EP1430110A2

EP1430110A2 - Novel antibodies that bind to antigenic polypeptides, nucleic acids and encodingthe antigens, and methods of use.

Info

Publication number: EP1430110A2
Application number: EP02736496A
Authority: EP
Inventors: Luca Rastelli; Peter S. Mezes; Glennda Smithson; Xiaojia Guo; Valerie Gerlach; Stacie J. Casman; Ferenc L. Boldog; Li Li; Bryan D. Zerhusen; Velizar T. Tchernev; Esha A. Gangolli; Corine A. M. Vernet; Carol E.A. Pena; Catherine E. Burgess; Xiaohong Liu; Kimberly A. Spytek; Daniel K.A. Rieger; Linda Gorman; Steven K. Spaderna; Edward Z. Voss
Original assignee: CuraGen Corp
Current assignee: CuraGen Corp
Priority date: 2001-03-08
Filing date: 2002-03-08
Publication date: 2004-06-23

Abstract

Disclosed herein are nucleic acid sequences that encode polypeptides. Also disclosed are antibodies, which immunospecifically-bind to the polypeptide, as well as derivatives, variants, mutants, or fragments of the aforementioned polypeptide, polynucleotide, or antibody. The invention further discloses therapeutic, diagnostic and research methods for diagnosis, treatment, and prevention of disorders involving any one of these novel human nucleic acids, polypeptides, or antibodies, or fragments thereof.

Description

NOVEL ANTIBODIES THAT BIND TO ANTIGENIC POLYPEPTIDES, NUCLEIC ACD3S ENCODING THE ANTIGENS, AND METHODS OF USE

FIELD OF THE INVENTION

The present invention relates to novel antibodies that bind immunospecifically to antigenic polypeptides, wherein the polypeptides have characteristic properties related to biochemical or physiological responses in a cell, a tissue, an organ or an organism. The novel polypeptides are gene products of novel genes, or are specified biologically active fragments or derivatives thereof. Methods of use of the antibodies encompass procedures for diagnostic and prognostic assay ofthe polypeptides, as well as methods of treating diverse pathological conditions.

BACKGROUND OF THE INVENTION Eukaryotic cells are characterized by biochemical and physiological processes which under normal conditions are exquisitely balanced to achieve the preservation and propagation ofthe cells. When such cells are components of multicellular organisms such as vertebrates, or more particularly organisms such as mammals, the regulation ofthe biochemical and physiological processes involves intricate signaling pathways. Frequently, such signaling pathways are constituted of extracellular signaling proteins, cellular receptors that bind the signaling proteins and signal transducing components located within the cells.

Signaling proteins may be classified as endocrine effectors, paracrine effectors or autocrine effectors. Endocrine effectors are signaling molecules secreted by a given organ into the circulatory system, which are then transported to a distant target organ or tissue. The target cells include the receptors for the endocrine effector, and when the endocrine effector binds, a signaling cascade is induced. Paracrine effectors involve secreting cells and receptor cells in close proximity to each other, for example two different classes of cells in the same tissue or organ. One class of cells secretes the paracrine effector, which then reaches the second class of cells, for example by diffusion through the extracellular fluid. The second class of cells contains the receptors for the paracrine effector; binding ofthe effector results in induction ofthe signaling cascade that elicits the corresponding biochemical or physiological effect. Autocrine effectors are highly analogous to paracrine effectors, except that the same cell type that secretes the autocrine effector also contains the receptor. Thus the autocrine effector binds to receptors on the same cell, or on identical neighboring cells. The binding process then elicits the characteristic biochemical or physiological effect. Signaling processes may elicit a variety of effects on cells and tissues including by way of nonlimiting example induction of cell or tissue proliferation, suppression of growth or proliferation, induction of differentiation or maturation of a cell or tissue, and suppression of differentiation or maturation of a cell or tissue. Many pathological conditions involve dysregulation of expression of important effector proteins. In certain classes of pathologies the dysregulation is manifested as elevated or excessive synthesis and secretion of protein effectors. In a clinical setting a subject may be suspected of suffering from a condition brought on by elevated or excessive levels of a protein effector of interest. Antibodies are multichain proteins that bind specifically to a given antigen, and poorly or not at all to substances deemed not to be a cognate antigen. Antibodies are comprised of two short chains termed light chains and two long chains termed heavy chains. ^' These chains are constituted of immunoglobulin domains, of which generally there are two classes: one variable domain per chain and one constant domain in light chains and three or more constant domains in heavy chains. The antigen-specific portion of the immunoglobulin molecules resides in the variable domains; the variable domains of one light chain and one heavy chain associate with each other to generate the antigen-binding moiety. Antibodies that bind immunospecifically to a cognate or target antigen bind with high affinities. Accordingly, they are useful in assaying specifically for the presence ofthe antigen in a sample. In addition, they have the potential of inactivating the activity of the antigen.

Therefore there is a need to assay for the level ofthe protein effector of interest in a biological sample from such a subject, and to compare the level with that characteristic of a nonpathological condition. In particular, there is a need for such an assay based on the use of an antibody that binds immunospecifically to the antigen. There further is a need to inhibit the activity of the protein effector in cases where a pathological condition arises from elevated or excessive levels of the effector based on the use of an antibody that binds immunospecifically to the effector. Thus there is a need for the antibody as a product of manufacture. There further is a need for a method of treatment of a pathological condition brought on by an elevated or excessive level ofthe protein effector of interest based on administering the antibody to the subject.

SUMMARY OF THE INVENTION The invention is based in part upon the discovery of nucleic acid sequences encoding novel polypeptides. The novel nucleic acids and polypeptides are referred to herein as NOVX, or NOV1, NON2, ΝOV3, etc. nucleic acids and polypeptides. These nucleic acids and polypeptides, as well as derivatives, homologs, analogs and fragments thereof, will hereinafter be collectively designated as "NOVX" nucleic acid or polypeptide sequences. In one aspect, the invention provides an isolated polypeptide comprising a mature form of a NOVX amino acid. The polypeptide can be, for example, a NOVX amino acid sequence or a variant of a NOVX amino acid sequence, wherein any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed. The invention also includes fragments of any of NOVX polypeptides. In another aspect, the invention also includes an isolated nucleic acid that encodes a NOVX polypeptide, or a fragment, homolog, analog or derivative thereof.

Also included in the invention is a NOVX polypeptide that is a naturally occurring variant of a NOVX sequence. In one embodiment, the variant includes an amino acid sequence that is the translation of a nucleic acid sequence differing by a single nucleotide from a NOVX nucleic acid sequence. In another embodiment, the NOVX polypeptide is a variant polypeptide described therein, wherein any amino acid specified in the chosen sequence is changed to provide a conservative substitution.

In another aspect, invention provides a method for determining the presence or amount ofthe NOVX polypeptide in a sample by providing a sample; introducing the sample to an antibody that binds immunospecifically to the polypeptide; and determining the presence or amount of antibody bound to the NOVX polypeptide, thereby determining the presence or amount ofthe NOVX polypeptide in the sample.

In yet another aspect, the invention includes a method for determining the presence of or predisposition to a disease associated with altered levels of a NOVX polypeptide in a mammalian subject by measuring the level of expression ofthe polypeptide in a sample from the first mammalian subject; and comparing the amount ofthe polypeptide in the sample of the first step to the amount ofthe polypeptide present in a control sample from a second mammalian subject known not to have, or not to be predisposed to, the disease. An alteration in the expression level ofthe polypeptide in the first subject as compared to the control sample indicates the presence of or predisposition to the disease. In another aspect, the invention includes pharmaceutical compositions that include therapeutically- or prophylactically-effective amounts of a therapeutic and a pharmaceutically-acceptable carrier. The therapeutic can be, e.g., a NOVX nucleic acid, a NOVX polypeptide, or an antibody specific for a NOVX polypeptide. In a further aspect, the invention includes, in one or more containers, a therapeutically- or prophylactically-effective amount of this pharmaceutical composition.

In still another aspect, the invention provides the use of a therapeutic in the manufacture of a medicament for treating a syndrome associated with a human disease that is associated with a NOVX polypeptide.

In a further aspect, the invention provides a method for modulating the activity of a NOVX polypeptide by contacting a cell sample expressing the NOVX polypeptide with antibody that binds the NOVX polypeptide in an amount sufficient to modulate the activity of the polypeptide. The invention also includes an isolated nucleic acid that encodes a NOVX polypeptide, or a fragment, homolog, analog or derivative thereof. In a preferred embodiment, the nucleic acid molecule comprises the nucleotide sequence of a naturally occurring allelic nucleic acid variant. In another embodiment, the nucleic acid encodes a variant polypeptide, wherein the variant polypeptide has the polypeptide sequence of a naturally occurring polypeptide variant. In another embodiment, the nucleic acid molecule differs by a single nucleotide from a NOVX nucleic acid sequence. In one embodiment, the NOVX nucleic acid molecule hybridizes under stringent conditions to the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101, or a complement ofthe nucleotide sequence. In one embodiment, the invention provides a nucleic acid molecule wherein the nucleic acid mcludes the nucleotide sequence of a naturally occurring allelic nucleic acid variant.

Also included in the invention is a vector containing one or more ofthe nucleic acids described herein, and a cell containing the vectors or nucleic acids described herein. The mvention is also directed to host cells transformed with a vector comprising any ofthe nucleic acid molecules described above.

In yet another aspect, the mvention provides for a method for determining the presence or amount of a nucleic acid molecule in a sample by contacting a sample with a probe that binds a NOVX nucleic acid and determining the amount ofthe probe that is bound to the NOVX nucleic acid. For example the NOVX nucleic may be a marker for cell or tissue type such as a cell or tissue type that is cancerous.

In yet a further aspect, the invention provides a method for determining the presence of or predisposition to a disease associated with altered levels of a nucleic acid molecule in a first mammalian subject, wherein an alteration in the level ofthe nucleic acid in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.

The invention further provides an antibody that binds immunospecifically to a NOVX polypeptide. The NOVX antibody may be monoclonal, humanized, or a fully human antibody. Preferably, the antibody has a dissociation constant for the binding ofthe NOVX polypeptide to the antibody less than 1 x 10^"9 M. More preferably, the NOVX antibody neutralizes the activity ofthe NOVX polypeptide.

In a further aspect, the invention provides for the use of a therapeutic in the manufacture of a medicament for treating a syndrome associated with a human disease, associated with a NOVX polypeptide. Preferably the therapeutic is a NOVX antibody.

In yet a further aspect, the invention provides a method of treating or preventing a NOVX-associated disorder, a method of treating a pathological state in a mammal, and a method of treating or preventing a pathology associated with a polypeptide by administering a NOVX antibody to a subject in an amount sufficient to treat or prevent the disorder. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing ofthe present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Other features and advantages ofthe mvention will be apparent from the following detailed description and claims. DETAD ED DESCRIPTION OF THE INVENTION

The present invention provides novel nucleotides and polypeptides encoded thereby. Included in the invention are the novel nucleic acid sequences, their encoded polypeptides, antibodies, and other related compunds. The sequences are collectively referred to herein as "NOVX nucleic acids" or "NOVX polynucleotides" and the corresponding encoded polypeptides are referred to as "NOVX polypeptides" or "NOVX proteins." Unless indicated otherwise, "NOVX" is meant to refer to any ofthe novel sequences disclosed herein. Table 1 provides a summary ofthe NOVX nucleic acids and their encoded polypeptides. TABLE 1. NOVX Polynucleotide and Polypeptide Sequences and Corresponding

SEQ JD Numbers

Table 1 indicates homology of NOVX nucleic acids to known protein families. Thus, the nucleic acids and polypeptides, antibodies and related compounds according to the invention corresponding to a NOVX as identified in column 1 of Table 1 will be useful in therapeutic and diagnostic applications implicated in, for example, pathologies and disorders associated with the known protein families identified in column 5 of Table 1.

NOVX nucleic acids and their encoded polypeptides are useful in a variety of applications and contexts. The various NOVX nucleic acids and polypeptides according to the invention are useful as novel members ofthe protein families according to the presence of domains and sequence relatedness to previously described proteins. Additionally, NOVX nucleic acids and polypeptides can also be used to identify proteins that are members ofthe family to which the NOVX polypeptides belong.

Consistent with other known members ofthe family of proteins, identified in column 5 of Table 1, the NOVX polypeptides ofthe present invention show homology to, and contain domains that are characteristic of, other members of such protein families. Details of the sequence relatedness and domain analysis for each NOVX are presented in Example A.

The NOVX nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOVX activity or function. Specifically, the nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit diseases associated with the protein families listed in Table 1.

The NOVX nucleic acids and polypeptides are also useful for detecting specific cell types. Details ofthe expression analysis for each NOVX are presented in Example B. Accordingly, the NOVX nucleic acids, polypeptides, antibodies and related compounds according to the invention will have diagnostic and therapeutic applications in the detection of a variety of diseases with differential expression in normal vs. diseased tissues, e.g.a variety of cancers.

Additional utilities for NOVX nucleic acids and polypeptides according to the invention are disclosed herein.

NOVX clones

NOVX nucleic acids and their encoded polypeptides are useful in a variety of applications and contexts. The various NOVX nucleic acids and polypeptides according to the invention are useful as novel members ofthe protein families according to the presence of domains and sequence relatedness to previously described proteins. Additionally, NOVX nucleic acids and polypeptides can also be used to identify proteins that are members ofthe family to which the NOVX polypeptides belong. The NOVX genes and their corresponding encoded proteins are useful for preventing, treating or ameliorating medical conditions, e.g., by protein or gene therapy. Pathological conditions can be diagnosed by determining the amount ofthe new protein in a sample or by determining the presence of mutations in the new genes. Specific uses are described for each ofthe NOVX genes, based on the tissues in which they are most highly expressed. Uses include developing products for the diagnosis or treatment of a variety of diseases and disorders.

The NOVX nucleic acids and proteins ofthe invention are useful in potential diagnostic and therapeutic applications and as a research tool. These include serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo (vi) biological defense weapon.

In one specific embodiment, the invention includes an isolated polypeptide comprising an amino acid sequence selected from the group consisting of: (a) a mature form ofthe amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 101; (b) a variant of a mature form ofthe amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 101, wherein any amino acid in the mature form is changed to a different amino acid, provided that no more than 15% ofthe amino acid residues in the sequence ofthe mature form are so changed; (c) an amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 101; (d) a variant ofthe amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 101 wherein any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% ofthe amino acid residues in the sequence are so changed; and (e) a fragment of any of (a) through (d).

In another specific embodiment, the invention includes an isolated nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of: (a) a mature form ofthe amino acid sequence given SEQ ID NO: 2n, wherein n is an integer between 1 and 101; (b) a variant of a mature form ofthe amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 101 wherein any amino acid in the mature form of the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence ofthe mature form are so changed; (c) the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 101; (d) a variant ofthe amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 101, in which any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% ofthe amino acid residues in the sequence are so changed; (e) a nucleic acid fragment encoding at least a portion of a polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 101 or any variant of said polypeptide wherein any amino acid ofthe chosen sequence is changed to a different amino acid, provided that no more than 10% ofthe amino acid residues in the sequence are so changed; and (f) the complement of any of said nucleic acid molecules. In yet another specific embodiment, the invention mcludes an isolated nucleic acid molecule, wherein said nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of: (a) the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101; (b) a nucleotide sequence wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101 is changed from that selected from the group consisting ofthe chosen sequence to a different nucleotide provided that no more than 15% ofthe nucleotides are so changed; (c) a nucleic acid fragment ofthe sequence selected from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101; and (d) a nucleic acid fragment wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-l, wherein n is an integer between 1 and 101 is changed from that selected from the group consisting ofthe chosen sequence to a different nucleotide provided that no more than 15%) ofthe nucleotides are so changed.

NOVX Nucleic Acids and Polypeptides One aspect ofthe invention pertains to isolated nucleic acid molecules that encode

NOVX polypeptides or biologically active portions thereof. Also included in the invention are nucleic acid fragments sufficient for use as hybridization probes to identify NOVX- encoding nucleic acids (e.g., NOVX mRNA's) and fragments for use as PCR primers for the amplification and/or mutation of NOVX nucleic acid molecules. As used herein, the term "nucleic acid molecule" is intended to include DNA molecules (e.g. , cDNA or genomic DNA), RNA molecules (e.g., mRNA), analogs ofthe DNA or RNA generated using nucleotide analogs, and derivatives, fragments and homologs thereof. The nucleic acid molecule may be single-stranded or double-stranded, but preferably is comprised double- stranded DNA. A NOVX nucleic acid can encode a mature NOVX polypeptide. As used herein, a

"mature" form of a polypeptide or protein disclosed in the present invention is the product of a naturally occurring polypeptide or precursor form or proprotein. The naturally occurring polypeptide, precursor or proprotein includes, by way of nonlimiting example, the full-length gene product, encoded by the corresponding gene. Alternatively, it may be defined as the polypeptide, precursor or proprotein encoded by an ORF described herein. The product "mature" form arises, again by way of nonlimiting example, as a result of one or more naturally occurring processing steps as they may take place within the cell, or host cell, in which the gene product arises. Examples of such processing steps leading to a "mature" form of a polypeptide or protein include the cleavage ofthe N-terminal methionine residue encoded by the initiation codon of an ORF, or the proteolytic cleavage of a signal peptide or leader sequence. Thus a mature form arising from a precursor polypeptide or protein that has residues 1 to N, where residue 1 is the N-terminal methionine, would have residues 2 through N remaining after removal ofthe N-terminal methionine. Alternatively, a mature form arising from a precursor polypeptide or protein having residues 1 to N, in which an N- terminal signal sequence from residue 1 to residue M is cleaved, would have the residues from residue M+1 to residue N remaining. Further as used herein, a "mature" form of a polypeptide or protein may arise from a step of post-translational modification other than a proteolytic cleavage event. Such additional processes include, by way of non-limiting example, glycosylation, myristylation or phosphorylation. In general, a mature polypeptide or protein may result from the operation of only one of these processes, or a combination of any of them.

The term "probes", as utilized herein, refers to nucleic acid sequences of variable length, preferably between at least about 10 nucleotides (nt), 100 nt, or as many as approximately, e.g., 6,000 nt, depending upon the specific use. Probes are used in the detection of identical, similar, or complementary nucleic acid sequences. Longer length probes are generally obtained from a natural or recombinant source, are highly specific, and much slower to hybridize than shorter-length oligomer probes. Probes may be single- or double-stranded and designed to have specificity in PCR, membrane-based hybridization technologies, or ELISA-like technologies.

The term "isolated" nucleic acid molecule, as utilized herein, is one, which is separated from other nucleic acid molecules which are present in the natural source ofthe nucleic acid. Preferably, an "isolated" nucleic acid is free of sequences which naturally flank the nucleic acid (i. e. , sequences located at the 5'- and 3 '-termini ofthe nucleic acid) in the genomic DNA ofthe organism from which the nucleic acid is derived. For example, in various embodiments, the isolated NOVX nucleic acid molecules can contain less than about 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of nucleotide sequences which naturally flank the nucleic acid molecule in genomic DNA ofthe cell/tissue from which the nucleic acid is derived (e.g., brain, heart, liver, spleen, etc.). Moreover, an "isolated" nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material or culture medium when produced by recombinant techniques, or of chemical precursors or other chemicals when chemically synthesized.

A nucleic acid molecule ofthe invention, e.g., a nucleic acid molecule having the nucleotide sequence of SEQ ID NO:2«-l, wherein n is an integer between 1-101, or a complement of this aforementioned nucleotide sequence, can be isolated using standard molecular biology techniques and the sequence information provided herein. Using all or a portion ofthe nucleic acid sequence of SEQ ID NO:2n-l, wherein n is an integer between 1- 101, as a hybridization probe, NOVX molecules can be isolated using standard hybridization and cloning techniques (e.g., as described in Sambrook, et al., (eds.), MOLECULAR CLONING: A LABORATORY MANUAL 2^nd Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989; and Ausubel, et al., (eds.), CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, NY, 1993.) A nucleic acid of the invention can be amplified using cDNA, mRNA or alternatively, genomic DNA, as a template and appropriate oligonucleotide primers according to standard PCR amplification techniques. The nucleic acid so amplified can be cloned into an appropriate vector and characterized by DNA sequence analysis. Furthermore, oligonucleotides corresponding to NOVX nucleotide sequences can be prepared by standard synthetic techniques, e.g., using an automated DNA synthesizer.

As used herein, the term "oligonucleotide" refers to a series of linked nucleotide residues, which oligonucleotide has a sufficient number of nucleotide bases to be used in a PCR reaction. A short oligonucleotide sequence may be based on, or designed from, a genomic or cDNA sequence and is used to amplify, confirm, or reveal the presence of an identical, similar or complementary DNA or RNA in a particular cell or tissue.

Oligonucleotides comprise portions of a nucleic acid sequence having about 10 nt, 50 nt, or 100 nt in length, preferably about 15 nt to 30 nt in length. In one embodiment ofthe invention, an oligonucleotide comprising a nucleic acid molecule less than 100 nt in length would further comprise at least 6 contiguous nucleotides of SEQ ID NO:27*-l, wherein n is an integer between 1-101 , or a complement thereof. Oligonucleotides may be chemically synthesized and may also be used as probes.

In another embodiment, an isolated nucleic acid molecule ofthe invention comprises a nucleic acid molecule that is a complement ofthe nucleotide sequence SEQ ID NO:2n-l, wherein n is an integer between 1-101, or a portion of this nucleotide sequence (e.g., a fragment that can be used as a probe or primer or a fragment encoding a biologically-active portion of a NOVX polypeptide). A nucleic acid molecule that is complementary to the nucleotide sequence of SEQ ID NO:2«-l, wherein n is an integer between 1-101, is one that is sufficiently complementary to the nucleotide sequence of SEQ ID NO:2n-l, wherein n is an integer between 1-101, that it can hydrogen bond with little or no mismatches to the nucleotide sequence of SEQ ID ^~HO:2n-l, wherein n is an integer between 1-101, thereby forming a stable duplex.

As used herein, the term "complementary" refers to Watson-Crick or Hoogsteen base pairing between nucleotides units of a nucleic acid molecule, and the term "binding" means the physical or chemical interaction between two polypeptides or compounds or associated polypeptides or compounds or combinations thereof. Binding includes ionic, non-ionic, van der Waals, hydrophobic interactions, and the like. A physical interaction can be either direct or indirect. Indirect interactions may be through or due to the effects of another polypeptide or compound. Direct binding refers to interactions that do not take place through, or due to, the effect of another polypeptide or compound, but instead are without other substantial chemical intermediates.

Fragments provided herein are defined as sequences of at least 6 (contiguous) nucleic acids or at least 4 (contiguous) amino acids, a length sufficient to allow for specific hybridization in the case of nucleic acids or for specific recognition of an epitope in the case of amino acids, respectively, and are at most some portion less than a full length sequence. Fragments may be derived from any contiguous portion of a nucleic acid or amino acid sequence of choice. Derivatives are nucleic acid sequences or amino acid sequences formed from the native compounds either directly or by modification or partial substitution. Analogs are nucleic acid sequences or amino acid sequences that have a structure similar to, but not identical to, the native compound but differs from it in respect to certain components or side chains. Analogs may be synthetic or from a different evolutionary origin and may have a similar or opposite metabolic activity compared to wild type. Homologs are nucleic acid sequences or amino acid sequences of a particular gene that are derived from different species. A full-length NOVX clone is identified as containing an ATG translation start codon and an in-frame stop codon. Any disclosed NOVX nucleotide sequence lacking an ATG start codon therefore encodes a truncated C-terminal fragment ofthe respective NOVX polypeptide, and requires that the corresponding full-length cDNA extend in the 5' direction ofthe disclosed sequence. Any disclosed NOVX nucleotide sequence lacking an in-frame stop codon similarly encodes a truncated N-terminal fragment ofthe respective NOVX polypeptide, and requires that the corresponding full-length cDNA extend in the 3' direction ofthe disclosed sequence.

Derivatives and analogs may be full length or other than full length, if the derivative or analog contains a modified nucleic acid or amino acid, as described below. Derivatives or analogs ofthe nucleic acids or proteins ofthe invention include, but are not limited to, molecules comprising regions that are substantially homologous to the nucleic acids or proteins ofthe mvention, in various embodiments, by at least about 70%, 80%, or 95% identity (with a preferred identity of 80-95%) over a nucleic acid or amino acid sequence of identical size or when compared to an aligned sequence in which the alignment is done by a computer homology program known in the art, or whose encoding nucleic acid is capable of hybridizing to the complement of a sequence encoding the aforementioned proteins under stringent, moderately stringent, or low stringent conditions. See e.g. Ausubel, et al, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, NY, 1993, and below.

A "homologous nucleic acid sequence" or "homologous amino acid sequence," or variations thereof, refer to sequences characterized by a homology at the nucleotide level or amino acid level as discussed above. Homologous nucleotide sequences encode those sequences coding for isoforms of NOVX polypeptides. Isoforms can be expressed in different tissues ofthe same organism as a result of, for example, alternative splicing of RNA. Alternatively, isoforms can be encoded by different genes. In the mvention, homologous nucleotide sequences include nucleotide sequences encoding for a NOVX polypeptide of species other than humans, including, but not limited to: vertebrates, and thus can include, e.g., frog, mouse, rat, rabbit, dog, cat cow, horse, and other organisms. Homologous nucleotide sequences also include, but are not limited to, naturally occurring allelic variations and mutations ofthe nucleotide sequences set forth herein. A homologous nucleotide sequence does not, however, include the exact nucleotide sequence encoding human NOVX protein. Homologous nucleic acid sequences include those nucleic acid sequences that encode conservative amino acid substitutions (see below) in SEQ ID NO:2«-l, wherein n is an integer between 1 - 101 , as well as a polypeptide possessing NOVX biological activity. Various biological activities ofthe NOVX proteins are described below.

A NOVX polypeptide is encoded by the open reading frame ("ORF") of a NOVX nucleic acid. An ORF corresponds to a nucleotide sequence that could potentially be translated into a polypeptide. A stretch of nucleic acids comprising an ORF is uninterrupted by a stop codon. An ORF that represents the coding sequence for a full protein begins with an ATG "start" codon and terminates with one ofthe three "stop" codons, namely, TAA, TAG, or TGA. For the purposes of this invention, an ORF may be any part of a coding sequence, with or without a start codon, a stop codon, or both. For an ORF to be considered as a good candidate for coding for a bonaflde cellular protein, a minimum size requirement is often set, e.g., a stretch of DNA that would encode a protein of 50 amino acids or more.

The nucleotide sequences determined from the cloning ofthe human NOVX genes allows for the generation of probes and primers designed for use in identifying and/or cloning NOVX homologues in other cell types, e.g. from other tissues, as well as NOVX homologues from other vertebrates. The probe/primer typically comprises substantially purified oligonucleotide. The oligonucleotide typically comprises a region of nucleotide sequence that hybridizes under stringent conditions to at least about 12, 25, 50, 100, 150, 200, 250, 300, 350 or 400 consecutive sense strand nucleotide sequence of SEQ ID NO:2n-l, wherein n is an integer between 1-101; or an anti-sense strand nucleotide sequence of SEQ ID NO:272-l, wherein n is an integer between 1-101 ; or of a naturally occurring mutant of SEQ ID NO:2«- 1 , wherein n is an integer between 1-101.

Probes based on the human NOVX nucleotide sequences can be used to detect transcripts or genomic sequences encoding the same or homologous proteins. In various embodiments, the probe further comprises a label group attached thereto, e.g. the label group can be a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor. Such probes can be used as a part of a diagnostic test kit for identifying cells or tissues which mis- express a NOVX protein, such as by measuring a level of a NOVX-encoding nucleic acid in a sample of cells from a subject e.g., detecting NOVX mRNA levels or determining whether a genomic NOVX gene has been mutated or deleted. "A polypeptide having a biologically-active portion of a NOVX polypeptide" refers to polypeptides exhibiting activity similar, but not necessarily identical to, an activity of a polypeptide ofthe invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. A nucleic acid fragment encoding a "biologically- active portion of NOVX" can be prepared by isolating a portion of SEQ ID NO:2«-l, wherein n is an integer between 1-101 , that encodes a polypeptide having a NOVX biological activity (the biological activities ofthe NOVX proteins are described below), expressing the encoded portion of NOVX protein (e.g., by recombinant expression in vitro) and assessing the activity ofthe encoded portion of NOVX.

NOVX Nucleic Acid and Polypeptide Variants The invention further encompasses nucleic acid molecules that differ from the nucleotide sequences of SEQ ID NO:2«-l, wherein n is an integer between 1-101, due to degeneracy ofthe genetic code and thus encode the same NOVX proteins as that encoded by the nucleotide sequences of SEQ ID NO:2«-l, wherein n is an integer between 1-101. In another embodiment, an isolated nucleic acid molecule ofthe invention has a nucleotide sequence encoding a protein having an amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1-101.

In addition to the human NOVX nucleotide sequences of SEQ ID NO:2«-l, wherein n is an integer between 1-101, it will be appreciated by those skilled in the art that DNA sequence polymorphisms that lead to changes in the amino acid sequences ofthe NOVX polypeptides may exist within a population (e.g., the human population). Such genetic polymorphism in the NOVX genes may exist among individuals within a population due to natural allelic variation. As used herein, the terms "gene" and "recombinant gene" refer to nucleic acid molecules comprising an open reading frame (ORF) encoding a NOVX protein, preferably a vertebrate NOVX protein. Such natural allelic variations can typically result in 1-5% variance in the nucleotide sequence ofthe NOVX genes. Any and all such nucleotide variations and resulting amino acid polymorphisms in the NOVX polypeptides, which are the result of natural allelic variation and that do not alter the functional activity ofthe NOVX polypeptides, are intended to be within the scope ofthe invention.

Moreover, nucleic acid molecules encoding NOVX proteins from other species, and thus that have a nucleotide sequence that differs from any one ofthe human SEQ ID NO : 277- 1, wherein n is an integer between 1-101, are intended to be within the scope ofthe invention. Nucleic acid molecules corresponding to natural allelic variants and homologues ofthe NOVX cDNAs of the invention can be isolated based on their homology to the human NOVX nucleic acids disclosed herein using the human cDNAs, or a portion thereof, as a hybridization probe according to standard hybridization techniques under stringent hybridization conditions.

Accordingly, in another embodiment, an isolated nucleic acid molecule ofthe invention is at least 6 nucleotides in length and hybridizes under stringent conditions to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:277-l, wherein n is an integer between 1-101. In another embodiment, the nucleic acid is at least 10, 25, 50, 100, 250, 500, 750, 1000, 1500, or 2000 or more nucleotides in length. In yet another embodiment, an isolated nucleic acid molecule ofthe invention hybridizes to the coding region. As used herein, the term "hybridizes under stringent conditions" is intended to describe conditions for hybridization and washing under which nucleotide sequences at least 60% homologous to each other typically remain hybridized to each other.

Homologs (t.e., nucleic acids encoding NOVX proteins derived from species other than human) or other related sequences (e.g., paralogs) can be obtained by low, moderate or high stringency hybridization with all or a portion ofthe particular human sequence as a probe using methods well known in the art for nucleic acid hybridization and cloning.

As used herein, the phrase "stringent hybridization conditions" refers to conditions under which a probe, primer or oligonucleotide will hybridize to its target sequence, but to no other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances. Longer sequences hybridize specifically at higher temperatures than shorter sequences. Generally, stringent conditions are selected to be about 5 °C lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength and pH. The Tm is the temperature (under defined ionic strength, pH and nucleic acid concentration) at which 50% ofthe probes complementary to the target sequence hybridize to the target sequence at equilibrium. Since the target sequences are generally present at excess, at Tm, 50% ofthe probes are occupied at equilibrium. Typically, stringent conditions will be those in which the salt concentration is less than about 1.0 M sodium ion, typically about 0.01 to 1.0 M sodium ion (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30°C for short probes, primers or oligonucleotides (e.g., 10 nt to 50 nt) and at least about 60°C for longer probes, primers and oligonucleotides. Stringent conditions may also be achieved with the addition of destabilizing agents, such as formamide.

Stringent conditions are known to those skilled in the art and can be found in Ausubel, et al., (eds.), CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6. Preferably, the conditions are such that sequences at least about 65%, 70%, 75%, 85%, 90%, 95%, 98%, or 99% homologous to each other typically remain hybridized to each other. A non-limiting example of stringent hybridization conditions are hybridization in a high salt buffer comprising 6X SSC, 50 mM Tris-HCl (pH 7.5), 1 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.02% BSA, and 500 mg/ml denatured salmon sperm DNA at 65°C, followed by one or more washes in 0.2X SSC, 0.01% BSA at 50°C. An isolated nucleic acid molecule ofthe mvention that hybridizes under stringent conditions to any one ofthe sequences of SEQ ID NO:2n-l, wherein n is an integer between 1-101, corresponds to a naturally-occurring nucleic acid molecule. As used herein, a "naturally-occurring" nucleic acid molecule refers to an RNA or DNA molecule having a nucleotide sequence that occurs in nature (e.g., encodes a natural protein).

In a second embodiment, a nucleic acid sequence that is hybridizable to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:2»-l, wherein n is an integer between 1-101, or fragments, analogs or derivatives thereof, under conditions of moderate stringency is provided. A non-limiting example of moderate stringency hybridization conditions are hybridization in 6X SSC, 5X Reinhardt's solution, 0.5% SDS and 100 mg/ml denatured salmon sperm DNA at 55°C, followed by one or more washes in IX SSC, 0.1%» SDS at 37°C. Other conditions of moderate stringency that may be used are well-known within the art. See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, and Krieger, 1990; GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY.

In a third embodiment, a nucleic acid that is hybridizable to the nucleic acid molecule comprising the nucleotide sequences of SEQ ID NO:2τ7-l, wherein n is an integer between 1- 101, or fragments, analogs or derivatives thereof, under conditions of low stringency, is provided. A non-limiting example of low stringency hybridization conditions are hybridization in 35% formamide, 5X SSC, 50 mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02%) Ficoll, 0.2% BSA, 100 mg/ml denatured salmon sperm DNA, 10% (wt/volt) dextran sulfate at 40°C, followed by one or more washes in 2X SSC, 25 mM Tris-HCl (pH 7.4), 5 mM EDTA, and 0.1% SDS at 50°C. Other conditions of low stringency that may be used are well known in the art (e.g., as employed for cross-species hybridizations). See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, and Kriegler, 1990, GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY; Shilo and Weinberg, 1981. Proc Natl Acad Sci USA 78: 6789-6792.

Conservative Mutations

In addition to naturally-occurring allelic variants of NOVX sequences that may exist in the population, the skilled artisan will further appreciate that changes can be introduced by mutation into the nucleotide sequences of SEQ ID NO:277-l, wherein 7 is an integer between 1-101, thereby leading to changes in the amino acid sequences of the encoded NOVX proteins, without altering the functional ability of said NOVX proteins. For example, nucleotide substitutions leading to amino acid substitutions at "non-essential" amino acid residues can be made in the sequence of SEQ ID NO: 277, wherein 77 is an integer between 1- 101. A "non-essential" amino acid residue is a residue that can be altered from the wild-type sequences ofthe NOVX proteins without altering their biological activity, whereas an

"essential" amino acid residue is required for such biological activity. For example, amino acid residues that are conserved among the NOVX proteins ofthe invention are particularly non-amenable to alteration. Amino acids for which conservative substitutions can be made are well-known within the art. Another aspect of the invention pertains to nucleic acid molecules encoding NOVX proteins that contain changes in amino acid residues that are not essential for activity. Such NOVX proteins differ in amino acid sequence from any one of SEQ ID NO:2τ7-l, wherein n is an integer between 1-101, yet retain biological activity. In one embodiment, the isolated nucleic acid molecule comprises a nucleotide sequence encoding a protein, wherein the protein comprises an amino acid sequence at least about 45%> homologous to the amino acid sequences of SEQ ID NO:2τ7, wherein n is an integer between 1-101. Preferably, the protein encoded by the nucleic acid molecule is at least about 60% homologous to SEQ ID NO:2τ7, wherein n is an integer between 1-101; more preferably at least about 70%) homologous to SEQ ID NO:2?7, wherein 7? is an integer between 1-101 ; still more preferably at least about 80% homologous to SEQ ID NO:277, wherein 7 is an integer between 1-101; even more preferably at least about 90% homologous to SEQ ID NO:2τ7, wherein 77 is an integer between 1-101; and most preferably at least about 95% homologous to SEQ ID NO:2τ7, wherein n is an integer between 1-101. An isolated nucleic acid molecule encoding a NOVX protein homologous to the protein of SEQ ID NO:277, wherein 77 is an integer between 1-101, can be created by introducing one or more nucleotide substitutions, additions or deletions into the nucleotide sequence of SEQ ID NO:2τ7-l, wherein 7? is an integer between 1-101, such that one or more amino acid substitutions, additions or deletions are introduced into the encoded protein. Mutations can be introduced into any of SEQ ID NO:277-l, wherein n is an integer between 1-101, by standard techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis. Preferably, conservative amino acid substitutions are made at one or more predicted, non-essential amino acid residues. A "conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined within the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, a predicted non-essential amino acid residue in the NOVX protein is replaced with another amino acid residue from the same side chain family. Alternatively, in another embodiment, mutations can be introduced randomly along all or part of a NOVX coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for NOVX biological activity to identify mutants that retain activity. Following mutagenesis of any one of SEQ ID NO: 277-1, wherein n is an integer between 1-101, the encoded protein can be expressed by any recombinant technology known in the art and the activity ofthe protein can be determined. The relatedness of amino acid families may also be determined based on side chain interactions. Substituted amino acids may be fully conserved "strong" residues or fully conserved "weak" residues. The "strong" group of conserved amino acid residues may be any one ofthe following groups: STA, NEQK, NHQK, NDEQ, QHRK, MILV, MILF, HY, FYW, wherein the single letter amino acid codes are grouped by those amino acids that may be substituted for each other. Likewise, the "weak" group of conserved residues may be any one ofthe following: CSA, ATV, SAG, STNK, STPA, SGND, SNDEQK, NDEQHK, NEQHRK, VLIM, HFY, wherein the letters within each group represent the single letter amino acid code. In one embodiment, a mutant NOVX protein can be assayed for (t) the ability to form protein:protem interactions with other NOVX proteins, other cell-surface proteins, or biologically-active portions thereof, (ii) complex formation between a mutant NOVX protein and a NOVX ligand; or (iii) the ability of a mutant NOVX protein to bind to an intracellular target protein or biologically-active portion thereof; (e.g. avidin proteins). In yet another embodiment, a mutant NOVX protein can be assayed for the ability to regulate a specific biological function (e.g., regulation of insulin release).

Antisense Nucleic Acids

Another aspect ofthe 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:2τ7-l, wherein 7 is an integer between 1-101, 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 comprise a sequence complementary to at least about 10, 25, 50, 100, 250 or 500 nucleotides or an entire NOVX coding strand, or to only a portion thereof. Nucleic acid molecules encoding fragments, homologs, derivatives and analogs of a NOVX protein of SEQ ID NO: 277, wherein n is an integer between 1-101, or antisense nucleic acids complementary to a NOVX nucleic acid sequence of SEQ ID NO:277-l, wherein 77 is an integer between 1 - 101 , are additionally provided.

In one embodiment, an antisense nucleic acid molecule is antisense to a "coding region" ofthe coding strand of a nucleotide sequence encoding a NOVX protein. The term "coding region" refers to the region ofthe nucleotide sequence comprising codons which are translated into amino acid residues. In another embodiment, the antisense nucleic acid molecule is antisense to a "noncoding region" ofthe coding strand of a nucleotide sequence encoding the NOVX protein. The term "noncoding region" refers to 5' and 3' sequences which 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 the NOVX protein disclosed herein, antisense nucleic acids ofthe 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 NOVX mRNA, but more preferably is an oligonucleotide that is antisense to only a portion ofthe coding or noncoding region of NOVX mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of NOVX 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 ofthe 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-occurring nucleotides or variously modified nucleotides designed to increase the biological stability ofthe molecules or to increase the physical stability ofthe 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-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl- 2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosme, 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-diaminopurme. 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 ofthe invention are typically administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a NOVX protein to thereby inhibit expression of the protein (e.g. , by inhibiting transcription and/or 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 ofthe double helix. An example of a route of administration of antisense nucleic acid molecules ofthe 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 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 nucleic acid 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.

