., Blood 81:2903-2915, 1993.

Assays for stem cell survival and differentiation (which will identify, among others, proteins that regulate lympho-hematopoiesis) include, without limitation, those described in:
Methylcellulose colony forming assays, Freshney, M. G. In Culture of Hematopoietic Cells.
R. I. Freshney, et al. eds. Vol pp. 265-268, Wiley-Liss, Inc., New York, N.Y.
1994;
5 Hirayama et al., Proc. Natl. Acad. Sci. USA 89:5907-5911, 1992; Primitive hematopoietic colony forming cells with high proliferative potential, McNiece, I. I~. and Briddell, R. A. In Culture of Hematopoietic Cells. R. I. Freshney, et al. eds. Vol pp. 23-39, Wiley-Liss, Inc., New York, N.Y. 1994; Neben et al., Experimental Hematology 22:353-359, 1994;
Cobblestone area forming cell assay, Ploemacher, R. E. In Culture of Hematopoietic Cells.
10 R. I. Freshney, et al. eds. Vol pp. 1-21, Wiley-Liss, Inc., New York, N.Y.
1994; Long term bone marrow cultures in the presence of stromal cells, Spooncer, E., Dexter, M. and Allen, T. In Culture of Hematopoietic Cells. R. I. Freshney, et al. eds. Vol pp. 163-179, Wiley-Liss, Inc., New York, N.Y. 1994; Long term culture initiating cell assay, Sutherland, H. J. In . Culture of Hematopoietic Cells. R. I. Freshney, et al. eds. Vol pp. 139-162, Wiley-Liss, Inc., 15 New York, N.Y. 1994.
4.10.6 TJSSZTE ~1~~WTH ACTIVITY
A polypeptide of the present invention also may be involved in bone, cartilage, tendon, ligament and/or nerve tissue growth or regeneration, as well as in wound healing and 20 tissue repair and replacement, and in healing of burns, incisions and ulcers.
A polypeptide of the present invention which induces cartilage and/or bone growth in circumstances where bone is not normally formed, has application in the healing of bone fractures and cartilage damage or defects in humans and other animals.
Compositions of a polypeptide, antibody, binding partner, or other modulator of the invention may have 25 prophylactic use in closed as well as open fracture reduction and also in the improved fixation of artificial joints. De novo bone formation induced by an osteogenic agent contributes to the repair of congenital, trauma induced, or oncologic resection induced craniofacial defects, and also is useful in cosmetic plastic surgery.
A polypeptide of this invention may also be involved in attracting bone-forming 30 cells, stimulating growth of bone-forming cells, or inducing differentiation of progenitors of bone-forming cells. Treatment of osteoporosis, osteoarthritis, bone degenerative disorders, or periodontal disease, such as through stimulation of bone and/or cartilage repair or by blocking inflammation or processes of tissue destruction (collagenase activity, osteoclast activity, etc.) mediated by inflammatory processes may also be possible using the composition of the invention.
Another category of tissue regeneration activity that may involve the polypeptide of the present invention is tendon/ligament formation. Induction of tendon/ligament-like tissue or other tissue formation in circumstances where such tissue is not normally formed, has application in the healing of tendon or ligament tears, deformities and other tendon or ligament defects in humans and other animals. Such a preparation employing a tendon/ligament-like tissue inducing protein may have prophylactic use in preventing damage to tendon or ligament tissue, as well as use in the improved fixation of tendon or ligament to bone or other tissues, and in repairing defects to tendon or ligament tissue. De novo tendon/ligament-like tissue formation induced by a composition of the present invention contributes to the repair of congenital, trauma induced, or other tendon or ligament defects of other origin, and is also useful in cosmetic plastic surgery for attachment or repair of tendons or ligaments. The compositions of the present invention may provide environment to attract tendon- or ligament-fornling cells, stimulate growth of tendon- or ligament-forming cells, induce differentiati~n of progenitors of tendon- or ligament-forming cells, or induce growth of tendon/ligament cells ~r progenitors ~ vtv~ for return ih. vav~ t~
effect tissue repair. The compositions of the invention may also be useful in the treatment ~f tendinitis, carpal tunnel syndrome and other tendon or ligament defects. The compositions may also include an appropriate matrix and/or sequestering agent as a carrier as is well kn~wn in the art.
The compositions of the present invention may also be useful for proliferation ~f neural cells and for regeneration of nerve and brain tissue, i.e. for the treatment of central and peripheral nervous system diseases and neuropathies, as well as mechanical and traumatic disorders, which involve degeneration, death or trauma to neural cells or nerve tissue. More specifically, a composition may be used in the treatment of diseases of the peripheral nervous system, such as peripheral nerve injuries, peripheral neuropathy and localized neuropathies, and central nervous system diseases, such as Alzheimer's, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Shy-Drager syndrome. Further conditions which may be treated in accordance with the present invention include mechanical and traumatic disorders, such as spinal cord disorders, head trauma and cerebrovascular diseases such as stroke. Peripheral neuropathies resulting from chemotherapy or other medical therapies may also be treatable using a composition of the invention.
Compositions of the invention may also be useful to promote better or faster closure of non-healing wounds, including without limitation pressure ulcers, ulcers associated with vascular insufficiency, surgical and traumatic wounds, and the like.
Compositions of the present invention may also be involved in the generation or regeneration of other tissues, such as organs (including, for example, pancreas, liver, intestine, kidney, skin, endothelium), muscle (smooth, skeletal or cardiac) and vascular (including vascular endothelium) tissue, or for promoting the growth of cells comprising such tissues. Part of the desired effects may be by inhibition or modulation of fibrotic scarring may allow normal tissue to regenerate. A polypeptide of the present invention rnay also exhibit angiogenic activity.
A composition of the present invention may also be useful for gut protection or regeneration and treatment of lung or liver fibrosis, reperfusion injury in various tissues, and conditions resulting from systemic cytokine damage.
A composition of the present invention may also be useful for promoting or inhibiting differentiation of tissues described above from precursor tissues or cells; or for inhibiting the growth of tissues described above.
Therapeutic compositions of the invention can be used in the following:
Assays for tissue generation activity include, without limitation, those described in:
International Patent Publication I~To. W~95116035 (bone, cartilage, tendon)e International Patent Publication 1'To. W~95/05846 (nerve, neuronal)9 International Patent Publication IVo.
W~91/07491 (skin, endothelium).
Assays for wound healing activity include, without limitation, those described in:
Winter, Epidermal Wound Healing, pps. 71-112 (Maibach, H. I. and Rovee, D. T., eds.), Year Book Medical Publishers, Inc., Chicago, as modified by Eaglstein and Mertz, J. Invest.
Dermatol 71:382-84 (1978).
4.10.7 IMMUNE STIMULATING OR SUPPRESSING ACTIVITY
A polypeptide of the present invention may also exhibit immune stimulating or immune suppressing activity, including without limitation the activities for which assays are described herein. A polynucleotide of the invention can encode a polypeptide exhibiting such activities. A protein may be useful in the treatment of various immune deficiencies and disorders (including severe combined immunodeficiency (SCID)), e.g., in regulating (up or down) growth and proliferation of T and/or B lymphocytes, as well as effecting the cytolytic activity of NL cells and other cell populations. These immune deficiencies may be genetic or be caused by viral (e.g., HIV) as well as bacterial or fungal infections, or may result from autoimmune disorders. More specifically, infectious diseases causes by viral, bacterial, fungal or other infection may be treatable using a protein of the present invention, including infections by HIV, hepatitis viruses, herpes viruses, mycobacteria, Leishmania spp., malaria spp. and various fungal infections such as candidiasis. Of course, in this regard, proteins of the present invention may also be useful where a boost to the immune system generally may be desirable, i.e., in the treatment of cancer.
Autoimmune disorders which may be treated using a protein of the present invention include, for example, connective tissue disease, multiple sclerosis, systemic lupus eiythematosus, rheumatoid arthritis, autoimmune pulmonary inflammation, Guillain-Barre syndrome, autoimmune thyroiditis, insulin dependent diabetes mellitis, myasthenia gravis, graft-versus-host disease and autoimmune inflammatory eye disease. Such a protein (~r antagonists thereof, including antib~dies) of the present invention may also to be useful in the treatment of allergic reactions and conditions (e.~., anaphylaxis, serum sickness, drug reactions, food allergies, insect venom allergies, mastocytosis, allergic rhinitis, hypersensitivity pneumonitis, urticaria, angioedema, eczema, atopic dernlatitis, allergic contact dermatitis, erythema multiforme, Stevens-Johnson syndrome, allergic conjunctivitis, atopic keratoconjunctivitis, venereal keratoconjunctivitis, giant papillary conjunctivitis and contact allergies), such as asthma (particularly allergic asthma) or other respiratory problems. Other conditions, in which immune suppression is desired (including, f~r example, organ transplantation), may also be treatable using a protein (or antagonists thereof) of the present invention. The therapeutic effects of the polypeptides or antagonists thereof on allergic reactions can be evaluated by in vivo animals models such as the cumulative contact enhancement test (Lastbom et al., Toxicology 125: 59-66, 1998), skin prick test (Hoffmann et al., Allergy 54: 446-54, 1999), guinea pig skin sensitization test (Voter et al., Arch. Toxocol. 73: 501-9), and murine local lymph node assay (Limber et al., J. Toxicol. Environ. Health 53: 563-79).
Using the proteins of the invention it may also be possible to modulate immune responses, in a number of ways. Down regulation may be in the form of inhibiting or blocking an immune response already in progress or may involve preventing the induction of an immune response. The functions of activated T cells may be inhibited by suppressing T
cell responses or by inducing specific tolerance in T cells, or both.
Immunosuppression of T
cell responses is generally an active, non-antigen-specific, process which requires continuous exposure of the T cells to the suppressive agent. Tolerance, which involves inducing non-responsiveness or energy in T cells, is distinguishable from immunosuppression in that it is generally antigen-speciftc and persists after exposure to the tolerizing agent has ceased.
Operationally, tolerance can be demonstrated by the lack of a T cell response upon reexposure to specific antigen in the absence of the tolerizing agent.
Down regulating or preventing one or more antigen functions (including without limitation B lymphocyte antigen functions (such as, for example, B7)), e.g., preventing high level lymphokine synthesis by activated T cells, will be useful in situations of tissue, skin and organ transplantation and in graft-versus-host disease (GVHD). For example, blockage of T cell function should result in reduced tissue destruction in tissue transplantation.
Typically, in tissue transplants, rejection of the transplant is initiated through its recognition as foreign by T cells, followed by an immune reaction that destroys the transplant. The administration of a therapeutic composition of the invention may prevent cytokine synthesis by immune cells, such as T cells, and thus acts as an immunosuppressant.
I~Ioreover, a lack of costimulation may also be sufficient to energize the T cells, thereby inducing tolerance in a subject. Induction of long-term tolerance by B lymphocyte antigen-blocking reagents may avoid the necessity of repeated administration of these blocking reagents. To achieve sufficient immunosuppression or tolerance in a subject, it may also be necessary to block the function of a combination of B ly~nphocyte antigens.
The efficacy of particular therapeutic compositions in preventing organ transplant rejection or GVHD can be assessed using animal models that are predictive of efficacy in humans. Examples of appropriate systems which can be used include allogeneic cardiac grafts in rats and xenogeneic pancreatic islet cell grafts in mice, both of which have been used to examine the immunosuppressive effects of CTLA4Ig fusion proteins in vivo as described in Lenschow et al., Science 257:789-792 (1992) and Turka et al., Proc. Natl. Aced.
Sci LTSA, 89:11102-11105 (1992). In addition, murine models of GVHD (see Paul ed., Fundamental Immunology, Raven Press, New York, 1989, pp. 846-847) can be used to determine the effect of therapeutic compositions of the invention on the development of that disease.

Blocking antigen function may also be therapeutically useful for treating autoimmune diseases. Many autoimmune disorders are the result of inappropriate activation of T cells that are reactive against self tissue and which promote the production of cytokines and autoantibodies involved in the pathology of the diseases. Preventing the activation of 5 autoreactive T cells may reduce or eliminate disease symptoms.
Administration of reagents which block stimulation of T cells can be used to inhibit T cell activation and prevent production of autoantibodies or T cell-derived cytokines which may be involved in the disease process. Additionally, blocking reagents may induce antigen-specific tolerance of autoreactive T cells which could lead to long-term relief from the disease.
The efficacy of 10 blocking reagents in preventing or alleviating autoimmune disorders can be determined using a number of well-characterized animal models of human autoimmune diseases.
Examples include murine experimental autoimmune encephalitis, systemic lupus erythmatosis in MRL/lpr/lpr mice or NZB hybrid mice, murine autoimmune collagen arthritis, diabetes mellitus in NOD mice and BB rats, and murine experimental myasthenia 15 gravis (see Paul ed., Fundamental Immunology, Raven Press, New York, 199, pp.
X40-856).
LTpregulation of an antigen function (e.g., a B lymphocyte antigen function), as a means of up regulating immune responses, may also be useful in therapy.
Upregulation of immune responses may be in the form of enhancing an existing immune response or eliciting 20 an initial immune response. For example, enhancing an immune response may be useful in cases of viral infection, including systemic viral diseases such as influenza, the coanmon cold, and encephalitis.
Alternatively, anti-viral immune responses may be enhanced in an infected patient by removing T cells from the patient, costimulating the T cells in vitro with viral antigen-pulsed 25 APCs either expressing a peptide of the present invention or together with a stimulatory form of a soluble peptide of the present invention and reintroducing the in vitro activated T
cells into the patient. Another method of enhancing anti-viral immune responses would be to isolate infected cells from a patient, transfect them with a nucleic acid encoding a protein of the present invention as described herein such that the cells express all or a portion of the 30 protein on their surface, and reintroduce the transfected cells into the patient. The infected cells would now be capable of delivering a costimulatory signal to, and thereby activate, T
cells in vivo.

A polypeptide of the present invention may provide the necessary stimulation signal to T cells to induce a T cell mediated immune response against the transfected tumor cells.
In addition, tumor cells which lack MHC class I or MHC class II molecules, or which fail to reexpress sufficient mounts of MHC class I or MHC class II molecules, can be transfected with nucleic acid encoding all or a portion of (e.g., a cytoplasmic-domain truncated portion) of an MHC class I alpha chain protein and (32 microglobulin protein or an MHC
class II
alpha chain protein and an MHC class II beta chain protein to thereby express MHC class I
or MHC class II proteins on the cell surface. Expression of the appropriate class I or class II
MHC in conjunction with a peptide having the activity of a B lymphocyte antigen (e.g., B7-1, B7-2, B7-3) induces a T cell mediated immune response against the transfected tumor cell. Optionally, a gene encoding an antisense construct which blocks expression of an MHC
class II associated protein, such as the invariant chain, can also be cotransfected with a I~NA
encoding a peptide having the activity of a B lymphocyte antigen to promote presentation of tumor associated antigens and induce tumor specific immunity. Thus, the induction of a T
cell mediated immune response in a human subject may be sufficient to overcome tumor-specific tolerance in the subject.
The activity of a protein of the invention may, among other means, be measured by the following methods:
Suitable assays for thymocyte or splenocyte cytotoxicity include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A.
M. I~ruisbeek, I~. H. Margulies, E. M. Shevach, ~. Strober, Pub. C'areene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19;
Chapter 7, Immunologic studies in Humans); Herrmann et al., Proc. Natl. Acad.
Sci. USA
78:2488-2492, 1981; Herrmann et al., J. Immunol. 128:1968-1974, 1982; Handa et al., J.
Immunol. 135:1564-1572, 1985; Takai et al., I. Immunol. 137:3494-3500, 1986;
Takai et al., J. Immunol. 140:508-512, 1988; Bowman et al., J. Virology 61:1992-1998;
Bertagnolli et al., Cellular Immunology 133:327-341, 1991; Brown et al., J. Immunol. 153:3079-3092, 1994.
Assays for T-cell-dependent immunoglobulin responses and isotype switching (which will identify, among others, proteins that modulate T-cell dependent antibody responses and that affect Thl/Th2 profiles) include, without limitation, those described in:
Maliszewski, J. Immunol. 144:3028-3033, 1990; and Assays for B cell function:
In vitro antibody production, Mond, J. J. and Brunswick, M. In Current Protocols in Immunology. J.
E. e.a. Coligan eds. Vol 1 pp. 3.8.1-3.8.16, John Wiley and Sons, Toronto.
1994.
Mixed lymphocyte reaction (MLR) assays (which will identify, among others, proteins that generate predominantly Thl and CTL responses) include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A.
M. Kruisbeek, D. H. Margulies, E. M. Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19;
Chapter 7, Immunologic studies in Humans); Takai et al., J. Immunol. 137:3494-3500, 1986;
Takai et al., J. Immunol. 140:508-512, 1988; Bertagnolli et al., J. Immunol.
149:3778-3783, 1992.
Dendritic cell-dependent assays (which will identify, among others, proteins expressed by dendritic cells that activate naive T-cells) include, without limitation, those described in: Guery et al., J. Immunol. 134:536-544, 1995; Inaba et al., Journal of Experimental Medicine 173:549-559, 1991; Macatonia et al., Journal of Immunology 154:5071-5079, 1995; Porgador et al., Journal of Experimental Medicine 182:255-260, 1995; Nair et al., Journal of Virology 67:4062-4069, 1993; Huang et al., Science 264:961-965, 1994; Macatonia et al., Journal of Experimental Medicine 169:1255-1264, 1989; Bhardwaj et al., Journal of Clinical Investigation 94:797-807, 1994; and Inaba et al., Journal of Experimental Medicine 172:631-640, 1990.
Assays for lymphocyte survival/apoptosis (which will identify, among others, proteins that prevent apoptosis after superantigen induction and proteins that regulate lymphocyte homeostasis) include, without limitation, those described in: Dart' lciewic~ et al., Cytometry 13:795-808, 1992; Gorczyca et al., Leukemia 7:659-670, 1993;
Gorczyca et al., Cancer Research 53:1945-1951, 1993; Itoh et al., Cell 66:233-243, 1991;
Zacharchuk, Journal of Immunology 145:4037-4045, 1990; Zamai et al., Cytometry 14:891-897, 1993;
Gorczyca et al., International Journal of ~ncology 1:639-648, 1992.
Assays for proteins that influence early steps of T-cell commitment and development include, without limitation, those described in: Antica et al., Blood 84:111-117, 1994; Fine et al., Cellular Immunology 155:111-122, 1994; Galy et al., Blood 85:2770-2778, 1995;
Toki et al., Proc. Nat. Acad Sci. USA 88:7548-7551, 1991.
4.10.8 ACTIVIN/INHIBIN ACTIVITY

A polypeptide of the present invention may also exhibit activin- or inhibin-related activities. A polynucleotide of the invention may encode a polypeptide exhibiting such characteristics. Inhibins are characterized by their ability to inhibit the release of follicle stimulating hormone (FSH), while activins and are characterized by their ability to stimulate the release of follicle stimulating hormone (FSH). Thus, a polypeptide of the present invention, alone or in heterodimers with a member of the inhibin family, may be useful as a contraceptive based on the ability of inhibins to decrease fertility in female mammals and decrease spermatogenesis in male mammals. Administration of sufficient amounts of other inhibins can induce infertility in these mammals. Alternatively, the polypeptide of the invention, as a homodimer or as a heterodimer with other protein subunits of the inhibin group, may be useful as a fertility inducing therapeutic, based upon the ability of activin molecules in stimulating FSH release from cells of the anterior pituitary.
See, for example, U.S. Pat. No. 4,798,885. A polypeptide of the invention may also be useful for advancement of the onset of fertility in sexually immature mammals, so as to increase the lifetime reproductive performance of domestic animals such as, but not limited to, cows, sheep and pigs.
The activity of a polypeptide of the invention may, among other means, be measured by the following methods.
Assays for activin/inhibin activity include, without limitation, those described in:
Vale et al., Endocrinology 91:562-572, 1972; Ling et al., Nature 321:779-782, 1986; Vale et al., Nature 321:776-779, 1986; I~JLason et al., Nature 318:659-663, 1955;
Forage et al., Pros.
Natl. Acad. Sci. USA 83:3091-3095, 1986.
4.10.9 CHEMOTACTIC/CHEM~KINETIC ACTIVITY
A polypeptide of the present invention may be involved in chemotactic or chemokinetic activity for mammalian cells, including, for example, monocytes, fibroblasts, neutrophils, T-cells, mast cells, eosinophils, epithelial and/or endothelial cells. A
polynucleotide of the invention can encode a polypeptide exhibiting such attributes.
Chemotactic and chemokinetic receptor activation can be used to mobilize or attract a desired cell population to a desired site of action. Chemotactic or chemokinetic compositions (e.g. proteins, antibodies, binding partners, or modulators of the invention) provide particular advantages in treatment of wounds and other trauma to tissues, as well as in treatment of localized infections. For example, attraction of lymphocytes, monocytes or neutrophils to tumors or sites of infection may result in improved immune responses against the tumor or infecting agent.
A protein or peptide has chemotactic activity for a particular cell population if it can stimulate, directly or indirectly, the directed orientation or movement of such cell population. Preferably, the protein or peptide has the ability to directly stimulate directed movement of cells. Whether a particular protein has chemotactic activity for a population of cells can be readily determined by employing such protein or peptide in any known assay for cell chemotaxis.
Therapeutic compositions of the invention can be used in the following:
Assays for chemotactic activity (which will identify proteins that induce or prevent chemotaxis) consist of assays that measure the ability of a protein to induce the migration of cells across a membrane as well as the ability of a protein to induce the adhesion of one cell population to another cell population. Suitable assays for movement and adhesion include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E.
Coligan, A. M. I~ruisbeek, D. H. Marguiles, E. M. Shevach, W. Strober, Pub.
Greene Publishing Associates and Wiley-Interscience (Chapter 6.12, Measurement of alpha and beta Chemokines 6.12.1-6.12.28; Taub et al. J. Clin. Invest. 95:1370-1376, 1995;
Lind et al.
APMIS 103:140-146, 1995; Muller et al Eur. J. Immunol. 25:1744-1748; Gruber et al. J. of Immunol. 152:5860-5867, 1994; Johnston et al. J. of Immunol. 153:1762-1768, 1994.
4.10.10 ~TlEl~I~~~I°AT1~C AI's ~CH~~i~L~~"1~ AC'Tl~flT~
A polypeptide of the invention may also be involved in hemostatis or thrombolysis or thrombosis. A polynucleotide of the invention can encode a polypeptide exhibiting such attributes. Compositions may be useful in treatment of various coagulation disorders (including hereditary disorders, such as hemophiliac) or to enhance coagulation and other hemostatic events in treating wounds resulting from trauma, surgery or other causes. A
composition of the invention may also be useful for dissolving or inhibiting formation of thromboses and for treatment and prevention of conditions resulting therefrom (such as, for example, infarction of cardiac and central nervous system vessels (e.g., stroke).
Therapeutic compositions of the invention can be used in the following:
Assay for hemostatic and thrombolytic activity include, without limitation, those described in: Linet et al., J. Clin. Pharmacol. 26:131-140, 1986; Burdick et al., Thrombosis Res. 45:413-419, 1987; Humphrey et al., Fibrinolysis 5:71-79 (1991); Schaub, Prostaglandins 35:467-474, 1988.
4.10.11 CANCER DIAGNOSIS AND THERAPY
5 Polypeptides of the invention may be involved in cancer cell generation, proliferation or metastasis. Detection of the presence or amount of polynucleotides or polypeptides of the invention may be useful for the diagnosis and/or prognosis of one or more types of cancer.
For example, the presence or increased expression of a polynucleotide/polypeptide of the invention may indicate a hereditary risk of cancer, a precancerous condition, or an ongoing 10 malignancy. Conversely, a defect in the gene or absence of the polypeptide may be associated with a cancer condition. Identification of single nucleotide polymorphisms associated with cancer or a predisposition to cancer may also be useful for diagnosis or prognosis.
Cancer treatments promote tumor regression by inhibiting tumor cell proliferation, 15 inhibiting angiogenesis (growth of new blood vessels that is necessary to support tumor growth) and/or prohibiting metastasis by reducing tumor cell motility or invasiveness.
Therapeutic compositions of the inveaxtion may be effective in adult and pediatric oncology including in solid phase tumors/malignancies, locally advanced tumors, human soft tissue sarcomas, metastatic cancer, including lymphatic metastases, blood cell malignancies 20 including multiple myeloma, acute and chronic leukemias, and lymphomas, head and neck cancers including mouth cancer, larynx can cer and thyroid cancer, lung cancers including small cell carcinoma and non-Snlall cell cancers, breast cancers including small cell carcinoma and ductal carcinoma, gastrointestinal cancers including esophageal cancer, stomach cancer, colon cancer, colorectal cancer and polyps associated with colorectal 25 neoplasia, pancreatic cancers, liver cancer, urologic cancers including bladder cancer and prostate cancer, malignancies of the female genital tract including ovarian carcinoma, uterine (including endometrial) cancers, and solid tumor in the ovarian follicle, kidney cancers including renal cell carcinoma, brain cancers including intrinsic brain tumors, neuroblastoma, astrocytic brain tumors, gliomas, metastatic tumor cell invasion in the central 30 nervous system, bone cancers including osteomas, skin cancers including malignant melanoma, tumor progression of human skin keratinocytes, squamous cell carcinoma, basal cell carcinoma, hemangiopericytoma and I~arposi's sarcoma.
Polypeptides, polynucleotides, or modulators of polypeptides of the invention (including inhibitors and stimulators of the biological activity of the polypeptide of the invention) may be administered to treat cancer. Therapeutic compositions can be administered in therapeutically effective dosages alone or in combination with adjuvant cancer therapy such as surgery, chemotherapy, radiotherapy, thermotherapy, and laser therapy, and may provide a beneficial effect, e.g. reducing tumor size, slowing rate of tumor growth, inhibiting metastasis, or otherwise improving overall clinical condition, without necessarily eradicating the cancer.
The composition can also be administered in therapeutically effective amounts as a portion of an anti-cancer cocktail. An anti-cancer cocktail is a mixture of the polypeptide or modulator of the invention with one or more anti-cancer drugs in addition to a pharnlaceutically acceptable carrier for delivery. The use of anti-cancer cocktails as a cancer treatment is routine. Anti-cancer drugs that are well known in the art and can be used as a treatment in combination with the polypeptide or modulator of the invention include:
Actinomycin D, Aminoglutethimide, Asparaginase, Bleomycin, Busulfan, Carboplatin, Carmustine, Chlorambucil, Cisplatin (cis-DDP), Cyclophosphamide, Cytarabine HCl (Cytosine arabinoside), Dacarbazine, Dactinomycin, Daun~rubicin HCI, Doxorubicin HCI, Estramustine phosphate sodium, Etoposide (V16-213), Floxuridine, 5-Fluorouracil (5-Fu), Flutamide, Hydroxyurea (hydroxycarbamide), Ifosfamide, Interferon Alpha-2a, Interferon Alpha-2,b, Leuprolide acetate (LHRH-releasing factor analog), Lomustine, Mechlorethamine HCl (nitrogen mustard), Melphalan, Mercaptopurine, Mesna, Methotrexate (MTX), Mitomycin, Mitoxantrone HCI, ~ctreotide, Plicamycin, Procarbazine HCI, Streptozocin, Tamoxifen citrate, Thioguanine, Thi~tepa, Vinblastine sulfate, Vincristine sulfate, Amsacrine, Azacitidine, Hexamethylmelamine, Interleukin-2, Mitoguazone, Pentostatin, Semustine, Teniposide, and Vindesine sulfate.
In addition, therapeutic compositions of the invention may be used for prophylactic treatment of cancer. There are hereditary conditions and/or environmental situations (e.g.
exposure to carcinogens) known in the art that predispose an individual to developing cancers. Under these circumstances, it may be beneficial to treat these individuals with therapeutically effective doses of the polypeptide of the invention to reduce the risk of developing cancers.
In vitro models can be used to determine the effective doses of the polypeptide of the invention as a potential cancer treatment. These ira vitro models include proliferation assays of cultured tumor cells, growth of cultured tumor cells in soft agar (see Freshney, (1987) Culture of Animal Cells: A Manual of Basic Technique, Wily-Liss, New York, NY
Ch 18 and Ch 21), tumor systems in nude mice as described in Giovanella et al., J.
Natl. Can. Inst., 52: 921-30 (1974), mobility and invasive potential of tumor cells in Boyden Chamber assays as described in Pilkington et al., Anticancer Res., 17: 4107-9 (1997), and angiogenesis assays such as induction of vascularization of the chick chorioallantoic membrane or induction of vascular endothelial cell migration as described in Ribatta et al., Intl. J. Dev.
Biol., 40: 1189-97 (1999) and Li et al., Clin. Exp. Metastasis, 17:423-9 (1999), respectively.
Suitable tumor cells lines are available, e.g. from American Type Tissue Culture Collection catalogs.
4.10.12 RECEPTOR/LIGAND ACTIVITY
A polypeptide of the present invention may also demonstrate activity as receptor, receptor ligand or inhibitor or agonist of receptor/ligand interactions. A
polynucleotide of the invention can encode a polypeptide exhibiting such characteristics.
Examples of such receptors and ligands include, without limitation, cytokine receptors and their ligands, receptor kinases and their ligands, receptor phosphatases and their ligands, receptors involved in cell-cell interactions and their ligands (including without limitation, cellular adhesion molecules (such as selectins, integrins and their ligands) and recept~r/ligand pairs involved in antigen presentation, antigen recognition and development of cellular and humoral immune responses. Receptors and ligands are also useful for screening of potential peptide ~r small molecule inhibitors of the relevant receptor/ligand interaction. A protein of the present invention (including, without limitation, fragments of receptors and ligands) may themselves be useful as inhibitors of receptor/ligand interactions.
'The activity of a polypeptide of the invention may, among other means, be measured by the following methods:
Suitable assays for receptor-ligand activity include without limitation those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A. M. I~ruisbeek, D.
H.
Margulies, E. M. Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 7.28, Measurement of Cellular Adhesion under static conditions 7.28.1- 7.28.22), Takai et al., Proc. Natl. Acad. Sci. LTSA 84:6864-6868, 1987; Bierer et al., J. Exp. Med. 168:1145-1156, 1988; Rosenstein et al., J. Exp. Med. 169:149-160 1989;
Stoltenborg et al., J. Immunol. Methods 175:59-68, 1994; Stitt et al., Cell 80:661-670, 1995.

By way of example, the polypeptides of the invention may be used as a receptor for a ligand(s) thereby transmitting the biological activity of that ligand(s).
Ligands may be identified through binding assays, affinity chromatography, dihybrid screening assays, BIAcore assays, gel overlay assays, or other methods known in the art.
Studies characterizing drugs or proteins as agonist or antagonist or partial agonists or a partial antagonist require the use of other proteins as competing ligands.
The polypeptides of the present invention or ligand(s) thereof may be labeled by being coupled to radioisotopes, colorimetric molecules or a toxin molecules by conventional methods.
("Guide to Protein Purification" Murray P. Deutscher (ed) Methods in Enzymology Vol. 182 (1990) Academic Press, Inc. San Diego). Examples of radioisotopes include, but are not limited to, tritium and carbon-14 . Examples of colorimetric molecules include, but are not limited to, fluorescent molecules such as fluorescamine, or rhodamine or other colorimetric molecules. Examples of toxins include, but are not limited, to ricin.
4.10.13 DRUG SCREENING
This invention is particularly useful for screening chemical compounds by using the novel polypeptides ~r binding fragments thereof in any of a variety of drug screening techniques. The polypeptides or fragments employed in such a test may either be flee in solution, affixed to a solid support, borne on a cell surface or located intracellularly. One method of drug screening utilizes eukaryotic or prokaryotic host cells which are stably transformed v~ith recombinant amcleic acids e~epressing the polypeptidc or a fragment thereof. Drugs are screened against such transformed cells in competitive binding assays.
Such cells, either in viable or fixed form, can be used for standard binding assays. ~ne may measure, for example, the formation of complexes between polypeptides of the invention or fiagments and the agent being tested or examine the diminution in complex forniation between the novel polypeptides and an appropriate cell line, which are well known in the art.
Sources for test compounds that may be screened for ability to bind to or modulate (i.e., increase or decrease) the activity of polypeptides of the invention include (1) inorganic and organic chemical libraries, (2) natural product libraries, and (3) combinatorial libraries comprised of either random or mimetic peptides, oligonucleotides or organic molecules.
Chemical libraries may be readily synthesized or purchased from a number of commercial sources, and may include structural analogs of known compounds or compounds that are identified as "hits" or "leads" via natural product screening.

The sources of natural product libraries are microorganisms (including bacteria and fungi), animals, plants or other vegetation, or marine organisms, and libraries of mixtures for screening may be created by: (1) fermentation and extraction of broths from soil, plant or marine microorganisms or (2) extraction of the organisms themselves. Natural product libraries include polyketides, non-ribosomal peptides, and (non-naturally occurring) variants thereof. For a review, see Sciezzce 282:63-68 (1998).
Combinatorial libraries are composed of large numbers of peptides, oligonucleotides or organic compounds and can be readily prepared by traditional automated synthesis methods, PCR, cloning or proprietary synthetic methods. Of particular interest are peptide and oligonucleotide combinatorial libraries. Still other libraries of interest include peptide, protein, peptidomimetic, multiparallel synthetic collection, recombinatorial, and polypeptide libraries. For a review of combinatorial chemistry and libraries created therefrom, see Myers, Gui~>~. Opirz. Biotechnol. 8:701-707 (1997). For reviews and examples of peptidomirnetic libraries, see Al-Obeidi et al., Mol. Biateclzzzol, 9(3):205-23 (1998); Hruby et al., C'uz~r O,nizz Cherrz Biol, 1(1):114-19 (1997); Dorner et al., Bio~Yg Med Claezra, 4(5):709-15 (1996) (alkylated dipeptides).
Identification of modulators through use of the various libraries described herein permits modification of the candidate "hit" (or "lead") to optimize the capacity of the "hit"
to bind a polypeptide of the invention. The molecules identified in the binding assay are then tested for antagonist or agonist activity in irz viv~ tissue culture or animal models that are well known in the art. In brief, the molecules are titrated into a plurality of cell cultures or animals and then tested for either cell/animal death or prolonged survival of the animal/cells.
The binding molecules thus identified may be complexed with toxins, e.g., ricin or cholera, or with other compounds that are toxic to cells such as radioisotopes. 'The toxin-binding molecule complex is then targeted to a tumor or other cell by the specificity of the binding molecule for a polypeptide of the invention. Alternatively, the binding molecules may be complexed with imaging agents for targeting and imaging purposes.
4.10.14 ASSAY FOR RECEPTOR ACTIVITY
The invention also provides methods to detect specific binding of a polypeptide e.g. a ligand or a receptor. The art provides numerous assays particularly useful for identifying previously unknown binding partners for receptor polypeptides of the invention. For example, expression cloning using mammalian or bacterial cells, or dihybrid screening assays can be used to identify polynucleotides encoding binding partners. As another example, affinity chromatography with the appropriate immobilized polypeptide of the invention can be used to isolate polypeptides that recognize and bind polypeptides of the invention. There are a number of different libraries used for the identification of 5 compounds, and in particular small molecules, that modulate (i. e., increase or decrease) biological activity of a polypeptide of the invention. Ligands for receptor polypeptides of the invention can also be identified by adding exogenous ligands, or cocktails of ligands to two cells populations that are genetically identical except for the expression of the receptor of the invention: one cell population expresses the receptor of the invention whereas the other does 10 not. The responses of the two cell populations to the addition of ligands(s) are then compared. Alternatively, an expression library can be co-expressed with the polypeptide of the invention in cells and assayed for an autocrine response to identify potential ligand(s). As still another example, BIAcore assays, gel overlay assays, or other methods known in the art can be used to identify binding partner polypeptides, including, (1) organic and inorganic 15 chemical libraries, (2) natural product libraries, and (3) combinatorial libraries comprised of random peptides, oligonucleotides or organic molecules.
The role of downstream intracellular signaling molecules in the signaling cascade of the polypeptide of the invention can be deternzined. For example, a chimeric protein in which the cytoplasmic domain of the polypeptide of the invention is fused to the 20 extracellular portion of a protein, whose ligand has been identified, is produced in a host cell. 'The cell is then incubated with the ligand specific for the extracellular portion of the chimeric protein, thereby activating the chimeric receptor. Known downstream proteins involved in intracellular signaling can then be assayed for expected modifications i.e.
phosphorylation. ~ther methods known to those in the art can also be used to identify 25 signaling molecules involved in receptor activity.
4.10.15 ANTI-INFLAMMATOlIY ACTIVITY
Compositions of the present invention may also exhibit anti-inflammatory activity.
The anti-inflammatory activity may be achieved by providing a stimulus to cells involved in 30 the inflammatory response, by inhibiting or promoting cell-cell interactions (such as, for example, cell adhesion), by inhibiting or promoting chemotaxis of cells involved in the inflammatory process, inhibiting or promoting cell extravasation, or by stimulating or suppressing production of other factors which more directly inhibit or promote an inflammatory response. Compositions with such activities can be used to treat inflammatory conditions including chronic or acute conditions), including without limitation intimation associated with infection (such as septic shock, sepsis or systemic inflammatory response syndrome (SIRS)), ischemia-reperfusion injury, endotoxin lethality, arthritis, complement-mediated hyperacute rejection, nephritis, cytokine or chemokine-induced lung injury, inflammatory bowel disease, Crohn's disease or resulting from over production of cytokines such as TNF or IL-1. Compositions of the invention may also be useful to treat anaphylaxis and hypersensitivity to an antigenic substance or material.
Compositions of this invention may be utilized to prevent or treat conditions such as, but not limited to, sepsis, acute pancreatitis, endotoxin shock, cytokine induced shock, rheumatoid arthritis, chronic inflammatory arthritis, pancreatic cell damage from diabetes mellitus type 1, graft versus host disease, inflanunatory bowel disease, inflamation associated with pulmonary disease, other autoimmune disease or inflammatory disease, an antiproliferative agent such as for acute or chronic mylegenous leukemia or in the prevention of premature labor secondary to intrauterine infections.
4.10.16 LEUI~MI~S
Leukemias and related disorders may be treated or prevented by administration of a therapeutic that promotes or inhibits function of the polynucleotides and/or polypeptides of the invention. Such leukemias and related disorders include but are not limited to acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia, chronic leukemia, chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia (for a review of such disorders, see Fishman et al., 195, Medicine, 2,d Ed., J.B. Lippincott Co., Philadelphia).
4.10.17 NERVOUS SYSTEM DISORDERS
Nervous system disorders, involving cell types which can be tested for efficacy of intervention with compounds that modulate the activity of the polynucleotides and/or polypeptides of the invention, and which can be treated upon thus observing an indication of therapeutic utility, include but are not limited to nervous system injuries, and diseases or disorders which result in either a disconnection of axons, a diminution or degeneration of neurons, or demyelination. Nervous system lesions which may be treated in a patient (including human and non-human mammalian patients) according to the invention include but are not limited to the following lesions of either the central (including spinal cord, brain) or peripheral nervous systems:
(i) traumatic lesions, including lesions caused by physical injury or associated with surgery, for example, lesions which sever a portion of the nervous system, or compression injuries;
(ii) ischemic lesions, in which a lack of oxygen in a portion of the nervous system results in neuronal injury or death, including cerebral infarction or ischemia, or spinal cord infarction or ischemia;
(iii) infectious lesions, in which a portion of the nervous system is destroyed or injured as a result of infection, for example, by an abscess or associated with infection by human immunodericiency virus, herpes zoster, or herpes simplex virus or with Lyme disease, tuberculosis, syphilis;
(iv) degenerative lesions, in which a portion of the nervous system is destroyed or injured as a result of a degenerative process including but not limited to degeneration associated with Parkins~n's disease, Alzheimer's disease, Huntington's chorea, or amyotrophic lateral sclerosis;
(v) lesions associated with nutritional diseases or disorders, in which a portion ~f the nervous system is destroyed or injured by a nutritional disorder or dis~rder ~f metabolism including but not limited to, vitamin B 12 deficiency, folic acid deficiency, Wernicke disease, tobacco-alcohol amblyopia, Marchiafava-Bignami disease (primary degeneration of the c~rpus callesum), and alcoholic cerebellar degeneration;
(vi) neurological lesions associated with systemic diseases including but not limited to diabetes (diabetic neur~pathy, Bell's palsy), systemic lupus erythematosus, carcinoma, or sarcoidosis;
(vii) lesions caused by toxic substances including alcohol, lead, or particular neurotoxins; and (viii) demyelinated lesions in which a portion of the nervous system is destroyed or injured by a demyelinating disease including but not limited to multiple sclerosis, human immunodeficiency virus-associated myelopathy, transverse myelopathy or various etiologies, progressive multifocal leukoencephalopathy, and central pontine myelinolysis.
Therapeutics which are useful according to the invention for treatment of a nervous system disorder may be selected by testing for biological activity in promoting the survival or differentiation of neurons. For example, and not by way of limitation, therapeutics which elicit any of the following effects may be useful according to the invention:
(i) increased survival time of neurons in culture;
(ii) increased sprouting of neurons in culture or in vivo;
(iii) increased production of a neuron-associated molecule in culture or in vivo, e.g., choline acetyltransferase or acetylcholinesterase with respect to motor neurons; or (iv) decreased symptoms of neuron dysfunction in vivo.
Such effects may be measured by any method known in the art. In preferred, non-limiting embodiments, increased survival of neurons may be measured by the method set forth in Arakawa et al. (1990, J. Neurosci. 10:3507-3515); increased sprouting of neurons may be detected by methods set forth in Pestronk et al. (1980, Exp. Neurol.
70:65-82) or Brown et al. (1981, Ann. Rev. Neurosci. 4:17-42); increased production of neuron-associated molecules may be measured by bioassay, enzymatic assay, antibody binding, Northern blot assay, etc., depending on the molecule to be measured;
and motor neuron dysfunction may be measured by assessing the physical manifestation of motor neuron disorder, e.g., weakness, motor neuron conduction velocity, or functional disability.
In speciEc embodiments, motor neuron disorders that may be treated according to the invention include but are not limited to disorders such as infarction, infection, exp~sure to toxin, trauma, surgical damage, degenerative disease or malignancy that may affect motor neurons as well as other components of the nervous system, as well as disorders that selectively affect neurons such as amyotrophic lateral sclerosis, and including but not limited to progressive spinal muscular atrophy, progressive bulbar palsy, primary lateral sclerosis, infantile and juvenile muscular atrophy, progressive bulbar paralysis of childhood (Fazio-Londe syndrome), poliomyelitis and the post polio syndrome, and Hereditary Motorsensory Neuropathy (Charcot-Marie-Tooth Disease).
4.10.18 OTHER ACTIVITIES
A polypeptide of the invention may also exhibit one or more of the following additional activities or effects: inhibiting the growth, infection or function of, or killing, infectious agents, including, without limitation, bacteria, viruses, fungi and other parasites;
effecting (suppressing or eiW ancing) bodily characteristics, including, without limitation, height, weight, hair color, eye color, skin, fat to lean ratio or other tissue pigmentation, or organ or body part size or shape (such as, for example, breast augmentation or diminution, change in bone form or shape); effecting biorhythms or circadian cycles or rhythms;
effecting the fertility of male or female subjects; effecting the metabolism, catabolism, anabolism, processing, utilization, storage or elimination of dietary fat, lipid, protein, carbohydrate, vitamins, minerals, co-factors or other nutritional factors or component(s);
effecting behavioral characteristics, including, without limitation, appetite, libido, stress, cognition (including cognitive disorders), depression (including depressive disorders) and violent behaviors; providing analgesic effects or other pain reducing effects;
promoting differentiation and growth of embryonic stem cells in lineages other than hematopoietic lineages; hormonal or endocrine activity; in the case of enzymes, correcting deficiencies of the enzyme and treating deficiency-related diseases; treatment of hyperproliferative disorders (such as, for example, psoriasis); immunoglobulin-like activity (such as, for example, the ability to bind antigens or complement); and the ability to act as an antigen in a vaccine composition to raise an immune response against such protein or another material or entity which is cross-reactive with such protein.
4.10.19 I7IZi;T~TTIFICA'I°I~T'~ ~F P~LI~RPI~IST~I~
T'he demonstration of polymorphisms makes possible the identification of such polymorphisms in human subjects and the pharmacogenetic use of this information for diagnosis and treatment. Such polymorphisms may be associated with, e.g., differential predisposition or susceptibility to various disease states (such as disorders involving inflammation or nnmune response) or a differential response to drdbg administration, and this genetic information can be used to tailor preventive or therapeutic treatment appropriately.
For example, the existence of a polymorphism associated with a predisposition to inflammation or autoimmune disease makes possible the diagnosis of this condition in humans by identifying the presence of the polymorphism.
Polymorphisms can be identified in a variety of ways known in the art which all generally involve obtaining a sample from a patient, analyzing DNA from the sample, optionally involving isolation or amplification of the DNA, and identifying the presence of the polymorphism in the DNA. For example, PCR may be used to amplify an appropriate fragment of genomic DNA which may then be sequenced. Alternatively, the DNA
may be subjected to allele-specific oligonucleotide hybridization (in which appropriate oligonucleotides are hybridized to the DNA under conditions permitting detection of a single base mismatch) or to a single nucleotide extension assay (in which an oligonucleotide that hybridizes immediately adjacent to the position of the polymorphism is extended with one or more labeled nucleotides). In addition, traditional restriction fragment length polymorphism analysis (using restriction enzymes that provide differential digestion of the genomic DNA
depending on the presence or absence of the polymorphism) may be performed.
Arrays with nucleotide sequences of the present invention can be used to detect polymorphisms. The array can comprise modified nucleotide sequences of the present invention in order to detect the nucleotide sequences of the present invention. In the alternative, any one of the nucleotide sequences of the present invention can be placed on the array to detect changes from those sequences.
10 Alternatively a polymorphism resulting in a change in the amino acid sequence could also be detected by detecting a corresponding change in amino acid sequence of the protein, e.g., by an antibody specific to the variant sequence.
4.10.20 ARTHRITIS AND INFLAMMATION
15 The immunosuppressive effects of the compositions of the invention against rheumatoid arthritis is determined in an experimental animal model system. The experimental model system is adjuvant induced arthritis in rats, and the protocol is described by J. Holoshitz, et at., 1983, Science, 219:56, or by 13. V6~aksman et al., 1963, Int. Arch.
Allergy Appl. Immunol., 23:129. Induction of the disease can be caused by a single 20 injection, generally intradermally, of a suspension of killed Mycobacterium tuberculosis in complete Freund's adjuvant (CFA). T'he route of injection can vary, but rats may be injected at the base of the tail with an adjuvant mixture. T'he polypeptide is administered in phosphate buffered solution (PBS) at a dose of about 1-5 mg/kg. The control consists of administering PBS only.
25 The procedure for testing the effects of the test compound would consist of intradermally injecting killed Mycobacterium tuberculosis in CFA followed by immediately administering the test compound and subsequent treatment every other day until day 24. At 14, 15, 18, 20, 22, and 24 days after injection of Mycobacterium CFA, an overall arthritis score may be obtained as described by J. Holoskitz above. An analysis of the data would 30 reveal that the test compound would have a dramatic affect on the swelling of the joints as measured by a decrease of the arthritis score.
4.11 THERAPEUTIC METHODS

The compositions (including polypeptide fragments, analogs, variants and antibodies or other binding partners or modulators including antisense polynucleotides) of the invention have numerous applications in a variety of therapeutic methods. Examples of therapeutic applications include, but are not limited to, those exemplified herein.
4.11.1 EXAMPLE
One embodiment of the invention is the administration of an effective amount of the polypeptides or other composition of the invention to individuals affected by a disease or disorder that can be modulated by regulating the peptides of the invention.
While the mode of administration is not particularly important, parenteral administration is preferred. An exemplary mode of administration is to deliver an intravenous bolus. The dosage of the polypeptides or other composition of the invention will normally be determined by the prescribing physician. It is to be expected that the dosage will vary according to the age, weight, condition and response of the individual patient. Typically, the amount of polypeptide administered per dose will be in the range of about 0.01 pg/kg to 100 mg/kg of body weight, with the preferred dose being about 0.1 ~glkg to 10 mg/kg of patient body weight. For parenteral administration, polypeptides of the invention will be formulated in an injectable fornz combined with a pharmaceutically acceptable parenteral vehicle. Such vehicles are well known in the art and examples include water, saline, Ringer's solution, dextrose solution, and solutions consisting of small amounts of the human serum albumin.
The vehicle may contain minor amounts of additives that maintain the isotonicity and stability of the polypeptide or other active ingredient. The preparation of such solutions is within the skill of the art.
4.12 PHA CEUTICAL FORMULATIONS AND ROUTES OF
ADMINISTRATION
A protein or other composition of the present invention (from whatever source derived, including without limitation from recombinant and non-recombinant sources and including antibodies and other binding partners of the polypeptides of the invention) may be administered to a patient in need, by itself, or in pharmaceutical compositions where it is mixed with suitable Garners or excipient(s) at doses to treat or ameliorate a variety of disorders. Such a composition may optionally contain (in addition to protein or other active ingredient and a carrier) diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s). The characteristics of the carrier will depend on the route of administration.
The pharmaceutical composition of the invention may also contain cytokines, lymphokines, or other hematopoietic factors such as M-CSF, GM-CSF, TNF, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IFN, TNFO, TNF1, TNF2, G-CSF, Meg-CSF, thrombopoietin, stem cell factor, and erythropoietin. In further compositions, proteins of the invention may be combined with other agents beneficial to the treatment of the disease or disorder in question. These agents include various growth factors such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factors (TGF-a and TGF-(3), insulin-like growth factor (IGF)~ as well as cytokines described herein.
The pharmaceutical composition may further contain other agents which either enhance the activity of the protein or other active ingredient or complement its activity or use in treatment. Such additional factors and/or agents may be included in the pharmaceutical composition to produce a synergistic effect with protein or other active ingredient of the invention, or to minimize side effects. Conversely, protein or other active ingredient of the present invention may be included in formulations of the particular clotting factor, cytokine, lymphokine, other hematopoietic factor, thrombolytic or anti-thrombotic factor, or anti- inflammatory agent to minimize side effects of the clotting factor, cytokine, lyrnphokinc, other hernatopoietic factor, thrornbolytic or anti-thrornbotic factor, or anti-inflarnmat~ry agent (such as IL-lRa, IL-1 Hyl, IL-1 Hy2, anti-TNF, c~rticoster~ids, imrnunosuppressive agents). A protein ~f the present invention may be active in multimers (e.g., heterodimers or homodirners) or complexes with itself or other proteins. As a result, pharmaceutical compositions of the invention may comprise a protein ~f the inventi~n in such multimeric or complexed form.
As an alternative to being included in a pharmaceutical composition of the invention including a first protein, a second protein or a therapeutic agent may be concurrently administered with the first protein (e.g., at the same time, or at differing times provided that therapeutic concentrations of the combination of agents is achieved at the treatment site).
Techniques for formulation and administration of the compounds of the instant application may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, latest edition. A therapeutically effective dose further refers to that amount of the compound sufficient to result in amelioration of symptoms, e.g., treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions. When applied to an individual active ingredient, administered alone, a therapeutically effective dose refers to that ingredient alone. When applied to a combination, a therapeutically effective dose refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
In practicing the method of treatment or use of the present invention, a therapeutically effective amount of protein or other active ingredient of the present invention is administered to a mammal having a condition to be treated. Protein or other active ingredient of the present invention may be administered in accordance with the method of the invention either alone or in combination with other therapies such as treatments employing cytokines, lymphokines or other hematopoietic factors. When co-administered with one or more cytokines, lymphokines or other hematopoietic factors, protein or other active ingredient of the present invention may be administered either simultaneously with the cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors, or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering protein or other active ingredient of the present invention in combination with cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors.
~~.12.1 ~~~TLTT~~ ~1F A~T~I~~1I~~L°P~A'I"1~I~~T
Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
Administration of protein or other active ingredient of the present invention used in the pharmaceutical composition or to practice the method of the present invention can be carried out in a variety of conventional ways, such as oral ingestion, inhalation, topical application or cutaneous, subcutaneous, intraperitoneal, parenteral or intravenous injection. Intravenous administration to the patient is preferred.
Alternately, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into a arthritic joints or in fibrotic tissue, often in a depot or sustained release formulation. In order to prevent the scarring process frequently occurnng as complication of glaucoma surgery, the compounds may be administered topically, for example, as eye drops. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with a specific antibody, targeting, for example, arthritic or fibrotic tissue. The liposomes will be targeted to and taken up selectively by the afflicted tissue.
The polypeptides of the invention are administered by any route that delivers an effective dosage to the desired site of action. The determination of a suitable route of administration and an effective dosage for a particular indication is within the level of skill in the art. Preferably for wound treatment, one administers the therapeutic compound directly to the site. Suitable dosage ranges for the polypeptides of the invention can be extrapolated from these dosages or from similar studies in appropriate animal models.
Dosages can then be adjusted as necessary by the clinician to provide maximal therapeutic benefit.
4.12.2 C~I~SITI~I~dS/F~I~LU~.ATI~I~TS
Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in a conventional manner using ~ne or more physiologically acceptable earners comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. These pharmaceutical compositions may be manufactured in a manner that is itself known, ~e.~., by means of conventi~nal mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilising processes. Proper formulation is dependent upon the route of administration ch~sen. When a therapeutically effective amount of protein or other active ingredient of the present invention is administered orally, protein or other active ingredient of the present invention will be in the form of a tablet, capsule, powder, solution or elixir. When administered in tablet form, the pharmaceutical composition of the invention may additionally contain a solid carrier such as a gelatin or an adjuvant. The tablet, capsule, and powder contain from about 5 to 95% protein or other active ingredient of the present ' invention, and preferably from about 25 to 90% protein or other active ingredient of the present invention. When administered in liquid form, a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils may be added. The liquid form of the pharmaceutical composition may further contain physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol. When administered in liquid form, the pharmaceutical composition contains from about 0.5 to 90%
by weight of protein or other active ingredient of the present invention, and preferably from 5 about 1 to 50% protein or other active ingredient of the present invention.
When a therapeutically effective amount of protein or other active ingredient of the present invention is administered by intravenous, cutaneous or subcutaneous.injection, protein or other active ingredient of the present invention will be in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally 10 acceptable protein or other active ingredient solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A preferred pharmaceutical composition for intravenous, cutaneous, or subcutaneous injection should contain, in addition to protein or other active ingredient of the present invention, an isotonic vehicle such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride 15 Injection, Lactated Ringer's Injection, or other vehicle as known in the art. The pharmaceutical composition of the present invention may also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those of skill in the art. For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or 20 physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such 25 carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurnes, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained from a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable 30 excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampules or in mufti-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
A pharmaceutical carrier for the hydrophobic compounds of the invention is a co-solvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The co-solvent system may be the VPD co-solvent system.
VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD
co-solvent system (~PD:~W) consists of VPD diluted 1:1 v~ith a 5°/~
dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose. Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable 7~
matrices of solid hydrophobic polymers containing the therapeutic agent.
Various types of sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein or other active ingredient stabilization may be employed.
The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, ~ gelatin, and polymers such as polyethylene glycols. Many of the active ingredients of the invention may be provided as salts with pharmaceutically compatible counter ions. Such pharmaceutically acceptable base addition salts are those salts which retain the biological effectiveness and properties of the free acids and which are obtained by reaction with inorganic or organic bases such as sodium hydroxide, magnesium hydroxide, ammonia, trialkylamine, dialkylamine, monoalkylamine, dibasic amino acids, sodium acetate, potassium benzoate, tricthanol amine and the like.
The pharmaceutical composition of the invention may be in the form of a complex of the proteins) or other active ingredients) of present invention along with protein or peptide antigens. The protein and/or peptide antigen will deliver a stimulatory signal to both B and T
lymphocytes. B lymphocytes will respond to antigen through their surface immunoglobulin receptor. T lymphocytes will respond to antigen through the T cell receptor (TCIt) following presentation of the antigen by MHO proteins. MHC and structurally related proteins including those encoded by class I and class II MHC genes on host cells will serve to present the peptide antigens) to T lymphocytes. The antigen components could also be supplied as purified MHC-peptide complexes alone or with co-stimulatory molecules that can directly signal T cells. Alternatively antibodies able to bind surface immunoglobulin and other molecules on B cells as well as antibodies able to bind the TCR and other molecules on T cells can be combined with the pharmaceutical composition of the invention.
The pharmaceutical composition of the invention may be in the form of a liposome in which protein of the present invention is combined, in addition to other pharmaceutically acceptable tamers, with amphipathic agents such as lipids which exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers in aqueous solution.
Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithins, phospholipids, saponin, bile acids, and the like.
Preparation of such liposomal formulations is within the level of skill in the art, as disclosed, for example, in U.S. Patent Nos. 4,235,871; 4,501,728; 4,837,028; and 4,737,323, all of which are incorporated herein by reference.
The amount of protein or other active ingredient of the present invention in the pharmaceutical composition of the present invention will depend upon the nature and severity of the condition being treated, and on the nature of prior treatments which the patient has undergone. Ultimately, the attending physician will decide the amount of protein or other active ingredient of the present invention with which to treat each individual patient.
Initially, the attending physician will administer low doses of protein or other active ingredient of the present invention and observe the patient's response. Larger doses of protein or other active ingredient of the present invention may be administered until the optimal therapeutic effect is obtained for the patient, and at that point the dosage is not increased further. It is contemplated that the various pharmaceutical compositions used to practice the method of the present invention should contain about 0.01 ~g to about 100 mg (preferably about 0.1 ~g to about 10 mg, more preferably about 0.1 ~g to about 1 mg) of protein or other active ingredient of the present invention per kg body weight. For compositions of the present invention which are useful for bone, cartilage, tendon or ligament regeneration, the therapeutic method includes administering the composition topically, systematically, or locally as an implant or device. When administered, the therapeutic composition for use in this invention is, of course, in a pyrogen-free, physiologically acceptable form. Further, the composition may desirably be encapsulated or injected in a viscous form for delivery to the site of bone, cartilage or tissue damage.
Topical administration may be suitable for wound healing and tissue repaix.
Therapeutically useful agents other than a protein or other active ingredient of the invention which may also optionally be included in the composition as described above, may alternatively or additionally, be administered simultaneously or sequentially with the composition in the methods of the invention. Preferably for bone and/or cartilage formation, the composition would include a matrix capable of delivering the protein-containing or other active ingredient-containing composition to the site of bone andlor cartilage damage, providing a structure for the developing bone and cartilage and optimally capable of being resorbed into the body. Such matrices may be formed of materials presently in use fox other implanted medical applications.