In yet another embodiment, the antisense nucleic acid molecule ofthe invention is an α-anomeric nucleic acid molecule. An oc-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual β-units, the strands run parallel to each other. See, e.g., Gaultier, et al., 1987. Nucl. Acids Res. 15: 6625-6641. The antisense nucleic acid molecule can also comprise a 2'-o-methylribonucleotide (See, e.g., Inoue, et al. 1987. Nucl. Acids Res. 15: 6131-6148) or a chimeric RNA-DNA analogue (See, e.g., Inoue, et al., 1987. FEBSLett. 215: 327-330.

Ribozymes and PNA Moieties

Nucleic acid modifications include, by way of non-limiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability ofthe modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject.

In one embodiment, an antisense nucleic acid ofthe invention is a ribozyme. 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 as described in

Haselhoff and Gerlach 1988. Nature 334: 585-591) can be used to catalytically cleave NOVX mRNA transcripts to thereby inhibit translation of NOVX mRNA. A ribozyme having specificity for a NOVX-encoding nucleic acid can be designed based upon the nucleotide sequence of a NOVX cDNA disclosed herein (t.e., any one of SEQ ID NO:2τ7-l, wherein n is an integer between 1-101). For example, a derivative of a Tetrahymena L- 19 IVS RNA can be constructed in which the nucleotide sequence ofthe active site is complementary to the nucleotide sequence to be cleaved in a NOVX-encoding mRNA. See, e.g., U.S. Patent 4,987,071 to Cech, et al. and U.S. Patent 5,116,742 to Cech, et al. NOVX mRNA can also 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) Science 261 : 1411-1418.

Alternatively, NOVX gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region ofthe NOVX nucleic acid (e.g., the NOVX promoter and/or enhancers) to form triple helical structures that prevent transcription of the NOVX gene in target cells. See, e.g., Helene, 1991. Anticancer Drug Des. 6: 569-84; Helene, et al. 1992. Ann. N.Y. Acad. Sci. 660: 27-36; Maher, 1992. Bioassays 14: 807-15.

In various embodiments, the NOVX nucleic acids can be modified at the base moiety, sugar moiety or phosphate backbone to improve, e.g., the stability, hybridization, or solubility ofthe molecule. For example, the deoxyribose phosphate backbone ofthe nucleic acids can be modified to generate peptide nucleic acids. See, e.g., Hyrup, et al, 1996. Bioorg Med Chem 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 nucleotide bases 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 oligomer can be performed using standard solid phase peptide synthesis protocols as described in Hyrup, et al, 1996. supra; Perry-O'Keefe, et al, 1996. Proc. Natl. Acad. Sci. USA 93: 14670-14675.

PNAs of NOVX can be used in therapeutic and diagnostic applications. For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication. PNAs of NOVX can also be used, for example, in the analysis of single base pair mutations in a gene (e.g., PNA directed PCR clamping; as artificial restriction enzymes when used in combination with other enzymes, e.g, Si nucleases (See, Hyrup, et al, I996.supra); or as probes or primers for DNA sequence and hybridization (See, Hyrup, et al, 1996, supra; Perry-O'Keefe, et al, 1996. supra).

In another embodiment, PNAs of NOVX 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 of NOVX 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 nucleotide bases, and orientation (see, Hyrup, et al., 1996. supra). The synthesis of PNA-DNA chimeras can be performed as described in Hyrup, et al, 1996. supra and Finn, et al, 1996. Nucl Acids Res 24: 3357-3363. 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. See, e.g., Mag, et al, 1989. Nucl Acid Res 17: 5973-5988.

PNA monomers are then coupled in a stepwise manner to produce a chimeric molecule with a 5' PNA segment and a 3' DNA segment. See, e.g., Finn, et al, 1996. supra. Alternatively, chimeric molecules can be synthesized with a 5' DNA segment and a 3' PNA segment. See, e.g., Petersen, etal, 1915. Bioorg. Med. Chem. 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 vivo), or agents facilitating transport across the cell membrane (see, e.g., Letsinger, et al, 1989. Proc. Natl. Acad. Sci. U.S.A. 86: 6553-6556; Lemaitre, et al, 1987. Proc. Natl. Acad. Sci. 84: 648-652; PCT Publication No. WO88/09810) or the blood-brain barrier (see, e.g. , PCT Publication No. WO 89/10134). In addition, oligonucleotides can be modified with hybridization triggered cleavage agents (see, e.g., Krol, et al, 1988. BioTechniques 6:958-976) or intercalating agents (see, e.g., Zon, 1988. Pharrn. 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, and the like.

NOVX Polypeptides

A polypeptide according to the invention includes a polypeptide including the amino acid sequence of NOVX polypeptides whose sequences are provided in any one of SEQ ID NO:277, wherein 77 is an integer between 1-101. The invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residues shown in any one of SEQ ID NO:2τ?, wherein 77 is an integer between 1-101, while still encoding a protein that maintains its NOVX activities and physiological functions, or a functional fragment thereof.

In general, a NOVX variant that preserves NOVX-like function includes any variant in which residues at a particular position in the sequence have been substituted by other amino acids, and further include the possibility of inserting an additional residue or residues between two residues ofthe parent protein as well as the possibility of deleting one or more residues from the parent sequence. Any amino acid substitution, insertion, or deletion is encompassed by the invention. In favorable circumstances, the substitution is a conservative substitution as defined above.

One aspect ofthe invention pertains to isolated NOVX proteins, and biologically- active portions thereof, or derivatives, fragments, analogs or homologs thereof. Also provided are polypeptide fragments suitable for use as immunogens to raise anti-NOVX antibodies. In one embodiment, native NOVX proteins can be isolated from cells or tissue sources by an appropriate purification scheme using standard protein purification techniques. In another embodiment, NOVX proteins are produced by recombinant DNA techniques. Alternative to recombinant expression, a NOVX protein or polypeptide can be synthesized chemically using standard peptide synthesis techniques.

An "isolated" or "purified" polypeptide or protein or biologically-active portion thereof is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the NOVX protein is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized. The language "substantially free of cellular material" includes preparations of NOVX proteins in which the protein is separated from cellular components ofthe cells from which it is isolated or recombinantly- produced. In one embodiment, the language "substantially free of cellular material" includes preparations of NOVX proteins having less than about 30% (by dry weight) of non-NOVX proteins (also referred to herein as a "contaminating protein"), more preferably less than about 20% of non-NOVX proteins, still more preferably less than about 10%> of non-NOVX proteins, and most preferably less than about 5% of non-NOVX proteins. When the NOVX protein or biologically-active portion thereof is recornbinantiy-produced, it is also preferably substantially free of culture medium, i.e., culture medium represents less than about 20%, more preferably less than about 10%, and most preferably less than about 5% ofthe volume of the NOVX protein preparation.

The language "substantially free of chemical precursors or other chemicals" includes preparations of NOVX proteins in which the protein is separated from chemical precursors or other chemicals that are involved in the synthesis ofthe protein. In one embodiment, the language "substantially free of chemical precursors or other chemicals" mcludes preparations of NOVX proteins having less than about 30% (by dry weight) of chemical precursors or non-NOVX chemicals, more preferably less than about 20%> chemical precursors or non-NOVX chemicals, still more preferably less than about 10% chemical precursors or non-NOVX chemicals, and most preferably less than about 5% chemical precursors or non-NOVX chemicals. Biologically-active portions of NOVX proteins include peptides comprising amino acid sequences sufficiently homologous to or derived from the amino acid sequences ofthe NOVX proteins (e.g., the amino acid sequence of SEQ ID NO:2TΪ, wherein n is an integer between 1-101) that include fewer amino acids than the full-length NOVX proteins, and exhibit at least one activity of a NOVX protein. Typically, biologically-active portions comprise a domain or motif with at least one activity of the NOVX protein. A biologically- active portion of a NOVX protein can be a polypeptide which is, for example, 10, 25, 50, 100 or more amino acid residues in length.

Moreover, other biologically-active portions, in which other regions ofthe protein are deleted, can be prepared by recombinant techniques and evaluated for one or more ofthe functional activities of a native NOVX protein.

In an embodiment, the NOVX protein has an amino acid sequence of SEQ ID NO: 2 , wherein 77 is an integer between 1-101. In other embodiments, the NOVX protein is substantially homologous to SEQ ID NO:277, wherein 77 is an integer between 1-101, and retains the functional activity ofthe protein of SEQ ID NO:2λ7, wherein n is an integer between 1-101, yet differs in amino acid sequence due to natural allelic variation or mutagenesis, as described in detail, below. Accordingly, in another embodiment, the NOVX protein is a protein that comprises an amino acid sequence at least about 45% homologous to the amino acid sequence of SEQ ID NO:2τ7, wherein n is an integer between 1-101, and retains the functional activity ofthe NOVX proteins of SEQ ID NO:277, wherein ?7 is an integer between 1-101.

Determining Homology Between Two or More Sequences

To determine the percent homology of two amino acid sequences or of two nucleic acids, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are homologous at that position (i.e., as used herein amino acid or nucleic acid "homology" is equivalent to amino acid or nucleic acid "identity").

The nucleic acid sequence homology may be determined as the degree of identity between two sequences. The homology may be determined using computer programs known in the art, such as GAP software provided in the GCG program package. See, Needleman and Wunsch, 1970. JMol Biol 48: 443-453. Using GCG GAP software with the following settings for nucleic acid sequence comparison: GAP creation penalty of 5.0 and GAP extension penalty of 0.3, the coding region ofthe analogous nucleic acid sequences referred to above exhibits a degree of identity preferably of at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%), with the CDS (encoding) part of the DNA sequence of SEQ ID NO:277-l, wherein ?7 is an integer between 1-101.

The term "sequence identity" refers to the degree to which two polynucleotide or polypeptide sequences are identical on a residue-by-residue basis over a particular region of comparison. The term "percentage of sequence identity" is calculated by comparing two optimally aligned sequences over that region of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U, or I, in the case of nucleic acids) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the region of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity. The term "substantial identity" as used herein denotes a characteristic of a polynucleotide sequence, wherein the polynucleotide comprises a sequence that has at least 80 percent sequence identity, preferably at least 85 percent identity and often 90 to 95 percent sequence identity, more usually at least 99 percent sequence identity as compared to a reference sequence over a comparison region.

Chimeric and Fusion Proteins

The invention also provides NOVX chimeric or fusion proteins. As used herein, a NOVX "chimeric protein" or "fusion protein" comprises a NOVX polypeptide operatively- linked to a non-NOVX polypeptide. An "NOVX polypeptide" refers to a polypeptide having an amino acid sequence corresponding to a NOVX protein of SEQ ID NO:272, wherein ?7 is an integer between 1-101, whereas a "non-NOVX polypeptide" refers to a polypeptide having an amino acid sequence corresponding to a protein that is not substantially homologous to the NOVX protein, e.g., a protein that is different from the NOVX protein and that is derived from the same or a different organism. Within a NOVX fusion protein the NOVX polypeptide can correspond to all or a portion of a NOVX protein. In one embodiment, a NOVX fusion protein comprises at least one biologically-active portion of a NOVX protein. In another embodiment, a NOVX fusion protein comprises at least two biologically-active portions of a NOVX protein. In yet another embodiment, a NOVX fusion protein comprises at least three biologically-active portions of a NOVX protein. Within the fusion protein, the term "operatively-linked" is intended to indicate that the NOVX polypeptide and the non-NOVX polypeptide are fused in-frame with one another. The non-NOVX polypeptide can be fused to the N-terminus or C-terminus ofthe NOVX polypeptide.

In one embodiment, the fusion protein is a GST-NO VX fusion protein in which the NOVX sequences are fused to the C-terminus ofthe GST (glutathione S-transferase) sequences. Such fusion proteins can facilitate the purification of recombinant NOVX polypeptides.

In another embodiment, the fusion protein is a NOVX protein containing a heterologous signal sequence at its N-terminus. In certain host cells (e.g., mammalian host cells), expression and/or secretion of NOVX can be increased through use of a heterologous signal sequence.

In yet another embodiment, the fusion protein is a NOVX-immunoglobulin fusion protein in which the NOVX sequences are fused to sequences derived from a member ofthe immunoglobulin protein family. The NOVX-immunoglobulin fusion proteins ofthe invention can be incoφorated into pharmaceutical compositions and administered to a subject to inhibit an interaction between a NOVX ligand and a NOVX protein on the surface of a cell, to thereby suppress NOVX-mediated signal transduction in vivo. The NOVX- immunoglobulin fusion proteins can be used to affect the bioavailability of a NOVX cognate ligand. Inhibition of the NOVX ligand/NOVX interaction may be useful therapeutically for both the treatment of proliferative and differentiative disorders, as well as modulating (e.g. promoting or inhibiting) cell survival. Moreover, the NOVX-immunoglobulin fusion proteins ofthe invention can be used as immunogens to produce anti-NOVX antibodies in a subject, to purify NOVX ligands, and in screening assays to identify molecules that inhibit the interaction of NOVX with a NOVX ligand.

A NOVX chimeric or fusion protein ofthe invention can be produced by standard recombinant DNA techniques. For 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 appropriate termini, filling-in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and enzymatic ligation. In another embodiment, 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 to generate a chimeric gene sequence (see, e.g., Ausubel, et al. (eds.) CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, 1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g. , a GST polypeptide). A NOVX-encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the NOVX protein.

NOVX Agonists and Antagonists

The invention also pertains to variants ofthe NOVX proteins that function as either NOVX agonists (i.e., mimetics) or as NOVX antagonists. Nariants ofthe ΝOVX protein can be generated by mutagenesis (e.g. , discrete point mutation or truncation of the ΝOVX protein). An agonist ofthe ΝOVX protein can retain substantially the same, or a subset of, the biological activities ofthe naturally occurring form ofthe ΝOVX protein. An antagonist ofthe ΝOVX protein can inhibit one or more ofthe activities ofthe naturally occurring form ofthe ΝOVX protein by, for example, competitively binding to a downstream or upstream member of a cellular signaling cascade which includes the NOVX protein. Thus, specific biological effects can be elicited by treatment with a variant of limited function. In one embodiment, treatment of a subject with a variant having a subset ofthe biological activities ofthe naturally occurring form ofthe protein has fewer side effects in a subject relative to treatment with the naturally occurring form of the NOVX proteins.

Variants ofthe NOVX proteins that function as either NOVX agonists (i.e., mimetics) or as NOVX antagonists can be identified by screening combinatorial libraries of mutants (e.g., truncation mutants) ofthe NOVX proteins for NOVX protein agonist or antagonist activity. In one embodiment, a variegated library of NOVX variants is generated by combinatorial mutagenesis at the nucleic acid level and is encoded by a variegated gene library. A variegated library of NOVX variants can be produced by, for example, enzymatically ligating a mixture of synthetic oligonucleotides into gene sequences such that a degenerate set of potential NOVX sequences is expressible as individual polypeptides, or alternatively, as a set of larger fusion proteins (e.g., for phage display) containing the set of NOVX sequences therein. There are a variety of methods which can be used to produce libraries of potential NOVX variants from a degenerate oligonucleotide sequence. Chemical synthesis of a degenerate gene sequence can be performed in an automatic DNA synthesizer, and the synthetic gene then ligated into an appropriate expression vector. Use of a degenerate set of genes allows for the provision, in one mixture, of all ofthe sequences encoding the desired set of potential NOVX sequences. Methods for synthesizing degenerate oligonucleotides are well-known within the art. See, e.g., Narang, 1983. Tetrahedron 39: 3; Itakura, et al, 1984. Annu. Rev. Biochem. 53: 323; Itakura, et al, 1984. Science 198: 1056; Ike, et al, 1983. Nucl. Acids Res. 11 : 477.

Polypeptide Libraries

In addition, libraries of fragments ofthe NOVX protein coding sequences can be used to generate a variegated population of NOVX fragments for screening and subsequent selection of variants of a NOVX protein. In one embodiment, a library of coding sequence fragments can be generated by treating a double stranded PCR fragment of a NOVX coding sequence with a nuclease under conditions wherein nicking occurs only about once per molecule, denaturing the double stranded DNA, renaturing the DNA to form double-stranded DNA that can include sense/antisense pairs from different nicked products, removing single stranded portions from reformed duplexes by treatment with Si nuclease, and ligating the resulting fragment library into an expression vector. By this method, expression libraries can be derived which encodes N-terminal and internal fragments of various sizes ofthe NOVX proteins.

Various techniques are known in the art for screening gene products of combinatorial libraries made by point mutations or truncation, and for screening cDNA libraries for gene products having a selected property. Such techniques are adaptable for rapid screening ofthe gene libraries generated by the combinatorial mutagenesis of NOVX proteins. The most widely used techniques, which are amenable to high throughput analysis, for screening large gene libraries typically include cloning the gene library into replicable expression vectors, transforming appropriate cells with the resulting library of vectors, and expressing the combinatorial genes under conditions in which detection of a desired activity facilitates isolation ofthe vector encoding the gene whose product was detected. Recursive ensemble mutagenesis (REM), a new technique that enhances the frequency of functional mutants in the libraries, can be used in combination with the screening assays to identify NOVX variants. See, e.g., Arkin and Yourvan, 1992. Proc. Natl. Acad. Sci. USA 89: 7811-7815; Delgrave, et al, 1993. Protein Engineering 6:327-331.

NOVX Antibodies

The term "antibody" as used herein refers to immunoglobulin molecules and immunologically active portions 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, F_ab, Fab' and F(_ab')₂ fragments, and an F_ab expression library. In general, antibody molecules obtained from humans relates to any ofthe classes IgG, IgM, IgA, IgE and IgD, which differ from one another by the nature ofthe 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 protein ofthe invention intended to serve as an antigen, or a portion or fragment thereof, 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 ofthe antigen for use as immunogens. An antigenic peptide fragment comprises at least 6 amino acid residues ofthe amino acid sequence ofthe full length protein, such as an amino acid sequence of SEQ ID NO:2τ7, wherein ?7 is an integer between 1-101, 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 ofthe protein that are located on its surface; commonly these are hydrophilic regions.

In certain embodiments ofthe invention, at least one epitope encompassed by the antigenic peptide is a region of NOVX that is located on the surface ofthe protein, e.g., a hydrophilic region. A hydrophobicity analysis ofthe human NOVX protein sequence will indicate which regions of a NOVX polypeptide are particularly hydrophilic and, therefore, 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; Kyte and Doolittle 1982, J. Mol. Biol 157: 105-142, each incoφorated herein by reference in their entirety. Antibodies that are specific for one or more domains within an antigenic protein, or derivatives, fragments, analogs or homologs thereof, are also provided herein. The term "epitope" includes any protein determinant capable of specific binding to an immunoglobulin or T-cell receptor. Epitopic determinants usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three dimensional structural characteristics, as well as specific charge characteristics. A NOVX polyppeptide or a fragment thereof comprises at least one antigenic epitope. An anti-NOVX antibody of the present invention is said to specifically bind to antigen NOVX when the equilibrium binding constant (K_D) is <1 μM, preferably < 100 nM, more preferably < 10 nM, and most preferably < 100 pM to about 1 pM, as measured by assays such as radioligand binding assays or similar assays known to those skilled in the art. A protein ofthe 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.

Various procedures known within the art may be used for the production of polyclonal or monoclonal antibodies directed against a protein ofthe 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, incoφorated herein by reference). Some of these antibodies are discussed below. 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 ofthe 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 which 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 ofthe immunoglobulin sought, or an epitope thereof, may be immobilized on a column to purify the immune specific antibody by immunoaffinity chromatography. Purification of immunoglobulins is discussed, for example, by D. Wilkinson (The Scientist, published by The Scientist, Inc., Philadelphia PA, Vol. 14, No. 8 (April 17, 2000), pp. 25-28).

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 ofthe population. MAbs thus contain an antigen binding site capable of immunoreacting with a particular epitope ofthe 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, or other appropriate host 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, Monoclonal 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 ofthe 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. Immunol.. 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 techniques and assays are known in the art. The binding affinity ofthe monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal. Biochem., 107:220 (1980). It is an objective, especially important in therapeutic applications of monoclonal antibodies, to identify antibodies having a high degree of specificity and a high binding affinity for the target antigen.

After the desired hybridoma cells are identified, the clones can be subcloned by limiting dilution procedures and grown by standard methods (Goding, 1986). Suitable culture media for this puφose 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 monoclonal antibodies can also be made by recombinant DNA methods, such as those described in U.S. Patent No. 4,816,567. DNA encoding the monoclonal antibodies of the mvention 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 ofthe 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 immunoglobulin 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 ofthe homologous murine sequences (U.S. Patent No. 4,816,567; Morrison, Nature 368, 812-13 (1994)) or by covalently joining to the immunoglobulin coding sequence all or part ofthe coding sequence for a non- immunoglobulin polypeptide. Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody ofthe invention, or can be substituted for the variable domains of one antigen-combining site of an antibody ofthe invention to create a chimeric bivalent antibody.

Humanized Antibodies

The antibodies directed against the protein antigens ofthe 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. Humanized 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 ofthe sequence of a human immunoglobulin, and contain minimal sequence derived from a non- human immunoglobulin. Humanization can be performed following the method of Winter and co-workers (Jones 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 U.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 which 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 ofthe CDR regions correspond to those of a non-human immunoglobulin and all or substantially all ofthe 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)).

Human Antibodies

Fully human antibodies essentially relate to antibody molecules in which the entire sequence 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 B-cell hybridoma technique (see Kozbor, 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 THERAPY, 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: 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 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; 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 ( ature 368. 812-13 (1994)); Fishwild et al,( Nature Biotechnologv 14, 845-51 (1996)); Neuberger (Nature

Biotechnology 14, 826 (1996)); and Lonberg and Huszar (Intern. Rev. Immunol. 13 65-93 (1995)).

Human antibodies may additionally be produced using transgenic nonhuman animals which 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

WO94/02602). 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 incoφorated, for example, using yeast artificial chromosomes containing the requisite human DNA segments. An animal which provides all the desired modifications is then obtained as progeny by crossbreeding intermediate transgenic animals containing fewer than the full complement ofthe 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 which 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 U.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 ofthe 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 marker; 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 U.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.

F_ab 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 ofthe invention (see e.g., U.S. Patent No. 4,946,778). In addition, methods can be adapted for the construction of F_ab expression libraries (see e.g., Huse, et al., 1989 Science 246: 1275-1281) to allow rapid and effective identification of monoclonal F_ab 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 F_a fragment generated by reducing the disulfide bridges of an F(_ay)₂ fragment; (iii) an F_ab fragment generated by the treatment ofthe antibody molecule with papain and a reducing agent and (iv) F_v fragments.

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 ofthe binding specificities is for an antigenic protein ofthe 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 ofthe random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture often different antibody molecules, of which only one has the correct bispecific structure. The purification ofthe 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., EMBO J.. 10:3655-3659 (1991).

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 ofthe hinge, CH2, and CH3 regions. It is preferred to have the first heavy-chain constant region (CHI) 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 which are recovered from recombinant cell culture. The preferred interface comprises at least a part ofthe CH3 region of an antibody constant domain. In this method, one or more small amino acid side chains from the interface ofthe 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 chain(s) are created on the interface ofthe 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 ofthe heterodimer over other unwanted end-products such as homodimers.

Bispecific 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 linkage. Brennan 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 ofthe 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 ofthe Fab'-TNB derivatives is then reconverted to the Fab'-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount ofthe 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 bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. Kostelny 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 (V_H) connected to a light-chain variable domain (V_L) by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the V_H and V_L domains of one fragment are forced to pair with the complementary V_L and V_H 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).

Exemplary bispecific antibodies can bind to two different epitopes, at least one of which originates in the protein antigen ofthe invention. Alternatively, an anti-antigenic arm 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 (FcγR), such as FcγRI (CD64), FcγRII (CD32) and FcγRIII (CD 16) 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 bispecific antibody of interest binds the protein antigen described herein and further binds tissue factor (TF).

Heteroconjugate Antibodies

Heteroconjugate antibodies are also within the scope ofthe 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 (U.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 puφose include iminothiolate and methyl-4-mercaptobutyrirmdate and those disclosed, for example, in U.S. Patent No. 4,676,980.

Effector Function Engineering It can be desirable to modify the antibody of the invention with respect to effector function, so as to enhance, e.g., the effectiveness ofthe antibody in treating cancer. For example, cysteine residue(s) 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 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 Research, 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., Anti-Cancer Drug Design, 3: 219-230 (1989).

Immunoconjugates

The invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g., an enzymatically active 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 ²¹²Bi, ¹³¹1, ¹³¹In, ⁹⁰Y, and ¹⁸⁶Re.

Conjugates ofthe 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 dimethyl adipimidate HCL), active esters (such as disuccimmidyl 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 l-isothiocyanatobenzyl-3- methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See W094/11026.

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 conjugate from the circulation using a clearing agent and then administration of a "ligand" (e.g., avidin) that is in turn conjugated to a cytotoxic agent.

lmmunoliposonies The antibodies disclosed herein can also be formulated as imrnunoliposomes.

Liposomes containing the antibody are prepared by methods known in the art, such as described in Epstein et al., Proc. Natl. Acad. Sci. USA. 82: 3688 (1985); Hwang et al., Proc. Natl Acad. Sci. USA. J7: 4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Patent No. 5,013,556. Particularly useful liposomes can be generated by the reverse-phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG- derivatized phosphatidylethanolamme (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter. Fab' fragments ofthe antibody ofthe present mvention can be conjugated to the liposomes as described in Martin et al .. J. Biol. Chem.. 257: 286-288 (1982) via a disulfide-interchange reaction. A chemotherapeutic agent (such as Doxorubicin) is optionally contained within the liposome. See Gabizon et al., j. National Cancer Inst. 81(19): 1484 (1989).

Diagnostic Applications of Antibodies Directed Against the Proteins ofthe Invention

Antibodies directed against a protein ofthe invention may be used in methods known within the art relating to the localization and/or quantitation ofthe protein (e.g., for use in measuring levels ofthe protein within appropriate physiological samples, for use in diagnostic methods, for use in imaging the protein, and the like). In a given embodiment, antibodies against the proteins, or derivatives, fragments, analogs or homologs thereof, that contain the antigen binding domain, are utilized as pharmacologically-active compounds (see below).

An antibody specific for a protein ofthe invention can be used to isolate the protein by standard techniques, such as immunoaffinity chromatography or immunoprecipitation. Such an antibody can facilitate the purification ofthe natural protein antigen from cells and of recombinantly produced antigen expressed in host cells. Moreover, such an antibody can be used to detect the antigenic protein (e.g., in a cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression ofthe antigenic protein. Antibodies directed against the protein can be used diagnostically to monitor protein levels in tissue as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling (i.e., physically linking) the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include ¹²⁵1, ¹³¹1, ³⁵S or ³H.

Antibody Therapeutics

Antibodies ofthe invention, including polyclonal, monoclonal, humanized and fully human antibodies, may used as therapeutic agents. Such agents will generally be employed to treat or prevent a disease or pathology in a subject. An antibody preparation, preferably one having high specificity and high affinity for its target antigen, is administered to the subject and will generally have an effect due to its binding with the target. Such an effect may be one of two kinds, depending on the specific nature ofthe interaction between the given antibody molecule and the target antigen in question. In the first instance, administration ofthe antibody may abrogate or inhibit the binding ofthe target with an endogenous ligand to which it naturally binds. In this case, the antibody binds to the target and masks a binding site ofthe naturally occurring ligand, wherein the ligand serves as an effector molecule. Thus the receptor mediates a signal transduction pathway for which ligand is responsible. Alternatively, the effect may be one in which the antibody elicits a physiological result by virtue of binding to an effector binding site on the target molecule. In this case the target, a receptor having an endogenous ligand which may be absent or defective in the disease or pathology, binds the antibody as a surrogate effector ligand, initiating a receptor- based signal transduction event by the receptor. A therapeutically effective amount of an antibody of the invention relates generally to the amount needed to achieve a therapeutic objective. As noted above, this may be a binding interaction between the antibody and its target antigen that, in certain cases, interferes with the functioning ofthe target, and in other cases, promotes a physiological response. The amount required to be administered will furthermore depend on the binding affinity ofthe antibody for its specific antigen, and will also depend on the rate at which an administered antibody is depleted from the free volume other subject to which it is administered. Common ranges for therapeutically effective dosing of an antibody or antibody fragment ofthe invention may be, by way of nonlimiting example, from about 0.1 mg/kg body weight to about 50 mg/kg body weight. Common dosing frequencies may range, for example, from twice daily to once a week.

Pharmaceutical Compositions of Antibodies

Antibodies specifically binding a protein ofthe invention, as well as other molecules identified by the screening assays disclosed herein, can be administered for the treatment of various disorders in the form of pharmaceutical compositions. Principles and considerations involved in preparing such compositions, as well as guidance in the choice of components are provided, for example, in Remington : The Science And Practice Of Pharmacy 19th ed. (Alfonso R. Gennaro, et al., editors) Mack Pub. Co., Easton, Pa. : 1995; Drug Absoφtion Enhancement : Concepts, Possibilities, Limitations, And Trends, Harwood Academic Publishers, Langhorne, Pa., 1994; and Peptide And Protein Drug Delivery (Advances In Parenteral Sciences, Vol. 4), 1991, M. Dekker, New York.

If the antigenic protein is intracellular and whole antibodies are used as inhibitors, internalizing antibodies are preferred. However, liposomes can also be used to deliver the antibody, or an antibody fragment, into cells. Where antibody fragments are used, the smallest inhibitory fragment that specifically binds to the binding domain ofthe target protein is preferred. For example, based upon the variable-region sequences of an antibody, peptide molecules can be designed that retain the ability to bind the target protein sequence. Such peptides can be synthesized chemically and/or produced by recombinant DNA technology. See, e.g., Marasco et al., Proc Natl. Acad. Sci. USA, 90: 7889-7893 (1993). The formulation herein can also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Alternatively, or in addition, the composition can comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent. Such molecules are suitably present in combination in amounts that are effective for the puφose intended.

The active ingredients can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules) or in macroemulsions.

The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes. Sustained-release preparations can be prepared. Suitable examples of sustained- release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polyketides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and γ ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT ™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene- vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods.

ELISA Assay

An agent for detecting an analyte protein is an antibody capable of binding to an analyte protein, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g-., F_a or F(_ab)₂) can be used. The term "labeled", with regard to the probe or antibody, is intended to encompass direct labeling ofthe probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term "biological sample" is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. Included within the usage ofthe term "biological sample", therefore, is blood and a fraction or component of blood including blood serum, blood plasma, or lymph. That is, the detection method of the invention can be used to detect an analyte mRNA, protein, or genomic DNA in a biological sample in vitro as well as 77 vivo. For example, 777 vitro techniques for detection of an analyte mRNA include Northern hybridizations and in situ hybridizations. J77 vitro techniques for detection of an analyte protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of an analyte genomic DNA include Southern hybridizations. Procedures for conducting immunoassays are described, for example in "ELISA: Theory and Practice: Methods in Molecular Biology", Vol. 42, J. R. Crowther (Ed.) Human Press, Totowa, NJ, 1995;

"Immunoassay", E. Diamandis and T. Christopoulus, Academic Press, Inc., San Diego, CA, 1996; and "Practice and Thory of Enzyme Immunoassays", P. Tijssen, Elsevier Science Publishers, Amsterdam, 1985. Furthermore, 777 vivo techniques for detection of an analyte protein include introducing into a subject a labeled anti-an analyte protein antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.

NOVX Recombinant Expression Vectors and Host Cells

Another aspect ofthe invention pertains to vectors, preferably expression vectors, containing a nucleic acid encoding a NOVX protein, or derivatives, fragments, analogs or homologs thereof. As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which refers to a circular double stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively-linked. Such vectors are referred to herein as "expression vectors". In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, "plasmid" and "vector" can be used interchangeably as the plasmid is the most commonly used form of vector. However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions. The recombinant expression vectors ofthe invention comprise a nucleic acid ofthe invention in a form suitable for expression ofthe nucleic acid in a host cell, which means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis ofthe host cells to be used for expression, that is operatively-linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, "operably-linked" is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner that allows for expression ofthe nucleotide sequence (e.g., in at. in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell).

The term "regulatory sequence" is intended to mcludes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, for example, in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Regulatory sequences include those that direct constitutive expression of a nucleotide sequence in many types of host cell and those that direct expression ofthe nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design ofthe expression vector can depend on such factors as the choice ofthe host cell to be transformed, the level of expression of protein desired, etc. The expression vectors ofthe invention can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein (e.g., NOVX proteins, mutant forms of NOVX proteins, fusion proteins, etc.).

The recombinant expression vectors ofthe invention can be designed for expression of NOVX proteins in prokaryotic or eukaryotic cells. For example, NOVX proteins can be expressed in bacterial cells such as Escherichia coli, insect cells (using baculovirus expression vectors) yeast cells or mammalian cells. Suitable host cells are discussed further in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.

Expression of proteins in prokaryotes is most often carried out in Escherichia coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion proteins. Fusion vectors add a number of amino acids to a protein encoded therein, usually to the amino terminus ofthe recombinant protein. Such fusion vectors typically serve three puφoses: (i) to increase expression of recombinant protein; (ii) to increase the solubility ofthe recombinant protein; and (iii) to aid in the purification ofthe recombinant protein by acting as a ligand in affinity purification. Often, in fusion expression vectors, a proteolytic cleavage site is introduced at the junction ofthe fusion moiety and the recombinant protein to enable separation ofthe recombinant protein from the fusion moiety subsequent to purification ofthe fusion protein. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin and enterokinase. Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith and Johnson, 1988. Ge77e 67: 31-40), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, NJ.) that fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein.

Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amrann et al, (1988) Gene 69:301-315) andpET lid (Srudier et al, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 60-89). One strategy to maximize recombinant protein expression in E. coli is to express the protein in a host bacteria with an impaired capacity to proteolytically cleave the recombinant protein. See, e.g., Gottesman, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 119-128. Another strategy is to alter the nucleic acid sequence ofthe nucleic acid to be inserted into an expression vector so that the individual codons for each amino acid are those preferentially utilized in E. coli (see, e.g., Wada, et al, 1992. Nucl. Acids Res. 20: 2111-2118). Such alteration of nucleic acid sequences ofthe invention can be carried out by standard DNA synthesis techniques.

In another embodiment, the NOVX expression vector is a yeast expression vector. Examples of vectors for expression in yeast Saccharomyces cerivisae include pYepSecl (Baldari, et al, 1987. EMBO J. 6: 229-234), pMFa (Kurjan and Herskowitz, 1982. Cell 30: 933-943), ρJRY88 (Schultz et al, 1987. Gene 54: 113-123), pYES2 (Invitrogen Coφoration, San Diego, Calif.), and picZ (InVitrogen Coφ, San Diego, Calif.).

Alternatively, NOVX can be expressed in insect cells using baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., SF9 cells) include the pAc series (Smith, etal, 1983. Mol. Cell. Biol. 3: 2156-2165) and the pVL series (Lucklow and Summers, 1989. Virology 170: 31-39).

In yet another embodiment, a nucleic acid ofthe invention is expressed in mammalian cells using a mammalian expression vector. Examples of mammalian expression vectors include pCDM8 (Seed, 1987. Nαtwre 329: 840) and pMT2PC (Kaufman, et al, 1987. EMBO J. 6: 187-195). When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, adenovirus 2, cytomegalo virus, and simian virus 40. For other suitable expression systems for both prokaryotic and eukaryotic cells see, e.g., Chapters 16 and 17 of Sambrook, et al, MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989.

In another embodiment, the recombinant mammalian expression vector is capable of directing expression ofthe nucleic acid preferentially in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid). Tissue-specific regulatory elements are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert, et al, 1987. Genes Dev. 1: 268-277), lymphoid-specific promoters (Calame and Eaton, 1988. Adv. Immunol. 43: 235-275), in particular promoters of T cell receptors (Winoto and Baltimore, 1989. EMBOJ. 8: 729-733) and immunoglobulins (Banerji, et al, 1983. Cell 33: 729-740; Queen and Baltimore, 1983. Cell 33: 741-748), neuron-specific promoters (e.g., the neurofilament promoter; Byrne and Ruddle, 1989. Proc. Natl Acad. Sci. USA 86: 5473-5477), pancreas-specific promoters (Edlund, et al, 1985. Science 230: 912-916), and mammary gland-specific promoters (e.g. , milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Publication No. 264,166). Developmentally-regulated promoters are also encompassed, e.g., the murine hox promoters (Kessel and Gruss, 1990. Science 249: 374-379) and the α-fetoprotein promoter (Campes and Tilghman, 1989. Genes Dev. 3: 537-546). The invention further provides a recombinant expression vector comprising a DNA molecule ofthe invention cloned into the expression vector in an antisense orientation. That is, the DNA molecule is operatively-linked to a regulatory sequence in a manner that allows for expression (by transcription ofthe DNA molecule) of an RNA molecule that is antisense to NOVX mRNA. Regulatory sequences operatively linked to a nucleic acid cloned in the antisense orientation can be chosen that direct the continuous expression of the antisense RNA molecule in a variety of cell types, for instance viral promoters and/or enhancers, or regulatory sequences can be chosen that direct constitutive, tissue specific or cell type specific expression of antisense RNA. The antisense expression vector can be in the form of a recombinant plasmid, phagemid or attenuated virus in which antisense nucleic acids are produced under the control of a high efficiency regulatory region, the activity of which can be determined by the cell type into which the vector is introduced. For a discussion ofthe regulation of gene expression using antisense genes see, e.g., Weintraub, et al, "Antisense RNA as a molecular tool for genetic analysis," Reviews-Trends in Genetics, Vol. 1(1) 1986. Another aspect ofthe invention pertains to host cells into which a recombinant expression vector ofthe invention has been introduced. The terms "host cell" and

"recombinant host cell" are used interchangeably herein. It is understood that such terms refer not only to the particular subject cell but also to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope ofthe term as used herein.

A host cell can be any prokaryotic or eukaryotic cell. For example, NOVX protein can be expressed in bacterial cells such as E. coli, insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS cells). Other suitable host cells are known to those skilled in the art. Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. As used herein, the terms "transformation" and "transfection" are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, or electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook, et al. (MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989), and other laboratory manuals.

For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Various selectable markers include those that confer resistance to drugs, such as G418, hygromycin and methotrexate. Nucleic acid encoding a selectable marker can be introduced into a host cell on the same vector as that encoding NOVX or can be introduced on a separate vector. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have incoφorated the selectable marker gene will survive, while the other cells die).

A host cell ofthe invention, such as a prokaryotic or eukaryotic host cell in culture, can be used to produce (t.e. , express) NOVX protein. Accordingly, the invention further provides methods for producing NOVX protein using the host cells ofthe invention. In one embodiment, the method comprises culturing the host cell of invention (into which a recombinant expression vector encoding NOVX protein has been introduced) in a suitable medium such that NOVX protein is produced. In another embodiment, the method further comprises isolating NOVX protein from the medium or the host cell.

Transgenic NOVX Animals

The host cells ofthe invention can also be used to produce non-human transgenic animals. For example, in one embodiment, a host cell ofthe invention is a fertilized oocyte or an embryonic stem cell into which NOVX protein-coding sequences have been introduced. Such host cells can then be used to create non-human transgenic animals in which exogenous NOVX sequences have been introduced into their genome or homologous recombinant animals in which endogenous NOVX sequences have been altered. Such animals are useful for studying the function and/or activity of NOVX protein and for identifying and/or evaluating modulators of NOVX protein activity. As used herein, a "transgenic animal" is a non-human animal, preferably a mammal, more preferably a rodent such as a rat or mouse, in which one or more ofthe cells ofthe animal includes a transgene. Other examples of transgenic animals include non-human primates, sheep, dogs, cows, goats, chickens, amphibians, etc. A transgene is exogenous DNA that is integrated into the genome of a cell from which a transgenic animal develops and that remains in the genome ofthe mature animal, thereby directing the expression of an encoded gene product in one or more cell types or tissues ofthe transgenic animal. As used herein, a "homologous recombinant animal" is a non-human animal, preferably a mammal, more preferably a mouse, in which an endogenous NOVX gene has been altered by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell ofthe animal, e.g., an embryonic cell ofthe animal, prior to development ofthe animal. A transgenic animal ofthe invention can be created by introducing NOVX-encoding nucleic acid into the male pronuclei of a fertilized oocyte (e.g., by microinjection, retroviral infection) and allowing the oocyte to develop in a pseudopregnant female foster animal. The human NOVX cDNA sequences, i.e., any one of SEQ ID NO:277-l, wherein 77 is an integer between 1-101, can be introduced as a transgene into the genome of a non-human animal. Alternatively, a non-human homologue ofthe human NOVX gene, such as a mouse NOVX gene, can be isolated based on hybridization to the human NOVX cDNA (described further supra) and used as a transgene. Intronic sequences and polyadenylation signals can also be included in the transgene to increase the efficiency of expression ofthe transgene. A tissue-specific regulatory sequence(s) can be operably-linked to the NOVX transgene to direct expression of NOVX protein to particular cells. Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Patent Nos. 4,736,866; 4,870,009; and 4,873,191; and Hogan, 1986. In: MANIPULATING THE MOUSE EMBRYO, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence ofthe NOVX transgene in its genome and/or expression of NOVX mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene-encoding NOVX protein can further be bred to other transgenic animals carrying other transgenes.

To create a homologous recombinant animal, a vector is prepared which contains at least a portion of a NOVX gene into which a deletion, addition or substitution has been introduced to thereby alter, e.g., functionally disrupt, the NOVX gene. The NOVX gene can be a human gene (e.g., the cDNA of any one of SEQ ID NO: 277-1, wherein 77 is an integer between 1-101), but more preferably, is a non-human homologue of a human NOVX gene. For example, a mouse homologue of human NOVX gene of SEQ ID NO:2τ?.-l, wherein 77 is an integer between 1-101, can be used to construct a homologous recombination vector suitable for altering an endogenous NOVX gene in the mouse genome. In one embodiment, the vector is designed such that, upon homologous recombination, the endogenous NOVX gene is functionally disrupted (t.e., no longer encodes a functional protein; also referred to as a "knock out" vector).

Alternatively, the vector can be designed such that, upon homologous recombination, the endogenous NOVX gene is mutated or otherwise altered but still encodes functional protein (e.g., the upstream regulatory region can be altered to thereby alter the expression of the endogenous NOVX protein). In the homologous recombination vector, the altered portion ofthe NOVX gene is flanked at its 5'- and 3 '-termini by additional nucleic acid ofthe NOVX gene to allow for homologous recombination to occur between the exogenous NOVX gene carried by the vector and an endogenous NOVX gene in an embryonic stem cell. The additional flanking NOVX nucleic acid is of sufficient length for successful homologous recombination with the endogenous gene. Typically, several kilobases of flanking DNA (both at the 5'- and 3'-termini) are included in the vector. See, e.g., Thomas, et al, 1987. Cell 51 : 503 for a description of homologous recombination vectors. The vector is ten introduced into an embryonic stem cell line (e.g., by electroporation) and cells in which the introduced NOVX gene has homologously-recombined with the endogenous NOVX gene are selected. See, e.g., Li, et al, 1992. Ce// 69: 915.

The selected cells are then injected into a blastocyst of an animal (e.g., a mouse) to form aggregation chimeras. See, e.g., Bradley, 1987. In: TERATOCARCINOMAS AND EMBRYONIC STEM CELLS: A PRACTICAL APPROACH, Robertson, ed. IRL, Oxford, pp. 113- 152. A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term. Progeny harboring the homologously- recombined DNA in their germ cells can be used to breed animals in which all cells ofthe animal contain the homologously-recombined DNA by germline transmission ofthe transgene. Methods for constructing homologous recombination vectors and homologous recombinant animals are described further in Bradley, 1991. Curr. Opin. Biotechnol. 2:

823-829; PCT International Publication Nos.: WO 90/11354; WO 91/01140; WO 92/0968; and WO 93/04169.

In another embodiment, transgenic non-humans animals can be produced that contain selected systems that allow for regulated expression ofthe transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage PI. For a description ofthe cre/loxP recombinase system, See, e.g., Lakso, et al, 1992. Proc. Natl. Acad. Sci. USA 89: 6232-6236. Another example of a recombinase system is the FLP recombinase system of Saccharomyces cerevisiae. See, O'Gorman, et al, 1991. Science 251:1351-1355. If a cre/loxP recombinase system is used to regulate expression ofthe transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are required. Such animals can be provided through the construction of "double" transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected protein and the other containing a transgene encoding a recombinase. Clones ofthe non-human transgenic animals described herein can also be produced according to the methods described in Wilmut, et al, 1997. Nature 385: 810-813. In brief, a cell (e.g., a somatic cell) from the transgenic animal can be isolated and induced to exit the growth cycle and enter G₀ phase. The quiescent cell can then be fused, e.g., through the use of electrical pulses, to an enucleated oocyte from an animal ofthe same species from which the quiescent cell is isolated. The reconstructed oocyte is then cultured such that it develops to morula or blastocyte and then transferred to pseudopregnant female foster animal. The offspring borne of this female foster animal will be a clone ofthe animal from which the cell (e.g., the somatic cell) is isolated.

Pharmaceutical Compositions The NOVX nucleic acid molecules, NOVX proteins, and anti-NOVX antibodies (also referred to herein as "active compounds") ofthe invention, and derivatives, fragments, analogs and homologs thereof, can be incoφorated into pharmaceutical compositions suitable for administration. Such compositions typically comprise the nucleic acid molecule, protein, or antibody and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absoφtion delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incoφorated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, finger's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incoφorated into the compositions.

A pharmaceutical composition ofthe invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermai (t.e., topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL (BASF, Parsippany, NJ.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersion and by the use of surfactants. Prevention ofthe action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absoφtion ofthe injectable compositions can be brought about by including in the composition an agent which delays absoφtion, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incoφorating the active compound (e.g., a NOVX protein or anti-NOVX antibody) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incoφorating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the puφose of oral therapeutic administration, the active compound can be incoφorated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part ofthe composition. The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration can also be by transmucosal or transdermai means. For transmucosal or transdermai administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermai administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Coφoration and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811. It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms ofthe invention are dictated by and directly dependent on the unique characteristics ofthe active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

The nucleic acid molecules ofthe invention can be inserted into vectors and used as gene therapy vectors. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see, e.g., U.S. Patent No. 5,328,470) or by stereotactic injection (see, e.g., Chen, et al, 1994. Proc. Natl. Acad. Sci. USA 91: 3054-3057). The pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g., retroviral vectors, the pharmaceutical preparation can include one or more cells that produce the gene delivery system.

The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. Screening and Detection Methods

The isolated nucleic acid molecules ofthe invention can be used to express NOVX protein (e.g., via a recombinant expression vector in a host cell in gene therapy applications), to detect NOVX mRNA (e.g., in a biological sample) or a genetic lesion in a NOVX gene, and to modulate NOVX activity, as described further, below. In addition, the NOVX proteins can be used to screen drugs or compounds that modulate the NOVX protein activity or expression as well as to treat disorders characterized by insufficient or excessive production of NOVX protein or production of NOVX protein forms that have decreased or aberrant activity compared to NOVX wild-type protein (e.g.; diabetes (regulates insulin release); obesity (binds and transport lipids); metabolic disturbances associated with obesity, the metabolic syndrome X as well as anorexia and wasting disorders associated with chronic diseases and various cancers, and infectious disease(possesses anti-microbial activity) and the various dyslipidemias. In addition, the anti-NOVX antibodies ofthe invention can be used to detect and isolate NOVX proteins and modulate NOVX activity. In yet a further aspect, the invention can be used in methods to influence appetite, absoφtion of nutrients and the disposition of metabolic substrates in both a positive and negative fashion.

The invention further pertains to novel agents identified by the screening assays described herein and uses thereof for treatments as described, supra.

Screening Assays

The invention provides a method (also referred to herein as a "screening assay") for identifying modulators, i.e., candidate or test compounds or agents (e.g., peptides, peptidomimetics, small molecules or other drugs) that bind to NOVX proteins or have a stimulatory or inhibitory effect on, e.g., NOVX protein expression or NOVX protein activity. The invention also includes compounds identified in the screening assays described herein. In one embodiment, the invention provides assays for screening candidate or test compounds which bind to or modulate the activity ofthe membrane-bound form of a NOVX protein or polypeptide or biologically-active portion thereof. The test compounds ofthe invention can be obtained using any ofthe numerous approaches in combinatorial library methods known in the art, including: biological libraries; spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the "one-bead one-compound" library method; and synthetic library methods using affinity chromatography selection. The biological library approach is limited to peptide libraries, while the other four approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds. See, e.g., Lam, 199 '. Anticancer Drug Design 12: 145.

A "small molecule" as used herein, is meant to refer to a composition that has a molecular weight of less than about 5 kD and most preferably less than about 4 kD. Small molecules can be, e.g., nucleic acids, peptides, polypeptides, peptidomimetics, carbohydrates, lipids or other organic or inorganic molecules. Libraries of chemical and/or biological mixtures, such as fungal, bacterial, or algal extracts, are known in the art and can be screened with any ofthe assays ofthe invention.

Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: DeWitt, et al, 1993. Proc. Natl Acad. Sci. U.S.A. 90: 6909; Erb, et al, 1994. Proc. Natl. Acad. Sci. U.S.A. 91: 11422; Zuckermann, et al, 1994. J. Med. Chem. 37: 2678; Cho, et al, 1993. Science 261: 1303; Carrell, et al, 1994. Angew. Chem. Int. Ed. Engl. 33: 2059; Carell, et al, 1994. Angew. Chem. Int. Ed. Engl. 33: 2061; and Gallop, et al, 1994. J. Med. Chem. 37: 1233. Libraries of compounds may be presented in solution (e.g., Houghten, 1992.

Biotechniques 13: 412-421), or on beads (Lam, 1991. Nature 354: 82-84), on chips (Fodor, 1993. Nature 364: 555-556), bacteria (Ladner, U.S. Patent No. 5,223,409), spores (Ladner, U.S. Patent 5,233,409), plasmids (Cull, et al, 1992. Proc. Natl. Acad. Sci. USA 89: 1865-1869) or on phage (Scott and Smith, 1990. Scteτ7ce 249: 386-390; Devlin, 1990. Science 249: 404-406; Cwirla, et al, 1990. Proc. Natl. Acad. Sci. U.S.A. 87: 6378-6382; Felici, 1991. J. Mol Biol. 222: 301-310; Ladner, U.S. Patent No. 5,233,409.).

In one embodiment, an assay is a cell-based assay in which a cell which expresses a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface is contacted with a test compound and the ability ofthe test compound to bind to a NOVX protein determined. The cell, for example, can of mammalian origin or a yeast cell. Determining the ability of the test compound to bind to the NOVX protein can be accomplished, for example, by coupling the test compound with a radioisotope or enzymatic label such that binding ofthe test compound to the NOVX protein or biologically-active portion thereof can be determined by detecting the labeled compound in a complex. For example, test compounds can be labeled with ¹²⁵1, ³⁵S, ¹⁴C, or ³H, either directly or indirectly, and the radioisotope detected by direct counting of radioemission or by scintillation counting. Alternatively, test compounds can be enzymatically-labeled with, for example, horseradish peroxidase, alkaline phosphatase, or luciferase, and the enzymatic label detected by determination of conversion of an appropriate substrate to product. In one embodiment, the assay comprises contacting a cell which expresses a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface with a known compound which binds NOVX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability ofthe test compound to interact with a NOVX protein, wherein determining the ability ofthe test compound to interact with a NOVX protein comprises determining the ability ofthe test compound to preferentially bind to NOVX protein or a biologically-active portion thereof as compared to the known compound.

In another embodiment, an assay is a cell-based assay comprising contacting a cell expressing a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface with a test compound and determining the ability of the test compound to modulate (e.g., stimulate or inhibit) the activity ofthe NOVX protein or biologically-active portion thereof. Determining the ability ofthe test compound to modulate the activity of NOVX or a biologically-active portion thereof can be accomplished, for example, by determining the ability of the NOVX protein to bind to or interact with a NOVX target molecule. As used herein, a "target molecule" is a molecule with which a NOVX protein binds or interacts in nature, for example, a molecule on the surface of a cell which expresses a NOVX interacting protein, a molecule on the surface of a second cell, a molecule in the extracellular milieu, a molecule associated with the internal surface of a cell membrane or a cytoplasmic molecule. A NOVX target molecule can be a non-NOVX molecule or a NOVX protein or polypeptide of the invention. In one embodiment, a NOVX target molecule is a component of a signal transduction pathway that facilitates transduction of an extracellular signal (e.g. a signal generated by binding of a compound to a membrane-bound NOVX molecule) through the cell membrane and into the cell. The target, for example, can be a second intercellular protein that has catalytic activity or a protein that facilitates the association of downstream signaling molecules with NOVX.

Determining the ability ofthe NOVX protein to bind to or interact with a NOVX target molecule can be accomplished by one ofthe methods described above for determining direct binding. In one embodiment, determining the ability ofthe NOVX protein to bind to or interact with a NOVX target molecule can be accomplished by determining the activity ofthe target molecule. For example, the activity ofthe target molecule can be determined by detecting induction of a cellular second messenger ofthe target (i.e. intracellular Ca ⁺, diacylglycerol, IP₃, etc.), detecting catalytic/enzymatic activity ofthe target an appropriate substrate, detecting the induction of a reporter gene (comprising a NOVX-responsive regulatory element operatively linked to a nucleic acid encoding a detectable marker, e.g., luciferase), or detecting a cellular response, for example, cell survival, cellular differentiation, or cell proliferation.

In yet another embodiment, an assay ofthe mvention is a cell-free assay comprising contacting a NOVX protein or biologically-active portion thereof with a test compound and determining the ability ofthe test compound to bind to the NOVX protein or biologically- active portion thereof. Binding ofthe test compound to the NOVX protein can be determined either directly or indirectly as described above. In one such embodiment, the assay comprises contacting the NOVX protein or biologically-active portion thereof with a known compound which binds NOVX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability ofthe test compound to interact with a NOVX protein, wherein determining the ability ofthe test compound to interact with a NOVX protein comprises determining the ability ofthe test compound to preferentially bind to NOVX or biologically-active portion thereof as compared to the known compound.

In still another embodiment, an assay is a cell-free assay comprising contacting NOVX protein or biologically-active portion thereof with a test compound and determining the ability ofthe test compound to modulate (e.g. stimulate or inhibit) the activity ofthe NOVX protein or biologically-active portion thereof. Determining the ability ofthe test compound to modulate the activity of NOVX can be accomplished, for example, by determining the ability ofthe NOVX protein to bind to a NOVX target molecule by one of the methods described above for determining direct binding. In an alternative embodiment, determining the ability ofthe test compound to modulate the activity of NOVX protein can be accomplished by determining the ability ofthe NOVX protein further modulate a NOVX target molecule. For example, the catalytic/enzymatic activity ofthe target molecule on an appropriate substrate can be determined as described, supra. In yet another embodiment, the cell-free assay comprises contacting the NOVX protein or biologically-active portion thereof with a known compound which binds NOVX protein to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability ofthe test compound to interact with a NOVX protein, wherein determining the ability ofthe test compound to interact with a NOVX protein comprises determining the ability of the NOVX protein to preferentially bind to or modulate the activity of a NOVX target molecule.

The cell-free assays ofthe invention are amenable to use of both the soluble form or the membrane-bound form of NOVX protein. In the case of cell-free assays comprising the membrane-bound form of NOVX protein, it may be desirable to utilize a solubilizing agent such that the membrane-bound form of NOVX protein is maintained in solution. Examples of such solubilizing agents include non-ionic detergents such as n-octylglucoside, n-dodecylglucoside, n-dodecylmaltoside, octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, Triton^® X-100, Triton^® X-l 14, Thesit^®, Isotridecypoly(ethylene glycol ether)_n, N-dodecyl~N,N-dimethyl-3-ammonio-l -propane sulfonate, 3-(3-cholamidopropyl) dimethylamminiol-1 -propane sulfonate (CHAPS), or 3-(3-cholamidopropyl)dimethylamminiol-2-hydroxy-l -propane sulfonate (CHAPSO).

In more than one embodiment ofthe above assay methods ofthe invention, it may be desirable to immobilize either NOVX protein or its target molecule to facilitate separation of complexed from uncomplexed forms of one or both of the proteins, as well as to accommodate automation ofthe assay. Binding of a test compound to NOVX protein, or interaction of NOVX protein with a target molecule in the presence and absence of a candidate compound, can be accomplished in any vessel suitable for containing the reactants. Examples of such vessels include microtiter plates, test tubes, and micro-centrifuge tubes. In one embodiment, a fusion protein can be provided that adds a domain that allows one or both ofthe proteins to be bound to a matrix. For example, GST-NO VX fusion proteins or GST- target fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, MO) or glutathione derivatized microtiter plates, that are then combined with the test compound or the test compound and either the non-adsorbed target protein or NOVX protein, and the mixture is incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtiter plate wells are washed to remove any unbound components, the matrix immobilized in the case of beads, complex determined either directly or indirectly, for example, as described, supra. Alternatively, the complexes can be dissociated from the matrix, and the level of NOVX protein binding or activity determined using standard techniques.

Other techniques for immobilizing proteins on matrices can also be used in the screening assays ofthe invention. For example, either the NOVX protein or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin. Biotinylated NOVX protein or target molecules can be prepared from biotin-NHS (N-hydroxy-succinimide) using techniques well-known within the art (e.g. , biotinylation kit, Pierce Chemicals, Rockford, 111.), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). Alternatively, antibodies reactive with NOVX protein or target molecules, but which do not interfere with binding ofthe NOVX protein to its target molecule, can be derivatized to the wells ofthe plate, and unbound target or NOVX protein trapped in the wells by antibody conjugation. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the NOVX protein or target molecule, as well as enzyme-linked assays that rely on detecting an enzymatic activity associated with the NOVX protein or target molecule.

In another embodiment, modulators of NOVX protein expression are identified in a method wherein a cell is contacted with a candidate compound and the expression of NOVX mRNA or protein in the cell is determined. The level of expression of NOVX mRNA or protein in the presence ofthe candidate compound is compared to the level of expression of NOVX mRNA or protein in the absence ofthe candidate compound. The candidate compound can then be identified as a modulator of NOVX mRNA or protein expression based upon this comparison. For example, when expression of NOVX mRNA or protein is greater (i.e., statistically significantly greater) in the presence ofthe candidate compound than in its absence, the candidate compound is identified as a stimulator of NOVX mRNA or protein expression. Alternatively, when expression of NOVX mRNA or protein is less

(statistically significantly less) in the presence ofthe candidate compound than in its absence, the candidate compound is identified as an inhibitor of NOVX mRNA or protein expression. The level of NOVX mRNA or protein expression in the cells can be determined by methods described herein for detecting NOVX mRNA or protein. In yet another aspect ofthe invention, the NOVX proteins can be used as "bait proteins" in a two-hybrid assay or three hybrid assay (see, e.g., U.S. Patent No. 5,283,317; Zervos, et al, 1993. Cell ll: 223-232; Madura, et al, 1993. J. Biol. Chem. 268: 12046-12054; Bartel, et al, 1993. Biotechniques 14: 920-924; Iwabuchi, et al, 1993. Oncogene 8: 1693-1696; and Brent WO 94/10300), to identify other proteins that bind to or interact with NOVX ("NOVX-binding proteins" or "NOVX-bp") and modulate NOVX activity. Such NOVX-binding proteins are also involved in the propagation of signals by the NOVX proteins as, for example, upstream or downstream elements ofthe NOVX pathway. The two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains. Briefly, the assay utilizes two different DNA constructs. In one construct, the gene that codes for NOVX is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein ("prey" or "sample") is fused to a gene that codes for the activation domain ofthe known transcription factor. If the "bait" and the "prey" proteins are able to interact, in vivo, forming a NOVX-dependent complex, the DNA-binding and activation domains ofthe transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) that is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression ofthe reporter gene can be detected and cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene that encodes the protein which interacts with NOVX.

The invention further pertains to novel agents identified by the aforementioned screening assays and uses thereof for treatments as described herein.

Detection Assays Portions or fragments ofthe cDNA sequences identified herein (and the corresponding complete gene sequences) can be used in numerous ways as polynucleotide reagents. By way of example, and not of limitation, these sequences can be used to: (i) map their respective genes on a chromosome; and, thus, locate gene regions associated with genetic disease; (ii) identify an individual from a minute biological sample (tissue typing); and (iii) aid in forensic identification of a biological sample. Some of these applications are described in the subsections, below.

Chromosome Mapping

Once the sequence (or a portion ofthe sequence) of a gene has been isolated, this sequence can be used to map the location of the gene on a chromosome. This process is called chromosome mapping. Accordingly, portions or fragments ofthe NOVX sequences of SEQ ID NO:2τ?-l, wherein 77 is an integer between 1-101, or fragments or derivatives thereof, can be used to map the location ofthe NOVX genes, respectively, on a chromosome. The mapping ofthe NOVX sequences to chromosomes is an important first step in correlating these sequences with genes associated with disease.

Briefly, NOVX genes can be mapped to chromosomes by preparing PCR primers (preferably 15-25 bp in length) from the NOVX sequences. Computer analysis ofthe NOVX, sequences can be used to rapidly select primers that do not span more than one exon in the genomic DNA, thus complicating the amplification process. These primers can then be used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to the NOVX sequences will yield an amplified fragment. Somatic cell hybrids are prepared by fusing somatic cells from different mammals (e.g., human and mouse cells). As hybrids of human and mouse cells grow and divide, they gradually lose human chromosomes in random order, but retain the mouse chromosomes. By using media in which mouse cells cannot grow, because they lack a particular enzyme, but in which human cells can, the one human chromosome that contains the gene encoding the needed enzyme will be retained. By using various media, panels of hybrid cell lines can be established. Each cell line in a panel contains either a single human chromosome or a small number of human chromosomes, and a full set of mouse chromosomes, allowing easy mapping of individual genes to specific human chromosomes. See, e.g., D'Eustachio, et al, 1983. Science 220: 919-924. Somatic cell hybrids containing only fragments of human chromosomes can also be produced by using human chromosomes with tianslocations and deletions.

PCR mapping of somatic cell hybrids is a rapid procedure for assigning a particular sequence to a particular chromosome. Three or more sequences can be assigned per day using a single thermal cycler. Using the NOVX sequences to design oligonucleotide primers, sub-localization can be achieved with panels of fragments from specific chromosomes.

Fluorescence in situ hybridization (FISH) of a DNA sequence to a metaphase chromosomal spread can further be used to provide a precise chromosomal location in one step. Chromosome spreads can be made using cells whose division has been blocked in metaphase by a chemical like colcemid that disrupts the mitotic spindle. The chromosomes can be treated briefly with trypsin, and then stained with Giemsa. A pattern of light and dark bands develops on each chromosome, so that the chromosomes can be identified individually. The FISH technique can be used with a DNA sequence as short as 500 or 600 bases. However, clones larger than 1,000 bases have a higher likelihood of binding to a unique chromosomal location with sufficient signal intensity for simple detection. Preferably 1,000 bases, and more preferably 2,000 bases, will suffice to get good results at a reasonable amount of time. For a review of this technique, see, Verma, et al, HUMAN CHROMOSOMES: A MANUAL OF BASIC TECHNIQUES (Pergamon Press, New York 1988).

Reagents for chromosome mapping can be used individually to mark a single chromosome or a single site on that chromosome, or panels of reagents can be used for marking multiple sites and/or multiple chromosomes. Reagents corresponding to noncoding regions ofthe genes actually are preferred for mapping puφoses. Coding sequences are more likely to be conserved within gene families, thus increasing the chance of cross hybridizations during chromosomal mapping. Once a sequence has been mapped to a precise chromosomal location, the physical position ofthe sequence on the chromosome can be correlated with genetic map data. Such data are found, e.g., in McKusick, MENDELIAN INHERITANCE IN MAN, available on-line through Johns Hopkins University Welch Medical Library). The relationship between genes and disease, mapped to the same chromosomal region, can then be identified through linkage analysis (co-inheritance of physically adjacent genes), described in, e.g., Egeland, et al, 1987. Nature, 325: 783-787.

Moreover, differences in the DΝA sequences between individuals affected and unaffected with a disease associated with the ΝOVX gene, can be determined. If a mutation is observed in some or all ofthe affected individuals but not in any unaffected individuals, then the mutation is likely to be the causative agent ofthe particular disease. Comparison of affected and unaffected individuals generally involves first looking for structural alterations in the chromosomes, such as deletions or tianslocations that are visible from chromosome spreads or detectable using PCR based on that DΝA sequence. Ultimately, complete sequencing of genes from several individuals can be performed to confirm the presence of a mutation and to distinguish mutations from polymoφhisms.

Tissue Typing

The ΝOVX sequences ofthe invention can also be used to identify individuals from minute biological samples. In this technique, an individual's genomic DΝA is digested with one or more restriction enzymes, and probed on a Southern blot to yield unique bands for identification. The sequences ofthe invention are useful as additional DΝA markers for RFLP ("restriction fragment length polymoφhisms," described in U.S. Patent o. 5,272,057). Furthermore, the sequences ofthe invention can be used to provide an alternative technique that determines the actual base-by-base DNA sequence of selected portions of an individual's genome. Thus, the NOVX sequences described herein can be used to prepare two PCR primers from the 5'- and 3'-termini ofthe sequences. These primers can then be used to amplify an individual's DNA and subsequently sequence it. Panels of corresponding DNA sequences from individuals, prepared in this manner, can provide unique individual identifications, as each individual will have a unique set of such DNA sequences due to allelic differences. The sequences ofthe invention can be used to obtain such identification sequences from individuals and from tissue. The NOVX sequences ofthe invention uniquely represent portions ofthe human genome. Allelic variation occurs to some degree in the coding regions of these sequences, and to a greater degree in the noncoding regions. It is estimated that allelic variation between individual humans occurs with a frequency of about once per each 500 bases. Much of the allelic variation is due to single nucleotide polymoφhisms (SNPs), which include restriction fragment length polymoφhisms (RFLPs).

Each ofthe sequences described herein can, to some degree, be used as a standard against which DNA from an individual can be compared for identification puφoses. Because greater numbers of polymoφhisms occur in the noncoding regions, fewer sequences are necessary to differentiate individuals. The noncoding sequences can comfortably provide positive individual identification with a panel of perhaps 10 to 1,000 primers that each yield a noncoding amplified sequence of 100 bases. If coding sequences, such as those of SEQ ID NO:2?z-l, wherein 77 is an integer between 1-101, are used, a more appropriate number of primers for positive individual identification would be 500-2,000.

Predictive Medicine

The invention also pertains to the field of predictive medicine in which diagnostic assays, prognostic assays, pharmacogenomics, and monitoring clinical trials are used for prognostic (predictive) puφoses to thereby treat an individual prophylactically. Accordingly, one aspect ofthe invention relates to diagnostic assays for determining NOVX protein and/or nucleic acid expression as well as NOVX activity, in the context of a biological sample (e.g. , blood, serum, cells, tissue) to thereby determine whether an individual is afflicted with a disease or disorder, or is at risk of developing a disorder, associated with aberrant NOVX expression or activity. The disorders include metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers. The invention also provides for prognostic (or predictive) assays for determining whether an individual is at risk of developing a disorder associated with NOVX protein, nucleic acid expression or activity. For example, mutations in a NOVX gene can be assayed in a biological sample. Such assays can be used for prognostic or predictive puφose to thereby prophylactically treat an individual prior to the onset of a disorder characterized by or associated with NOVX protein, nucleic acid expression, or biological activity. Another aspect ofthe invention provides methods for determining NOVX protein, nucleic acid expression or activity in an individual to thereby select appropriate therapeutic or prophylactic agents for that individual (referred to herein as "pharmacogenomics"). Pharmacogenomics allows for the selection of agents (e.g., drugs) for therapeutic or prophylactic treatment of an individual based on the genotype of the individual (e. g. , the genotype ofthe individual examined to determine the ability ofthe individual to respond to a particular agent.)

Yet another aspect ofthe invention pertains to monitoring the influence of agents (e.g., drugs, compounds) on the expression or activity of NOVX in clinical trials. These and other agents are described in further detail in the following sections.

Diagnostic Assays

An exemplary method for detecting the presence or absence of NOVX in a biological sample involves obtaining a biological sample from a test subject and contacting the biological sample with a compound or an agent capable of detecting NOVX protein or nucleic acid (e.g., mRNA, genomic DNA) that encodes NOVX protein such that the presence of NOVX is detected in the biological sample. An agent for detecting NOVX mRNA or genomic DNA is a labeled nucleic acid probe capable of hybridizing to NOVX mRNA or genomic DNA. The nucleic acid probe can be, for example, a full-length NOVX nucleic acid, such as the nucleic acid of SEQ ID NO:277-l, wherein 77 is an integer between 1-101, or a portion thereof, such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to NOVX RNA or genomic DNA. Other suitable probes for use in the diagnostic assays of the invention are described herein. An agent for detecting NOVX protein is an antibody capable of binding to NOVX protein, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., Fab or F(ab')₂) can be used. The term "labeled", with regard to the probe or antibody, is intended to encompass direct labeling ofthe probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling ofthe probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term "biological sample" is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. That is, the detection method ofthe invention can be used to detect NOVX mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of NOVX mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of NOVX protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of NOVX genomic DNA include Southern hybridizations. Furthermore, 7 vivo techniques for detection of NOVX protein include introducing into a subject a labeled anti-NOVX antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.

In one embodiment, the biological sample contains protein molecules from the test subject. Alternatively, the biological sample can contain mRNA molecules from the test subject or genomic DNA molecules from the test subject. A preferred biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject.

In another embodiment, the methods further involve obtaining a control biological sample from a control subject, contacting the control sample with a compound or agent capable of detecting NOVX protein, mRNA, or genomic DNA, such that the presence of NOVX protein, mRNA or genomic DNA is detected in the biological sample, and comparing the presence of NOVX protein, mRNA or genomic DNA in the control sample with the presence of NOVX protein, mRNA or genomic DNA in the test sample.

The invention also encompasses kits for detecting the presence of NOVX in a biological sample. For example, the kit can comprise: a labeled compound or agent capable of detecting NOVX protein or mRNA in a biological sample; means for determining the amount of NOVX in the sample; and means for comparing the amount of NOVX in the sample with a standard. The compound or agent can be packaged in a suitable container. The kit can further comprise instructions for using the kit to detect NOVX protein or nucleic acid.

Prognostic Assays

The diagnostic methods described herein can furthermore be utilized to identify subjects having or at risk of developing a disease or disorder associated with aberrant NOVX expression or activity. For example, the assays described herein, such as the preceding diagnostic assays or the following assays, can be utilized to identify a subject having or at risk of developing a disorder associated with NOVX protein, nucleic acid expression or activity. Alternatively, the prognostic assays can be utilized to identify a subject having or at risk for developing a disease or disorder. Thus, the invention provides a method for identifying a disease or disorder associated with aberrant NOVX expression or activity in which a test sample is obtained from a subject and NOVX protein or nucleic acid (e.g. , mRNA, genomic DNA) is detected, wherein the presence of NOVX protein or nucleic acid is diagnostic for a subject having or at risk of developing a disease or disorder associated with aberrant NOVX expression or activity. As used herein, a "test sample" refers to a biological sample obtained from a subject of interest. For example, a test sample can be a biological fluid (e.g., serum), cell sample, or tissue.

Furthermore, the prognostic assays described herein can be used to determine whether a subject can be administered an agent (e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate) to treat a disease or disorder associated with aberrant NOVX expression or activity. For example, such methods can be used to determine whether a subject can be effectively treated with an agent for a disorder. Thus, the invention provides methods for determining whether a subject can be effectively treated with an agent for a disorder associated with aberrant NOVX expression or activity in which a test sample is obtained and NOVX protein or nucleic acid is detected (e.g., wherein the presence of NOVX protein or nucleic acid is diagnostic for a subject that can be administered the agent to treat a disorder associated with aberrant NOVX expression or activity).

The methods ofthe invention can also be used to detect genetic lesions in a NOVX gene, thereby determining if a subject with the lesioned gene is at risk for a disorder characterized by aberrant cell proliferation and/or differentiation. In various embodiments, the methods include detecting, in a sample of cells from the subject, the presence or absence of a genetic lesion characterized by at least one of an alteration affecting the integrity of a gene encoding a NOVX-protein, or the misexpression ofthe NOVX gene. For example, such genetic lesions can be detected by ascertaining the existence of at least one of: (i) a deletion of one or more nucleotides from a NOVX gene; (ii) an addition of one or more nucleotides to a NOVX gene; (iii) a substitution of one or more nucleotides of a NOVX gene, (iv) a chromosomal rearrangement of a NOVX gene; (v) an alteration in the level of a messenger RNA transcript of a NOVX gene, (vi) aberrant modification of a NOVX gene, such as ofthe methylation pattern ofthe genomic DNA, (vii) the presence of a non- wild-type splicing pattern of a messenger RNA transcript of a NOVX gene, (vm) a non-wild-type level of a NOVX protein, (ix) allelic loss of a NOVX gene, and (x) inappropriate post-translational modification of a NOVX protein. As described herein, there are a large number of assay techniques known in the art which can be used for detecting lesions in a NOVX gene. A preferred biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject. However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells.

In certain embodiments, detection ofthe lesion involves the use of a probe/primer in a polymerase chain reaction (PCR) (see, e.g., U.S. Patent Nos. 4,683,195 and 4,683,202), such as anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran, et al, 1988. Scz^'eτ7ce 241 : 1077-1080; and Nakazawa, et al, 1994. Proc. Natl.

Acad. Sci. USA 91 : 360-364), the latter of which can be particularly useful for detecting point mutations in the NOVX-gene (see, Abravaya, et al, 1995. Nucl. Acids Res. 23: 675-682). This method can include the steps of collecting a sample of cells from a patient, isolating nucleic acid (e.g., genomic, mRNA or both) from the cells ofthe sample, contacting the nucleic acid sample with one or more primers that specifically hybridize to a NOVX gene under conditions such that hybridization and amplification ofthe NOVX gene (if present) occurs, and detecting the presence or absence of an amplification product, or detecting the size ofthe amplification product and comparing the length to a control sample. It is anticipated that PCR and/or LCR may be desirable to use as a preliminary amplification step in conjunction with any ofthe techniques used for detecting mutations described herein.

Alternative amplification methods include: self sustained sequence replication (see, | Guatelli, et al, 1990. Proc. Natl. Acad. Sci. USA 87: 1874-1878), transcriptional amplification system (see, Kwoh, et al, 1989. Proc. Natl. Acad. Sci. USA 86: 1173-1177); Qβ Replicase (see, Lizardi, et al, 1988. BioTechnology 6: 1197), or any other nucleic acid amplification method, followed by the detection ofthe amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers.

In an alternative embodiment, mutations in a NOVX gene from a sample cell can be identified by alterations in restriction enzyme cleavage patterns. For example, sample and control DNA is isolated, amplified (optionally), digested with one or more restriction endonucleases, and fragment length sizes are determined by gel electrophoresis and compared. Differences in fragment length sizes between sample and control DNA indicates mutations in the sample DNA. Moreover, the use of sequence specific ribozymes (see, e.g., U.S. Patent No. 5,493,531) can be used to score for the presence of specific mutations by development or loss of a ribozyme cleavage site.

In other embodiments, genetic mutations in NOVX can be identified by hybridizing a sample and control nucleic acids, e.g., DNA or RNA, to high-density anays containing hundreds or thousands of oligonucleotides probes. See, e.g., Cronin, et al, 1996. Human Mutation 7: 244-255; Kozal, et al, 1996. Nat. Med. 2: 753-759. For example, genetic mutations in NOVX can be identified in two dimensional arrays containing light-generated DNA probes as described in Cronin, et al, supra. Briefly, a first hybridization array of probes can be used to scan through long stretches of DNA in a sample and control to identify base changes between the sequences by making linear arrays of sequential overlapping probes. This step allows the identification of point mutations. This is followed by a second hybridization array that allows the characterization of specific mutations by using smaller, specialized probe arrays complementary to all variants or mutations detected. Each mutation array is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene.

In yet another embodiment, any of a variety of sequencing reactions known in the art can be used to directly sequence the NOVX gene and detect mutations by comparing the sequence ofthe sample NOVX with the corresponding wild-type (control) sequence. Examples of sequencing reactions include those based on techniques developed by Maxim and Gilbert, 1977. Proc. Natl Acad. Sci. USA 74: 560 or Sanger, 1977. Proc. Natl Acad. Sci. USA 74: 5463. It is also contemplated that any of a variety of automated sequencing procedures can be utilized when performing the diagnostic assays (see, e.g., Naeve, et al, 1995. Biotechniques 19: 448), including sequencing by mass spectiomefry (see, e.g., PCT International Publication No. WO 94/16101; Cohen, et al, 1996. Adv. Chromatography 36: 127-162; and Griffin, et al, 1993. Appl. Biochem. Biotechnol 38: 147-159).

Other methods for detecting mutations in the NOVX gene include methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA heteroduplexes. See, e.g., Myers, etal, 1985. Science 230: 1242. In general, the art technique of "mismatch cleavage" starts by providing heteroduplexes of formed by hybridizing (labeled) RNA or DNA containing the wild-type NOVX sequence with potentially mutant RNA or DNA obtained from a tissue sample. The double-stranded duplexes are treated with an agent that cleaves single-stranded regions ofthe duplex such as which will exist due to basepair mismatches between the control and sample strands. For instance, RNA/DNA duplexes can be treated with RNase and DNA/DNA hybrids treated with Si, nuclease to enzymatically digesting the mismatched regions. In other embodiments, either DNA/DNA or RNA/DNA duplexes can be treated with hydroxylamine or osmium tefroxide and with piperidine in order to digest mismatched regions. After digestion ofthe mismatched regions, the resulting material is then separated by size on denaturing polyacrylamide gels to determine the site of mutation. See, e.g., Cotton, etal, 1988. Proc. Natl. Acad. Sci. USA 85: 4397; Saleeba, et al, 1992. Methods Enzymol. 211: 286-295. In an embodiment, the control DNA or RNA can be labeled for detection.

In still another embodiment, the mismatch cleavage reaction employs one or more proteins that recognize mismatched base pairs in double-stranded DNA (so called "DNA mismatch repair" enzymes) in defined systems for detecting and mapping point mutations in NOVX cDNAs obtained from samples of cells. For example, the mutY enzyme of E. coli cleaves A at G/A mismatches and the thymidine DNA glycosylase from HeLa cells cleaves T at G/T mismatches. See, e.g., Hsu, et al, 1994. Carcinogenesis 15: 1657-1662. According to an exemplary embodiment, a probe based on a NOVX sequence, e.g., a wild-type NOVX sequence, is hybridized to a cDNA or other DNA product from a test cell(s). The duplex is treated with a DNA mismatch repair enzyme, and the cleavage products, if any, can be detected from electrophoresis protocols or the like. See, e.g., U.S. Patent No. 5,459,039.

In other embodiments, alterations in electiophoretic mobility will be used to identify mutations in NOVX genes. For example, single strand conformation polymoφhism (SSCP) may be used to detect differences in electiophoretic mobility between mutant and wild type nucleic acids. See, e.g., Orita, etal, 1989. Proc. Natl. Acad. Sci. USA: 86: 2766; Cotton, 1993. Mutat. Res. 285: 125-144; Hayashi, 1992. Genet. Anal. Tech. Appl. 9: 73-79. Single-stranded DNA fragments of sample and confrol NOVX nucleic acids will be denatured and allowed to renature. The secondary structure of single-stranded nucleic acids varies according to sequence, the resulting alteration in electiophoretic mobility enables the detection of even a single base change. The DNA fragments may be labeled or detected with labeled probes. The sensitivity ofthe assay may be enhanced by using RNA (rather than DNA), in which the secondary structure is more sensitive to a change in sequence. In one embodiment, the subject method utilizes heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of changes in electiophoretic mobility. See, e.g., Keen, et al, 1991. Trends Genet. 7: 5.

In yet another embodiment, the movement of mutant or wild-type fragments in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGΕ). See, e.g., Myers, et al, 1985. Nature 313: 495. When DGGΕ is used as the method of analysis, DNA will be modified to insure that it does not completely denature, for example by adding a GC clamp of approximately 40 bp of high-melting GC-rich DNA by PCR. In a further embodiment, a temperature gradient is used in place of a denaturing gradient to identify differences in the mobility of control and sample DNA. See, e.g., Rosenbaum and Reissner, 1987 '. Biophys. Chem. 265: 12753.