The choice of matrix material is based on biocompatibility, biodegradability, mechanical properties, cosmetic appearance and interface properties. The particular application of the compositions will define the appropriate formulation.
Potential matrices for the compositions may be biodegradable and chemically defined calcium sulfate, 5 tricalcium phosphate, hydroxyapatite, polylactic acid, polyglycolic acid and polyanhydrides.
Other potential materials are biodegradable and biologically well-defined, such as bone or dernzal collagen. Further matrices are comprised of pure proteins or extracellular matrix components. Other potential matrices are nonbiodegradable and chemically defined, such as sintered hydroxyapatite, bioglass, aluminates, or other cexamics. Matrices may be comprised 10 of combinations of any of the above-mentioned types of material, such as polylactic acid and hydroxyapatite or collagen and tricalcium phosphate. The bioceramics may be altered in composition, such as in calcium-aluminate-phosphate and processing to alter pore size, particle size, particle shape, and biodegradability. Presently preferred is a 50:50 (mole weight) copolymer of lactic acid and glycolic acid in the form of porous particles having 15 diameters ranging from 150 to 800 microns. In some applications, it will be useful to utilize a sequestering agent, such as carboxymethyl cellulose or autologous blood clot, to prevent the protein compositions from disassociating from the matrix.
A preferred family of sequestering agents is cellulosic materials such as alkylcelluloses (including hydroxyalkylcelluloses), including methylcellulose, 20 ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl-methylcellulose, and carbol~ymethylcellulose, the most preferred being cationic salts of carboxymethylcellulase (CMC). Other preferred sequestering agents include hyaluronic acid, sodium alginate, polyethylene glycol), polyoxyethylene oxide, carboxyvinyl polymer and polyvinyl alcohol). The amount of sequestering agent useful 25 herein is 0.5-20 wt %, preferably 1-10 wt % based on total formulation weight, which represents the amount necessary to prevent desorption of the protein from the polymer matrix and to provide appropriate handling of the composition, yet not so much that the progenitor cells are prevented from infiltrating the matrix, thereby providing the protein the opportunity to assist the osteogenic activity of the progenitor cells. In further compositions, 30 proteins or other active ingredients of the invention may be combined with other agents beneficial to the treatment of the bone andlor cartilage defect, wound, or tissue in question.
These agents include various growth factors such as epidermal growth factor (EGF), platelet derived growth factor (PDGF), transforming growth factors (TGF-oc and TGF-(3), and insulin-like growth factor (IGF).
The therapeutic compositions are also presently valuable for veterinary applications.
Particularly domestic animals and thoroughbred horses, in addition to humans, are desired patients for such treatment with proteins or other active ingredients of the present invention.
The dosage regimen of a protein-containing pharmaceutical composition to be used in tissue regeneration will be determined by the attending physician considering various factors which modify the action of the proteins, e.g., amount of tissue weight desired to be formed, the site of damage, the condition of the damaged tissue, the size of a wound, type of damaged tissue (e.g., bone), the patient's age, sex, and diet, the severity of any infection, time of administration and other clinical factors. The dosage may vary with the type of matrix used in the reconstitution and with inclusion of other proteins in the pharmaceutical composition.
For example, the addition of other known growth factors, such as IGF I
(insulin like growth factor I), to the final composition, may also effect the dosage. Progress can be monitored by periodic assessment of tissue/bone growth and/or repair, for example, X-rays, histomorphomctric determinations and tetracycline labeling.
Polynucleotides of the present invention can also be used for gene therapy.
Such polynucleotides can be introduced either in vivo or ex vivo into cells for expression in a mammalian subject. Polynucleotides of the invention may also be administered by other known methods for introduction of nucleic acid into a cell or organism (including, without limitation, in the form of viral vectors or naked D1~IA). Cells may also be cultured ex vivo in the presence of proteins of the present invention in order to proliferate or to produce a desired effect on or activity in such cells. Treated cells can then be introduced in vivo for therapeutic purposes.
4.12.3 EFFECTIVE DOSAGE
Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated. Determination of the effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. For any compound used in the method of the invention, the therapeutically effective dose can be ~2 estimated initially from appropriate in vitro assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that can be used to more accurately determine useful doses in humans. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the ICso as determined in cell culture (i.e., the concentration of the test compound which achieves a half maximal inhibition of the protein's biological activity). Such information can be used to more accurately determine useful doses in humans.
A therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms or a prolongation of survival in a patient. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.~., for determining the LDSo (the dose lethal to 50%
of the population) and the EDso (the dose therapeutically effective in 50% of the population).
The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LDso and EDso. Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the EDSo with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. See, e.~., Fingl et al., 1759 in "The Pharmacol~gical basis of 'Therapeutics", Ch.
1 p.l . Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the desired effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from ira vtt~°o data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
Dosage intervals can also be determined using MEC value. Compounds should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

An exemplary dosage regimen for polypeptides or other compositions of the invention will be in the range of about 0.01 ~,g/kg to 100 mg/lcg of body weight daily, with the preferred dose being about 0.1 p,g/kg to 25 mg/kg of patient body weight daily, varying in adults and children. Dosing may be once daily, or equivalent doses may be delivered at longer or shorter intervals.
The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's age and weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
4.12.4 PACKAGING
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
4.13 ANTIBODIES
Also included in the invention are antibodies to proteins, or fragments of proteins of the lnvelltl~n. The term "antibody" as used herein refers to immunoglobulin molecules and immunologically active poutions of immunoglobulin (Ig) molecules, i.e., molecules that contain an antigen-binding site that specifically binds (immunoreacts with) an antigen. Such antibodies include, but are not limited to, polyclonal, monoclonal, chimeric, single chain, Fib, Fab> and F~ab~)2 fragments, and an Fab expression library. In general, an antibody molecule obtained from humans relates to any of the classes IgG, IgM, IgA, IgE and IgD, which differ from one another by the nature of the heavy chain present in the molecule.
Certain classes have subclasses as well, such as IgGI, IgG2, and others. Furthermore, in humans, the light chain may be a kappa chain or a lambda chain. Reference herein to antibodies includes a reference to all such classes, subclasses and types of human antibody species.
An isolated related protein of the invention may be intended to serve as an antigen, or a portion or fragment thereof, and additionally can be used as an immunogen to generate antibodies that immunospecifically bind the antigen, using standard techniques for polyclonal and monoclonal antibody preparation. The full-length protein can be used or, alternatively, the invention provides antigenic peptide fragments of the antigen for use as immunogens. An antigenic peptide fragment comprises at least 6 amino acid residues of the amino acid sequence of the full length protein, such as an amino acid sequence shown in SEQ ID NO: 685-1368, or 1967-2564, or Tables 3A, 3B, 5, 7, or 8, and encompasses an epitope thereof such that an antibody raised against the peptide forms a specific immune complex with the full length protein or with any fragment that contains the epitope.
Preferably, the antigenic peptide comprises at least 10 amino acid residues, or at least 15 amino acid residues, or at least 20 amino acid residues, or at least 30 amino acid residues.
Preferred epitopes encompassed by the antigenic peptide are regions of the protein that are located on its surface; commonly these are hydrophilic regions.
In certain embodiments of the invention, at least one epitope encompassed by the antigenic peptide is a surface region of the protein, e.g., a hydrophilic region. A
hydrophobicity analysis of the human related protein sequence will indicate which regions of a related protein are particularly hydrophilic and, therefore, are likely to encode surface residues useful for targeting antibody production. As a means for targeting antibody production, hydropathy plots showing regions of hydrophilicity and hydrophobicity may be generated by any method well known in the art, including, for example, the Kyte Doolittle or the Hopp Woods methods, either with or without Fourier transformation. See, e.g., Hopp and Woods, 1981, Proc. Nat. Acad. Sci. USA 78: 3824-3828; I~yte and Doolittle 1982, J. Mol.
Biol. 157: 105-1429 each of which is incorporated herein by reference in its entiret~r.
Antibodies that are specific for one or more domains within an antigenic protein, or derivatives, fragments, analogs or homologs thereof, are also provided herein.
A protein of the invention, or a derivative, fragment, analog, homolog or ortholog thereof, may be utilized as an immunogen in the generation of antibodies that immunospecifically bind these protein components.
The term "specific for" indicates that the variable regions of the antibodies of the invention recognize and bind polypeptides of the invention exclusively (i.e., able to distinguish the polypeptide of the invention from other similar polypeptides despite sequence identity, homology, or similarity found in the family of polypeptides), but may also interact with other proteins (for example, S. auf°eus protein A or other antibodies in ELISA
techniques) through interactions with sequences outside the variable region of the antibodies, and in particular, in the constant region of the molecule. Screening assays to determine binding specificity of an antibody of the invention are well known and routinely practiced in the art. For a comprehensive discussion of such assays, see Harlow et al.
(Eds), Antibodies A Laboratory Manual; Cold Spring Harbor Laboratory; Cold Spring Harbor, NY
(1988), Chapter 6. Antibodies that recognize and bind fragments of the polypeptides of the invention are also contemplated, provided that the antibodies are first and foremost specific for, as defined above, full-length polypeptides of the invention. As with antibodies that are specific for full length polypeptides of the invention, antibodies of the invention that recognize fragments are those which can distinguish polypeptides from the same family of polypeptides despite inherent sequence identity, homology, or similarity found in the family 10 of proteins.
Antibodies of the invention are useful for, for example, therapeutic purposes (by modulating activity of a polypeptide of the invention), diagnostic puzposes to detect or quantitate a polypeptide of the invention, as well as purification of a polypeptide of the invention. Fits comprising an antibody of the invention for any of the purposes described 15 herein are also comprehended. In general, a kit of the invention also includes a control antigen for which the antibody is immunospecific. The invention further provides a hybridoma that produces an antibody according to the invention. Antibodies of the invention are useful for detection and/or purification of the polypeptides of the invention.
Monoclonal antibodies binding to the protein of the invention may be useful 20 diagnostic agents for the immunodetection of the protein. Neutralizing monoclonal antibodies binding to the protein may also be useful therapeutics for b~th c~nditions associated with the protein and also in the treatment of some forms ~f cancer where abn~rmal expression of the protein is involved. In the case of cancerous cells or leukemic cells, neutralizing monoclonal antibodies against the protein may be useful in detecting and 25 preventing the metastatic spread of the cancerous cells, which may be mediated by the protein.
The labeled antibodies of the present invention can be used for izz vitro, lzz vivo, and izz situ assays t~ identify cells or tissues in which a fragment of the polypeptide of interest is expressed. The antibodies may also be used directly in therapies or other diagnostics. The 30 present invention further provides the above-described antibodies immobilized on a solid support. Examples of such solid supports include plastics such as polycarbonate, complex carbohydrates such as agarose and Sepharose~, acrylic resins and such as polyacrylamide and latex beads. Techniques for coupling antibodies to such solid supports are well known in the art (Weir, D.M. et al., "Handbook of Experimental Immunology" 4th Ed., Blackwell Scientific Publications, Oxford, England, Chapter 10 (1986); Jacoby, W.D. et al., Meth.
Enzym. 34 Academic Press, N.Y. (1974)). The immobilized antibodies of the present invention can be used for in vitro, in vivo, and in situ assays as well as for immuno-affinity purification of the proteins of the present invention.
Various procedures known within the art may be used for the production of polyclonal or monoclonal antibodies directed against a protein of the invention, or against derivatives, fragments, analogs homologs or orthologs thereof (see, for example, Antibodies:
A Laboratory Manual, Harlow E, and Lane D, 1988, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, incorporated herein by reference). Some of these antibodies are discussed below.
4.13.1 POLYCLONAL ANTIBODIES
For the production of polyclonal antibodies, various suitable host animals (e.g., rabbit, goat, mouse or other mammal) may be immunized by one or more injections with the native protein, a synthetic variant thereof, or a derivative of the foregoing.
An appropriate immunogenic preparation can contain, for example, the naturally occurring immunogenic protein, a chemically synthesized polypeptide representing the immunogenic protein, or a recombinantly expressed immunogenic protein. Furthermore, the protein may be conjugated to a second protein known to be immunogenic in the mammal being immunized.
Examples of such immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor. The preparation can further include an adjuvant. Various adjuvants used to increase the immunological response include, but are not limited to, Freund's (complete and incomplete), mineral gels (e.g., aluminum hydroxide), surface-active substances (e.g., lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, dinitrophenol, etc.), adjuvants usable in humans such as Bacille Calmette-Guerin and Corynebacterium parvum, or similar immunostimulatory agents. Additional examples of adjuvants that can be employed include MPL-TDM
adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate).
The polyclonal antibody molecules directed against the immunogenic protein can be isolated from the mammal (e.g., from the blood) and further purified by well known techniques, such as affinity chromatography using protein A or protein G, which provide primarily the IgG fraction of immune serum. Subsequently, or alternatively, the specific antigen which is the target of the immunoglobulin sought, or an epitope thereof, may be immobilized on a column to purify the immune specific antibody by immunoaf~nity chromatography. Purification of immunoglobulins is discussed, for example, by D.
Wilkinson (The Scientist, published by The Scientist, Inc., Philadelphia PA, Vol. 14, No. 8 S (April 17, 2000), pp. 25-28).
4.13.2 MONOCLONAL ANTIBODIES
The term "monoclonal antibody" (MAb) or "monoclonal antibody composition", as used herein, refers to a population of antibody molecules that contain only one molecular species of antibody molecule consisting of a unique light chain gene product and a unique heavy chain gene product. In particular, the complementarity determining regions (CDRs) of the monoclonal antibody are identical in all the molecules of the population. MAbs thus contain an antigen-binding site capable of immunoreacting with a particular epitope of the antigen characterized by a unique binding affinity for it.
Monoclonal antibodies can be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature, 256, 495 (1975). In a hybridoma method, a mouse, hamster, ~r other appropriate h~st animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes can be immunized in vitro.
The immunizing agent will typically include the protein antigen, a fragment thereof or a fusion protein thereof. Generally, either peripheral blood lymphocytes are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (Goding, Monocl~nal Antibodies: Principles and Practice, Academic Press, (1986) pp. 59-103). Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin. Usually, rat or mouse myeloma cell lines are employed. The hybridoma cells can be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells. For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine ("HAT
medium"), which substances prevent the growth of HGPRT-deficient cells.
Preferred immortalized cell lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. More preferred immortalized cell lines are murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, California and the American Type Culture Collection, Manassas, Virginia.
Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies (Kozbor, J. Imrnunol., 133:3001 (1984);
Brodeur et al., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp. 51-63).
The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the antigen.
Preferably, the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA). Such tcclmiqucs and assays are known in the art. The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal. Biochem., 107, 220 (1980).
Preferably, antibodies having a high degree of specificity and a high binding affinity for the target antigen are isolated.
After the desired hybridoma cells are identified, the clones can be subcloned by limiting dilution procedures and grown by standard meth~ds. Suitable culture media f~r this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium. Alternatively, the hybridoma cells can be grown in vivo as ascites in a mammal.
The monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.
The monocl~nal antibodies can also be made by recombinant DNA methods, such as those described in LT.S. Patent No. 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the ' heavy and light chains of murine antibodies). The hybridoma cells of the invention serve as a preferred source of such DNA. Once isolated, the DNA can be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce imrnunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA
also can be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences (U.S.
Patent No.
4,816,567; Mornson, Nature 368, 812-13 (1994)) or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody.
4.13.3 HUMANIZED ANTIBODIES
The antibodies directed against the protein antigens of the invention can further comprise humanized antibodies or human antibodies. These antibodies are suitable for administration to humans without engendering an immune response by the human against the administered immunoglobulin. Humani2ed forms of antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab')2 or other antigen-binding subsequences of antibodies) that are principally comprised of the sequence of a human immunoglcbulin, and contain minimal sequence derived from a n~n-human immunoglobulin. Humanization can be performed following the method of Winter and co-workers (3ones et al., Nature, 321, 522-525 (1986); Riechmann et al., Nature, 332, 323-327 (1988); Verhoeyen et al., Science, 239, 1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. (See also LT.S. Patent No. 5,225,539). In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies can also comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin (Jones et al., 1986; Riechmann et al., 1988; and Presta, Curr. Op. Struct.
Biol., 2, 593-596 (1992)).
5 4.13.4 HUMAN ANTIBODIES
Fully human antibodies relate to antibody molecules in which essentially the entire sequences of both the light chain and the heavy chain, including the CDRs, arise from human genes. Such antibodies are termed "human antibodies", or "fully human antibodies"
herein. Human monoclonal antibodies can be prepared by the trioma technique;
the human 10 B-cell hybridoma technique (see I~ozbor, et al., 1983 Immunol Today 4: 72) and the EBV
hybridoma technique to produce human monoclonal antibodies (see Cole, et al., 1985 In:
Monoclonal Antibodies and Cancer Thexapy, Alan R. Liss, Inc., pp. 77-96).
Human monoclonal antibodies may be utilized in the practice of the present invention and may be produced by using human hybridomas (see Cote, et al., 1983. Proc Natl Acad Sci USA 80, 15 2026-2030) or by transforming human B-cells with Epstein Barr Virus in vitro (see Cole, et al., 1985 In: Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96).
In addition, human antibodies can also be produced using additional techniques, including phage display libraries (Hoogenboom and Winter, J. Mol. Biol., 227, 381 (1991);
Marks et al., J. Mol. Biol., 222:581 (1991)). Similarly, human antibodies can be made by 20 introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated.
Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire.
This approach is described, for example, in U.S. Patent Nos. 5,545,807;
5,545,806;
25 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in Marks et al.
(Bio/Technology 10, 779-783 (1992)); Lonberg et al. (Nature 368, 856-859 (1994)); Morrison (Nature 368, 812-13 (1994)); Fishwild et al, (Nature Biotechnology 14, 845-51 (1996)); Neuberger (Nature Biotechnology 14, 826 (1996)); and Lonberg and Huszar (Intern. Rev. Immunol.
13, 65-93 (1995)).
30 Human antibodies may additionally be produced using transgenic nonhuman animals that are modified so as to produce fully human antibodies rather than the animal's endogenous antibodies in response to challenge by an antigen. (See PCT
publication W094/02602). The endogenous genes encoding the heavy and light immunoglobulin chains in the nonhuman host have been incapacitated, and active loci encoding human heavy and light chain immunoglobulins are inserted into the host's genome. The human genes are incorporated, for example, using yeast artificial chromosomes containing the requisite human DNA segments. An animal which provides all the desired modiftcations is then obtained as progeny by crossbreeding intermediate transgenic animals containing fewer than the full complement of the modifications. The preferred embodiment of such a nonhuman animal is a mouse, and is termed the Xenomouse~ as disclosed in PCT
publications WO
96/33735 and WO 96/34096. This animal produces B cells that secrete fully human immunoglobulins. The antibodies can be obtained directly from the animal after immunization with an immunogen of interest, as, for example, a preparation of a polyclonal antibody, or alternatively from immortalized B cells derived from the animal, such as hybridomas producing monoclonal antibodies. Additionally, the genes encoding the immunoglobulins with human variable regions can be recovered and expressed to obtain the antibodies directly, or can be further modified to obtain analogs of antibodies such as, for example, single chain Fv molecules.
An example of a method of producing a nonhuman host, exemplified as a mouse, lacking expression of an endogenous immunoglobulin heavy chain is disclosed in IJ.S.
Patent No. 5,939,598. It can be obtained by a method including deleting the J
segment genes from at least one endogenous heavy chain locus in an embryonic stem cell to prevent rearrangement of the locus and to prevent formation of a transcript of a rearranged immunoglobulin heavy chain locus, the deletion being effected by a targeting vector containing a gene encoding a selectable markers and producing from the embryonic stem cell a transgenic mouse whose somatic and germ cells contain the gene encoding the selectable marker.
A method for producing an antibody of interest, such as a human antibody, is disclosed in LT.S. Patent No. 5,916,771. It includes introducing an expression vector that contains a nucleotide sequence encoding a heavy chain into one mammalian host cell in culture, introducing an expression vector containing a nucleotide sequence encoding a light chain into another mammalian host cell, and fusing the two cells to form a hybrid cell. The hybrid cell expresses an antibody containing the heavy chain and the light chain.
In a further improvement on this procedure, a method for identifying a clinically relevant epitope on an immunogen, and a correlative method for selecting an antibody that binds immunospecifically to the relevant epitope with high affinity, are disclosed in PCT
publication WO 99/53049.
4.13.5 FAB FRAGMENTS AND SINGLE CHAIN ANTIBODIES
According to the invention, techniques can be adapted for the production of single-chain antibodies specific to an antigenic protein of the invention (see e.g., U.S. Patent No. 4,946,778). In addition, methods can be adapted for the construction of Fab expression libraries (see e.g., Huse, et al., 1989 Science 246, 1275-1281) to allow rapid and effective identification of monoclonal Fab fragments with the desired specificity for a protein or derivatives, fragments, analogs or homologs thereof. Antibody fragments that contain the idiotypes to a protein antigen may be produced by techniques known in the art including, but not limited to: (i) an F(ab')2 fragment produced by pepsin digestion of an antibody molecule;
(ii) an Fab fragment generated by reducing the disulfide bridges of an F~ab~~2 fragment; (iii) an Fab fragment generated by the treatment of the antibody molecule with papain and a reducing agent and (iv) F~ fragments.
4.13.6 BISPECIFIC ANTIBODIES
Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens. In the present case, one of the binding specificities is for an antigenic protein of the invention. The second binding target is any other antigen, and advantageously is a cell-surface protein or receptor or receptor subunit.
Methods for making bispecific antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-chain/light-chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, Nature, 305, 537-539 (1983)). Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule is usually accomplished by affinity chromatography steps. Similar procedures are disclosed in WO
93/08829, published 13 May'1993, and in Traunecker et al., 1991 EMBO J., 10, 3655-3659.
Antibody variable domains with the desired binding specificities (antibody-antigen combining sites) can be fused to immunoglobulin constant domain sequences. The fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. It is preferred to have the first heavy-chain constant region (CH1) containing the site necessary for light-chain binding present in at least one of the fusions. DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host organism. For further details of generating bispecific antibodies see, for example, Suresh et al., Methods in Enzymology, 121, 210 (1986).
According to another approach described in WO 96!27011, the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers that are recovered from recombinant cell culture. The preferred interface comprises at least a part of the CH3 region of an antibody constant domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g. tyrosine or tryptophan). Compensatory "cavities" of identical or similar size to the large side chains) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g.
alanine or threonine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers.
Eispeci~c antibodies can be prepared as full-length antibodies or antibody fragments (e.g. F(ab')2 bispecific antibodies). Techniques for generating bispecific antibodies from antibody fragments have been described in the literature. For example, bispecific antibodies can be prepared using chemical linl~age. l3rennan et al., Science 229, 81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab')2 fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation.
The Fab' fragments generated are then converted to thionitrobenzoate (TNB) derivatives.
One of the Fab'-TNB derivatives is then reconverted to the Fab'-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab'-TNB
derivative to form the bispecific antibody. The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes.
Additionally, Fab' fragments can be directly recovered from E. coli and chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med, 175, 217-225 (1992) describe the production of a fully humanized bispecific antibody F(ab')2 molecule. Each Fab' fragment was separately secreted from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody. The bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T
cells, as well as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets.
Various techniques for making and isolating bispecifrc antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. I~ostelny et al., J. Immunol.
148(5), 1547-1553 (1992). The leucine zipper peptides from the Fos and Jun proteins were linked to the Fab' portions of two different antibodies by gene fusion. The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be utilized for the production of antibody homodimers.
The "diabody" technology described by Hollinger et al., Proc. Natl. Acad. Sci.
USA 90, 6444-6448 (1993) has provided an alternative mechanism for making bispecific antibody fragments. The fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the VH and VL domains of one fragment are forced to pair with the complementary VL and VH domains of another fragment, thereby forming two antigen-binding sites. Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported.
See, Gruber et al., J. Immunol. 152, 5368 (1994).
Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147 60 (1991).
E<~emplary bispecific antibodies can bind to two different epitopes, at least one of which originates in the protein antigen of the invention. Alternatively, an anti-antigenic ann of an immunoglobulin molecule can be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2, CD3, CD28, or B7), or Fc receptors for IgG (FcyR), such as FcyRI (CD64), FcyRII (CD32) and FcyRIII (CD16) so as to focus cellular defense mechanisms to the cell expressing the particular antigen.
Bispecific antibodies can also be used to direct cytotoxic agents to cells which express a particular antigen. These antibodies possess an antigen-binding arm and an arm which binds a cytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA.
Another bispeciBc antibody of interest binds the protein antigen described herein and further binds tissue factor (TF).

4.13.7 HETEROCONJUGATE ANTIBODIES
Heteroconjugate antibodies are also within the scope of the present invention.
Heteroconjugate antibodies are composed of two covalently joined antibodies.
Such antibodies have, for example, been proposed to target immune system cells to unwanted cells 5 (IT.S. Patent No. 4,676,980), and for treatment of HIV infection (WO
91/00360; WO
92/200373; EP 03089). It is contemplated that the antibodies can be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins can be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include 10 iminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, for example, in U.S.
Patent No. 4,676,980.
4.13.8 EFFECTOR FUNCTION ENGINEERING
It can be desirable to modify the antibody of the invention with respect to effector 15 function, so as to enhance, e.g., the effectiveness of the antibody in treating cancer. For example, cysteine residues) can be introduced into the Fc region, thereby allowing interchain disulfide bond formation in this region. The homodimeric antibody thus generated can have improved internalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). See Caron et 20 al., J. Exp Med., 176, 1191-1195 (1992) and Shopes, J. Immunol., 148, 2918-2922 (1992).
Homodimeric antibodies with enhanced anti-tumor activity can also be prepared using heterobifunctional cross-linkers as described in Wolff et al. Cancer Pvesearch, 53, 2560-2565 (1993). Alternatively, an antibody can be engineered that has dual Fc regions and can thereby have enhanced complement lysis and ADCC capabilities. See Stevenson et al., 25 Anti-Cancer Drug Design, 3, 219-230 (1989).
4.13.9 IMMiJNOCONJUGATES
The invention also peutains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g., an enzymatically active 30 toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate).
Chemotherapeutic agents useful in the generation of such immunoconjugates have been described above. Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A
chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A
chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. A variety of radionuclides are available for the production of radioconjugated antibodies. Examples include zl2Bi, 1311, l3iln, goY, and 186Re.
Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dirnethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science, 238: 1098 (1987). Carbon-14-labeled 1-isothi~cyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chclating agent for conjugation of radionucleotide to the antibody. Sec WO94/11026.
In another embodiment, the antibody can be conjugated to a "receptor" (such streptavidin) for utilization in tumor pretargeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound ca~njugatc from the circulation using a clearing agent and then administration of a "ligand" (e.g., avidin) that is in turn c~njugated t~ a cytotoxic agent.
4.14 COMPUTER READABLE SEQUENCES
In one application of this embodiment, a nucleotide sequence of the present invention can be recorded on computer readable media. As used herein, "computer readable media"
refers to any medium which can be read and accessed directly by a computer.
Such media include, but are not limited to: magnetic storage media, such as floppy discs, hard disc storage medium, and magnetic tape; optical storage media such as CD-ROM;
electrical storage media such as RAM and ROM; and hybrids of these categories such as magnetic/optical storage media. A skilled artisan can readily appreciate how any of the presently known computer readable mediums can be used to create a manufacture comprising computer readable medium having recorded thereon a nucleotide sequence of the present invention. As used herein, "recorded" refers to a process for storing information on computer readable medium. A skilled artisan can readily adopt any of the presently known methods for recording information on computer readable medium to generate manufactures comprising the nucleotide sequence information of the present invention.
A variety of data storage structures are available to a skilled artisan for creating a computer readable medium having recorded thereon a nucleotide sequence of the present invention. The choice of the data storage structure will generally be based on the means chosen to access the stored information. In addition, a variety of data processor programs and formats can be used to store the nucleotide sequence information of the present invention on computer readable medium. The sequence information can be represented in a word processing text file, formatted in commercially-available software such as WordPerfect and Microsoft Word, or represented in the form of an ASCII file, stored in a database application, such as DB2, Sybase, Oracle, or the like. A skilled artisan can readily adapt any number of data processor structuring formats (e.~. text ftle or database) in order to obtain computer readable medium having recorded thereon the nucleotide sequence information of the present invention.
By providing any of the nucleotide sequences SEQ ID NO: 1-684, or 1369-1966 or a representative fragment thereof; or a nucleotide sequence at least 95%
identical to any of the nucleotide sequences of SEQ ID INTO: 1-684, or 1369-1966 in computer readable form, a skilled artisan can routinely access the sequence information for a variety of purposes.
Computer software is publicly available which allows a skilled artisan to access sequence information provided in a computer readable medium. The examples which follow demonstrate how software which implements the BLAST (Altschul et al., J. Mol.
Biol.
215:403-410 (1990)) and BLAZE (Brutlag et al., Comp. Chem. 17:203-207 (1993)) search algorithms on a Sybase system is used to identify open reading frames (ORFs) within a nucleic acid sequence. Such ORFs may be protein-encoding fragments and may be useful in producing commercially important proteins such as enzymes used in fermentation reactions and in the production of commercially useful metabolites.
As used herein, "a computer-based system" refers to the hardware means, software means, and data storage means used to analyze the nucleotide sequence information of the present invention. The minimum hardware means of the computer-based systems of the present invention comprises a central processing unit (CPU), input means, output means, and data storage means. A skilled artisan can readily appreciate that any one of the currently available computer-based systems are suitable for use in the present invention. As stated above, the computer-based systems of the present invention comprise a data storage means having stored therein a nucleotide sequence of the present invention and the necessary hardware means and software means for supporting and implementing a search means. As used herein, "data storage means" refers to memory which can store nucleotide sequence information of the present invention, or a memory access means which can access manufactures having recorded thereon the nucleotide sequence information of the present invention.
As used herein, "search means" refers to one or more programs which are implemented on the computer-based system to compare a target sequence or target structural motif with the sequence information stored within the data storage means.
Search means are used to identify fragments or regions of a known sequence which match a particular target sequence or target motif A variety of known algorithms are disclosed publicly and a variety of commercially available software for conducting search means arc and can be used in the computer-based systems of the present invention. Examples of such software includes, but is not limited to, Smith-Waterman, lVIacPattcrn (EMBL), )3LASTN and 13LASTA
(NP~LYPEPTIDEIA). A skilled artisan can readily recognize that any one of the available algorithms or implementing software packages for conducting homology searches can be adapted for use in the present computer-based systems. As used herein, a "target sequence"
can be any nucleic acid or amino acid sequence of six or more nucleotides or two or more amino acids. A skilled artisan can readily recognize that the longer a target sequence is, the less likely a target sequence will be present as a random occurrence in the database. The most preferred sequence length of a target sequence is from about 10 to 300 amino acids, more preferably from about 30 to 100 nucleotide residues. However, it is well recognized that searches for commercially important fragments, such as sequence fragments involved in gene expression and protein processing, may be of shorter length.
As used herein, "a target structural motif," or "target motif," refers to any rationally selected sequence or combination of sequences in which the sequences) are chosen based on a three-dimensional configuration which is formed upon the folding of the target motif.
There are a variety of target motifs knowxn in the art. Protein target motifs include, but are not limited to, enzyme active sites and signal sequences. Nucleic acid target motifs include, but are not limited to, promoter sequences, hairpin structures and inducible expression elements (protein binding sequences).
4.15 TRIPLE HELIX FORMATION
In addition, the fragments of the present invention, as broadly described, can be used to control gene expression through triple helix formation or antisense DNA or RNA, both of which methods are based on the binding of a polynucleotide sequence to DNA or RNA.
Polynucleotides suitable for use in these methods are preferably 20 to 40 bases in length and are designed to be complementary to a region of the gene involved in transcription (triple helix-see Lee et al., Nucl. Acids Res. 6, 3073 (1979); Cooney et al., Science 15241, 456 (1988); and Dervan et al., Science 251, 1360 (1991)) or to the mRNA itself (antisense-~hnno, J. Neurochem. 56:560 (1991); ~ligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, FL (1988)). Triple helix-formation optimally results in a shut-off of RNA transcription from DNA, while antisense RNA
hybridization blocks translation of an mRNA molecule into polypeptide. Both techniques have been demonstrated to be effective in model systems. Inforniation contained in the sequences of the present invention is necessary for the design of an antisense or triple helix oligonucleotide.
4.16 DIAGNOSTIC ASSAYS AND KITS
The present invention further provides methods to identify the presence or expression of one of the ~RFs of the present invention, or homolog thereof, in a test sample, using a nucleic acid probe or antibodies of the present invention, optionally conjugated or otherwise associated with a suitable label.
In general, methods for detecting a polynucleotide of the invention can comprise contacting a sample with a compound that binds to and forms a complex with the polynucleotide for a period sufficient to form the complex, and detecting the complex, so that if a complex is detected, a polynucleotide of the invention is detected in the sample.
Such methods can also comprise contacting a sample under stringent hybridization conditions with nucleic acid primers that anneal to a polynucleotide of the invention under such conditions, and amplifying annealed polynucleotides, so that if a polynucleotide is ampliEed, a polynucleotide of the invention is detected in the sample.

In general, methods for detecting a polypeptide of the invention can comprise contacting a sample with a compound that binds to and forms a complex with the polypeptide for a period sufficient to form the complex, and detecting the complex, so that if a complex is detected, a polypeptide of the invention is detected in the sample.
In detail, such methods comprise incubating a test sample with one or more of the antibodies or one or more of the nucleic acid probes of the present invention and assaying for binding of the nucleic acid probes or antibodies to components within the test sample.
Conditions for incubating a nucleic acid probe or antibody with a test sample vary.
Incubation conditions depend on the format employed in the assay, the detection methods employed, and the type and nature of the nucleic acid probe or antibody used in the assay.
~ne skilled in the art will recognize that any one of the commonly available hybridization, amplification or immunological assay formats can readily be adapted to employ the nucleic acid probes or antibodies of the present invention. Examples of such assays can be found in Chard, T., An Introduction to Radioimmunoassay and Related Techniques, Elsevier Science Publishers, Amsterdam, The Netherlands (1986); Bullock, G.R. et al., Techniques in Immunocytochemistry, l~cademic Press, ~rlando, FL Vol. 1 (1982), Vol. 2 (1983), Vol. 3 (1985); Tijssen, P., Practice and Theory of immunoassays: Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers, Amsterdam, The Netherlands (1985). The test samples of the present invention include cells, protein or membrane extracts of cells, or biological fluids such as sputum, blood, serum, plasma, or urine. The test sample used in the above-described method will vary based on the assay format, nature of the detection method and the tissues, cells or extracts used as the sample to be assayed. Methods for preparing protein extracts or membrane extracts of cells are well known in the art and can be readily be adapted in order to obtain a sample which is compatible with the system utilized.
In another embodiment of the present invention, kits are provided which contain the necessary reagents to carry out the assays of the present invention.
Specifically, the invention provides a compartment kit to receive, in close confinement, one or more containers which comprises: (a) a first container comprising one of the probes or antibodies of the present invention; and (b) one or more other containers comprising one or more of the following: wash reagents, reagents capable of detecting presence of a bound probe or antibody.

In detail, a compartment kit includes any kit in which reagents are contained in separate containers. Such containers include small glass containers, plastic containers or strips of plastic or paper. Such containers allows one to efEciently transfer reagents from one compartment to another compartment such that the samples and reagents are not cross-contaminated, and the agents or solutions of each container can be added in a quantitative fashion from one compartment to another. Such containers will include a container which will accept the test sample, a container which contains the antibodies used in the assay, containers which contain wash reagents (such as phosphate buffered saline, Tris-buffers, etc.), and containers which contain the reagents used to detect the bound antibody or probe. Types of detection reagents include labeled nucleic acid probes, labeled secondary antibodies, or in the alternative, if the primary antibody is labeled, the enzymatic, or antibody binding reagents which are capable of reacting with the labeled antibody. One skilled in the art will readily recognize that the disclosed probes and antibodies of the present invention can be readily incorporated into one of the established kit formats which are well kn~wn in the art.
4.17 IDI~AI. Il~IA~ING
The novel polypeptides and binding partners of the invention are useful in medical imaging of sites expressing the molecules of the invention (e.g., where the polypeptide of the invention is involved in the immune response, for imaging sites of inflammation or infection). See, e.g., I~:unkel et al., U.S. Pat. hTO. 5,413,778. Such methods involve cheanical attachment of a labeling ~r imaging agent, administration of the labeled polypeptide to a subject in a pharmaceutically acceptable carrier, and imaging the labeled polypeptide in viv~ at the target site.
4.18 SCREENING ASSAYS
Using the isolated proteins and p~lynucleotides of the invention, the present invention further provides methods of obtaining and identifying agents which bind to a polypeptide encoded by an ORF corresponding to any of the nucleotide sequences set forth in SEQ ID NO: 1-684, or 1369-1966, or bind to a specific domain of the polypeptide encoded by the nucleic acid. In detail, said method comprises the steps of:
(a) contacting an agent with an isolated protein encoded by an ORF of the present invention, or nucleic acid of the invention; and (b) determining whether the agent binds to said protein or said nucleic acid.
In general, therefore, such methods for identifying compounds that bind to a polynucleotide of the invention can comprise contacting a compound with a polynucleotide of the invention for a time sufficient to form a polynucleotide/compound complex, and detecting the complex, so that if a polynucleotide/compound complex is detected, a compound that binds to a polynucleotide of the invention is identified.
Likewise, in general, therefore, such methods for identifying compounds that bind to a polypeptide of the invention can comprise contacting a compound with a polypeptide of the invention for a time sufficient to form a polypeptide/compound complex, and detecting the complex, so that if a polypeptide/compound complex is detected, a compound that binds to a polynucleotide of the invention is identified.
Methods for identifying compounds that bind to a polypeptide of the invention can also comprise contacting a compound with a polypeptide of the invention in a cell for a time sufficient to form a polypeptide/compound complex, wherein the complex drives expression of a receptor gene sequence in the cell, and detecting the complex by detecting reporter gene sequence expression, so that if a polypeptide/compound complex is detected, a compound that binds a polypeptide of the invention is identified.
Compounds identified via such methods can include compounds which modulate the activity of a polypeptide of the invention (that is, increase or decrease its activity, relative to activity observed in the absence of the compound). Alternatively, compounds identified via such methods can include compounds which modulate the expression of a polynucleotide of the invention (that is, increase or decrease expression relative to expression levels observed in the absence of the compound). Compounds, such as compounds identified via the methods of the invention, can be tested using standard assays well known to those of skill in the art for their ability to modulate activity/expression.
The agents screened in the above assay can be, but are not limited to, peptides, carbohydrates, vitamin derivatives, or other pharmaceutical agents. The agents can be selected and screened at random or rationally selected or designed using protein modeling techniques.
For random screening, agents such as peptides, carbohydrates, pharmaceutical agents and the like are selected at random and are assayed for their ability to bind to the protein encoded by the ORF of the present invention. Alternatively, agents may be rationally selected or designed. As used herein, an agent is said to be "rationally selected or designed"

when the agent is chosen based on the configuration of the particular protein.
For example, one skilled in the art can readily adapt currently available procedures to generate peptides, pharniaceutical agents and the like, capable of binding to a specific peptide sequence, in order to generate rationally designed antipeptide peptides, for example see Hurby et al., Application of Synthetic Peptides: Antisense Peptides," In Synthetic Peptides, A User's Guide, W.H. Freeman, NY (1992), pp. 289-307, and Kaspczak et al., Biochemistry 28:9230-8 (1989), or pharmaceutical agents, or the like.
In addition to the foregoing, one class of agents of the present invention, as broadly described, can be used to control gene expression through binding to one of the ORFs or EMFs of the present invention. As described above, such agents can be randomly screened or rationally designedlselected. Targeting the ORF or EMF allows a skilled artisan to design sequence specific or element specific agents, modulating the expression of either a single ORF or multiple ORFs which rely on the same EMF for expression control. One class of DNA binding agents are agents which contain base residues which hybridize or form a triple helix formation by binding to DNA or RNA. Such agents can be based on the classic phosphodiester, ribonucleic acid backbone, or can be a variety of sulfhydryl or polymeric derivatives which have base attachment capacity.
Agents suitable for use in these methods preferably contain 20 to 40 bases and are designed to be complementary to a region of the gene involved in transcription (triple helix -see Lee et al., Nucl. Acids Res. 6, 3073 (1979); Cooney et al., Science 241, 456 (1988); and Dervan et al., Science 251, 1360 (1991)) or to the mRNA itself (antisense-OkaIl~, J.
Neurochem. 56, 560 (1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, FL (1988)). Triple helix-formation optimally results in a shut-off of RNA transcription from DNA, while antisense RNA hybridization blocks translation of an mRNA molecule into polypeptide. Both techniques have been demonstrated to be effective in model systems. Information contained in the sequences of the present invention is necessary for the design of an antisense or triple helix oligonucleotide and other DNA binding agents.
Agents which bind to a protein encoded by one of the ORFs of the present invention can be used as a diagnostic agent. Agents which bind to a protein encoded by one of the ORFs of the present invention can be formulated using known techniques to generate a pharmaceutical composition.

4.19 USE OF NUCLEIC ACIDS AS PROBES
Another aspect of the subject invention is to provide for polypeptide-specific nucleic acid hybridization probes capable of hybridizing with naturally occurnng nucleotide sequences. The hybridization probes of the subject invention may be derived from any of the nucleotide sequences SEQ ID NO: 1-684, or 1369-1966. Because the corresponding gene is only expressed in a limited number of tissues, a hybridization probe derived from any of the nucleotide sequences SEQ ID NO: 1-684, or 1369-1966 can be used as an indicator of the presence of RNA of cell type of such a tissue in a sample.
Any suitable hybridization technique can be employed, such as, for example, in situ hybridization. PCR as described in US Patents Nos. 4,683,195 and 4,965,188 provides additional uses for oligonucleotides based upon the nucleotide sequences. Such probes used in PCR may be of recombinant origin, may be chemically synthesized, or a mixture of both.
The probe will comprise a discrete nucleotide sequence for the detection of identical sequences or a degenerate pool of possible sequences for identiEcation of closely related genomic sequences.
Other means for producing speciEc hybridization probes for nucleic acids include the cloning of nucleic acid sequences into vectors for the production of mRNA
probes. Such vectors are known in the art and are commercially available and may be used to synthesize RNA probes irt vitro by means of the addition of the appropriate RNA
polymerise as T7 or SP6 RNA polymerise and the appropriate radioactively labeled nucleotides. The nucleotide sequences may be used to construct hybridization probes for mapping their respective genomic sequences. The nucleotide sequence provided herein may be mapped to a chromosome or specific regions of a chromosome using well-known genetic and/or chromosomal mapping techniques. These techniques include in situ hybridization, linkage analysis against known chromosomal markers, hybridization screening with libraries or flow-sorted chromosomal preparations specific to known chromosomes, and the like. The technique of fluorescent in situ hybridization of chromosome spreads has been described, among other places, in Verma et al (1988) Human Chromosomes: A Manual of Basic Techniques, Pergamon Press, New York NY.
Fluorescent ifa situ hybridization of chromosomal preparations and other physical chromosome mapping techniques may be correlated with additional genetic map data.
Examples of genetic map data can be found in the 1994 Genome Issue of Science (265:1981 f). Correlation between the location of a nucleic acid on a physical chromosomal map and a specific disease (or predisposition to a specific disease) may help delimit the region of DNA associated with that genetic disease. The nucleotide sequences of the subject invention may be used to detect differences in gene sequences between normal, carrier or affected individuals.
4.20 PREPARATION OF SUPPORT BOUND OLIGONUCLEOTIDES
Oligonucleotides, i.e., small nucleic acid segments, may be readily prepared by, for example, directly synthesizing the oligonucleotide by chemical means, as is commonly practiced using an automated oligonucleotide synthesizer.
Support bound oligonucleotides may be prepared by any of the methods known to those of skill in the art using any suitable support such as glass, polystyrene or Teflon. One strategy is to precisely spot oligonucleotides synthesized by standard synthesizers.
Immobilization can be achieved using passive adsorption (Inouye ~ Hondo, (1990) J. Clin.
Microbiol. 28(6), 1469-72); using LTV light (Nagata et al., 1985; Dahlen et al., 1987; Morrissey ~
Collins, (1989) Mol.
Cell Probes 3(2) 189-207) or by covalent binding of base modified DNA (I~eller et al., 1988;
1989); all references being specifically incorporated herein.
Another strategy that may be employed is the use of the strong biotin-streptavidin interaction as a linker. For example, Broude et al. (1994) Proc. Natl. Acad.
Sci. LJSA 91(8), 3072-6, describe the use of biotinylated probes, although these are duplex probes, that are immobilized on streptavidin-coated magnetic beads. Streptavidin-coated beads may be purchased from Dynal, Oslo. Of course, this same linking chemistry is applicable to coating any surface with streptavidin. Biotinylated probes may be purchased from various sources, such as, e.g., Operon Technologies (Alameda, CA).
Nunc Laboratories (Naperville, IL) is also selling suitable material that could be used.
Nunc Laboratories have developed a method by which DNA can be covalently bound to the microwell surface termed Covalink NH. CovaLink NH is a polystyrene surface grafted with secondary amino groups (>NH) that serve as bridgeheads for further covalent coupling.
CovaLink Modules may be purchased from Nunc Laboratories. DNA molecules may be bound to CovaLink exclusively at the 5'-end by a phosphoramidate bond, allowing immobilization of more than 1 pmol of DNA (Rasmussen et al., (1991) Anal. Biochem. 198(1) 138-42).
The use of CovaLink NH strips for covalent binding of DNA molecules at the 5'-end has been described (Rasmussen et al., (1991). In this technology, a phosphoramidate bond is employed (Chu et al., (1983) Nucleic Acids Res. 11(8) 6513-29). This is beneficial as immobilization using only a single covalent bond is preferred. The phosphoramidate bond joins the DNA to the CovaLink NH secondary amino groups that are positioned at the end of spacer arms covalently grafted onto the polystyrene surface through a 2 nm long spacer arm. To link an oligonucleotide to CovaLinlc NH via an phosphoramidate bond, the oligonucleotide terminus must have a 5'-end phosphate group. It is, perhaps, even possible for biotin to be covalently bound to CovaLink and then streptavidin used to bind the probes.
More specifically, the linkage method includes dissolving DNA in water (7.5 ngl~l) and denaturing for 10 min. at 95°C and cooling on ice for 10 min. Ice-cold 0.1 M 1-methylimidazole, pH 7.0 (1-MeIm~), is then added to a final concentration of 10 mM 1-Melm~.
A ss DNA solution is then dispensed into CovaLink NH strips (75 ~1/well) standing on ice.
Carbodiimide 0.2 M 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), dissolved in 10 mM 1-MeIm~, is made fresh and 25 pl added per well. The strips are incubated for 5 hours at 50°C. After incubation the strips are washed using, e.g., Nunc-Immuno Wash;
first the wells are washed 3 times, then they are soaked with washing solution for 5 min., and finally they are washed 3 times (where in the washing solution is 0.4 N NaOH, 0.25% SDS
heated to 50°C).
It is contemplated that a further suitable method for use with the present invention is that described in PCT Patent Application W~ 90/03382 (Southern ~ Maskos), incorporated herein by reference. This method of preparing an oligonucleotide bound to a support involves attaching a nucleoside 3'-reagent through the phosphate group by a covalent phosphodiester link to aliphatic hydroxyl groups carried by the support. The oligonucleotide is then synthesized on the supported nucleoside and protecting groups removed from the synthetic oligonucleotide chain under standard conditions that do not cleave the oligonucleotide from the support.
Suitable reagents include nucleoside phosphoramidite and nucleoside hydrogen phosphorate.
An on-chip strategy for the preparation of DNA probe for the preparation of DNA probe arrays may be employed. For example, addressable laser-activated photodeprotection may be employed in the chemical synthesis of oligonucleotides directly on a glass surface, as described by Fodor et cd. (1991) Science 251 (4995), 767-73, incorporated herein by reference. Probes may also be immobilized on nylon supports as described by Van Ness et cxl.
(1991) Nucleic Acids Res., 19(12) 3345-50; or linked to Teflon using the method of Duncan ~z Cavalier (1988) Anal. Biochem. 169(1), 104-8; all references being specifically incorporated herein.
To link an oligonucleotide to a nylon support, as described by Van Ness et al.
(1991), requires activation of the nylon surface via alkylation and selective activation of the 5'-amine of oligonucleotides with cyanuric chloride.

One particular way to prepare support bound oligonucleotides is to utilize the light-generated synthesis described by Pease et al., (1994) Proc. Nat'l. Acad.
Sci., USA 91 (11), 5022-6, incorporated herein~by reference). These authors used current photolithographic techniques to generate arrays of immobilized oligonucleotide probes (DNA
chips). These methods, in which light is used to direct the synthesis of oligonucleotide probes in high-density, miniaturized arrays, utilize photolabile 5'-protected N aryl-deoxynucleoside phosphoramidites, surface linker chemistry and versatile combinatorial synthesis strategies. A
matrix of 256 spatially defined oligonucleotide probes may be generated in this manner.
4.21 PREPARATION OF NUCLEIC ACID FRAGMENTS
The nucleic acids may be obtained from any appropriate source, such as cDNAs, genomic DNA, chromosomal DNA, microdissected chromosome bands, cosmid or YAC
inserts, and RNA, including mRNA without any amplification steps. For example, Sambrook et al. (1989) describes three protocols for the isolation of high molecular weight DNA from mammalian cells (p. 9.14-9.23).
DNA fragments may be prepared as clones in TvIl3, plasmid or lambda vectors and/or prepared directly from genomic DNA or cDNA by PCR or other amplification methods.
Samples may be prepared or dispensed in multiwcll plates. About 100-1000 ng of DNA
samples may be prepared in 2-500 ml of final volume.
The nucleic acids would then be fragmented by any of the methods known to those of skill in the art including, for example, using restriction enzymes as described at 9.24-9.28 of Sambrook et al. (1989), shearing by ultrasound and NaOFI treatment.
Low pressure shearing is also appropriate, as described by Schriefer et al.
(1990) Nucleic Acids Res. 18(24), 7455-6, incorporated herein by reference). In this method, DNA
samples are passed through a small French pressure cell at a variety of low to intermediate pressures. A lever device allows controlled application of low to intermediate pressures to the cell. The results of these studies indicate that low-pressure shearing is a useful alternative to sonic and enzymatic DNA fragmentation methods.
One particularly suitable way for fragmenting DNA is contemplated to be that using the two base recognition endonuclease, CviJI, described by Fitzgerald et al.
(1992) Nucleic Acids Res. 20(14) 3753-62. These authors described an approach for the rapid fragmentation and fractionation of DNA into particular sizes that they contemplated to be suitable for shotgun cloning and sequencing.

The restriction endonuclease CviJI normally cleaves the recognition sequence PuGCPy between the G and C to leave blunt ends. Atypical reaction conditions, which alter the specificity of this enzyme (CviJI**), yield a quasi-random distribution of DNA
fragments form the small molecule pUCl9 (2688 base pairs). Fitzgerald et al.
(1992),quantitatively evaluated the randomness of this fragmentation strategy, using a CviJI** digest of pUCl9 that was size fractionated by a rapid gel filtration method and directly ligated, without end repair, to a lac Z
minus M13 cloning vector. Sequence analysis of 76 clones showed that CviJI**
restricts pyGCPy and PuGCPu, in addition to PuGCPy sites, and that new sequence data is accumulated at a rate consistent with random fragmentation.
As reported in the literature, advantages of this approach compared to sonication and agarose gel fractionation include: smaller amounts of DNA are required (0.2-0.5 pg instead of 2-5 p,g); and fewer steps are involved (no preligation, end repair, chemical extraction, or agarose gel electrophoresis and elution are needed).
Irrespective of the manner in which the nucleic acid fragments are obtained or prepared, it is important to denature the DNA to give single stranded pieces available for hybridization.
This is achieved by incubating the DNA solution for 2-5 minutes at 80-90°C. The solution is then cooled quickly to 2°C to prevent renaturation of the DNA fragments before they are contacted with the chip. Phosphate groups must also be removed from genomic DNA by methods known in the art.
4.22 PPA~A'~°ION ~F IDNA ~S
Arrays may be prepared by spotting DNA samples on a support such as a nylon membrane. Spotting may be performed by using arrays of metal pins (the positions of which correspond to an array of wells in a microtiter plate) to repeated by transfer of about 20 nl of a DNA solution to a nylon membrane. By offset printing, a density of dots higher than the density of the wells is achieved. One to 25 dots may be accommodated in 1 mm2, depending on the type of label used. By avoiding spotting in some preselected number of rows and columns, separate subsets (subarrays) may be formed. Samples in one subarray may be the same genomic segment of DNA (or the same gene) from different individuals, or may be different, overlapped genomic clones. Each of the subarrays may represent replica spotting of the same samples. In one example, a selected gene segment may be amplified from 64 patients. For each patient, the amplified gene segment may be in one 96-well plate (all 96 wells containing the same sample).
A plate for each of the 64 patients is prepared. By using a 96-pin device, all samples may be spotted on one 8 x 12 cm membrane. Subarrays may contain 64 samples, one from each patient.
Where the 96 subarrays are identical, the dot span may be 1 mm2 and there may be a 1 mm space between subarrays.
Another approach is to use membranes or plates (available from NUNC, Naperville, Illinois) which may be partitioned by physical spacers e.g. a plastic grid molded over the membrane, the grid being similar to the sort of membrane applied to the bottom of multiwell plates, or hydrophobic strips. A fixed physical spacer is not preferred for imaging by exposure to flat phosphor-storage screens or x-ray films.
The present invention is illustrated in the following examples. Upon consideration of the present disclosure, one of skill in the art will appreciate that many other embodiments and variations may be made in the scope of the present invention. Accordingly, it is intended that the broader aspects of the present invention not be limited to the disclosure of the following examples. The present invention is not to be limited in scope by the exemplified embodiments which are intended as illustrations of single aspects of the invention, and compositions and methods which are functionally equivalent are within the scope of the invention. Indeed, numerous modifications and variations in the practice of the invention are expected to occur to those skilled in the art upon consideration of the present preferred embodiments. Consequently, the only limitations which should be placed upon the scope of the invention are those which appear in the appended claims.
All references cited within the body of the instant specification are hereby incorporated by reference in their entirety.
5.0 E~~LE~"
5.1 E LE 1 Novel Nucleic Acid Seguences Obtained From Various Libraries A plurality of novel nucleic acids were obtained from cDNA libraries prepared from various human tissues and in some cases isolated from a genomic library derived from human chromosome using standard PCR, SBIi sequence signature analysis and Banger sequencing techniques. The inserts of the library were amplified with PCR using primers specific for the vector sequences which flank the inserts. Clones from cDNA libraries were spotted on nylon membrane filters and screened with oligonucleotide probes (e.g., 7-mers) to obtain signature sequences. The clones were clustered into groups of similar or identical sequences.
Representative clones were selected for sequencing.

In some cases, the 5' sequence of the amplified inserts was then deduced using a typical Sanger sequencing protocol. PCR products were purified and subjected to fluorescent dye terminator cycle sequencing. Single pass gel sequencing was done using a 377 Applied Biosystems (ABI) sequencer to obtain the novel nucleic acid sequences.
5.2 EXAMPLE 2 Assemblage of Novel Nucleic Acids The contigs or nucleic acids of the present invention, designated as SEQ ID
NO: 1369-1966 were assembled using an EST sequence as a seed. Then a recursive algorithm was used to extend the seed EST into an extended assemblage, by pulling additional sequences from different databases (i.e., Hyseq's database containing EST sequences, dbEST, gb pri, and LTniGene, and exons from public domain genomic sequences predicated by GenScan) that belong to this assemblage. The algorithm terminated when there were no additional sequences from the above databases that would extend the assemblage. Further, inclusion of component sequences into the assemblage was based on a BLASTN hit to the extending assemblage with BLAST score greater than 300 and percent identity greater than 95~/0.
Table 7 sets forth the novel predicted polypeptides (including proteins), SEA
~ NO:
1967-2564, encoded by the novel polynucleotides (SEQ ID NO: 1369-1966) of the present invention, and their corresponding translation start and stop nucleotide locations to each of SEA
ID NO: 1369-1966. Table 7 also indicates the method by which the polypeptide was predicted.
Method A refers to a polypeptide obtained by using a software program called FAST' (available from http://fasta.bioch.vir~inia.edu) which selects a polypeptidc based on a comparison of the translated novel polynucleotide to l~nown polynucleotides ('6~3.R. Pearson, Methods in Enzymology, 183:63-98 (1990), herein incorporated by reference).
Method B
refers to a polypeptide obtained by using a software program called GenScan for human/vertebrate sequences (available from Stanford University, Office of Technology Licensing) that predicts the polypeptide based on a probabilistic model of gene structure/compositional properties (C. Burge and S. Karlin, J. Mol. Biol., 268:78-94 (1997), incorporated herein by reference). Method C refers to a polypeptide obtained by using a Hyseq proprietary software program that translates the novel polynucleotide and its complementary strand into six possible amino acid sequences (forward and reverse frames) and chooses the polypeptide with the longest open reading frame.

5.3 EXAMPLE 3 Novel Nucleic Acids The novel nucleic acids of the present invention were assembled from sequences that were obtained from a cDNA library by methods described in Example 1 above, and in some cases sequences obtained from one or more public databases. The nucleic acids were assembled using an EST sequence as a seed. Then a recursive algorithm was used to extend the seed EST into an extended assemblage, by pulling additional sequences from different databases (Hyseq's database containing EST sequences, dbEST, gb pri, and UniGene) that belong to this assemblage. The algorithm terminated when there was no additional sequences from the above databases that would extend the assemblage. Inclusion of component sequences into the assemblage was based on a BLASTN hit to the extending assemblage with BLAST
score greater than 300 and percent identity greater than 95%.
Using PHRAP (TJniv. of Washington) or CAP4 (Paracel), a full-length gene cDNA
sequence and its corresponding protein sequence were generated from the assemblage. Any frame shifts and incorrect stop codons were corrected by hand editing. During editing, the sequences were checked using FAST Y and/or BLAST against Genebank (i.e., dbEST, gb pri, UniGene, and Genpept) and the Geneseq (Dervvent). Other computer programs which may have been used in the editing process were phredPhrap and Conned (University of Washington) and ed-ready, ed-ext and cg-zip-2 (Hyseq, Inc.). The full-length nucleotide and amino acid sequences, including splice variants resulting from these procedures are shown in the Sequence Listing as SEQ ff~ NO: 1-1368.
The nucleic acid sequences ofthe present invention were conftrmed to have at least one transmembrane domain using the TMpred program (htta://www.ch.embnet.or~/software/TMPRED form html). One of skill in the art will recognize that the proteins of the present invention may be utilized as either a membrane-bound target or a soluble protein.
Table 1 shows the various tissue sources of SEQ ID NO: 1-684.
The homologs for polypeptides SEQ TD NO: 685-1368 that correspond to nucleotide sequences SEQ ID NO: 1-684 were obtained by a BLASTP version 2.Oa1 19MP-WashU
searches against Genpept and Geneseq (Derwent) using BLAST algorithm. The results showing homologues for SEQ ID NO: 685-1368 are shown in Tables 2A and 2B.
Using eMatrix software package (Stanford University, Stanford, CA) (Wu et al., J.
Comp. Biol., Vol. 6, 219-235 (1999), httb://motif.stanford.edu/ematrix-search/
herein incorporated by reference), all the polypeptide sequences were examined to determine whether they had identifiable signature regions. Scoring matrices of the eMatrix software package are derived from the BLOCKS, PRINTS, PFAM, PRODOM, and DOMO
databases. Tables 3A and 3B show the accession number of the homologous eMatrix signature found in the indicated polypeptide sequence, its description, and the results obtained which include accession number subtype; raw score; p-value; and the position of signature in amino acid sequence.
Using the Pfam software program (Sonnhammer et al., Nucleic Acids Res., Vol.
26(1) pp. 320-322 (1998) herein incorporated by reference) all the polypeptide sequences were examined for domains with homology to certain peptide domains. Tables 4A
and 4B
show the name of the Pfam model found, the description, the e-value and the Pfam score for the identified model within the sequence. Further description of the Pfam models can be found at http://pfam.wustl.edu/.
Table 5 shows the position of the signal peptide in each of the polypeptides and the maximum score and mean score associated with that signal peptide using Neural Network SignalP V 1.1 program (fiom Center for Biological Sequence Analysis, The Technical University of Denmark). The process for identifying prokaryotic and eukaryotic signal peptides and their cleavage sites arc also disclosed by Henrik Nielson, Jacob Engelbrecht, Soren Brunak, and Gunnar von Heijne in the publication " IdentiEcation of prokaryotic and eukaryotic signal peptides and prediction of their cleavage sites" Protein Engineering, Vol.
10, no. 1, pp. 1-6 (1997), incorporated herein by reference. A maximum S score and a mean S score, as described in the Nielson et al reference, was obtained for the polypeptidc sequences.
Table 6 correlates nucleotide sequences of the invention to a specific chromosomal location when assignable.
Table 8 shows the number of transmembrane regions, their location(s), and TMPred score obtained, for each of the SEQ ID NO: 685-1368 that had a TMPred score of 500 or greater, using the TMpred program (http:l/www.ch.embnet.or~/software/TMPRED form.html).
Table 9 is a correlation table of the novel polynucleotide sequences SEQ ID
NO: 1-684, their corresponding polypeptide sequences SEQ ID NO: 685-1368, their corresponding priority contig nucleotide sequences SEQ ID NO: 1369-1966, their corresponding priority contig polypeptide sequences SEQ ID NO: 1967-2564, and the US serial number of the priority application (all of which are herein incorporated in their entirety), in which the contig sequence was filed.

Tissue Ori Librar /RNA HYSEQ Librar SEQ ID NOS:
in Source Name adult brain GIBCO AB3001 39-40 56 68 adult brain GIBCO ABD003 10 13 15 17-20 adult brain Clontech ABR001 7 18 22 24 29 adult brain Clontech ABR006 7-8 10 13 16 TA13T,F 1 Tissue Ori Librar /RNA HYSEQ Librar SEQ ID NOS:
in Source Name adult brain Clontech ABR008 7-8 10 14 19 21 l34 139-140 144 343 346 349 35l adult brain Clontech ABRO11 289 384 537 adult brain BioChain ABR012 26 384 607 adult brain BioChain ABR013 20 79 153 220 adult brain Invitrogen ABR014 48-50 52 106 170 Tissue Ori Librar /RNA HYSEQ Librar SEQ ID NOS:
in Source Name adult brain Invitrogen ABR015 20 46 106 150 l53 adult brain Invitrogen ABR016 60 69 153 368 adult brain Invitrogen ABT004 10 16 24 29 43 cultured Stratagene ADP001 10 19-20 23 26 preadipocytes 68 70 106 116-117 330 349 35l 361 adrenal glandClontech ADR002 10 18 25 27 29 Tissue Ori Librar /RNA I3YSEQ Libra SEQ ID NOS:
in Source Name adult heart GIBCO AHR001 5 16 18 24-26 150 154 158-l59 573 586-587 60l adult kidney GIBCO AKD001 5 10 12-13 16 Tissue Ori Librar /RNA HYSEQ Libra NameSEQ ID NOS:
in Source 518-519 52l-522 adult kidney Invitrogen AKT002 6 8 10 14-15 116-117 l26 150 adult lung GIBCO AhG001 13 22 26 63 66 lymph node Clontech ALN001 13 26 33 54 56 young liver GIBCO ALV001 5 10 13 24-25 Tissue OriginLibrar /RNA ~HS'SEQ Library SEQ ID_ NOS:
Source Name adult liver Invitrogen ALV002 5 14 16-17 19 adult liver Clontech ALV003 7 18-19 24 38 adult ~vary~ Invitrogen AOV001 5 7-8 10 12 14 154 157-l61 171-Tissue Ori Librai '/RNA HYSEQ Librar SEQ ID NOS:
in Source ~ Name adult placentaClontech APL001 1-4 63-64 66 placenta , Invitrogen APL002 1-4 7 51 68 85 adult spleen GIBCO ASP001 7 13-14 17 26 l20 135 137 141-adult testis GIBCO ATS001 5 10 19 29 39 ll6-150 153 172 l75-Tissue OriginLibrary/RNA IiYSEQ Librar SEQ ID NOS:
Source Name adult bladderInvitrogen BLD001 5 10 26 51 65 bone marrow Clontech BMD001 5 7 30-31 34 165 172 l77 198 bone marrow GF BMD002 7-8 12 14 17 Tissue Ori Librar /RNA HYSEQ Librar SEQ ID NOS:
in Source Name 491-.492 499 bone marrow Clontech BMD004 507 522 bone marrow Clontech BMD007 368 504-506 *Mixture of Various VendorsCGd010 99 132-133 165 tissues - 237-241 275-278 mRNA

*Mixture of Various VendorsCGd011 33 42 153 168-169 tissues - 178 213-214 mRNA 245 Mixture of Various VendorsCGd012 5 14 18 21 24 tissues - 33 35 39 42 mRNA 44 46 TABLE l Tissue Ori Librar /RNA IiYSEQ Librar SE ID NOS:
in Source Name *Mixture of Various VendorsCGd013 56 58 61-62 70 l6 131 tissues - 160-161 163-l64 mRNA

193 247 290 31l *Mixture of Various VendorsCGd015 1-5 8 14 17 52 tissues - 68 87 215 228 mRNA 259-*Mixture of Various VendorsCGdOl6 10 14 19 24-28 l6 33 tissues - 57 65 70 76 112-mRNA

adult colon Invitrogen CLN001 5 10 14 29 35 adult cervix BioChain CVX001 7 10 14 16 18 Tissue Ori Library/RNA Iii'SEQ Librar SEQ ID NOS:
in Source Name diaphragm BioChain DIA002 93 l34 308 402 endothelial Stratagene EDT001 7 10 12 17 19 cells 29 34 36 39 117 127 l31 507 510 5l8 fetal brain Clontech FBR001 8 24 54 56 59 fetal brain Clontech FBR004 20 53 160-l61 fetal brain Clontech FBR006 7-8 10 15 18-19 Tissue Ori Librar /RNA NYSE Librar SEQ ID NOS:
in Source Name 140.147-l48 155 163 l65 170 179-l80 189-190 208 fetal brain Clontech FBRs03 17 371 fetal brain Invitrogen FBT002 7 10 29 43 47-49 fetal heart Invitrogen FHR001 8 14-15 20 24-26 Tissue Ori Library/RNA HYSEQ Librar SEQ ID NOS:
in Source Name fetal kidney Clontech FKD001 26 62 96 106 fetal kidney Clontech FKD002 46 54 64 68 85 fetal kidney Invitrogen FKD007 227 fetal lung Clontech FLG001 25 40 56 75 93 fetal lung Invitrogen FLG003 5 7 10 16 22 fetal lung Clontech FLG004 305 fetal liver- Columbia FLS001 1-5 7-8 10 12 spleen University 17 19-20 24-27 Tissue Ori Librar /RNA HYSEQ Librar SEQ ID NOS:
in Source Name l55 168-169 177-308 314 3l6-318 fetal liver- Columbia FL5002 2-5 7-8 10 12 spleen University 17 19 24 26-27 Tissue Ori Librar /RNA I3YSEQ Libra SEQ ID NOS:
in Source Name 478 48l-482 486-516 5l8 521-522 fetal liver- Columbia FLS003 2-5 14 l8 20 spleen University 44 62 64 68 80-83 fetal liver Invitrogen FLV001 5 10 24 46 52 fetal liver Clontech FLV002 10 24 140 153 l70 Tissue Ori Librai /RNA HYSEQ Librar SEQ ID NOS:
in Source Name fetal liver Clontech FLV004 5 13-14 18 20 170-172 2l8-219 fetal muscle Invitrogen FM5001 5 16 24-26 64 fetal muscle Invitrogen FMS002 6 15-l6 21 26 l59 167-169 171 fetal skin Invitrogen FSK001 5 7-8 10 14-17 Tissue Ori Librar /RNA HYSEQ Librar SEQ ID NOS:
in Source Name fetal skin Invitrogen FSK002 5 10 16 18 20 41l 417-418 422 441 451 453,.462 530 532 54l 543 fetal spleen BioChain FSP001 26 87 371 461 umbilical cordBioChain FUC001 5 18 20 26 40 Tissue Ori Librar /RNA I3YSEQ Librar SE ID NOS:
in Source Name fetal brain GIBCO HFB001 5 10 18-21 27 macrophage Invitrogen HMP001 18 26 43 64 118 infant brain Columbia IB2002 7 14 16-17 21 University 25-26 29 40 47-50 TABLE l Tissue Ori Library/RNA HYSE Librar NameSEQ ID NOS:
in Source 604-605 607 6l0 infant brain Columbia IB2003 7 10 16 19-20 University 29 35 43 46-50 infant brain Columbia IBM002 47-50 84 151-152 University 157 188-189 209 Tissue Ori Library/RNA HYSEQ Library SEQ ID NOS:
iu Source Name infant brain Columbia IBS001 10 16 29 46-50 University 58 67 78 80-82 lung, Stratagene LFB001 5 7 16 19 40 fibroblast 61-62 68 83 lung tumor Invitrogen LGT002 5-7 10 15-16 18-l9 lymphocytes ATCC LPC001 13 16 18 20 Tissue Ori Librar /RNA IiYSEQ Librar SEQ ID NOS:
in Source Name leukocyte GIBCO hUC001 10 16 18 24 34 94 98 l06 109 526 530 535 54l leukocyte Clontech LUC003 20 47-49 52 56 melanoma from-Clontech MEL004 14 25 34 47-49 cell-line-ATCC- 64 66 83 92 106 #CRL-1424 l39 150 162 173-Tissue Ori Librar /RNA IiYSEQ Librar SEQ ID NOS:
in Source Name l74 189 192 210 mammary glandInvitrogen MMG001 5 7 10 16-17 l44 150-152 158--623 627 63l-632 induced neuron-Stratagene NTD001 17 20 23 68 79 cells 153 155 181-182 retinoic acid-5tratagene NTR001 7 23 56 68 70 induced- 186 189 213-214 neuronal-cells 290 293 342 461 neuronal cellsStratagene NTU001 7 29 42 68 70 Tissue OriginLibrar /RNA IiYSEQ Librar SEQ ID NOS:
Source Name pituitary Clontech PIT004 2-4 47-49 56 gland 68 72 93 l37-138 141-l42 placenta Clontech PLA003 1-5 7 12 26 37 350-351 359 37l prostate Clontech PRT001 20 25 56 173-174 rectum Tnvitrogen REC001 7 10 20 47-50 salivary glandClontech SAL001 5 10 22 25 43 Tissue Ori Libra /RNA HYSEQ Librar SEQ ID NOS:
in Source Name 323 351 368 37l saliva gland Clontech SALs03 20 skin fibroblastATCC SFB001 208 skin fibroblastATCC SFB002 208 small intestineClontech SINOOl 5 7-8 10 15 24 l00 106 108 111 skeletal muscleClontech SKM001 5 62 101 104 skeletal muscleClontech SKM002 208 507 spinal cord Clontech SPC001 13 15 26-27 33-34 Tissue Ori Librar /RNA HYSEQ Librar SEQ ID NOS:
in Source Name adult spleen Clontech SPLc01 7 9 13 l7 26 bone marrow null STM001 7 43 162 252 stomach Clontech ST0001 67 93 95 135 thalamus Clontech THA002 10 18 24 33 47-50 thymus Clontech THM001 5 12 39-40 43 Tissue Ori Librar /RNASourceIi1'SEQ LibrarySE ID NOS:
in Name thymus Clontech THMc02 5 8 10 12 25 159.163-165 179 a thyroid gland Clontech THR001 6 14-15 19 26 . 131 137 141-142 Tissue Ori in Librar /RNA HYSEQ Librar SEQ ID NOS:
Source Name 626 63l-632 635 trachea Clontech TRC001 7 22 38 40 56 uterus Clontech UTR001 l7 36 70 76 103 *The 16 tissue/mRNAs and their vendor sources are as follows: 1) Normal adult brain mRNA (Invitrogen), 2) Normal adult kidney mRNA (Invitrogen), 3) Normal fetal brain mRNA (Invitrogen), 4) Normal adult liver mRNA
(Invitrogen), 5) Normal fetal kidney mRNA (Invitrogen), 6) Normal fetal liver mRNA (Invitrogen), 7) normal fetal skin mRNA (Invitrogen), 8) human adrenal gland mRNA (Clontech), 9) Human bone marrow mRNA (Clontech), 10) Human leukemia lymphoblastic mRNA (Clontech), 11) Human thymus mRNA
(Clontech), 12) human lymph node mRNA (Clontech), 13) human so\spinal cord mRNA (Clontech), 14) human thyroid mRNA (Clontech), 15) human esophagus mRNA (BioChain), 16) human conceptional umbilical cord mRNA (BioChain).

SEQ Hit ID Species Description S Percentage ID scoreidenti 685 gi183150 Homo Sapienschorionic somatomammotropin320 100 685 gi181127 Homo Sapienschorionic somatomammotropin275 96 precursor 685 gi183153 Homo Sapienschorionic somatomammotropin275 96 686 gi183178 Homo SapienshGH-V2 1033 78 686 gi183153 Homo Sapienschorionic somatomammotropin710 87 686 gi387024 Homo Sapiensplacental facto en hormone710 87 precursor 688 gi183178 Homo SapienshGH-V2 1051 79 688 gi181121 Homo Sapienschorionic somatomammotropin788 95 688 gi183151 Homo Sapienschorionic somatomammotropin788 95 689 gi12653501Homo SapiensSimilar to serine (or 1242 99 cysteine) proteinase inhibitor, Glade F (alpha-2 antiplasmin, pigment epithelium derived factor).
member 1 689 gi15217079Homo Sapienspigment epithelium-derived1242 99 factor 689 gi189778 Homo Sapienspigment epithelial-differentiating1242 99 factor 690 gi17128288synthetic Primer 1 1150 99 construct 690 gi20269957Sus scrofaphospholipase C delta 1033 88 690 gi21307610Mus musculusphospholipase C delta 909 77 691 gi17864023Homo SapiensKCCR13L 3524 100 691 gi21483462DrosophilaLD44686p 533 36 melano aster 691 gi21741717Ory~a sativao'991113_30.22 127 29 692 gi17428818Ralstonia GALA PROTEIN 3 117 32 solanacearum 692 gi21536497.~rabidopsisF-box protein family, 115 30 thaliana AtFBL4~

692 gi12581504TrypanosomeGUl 115 33 brucei 693 gi437662 Oryctolagusinterleukin-8 receptor 194 61 cuniculus subtype B

693 gi186378 Homo sapiensinterleukin 8 receptor 178 57 B

693 gi1109691Homo Sapiensinterleulsin-8 receptor178 57 type B

694 13335098 Homo sapiensCD39L2 2520 100 694 gi11230487Rattus NTPDase6 2065 86 norvegicus 694 gi5139519Mus musculusnucleoside diphosphatase1008 53 (ER-UDPase) 695 gi21928620Homo sapiensseven transmembrane 1858 100 helix receptor 695 gi16566319Homo SapiensG protein-coupledreceptor1843 99 695 gi6644328Rattus orphan G protein-coupled822 50 norvegicusreceptor 696 gi7110216Homo sapiensC-type lectin-like receptor-1851 99 696 gi7109731Homo SapiensC-type lectin-like receptor-2256 31 696 gi20381202Mus musculusSimilar to C-type (calcium196 27 dependent, carbohydrate recognition domain) lectin, superfamily member 12 697 gi22449809Chaoborus cytochrome oxidase I 50 44 trivitattus 697 gi2351328Newcastle fusion protein 59 44 disease virus 697 gi21311450Galleria antifungal peptide gallerimycin55 33 i mellonella 698 gi18089247Homo SapiensSimilar to ectonucleoside2104 100 triphosphate diphosphohydrolase 5 SEQ Hit ID Species Description S Percentage ID scoreidenti 698 gi3335102Homo SapiensCD39L4 2104 100 698 gi15076827Homo SapiensPcph proto-oncogene 2090 99 protein 699 gi151242 Pseudomonasheat shock protein 79 38 aeruginosa 699 gi9950616PseudomonasGroES protein 79 38 aeruginosa 699 gi2564287PseudomonasHsplO protein 79 44 stutzeri 701 gi20521055Homo SapiensStart codon is not identified724 32 701 gi17225457Homo Sapiensautism-related protein 676 32 701 gi15145797Sus scrofabasic proline-rich protein156 27 702 gi20810589Homo Sapienssimilar to arsenite 833 99 inducible RNA
associated protein 702 gi9651711Mus musculusarsenite inducible RNA 687 80 associated protein 702 gi17390981Homo SapiensSimilar to RIICEN cDNA 535 59 gene 703 gi6624130Rattus similar to 45 kDa secretory2150 100 norvegicusprotein ;

703 gi13241652Rattus supernatant protein 2040 93 norvegicusfactor 703 gi19548982Bos taurustocopherol-associated 1930 90 protein 704 gi13177766Homo SapiensSimilar to presenilins 1761 99 associated rhomboid-like protein 704 gi15559382Homo Sapienspresenilins associated 1094 98 rhomboid-like _ protein 704 gi7959883Homo SapiensPR~2207 671 82 705 gi1864091Rattus PSD-95/SAP90-associated5005 95 norvegicusprotein-3 705 gi2454510Homo SapiensPSD-95/SAP90-associated1338 55 protein-2 705 gi6979173Homo Sapiensdiscs, large (Drosophila)1011 45 homolog-associated protein 2 706 gil 1877274Homo SapiensdJ726C3.2 (novel protein)2260 99 706 gi21667210Hozno Sapiensbactericidal/permeability-increasing2260 99 protein-like 1 706 gi20387087~ncorhynchuSLBP (LPs binding protein)/BPI349 26 mylciss (bactericidal/permeability-increasing protein) like-2 707 gi7291716DrosophilaCG11388-FA 648 39 melanogaster 707 gi16768190DrosophilaGH22974p 647 39 melanogaster 707 gi3954938Homo Sapiensacetylglucosaminyltransferase-like171 23 protein 708 gi14334082Mus musculusthymus LIM protein TLP-A479 87 708 gi14334084Mus musculusthymus LIM protein TLP-B397 79 708 gi487284 Rattus CRP2 (cysteine-rich 367 75 norvegicusprotein 2) 710 gi556299 Mus musculusalpha-2 type IV collagen8129 83 710 gi30076 Homo Sapiensalpha-2 chain precursor5916 100 (AA -25 to 1018) (3416 is 2nd base in codon) 710 115991848Homo SapiensA type IV collagen 4239 51 711 gi7861733Homo Sapienslow density lipoprotein2583 99 receptor related 1 protein-deleted in tumor 711 gi8926243Mus musculuslow density lipoprotein2409 91 receptor related 6 protein LRP1B/LRP-DIT

SEQ Hit ID Species Description S Percentage ID scoreidenti 711 gi438007 Gallus alpha-2-macroglobulin 1419 63 gallus receptor 7 712 gi17298315Homo Sapienscandidate tumor suppresser848 100 protein 712 gi7861733Homo sapienslow density lipoprotein848 100 receptor related protein-deleted in tumor 712 gi8926243Mus musculuslow density lipoprotein731 83 receptor related protein LRP1B/LRP-DIT

713 gi16877754Homo sapiensSimilar to RIKEN cDNA 574 56 gene 713 gi20071811Mus musculusSimilar to RIKEN cDNA 493 60 gene 713 gi1340174Homo sapienstype III procollagen 97 40 (aa 892-1023) 714 gi157409 Drosophilafat protein 1802 31 melanogaster 714 gi4887715Drosophilaadherin 1500 36 melanogaster 714 gi1107687Homo Sapienshomologue of Drosophila1514 30 Fat protein _ gi157409 Drosophilafat protein 1808 31 715 melanogaster 715 gi4887715Drosophilaadherin 1500 36 melanogaster 715 i 1107687Homo Sapienshomolo a of Drosophila 1514 30 Fat protein 716 117865311Homo Sapiensdipeptidyl peptidase-like2562 99 protein 9 716 gi3513303Homo Sapiens826984_1 2700 98 716 gi11095188Homo Sapiensdipeptidyl peptidase 1397 53 717 gi2689444Homo Sapiens~NF134~ 1160 54 717 gi21314~977Homo SapiensSimilar to zinc finger 1038 51 protein 17 (HPF3, K~X 10) 717 gi 13543419Homo SapiensSimilar to zinc finger 1000 51 protein 304 718 gi7582294Homo SapiensBM-011 881 100 718 gi13937769Homo SapiensSimilar to RIICEN cDNA 781 98 ene 718 ' 178997 Homo Sapiensarginine-rich nuclear 224 38 protein 719 gi1620870Ciona myoplasmin-C1 412 28 intestinalis 719 gi7416980Argopectenmyosin heavy chain catch279 23 irradians (smooth) muscle specific isoform 719 gi7416982Argopectenmyosin heavy chain cardiac279 23 irradians muscle specific isoform 1 720 gi13872813Homo Sapiensfibulin-6 1376 100 720 gi14575679Homo Sapienshemicentin 1372 99 720 gi3328186Caenorhabditishemicentin precursor 1695 30 elegans 721 gi3822553Gallus nuclear calmodulin-binding1492 64 gallus protein 721 gi3329496Mus musculusheterogenous nuclear 1501 45 ribonucleoprotein U

721 gi624918 Rattus SP120 1498 45 norvegicus 722 gi17223626Homo SapiensATP-binding cassette 7966 99 722 '17223624Homo SapiensATP-binding cassette 5160 61 722 gi17223622Homo SapiensATP-bindin cassette 5108 61 723 gi13374079Homo SapiensTAFII140 protein 3677 99 723 gi13374178Mus musculusTAFII140 protein 3202 84 SEQ Hit ID Species Description S Percentage ID scoreidenti 723 gi205686 Rattus heavy neurofilament 335 26 norvegicussubunit 724 gi17429038Ralstonia PROBABLE ACYL-COA 661 61 solanacearumDEHYDROGENASE
OXIDOREDUCTASE PROTEIN

724 gi9948609Pseudomonasprobable acyl-CoA dehydrogenase619 62 aeruginosa 724 gi13421911Caulobacteracyl-CoA dehydrogenase 559 59 crescentusfamily protein 725 gi6752658Homo Sapiensepidermal growth factor3055 99 repeat containing protein 725 gi16040981Mus musculusPOEM 884 51 725 ' 15430246Mus musculusnephronectin short isoform884 51 726 gi6531661CaenorhabditisL1N-41A 844 50 elegans 726 gi6531663CaenorhabditisLIN-41B 844 50 elegans 726 gi 12407367Homo Sapienstripartite motif protein769 30 727 gi1504026Homo Sapienssimilar to C.elegans 5833 99 protein (Z37093) 727 gi2896796Homo SapiensD1013901 5115 99 727 gi2522322Homo SapiensPTPLl-associated RhoGAP1497 36 728 gi13274120Homo sapienSdJ55C23.5.1 (vanin 3, 1467 99 isoform 1) 728 gi7160973Homo sapiensVNN3 protein 1213 96 728 gi6102996Mus musculusVanin-3 1018 79 729 gi9581879Homo Sapiensdisintegrin metalloproteinase5723 99 with thrombospondin repeats 729 gi19171176Homo Sapiensmetalloprotease disintegrin1669 50 15 with thrombospondin domains 729 gi11095299Rattus ADA1VITS-1 1772 40 norve icus 730 gi21063967DrosophilaAT05453p 396 32 melanogaster 730 gi5911409Drosophilafu~~y 396 32 melanogaster 730 gi2564657DrosophilaFu~~y 396 32 melano aster 731 gi15217171Homo SapiensCD81 partner 3 2302 100 731 gi15488017Homo sapiensEWI2 2302 100 731 gi15593237Mus musculusimmunoglobulin superfamily2186 92 receptor PGRL

732 115217171Homo SapiensCD81 partner 3 3200 100 732 gi15488017Homo SapiensEWI2 3200 100 732 gi15593237Mus musculusimmunoglobulin superfamily2867 88 receptor PGRL

733 gi15217171Homo SapiensCD81 partner 3 1303 96 733 gi15488017Homo SapiensEWI2 1303 96 733 gi22266726Homo SapiensLIR-D1 precursor 1303 96 734 121748480Homo SapiensFLJ00271 protein 605 100 734 gi22266726Homo SapiensLIR-D1 precursor 514 79 734 gi15217171Homo SapiensCD81 partner 3 514 79 735 gi2196872Homo SapiensLsc homologue 203 30 735 11389756 Mus musculusLsc 199 31 735 gi11276027Rattus LSC 199 31 SEQ Hit ID Species Description S Percentage ID scoreidenti norvegicus 736 gi14336728Homo Sapienspossible integral membrane331 32 736 gi18043242Mus musculusRIKEN cDNA 2400010615 331 31 ene 736 gi8895014Hepatitis HBsAg 68 48 B
virus 737 gi20071204Mus musculusSimilar to paraspeckle 185 28 protein 1 737 gi18104577Homo Sapiensparaspeckle protein 175 27 1 alpha isoform 737 gi13528666Homo SapiensSimilar to splicing 179 31 factor proline/glutamine rich (polypyrimidine tract-binding protein-associated) 738 gi12002000Homo SapiensMy029 protein 415 100 738 gi348140 Human T- rex 68 39 lymphotropic virus 2 738 gi404041 Human T- rex protein 68 39 lymphotropic virus 2 739 gi4680090Human envelope glycoprotein 89 31 immunodeficien cy virus type 1 740 gi21627272DrosophilaCG12765-PA 166 38 melanogaster 740 gi19528077DrosophilaAT24025p 166 38 melanogaster 740 gi1066820Murray nonstructural protein 66 28 Valley encephalitis virus 741 gi9916 Plasmodiumliver stage antigen 468 26 falciparum 741 gi1747 Oryctolagustrichohyalin 414 24 cuniculus 741 1295941 Ovis criestrichohyalin 395 24 742 gi98454=85Homo Sapiensprotocadherin-9 6235 100 742 gi15054521Homo Sapiensprotocadherin-S 3390 58 742 gi13161060Homo Sapiensprotocadherin 11 3382 58 743 gi5688958Homo SapiensPMMLP 2405 100 743 121594625Mus musculusRII~EN cDNA 4931406N15 2241 92 gene 743 gi16797814~Drosophilaphosphomannomutase 45A 1194 51 melanogaster 744 gi21734445Rattus BMP/Retinoic acid-inducible3987 94 norvegicusneurai-specific protein-2 744 gi20988899Mus musculussimilar to deleted in 2952 70 bladder cancer chromosome region candidate 744 gi21734447Rattus BMP/Retinoic acid-inducible2951 70 norvegicusneural-specific protein-3 745 12739353 Homo SapiensZNF91L 2075 69 745 gi1017722Homo Sapiensrepressor transcriptional2044 71 factor 745 gi4559318Homo SapiensBC273239_1 2031 67 746 11017722 Homo Sapiensrepressor transcriptional2144 73 factor 746 gi2739353Homo SapiensZNF91L 2054 70 746 gi186774 Homo Sapienszinc finger protein 2035 70 747 119683999Homo Sapienscoated vesicle membrane1010 99 protein 747 gi1212965Homo Sapienstransmembrane protein 1010 99 747 gi1213221Rattus transmembrane protein 1006 98 norvegicus SEQ Hit ID Species Description S Percentage ID scoreidenti 748 gi1199524Homo Sapiensacidphosphatase 2b36 98 748 gi34263 Homo Sapiensacid phosphatase precursor2036 98 protein 748 gi13111975Homo Sapiensacid phosphatase 2, 2032 98 lysosomal 749 gi15625570Homo Sapienscentaurin betas 2970 83 749 14688902Homo Sapienscentaurin beta2 1708 64 749 1436228 Homo SapiensStart codon is not identified1387 70 750 gi10197642Homo SapiensMDS022 647 100 750 gi19683046DictyosteliumHYPOTHETICAL 21.8 KDA 94 26 discoideum PROTEIN.

750 gi6841554Homo SapiensHSPC166 93 24 751 gi5630080Homo Sapienssimilar to HUB 1; similar696 48 to BAA24380 (PID:g2789430) 751 gi2789430Homo Sapiensrepressor protein 702 39 7 gi18614026Homo Sapienszinc finger DNA binding1004 41 51 protein p71 _ gi12140290Homo SapiensbA12M19.2.1 (vacuolar 2885 92 752 protein sorting protein 16 (VPS16)) 752 gi11345382Homo sapiensvacuolar protein sorting2885 92 protein 16 752 gi19343731Mus musculusvacuolar protein sorting2803 89 16 (yeast homology 753 120987877Mus musculussimilar to Nogo receptor905 58 753 gi9280025Macaca Nogo receptor 808 49 fascicularis 753 gi15080005Homo Sapiensno o receptor 796 4~8 754 gi 177870Homo Sapiensalpha-2-macro lobulin 2714 39 precursor 754 gi579592Homo sapiensalpha 2-macroglobulin 2708 39 754 gi579594Homo Sapiensalpha 2-macro lobulin 2700 39 755 gi4929790Homo Sapiensangiopoietin-related 1423 89 protein 3 755 ' 13159474Homo SapiensCG006-alt2 1416 88 755 gi5639997Mus musculusangiopoietin-related 1109 77 protein 3 756 '200057 Mus musculusneuronal glycoprotein 4821 87 756 gi563133Rattus BIG-1 protein 4778 87 norvegicus 756 gi1016012RattuS neural cell adhesion 3867 68 norvegicus protein BIG-2 precursor 757 gi6273399Homo sapiensmelanoma-associated 344 33 antigen MG50 757 gi1504040Homo Sapienssimilar to D.melanogaster344 33 peroxidasin(U11052) 757 gi14495561Homo Sapiensbrain tumor associated 324 27 protein LRRC4 758 gi6273399Homo Sapiensmelanoma-associated 344 33 antigen MG50 758 gi1504040Homo Sapienssimilar to D.melanogaster344 33 peroxidasin(Ul 1052) 758 gi14495561Homo Sapiensbrain tumor associated 329 26 protein LRRC4 759 gi5525078Rattus seven transmembrane 5062 72 norvegicus receptor 759 121929093Homo Sapiensseven transmembrane 1712 88 helix receptor 759 gi4164023Bos taurus latrophilin 2 splice 383 27 variant baaaf 760 gi10440398Homo SapiensFLJ00032 protein 1261 57 760 gi11917507Homo SapiensHPF1 protein 1258 60 760 gi13752754Homo Sapienszinc finger 1111 1253 60 761 gi3628757Homo SapiensFICl 1436 54 761 gi13097633Homo SapiensSimilar to ATPase, Class1221 60 I, type 8B, member 1 761 gi20147219ArabidopsisAt1g59820/F23H11_14 1637 41 thaliana SEQ Hit ID Species Description S Percentage ID scoreidenti 762 gi11527987Gallus immunoglobulin-like 97 30 gallus receptor CHIR-A

762 gi432214 Human envelope glycoprotein 43 39 gp120 immunodeficien cy virus type 1 762 gi15026993Homo SapiensMUCSAC protein 64 38 763 gi11558486Homo SapiensB-cell lymphoma/leukaemia1314 99 11A short form 763 gi7546791Mus musculusCTIP1 protein 1149 99 763 gi7650184Mus musculusecotropic viral integration1155 95 site 9 isoform C

764 gi22085890Rattus FHA-HIT 1426 82 norvegicus 764 gi21430028DrosophilaGM01362p 338 40 melanogaster 764 gi21166012Dictyostelium2410016G21RIK PROTEIN 279 26 discoideum 765 gi22085890Rattus FHA-HIT 214 88 norvegicus 765 gi5764101Homo Sapienspolynucleotide kinase-3'-phosphatase95 50 765 gi5712131Homo SapiensDEM1 protein 93 50 766 gi22085890Rattus FHA-HIT 278 89 norvegicus 766 gi5764101Homo sapienspolynucleotide Icinase-3'-phosphatase109 46 766 gi5712131Homo SapiensDEM1 protein 107 46 768 gi 15186770Homo sapienslysyl oxidise-like protein1818 96 768 gi14009597Homo Sapienslysyl oxidise-like 3 1818 96 protein 768 gi15030096Mus musculusSimilar to lysyl oxidise-like1715 92 769 gi3954938Homo Sapiensacetylglucosaminyltransferase-like2298 70 protein 769 gi3954978Mus musculusacetylglucosaminyltransferase-like2298 70 protein 769 gi10834722Homo SapiensPP5656 892 91 770 gi7209723Homo SapiensVdD-repeat like Scqucnce2476 99 770 gi8217485Homo sapiensdJ1092A11.3 (WD rcpcit 2473 99 domain) 770 gi7209721Mus musculusDD57 2243 88 771 gi18676632Homo SapiensFLJ00215 protein 1943 99 771 gi18447198DrosophilaGH09355p 140 19 melanogaster 771 gi295671 Saccharomycesselected as a weak suppressor119 22 of a mutant cerevisiaeof the subunit AC40 of DNA dependant RNA polymerise I and III

772 gi10799166Homo Sapiensprotein kinase Njmu-Rl 1915 99 772 gi21104460Homo SapiensOIC/SW-CL.19 549 100 772 gi14290030Human pol protein 68 30 immunodeficien cy virus type 1 773 gi4186023Homo SapiensCDS2 protein 2376 100 773 gi19344052Homo Sapienssimilar to PHOSPHATIDATE2376 100 CYTIDYLYLTRANSFERASE
2 (CDP-DIGLYCERIDE SYNTHETASE
2) (CDP-DIGLYCERIDE

PYROPHOSPHORYLASE 2) (CDP-DIACYLGLYCEROL SYNTHASE
2) (CDS 2) (CTP:PHOSPHATIDATE

CYTIDYLYLTRANSFERASE
2) (CDP-SEQ Hit ID Species Description ~ Percentage S

ID scoreidenti DAG SYNTHASE 2) (CDP-DG

SYNTHETASE 2)...

773 gi13277972Mus musculusSimilarto CDP-diacylglycerolsynthase2289 96 (phosphatidate cytidylyltransferase) 774 gi17862928DrosophilaSD03549p 125 35 melanogaster 774 gi18077663Mus musculuscockayne syndrome group117 38 A

774 gi14091657Mangifera F6N15.8-like protein 107 29 indica 776 gi18676664Homo SapiensFLJ00231 protein 1473 99 776 gi163b3748Homo Sapienstweety-like protein 1053 41 776 116303750Musmusculustweetyhomolo 2 987 39 777 gi8118032Homo Sapiensorphan G-protein coupled939 98 receptor 777 gi16877193Homo SapiensG protein-coupled receptor,939 98 family C, group 5, member C

777 gi9588669Homo SapiensGPRCSC 939 98 778 gi20380605Mus musculusRIKEN cDNA 8430424D23 836 91 ene 778 gi16769562DrosophilaLD38910p , 333 47 melanogaster 778 gi7302978DrosophilaCG8441-PA 333 47 melanogaster 779 gi16041781Homo SapiensSimilar to RII~EN cDNA 776 99 gene 779 gi21430012DrosophilaGH27470p 333 53 melanogaster 779 gi15074454Sinorhi~obiumC~NSERVED HYP~THETICAL 239 43 meliloti PROTEIN

780 gi13959018Homo Sapiensendothelial cell-selective902 100 adhesion molecule 780 gi13991773Mus musculusendothelial cell-selective643 70 adhesion molecule 780 11814277 Homo SapiensA33 antigen precursor 229 34 781 gi8164184Homo Sapiens22kDa peroxisomal membrane1013 100 protein-like 781 ' 15422171Homo sapiens22 kDa peroxisomal membrane1013 100 protein 2 781 gi297437 Rattus peroxisomal membrane 798 76 protein norvegicus 782 gi7621329StreptococcusSic1.245 214 39 pyogenes 782 gi7620883StreptococcusSic1.23 215 39 pyogenes 782 gi7620875StreptococcusSic1.19 215 39 pyogenes 783 gi62877 Gallus type VI collagen alpha-2751 41 gallus subunit ~

preprotein 783 gi62882 Gallus type VI collagen subunit751 41 gallus alpha2 783 gi211616 Gallus type VI collagen, alpha-2747 45 gallus subunit 784 gi17945608DrosophilaRE26969p 829 48 melano aster 784 gi3877350Caenorhabditiscontains similarity 572 38 to Pfam domain:

elegans PF01598 (Sterol desaturase), Score=307.6, E-value=4.7e-89, N=1 784 gi3877351Caenorhabditiscontains similarity 546 38 to Pfam domain:

elegans PF01598 (Sterol desaturase), Score=303.0, E-value=l.le-87, N=1 SEQ Hit ID Species Description S Percentage ID scoreidenti 785 gi17066106Homo SapiensNovex-3 Titin Isoform 8832 99 785 gi21238628Sparisoma thin-like protein 519 62 viride 785 gi21238630Sparisoma titin-like protein 519 62 aurofrenatum 787 gi2230840Ginkgo ndhB 54 54 biloba 787 gi2230828Dioon edulendhB 52 50 787 gi9279991Sequoia maturase 60 36 sempervirens 788 gi18676610Homo SapiensFLJ00204 protein 204 27 788 gi3002588Mus musculusPlenty of SH3s; POSH 206 25 788 gi14b7665Mus musculusSH3P3 134 45 789 gi18676610Homo SapiensFLJ00204 protein 262 27 789 13002588 Mus musculusPlenty of SH3s; POSH 220 25 789 gi1407665Mus musculusSH3P3 140 33 790 gi182483 Homo Sapiensprefibroblast collagenase531 88 inhibitor 790 gi490094 Homo SapiensTIMP 531 88 790 gi189382 Homo Sapienscollagenase inhibitor 531 88 791 gi7110216Homo SapiensC-type lectin-like receptor-1851 99 791 gi7109731Homo SapiensC-type lectin-like receptor-2256 31 791 gi1902982Bos tauruslectin-like oxidized 303 31 I,DL receptor 792 gi5802604Cavia porcellusUDP glucuronosyltransferase1783 73 792 gi19387963Mus musculusRIKEN cDNA 2010321J07 1709 69 gene 792 '4753766 Homo SapiensUDP glucuronosyltransferase1598 67 793 gi3688090Homo SapiensR32611_2 786 91 793 16841228 Homo sapiensHSPC289 638 78 793 gi21618688Mus musculusRIKEN cDNA 5830498014 445 52 gene 794 gi9963861Homo sapiensCytl9 1729 99 794 gi15488645Mus musculusmethyltransferase Cytl91555 76 794 gi18150409Rattus S-adenosylmethionine:arsenic1516 76 norvegicus(III) methyltransferase 795 '11877243Homo SapiensSSFl/P2~'11 chimeric 1957 95 protein 795 gi21619996Homo Sapienspeter pan homolo (Drosophila)2080 99 795 gi14602631Homo Sapienspeter pan (Drosophila) 2080 99 homolog 796 gi20330550Homo SapiensNK inhibitory receptor 799 98 precursor 796 gi20380183Homo SapiensSimilar to CMRF35 leukocyte727 92 immunoglobulin-like receptor 796 gi20381405Homo Sapienssimilar to CMRF35 leukocyte423 57 immunoglobulin-like receptor; CMRF35 antigen 797 120330550Homo SapiensNK inhibitory receptor 799 98 precursor 797 gi20380183Homo Sapienssimilar to CMRF35 leukocyte727 92 immunoglobulin-like receptor 797 gi20381405Homo Sapienssimilar to CMRF35 leukocyte423 57 immunoglobulin-like receptor; CMRF35 antigen 798 gi20330550Homo SapiensNK inhibitory receptor 1469 94 precursor 798 gi20380183Homo Sapienssimilar to CMRF35 leukocyte690 84 immuno lobulin-like receptor 798 gi20330544Mus musculuspolymeric immunoglobulin416 52 receptor 3 precursor 799 gi18307481Homo Sapiensphosphoinositide-binding2122 100 proteins 799 gi3930781Homo Sapiensconnector enhancer of 346 34 KSR-like protein CNKl SEQ Hit ID Species Description S Percentage ID scoreidenti 799 gi4151807Rattus membrane-associated 455 37 norvegicusguanylate kinase-interacting protein 2 Maguin-2 800 gi15929988Homo SapiensSimilar to TLH29 protein417 89 precursor 800 gi11493982Homo SapiensTLH29 protein precursor274 72 800 120147034Mus musculusinterferon stimulated 235 68 ene 12 801 gi15929988Homo SapiensSimilar to T'LH29 protein445 100 precursor, clone MGC:21991 IMAGE:4398045, mRNA, complete cds.

801 AAW54040 Homo SapiensHuman interferon-inducible432 97 protein, HIFI.

801 gi11493982Homo SapiensTLH29 protein precursor303 70 (TLH29) mRNA, complete cds.

802 gi12082725Mus musculusB cell phosphoinositide3561 84 3-kinase adaptor 802 gi12082723Gallus B cell phosphoinositide2840 69 gallus 3-kinase adaptor 802 gi20987486Homo Sapienssimilar to B cell phosphoinositide1830 97 kinase adaptor 803 gi7959809Homo SapiensPR01082 545 100 803 gi7767407Avian 5a protein 61 26 infectious bronchitis virus 803 gi15073792SinorhizobiumPUTATIVE FOSMIDOMI'C1N 71 38 meliloti RESISTANCE ANTIBIOTIC
RESISTANCE TRANSMEMBRANE
PROTEIN

804 115384=843Homo SapiensNTB-A receptor 1700 100 804 gi1538484~1Homo Sapiensactivatin Nl~receptor 1687 99 804 gi9887089Mus musculuslymphocyte antigen 108 637 44 isoform 1 805 gi17979255ArabidopsisAT5g495501I~6M13_10 211 72 thaliana 805 gi10177621Arabidopsisphytoene dehydrogenase-like195 75 thaliana 805 gi14023915Mesorhizobiumphytoene dehydrogenase 182 62 loti 806 gi14270364~Mus musculusEpigon protoin 386 71 806 gi755468 Xenopus transmembrane protein 120 36 laevis 806 gi7799191Mus musculustomoregulin-1 125 52 807 gi14270364Mus musculusEpigen protein 386 71 807 gi755468 Xenopus transmembrane protein 120 36 laevis 807 gi7799191Mus musculustomore lin-1 125 52 808 gi14~270364Mus musculusEpi en protein 386 71 808 gi755468 Xenopus transmembrane protein 120 36 laevis 808 gi7799191Mus musculustomoregulin-1 125 52 809 gi3068592Mus musculuspunt 201 41 809 gi22003417Daniorerioneogenin 193 40 809 gi1881477Mus musculusneo enin protein 167 33 810 ' 15072404Raja erinaceaor anic solute transporter92 41 beta 810 gi143486 Bacillus levansucrase 59 37 subtilis 810 gi143484 Bacillus levansucrase (sacB) 58 35 subtilis 811 gi18650588Homo Sapiensretinoic acid early 1124 99 transcript 1 811 gi13128925Homo SapiensULBP2 protein 1070 94 811 gi21961213Homo sapiensUL16 binding protein 1070 94 812 gi9280405Homo sa adlican 1372 46 iens 812 gi3328186Caenorhabditishemicentin precursor 475 29 elegans SEQ Hit ID Species Description S Percentage ID scoreidenti 812 114575679Homo Sapienshemicentin 493 28 814 gi9280405Homo Sapiensadlican 2438 35 814 gi14575679Homo Sapienshemicentin 688 25 814 gi3328186Caenorhabditishemicentin precursor 586 26 elegans 815 gi21619635Homo Sapienssimilar to Alu subfamily270 60 SQ sequence contamination warning entry 815 gi6650810Homo SapiensPR01902 264 63 815 gi3002527Homo Sapiensneuronal thread protein247 62 AD7c-NTP

816 gi6707435Homo Sapiensapolipoprotein AS 1864 100 816 gi12240284Mus musculusapolipoprotein AS 1310 72 816 gi6707431Rattus apolipoprotein AS 1293 72 norvegicus 817 gi6707435Homo Sapiensapolipoprotein AS 1864 100 817 gi12240284Mus musculusapolipoprotein A5 1310 72 817 gi6707431Rattus apolipoprotein AS 1293 72 norvegicus 818 gi12751065Homo SapiensPNAS-25 360 81 818 gi1208732Drosophilaovary2 276 33 melanogaster 818 gi21428518DrosophilaLD33046p 275 33 melanogaster 819 gi5771420Homo Sapiensgroup IID secretory 852 100 phospholipase A2 819 16453793 Homo sapiensphospholipase A2 846 99 819 gi10862736Homo SapiensdJ169O23.3 (phospholipase846 99 A2 group IID) 820 gi6015448Hylobates dopamine receptor D4 79 35 lar 820 gi5059331Human major capsid protein 85 29 papillomavirus type 83 820 gi 13278034Mus musculusSimilar to selectin, 83 35 platelet (p-selectin) ligand 821 gi12654~883Homo SapiensrTS beta protein 2112 96 821 gi 1150421Homo SapiensrTSbeta 2112 96 821 gi11094~019Homo SapiensRTS beta 2106 96 822 gi12803167Homo Sapiensnucleosome assembly 1728 99 protein 1-like 1 822 gi189067 Homo SapiensNAP 1728 99 822 gi220496 Mus musculusnucleosome assembly 1718 98 protein-1 823 gi 13432042Homo Sapiensintegrin-linked kinase-associated2009 99 serine/threonine phosphatase 823 gi20072498Mus musculusSimilar to protein phosphatase1926 94 823 gi3777604Rattus protein phosphatase 1922 94 norvegicus2C

824 gi7768636Xenopus ICielin 242 36 laevis 824 gi6979313Mus musculuscysteine-rich repeat-containing183 30 protein 824 gi11527817Homo SapiensCRIM1 protein 178 30 825 gi21928259Homo Sapiensseven transmembrane 1023 100 helix receptor 825 gi18480746Mus musculusolfactory receptor MOR261-10864 84 825 gi18480744Mus musculusolfactoryreceptor MOR261-9858 82 826 gi21928655Homo sapiensseven transmembrane 1458 93 helix receptor 826 gi18480746Mus musculusolfactory receptor MOR261-101280 79 826 118480744Mus musculusolfactory receptor MOR261-91258 78 827 16760369 Mus musculusODZ3 364 95 SEQ Hit ID Species Description S Percentage ID scoreidenti 827 gi4760780Mus musculusTen-m3 364 95 827 gi5307761Danio rerioten-m3 310 78 828 gi21205852Homo SapiensT-cell activation Rho 3756 100 GTPase activating protein; TA-GAP

828 gi21205854Homo SapiensT-cell activation Rho 2850 100 GTPase activating protein splice variant 1; TA-GAP

828 gi16265938Homo SapiensFKSG15 24_3998 829 gi10432396Homo sapiensdJ947L8.1.5 (novel CUB 383 62 domain protein) 829 gi14787176Mus musculusCSMD1 373 61 _ gi14787181Homo SapiensCUB and sushi multiple 369 60 829 domains protein 1 short form 830 gi10432396Homo sapiensdJ947L8.1.5 (novel CUB 383 62 domain protein) 830 gi14787176Mus musculusCSMD1 373 61 830 gi14787181Homo SapiensCUB and sushi multiple 369 60 ' domains protein 1 short form 831 gi532124 Dictyosteliummyosin IC 525 41 discoideum 831 gi6472600Chara corallinaunconventional myosin 511 43 heavy chain 831 gi9453839Chara corallinamyosin 511 43 832 gi8953751Arabidopsismyosin heavy chain MYA2646 40 thaliana 832 gi6472600Chara corallinaunconventional myosin 646 39 heavy chain 832 '9453839 Chara corallinamyosin 646 39 833 gi17066528Canis familiarisimmunoglobulin gamma 42 38 heavy chain C

833 gi21113238XanthomonasIS1595transposase 50 43 campestris pv.
campestris str.