Examples of other techniques for detecting point mutations include, but are not limited to, selective oligonucleotide hybridization, selective amplification, or selective primer extension. For example, oligonucleotide primers may be prepared in which the known mutation is placed centrally and then hybridized to target DNA under conditions that permit hybridization only if a perfect match is found. See, e.g., Saiki, et al, 1986. Nature 324: 163; Saiki, et al, 1989. Proc. Natl. Acad. Sci. USA 86: 6230. Such allele specific oligonucleotides are hybridized to PCR amplified target DNA or a number of different mutations when the oligonucleotides are attached to the hybridizing membrane and hybridized with labeled target DNA. Alternatively, allele specific amplification technology that depends on selective PCR amplification may be used in conjunction with the instant invention. Oligonucleotides used as primers for specific amplification may carry the mutation of interest in the center ofthe molecule (so that amplification depends on differential hybridization; see, e.g, Gibbs, et al, 1989. Nucl Acids Res. 17: 2437-2448) or at the extreme 3'-terminus of one primer where, under appropriate conditions, mismatch can prevent, or reduce polymerase extension (see, e.g., Prossner, 1993. Tibtech. 11 : 238). In addition it may be desirable to introduce a novel restriction site in the region ofthe mutation to create cleavage-based detection. See, e.g., Gasparini, et al, 1992. Mol. Cell Probes 6: 1. It is anticipated that in certain embodiments amplification may also be performed using Taq ligase for amplification. See, e.g., Barany, 1991. Proc. Natl. Acad. Sci. USA 88: 189. In such cases, ligation will occur only if there is a perfect match at the 3 '-terminus ofthe 5' sequence, making it possible to detect the presence of a known mutation at a specific site by looking for the presence or absence of amplification.

The methods described herein may be performed, for example, by utilizing pre-packaged diagnostic kits comprising at least one probe nucleic acid or antibody reagent described herein, which may be conveniently used, e.g., in clinical settings to diagnose patients exhibiting symptoms or family history of a disease or illness involving a NOVX gene.

Furthermore, any cell type or tissue, preferably peripheral blood leukocytes, in which NOVX is expressed may be utilized in the prognostic assays described herein. However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells.

Pharmacogenomics Agents, or modulators that have a stimulatory or inhibitory effect on NOVX activity

(e.g., NOVX gene expression), as identified by a screening assay described herein can be _λ administered to individuals to treat (prophylactically or therapeutically) disorders (The disorders include metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer- associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers.) In conjunction with such treatment, the pharmacogenomics (z.e., the study ofthe relationship between an individual's genotype and that individual's response to a foreign compound or drug) ofthe individual may be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration ofthe pharmacologically active drug. Thus, the pharmacogenomics ofthe individual permits the selection of effective agents (e.g., drugs) for prophylactic or therapeutic treatments based on a consideration of the individual's genotype. Such pharmacogenomics can further be used to determine appropriate dosages and therapeutic regimens. Accordingly, the activity of NOVX protein, expression of NOVX nucleic acid, or mutation content of NOVX genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment ofthe individual.

Pharmacogenomics deals with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal action in affected persons.

See e.g., Eichelbaum, 1996. Clin. Exp. Pharmacol. Physiol, 23: 983-985; Linder, 1997. Clin. Chem., 43: 254-266. In general, two types of pharmacogenetic conditions can be differentiated. Genetic conditions transmitted as a single factor altering the way drugs act on the body (altered drug action) or genetic conditions transmitted as single factors altering the way the body acts on drugs (altered drug metabolism). These pharmacogenetic conditions can occur either as rare defects or as polymoφhisms. For example, glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common inherited enzymopathy in which the main clinical complication is hemolysis after ingestion of oxidant drugs (anti-malarials, sulfonamides, analgesics, nitrofurans) and consumption of fava beans. As an illustrative embodiment, the activity of drug metabolizing enzymes is a major determinant of both the intensity and duration of drug action. The discovery of genetic polymoφhisms of drug metabolizing enzymes (e.g., N-acetyltransferase 2 (NAT 2) and cytochrome PREGNANCY ZONE PROTEIN PRECURSOR enzymes CYP2D6 and CYP2C19) has provided an explanation as to why some patients do not obtain the expected drug effects or show exaggerated drug response and serious toxicity after taking the standard and safe dose of a drug. These polymoφhisms are expressed in two phenotypes in the population, the extensive metabolizer (EM) and poor metabolizer (PM). The prevalence of PM is different among different populations. For example, the gene coding for CYP2D6 is highly polymoφhic and several mutations have been identified in PM, which all lead to the absence of functional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C19 quite frequently experience exaggerated drug response and side effects when they receive standard doses. If a metabolite is the active therapeutic moiety, PM show no therapeutic response, as demonstrated for the analgesic effect of codeine mediated by its CYP2D6-formed metabolite moφhine. At the other extreme are the so called ultra-rapid metabolizers who do not respond to standard doses. Recently, the molecular basis of ultra-rapid metabolism has been identified to be due to CYP2D6 gene amplification.

Thus, the activity of NOVX protein, expression of NOVX nucleic acid, or mutation content of NOVX genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment ofthe individual. In addition, pharmacogenetic studies can be used to apply genotyping of polymoφhic alleles encoding drug-metabolizing enzymes to the identification of an individual's drug responsiveness phenotype. This knowledge, when applied to dosing or drug selection, can avoid adverse reactions or therapeutic failure and thus enhance therapeutic or prophylactic efficiency when treating a subject with a NOVX modulator, such as a modulator identified by one ofthe exemplary screening assays described herein.

Monitoring of Effects During Clinical Trials

Monitoring the influence of agents (e.g., drugs, compounds) on the expression or activity of NOVX (e.g., the ability to modulate aberrant cell proliferation and/or differentiation) can be applied not only in basic drug screening, but also in clinical trials. For example, the effectiveness of an agent determined by a screening assay as described herein to increase NOVX gene expression, protein levels, or upregulate NOVX activity, can be monitored in clinical trails of subjects exhibiting decreased NOVX gene expression, protein levels, or downregulated NOVX activity. Alternatively, the effectiveness of an agent determined by a screening assay to decrease NOVX gene expression, protein levels, or downregulate NOVX activity, can be monitored in clinical trails of subjects exhibiting increased NOVX gene expression, protein levels, or upregulated NOVX activity. In such clinical trials, the expression or activity of NOVX and, preferably, other genes that have been implicated in, for example, a cellular proliferation or immune disorder can be used as a "read out" or markers of the immune responsiveness of a particular cell.

By way of example, and not of limitation, genes, including NOVX, that are modulated in cells by treatment with an agent (e.g., compound, drug or small molecule) that modulates NOVX activity (e.g. , identified in a screening assay as described herein) can be identified. Thus, to study the effect of agents on cellular proliferation disorders, for example, in a clinical trial, cells can be isolated and RNA prepared and analyzed for the levels of expression of NOVX and other genes implicated in the disorder. The levels of gene expression (z.e., a gene expression pattern) can be quantified by Northern blot analysis or RT-PCR, as described herein, or alternatively by measuring the amount of protein produced, by one ofthe methods as described herein, or by measuring the levels of activity of NOVX or other genes. In this manner, the gene expression pattern can serve as a marker, indicative of the physiological response ofthe cells to the agent. Accordingly, this response state may be determined before, and at various points during, treatment ofthe individual with the agent. In one embodiment, the invention provides a method for monitoring the effectiveness of treatment of a subject with an agent (e.g., an agonist, antagonist, protein, peptide, peptidomimetic, nucleic acid, small molecule, or other drug candidate identified by the screening assays described herein) comprising the steps of (i) obtaining a pre-administration sample from a subject prior to administration ofthe agent; (ii) detecting the level of expression of a NOVX protein, mRNA, or genomic DNA in the preadministration sample; (iii) obtaining one or more post-administration samples from the subject; (iv) detecting the level of expression or activity ofthe NOVX protein, mRNA, or genomic DNA in the post-administration samples; (v) comparing the level of expression or activity ofthe NOVX protein, mRNA, or genomic DNA in the pre-administration sample with the NOVX protein, mRNA, or genomic DNA in the post administration sample or samples; and (vt) altering the adminisfration ofthe agent to the subject accordingly. For example, increased administration ofthe agent may be desirable to increase the expression or activity of NOVX to higher levels than detected, i.e., to increase the effectiveness ofthe agent. Alternatively, decreased administration ofthe agent may be desirable to decrease expression or activity of NOVX to lower levels than detected, i.e., to decrease the effectiveness ofthe agent.

Methods of Treatment

The invention provides for both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a disorder or having a disorder associated with aberrant NOVX expression or activity. The disorders include cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, transplantation, adrenoleukodystrophy, congenital adrenal hypeφlasia, prostate cancer, neoplasm; adenocarcinoma, lymphoma, uterus cancer, fertility, hemophilia, hypercoagulation, idiopathic thrombocytopenic puφura, immunodeficiencies, graft versus host disease, AIDS, bronchial asthma, Crohn's disease; multiple sclerosis, treatment of Albright Hereditary Ostoeodystrophy, and other diseases, disorders and conditions ofthe like. These methods of treatment will be discussed more fully, below.

Disease and Disorders

Diseases and disorders that are characterized by increased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be freated with Therapeutics that antagonize (i.e., reduce or inhibit) activity. Therapeutics that antagonize activity may be administered in a therapeutic or prophylactic manner. Therapeutics that may be utilized include, but are not limited to: (i) an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; (ii) antibodies to an aforementioned peptide; (iii) nucleic acids encoding an aforementioned peptide; (iv) administration of antisense nucleic acid and nucleic acids that are "dysfunctional" (i.e., due to a heterologous insertion within the coding sequences of coding sequences to an aforementioned peptide) that are utilized to "knockout" endogenous function of an aforementioned peptide by homologous recombination (see, e.g., Capecchi, 1989. Science 244: 1288-1292); or (v) modulators ( i.e., inhibitors, agonists and antagonists, including additional peptide mimetic ofthe invention or antibodies specific to a peptide ofthe invention) that alter the interaction between an aforementioned peptide and its binding partner.

Diseases and disorders that are characterized by decreased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be freated with Therapeutics that increase (i.e., are agonists to) activity. Therapeutics that upregulate activity may be administered in a therapeutic or prophylactic manner. Therapeutics that may be utilized include, but are not limited to, an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; or an agonist that increases bioavailability. Increased or decreased levels can be readily detected by quantifying peptide and/or

RNA, by obtaining a patient tissue sample (e.g., from biopsy tissue) and assaying it in vitro for RNA or peptide levels, structure and/or activity ofthe expressed peptides (or mRNAs of an aforementioned peptide). Methods that are well-known within the art include, but are not limited to, immunoassays (e.g., by Western blot analysis, immunoprecipitation followed by sodium dodecyl sulfate (SDS) polyacrylamide gel elecfrophoresis, immunocytochemistry, etc.) and/or hybridization assays to detect expression of mRNAs (e.g., Northern assays, dot blots, »7 situ hybridization, and the like).

Prophylactic Methods In one aspect, the invention provides a method for preventing, in a subject, a disease or condition associated with an aberrant NOVX expression or activity, by administering to the subject an agent that modulates NOVX expression or at least one NOVX activity. Subjects at risk for a disease that is caused or contributed to by aberrant NOVX expression or activity can be identified by, for example, any or a combination of diagnostic or prognostic assays as described herein. Administration of a prophylactic agent can occur prior to the manifestation of symptoms characteristic ofthe NOVX aberrancy, such that a disease or disorder is prevented or, alternatively, delayed in its progression. Depending upon the type of NOVX aberrancy, for example, a NOVX agonist or NOVX antagonist agent can be used for treating the subject. The appropriate agent can be determined based on screening assays described herein. The prophylactic methods of the invention are further discussed in the following subsections.

Therapeutic Methods

Another aspect ofthe invention pertains to methods of modulating NOVX expression or activity for therapeutic puφoses. The modulatory method of the invention involves contacting a cell with an agent that modulates one or more ofthe activities of NOVX protein activity associated with the cell. An agent that modulates NOVX protein activity can be an agent as described herein, such as a nucleic acid or a protein, a naturally-occurring cognate ligand of a NOVX protein, a peptide, a NOVX peptidomimetic, or other small molecule. In one embodiment, the agent stimulates one or more NOVX protein activity. Examples of such stimulatory agents include active NOVX protein and a nucleic acid molecule encoding NOVX that has been introduced into the cell. In another embodiment, the agent inhibits one or more NOVX protein activity. Examples of such inhibitory agents include antisense NOVX nucleic acid molecules and anti-NOVX antibodies. These modulatory methods can be performed in vitro (e.g., by culturing the cell with the agent) or, alternatively, 777 vivo (e.g., by administering the agent to a subject). As such, the invention provides methods of treating an individual afflicted with a disease or disorder characterized by aberrant expression or activity of a NOVX protein or nucleic acid molecule. In one embodiment, the method involves administering an agent (e.g., an agent identified by a screening assay described herein), or combination of agents that modulates (e.g., up-regulates or down-regulates) NOVX expression or activity. In another embodiment, the method involves administering a NOVX protein or nucleic acid molecule as therapy to compensate for reduced or aberrant NOVX expression or activity. Stimulation of NOVX activity is desirable in situations in which NOVX is abnormally downregulated and/or in which increased NOVX activity has a beneficial effect. One example of such a situation is where a subject has a disorder characterized by aberrant cell proliferation and/or differentiation (e.g., cancer or immune associated disorders). Another example of such a situation is where the subject has a gestational disease (e.g., preclampsia).

Determination of the Biological Effect of the Therapeutic

In various embodiments ofthe invention, suitable in vitro or in vivo assays are performed to determine the effect of a specific Therapeutic and whether its administration is indicated for treatment ofthe affected tissue.

In various specific embodiments, in vitro assays may be performed with representative cells ofthe type(s) involved in the patient's disorder, to determine if a given Therapeutic exerts the desired effect upon the cell type(s). Compounds for use in therapy may be tested in suitable animal model systems including, but not limited to rats, mice, chicken, cows, monkeys, rabbits, and the like, prior to testing in human subjects. Similarly, for in vivo testing, any ofthe animal model system known in the art may be used prior to adminisfration to human subjects. Prophylactic and Therapeutic Uses of the Compositions of the Invention

The NOVX nucleic acids and proteins ofthe invention are useful in potential prophylactic and therapeutic applications implicated in a variety of disorders including, but not limited to: metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer- associated cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers.

As an example, a cDNA encoding the NOVX protein ofthe invention may be useful in gene therapy, and the protein may be useful when administered to a subject in need thereof. By way of non-limiting example, the compositions ofthe invention will have efficacy for treatment of patients suffering from: metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, hematopoietic disorders, and the various dyslipidemias.

Both the novel nucleic acid encoding the NOVX protein, and the NOVX protein of the mvention, or fragments thereof, may also be useful in diagnostic applications, wherein the presence or amount ofthe nucleic acid or the protein are to be assessed. A further use could be as an anti-bacterial molecule (z.e., some peptides have been found to possess anti-bacterial properties). These materials are further useful in the generation of antibodies, which immunospecifically-bind to the novel substances ofthe invention for use in therapeutic or diagnostic methods.

EXAMPLES

Example A: Polynucleotide and Polypeptide Sequences, and Homology Data Example 1.

The NOVl clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 1A.

Table 1 A. NOVl Sequence Analysis

SEQ ID NO: 1 8554 bp

NOVl a, GCACCCCGACAAGATGCCCAAGCGCGCGCACTGGGGGGCCCTCTCTGTGGTGCTGATC

CG58546-01 DNA CTGCTTTGGGGTCATCCGCGAGTGGCGCTGGCCTGCCCTCATCCTTGTGCCTGCTACG TCCCCAGCGAGGTCCACTGCACGTTCCGATCCCTGGCTTCTGTGCCCGCTGGCATTGC Sequence TAAACATGTGGAAAGAATCAATTTGGGGTTTGGAAATAGCATACAGGCCCTGTCAGAA ACCTCATTTGCAGGACTGACCAAGTTGGAGCTACTTATGATTCACGGCAATGAGATCC CAAGCATCCCCGATGGAGCTTTAAGAGACCTCAGCTCTCTTCAGGTTTTCAAGTTCAG CTACAACAAGCTGAGAGTGATCACAGGACAGACCCTCCAGGGTCTCTCTAACTTAATG AGGCTGCACATTGACCACAACAAGATCGAGTTTATCCACCCTCAAGCTTTCAACGGCT TAACGTCTCTGAGGCTACTCCATTTGGAAGGAAATCTCCTCCACCAGCTGCACCCCAG CACCTTCTCCACGTTCACATTTTTGGATTATTTCAGACTCTCCACCATAAGGCACCTC TACTTAGCAGAGAACATGGTTAGAACTCTTCCTGCCAGCATGCTTCGGAACATGCCGC TTCTGGAGAATCTTTACTTGCAGGGAAATCCGTGGACCTGCGATTGTGAGATGAGATG GTTTTTGGAATGGGATGCAAAATCCAGAGGAATTCTGAAGTGTAAAAAGGACAAAGCT TATGAAGGCGGTCAGTTGTGTGCAATGTGCTTCAGTCCAAAGAAGTTGTACAAACATG AGATTCACAAGCTGAAGGACCTGACTTGTCTGAAGCCTTCCATAGAGTCTCCTCTGAG ACAGAACAGGAGCAGGAGTATTGAGGAGGAGCAAAAACAAGAAGAGAATGGTGACAGC CAGCTCATCCTGGAGAAAATCCAACTTCCCCAGTGGAGCATCTCTTTGAATATGACTG ATGAGCACGGGAACCTGGTGAACTTGGTGTGTGACATCAAGAAACCAATGGATGTGTA CAAAATTCACTTGAACCAAACAGATCCTCCAGATATTGACATAAATGCAATGGTTGCC TTGGACTTTGAGTATCCAATGACCCAGGAAAACTATGAAAATCTATGGAAATTGATAG CATACTACAGTGAAGTTCCCATGAAGCTACACAGAGAGCTCATGCTCAGCAAACACCC CAGAGTCAGCTACCAGTACAGGCAAGATGCCGATGAAGAAGCTCTTTACTACACAGGT GTGAGAGCCCAGATTCTTGCAGAACCAGAATGGATCATGCAGCCATCCATAGATATCC AGCTGAACCGACCTCAGAGTACGGCCAAGAAGGTGCTACTTTCCTACTACAACCAGTA TTCTCAAACAATAGCCACCAAAGATACAAGGCAGGCTCGGGGCAGAAGCTGGGTAATG ATTGAGCCTAGTAGAGCTGTGCAAAAAGATCAGACTGTCCTGGAAGGGGGTCGATGCC AGTTGAGCTGCAATGTGAAAGCTTCTGAGAGTCCATCTATCTTCTGGGTGCTTCCAGA TGGCTCCATCCTGAAAGTGCCTGTGGATGACCCAGACAGCAAGTTCTCCATTCTCAGC AGTGGCTGGCTGAGGATCAAGTCCATGGAGCCATCTGACTCGGGCTTGTACCAGTGCA TTGCTCAAGTGAGGGATGAAATGGACCGCATGGTATATAGGGTACTTGTGCAGTCTCC CTCCACTCAGCCAGCCGAGAAAGACACAGTGACAATTGGCAAGAACCCAGGGGAGCCA GTGATGTTGCCTTGCAATGCTTTAGCTATACCCGAAGCCCACCTTAGCTGGATTCTTC CAAACAGAAGGATAATTAATGATTTGGCTAACACATCACATGTATACATGCTGCCAAA TGGAACTCTTTCCATCCCAAAGGTCCAAGTCAGTGACAGTGGTTACCACAGATGTGTG GCTGTGAACCAGCATGGGGCAGACCATATCACGGTGGGAATCACAGTGACCAAGAAAG GTTCTGGCTCGCCATCCAAAAGAGGCAGATGGCCAGGTCCAAAGGCTCTTTCCAGATC CAAAGGCTCTTTCCAGATGAGAGAAGACATCGTGGAGGATGAAGGGGTCTCAGGCACG GGAGATGAAGAGAACACTTCAAGGAGACTTCTACATCCAAAGCACCAAGAGGCGTTCC TCAAAACAAAGGATGATGCCATCAATGGAGATAAGAAAGCCAAGAAAGGGAGAAGAAA GCTGAAACTCTGGAAGCATTCAGAAAAAGAACCAGAGACCAGTGTTGCAGAAGATCTC AGAGTGTTTGAATCAAGACGAAGGATAAACGTGGCAAACAAACAGATTAATCCGGAGC ACTGGGCTGATATTTTAGCCAAAGTCTTTGGGAAAAATCTCCCTACAGGCACAGAAGT ATCCCCAATTATTAAAACCACAAGTTCTCCATTCTTGAGCCTAGTAGTCACACCACCT TTGCCTGCTGTTTCTCCCCCCTTGGCATCTCCAATACAGACAGCAACAAGTGCTGAAG AATCCTCAGCAGATGTACCTCTACTCAGCGAAGGAAAGCACATTTTGAGTACCATTTC CTCAGCCAGCATGGGACTAGAACACCACAACAATGGAGTTATTCTTGTTGAACCTGAA GTAACAAGCACACCTCTGGAAGAAGTTGTTGATGAGTATTCCAAGAAGACTGAGGAGA TGACTTCCACTGAAGGCGACCTGAAGGGGACTGCAGCCTCTACACTTATATCTGAGCC TTATGAACAATCTCCTACTCTACACACCTTAGACACAGTCTATGAAGAGCCCACCCAT GAAGAGACGGAAACAGAGGGTTGGTCTGCAGCAGATGTTGGATCCTCACCAGATCCCA CATCCAGTGAGTATGAGCTTCCATTGGTTGTTGTCTCCTTGGCTGAGTCTAAGCCTGT GCAATACTTTGACCCAGATTTGGAGACTAATTCACAACCACATGAGGATAACATAAAA GAATACAGTTTTGCACACCTTACTCCAACCGCCATCATCTGGTTTAATGACTCTAGTA CATCACTGTCATTTGAGGATTCTACTGTAGGGGAACAAGGTGTCCCAGGCAAATCACA TCTACAAGGACCGACAGAGAACATCCAGCTTGTGAAAAGTAGTTTTAGCACTCAAGAC ACCTTATTGATTAAAAAAGGTATGAAAGAGATGTCTCAGACACTACAGGGAGGAAATA TGCTAGAGGGAGACCCTACACACTCCAGAAGTTCTGAGAATGAGGGCCAAGAGAGCAA ATCCATCACTTTACCTGACTCCACACTGGGTATAACGAGCAGTACGTCTCCAGTTAAG AAGCCTGCGGAAACCACAGTTGTCACCCTGCTACACAAAGACACCACAACAGAAACAA CTCCAAGGCAAAAAGTGGCTTCATCATCCACCATGAGCACTCACCCTTCTCGAAGGAG ACCCAATGGGAGAAAATTACACCCTCACAAATTCCACCACCGGCACAAGCAAACCCCA CCCACAACTTTTGCTCCATTAGAGACTTTTTCTACTCAACCAACTCAAGCAACTGACA TTAAGATTTCAAATCAAATGGAGAGTTCTCTGGTTCCTACATCTTGGGAGATTAACAC AGTTAATACCCCCAAACAGCTGGAAATGGAGAAGAATGTAGAGCTCATATCAAAGGGA ACTCCACGGAGAAAACACGGGAAGAGGCCAAACAAACATCGATATACCCCTTCTACAG TGAGTTCAAGAGCATCTGCATCCAAGCCCAGCCCTTCTCCAGAAAATAAACATAGAAA CATTGTTACTCCCAGTTCAGAAACTACACTTTTGCCTAGAAATGTTTCTCTGAAAACT GAGGGCGTTTATGATTCCTTAGATTACACGACAACCACCAGAAAAATACATTCATCTC ACCATAAAGTCCAAGACACACTTCCAGTCATGTATAAACCCACATCAGATGGAAAAGA AATTCAGGATGATGTTGCCACAAATGTTGACAAACATAAAAGTGACATTTTAGTCCCT GGTGAGTCAATTACAAATGTCACACAAACTTCTCGCTCCTTGGTCTCCACTATGGGAG AATTTAAGGAAGAATCCTCTCCTGTGGGCTTTCCAGGAATTCCAACCTGGAATCCCTC AAGGAAAGCTCAGCCTGGGAGGCTACAGACAGACATACATGTTACCACTTCTGGGGAA ACCCCTACAGACCCTCCCCTTGTTAACGAGCTTGAGGATGTGGATTTTACTTCTGAGT TTTTGTCCTCTGTGACAGTCTCCACACCATTTCACCAGGAAGAAGCTGGTTTTTCCAC AATTCTCTCAAGCATAAAAGTGGAGATGGCTTCAAGTCAGGTAGAAACTACCACCCTT GGTCAAGATCATCATGAAACCACTGTGGCTATTCTCCACTCTGAAACTAGACCACAGA ATCACATCCTTACTGCTGCCTGGATGAAGGAGCCAGCATCTTTGTCCCCTCCCATGAT TCTCCTGTCTTTGGGACAAACCACCACCACTAAGCCAGAACTTCTCAGTCCAAGAACA TCTCAAATATGTAAAGATTCCAAGGAAAATGTTTTCTTGAATTACATGGGGAATCCAG AAACAGAAGCAACCCCAGTGAAAAATGAAGGAACACAGCGTATGTCAGGGCCAAATGA ATTATCAACACCATCTTCTGACCACGATGCATTTAACTTGTCTACAAAGCTAGAATTG GAAAAGCAAGTATTTGATAGTAGGAGTCTAACACGTGGCCCAGATAGCCACCACCAGG ATGGAAGAGTTCATGCTTCTCATCAACTAACCAGAATCCCTGCCAAACCCATCCTACC AACAGGAACAGTGAGGCTGCCTGAAATGTCCACACAAAGCACTTCCAGATACTTTGTA ACTTTCCAGCCACCTCATCACGGGACCAACAAACCAGAAATAACTACATATCCTTCTA GGGCTTTGCCAGAGAGCAAACAGTTTACAACTCCAAGAGTAGCAAGTACAACTCCTCT CCTATCACACATGTCCAAACCCAGCATTTCTAGTAAGTTTGCTGACCTAAGAACTGAC CAATCCAATGGCTCCTACAAAGTGTTTGGAAATAGCAACATCCCTGAGGCAAGAAACT CAGTTGGAAAGCCTCTCAGTCCAAGAATTTATCATTATTCCAATGGAAGACTCCCTTT CTTTACCAACAGGACTCTTTCTTTTTCACAGTTGGGAGTCACCCGGAGACCCCAGATA CCCTCTTCTCCTGTCCCAGTAATGAGAGAGAGAAAAGTTAATCCAGGTTCCTACAATA GGATATATTCCCATAGCACCTTCCATCTGGACTTTGGCCTTCCAGCACCTCCACTGTT GCACACTCCATGGACCATGGTATCACCCCCAACTAACTTACAGAATATCCCTATGGTC TCATCCACCCAGAGTTCTGTCTCCTTTATAACATCTTCTGTCCAGTCCTCAGGAAGCA TCCACCAAAGCGGCTCAAAGTTCTTTGCAGGAGGACCGCCTGCATCCAAATTCTGGCC TCTTGGGGAAAAGCCCCAAATCCTCACCAAGTCCCCACAGACTGTGTCTGTCACTGCT GAAACGGACGCTGTGTTCCCGTGTGAGGCAATAGGAAAACCAAAGCCTTTCGTTACTT GGACAAAAGTTTCCACATCTCCAGGAGTTCTTATGACTCCGAATACCAGGATACAACG GTTTGAGGTTCTCAAGAACGGTACCTTAGTGATAAGGAAGTTTCAAGTGCAAGATCGA GGCCAGTATATGTGCACCGCCAGCAACCTGTACGGCCTGGACAGGATGGTGGTCTTTC TCTGGGTCACCGTGCAGCAACCTCAAATCCTAGCCTCCCACTACCAGGACGTCACCGT CTACCTGGGAGACACCATTACAATGGAGTGTCTGGCGAAAGGGACCCCAGCCCCCCAA ATTTCCTGGATCTTCCGTGACAGGAGGGTGTGGCAAACTCTGTCCTCCGTGGAGGGCC GGATCACCCTGCACCAAAACCGGACCCTTTCCATCAAGGAGGCGTCCTTCTCAGACAG AGGCGTCTATAAGTGCGTGGCCAGCAACGCAACCCGGGCGGACAGCGTGTCCATCCGC CTACACGTGGCGGCACTGCCCCCCATTATCCACCAGGAGAAGCTGGAGAACATCTCGC TGCCCCCGGGGCTCAGCATTCACATTCACTGCACTGCCAAAGCTGCGCCCCTGCCCAG CGTGCTCTGGGTGCTCGGGGATGGTACCCAAATCCGCCCCTCGCATTTCCTCCACCGG AACTTGTTTGTTTTCCCCAACGGGACGCTCTACATCTGCAACCTCGCGCCCAAGGACA GCGGGCGCTATGAGTGCGTGGCCGCCAACCTGATCGGCTCCGCGCGCAGTACGGTGCA GCTGAACGTGCAGCGCGCAGCAGCGAACGTGCAGCGCGCAGCAGCGAACGTGCAGCGC GCCAACGCGCGCATCACGGGCACCTCCTCGCAGAGGACGGACGTCAGGTACGGAGGGA CCCTCAAGCTGGACTGCAGCGCCTCGGGGGATCCCTGGCCGCGCATCCTCTGGAGGCT GCCGTCCAAGAGGACGATCGACGCGCTTTTCAGTTTTGATAGTAGAATCAAGGTGTTT GCCAACAGGACCCTGGTGGTGAAATCAATGACAGACAAAGACGCCGGAGATTACCTGT GTGTAGCTCGAAATAAGGTTGGTGATGACTGCGTGGTGCTCAAGGTGGATGTGATGAT GAAACCGGCCAAGATTGAACACAAGGAGGAGAACGACCACAAAGTCTTCTACAGGGGT GACCTGAAAGTGGACTGTGTGGCCACTGGACTTCCCAATCCCGAGATCTCCTGGAGCC TCCTGGATGGGAGTCTGGTGAACTCCTTCATGCAGTCAGATGACAGTGGTGGACGCAC CAAGCACTATGTGGTCTTCAACAATGGGACACTCTACTTCAGTGAAGTGGGGATGAGG GAGGAAGGAGACTACACCTGCTTTGCTGAAAATCAGGTTGGGAAGGATGAGATGAGAG TCAGAGTCAAGATGGTGACACCTGCCACCATCTGGAACAAGACTTACTTGGCAGTTCA GGTACCCTATGGAGATGTGGTCACTGTAACCTGTGAGGCCAAAGGAGAACCCATGCCC AAGGTGACTTGGTTGTCCCCAGCCAACAGGGTGATCCCCACCTCCTCTGAGAAGTATC AGATATACCAATATGGCACTCTCCTTATTCAGAAAGCCCAGTGCTCTGACAGCGGCAA CTACACCTGCCTGGTCAGGAACAGTGCCGGAGAGGATAGGAAGACAGTGTGGATTCAC GTCAACCTCCAGCCACCCAAGATCAATGGTAACCCCAACCCCATCACCACCGTGTGGG AGATAGCAGCCGGGGGCAGTCGGAAACTGATTGACTGCAAAGCTGAAGGCATCCCCAC CCCGAGGGTGTTATGGGCTTTTCCCGAGGGTGTGGTTCTGCCAGATCCATACTATGGA AACCGGATCACTGTCCATGGCAACGGTTCCCTGGACATCAGGAGTTTGAGGAAGAGCG ACTCCGTCCAGCTGGTATGCATGGCACGCAACGAGGGAGGGGAGGCGAGGTTGATCGT GCAGCTCACTGTCCTGGAGCCCATGGAGAAACCCATCTTCCACGACCCGATCAGCGAG AAGATCACGGCCATGGCGGGCCACACCATCAGCCTCAACTGCTCTGCCGCGGGGACCC TGACACCCAGCCTGGTGTGGGTCCTTCCCAATGGCACCGATCTGCAGAGTGGACAGCA GCTGCAGCGCTTCTACCACAAGGCTGACGGCATGCTACACATTAGCGGTCTCTCCTCG GTGGACGCCGGGGCCTACCGCTGCGTGGCCCGCAATGCCGCGGGCCACACGGAGAGGC TGGTCTCCCTGAAGGTGGGACTGAAGCCAGAAGCAAACAAGCAGTATCATAACCTGGT CAGCATCATCAATGGTGAGACCCTGAAGCTCCCCTGCACCCCTCCTGCAGCTGGGCAG GGACATTTCTCCTGGACACTCCCCAATGGCATGCATCTGGAGGGCCCCCAAACCCTGG GACGCGTTTCTCTTCTGGACAATGGCACCCTCACGGTTCGTGAGGCCTCGGTGTTTGA CAGGGGTACCTATGTATGCAGGATGGAGACGGCGTACGGCCCTTCGGTCACCAGCATC CCCGTGATTGTGATCGCCTATCCTCCCCGGATCACCAGCGAGCCTACCCCAGTCATCT ACACCCGTCCCGGGAACACCGTGAAACTGAACTGCATGGCTATGGGGATTCCCAAAGG TGACATCACGTGGGAGTTACCGGATAAGTTGCATCTGAAGGCAGGGGTTCAGGCTCGT CTGTATGGAAACAGATTTCTTCACCCCCAGGGATCACTGACCATCCAGCAGGCCAGAC GGAGAGACGCTGGCTTCTACAAGTGCACGGCAAAAAACATTCTCAGCAGTGACTCCAA AACAACTTATATCCATGTCTTCTGAAAT

ORF Start: ATG at 14 ORF Stop: TGA at 8549

SEQ ID NO: 2 2845 aa MW at 315664.5kD

NOVla, MPKRAH GALSWLI L GHPRVALACPHPCACYVPSEVHCTFRSLASVPAGIAKHVE CG58546-01 RINLGFGNSIQALSETSFAGLTK ELLMIHGNEIPSIPDGA RDLSSLQVFKFSYNKL RVITGQTLQGLSNLMRLHIDHNKIEFIHPQAFNGLTSLRL HLEGN LHQ HPSTFST Protein Sequence FTF DYFRLSTIRHLYLAENMVRTLPAS LRNMPLLEN Y QGNP TCDCEMR F E DAKSRGILKCKKDKAYEGGQLCAMCFSPKKLYKHEIHKLKDLTCLKPSIESP RQNRS RSIEEEQKQEENGDSQ I EKIQ PQWSISLNMTDEHGNLVNLVCDIKKP DVYKIHL MQTDPPDIDINAMVA DFEYPMTQENYENL KLIAYYSEVPMKLHRELM SKHPRVSY QYRQDADEEALYYTGVRAQILAEPE IMQPSIDIQLNRPQSTAKKVLSYYNQYSQTI ATKDTRQARGRSWVMIEPSRAVQKDQTVLEGGRCQLSCNVKASESPSIFWVLPDGSIL KVPVDDPDSKFSI SSG RIKSMEPSDSGLYQCIAQVRDEMDRMVYRV VQSPSTQP AEKDTVTIGK PGEPVM PCNALAIPEAHLS I PNRRIIND ANTSHVY LPNGTLS IPKVQVSDSGYHRCVAVNQHGADHITVGITVTK GSGSPS RGR PGPKA SRSKGSF QMREDIVEDEGVSGTGDEENTSRR HPKHQEAFLKTKDDAINGDKKAKKGRRK KLW KHSEKEPETSVAEDLRVFESRRRINVANKQINPEHWADILAKVFGKNLPTGTEVSPII KTTSSPF SLWTPPLPAVSPP ASPIQTATSAEESSADVPLLSEGKHI STISSASM G ΞHHNNGVI VΞPEVTSTPLEEWDEYSK TEE TSTEGDLKGTAAST ISEPYEQS PTLHT DTVYEEPTHEETETEG SAADVGSSPDPTSSEYELPLVWSLAESKPVQYFD PD ETNSQPHEDNIKEYSFAH TPTAII FNDSSTSLSFEDSTVGEQGVPGKSHLQGP TENIQLVKSSFSTQDTLLIKKGMKEMSQT QGGNM EGDPTHSRSSENEGQESKSITL PDSTLGITSSTSPVKKPAETTWTLLHKDTTTETTPRQKVASSSTMSTHPSRRRPNGR KLHPHKFHHRHKQTPPTTFAP ΞTFSTQPTQATDIKISNQMESS VPTS EINTVNTP KQLEMEKNVELISKGTPRRKHGKRPNKHRYTPSTVSSRASASKPSPSPENKHR IVTP SSETTL PRNVSLKTEGVYDSLDYTTTTRKIHSSHHKVQDTLPVMYKPTSDGKEIQDD VAT VDKHKSDILVPGESITNVTQTSRS VSTMGEFKEESSPVGFPGIPT NPSRKAQ PGRLQTDIHVTTSGETPTDPPLVNE EDVDFTSEFLSSV VSTPFHQEEAGFSTILSS I VE ASSQVETTTLGQDHHETTVAILHSETRPQNHI TAAWMKEPASLSPPMILLS GQTTTTKPELLSPRTSQICKDS ENVF NYMGNPETEATPVKNEGTQRMSGPNE STP SSDHDAFNLSTKLELEKQVFDSRSLTRGPDSHHQDGRVHASHQ TRIPAKPI PTGTV RLPEMSTQSTSRYFVTFQPPHHGTNKPEITTYPSRALPESKQFTTPRVASTTPL SH SKPSISSKFADLRTDQSNGSYKVFGNSNIPEARNSVGKPLSPRIYHYSNGRLPFFTNR T SFSQLGVTRRPQIPSSPVPVMRERKVNPGSYNRIYSHSTFHLDFGLPAPPL HTP TJVSPPTNLQNIPMVSSTQSSVSFITSSVQSSGSIHQSGSKFFAGGPPASKFWPLGE PQILTKSPQTVSVTAETDAVFPCEAIGKPKPFVTWTKVSTSPGVLMTPNTRIQRFEVL K GTLVIRKFQVQDRGQYMCTASN YG DRMWFLWVTVQQPQI ASHYQDVTVYLGD TITMECLA GTPAPQIS IFRDRRV QT SSVΞGRITLHQNRTLSIKEASFSDRGVYK CVASNATRADSVSIRLHVAA PPIIHQEKLENIS PPGLSIHIHCTAKAAPLPSVL V LGDGTQIRPSHF HRNLFVFPNGTLYICNLAPKDSGRYECVAANLIGSARSTVQLNVQ RAAANVQRAAANVQRANARITGTSSQRTDVRYGGTLKLDCSASGDP PRILWRLPSKR TIDA FSFDSRIKVFANRT VVKSMTDKDAGDYLCVARNKVGDDCVVL VDVMMKPAK IEHKEENDHKVFYRGDLKVDCVATG PNPEIS SLLDGS VNSFMQSDDSGGRTKHYV VFNNGTLYFSEVGMREEGDYTCFAENQVGKDEMRVRVKMV PATIWNKTY AVQVPYG DWTVTCEAKGΞPMPKVTWLSPANRVIPTSSEKYQIYQYGTLLIQKAQCSDSGNYTCL VRNSAGEDRKTVWIHVN QPPKINGNPNPITTVWEIAAGGSRK IDCKAEGIPTPRVL AFPEGW PDPYYGNRITVHGNGSLDIRS RKSDSVQ VCMARNEGGEAR IVQLTV LEPMEKPIFHDPISEKITAAGHTISLNCSAAGTLTPS V V PNGTDLQSGQQLQRF YHKADGM HISGLSSVDAGAYRCVARNAAGHTERLVS KVG KPEANKQYHNLVSIIN GET KLPCTPPAAGQGHFS TLPNGMHLEGPQTLGRVSLLDNGTLTVREASVFDRGTY VCRMETAYGPSVTSIPVIVIAYPPRITSEPTPVIYTRPGNTVPCNCMAMGIPKGDIT ELPDKLHLKAGVQAR YGNRFLHPQGSLTIQQARRRDAGFYKCTAKNI SSDSKTTYI HVF

SEQ ID NO: 3 762 bp

NOVlb, CGGCCGTGCCCTCATCCTTGTGCCTGCTACGTCCCCAGCGAGGTCCACTGCACGTTCC

174307918 DNA GATCCCTGGCTTCCGTGCCCGCTGGCATTGCTAAACACGTGGAAAGAATCAATTTGGG GTTTAATAGCATACAGGCCCTGTCAGAAACCTCATTTGCAGGACTGACCAAGTTGGAG Sequence CTACTTATGATTCACGGCAATGAGATCCCAAGCATCCCCGATGGAGCTTTAAGAGACC TCAGCTCTCTTCAGGTTTTCAAGTTCAGCTACAACAAGCTGAGAGTGATCACAGGACA GACCCTCCAGGGTCTCTCTAACTTAATGAGGCTGCACATTGACCACAACAAGATCGAG TTTATCCACCCTCAAGCTTTCAACGGCTTAACGTCTCTGAGGCTACTCCATTTGGAAG GAAATCTCCTCCACCAGCTGCACCCCAGCACCTTCTCCACGTTCACATTTTTGGATTA TTTCAGACTCTCCACCATAAGGCACCTCTACTTCGCAGAGAACATGGTTAGAACTCTT CCTGCCAGCATGCTTCGGAACATGCCGCTTCTGGAGAATCTTTACTTGCAGGGAAATC CGTGGACCTGCGATTGTGAGATGAGATGGTTTTTGGAATGGGATGCAAAATCCAGAGG AATTCTGAAGTGTAAAAAGGACAAAGCTTATGAAGGCGGTCAGTTGTGTGCAATGTGC TTCAGTCCAAAGAAGTTGTACAAACATGAGATTCACAAGCTGAAGGACCTGACTTGTC TGCTCGAG

ORF Start: CGG at 1 ORF Stop: it at 763

SEQ ID NO: 4 254 aa MWat29088.6kD

NOVlb, RPCPHPCACYVPSEVHCTFRSLASVPAGIAKHVERIN GFNSIQA SETSFAG TKLE

174307918 Protein LL IHGNEIPSIPDGA RDLSSLQVFKFSYNK RVITGQTLQGLSN MRLHIDHNKIE FIHPQAFNG TSLR LHLEGN HQLHPSTFSTFTFLDYFR STIRHLYFAΞN VRTL Sequence PAS LRNMP LENLYLQGNP TCDCEMR FLEWDAKSRGILKCKKDKAYEGGQLCAMC FSPKKLY HEIHKLKDLTCLLE

Sequence comparison ofthe above protein sequences yields the following sequence relationships shown in Table IB.