833 gi16413516Listeria similar to B. subtilis 56 37 innocua YIaI protein 834 gi7248845Homo Sapienstestican-1 2429 99 834 gi793845 Homo Sapienstestican 2429 99 834 gi21265163Homo Sapienssparc/osteonectin, cv,~cv2425 99 and kazal-lilts domains proteo lycan (testican) 835 gi12804465Homo Sapiensprostate cancer overexpressed1632 59 gene 1 835 gi3462515Homo SapiensPB39 1632 59 835 gi 13111981Homo SapiensSimilar to selectively 283 34 expressed in embryonic epithelia protein-1 836 gi12804465Homo Sapiensprostate cancer overexpressed1637 59 gene 1 836 gi3462515Homo SapiensPB39 1637 59 836 gi13111981Homo SapiensSimilar to selectively 283 34 expressed in embryonic epithelia protein-1 837 gi7689029Homo Sapiensuncharacterized hypothalamus664 100 protein 837 gi17391348Homo SapiensSimilar to brain expressed,664 100 X-linked 1 837 gi9963771Homo Sapiensovarian granulosa cell 664 100 13.0 lcDa protein hGR74 homolog 838 gi4585574Rattus Slitl 287 35 norvegicus 838 '17380582Homo SapiensSLIT1 isoform B 279 35 838 gi4049587Homo SapiensSlit-2 protein 297 35 839 gi15488920Homo SapiensSimilar to RIKEN cDNA 632 100 gene 839 gi19354289Mus musculusRIKEN cDNA 2010107623 570 92 gene 839 12267416 Hepatitis hepatitis delta antigen76 33 D

SEQ Hit ID Species Description S Percentage ID scoreidenti virus 840 gi21619776Homo SapiensSimilar to RIKEN cDNA 2491 100 gene 840 gi20988071Mus musculusSimilar to RIKEN cDNA 921 80 gene 840 gi14531291Mus musculushigh mobility group 87 34 protein isoform I

841 gi21667649Drosophilamyosin binding subunit 231 29 melano of myosin aster phosphatase 841 gi21392168DrosophilaRE63915p 231 29 melanogaster 841 gi3929221Homo SapiensTRF1-interacting ankyrin-related183 32 ADP-ribose polymerase 842 gi12408286Homo Sapiensapolipoprotein L-IV 1742 100 splice variant a 842 gi13374351Homo Sapiensapolipoprotein L4 1728 99 842 gi12408285Homo Sapiensapolipoprotein L-IV 1683 98 splice variant b 843 112408286Homo Sapiensapolipoprotein L-IV 1737 99 splice variant a 843 gi13374351Homo Sapiensapolipoprotein L4 1723 99 843 gi12408285Homo sapiensapolipoprotein L-IV 1678 98 splice variant b 844 gi21744725Homo Sapiensglycosyl-phosphatidyl-inositol-MAM2296 100 844 gi7529598Homo SapiensdJ402N21.3 (novel protein1048 100 with Immuno lobulin domains) 844 gi7529599Homo SapiensdJ402N21.1 (novel protein)662 100 845 gi21744~725Homo Sapienslycosyl-phosphatidyl-inositol-MAM5051 100 845 gi7529598Homo sapienSdJ402N21.3 (novel protein1548 99 with Immuno lobulin domains) 845 gi7529597Homo SapiensdJ402N21.2 (novel protein1474 100 with MAM
domain) 846 gi4007758Schi~osacoharoconserved protein; similar633 34 myces pombeto S. cerevisiae 846 gi1066493SaccharomycesWeak similarity near 482 32 cerevisiaeC-terminus to RNA
Polymerase beta subunit (Swiss Prot.
accession number P11213) and CCAAT-binding transcription factor (PIR
accession number A36368) 84=6gi18086412ArabidopsisAt2g17250/T23A1.11 420 44 thaliana 847 gi14701768Homo SapiensVam6/Vps39-like protein3499 96 847 gi14280050Homo SapiensVps39/Vam6-like protein3499 96 847 118857927Mus musculusVPS39 long isoform 3409 93 848 gi3811347Homo Sapienscytosolic phospholipase1209 44 A2 beta 848 gi4886978Homo sapienscytosolic phospholipase1209 44 A2 beta;
cPLA2beta 848 gi190004 Homo Sapiensphosphatidylcholine 512 35 2-acylhydrolase 849 gi7291437DrosophilaCG4071-PA 516 51 melanogaster 849 gi17946619DrosophilaRH31535p 217 42 melanogaster 849 gi21645615DrosophilaCG4071-PB 217 42 melanogaster 850 gi13161409Mus musculusfamily 4 cytochrome 444 73 850 gi5263306Coptotermesfamily 4 cytochrome 200 41 acinaciformisP450 850 gi13182964Mus musculuscytochrome P450 CYP4F13196 38 851 gi13447749Homo Sapiensfibroblast growth factor2475 98 receptor 5 851 gi10944887Homo SapiensFGFR-like protein 2475 98 SEQ Hit ID Species Description S Percentage ID scoreidenti 851 gi13183618Homo SapiensFGF homologous factor 2421 97 receptor 852 gi13447749Homo Sapiensfibroblast growth factor2701 99 receptor 5 852 gi10944887Homo SapiensFGFR-like protein 2701 99 852 gi13183618Homo SapiensFGF homologous factor 2647 98 receptor 853 113183618Homo SapiensFGF homolo ous factor 583 98 receptor 853 gi13447749Homo Sapiensfibroblast owth factor 583 98 receptor 5 853 gi10944887Homo SapiensFGFR-like protein 583 98 854 gi643656 Rattus synaptotagmin VII 2035 95 norvegicus 854 gi12667446Rattus synaptotagmin VIIs 2035 95 norvegicus 854 gi6136786Mus musculussynaptotagmin VII 2026 95 855 gi12053709Homo Sapiensa disintegrin-like and 8842 100 metalloprotease (reprolysin type) with thrombospondin type 1 motif, 12 855 gi5923788Homo Sapienszinc metalloprotease 2489 58 855 gi19171178Homo Sapiensmetalloprotease disintegrin1598 39 16 with thrombospondin type I motif 856 gi15929988Homo SapiensSimilar to TLH29 protein155 86 precursor 856 gi7649139Homo SapienspIFI27-like protein 83 44 856 gi11493982Homo SapiensTLH29 protein precursor83 44 857 gi13542874IVIus musculusSimilar to CGI-67 protein1299 74 857 gi21707079Homo Sapienssimilar to RII~EN cDNA 1278 75 857 gi4929603Homo SapiensCGI-67 protein 1087 81 858 gi13542874Mus musculuSSimilar to CGI-67 protein1299 74 858 gi21707079Homo sapienSsimilar to RII~EN cDNA 1279 73 858 gi4929603Homo SapiensCGI-67 protein 1087 81 859 gi21595166Mus musculuSRIICEN cDNA 4933425F03 1823 83 gene 859 gi16359267Mus musculusSimilar to RIKEN cDNA 1822 83 gene 859 gi21619888Homo SapiensSimilar to RII~EN cDNA 1542 98 ene 860 121595166MuS musculusRII~EN cDNA 4933425F03 2278 88 gene 860 gi16359267Mus muSCUlusSimilar to RIIfEN cDNA 2277 88 gene 860 gi21619888Homo SapiensSimilar to RII~EN cDNA 1958 99 gene 861 gi11493463Homo SapiensPR~2852 301 75 861 gi14189960Homo SapiensPR~0764 271 65 861 gi21104464Homo Sapiens~I~/SW-CL.41 264 70 863 gi21320872Mus musculusCog8 2747 88 863 gi17862986DrosophilaSD07339p 795 45 melano aster 863 gi5922593Schizosaccharopi008 230 21 myces pombe 864 gi21618851Mus musculusRII~EEN cDNA 2610510L01882 92 gene 864 gi20977573Danio rerioU1 small nuclear ribonucleoprotein75 32 C

864 gi1562574Mus musculusU1 snRNP-specific protein75 32 C

865 gi17862312DrosophilaLD21841p 646 41 melanogaster 865 gi22294210ThermosynechoWD-40 repeat protein 123 27 coccus elongatus 865 gi886024 ThermomonospPkwA 124 25 SEQ Hit ID Species Description S Percentage ID scoreidenti ora curvata 866 gi3878846CaenorhabditisROSD7.3 119 37 elegans 866 gi1685056Xenopus Pax6 87 24 laevis 866 gi8132389Xenopus paired domain transcription81 23 laevis factor variant A

867 gi12406973Homo Sapiensalanine-glyoxylate aminotransferase2740 100 867 gi1944136Rattus beta-alanine-pyruvate 2255 83 norvegicusaminotransferase 867 gi1000448Rattus Rat kidney AGT2 precursor2208 81 norvegicus 868 112406973Homo Sapiensalanine-glyoxylate aminotransferase1870 98 868 gi1944136Rattus beta-alanine-pyruvate 1630 86 norvegicusaminotransferase 868 gi1000448Rattus Rat kidney AGT2 precursor1583 84 norvegicus 869 gi4165315Sus scrofakallilcrein 468 42 869 gi190263 Homo Sapiensplasma prekallikrein 467 38 869 gi8809781Homo Sapiensplasma kallikrein precursor467 38 870 gi17985046Brucella GLYCOSYL TRANSFERASE 137 28 melitensis 870 gi5478237Brucella Bme7 137 28 melitensis 870 gi2090678~MethanosarcinaTransposase 126 25 mazei Goel 871 gi4565840Cnemidophoruscytochrome b oxidase 76 41 ti is 871 gi15023030ClostridiumUncharacterized membrane72 44 acetobutylicumprotein, ortholog YYAS B.subtilis 871 gi7549241Barbatia cytochrome oxidase subunit71 28 tenera I

872 18705222 Homo SapiensIL-17B receptor 1998 100 872 i924~6433Homo SapiensIL-17 receptor homolog 1996 99 precursor 872 gi9246429Mus musculusIL-17 receptorhomolo 1x04 76 precursor 873 gi18676472Homo sapiensFLJ00133 protein 6475 100 873 gi186764~98Homo sapiensFLJ00146 protein 2352 100 873 gi161467 Strongylocentrofibropellin Ia 1246 38 tus purpuratus 874 gi213198 Petromyzonfibrinogen alpha chain 89 39 marinus 874 gi15292317DrosophilaLD46863p 87 34 melano aster 874 gi4877921Streptococcusserum opacity factor 81 33 pyogenes precursor 875 gi14249936Homo SapiensSimilar to S-adenosylhomocysteine2582 97 hydrolase-like 1 875 gi17390493Mus musculusS-adenosylhomocysteine 2429 92 hydrolase-like 1 875 gi2852125Homo SapiensS-adenosyl homocysteine2429 92 hydrolase homolog 876 114279990Homo Sapiensubiquitin UBF-fl 458 100 876 gi6706799Homo SapiensdJ447F3.2.1 (ubiquitin-conjugating214 74 enzyme E2 H10 (isoform 1)) 876 gi14043322Homo Sapiensubiquitin carrier protein214 74 877 gi20086516Homo Sapiensprominin-related protein4241 99 877 gi20086520Mus musculusprominin-related protein3157 73 SEQ Hit H) Species Description S Percentage ID scoreidenti 877 gi19909067Rattus testosterone-regulatedprominin-related2920 69 norvegicusprotein 878 gi 13159480Homo SapiensTranslation may initiate2104 100 at the ATG
codon at nucleotides 40-42 or the ATG at nucleotides 43-45 878 gi21483846Sus scrofafibrinogen-like protein406 36 878 gi9229906Ciona fibrinogen-like protein408 36 intestinalis 879 gi13159480Homo SapiensTranslation may initiate2100 99 at the ATG
codon at nucleotides 40-42 or the ATG at nucleotides 43-45 879 gi21483846Sus scrofafibrinogen-like protein406 36 879 gi9229906Ciona fibrinogen-like protein408 36 intestinalis 880 gi13159480Homo SapiensTranslation may initiate2100 99 at the ATG
codon at nucleotides 40-42 or the ATG at nucleotides 43-45 880 gi21483846Sus scrofafibrinogen-like protein406 36 880 gi9229906Ciona fibrinogen-like protein408 36 intestinalis 881 gi11493483Homo SapiensPR02550 322 66 881 gi7770139Homo SapiensPR01722 318 69 881 gi 1872200Homo Sapiensalternatively spliced 304. 72 product using axon 882 gi10175777Bacillus protease speciEc for 67 34 haloduransphage lambda cII
repressor 882 gi15558903Xenopus Tob 64 51 laevis 882 gi21998835Rattus monocarboxylate transporter67 33 norvegicus8 883 118073362Homo Sapienscystine/ lutamate transporter2552 100 883 gi11493652Homo Sapienscalcium channel bloclcer2552 100 resistance protein CCBRl 883 gi13924720Homo Sapienscystinelglutamate transporter2552 100 xCT

884 gi507213 Homo Sapiensserine kinase 1797 97 884 gi14252988Homo SapiensSRPI~la protein kinase 1797 97 884 gi3135975Homo SapiensdJ4.22H11.1.1 (Serine 1796 98 I~inase) (isoform 1) 885 gi9837288Homo SapiensC-type lectin 271 54 885 gi6651065Homo Sapienslectin-like NIC cell 271 54 receptor LLT1 885 gi18044358Homo SapiensSimilar to lectin-like 270 57 NIA cell receptor 886 gi22164066Homo sapiensneuroblastoma-amplified7571 99 protein 886 gi5833317Oryzias mixed lineage leukemia-like89 23 latipes protein 886 gi7108717Nicotiana MAR-binding protein 89 31 tabacum MFP1 homolog 887 gi22164066Homo Sapiensneuroblastoma-amplified6897 98 protein 887 gi5833317Oryzias mixed lineage leukemia-like89 23 latipes protein 888 gi17430957Ralstonia HYPOTHETICAL TRANSMEMBRANE453 40 solanacearumPROTEIN

888 gi13421965CaulobacterM20/M25/M40 family peptidase377 38 crescentus 888 gi2330791Schizosaccharocarboxypeptidases precursor352 33 myces pombe 889 gi11558029Homo Sapiensorganic canon transporter1860 99 889 gi18088251Homo SapiensSimilar to hBOIT for 1206 97 potent brain type or anic ion transporter SEQ Hit ID Species Description S Percentage ID scoreidenti 889 gi9663117Homo Sapiens_ 1852 99 organic cation transporter X90 gi344112 synthetic chloramphenicol acetyltransferase57 28 construct and carboxy terminal fusion protein 890 gi412284 synthetic carboxy terminal fusion57 28 construct protein 890 gi13122523Barbus ATP synthase 8 56 28 brachycephalus 891 '13375149Homo SapiensdJ1118M15.2 (Novel protein)538 98 891 gi7259265Mus musculuscontains transmembrane 269 48 (TM) region 891 gi1806278Rattus glycoprotein 56 143 35 norvegicus 892 gi16589003Homo Sapiensbromodomain-containing 6353 99 892 gi9931486Mus musculuscell proliferation related5635 90 protein CAP

892 gi 18308125Mus musculusbromodomain-containing 5633 90 protein BRD4 long variant 893 gi15420828Homo SapiensNOE3-1 2504 99 893 gi19386926Rattus optimedin form B 2484 98 norvegicus 893 gi19386930Mus musculusoptimedin form B 2484 98 894 gi10336599Xenopus follistatin-related 234 32 laevis protein 894 gi349006 Mus musculusTGF-beta-inducible protein225 29 894 gi20810033Mus musculusfollistatin-like 223 29 895 gi5002565Talcifugu cysteine conjugate beta-lyase1244 55 rubripes 895 gi758591 Homo Sapiensglutamine--phenylpyruvate1201 51 aminotransferase 895 gi154~25868Aedes aegyptikynurenine aminotransferase1188 55 896 gi20522012Homo Sapienssimilar to an actin 1312 57 bundling protein, dematn.

896 gi2337952Homo sapiensactin-bindin double-zinc-finger1312 57 protein 896 gi21666433Mus musculusactin-binding LIM protein1305 57 1 medium isoform 898 gi6716518Mus musculusdoublccortin-like kinasc821 52 898 gi21619202Homo sapiensSimilar to doublecortin810 51 and CaM kinase-like 1 898 gi20152113DrosophilaRE56868p 778 45 melanogaster 899 gi9280108Macaca membrane-associated 1907 97 fascicularisprostaglandin E
synthase-2 899 gi9757960Arabidopsiscontains similarity 396 50 thaliana to glutathione-S-transferaselglutaredoxin~gene_id:MJC20.

899 gi17944528DrosophilaRH17614p 566 42 melanogaster 900 gi4894854Homo Sapienscomplement Clq A chain 1308 99 precursor 900 gi20988805Homo Sapienscomplement component 1308 99 1, q subcomponent, alpha polypeptide 900 gi12805247Mus musculuscomplement component 945 70 1, q subcomponent, alpha polypeptide 901 gi 10176989Arabidopsiscontains similarity 86 34 thaliana to hedgehog-interacting protein~gene id:MYH19.17 901 gi456384 Blastocrithidiaapocytochrome B 41 50 culicis 902 gi2565046Homo sa CAGF28 3775 97 iens 902 '21707458Homo sapiensPAX transcription activation2709 87 domain SEQ Hit ID Species Description S Percentage ID scoreidenti interacting protein 1 like 902 gi4336734Mus musculusPax transcription activation2473 80 domain interacting protein PTIP

903 gi4336734Mus musculusPax transcription activation531 93 domain interacting protein PTIP

903 gi14164561Xenopus Swift 467 79 laevis 903 gi12382298Human OrfKlO 48 34 herpesvirus 904 gi19353375Mus musculusRII~EN cDNA 1110031I02 745 78 gene 904 gi15929776Homo Sapiensgrowth suppressor 1 137 41 904 gi5805194Rattus leprecan 137 41 norvegicus 905 gi2443352Mus musculusplatelet glycoprotein 150 45 Ib beta 905 gi21355064Homo sapiensplatelet glycoprotein 146 43 Ib beta chain 905 gi306792 Homo sapiensplatelet glycoprotein 146 43 Ib beta chain precursor 906 gi13991166Homo Sapienssialic acid-binding 1174 100 immunoglobulin-like lectin-like short splice variant 906 gi13991167Homo Sapienssialic acid-binding 1174 100 immunoglobulin-like lectin-like long splice variant 906 gi14625822Homo SapiensSiglec-Ll 1174 100 907 gi21708018Mus musculusRIKEN cDNA 2700029E10 626 66 gene 907 gi7547035Homo SapiensSGC32445 protein 474 63 907 gi21626575DrosophilaCG30193-PA 457 55 melanogaster 908 '6273399 Homo Sapiensmelanoma-associated 2748 60 anti en MG50 908 gi1504040Homo Sapienssimilar to D.melanogaster2748 60 peroxidasin(U11052) 908 gi531385 Drosophilaperoxidasin precursor 1721 42 melanogaster 909 gi6273399Homo Sapiensmelanoma-associated 2748 60 antigen MG50 909 gi1504040Homo Sapienssimilar to D.melanogaster2748 60 peroxidasin(U 11052) 909 gi531385 Drosophilaperoxidasin precursor 1721 42 melanogaster 910 gi6273399Homo Sapiensmelanoma-associated 2799 59 antigen MG50 910 gi1504040Homo Sapienssimilar to D.melanogaster2799 59 peroxidasin(U11052) 910 gi531385 Drosophilaperoxidasin precursor 1708 41 melanogaster 911 gi18182323Mus musculuscrumbs-like protein 777 31 1 precursor 911 gi6014482Homo SapiensCRB1 754 30 911 gi18175289Homo SapiensCRB1 isoform I precursor754 30 912 gi6650802Homo SapiensPR01848 205 56 912 121104464Homo SapiensOIC/SW-CL.41 188 61 912 gi11493463Homo SapiensPRO2852 175 54 913 gi6808611Homo Sapiens88-kDa Golgi protein 3237 99 913 gi6969980Homo Sapiensgolgin 67 2345 98 913 gi7211438Homo Sapiensgolgin-67 2330 98 914 gi3073'77Homo SapiensCAMP-dependent protein 1957 99 kinase RI-beta regulatory subunit 914 gi200365 Mus musculuscAMP-dependent protein 1886 94 kinase regulatory subunit 914 gi15030299Mus musculusSimilar to protein kinase,1881 94 cAMP

SEQ Hit ID Species Description S Percentage ID scoreidenti dependent regulatory, type I beta 915 gi20306468Mus musculusSimilar to RIKEN cDNA 382 41 gene 915 gi7161798Homo SapiensdJ470B24.1.1 (myeloid/lymphoid130 32 or mixed-lineage leukemia (trithorax (Drosophila) homology;
translocated to, 4 (AF-6) (isoform 1)) 915 gi7161797Homo SapiensdJ470B24.1.2 (myeloid/lymphoid130 32 or mixed-lineage leukemia (trithorax (Drosophila) homology;
translocated to, 4 (AF-6) (isoform 2)) 916 gi1845577Mus musculusarachidonate 12(S)-lipoxygenase2633 77 916 gi3645913Mus musculus12(S)-li ox enase 2633 77 916 ' 15489302Mus musculusSimilar to arachidonate2631 77 15-lipoxygenase 917 gi15489302Mus musculusSimilar to arachidonate751 78 15-lipoxygenase 917 gi1845577Mus musculusarachidonate 12(S)-lipoxy748 78 enase 917 gi1101886Mus musculusarachidonate lipoxygenase748 78 918 gi15489302Mus musculusSimilar to arachidonate1266 75 15-lipoxygenase 918 ' 1845577Mus musculusarachidonate 12(S)-lipoxygenase1263 75 918 11101886 Mus musculusarachidonate lipoxygenase1263 75 919 gi13661964LeishmaniaL344.3 108 21 maj or 919 gi17135639Nostoc WD-repeat protein 95 21 sp. PCC

919 gi11139242Homo sapiensmeiotic recombination 93 25 protein REC14 920 gi17862298DrosophilaLD21662p 627 42 melanogaster 920 gi2425111Dictyostelium~ipA 122 28 discoideum 920 gi641958 Homo Sapiensnon-muscle myosin B 118 24 921 18132683 Homo Sapienscytokine-like protein 241 64 921 112751073Homo SapiensPNAS-31 74 92 921 gi11323101Saint CroixVP4 79 32 river virus 922 gi8132683Homo sapienscytolcine-like protein 241 64 922 ' 12751073Homo SapiensPNAS-31 74 92 922 gi 11323101Saint CroixVP4 79 32 river virus 923 gi8132683Homo Sapienscytokine-like protein 384 73 923 ' 12751073Homo SapiensPNAS-31 74 92 923 gi216168 Bacteriophagepromoter 3 protein 56 37 924 gi8132683Homo sapienscytolcine-like protein 263 98 924 gi1143067Canis familiarisalpha-L-fucosidase 69 59 924 1309444 Mus musculusMRI~ 58 65 925 '8132683 Homo Sapienscytolcine-lilee protein591 100 925 13406819 Mus musculusgrowth factor receptor 64 60 925 gi12724591LactococcusUNKNOWN PROTEIN 41 37 lactis subsp.
lactis 926 gi17975777Homo Sapiensvesicular inhibitory 2741 99 amino acid transporter 926 gi13396317Homo SapiensbA122O1.1 (A novel protein2741 99 (ortholog of the mouse vesicular inhibitory amino acid transporter, VIAAT)) SEQ Hit ID Species Description ~S Percentage ID scoreidenti 926 gi2587061Rattus vesicular GABA transporter2694 98 norvegicus 927 gi3097285Rattus ZOG 670 39 norvegicus 927 gi802014 Rattus preadipocyte factor 665 39 norvegicus 927 113365691Mus musculusdlk (Delta like) 649 39 928 gi6624073Homo Sapienssimilar to hepatitis 1757 93 delta antigen interacting protein A ; similar to AAB05928.1 (PID:g1488314) 928 gi1488314Homo Sapienshepatitis delta antigen274 45 interacting protein A

928 gi16768374DrosophilaGM03282p 359 37 melanogaster 929 gi4337106Homo SapiensBAT4 864 98 929 gi14250638Homo SapiensSimilar to DNA segment,864 98 Chr 17, human 929 '3941733 Mus musculusBAT4 581 71 930 gi9759107Arabidopsisphosphate/phosphoenolpyruvate289 30 thaliana translocator protein-like 930 gi21536504Arabidopsisphosphate/phosphoenolpyruvate245 27 thaliana translocator-like protein 930 gi8778643ArabidopsisF5011.25 235 29 thaliana 931 '5852981 Homo sapienscardiotrophin-like cytokine1204 99 CLC

931 gi6007641Homo sapiensneurotrophin-1/B-cell 1204 99 stimulating factor-3 931 gi15277895Homo SapiensSimilar to cardiotrophin-like1204 99 cytokine;

neurotrophin-1/B-cell stimulating factor-3 932 gi22003732Homo sapiensMTLC 853 99 932 gi18490933Homo SapiensSimilar to RIKEN cDNA 846 98 gene ' 932 gi20453974Mus musculusMT-MC1 718 82 933 gi9958075ArabidopsisPutativo methionine 739 53 aminopeptidase thaliana 933 gi11320956Arabidopsismethionine aminopeptidase-like739 53 protein thaliana 933 gi21553973Arabidopsismethionyl aminopeptidase-like717 52 protein thaliana 934 gi4104963Rattus neurexophilin 4 1493 90 norvegicus 934 11336013 Mus musculusneurexophilin 2 327 65 934 14105164 Homo Sapiensneurexophilin 2 323 65 935 gi15025812ClostridiumMethyl-accepting chemotaxis65 38 protein acetobutylicumwith HAMP domain 935 gi17224936Trypanosomecorset-associated protein63 31 brucei 935 gi15025892ClostridiumRibosome-associated 48 38 protein Y (PSrp-1) acetobutylicum 936 gi16197625Arabidopsisanaphase promoting complex64 32 subunit 11 thaliana 936 gi10834682Homo SapiensPP3958 74 46 937 gi19387136Homo SapiensPYRIN-containing APAFl-like874 99 protein S

937 gi202806 Rattus vasopressin receptor 561 68 norvegicus 937 gi21410402Mus musculusexpressed sequence AI504961532 67 SEQ Hit ID Species Description S Percentage ID scoreidenti 938 gi11321325Homo SapiensLin-7b 1030 100 938 gi20381193Homo SapiensLin-7b protein; likely 1030 100 ortholog of mouse LIN-7B; mammalian LIN-7 protein 2 938 gi3885828Rattus lin-7-A 1019 98 norvegicus 939 gi14349125Homo Sapiensalpha2-glucosyltransferase738 96 939 gi3513451Rattus potassium channel regulator718 93 norve icus1 939 gi21711799DrosophilaRH44301p 142 32 melanogaster 940 gi12803183Homo Sapienspolypyrimidine tract 1527 91 binding protein (heterogeneous nuclear ribonucleoprotein I) 940 gi32354 Homo Sapiensnuclear ribonucleoprotein1527 91 940 135772 Homo Sapienspolypirimidine tract 1527 91 binding protein 941 gi6752658Homo Sapiensepidermal growth factor3046 99 repeat containing protein 941 gi16040981Mus musculusP~EM 884 51 941 115430246Mus musculusnephronectin short isoform884 51 942 gi6752658Homo Sapiensepidermal growth factor3036 98 repeat containing protein 942 gi16040981Mus musculusPOEM 884 51 942 gi15430246Mus musculusnephronectin short isoform884 51 943 i 17980969Homo Sapienssel4-3r protein 5146 99 943 gi11385648Homo SapiensCTCL tumor anti en sel4-33867 99 943 17960216 Homo sapiensRACK-like protein PRI~CBP13124 99 944 gi17980969Homo Sapienssel4-3r protein 3140 99 944 gi13677201Homo sapiensdJ569M23.1.2 (protein 2771 100 kinase C binding protein l,isoform 2) 944 gi13677198Homo SapiensdJ569M23.1.3 (protein 2638 96 kinase C binding protein l, isoform 3 (DKFZp564P1772)) 945 gi17980969Homo Sapienssel4-3rprotein 3550 84 94.5gi13677201Homo sapiensdJ569M23.1.2 (protein 2771 100 kinase C binding protein 1, isoform 2) 945 gi13677198Homo SapiensdJ569M23.1.3 (protein 2638 96 kinase C binding protein 1, isoform 3 (DI~FF~p564P1772)) 946 gi17980969Homo Sapienssel4-3r protein 3550 84 946 gi13677198Homo sapiensdJ569M23.1.3 (protein 2380 90 kinase C binding protein 1, isoform 3 (DICFZp564P1772)) 946 gi13677201Homo SapiensdJ569M23.1.2 (protein 2377 90 kinase C binding protein 1, isoform 2) 947 gi14043211Homo sapiensSimilar to RII~EN cDNA 2410 98 gene 947 gi22204070Macaca metabotropic lutamate 91 42 mulatta receptor 1 947 gi170454 Lycopersiconcell wall hydroxyproline-rich70 39 esculentumglycoprotein 948 gi14972753Streptococcusalcoholdehydrogenase,zinc-containing51 33 pneumoniae 948 gi20152351Avian spike glycoprotein S 68 34 infectious1 subunit bronchitis virus 948 gi9658106Vibrio polyhydroxyalkanoic 67 26 cholerae acid synthase 949 gi19387136Homo SapiensPYRIN-containin APAFl-like1738 99 protein 5 949 gi202806 Rattus vasopressin receptor 1037 64 ~

SEQ Hit ID Species Description S Percentage ID scoreidenti norvegicus 949 gi21410402Mus musculusexpressedsequence AI504961988 63 950 gi3978472Rattus potassium channel subunit5393 88 norve icus 950 gi20338417Gallus potassium channel subunit4792 88 gallus 950 gi7303760DrosophilaCG12904-PA 981 62 melanogaster 951 gi18147612Homo sa metalloprotease disintegrin3535 99 iens 951 gi21908028Homo Sapiensa disintegrin and metalloprotease3535 99 domain 951 gi13157560Homo SapiensdJ964F7.1 (novel disintegrin3078 99 and reprolysin metalloproteinase family protein) 952 gi18606367Mus musculusRIKEN cDNA 4930570003 715 92 gene 952 gi9971130Schizosaccharohuman downs syndrome 72 31 myces pombecritical region-like 952 gi5708224RhodoblastusLH2alpha5 60 31 acidophilus 953 gi15420879Mus musculusankyrin repeat-containing2053 82 SOCS box protein 10 953 gi18092200Homo SapiensASB-10 1909 98 953 gi18031949Mus musculusSOCS box protein ASB-18816 45 954 gi491284 synthetic IFN-pseudo-omega 2 799 98 construct 954 gi386800 Homo Sapiensinterferon-alpha 330 72 954 1490110 Homo Sapiensinterferon-omega 1 330 72 955 gi9844580Homo SapiensdJ1153D9.4 (novel protein)623 84 955 gi9844579Homo SapiensdJ1153D9.3 (novel protein)450 97 955 gi 15928971Homo SapiensSimilar to neuronal 430 90 thread protein 956 gi12804321Homo Sapiensperoxisomal short-chain685 100 alcohol dehydrogenase 956 gi19113668Homo SapiensNADP-dependent retinol 878 100 dehydrogenase short isoform 956 gil 1559412Homo SapiensNADPH-dependent retinol587 100 dehydrogenase/reductase 957 gi12718818Mus musculussulfhydryl oxidase 496 49 957 gi12718820Rattus sulfhydryl oxidase 489 47 norvegicus 957 gi12483919Rattus FAD-dependent sulfhydryl489 47 norvegicusoxidase-2 958 112958660Homo Sapiensacid phosphatase 2252 100 958 gi12958663Homo Sapiensacid phosphatase variant1285 99 958 gi52871 Mus musculuslysosomal acid phosphatase837 45 959 gi28966 Homo Sapiensalpha 1-antitrypsin 1703 100 959 gi6855601Homo SapiensPR00684 1703 100 959 111493443Homo SapiensPR02209 1703 100 960 gi28966 Homo Sapiensalpha 1-antitrypsin 1080 100 960 gi11493443Homo SapiensPR02209 1080 100 960 gi177829 Homo Sapiensalpha-1-antitrypsin 1080 100 961 gi28966 Homo Sapiensalpha 1-antitrypsin 1239 100 961 111493443Homo SapiensPR02209 1239 100 961 gi177829 Homo Sapiensalpha-1-antitrypsin 1239 100 962 gi28966 Homo Sapiensalpha 1-antitrypsin 1574 93 962 gi11493443Homo SapiensPR02209 1574 93 SEQ Hit ID Species Description S Percentage ID scoreidenti 962 gi177829 Homo Sapiensalpha-1-antitrypsin 1574 93 963 gi6706993Streptomycesmethyltransferase 83 26 coelicolor A3(2) 963 gi7303904DrosophilaCG13954-PA 85 53 melanogaster 964 gi2632092Pongo fertilin alpha protein 4128 92 pygmaeus 964 gi794073 Macaca fertilin alpha-I 3136 74 fascicularis 964 gi1841702Macaca fertilin alpha-I isoform3136 74 fascicularis 965 gi4107229Homo Sapienslipophilin A 454 1 _ 965 gi4107231Homo Sapienslipophilin B 267 __ 965 gi17887359~ryctolaguslipophilin AL2 248 54 cuniculus 966 gi3335100Homo sapiensCD39L3 2816 100 966 gi13817037Homo SapiensE-type ATPase 2812 99 966 gi20988653Homo SapiensSimilar to ectonucleoside2413 99 triphosphate diphosphohydrolase 3 967 gi6942096Mus musculusCBLN3 936 93 967 gi180251 Homo Sapiensprecerebellin 549 57 967 gi5702371Mus musculusprecerebellin-1 542 56 968 gi17390957Mus musculusSimilar to RII~EN cDNA 129 32 gene 968 gi16410838Listeria similar to multidrug-efflux95 27 monocytogenestransporter 968 gi4914624Listeria multidrug resistance 95 27 monocytogenestransporter 969 gi17390957Mus musculusSimilar to RII~EN cDNA 191 26 gene 969 gi2828808Bacillus glucose transporter 100 23 subtilis 969 gi14~02314~8Z'~Icsorhi~obiumprobable fosmidomyoin 112 25 loti resistance protein 970 ' 13161123Homo Sapienstranscript Y 10 151 54 970 gi4545317Acipenser immunoglobulin light 160 25 ruthenus chain precursor 970 gi9937599Salmo truttaMHC class I heavy chain160 31 971 gi4160197Homo SapiensdJ327J16.2 (supported 2515 99 by GENSCAN
and GENEWISE) 971 gi2253263Rattus neuronal pentraxin receptor2238 89 norvegicus 971 gi12744624Mus musculusneuronal pentraxin receptor2212 88 972 gi4760782Mus musculusTen-m4 4188 96 972 gi3170615Mus musculusDOC4 4166 96 972 gi5307785Danio rerioten-m4 3537 78 973 gi14714932Homo SapiensSimilar to nuclear factor3770 100 (erythroid-derived 2)-like 1 973 gi473090 Mus musculusNFE2-related factor 3644 96 973 gi3978250Mus musculusNrfl splice variant 3280 96 D

974 gi7716100Rattus selective LIM binding 8413 95 norve 'cusfactor 974 gi17044301Leishmaniapossible LIM-binding 2139 36 maj or factor 974 gi10440379Homo sapiensFLJ00025 protein 135 25 SEQ Hit ID Species Description S Percentage ID scoreidenti 975 gi20799661Mus musculusmucolipin-2 1593 72 975 gi20987535Mus musculusRIKEN cDNA 3300002004 1590 71 gene 975 gi19072756Mus musculusmucolipin-3 1136 51 976 gi20799661Mus musculusmucolipin-2 2394 83 976 gi20987535Mus musculusRIKEN cDNA 3300002004 2391 82 gene 976 119072754Homo Sapiensmucolipin-3 1674 59 977 gi403020 Mus musculusEn-2/lacZ fusion protein988 96 977 gi14193747Mus musculuszinc finger 142 258 24 977 gi1510147Homo sapienssimilar to Human zinc 223 20 finger protein(ZNF 142) 978 gi10581238HalobacteriumVng1783h 54 46 sp. NRC-1 978 gi19699294ArabidopsisAT3g48750/T21J18 20 73 30 thaliana 979 '7959724 Homo SapiensPR00929 63 30 979 gi13540242Anopheles NADH dehydrogenase subunit62 31 stephensi 5 979 gi20904847Methanosarcina8-oxoguanine DNA glycosylase64 40 mazei Goel 980 gi5281519Homo SapiensHTRA serine protease 2164 100 980 gi1513059Homo Sapiensserin protease with 2164 100 IGF-binding motif 980 gi1621244Homo Sapiensnovel serine protease, 2164 100 981 gi7008025Callithrixprochymosin 832 68 jacchus 981 gi19851892Bos tauruschymosin precursor 515 77 981 gi162860 Bos tauruspreprochymosin b 752 62 982 gi18461371Rattus sulfatase FP 276 68 norveaicus 982 gi21961489Mus musculusSimilar to sulfatase 276 68 FP

982 gi15430244Coturnix N-acetylglucosamine-6-sulfatase263 68 coturnix 983 gi3043872Lactococcustransmembrane protein 69 32 lactic Tmp3 983 gi17428881Ralstonia CONSERVED HYPOTHETICAL 62 34 solanacearumPROTEIN

983 gi433707 Zea mat's prolin rich protein 63 48 984 gi6013463Bothrops carboxypeptidase homolog826 46 jararaca 984 gi9558448Mus musculuscarboxypeptidase R 812 45 984 gi7416967Mus musculusthrombin-activatable 812 45 fibrinolysis inhibitor 985 gi6013463Bothrops carboxypeptidase homolog826 46 jararaca 985 19558448 Mus musculuscarboxypeptidase R 812 45 985 gi7416967Mus musculusthrombin-activatable 812 45 fibrinolysis inhibitor 986 gi11545707Homo SapiensISCL12 845 100 986 gi20381021Mus musculusRIKEN cDNA 2310020H20 807 96 gene 986 gi11545705Homo SapiensISCUl 663 99 987 gi12314022Homo SapiensdJ553F4.4 (Novel protein881 89 similar to Drosophila CG8055 protein) 987 gi22417143Homo sapiensCGI-301 protein 853 100 987 gi13182765Homo SapiensCDA04 560 60 988 gi52959 Mus musculusprecursor polypeptide 146 34 (AA -26 to 108) 988 gi198922 Mus musculuslymphocyte differentiation145 34 antigen 988 gi198926 Mus musculusLy-6A.2 alloantigen 145 34 SEQ Hit ID Species Description S Percentage ID scoreidenti 990 gi15990480Homo SapiensSimilar to AE-binding 1570 100 protein 2 990 gi4106464Mus musculusAE-1 bindin protein 1555 98 990 gi21595036Mus musculusAE binding protein 2 1555 98 991 gi23903 Homo Sapiens63kDa protein kinase 2897 99 991 gi204058 Rattus extracellular signal-related1499 62 norvegicuskinase 3 991 gi16306437Homo SapiensERK-3 1492 62 992 gi17016967Homo SapiensNUANCE 3403 90 992 gi17861384Homo Sapiensnesprin-2 gamma 3403 90 992 '21748548Homo SapiensFLJ00347 protein 3403 90 993 120070711Homo Sapienssimilar to RIKEN cDNA 997 100 993 gi18204756Mus musculusSimilar to RII~EN cDNA 626 68 gene 993 gi7304139DrosophilaCG12159-PA 111 28 melanogaster 994 gi14278927Mus musculusgliacolin 866 68 994 gi10566471Mus musculusGliacolin 866 68 994 gi3747099Mus musculusClq-related factor 734 67 995 gi20987689Homo SapiensSimilar to allantoicase1838 99 995 gi14718648Homo Sapiensallantoicase 1633 99 995 gi9255889Mus musculusallantoicase 1476 77 997 gi2522208Homo SapiensRas-GRF2 6407 99 997 gi5882290Homo sapiensRas guanine nucleotide 6401 99 exchange factor 2 997 gi57665 Rattus P140 RAS-GRF 4121 65 rattus 998 gi22038159Homo Sapiensziziminl 8544 100 998 '14597976Homo Sapienshuman CLASP-4. 3533 56 998 gi550420 Rattus trg 2842 87 norvegicus 999 gi 17861850DrosophilaGM03763p 334 70 melanogaster 999 gi17862036DrosophilaLD05823p 265 47 melanogaster 999 '10178624.Mus znusculusSETA bindin protein 215 4.5 1; SB1 1000gi21594273Homo SapiensSAC2 suppresser of actin3626 100 mutations 2-like (yeast) 1000gi14041697Homo SapiensdJ1033B10.5.1 (SAC2 3587 99 (suppresser of actin mutations 2, yeast, homology-like (AREl), isoform 1) 1000gi3850063Rattus ARE1 3576 98 norvegicus 1001gi1438534Rattus rA9 4002 61 norvegicus 1001gi1438532Rattus rAl 430 36 norvegicus 1001gi9438033Homo sapiensser/arg-rich pre-mRNA 407 35 splicing factor 1002gi1438534Rattus rA9 4002 61 norvegicus 1002gi9438033Homo Sapiensser/arg-rich pre-mRNA 407 35 splicing factor 1002gi10440402Homo SapiensFLJ00034 protein 407 35 1003gi1675220CricetulusSREBP cleavage activating6200 92 griseus protein 1003gi20378357DrosophilaER- of i escort protein810 39 SEQ Hit ID Species Description S Percentage ID scoreidenti melanogaster 1003gi10728147DrosophilaCG8356-PA 810 39 melanogaster 1004112652851Homo Sapienspotassium channel modulatory1987 100 factor 1004'4838557 Mus musculusDEBT-91 1453 96 1004gi16768790DrosophilaLD03515p 876 63 melanogaster 1005gi7270532ArabidopsisDNA-directed RNA polymerase173 29 thaliana (EC
2.7.7.6) II largest chain 1005gi16505 ArabidopsisRNA polymerase II 173 29 thaliana 1005gi16494 ArabidopsisDNA-directed RNA polymerase173 29 thaliana 1006gi11875318Mus musculussynaptotagmin XIII 2004 89 1006gi21410154Mus musculussynaptotagmin 13 2004 89 1006gi11119239Rattus synaptotagmin 13 2000 89 norvegicus 1007gi3800881Homo SapiensRanBP7/importin 7 5447 100 1007gi11342591Mus musculusRanBP7/importin 7 5418 99 1007gi11544639Homo Sapiensimportin7 5307 100 1008gi5578958Homo SapiensdJ475B7.2 (novel protein)3770 99 1008gi18676522Homo SapiensFLJ00158 protein 1512 100 1008gi21595156Mus musculusSimilar to RII~EN cDNA 1151 71 gene 1009gi4406393Bos taurusdifferentiation enhancing4699 95 factor 1 1009gi4063614Mus musculusADP-ribosylation factor-directed4694 94 GTPase activating protein isoform a 1009gi4063616Mus musculusADP-ribosylation factor-directed3186 79 GTPase activating protein isofonn b 1010gi16411927Listeria 1mo2439 57 52 monocytogenes 1010gi16415055Listeria 1in2533 61 ~7 innocua 1010gi2983786f~quife~ glucose-1-phosphate 70 39 aeolicus thymidylyltransferase 1011gi9280405Homo Sapiensadlican 1631 47 1011gi13872813Homo Sapienstibulin-6 502. 28 1011gi3328186Caenorhabditishemicentin precursor 539 27 elegans 1012gi4001698Sus scrofamat-8 67 30 1012gi2622724Methanothermoconserved protein 82 29 bacter thermautotrophi cus str.
Delta H

1012gi498166 Mus musculuszona-pellucida-bindin 85 27 protein (sp38) 1013gi 17511816Homo SapiensSimilar to RIICEN cDNA 1468 99 gene 1013gi7211438Homo Sapiensgolgin-67 100 30 1013gi6003208Human p17 protein 84 29 immunodeficien cy virus type 1 1014gi 17511816Homo SapiensSimilar to RIKEN cDNA 878 100 gene 1014gi6003208Human p17 protein 84 29 immunodeficien cy virus type 1 SEQ Hit ID Species Description S Percentage ID scoreidenti 1014gi21957065Yersinia uroporphyrinogen III 90 34 pestis methylase I~IM

1015gi2246401Homo Sapienscentrin 842 100 1015gi13529248Homo Sapienscentrin, EF-hand protein,839 99 3 (CDC31 yeast homology 1015gi2246424Mus musculuscentrin 832 98 1016gi17428765Ralstonia CONSERVED HYPOTHETICAL 530 43 solanacearumPROTEIN

1016gi15155946AgrobacteriumAGR C_1725p , 379 41 tumefaciens str.
C58 (Cereon) 1016gi15073913SinorhizobiumCONSERVED HYPOTHETICAL 372 39 meliloti PROTEIN

1017gi17428765Ralstonia CONSERVED HYPOTHETICAL 381 43 solanacearumPROTEIN

1017gi15073913SinorhizobiumCONSERVED HYPOTHETICAL 367 48 meliloti PROTEIN

1017gi12543118CorynebacteriuRXC01693 265 30 m glutamicum 1018gi6693701Homo Sapiensmelanopsin 2234 91 1018gi21928729Homo Sapiensseven transmembrane 2190 99 helix receptor 1018gi6693703Mus musculusmelanopsin 1735 73 1019gi439296 Homo Sapiensgarp 822 37 1019gi6572272Homo SapiensdJ756G23.1 (novel Leucine243 34 Rich Protein) 1019gi19344010Homo Sapiensinsulin-like growth 293 29 factor binding protein, acid labile subunit 1020'15706421Homo Sapiensmiddle-chain aryl-CoA 1346 99 synthetasel 1020gi15487302Homo Sapiensmedium-chain acyl-CoA 1346 99 synthetase 1020gi5019275Bos taurusxenobiotic/medium-chain1088 78 fatty acid:CoA
ligase form XL-III

1021gi6650766Homo SapiensPDZ domain-containing 6216 100 guanine nucleotide exchan a factor I

1021gi20386206Homo sapienSPDT domain-containing 5822 98 guanine nucleotide exchange factor PDT-GEF2 1021gi18874700Homo sapiensRapl guanine nucleotide-exchange5803 98 factor 1022gi20386206Homo sapiensPDT domain-containing 5942 100 guanine nucleotide exchange factor PDZ-GEF2 1022gi18874700Homo SapiensRapl guanine nucleotide-exchange5923 99 factor 1022gi18874698Homo SapiensRapl guanine nucleotide-exchange5923 99 factor 1023gi13810306Homo Sapienstransmembrane protein 268 37 1023gi18250724Mus musculustransmembrane protein 264 37 1023gi20270907OncorhynchusVHSV-induced protein-5 243 33 myleiss 1024gi21779869Homo SapiensIL-17RE 2896 100 1024gi21779866Mus musculusIL-17RE 1394 74 1024gi21779857Homo SapiensIL-17RC 246 29 1025gi21779869Homo SapiensIL-17RE 2928 100 1025gi21779866Mus musculusIL-17RE 1388 75 1025gi21779857Homo SapiensIL-17RC 246 29 1026gi14150450Rattus UDP-GaINAc:polypeptide 1352 93 norvegicusN-acetylgalactosaminyltransferase 1026gi16769916DrosophilaSD10722p 473 38 SEQ Hit ID Species Description S Percentage ID scoreidenti melanogaster 1026gi21627105DrosophilaCG30463-PA 417 38 melanogaster 1027gi15217067Homo Sapiensstem cell factor isoform1013 95 10271337934 Homo Sapiensstem cell factor 1013 95 1027gi1827477Felis catusstem cell factor 893 84 1028gi1377894Homo SapiensOB-cadherin-1 1478 64 1028gi1377895Homo SapiensOB-cadherin-2 1478 64 1028gi506404 Homo Sapienscadherin-11 1474 63 1029gi1377894Homo SapiensOB-cadherin-1 1628 56 1029gi1377895Homo SapiensOB-cadherin-2 1628 56 1029gi506404 Homo Sapienscadherin-11 1623 56 1030gi1398903Mus musculusCa2+ dependent activator6314 90 protein for secretion 1030gi577428 Rattus Ca2+-dependent activator5003 96 norvegicusprotein;
calcium-dependent actin-binding protein 1030gi6980012Drosophilasecretion calcium-dependent3540 60 melano activator aster protein 1031gi217705 Sus scrofadipeptidase precursor 781 51 1031gi2102 Susscrofa dipeptidase 781 51 1031gi8248922Homo Sapiensrenal dipeptidase; RDP 762 50 1032gi18073362Homo Sapienscystine/glutamate transporter2552 100 1032gi11493652Homo Sapienscalcium channel blocker2552 100 resistance protein CCBRl 1032gi 13924720Homo Sapienscystine/glutamate transporter2562 100 xCT