Further analysis ofthe NOVla protein yielded the following properties shown in Table IC.

Table IC. Protein Sequence Properties NOVla

PSort 0.4371 probability located in outside; 0.1900 probability located in lysosome analysis: (lumen); 0.1800 probability located in nucleus; 0.1000 probability located in endoplasmic reticulum (membrane)

SignalP Cleavage site between residues 27 and 28 analysis:

A search ofthe NOVla protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table ID.

In a BLAST search of public sequence databases, the NOVla protein was found to have homology to the proteins shown in the BLASTP data in Table IE.

PFam analysis indicates that the NOVla protein contains the domains shown in the Table IF.

Example 2.

The NOV2 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 2A.

Sequence comparison ofthe above protein sequences yields the following sequence relationships shown in Table 2B.

Further analysis ofthe NOV2a protein yielded the following properties shown in Table 2C.

Table 2C. Protein Sequence Properties NOV2a

PSort 0.6850 probability located in endoplasmic reticulum (membrane); 0.6400 analysis: probability located in plasma membrane; 0.4600 probability located in Golgi body; 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 36 and 37 analysis:

A search ofthe NOV2a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 2D.

In a BLAST search of public sequence databases, the NOV2a protein was found to have homology to the proteins shown in the BLASTP data in Table 2E.

PFam analysis indicates that the NOV2a protein contains the domains shown in the Table 2F.

Table 2F. Domain Analysis of NOV2a

Example 3.

The NOV3 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 3A.

Further analysis ofthe NOV3a protein yielded the following properties shown in Table 3B.

Table 3B. Protein Sequence Properties NOV3a

PSort 0.6000 probability located in plasma membrane; 0.4000 probability located in analysis: Golgi body; 0.3000 probability located in endoplasmic reticulum (membrane); 0.0300 probability located in mitochondrial inner membrane

SignalP No Known Signal Sequence Indicated analysis:

A search ofthe NOV3a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 3C.

In a BLAST search of public sequence databases, the NOV3a protein was found to have homology to the proteins shown in the BLASTP data in Table 3D.

Table 3D. Public BLASTP Results for NOV3a

Protein NOV3a Identities/

Accession Protein/Organism/Length Residues/ Similarities for Expect

Number Match the Matched Value

Residues Portion

PFam analysis indicates that the NOV3a protein contains the domains shown in the Table 3E.

Example 4.

The NOV4 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 4A.

Sequence comparison ofthe above protein sequences yields the following sequence relationships shown in Table 4B.

Further analysis ofthe NOV4a protein yielded the following properties shown in Table 4C.

Table 4C. Protein Sequence Properties NOV4a

PSort 0.6000 probability located in plasma membrane; 0.4318 probability located in analysis: mitochondrial inner membrane; 0.4000 probability located in Golgi body; 0.3000 probability located in endoplasmic reticulum (membrane)

SignalP No Known Signal Sequence Indicated analysis: A search ofthe NOV4a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 4D.

In a BLAST search of public sequence databases, the NOV4a protein was found to have homology to the proteins shown in the BLASTP data in Table 4E.

PFam analysis indicates that the NOV4a protein contains the domains shown in the Table 4F.

Example 5.

The NOV5 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 5A.

GGGCCCTGGACCCTTACAAGCCGCGGCGGGCGGGCTTCGGGGAGAGTCGTAGCCGGCG CAGGTCTGGGCGCGCCAAGCGTTTCGTGTCTATCCCGCGGTACGTGGAGACGCTGGTG GTCGCGGACGAGTCAATGGTCAAGTTCCACGGCGCGGACCTGGAACATTATCTGCTGA CGCTGCTGGCAACGGCGGCGCGACTCTACCGCCATCCCAGCATCCTCAACCCCATCAA CATCGTTGTGGTCAAGGTGCTGCTTCTTAGAGATCGTGACTCCGGGCCCAAGGTCACC GGCAATGCGGCCCTGACGCTGCGCAACTTCTGTGCCTGGCAGAAGAAGCTGAACAAAG TGAGTGACAAGCACCCCGAGTACTGGGACACTGCCATCCTCTTCACCAGGCAGGACCT GTGTGGAGCCACCACCTGTGACACCCTGGGCATGGCTGATGTGGGTACCATGTGTGAC CCCAAGAGAAGCTGCTCTGTCATTGAGGACGATGGGCTTCCATCAGCCTTCACCACTG CCCACGAGCTGGGTCACGTGTTCAACATGCCCCATGACAATGTGAAAGTCTGTGAGGA GGTGTTTGGGAAGCTCCGAGCCAACCACATGATGTCCCCGACCCTCATCCAGATCGAC CGTGCCAACCCCTGGTCAGCCTGCAGTGCTGCCATCATCACCGACTTCCTGGACAGCG GGCACGGTGACTGCCTCCTGGACCAACCCAGCAAGCCCATCTCCCTGCCCGAGGATCT GCCGGGCGCCAGCTACACCCTGAGCCAGCAGTGCGAGCTGGCTTTTGGCGTGGGCTCC AAGCCCTGTCCTTACATGCAGTACTGCACCAAGCTGTGGTGCACCGGGAAGGCCAAGG GACAGATGGTGTGCCAGACCCGCCACTTCCCCTGGGCCGATGGCACCAGCTGTGGCGA GGGCAAGCTCTGCCTCAAAGGGGCCTGCGTGGAGAGACACAACCTCAACAAGCACTCT TCCTCACAGGTGGATGGTTCCTGGGCCAAATGGGATCCCTATGGCCCCTGCTCGCGCA CATGTGGTGGGGGCGTGCAGCTGGCCAGGAGGCAGTGCACCAACCCCACCCCTGCCAA CGGGGGCAAGTACTGCGAGGGAGTGAGGGTGAAATACCGATCCTGCAATCTGGAGCCC TGCCCCAGCTCCGGAAAGAGCTTCCGGGAGGAGCAGTGTGAGGCTTTCAACGGCTACA ACCACAGCACCAACCGGCTCACTCTCGCCGTGGCATGGGTGCCCAAGTACTCCGGCGT GTCTCCCCGGGACAAGTGCAAGCTCATCTGCCGAGCCAATGGCACTGGCTACTTCTAT GTGCTGGCACCCAAGGTGGTGGACGGCACGCTGTGCTCTCCTGACTCCACCTCCGTCT GTGTCCAAGGCAAGTGCATCAAGGCTGGCTGTGATGGGAACCTGGGCTCCAAGAAGAG ATTCGACAAGTGTGGGGTGTGTGGGGGAGACAATAAGAGCTGCAAGAAGGTGACTGGA CTCCTTTCCCCCGCCAGGCATGGCTACAATTTCGTGGTGGCCATCCCCGCAGGCGCCT CAAGCATCGACATCCGCCAGCGCGGTTACAAAGGGCTGATCGGGGATGACAACTACCT GGCTCTGAAGAACAGCCAAGGCAAGTACCTGCTCAACGGGCATTTCGTGGTGTCGGCG GTGGAGCGGGACCTGGTGGTGAAGGGCAGTCTGCTGCGGTACAGCGGCACGGGCACAG CGGTGGAGAGCCTGCAGGCTTCCCGGCCCATCCTGGAGCCGCTGACCGTGGAGGTCCT CTCCGTGGGGAAGATGACACCGCCCCGGGTCCGCTACTCCTTCTATCTGCCCAAAGAG CCTCGGGAGGACAAGTCCTCTCATCCCCCGGCACGCTGGGTGGCTGGCAGCTGGGGGC CGTGCTCCGCGAGCTGCGGCAGTGGCCTGCAGAAGCGGGCGGTGGACTGGCGGGGCTC CGCCGGGCAGCGCACGGTCCCTGCCTGTGATGCAGCCCATCGGCCCGTGGAGACACAA GCCTGCGGGGAGCCCTGCCCCACCTGGGAGCTCAGCGCCTGGTCACCCTGCTCCAAGA GCTGCGGCCGGGGATTTCAGAGGCGCTCACTCAAGTGTGTGGGCCACGGAGGCCGGCT GCTGGCCCGGGACCAGTGCAACTTGCACCGCAAGCCCCAGGAGCTGGACTTCTGCGTC CTGAGGCCGTGCTGAGTGGG

ORF Start: ATG at 25 ORF Stop: TGA at 2797

SEQ ID NO: 28 924 aa MWatl00396.3kD

NOV5a, MLLLGILTLAFAGRTAGGSEPEREVWPIRLDPDINGRRYYWRGPEDSGDQGLIFQIT CG57829-01 AFQEDFYLHLTPDAQFLAPAFSTEHLGVPLQGLTGGSSDLRRCFYSGDVNAEPDSFAA VSLCGGLRGAFGYRGAEYVISPLPNASAPAAQRNSQGAHLLQRRGVPGGPSGDPTSRC Protein Sequence GVASG NPAILRALDPYKPRRAGFGESRSRRRSGRAKRFVSIPRYVETLWADESMVK F^'HGADLEHYLLTLLATAARLYRHPSILNPINIWVKVLLLRDRDSGPKVTGNAALTLR NFCAWQKKLNKVSDKHPEY DTAILFTRQDLCGATTCDTLGMADVGTMCDPKRSCSVI EDDGLPSAFTTAHELGHVFNMPHD VKVCEEVFGKLRANH MSPTLIQIDRANP SAC SAAIITDFLDSGHGDCLLDQPSKPISLPEDLPGASYTLSQQCELAFGVGSKPCPYMQY CTKL CTGKAKGQMVCQTRHFPWADGTSCGEGKLCLKGACVERHNLNKHSSSQVDGSW AK DPYGPCSRTCGGGVQLARRQCTNPTPA GGKYCEGVRVKYRSCNLEPCPSSGKSF REEQCEAFWGYNHSTNRLTLAVA VPKYSGVSPRDKCKLICRANGTGYFYVLAPKVVD GTLCSPDSTSVCVQGKCIKAGCDGNLGSKKRFDKCGVCGGDNKSCKKVTGLLSPARHG YNFWAIPAGASSIDIRQRGYKGLIGDDNYLALKNSQGKYLLNGHFWSAVERDLWK GSLLRYSGTGTAVESLQASRPILEPLTVEVLSVGKMTPPRVRYSFYLPKEPREDKSSH PPAR VAGS GPCSASCGSGLQKRAVDWRGSAGQRTVPACDAAHRPVETQACGEPCPT WELSA SPCSKSCGRGFQRRSLKCVGHGGRLLARDQCNLHRKPQELDFCVLRPC

SEQ ID NO: 29 2297 bp NOV5b, CGCGGCGGTGCGCTGCCCGGCGCCATGCTTCTGCTGGGCATCCTAACCCTGGCTTTCG

CG57829-05 DNA CCGGGCGAACCGCTGGAGGCTCTGAGCCAGAGCGGGAGGTAGTCGTTCCCATCCGACT GGACCCGGACATTAACGGCCGCCGCTACTACTGGCGGGGTCCCGAGGACTCCGGGGAT Sequence CAGGGACTCATTTTTCAGATCACAGCATTTCAGGAGGACTTTTACCTACACCTGACGC CGGATGCTCAGTTCTTGGCTCCCGCCTTCTCCACTGAGCATCTGGGCGTCCCCCTCCA GGGGCTCACCGGGGGCTCTTCAGACCTGCGACGCTGCTTCTATTCTGGGGACGTGAAC GCCGAGCCGGACTCGTTCGCTGCTGTGAGCCTGTGCGGGGGGCTCCGCGGAGCCTTTG GCTACCGAGGCGCCGAGTATGTCATTAGCCCGCTGCCCAATGCTAGCGCGCCGGCGGC GCAGCGCAACAGCCAGGGCGCACACCTTCTCCAGCGCCGGGGTGTTCCGGGCGGGCCT TCCGGAGACCCCACCTCTCGCTGCGGGGTGGCCTCGGGCTGGAACCCCGCCATCCTAC GGGCCCTGGACCCTTACAAGCCGCGGCGGGCGGGCTTCGGGGAGAGTCGTAGCCGGCG CAGGTCTGGGCGCGCCAAGCGTTTCGTGTCTATCCCGCGGTACGTGGAGACGCTGGTG GTCGCGGACGAGTCAATGGTCAAGTTCCACGGCGCGGACCTGGAACATTATCTGCTGA CGCTGCTGGCAACGGCGGCGCGACTCTACCGCCATCCCAGCATCCTCAACCCCATCAA CATCGTTGTGGTCAAGGTGCTGCTTCTTAGAGATCGTGACTCCGGGCCCAAGGTCACC GGCAATGCGGCCCTGACGCTGCGCAACTTCTGTGCCTGGCAGAAGAAGCTGAACAAAG TGAGTGACAAGCACCCCGAGTACTGGGACACTGCCATCCTCTTCACCAGGCAGGTGGA TGGTTCCTGGGCCAAATGGGATCCCTATGGCCCCTGCTCGCGCACATGTGGTGGGGGC GTGCAGCTGGCCAGGAGGCAGTGCACCAACCCCACCCCTGCCAACGGGGGCAAGTACT GCGAGGGAGTGAGGGTGAAATACCGATCCTGCAATCTGGAGCCCTGCCCCAGCTCAGC CTCCGGAAAGAGCTTCCGGGAGGAGCAGTGTGAGGCTTTCAACGGCTACAACCACAGC ACCAACCGGCTCACTCTCGCCGTGGCATGGGTGCCCAAGTACTCCGGCGTGTCTCCCC GGGACAAGTGCAAGCTCATCTGCCGAGCCAATGGCACTGGCTACTTCTATGTGCTGGC ACCCAAGGTGGTGGACGGCACGCTGTGCTCTCCTGACTCCACCTCCGTCTGTGTCCAA GGCAAGTGCATCAAGGCTGGCTGTGATGGGAACCTGGGCTCCAAGAAGAGATTCGACA AGTGTGGGGTGTGTGGGGGAGACAATAAGAGCTGCAAGAAGGTGACTGGACTCTTCAC CAAGCCCATGCATGGCTACAATTTCGTGGTGGCCATCCCCGCAGGCGCCTCAAGCATC GACATCCGCCAGCGCGGTTACAAAGGGCTGATCGGGGATGACAACTACCTGGCTCTGA AGAACAGCCAAGGCAAGTACCTGCTCAACGGGCATTTCGTGGTGTCGGCGGTGGAGCG GGACCTGGTGGTGAAGGGCAGTCTGCTGCGGTACAGCGGCACGGGCACAGCGGTGGAG AGCCTGCAGGCTTCCCGGCCCATCCTGGAGCCGCTGACCGTGGAGGTCCTCTCCGTGG GGAAGATGACACCGCCCCGGGTCCGCTACTCCTTCTATCTGCCCAAAGAGCCTCGGGA GGACAAGTCCTCTCATCCCAAGGACCCCCGGGGACCCTCTGTCTTGCACAACAGCGTC CTCAGCCTCTCCAACCAGGTGGAGCAGCCGGACGACAGGCCCCCTGCACGCTGGGTGG CTGGCAGCTGGGGGCCGTGCTCCGCGAGCTGCGGCAGTGGCCTGCAGAAGCGGGCGGT GGACTGCCGGGGCTCCGCCGGGCAGCGCACGGTCCCTGCCTGTGATGCAGCCCATCGG CCCGTGGAGACACAAGCCTGCGGGGAGCCCTGCCCCACCTGGGAGCTCAGCGCCTGGT CACCCTGCTCCAAGAGCTGCGGCCGGGGATTTCAGAGGCGCTCACTCAAGTGTGTGGG CCACGGAGGCCGGCTGCTGGCCCGGGACCAGTGCAACTTGCACCGCAAGCCCCAGGAG CTGGACTTCTGCGTCCTGAGGCCGTGCTGAGTGGG

ORF Start: ATG at 25 ORF Stop: TGA at 2290

SEQ ID NO: 30 755 aa MW at 82147.6kD

NOV5b, MLLLGILTLAFAGRTAGGSEPEREVWPIRLDPDINGRRYY RGPEDSGDQGLIFQIT CG57829-05 AFQEDFYLHLTPDAQFLAPAFSTEHLGVPLQGLTGGSSDLRRCFYSGDVNAEPDSFAA Protein Sequence VSLCGGLRGAFGYRGAEYVISPLPNASAPAAQRNSQGAHLLQRRGVPGGPSGDPTSRC GVASG NPAILRALDPYKPRRAGFGESRSRRRSGRAKRFVSIPRYVETLWADESMVK FHGADLEHYLLTLLATAARLYRHPSILNPINIVWKVLLLRDRDSGPKVTGNAALTLR NFCA QKKLNKVSDKHPEYWDTAILFTRQVDGS AK DPYGPCSRTCGGGVQLARRQC TNPTPANGGKYCEGVRVKYRSCNLEPCPSSASGKSFREEQCEAFNGYNHSTNRLTLAV AWVPKYSGVSPRDKCKLICRANGTGYFYVLAPKVVDGTLCSPDSTSVCVQGKCIKAGC DGNLGSKKRFDKCGVCGGDNKSCKKVTGLFTKPMHGYNFWAIPAGASSIDIRQRGYK GLIGDDNYLALKNSQGKYLLNGHF SAVERDLWKGSLLRYSGTGTAVESLQASRPI LEPLTVEVLSVGKMTPPRVRYSFYLPKEPREDKSSHPKDPRGPSVLHNSVLSLSNQVE QPDDRPPARWVAGS GPCSASCGSGLQKRAVDCRGSAGQRTVPACDAAHRPVETQACG EPCPTWELSA SPCSKSCGRGFQRRSLKCVGHGGRLLARDQCNLHRKPQELDFCVLRP C

SEQ ID NO: 31 555 bp

NOV5c, AGATCTCGGTACGTGGAGACGCTGGTGGTCGCGGACGAGTCAATGGTCAAGTTCCACG

Sequence comparison ofthe above protein sequences yields the following sequence relationships shown in Table 5B.

Further analysis ofthe NOV5a protein yielded the following properties shown in Table 5C.

Table 5C. Protein Sequence Properties NOV5a

PSort 0.5469 probability located in outside; 0.1900 probability located in lysosome analysis: (lumen); 0.1000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 18 and 19 analysis:

A search ofthe NOV5a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 5D.

In a BLAST search of public sequence databases, the NOV5a protein was found to have homology to the proteins shown in the BLASTP data in Table 5E.

PFam analysis indicates that the NOV5a protein contains the domains shown in the Table 5F.

Example 6.

The NOV6 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 6A.

Table 6A. NOV6 Sequence Analysis

SEQ ID NO: 39 2633 bp

NOV6a, ATTTTCTAACACATTTCTACAATATAATGCATTGTGGATTACTTCATATTGACCAGGA

CG59197-01 DNA TATTGTCAATACAATCATCAAACACTGCTCACCTCAATTTTTTTCACTTGGTTTGCCT GGTGCCACAATGCTTATTATGGATTTTATTGTAGCAGCTGGTAGAGTGGCTTCTTCAG

Sequence CTTTTCTCAATGCACCAAGAGTAGAAGCACAAGTTCTTCTGGGATCTTTGGTTTGCTT TCCCAACTTATATTGTGAACTGCCTTCTCTTCATCCCAACATTCCTGATGTTGCTGTG TCTCAGTTTACAGATGTTAAGGAACTTATAATCAAAACTGTATTAAGCTCGGCAAGAG ATGAGCCCTCTGGTCCTGCACGGTGTGTAGCACTTTGTAGTTTAGGTATTTGGATTTG TGAAGAACTAGTCCATGAGTCTCATCATCCTCAAATTAAGGAAGCTCTGAATGTGATT TGTGTTTCCTTAAAGTTTACTAATAAAACAGTAGCCCACGTAGCTTGTAACATGCTTC ACATGCTGGTTCATTATGTACCTAGACTTCAGATTTACCAGCCTGATTCTCCCTTGAA AATTATTCAAATCCTAATAGCTACCATCACCCATCTTTTACCAAGTACAGAGGCTTCA TCTTATGAAATGGACAAGAGGTTGGTAGTATCTTTACTTCTCTGCCTTCTGGACTGGA TCATGGCCTTACCTCTAAAGACACTGCTCCAACCATTTCATGCTACGGGAGCAGAAAG CGATAAAACAGAAAAATCTGTTCTCAATTGCATTTATAAGGTATTACATGGGTGTGTT TATGGAGCTCAGTGTTTTAGCAATCCAAGGTATTTTCCCATGAGCCTCTCTGATTTGG CATCTGTAGATTATGATCCTTTTATGCATTTGGAAAGTCTGAAAGAGCCTGAGCCTCT GCACTCTCCTGACTCAGAACGATCTTCTAAACTCCAGCCAGTAACAGAAGTGAAAACT CAAATGCAGCATGGATTAATCTCTATAGCAGCCCGCACTGTTATTACACATCTGGTAA ATCACCTGGGCCATTATCCAATGAGCGGTGGTCCTGCTATGCTAACAAGTCAGGTGTG TGAAAATCACGACAATCATTACAGTGAAAGTACTGAACTTTCTCCTGAACTCTTTGAG AGTCCAAATATCCAGTTCTTTGTGTTAAATAATACAACCTTAGTGTCCTGTATCCAGA TCAGATCAGAAGAGAATATGCCTGGAGGAGGTTTATCTGCTGGCCTTGCATCAGCCAA TTCAAATGTCAGAATCATAGTACGTGATCTCTCTGGAAAATATTCATGGGATTCTGCT ATACTGTATGGCCCACCTCCTGTAAGTGGCTTGTCAGAACCTACATCTTTCATGCTTT CATTGTCTCACCAAGAGAAGCCAGAAGAGCCTCCGACATCTAATGAATGCTTAGAAGA TATAACCGTAAAAGATGGACTTTCTCTCCAGTTTAAAAGATTTAGAGAAACTGTACCA ACTTGGGATACAATAAGAGATGAAGAAGATGTTCTTGATGAGCTCTTGCAGTATTTGG GTGTTACTAGTCCTGAATGCTTACAGAGAACTGGAATCTCACTTAATATTCCTGCTCC ACAACCTGTGTGCATTTCTGAAAAACAAGAAAATGATGTTATTAATGCTATCCTTAAG CAACATACAGAAGAAAAAGAATTTGTTGAGAAGCACTTTAATGACTTAAACATGAAAG CTGTGGAACAAGATGAACCAATACCTCAAAAACCTCAGTCAGCATTTTATTATTGCAG ATTGCTTCTTAGTATATTGGGAATGAATTCCTGGGACAAACGGAGGAGCTTTCATCTC CTGAAGAAAAATGAAAAGCTACTTAGAGAACTTAGGAACTTGGATTCAAGGCAGTGGC GAGAGACACACAAGATTGCAGTATTTTATGTTGCTGAAGGACAAGAAGACAAACACTC CATTCTCACCAATACAGGAGGAAGTCAAGCATATGAAGATTTTGTAGCTGGTCTTGGT TGGGAGGTAAATCTTACAAACCATTGTGGTTTTATGGGAGGACTACAAAAAAACAAAA GCACTGGATTGACCACTCCATATTTTGCTACCTCTACAGTAGAGGTAATATTTCACGT GTCAACAAGAATGCCTTCTGATTCTGATGATTCTTTGACCAAAAAATTGAGACATTTG GGAAATGATGAAGTGCACATTGTTTGGTCAGAGCATACTAGAGACTACAGGAGAGGAA TTATTCCCACAGAATTTGGTGATGTCCTTATTGTAATATATCCAATGAAAAATCACAT GTTCAGTATTCAGATAATGAAAAAACCAGAGGTACCCTTCTTTGGTCCCCTTTTTGAT GGTGCTATTGTGAATGGAAAGGTTCTACCCATTATGGTTAGAGCAACAGCTATAAATG CAAGCCGTGCTCTGAAATCTCTGATTCCATTGTATCAAAACTTGTATGAGGAGAGAGC ACGATACCTGCAAACAATTGTCCAGCACCACTTAGAACCAACAACATTTGAAGATTTT GCAGCACAGGTTTTTTCTCCAGCTCCCTACCACCATTTACCATCTGATGCCGGTAAGA TTAAAAGCGAGTATTAGTTACTT

ORF Start: ATG at 27 ORF Stop: TAG at 2625

SEQ ID NO: 40 866 aa MW at 97197.4kD

NOV6a, MHCGLLHIDQDIVNTIIKHCSPQFFSLGLPGATMLIMDFIVAAGRVASSAFLNAPRVE CG59197-01 AQVLLGSLVCFPNLYCELPSLHPNIPDVAVSQFTDVKELIIKTVLSSARDEPSGPARC VALCSLGI ICEELVHESHHPQIKEALNVICVSLKFTNKTVAHVAC MLHMLVHYVPR Protein Sequence LQIYQPDSPLKIIQILIATITHLLPSTEASSYΞMDKRLWSLLLCLLDWIMALPLKTL LQPFHATGAESDKTEKSVLNCIYKVLHGCVYGAQCFSNPRYFPMSLSDLASVDYDPFM HLESLKEPEPLHSPDSERSSKLQPVTEVKTQMQHGLISIAARTVITHLVNHLGHYPMS GGPAMLTSQVCENHDNHYSESTELSPELFESPNIQFFVLNNTTLVSCIQIRSEENMPG GGLSAGLASANS VRIIVRDLSGKYS DSAILYGPPPVSGLSEPTSFMLSLSHQEKPE EPPTSNECLEDITVKDGLSLQFKRFRETVPT DTIRDEEDVLDELLQYLGVTSPECLQ RTGISLNIPAPQPVCISEKQENDVINAILKQHTEEKEFVEKHFNDL MKAVEQDEPIP QKPQSAFYYCRLLLSILGMNSWDKRRSFHLLKKNEKLLRELRNLDSRQWRETHKIAVF YVAEGQEDKHSILTNTGGSQAYEDFVAGLGWEVNLTNHCGFMGGLQKNKSTGLTTPYF ATSTVEVIFHVSTRMPSDSDDSLTKKLRHLGNDEVHIV SEHTRDYRRGIIPTEFGDV LIVIYPMKNHMFSIQIMKKPEVPFFGPLFDGAIVNGKVLPIMVRATAINASRALKSLI PLYQNLYEERARYLQTIVQHHLEPTTFEDFAAQVFSPAPYHHLPSDAGKIKSEY

SEQ ID NO: 41 1923 bp

NOV6b, GGATCCAAGACACTGCTCCAACCATTTCATGCTACGGGAGCAGAAAGCGATAAAACAG 188822075 DNA AAAAATCTGTTCTCAATTGCATTTATAAGGTTTTACATGGGTGTGTTTATGGAGCTCA GTGTTTTAGCAATCCAAGGTATTTTCCCATGAGCCTCTCTGATTTGGCATCTGTAGAT Sequence TATGATCCTTTTATGCATTTGGAAAGTCTGAAAGAGCCTGAGCCTCTGCACTCTCCTG ACTCAGAACGATCTTCTAAACTCCAGCCAGTAACAGAAGTGAAAACTCAAATGCAGCA

Sequence comparison ofthe above protein sequences yields the following sequence relationships shown in Table 6B.

Table 6B. Comparison of NOV6a against NOV6b and NOV6c.

NOV6a Residues/ Identities/

Protein Sequence Match Residues Similarities for the Matched Region

NOV6b 230..866 606/637 (95%) 3..639 606/637 (95%)

Further analysis of the NOV6a protein yielded the following properties shown in Table 6C. Table 6C. Protein Sequence Properties NO 6a

PSort 0.7900 probability located in plasma membrane; 0.3000 probability located in analysis: microbody (peroxisome); 0.3000 probability located in Golgi body; 0.2000 probability located in endoplasmic reticulum (membrane)

SignalP No Known Signal Sequence Indicated analysis:

A search ofthe NOV6a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 6D.

Table 6D. Geneseq Results for NOV6a

NOV6a Identities/

Geneseq Protein/Organism/Length [Patent Residues/ Similarities for Expect Identifier #, Date] Match the Matched Value Residues Region

AAB41763 Human ORFX ORF1527 445..859 410/415 (98%) 0.0 polypeptide sequence SEQ ID 1..415 410/415 (98%) NO:3054 - Homo sapiens, 417 aa. [WO200058473-A2, 05-OCT-2000]

AAB93704 Human protein sequence SEQ ID 177-864 389/693 (56%) 0.0 NO: 13287 - Homo sapiens, 704 aa. 1..658 491/693 (70%) [EP1074617-A2, 07-FEB-2001]

AAB95195 Human protein sequence SEQ ID 599..819 186/221 (84%) e-107 NO: 17282 - Homo sapiens, 227 aa. 1..221 203/221 (91%) [EP1074617-A2, 07-FEB-2001]

AAR77223 Tuberous sclerosis 2 TSC2 gene 610..857 70/260 (26%) 3e-20 product - Homo sapiens, 1784 aa. 1497..1755 128/260 (48%) [W09518226-A, 06-JUL-1995]

AAW95629 Homo sapiens secreted protein gene 616..781 50/172 (29%) le-14 clone gml96_4 - Homo sapiens, 322 17..188 89/172 (51%) aa. [WO9856805-A1, 17-DEC-1998]

In a BLAST search of public sequence databases, the NOV6a protein was found to have homology to the proteins shown in the BLASTP data in Table 6E.

PFam analysis indicates that the NOV6a protein contains the domains shown in the Table 6F.

Example 7.

The NOV7 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 7A.

Further analysis ofthe NOV7a protein yielded the following properties shown in Table 7B.

Table 7B. Protein Sequence Properties NOV7a PSort 0.5500 probability located in endoplasmic reticulum (membrane); 0.1900 analysis: probability located in lysosome (lumen); 0.1421 probability located in microbody (peroxisome); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 40 and 41 analysis:

A search ofthe NOV7a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 7C.

In a BLAST search of public sequence databases, the NOV7a protein was found to have homology to the proteins shown in the BLASTP data in Table 7D.

Table 7D. Public BLASTP Results for NOV7a

NOV7a Identities/

Protein Residues/ Similarities for Expect

Accession < Protein/Organism Length ed Value

Number Match the Match Residues Portion

PFam analysis indicates that the NON7a protein contains the domains shown in the Table 7E.

Table 7E. Domain Analysis of ΝOV7a

Identities/

Pfam Domain NO 7a Match Region Similarities Expect Value for the Matched Region ig: domain 1 of 1 53..131 12/83 (14%) 0.00096 53/83 (64%)

Example 8.

The NOV8 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 8A.

Further analysis ofthe NOV8a protein yielded the following properties shown in Table 8B.

Table 8B. Protein Sequence Properties NOV8a

PSort J 0.4600 probability located in plasma membrane; 0.1000 probability located in analysis: endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen); 0.1000 probability located in outside

SignalP Cleavage site between residues 19 and 20 analysis:

A search ofthe NOV8a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 8C.

In a BLAST search of public sequence databases, the NOV8a protein was found to have homology to the proteins shown in the BLASTP data in Table 8D.

PFam analysis indicates that the NOV8a protein contains the domains shown in the Table 8E.

Example 9.

The NOV9 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 9A.

Table 9A. NOV9 Sequence Analysis

SEQ ID NO: 47 958 bp

NOV9a, AAAACATGGCAGCCAAAGTGTTTGAGTCCACGGGTAAGTTTGGCTTGGCCTTAGCTGT

CG58180-01 DNA TGCAGGACTTGGCCTTAGCTGTTGCAGGAGACCTGTGAACTCTGCCTTATATAATGTG GATGTTGGGCACAGAGCTGTCATCTTTGACAGATTCCAGGACAAACAGGACATTGTGG Sequence TAGGGGACTCACTTTCTCATCCCATGGGTACAGAAACCAATTATCTTTGCCTTTCTCC ACCACGTAATGTACCAATCATCACTGGTAGCAAAGATTTACAGAATGTCAATATCACA CTGCGCATCATCTTCCAGCCTGTTGCTAGCCAGCTTCCTCGCATCTTCACCAGCATCG GAGAGGACTATGATGAGCCTGTGCTGACGTACATCACGACCGAGATCCTCAAGTCAGT GGTGGCTCGCTTTGATGCTGGAGAAGTTATCACTCAGAGAGAGCTGGTCTCCAGGCAG GTGAGCAACGACCTTACGGAGCAAGCAGCCACATTTGGGCTCATCCTGGACGACGTGT CCTTGACATATCTGACCTTTGGAAAGGAGTTCACAGAAGCAGTGGAAGCCAAACAGGT GGCTCAGCAGGAAGCAGAGAGGGCCAGATTTGTGAAGGAAAAGGCTGAGCAGCAGAAA AAGGCTGAGCAGCAGAAAAAGGTTGAGCAGCAGAAAAAGGCAGCCGTGATCTCTGCTG AGGGCGACTCCAAGGCAACCGAGCTGATTGCCAACTCACTGGCCACCGCGGGGGACGG CCTGATGGAGCTGTGCAAGTTGGAAGCCGCGGAGTCTCGGAACATGACCTACCTGCCG GCGGGGCAGTCCGCTCCTCCGGCTGCCCCATGAGGGCCCACCCTGCCTGCACCTCCGC

AGGCTGACTGGGCCACAGCCCCAATGATTCTTAACACTGCCTTACCCCCCTACCCCAG

AAATCACTGAAATTTCATAATTGGCTTAAA

ORF Start: ATG at 6 ORF Stop: TGA at 843

SEQ ID NO: 48 279 aa MW at 30368.2kD

NOV9a, MAAKVFE STGKFGLALAVAGLGLS CCRRPVNS ALYNVDVGHRAVI FDRFQDKQD I VVG CG58180-01 DSLSHPMGTETNYLCLSPPRNVPIITGSKDLQNVNITLRIIFQPVASQLPRIFTSIGE DYDEPVLTYITTEILKSWARFDAGEVITQRELVSRQVSNDLTEQAATFGLILDDVSL Protein Sequence TYLTFGKEFTEAVEAKQVAQQEAERARFVKEKAEQQKKAEQQKKVEQQKKAAVISAEG DSKATELIANSLATAGDGLMELCKLEAAESRNMTYLPAGQSAPPAAP

Further analysis ofthe NOV9a protein yielded the following properties shown in Table 9B.

Table 9B. Protein Sequence Properties NOV9a

PSort 0.3700 probability located in outside; 0.1900 probability located in lysosome analysis: (lumen); 0.1000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 33 and 34 analysis: A search ofthe N0V9a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 9C.

In a BLAST search of public sequence databases, the NOV9a protein was found to have homology to the proteins shown in the BLASTP data in Table 9D.

PFam analysis indicates that the NOV9a protein contains the domains shown in the Table 9E.

Example 10.

The NOV10 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 10A.

Table 10A. NOV10 Sequence Analysis

SEQ ID NO: 49 2482 bp

NOVlOa, CGGCCACATAAGATATTATCTACACAAAAGCTTATTTAGGAATGACCAATGAGCTCAA

CG59199-01 DNA CTTAAATTTATTAGAAATCTGATTAGCATTATAAATCAACTGACTTTTAGGAGCATAG

GCTTTGGCGCTACAGGGATCTGGCTTGAACCTCATTGAGGCCACTGATTGGTGAGTGA

Sequence CCTTAAGCAAGTCTCTTTACCTTGTTAGGGCACAATTTCCTCTCGGAATTGTGAAATG

GGTTTAATTACACCAGCTTACATCCCAACCATCAGCAAGTCCTCTTGTATGTAACCAT

CTCCAACACAGAAAGGGGATCTGCCCATGTTCTACCATCCTCACCTTTCTCCAAGCCA

CTACAACCTCTCACAACAGCCTTCCAATTGGTCTCCCTAAACTCTTATCCCCCCTACA

CCCCGTTCTCAGTCCTCAGTCCTTGCCCTAGGCTGGTAGCCCACTCCTTGCCCGCCCC

CCGCCTTCCTCCCATCTCCCCCTCCTCTCCCCGGCCCCCAGCACCTTCTGCATCCCAG

CCTACCTAGCCTACTCCTCCTCTTCCTGGCCCTCTTCCCCAGGCTCCAGGCTGGGGGG

TGCTCGCGTCTCCCCTGTAGGCCAGAGCAGCCCCAAGTTCTGGGGGCGGTGGGGCTGC

TGCTTTATCCCCATGGCGCTGCCATCACTTCTGCTGTTGGTGGCAGCCCTGGCAGGTG

GGGTGCGTCCTCCCGGGGCGCGGAACCTGACGCTGGCGGTGGTGCTGCCAGAACACAA CCTGAGCTATGCCTGGGCCTGGCCACGGGTGGGACCCGCTGTGGCACTAGCTGTGGAG GCTCTGGGCCGGGCACTGCCCGTGGACCTGCGGTTTGTCAGCTCCGAACTGGAAGGCG CCTGCTCTGAGTACCTGGCACCGCTGAGCGCTGTGGACCTCAAGCTGTACCATGACCC CGACCTGCTGTTAGGTCCCGGTTGCGTGTACCCTGCTGCCTCTGTGGCCCGCTTTGCC TCCCACTGGCGCCTTCCCCTGCTGACTGCGGGTGCTGTGGCCTCTGGTTTTTCGGCTA AGAATGACCATTATCGTACCCTGGTTCGCACTGGCCCCTCTGCTCCCAAGCTGGGTGA GTTTGTGGTGACACTACACGGGCACTTCAATTGGACTGCCCGTGCTGCCTTGCTCTAC CTGGATGCTCGCACAGATGACCGGCCTCACTACTTCACCATCGAGGGCGTCTTTGAGG CCCTGCAGGGCAGCAACCTCAGTGTGCAGCACCAGGTGTATGCCCGAGAGCCAGGGGG CCCCGAGCAGGCCACCCACTTCATCCGGGCCAACGGGCGCATTGTGTATATCTGCGGC CCTCTGGAGATGCTGCATGAGATCCTGCTTCAGGCCCAGAGGGAGAATCTGACCAATG GGGATTATGTCTTCTTTTACCTGGATGTCTTTGGGGAGAGTCTCCGTGCAGGCCCCAC AAGTGATACAGGCCGGCCCTGGCAGGACAATCGCACCCGGGAACAGGCCCAGGCCCTC AGAGAGGCCTTTCAGACTGTATTGGTGATCACGTACCGAGAACCCCCAAATCCTGAGT ATCAGGAATTCCAGAATCGTCTGCTGATAAGAGCCCGGGAAGACTTTGGTGTGGAGCT GGGCCCTTCCCTGATGAACCTCATCGCTGGCTGCTTCTATGATGGGATCCTGCTATAT

Further analysis ofthe NOVlOa protein yielded the following properties shown in Table 10B.

Table 10B. Protein Sequence Properties NOVlOa

PSort 0.8650 probability located in lysosome (lumen); 0.5517 probability located in analysis: outside; 0.1000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 17 and 18 analysis:

A search ofthe NOVlOa protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table IOC.