1033gi17028348Homo SapiensSimilar to methylenetetrahydrofolate3748 100 dehydrogenase (NADP+
dependent), methenyltetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthetase 1033120987924Mus musculusSimilar to DI~FZPS86G15173473 92 protein 1033gi307178 Homo SapiensMDMCSF (EC 1.5.1.5; 2839 62 EC 3.5.4.9; EC
6.3.4.3) 1034gi632676 Saccharomyces~1r410v,~p 598 44 cerevisiae 1034gi4070 Saccharomycesnufl 120 20 cerevisiae 1034gi312175 SaccharomycesSPC110/NUF1 120 20 cerevisiae 1035gi11066463Rattus I2hoGEF glutamate transport5589 80 norvegicusmodulator 1035' 19387126Mus musculusanine nucleotide exchange1794 37 factor 1035'7110160 Homo Sapiensanine nucleotide exchange1792 37 factor 1036gi2921821Rattus cytochrome P450 IIE1 68 28 norvegicus 1036gi8515399Human attachment glycoprotein64 29 respiratoryG
syncytial virus 1036gi5901834DrosophilaBcDNA.GH09358 95 23 melanogaster 1037gi17128288synthetic Primer 1 1689 100 construct 1037'20269957Sus scrofaphospholipase C delta 1469 85 1037121307610Mus musculusphospholipase C delta 1327 77 1038gi6978948Homo Sapiensvaccinia related kinase76 24 SEQ Hit ID Species Description S Percentage ID scoreidenti 1038gi349667 Carnobacteriumcarnobacteriocin A 60 41 piscicola 1038gi406315 Carnobacteriumpiscicolin 61 60 41 piscicola 1039gi4159884Homo Sapienssimilar to mouse olfactory1597 99 receptor 13;
similar to P34984 (PID:g464305) 1039gi9368991Homo SapiensdJ1005H11.1 (7 TRANSMEMBRANE1410 100 RECEPTOR (RHODOPSIN
FAMILY) (OLFACTORY RECEPTOR
LIKE) PROTEIN)) 1039gi18480186Mus musculusolfactory receptor MOR261-61323 81 1040gi311626 Homo Sapiensthrombospondin-4 4787 99 1040gi3860231Mus musculusthrombospondin-4 4557 93 1040gi929835 Rattus thrombospondin-4 4547 93 norvegicus 1041gi14043083Homo Sapienssperm associated antigen660 100 1041gi3116015Homo Sapienssperm specific protein _ 98 1041gi10801148Mus musculusJNK/SAl'K-associated 98 41 protein 1 1042gi21654741Homo Sapienspeptide/histidine trans1746 98 orter 1042gi2208839Rattus peptide/histidine transporter1469 79 norvegicus 1042gi16740719Mus musculusSimilar to peptide transporter1453 83 1043gi21392228DrosophilaRH61354p 1221 41 melano aster 1043gi19353264Homo sapiensSimilar to dishevelled 2224 65 associated activator of morphogenesis 2 1043gi2947238Homo Sapiensdiaphanous 1 717 32 1044gi 15929979Homo SapiensSimilar to zinc finger 2476 100 protein 345 1044' 18643896Homo Sapienszinc finger protein 1656 53 1044gi1020145Homo SapiensDNA binding protein 1656 53 1045gi12655913Homo sapienssprouty-4A 386 98 1045gi4850326Mus musculussprouty-4 323 81 1045gi5917720Mus musculussprouty 4 323 81 1046gi4539525Homo sapiensNAALADase II protein 3881 100 1046gi3211746Sus scrofafolylpoly-gamma-glutamate2824 70 carboxypeptidase 1046gi2897946Homo Sapiensprostate-specific membrane2787 69 antigen 1047gi5420389Leishmaniaproteophosphoglycan 139 23 maj or 1047gi915207 Sus scrofagastric mucin 123 22 1047gi13592175Leishmaniappg3 125 23 major 1048gi5918167Homo Sapiensplexin-B1/SEP receptor 2104 54 1048gi6010211Homo Sapienssemaphorin receptor 2103 54 1048gi1655432Mus musculusplexin 2 1517 30 1049gi15990515Homo SapiensSimilar to RIKEN cDNA 3035 100 gene 1049gi18380977Mus musculusRIKEN cDNA 0610020I02 2792 92 gene 1049gi2384732Rattus NAC-1 protein 1269 57 norve 'cus 1050gi15088540Homo Sapienssterolin-2 3127 99 1050gi11692802Homo SapiensABCG8 3123 99 1050gi15146444Homo Sapienssterolin-2 3120 99 1051gi12652851Homo Sapienspotassium channel modulatory1987 100 ~ ~ ~ factor SEQ Hit H) Species Description S Percentage ID scoreidentit 1051gi4838557Mus musculusDEBT-91 145396 1051gi16768790DrosophilaLD03515p 876 63 melanogaster 1052gi33730 Homo Sapiensimmuno lobulin lambda 716 71 light chain 1052gi33395 Homo Sapienslambda-chain precursor 703 70 (AA -20 to 215) 1052gi33744 Homo Sapiensimmuno lobulin lambda 697 68 light chain 1053gi21388773Homo Sapiensla~ingle-containing protein1552100 1053gi21623530Homo Sapienskringle-containing transmembrane123899 protein 1053gi21388775Homo Sapienskringle-containing protein1241100 1054gi14495324Homo SapiensCMRF35A 421 48 1054gi18490143Homo SapiensCMRF35 leukocyte immunoglobulin-like421 48 receptor 1054gi396170 Homo SapiensCMRF-35 antigen 421 48 1055'4468256 Homo SapiensMHC class I antigen 1974100 1055gi32139 Homo SapiensHLA-Al 1E protein precursor191297 (AA -24 to 341) 1055gi487909 Homo sapiensHLA-Al l antigen Al 1.1 191297 1056gi21667214Homo Sapiensbactericidal/permeability-increasing741 100 protein-like 3 1056gi57732 Rattus potential li and-binding215 35 rattus protein 1056gi118'77276Homo SapiensdJ726C3.5 (ortholog of 176 32 potential ligand binding protein RY2G5 (Rat)) 1057gi21667214Homo Sapiensbactericidal/permeability-increasing222699 protein-like 3 1057gi57732 Rattus potential ligand-bindin 579 32 rattus protein 1057gi11877276Homo SapiensdJ726C3.5 (ortholog of 540 31 potential li and bindin protein RY2G5 (Rat)) 1058gi21667214Homo Sapiensbactericidal/permeability-increasing191999 protein-like 3 1058157732 Rattus potential ligand-bindin 485 33 rattus protein 1058gi11877276Homo SapiensdJ726C3.5 (ortholog of 447 31 potential ligand binding protein RY2G5 (Rat)) 1059gi21667214=Homo Sapiensbactericidal/permeability-increasing184=2100 protein-like 3 1059gi57732 Rattus potential ligand-binding485 33 rattus protein 1059gi11877276Homo SapiensdJ726C3.5 (ortholog of 447 31 potential ligand binding protein RY2G5 (Rat)) 1060gi23911 Homo Sapienspolypeptide 7B2 precursor1148100 1060'7718079 Homo Sapiensneuroendocrine protein 1148100 1060gi13529158Homo Sapienssecretory granule, neuroendocrine113199 protein 1 (7B2 protein) 1061gi18698601Homo SapiensSmith-Magenis syndrome 2325100 chromosome region candidate 7 protein 1061gi15073752SinorhizobiumHYPOTHETICAL TRANSMEMBRANE90 29 meliloti SIGNAL PEPTIDE PRQTEIN

1061gi13623063Streptococcusheat shock protein - 70 32 pyogenes cochaperonin GAS

1062gi4128041Homo Sapiensclaudin-9 protein 1116100 1062gi4325296Mus musculusclaudin-9 107895 1062gi14286272Homo Sapiensclaudin 6 826 71 1063gi14286258Homo Sapiensribosomal protein L29 432 65 1063gi1215742Homo SapiensHIP 432 65 ~ gi793843 Homo sapiensribosomal protein L29 432 65 1063~ ~ ~
~

SEQ Hit ID Species Description S Percentage ID scoreidenti 1064gi6601555Rattus glutamate receptor interacting3560 86 norvegicusprotein 2 1064gi3639077Rattus AMPA receptor binding 2743 88 norvegicusprotein 1064gi1890856Rattus AMPA receptor interacting1925 59 norvegicusprotein GRIP

1065gi3288852Homo Sapiensdisabled-1 2865 99 1065gi1771282Mus musculusmDab555 protein 2797 96 1065gi22095317Gallus disabled-1 2630 90 gallus 1066gi3002527Homo Sapiensneuronal thread protein164 86 AD7c-NTP

1066gi4336401Homo Sapiensbeta glucuronidase isoform127 72 d 1066gi4336402Homo Sapiensbeta glucuronidase isoform127 72 c 1067115430703Homo Sapienstestis specific serinelthreonine1858 99 kinase 2 1067gi2738898Mus musculusprotein kinase 1686 89 1067gi15283993Homo Sapienstestis-specific serine/threonine1230 77 kinase 1 1068gi13543568Homo sapiensprostaglandin D2 synthase977 96 (2lkD, brain) 1068gi12963879Homo Sapiensprostaglandin D synthase977 96 1068gi189772 Homo Sapiensprostaglandin D2 synthase977 96 1069gi13279311Homo SapiensSimilar to RIKEN cDNA 1416 96 gene 1069gi14336718Homo Sapienssimilar to HAGH 1157 100 1069gi20988885Mus musculusRIKEN cDNA 1500017E18 1151 79 gene 1070gi13397835Homo sapiensannexin A13 isoform 1795 99 b 1070gi757784 Canis familiarisannexin 2~IIIb 1621 89 1070gi21218387~ryctolagusannexin XIIIb 1589 88 cuniculus 1071gi21707908Homo Sapienssolute carrier family 3129 98 6 (neurotransmitter transporter, GABA), member 1 1071gi31658 Homo SapiensGABA transporter 3114 98 1071gi204222 Rattus GABA transporter protein3097 96 norvegicus 1072gi7160975Homo Sapiensvoltage-gated sodium 834 100 channel beta-3 subunit 1072gi7161889Rattus voltage-gated sodium 823 98 norvegicuschannel beta-3 subunit 1072gi14165176Rattus sodium channel beta 823 98 norvegicus3 subunit 1074gi18676470Homo SapiensFLJ00132 protein 2515 99 1074gi21430928DrosophilaSD27341p 324 38 melanogaster 1074gi20197056Arabidopsisexpressed protein 206 29 thaliana 1075gi452751 Gallus Gal beta 1,4 GIcNAc 949 54 gallus alpha 2,6-sialyltransferase 1075gi2295223unidentifiedGALACTOSYLTRANSFERASE- 856 48 SIALYLTRANSFERASE HYBRID
PROTEIN

1075gi29434 Homo Sapiensbeta-galactoside alpha-2,6-856 48 sialyltransferase 1076gi13344997Homo SapiensCat Eye Syndrome critical2223 100 region protein isoform 2 1076gi13344995Homo SapiensCat Eye Syndrome critical2002 99 region protein isoform 1 1076gi15928451Mus musculusSimilar to cat eye syndrome1649 76 chromosome re ion, candidate 5 SEQ Hit ID Species Description S Percentage ID scoreidenti 1077gi13344997Homo SapiensCat Eye Syndrome critical1662 96 region protein isoform 2 1077gi13344995Homo SapiensCat Eye Syndrome critical1662 96 region protein isoform 1 1077gi15928451Mus musculusSimilar to cat eye syndrome1294 75 chromosome region, candidate 5 1078i 177870 Homo Sapiensalpha-2-macro lobulin 2714 39 precursor 10781579592 Homo Sapiensalpha 2-macroglobulin 2708 39 10781579594 Homo Sapiensalpha 2-macroglobulin 2700 39 1079gi671864 Gallus ovomacroglobulin, ovostatin1300 34 gallus 1079gi579594 Homo Sapiensalpha 2-macroglobulin 1297 35 1079gi177870 Homo Sapiensalpha-2-macroglobulin 1296 35 precursor 1080gi671865 Gallus ovomacroglobulin, ovostatin806 32 gallus 1080gi177870 Homo Sapiensalpha-2-macroglobulinprecursor769 31 1080gi579592 Homo Sapiensalpha 2-macroglobulin 769 31 1081gi177870 Homo Sapiensalpha-2-macroglobulin 2732 40 precursor 1081gi579592 Homo Sapiensalpha 2-macroglobulin 2726 40 1081gi579594 Homo Sapiensalpha 2-macroglobulin 2718 39 10821579594 Homo Sapiensalpha 2-macroglobulin 1297 35 1082gi177870 Homo Sapiensalpha-2-macro lobulin 1296 35 precursor 1082gi579592 Homo Sapiensalpha 2-macroglobulin 1296 35 1083gi404389 Mus sp. carboxylesterase; Es-male2006 66 1083gi213101 Anas thioesterase B 1261 46 platyrhynchos 1083gi2058318Homo sapienScarboxylesterase 1253 47 1084gi207286 Rattus TGF-beta masking protein8731 89 norvegicuslarge subunit 1084gi3493176Mus musculuslatent TGF beta binding8640 88 protein 1084gi19909128Homo Sapienstransforming growth 7763 99 factor-beta binding protein-1 S

1085gi17985371Homo SapiensI3 binding protein 861 100 1085gi21961229Homo SapiensBkI3 binding protein 861 100 1085gi184=668081-Iomo cervical cancer 1 proto-oncogene-binding853 99 sapienS pr~tein I~G19 1086gi222833 Gallus M-protein 2953 42 gallus 1086gi407097 Homo Sapiens165kD protein 29 42 1086gi2950347Mus musculusM-protein _ 42 1087gi12655165Homo Sapienszinc linger protein 696 65 1087gi4894364Homo Sapienszinc finger protein 696 65 1087gi21327296Homo Sapienszinc finger protein 495 46 1088gi2689441Homo SapiensF18547_1 188 37 1088gi1613848Homo Sapienszinc finger protein 316 49 zfp6 1088121327296Homo Sapienszinc finger protein 203 38 1089112655460Homo Sapienskeratin associated protein929 75 4.12 1089gi13278825Homo SapiensSimilar to RII~EN cDNA 929 75 gene 1089gi12655464Homo Sapienskeratin associated protein900 83 4.15 1090gi12655460Homo Sapienskeratin associated protein403 85 4.12 1090gi13278825Homo SapiensSimilar to RIKEN cDNA 403 85 gene 1090gi12655442Homo Sapienskeratin associated protein397 84 4.2 1091112655464Homo Sapienskeratin associated rotein1260 100 4.15 1091gi12655452Homo Sapienskeratin associated protein1222 90 4.7 1091gi12655460Homo Sapienskeratin associated protein1156 88 4.12 SEQ Hit ID Species Description S Percentage ID scoreidenti 1092gi15722084Homo SapiensbA304I5.1 (novel lipase)1991 100 1092gi21594466Mus musculusRIKEN cDNA 4632427023 1928 87 gene 1092gi460143 Homo Sapienslysosomal acid lipase/cholesteryl1290 60 ester hydrolase 1093gi21594466Mus musculusRIKEN cDNA 4632427023 1957 88 gene 1093gi15722084Homo SapiensbA304I5.1 (novel lipase)1935 100 1093gi460143 Homo Sapienslysosomal acid lipase/cholesteryl1290 60 ester hydrolase 1094'8118040 Homo sa orphan G-protein coupled1804 99 iens receptor 1094gi8118052Mus musculusorphan G-protein coupled1306 82 receptor 1094gi13177796Homo sapiensretinoic acid induced 728 45 1095gi18129609Homo sapiensdiacylglycerol acyltransferase600 49 1095gi15099951Mus musculusdiacylglycerol acyltransferase599 49 1095gi17426446Homo SapiensbA351I~23.5 (novel protein)572 54 1096gi17225337Homo Sapiensdendritic lectin 1134 95 1096gi17224598Homo Sapiensblood dendritic cell 1134 95 antigen 2 protein 1096gi17225339Homo Sapiensdendritic lectin b isoform918 94 1097gi17225337Homo Sapiensdendritic lectin 1182 99 1097gi17224598Homo Sapiensblood dendritic cell 1182 99 antigen 2 protein 1097' 17225339Homo Sapiensdendritic lectin b isoform966 99 1098121929119Homo Sapiensseven transmembrane 1595 100 helix receptor 1098118479834Mus musculusolfactory receptor M~R144-11223 77 1098gi18480806Mus musculusolfactoryreceptor M~R143-11163 70 1099gi5911169Homo Sapienstransmembrane mucin 3049 99 1099gi19526645Homo Sapiensintestinal membrane 815 32 mucin MUC17 1099gi5911171Homo Sapiensmucin 11 684 4~7 1100gi37198 Homo SapiensTMl-CEA preprotein 455 34 1100gi179440 Homo Sapiensbiliary glycoprotein 455 34 I precursor 1100gi550031 Homo SapiensBGPc 455 34 1101gi6273399Homo Sapiensmelanoma-associated 4733 60 antigen MG50 1101gi1504040Homo sapienssimilar to D.melanogaster4733 60 peroxidasin(U11052) 1101gi531385 Drosophilaperoxidasin precursor 2013 39 melanogaster 1102gi6273399Homo Sapiensmelanoma-associated 4458 60 antigen MG50 1102gi1504040Homo Sapienssimilar to D.melanogaster4458 60 peroxidasin(Ul 1052) 1102gi531385 Drosophilaperoxidasin precursor 2013 39 melano aster 1103gi7264653Mus musculusICiaa0575 2398 61 1103gi11611734Homo SapiensGREBla 513 46 1103gi915208 Sus scrofagastric mucin 128 30 1104gi20219008Chlamydomonacoiled-coil flagellar 682 36 s reinhardtiiprotein 1104gi16519041Drosophilaoccludin-like protein 203 23 melanogaster 1104gi3549261Dictyosteliuminteraptin 175 22 discoideum 1105gi12654511Homo SapiensATP-dependant interferon693 96 response protein 1 1105gi17390689Homo SapiensATP-dependant interferon693 96 responsive 1105gi10862826Homo SapiensADIRl 689 95 1106gi15215375Homo SapiensRNA bindin motif protein325 72 1106gi21666372Homo Sapiensswan 325 72 ~ ~

SEQ Hit ID Species Description S Percentage ID scoreidenti 1106gi19070194Homo SapiensSWAN 325 72 1107gi18157547Mus musculuspecanex-like 3 3262 97 1107gi6650377Mus musculuspecanex 1 2530 74 1107gi15076843Homo Sapienspecanex-like protein 2526 74 1108gi18157547Mus musculuspecanex-like 3 3138 97 1108gi6650377Mus musculuspecanex 1 2409 73 1108gi15076843Homo Sapienspecanex-like protein 2405 73 1109gi7770237Homo SapiensPR02822 233 59 1109gi21595759Homo Sapienssimilar to HC6 211 71 1109gi3002527Homo Sapiensneuronal thread protein209 67 AD7c-NTP

1110gi18159337PyrobaculumpaREP8 77 30 aerophilum 1110gi1658310Homo Sapiensleukocyte surface protein97 26 1110gi7638235Mus musculusimmunoglobulin heavy 77 25 chain variable domain 1111gi4263743Homo Sapienssimilar to UNC-93; similar1575 100 to U89424 (PID:g3642687) 1111gi12043567Homo Sapiensunc-93 related protein 1571 99 1111' 17390915Mus musculusSimilar to unc93 (C.elegans)1372 87 homolog B

1113gi4153873Homo Sapienssimilar to weal-like 2810 100 protein kinase;
similar to P30291 (PID:g1351419) 1113gi644770 Xenopus WeelA kinase 1166 64 laevis 1113gi2827996Xenopus weal homolog 1166 64 laevis 1114gi6606119Dothidea DNA-dependent RNA polymerase81 32 insculpta II
RPB14~0 1114gi2796053Mus musculusT cell receptor beta 54~ 48 chain 1115gi20372871Clarkia cytosolic phosphoglucose56 28 similis isomerase 1116gi21708029Homo Sapienssimilar to Alu subfamily135 70 Sf~ sequence contamination warnin entry 1116gi11493409Homo SapiensPRO0898 129 59 1116gi6650818Homo sapiensPRO1992 110 70 1117gi13810898Rattus inhibin binding protein310 37 norvegicuslong isoform 1117gi2645890Homo SapiensIGSF1 326 40 1117gi2370143Homo Sapiensimmunoglobulin-like 326 40 domain-containing 1118gi13810898Rattus inhibin binding protein310 37 norvegicuslong isoform 1118gi2645890Homo SapiensIGSF1 312 38 1118gi2370143Homo Sapiensimmunoglobulin-like 312 38 domain-containing 1119gi21707128Homo SapiensRan binding protein 5047 99 1119gi20987296Mus musculusSimilar to Ran bindingprotein4898 96 1119gi17862636DrosophilaLD41918p 1191 38 melano aster 1120gi18652832Homo SapiensASPP1 protein 5703 99 1120gi16197705Homo SapiensASPP2 protein 1556 42 1120gi1399805Homo SapiensBbp/53BI'2 1556 42 1121gi18448478Aotus chorionic gonadotropin 47 59 trivirgatusbeta subunit 1121gi5670272Human Kl glycoprotein 67 38 herpesvirus 1121gi9886851Human Kl protein 63 36 herpesvirus TART,F 2 A
SEQ Hit H) Species Description S Percentage ID scoreidenti 1122gi2598461Homo SapiensdJ408N23.1 (suppression 188797 of tumorigenicity 13 (colon carcinoma) (Hsp70-interacting protein) (Progesterone receptor associated P48 protein)) 1122gi904032 Homo Sapiensp48 186996 1122gi21218374Homo SapiensFAM10A5 181493 112318927428 Homo Sapiensotoraplin 676 100 1123i 12619173Homo Sapiensmelanoma inhibitory activity676 100 like protein 1123gi11323317Homo SapiensdJ705D16.2 (Otoraplin) 676 100 1124gi12034719Mus musculusankyrin-like protein 462 46 1124gi13469729Homo Sapiensbreast cancer antigen 448 50 1124gi21618588Homo Sapienstestis-specific ankyrin 381 47 motif containing protein 1125gi13469729Homo Sapiensbreast cancer antigen 364 51 1125gi12034719Mus musculusankyrin-like protein 379 46 1125gi21618588Homo sapienstestis-specific ankyrin 345 49 motif containing protein 1126gi7770139Homo SapiensPRO1722 263 60 1126gi 11493483Homo SapiensPRO2550 263 67 1126gi8572229Homo Sapiensubiquitous TPR-motif 249 61 protein Y isoform 1127gi6907090_ Similar to Oryza sativa 86 35 Oryza sativaroot-specific (japonica RCc3 mRNA. (L27208) cultivar-group) 1127gi5902450Cercopithecineglycoprotin G 58 41 herpesvirus 1127gi12750734Homo SapiensL-type voltage-dependent56 48 calcium channel 1128gi16878260Homo sapiensSimilar to angiotensin 726 100 II, type I receptor-associated protein 1128gi16588454Homo SapiensAGTRAP protein 705 95 1128gi9621816Homo SapiensATRAP 705 95 1129gi 17986216Homo sapienscell recognition molecule186498 1129gi12330704Mus musculuscell reco iition molecule137671 1129gi21961652Mus musculuscell recognition protein137671 1130gi17986216Homo Sapienscell reco ition molecule681299 1130gi18390059Homo Sapienscell recognition protein475470 1130121961652Mus musculuscell recognition protein472468 1131gi21552969Mus musculusVVilliams-Beuren syndrome310097 critical region ene 17 1131gi10336504~Homo sapiensUDP-GaINAc: polypeptide 202061 N-acetylgalactosaminyltransferase 1131gi11041469Macaca UDP-GaINAc: polypeptide 191358 fascicularisN-acetyl alactosaminyltransferase 1132gi13625176Homo Sapiensthrombospondin 586 46 1132gi14627121Homo sapiensdJ824F16.3 (novel protein544 46 similar to mouse thrombospondin type 1 domain protein R-spondin) 1132gi4519541Mus musculusthrombospondin type 1 511 43 domain 1133gi5305333Mus musculusprotein kinase Myak-S 865 50 1133gi18314319MesocricetusMx-interacting protein 865 50 auratus kinase PKM

1133gi5815143Mus musculusnuclear body associated 865 50 kinase 2a 1134gi14022292Mesorhizobiumcell division protein 45 36 loti SEQ Hit ID Species Description S Percentage ID scoreidenti 1134gi180143 Homo SapiensCD53 glycoprotein 45 53 _1134gi180141 Homo Sapienscell surface antigen 45 53 1135gi14571502Homo Sapienscalcium-promoted Ras 4174 99 inactivator 1135gi2822157Homo sapienssimilar to GTl'ase-activating3961 99 proteins;
35% similar to JC5047 (PID: 2136083) 1135gi4185294Homo SapiensrasGAP-activating-like 1898 49 protein 1136gi11527987Gallus immunoglobulin-like 97 30 gallus receptorCHIR-A

1136gi432214 Human envelope glycoprotein 43 39 immunodeiiciengp120 cy virus type 1 1136gi15026993Homo sapiensMUCSAC protein 64 38 1137gi15128103Mus musculusnephronectin 2971 87 1137gi15430248Mus musculusnephronectin lon isoform2640 80 1137gi16040981Mus musculusPOEM 2374 87 1139gi7638247Homo Sapiensmesenchymal stem cell 595 100 protein DSCD75 1139gi17946258DrosophilaRE58349p 165 34 melanogaster 1139gi21464462DrosophilaRH58440p 158 36 melanogaster 1140gi21619491Homo Sapienssimilar to expressed 235 83 sequence AW049604 1140gi6572294Homo SapiensbA262A13.1 (novel protein)126 48 1140gi215692 Bacteriophagegop protein 87 28 1141gi21619491Homo Sapienssimilar to expressed 454 82 sequence AW049604~

1141gi6572294Homo SapiensbA262A13.1 (novel protein)239 48 1141gi215692 I3acteriophagegop protein 84 33 1142gi20306274Homo Sapienstesticular haploid expressed1487 80 gene 1142gi10443967HomosapiensTHEGprotein _ 80 1142gi7416134Homo Sapienstestis-specific gene 1487 80 1143gi21928259Homo Sapiensseven transmembrane 1023 100 helix receptor 1143gi18480746Mus musculusolfactory receptor M~R261-10864 84 1143~i18480744Mus musculusolfactory receptor M~R261-9858 82 1144gi21928655Homo sapiensseven transmembrane 1458 93 helix receptor 1144gi18480746Mus musculusolfactory receptor M~R261-101280 79 1144gi18480744Mus musculusolfactory receptor M~R261-91258 78 1145gi1707674Streptomyceselongation factor G 52 34 cinnamoneus 1146gi15779092Homo SapiensSimilar to syntaxin 1295 100 1146gi7707424Homo Sapienssyntaxin 18 1295 100 1146118203931Mus musculusSimilar to syntaxin 873 90 1147114573319Homo Sapiensinterleukin-1 HY2 812 99 1147gi18025344Homo Sapiensinterleuldn-1 receptor 809 99 antagonist-like FILL theta 1147gi19068192Mus musculusIL-1F10 662 82 1148gi4103158Mus musculushair keratin acidic 1116 72 5; Ha5 keratin 1148gi3724107Homo Sapienskeratin, type I 1114 72 1148gi1668744Homo SapiensHHaS hair leeratin type1114 72 I intermediate filament 1149gi19353375Mus musculusRII~EN cDNA 1110031I02 1417 84 gene 1149gi6166378Mus musculusgrowth suppressor 1L 141 30 1149gi15929776Homo Sapiensgrowth suppressor 1 137 41 1150gi13623421Homo SapiensSimilar to RIKEN cDNA 1336 90 gene TART.F 7 A
SEQ Hit ID Species Description S Percentage ID scoreidentit 1150gi19484086Mus musculusRIKEN cDNA 5730589L02 128786 gene 1150gi1699265Homo Sapiensmalignant cell expression-enhanced392 57 gene/tumor progression-enhanced gene 1151gi15419605Canis familiarismasticatory epithelia 120455 keratin 2p 1151gi14595019Homo Sapienskeratin 6 irs 117554 1151gi6092075Mus musculustype II cytokeratin 111651 1152gi11066090Homo Sapiensmatrix metalloprotease 138296 1152gi12006364Tupaia matrix metalloproteinase-27112180 belan eri 1152gi3511149Gallus matrix metalloproteinase663 57 gallus 1153gi11066090Homo Sapiensmatrix metalloprotease 138296 1153gi12006364Tupaia matrixmetalloproteinase-27112180 belan eri 1153gi3511149Gallus matrix metalloproteinase663 57 gallus 1154gi6689894Homo SapiensSuppressor of Fused 2599100 1154gi5739507Homo Sapienssuppressor of fused 259499 1154gi4468628Mus musculusSu(fu) protein 254197 1155gi21667212Homo Sapiensbactericidal/permeability-increasing2600100 protein-like 2 1155gi20387085OncorhynchusLBP (LPS binding protein)/BPI690 31 mykiss (bactericidal/permeability-increasing protein)-1 1155gi20387087OncorhynchusLBP (LPS binding protein)/BPI685 30 mykiss (bactericidal/permeability-increasing protein) like-2 1156gi11229139Homo SapiensbB152O15.3 (SRY (sex 2066100 determining region Y)-box 18) 1156gi12082687Hoano SapiensSry-related HMG-box protein2066100 1156gi8894593Homo SapiensSOX18 protein 2066100 1157gi19526647Homo Sapiensoxidored-vitro domain-containin837 85 protein 1157gi7303522DrosophilaCG13178-PA 172 31 melanogaster 1157gi16304~788Mus musculusbendless-like ubiquitin 83 28 conjugating enzyme 1158gi19526647Homo Sapiensoxidored-vitro domain-containing837 85 protein 1158gi7303522DrosophilaCG13178-PA 172 31 melanogaster 1158gi16304788Mus musculusbendless-like ubiquitin 83 28 conjugating enzyme 1159gi1794221Mus musculusDNA ligase III-beta 298789 1159gi1794223Mus musculusDNA ligase III-alpha 298789 1159gi19550955Homo Sapiensligase III, DNA, ATP-dependent2875100 1160gi15667919Homo SapiensSERPINB12 167899 1160gi12597188Homo Sapienssquamous cell carcinoma 749 48 antigen 2 1160gi1235617Homo Sapienssquamous cell carcinoma 749 48 antigen 1161gi15141587Eulemur olfactory receptor 67 34 rubriventer 1161gi21739229Oryza sativaOSJNBa0072F16.8 67 43 1161gi21629328LeishmaniaL3561.8 65 37 maj or 1162gi2589190Homo Sapiensskin-specific protein 68 39 1162gi38232 Pan troglodytesimmunoglobulin alpha 61 39 heavy chain 1162gi14021730Mesorhizobiumc-type cytochrome biogenesis68 31 loti protein SEQ Hit ID Species Description S Percentage ID scoreidenti 1163gi7228149Mus musculusATFa-associatedfactor 354 50 1163gi7303705DrosophilaCG12340-PA 193 24 melanogaster 1163gi5052666DrosophilaBcDNA.LD26050 193 24 melanogaster 1164gi20901968CaenorhabditisC. elegans RPL-36 protein71 34 elegans (correspondin sequence F37C12.4) 1165gi5911451Drosophilacytochrome oxidase III 43 41 nannoptera 1165gi13276253Homo SapiensT-cell receptor beta 56 34 chain VJ region 1165gi3928896Homo SapiensSH2 domain protein lA 55 38 isoform C

1166gi20381326Homo SapiensSimilar to caspase 8, 263 100 apoptosis-related cysteine protease 1166gi14211398Homo Sapienscaspase-8L 263 100 1166gi19401524Homo Sapiensprocaspase-8 223 95 1167gi10440448Homo SapiensFLJ00060 protein 1204 98 1167gi3983420Homo SapiensKIR3DL1-like natural 693 47 killer cell receptor 1167gi13560453Homo Sapienskiller cell immunoglobulin-like693 47 receptor 1168gi1799570Rattus TIP120 4573 99 norvegicus 1168gi7688703Homo sapiensTIP120 protein 4573 99 1168gi5811583Rattus TIP120-family protein 2735 57 norve 'cus 1169' 13016701Homo Sapiensactivating coreceptor 1226 100 NI~p80 1169gi7188567Homo Sapienslectin-like receptor 1226 100 Fl 1169gi22449867Macaca NKp80 NK receptor 1122 90 fascicularis 1170gi14027275Mesorhizobiumnodulation protein node,70 27 3-oxoacyl-(acyl loti carrier protein) reductase 1170gi1531618Rhizobium NodG 68 26 sp.

1170gi6899062Llreaplasmascryl-tRNA synthctasc 70 31 urealyticum 1171gi3021409Homo Sapienstransducin (beta) like 3057 100 1 protein 1171gi13161069Homo Sapienstransducin beta-like 2548 91 1171gi12642596Homo Sapiensnuclear receptor co-repressor/HDAC32431 86 complex subunit TBLRl 1172gi13623421Homo SapiensSimilar to RIKEN cDNA 380 69 gene, clone MGC:13124 IMAGE:4110925, mRNA, complete cds.

1172gi12803383Homo Sapiensclone MGC:2099 IMAGE:3051525,376 68 mRNA, complete cds.

1172gi13111983Homo Sapiensclone MGC:4221 IMAGE:2958347,376 68 mRNA, complete cds.

1173gi13623421Homo SapiensSimilar to RII~EN cDNA 380 69 gene, clone MGC:13124 IMAGE:4110925, mRNA, complete cds.

1173gi12803383Homo Sapiensclone MGC:2099IMAGE:3051525,376 68 mRNA, complete cds.

1173gi13111983Homo sapiensclone MGC:4221 IMAGE:2958347,376 68 mRNA, complete cds.

1174gi13623421Homo sapiensSimilar to RII~EN cDNA 1830 99 gene 1174gi19484086Mus musculusRIKEN cDNA 5730589L02 1802 95 gene TART,Ti.7 A
SEQ Hit ID Species Description S Percentage ID scoreidenti 1174gi1699265Homo Sapiensmalignant cell expression-enhanced930 81 gene/tumor progression-enhanced gene 1175' 13182755Homo SapiensHPHRP 1210100 1175gi15929309Homo Sapiensphosphotriesterase related1210100 1175gi881499 Mus musculusparathion hydrolase (phosphotriesterase)-106986 related protein 1176gi552075 Chironomusgiant secretory protein 71 28 tentans 1176gi15419013Toxoplasmasubtilisin-like protein 71 34 gondii 1176gi156534 Chironomusgiant secretory protein 66 28 (gsp) tentans 1177gi5458910PyrococcusFLAGELLA-RELATED PROTEIN103 24 C

abyssi 1177gi487272 EnterococcusNa+ -ATPase subunit F 90 31 hirae 1177gi9229886Ciona ezrin/radixin/moesin 111 27 (ERM)-like protein intestinalis 1178gi21554060Arabidopsisphytocyanin 44 43 thaliana 1178gi205640 Rattus acetylcholine receptor 53 44 alpha subunit norvegicus 1178gi4028904Rattus nicotinic acetylcholine 53 44 receptor alpha 4 norvegicussubunit 1179gi 18375961Neurosporarelated to ARCH protein 53 44 crassa 1179gi2935025Rhodococcusprotocatechuate dioxygenase38 38 alpha opacus subunit 1179gi13421646CaulobacterspoU rRNA methylase family39 40 protein crescentus 1180gi14348558Homo SapienscDNA encoding protease 82 38 domain of endotheliase 1 1180gi1245184.Danio rerio~g01 66 33 1180gi6137097Homo Sapiensscrine protease DESC1 82 38 1181gi19528151DrosophilaAT26759p 59 35 melanogaster 1181gi16768554DrosophilaGM08606p 59 35 melanogaster 1181gi7291750DrosophilaCG4065-PA 59 35 melano aster 1182gi13377880Cricetulusarginine N-methyltransferase325385 p82 isoform longicaudatus 1182gi13377882Cricetulusarginine N-methyltransferase325385 p77 isoform longicaudatus 1182gi21626587DrosophilaCG9882-PA 121336 melanogaster 1183gi191185 Cricetulusphosphatidylserine decarboxylase113088 griseus 1183gi5921491Homo SapiensdJ858B16.2 (phosphatidylserine122096 decarboxylase (PSSC, EC 4.1.1.65)) 1183gi16306618Homo Sapiensphosphatidylserine decarboxylase122096 1184gi11907580Mus musculusTSC22-related inducible 894 87 leucine zipper 3c 1184gi5231131Homo SapiensTSC-22 related protein 460 98 1~0 SEQ Hit ID Species Description S Percentage ID scoreidenti 1184gi5919161Homo SapiensTSC-22-like Protein 460 98 1185gi13874437Homo Sapienscerebral protein-11 1461 68 1185gi15292367DrosophilaLD47668p 510 41 melanogaster 1185gi2443444Homo SapiensTEX28 310 40 1186gi13543940Homo SapiensSimilar to RIKEN cDNA 2568 99 gene 1186gi18204520Mus musculusRIICEN cDNA 2610017609 2381 91 gene 1186gi16923351Homo SapiensRbBP-35 1434 99 1187gi18676660Homo SapiensFLJ00229 protein 931 91 1187gi5824711Caenorhabditissimilar to 7TM chemoreceptor80 20 elegans (srd-family) 1187gi8825622Rattus T cell receptor 68 36 norvegicus 1188gi17865311Homo Sapiensdipeptidyl peptidase-like4646 100 protein 9 1188gi11095188Homo Sapiensdipeptidyl peptidase 2876 60 1188gi21265133Homo SapiensSimilar to dipeptidylpeptidase2217 58 1189gi17865311Homo sapiensdipeptidyl peptidase-like4069 100 protein 9 1189gi11095188Homo Sapiensdipeptidyl peptidase 2454 59 1189gi21265133Homo SapiensSimilar to dipeptidylpeptidase2455 56 1190gi17865311Homo Sapiensdipeptidyl peptidase-like4542 98 protein 9 1190gi11095188Homo Sapiensdipeptidyl peptidase 2810 60 1190gi21265133Homo SapiensSimilar to dipeptidylpeptidase2151 57 1191gi337508 Homo sapiensribosomal protein 554 99 1191gi57724 Rattus ribosomal protein S25 554 99 rattus 1191gi12805251Mus musculusribosomal protein S25 554 99 1192gi208176 synthetic D2-T antigen 61 40 construct 1193gi7328583Drosophilamechanosensorytransduction851 28 melanogasterchannel NOMPC

1193gi7385113Bos taurusankyrin 1 777 30 1193gi11065673CaenorhabditisI'71A12B.4 778 28 ele ans 1194gi7672669Homo sapiensserine protease Htra2 1890 100 1194gi12652695Homo sapiensHtrA-like serine protease1890 100 1194gi5870865Homo Sapiensserine protease 1890 100 11951349449 Homo SapiensA3 adenosine receptor 904 100 1195113559064Homo SapiensbA552M11.6 (adenosine 904 100 A3 receptor) 1195120988265Homo Sapiensadenosine A3 receptor 904 100 1196gi21645219DrosophilaCCa15671-PA 299 37 melanogaster 1196gi9864185DrosophilaCrossveinless 2 299 37 melanogaster 1196gi7768636Xenopus I~ielin 276 34 laevis 1197gi18480772Mus musculusolfactory receptor MOR101-21415 84 1197gi18479346Mus musculusolfactory receptor MOR101-11334 82 1197gi3769616Rattus olfactory receptor 973 86 norvegicus 1198gi498768 Serratia Deoxyadenosyl-methyltransferase339 51 marcescens 1198gi10799034Vibrio DNA adenine methylase 332 54 cholerae 1198gi10799036Yersinia DNA adenine methylase 331 52 pseudotubercul osis TART.F ?. A
SEQ Hit ID Species Description S Percentage ID scoreidenti 1199 gi16974751Gallus CALII 338 37 gallus 1199 gi666121Xenopus cpl-1 293 33 laevis 1199 gi1213589Xenopus Prostaglandin D Synthase292 33 laevis 1200 gi22296200Thermosynechoasparaginyl-tRNA synthetase105746 coccus elongatus 1200 gi17132791Nostoc asparaginyl-tRNA synthetase102746 sp. PCC

1200 gi19713460FusobacteriumAsparaginyl-tItNA synthetase101343 nucleatum subsp.

nucleatum 1201 gi18088970Homo SapiensSimilar to RIICEN cDNA 126399 gene 1201 gi20067381Homo SapiensALMS1 protein 249 41 1201 gi21552774Mus musculusAlmstrom syndrome 1 protein219 38 1202 gi347134Homo Sapienssuccinate dehydrogenase 495 92 flavoprotein subunit 1202 gi12655061Homo Sapienssuccinate dehydrogenase 495 92 complex, subunit A, flavoprotein (F ) 1202 gi506338Homo Sapiensflavoprotein subunit 495 92 of complex II

1203 gi18490322Homo SapiensSimilar to RII~EN cDNA 224199 enc 1203 gi21928186Mus musculusGPI-gamma 4; GPI amma4 147161 1203 gi17946082DrosophilaI2E54096p 688 47 melanogaster 1204 gi9957165Homo SapiensalphaCP-3 1722100 1204 gi9957161Mus musculusalphaCP-3 170899 1204 gi15082311Homo SapiensSimilar to poly(rC)-binding840 99 protein 3 1205 gi14574118CaenorhabditisC. elegans DPY-19 protein239 31 elegans (corresponding sequence F22B7.10) 1205 gi12328595HeterodoxusNADH dehg~diogenaSe subuuit7~ 29 macropus 1205 gi18378695Bufo maculatesNADH dehydro enase subunit75 24 1206 gi189760Homo Sapienspyruvate dehydrogenase 171096 beta-subunit 1206 gi189762Homo Sapienspyruvate dehydrogenase 171096 E1-beta subunit 1206 gi190792Homo Sapienspyruvate dehydrogenase 171096 E1-beta subunit precursor 1207 gi688292Homo Sapienscalmitine; calsequestrine2029100 1207 gi2618621Mus musculusskeletal muscle calsequestrin193894 1207 gi164842Oryctolaguscalsequestrin 190894 cuniculus 1208 gi22295775Thermosynechoperiplasmic sugar-binding65 35 protein of coccus sugar ABC transporter elongates 1208 gi2622963Methanothermoconserved protein 59 30 batter thermautotrophi cus str.
Delta H

1208 gi18377999Drysdalia NADH dehydrogenase subunit61 34 coronata 1209 gi11034760Homo SapiensNIBAN 369299 1209 gi10432376Homo SapiensbG56G5.1 (novel protein)333499 1209 gi11022733Mus musculusNiban 232067 ~reur ~ ~ w SEQ Hit ID Species ~ Description S Percentage ID

scoreidenti 1210 gi2982508Homo SapiensTCR beta chain 129293 1210 gi3002925Homo SapiensT cell receptor beta 128193 chain 1210 gi36733 Homo SapiensT cell antigen receptor 102875 beta chain 1211 gi12006041Homo SapiensAD038 761 98 1211 gi14189960Homo SapiensPR00764 141 53 1211 gi 19072857Homo Sapienslung squamous cell cancer129 60 related protein 1213 gi2995719Homo Sapiensprotocadherin 43 4792100 1213 gi20072790Homo Sapiensprotocadherin gamma subfamily477799 C, 3 1213 gi5456977Homo Sapiensprotocadherin gamma C3 477799 1214 gi337487Homo SapiensRo ribonucleoprotein 174799 autoantigen (Ro/SS-A) precursor 1214 gi179882Homo Sapienscalreticulin 174799 1214 gi22203354Cricetuluscalreticulin 168795 griseus 1215 gi200964Mus musculusserene 2 ultra high sulfur319 52 protein 1215 gi3228237Homo sapiensultra high sulfer keratin281 49 1215 gi200962Mus musculusserene 1 ultra high sulfur281 50 protein 1216 gi13940422Macaca ATPase subunit 8 56 31 sylvanus 1217 gi5917716Gallus sprouty 2 60 45 gallus 1217 gi 14275701Influenza matrix protein 2 62 32 virus 1217 gi2738577Homo Sapiensconnexin46.6 54 50 1218 gi17223709Homo Sapiensselenoprotein SeIM 235 100 1218 gi17223711Mus musculusselenoprotein SeIM 188 78 1218 gi7380925Bos taurusFc gamma receptor III 73 45 1219 gi15025778ClostridiumPredicted membrane protein50 36 acetobutylicum 1219 gi13752743Serratia TrpG 65 51 marcescens 1219 gi20906991MethanosarcinaCation transporter 62 29 mazei Goel 1220 gi535358Ncisseria Opa15063G 60 50 gonorrhoeac 1220 gi1480793Neisseria OpaIl 58 47 meningitides 1221 gi992950Homo SapiensOPN-c 142698 1221 gi189151Homo Sapiensnephropontin precursor 137790 1221 gi1001963Homo Sapiensosteopontin 137790 ' 1223 gi18088363Homo Sapiensadvanced glycosylation 200499 end product-specific receptor 1223 gi1841550Homo Sapiensreceptor for advanced 200499 glycosylation end products 1223 '6691626Homo Sapiensadvanced glycation endproducts200499 receptor 1224 gi3157464Thermus rote al membrane protein77 38 sp. A4~

1224 gi8778370ArabidopsisF15O4.23 65 37 thaliana 1224 gi15156782AgrobacteriumAGR C 3106p 59 34 tumefaciens str.

C58 (Cereon) 1225 gi37231 Homo SapiensDNA topoisomerase II 806199 , 1225 gi3869382Homo SapiensDNA topoisomerase II 804899 beta 1225 gi790988CricetulusDNA topoisomerase (ATP-hydrolysing)789297 l ongicaudatus SEQ Hit ID Species Description S Percentage ID scoreidenti 1226gi10041309Homo sapienshFATPl 3336 98 1226gi1881713Rattus fatty acid transport 3031 87 protein norvegicus 1226gi10041307Rattus rFATP 3031 87 sp.

1227gi3309176Mus musculusCOP9 complex subunit 796 94 7b 1227gi15215085Mus musculusSimilar to COP9 (constitutive793 93 photomorphogenic), subunit 7b (Arabidopsis) 1227gi19909525Homo sapiensDERP10 (dermal papilla 467 56 derived protein 10) 1228gi6942096Mus musculusCBLN3 938 93 1228gi180251 Homo Sapiensprecerebellin 551 58 1228gi5702371Mus musculusprecerebellin-1 544 57 1229gi17861952DrosophilaLD01947p 1384 50 melanogaster 1229gi6850946Homo SapiensdJ322I12.1 (novel protein336 100 similar to C.

elegans C05C8.6 (Tr:016313)) 1229gi21411108Mus musculusSimilar to BTB domain 211 32 protein BDPL

1230gi8132557Drosophilaankyrin 2 729 30 melano aster 1230gi710551 Mus musculusankyrin 3 734 29 1230gi1841966Rattus ankyrin 700 30 norvegicus 1231gi21667212Homo Sapiensbactericidal/permeability-increasing2384 98 protein-like 2 1231gi20387085OncorhynchusLBP (LPS binding protein)/BPI672 31 mykiss (bactericidal/permeability-increasing protein)-1 1231gi20387087OncorhynchusLBP (LPS binding protein)/BPI667 30 myleiss (bactericidal/permeability-increasing protein) like-2 1232gi21667212Homo Sapiensbactericidal/permeability-increasing2389 99 protein-like 2 1232gi20387085OncorhynchusLBP (LPS binding protein)/BPI664= 31 mykiss (bactericidal/permeability-increasing protein)-1 1232gi20387087OncorhynchusLBP (LPS binding protein)IBPI659 30 mykiss (bactericidal/permeability-increasing protein) like-2 1233gi21667212Homo Sapiensbactericidal/permeability-increasing2595 99 protein-like 2 1233gi20387085OncorhynchusLBP (LPS binding protein)/BPI698 31 myleiss (bactericidal/permeability-increasing protein)-1 1233gi20387087OncorhynchusLBP (LPS binding protein)/BPI693 30 mykiss (bactericidal/permeability-increasing protein) like-2 1234gi19569876DictyosteliumSIMILAR TO HYPOTHETICAL247 26 26.2 discoideumKD PROTEIN

1234gi2191168Arabidopsiscontains similarity 187 27 to myosin heavy chain thaliana 1234gi603379 SaccharomycesYer139cp 145 28 cerevisiae 1235gi11493528Homo SapiensPR01953 671 100 1235gi19912632Eulemur HC class II antigen ~ ~ 33 ~ 56 SEQ Hit ID Species Description S Percentage ID scoreidenti rubriventer 1235gi19912630Eulemur MHC class II antigen 55 33 macaco macaco 1236gi17065951Ostertagiacollagen 70 35 ostertagi 1236gi158077 Drosophilaperiod protein 69 38 robusta 1236gi497417 Glycine dehydrin-like protein 81 27 max 1237gi3068592Mus musculuspunc 2396 94 1237gi19570398Homo SapienshDDM36 890 41 1237gi11862941Mus musculusDDM36E 892 41 1238gi12667401Homo SapiensNUF2R 2347 99 1238gi14317902Homo Sapiensleinetochore protein 2347 99 Nuf2 1238gi12667403Mus musculusNUF2R 1754 73 1239gi2494126ArabidopsisContains similarity 94 23 thaliana to Chlamydia outer membrane protein (gb~X53512).

1239gi19887475MethanopyrusUncharacterized protein68 34 kandleri conserved in AV 19 archaea 1239gi21646173Chlorobiumribosomal protein S20 67 29 tepidum TLS

1240121634825Homo Sapienssemaphorin 6D isoform 5658 98 1240gi21634823Homo Sapienssemaphorin 6D isoform 3106 96 1240gi21634827Homo Sapienssemaphorin 6D isoform 3106 99 1241gi9949555Pseudomonasprobable pyruvate dehydrogenase71 35 aeruginosaE1 component, alpha subunit 1241gi48708 MycobacteriumORFal (AA 1 - 74) 58 37 tuberculosis 1241gi307352 Homo Sapiensprothymosin alpha 54 35 1242gi9106331Xylella 3-dehydroquinate synthase43 34~
fastidiosa 9a5c 1242gi13700302Staphylococcusxanthine phosphoribosyltransferase45 35 aureus subsp.
aureus 1242gi21203529Staphylococcusxanthine phosphoribosyltransferase45 35 aureus subsp.
aureus 1243gi21671105Homo SapiensRAD52B 1134 100 1243gi20070921Mus musculusRII~EN cDNA 2410008M22 829 74 gene 1243gi21594785Homo SapiensSimilar to RII~EN cDNA 572 97 ene 1244gi6013381Rattus TM6P1 147 47 norvegicus 1244119353944Mus musculusRIICEN cDNA 2610318618 127 31 gene 1244gi20270909OncorhynchusVHSV-induced protein-6 118 31 mykiss 1245gi6013381Rattus TM6P1 272 36 norvegicus 1245gi21428644DrosophilaLP10820p 256 42 melanogaster 1245gi20270909OncorhynchusVHSV-induced protein-6 190 29 mykiss 1246111993700Homo Sapiensmelastatin 2 1194 100 1246gi3243075Homo Sapiensmelastatin 1 1057 83 1246gi3047242Mus musculusmelastatin 1050 83 1247118044366Homo SapiensSimilar to MEGF10 protein3468 99 SEQ Hit ID Species Description S Percentage ID scoreidenti 1247gi17386053Mus musculusJedi protein 2280 51 1247gi18252658Mus musculusJedi-736 protein 2280 51 1248gi20987880Mus musculusSimilar to PTH-responsive3586 87 osteosarcoma B 1 protein 1248'4588087 Homo SapiensPTH-responsive osteosarcoma2264 92 B1 protein 1248gi21595711Homo SapiensSimilar to PTH-responsive1546 100 osteosarcoma B 1 protein 1249gi19913471Homo sapienssimilar to dJ84N20.1.1 1265 99 (novel protein, isoform 1) 1249gi13591434Homo SapiensdJ84N20.1.2 (novel protein,1160 100 isoform 2) 1249gi13591435Homo SapiensdJ84N20.1.1 (novel protein,976 99 isoform 1) 1250gi16605581Homo SapiensH-rev107-like protein 1451 100 1250'21707989Homo SapiensSimilar to H-rev107-like1376 96 protein 5 125016048565 Homo sapiensretinoid inducible gene382 54 1251gi21263094Rattus tramdorin 1 1667 81 norvegicus 1251gi21263092Mus musculustramdorin 1 1664 82 1251gi21908026Mus musculusproton/amino acid transporter1664 82 1252gi14571904Rattus lysosomal amino acid 1690 87 norvegicustransporter 1 1252gi21908024Mus musculusproton/amino acid transporter1685 87 1252gi21263092Mus musculustramdorin 1 1294 66 1253'21595630Homo SapiensSimilar to forkhead 75 44 box L2 1253gi10580569Halobacteriumtraps lesion repair; 69 51 sp. NRC-1 YqjH

1253gi557673 Sus scrofaBM88 antigen 72 41 1254gi1669500Mus musculusfibroblast growth factor917 90 homologous factor 1 1254gi1563885Homo Sapiensfibroblast growth factor917 90 homologous factor 1 1254gi14317951Rattus fibroblast growth factor916 98 norvegicushomologous factor 1B

1255gi13529143Homo SapiensSimilar to RII~EN cDNA 779 100 ge112 1255gi19263005~ Ciona leucine-rich repeat 759 75 intestinalisdynein light chain 1255gi2760161Anthocidarisouter arm dynein light 656 68 crassispinachain 2 1256gi12666529Mus musculusb,b-carotene-9',10'-dioxygenase2356 80 1256gi4001821Ambystoma RPE65 protein; retinal 1125 44 tigrinum pigment epithelium 65-protein 1256111990268Mus musculusbeta,beta-carotene 15,15'-dioxygenase1110 42 1257112666529Mus musculusb,b-carotene-9',10'-dioxygenase2305 81 1257_ Ambystoma RPE65 protein; retinal 1122 44 gi4001821ti ~inum pigment epithelium 65-protein 1257gi11990268Mus musculusbeta,beta-carotene 15,15'-dioxygenase1113 42 1258gi18490501Mus musculusRIKEN cDNA 2010002A20 868 76 gene 1258gi61 Bos tauruscalmodulin-independent 166 29 adenylate ~
cyclase 1258gi15559697Homo SapiensSimilar to neural cell 165 29 adhesion molecule 1 1259gi21748488Homo SapiensFLJ00277 protein 50 52 1259'2331293 Mus musculuspreprocortistatin 73 40 1259gi1335910Rattus preprocortistatin 58 36 norve 'cus SEQ Hit ID Species Description S Percentage ID scoreidenti 126011079734 Mus musculuscitron 1291 94 1260gi3599509Mus musculusrho/rac-interacting 1286 94 citron kinase 1260gi2745840Rattus postsynaptic density 1262 93 norvegicusprotein; citron 1261gi14715029Mus musculusserine (or cysteine) 407 39 proteinase inhibitor, Glade E (nexin, plasminogen activator inhibitor type 1), member 1261gi551065 Mus musculusprotease-nexin 1 406 38 1261gi412157 Homo Sapiensglia-derived neurite-promoting397 38 factor (GdNPF) 1262gi4323581Homo Sapienssenescence-associated 223 97 epithelial membrane protein 1262gi15214678Homo Sapiensclaudin 1 223 97 1262gi7381083Homo Sapiensclaudin-1 223 97 1263gi21634445Homo SapiensGTP-binding protein 449 57 Sara 1263gi13542685Mus musculusSARI protein 446 54 1263gi8926205Homo SapiensSARI 445 54 1264gi11558264Homo Sapienssphin osine-1-phosphatase697 37 1264gi13447199Homo sapienssphingosine-1-pliosphate683 37 phosphatase 1264gi9623190Mus musculussphingosine-1-phosphate691 38 phosphohydrolase 1265gil4 Bos taurusBoWCl.l 1026 37 1265gi5107945Homo SapiensCD163 1093 40 1265gi312142 Homo SapiensM130 antigen 1093 40 1266gil4 Bos taurusBoWCl.l 1026 37 1266gi5107945Homo SapiensCD163 1093 40 12661312142 Homo SapiensM130 anti en 1093 40 1267gi18873700Necator NADH dehydrogenase subunit69 32 americanus2 1267gi20338417Gallus potassium channel subunit57 31 gallus 1267gi396416 Escherichiasimilar to Neurospora 72 42 coli crassa phosphate-repressible phosphate permease 1268gi216194~91Homo Sapienssimilar to expressed 778 100 sequence AW049604 1268gi6572294Homo SapiensbA262A13.1 (novel protein)251 49 1268gi161662 Tribolium zinc finger protein 60 26 castaneum 1269gi21591552Haemophiluscell filamentation-like55 31 influenzaeprotein biotype aegyptius 1269gi1762771Pleurodeleshomeodomain-containing 66 35 waltl protein 1269gi19528253DrosophilaGH13327p 53 41 melanogaster 1270118033185Danio rerioUNC45-related protein 3103 73 1270112248757Homo SapiensSMAP-1 2393 57 1270gi12248771Homo sapiensSMAP-lb 2393 57 1271gi21064657DrosophilaRH01479p 185 39 melanogaster 1271gi7304173DrosophilaCG1577-PA 185 39 melanogaster 1271gi20150011PseudomonasMmpIV 89 36 fluorescens 1272gi9366656Trypanosomaprobable similar to 76 55 ring-h2 finger protein SEQ Hit ID Species Description S Percentage ID scoreidenti brucei rhala.