In a BLAST search of public sequence databases, the NOVlOa protein was found to have homology to the proteins shown in the BLASTP data in Table 10D.

PFam analysis indicates that the NOVlOa protein contains the domains shown in the Table 10E.

Example 11.

The NOVl 1 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 11 A.

Table 11A. NOV11 Sequence Analysis

SEQ ID NO: 51 2372 bp

NOVl la, TCCCATTTGACTGCATTTTCTTTGGTCAAAGGCTTCCTTATTCATGGGACCTGCCTGG CG59249-01 DNA GTCCAGGACCCCTTGACAGGTGCTCTCTGGCTGCCTGTCCTCTGGGCACTCTTGTCCC Sequence AGGTCTATTGTTTTCATGACCCACCAGGATGGCGCTTCACTTCCTCAGAAATTGTGAT CCCCAGGAAAGTGCCCCACAAGAGGGGTGGAGTTGAGATGCCAGACCAGCTCTCTTAC AGCATGCGTTTCCGGGGCCAAAGACACGTGATTCACATGAAGCTCAAGAAGAACATGA TGCCCAGACATTTACCTGTTTTTACTGATAATGACCAAGGGGCCATGCAGGAGAACTA CCCTTTTGTCCCACGAGACTGTTACTATGACTGCTACCTGGAAGGGGTTCCTGGGTCT GCGGCCACATTGGACACCTGCCGTGGAGGTCTGCATGGCATGCTGCAGGTGGATGACT TGACTTACGAAATCAAACACCTGGAGGCTTCTTCCAAATTTGAGCATGTAGTATCTCT GCTTGTGTCAGAAGAAAGACCAGGAGAGGCTAGTAGATGTAAGACTGAAGGGGAAGAG ATAGATCAAGAATCTGAAAAGGTAAAACTGGCTGAAACTCCCAGAGCAGGCCACGTTT ATTTGTGGAGGCATCATAGAAAAAACTTGAAAATTCACTACACGGTTACTCGTGGATT ATTCATGCGGAACCCTAATGTGTCACATATAATAGAGAATGTAGTGATTATTAACAGC ATCATACATACCATTTTCAAACCAGTTTATTTAAATGTCTATATATGTGTTTTGTGCA TATGGAATCAAAAGGATGCAGTACTATTTTCTGCTAGCAGGCCAGGCCACGTTGCTGT AGAACTGTTTGGTGTGTGGAAATATCACAATTTGTATTCAGAAATTTCACATGATACC TCAGTTGTTTTTACATCAAATCGACTTGGAAACAGTGAGTGTTATGCCAGCTTTGATG GAATATGCACCCCCAACTGGGGAGCAATGTTTGTGTATATAATGAGGTATCACCTATT TAGGGGGGCATGTGTTACAGCACATGCACTAGGTCATAACATGGGCTTGAGACATGAT TCTGTTGGTTGTTATTGTTTTCGACGAACCAACTGTCTCATGAGCAATTGTTCTTATG AGATAATTCAACGCAAGTTTAATCAATGGGATCCTTGTTTGAGTGCTCCAAATGTTCC ATACACTAATTTTCCATACGTAGCTCCTCGTTGTGGAGACAAGATCAAAAATCAGAGG GAAGAATGTGACTGTGGCTCCCTTAAAGATTGTGCCAGTGATAGATGTTGTGAGACCT CTTGTACCCTTTCTCTTGGCAGTGTTTGCAATACAGGACTTTGCTGCCATAAGTGTAA ATATGCTGCCCCTGGAGTGGTTTGCAGAGACTTGGGTGGTATATGTGATCTACCGGAA TACTGTGATGGGAAAAAGGAAGAGTGTCCAAATGACATCTACATCCAGGATGGAACCC CATGTTCAGCAGTATCTGTTTGTATAAGAGGAAACTGCAGTGACCGTGATATGCAGTG TCAAGCCCTTTTTGGCTACCAAGTGAAAGACGGTTCCCCAGCGTGCTATCGAAAATTG AATAGGATTGGTAACCGATTTGGAAACTGTGGGGTTATTCTACGGCGAGGGGGAAGTA GACCTTTTCCATGTGAAGAAGATGATGTTTTTTGTGGAATGTTGCACTGTAGCGGTGT CAGCCACATTCCCGGTGGAGGTGAGCACACTACATTTTGTAATATATTAGTACACGAC ATAAAAGAAGAAAAATGCTTTGGCTATGAAGCACACCAGGGGACAGACTTGCCAGAAA TGGGGCTGGTAGTGGATGGTGCAACCTGTGGCCCAGGGAGCTACTGTCTTAAACGCAA TTGTACTTTTTATCAAGACCTGCATTTTGAGTGTGATCTTAAAACATGCAATTACAAA GGAGTATGTAACAACAAAAAACATTGTCATTGTCTGCATGAGTGGCAACCACCAACAT GTGAACTGAGAGGAAAAGGAGGTAGTATAGATAGTGGCCCTCTACCTGACAAACAATA TCGTATTGCAGGCAGCATACTTGTAAATACAAACCGAGCACTAGTTTTAATATGTATT CGTTACATCCTTTTTGTGGTTTCGCTTCTCTTTGGTGGCTTTTCACAAGCAATACAAT GTTAGGGAAGAGAAAGGAAAAGAGCCCACACAATGGAGTAAATTACATTGACACTTAC

TGGGAGATATAATCAATAGTCACTCTGACAATTACATCATCTTTTAGCAATTCTGATG

TCATCTTGAAATAAAATCACTTGGCAATTTAAAAAGGTCTGTGTGTTTAAAT

ORF Start: ATG at 44 ORF Stop: TAG at 2207

SEQ ID NO: 52 721 aa MW at 81098.2kD

NOVl la, MGPAVQDPLTGALWLPVLWALLSQVYCFHDPPG RFTSSEIVIPRKVPHKRGGVEMP CG59249-01 DQLSYSMRFRGQRHVIHMKLKKNMMPRHLPVFTDNDQGAMQENYPFVPRDCYYDCYLE GVPGSAATLDTCRGGLHGMLQVDDLTYEIKHLEASSKFEHWSLLVSEERPGEASRCK Protein Sequence TEGEEIDQESEKVKLAETPRAGHVYLWRHHRKNLKIHYTVTRGLFMRNP VSHIIENV VIINSIIHTIFKPVYLNVYICVLCIW QKDAVLFSASRPGHVAVELFGV KYHNLYSE ISHDTSWFTSNRLGNSECYASFDGICTPN GAMFVYIMRYHLFRGACVTAHALGHNM GLRHDSVGCYCFRRTNCLMSNCSYEIIQRKFtfQWDPCLSAP VPYTNFPYVAPRCGDK IKNQREECDCGSLKDCASDRCCETSCTLSLGSVCNTGLCCHKCKYAAPGWCRDLGGI CDLPEYCDGKKEECPNDIYIQDGTPCSAVSVCIRGNCSDRDMQCQALFGYQVKDGSPA CYRKLNRIGNRFGNCGVILRRGGSRPFPCEEDDVFCGMLHCSGVSHIPGGGEHTTFCN ILVHDIKEEKCFGYEAHQGTDLPEMGLWDGATCGPGSYCLKRNCTFYQDLHFECDLK TCNYKGVCNNKKHCHCLHEWQPPTCELRGKGGSIDSGPLPDKQYRIAGSILV TNRAL VLICIRYILFWSLLFGGFSQAIQC

SEQ ID NO: 53 2429 bp

NOVl lb, TCCCATTTGACTGCATTTTCTTTGGTCAAAGGCTTCCTTATTCATGGGACCTGCCTGG CG59249-02 DNA GTCCAGGACCCCTTGACAGGTGCTCTCTGGCTGCCTGTCCTCTGGGCACTCTTGTCCC AGGTCTATTGTTTTCATGACCCACCAGGATGGCGCTTCACTTCCTCAGAAATTGTGAT Sequence CCCCAGGAAAGTGCCCCACAAGAGGGGTGGAGTTGAGATGCCAGACCAGCTCTCTTAC AGCATGCGTTTCCGGGGCCAAAGACACGTGATTCACATGAAGCTCAAGAAGAACATGA TGCCCAGACATTTACCTGTTTTTACTGATAATGACCAAGGGGCCATGCAGGAGAACTA CCCTTTTGTCCCACGAGACTGTTACTATGACTGCTACCTGGAAGGGGTTCCTGGGTCT GCGGCCACATTGGACACCTGCCGTGGAGGTCTGCATGGCATGCTGCAGGTGGATGACT TGACTTACGAAATCAAACCCCTGGAGGCTTCTTCCAAATTTGAGCATGTAGTATCTCT GCTTGTGTCAGAAGAAAGACCAGGAGAGGCTAGTGGATGTATGACTGAAGGGGAAGAG ATAGATCAAGAATCTGAAAAGGTAAAACTGGCTGAAACTCCCAGAGCAGGCCACGTTT ATTTGTGGAGGCATCATAGAAAAAACTTGAAAATTCACTACACGGTTACTCGTGGATT ATTCATGCGGAACCCTAATGTGTCACATATAATAGAGAATGTAGTGATTATTAACAGC ATCATACATACCATTTTCAAACCAGTTTATTTAAATGTCTATATATGTGTTTTGTGCA TATGGAATCAAAAGGATGCAGTACTATTTTCTGCTAGCAGGCCGGGCCACGTTGCTGT AGAACTGTTTGGTGTGTGGAAATATCACAATTTGTATTCAGAGATTTCACATGATGCC TCAGTTGTTTTTACATCAAATCGACTTGGAAACAGTGAGTGTTATGCCAGCTTTGATG GAATATGCACCCCCAACTGGGGAGCAATGTTTGTGTATATAATGAGGTATCACCTATT TAGGGGGGCATGTGTTACAGCACATGCACTAGGTCATAACATGGGCTTGAGACATGAT TCTGTTGGTTGTTATTGTTTTCGACGAACCAACTATCTCATGGCTCCTGTTCCTGATC TTAATGATATGATGAGCAATTGTTCTTATGAGATAATTCAACGCAAGTTTAATCAATG GGATCCTTGTTTGAGTGCTCCAAATGTTCCATACACTAATTTTCCATACGTAGCTCCT CGTTGTGGAGACAAGATCAAAAATCAGAGGGAAGAATGTGACTGTGGCTCCCTTAAAG ATTGTGCCAGTGATAGATGTTGTGAGACCTCTTGTACCCTTTCTCTTGGCAGTGTTTG CAATACAGGACTTTGCTGCCATAAGTGTAAATATGCTGCCCCTGGAGTGGTTTGCAGA GACTTGGGTGGTATATGTGATCTACCGGAATACTGTGATGGGAAAAAGGAAGAGTGTC CAAATGACATCTACATCCAGGATGGAACCCCATGTTCAGCAGTATCTGTTTGTATAAG AGGAAACTGCAGTGACCGTGATATGCAGTGTCAAGCCCTTTTTGGCTACCAAGTGAAA GACGGTTCCCCAGCGTGCTATCGAAAATTGAATAGGATTGGTAACCGATTTGGAAACT GTGGGGTTATTCTACGGCGAGGGGGAAGTAGACCTTTTCCATGTGAAGAAGATGATGT TTTTTGTGGAATGTTGCACTGTAGCGGTGTCAGCCACATTCCCGGTGGAGGTGAGCAC ACTACATTTTGTAATATATTAGTACACGACATAAAAGAAGAAAAATGCTTTGGCTATG AAGCACACCAGGGGACAGACTTGCCAGAAATGGGGCTGGTAGTGGATGGTGCAACCTG TGGCCCAGGGAGCTACTGTCTTAAACGCAATTGTACTTTTTATCAAGACCTGCATTTT GAGTGTGATCTTAAAACATGCAATTACAAAGGAGTATGTAGCAACAAAAAACATTGTC ATTGTCTGCATGAGTGGCAACCACCAACATGTGAACTGAGAGGAAAAGGAGGTAGTAT AGATAGTGGCCCTCTACCTGACAAACAATATCGTATTGCAGGCAGCATACTTGTAAAT ACAAACCGAGCACTAGTTTTAATATGTATTCGTTACATCCTTTTTGTGGTTTCGCTTC TCTTTGGTGGCTTTTCACAAGCAATACAATGTTAGGGAAGAGAAAGGAAAAGAGCCCA

CACAATGGAGTAAATTACATTGACACTTACTGGGAGATATAATCAATAGTCACTCTGA

CAATTACATCATCTTTTAGCAATTCTGATGTCATCTTGAAATAAAATCACTTGGCAAT

TTAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGG

ORF Start: ATG at 44 ORF Stop: TAG at 2237

SEQ ID NO: 54 731 aa MW at 82049.3kD

NOVl lb, MGPAVQDPLTGAL LPVL ALLSQVYCFHDPPGWRFTSSEIVIPRKVPHKRGGVEMP CG59249-02 DQLSYSMRFRGQRHVIHMKLKKNMMPRHLPVFTDNDQGAMQENYPFVPRDCYYDCYLE GVPGSAATLDTCRGGLHGMLQVDDLTYEIKPLEASSKFEHWSLLVSEERPGEASGCM Protein Sequence TEGEEIDQESEKVKLAETPRAGHVYL RHHRKNLKIHYTVTRGLFMRNPNVSHIIENV VIINSIIHTIFKPVYLNVYICVLCI NQKDAVLFSASRPGHVAVELFGV KYHNLYSE ISHDASWFTSNRLGNSECYASFDGICTPN GAMFVYIMRYHLFRGACVTAHALGHNM GLRHDSVGCYCFRRTNYLMAPVPDLNDMMSNCSYEIIQRKFNQWDPCLSAPMVPYTNF PYVAPRCGDKIK QREECDCGSLKDCASDRCCETSCTLSLGSVCNTGLCCHKCKYAAP GWCRDLGGICDLPEYCDGKKEECPNDIYIQDGTPCSAVSVCIRGNCSDRDMQCQALF GYQVKDGSPACYRKLNRIGNRFGNCGVILRRGGSRPFPCEEDDVFCGMLHCSGVSHIP GGGEHTTFCNILVHDIKEEKCFGYEAHQGTDLPEMGLWDGATCGPGSYCLKR CTFY QDLHFECDLKTCNYKGVCSNKKHCHCLHEWQPPTCELRGKGGSIDSGPLPDKQYRIAG SILVNTNRALVLICIRYILFWSLLFGGFSQAIQC

Sequence comparison ofthe above protein sequences yields the following sequence relationships shown in Table 1 IB.

Further analysis ofthe NOVl la protein yielded the following properties shown in Table 1 IC.

Table HC. Protein Sequence Properties NOVlla

PSort 0.8056 probability located in plasma membrane; 0.2800 probability located in analysis: endoplasmic reticulum (membrane); 0.2000 probability located in lysosome (membrane); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 29 and 30 analysis:

A search ofthe NOVl la protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 1 ID.

Table 11D. Geneseq Results for NOVlla

In a BLAST search of public sequence databases, the NOVl la protein was found to have homology to the proteins shown in the BLASTP data in Table 1 IE.

PFam analysis indicates that the NOVl la protein contains the domains shown in the Table 11F.

Example 12.

The NOVl 2 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 12A.

Table 12A. NOV12 Sequence Analysis

SEQ ID NO: 55 3874 bp

NOV12a, ACAACTGTGATGATCCACTAGCATCCCTGCTCTCTCCAATGGCTTTTTCCAGTTCCTC CG58577-01 DNA AGACCTCACTGGCACTCACAGCCCAGCTCAACTCAACTGGAGAGTTGGAACTGGCGGT TGGTCCCCAGCAGATTCCAATGCTCAACAGTGGCTCCAGATGGACCTGGGAAACAGAG Sequence TAGAGATTACAGCAGTGGCCACGCAGGGAAGATACGGAAGCTCTGACTGGGTGACGAG TTACAGCCTGATGTTCAGTGACACAGGACGCAACTGGAAACAGTACAAACAAGAAGAC AGCATCTGGACCTTTGCAGGAAACATGAATGCTGACAGCGTGGTGCACCACAAGCTAT TGCACTCAGTGAGAGCCCGATTTGTTCGCTTTGTGCCCCTGGAATGGAATCCCAGTGG GAAGATTGGCATGAGAGTCGAGGTCTACGGATGTTCCTATAATGTTGCTGACTTTGAT GGCCGAAGCTCACTTCTGTACAGGTTCAATCAGAAGTTGATGAGTACTCTCAAAGATG TGATCTCCCTGAAGTTCAAGAGCATGCAAGGAGATGGGGTCCTGTTCCATGGAGAAGG TCAGCGTGGAGACCACATCACCTTGGAACTCCAGAAGGGGAGGCTCGCCCTACACCTC AATTTGGGTGACAGCAAAGCGCGGCTCAGCAGCAGCTTGCCCTCTGCCACCCTGGGCA GCCTCCTGGATGACCAGCACTGGCACTCGGTCCTCATTGAGCGGGTGGGCAAGCAGGT GAACTTCACGGTGGACAAGCACACACAGCACTTCCGCACCAAGGGCGAGACGGATGCC TTAGACATTGACTATGAGCTTAGTTTTGGAGGAATTCCAGTACCAGGAAAACCTGGGA CCTTTTTAAAGAAAAACTTCCATGGATGCATCGAAAACCTTTACTACAATGGAGTAAA CATAATTGACCTGGCTAAGAGACGAAAGCATCAGATCTATACTGTGGGCAATGTCACT TTTTCCTGCTCCGAACCACAGATTGTGCCCATCACATTTGTCAACTCCAGCGGCAGCT ATTTGCTGCTGCCCGGCACCCCCCAAATTGATGGGCTCTCAGTGAGTTTCCAGTTTCG AACATGGAACAAGGATGGTCTGCTTCTGTCCACAGAGCTGTCTGAGGGCTCGGGAACC CTGCTGCTGAGCCTGGAGGGTGGAATCCTGAGACTCGTGATTCAGAAAATGACAGAAC GCGTAGCTGAAATCCTCACAGGCAGCAACTTGAATGATGGCCTGTGGCACTCGGTTAG CATCAACGCCAGGAGGAACCGCATCACGCTCACTCTGGATGATGAAGCAGCACCCCCG GCTCCAGACAGCACTTGGGTGCAGATTTATTCTGGAAATAGCTACTATTTTGGAGGTT GCCCCGACAATCTCACCGATTCCCAATGTTTAAATCCCATTAAGGCTTTCCAAGGCTG CATGAGGCTCATCTTTATTGATAACCAGCCCAAGGACCTCATTTCAGTTCAGCAAGGT TCCCTGGGGAATTTTAGTGATTTACACATTGATCTGTGTAGCATCAAAGACAGGTGTT TGCCAAACTACTGTGAACATGGAAGGAAGTTGTTCCCAGTCCTGGACTACCTTTTCTA TTGTAACTGCAGTGACACAAGTTACACTGGTGCCACCTGCCACAACTCCATCTACGAG CAATCCTGCGAGGTGTACAGGCACCAGGGGAATACAGCCGGCTTCTTCTACATCGACT CAGATGGCAGCGGCCCACTGGGACCTCTCCAGGTGTACTGCAATATCACTGAGGACAA GATCTGGACATCAGTGCAGCACAACAATACAGAGCTGACCCGAGTGCGGGGCGCTAAC CCTGAGAAGCCCTATGCCATGGCCTTGGACTACGGGGGCAGCATGGAACAGCTGGAGG CCGTGATCGACGGCTCTGAGCACTGTGAGCAGGAGGTGGCCTACCACTGCAGGAGGTC CCGCCTGCTCAACACGCCGGATGGAACACCATTTACCTGGTGGATTGGGCGGTCCAAT GAAAGGCACCCTTACTGGGGAGGTTCCCCTCCTGGGGTCCAGCAGTGTGAGTGTGGCC TAGACGAGAGCTGCCTGGACATTCAGCACTTTTGCAATTGCGACGCTGACAAGGAAAA TGATACTGGCTTTCTTTCCTTCAAAGACCACTTGCCTGTCACTCAGATAGTTATCACT GATACCGACAGATCAAACTCAGAAGCCGCTTGGAGAATTGGTCCCTTGCGTTGCTATG GTGACCGACGCTTCTGGAACGCCGTCTCATTTTATACAGAAGCCTCTTACCTCCACTT TCCTACCTTCCATGCGGAATTCAGTGCCGATATTTCCTTCTTTTTTAAAACCACAGCA TTATCCGGAGTTTTCCTAGAAAATCTTGGCATTAAAGACTTCATTCGACTCGAAATAA GCTCTCCTTCAGAGATCACCTTTGCCATCGATGTTGGGAATGGTCCTGTGGAGCTTGT AGTCCAGTCTCCTTCTCTTCTGAATGACAACCAATGGCACTATGTCCGGGCTGAGAGG AACCTCAAGGAGACCTCCCTGCAGGTGGACAACCTTCCAAGGAGCACCAGGGAGACGT CGGAGGAGGGCCATTTTCGACTGCAGCTGAACAGCCAGTTGTTTGTAGGGGGAACGTC ATCCAGACAGAAAGGCTTCCTAGGATGCATTCGCTCCTTACACTTGAATGGACAGAAA ATGGACCTGGAAGAGAGGGCAAAGGTCACATCTGGAGTCAGGCCAGGCTGCCCCGGCC ACTGCAGCAGCTACGGCAGCATCTGCCACAACGGGGGCAAGTGTGTGGAGAAGCACAA TGGCTACCTGTGTGATTGCACCAATTCACCTTATGAAGGGCCCTTTTGCAAAAAAGAG GTTTCTGCTGTTTTTGAGGCTGGCACGTCGGTTACTTACATGTTTCAAGAACCCTATC CTGTGACCAAGAATATAAGCCTCTCATCCTCAGCTATTTACACAGATTCAGCTCCATC CAAGGAAAACATTGCACTTAGCTTTGTGACAACCCAGGCACCCAGTCTTTTGCTCTTT ATCAATTCTTCTTCTCAGGACTTCGTGGTTGTTCTGCTCTGCAAGAATGGAAGCTTAC AGGTTCGCTATCACCTAAACAAGGAAGAAACCCATGTATTCACCATTGATGCAGATAA CTTTGCTAACAGAAGGATGCACCACTTGAAGATTAACCGAGAGGGAAGAGAGCTTACC ATTCAGGTACCTTCCTTACTTTCTCCTGCTTCAGCCAATATGGACCAGCAACTTCGAC TCAGTTATAACTTCTCTCCGGAAGTAGAGTTCAGGGTTATAAGGTCACTCACCTTGGG CAAAGTCACAGAGAATCTTGGTTTGGATTCTGAAGTTGCTAAAGCAAATGCCATGGGT TTTGCTGGATGCATGTCTTCCGTCCAGTACAACCACATAGCACCACTGAAGGCTGCCC TGCGCCATGCCACTGTCGCGCCTGTGACTGTCCATGGGACCTTGACGGAATCCAGCTG TGGCTTCATGGTGGACTCAGATGTGAATGCAGTGACCACGGTGCATTCTTCATCAGAT CCTTTTGGGAAGACAGATGAGCGGGAACCACTCACAAATGCTGTTCGAAGTGATTCGG CAGTCATCGGAGGGGTGATAGCAGTGGTGATATTCATCATCTTCTGTATCATCGGCAT CATGACCCGGTTCCTCTACCAGCACAAGCAGTCACATCGTACGAGCCAGATGAAGGAG AAGGAATATCCAGAAAATTTGGACAGTTCCTTCAGAAATGAAATTGACTTGCAAAACA CAGTGAGCGAGTGTAAACGGGAATATTTCATCTGAGAAACTGCAGG

ORF Start: AAC at 3 ORF Stop: TGA at 3861

SEQ ID NO: 56 1286 aa MW at 143343 JkD

NOV12a, NCDDPLASLLSPMAFSSSSDLTGTHSPAQLNWRVGTGGWSPADSNAQQWLQMDLGNRV CG58577-01 EITAVATQGRYGSSDWVTSYSLMFSDTGRNWKQYKQEDSIWTFAGNMNADSWHHKLL Protein Sequence HSVRARFVRFVPLEWNPSGKIGMRVEVYGCSYNVADFDGRSSLLYRFNQKLMSTLKDV ISLKFKSMQGDGVLFHGEGQRGDHITLELQKGRLALHLNLGDSKARLSSSLPSATLGS LLDDQHWHSVLIERVGKQVNFTVDKHTQHFRTKGETDALDIDYELSFGGIPVPGKPGT FLKKNFHGCIENLYYNGVNIIDLAKRRKHQIYTVGNVTFSCSΞPQIVPITFVNSSGSY

Sequence comparison ofthe above protein sequences yields the following sequence relationships shown in Table 12B.

Further analysis ofthe NOVl 2a protein yielded the following properties shown in Table 12C.

Table 12C. Protein Sequence Properties NO 12a

PSort 0.7000 probability located in plasma membrane; 0.4467 probability located in analysis: microbody (peroxisome); 0.3000 probability located in nucleus; 0.2000 probability located in endoplasmic reticulum (membrane)

No Known Signal Sequence Indicated analysis:

A search ofthe NOVl 2a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 12D.

In a BLAST search of public sequence databases, the NOVl 2a protein was found to have homology to the proteins shown in the BLASTP data in Table 12E.

PFam analysis indicates that the NOVl 2a protein contains the domains shown in the Table 12F.

Example 13.

The NOVl 3 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 13 A.