1272gi6714271ArabidopsisF6N18.7 59 36 thaliana 1272gi10440424Homo SapiensFLJ00047 protein 74 50 1273gi15823642Homo SapiensALS2CR7 2038 100 1273gi2645810Mus musculusPftaire-1 1195 68 1273gi2392814Mus musculusPFTAIRE kinase 1190 67 1274gi2407911Homo Sapiensdifferentially expressed714 96 in Fanconi anemia 1274gi21595389Homo Sapienssimilar to FYVE finger-containing89 27 phosphoinositide kinase (1-phosphatidylinositol-4-phosphate ldnase) (PIPSK) (PtdIns(4)P-5-lcinase) (p235) 1274gi330134 human latency-related protein87 46 herpesvirus 1275gi21908028Homo Sapiensa disintegrin and metalloprotease4205 97 domain 1275gi18147612Homo Sapiensmetalloprotease disintegrin4204 97 1275gi13157560Homo SapiensdJ964F7.1 (novel disintegrin3916 97 and reprolysin metalloproteinase family protein) 1276gi530876 Chlamydomonaamino acid feature: 138 35 Rod protein domain, s reinhardtiias 266 .. 468; amino acid feature:

lobular protein domain, as 32 .. 265 1276gi141852 Actinomycessialidase 137 30 viscosus 1276gi13926258ArabidopsisAT5g10430/F12B17_220 110 34 thaliana 1277gi15291913DrosophilaLD31582p 201 36 melanogaster 1277gi16648042DrosophilaGH07105p 131 39 melanogaster 1277gi164~16111Neurosporarelated to supprcssor 129 43 protein SPT23 crassa 1278gi544755 ~ryctolagusaminopeptidasc N; APN 1016 38 cuniculus 1278gi525287 Susscrofa aminopeptidase N. 1012 39 1278gi205109 Rattus ltidney ~n-peptidase 1004 39 precursor norve icus 1279gi13559063Homo SapiensbA552M11.5 (novel protein)747 100 1279gi9963863Homo SapiensAD026 738 98 1279gi19263987Homo Sapienssimilar to CMRF35 ANTIGEN131 32 PRECURSOR

1280gi2773306Equus caballustype II colla en 69 31 1280gi3687594Canis familiaristype IIB procollagen 69 31 1280gi8918871YccA of 96 pct identical to 64 26 gp:AB021078 30 plasmi d ColIb-P9 [Plasmid F

1281gi9927307Mus musculusjunctophilin type 3 59 42 1281gi5881591Gallus homeodomain protein 78 38 gallus 1281gi11095167Bacteriophagegp38 76 34 ARl 1282gi13938232Homo SapiensSimilar to RII~EN cDNA 78 32 gene 1282gi13883774MycobacteriumNAD-dependent epimerase/dehydratase83 31 SEQ Hit ID Species Description S Percentage ID scoreidenti tuberculosisfamily protein 1282gi5881591Gallus homeodomain protein 78 38 gallus 1283gi13938232Homo SapiensSimilar to RIKEN cDNA 78 32 gene 1283gi13883774MycobacteriumNAD-dependent epimerase/dehydratase83 31 tuberculosisfamily protein 12 gi5881591Gallus homeodomain protein 78 38 83 gallus _ gi15779156Homo SapiensSimilar to RIKEN cDNA 4057 100 gene 1284gi13097045Mus musculusSimilar to RIKEN cDNA 1727 91 gene 1284gi18447388DrosophilaRE05944p 716 32 melanogaster 1285gi21626874DrosophilaCG9410-PB 354 46 melanogaster 1285gi7302281DrosophilaCG9410-PA 354 46 melanogaster 1285gi21166086DictyosteliumNucleoside diphosphate 164 30 discoideumkinase 1286gi20977688Xenopus tumorhead 146 33 laevis 1286gi19070822Mus musculusMyb protein P42P~P 132 29 1286gi9652255~vis ariasDNA binding protein 76 26 pur-alpha 1287gi 1006932Visna virusenvelope polyprotein 61 48 1287gi6469042Mus musculuSC184M protein 73 28 1287gi20988388Mus musculusSimilar to mammary tumor73 28 virus receptor 1288gi12309630Homo SapiensbA438B23.1 (neuronal 319 31 leucine-rich repeat protein) 1288gi6273399Homo Sapiensmelanoma-associated 322 31 antigen MG50 1288gi1504040Homo Sapienssimilar to D.melanogaster322 31 pero~idasin(LJl 1052) 1289gi16769274DrosophilaLD22423p 222 24=
melanogaster 1289gi18700635Homo Sapiensimportin 4 113 23 1289gi13277562Homo SapiensSimilar to RII~EN cDNA 113 23 8430408~15 gene 1290gi21391486Mus musculusleucine-rich repeat 430 43 domain-containing protein 1290gi21623740Rattus Leucine-rich repeat-containing425 43 norvegicusprotein 3 1290gi21391484Homo Sapiensleucine-rich repeat 392 39 domain-containing protein 1291gi21624340Homo Sapiensceramide kinase 1611 100 1291gi21624342Mus musculusceramide kinases 1374 86 1291gi16768660DrosophilaHL01538p 292 41 melanogaster 1292gi50369 Mus musculusprecursor protein (AA 204 32 -34 to 244) 1292gi312590 Mus musculusbiliary glycoprotein 204 32 1292gi3549152Homo SapiensR29124_1 187 32 1293gi50369 Mus musculusprecursor protein (AA 204 32 -34 to 244) 1293gi312590 Mus musculusbiliary glycoprotein 204 32 1293gi3549152Homo SapiensR29124_1 187 32 1294121411450Mus musculussimilar to FLJ00179 1159 91 protein SEQ Hit ID Species Description S Percentage ID scoreidenti 1294gi18676564Homo sapiensFLJ00179 protein 993 99 1294gi17945392DrosophilaRE17452p 486 59 melanogaster 1295gi7708438Homo SapiensdJ885A10.1 (similar 1020 100 to cerebellin precursor) 1295gi5702371Mus musculusprecerebellin-1 699 70 1295gi180251 Homo Sapiensprecerebellin 696 74 1296gi3901028Homo Sapiensneurotensin receptor 1436 100 1296gi1483580Rattus NTR2 receptor 1073 76 norvegicus 1296gi17646096Mus musculuslow affinity neurotensin1072 77 receptor 1298gi6624583Homo SapiensdJ61B2.1 (bullous pemphigoid1342 100 antigen 1 6 (230/240kD) isoform 3) 1298gi403124 Homo Sapiensbullous pemphigoid antigen9121 92 1298gi15077861Mus musculusbullous pemphigoid antigen6442 67 1-a 1299gi2114176Homo Sapiensp97 homologous protein 100 23 1299gi12654337Homo Sapienscraniofacial development100 23 protein 1 1299gi3341899Homo SapiensBCNT 100 23 1300gi6572294Homo SapiensbA262A13.1 (novel protein)499 100 1300gi21619491Homo Sapienssimilar to expressed 260 42 sequence AW049604 1300gi2460196Monodelphisimmunoglobulin Igh@ 65 37 domestica variable domain 1301gi18676652Homo SapiensFLJ00225 protein 779 100 1301Qi2632952Bacillus yebD 66 51 subtilis _ gi20749947Drosophilafruitless class I male 50 40 1301 virilis isoform 1302gi18676652Homo SapiensFLJ00225 protein 444 97 1302gi2632952Bacillus yebD 59 48 subtilis _ gi342299 Macaca preprosomatostatin 226 100 1303 fascicularis 1303gi338288 Homo Sapienspreprosomatostatin I 226 100 1303121619156Homo Sapienssomatostatin 226 100 1304gi1424.9944Hoano sapicnsSimilar to bromodomain-containing109 30 1304gi2865615Lcislxmaniaacidic ribosomal protein93 36 peruviana P1 1304gi343452 Tarsius involucrin 114 24 bancanus 1305gi219894 Homo Sapiens80I~-L protein 124 26 1305gi187387 Homo Sapiensmyristoylated alanine-rich122 26 C-kinase substrate 1305gi13562004Nephila major ampullate spidroin140 33 madagascariens2-like protein is 1306gi21744725Homo Sapienslycosyl-phosphatidyl-inositol-MAM1548 48 1306gi7529597Homo SapiensdJ402N21.2 (novel protein657 53 with MAM
domain) 1306gi7529598Homo SapiensdJ402N21.3 (novel protein591 52 with Immunoglobulin domains) 1307gi4455102Brassica pollen-specific protein72 44 rapa BAN102 1307gi4096227OryctolagusIg heavy chain 68 31 cuniculus 1307gi17017359Talaromyces605 ribosomal protein 60 43 emersonii L2 1308gi17429038Ralstonia PROBABLE ACYL-COA 1166 56 SEQ Hit ID Species Description S Percentage ID scoreidenti solanacearumDEHYDROGENASE
OXIDOREDUCTASE PROTEIN

1308gi9948609Pseudomonasprobable acyl-CoA dehydrogenase1121 57 aeruginosa 1308gi13421911Caulobacteracyl-CoA dehydrogenase 1058 54 crescentusfamily protein 1309gi17429038Ralstonia PROBABLE ACYL-COA 1166 56 solanacearumDEHYDROGENASE
OXIDOREDUCTASE PROTEIN

1309gi9948609Pseudomonasprobable acyl-CoA dehydrogenase1121 57 aeruginosa 1309gi13421911Caulobacteracyl-CoA dehydrogenase 1058 54 crescentusfamily protein 1310gi 19070124Mus musculuszinc transporter-like 1087 95 3 protein 1310'20563194Mus musculuszinc transporter 6 1075 94 1310gi9803033CaenorhabditisC. elegans TOC-1 protein279 38 elegans (corresponding sequence ZC395.3) 1311gi854065 Human U88 260 33 herpesvirus 1311gi21928439Homo Sapiensseven transmembrane 174 29 helix receptor 1311gi18893248Pyrococcussmc-like 177 24 furiosus DSM

1312gi5295832Homo SapiensdJ21018.2 (protein similar1142 100 to collagen) 1312gi6526769Homo SapiensHRIHFB2003 1055 97 1312gi7291408DrosophilaCG11206-PA 738 4~1 melano aster 1313gi19263985Homo SapiensSimilar to RIKEN cDNA 1565 99 gene 1313gi19528309DrosophilaLD02310p 573 55 melanogaster 1313gi7106870Homo SapiensHSPC24~0 227 30 _ gi22090626Homo SapiensHECT domain protein 1169 99 1314gi6841194Homo SapiensHSPC272 9665 99 1314gi20151907DrosophilaSD03277p 1833 75 melanogaster 1315gi21542541Homo SapiensSimilar to HTPAP protein766 100 1315gi13182757Homo SapiensHTPAP 473 100 1315gi 14020949Arabidopsisphosphatidic acid phosphatase317 50 thaliana 1316gi21542541Homo sapiensSimilar to HTPAP protein1204 99 1316gi13182757Homo SapiensHTPAP 915 100 1316gi14020949Arabidopsisphosphatidic acid phosphatase460 41 thaliana 1317gi180164 Homo SapiensCD7 antigen protein 1135 93 1317'732757 Homo SapiensCD7 antigen 1135 93 1317gi14424540Homo SapiensCD7 antigen (p41) 1135 93 1319gi16416764Homo SapiensFKSG16 2369 99 1319gi13905212Mus musculusRIKEN cDNA 1200006F02 1833 75 gene 1319gi14715055Homo SapiensSimilar to RIKEN cDNA 418 32 ene 1320gi16416764Homo SapiensFKSG16 323 98 SEQ Hit ID Species Description S Percentage ID scoreidenti 1320gi13905212Mus musculusRII~EN cDNA 1200006F02 257 77 gene 1320gi 14715055Homo SapiensSimilar to RIKEN cDNA 97 33 gene 1321gi10834558Rattus proline arginine-rich 392 32 norvegicus end leucine-rich repeat protein 1321gi21618473Homo Sapiensproline arginine-rich 389 32 end leucine-rich repeat protein 1321gi1145773Homo sapiensprolar in 389 32 1322gi20258604Homo Sapienssialic acid binding 1473 84 Ig-like lectin 5 1322gi2411475Homo SapiensOB binding protein-2 1473 84 1322gi5759106Homo Sapienssialic acid binding 1473 84 Ig-like lectin-5; siglec-1323gi20258604Homo Sapienssialic acid binding 1375 87 I -like lectin S

1323gi2411475Homo SapiensOB binding protein-2 1375 87 1323gi5759106Homo Sapienssialic acid binding 1375 87 Ig-like lectin-5; siglec-1324gi20987759Homo SapiensSimilar to ADAMTS-like 886 99 1324gi15099921Homo SapiensADAM-TS related protein874 98 1324gi13183078Homo Sapiensa disintegrin-like and 603 73 metalloprotease domain with thrombospondin type I
motifs-like 3 1326gi757915Homo SapiensapoCII protein 427 89 1326gi178836Homo Sapiensapolipoprotein C-II 427 89 1326gi342077Macaca apolipoprotein C-II 371 78 fascicularis 1327gi21619424Homo SapiensSimilar to LOC150580 477 100 1327gi12656449Plasmodium erythrocyte membrane 63 25 falciparum protein 1 1327gi15384029uncultured extracellularprotein 64 31 crenarchaeote 1329gi16033597Homo SapiensSH2 domain-containing 1003 99 phosphatase anchor protein 2d 1329gi16033591Homo SapiensSH2 domain-containing 991 99 phosphatase anchor protein 2b 1329gi1809265~Homo Sapiensimmunoglobulin superfamilyreceptor985 99 translocation associated protein 3 1330gi4877582Homo Sapienslipoma HMGIC fusion 728 63 partner 1330gi14272235Homo SapiensbA183L8.1 (lipoma HMGIC445 61 fusion partner) 1330gi15292437Drosophila LP10272p 187 25 melanogaster 1331117426418Mus musculuscalmodulin-related protein788 100 1331gi12060826Homo Sapiensserologically defined 610 77 breast cancer antigen NY-BR-20 1331gi5932428Myxine calmodulin 316 44 glutinosa 1332gi17862436Drosophila LD27564p 152 26 melano aster 1332gi13311009Homo SapiensNYD-SP16 78 26 1333gi13279251Homo SapiensSimilar to wingless-related2000 100 MMTV
integration site 6 1333gi11693044Homo SapiensWNT6 precursor 2000 100 1333114133265Homo SapiensWNT6 2000 100 1334gi20135611Homo Sapienszinc transporter ZnT-5 463 94 SEQ Hit ID Species Description S Percentage ID scoreidenti 1334gi19744304Homo Sapienszinc transporter 5 463 94 1334gi19744306Mus musculuszinc transporter 5 407 85 1335gi18480366Mus musculusolfactory receptor MOR145-1310 74 1335gi21928214Homo Sapiensseven transmembrane 301 77 helix receptor 1335'2447219 Homo sapiensOLF4 295 71 1336120988856Homo Sapiensprotein inhibitor of 3277 100 activated STAT3 1336gi4996563Homo Sapiensprotein inhibitor of 3277 100 activatied STAT3 1336gi17149822Rattus potassium channel regulatory3211 96 norvegicusprotein KChAP

133714469173 Gallus delta-9 desaturase 1149 71 gallus 1337119908266Chanos stearoyl-CoA desaturase1140 65 chanos 1337gi5738564Ctenopharyngodelta-9-desaturase 1132 70 don idella 1338gi14030861Homo Sapiensparaneoplastic neuronal1830 99 anti en MA1 1338gi18478557Rattus paraneoplastic onconeuronal1752 93 norvegicusprotein MAl 1338gi15929183Homo Sapiensmodulator of apoptosis 990 56 1339gi5452942Mus musculusglucosidase II beta-subunit134 56 1339' 163157 Bos taurushigh-mobility-group 120 43 protein 1339gi15076513Mus musculus22 klla neuronal tissue-eniiched131 26 acidic protein 1341gi11177514Homo Sapienstandem pore domain potassium2234 100 channel 1341gi11177510Rattus tandem pore domain potassium2215 98 norvegicuschannel 1341gi1521S363Homo Sapienspotassium channel, subfamily1346 65 I~, member 1342gi14336716Homo Sapienssimilar to FBan0003337 1216 100 1342gi20987336Mus musculusRII~EN cDNA A930016P21 427 50 gene 1342gi19886829MethanopyrusSAM-dependent methyltransferase104 31 kandleri AVl9 1343gi19570398Homo SapienshI~DM36 1138 43 1343gi11862939Mus muSCUlusI2I~M36 1134=43 1343gi11862941Mus muSCUlusDI~M36E 1125 43 1344gi21744725Homo Sapienslycosyl-phosphatidyl-inositol-MAM4898 98 1344gi7529598Homo sapiensdJ402N21.3 tnovel protein1548 99 with Immunoglobulin domains) 1344gi7529597Homo sapiensdJ402N21.2 (novel protein1321 94 with MAM
domain) 1345112276198Homo SapiensFI~SG40 1020 100 1345gi12408250Homo SapiensFI~SG28 1020 100 1345'18652934XenopuslaevisMig30 649 49 1346gi16769552I7rosophilaLD38375p 1354 41 melano aster 1346gi7523707ArabidopsisPutative membrane protein1105 39 thaliana 1346gi1632829PlasmodiumAARP2 protein 467 36 falciparum 1347gi20987450Homo SapiensLOC146433 1162 95 1347gi3093373Mus musculussmall proline-rich protein64 39 1347gi912799 Homo Sapienstype I hair keratin 63 33 1348gi1016012Rattus neural cell adhesion 5093 93 norvegicusprotein BIG-2 precursor 1348gi19913548Homo Sapienssimilar to axonal-associated3630 99 cell adhesion SEQ Hit ID Species Description S Percentage ID scoreidenti molecule 1348gi200057 Mus musculusneuronal glycoprotein 3630 64 1349gi15292437DrosophilaLP10272p 441 39 melanogaster 1349'4877582 Homo Sapienslipoma HMGIC fusion 221 28 partner 1349gi16648454DrosophilaSD01285p 162 24 melanogaster 1350gi13097705Homo Sapiensserine (or cysteine) 1925 97 proteinase inhibitor, Glade A (alpha-1 antiproteinase, antitrypsin), member 1350gi1340142Homo Sapiensalphal-antichymotrypsin1921 97 1350gi4165890Homo Sapiensalpha-1-antichymotrypsin1850 97 precursor 1351gi21618556Homo Sapienstrophinin associated 3134 84 protein (tastin) 1351gi905356 Homo Sapienstastin 3129 84 1351gi7861746Mus musculusGABA-A receptor epsilon-like165 40 subunit 1352gi12053849Homo sapiensDREV protein 1689 100 1352gi12053851Homo SapiensDREVl protein 1676 99 1352112055091Mus musculusDREV protein 1655 97 1353gi14627081Homo Sapienscaspase-1 dominant-negative492 100 inhibitor Pseudo-ICE

1353gi21707335Homo sapiensSimilar to CARD only 462 100 protein 1353gi186286 Homo Sapiensinterleukin 1-beta convertase445 92 1354gi17431573Ralstonia PUTATIVE LIPGPR~TEIN 82 42 solanacearumTRANSMEMBRANE

1354gi995704 SaccharomycesL3149 69 23 cerevisiae 1354gi1256899SaccharomycesYr1138wp 69 23 cerevisiae 1355gi12034719Mus musculusankyrin-like protein 413 43 1355gi13469729Homo Sapiensbreast cancer anti en 415 49 1355gi21618588Homo Sapienstestis-specific ankyrin362 46 motif containing pl'Otelll 1356gi8272557RattuS protein kinaSe WNI~.1 5439 73 norve icuS

1356gi6933864Homo Sapienskinase deficient protein3408 100 ICDP

1356gi19032238Homo Sapiensprotein Icinase WNI~3 1664 56 1357gi8272557Rattus protein kinase WNICl 5439 73 norvegicus 1357gi6933864Homo Sapienskinase deficient protein1159 98 I~DP

1357gi19032238Homo Sapiensprotein kinase WNK3 530 40 1358gi10946203Homo Sapiensneuromedin U receptor 785 100 1358gi9944990Homo Sapiensneuromedin U receptor-type785 100 1358gi16877377Homo sapiensneuromedin U receptor 785 100 1359gi17861592DrosophilaGH13807p 1234 45 melanogaster 1359gi18376566CaenorhabditisY105E8A.20 964 49 elegans 1359gi9368514Leishmaniamethionyl-tRNA synthetase963 42 maj or 1360gi17389919Homo SapiensSimilar to major histocompatibility819 100 complex, class II, DP
beta 1 1360gi575494 Homo SapiensMHC class II lymphocyte437 72 antigen beta chain 1360gi188479 Homo SapiensHLA-DPB1 437 72 SEQ Hit ID Species Description S Percentage ID . identi score 1361gi3342737Homo Sapiens826660 2, partial CDS 1025 97 1361gi14625940Homo sapiensinterleukin-10 42 53 1361gi3005997okra yellowAC2 77 35 vein mosaic virus 1362gi3342737Homo Sapiens826660 2, partial CDS 1001 94 1362gi14625940Homo Sapiensinterleukin-10 42 53 1362gi3005997okra yellowAC2 77 35 vein mosaic virus 1363gi13991167Homo Sapienssialic acid-binding 2879 99 immunoglobulin-like lectin-like long splice variant 1363gi14625822Homo SapiensSiglec-Ll 2879 99 1363gi15824310Pan troglodytessialic acid-binding 2804 97 lectin Siglec-Ll 1364gi20072749Homo Sapienssimilar to interferon 879 100 alpha/beta receptor 1364gi571296 Homo SapiensCRFB4 188 27 1364'4028135 Gallus interferon alpha/beta 195 27 anus receptor 1 1365gi8572055Homo Sapiensinterleukin-1 receptor 823 100 antagonist homolog 1365gi6049805Homo Sapiensinterleukin-1 receptor 823 100 antagonist homolog 1365'6165334 Homo Sapiensinterleukin-1-like protein-1823 100 1366gi177870 Homo Sapiensalpha-2-macroglobulin 2780 40 precursor 1366gi579594 Homo Sapiensalpha 2-macroglobulin 2775 4~0 1366gi579592 Homo sapiensalpha 2-macroglobulin 2774 40 1367gi4574224Fundulus multidrug resistance 287 49 heteroclitustransporter homolog 1367gi19743730Rattus ATP-binding cassette 285 50 norvegicusprotein Blb 1367gi34525 Homo SapiensP-glycoprotein (431 273 50 AA) 13681198922 Mus musculuslymphocyte differentiation713 100 anti en 1368gi198926 Mus musculusLy-6A.2 alloantigen 713 100 1368gi198930 Mus musculusdifferentiation antigen713 100 ~ ~ ~ Ly-6E/A

SEQ Hit Species Description S Percentage_ ID ID I scoredenti 685 gi183150Homo Sapiens chorionic somatomammotropin320 100 685 gi23271170Homo Sapiens chorionic somatomammotropin275 96 hormone 2 685 gi28188743Pan troglodytesplacental lactogen 279 98 PL-B

686 gi183178Homo Sapiens hGH-V2 1033 78 686 gi23271170Homo sapiens chorionic somatomammotropin707 92 hormone 2 686 gi28188743Pan troglodytesplacental lactogen 715 94 PL-B

688 gi18088830Homo Sapiens AAH20756 785 100 688 gi183178Homo Sapiens hGH-V2 1051 79 688 gi30582691Homo Sapiens 785 100 689 gi12653501Homo Sapiens SERPINFl protein 2003 95 689 gi30583283Homo Sapiens , member 1 2003 95 689 gi30585311synthetic , member 1 2003 95 construct 690 gi20269957Sus scrofa AF498759_1 phospholipase1033 88 C
delta 4 690 121307610Mus musculus phospholipase C 909 77 delta 4 690 gi571466Rattus norvegicusphospholipase C 893 76 delta-4 691 gi17864023Homo Sapiens AF450090_1 KCCR13L 3524 100 691 gi22760385Homo Sapiens unnamed protein 3515 99 product 691 gi22761016Homo Sapiens unnamed protein 3524 100 product 692 gi12697933Homo Sapiens I~IAA1694 protein 3850 100 692 120380030Mus musculus 4933407C03Rik protein3251 98 692 gi2765254.7Homo Sapiens truncated c-Maf 3506 99 inducing protein 693 gi437662~ryctolagus interleulcin-8 receptor188 61 cuniculus subtype B

693 gi511803Homo sapiens interleukin-8 receptor172 57 type B

693 gi576679Homo Sapiens interleukin 8 receptor172 57 B

694 gi32966069Homo Sapiens CD39L2 nucleotidase2514 99 694 gi3335098Homo Sapiens CD39L2 2520 100 694 14691263I-Iomo sapiens 2513 99 695 gi16566319Homo sapiens AF411107_1 G protein-184=399 coupled receptor 695 gi21928620Homo Sapiens seven transmembrane1858 100 helix receptor 695 gi22293641Homo Sapiens putative orphan 845 51 G protein-coupled receptor 696 '24660226Homo Sapiens C-type lectin-like 14.6090 receptor-1 696 gi7110216Homo sapiens AF200949_1 C-type 1458 90 lectin-like receptor-1 696 gi7110218Mus musculus AF201457_1 C-type 322 29 lectin-like receptor 2 698 gi18089247Homo Sapiens AAH20966 Similar 2104 100 to ectonucleoside triphosphate diphosphohydrolase 698 gi30584801synthetic Homo Sapiens ectonucleoside2104 100 construct triphosphate diphosphohydrolase 698 gi3335102Homo Sapiens CD39L4 2104 100 699 1804761Homo Sapiens putative 247 77 700 gi16184225Drosophila LD24527p 666 42 melanogaster SEQ Hit_ID Species Description S Percentage-ID score I denti 700 gi27447597Drosophila transcriptional 666 42 adapter 2S

melanogaster 700 gi7298997Drosophila CG9638-PA 666 42 melanogaster 701 gi17225457Homo SapiensAF326917_1 autism-related1272 36 protein 1 701 '27817314Danio rerio 1234 36 701 gi29468246Homo SapiensXTP9 3605 99 702 gi20810589Homo Sapienssimilar to arsenite833 99 inducible RNA associated protein 702 gi22945274Drosophila CG12795-PA 455 54 melanogaster 702 gi9651711Mus musculusAF224494_1 arsenite687 80 inducible RNA associated protein 703 gi13241652Rattus norvegicusAF309558_1 supernatant2040 93 protein factor 703 gi13543184Mus musculusSEC14-like 2 2038 93 703 gi6624130Rattus norvegicusAC004832_1 similar 2150 100 to 45 kDa secretory protein 704 gi11066250Homo SapiensAF197937_1 presenilins1693 86 associated rhomboid-like protein 704 gi13177766Homo SapiensAAH03653 Similar 1761 99 to prescnilins associated rhomboid-like protein 704 gi15559382Homo SapiensAAH14058 presenilins1696 86 associated rhomboid-like protein 705 gi1864091Rattus norvegicusPSD-95/SAP90-associated4997 95 protein-3 705 gi2454510Homo SapiensPSD-95/SAP90-associated2105 47 protein-2 705 gi6979175Homo SapiensAF119818_1 homolog-2089 47 associated protein 706 gi11877274Homo Sapiens 2260 99 706 gi21667210Homo SapiensAF4=65765_1 2260 99 bactericidal/permeability-increasing protein-like 706 gi21706776Homo SapiensBactcricidallpermeability-2253 99 increasing protein-like 707 gi16768190Drosophila GH22974p 647 41 melanogaster 707 gi24659527Homo Sapiens 2006 100 707 gi7291716Drosophila CG11388-PA 648 41 melanogaster 708 gi14334082Mus musculusAF367970_1 thymus 479 87 LIM

protein TLP-A

708 gi14335908Mus musculusthymus LIM protein 479 87 TLP-A

708 gi14335909Mus musculusthymus LIM protein 396 90 TLP-B

709 gi12804105Homosapiens AAH02905 Similar 2090 100 to CG15084 gene product 709 gi13649459Homo SapiensAF250306_1 putative2090 100 protein 709 gi18204670Mus musculus4930527D15Rik protein1015 96 710 gi1674440Homo Sapienscollagen type IV 4222 51 ~ ~ ~ a6 chain SEQ Hit Species Description S Percentage_ ID ID score I denti 710 gi1674441Homo Sapiens collagen type IV 4222 51 a6 chain 710 gi556299IvIus musculusalpha-2 type IV 8126 83 collagen 711 gi438007Gallus gallusalpha-2-macroglobulin1574260 receptor 711 gi7861733Homo Sapiens AF176832_1 low density2365499 lipoprotein receptor related protein-deleted in tumor 711 gi8926243Mus musculus AF270884_1 low density2309892 lipoprotein receptor related protein LRP1B/LRP-DIT

712 gi17298315Homo Sapiens candidate tumor 848 100 suppressor protein 712 gi7861733Homo Sapiens AF176832_1 low density848 100 lipoprotein receptor related protein-deleted in tumor 712 gi8926243Mus musculus AF270884_1 low density731 83 lipoprotein receptor related protein LRP1B/LRP-DIT

713 gi13544080Homo Sapiens AAH06171 hypothetical1133 100 protein MGC2731 713 gi20071811Musmusculus 5830411ElORikprotein492 55 713 gi33589496Drosophila LD31278p 4b1 44 melanogaster 714 gi1574.09Drosophila fat protein 3001 40 melano aster 714 gi22945533Drosophila CG17941-PA 2292 34 melanogaster 714 gi7295732Drosophila CG3352-PA 3015 40 melanogaster 715 gi1574.09Drosophila fat protein 3007 40 melanogaster 715 gi22945533Drosophila CG17941-PA 2289 34 melanogaster 715 gi7295732Drosophila CG3352-PA 3021 40 melanogaster 716 gi17865311I-Iomo SapiensAF452102 1 dipeptidyl4370 95 peptidase-like protein 716 gi27549552Homo Sapiens dipeptidyl peptidase4370 95 IV-related protein-2 7_16 gi29293087Homo Sapiens dipeptidyl peptidase4511 95 717 gi2689444Homo Sapiens ZNF134 1252 57 717 gi31565347Homo Sapiens LOC284018 protein 1252 57 717 gi9968290Homo Sapiens zinc finger protein1094 47 718 gi23468368Mus musculus 1200013F24Rile protein690 90 718 gi27695305Mus musculus 1200013F24Rik protein715 91 718 gi7582294Homo Sapiens AF208853 1 BM-011 881 100 719 gi1620870Ciona intestinalismyo~lasmin-Cl 410 27 719 gi7416982Argopecten myosin heavy chain 255 20 irradians cardiac muscle s ecific isoform 1 719 gi7416983Argopecten myosin heavy chain 255 20 irradians cardiac muscle specific isoform 2 720 gi13872813Homo Sapiens fibulin-6 13764100 720 gi14575679Homo Sapiens AF156100 1 hemicentin1372099 720 gi3879658Caenorhabditis 1636 29 elegans 721 gi13177673Homo Sapiens AAH03621 1520 45 ~

SEQ Hit ID Species Description S Percentage_ ID score I dentit 721 gi19354327Homo Sapiens 1520 45 721 gi3822553Gallus gallusnuclear calmodulin-binding2238 61 protein 722 117223626Homo SapiensATP-bindin cassette7963 99 722 gi32350914Homo SapiensATP-binding cassette7943 99 sub-family A member .

722 gi32350969Homo SapiensATP-binding cassette7943 99 sub-family A member 723 gi13374079Homo SapiensTAFII140 protein 3677 99 723 gi13374178Mus musculusTAFII140 protein 3193 84 723 gi28175603Homo SapiensTAF3 protein ' 2772 99 724 gi17429038Ralstonia PROBABLE ACYL-COA 658 61 solanacearumDEHYDROGENASE

OXIDOREDUCTASE

PROTEIN

724 gi22776354Oceanobacillusacyl-CoA dehydrogenase638 63 iheyensis 724 gi28280023Mus musculus5730439ElORik protein946 85 725 gi21522768Homo Sapiensunnamed protein 3060 100 product 725 gi24047224Homo SapiensSimilar to EGF-like-domain,3060 100 multiple 6 725 gi6752658Homo SapiensAF186084_1 epidermal3055 99 growth factor repeat containing protein 726 gi1453034~2Caenorhabditis 1008 36 elegans 726 gi6531661CaenorhabditisAF195610_1 LIN-41A 1008 36 elegans 726 gi6531663CaenorhabditisAF195611_1 LIN-41B 1008 36 elegans 727 '1504026Homo Sapiens 5833 99 727 gi22725157Homo Sapiensminor histocompatibility5833 99 antigen HA-1 727 gi23272016Homo SapiensSimilar to PTPLl-aSSOCiatcd5690 98 RhoGAP 1 728 gi13274120Homo Sapiens 1467 99 728 '6102996Mus musculus~lanin-3 1018 79 728 gi7160973Homo SapienstTNN3 protein 1213 96 729 gi27463365Homo sapiensa disintegrin-like 8961 99 and metalloprotease with thrombospondin type 1 motifs 729 gi28804249Mus musculusmetalloprotease-disintegrin4974 55 protease 729 gi9581879Homo SapiensAF261918_1 disintegrin5723 99 metalloproteinase with thrombospondin repeats 730 gi21063967Drosophila AT05453p 382 31 melanogaster 730 gi5911409Drosophila fuzzy 382 31 melanogaster 730 gi7297412Drosophila CG13396-PA 382 31 melanogaster 731 gi15488017Homo SapiensAF407274_1 EWI2 2302 100 731 gi27497567Homo Sapienskeratinocytes associated2302 100 transmembrane protein SEQ Hit ID Species Description S Percentage_ ID I scoredenti 731 gi31753233Homo sapiensImmunoglobulin superfamily,2302 100 member 8 732 gi15488017Homo SapiensAF407274_1 EWI2 3200 100 732 gi27497567Homo Sapienskeratinocytes associated3200 100 transmembrane protein 732 gi31753233Homo SapiensImmunoglobulin superfamily,3200 100 member 8 733 gi22266726Homo SapiensAF311906_1 LIR-D1 1303 96 precursor 733 gi27497567Homo Sapienskeratinocytes associated1303 96 transmembrane protein 733 gi31753233Homo SapiensImmunoglobulin superfamily,1303 96 member 8 734 gi21748480Homo SapiensFLJ00271 protein 605 100 734 gi27497567Homo Sapienskeratinocytes associated513 79 transmembrane protein 734 gi31753233Homo SapiensImmunoglobulin superfamily,513 79 member 8 735 gi31455457Homo Sapiensputative NFkB activating583 44 ' protein 735 gi7022838Homo Sapiensunnamed protein 1794 99 product 735 gi7293694Drosophila CG7323-PA 339 36 melanogaster 736 gi12804169Homo sapiensAAH0294.2 34.9497 736 gi15779178Homo SapiensAAH14652 Similar 3532 97 to hypothetical protein 736 gi18088939Homo SapiensAAH21143 3494 97 737 gi12836469Mus musculusunnamed protein 3495 87 product 737 gi26351115Mus musculusunnamed protein 3466 87 product 737 gi30721603Mus musculusRAVERl 3466 87 738 gi12002000Homo SapiensAF061732 1 My029 415 100 protein 739 115489209Mus musculusBC013712 protein 266 31 739 121757804=Homo Sapiensunnamed protein 1226 96 product 739 gi26354=220MuS musculusunnamed protein 1130 79 product 740 gi15341806Homo sapienSAAH13073 2008 100 740 gi19528077Drosophila AT24025p 165 38 melanogaster 740 gi21627272Drosophila CG12765-PA 167 24 melanogaster 741 gi23495223Plasmodium AE014834_50 liver 407 23 falciparum stage 3D7 antigen, putative 741 gi32492940Homo Sapiensmedulloblastoma 536 25 antigen MU-MB-20.201 741 gi9916 Plasmodium liver stage antigen393 24 falciparum 742 gi13161060Homo SapiensAF332217_1 protocadherin3354 58 742 gi15054521Homo SapiensAF217288_1 protocadherin-S3362 58 742 -gi9845485Homo SapiensAF169692_1 protocadherin-96235 100 743 ' 16552038Homo Sapiensunnamed protein 2404 99 product 743 121410124Mus musculus3230402E02Rik protein1501 61 743 gi5688958Homo SapiensPMMLP 2405 100 744 gi21734445Rattus norvegicusBMP/Retinoic acid-inducible3987 94 neurai-specific protein-2 744 gi21734447Rattus norvegicusBMP/Retinoic acid-inducible2948 70 ~ ~

SEQ Hit Species Description S Percentage_ ID ID I scoredenti neural-specific protein-3 744 gi30348610Gallus gallusBMP/retinoic acid-inducible2090 52 neural-specific protein 745 12739353Homo sapiens ZNF91L 2077 69 745 gi27693081Homo Sapiens 2054 71 ' 745 gi30421228Homo Sapiens zinc finger protein2486 96 746 gi23272677Homo Sapiens Similar to zinc 2472 78 finger protein 746 gi26251755Homo Sapiens ZNF431 protein 2480 79 746 gi30421228Homo Sapiens zinc finger protein3174 100 747 gi1212965Homo Sapiens transmembrane protein1010 99 747 gi1213221Rattus norvegicustransmembrane protein1006 98 747 gi19683999Homo Sapiens coated vesicle membrane1010 99 protein 748 gi1199524Homo Sapiens acidphosphatase 2147 95 748 gi13111975Homo Sapiens AAH03160 acidphosphatase2143 95 2, lysosomal 748 gi30584617synthetic Homo Sapiens acid 2143 95 construct phosphatase 2, lysosomal 749 gi15625570Homo Sapiens AF411981_1 centaurin3851 95 betas 749 gi28422704Homo Sapiens CENTBS protein 2912 100 _ 749 gi30109272Homo Sapiens CENTBS protein 4175 99 750 gi10197642Homo Sapiens AF182421 1 MI~S022 647 100 750 115929423Homo Sapiens Hypothetical protein938 100 750 gi30277696Mus musculus D5Buc26e protein 423 78 751 gi18614026Homo Sapiens zinc finger DNA 998 4~0 binding protein p71 751 gi27693858Homo Sapiens zinc fin er protein998 40 751 '5630080Homo sapiens AC004890 2 984 36 752 gi11345382Homo Sapiens AF308801_1 vacuolar3724 95 protein sorting protein 752 gi12140290Homo Sapiens 3724 95 752 gi15553046Mus musculuS ~Tpsl6 3628 92 753 gi30141048Homo Sapiens Nogo-66 receptor 2226 100 homolog-1 753 gi30141052Rattus norvegicusNogo-66 receptor 2130 95 homolo -1 753 gi32351287Rattus norvegicusNogo-66 receptor 916 51 homolog 2 754 gi177870Homo Sapiens alpha-2-macroglobulin2718 39 precursor 754 gi25303946Homo Sapiens alpha-2-macroglobulin2718 39 754 gi579592Homo Sapiens alpha 2-macroglobulin2712 39 755 gi18044501Mus musculus angiopoietin-like 1692 70 755 gi4929790Homo Sapiens AF152562_1 angiopoietin-2210 93 related protein 755 gi5639997Mus musculus AF162224_1 angiopoietin-1692 70 related protein 756 gi200057Mus musculus neuronal lycoprotein4821 87 756 gi29837411Homo Sapiens BIG-2 3898 69 756 gi563133Rattus norvegicusBIG-1 protein 4778 87 757 gi16550078Homo Sapiens unnamed protein 3710 99 product 757 gi28175743Homo Sapiens similar to hypothetical3714 100 protein 757 gi30354720Mus musculus AI427653 protein 3609 96 7_58 gi26329813Mus musculus unnamed protein 3627 93 product 758 gi28175743Homo Sapiens similar to hypothetical3612 98 protein SEQ Hit ID Species ~ Description S scorePercentage_ ID Identi 758 gi30354720Mus musculus AI427653 protein 3520 95 759 gi21929093Homo Sapiens seven transmembrane1718 88 helix receptor 759 gi24286029Homo Sapiens G-protein coupled 6772 98 receptor 759 gi5525078Rattus norvegicusseven transmembrane5048 72 receptor 760 110440398Homo Sapiens FLJ00032 protein 1257 61 760 111917507Homo Sapiens HPFl protein 1254 62 760 gi15929737Mus musculus similar to KRAB 1249 58 zinc finger protein KR18 761 gi13097633Homo Sapiens AAH03534 Similar 2325 53 to ATPase, Class I, type 8B, member 1 761 gi33440008Homo Sapiens possible aminophospholipid3473 66 translocase ATP8B2 761 gi3628757Homo Sapiens FIC1 2576 53 763 gi11558486Homo Sapiens B-cell lymphoma/leukaemia1314 99 11A short form 763 gi18089267Homo Sapiens AAH21098 1153 100 763 gi30410854Mus musculus 1312 98 764 gi32394378Homo Sapiens forkhead-associated1808 100 domain histidine-triad like protein 764 gi32394380Bos taurus forkhead-associated1638 89 domain histidine-triad like protein 764 gi32394382Sus scrofa forkhead-associated1681 91 domain histidine-triad like protein 765 gi31455403Homo Sapiens aprataxin 241 97 765 gi31455405Homo Sapiens aprataxin 235 100 765 gi32394378Homo Sapiens forkhead-associated241 97 domain histidine-triad like protein 766 gi31455403Homo Sapiens aprataxin 318 100 766 gi323943'78Homo Sapiens forkhead-associated318 100 domain histidine-triad like protein 766 gi32394382Sus scrofa forkhead-associated307 93 domain histidine-triad like protein 767 gi26454883Homo Sapiens hypothetical protein1181 100 767 gi6523797Homo Sapiens AF110775_1 adrenal1181 100 gland protein AD-002 767 gi6841518Homo Sapiens AF161497_1 HSPC1481178 99 768 gi14009597Homo Sapiens AF282619_1 lysyl 1816 98 oxidase-like 3 protein 768 gi14486600Homo Sapiens AF311313_1 lysyl 1816 98 oxidase-like 3 protein 768 gi15186770Homo Sapiens AF284815_1 lysyl 1816 98 oxidase-like protein 769 gi22713410Homo Sapiens GYLTL1B protein 3229 100 769 gi3954938Homo Sapiens acetylglucosaminyltransferase-2292 70 like protein 769 gi3954978Mus musculus acetylglucosaminyltransferase-2292 70 like protein 770 gi7209721Mus musculus DD57 2243 88 770 '7209723Homo Sapiens WD-repeat like 2476 99 sequence 770 gi8217485Homo Sapiens 2473 99 771 gi16552001Homo Sapiens unnamed protein 3169 100 product SEQ Hit Species Description S Percentage_ ID ID score Identi 771 ' 18676632Homo Sapiens FLJ00215 protein 1943 99 771 gi21706685Mus musculus 9630058J23Rilc protein860 59 772 gi10799166Homo Sapiens AF305686_1 protein 1915 99 kinase Njmu-Rl 772 '32425794Homo sapiens NJMU-Rl protein 1888 100 772 gi32450708Homo Sapiens NJMU-Rl protein 1888 100 773 gi13277972Mus musculus phosphatidate 2286 96 cytidylyltransferase 773 ' 19344052Homo Sapiens 2376 100 .

773 gi4186023Homo Sapiens CDS2 protein 2376 100 774 gi17511840Homo Sapiens AAH18769 2251 99 774 gi20988879Homo Sapiens Similar to hypothetical2251 99 gene supported by AL133057;

BC018769; BC009436;

AL133057; AL133057;

774 gi29387317Mus musculus 1200011O22Rik protein1792 79 775 gi13936996Human herpesvirusORF73 219 21 775 gi2246532Human herpesvirusORF 73, contains 226 19 8 large complex repeat CR

775 gi30526291Saimiriine latency associated 219 31 nuclear herpesvirus antigen 776 gi13477379Homo sapiens TTYH2 protein 1037 41 776 118676664Homo Sapiens FLJ00231 protein 1796 91 776 gi28422735Xenopus laevis 104 40 777 gi16877193Homo Sapiens AAH16860 Gprotein-coupled939 98 receptor, family C, group 5, member C

777 gi30583709Homo Sapiens G protein-coupled 939 98 receptor, family C, group 5, member C

777 gi8118032Homo Sapiens AF207989_1 orphan 939 98 G-protein coupled receptor 778 115679980Homo Sapiens 0114 protein 930 99 778 gi16769562Drosophila LD38910p 328 47 melanogaster 778 gi7302978Drosophila CG8441-PA 328 47 melanogaster 779 gi10726751Drosophila CG13623-PA 333 53 melano aster 779 gi21430012Drosophila GH27470p 333 53 melanogaster 779 gi7406400Arabidopsis putative protein 317 45 thaliana 780 gi13959018Homo Sapiens AF361746_1 endothelial902 100 cell-selective adhesion molecule 780 gi13991773Mus musculus AF361882_l endothelial640 70 cell-selective adhesion molecule 780 gi29165726Mus musculus Endothelial cell-selective640 70 adhesion molecule 781 gi15422171Homo Sapiens 22 kDa peroxisomal 1013 100 membrane protein 2 781 gi297437Rattus norvegicusperoxisomal membrane795 76 protein 781 gi8164184Homo Sapiens 22kDa peroxisomal 1013 100 membrane protein-like 782 gi7620875StreptococcusAF232324_1 Sic1.19 203 41 pyogenes SEQ Hit ID Species Description S Percentage_ ID I scoredenti 782 gi7620883StreptococcusAF232328_1 Sic1.23 203 39 pyogenes 782 gi7621271StreptococcusAF232522_1 Sic1.217203 39 pyogenes 783 gi62877 Gallus gallustype VI collagen 734 42 alpha-2 subunit preprotein 783 gi62881 Gallus gallustype VI collagen 734 42 subunit alpha2 783 gi62882 Gallus gallustype VI collagen 734 42 subunit alpha2 784 gi17945608Drosophila RE26969p 829 48 melanogaster 784 gi7292879Drosophila CG1998-PA 829 48 melano aster 784 gi7292910Drosophila CG11162-PA 597 42 melanogaster 785 gi17066106Homo SapiensNovex-3 Titin Isoform8832 99 785 121238650Calotomus titin-like protein 519 62 carolinus 785 gi27696390Xenopus laevisSimilar to titin 816 48 786 gi17979434Arabidopsis putative adenylate 193 22 thaliana kinase 786 gi22136756Arabidopsis putative adenylate 193 22 thaliana kinase 786 gi30180922NitrosomonasAdenylate kinase 201 27 europaea ATCC

787 gi9967224Macaca fascicularishypothetical protein337 98 788 gi18676610Homo SapiensFLJ00204 protein 195 25 788 '26389725Mus musculusunnamed protein 1390 76 product 788 13002588Mus musculusPlenty of SH3s; 197 24 P~SH

789 gi18676610Homo SapiensFLJ00204 protein 250 26 789 gi26329287Mus musculusunnamed protein 1646 75 product 789 gi26389725Mus musculusunnamed protein 1646 75 product 790 gi12654107Homo SapiensAAI-I00866 531 88 790 ' 13937969Homo sapiensTIMP 1 protein 531 88 790 1189382 Homo Sapienscollagenase inhibitor531 88 791 124660226Homo SapiensC-type lectin-like 1367 90 receptor-1 791 gi7110216Homo SapiensAF200949_1 C-type 1365 90 lectin-like receptor-1 791 gi7110218Mus musculusAF201457_1 C-type 312 29 lectin-like receptor 2 792 gi10441350Mus musculusolfactory UDP 1557 68 lucuronosyltransferase 792 gi4753766Homo SapiensUDP glucuronosyltransferase1593 67 792 gi5802604Cavia porcellusUDP glucuronosyltransferase1781 72 793 gi13325266Homo SapiensAAH04450 hypothetical888 100 protein MGC2650 793 gi3688090Homo SapiensR32611_2 796 91 793 gi6841228Homo SapiensAF161407_1 HSPC289 645 77 794 115488645Mus musculusmethyltransferase 1552 76 Cytl9 794 gi18150409Rattus norvegicusAF393243_1 methyltransferase1518 76 794 gi9963861Homo SapiensAF226730_1 Cytl9 1729 99 795 111877243Homo SapiensSSFl/P2Y11 chimeric3802 95 protein 795 g'i14602631Homo SapiensPeter pan homolog 2080 99 795 gi21619996Homo Sapiens 2080 99 SEQ Hit_ID Species Description S Percentage_ ID score I denti 796 gi20330550Homo SapiensAF251706_1 NK inhibitory799 98 receptor precursor 796 gi30962593Homo sapiensAF375481_1 immune 800 99 receptor expressed on myeloid cells splice variant 2 796 gi31790204Homo Sapiensinhibitory receptor805 99 IREMl 797 gi20330550Homo SapiensAF251706_1 NK inhibitory799 98 receptor precursor 797 gi30962593Homo SapiensAF375481_1 immune 800 99 receptor expressed on myeloid cells splice variant 2 797 gi31790204Homo Sapiensinhibitory receptor805 99 IREMl 798 gi20330550Homo SapiensAF251706_1 NK inhibitory1480 94 receptor precursor 798 gi30962591Homo SapiensAF375480_1 immune 1401 93 receptor expressed on myeloid cells splice variant 1 798 131790204Homo Sapiensinhibitory receptor1478 94 IREMl 799 gi18307481Homo Sapiensphosphoinositide-binding2122 100 proteins 799 gi27695704Mus musculusConnector enhancer 678 36 of KSR2 799 gi29691916Rattus norvegicusinteractor protein 1651 _ for cytohesin 79 exchange factors 800 gil 1493982Homo SapiensAF208232_1 TLH29 274 72 protein precursor 800 gi15929988Homo SapiensAAH15423 Similar 424 89 to TLH29 protein precursor 800 gi21618549Homo SapiensTLH29 protein precursor274 72 801 gi11493982Homo SapiensAF208232_1 TLH29 303 70 protein precursor 801 gi15929988Homo SapiensAAH15423 Similar 445 100 to TLH29 protein precursor 801 gi2161854~9Homo SapiensTLH29 protein precursor303 70 802 gi12082723~'aalluS AF293805_1 B cell 2825 69 gallus phosphoinositide 3-kinase adaptor 802 gi12082725Mus musculusAF293806_1 B cell 3557 84 phosphoinositide 3-kinase adaptor 802 gi12082811Callus gallusAF315784_1 B cell 2330 73 phosphoinositide 3-lcinase adaptor 803 gi7959809Homo SapiensAF116721_55 PR~1082545 100 804 gi15384841Homo Sapiensactivatin NK receptor1684 99 804 gi15384843Homosapiens NTB-Areceptor 1700 100 804 gi9887089Mus musculusAF248635_1 lymphocyte615 43 anti en 108 isoform 805 gi10177621Arabidopsis phytoene dehydrogenase-like195 75 thaliana 805 gi17979255Arabidopsis AT5g49550/K6M13_10 211 72 thaliana 805 gi29028742Arabidopsis At5g49550/K6M13 211 72 thaliana 10 806 ' 14270364Mus musculusEpigen protein 378 71 806 gi6272269Rattus norveNC1 rotein 122 52 'cus 806 gi7799191Mus musculustomore ulin-1 122 52 807 gi14270364Mus musculusEpigen protein 378 71 807 gi6272269Rattus norvegicusNCl protein 122 52 SEQ Hit ID Species Description S scorePercentage-ID Identi 807 7799191 Mus musculus tomoregulin-1 122 52 808 gi14270364Mus musculus Epigen protein 378 71 808 gi6272269Rattus norvegicusNC1 protein 122 52 808 gi7799191Mus musculus tomoregulin-1 122 52 809 gi27469556Homo Sapiens Putative neuronal 212 39 cell adhesion molecule 809 gi29289929Danio rerio neogenin 185 39 809 gi3068592Mus musculus punc 198 41 810 gi30348897Homo Sapiens organic solute 643 99 transporter beta 810 gi30348901Ivlus musculusorganic solute 365 62 transporter beta 811 gi18650584Homo Sapiens retinoic acid early1070 94 transcript 1 811 gi18650588Homo Sapiens retinoic acid early1124 99 transcript 1 811 gi21961213Homo Sapiens UL16 binding protein1070 94 812 gi13872813Homo Sapiens fibulin-6 485 30 812 gi14575679Homo Sapiens AF156100_1 hemicentin485 30 812 '9280405Homo Sapiens AF245505_1 adlican1372 46 813 gi13872813Homo Sapiens fibulin-6 861 29 813 gi14575679Homo Sapiens AF156100_1 hemicentin857 29 813 gi9280405Homo Sapiens AF245505_1 adlican2436 35 814 gi13872813Homo Sapiens fibulin-6 861 29 814 gi14575679Homo Sapiens AF156100_1 hemicentin857 29 814 gi9280405Homo Sapiens AF245505 1 adlican2436 35 815 gi21619635Homo sapiens similar to Alu 267 60 subfamily S(~
sequence contamination warning entry 815 gi3002527Homo Sapiens neuronal thread 244 62 protein AD7c-NTP

815 gi6650810Homo Sapiens AF118094 21 PR~1902261 63 816 gi12240284Mus musculus AF327059_1 apolipoprotein1300 72 AS

816 gi6707433Homo Sapiens AF202889_1 apolipoprotein1864 100 AS

816 gi6707435Homo Sapiens AF202890_1 apolipoprotein1864 100 AS

817 gi12240284Mus musculus AF327059_1 apolipoprotein1300 72 AS

817 gi6707433Homo Sapiens AF202889_1 apolipoprotein1864 100 AS

817 gi6707435Homo Sapiens AF202890_1 apolipoprotein1864 100 AS

818 gi13111784Homo Sapiens AAH03081 hypothetical1720 99 protein FLJ10637 818 gi13543037Mus musculus 4933424BO1Rik protein958 80 818 gi14249965Homo Sapiens AAH08368 hypothetical1724 100 protein FLJ10637 819 gi19344001Homo Sapiens phospholipase A2, 846 99 group IID

819 gi5771420Homo Sapiens AF112982_1 group 852 100 IID
secretory phospholipase 819 gi6453793Homo Sapiens AF188625_1 phospholipase846 99 820 gi21751722Homo sapiens unnamed protein 688 84 product 820 126342939Mus musculus unnamed protein 496 59 product 821 gi11094019Homo Sapiens AF305057 2 RTS 2116 96 beta 821 gi1150421Homo Sapiens rTSbeta 2122 96 SEQ Hit ID Species ~ Description S_scorePercentage_ ID

Identi 821 gi12654883Homo SapiensAAH01285 rTS beta 2122 96 protein 822 gi12803167Homo SapiensAAH02387 nucleosome1728 99 assembly protein 1-like 1 822 gi189067Homo SapiensNAP 1728 99 822 gi30582885Homo Sapiensnucleosome assembly1728 99 protein 1-like 2 823 gi13432042Homo Sapiensintegrin-linked 2009 99 kinase-associated serine/threonine phosphatase 2C

823 gi16306907Homo sapiensAAH06576 integrin-linked2009 99 lcinase-associated serine/threonine phosphatase 823 120072498Musmusculus 0710007A14Rikprotein1926 94 824 gi28175169Mus musculus1300015B04Rik protein835 73 824 gi28848867Homo SapiensURGl l 1164 100 824 gi7768636Xenopus laevisI~ielin 239 36 825 gi21928259Homo Sapiensseven transmembrane1023 100 helix receptor 825 gi21928496Homo Sapiensseven transmembrane1023 100 helix receptor 825 gi21928655Homo Sapiensseven transmembrane916 89 helix receptor 826 gi18480746Mus musculusolfactory receptor 1278 79 M~R261-10 826 gi21928655Homo Sapiensseven transmembrane1456 93 helix receptor 826 gi32052225Mus musculusolfactory receptor 1278 79 GA_x6I~02T2P3E9-4341246-827 gi4760780Mus musculusTen-m3 364 95 827 gi5307761Danio rerio ten-m3 310 78 827 gi6760369Mus musculusAF195418_1 ~DZ3 364 95 828 gi16265938Homo SapiensAF314817_1 FI~SG15 2437 98 828 gi21205852Homo SapiensAF3854~29_1 T-cell 3756 100 activation Rho GTPase activating protein;

TA-GAP

828 gi21205854Homo SapiensAF385430_1 T-cell 2850 100 activation Rho GTPase activating protein splice variant 1;
TA-GAP

829 gi10432396Homo Sapiens 383 62 829 gi30908443Homo SapiensCUB and sushi multiple388 63 domains 2 829 gi30908445Homo SapiensCUB and sushi multiple549 100 domains 3 830 gi10432396Homo Sapiens 383 62 830 gi30908443Homo SapiensCUB and sushi multiple388 63 domains 2 830 gi30908445Homo SapiensCUB and sushi multiple549 100 domains 3 831 gi3342148Chlamydomonasmyosin heavy chain 499 37 reinhardtii 831 gi532124Dictyosteliummyosin IC 517 41 discoideum 831 gi8953751Arabidopsis myosin heavy chain 492 41 thaliana MYA2 832 gi6472600Chara corallinaunconventional myosin621 38 heavy SEQ Hit Species Description S Percentage-ID ID I scoredenti chain 832 gi8953751Arabidopsis myosin heavy chain 621 38 thaliana M1'A2 832 gi9453839Chara corallinamyosin 621 38 834 gi21265163Homo Sapiens 2424 99 834 gi7248845Homo sa iens AF231124 1 testican-12428 99 834 gi793845Homo Sapiens testican 2428 99 835 gi20380774Homo Sapiens 2930 99 835 gi22761091Homo Sapiens unnamed protein 2350 99 product 835 gi27502762Mus musculus hypothetical protein2712 90 836 gi20380774Homo Sapiens 2946 100 836 gi22 Homo Sapiens unnamed protein 2366 100 761091 product 836 _ Mus musculus hypothetical protein2728 91 gi27502762 MGC28931 837 gi17391348Homo Sapiens AAH18615 Similar 664 100 to brain expressed, X-linked 837 gi7689029Homo Sapiens AF220189_1 uncharacterized664 100 hypothalamus protein 837 gi9963771Homo Sapiens AF183416_1 ovarian 664 100 granulosa cell 13.0 kDa protein h6R74 homolo 838 gi15215122Mus musculus chondroadherin 428 31 838 gi29571143MuS museulus 5430427N1112i1c 430 27 protein 838 gi30908853Homo Sapiens synleurin 3201 100 839 gi12842465Mus musculus unnamed protein 567 92 product 839 gi15488920Homo Sapiens AAH13587 Similar 632 100 to RIKEN
cDNA 2010107623 gene 839 gi19354289Mus musculuS RIICEN cDNA 2010107623567 92 gene 840 ' 16549697Homo Sapiens unnamed protein 2483 99 product 840 gi20988071Mus musculus 2600011E07Rik protein919 80 840 gi21619776Homo Sapiens Similar to I~IICEN 2491 100 cI~NA
2600011E07 ~ene 841 gi12963869Mus musculuS gene trap ankyrin 223 30 repeat containing protein 841 gi28565117Drosophila myosin phosphatase 228 22 melanogaster DMBS-S

841 gi30138665Nitrosomonas Ankyrin-repeat 228 31 europaea ATCC

842 gi12408272Homo Sapiens apolipoprotein L-IV1742 100 splice variant a 842 gi12408286Homo Sapiens apolipoprotein L-IV1742 100 splice variant a 842 gi13374351Homo sapiens AF305226_1 apolipoprotein1725 99 843 gi12408272Homo Sapiens apolipoprotein L-IV1737 99 splice variant a 843 gi12408286Homo Sapiens apolipoprotein L-IV1737 99 splice variant a 843 gi13374351Homo Sapiens AF305226_1 apolipoprotein1720 99 844 gi21744725Homo Sapiens AF478693_1 glycosyl-2296 100 phosphatidyl-inositol-MAM

844 gi25005318Sus scrofa MAM domain containing1804 93 ~ ~

SEQ Hit ID Species Description S Percentage_ ID score I denti glycosylphosphatidylinositol anchor 1 844 gi25005320Sus scrofa glycosylphosphatidylinositol1673 92 anchor 1 protein 845 gi21744725Homo SapiensAF478693_1 glycosyl-5051 100 phosphatidyl-inositol-MAM

845 gi25005318Sus scrofa MAM domain containing4481 95 glycosylphosphatidylinositol anchor 1 845 gi25005320Sus scrofa glycosylphosphatidylinositol4350 95 anchor 1 protein 846 gi1066493SaccharomycesYpr144cp 572 30 cerevisiae 846 gi32487557Oryza sativaOSJNBa0013K16.9 565 32 (japonica cultivar-oup) 846 gi4007758SchizosaccharomyceSPBC1604.06c 613 33 spombe 847 gi14280050Homo SapiensVps39/Vam6-like 3913 88 protein 847 gi14701768Homo SapiensVam6Nps39-like protein3990 89 847 gi23273399Homo Sapiens 4079 98 848 gi23273399Homo Sapiens 4095 99 848 gi25059032Mus musculus 3128 72 848 gi29467442Homo Sapienscytosolic phospholipase1512 4~1 delta 849 gi14603301Homo SapiensHypothetical protein986 100 849 gi7291437Drosophila CG4071-PA 510 49 melanogaster 849 gi9955513Arabidopsis putative protein 340 36 thaliana 850 gi13161409Mus musculusfamily 4 cytochrome444 73 850 gi13182964Mus musculusAF233643_1 cytochrome196 38 850 gi 13278244Mus musculuscytochromo P450, 196 38 family 4~, subfamily f, polypeptide 851 gi10944887Homo SapiensFGFR-like protein 2475 98 851 gi13183618Homo SapiensAF312678_1 FGF homologous2424 97 factor receptor 851 gi13447749Homo SapiensAF279689_1 fibroblast2475 98 growth factor receptor 852 110944887Homo SapiensFGFR-like protein 2701 99 852 gi13183618Homo SapiensAF312678_1 FGF homologous2650 98 factor receptor 852 gi13447749Homo SapiensAF279689_1 fibroblast2701 99 growth factor receptor 853 110944887Homo SapiensFGFR-like protein 583 98 853 gi13183618Homo sapiensAF312678_1 FGF homologous583 98 factor receptor 853 gi13447749Homo sapiensAF279689_1 fibroblast583 98 growth factor receptor 854 gi12667446Rattus norvegicusAF336854_1 synaptotagmin2034 95 VIIs 854 gi6136786Mus musculussynaptotagmin VII 2025 95 854 gi643656Rattus norvegicussynaptotagmin VII 2034 95 855 gi12053709Homo Sapienswith thrombospondin8842 100 type 1 motif, 12 SEQ Hit Species Description S Percentage_ ID ID I scoredenti 855 gi27817773Mus musculus metalloprotease 7094 80 disintegrin 12 protein 855 gi5923788Homo Sapiens AF140675_1 zinc 2471 51 metalloprotease 856 gi15929988Homo Sapiens AAH15423 Similar 179 48 to TLH29 protein precursor 857 gi13542874Mus musculus Similar to RII~EN 1301 74 cDNA

857 gi17391206Mus musculus RII~EN cDNA 2210412D011591 94 857 gi28277574Danio rerio Similar to RIKEN 1377 79 cDNA
2210412D01 gene 858 gi13542874Mus musculus Similar to RIKEN 1301 72 cDNA

858 gi17391206Mus musculus RIKEN cDNA 2210412D011591 94 858 gi28277574Danio rerio Similar to RIKEN 1343 79 cDNA
2210412D01 gene 859 gi20071312Mus musculus 4933425F03Rik protein1219 80 859 gi217732~ryctolagus macrophagescavengerreceptor602 38 cuniculus type I subunit 859 gi33391740Homo Sapiens MGC45780 1521 98 860 gi20071312Mus musculus 4933425F03Rilc protein1321 86 860 gi33391740Homo Sapiens MGC45780 1656 87 860 gi6478784Mus musculus scavengei receptor 679 34 type A SR-A

861 gi11493463Homo Sapiens AF130117 38 PR~2852298 75 861 gi21748687Homo Sapiens unnamed protein 319 72 product 861 gi28801453Homo Sapiens unnamed protein 325 77 product 862 ' 14456629Homo Sapiens 1232 50 862 gi15081398Homo Sapiens AF395541_1 kruppel-like~ 54 zinc 1245 finger protein 862 gi29476835Homo Sapiens 1222 47 863 gi16551721Homo Sapiens unnamed protein 3124 99 product 863 gi21320872MuS muSCUlus Cog8 2744 87 863 gi7297851Drosophila CG6488-PA 1143 43 melanogaster 864 gi16307258Homo Sapiens AAH09717 hypothetical942 100 protein 864 gi22945521Drosophila CG31922-PA 165 33 melanogaster 864 gi7242597Homo Sapiens hypothetical protein942 100 865 gi23274241Homo Sapiens KIAA1892-lilee 2039 86 865 gi26332114Mus musculus unnamed protein 1964 82 product 865 gi26345386Mus musculus unnamed protein 1964 82 product 866 gi1562~885Homo Sapiens I'IAA1913 protein 2495 100 866 gi26339494Mus musculus unnamed protein 2312 90 product 866 gi28279830Homo Sapiens KIAA1913 protein 2495 100 867 ' 1000448Rattus norvegicusRat kidney AGT2 2202 81 precursor 867 gi12406973Homo Sapiens alanine-glyoxylate 2740 100 aminotransferase 867 gi1944136Rattus norvegicusbeta-alanine-pyruvate2249 83 aminotransferase 868 11000448Rattus norvegicusRat kidney AGT2 1583 84 precursor 868 gi12406973Homo Sapiens alanine-glyoxylate 1870 98 aminotransferase SEQ Hit_ID Species Description S Percentage_ ID I scoredenti 868 gi1944136Rattus norvegicusbeta-alanine-pyruvate1630 86 aminotransferase 869 gi26892205Homo Sapiens 1 448 39 869 gi29436673Mus musculus 1700049K14Rik protein1732 99 869 gi4165315Sus scrofa kallikrein 452 41 870 gi17985046Brucella melitensisGLYCOSYL TRANSFERASE130 28 870 gi20515259Thermoanaerobacterpredicted glycosyltransferases133 32 tengcongensis 870 gi4455730Streptomyces putative transferase140 32 coelicolor A3(2) 872 gi13649477Homo Sapiens AF250309_1 putative1998 100 cytokine receptor CRL4 precusor 872 gi30584223synthetic Homo Sapiens interleukin1998 100 construct 17B
receptor 872 gi8705222Homo Sapiens AF212365_1 IL-17B 1998 100 receptor 873 gi18676472Homo Sapiens FLJ00133 protein 6475 100 873 gi20379832Homo Sapiens FLJ00133 protein 3072 94 873 gi29568116Mus musculus secreted protein 3973 84 875 gi14249936Homo Sapiens AAH08349 Similar 2581 100 to S-adenosylhomocysteine hydrolase-like 1 875 gi16588687Homo Sapiens AF315687_1 S- 2429 92 adenosylhomocysteine hydrolase-like protein 875 gi27692283Mus musculus S-adenosylhomocysteine2429 92 hydrolase-lilee 876 gi14279990Homo Sapiens AF294842_1 ubiquitin458 100 UBF-fl 876 gi29791813Homo Sapiens Ubiquitin-conjugating212 74 enzyme E2C, isoform 1 876 gi30583439Homo Sapiens ubiquitin-conjugating212 74 enzyme 877 gi20086516Homo sapions AF245303_1 prominin-24~24~199 variant A

877 gi20086518Homo sapiens AF245304_1 prominin-24241 99 variant B

877 '24637566Rattusnorvegicusprominin-2 3224 74 878 129351676Homo Sapiens An iopoietin-like 2104 100 878 129468510Homo Sapiens putative fibrinogen-like2099 99 protein 878 gi29791750Homo sapiens angiopoietin-like 392 37 879 gi29351676Homo Sapiens Angiopoietin-like 2100 99 879 gi29468510Homo Sapiens putative fibrinogen-like2095 99 protein 879 gi29791750Homo sapiens angiopoietin-like 392 37 880 129351676Homo Sapiens Angiopoietin-like 2100 99 880 gi29468510Homo Sapiens putative fibrino 2095 99 en-like protein 880 gi29791750Homo Sapiens angiopoietin-like 392 37 881 gi11493483Homo Sapiens AF130117 48 PRO2550319 66 881 gi1872200Homo Sapiens alternatively spliced303 56 product usin exon 13A

881 gi7770139Homo Sapiens AF119917 13 PR01722318 69 882 gi13543706Homo Sapiens AAH06003 349 100 882 gi20988061Mus musculus 1810b13D10Rik protein333 92 882 gi21619079Homo Sapiens 349 100 883 gi11493652Homo Sapiens AF200708 1 calcium 2552 100 ~ ~ ~ channel SEQ Hit_ID Species Description S Percentage_ ID I scoredenti Mocker resistance protein 883 gi13924720Homo sapiensAF252872_1 cystine/glutamate2552 100 transporter xCT

883 gi15082352Homo SapiensAAH12087 member 2552 100 884 gi14252988Homo SapiensSRPKlaprotein kinase2297 86 884 gi23468345Homo SapiensSFRS protein kinase2304 87 884 gi507213Homo Sapiensserine kinase 2297 86 885 gi18044358Homo SapiensAAH19883 Similar 270 57 to lectin-like NK cell receptor 885 gi9837288Homo SapiensC-type lectin 270 57 885 gi9837292Homo SapiensC-type lectin 270 57 886 gi22164066Homo SapiensAF388385_1 neurolilastoma-7571 99 amplified protein 886 gi30353863Homo sapiensNAG protein 7227 99 886 gi4337460Homo Sapiensneuroblastoma-amplified6886 99 protein 887 gi22164066Homo SapiensAF388385_1 neuroblastoma-7309 96 amplified protein 887 gi30353863Homo SapiensNAG protein 6965 96 887 gi4337460Homo sapiensneuroblastoma-amplified6624 96 protein 888 gi18645094uncultured M20/M25/M40 family 383 38 proteobaeteriumpeptidase, putative 888 119387947Mus musculusLOC212933 protein 510 73 888 gi28806353Vibrio putative M20/M25/M40387 35 parahaemolyticusfamily peptidase 889 gi11558029Homo sapiensorganic ration transporter1857 99 889 gi18088251Homo SapiensAAH20565 Similar 1839 95 to hBOIT
for potent brain type organic ion transporter 889 '9663117Homo Sapiensorganic ration transporter1849 99 890 gi21732438Homo Sapienshypothetical protein977 100 890 gi26330392MuS muSCUlusunnamed protein 765 80 product 890 gi26390211Mus musculusunnamed protein 765 80 product 891 gi13375149Homo Sapiens 853 90 891 gi20072584Mus musculuscDNA sequence BC027127259 37 891 gi7259265Mus musculusre 'on 277 47 892 gi16589003Homo SapiensAF386649_1 bromodomain-6353 99 containing 4 892 gi18308125Mus musculusAF461395_1 bromodomain-5992 92 containing protein BRD4 long variant 892 gi9931486Mus musculusAF273217_1 cell 5994 92 proliferation related protein CAP

893 gi15420828Homo SapiensAF397392_1 NOE3-1 2504 99 893 gi19386926Rattus norvegicusAF442822_1 optimedin2484 98 form B

893 gi19386930Mus musculusAF442824 1 optimedin2484 98 form B

894 gi22209078Homo Sapienshypothetical protein4474 99 DKFZp566D234 894 gi26337809Mus musculusunnamed protein 4135 91 product 894 gi6330966Homo SapiensKIAA1263 protein 4492 100 895 gi12654031Homo sapiensAAH00819 Similar 1538 99 to CG6950 gene product SEQ Hit ID Species D escription S scorePercentage_ ID

I denti 895 gi5002565Takifugu rubripescysteine conjugate1235 55 beta-lyase 895 gi758591Homo Sapiens glutamine--phenylpyruvate1193 51 aminotransferase 896 '14017833Homo Sapiens KIAA1808 protein 2905 99 896 gi21666433Mus~musculus AF404775_1 actin-binding1498 60 LIM protein 1 medium isoform 896 gi30259308Mus musculus actin-binding LIM 2799 86 protein 2 897 gi2062399Rattus norvegicusprotein serine/threonine818 52 kinase 897 gi6716518Mus musculus AF1551 doublecortin-like818 52 kinase 897 gi6716522Mus musculus AF155821 1 CPG16 818 52 898 gi2062399Rattus norvegicusprotein serine/threonine818 52 kinase 898 gi6716518Mus musculus AF1551 doublecortin-like818 52 kinase 898 gi6716522Mus musculus AF155821_1 CPG16 818 52 899 gi13436035Mus musculus prostaglandin E 1583 83 synthase 2 899 gi29179467Danio rerio Similar to prostaglandin1079 60 E

synthase 2 899 gi9280108Macaca fascicularismembrane-associated1907 97 prostaglandin E
synthase-2 900 gi12805247Mus musculus Complement component945 70 1, q subcomponent, alpha polypeptide 900 gi20988805Homo Sapiens complement component1308 99 1, q subcomponent, alpha polypeptide 900 gi4894854Homo Sapiens AF135157_1 complement1308 99 Clq A chain precursor 901 gi 12841760Mus musculus unnamed protein 928 80 product 901 gi 12846817Mus musculus unnamed protein 931 80 product 901 gi30802090Homo Sapiens Similar to RIKEI~11127 100 cDNA

1810059622 gene 902 gi21707458Homo Sapiens PAS transcription 2704 87 activation domain interacting protein 1 like 902 gi2565046Homo Sapiens CAGF28 3771 97 902 gi4336734Mus musculus Pax transcription 4115 77 activation domain interacting protein PTIP

903 114164561Xenopus laevisAF172855 1 Swift 467 79 903 gi4336734Mus musculus Pax transcription 531 93 activation domain interacting protein PTIP

904 gi15929776Homo Sapiens AAH15309 growth 135 41 suppressor 904 gi23271416Mus musculus Leprel protein 135 41 904 gi30582917Homo Sapiens 1 135 41 905 gi2443352Mus musculus platelet glycoprotein149 45 Ib beta 905 gi30908853Homo sapiens synleurin 1549 100 905 gi6808603Homo Sapiens AF169675_1 leucine-rich147 40 repeat transmembrane protein 906 gi13991167Homo Sapiens sialic acid-binding1174 100 immunoglobulin-like lectin-like long splice variant TART.F'7 R
SEQ Hit ID Species Description S scorePercentage_ ID Identi 906 gi14625822Homo Sapiens AF282256 1 Siglec-Ll1174 100 906 gi23272769Homo Sapiens SIGLEC-like 1 1174 100 907 gi13435476Mus musculus DNA segment, Chr 900 95 10, University of California at Los Angeles 1 907 gi28279553Danio rerio Similar to DNA 750 87 segment, Chr 10, University of California at Los Angeles 1 907 gi29144983Mus musculus DNA segment, Chr 657 67 6, ERATO
Doi 253, expressed 908 gi1504040Homo Sapiens 4470 56 908 gi6273399Homo Sapiens AF200348_1 melanoma-4470 56 associated antigen 908 gi7292259Drosophila CG12002-PA 2536 36 melanogaster 909 gi1504040Homo sapiens 4470 56 909 gi6273399Homo sapiens AF200348_1 melanoma-4470 56 associated antigen 909 gi7292259Drosophila CG12002-PA 2536 36 melanogaster 910 gi1504040Homo Sapiens 4112 56 910 gi6273399Homo Sapiens AF200348_1 melanoma-4112 56 associated anti en MG50 910 gi7292259Drosophila CG12002-PA 2388 36 melano aster 911 gi18175295Homo Sapiens CRB1 isofonn II 1258 28 precursor 911 gi18182323Mus musculus AF406641_1 crumbs-like1242 29 protein 1 precursor 911 gi29144951Mus musculus 5930402A21 protein4084 72 912 gi11493463Homo Sapiens AF130117 38 PR02852173 54 912 gi21104464Homo Sapiens OK/SW-CL.41 184 61 912 gi6650802Homo Sapiens AF118094 17 PRO1848200 56 913 gi6808611Homo sapiens AF204=231_1 88-kDa3237 99 Golgi protein 913 gi6969980Homo sapicns AF163441 1 0l in 2345 98 913 gi7211438Homo Sapiens AF164622 2327 98 1 olgin-67 914 gi15030299Mus musculus _ 1881 94 protein kinase, CAMP
dependent regulatory, type I
beta 914 gi200365Mus musculus CAMP-dependent 1886 94 protein kinase regulatory subunit 914 gi307377Homo Sapiens CAMP-dependent 1957 99 protein kinase RI-beta regulatory subunit 915 114017915Homo Sapiens I~IAA1849 protein 3460 100 915 17022002Homo Sapiens unnamed protein 3074 100 product 915 gi7022284Homo Sapiens unnamed protein 3460 100 product 916 gi1845577Mus musculus -lipoxygenase 2619 77 916 gi30047223Mus musculus Arachidonate lipoxygenase,2617 77 epidermal 916 gi3645913Mus musculus -lipoxygenase 2619 77 917 gi15489302Mus musculus arachidonate lipoxygenase,1142 69 epidermal 917 11845577Mus musculus -lipoxygenase 1139 69 917 gi30047223Mus musculus Arachidonate lipoxy1142 69 enase, SEQ Hit ID Species Description S Percentage_ ID I scoredenti epidermal 918 gi15489302Mus musculusarachidonate lipoxygenase,1263 75 epidermal 918 '1845577Mus musculus-lipoxygenase 1260 75 918 gi30047223Mus musculusArachidonate lipoxygenase,1263 75 epidermal 919 gi12053299Homo Sapienshypothetical protein2183 100 919 122478033Homo sa ienshypothetical protein3409 91 919 gi22945612Drosophila CG31652-PA 131 23 melanogaster 920 gi14198207Mus musculushypothetical protein1599 98 920 gi19343692Homo Sapiens 1625 100 920 gi7294965Drosophila CG4452-PA 615 40 melanogaster 921 gi21594983Homo Sapienscytokine-like protein238 74 921 gi8132683Homo SapiensAF193766_1 cytokine-like238 74 protein C17 922 gi21594983Homo Sapienscytokine-like protein238 74 922 gi8132683Homo SapiensAF193766_1 cytokine-like238 74 protein C 17 923 121594983Homo Sapienscytokine-like protein381 81 923 gi8132683Homo SapiensAF193766_1 cytokine-like381 81 protein C17 924 gi21594983Homo Sapienscytokine-like protein263 98 _ gi8132683Homo sapiensAF193766_1 cytolcine-like263 98 924 protein C17 925 gi21594983Homo sapienscytokine-like protein591 100 925 gi8132683Homo SapiensAF193766_1 cytokine-like591 100 protein C17 926 gi13396317Homo Sapiens 2741 99 _ gi17975777Homo Sapiensvesicular inhibitory2741 99 926 amino acid transporter 926 gi31566392Homo Sapiensvesicular inhibitory2741 99 amino acid transporter 927 '22507470Mus musculusAI4134~81 protein 2042 92 927 gi3097285Rattus norvegicusZ~G 658 39 927 '802014 Rattus norvepreadipocyte factor653 39 icus 1 928 gi16768374Drosophila GM03282p 357 36 melanogaster 928 gi18088059Mus musculusE030025D05Rik protein1600 89 928 gi6624073Homo SapiensAC007743_1 similar 1755 93 to hepatitis delta antigen interacting protein A

929 gi14250638Homo SapiensAAH08783 Similar 864 97 to DNA
segment, Chr 17, human 929 gi3941733Mus musculusAAC82476 BAT4 582 70 929 gi4337106Homo SapiensAAD18082 BAT4 864 97 930 gi27476065Oryza sativaPutative 266 30 (japonica phosphate/phosphoenolpyruvate cultivar- translocator protein group) 930 gi5911433Rattus norvegicusAF182714_1 putative621 88 phosphatelphosphoenolpyruvate translocator 930 19759107Arabidopsis 282 30 thaliana SEQ Hit_ID Species Description S Percentage_ ID I scoredenti phosphate/phosphoenolpyruvate translocator protein-like 931 gi15277895Homosapiens AAH12939 1204 99 ~ Similar to cardiotrophin-like cytokine;
neurotrophin-1/B-cell stimulating factor-3 931 gi16356643Homo Sapiens cardiotrophin-like 1204 99 cytokine 931 gi6007643Homo Sapiens neurotrophin-1/B-cell 1204 99 stimulating factor-3 932 gi18490933Homo Sapiens FLJ21269 846 98 protein 932 gi20268674Mus musculus MT-MC1 715 82 932 gi22003732Homo Sapiens AF527367_1 853 99 MTLC

933 gi15982236Mus musculus putative 1095 94 methionyl aminopeptidase 933 gi23306398Arabidopsis , putative 744 50 thaliana 933 gi24899771Arabidopsis , putative 744 50 thaliana 934 gi1336013Mus musculus neurexophilin 550 45 934 gi22477181Homo Sapiens Similar 1649 99 to neurexophilin 934 gi4104963Rattus norvegicusneurexophilin 1493 90 935 gi12852913Mus musculus unnamed 193 75 protein product 935 126326067Mus musculus unnamed 193 75 protein product 937 gi19387136Homo Sapiens AF479748_1 874 99 PYRIN-containing APAF1-like protein 937 gi202806Rattus norvegicusvasopressin 561 68 receptor 937 gi28436366Homo Sapiens NALP6 874 99 938 gi11321325Homo Sapiens AF311862 1030 100 1 Lin-7b 938 gi20381193Homo Sapiens Lin-7b protein; 1030 100 likely ortholog of mouse LIN-7B;
mammalian LIN-7 protein 938 gi3885828Rattus norvegicuslin-7-A 1019 98 939 gi14349125Homo Sapiens alpha2-glucosyltransferase 738 96 939 gi32490259~ry~,a sativa~SJNBb0116If07.1 190 36 japonica cultivar-group) 939 13513451Rattus norvegicuspotassium 718 93 channel regulator 940 113325140Homo Sapiens AAH04383 2693 100 940 gi35768Homo Sapiens polypirimidine 2693 100 tract binding protein 940 gi35774~Homo Sapiens 2693 100 941 gi21522774Homo Sapiens unnamed product 3068 100 protein 941 gi24047224Homo Sapiens Similar 3048 99 to EGF-like-domain, multiple 941 gi6752658Homo Sapiens AF186084_1 3043 99 epidermal growth factor repeat containing protein 942 gi21522772Homo Sapiens unnamed 3102 100 protein product 942 gi24047224Homo sapiens Similar 3043 98 to EGF-like-domain, multiple 942 gi6752658Homo Sapiens AF186084_1 3038 98 epidermal growth factor repeat containing protein 943 gi11385648Homo Sapiens AF273045_1 3867 99 C'TCL tumor antigen sel4-3 943 gi17980969Homo Sapiens AF454056_1 5146 99 sel4-3r protein 943 gi29165763Mus musculus 3632413B07Rik 5213 82 protein SEQ Hit Species Description S scorePercentage_ ID ID I denti 944 gi13677201Homo Sapiens 2771 100 944 gi17980969Homo Sapiens AF454056 1 sel4-3r3140 99 protein 944 gi29165763Mus musculus 3632413B07Rik protein3613 89 945 gi11385648Homo Sapiens AF273045_1 CTCL 3806 94 tumor anti en sel4-3 945 gi17980969Homo Sapiens AF454056_1 sel4-3r5085 95 protein 945 gi29165763Mus musculus 3632413B07Rik protein5492 85 946 gi11385648Homo Sapiens AF273045_1 CTCL 3806 94 tumor antigen sel4-3 946 gi17980969Homosapiens AF454056_1 sel4-3r5085 95 protein 946 gi29165763Mus musculus 3632413B07Rik protein5566 87 947 gi14043211Homo Sapiens AAH07594 Similar 2410 98 to RIKEN
cDNA 4931428F04 ene 947 '21739633Homo Sapiens hypothetical protein2430 97 947 '25058997Mus musculus 1110003N121Rik 941 63 protein 949 gi19387136Homo Sapiens AF479748_1 PYRIN- 1735 99 containing APAF1-like protein 949 gi202806Rattus norve vasopressin receptor1030 64 'cus 949 gi28436366Homo Sapiens NALP6 1735 99 950 gi20338417Callus galluspotassium channel 5079 88 subunit 950 gi3875660Caenorhabditis 2164 45 ele ans 950 gi3978472Ratkus norvegicuspotassium channel 5376 90 subunit 951 gi18147612Homo Sapiens metalloprotease 4376 96 disintegrin 951 gi21908028Homo sapiens AF466287_1 a disintegrin4360 96 and metalloprotease domain 33 951 gi21908030Homo Sapiens a disintegrin and 4360 96 metalloprotease domain 33 952 i 12841733Mus musculus unnamed protein 715 92 product 952 gi18606367Mus musculus RIKEN cDNA 4930570003715 92 952 gi31581976Homo sapiens FLJ20489 protein 472 100 953 gi154.20879Mus musculus AF398971_1 ankyrin204.9 83 repeat-containing S~CS
box protein 953 gi18031949Mus musculus S~CS box protein 800 44 953 gi18092200Homo Sapiens AF417920_1 ASB-10 2174 91 954 gi32707Homo Sapiens interferon-omega 337 51 l 954 '386800Homo Sapiens interferon-alpha 340 51 954 1491284synthetic IFN-pseudo-ome 799 98 construct a 2 955 gi15928971Homo Sapiens AAH14951 Similar 430 90 to neuronal thread protein 955 gi9844579Homo Sapiens 450 97 955 gi9844580Homo Sapiens 623 84 956 gi11559412Homo Sapiens NADPH-dependent 587 100 retinol dehydrogenase/reductase 956 gi12804321Homo Sapiens AAH03019 peroxisomal685 100 short-chain alcohol dehydrogenase 956 gi19113668Homosapiens NADP-dependentretinol878 100 dehydrogenase short isoform 957 122658418Mus musculus cDNA sequence BC0309341499 68 957 gi28838433Homo Sapiens DI~FZp762A2013 1759 82 protein 957 gi30842594Homo Sapiens putative sulfhydryl1668 78 oxidase precursor SEQ Hit Species Description S Percentage_ ID ID I scoredenti 958 gi12958660Homo Sapiens AF321918_1 acid 2252 100 phosphatase 958 gi12958663Homo Sapiens AF321918 4 acid 1285 99 phosphatase variant 3 958 gi52871Mus musculus lysosomal acid phosphatase832 45 959 gi11493443~Homo Sapiens AF130117 27 PR022091703 100 959 '28966 Homo Sapiens alpha 1-antitrypsin1703 100 959 gi6855601Homo Sapiens AF113676_1 PR00684 1703 100 960 gi11493443Homo Sapiens AF130117 27 PR022092040 95 960 gi177829Homo Sapiens alpha-1-antitrypsin2040 95 960 gi28966Homo Sapiens alpha 1-antitrypsin2040 95 961 il 1493443Homo Sapiens AF130117_27 PR022092025 95 961 gi177829Homo Sapiens alpha-1-antitrypsin2025 95 961 gi28966Homo Sapiens alpha 1-antitrypsin2025 95 962 gi11493443Homo Sapiens AF130117 27 PR022092036 95 962 1177829Homo Sapiens alpha-1-antitrypsin2036 95 962 gi28966Homo Sapiens alpha 1-antitrypsin2036 95 964 gi1841702Macaca fascicularisfertilin alpha-I 3138 70 isoform 964 gi2632092Pon o pygmaeusfertilin alpha protein4125 92 964 gi794073Macaca fascicularisfertilin alpha-I 3138 70 965 gi17887359Oryctolagus lipophilin AL2 248 54 cuniculus 965 gi4107229Homo Sapiens lipophilin A 454 100 965 gi4107231Homo Sapiens lipophilin B 267 60 966 gi13817037Homo Sapiens E-type ATPase 2812 99 966 gi20988653Homo Sapiens Similar to ectonucleoside2413 99 triphosphate diphosphohydrolase 966 gi3335100Homo Sapiens CD39L3 2816 100 967 gi180251Homo sapiens precerebellin 542 57 967 16942096Mus musculus CBLN3 936 93 967 gi694209$Mus musculus AF218380 1 CBLN3 936 93 968 ' 18255724Mus musculus LOC215928 protein 131 28 968 gi21750370Homo Sapiens unnamed protein 1136 100 product 968 gi28460663Rattus norvegicusNa+ dependent glucose185 30 transporter 1 969 gi21750370Homo Sapiens unnamed protein 254.599 product 969 gi22328120Homo Sapiens hypothetical protein2077 99 DICFZp761N1114 969 gi26332881Mus musculus unnamed protein 2116 86 product 970 gi13161123Homo Sapiens AF332239_1 transcript147 54 970 gi4545317Acipenser AF129437_1 immunoglobulin149 25 ruthenus light chain precursor 970 gi9937599Salmo trutta AF296378_1 MHC class153 31 I
heavy chain 971 gi12964746Mus musculus AF316612_1 neuronal2207 88 pentraxin receptor 971 gi2253263Rattus norvegicusneuronal pentraxin 2232 89 receptor 971 gi4160197Homo Sapiens 2512 99 972 gi27884137Danio rerio 3553 78 972 gi3170615Mus musculus DOC4 4166 96 972 gi4760782Mus musculus Ten-m4 4188 96 , 973 gi14714932Homo Sapiens AAH10623 -like 1 3770 100 973 121748606Homo sa iens FLJ00380 protein 372_996 973 gi541678Homo Sapiens hbZl7 3729 96 ~

2,1~

SEQ Hit_ID Species Description S Percentage_ ID I scoredenti 974 gi17044301Leishmania possible LIM-binding2875 36 major factor 974 gi23095182Drosophila CG13809-PA 3997 46 melanogaster 974 gi7716100Rattus norvegicusAF226993_1 selective8413 95 LIM
binding factor 975 gi20799661Mus musculus AF503575 1 mucolipin-21593 71 975 gi24417793Mus musculus mucolipin 2 1593 71 975 '24417795Homo Sapiens mucolipin 2 1912 86 976 '20799661Mus musculus AF503575_1 mucolipin-22394 83 976 gi24417793Mus musculus mucolipin 2 2394 83 976 gi24417795Homo Sapiens mucolipin 2 2817 99 977 gi1510147Homo sapiens 309 23 977 gi22477432Homo sapiens DI~F'ZP762N2316 4532 91 protein 977 gi403020,Mus musculus En-2/IacZ fusion 988 96 protein 980 gi1513059Homo sapieiisserin protease with2203 92 IGF-binding motif 980 gi1621244Homo Sapiens novel serine protease,2203 92 980 gi5281519Homo Sapiens AF157623_1 HTRA 2203 92 serine protease 981 gi11990126Camelus chymosin 1187 56 dromedarius 981 1540097Sus scrofa preprochymosin 1187 58 981 gi7008025Callithrix prochymosin 1346 64 jacchus 982 gi27356934Homo Sapiens extracellular sulfatase293 100 982 gi27356938Mus musculus extracellular sulfatase288 100 982 gi28191290Homo Sapiens sulfatase SULF1 276 68 precursor 984 gi27124671Homo Sapiens Zn-carboxypeptidase2008 99 984 gi27529696Paralichthys carboxypeptidase 808 4.9 olivaceus B

984 gi6013463Bothrops jararacacarboxypeptidase 817 46 homolo 985 gi27124671Homo Sapiens Zn-carboxypeptidase2008 99 985 gi27529696Paralichthys carboxypeptidase 808 49 olivaccus B

985 gi6013463Bothrops jararacacarboxypeptidase 817 46 homolog 986 '11545705Homo Sapiens ISCUl 663 99 986 gi11545707Homo Sapiens ISCU2 845 100 986 gi20381021Mus musculus Nifu-pendin protein807 96 987 gi12314022Homo Sapiens 883 89 987 gi22417143Homo Sapiens CGI-301 protein 853 100 987 gi32879760Homo Sapiens Snf7 homologue associated883 89 with Alix 1 988 gi12805221Mus musculus Lymphocyte antigen 137 33 complex, locus A

988 gi198924.Mus musculus Ly-6A.2 137 33 988 gi201113Mus musculus T-cell activation 137 33 protein 989 gi17512406Mus musculus differential display1063 67 and activated by p53 989 gi25166615Homo Sapiens AF223000_1 DDA3-like1673 99 protein 989 gi25166621Homo Sapiens AF322891_1 DDA3-like1673 99 protein 990 gi15990480Homo Sapiens -binding protein 1570 100 990 gi21961217Homo Sapiens -binding protein 1570 100 990 122213050Mus musculus B230313N05Rik protein1555 98 SEQ Hit Species Description S Percentage_ ID ID I scoredenti 991 gi204058Rattus norvegicusextracellular signal-related1497 62 kinase 3 991 gi23903Homo Sapiens 63kDa protein kinase2894 99 991 gi27882123Danio rerio Similar to mitogen-activated1670 61 protein kinase 4 992 gi17016967Homo Sapiens AF435011 1 NUANCE 5643 97 992 gi17861384Homo Sapiens nesprin-2 gamma 5643 97 992 gi24417711Homo Sapiens nesprin-2 5643 97 993 gi18204756Musmusculus 2310044D20Rikprotein626 68 993 gi21706580Mus musculus A830073021Rik protein170 29 993 gi33328302Homo Sapiens NS5ATP6 997 100 994 gi19353133Mus musculus Clq-like 961 66 994 gi26996600Mus musculus Similar to Clq-like1468 94 994 gi32401227Homo Sapiens AF525315_1 Clq-domain1528 98 containing protein 995 gi14718648Homo Sapiens allantoicase 1633 99 995 gi20987689Homo Sapiens Similar to allantoicase1838 99 995 gi9255889Mus musculus AF278712 1 allantoicase1465 77 996 115617341Homo Sapiens LAG-3 protein precursor2813 99 996 gi30851187Homo Sapiens LAG3 protein 1906 99 996 gi579596Homo Sapiens lymphocyte protein 2651 98 997 gi13810285Rattus norvegicusguanine nucleotide 5813 91 release/exchange factor 997 gi2522208Homo sapiens Ras-GRF2 6407 99 997 gi5882290Homo sapiens Ras guanine nucleotide6401 99 exchange factor 998 gi22038159Homo Sapiens AF527605_1 ~iziminl8544 100 998 gi28374~168Mus musculus AA959601 protein 8001 92 998 gi31419757Mus musculus AA959601 protein 8001 92 999 gi10433672Homo Sapiens unnamed protein 1530 100 product 999 gi19263505Homo Sapiens hypothetical protein1530 100 999 gi23272394Homo Sapiens KCTI~2 protein 728 67 1000 gi14~04~1697Homo Sapiens 3585 99 1000 121594273Homo Sapiens 3626 100 1000 gi25303955Homo Sapiens 3600 100 1001 gi1438532Rattus norvegicusrAl 527 25 1001 gi1438534Rattus norvegicusrA9 4640 67 1001 gi27371336Homo Sapiens Similar to CTD-binding2008 97 SR-like protein rA9 1002 gi1438534Rattus norvegicusrA9 4640 67 1002 gi27371336Homo sapiens Similar to CTD-binding2008 97 SR-like protein rA9 1002 gi7296722Drosophila CG2926-PA 536 23 melanogaster 1003 gi1675220Cricetulus SREBP cleavage activating6194 92 griseus protein 1003 gi23240172Drosophila CG33131-PA 1077 32 melanogaster 1003 gi30048445Mus musculus Similar to SREBP 2600 89 CLEAVAGE-ACTIVATING
PROTEIN

1004 gi12652851Homo Sapiens AAH00178 potassium 1987 100 channel modulatory factor 1004 gi26453336Homo sapiens FIGC1 1983 99 ~

SEQ Hit Species Description S Percentage_ ID ID I scoredenti 1004 gi7677058Homo Sapiens AF155652_1 potassium1983 99 channel modulatory factor 1005 gi26341968Mus musculus unnamed protein 654 54 product 1005 gi27695389Mus musculus MGC58017 protein 1058 98 1005 130481648Homo Sapiens 654 54 1006 gi11875318Mus musculus synaptotagmin XIII 2004 89 1006 gi14210274Rattus norvegicusAF375466_1 synaptotagmin2000 89 1006 gi21410154Mus musculus synaptotagmin 13 2004 89 1007 gi11342591Mus musculus RanBP7/importin 5415 99 1007 gi32330683Mus musculus importin 7 5427 99 1007 gi3800881Homo Sapiens RanBP7limportin 5447 100 1008 gi17939650Homo Sapiens AAH19302 hypothetical3770 99 protein FLJ12525 1008 gi18676522Homo Sapiens FLJ00158 protein 1512 100 1008 127462078Homo Sapiens AF116730_1 MSTP060 3739 96 1009 gi28981429Mus musculus Ddefl protein 4690 95 1009 gi4063614Mus musculus ADP-ribosylation 4701 94 factor-directed GTPase activating protein isoform a 1009 gi4406393Bos taurus differentiation 4700 95 enhancing factor 1011 113872813Homo Sapiens fibulin-6 541 29 1011 ' 14575679Homo Sapiens AF156100 1 hemicentin537 29 1011 gi92804.05Homo Sapiens AF245505_1 adlican 1631 47 1012 gi1284.3704Mus musculus unnamed protein 1005 72 product 1013 gi12833251Mus musculus unnamed protein 710 58 product 1013 gi17511816Homo Sapiens AAH18758 Similar 1468 99 to RII~EN
cDNA 1110032022 gene 1013 gi20071678Mus musculus 710 58 1014 gi12833251Mus musculus unnamed protein 748 65 product 1014 gi17511816Homo Sapiens AAH18758 Similar 1288 90 to RIKEN
cDNA 1110032022 gene 1014. gi20071678Mus musculus 74=8 65 1015 gi13529248Homo Sapiens Centrin 3 839 99 1015 gi2246401Homo Sapiens centrin 842 100 1015 gi30582215Homo Sapiens 839 99 1016 gi31455256Homo Sapiens IMAGE3510317 protein2496 100 1016 132492907Homo Sapiens selenoprotein ~ 2496 100 1016 16572230Homo Sapiens 1879 99 1017 gi31455256Homo Sapiens IMAGE3510317 protein2142 100 1017 gi32492907Homo sapiens selenoprotein ~ 2142 100 1017 gi6572230Homo Sapiens 3997 99 1018 gi21928729Homo Sapiens seven transmembrane2190 99 helix receptor 1018 gi6693701Homo Sapiens AF147788 1 melanopsin2226 91 1018 gi6693703Mus musculus AF147789_1 melanopsin1729 74 1019 gi20072741Mus musculus E430025L02Rik protein2634 80 1019 gi28380382Drosophila CG4168-PA 309 29 melanogaster 1019 gi439296Homo Sapiens garp 793 37 1020 gi15487302Homo Sapiens medium-chain acyl-CoA1346 99 synthetase 1020 gi15706421Homo Sapiens middle-chain acyl-CoA1346 99 synthetase 1 22,1 SEQ Hit ID Species Description S Percentage_ ID score I denti 1020 gi5019275Bos taurus xenobiotic/medium-chain1088 78 fatty acid:CoA ligase form XL-III

1021 gi18874700Homo SapiensAF478469_1 Rapl 5803 98 guanine nucleotide-exchange factor 1021 gi20386206Homo SapiensAF478567_1 PDZ domain-5822 98 containing guanine nucleotide exchange factor 1021 gi6650766Homo SapiensAF117947_1 PDZ domain-6216 100 containing guanine nucleotide exchange factor I

1022 gi18874698Homo SapiensAF478468_1 Rapl 5923 99 guanine nucleotide-exchange factor 1022 gi18874700Homo SapiensAF478469_1 Rapl 5923 99 guanine nucleotide-exchange factor 1022 gi20386206Homo SapiensAF478567_1 PDZ domain-5942 100 containing guanine nucleotide exchange factor 1023 gi13810306Homo Sapienstransmembrane protein261 37 1023 ' 18250724Mus musculustransmembrane protein257 36 1023 gi20270907OncorhynchusAF483531_1 'IHSV-induced233 33 mylciss protein-5 1024 gi20071315Mus musculusAA589509 protein 1116 76 1024 gi21779866Mus musculusAF458068_1 IL-17RE 2052 66 1024 gi21779869Homo SapiensAF458069_1 IL-17RE 2896 100 1025 120071315Mus musculusAA589509 protein 1116 76 1025 gi21779866Mus musculusAF458068_1 IL-17RE 2028 72 1025 gi21779869Homo SapiensAF458069_1 IL-17RE 2928 100 1026 gi14150450Rattus norvegicusAF241241_1 UDP- 1350 93 GalNAc:polypeptide N-acetylgalactosaminyltransferase 1026 gi25809274Homo Sapienspolypeptide N- 1390 97 acetylgalactosaminyltransferase 1026 gi28268676Homo SapiensUDP-N-acetyl-alpha-D-1384 96 galactosamine:polypeptide N-aeetylgalactosaminyltransferase 1027 gi15217067Homo SapiensAF400436_1 stem 1019 95 cell factor isoform 1 1027 gi1827477Felis catus stem cell factor 896 84 1027 gi337934Homo sapiensstem cell factor 1019 95 1028 gi1377895Homo SapiensOB-cadherin-2 1572 56 1028 gi30171995Homo Sapienscadherin-24 2721 93 1028 gi30171998Homo Sapienscadherin-24 variant2987 99 1029 gi1377895Homo SapiensOB-cadherin-2 1621 60 1029 gi30171995Homo Sapienscadherin-24 2770 99 1029 '30171998Homo Sapienscadherin-24 variant2721 93 1030 gi1398903Mus musculusCa2+ dependent activator6763 94 protein for secretion 1030 gi21541504Homo SapiensAF458662_1 calcium-6440 93 dependent activator protein for SEQ Hit ID Species Description S scorePercentage-ID Identi secretion protein 1030 gi577428Rattus norvegicusCa2+-dependent 6449 93 activator protein; calcium-dependent actin-binding protein 1031 gi11071729Homo Sapiens putative dipeptidase1847 99 1031 gi11125344Homo Sapiens putative metallopeptidase1319 72 1031 gi32490515Mus musculus putative membrane-bound1313 71 dipeptidase-3 1032 gi11493652Homo Sapiens AF200708 1 calcium2552 100 channel blocker resistance protein 1032 gi13924720Homo Sapiens AF252872_1 cystine/glutamate2552 100 transporter xCT

1032 gi15082352Homo Sapiens AAH12087 member 2552 100 1033 gi17028348Homo sapiens DKFZP586G1517 protein3748 100 1033 gi20987924Mus musculus 2410004L15Rik protein3473 92 1033 gi29612455Mus musculus 2410004L15Rik protein3807 92 1034 gi19352987Homo sapiens Similar to KIAA04336348 98 protein 1034 gi2887437Homo Sapiens KIAA0433 6487 99 1034 gi31418648Mus musculus 4981 97 1035 gi11066463Rattus norvegicusAF225961_1 RhoGEF 6385 80 glutamate transport modulator 1035 gi19387126Mus musculus AF467766_1 guanine1778 33 nucleotide exchange factor 1035 gi7110160Homo Sapiens guanine nucleotide1792 38 exchange factor 1036 gi10726794Drosophila CG5521-PA 508 35 melanogaster 1036 gi24061707Mus musculus GAP-related interacting986 97 partner to E12 1036 gi4240257Homo Sapiens KIAA0884 protein 2491 100 1037 gi20269957Sus scrofa AF4.98759_1 phospholipase1472 85 C
delta 4.