Table 13A. NO 13 Sequence Analysis

SEQ ID NO: 71 14109 bp

NOVl 3a, TGTCGCTCAACGGGATGCCCCTGTACAACGACAGCTTCCATGAGATCTCACACAAGGG CG59237-01 DNA CCGGCGCCACACGCTGGTACTGAAGAGCATCCAGCGGGCTGATGCGGGCATAGTACGC GCCTCCTCCCTGAAGGTGTCGACCTCTGCCCGCCTGGAGGTCCGAGTGAAGCCGGTGG Sequence TGTTCCTGAAGGCGCTGGATGACCTGTCCGCAGAGGAGCGCGGCACCCTGGCCCTGCA GTGTGAAGTCTCTGACCCCGAGGCCCATGTGGTGTGGCGCAAAGATGGCGTGCAGCTG GGCCCCAGTGACAAGTATGACTTCCTGCACACGGCGGGCACGCGGGGGCTCGTGGTGC ATGACGTGAGCCCTGAAGACGCCGGCCTGTACACCTGCCACGTGGGCTCCGAGGAGAC CCGGGCCCGGGTCCGCGTGCACGATCTGCACGTGGGCATCACCAAGAGGCTGAAGACA ATGGAGGTGCTGGAAGGGGAAAGCTGCAGCTTTGAGTGCGTCCTGTCCCACGAGAGTG CCAGCGACCCGGCCATGTGGACAGTCGGTGGGAAGACAGTGGGCAGCTCCAGCCGCTT CCAGGCCACACGTCAGGGCCGAAAATACATCCTGGTGGTCCGGGAGGCTGCACCAAGT GATGCCGGGGAGGTGGTCTTCTCTGTGCGGGGCCTCACCTCCAAGGCCTCACTCATTG TCAGAGAGAGGCCGGCCGCCATCATCAAGCCCCTGGAAGACCAGTGGGTGGCGCCAGG GGAGGACGTGGAGCTGCGCTGTGAGCTGTCACGGGCGGGAACGCCCGTGCACTGGCTG AAGGACAGGAAGGCCATCCGCAAGAGCCAGAAGTATGATGTGGTCTGCGAGGGCACGA TGGCCATGCTGGTCATCCGCGGGGCCTCGCTCAAGGACGCGGGCGAGTACACGTGTGA GGTGGAGGCTTCCAAGAGCACAGCCAGCCTCCATGTGGAAGAAAAAGCAAACTGCTTC ACAGAGGAGCTGACCAATCTGCAGGTGGAGGAGAAAGGCACAGCTGTGTTCACGTGCA AGACGGAGCACCCCGCGGCCACAGTGACCTGGCGCAAGGGCCTCTTGGAGCTACGGGC CTCAGGGAAGCACCAGCCCAGCCAGGAGGGCCTGACCCTGCGCCTCACCATCAGTGCC CTGGAGAAGGCAGACAGCGACACCTATACCTGCGACATTGGCCAGGCCCAGTCCCGGG CCCAGCTCCTAGTGCAAGGCCGGAGAGTGCACATCATCGAGGACCTGGAGGATGTGGA TGTGCAGGAGGGCTCCTCGGCCACCTTCCGTTGCCGGATCTCCCCGGCCAACTACGAG CCTGTGCACTGGTTCCTGGACAAGACACCCCTGCATGCCAACGAGCTCAATGAGATCG ATGCCCAGCCCGGGGGCTACCACGTGCTGACCCTGCGGCAGCTGGCGCTCAAGGACTC GGGCACCATCTACTTTGAGGCGGGTGACCAGCGGGCCTCGGCCGCCCTGCGGGTCACT GAGAAGCCAAGCGTCTTCTCCCGGGAGCTCACAGATGCCACCATCACAGAGGGTGAGG ACTTGACCCTGGTGTGCGAGACCAGCACCTGCGACATTCCTGTGTGCTGGACCAAGGA TGGGAAGACCCTGCGGGGGTCTGCCCGGTGCCAGCTGAGCCATGAGGGCCACCGGGCC CAGCTGCTCATCACTGGGGCCACCCTGCAGGACAGTGGACGCTACAAGTGTGAGGCTG GGGGCGCCTGCAGCAGCTCCATTGTCAGGGTGCATGCGCGGCCAGTGCGGTTCCAGGA GGCCCTGAAGGACCTGGAGGTGCTGGAGGGTGGTGCTGCCACACTGCGCTGTGTGCTG TCATCTGTGGCTGCGCCCGTGAAGTGGTGCTATGGAAACAACGTCCTGAGGCCAGGTG ACAAATACAGCCTACGCCAGGAGGGTGCCATGCTGGAGCTGGTGGTCCGGAACCTCCG GCCGCAGGACAGCGGGCGGTACTCATGCTCCTTCGGGGACCAGACTACTTCTGCCACC CTCACAGTGACTGCCCTGCCTGCCCAGTTCATCGGGAAACTGAGAAACAAGGAGGCCA CAGAAGGGGCCACGGCCACGCTGCGGTGTGAGCTGAGCAAGGCAGCCCCTGTGGAGTG GAGAAAGGGGTCCGAGACCCTCAGAGATGGGGACAGATACTGTCTGAGGCAGGACGGG GCCATGTGTGAGCTGCAGATCCGTGGCCTGGCCATGGTGGATGCCGCGGAGTACTCGT GTGTGTGTGGAGAGGAGAGGACCTCAGCCTCACTCACCATCAGGCCCATGCCTGCCCA CTTCATAGGAAGACTGAGACACCAAGAGAGCATAGAAGGGGCCACAGCCACGCTGCGG TGTGAGCTGAGCAAGGCGGCCCCCGTGGAGTGGAGGAAGGGGCGTGAGAGCCTCAGAG ATGGGGACAGACATAGCCTGAGGCAGGACGGGGCTGTGTGCGAGCTGCAGATCTGTGG CCTGGCTGTGGCAGATGCTGGGGAGTACTCCTGTGTGTGTGGGGAGGAGAGGACCTCT GCCACTCTCACCGTGAAGGCCCTGCCAGCCAAGTTCACAGAGGGTCTGAGGAATGAAG AGGCCGTGGAAGGGGCCACAGCCATGTTGTGGTGTGAACTGAGCAAGGTGGCCCCTGT GGAGTGGAGGAAGGGGCCCGAGAACCTCAGAGATGGGGACAGATACATCCTGAGGCAG GAGGGGACCAGGTGTGAGCTGCAGATCTGTGGCCTGGCCATGGCGGACGCCGGGGAGT ACTTGTGTGTGTGCGGGCAGGAGAGGACCTCAGCCACGCTCACCATCAGGGCTCTGCC TGCCAGGTTCATAGAAGATGTGAAAAACCAGGAGGCCAGAGAAGGGGCCACGGCTGTG CTGCAGTGTGAGCTGAACAGTGCAGCCCCTGTGGAGTGGAGAAAGGGGTCTGAGACCC TTAGAGATGGGGACAGATACAGCCTGAGGCAGGACGGGACTAAATGTGAGCTGCAGAT TCGTGGCCTGGCCATGGCAGACACTGGGGAGTACTCGTGCGTGTGCGGGCAGGAGAGG ACCTCGGCTATGCTCACCGTCAGGGCTCTACCCATCAAGTTCACAGAGGGTCTGAGGA ACGAAGAGGCCACAGAAGGGGCAACAGCCGTGCTGCGGTGTGAGCTGAGCAAGATGGC CCCCGTGGAGTGGTGGAAGGGGCATGAGACCCTCAGAGATGGAGACAGACACAGCCTG AGGCAGGACGGGGCCAGGTGTGAGCTGCAGATCCGCGGCCTCGTGGCAGAGGACGCTG GGGAGTACCTGTGCATGTGCGGGAAGGAGAGGACCTCAGCCATGCTCACCGTCAGGGC CATGCCTTCCAAGTTCATAGAGGGTCTGAGGAATGAAGAGGCCACAGAAGGGGACACG GCCACGCTGTGGTGTGAGCTGAGCAAGGCGGCACCGGTGGAGTGGAGGAAGGGGCATG AGACCCTCAGAGATGGGGACAGACACAGCCTGAGGCAGGATGGGTCCAGGTGTGAGCT GCAGATCCGTGGCCTGGCTGTGGTGGATGCCGGGGAGTACTCGTGTGTGTGCGGGCAG GAGAGGACCTCAGCCACACTCACTGTCAGGGCCCTGCCTGCCAGATTCATAGAAGATG TGAAAAACCAGGAGGCCAGAGAAGGGGCCACGGCCGTGCTGCAATGTGAGCTGAGCAA GGCGGCCCCCGTGGAGTGGAGGAAGGGGTCTGAGACCCTCAGAGGTGGGGACAGATAC AGCCTGAGGCAGGATGGGACCAGATGTGAGCTGCAGATTCATGGCCTGTCTGTGGCAG ACACTGGGGAGTACTCGTGTGTGTGCGGGCAGGAGAGGACCTCGGCCACACTCACCGT CAGGGCCCTGCCTGCACGATTCACTCAAGATCTGAAGACCAAGGAGGCCTCAGAAGGG GCCACAGCTACACTGCAGTGTGAGCTGAGCAAGGTGGCCCCTGTGGAATGGAAGAAGG GTCCTGAGACCCTCAGAGATGGGGGCAGATACAGCCTGAAGCAGGATGGGACGAGGTG TGAGCTGCAGATCCATGACCTGTCTGTGGCGGATGCTGGGGAATACTCATGCATGTGT GGACAAGAGAGGACCTCGGCCACGCTCACTGTCAGGGCCCTGCCTGCCAGGTTCACAG AGGGTCTGAGGAATGAAGAGGCCATGGAAGGGGCCACAGCCACACTGCAATGTGAGCT GAGCAAGGCAGCCCCTGTGGAGTGGAGGAAAGGCCTTGAGGCTCTCAGAGATGGGGAC AAATACAGCCTGAGACAAGACGGGGCTGTGTGTGAGCTGCAGATTCATGGCCTGGCTA TGGCAGATAACGGGGTGTACTCATGTGTGTGTGGGCAGGAGAGGACCTCAGCTACACT CACTGTCAGGGCCCTGCCTGCCAGATTCATAGAGGATATGAGAAACCAGAAGGCCACA GAAGGGGCTACAGTCACATTGCAATGTAAGCTGAGAAAGGCGGCCCCCGTGGAGTGGA GAAAGGGGCCCAACACCCTCAAAGATGGGGACAGGTACAGCCTGAAGCAGGATGGGAC CAGTTGTGAGCTGCAGATTCGTGGCCTGGTCATAGCAGATGCTGGAGAATACTCGTGC ATATGTGAGCAGGAGAGGACCTCGGCCACGCTCACTGTCAGGGCCCTGCCGGCCAGAT TCATAGAAGATGTGAGAAATCACGAGGCCACAGAAGGGGCCACAGCTGTGCTGCAGTG TGAGCTGAGCAAGGCGGCCCCCGTGGAGTGGCGGAAGGGGTCTGAGACCCTCAGAGAT GGGGACAGATATAGCCTGAGGCAGGACGGGACGAGGTGTGAGCTGCAGATTCGTGGCC TGGCTGTGGAGGACACTGGAGAGTATTTGTGTGTGTGCGGGCAGGAGAGAACCTCAGC TACACTCACTGTCAGGGCCCTGCCAGCCAGATTCATAGACAACATGACAAACCAGGAA GCCAGAGAAGGGGCCACGGCCACACTGCACTGTGAACTGAGCAAGGTGGCCCCTGTGG AGTGGAGGAAGGGACCTGAAACCCTCCGAGATGGGGACAGACACAGCCTGAGGCAGGA TGGGTCCAGGTGTGAGCTGCAGATCCGTGGCCTGGCTGTGGTGGATGCCGGGGAGTAC TCGTGTGTGTGCGGGCAGGAGAGGACCTCAGCCACACTCACTGTCAGGGCCCTGCCTG CCAGATTCATAGAAGATGTGAAAAACCAGGAGGCCAGAGAAGGGGCCACGGCCGTGCT GCAATGTGAGCTGAGCAAGGCGGCCCCCGTGGAGTGGAGGAAGGGGTCTGAGACCCTC AGAGGTGGGGACAGATACAGCCTGAGGCAGGATGGGACCAGATGTGAGCTGCAGATTC ATGGCCTGTCTGTGGCAGACACTGGGGAGTACTCGTGTGTGTGCGGGCAGGAGAGGAC CTCGGCCACACTCACCGTCAGGGCCCTGCCTGCACGATTCACTCAAGATCTGAAGACC AAGGAGGCCTCAGAAGGGGCCACAGCTACACTGCAGTGTGAGCTGAGCAAGGTGGCCC CTGTGGAATGGAAGAAGGGTCCTGAGACCCTCAGAGATGGGGGCAGATACAGCCTGAA GCAGGATGGGACGAGGTGTGAGCTGCAGATCCATGACCTGTCTGTGGCGGATGCTGGG GAATACTCATGCATGTGTGGACAAGAGAGGACCTCGGCCACGCTCACTGTCAGGGACT GCCACACTCTTCACGTCATGCCACACTATCCCTTCCAGCTTCCTGGGCTGCTGAAGGA ACCAGAAGAAACTCTCATCTACATCCAGATTCCCTCTCCTGTGATACTGTTCACAGAG GGTCTGAGGAATGAAGAGGCCATGGAAGGGGCCACAGCCACACTGCAATGTGAGCTGA GCAAGGCAGCCCCTGTGGAGTGGAGGAAAGGCCTTGAGGCTCTCAGAGATGGGGACAA ATACAGCCTGAGACAAGACGGGGCTGTGTGTGAGCTGCAGATTCATGGCCTGGCTATG GCAGATAACGGGGTGTACTCATCCCTGCCTGCCAGATTCATAGAGGATATGAGAAACC AGAAGGCCACAGAAGGGGCTACAGTCACATTGCAATGTAAGCTGAGAAAGGCGGCCCC CGTGGAGTGGAGAAAGGGGCCCAACACCCTCAAAGATGGGGACAGGTACAGCCTGAAG CAGGATGGGACCAGTTGTGAGCTGCAGATTCGTGGCCTGGTCATAGCAGATGCTGGAG AATACTCGTGCATATGTGAGCAGGAGAGGACCTCGGCCACGCTCACTGTCAGGGCCCT GCCGGCCAGATTCATAGAAGATGTGAGAAATCACGAGGCCACAGAAGGGGCCACAGCT GTGCTGCAGTGTGAGCTGAGCAAGGCGGCCCCCGTGGAGTGGCGGAAGGGGTCTGAGA CCCTCAGAGATGGGGACAGATATAGCCTGAGGCAGGACGGGACGAGGTGTGAGCTGCA GATTCGTGGCCTGGCTGTGGAGGACACTGGAGAGTATTTGTGTGTGTGCGGGCAGGAG AGAACCTCAGCTACACTCACTGTCAGGGCCCTGCCAGCCAGATTCATAGACAACATGA CAAACCAGGAAGCCAGAGAAGGGGCCACGGCCACACTGCACTGTGAACTGAGCAAGGT GGCCCCTGTGGAGTGGAGGAAGGGACCTGAAACCCTCCGAGATGGGGACAGACACAGC CTGAGGCAGGATGGGACCAGGTGTGAGCTGCAGATTCGTGGCCTGTCTGTGGCAGATG CCGGGGAGTACTCGTGCGTGTGTGGGCAGGAGAGGACCTCAGCCACACTCACGATCAG GGCCCTGCCCGCCAAGTTCACAAAGGGTCTGAGGAATGAAGAGGCCACAGAAGGGGCC ACGGCTATGTTGCAGTGTGAGCTGAGCAAGGTGGCCCCTGTTGAGTGGAGGAAGGGAC CTGAAACCCTCAGAGATGGGGACAGATACAACCTGAGGCAGGATGGGACCAGATGTGA GCTGCAGATTCATGGCCTGTCCGTGGCAGACACTGGGGAGTACTCATGTGTATGTGGT CAGGAGAAGACGTCGGCCACTCTCACTGTCAAGGCCCCACAGCCAGTGTTCCGGGAGC CGCTGCAGAGTCTGCAGGCGGAGGAGGGCTCCACGGCCACCCTGCAGTGTGAGCTGTC TGAGCCCACTGCTACAGTGGTCTGGAGCAAGGGTGGCCTGCAGCTGCAGGCCAATGGG CGCCGGGAGCCACGGCTTCAGGGCTGCACCGCGGAGCTGGTGTTACAGGACCTACAAC GTGAAGACACTGGCGAATACACTTGCACCTGTGGCTCCCAGGCCACCAGTGCCACCCT CACTGTCACAGCTGCGCCTGTGCGGTTCCTCCGAGAGCTGCAGCACCAGGAGGTGGAT GAGGGAGGCACCGCACACTTATGCTGCGAGCTGAGCCGGGCGGGTGCGAGCGTGGAGT GGCGCAAGGGCTCCCTACAGCTCTTCCCTTGTGCCAAGTACCAGATGGTGCAGGATGG TGCAGCTGCAGAGCTGCTGGTACGCGGAGTGGAGCAGGAGGATGCGGGTGACTACACG TGTGACACGGGCCACACGCAGAGCATGGCCAGCCTCTCTGTCCGTGGAGGGCGTGGAG CTGCATGCGGGCCCCAAGTACGAGATGCGGCGCAGGGGGCCACGCGGGAGCTGCTGAT CCACCAACTGGAGGCCAAGGACACGGGCGAGTATGCCTGTGTGACAGGCGGCCAGAAA ACCGCTGCCTCCCTCAGGGTCACAGAGCCTGAGGTGACCATTGTACGGGGGCTGGTTG ATGCGGAGGTGACGGCCGATGAGGATGTTGAGTTCAGCTGTGAGGTGTCCAGGGCTGG AGCCACAGGCGTGCAGTGGTGCCTACAGGGCCTGCCACTGCAAAGCAATGAGGTGACA GAGGTGGCTGTGCGGGATGGCCGCATCCACACCCTGCGGCTGAAGGGCGTGACGCCCG AGGACGCTGGCACTGTCTCCTTCCATTTGGGAAACCATGCTTCCTCTGCCCAGCTCAC CGTCAGAGCTCCTGAGGTGACCATCCTGGAGCCCCTGCAGGACGTGCAGCTCAGAGGG GTGCCCCTGCAGGCCAACGAGATGAATGACATCACTGTGGAGCAGGGCACACTCCACC TGCTCACCCTGCACAAGGTGACCCTTGAGGATGCTGGAACTGTCAGTTTCCACGTGGG CACGTGTAGCTCTGAGGCCCAGCTGAAAGTCACAGAGGCAGTGCCGTGCCTGGTACGT GGCTTGCAGAATGTGGATGTCTTCGCGGGGGAGGTGGCCACGTTCTCCTGTGAGGATG GCCCCCAGAGCGCCATCGCTGTGCGAGATGGGATCTTTCACTCCCTCATGCTCTCGGG CCTGGGGGTGGCCGACTCCGGCACTGTCATCTTCCGCGCAGGGCCCCTGGTCTCCACG GCCAAGTTGTTGATCAAAGATCCCGTGGTGGAGGTGGTCAGTGCCATGCAGGACTTGG CCGTGGAGGAGGGTGGCTCGGCTGAGCTCCTCTGCCAGTATTCACGGCCCGTGCAGGC CACGTGGAAGATGGACGAGCGGGAGGTGCACACGGATGGGCACCGTGTCATCATAGAG CAGGACTGGAACGTGGCCAGGCTGACCTTCAGGCCGGCCTTGCCCTGTGACAGTGGCA TCTATTCTTGTGAGGCTGCGGGCACCCGCGTAGTGGCCCTGCTGCAAGTGCAAGCCAA GAACACGGTGGTGCGAGGGCTGGAGAATGTGGAGGCGCTGGAGGGCGGCGAGGCGCTG TTCGAGTGCCAGCTGTCCCAGCCCGAGGTGGCCGCCCACACCTGGCTGCTGGACGACG AACCCGTGCGCACCTCGGAGAACGCCGAGGTGGTCTTCTTCGAGAACGGCCTGCGCCA CCTGCTGCTGCTCAAAAACTTGCGGCCACAAGACAGCTGCCGGGTGACCTTCCTGGCT GGGGATATGGTGACGTCCGCATTCCTCACGGTCCGAGGTGACTGCGCTGTGCTGGTGC AGGGCTGGCGCCTGGAGATCCTGGAGCCTCTGAAAAACGCGGCGGTCCGGGCCGGCGC ACAGGCACGCTTCACCTGCACGCTCAGCGAGGCGGTGCCCGTGGGAGAGGCGTCCTGG TACATCAATGGCGCGGCAGTGCAGCCGGATGACAGCGACTGGACTGTCACCGCCGACG GCAGTCACCACGCCCTACTGCTGCGCAGCGCCCAGCCCCACCACGCCGGGGAGGTCAC CTTCGCTTGCCGCGACGCCGTGGCCTCTGCGCGGCTCACCGTGCTGGGCCTCCCTGAT CCCCCAGAGGATGCTGAGGTGGTGGCTCGCAGCAGCCACACTGTGACACTGTCTTGGG CAGCTCCCATGAGTGATGGAGGCGGTGGTCTCTGTGGCTACCGCGTGGAGGTGAAGGA GGGGGCCACAGGCCAGTGGCGGCTGTGCCACGAGCTGGTGCCTGGACCCGAGTGTGTG GTGGATGGCCTGGCCCCCGGGGAGACCTACCGCTTCCGTGTGGCAGCTGTGGGCCCTG TGGGTGCTGGGGAACCGGTTCACCTGCCCCAGACAGTGCGGCTTGAGCCACCGAAGCC TGTGCCTCCCCAGCCCTCAGCCCCTGAGAGCCGGCAGGTGGCAGCTGGTGAAGATGTC TGTCTGGAGCTTGAGGTGGTGGCTGAGGCTGGCGAGGTCATCTGGCACAAGGGAATGG AGCGCATCCAGCCCGGTGGGCGGTTCGAGGTGGTCTCCCAGGGTCGGCAACAGATGCT GGTGATCAAGGGCTTCACGGCAGAAGACCAGGGCGAGTACCACTGTGGCCTGGCTCAG GGCTCCATCTGCCCTGCGGCTGCCACCTTCCAGGTGGCACTGAGCCCAGCCTCTGTGG ATGAGGCCCCTCAGCCCAGCTTGCCCCCCGAGGCAGCCCAGGAGGGTGACCTGCACCT ACTGTGGGAGGCCCTGGCTCGGAAACGTCGCATGAGCCGTGAGCCCACGCTGGACTCC ATTAGCGAGCTGCCAGAGGAGGACGGCCGCTCGCAGCGCCTGCCACAGGAGGCAGAGG AGGTGGCACCTGATCTCTCTGAAGGCTACTCCACGGCCGATGAGCTGGCCCGCACTGG AGATGCTGACCTCTCACACACCAGCTCTGATGATGAGTCCCGGGCAGGCACCCCTTCC CTGGTCACCTACCTCAAGAAGGCTGGGAGGCCAGGCACCTCACCACTGGCCAGCAAGG TGAGCCCCCCCAACTTGGCCTGCAAGGAGAGGTTCCCCACGCCCCGGGCCGGCCGCAG CCTCCTGGGCTTCGTGGGGGCAGACCCAGCCTTTCCCGGCAGCGAGCGCTCGGCCAGG TGCACTAGGCGCTGTGCGGCCCCCCCTCCCCGCGAGTCCCTCAAGCGGGAACCTGCCT CGTGTCTCCCAGGAGCCATGGAGGCTGTGGAACTCGCCAGAAAACTGCAGGAGGAAGC TACGTGCTCCATCTGTCTGGATTACTTCACAGACCCTGTGATGACCACCTGTGGCCAC AACTTCTGCCGAGCGTGCATCCAGCTGAGCTGGGAAAAGGCGAGGGGCAAGAAGGGGA GGCGGAAGCGGAAGGGCTCCTTCCCCTGCCCCGAGTGCAGAGAGATGTCCCCGCAGAG GAACCTGCTGCCCAACCGGCTGCTGACCAAGGTGGCCGAGATGGCGCAGCAGCATCCT GGTCTGCAGAAGCAAGACCTGTGCCAGGAGCACCACGAGCCCCTCAAGCTTTTCTGCC AGAAGGACCAGAGCCCCATCTGTGTGGTGTGCAGGGAGTCCCGGGAGCACCGGCTGCA CAGGGTGCTGCCCGCCGAGGAGGCAGTGCAGGGGTACAAGTTGAAGCTGGAGGAGGAC ATGGAGTACCTTCGGGAGCAGATCACCAGGACAGGGAATCTGCAGGCCAGGGAGGAGC AGAGCTTAGCCGAGTGGCAGGGCAAGGTGAAGGAGCGGAGAGAACGCATTGTGCTGGA GTTTGAGAAGATGAACCTCTACCTGGTGGAAGAAGAGCAGAGGCTCCTCCAGGCTCTG GAGACGGAAGAAGAGGAGACTGCCAGCAGGCTCCGGGAGAGCGTGGCCTGCCTGGACC GGCAGGGTCACTCTCTGGAGCTGCTGCTGCTGCAGCTGGAGGAGCGGAGCACACAGGG GCCCCTCCAGATGCTGCAGGACATGAAGGAACCCCTGAGCAGGGCGGCGTTACTGGTG GTTCTAATTCATGGGATGAATCTTGTTGAGTTCCCAGTGGTCTCTCTGCCCAGCCCCC TGTACCTTATTGCCACCAAGGCCCACACACAATTGGGCCCGGGGACTCCCACCTTTGA CCCTGAATGCCCCACACCTCTCCCCATCTCTCCACCACCACGCCCATCTACAGAGGAT GTGGTGCCTGATGCCACCTCCGCGTACCCCTACCTCCTCCTGTATGAGAGCCGCCAGA GGCGCTACCTCGGCTCTTCGCCGGAGGGCAGTGGGTTCTGCAGCAAGGACCGATTTGT GGCTTACCCCTGTGCTGTGGGCCAGACGGCCTTCTCCTCTGGGAGGCACTACTGGGAG GTGGGCATGAACATCACCGGGGACGCGTTGTGGGCCCTGGGTGTGTGCAGGGACAACG TGAGCCGGAAAGACAGGGTCCCCAAGTGCCCCGAAAACGGCTTCTGGGTGGTGCAGCT GTCCAAGGGGACCAAGTACTTATCCACCTTCTCTGCCCTAACCCCGGTCATGCTGATG GAGCCTCCCAGCCACATGGGCATCTTCCTGGACTTCGAAGCCGGGGAAGTGTCCTTCT ACAGTGTAAGCGATGGGTCCCACCTGCACACCTACTCCCAGGCCACCTTCCCAGGCCC CCTGCAGCCTTTCTTCTGCCTGGGGGCTCCGAAGTCTGGTCAGATGGTCATCTCCACA GTGACCATGGCAGGGGTAAAAGACCTGGCCACAAGAACCGGAGCGGTGGTGACGCCAG CGCTCGGAGCCTACGCGCCCAGCGCTACCGAAACCCAGAGTCCTGCGCCCTGGAGTCC CCGCGCCCCGGAGCCCGAGCACCCGGGAGTCCCGAGCCTCGCGCCCCGGAGTGCCCGA GCCTGCGCCGCCGCACCCGGATACCCCGGGTCCCCGCGAGCTGCCGAGGCCGCCCGCC GCCGCCCCGCGGACAGTACCGCCTTCCTCCCCTCTGTCCGCGCCATGGCCGCCCCCGA CCTGTCCACCAACCTCCAGGAGGAGGCCACCTGCGCCATCTGCCTCGACTACTTCACG GATCCGGTGATGACCGACTGCGGCCACAACTTCTGCCGCGAGTGCATCCGGCGCTGCT GGGGCCAGCCCGAGGCCCGTACGCGTGCCCCGAGTGCCGCGAGCTGTCCCCGCAGAGG AACCTGCGGCCCAACCGCCCGCTTGCTAAGATGGCCGAGATGGCGCGGCGCCTGCACC CGCCGTCGCCGGTCCCGCAGGCGTGTGCCCGCGCACCGCGAGCCACTGGCCGCCTTCT GTGGCGACGAGCTGCGCCTCCTGTGTGCGGCCTGCGAGCGCTCTGGGGAGCACTGGGC GCACCGCGTTGGCCGCTGCAGGACGCGGCCGAAGACCTCAAGGCCCCTTGAGGCTGGG ACCATGGCCGCCAATGAGACCCTGCTCTCGGGGGCGAAGCTGGAGAAGTCACTGGAGC ATCTCCGGAAGCAGATGCAGGATGCGTTGCTGTTCCAAGCCCAGGCGGATGAGACCTG CGTCTTGTGGCAGGCAGAAGATGGTGGAGAGCAGCGGCAGAACGTGCTGCGTGAGTTC GAGCGTCTTCGCCGTTTGCTGGCAGAGGGAGGGACAGCAGCTGCTGCAGAGGCTGGAG AGGAGGAGCTGAAGCAGAGCGCCCACCTAGCTGAGCTCATCGCCGAGCTCGAGAGGCC GCTGCCAGCTGCCTGCGCTGGGGCTGCTGCAGGAGAGTCTTTTCCCATGTGTGGGCTC CACTCCCTGAGCCGGCCCCCTGGCGTGGGCTTTCCTTGGTGCACCCCCAAACCAGAAC CAGTGGACGCCCTGGCCTGTGCGTGGCGGCAGGGCTGCCAGACCCAGGTGGAGCCCAC AATGCTGCAGATGTGGCTGGGCGGCTTTGCACAGGGGGTGACACTGCTGCCGGCCTCT GGAGCCCAGCAGAACATCAGTCCAGGCACCGGCTCCTGGTTTCGATTGTCATTTCTAT TATTTAAGGGGTACAAGTGCAGTCAGAGTGTAGCCATCACCCGAATGGTGCACACTGT ACCCAAGACCAAACCCCCTTGTCGAGGCCAAGGTTCTCCTCTACCCCCAAGCCCTTCT CCTGCCGCCCCTGCACCCGGCCTTGTGACAGCCACCACCTGTTTCCAAATGACACCAG GGGTGGGCCGCCCACCCCAGGACATCAAGGACGCCCTGCGCAGGGTCCAGGATGTGAA GCTGCAGCCCCCAGAAGTTGTGCCTATGGAGCTGAGGACCGTGTGCAGGGTCCCGGGA CTGGTAGAGACACTGCGGAGGTTTCGAGGGGACGTGACCTTGGACCCGGACACCGCCA ACCCTGAGCTGATCCTGTCTGAAGACAGGCGGAGCGTGCAGCGGGGGGACCTACGGCA GGCCCTGCCGGACAGCCCAGAGCGCTTTGACCCCGGCCCCTGCGTGCTGGGCCAGGAG CGCTTCACCTCAGGCCGCCACTACTGGGAGGTGGAGGTTGGGGACCGCACCAGCTGGG CCCTGGGGGTGTGCAGGGAGAACGTGAACAGGAAGGAGAAGGGCGAGCTGTCCGCGGG CAACGGCTTCTGGATCCTGGTCTTCCTGGGGAGCTATTACAATTCCTCGGAACGGGCC TTGGCTCCACTCCGGGACCCACCCAGGCGCGTGGGGATCTTTCTGGACTACGAGGCTG GACATCTCTCTTTCTACAGTGCCACCGATGGGTCACTGCTATTCATCTTTCCCGAGAT CCCCTTCTCGGGGACGCTGCGGCCCCTCTTCTCACCCCTGTCCAGCAGCCCGACCCCG ATGACTATCTGCCGGCCGAAAGGTGGGTCCGGGGACACCCTGGCTCCCCAGTGACTCG GGCCCTCCTGGAGGA

ORF Start: ATG at 15 ORF Stop: TGA at 14088

SEQ ID NO: 72 4691 aa MW at 512894.2kD

NOV13a, MPLYNDSFHEISHKGRRHTLVLKSIQRADAGIVRASSLKVSTSARLEVRVKPWFLKA CG59237-01 LDDLSAEERGTLALQCEVSDPEAHWWRKDGVQLGPSDKYDFLHTAGTRGLWHDVSP EDAGLYTCHVGSEETRARVRVHDLHVGITKRLKTMEVLEGESCSFECVLSHESASDPA Protein Sequence MWTVGGKTVGSSSRFQATRQGRKYILWREAAPSDAGEWFSVRGLTSKASLIVRERP AAI KPLEDQWVAPGEDVELRCELSRAGTPVHWLKDRKAIRKSQKYDWCEGTMAMLV IRGASLKDAGEYTCEVEASKSTASLHVEEKANCFTEELTNLQVEEKGTAVFTCKTEHP AATVTWRKGLLELRASGKHQPSQEGLTLRLTISALEKADSDTYTCDIGQAQSRAQLLV QGRRVHIIEDLEDVDVQEGSSATFRCRISPANYEPVHWFLDKTPLHANELNEIDAQPG GYHVLTLRQLALKDSGTIYFEAGDQRASAALRVTEKPSVFSRELTDATITEGEDLTLV CETSTCDIPVCWTKDGKTLRGSARCQLSHEGHRAQLLITGATLQDSGRYKCEAGGACS SSIVRVHARPVRFQEALKDLEVLEGGAATLRCVLSSVAAPVKWCYGNNVLRPGDKYSL RQEGAMLELWRNLRPQDSGRYSCSFGDQTTSATLTVTALPAQFIGKLRNKEATEGAT ATLRCELSKAAPVEWRKGSETLRDGDRYCLRQDGAMCELQIRGLAMVDAAEYSCVCGE ERTSASLTIRPMPAHFIGRLRHQESIEGATATLRCELSKAAPVEWRKGRESLRDGDRH SLRQDGAVCELQICGLAVADAGEYSCVCGEERTSATLTVKALPAKFTEGLRNEEAVEG ATAMLWCELSKVAPVEWRKGPENLRDGDRYILRQEGTRCELQICGLAMADAGEYLCVC GQERTSATLTIRALPARFIEDVKNQEAREGATAVLQCΞLNSAAPVEWRKGSETLRDGD RYSLRQDGTKCELQIRGLAMADTGEYSCVCGQERTSAMLTVRALPIKFTEGLRNEEAT EGATAVLRCELSKMAPVEWWKGHETLRDGDRHSLRQDGARCΞLQIRGLVAEDAGEYLC MCGKERTSAMLTVRAMPSKFIEGLRNEEATEGDTATLWCELSKAAPVEWRKGHETLRD GDRHSLRQDGSRCELQIRGLAWDAGEYSCVCGQERTSATLTVRALPARFIEDVKNQE AREGATAVLQCELSKAAPVEWRKGSETLRGGDRYSLRQDGTRCELQIHGLSVADTGEY SCVCGQERTSATLTVRALPARFTQDLKTKEASEGATATLQCELSKVAPVEWKKGPETL RDGGRYSLKQDGTRCELQIHDLSVADAGEYSCMCGQERTSATLTVRALPARFTEGLRN EEAMEGATATLQCELSKAAPVEWRKGLEALRDGDKYSLRQDGAVCELQIHGLAMADNG VYSCVCGQERTSATLTVRALPARFIEDMRNQKATEGATVTLQCKLRKAAPVEWRKGPN TLKDGDRYSLKQDGTSCELQIRGLVIADAGEYSCICΞQERTSATLTVRALPARFIΞDV RNHEATEGATAVLQCELSKAAPVEWRKGSETLRDGDRYSLRQDGTRCELQIRGLAVED TGEYLCVCGQERTSATLTVRALPARFIDNMTNQEAREGATATLHCELSKVAPVEWRKG PETLRDGDRHSLRQDGSRCELQIRGLAWDAGEYSCVCGQERTSATLTVRALPARFIE DVKNQEAREGATAVLQCELSKAAPVEWRKGSETLRGGDRYSLRQDGTRCELQIHGLSV ADTGEYSCVCGQERTSATLTVRALPARFTQDLKTKEASEGATATLQCELSKVAPVEWK KGPETLRDGGRYSLKQDGTRCELQIHDLSVADAGEYSCMCGQERTSATLTVRDCHTLH VMPHYPFQLPGLLKEPEETLIYIQIPSPVILFTEGLRNEEAMEGATATLQCELSKAAP VEWRKGLEALRDGDKYSLRQDGAVCELQIHGLAMADNGVYSSLPARFIEDMRNQKATE GATVTLQCKLRKAAPVEWRKGPNTLKDGDRYSLKQDGTSCELQIRGLVIADAGEYSCI CEQERTSATLTVRALPARFIEDVRNHEATEGATAVLQCELSKAAPVEWRKGSETLRDG DRYSLRQDGTRCELQIRGLAVEDTGEYLCVCGQERTSATLTVRALPARFIDNMTNQEA REGATATLHCELSKVAPVEWRKGPETLRDGDRHSLRQDGTRCELQIRGLSVADAGEYS CVCGQERTSATLTIRALPAKFTKGLRNEEATEGATAMLQCELSKVAPVEWRKGPETLR DGDRYNLRQDGTRCELQIHGLSVADTGEYSCVCGQEKTSATLTVKAPQPVFREPLQSL QAEEGSTATLQCELSEPTATWWSKGGLQLQANGRREPRLQGCTAELVLQDLQREDTG EYTCTCGSQATSATLTVTAAPVRFLRELQHQEVDΞGGTAHLCCELSRAGASVEWRKGS LQLFPCAKYQMVQDGAAAELLVRGVEQEDAGDYTCDTGHTQSMASLSVRGGRGAACGP QVRDAAQGATRELLIHQLEAKDTGEYACVTGGQKTAASLRVTEPEVTIVRGLVDAEVT ADEDVEFSCΞVSRAGATGVQWCLQGLPLQSNEVTEVAVRDGRIHTLRLKGVTPΞDAGT VSFHLGNHASSAQLTVRAPEVTILEPLQDVQLRGVPLQANEMNDITVEQGTLHLLTLH KVTLEDAGTVSFHVGTCSSEAQLKVTEAVPCLVRGLQNVDVFAGEVATFSCEDGPQSA lAVRDGIFHSLMLSGLGVADSGTVIFRAGPLVSTAKLLIKDPWEWSAMQDLAVEEG GSAELLCQYSRPVQATWKMDEREVHTDGHRVIIEQDWNVARLTFRPALPCDSGIYSCE AAGTRWALLQVQAKNTWRGLENVEALEGGEALFECQLSQPEVAAHTWLLDDEPVRT SENAEWFFENGLRHLLLLKNLRPQDSCRVTFLAGDMVTSAFLTVRGDCAVLVQGWRL EILEPLKNAAVRAGAQARFTCTLSEAVPVGEASWYINGAAVQPDDSDWTVTADGSHHA LLLRSAQPHHAGEVTFACRDAVASARLTVLGLPDPPEDAEWARSSHTVTLSWAAPMS DGGGGLCGYRVEVKEGATGQWRLCHELVPGPECWDGLAPGETYRFRVAAVGPVGAGE PVHLPQTVRLEPPKPVPPQPSAPESRQVAAGEDVCLELEWAEAGEVIWHKGMERIQP GGRFEWSQGRQQMLVIKGFTAEDQGEYHCGLAQGSICPAAATFQVALSPASVDEAPQ PSLPPEAAQEGDLHLLWEALARKRRMSREPTLDSISELPEEDGRSQRLPQEAEEVAPD LSEGYSTADELARTGDADLSHTSSDDESRAGTPSLVTYLKKAGRPGTSPLASKVSPPN LACKERFPTPRAGRSLLGFVGADPAFPGSERSARCTRRCAAPPPRESLKREPASCLPG AMEAVELARKLQΞEATCSICLDYFTDPVMTTCGHNFCRACIQLSWEKARGKKGRRKRK GSFPCPECREMSPQRNLLPNRLLTKVAEMAQQHPGLQKQDLCQEHHEPLKLFCQKDQS PICWCRESREHRLHRVLPAEEAVQGYKLKLEEDMEYLREQITRTGNLQAREEQSLAE WQGKVKERRERIVLEFEKMNLYLVEEEQRLLQALETEEEETASRLRESVACLDRQGHS LELLLLQLEERSTQGPLQMLQDMKEPLSRAALLWLIHGMNLVEFPWSLPSPLYLIA TKAHTQLGPGTPTFDPECPTPLPISPPPRPSTEDWPDATSAYPYLLLYΞSRQRRYLG SSPEGSGFCSKDRFVAYPCAVGQTAFSSGRHYWEVGMNITGDALWALGVCRDNVSRKD RVPKCPENGFWWQLSKGTKYLSTFSALTPVMLMEPPSHMGIFLDFEAGEVSFYSVSD GSHLHTYSQATFPGPLQPFFCLGAPKSGQMVISTVTMAGVKDLATRTGAWTPALGAY APSATETQSPAPWSPRAPEPEHPGVPSLAPRSARACAAAPGYPGSPRAAΞAARRRPAD STAFLPSVRAMAAPDLSTNLQEEATCAICLDYFTDPVMTDCGHNFCRECIRRCWGQPE ARTRAPSAASCPRRGTCGPTARLLRWPRWRGACTRRRRSRRRVPAHREPLAAFCGDEL RLLCAACERSGEHWAHRVGRCRTRPKTSRPLEAGTMAANETLLSGAKLEKSLEHLRKQ MQDALLFQAQADETCVLWQAEDGGEQRQNVLREFERLRRLLAΞGGTAAAAEAGEEELK QSAHLAELIAELERPLPAACAGAAAGESFPMCGLHSLSRPPGVGFPWCTPKPEPVDAL ACAWRQGCQTQVEPTMLQMWLGGFAQGVTLLPASGAQQNISPGTGSWFRLSFLLFKGY KCSQSVAITRMVHTVPKTKPPCRGQGSPLPPSPSPAAPAPGLVTATTCFQMTPGVGRP PQDIKDALRRVQDVKLQPPEWPMELRTVCRVPGLVETLRRFRGDVTLDPDTANPELI LSEDRRSVQRGDLRQALPDSPERFDPGPCVLGQERFTSGRHYWEVEVGDRTSWALGVC RENVNRKEKGELSAGNGFWILVFLGSYYNSSERALAPLRDPPRRVGIFLDYEAGHLSF YSATDGSLLFIFPEIPFSGTLRPLFSPLSSSPTPMTICRPKGGSGDTLAPQ