1037 gi21307610Mus musculus phospholipase C 1327 77 delta 4 1037 gi571466Rattus norvegicusphospholipase C 1295 76 delta-4 1038 gi16552885Homo Sapiens unnamed protein 2084 99 product 1038 gi26326051Mus musculus unnamed protein 1085 54 product 1038 gi26327387Mus musculus unnamed protein 1085 54 product 1039 118480186Mus musculus olfactory receptor1323 81 M~R261-6 1039 gi32052343Mus musculus olfactory receptor1323 81 GA_x6K02T2P3E9-4384160-1039 19368991Homo Sapiens 14.10 100 1040 gi29791964Homo Sapiens Thrombospondin 4798 99 1040 gi311626Homo Sapiens thrombospondin-4 4787 99 1040 gi3860231Mus musculus thrombospondin-4 4557 93 1041 gi14043083Homo Sapiens AAH07524 sperm 660 100 associated antigen 9 1041 gi24460121Homo Sapiens AF327452_1 JNK-associated273 98 leucine-zipper protein 1041 gi29169179Homo Sapiens PHET 343 98 1042 gi21654741Homo Sapiens peptide/histidine 2771 95 transporter 1042 gi2208839Rattus norvegicuspeptide/histidine 2344 82 transporter SEQ Hit Species Description S Percentage_ ID ID I scoredenti 1042 gi33126130Homo Sapiens peptide/histidine 2736 94 transporter 1043 gi22831474Drosophila CG14622-PC 2508 47 melanogaster 1043 gi22831475Drosophila CG14622-PB 2508 47 melanogaster 1043 gi29477075Mus musculus Similar to dishevelled2521 93 associated activator of morphogenesis 1 1044 gi15929979Homo Sapiens AAH15418 Similar 2476 100 to zinc fin er protein 345 1044 gi33417243Mus musculus B230312I18Rik protein1788 57 1044 gi5080758Homo Sapiens AC007842 3 BC331191_11922 52 1045 gi12655913Homo Sapiens AF227516 1 sprouty-4A386 98 1045 gi12655915Homo Sapiens AF227517 1 sprouty-4C386 98 1045 gi29747900Mus musculus Sprouty homolog 320 81 1046 gi29692498Mus musculus NAAG-peptidase II 3447 88 1046 gi3211746Sus scrofa folylpoly-gamma-glutamate2819 70 carboxypeptidase 1046 gi4539525Homo Sapiens NAALADase II protein3881 100 1047 gi21750009Homo Sapiens unnamed protein 1414 99 product 1047 gi23512248Homo Sapiens Similar to DISC~ 676 53 Interacting Protein 2 1047 gi26449269Maraca fasciculariShypothetical protein1421 99 1048 15918167Homo Sapiens plexin-B1/SEP receptor3578 42 1048 16651051Mus musculus AF133093 2 plexin 3147 40 1048 19885259Homo Sapiens AF149019 1 plexin-B33140 40 1049 gi15081392Homo Sapiens AF395817 1 NAC1 1268 55 protein 1049 gi30931339Musmusculus Nacl-pending protein1254 57 1049 gi33392751Homo Sapiens NAC1 protein 1268 55 1050 gi11692802Homo Sapiens AF320294_l ABCG8 3123 99 1050 ' 15088540Homo Sapiens AF324494 1 sterolin-23127 99 1050 115146444Homo Sapiens AF351824~ 1 sterolin-23117 99 1051 gi12652851Homo Sapiens AAH00178 potassium 1987 100 channel modulatory factor 1051 gi26453336Homo Sapiens FIGC1 1983 99 1051 gi7677058Homo Sapiens AF155652_1 potassium1983 99 channel modulatory factor 1052 gi33395Homo Sapiens 703 70 1052 gi33730Homo Sapiens immunoglobulin lambda716 71 light chain 1052 gi33734Homo Sapiens immunoglobulin lambda716 71 light chain 1053 gi21388773Homo Sapiens kringle-containing 1764 80 protein 1053 gi21388775Homo Sapiens kringle-containing 1453 78 protein 1053 gi21623530Homo Sapiens kringle-containing 1458 68 transmembrane protein 1054 gi14495324Homo Sapiens CMRF35A 432 48 1054 gi18490143Homo Sapiens CM12F35 leukocyte 432 48 immunoglobulin-like receptor 1054 gi396170Homo Sapiens CMRF-35 antigen 432 48 1055 gi4468255Homo Sapiens MHC class I antigen1925 98 1055 gi4468256Homo Sapiens MHC class I antigen1974 100 1055 gi487909Homo Sapiens HLA-Al l antigen 1914 97 Al 1.1 1056 gi21667214Homo Sapiens AF465767 1 741 100 ~ ~

SEQ Hit Species Description S Percentage_ ID ID _ I scoredenti bactericidal/permeability-increasing protein-like 1056 gi32490539Homo Sapiens RY2G5 171 32 1056 gi57732Rattus rattuspotential ligand-binding210 35 protein 1057 gi21667214Homo Sapiens AF465767_1 2223 99 bactericidal/permeability-increasing protein-like 1057 132490539Homo Sapiens RY2G5 524 31 1057 gi57732Rattus rattuspotential ligand-binding564 32 protein 1058 gi21667214Homo Sapiens AF465767_1 1916 99 bactericidal/permeability-increasing protein-like 1058 gi32490539Homo Sapiens RY2G5 434 31 1058 gi57732Rattus rattuspotential ligand-binding473 33 protein 1059 gi21667214Homo Sapiens AF465767_1 1842 100 bactericidal/permeability-increasing protein-like 1059 gi32490539Homo Sapiens RY2G5 434 31 1059 gi57732Rattus rattuspotential ligand-binding473 33 protein 1060 gi13529158Homo Sapiens AAH05349 1128 99 1060 i529514~Sus scrofa neuronal endocrine 1092 95 protein 1060 17718079Homo Sapiens neuroendocrine protein1148 100 1061 gi15929030Homo Sapiens AAH14973 2325 100 1061 gi16551493Homo Sapiens unnamed protein 2321 99 product 1061 gi18698601Homo Sapiens AF467443_1 Smith-Magenis2325 100 syndrome chromosome region candidate 7 protein 1062 gi13543081Mus musculus claudin 6 822 70 1062 gi4128041Homo sapienS claudin-9 protein 1116 100 1062 gi4325296Mus muSCUlus olaudin-9 1078 95 1063 gi 121574.2Homo Sapiens HIP 434 65 1063 gi14286258Homo Sapiens AAH08926 ribosomal 434 65 protein 1063 gi793843Homo Sapiens ribosomal protein 434 65 1064 gi4587895Rattus norvegicusAF072509_1 glutamate3549 86 receptor interacting protein 2 1064 gi4731287Rattus norvegicusglutamate receptor 3281 81 interacting protein 2 1064 gi6601555Rattus norvegicusglutamate receptor 3549 86 interacting protein 2 1065 gi23496442Rattus norvegicusdisabled-1 2807 96 1065 gi3288852Homo Sapiens disabled-1 2865 99 1065 gi8118615Homo Sapiens AF263547_1 disabled-12842 99 1066 gi16877456Homo Sapiens AAH16974 1711 100 1066 gi20810324Homo Sapiens 1410 86 1066 gi26351033Mus musculus unnamed protein 1236 76 product 1067 gi15430703Homo Sapiens AF362953_1 testis 1858 99 specific serine/threonine kinase 2 1067 gi2738898Mus musculus protein kinase 1683 89 1067 gi33590489Rattus norvegicusserine/threonine 1754 92 kinase 22B

SEQ Hit ID Species Description S scorePercentage_ ID Identi 1068 gi12963879Homo Sapiensprostaglandin D 980 96 synthase 1068 gi13543568Homo SapiensPTGDS protein 980 96 1068 gi189772Homo Sapiensprostaglandin D2 980 96 synthase 1069 gi14336718Homo sapiensAE006464_18 similar1157 100 to HAGH

1069 gi20988885Mus musculus2810014I23Rik protein1153 79 1069 gi2459803Rattus norvegicusRSP29 645 48 1070 gi13397835Homo Sapiensannexin A13 isoform1795 99 b 1070 gi21218387Oryctolagus AF510726_1 annexin 1589 88 cuniculus XIIIb 1070 gi757784Canis familiarisannexin XIIIb 1621 89 1071 gi204222Rattus norvegicusGABA transporter 3094 96 protein 1071 gi21707908Homo Sapiens, member 1 3126 98 1071 gi31658 Homo SapiensGABA transporter 3111 98 1072 gi14165176Rattus norvegicusAF378093_1 sodium 823 98 channel beta 3 subunit 1072 gi7160975Homo Sapiensvoltage-gated sodium834 100 channel beta-3 subunit 1072 gi7161889Rattus norvegicusvoltage-gated sodium823 98 channel beta-3 subunit 1073 gi20381266Homo SapiensGlypican 2 3040 100 1073 gi440127Rattus norvegicuscerebroglycan 2506 82 1073 gi5911320Mus musculusAF105268_1 glypican-61164 44 1074 gi18676470Homo SapiensFLJ00132 protein 2515 99 1074 gi19344068Mus musculus2700038E08Rik protein3407 77 1074 gi23274106Mus musculus2700038E08Rik protein3407 77 1075 gi25396387Homo Sapiensalpha 2,6-sialyltransferase_ 100 1075 gi27650880Homo Sapiensbeta-galactoside 1183 100 alpha-2,6-sialyltransferase 1075 gi452751Gallus gallusGal beta 1,4 GIcNAc943 54 alpha 2,6-sialyltransferase 1076 gi13344995Homo SapiensCat Eye Syndrome 2002 99 critical region protein isoforna 1076 gi 13344997Homo SapiensCat Eye Syndrome 2223 100 critical region protein isoform 1076 gi27503696Homo SapiensSimilar to cat eye 2223 100 syndrome chromosome region, candidate 1077 gi13344995Homo SapiensCat Eye Syndrome 1662 96 critical region protein isoform 1077 gi13344997Homo SapiensCat Eye Syndrome 1662 96 critical region protein isoform 1077 gi27503696Homo SapiensSimilar to cat eye 1662 96 syndrome chromosome region, candidate 1078 gi177870Homo Sapiensalpha-2-macroglobulin2718 39 precursor 1078 '25303946Homo Sapiensalpha-2-macro lobulin2718 39 1078 1579592 Homo Sapiensal ha 2-macroglobulin2712 39 1079 gi25303946Homo Sapiensalpha-2-macroglobulin1290 35 1079 gi579592Homo Sapiensalpha 2-macroglobulin1290 35 1079 gi579594Homo Sapiensalpha 2-macroglobulin_ 36 1080 gi25303946Homo Sapiensalpha-2-macroglobulin761 31 ~ 1080gi671864Gallus gallusovomacroglobulin, _ 32 ~ ~ ~ ovostatin ~ 792 ~

SEQ Hit ID Species Description S Percentage_ ID I scoredenti 1080 gi671865Gallus gallusovomacroglobulin, 792 32 ovostatin 1081 gi177870Homo sapiensalpha-2-macroglobulin2736 39 precursor 1081 gi25303946Homo Sapiensalpha-2-macroglobulin2736 39 1081 gi579592Homo sapiensalpha 2-macroglobulin2730 39 1082 gi25303946Homo Sapiensalpha-2-macroglobulin1290 35 1082 gi579592Homo Sapiensalpha 2-macroglobulin1290 35 1082 gi579594Homo Sapiensalpha 2-macroglobulin1291 36 1083 gi17512361Mus musculusesterase 31 2029 66 1083 '29476863Mus musculusSimilar to esterase2022 66 1083 '404389 Mus sp. carboxylesterase; 2001 66 Es-male 1084 gi207286Rattus norvegicusTGF-beta masking 8721 89 protein large subunit 1084 gi26006334Mus musculuslatent transforming8630 88 growth factor beta binding protein 1L

1084 gi3493176Mus musculuslatent TGF beta 8627 88 binding protein 1085 117985371Homo SapiensI3 binding protein 861 100 1085 gi18466808Homo SapiensAF283671_1 cervical853 99 cancer 1 proto-oncogene-binding protein I~G19 1085 gi21961229Homo SapiensBRI3 binding protein861 100 1086 gi222833Gallus gallusM-protein 2924 42 1086 i295034~7Mus musculusM-protein 2908 42 1086 gi407097Homo Sapiens165kD protein 2912 42 1087 gi12655165Homo sapiensAAH01438 zinc finger693 65 protein 1087 gi30582545Homo Sapienszinc finger protein693 65 1087 gi4894364Homo Sapiens1~F067165_1 zinc 693 65 finger protein 3 1088 gi1613848Homo Sapienszinc finger protein311 49 zfp6 1088 130582545Homo Sapienszinc finger protein309 56 1088 gi4894364Homo SapiensAF067165_1 zinc 309 56 finger protein 3 1089 112655452Homo Sapienslematin associated 981 76 protein 4.7 1089 gi 12655460Homo Sapienskeratin asSOCiated 970 77 protein 4.12 1089 112655464Homo sapienskeratin associated 973 81 protein 4.15 1090 gi12655446Homo sapienskeratin associated 400 69 protein 4.4 1090 112655452Homo Sapienskeratin associated 383 81 protein 4.7 1090 gi12655460Homo Sapienskeratin associated 400 61 protein 4.12 1091 gi12655452Homo Sapienskeratin associated 1219 90 protein 4.7 1091 gi12655460Homo Sapienskeratin associated 1158 88 protein 4.12 1091 gi 12655464Homo Sapienskeratin associated 1260 100 protein 4.15 1092 gi15722084Homo Sapiens 1991 100 1092 gi434306Homo Sapienslysosomal acid lipase;1289 63 sterol esterase 1092 '506431 Homo sapienslysosomal acid lipase1289 63 1093 115722084Homo Sapiens 1935 100 1093 gi434306Homo Sapienslysosomal acid lipase;1289 63 sterol esterase 1093 gi506431Homo Sapienslysosomal acid lipase1289 63 1094 gi20152322Homo sapiensputative G-protein 1558 99 coupled receptor 1094 gi32526601Homo SapiensGPRCSD 1558 99 1094 gi8118040Homo Sapiens~ AF209923 1 orphan~ ~ 99 G-protein 1804 SEQ Hit_ID Species Description S scorePercentage_ ID I denti coupled receptor 1095 gi15099951Mus musculusAF384160_1 diacylglycerol596 49 acyltransferase 1095 gi18129609Homo SapiensAF384161_1 diacylglycerol597 49 acyltransferase 1095 gi27693972Mus musculusdiacylglycerol O- 596 49 acyltransferase 1096 gi17224598Homo SapiensAF293615_1 blood 1134 95 dendritic cell antigen 2 protein _1096 gi17225337Homo SapiensAF325459_1 dendritic1134 95 lectin 1096 gi17225339Homo SapiensAF325460_1 dendritic930 80 lectin b isoform 1097 gi17224598Homo SapiensAF293615_1 blood 1182 99 dendritic cell antigen 2 protein 1097 117225337Homo SapiensAF325459_1 dendritic1182 99 lectin 1097 gi17225339Homo SapiensAF325460_1 dendritic978 84 lectin b isoform 1098 gi18479834Mus musculusolfactory receptor 1220 77 1098 gi21929119Homo Sapiensseven transmembrane1595 100 helix receptor 1098 gi32063297Mus musculusolfactory receptor 1220 77 GA_x6K02T2PVTD-1099 gi19526645Homo SapiensAF430017_1 intestinal775 33 membrane mucin MUC17 1099 gi5911169Homo SapiensAF147790_1 transmembrane3049 99 mucin 12 1099 gi5911171Homo SapiensAF147791_1 mucin 671 54 1100 gi219497Homo sapiensbiliary glycoprotein446 34 1100 gi3172151Homo SapiensBGP _HUMAN 446 34 1100 gi37198 Homo SapiensTM1-CEA preprotein 446 34 1101 gi1504040Homo Sapiens 4709 60 1101 gi6273399Homo SapiensAF200348_1 melanoma-4709 60 associated antigen 1101 gi7292259DroSOphila CCa12002-PA 2660 38 melanogaster 1102 gi1504040Homo sapiens 4596 59 1102 gi6273399Homo sapiensAF200348_1 melanoma-4596 59 associated antigen 1102 gi7292259Drosophila CG12002-PA 2606 38 melanogaster 1103 ' 10435776Homo Sapiensunnamed protein 4413 99 product 1103 '11611734Homo SapiensAF245388_1 GREBla 510 46 1103 17264653Mus musculusAF180470 1 I~iaa05753121 53 1104 gi16519041Drosophila AF427496_1 occludin-like184 23 melanogasterprotein 1104 gi20219008ChlamydomonasAF394181_1 coiled-coil673 36 reinhardtii flagellar protein 1104 gi7301551Drosophila CG6059-PA 169 19 melanogaster 1105 gi 12654511Homo SapiensTorsin family 3, 693 96 member A

1105 gi 14043167Homo SapiensTorsin family 3, 693 96 member A

1105 gi 15079904Homo SapiensTorsin family 3, 693 96 member A

1106 gi21666374Mus musculusswan 325 72 ~ 1106gi21666376Mus musculusswan 325 72 ~ ~

SEQ Hit ID Species Description S scorePercentage-ID Identi 1106 gi29747798Mus musculus3000004N20Rik protein704 86 1107 gi15076843Homo SapiensAF233450_1 pecanex-like2759 68 protein 1 1107 118157547Mus musculusAF237953_1 pecanex-like4201 93 1107 16650377Mus musculusAF096286_1 pecanex 2767 67 1108 gi15076843Homo SapiensAF233450_1 pecanex-like2402 73 protein 1 1108 '18157547Mus musculusAF237953 1 pecanex-like3138 97 1108 16650377Mus musculusAF096286 1 pecanex 2406 73 1109 gi21595759Homo Sapienssimilar to HC6 211 71 1109 gi7020440Homo Sapiensunnamed protein 215 57 product 1109 gi7770237Homo SapiensAF119917_62 PR02822232 61 1110 gi26333913Mus musculusunnamed protein 749 83 product 1110 '26343633Mus musculusunnamed protein 749 83 product 1110 gi27370621Homo sapiensSimilar to hypothetical828 95 protein 1111 gi12043567Homo sapiensunc-93 related protein1571 99 1111 gi17390915Mus musculusunc93 homolo B 1367 87 1111 gi23271746Mus musculusUnc93b protein 1367 87 1112 gi15990461Homo SapiensAAH15612 ring finger2465 100 ' protein 1112 gi18490513Mus musculusRnf25 protein 1983 82 1112 gi29179411Mus musculusRing finger protein1988 82 1113 gi19716048Xenopus laevisWeelB kinase 1123 45 1113 gi2827996Xenopus laevisweel homolog 1291 51 1113 gi644770Xenopus laevisVVeelA kinase 1296 51 1115 gi15030119Mus musculus3110057O12Rik protein777 97 1115 gi23093574.Drosophila CG32112-PA 366 42 melanogaster 1115 gi23093575Drosophila CG32112-PB 397 47 melanogaster 1116 gi114.93409Homo sapiensAF130117 10 PR00898129 59 1116 gi21708029Homo Sapienssimilar to Alu subfamily135 70 S(~l sequence contamination warning entry 1116 gi28800991Homo Sapiensunnamed protein 124 67 product 1117 gi13810898Rattus norvegicusAF322216_1 inhibin 515 32 binding protein long isoform 1117 gi2370143Homo Sapiensimmunoglobulin-like503 32 domain-containin 1 1117 gi2645890Homo sapiensIGSF1 503 32 1118 gi2370143Homo Sapiensimmunoglobulin-like307 38 domain-containin 1 1118 gi32330685Mus musculusinhibin binding 310 38 protein/p120 long isoform 1118 gi32330691Mus musculusinhibin binding 310 38 protein/p120 variant 4 1119 gi21595190Mus musculus2510001A17Rile protein4878 95 1119 gi21707128Homo sapiensRan binding protein5047 99 1119 gi6650612Homo SapiensAF111109_1 Ran binding5047 99 protein 11 1120 11399805Homo SapiensBbp/53BP2 2078 46 1120 116197705Homo SapiensASPP2 protein 2439 47 1120 gi18652832Homo Sapiens~ ASPP1 protein ~ 5703~ 99 SEQ Hit ID Species Description S Percentage_ ID score I denti 1122 gi2598461Homo Sapiens 1893 97 1122 gi31418316Homo SapiensHeat shock 70kD 1893 97 protein binding protein 1122 gi4049268Homo sapiensputative tumor suppressor1893 97 1123 gi11991844Homo SapiensAF243505_1 fibrocyte-derived676 100 protein 1123 gi 12619173Homo Sapiensmelanoma inhibitory676 100 activity like protein 1123 gi 12668328Homo Sapiensmelanoma inhibitory676 100 activity like protein 1124 gi22760096Homo Sapiensunnamed protein 1047 89 product 1124 gi27883913Homo SapiensPOTE 525 46 1124 gi28279813Homo SapiensSimilar to hypothetical743 85 protein DKFZp434A 171 1125 gi11990779Homo Sapiens 548 43 1125 gi22760096Homo Sapiensunnamed protein 831 87 product 1125 gi28279813Homo SapiensSimilar to hypothetical743 85 protein DKFZp434A 171 1126 gi11493483Homo SapiensAF130117_48 PRO2550265 67 1126 gi1872200Homo Sapiensalternatively spliced259 66 product using exon 13A

1126 gi7770139Homo sapiensAF119917 13 PRO1722266 60 1128 gi16588454Homo sapiensAF312374 1 A(~TRAP 708 95 protein 1128 gi16878260Homosapiens AAH17328 Similar 726 100 to angiotensin II, type I receptor-associated protein 1128 gi9621816Homo sapiensAF165187 1 ATRAP 708 95 1129 gi12330704Mus musculusAF333770_l cell 1376 71 recognition molecule CASPR4 1129 gi17986216Homo SapiensAF333769_1 cell 1864 98 recognition molecule CASPR3 1129 121961652Mus musculuscontactin associated1376 71 protein 4 1130 gi17986216Homo SapiensAF333769_1 cell 6812 99 recognition molecule CASPR3 1130 gi18390059Homo sapiensAF463518_1 cell 4738 70 recognition protein CASPR4 1130 gi21961652Mus musculuscontactin associated4709 68 protein 4 1131 gi10336504Homo SapiensUDP-CaalNAc: polypeptide2014 61 N-acetylgalactosaminyltransferase 1131 gi21552746Homo SapiensAF410457_1 putative3157 99 polypeptide N-acetyl alactosaminyltransferase 1131 gi21552969Mus musculusAF467979_1 Williams-Beuren3098 97 syndrome critical region gene 1132 gi13625176Homo SapiensAF251057_1 thrombospondin575 46 1132 gi18490857Homo SapiensThrombospondin 575 46 1132 gi31127148Mus musculus2610028F08Rik protein860 96 1133 gi11907599Homo SapiensAF208291_1 protein 857 50 kinase HIPI~2 1133 gi5305331Mus musculusAF071070_1 protein 856 49 kinase Myak-L

1133 gi5815145Mus musculusAF170304_1 nuclear 856 49 body associated kinase 2b SEQ Hit_ID Species Description S scorePercentage-ID ' Identi 1134 gi22267965Homo SapiensSimilar to KIAA14233 100 protein 22 1134 gi7243227Homo SapiensHIAA1423 protein _ 100 1134 gi7300805Drosophila CG13409-PA _ 51 melanogaster 171 1135 ' 13529338Mus musculus 1862 48 1135 gi14571502Homo Sapienscalcium-promoted 4174 99 Ras inactivator 1135 14185294Homo SapiensrasGAP-activating-like1891 48 protein 1137 115128103Mus musculusAF397007 1 nephronectin2962 87 1137 gi15128105Mus musculusAF397008 1 nephronectin2934 85 1137 gi15430246Mus musculusnephronectin short 2802 83 isoform 1138 gi16041675Homo SapiensAAH15704 joined 2622 100 to JAZF1 1138 gi17862954Drosophila SD04959p 904 42 melanogaster 1138 gi30046920Mus musculusDllErtd530e protein1941 96 1139 gi12654929Homo SapiensAAH01311 mesenchymal719 74 stem cell protein DSCD75 1139 gi17512251Homo SapiensAAH19104 mesenchymal716 74 stem cell protein DSCD75 1139 gi7638247Homo SapiensAF242773_1 mesenchymal719 74 stem cell protein 1140 gi32967231Homo sapiensTAFA3 481 100 1140 gi32967237Homo SapiensTAFA3.2 923 100 1140 gi32967243Mus musculusTAFA3 390 82 1141 gi32967231Homo sapiensTAFA3 738 100 1141 gi32967237Homo SapiensTAFA3.2 481 100 1141 132967243Mus musculusTAFA3 634 87 1142 '10443967Homosapiens AF268610_1 THEGprotein1934 88 1142 gi20306274Homo sapienstesticular haploid 1934 88 expressed gene 1142 gi7416134Homo Sapienstestis-specific 1934 88 gene 1143 gi21928259Homo Sapiensseven transmembrane1023 100 helix receptor 1143 gi219284.96Homo Sapiensseven transmembrane1023 100 helix receptor 1143 gi21928655Homo Sapiensseven transmembrane916 89 helix receptor 1144 gi18480746Mus musculusolfactory receptor 1278 79 1144 gi21928655Homo Sapiensseven transmembrane1456 93 helix receptor 1144 gi32052225Mus musculusolfactory receptor 1278 79 GA_x6IC02T2P3E9-4341246-1146 gi15779092Homo sapiensAAH14613 Similar 1295 100 to syntaxin 1146 130583139Homo Sapienssyntaxin 18 1295 100 1146 gi30585223synthetic Homo Sapiens syntaxin1295 100 construct 18 1147 gi14573319Homo SapiensAF334755_1 interleukin-1812 99 1147 gi14573321Homo SapiensAF334756_1 interleukin-1812 99 1147 gi18025344Homo Sapiensinterleukin-1 receptor809 99 anta onist-like FILL theta 1148 gi 1668744Homo SapiensHHaS hair keratin 1114 72 type I

TART.F 7 R
SEQ Hit Species Description S scorePercentage_ ID ID

I denti intermediate filament 1148 gi3724107Homo sapiens type I hair keratin1114 72 1148 gi4103158Mus musculus hair keratin acidic1116 72 5; Ha5 keratin 1149 gi23271416Mus musculus Leprel protein 141 30 1149 gi30582917Homo Sapiens 1 139 30 1149 gi6166378Mus musculus AF165163_1 growth 143 30 suppressor 1L

1150 gi16550754Homosapiens unnamed protein 1337 90 roduct 1150 gi1699265Homo Sapiens malignant cell 389 57 expression-enhanced gene/tumor pro ession-enhanced ene 1150 gi27529955Mus musculus mBB 1 1284 86 1151 gi 14595019Homo Sapiens keratin 6 irs 1990 76 1151 gi18031724Mus musculus keratin protein 1948 75 I~6irs 1151 gi27901522Homo Sapiens keratin 6 irs3 2519 94 1152 gi11066090Homo Sapiens AF195192_1 matrix 2233 84 metalloprotease 1152 gi12006364Tupaia belangeriAF281673_1 matrix 1859 71 metalloproteinase-27 1152 gi3511149Gallus gallusmatrix metalloproteinase1213 50 1153 gi11066090Homo Sapiens AF195192_1 matrix 2233 84 metalloprotease 1153 gi12006364Tupaia belangeriAF281673_I matrix 1859 71 metalloproteinase-27 1153 gi3511149Gallus gallusmatrix metalloproteinase1213 50 1154 gi24710913Homo Sapiens suppressor of fused2599 100 1154 gi5739507Homo Sapiens AF175770_1 suppressor2594 99 of fused 1154 gi6689894Homo Sapiens AF159447_1 Suppressor2599 100 of Fused 1155 gi20387085~ncorhynchus -1 680 31 mykiss 1155 gi21667212Homo Sapiens AF465766_I 2600 100 bactericidal/permeability-increasing protein-like 1155 gi28173296Cyprinus carpiobactericidal permeability-702 31 increasing protein/lipopolysaccharide-binding protein 1156 gi12082687Homo Sapiens Sry-related HMG-box2066 100 protein 1156 gi24047297Homo Sapiens SRY-box 18 2066 100 1156 gi8894593Homo Sapiens S~318 protein 2066 100 1157 gi19526647Homo Sapiens AF462348_1 oxidored-nitro842 92 domain-containing protein 1157 gi21758574Homo Sapiens unnamed protein 922 97 product 1157 gi7303522Drosophila CG13178-PA 173 32 melanogaster 1158 gi19526647Homo Sapiens AF462348_1 oxidored-nitro842 92 domain-containing protein 1158 gi21758574Homo Sapiens unnamed protein 922 97 product 1158 gi7303522Drosophila CG13178-PA 173 32 melanogaster 1159 gi1794221Mus musculus DNA ligase III-beta2977 89 1159 gi1794223Mus musculus DNA li ase III-alpha2977 89 SEQ Hit_ID Species Description S Percentage_ ID I scoredenti 1159 gi29165722Mus musculus ligase III, DNA, 3010 89 ATP-dependent 1160 gi1052871Homo Sapiens squamous cell carcinoma879 45 antigen 2 1160 gi15667919Homo Sapiens AF411191 1 SERPINB122063 95 1160 gi887465Homo sapiens leupin 879 45 1163 gi29611342Homo Sapiens AF425650_1 MBDl- 352 52 containing chromatin associated factor 1163 gi7228149Mus musculus ATFa-associated 357 29 factor _ gi7303705Drosophila CG12340-PA 187 31 1163 melanogaster 1166 gi14211398Homo Sapiens AF380342_1 caspase-8L263 100 1166 gi19401527Homo Sapiens procaspase-8 223 95 1166 gi20381326Homo Sapiens Similar to caspase 263 100 8, apoptosis-related cysteine protease 1167 gi10440448Homo Sapiens FLJ00060 protein 1204 98 1167 gi30466084Bos taurus killer cell immunoglobulin-like800 53 receptor KIR3DS1 1167 gi30466086Bos taurus killer cell immunoglobulin-like783 53 receptor ICIR3DL1 1168 gi1799570Rattus norvegicusTIP120 4573 99 1168 gi29792160Homo Sapiens TIP120 protein 4586 99 1168 gi7688703Homo Sapiens AF157326 1 TIP120 4573 99 protein 1169 gi13016701Homo Sapiens activating coreceptor1226 100 NI~p80 1169 gi22449867Maraca fascicularisNI~p80 NK receptor 1122 90 1169 gi7188567Homo Sapiens AF175206_1 lectin-like1226 100 receptor F1 1171 gi21619190Homo sapiens -like 1X-linked 2785 100 1171 gi3021409Homo Sapiens like 1 protein 3057 100 1171 gi30353941Homo Sapiens TBL1X protein 3057 100 1172 gi1699265Homo sapiens malignant cell expression-671 65 onhane~d gene/tumor progression-enhanced gene 1172 gi27529955Mus musculus mBB 1 646 67 1172 gi33355691Homo Sapiens transmembrane channel-like642 100 protein 4 1173 gi1699265Homo Sapiens malignant cell expression-671 65 enhanced gene/tumor progression-enhanced gene 1173 127529955Mus musculus mBBl 646 67 1173 gi33355691Homo Sapiens transmembrane channel-like642 100 protein 4 1174 gi16550754Homo Sapiens unnamed protein 1881 100 product 1174 gi1699265Homo sapiens malignant cell expression-930 81 enhanced geneltumor pro ession-enhanced ene 1174 gi27529955Mus musculus mBB 1 1810 95 1175 gi13182755Homo Sapiens AF212237 1 HPHRP 1210 100 1175 gi15929309Homo Sapiens Phosphotriesterase 1210 100 related 1175 gi29791939Homo Sapiens phosphotriesterase 1210 100 related 1177 gi10047271Homo sapiens KIAA1598 protein 789 99 1177 gi22539701Mus musculus 4930506M07Rik protein818 96 1177 gi26349641Mus musculus unnamed protein 818 96 product SEQ_IDHit Species Description S_scorePercentage_ ID I denti 1178 gi14272704Homo Sapiens unnamed protein 157 96 product 1178 gi19575509Homo sapiens unnamed protein 164 100 product 1178 gi19575655Homo Sapiens unnamed protein 164 100 product 1182 gi13377880Cricetulus AF336043_1 arginine3253 85 lon icaudatusN-methyltransferase p82 isoform 1182 gi13377882Cricetulus AF336044_1 arginine3253 85 longicaudatusN-methyltransferase p77 isoform 1182 '13879453Mus musculus cDNA sequence BC0067053260 85 1183 gi14424574Homo Sapiens AAH09315 phosphatidylserine777 100 decarboxylase 1183 gi16306618Homo Sapiens AAH01482 phosphatidylserine1218 96 decarboxylase 1183 gi191185Cricetulus phosphatidylserine 1128 88 griseus decarboxylase 1184 gi10086253Homo Sapiens glucocorticoid-induced460 98 GILZ

1184 gi11907580Mus musculus AF201289_1 TSC22-related891 87 inducible leucine zipper 3c 1184 gi5919161Homo Sapiens AF183393_1 TSC-22-like460 98 Protein 1185 113874437Homo Sapiens cerebral protein-111457 68 1185 120987344Mus musculus LOC212904 protein 3064 89 1185 gi24980850Homo Sapiens 3283 100 1186 gi14~035978Homo Sapiens unnamed protein 2577 100 product 1186 gi14~272784Homo Sapiens unnamed protein 2577 100 product 1186 gi16923351Homo sapiens AF204270_1 RbBP-35 1431 99 1187 gi18676660Homo Sapiens FLJ00229 protein 930 97 1187 gi19343701Mus musculus RIKEN cDNA A630054L15913 93 1187 gi25955706Homo Sapiens Similar to hypothetical936 97 protein 1188 gi17865311Homo Sapiens AF452102 1 dipeptidyl4646 100 peptidase-like protein 1188 gi2754~9552Homo Sapiens dipeptidyl peptidase4646 100 IV-related protein-2 1188 129293087Homo Sapiens dipeptidyl peptidase4787 99 1189 gi17865311Homo Sapiens AF452102 1 dipeptidyl4384 95 peptidase-like protein 1189 gi27549552Homo Sapiens dipeptidyl peptidase4384 95 IV-related protein-2 1189 gi29293087Homo Sapiens dipeptidyl peptidase4525 95 1190 gi17865311Homo Sapiens AF452102 1 dipeptidyl4551 98 peptidase-like protein 1190 gi27549552Homo Sapiens dipeptidyl peptidase4551 98 IV-related protein-2 1190 gi29293087Homo Sapiens dipeptidyl peptidase4692 98 1191 113097642Homo Sapiens Ribosomal protein 554 99 1191 113279149Homo Sapiens Ribosomal protein 554 99 1191 gi13436422Homo Sapiens Ribosomal protein 554 99 1192 gi16549206Homo Sapiens unnamed protein 680 100 product 1193 gi21756739Homo Sapiens unnamed protein 4771 97 product 1193 gi6453538Homo Sapiens hypothetical protein4159 99 1193 gi6634025Homo Sapiens KIAA0379 protein 3467 67 1194 gi12652695Homo Sapiens AAH00096 HtrA-like 2116 93 serine protease 1194 gi5870865Homo Sapiens serine protease 2116 93 SEQ Hit Species Description S Percentage_ ID ID I scoredenti 1194 gi7672669Homo Sapiens AF141305_1 serine 2116 93 protease Htra2 1195 gi1387985Homo Sapiens A3 adenosine receptor904 100 1195 120988265Homo Sapiens adenosine A3 receptor904 100 1195 gi22658481Homo Sapiens adenosine receptor 904 100 1196 gi24078514Mus musculus AF454954 1 crossveinless-2988 91 1196 gi32816043Mus musculus BMP-binding endothelial988 91 regulator precursor protein 1196 gi32892146Homo Sapiens crossveinless-2 1085 100 1197 gi18479346Mus musculus olfactory receptor 1334 82 1197 gi 18480772Mus musculus olfactory receptor 1415 84 1197 gi32054443Mus musculus olfactory receptor 1415 84 GA_x6K02T2PBJ9-2443810-1198 gi16502169Salmonella putative DNA methylase751 93 enterica subsp. enterica serovar Typhi 1198 gi29137981Salmonella putative DNA methylase751 93 enterica subsp. enterica serovar Typhi Ty2 1198 gi498768Serratia marcescensDeoxyadenosyl- 330 51 methyltransferase 1199 gi1213589Xenopus laevisProsta landin D 290 33 Synthase 1199 gi16974751Gallus gallusCALM 335 37 1199 gi666121~enopus laeviscpl-1 291 33 1200 gi20987993Mus musculus MGC41336 protein 1212 90 1200 gi22296200Thermosynechococcasparaginyl-tRNA 1046 46 us elongatus synthetase 1200 gi32448516Pirellula asparaginyl-tRNA 1034 47 sp. synthetase 1201 gi20067381Homo Sapiens ALMS1 protein 242 41 1201 gi21552774Mus musculus AF425257_1 Almstrom217 38 syndrome 1 protein 1201 gi32693320Homo sapiens ALMS 1 protein 242 41 1202 gi12655061Homo Sapiens AAH01380 495 92 1202 gi23574788Maraca fascicularissuccinate dehydrogenase502 93 flavoprotein subunit 1202 gi5759173Homo Sapiens succinate dehydrogenase495 92 flavoprotein subunit 1203 gi21928186Mus musculus GPI-gamma 4; GPIgamma41466 61 1203 gi21928188Mus musculus GPI- amma 4; GPI 1466 61 amma4 1203 gi30931171Mus musculus GPI amma4 protein 1466 61 1204 gi15082311Homo Sapiens AAH12061 -binding 1534 92 protein 3 1204. gi9957161Mus musculus AF176327_l alphaCP-31708 99 1204 gi9957165Homo Sapiens AF176329_1 alphaCP-31722 100 1205 gi 14574118CaenorhabditisDumpy : shorter 233 31 ele ans than wild-type protein 19 1205 gi16553246Homo Sapiens unnamed protein 881 99 product 1205 gi21739662Homo Sapiens hypothetical protein830 95 1206 112653341Homo Sapiens AAH00439 beta 1742 94 1206 gi12804943Homo Sapiens AAH01924 beta 1742 94 1206 gi31071Homo Sapiens E-1 beta subunit 1742 94 of the pyruvate dehydrogenase complex 1207 gi164851Oryctolagus calsequestrinprecursor1908 94 ~ ~

SEQ Hit Species Description S Percentage_ ID ID I scoredenti cuniculus 1207 '2618621Mus musculus skeletal muscle 1938 94 calsequestrin 1207 gi688292Homo Sapiens calmitine; calsequestrine2029 100 1209 gi10432376Homo Sapiens 3334 99 1209 111034760Homo Sapiens NIBAN 3692 99 1209 '12620192Homo Sapiens AF288391 1 Clorf24 4775 99 1210 gi2982508Homo Sapiens TCR beta chain 1290 93 1210 gi3002925Homo Sapiens T cell receptor 1277 93 beta chain 1210 gi3089433Homo Sapiens T cell receptor 1028 75 beta chain 1211 gi12006041Homo Sapiens AF267857_1 AD038 761 98 1211 gi14189960Homo Sapiens AF305818_1 PR00764 141 53 1211 gi33338042Homo Sapiens AF173896_1 MSTP121 143 46 1213 gi17939498Homo Sapiens AAH19299 protocadherin4777 99 gamma subfamily C, 3 1213 gi20072790Homo sapiens protocadherin gamma4777 99 subfamily C, 3 1213 gi2995719Homo sapiens protocadherin 43 4792 100 1214 gi12803363Homo sapiens CALR protein 1747 99 1214 gi18088117Homo Sapiens AAH20493 calreticulin1747 99 1214 gi30583735Homo sapiens calreticulin 1747 99 1215 gi200962Mus musculus serine 1 ultra high254 38 sulfur protein 1215 gi200964Mus musculus serine 2 ultra high299 43 ' sulfur protein 1215 gi3228237Homo sapiens ultra hi h sulfer 248 36 keratin 1218 gi17223709Homo Sapiens selenoprotein SeIM 235 100 1218 gi17223711Mus musculus selenoprotein SeIM 188 78 1218 gi26351995Mus musculus unnamed protein 162 76 product 1221 gi1001963Homo Sapiens osteopontin 1400 90 1221 gi189151Homo Sapiens nephropontin precursor1400 90 1221 gi992950Homo Sapiens OPN-c 1426 98 1222 gi14326586Homo Sapiens AF386078 1 serine-cysteine2252 95 proteinase inhibitor Glade C
member 1 1222 1179130Homo Sapiens antithrombin III 2252 95 1222 gi583741synthetic Antithrombin III 2252 95 construct 1223 gi18088363Homo Sapiens AAH20669 advanced 2004 99 glycosylation end product-specific receptor 1223 gi1841550Homo Sapiens AAB47491 receptor 2004 99 for advanced glycosylation end products 1223 gi561659Homo Sapiens receptor of advanced2004 99 glycosylation end products of proteins 1224 gi13359193Homo Sapiens KIAA1660 protein 598 100 1225 gi37231Homo Sapiens DNA topoisomerase 8061 99 II

1225 gi3869382Homo Sapiens DNA topoisomerase 8048 99 II beta 1225 gi790988Cricetulus 7886 97 longicaudatus 1226 gi1881713Rattus norvegicusfatty acid transport3039 87 protein 1226 '20810561Mus musculus , member 1 3031 87 1226 gi563829Mus musculus fatty acid transport3031 87 protein 1227 gi15080010Homo Sapiens AAH11789 Similar 503 44 to COPS

SEQ Hit Species Description S Percentage-ID ID score Identi complex subunit 7a 1227 gi15215085Mus musculus Cops7b protein 885 71 1227 gi3309176Mus musculus COP9 complex subunit888 71 7b 1228 gi180251Homo Sapiens precerebellin 544 58 1228 16942096Mus musculus CBLN3 938 93 1228 16942098Mus musculus AF218380 1 CBLN3 938 93 1229 gi15620819Homo Sapiens I~IAA1880 protein 2851 99 1229 gi17861952Drosophila LD01947p 1382 50 melanogaster 1229 gi7291183Drosophila CG1826-PA 1382 50 melanogaster 1230 gi21756739Homo Sapiens unnamed protein 2878 58 product 1230 gi26354957Mus musculus unnamed protein 5453 95 product 1230 gi6634025Homo sapiens HIAA0379 protein 3166 57 1231 gi20387085Oncorhynchus -1 662 31 mykiss 1231 gi21667212Homo Sapiens AF465766_1 2384 98 bactericidal/permeability-increasing protein-like 1231 gi28173296Cyprinus carpiobactericidal permeability-680 31 increasing protein/lipopolysaccharide-binding protein 1232 gi20387085Oncorhynchus -1 654 31 mykiss 1232 gi21667212Homo sapiens AF465766_1 2389 99 bactericidal/permeability-increasing protein-like 1232 gi28173296Cyprinus carpiobactericidal permeability-672 30 increasing protein/lipopolysaccharide-binding protein 1233 gi20387085Oncorhynchus -1 688 31 mykiss 1233 gi21667212Homo Sapiens AF465766_1 2595 99 bactericidal/permeability-increasing protein-like 1233 gi28173296Cyprinus carpiobactericidal permeability-710 31 increasing protein/lipopolysaccharide-binding protein 1234 gi18257341Mus musculus Expressed sequence 2106 69 1234 gi2191168Arabidopsis contains similarity207 26 thaliana to myosin hea chain 1234 gi2879804SchizosaccharomyceSPAC23A1.16c 163 28 s pombe 1235 gi11493528Homo Sapiens AF130117 71 PR01953671 100 1236 gi21754036Homo Sapiens unnamed protein 998 99 product 1236 gi30411057Mus musculus RIKEN cDNA B230219D22954 93 1236 131565787Homo Sapiens FLJ37562 protein 1002 100 1237 gi27469556Homo Sapiens Putative neuronal 3516 99 cell adhesion molecule 1237 gi3068592Mus musculus punc 2976 86 1237 '4206390Homo Sapiens putative neuronal 1569 98 cell adhesion SEQ Hit_ID Species Description S_scorePercentage_ ID I denti molecule 1238 gi12667401Homo SapiensAF326731_l NUF2R 2347 99 1238 gi14317902Homo Sapienskinetochore protein2347 99 Nuf2 1238 gi18043223Mus musculusNUF2R protein 1754 73 1239 gi10435493Homo Sapiensunnamed protein 2702 99 product 1239 gi7022901Homo Sapiensunnamed protein 3682 99 product 1239 gi7688176Homo Sapienshypothetical protein3688 99 1240 gi21634823Homo SapiensAF389428_1 semaphorin5142 91 isoform 3 1240 gi21634825Homo SapiensAF389429_1 semaphorin5667 98 isoform 4 1240 gi21634827Homo SapiensAF389430_1 semaphorin3112 63 isoform 1 1241 gi14036200Homo Sapiensunnamed protein 245 97 product 1243 gi21671105Homo SapiensRAD52B 1134 100 1243 gi23468352Homo SapiensSimilar to RAD52B 963 99 1243 gi32967621Mus musculus2410008M22Rik protein828 74 1244 gi15928404Mus musculusFasting-inducible 185 36 integral membrane protein 1244 gi18490578Mus musculusA630041N19 protein 449 71 1244 gi20379926Mus musculusFasting-inducible 185 36 integral membrane protein 1245 118490578Mus musculusA630041N19 protein 875 70 1245 gi29792229Homo sapiensFLJ90024 protein _ 33 ____ 1245 gi6013381Rattus norvegicusAF186469_1 TM6P1 296 33 1246 gi28626251Homo Sapienscalcium-permeable 1194 100 store-operated channel TRPM3c 1246 gi28626253Homo Sapienscalcium-permeable 1194 100 store-operated channel TRPM3d 1246 gi28626255Homo Sapienscalcium-permeable 1194 100 store-operated channel TRPM3e 1247 gi17386053Mus musculusAF444274_1 Jedi 2269 50 protein 1247 gi 18044=366Homo SapiensAAH20198 Similar 3468 99 to MEGF10 protein 1247 gi18252658Mus musculusAF461685 1 Jedi-7362269 50 protein 1248 120987880Musmusculus E130103I17Rikprotein3580 87 1248 gi28204917Mus musculusE130103I17Rik protein3801 86 1248 gi4588087Homo sapiensAF095771-1 PTH-responsive4080 94 osteosarcoma B 1 protein 1249 gi13591434Homo Sapiens 1160 100 1249 gi13591435Homo sapiens 976 99 1249 gi19913471Homo Sapiens 1265 99 1250 gi16605581Homo SapiensH-rev107-like protein_ 100 1250 gi21707989Homo SapiensSimilar to H-rev107-like1382 96 protein 5 1250 gi6048565Homo SapiensAF092922_1 retinoid376 54 inducible gene 1 1251 gi21263094Rattus norveAF512430 1 tramdorin1665 81 icus 1 1251 127924388Mus musculusTramdorin 1 1668 82 1251 gi31871293Homo Sapiensprotonlamino acid 2010 99 transporter 2 1252 gi14571904Rattus norvegicusAF361239_1 lysosomal1931 78 amino acid transporter 1252 gi31324239Homo Sapiensproton-coupled amino2174 90 acid transporter SEQ Hit ID Species Description S Percentage_ ID score I denti 1252 '31871291Homo Sapiens_ 2195 90 proton/amino acid transporter 1 1254 gi1563885Homo Sapiensfibroblast growth 917 90 factor homologous factor 1254 gi1669500Mus musculusfibroblast growth 917 90 factor homologous factor 1254 gi20988932Mus musculusFgfl2 protein 916 98 1255 gi19263005Ciona intestinalisleucine-rich repeat759 75 dynein light chain 1255 gi2760161Anthocidarisouter arm dynein 658 67 light chain 2 crassispina 1255 gi7303901Drosophila CG8800-PA 554 58 melanogaster 1256 gi12666529Mus musculusb,b-carotene-9',10'-2356 80 dioxygenase 1256 gi12666531Homo Sapiensputative b,b-carotene-9',10'-2982 99 dioxygenase 1256 gi14582265Homo SapiensAF276432_1 putative2918 99 carotene dioxygenase 1257 gi12666529Mus musculusb,b-carotene-9',10'-2305 81 dioxygenase 1257 gi12666531Homo Sapiensputative b,b-carotene-9',10'-2850 96 dioxygenase 1257 gi14582265Homo SapiensAF276432_1 putative2786 95 carotene dioxygenase 1258 gi15559697Homo SapiensAAH14205 Similar 157 28 to neural cell adhesion molecule 1258 gi28703938Homo SapiensSimilar to neural 157 28 cell adhesion molecule 1 1258 gi61 Bos taurus calmodulin-independent158 28 adenylate cyclase 1260 gi1079734Mus musculuscitron 1291 94 1260 gi2745840Rattus norvegicuspostsynaptic density1262 93 protein;

citron 1260 gi3599509Mus musculusrho/rac-interacting1286 94 citron lcinase 1261 gi28277755Danio rerio proteinase inhibitor,479 30 Glade E, member 2 1261 gi28435507Sus scrofa nexin-1 467 30 1261 gi32485107Homo Sapiensnexin-related serine2002 92 protease inhibitor 1262 113383364Homo Sapiensclaudin-1 223 97 1262 gi15214678Homo SapiensAAH12471 claudin 223 97 1262 gi7381083Homo SapiensAF134160 1 claudin-1223 97 1263 gi13542685Mus musculusSARla gene homolog 441 54 1263 gi21634445Homo SapiensAF274026_1 GTP-binding446 57 protein Sara 1263 gi33150636Homo sapiensAF087897_1 GTP binding446 57 protein 1264 gi22902436Mus musculusSphingosine-1-phosphate717 38 phosphatase 1 1264 gi23345324Homo Sapienssphingosine 1-phosphate2073 100 phosphohydrolase 1264 gi29436890Mus musculusSimilar to sphingosine-1-1624 80 phosphate phosphotase 1265 gil4 Bos taurus BoWCl.l 1214 39 SEQ Hit_ID Species Description S scorePercentage_ ID I denti 1265 gi1480365Sus scrofa scavenger-receptor 1327 42 protein 1265 gi27464818Mus musculusscavengerreceptor 1339 44 cysteine-rich type 1 protein CD163c-alpha precursor 1266 gil4 Bos taurus BoWCl.l 1214 39 1266 gi1480365Sus scrofa scavenger-receptor 1327 42 protein 1266 gi27464818Mus musculusscavengerreceptorcysteine-1339 44 rich type 1 protein CD163c-alpha precursor 1268 gi21619491Homo Sapienssimilar to expressed778 100 sequence 1268 gi32967233Homo SapiensTAFA4 778 100 1268 gi32967245Mus musculusTAFA4 698 93 1270 gi18033185Danio rerio AF330001_1 LJNC45-related3100 73 protein 1270 gi27436424Mus musculusstriated muscle 3937 94 1270 gi27436426Homo Sapiensstriated muscle 4092 99 1271 gi21064657Drosophila RH01479p 182 39 melano aster 1271 gi28375475Homo Sapiensunnamed protein 639 99 product 1271 gi7304173Drosophila CG1577-PA 182 39 melano aster 1272 gi16876958Homo SapiensAAH16754 hypothetical410 100 protein MGC12217 1273 gi15823642Homo sapiensALS2CR7 2038 100 1273 gi32485022Homo Sapiensserine/threonine 2038 100 protein kinase 1273 gi32485027Homo Sapiensserine/threonine 2320 100 protein kinase 1274 gi12654893Homo SapiensAAH01291 400 97 1274 gi2407911Homo Sapiens0016 714 96 1274 gi6733554unidentifiedunnamed protein 710 96 product 1275 gi18147612Homo Sapiensmetalloprotease 4434 95 disintegrin 1275 gi21908028Homo SapiensAF466287_1 a disintegrin4434 95 and mctalloproteasc doanain 33 1275 gi21908030Homo Sapiensa disintegrin and 4434 95 metalloprotease domain 33 1276 gi16551401Homo Sapiensunnamed protein 2735 100 product 1276 gi4972116Arabidopsis putative proline-rich133 44 thaliana protein 1276 gi7269638Arabidopsis putative proline-rich133 44 thaliana protein 1277 gi15291913Drosophila LD31582p 204 23 melanogaster 1277 gi22477165Homo sapiens 2783 100 1277 gi26326895Mus musculusunnamed protein 1752 69 product 1278 gi3452275Pseudopleuronectesaminopeptidase N 1008 37 americanus 1278 gi525287Susscrofa aminopeptidase N. 1014 38 1278 gi544755Oryctolagus aminopeptidase N; 1021 37 cuniculus APN

1279 gi13559063Homo Sapiens 747 100 1279 gi24416538Mus musculus1700001D09Rik protein708 71 1279 gi9963863Homo SapiensAF226731_1 AD026 738 98 1281 gi20810533Homo Sapienshypothetical gene 414 100 supported by AK054745; AK054745;
AK054745; AK054745 1282 gi20810533Homo Sapienshypothetical gene 795 100 ~ ~ supported by SEQ Hit ID Species Description S scorePercentage_ ID I denti AK054745; AK054745;
AK054745; AK054745 1282 gi26345254Mus musculusunnamed protein 367 63 product 1282 '33244011Mus musculus 374 64 1283 gi20810533Homo Sapienshypothetical gene 789 99 supported by AK054745; AK054745;
AK054745; AK054745 1283 126345254Mus musculusunnamed protein 396 64 product 1283 gi33244011Mus musculus 403 65 1284 gi18447388Drosophila RE05944p 700 31 melanogaster 1284 gi21645210Drosophila CG30394-PA 700 31 melanogaster 1284 gi21645211Drosophila CG30394-PB 700 31 melano aster 1285 gi14035874Homo Sapiensunnamed protein 910 99 product 1285 gi14035876Homo Sapiensunnamed protein 853 99 product 1285 gi20070842Homo Sapienssimilar to hypothetical997 99 protein 1286 gi19070822Mus musculusAF364868_1 Myb protein145 23 1286 gi20977688~ienopus tumorhead 146 33 laevis 1286 gi27881626Homo SapiensL~C339344 protein 150 25 1287 ' 10433236Homo Sapiensunnamed protein 721 99 product 1288 gi13278415Mus musculuscDNA sequence BC0040182402 98 1288 126355239Mus musculusunnamed protein 2256 97 product 1288 gi30354720Mus musculuSAI427653 protein 1357 57 1289 gi12698037Homo SapiensKIAA1746 protein 5541 100 1289 gi16769274Drosophila LD22423p 210 24 melanogaster 1289 gi7298509Drosophila CG18398-PA 214 24 melanogaster 1290 gi21391484Homo Sapiensleucine-rich repeat397 39 domain-containing protein 1290 gi21391486Mus musculusleucine-rich repeat433 4~0 domain-containing protein 1290 gi21623740Rattus norvegicusLeucine-rich repeat-containing428 40 protein 3 1291 gi20269073Homo Sapiensputative lipid kinase2006 76 1291 121624340Homo Sapiensceramide kinase 2006 76 1291 gi21624342Mus musculusceramide kinases 1617 64 1292 gi312590Mus musculusbiliary glycoprotein193 32 1292 gi3549152Homo SapiensR29124_1 175 31 1292 gi7414626Rattus norvegicuscarcinoembryonic 176 31 antigen-related cell adhesion molecule, secreted isoform CEACAMla-1293 11197500Homo SapiensT-cell surface anti182 22 en 1293 121707370Homo Sapiens, sheep red blood 182 22 cell receptor 1293 gi312590Mus musculusbiliary glycoprotein193 32 1294 gi18676564Homo SapiensFLJ00179 protein 993 99 1294 gi21411450Mus musculusC230093N12Rilc protein1159 91 1294 gi28839684Homo SapiensSimilar to expressed1242 99 sequence DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME
NOTE POUR LE TOME / VOLUME NOTE:

Claims (26)

WHAT IS CLAIMED IS:

1. An isolated polynucleotide comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-684.

2. An isolated polynucleotide encoding a polypeptide with biological activity, wherein said polynucleotide hybridizes to the polynucleotide of claim 1 under stringent hybridization conditions.

3. An isolated polynucleotide encoding a polypeptide with biological activity, wherein said polynucleotide has greater than about 99% sequence identity with the polynucleotide of claim 1.

4. The polynucleotide of claim 1 wherein said polynucleotide is DNA.

5. An isolated polynucleotide of claim 1 wherein said polynucleotide comprises the complementary sequences.

6. A vector comprising the polynucleotide of claim 1.

7. An expression vector comprising the polynucleotide of claim 1.

8. A host cell genetically engineered to comprise the polynucleotide of claim 1.

9. A host cell genetically engineered to comprise the polynucleotide of claim operatively associated with a regulatory sequence that modulates expression of the polynucleotide in the host cell.

10. An isolated polypeptide, wherein the polypeptide is selected from the group consisting of:
(a) a polypeptide encoded by any one of the polynucleotides of claim 1;
and (b) a polypeptide encoded by a polynucleotide hybridizing under stringent conditions with any one of SEQ ID NO: 1-684.

11. A composition comprising the polypeptide of claim 10 and a carrier.

12. An antibody directed against the polypeptide of claim 10.

13. A method for detecting the polynucleotide of claim 1 in a sample, comprising:
a) contacting the sample with a compound that binds to and forms a complex with the polynucleotide of claim 1 for a period sufficient to form the complex; and b) detecting the complex, so that if a complex is detected, the polynucleotide of claim 1 is detected.

14. A method for detecting the polynucleotide of claim 1 in a sample, comprising:
a) contacting the sample under stringent hybridization conditions with nucleic acid primers that anneal to the polynucleotide of claim 1 under such conditions;
b) amplifying a product comprising at least a portion of the polynucleotide of claim 1; and c) detecting said product and thereby the polynucleotide of claim 1 in the sample.

15. The method of claim 14, wherein the polynucleotide is an RNA molecule and the method further comprises reverse transcribing an annealed RNA molecule into a cDNA
polynucleotide.

16. A method for detecting the polypeptide of claim 10 in a sample, comprising:
a) contacting the sample with a compound that binds to and forms a complex with the polypeptide under conditions and for a period sufficient to form the complex; and b) detecting formation of the complex, so that if a complex formation is detected, the polypeptide of claim 10 is detected.

17. A method for identifying a compound that binds to the polypeptide of claim 10, comprising:

a) contacting the compound with the polypeptide of claim 10 under conditions sufficient to form a polypeptide/compound complex; and b) detecting the complex, so that if the polypeptide/compound complex is detected, a compound that binds to the polypeptide of claim 10 is identified.

18. A method for identifying a compound that binds to the polypeptide of claim 10, comprising:
a) contacting the compound with the polypeptide of claim 10, in a cell, under conditions sufficient to form a polypeptide/compound complex, wherein the complex drives expression of a reporter gene sequence in the cell; and b) detecting the complex by detecting reporter gene sequence expression, so that if the polypeptide/compound complex is detected, a compound that binds to the polypeptide of claim 10 is identified.

19. A method of producing the polypeptide of claim 10, comprising, a) culturing a host cell comprising a polynucleotide sequence selected from the group consisting of any of the polynucleotides from SEQ ID NO: 1-684, under conditions sufficient to express the polypeptide in said cell; and b) isolating the polypeptide from the cell culture or cells of step (a).

20. An isolated polypeptide comprising an amino acid sequence selected from the group consisting of any one of the polypeptides SEQ ID NO: 685-1368.

21. The polypeptide of claim 20 wherein the polypeptide is provided on a polypeptide array.

22. A collection of polynucleotides, wherein the collection comprising of at least one of SEQ ID NO: 1-684.

23. The collection of claim 22, wherein the collection is provided on a nucleic acid array.

24. The collection of claim 23, wherein the array detects full-matches to any one of the polynucleotides in the collection.

25. The collection of claim 23, wherein the array detects mismatches to any one of the polynucleotides in the collection.

26. The collection of claim 22, wherein the collection is provided in a computer-readable format.