SEQ ID NO: 73 14061 bp

NOVl 3b, TGTCGCTCAACGGGATGCCCCTGTACAACGACAGCTTCCATGAGATCTCACACAAGGG CG59237-02 DNA CCGGCGCCACACGCTGGTACTGAAGAGCATCCAGCGGGCTGATGCGGGCATAGTACGC GCCTCCTCCCTGAAGGTGTCGACCTCTGCCCGCCTGGAGGTCCGAGTGAAGCCGGTGG Sequence TGTTCCTGAAGGCGCTGGATGACCTGTCCGCAGAGGAGCGCGGCACCCTGGCCCTGCA GTGTGAAGTCTCTGACCCCGAGGCCCATGTGGTGTGGCGCAAAGATGGCGTGCAGCTG GGCCCCAGTGACAAGTATGACTTCCTGCACACGGCGGGCACGCGGGGGCTCGTGGTGC ATGACGTGAGCCCTGAAGACGCCGGCCTGTACACCTGCCACGTGGGCTCCGAGGAGAC CCGGGCCCGGGTCCGCGTGCACGATCTGCACGTGGGCATCACCAAGAGGCTGAAGACA ATGGAGGTGCTGGAAGGGGAAAGCTGCAGCTTTGAGTGCGTCCTGTCCCACGAGAGTG CCAGCGACCCGGCCATGTGGACAGTCGGTGGGAAGACAGTGGGCAGCTCCAGCCGCTT CCAGGCCACACGTCAGGGCCGAAAATACATCCTGGTGGTCCGGGAGGCTGCACCAAGT GATGCCGGGGAGGTGGTCTTCTCTGTGCGGGGCCTCACCTCCAAGGCCTCACTCATTG TCAGAGAGAGGCCGGCCGCCATCATCAAGCCCCTGGAAGACCAGTGGGTGGCGCCAGG GGAGGACGTGGAGCTGCGCTGTGAGCTGTCACGGGCGGGAACGCCCGTGCACTGGCTG AAGGACAGGAAGGCCATCCGCAAGAGCCAGAAGTATGATGTGGTCTGCGAGGGCACGA TGGCCATGCTGGTCATCCGCGGGGCCTCGCTCAAGGACGCGGGCGAGTACACGTGTGA GGTGGAGGCTTCCAAGAGCACAGCCAGCCTCCATGTGGAAGAAAAAGCAAACTGCTTC ACAGAGGAGCTGACCAATCTGCAGGTGGAGGAGAAAGGCACAGCTGTGTTCACGTGCA AGACGGAGCACCCCGCGGCCACAGTGACCTGGCGCAAGGGCCTCTTGGAGCTACGGGC CTCAGGGAAGCACCAGCCCAGCCAGGAGGGCCTGACCCTGCGCCTCACCATCAGTGCC CTGGAGAAGGCAGACAGCGACACCTATACCTGCGACATTGGCCAGGCCCAGTCCCGGG CCCAGCTCCTAGTGCAAGGCCGGAGAGTGCACATCATCGAGGACCTGGAGGATGTGGA TGTGCAGGAGGGCTCCTCGGCCACCTTCCGTTGCCGGATCTCCCCGGCCAACTACGAG CCTGTGCACTGGTTCCTGGACAAGACACCCCTGCATGCCAACGAGCTCAATGAGATCG ATGCCCAGCCCGGGGGCTACCACGTGCTGACCCTGCGGCAGCTGGCGCTCAAGGACTC GGGCACCATCTACTTTGAGGCGGGTGACCAGCGGGCCTCGGCCGCCCTGCGGGTCACT GAGAAGCCAAGCGTCTTCTCCCGGGAGCTCACAGATGCCACCATCACAGAGGGTGAGG ACTTGACCCTGGTGTGCGAGACCAGCACCTGCGACATTCCTGTGTGCTGGACCAAGGA TGGGAAGACCCTGCGGGGGTCTGCCCGGTGCCAGCTGAGCCATGAGGGCCACCGGGCC CAGCTGCTCATCACTGGGGCCACCCTGCAGGACAGTGGACGCTACAAGTGTGAGGCTG GGGGCGCCTGCAGCAGCTCCATTGTCAGGGTGCATGCGCGGCCAGTGCGGTTCCAGGA GGCCCTGAAGGACCTGGAGGTGCTGGAGGGTGGTGCTGCCACACTGCGCTGTGTGCTG TCATCTGTGGCTGCGCCCGTGAAGTGGTGCTATGGAAACAACGTCCTGAGGCCAGGTG ACAAATACAGCCTACGCCAGGAGGGTGCCATGCTGGAGCTGGTGGTCCGGAACCTCCG GCCGCAGGACAGCGGGCGGTACTCATGCTCCTTCGGGGACCAGACTACTTCTGCCACC CTCACAGTGACTGCCCTGCCTGCCCAGTTCATCGGGAAACTGAGAAACAAGGAGGCCA CAGAAGGGGCCACGGCCACGCTGCGGTGTGAGCTGAGCAAGGCAGCCCCTGTGGAGTG GAGAAAGGGGTCCGAGACCCTCAGAGATGGGGACAGATACTGTCTGAGGCAGGACGGG GCCATGTGTGAGCTGCAGATCCGTGGCCTGGCCATGGTGGATGCCGCGGAGTACTCGT GTGTGTGTGGAGAGGAGAGGACCTCAGCCTCACTCACCATCAGGCCCATGCCTGCCCA CTTCATAGGAAGACTGAGACACCAAGAGAGCATAGAAGGGGCCACAGCCACGCTGCGG TGTGAGCTGAGCAAGGCGGCCCCCGTGGAGTGGAGGAAGGGGCGTGAGAGCCTCAGAG ATGGGGACAGACATAGCCTGAGGCAGGACGGGGCTGTGTGCGAGCTGCAGATCTGTGG CCTGGCTGTGGCAGATGCTGGGGAGTACTCCTGTGTGTGTGGGGAGGAGAGGACCTCT GCCACTCTCACCGTGAAGGCCCTGCCAGCCAAGTTCACAGAGGGTCTGAGGAATGAAG AGGCCGTGGAAGGGGCCACAGCCATGTTGTGGTGTGAACTGAGCAAGGTGGCCCCTGT GGAGTGGAGGAAGGGGCCCGAGAACCTCAGAGATGGGGACAGATACATCCTGAGGCAG GAGGGGACCAGGTGTGAGCTGCAGATCTGTGGCCTGGCCATGGCGGACGCCGGGGAGT ACTTGTGTGTGTGCGGGCAGGAGAGGACCTCAGCCACGCTCACCATCAGGGCTCTGCC TGCCAGGTTCATAGAAGATGTGAAAAACCAGGAGGCCAGAGAAGGGGCCACGGCTGTG CTGCAGTGTGAGCTGAACAGTGCAGCCCCTGTGGAGTGGAGAAAGGGGTCTGAGACCC TTAGAGATGGGGACAGATACAGCCTGAGGCAGGACGGGACTAAATGTGAGCTGCAGAT TCGTGGCCTGGCCATGGCAGACACTGGGGAGTACTCGTGCGTGTGCGGGCAGGAGAGG ACCTCGGCTATGCTCACCGTCAGGGCTCTACCCATCAAGTTCACAGAGGGTCTGAGGA ACGAAGAGGCCACAGAAGGGGCAACAGCCGTGCTGCGGTGTGAGCTGAGCAAGATGGC CCCCGTGGAGTGGTGGAAGGGGCATGAGACCCTCAGAGATGGAGACAGACACAGCCTG AGGCAGGACGGGGCCAGGTGTGAGCTGCAGATCCGCGGCCTCGTGGCAGAGGACGCTG GGGAGTACCTGTGCATGTGCGGGAAGGAGAGGACCTCAGCCATGCTCACCGTCAGGGC CATGCCTTCCAAGTTCATAGAGGGTCTGAGGAATGAAGAGGCCACAGAAGGGGACACG GCCACGCTGTGGTGTGAGCTGAGCAAGGCGGCACCGGTGGAGTGGAGGAAGGGGCATG AGACCCTCAGAGATGGGGACAGACACAGCCTGAGGCAGGATGGGTCCAGGTGTGAGCT GCAGATCCGTGGCCTGGCTGTGGTGGATGCCGGGGAGTACTCGTGTGTGTGCGGGCAG GAGAGGACCTCAGCCACACTCACTGTCAGGGCCCTGCCTGCCAGATTCATAGAAGATG TGAAAAACCAGGAGGCCAGAGAAGGGGCCACGGCCGTGCTGCAATGTGAGCTGAGCAA GGCGGCCCCCGTGGAGTGGAGGAAGGGGTCTGAGACCCTCAGAGGTGGGGACAGATAC AGCCTGAGGCAGGATGGGACCAGATGTGAGCTGCAGATTCATGGCCTGTCTGTGGCAG ACACTGGGGAGTACTCGTGTGTGTGCGGGCAGGAGAGGACCTCGGCCACACTCACCGT CAGGGCCCTGCCTGCACGATTCACTCAAGATCTGAAGACCAAGGAGGCCTCAGAAGGG GCCACAGCTACACTGCAGTGTGAGCTGAGCAAGGTGGCCCCTGTGGAATGGAAGAAGG GTCCTGAGACCCTCAGAGATGGGGGCAGATACAGCCTGAAGCAGGATGGGACGAGGTG TGAGCTGCAGATCCATGACCTGTCTGTGGCGGATGCTGGGGAATACTCATGCATGTGT GGACAAGAGAGGACCTCGGCCACGCTCACTGTCAGGGCCCTGCCTGCCAGGTTCACAG AGGGTCTGAGGAATGAAGAGGCCATGGAAGGGGCCACAGCCACACTGCAATGTGAGCT GAGCAAGGCAGCCCCTGTGGAGTGGAGGAAAGGCCTTGAGGCTCTCAGAGATGGGGAC AAATACAGCCTGAGACAAGACGGGGCTGTGTGTGAGCTGCAGATTCATGGCCTGGCTA TGGCAGATAACGGGGTGTACTCATGTGTGTGTGGGCAGGAGAGGACCTCAGCTACACT CACTGTCAGGGCCCTGCCTGCCAGATTCATAGAGGATATGAGAAACCAGAAGGCCACA GAAGGGGCTACAGTCACATTGCAATGTAAGCTGAGAAAGGCGGCCCCCGTGGAGTGGA GAAAGGGGCCCAACACCCTCAAAGATGGGGACAGGTACAGCCTGAAGCAGGATGGGAC CAGTTGTGAGCTGCAGATTCGTGGCCTGGTCATAGCAGATGCTGGAGAATACTCGTGC ATATGTGAGCAGGAGAGGACCTCGGCCACGCTCACTGTCAGGGCCCTGCCGGCCAGAT TCATAGAAGATGTGAGAAATCACGAGGCCACAGAAGGGGCCACAGCTGTGCTGCAGTG TGAGCTGAGCAAGGCGGCCCCCGTGGAGTGGCGGAAGGGGTCTGAGACCCTCAGAGAT GGGGACAGATATAGCCTGAGGCAGGACGGGACGAGGTGTGAGCTGCAGATTCGTGGCC TGGCTGTGGAGGACACTGGAGAGTATTTGTGTGTGTGCGGGCAGGAGAGAACCTCAGC TACACTCACTGTCAGGGCCCTGCCAGCCAGATTCATAGACAACATGACAAACCAGGAA GCCAGAGAAGGGGCCACGGCCACACTGCACTGTGAACTGAGCAAGGTGGCCCCTGTGG AGTGGAGGAAGGGACCTGAAACCCTCCGAGATGGGGACAGACACAGCCTGAGGCAGGA TGGGTCCAGGTGTGAGCTGCAGATCCGTGGCCTGGCTGTGGTGGATGCCGGGGAGTAC TCGTGTGTGTGCGGGCAGGAGAGGACCTCAGCCACACTCACTGTCAGGGCCCTGCCTG CCAGATTCATAGAAGATGTGAAAAACCAGGAGGCCAGAGAAGGGGCCACGGCCGTGCT GCAATGTGAGCTGAGCAAGGCGGCCCCCGTGGAGTGGAGGAAGGGGTCTGAGACCCTC AGAGGTGGGGACAGATACAGCCTGAGGCAGGATGGGACCAGATGTGAGCTGCAGATTC ATGGCCTGTCTGTGGCAGACACTGGGGAGTACTCGTGTGTGTGCGGGCAGGAGAGGAC CTCGGCCACACTCACCGTCAGGGCCCTGCCTGCACGATTCACTCAAGATCTGAAGACC AAGGAGGCCTCAGAAGGGGCCACAGCTACACTGCAGTGTGAGCTGAGCAAGGTGGCCC CTGTGGAATGGAAGAAGGGTCCTGAGACCCTCAGAGATGGGGGCAGATACAGCCTGAA GCAGGATGGGACGAGGTGTGAGCTGCAGATCCATGACCTGTCTGTGGCGGATGCTGGG GAATACTCATGCATGTGTGGACAAGAGAGGACCTCGGCCACGCTCACTGTCAGGGACT GCCACACTCTTCACGTCATGCCACACTATCCCTTCCAGCTTCCTGGGCTGCTGAAGGA ACCAGAAGAAACTCTCATCTACATCCAGATTCCCTCTCCTGTGATACTGTTCACAGAG GGTCTGAGGAATGAAGAGGCCATGGAAGGGGCCACAGCCACACTGCAATGTGAGCTGA GCAAGGCAGCCCCTGTGGAGTGGAGGAAAGGCCTTGAGGCTCTCAGAGATGGGGACAA ATACAGCCTGAGACAAGACGGGGCTGTGTGTGAGCTGCAGATTCATGGCCTGGCTATG GCAGATAACGGGGTGTACTCATCCCTGCCTGCCAGATTCATAGAGGATATGAGAAACC AGAAGGCCACAGAAGGGGCTACAGTCACATTGCAATGTAAGCTGAGAAAGGCGGCCCC CGTGGAGTGGAGAAAGGGGCCCAACACCCTCAAAGATGGGGACAGGTACAGCCTGAAG CAGGATGGGACCAGTTGTGAGCTGCAGATTCGTGGCCTGGTCATAGCAGATGCTGGAG AATACTCGTGCATATGTGAGCAGGAGAGGACCTCGGCCACGCTCACTGTCAGGGCCCT GCCGGCCAGATTCATAGAAGATGTGAGAAATCACGAGGCCACAGAAGGGGCCACAGCT GTGCTGCAGTGTGAGCTGAGCAAGGCGGCCCCCGTGGAGTGGCGGAAGGGGTCTGAGA CCCTCAGAGATGGGGACAGATATAGCCTGAGGCAGGACGGGACGAGGTGTGAGCTGCA GATTCGTGGCCTGGCTGTGGAGGACACTGGAGAGTATTTGTGTGTGTGCGGGCAGGAG AGAACCTCAGCTACACTCACTGTCAGGGCCCTGCCAGCCAGATTCATAGACAACATGA CAAACCAGGAAGCCAGAGAAGGGGCCACGGCCACACTGCACTGTGAACTGAGCAAGGT GGCCCCTGTGGAGTGGAGGAAGGGACCTGAAACCCTCCGAGATGGGGACAGACACAGC CTGAGGCAGGATGGGACCAGGTGTGAGCTGCAGATTCGTGGCCTGTCTGTGGCAGATG CCGGGGAGTACTCGTGCGTGTGTGGGCAGGAGAGGACCTCAGCCACACTCACGATCAG GGCCCTGCCCGCCAAGTTCACAAAGGGTCTGAGGAATGAAGAGGCCACAGAAGGGGCC ACGGCTATGTTGCAGTGTGAGCTGAGCAAGGTGGCCCCTGTTGAGTGGAGGAAGGGAC CTGAAACCCTCAGAGATGGGGACAGATACAACCTGAGGCAGGATGGGACCAGATGTGA GCTGCAGATTCATGGCCTGTCCGTGGCAGACACTGGGGAGTACTCATGTGTATGTGGT CAGGAGAAGACGTCGGCCACTCTCACTGTCAAGGCCCCACAGCCAGTGTTCCGGGAGC CGCTGCAGAGTCTGCAGGCGGAGGAGGGCTCCACGGCCACCCTGCAGTGTGAGCTGTC TGAGCCCACTGCTACAGTGGTCTGGAGCAAGGGTGGCCTGCAGCTGCAGGCCAATGGG CGCCGGGAGCCACGGCTTCAGGGCTGCACCGCGGAGCTGGTGTTACAGGACCTACAAC GTGAAGACACTGGCGAATACACTTGCACCTGTGGCTCCCAGGCCACCAGTGCCACCCT CACTGTCACAGCTGCGCCTGTGCGGTTCCTCCGAGAGCTGCAGCACCAGGAGGTGGAT GAGGGAGGCACCGCACACTTATGCTGCGAGCTGAGCCGGGCGGGTGCGAGCGTGGAGT GGCGCAAGGGCTCCCTACAGCTCTTCCCTTGTGCCAAGTACCAGATGGTGCAGGATGG TGCAGCTGCAGAGCTGCTGGTACGCGGAGTGGAGCAGGAGGATGCGGGTGACTACACG TGTGACACGGGCCACACGCAGAGCATGGCCAGCCTCTCTGTCCGTGGAGGGCGTGGAG CTGCATGCGGGCCCCAAGTACGAGATGCGGCGCAGGGGGCCACGCGGGAGCTGCTGAT CCACCAACTGGAGGCCAAGGACACGGGCGAGTATGCCTGTGTGACAGGCGGCCAGAAA ACCGCTGCCTCCCTCAGGGTCACAGAGCCTGAGGTGACCATTGTACGGGGGCTGGTTG ATGCGGAGGTGACGGCCGATGAGGATGTTGAGTTCAGCTGTGAGGTGTCCAGGGCTGG AGCCACAGGCGTGCAGTGGTGCCTACAGGGCCTGCCACTGCAAAGCAATGAGGTGACA GAGGTGGCTGTGCGGGATGGCCGCATCCACACCCTGCGGCTGAAGGGCGTGACGCCCG AGGACGCTGGCACTGTCTCCTTCCATTTGGGAAACCATGCTTCCTCTGCCCAGCTCAC CGTCAGAGCTCCTGAGGTGACCATCCTGGAGCCCCTGCAGGACGTGCAGCTCAGAGGG GTGCCCCTGCAGGCCAACGAGATGAATGACATCACTGTGGAGCAGGGCACACTCCACC TGCTCACCCTGCACAAGGTGACCCTTGAGGATGCTGGAACTGTCAGTTTCCACGTGGG CACGTGTAGCTCTGAGGCCCAGCTGAAAGTCACAGAGGCAGTGCCGTGCCTGGTACGT GGCTTGCAGAATGTGGATGTCTTCGCGGGGGAGGTGGCCACGTTCTCCTGTGAGGATG GCCCCCAGAGCGCCATCGCTGTGCGAGATGGGATCTTTCACTCCCTCATGCTCTCGGG CCTGGGGGTGGCCGACTCCGGCACTGTCATCTTCCGCGCAGGGCCCCTGGTCTCCACG GCCAAGTTGTTGATCAAAGATCCCGTGGTGGAGGTGGTCAGTGCCATGCAGGACTTGG CCGTGGAGGAGGGTGGCTCGGCTGAGCTCCTCTGCCAGTATTCACGGCCCGTGCAGGC CACGTGGAAGATGGACGAGCGGGAGGTGCACACGGATGGGCACCGTGTCATCATAGAG CAGGACTGGAACGTGGCCAGGCTGACCTTCAGGCCGGCCTTGCCCTGTGACAGTGGCA TCTATTCTTGTGAGGCTGCGGGCACCCGCGTAGTGGCCCTGCTGCAAGTGCAAGCCAA GAACACGGTGGTGCGAGGGCTGGAGAATGTGGAGGCGCTGGAGGGCGGCGAGGCGCTG TTCGAGTGCCAGCTGTCCCAGCCCGAGGTGGCCGCCCACACCTGGCTGCTGGACGACG AACCCGTGCGCACCTCGGAGAACGCCGAGGTGGTCTTCTTCGAGAACGGCCTGCGCCA CCTGCTGCTGCTCAAAAACTTGCGGCCACAAGACAGCTGCCGGGTGACCTTCCTGGCT GGGGATATGGTGACGTCCGCATTCCTCACGGTCCGAGGTGACTGCGCTGTGCTGGTGC AGGGCTGGCGCCTGGAGATCCTGGAGCCTCTGAAAAACGCGGCGGTCCGGGCCGGCGC ACAGGCACGCTTCACCTGCACGCTCAGCGAGGCGGTGCCCGTGGGAGAGGCGTCCTGG TACATCAATGGCGCGGCAGTGCAGCCGGATGACAGCGACTGGACTGTCACCGCCGACG GCAGTCACCACGCCCTACTGCTGCGCAGCGCCCAGCCCCACCACGCCGGGGAGGTCAC CTTCGCTTGCCGCGACGCCGTGGCCTCTGCGCGGCTCACCGTGCTGGGCCTCCCTGAT CCCCCAGAGGATGCTGAGGTGGTGGCTCGCAGCAGCCACACTGTGACACTGTCTTGGG CAGCTCCCATGAGTGATGGAGGCGGTGGTCTCTGTGGCTACCGCGTGGAGGTGAAGGA GGGGGCCACAGGCCAGTGGCGGCTGTGCCACGAGCTGGTGCCTGGACCCGAGTGTGTG GTGGATGGCCTGGCCCCCGGGGAGACCTACCGCTTCCGTGTGGCAGCTGTGGGCCCTG TGGGTGCTGGGGAACCGGTTCACCTGCCCCAGACAGTGCGGCTTGAGCCACCGAAGCC TGTGCCTCCCCAGCCCTCAGCCCCTGAGAGCCGGCAGGTGGCAGCTGGTGAAGATGTC TGTCTGGAGCTTGAGGTGGTGGCTGAGGCTGGCGAGGTCATCTGGCACAAGGGAATGG AGCGCATCCAGCCCGGTGGGCGGTTCGAGGTGGTCTCCCAGGGTCGGCAACAGATGCT GGTGATCAAGGGCTTCACGGCAGAAGACCAGGGCGAGTACCACTGTGGCCTGGCTCAG GGCTCCATCTGCCCTGCGGCTGCCACCTTCCAGGTGGCACTGAGCCCAGCCTCTGTGG ATGAGGCCCCTCAGCCCAGCTTGCCCCCCGAGGCAGCCCAGGAGGGTGACCTGCACCT ACTGTGGGAGGCCCTGGCTCGGAAACGTCGCATGAGCCGTGAGCCCACGCTGGACTCC ATTAGCGAGCTGCCAGAGGAGGACGGCCGCTCGCAGCGCCTGCCACAGGAGGCAGAGG AGGTGGCACCTGATCTCTCTGAAGGCTACTCCACGGCCGATGAGCTGGCCCGCACTGG AGATGCTGACCTCTCACACACCAGCTCTGATGATGAGTCCCGGGCAGGCACCCCTTCC CTGGTCACCTACCTCAAGAAGGCTGGGAGGCCAGGCACCTCACCACTGGCCAGCAAGG TGAGCCCCCCCAACTTGGCCTGCAAGGAGAGGTTCCCCACGCCCCGGGCCGGCCGCAG CCTCCTGGGCTTCGTGGGGGCAGACCCAGCCTTTCCCGGCAGCGAGCGCTCGGCCAGG TGCACTAGGCGCTGTGCGGCCCCCCCTCCCCGCGAGTCCCTCAAGCGGGAACCTGCCT CGTGTCTCCCAGGAGCCATGGAGGCTGTGGAACTCGCCAGAAAACTGCAGGAGGAAGC TACGTGCTCCATCTGTCTGGATTACTTCACAGACCCTGTGATGACCACCTGTGGCCAC AACTTCTGCCGAGCGTGCATCCAGCTGAGCTGGGAAAAGGCGAGGGGCAAGAAGGGGA GGCGGAAGCGGAAGGGCTCCTTCCCCTGCCCCGAGTGCAGAGAGATGTCCCCGCAGAG GAACCTGCTGCCCAACCGGCTGCTGACCAAGGTGGCCGAGATGGCGCAGCAGCATCCT GGTCTGCAGAAGCAAGACCTGTGCCAGGAGCACCACGAGCCCCTCAAGCTTTTCTGCC AGAAGGACCAGAGCCCCATCTGTGTGGTGTGCAGGGAGTCCCGGGAGCACCGGCTGCA CAGGGTGCTGCCCGCCGAGGAGGCAGTGCAGGGGTACAAGTTGAAGCTGGAGGAGGAC ATGGAGTACCTTCGGGAGCAGATCACCAGGACAGGGAATCTGCAGGCCAGGGAGGAGC AGAGCTTAGCCGAGTGGCAGGGCAAGGTGAAGGAGCGGAGAGAACGCATTGTGCTGGA GTTTGAGAAGATGAACCTCTACCTGGTGGAAGAAGAGCAGAGGCTCCTCCAGGCTCTG GAGACGGAAGAAGAGGAGACTGCCAGCAGGCTCCGGGAGAGCGTGGCCTGCCTGGACC GGCAGGGTCACTCTCTGGAGCTGCTGCTGCTGCAGCTGGAGGAGCGGAGCACACAGGG GCCCCTCCAGATGCTGCAGGACATGAAGGAACCCCTGAGCAGGGCGGCGTTACTGGTG GTTCTAATTCATGGGATGAATCTTGTTGAGTTCCCAGTGGTCTCTCTGCCCAGCCCCC TGTACCTTATTGCCACCAAGGCCCACACACAATTGGGCCCGGGGACTCCCACCTTTGA CCCTGAATGCCCCACACCTCTCCCCATCTCTCCACCACCACGCCCATCTACAGAGGAT GTGGTGCCTGATGCCACCTCCGCGTACCCCTACCTCCTCCTGTATGAGAGCCGCCAGA GGCGCTACCTCGGCTCTTCGCCGGAGGGCAGTGGGTTCTGCAGCAAGGACCGATTTGT GGCTTACCCCTGTGCTGTGGGCCAGACGGCCTTCTCCTCTGGGAGGCACTACTGGGAG GTGGGCATGAACATCACCGGGGACGCGTTGTGGGCCCTGGGTGTGTGCAGGGACAACG TGAGCCGGAAAGACAGGGTCCCCAAGTGCCCCGAAAACGGCTTCTGGGTGGTGCAGCT GTCCAAGGGGACCAAGTACTTATCCACCTTCTCTGCCCTAACCCCGGTCATGCTGATG GAGCCTCCCAGCCACATGGGCATCTTCCTGGACTTCGAAGCCGGGGAAGTGTCCTTCT ACAGTGTAAGCGATGGGTCCCACCTGCACACCTACTCCCAGGCCACCTTCCCAGGCCC CCTGCAGCCTTTCTTCTGCCTGGGGGCTCCGAAGTCTGGTCAGATGGTCATCTCCACA GTGACCATGGCAGGGGTAAAAGACCTGGCCACAAGAACCGGAGCGGTGGTGACGCCAG CGCTCGGAGCCTACGCGCCCAGCGCTACCGAAACCCAGAGTCCTGCGCCCTGGAGTCC CCGCGCCCCGGAGCCCGAGCACCCGGGAGTCCCGAGCCTCGCGCCCCGGAGTGCCCGA GCCTGCGCCGCCGCACCCGGATACCCCGGGTCCCCGCGAGCTGCCGAGGCCGCCCGCC GCCGCCCCGCGGACAGTACCGCCTTCCTCCCCTCTGTCCGCGCCATGGCCGCCCCCGA CCTGTCCACCAACCTCCAGGAGGAGGCCACCTGCGCCATCTGCCTCGACTACTTCACG GATCCGGTGATGACCGACTGCGGCCACAACTTCTGCCGCGAGTGCATCCGGCGCTGCT GGGGCCAGCCCGAGGGCCCGTACGCGTGCCCCGAGTGCCGCGAGCTGTCCCCGCAGAG GAACCTGCGGCCCAACCGCCCGCTTGCTAAGATGGCCGAGATGGCGCGGCGCCTGCAC CCGCCGTCGCCGGTCCCGCAGGGCGTGTGCCCCGCGCACCGCGAGCCACTGGCCGCCT TCTGTGGCGACGAGCTGCGCCTCCTGTGTGCGGCCTGCGAGCGCTCTGGGGAGCACTG GGCGCACCGCGTGCGGCCGCTGCAGGACGCGGCCGAAGACCTCAAGGCGAAGCTGGAG AAGTCACTGGAGCATCTCCGGAAGCAGATGCAGGATGCGTTGCTGTTCCAAGCCCAGG CGGATGAGACCTGCGTCTTGTGGCAGAAGATGGTGGAGAGCCAGCGGCAGAACGTGCT GGGTGAGTTCGAGCGTCTTCGCCGTTTGCTGGCAGAGGGAGGGACAGCAGCTGCTGCA GAGGCTGGAGAGGAGGAGCTGAAGCAGAGCGCCCACCTAGCTGAGCTCATCGCCGAGC TCGAGAGGCCGCTGCCAGCTGCCTGCGCTGGGGCTGCTGCAGGAGAGTCTTTTCCCAT GTGTGGGCTCCACTCCCTGAGCCGGCCCCCTGGCGTGGGCTTTCCTTGGTGCACCCCC AAACCAGAACCAGTGGACGCCCTGGCCTGTGCGTGGCGGCAGGGCTGCCAGACCCAGG TGGAGCCCACAATGCTGCAGATGTGGCTGGGCGGCTTTGCACAGGGGGTGACACTGCT GCCGGCCTCTGGAGCCCAGCAGAACATCAGTCCAGGCACCGGCTCCTGGTTTCGATTG TCATTTCTATTATTTAAGGGGTACAAGTGCAGTCAGAGTGTAGCCATCACCCGAATGG TGCACACTGTACCCAAGACCAAACCCCCTTGTCGAGGCCAAGGTTCTCCTCTACCCCC AAGCCCTTCTCCTGCCGCCCCTGCACCCGGCCTTGTGACAGCCACCACCTGTTTCCAA ATGACACCAGGGGTGGGCCGCCCACCCCAGGACATCAAGGACGCCCTGCGCAGGGTCC AGGATGTGAAGCTGCAGCCCCCAGAAGTTGTGCCTATGGAGCTGAGGACCGTGTGCAG GGTCCCGGGACTGGTAGAGACACTGCGGAGGTTTCGAGGGGACGTGACCTTGGACCCG GACACCGCCAACCCTGAGCTGATCCTGTCTGAAGACAGGCGGAGCGTGCAGCGGGGGG ACCTACGGCAGGCCCTGCCGGACAGCCCAGAGCGCTTTGACCCCGGCCCCTGCGTGCT GGGCCAGGAGCGCTTCACCTCAGGCCGCCACTACTGGGAGGTGGAGGTTGGGGACCGC ACCAGCTGGGCCCTGGGGGTGTGCAGGGAGAACGTGAACAGGAAGGAGAAGGGCGAGC TGTCCGCGGGCAACGGCTTCTGGATCCTGGTCTTCCTGGGGAGCTATTACAATTCCTC GGAACGGGCCTTGGCTCCACTCCGGGACCCACCCAGGCGCGTGGGGATCTTTCTGGAC TACGAGGCTGGACATCTCTCTTTCTACAGTGCCACCGATGGGTCACTGCTATTCATCT TTCCCGAGATCCCCTTCTCGGGGACGCTGCGGCCCCTCTTCTCACCCCTGTCCAGCAG CCCGACCCCGATGACTATCTGCCGGCCGAAAGGTGGGTCCGGGGACACCCTGGCTCCC CAGTGACTCGGGCCCTCCTGGAGGA

ORF Start: ATG at 15 ORF Stop: TGA at 14040

SEQ ID NO: 74 4675 aa MW at 511097.3kD

NOVl 3b, MPLYNDSFHEISHKGRRHTLVLKSIQRADAGIVRASSLKVSTSARLEVRVKPWFLKA CG59237-02 LDDLSAEERGTLALQCEVSDPEAHWWRKDGVQLGPSDKYDFLHTAGTRGLWHDVSP Protein Sequence EDAGLYTCHVGSEETRARVRVHDLHVGITKRLKTMEVLEGESCSFECVLSHESASDPA MWTVGGKTVGSSSRFQATRQGRKYILWREAAPSDAGEWFSVRGLTSKASLIVRERP AAIIKPLEDQWVAPGEDVELRCELSRAGTPVHWLKDRKAIRKSQKYDWCEGTMAMLV IRGASLKDAGEYTCEVEASKSTASLHVEEKANCFTEELTNLQVEEKGTAVFTCKTEHP AATVTWRKGLLELRASGKHQPSQEGLTLRLTISALEKADSDTYTCDIGQAQSRAQLLV QGRRVHIIEDLEDVDVQEGSSATFRCRISPANYEPVHWFLDKTPLHANELNEIDAQPG GYHVLTLRQLALKDSGTIYFEAGDQRASAALRVTEKPSVFSRELTDATITEGEDLTLV CETSTCDIPVCWTKDGKTLRGSARCQLSHEGHRAQLLITGATLQDSGRYKCEAGGACS SSIVRVHARPVRFQEALKDLEVLEGGAATLRCVLSSVAAPVKWCYGNNVLRPGDKYSL RQEGAMLELWRNLRPQDSGRYSCSFGDQTTSATLTVTALPAQFIGKLRNKEATEGAT ATLRCELSKAAPVEWRKGSETLRDGDRYCLRQDGAMCELQIRGLAMVDAAEYSCVCGE ERTSASLT RPMPAHFIGRLRHQESIEGATATLRCELSKAAPVΞWRKGRESLRDGDRH SLRQDGAVCELQICGLAVADAGEYSCVCGEERTSATLTVKALPAKFTEGLRNEEAVEG ATAMLWCELSKVAPVEWRKGPENLRDGDRYILRQEGTRCELQICGLAMADAGEYLCVC GQERTSATLTIRALPARFIEDVKNQEAREGATAVLQCELNSAAPVEWRKGSETLRDGD RYSLRQDGTKCELQIRGLAMADTGEYSCVCGQERTSAMLTVRALPIKFTEGLRNEEAT EGATAVLRCELSKMAPVEWWKGHETLRDGDRHSLRQDGARCELQIRGLVAEDAGEYLC MCGKERTSAMLTVRAMPSKFIEGLRNΞEATEGDTATLWCELSKAAPVEWRKGHETLRD GDRHSLRQDGSRCELQIRGLAWDAGEYSCVCGQERTSATLTVRALPARFIEDVKNQE AREGATAVLQCELSKAAPVEWRKGSETLRGGDRYSLRQDGTRCELQIHGLSVADTGEY SCVCGQERTSATLTVRALPARFTQDLKTKEASEGATATLQCELSKVAPVEWKKGPETL RDGGRYSLKQDGTRCΞLQIHDLSVADAGΞYSCMCGQERTSATLTVRALPARFTEGLRN EEAMEGATATLQCELSKAAPVEWRKGLEALRDGDKYSLRQDGAVCELQIHGLAMADNG VYSCVCGQERTSATLTVRALPARFIEDMRNQKATEGATVTLQCKLRKAAPVEWRKGPN TLKDGDRYSLKQDGTSCELQIRGLVIADAGEYSCICEQERTSATLTVRALPARFIEDV RNHEATEGATAVLQCELSKAAPVEWRKGSETLRDGDRYSLRQDGTRCELQIRGLAVED TGEYLCVCGQERTSATLTVRALPARFIDNMTNQEAREGATATLHCELSKVAPVEWRKG PETLRDGDRHSLRQDGSRCELQIRGLAWDAGEYSCVCGQERTSATLTVRALPARFIE DVKNQEAREGATAVLQCELSKAAPVEWRKGSETLRGGDRYSLRQDGTRCELQIHGLSV ADTGEYSCVCGQERTSATLTVRALPARFTQDLKTKEASEGATATLQCELSKVAPVEWK KGPETLRDGGRYSLKQDGTRCELQIHDLSVADAGEYSCMCGQERTSATLTVRDCHTLH VMPHYPFQLPGLLKEPEETLIYIQIPSPVILFTEGLRNEEAMEGATATLQCELSKAAP VEWRKGLEALRDGDKYSLRQDGAVCELQIHGLAMADNGVYSSLPARFIEDMRNQKATE GATVTLQCKLRKAAPVEWRKGPNTLKDGDRYSLKQDGTSCELQIRGLVIADAGEYSCI CEQERTSATLTVRALPARFIEDVRNHEATEGATAVLQCELSKAAPVEWRKGSETLRDG DRYSLRQDGTRCELQIRGLAVEDTGEYLCVCGQERTSATLTVRALPARFIDNMTNQEA REGATATLHCELSKVAPVEWRKGPETLRDGDRHSLRQDGTRCELQIRGLSVADAGEYS CVCGQERTSATLTIRALPAKFTKGLRNEEATEGATAMLQCELSKVAPVEWRKGPETLR DGDRYNLRQDGTRCELQIHGLSVADTGEYSCVCGQEKTSATLTVKAPQPVFRΞPLQSL QAEEGSTATLQCELSEPTATWWSKGGLQLQANGRREPRLQGCTAELVLQDLQREDTG EYTCTCGSQATSATLTVTAAPVRFLRELQHQEVDEGGTAHLCCELSRAGASVEWRKGS LQLFPCAKYQMVQDGAAAELLVRGVEQEDAGDYTCDTGHTQSMASLSVRGGRGAACGP QVRDAAQGATRELLIHQLEAKDTGEYACVTGGQKTAASLRVTEPEVTIVRGLVDAEVT ADEDVEFSCEVSRAGATGVQWCLQGLPLQSNEVTEVAVRDGRIHTLRLKGVTPEDAGT VSFHLGNHASSAQLTVRAPEVTILEPLQDVQLRGVPLQANEMNDITVEQGTLHLLTLH KVTLEDAGTVSFHVGTCSSEAQLKVTEAVPCLVRGLQNVDVFAGEVATFSCEDGPQSA IAVRDGIFHSLMLSGLGVADSGTVIFRAGPLVSTAKLLIKDPWEWSAMQDLAVEEG GSAELLCQYSRPVQATWKMDEREVHTDGHRVIIEQDWNVARLTFRPALPCDSGIYSCE AAGTRWALLQVQAKNTWRGLENVEALEGGEALFECQLSQPEVAAHTWLLDDEPVRT SENAEWFFENGLRHLLLLKNLRPQDSCRVTFLAGDMVTSAFLTVRGDCAVLVQGWRL EILEPLKNAAVRAGAQARFTCTLSEAVPVGEASWYINGAAVQPDDSDWTVTADGSHHA LLLRSAQPHHAGEVTFACRDAVASARLTVLGLPDPPEDAEWARSSHTVTLSWAAPMS DGGGGLCGYRVEVKEGATGQWRLCHELVPGPECWDGLAPGETYRFRVAAVGPVGAGE PVHLPQTVRLEPPKPVPPQPSAPESRQVAAGEDVCLELEWAEAGEVIWHKGMERIQP GGRFEWSQGRQQMLVIKGFTAEDQGEYHCGLAQGSICPAAATFQVALSPASVDEAPQ PSLPPEAAQEGDLHLLWΞALARKRRMSREPTLDSISELPEEDGRSQRLPQEAEEVAPD LSEGYSTADELARTGDADLSHTSSDDESRAGTPSLVTYLKKAGRPGTSPLASKVSPPN LACKERFPTPRAGRSLLGFVGADPAFPGSERSARCTRRCAAPPPRESLKREPASCLPG AMΞAVELARKLQEEATCSICLDYFTDPVMTTCGHNFCRACIQLSWEKARGKKGRRKRK GSFPCPECREMSPQRNLLPNRLLTKVAEMAQQHPGLQKQDLCQEHHEPLKLFCQKDQS PICWCRESREHRLHRVLPAEEAVQGYKLKLEEDMEYLREQITRTGNLQAREEQSLAE WQGKVKERRERIVLEFEKMNLYLVEEEQRLLQALETEEEETASRLRESVACLDRQGHS LELLLLQLEERSTQGPLQMLQDMKEPLSRAALLWLIHGMNLVEFPWSLPSPLYLIA TKAHTQLGPGTPTFDPECPTPLPISPPPRPSTEDWPDATSAYPYLLLYESRQRRYLG SSPEGSGFCSKDRFVAYPCAVGQTAFSSGRHYWEVGMNITGDALWALGVCRDNVSRKD RVPKCPENGFWWQLSKGTKYLSTFSALTPVMLMEPPSHMGIFLDFEAGEVSFYSVSD GSHLHTYSQATFPGPLQPFFCLGAPKSGQMVISTVTMAGVKDLATRTGAWTPALGAY APSATETQSPAPWSPRAPEPEHPGVPSLAPRSARACAAAPGYPGSPRAAEAARRRPAD STAFLPSVRAMAAPDLSTNLQEEATCAICLDYFTDPVMTDCGHNFCRECIRRCWGQPE GPYACPECRELSPQRNLRPNRPLAKMAEMARRLHPPSPVPQGVCPAHREPLAAFCGDE LRLLCAACERSGEHWAHRVRPLQDAAEDLKAKLEKSLEHLRKQMQDALLFQAQADETC VLWQKMVESQRQNVLGEFERLRRLLAEGGTAAAAEAGEEELKQSAHLAELIAELERPL PAACAGAAAGESFPMCGLHSLSRPPGVGFPWCTPKPEPVDALACAWRQGCQTQVEPTM LQMWLGGFAQGVTLLPASGAQQNISPGTGSWFRLSFLLFKGYKCSQSVAITRMVHTVP KTKPPCRGQGSPLPPSPSPAAPAPGLVTATTCFQMTPGVGRPPQDIKDALRRVQDVKL QPPEWPMELRTVCRVPGLVETLRRFRGDVTLDPDTANPELILSEDRRSVQRGDLRQA LPDSPERFDPGPCVLGQERFTSGRHYWEVEVGDRTSWALGVCRENVNRKEKGELSAGN GFWILVFLGSYYNSSERALAPLRDPPRRVGIFLDYEAGHLSFYSATDGSLLFIFPEIP FSGTLRPLFSPLSSSPTPMTICRPKGGSGDTLAPQ Sequence comparison ofthe above protein sequences yields the following sequence relationships shown in Table 13B.

Table 13B. Comparison of NOV13a against NOV13b and NOV13c.

NOV13a Residues/ Identities/

Protein Sequence Match Residues Similarities for the Matched Region

NOVl 3b 1..4691 4399/4696 (93%) 1..4675 4403/4696 (93%)

Further analysis ofthe NOVl 3 a protein yielded the following properties shown in Table 13C.

Table 13C. Protein Sequence Properties NOV13a

PSort 0.8500 probability located in endoplasmic reticulum (membrane); 0.4400 analysis: probability located in plasma membrane; 0.3500 probability located in nucleus; 0.3000 probability located in microbody (peroxisome)

SignalP No Known Signal Sequence Indicated analysis:

A search ofthe NOVl 3a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 13D.

In a BLAST search of public sequence databases, the NOV13a protein was found to have homology to the proteins shown in the BLASTP data in Table 13E.

PFam analysis indicates that the NOVl 3a protein contains the domains shown in the Table 13F.

Example 14.

The NOV14 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 14A.

FEWKPASSLRRWLAVCGIILVFLLAΞLNTFYLKFVLW PPEHYLVLLRLVFFVNVGGV AMREIYDFMDDPKPHKKLGPQAWLVAAITATELLIWKYDPHTLTLSLPFYISQCWTL GSVLALTWTVWRFFLRDITLRYKETRWQKWQNKDDQGSTVGNGDQHPLGLDEDLLGPG VAEGEGAPTPN

Further analysis ofthe NOV14a protein yielded the following properties shown in Table 14B.

Table 14B. Protein Sequence Properties NOV14a

SignalP Cleavage site between residues 8 and 9 analysis:

A search ofthe NOVl 4a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 14C.

In a BLAST search of public sequence databases, the NOV14a protein was found to have homology to the proteins shown in the BLASTP data in Table 14D.

PFam analysis indicates that the NOV14a protein contains the domains shown in the Table 14E.

Example 15.

The NOVl 5 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 15A.

Table 15A. NOV15 Sequence Analysis

Further analysis ofthe NOVl 5a protein yielded the following properties shown in Table 15B.

Table 15B. Protein Sequence Properties NOV15a

PSort 0.4600 probability located in plasma membrane; 0.1000 probability located in analysis: endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen); 0.1000 probability located in outside

SignalP Cleavage site between residues 25 and 26 analysis:

A search ofthe NOVl 5a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 15C.

Table 15C. Geneseq Results for NOV15a

NOV15a Identities/

In a BLAST search of public sequence databases, the NOVl 5a protein was found to have homology to the proteins shown in the BLASTP data in Table 15D.

PFam analysis indicates that the NOVl 5a protein contains the domains shown in the Table 15E.

Example 16.

The NOVl 6 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 16A.

Further analysis ofthe NOV16a protein yielded the following properties shown in Table 16B. Table 16B. Protein Sequence Properties NOV16a

PSort 0.4600 probability located in plasma membrane; 0.1357 probability located in analysis: microbody (peroxisome); 0.1000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 25 and 26 analysis:

A search ofthe NOVl 6a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 16C.

In a BLAST search of public sequence databases, the NOVl 6a protein was found to have homology to the proteins shown in the BLASTP data in Table 16D.

PFam analysis indocates that the NOVl 6a protein contains the domains shown in the Table 16E.

Example 17.

The NOVl 7 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 17A.

TGGTTGAGTTTGTGCACAGCTGGCAGGAGCAGGCCCCTAACCAGCCTCCAGGGCCCAC AACTTCCTCCCTGCCTCGCCCACCGTGCCTACAGCAGAACCCAGGAACCATGCAGGGC GTGTACGAGCAGTGTGAGGCTCTACTGCGGCCCCCCTTTGACGCCTGCCACGCCTACG TCAGCCCTCTGCCCTTCACAGCCAGTTGTACCAGTGATCTCTGCCAATCAATGGGTGA TGTAGCCACCTGGTGCCGGGCACTGGCGGAGTATGCCCGGGCGTGTGCCCAGGCAGGG CGGCCCTTGCAAGGCTGGAGGACCCAGCTCCGGCAATGCACTGTGCACTGCAAGGAGA AGGCCTTTACCTACAATGAGTGCATCGCCTGCTGCCCTGCCTCCTGCCATCCCCGGGC ATCCTGTGTGGACAGTGAGATCGCCTGTGTGGACGGCTGCTATTGCCCCAATGGGCTC ATCTTCGAGGATGGGGGCTGCGTGGCACCAGCTGAGTGTCCCTGTGAGTTTCACGGGA CTCTGTACCCACCTGGCTCTGTGGTGAAGGAAGACTGCAATACTTGCACATGCACCTC AGGCAAGTGGGAGTGCAGCACAGCTGTCTGCCCAGCTGAGTGCTCAGTGACTGGTGAC ATTCACTTCACAACCTTTGATGGCCGCCGGTACACGTTCCCCGCCACATGTCAGTACA TCCTGGCCAAGAGCCGCTCTTCGGGCACCTTCACCGTGACATTGCAGAATGCCCCATG TGGCCTGAACCAAGATGGAGCCTGTGTCCAGTCAGTGTCAGTGATTCTGCACCAGGAC CCTCGGAGGCAGGTGACCCTGACCCAGGCAGGGGATGTCCTTCTGTTTGACCAGTACA AGATCATCCCGCCATACACAGATGATGCCTTTGAGATCCGTAGGCTGTCCTCCGTGTT CCTGCGGGTGAGGACGAACGTGGGCGTGCGGGTGCTCTACGACCGTGAAGGGCTCCGA CTGTACCTGCAAGTGGACCAGCGATGGGTGGAGGATACCGTGGGCCTCTGCGGCACCT TCAATGGCAACACGCAGGATGACTTCCTGTCTCCAGTGGGTGTACCTGAGAGCACCCC ACAACTTTTTGGCAATTCCTGGAAAACACTTTCTGCTTGCTCCCCGCTGGTCTCTGGC TCCCCTCTGGACCCCTGCGATGTGCACCTGCAAGCCGCCTCCTACTCAGTGCAGGCCT GCAGCGTGCTCACGGGGGAGATGTTTGCGCCCTGCTCTGCGTTCCTGAGCCCCGTGCC CTACTTTGAGCAGTGCCGCAGGGATGCCTGCCGCTGCGGGCAGCCCTGCCTGTGCGCC ACACTGGCCCACTACGCCCACCTGTGCCGGCGCCATGGGCTCCCCGTTGATTTCCGCG CCCGCCTGCCAGCCTGTGCACTGTCCTGTGAGGCCTCCAAGGAGTATAGCCCCTGCGT GGCCCCGTGTGGACGTACCTGCCAGGACCTGGCCAGCCCTGAGGCCTGTGGGGTTGAT GGTGGCGATGACCTGAGCAGAGACGAGTGTGTGGAGGGCTGTGCCTGCCCACCGGACA CCTATCTGGACACCCAGGCTGACCTCTGTGTCCCCCGGAACCAGTGCTCCTGCCACTT CCAGGGAGTGGACTATCCCCCCGGAGACAGTGACATCCCATCCCTGGGCCACTGCCAC TGCAAAGATGGAGTCATGAGCTGTGATAGCAGAGCCCCAGCTGCTGCCTGCCCAGCAG GCCAGGTCTTCGTGAACTGCAGCGACCTGCACACGGACCTGGAGCTGAGCAGGGAGAG GACGTGTGAGCAGCAACTGCTGAACCTGAGCGTGTCAGCCCGTGGCCCCTGCCTCTCG GGCTGCGCCTGTCCCCAGGGTCTGCTCAGACACGGGGATGCATGTTTCCTGCCAGAGG AGTGCCCCTGCACTTGGAAGGGGAAGGAGTATTTCCCTGGGGACCAGGTGATGTCTCC TTGCCATACCTGTGTGTGCCAGCGGGGCTCATTCCAGTGCACCCTGCACCCTTGCGCC TCCACCTGCACTGCCTATGGGGACCGGCATTACCGCACGTTTGATGGGCTCCCGTTTG ACTTCGTGGGGGCATGCAAAGTGCACCTGGTCAAGAGCACATCAGATGTCAGCTTCTC TGTGATTGTAGAGAATGTGAACTGCTACAGCTCTGGCATGATCTGCAGGAAATTTATT TCCATCAACGTTGGGAACTCACTCATTGTCTTTGATGATGACTCCGGAAATCCTAGTC CAGAGAGCTTCCTGGATGACAAGCAGGAGGTCCACACATGGCGAGTGGGATTTTTCAC ACTGGTGCATTTCCCACAGGAGCACATCACCCTCTTGTGGGACCAGAGAACCACAGTG CACGTCCAGGCTGGGCCTCAGTGGCAGGGCCAGCTGGCGGGCCTCTGTGGGAACTTTG ACTTAAAAACCATCAATGAGATGAGGACCCCGGAGAACCTAGAGCTAACTAACCCCCA GGAGTTTGGCAGCAGTTGGGCTGCAGTTGAGTGCCCAGACACCCTCGATCCTCGGGAT ATGTGTGTCCTGAATCCTCTCCGAGAACCATTTGCCAAGAAGGAGTGCAGCATCCTGC TCAGTGAGGTGTTTGAGATCTGCCACCCTGTGGTTGATGTCACTTGGTTTTACTCAAA CTGCCTGACAGACACATGTGGCTGCAGCCAGGGTGGTGACTGTGAGTGCTTCTGTGCC AGCGTCTCCGCTTATGCCCACCAGTGTTGCCAGCATGGGGTGGCTGTTGACTGGCGAA CCCCCCGCCTCTGCCCGTATGACTGTGACTTCTTTAACAAAGTGCTAGGTAAGGGCCC CTATCAGCTATCCAGCTTGGCAGCCGGTGGTGCTCTGGTGGGCATGAAGGCGGTGGGC GATGACATAGTCCTAGTGAGGACAGAGGATGTGGCGCCAGCAGACATTGTGAGCTTCC TGCTGACAGCTGCTCTGTACAAGGCCAAGGCCCATGACCCAGATGTGGTGTCCCTGGA GGCAGCAGACAGACCCAACTTCTTCCTTCACGTCACAGCCAACGGGTCTCTGGAGCTG GCTAAGTGGCAGGGCCGTGACACCTTCCAACAGCATGCCTCCTTCTTGCTGCACCGGG GGACACGGCAGGCAGGCCTGGTGGCCCTGGAGTCCCTGGCCAAGCCCAGCTCCTTCCT CTATGTGTCGGGCGCGGTGCTGGCCCTGCGGCTGTACGAACACACAGAGGTGTTCCGC CGGGGCACACTCTTCCGCCTTCTGGATGCCAAGCCCTCGGGGGCTGCCTACCCCATCT GCGAGTGGCGCTACGATGCCTGTGCCAGCCCCTGCTTCCAAACCTGCCGGGACCCACG GGCAGCCAGCTGCCGGGACGTACCCAGGGTAGAAGGCTGTGTCCCTGTGTGCCCCACC CCCCAGGTCCTGGATGAAGTCACACAGAGATGTGTCTACTTGGAGGACTGTGTGGAGC CAGCAGTTTGGGTTCCCACAGAGGCCCTTGGCAATGAGACCCTCCCTCCCAGTCAAGG GTTGCCCACTCCCAGTGATGAGGAGCCACAGCTGTCACAGGAAAGCCCCAGGACCCCC ACCCACAGGCCAGCCCTCACCCCAGCTGCCCCACTCACCACAGCCCTGAACCCACCAG TGACAGCCACTGAGGAGCCAGTGGTGTCTCCAGGCCCCACCCAGACCACCCTGCAGCA GCCACTGGAGCTCACTGCATCTCAACTCCCCGCCGGCCCCACGGAGTCCCCAGCCAGC AAGGGAGTGACTGCCAGCCTCCTGGCCATCCCCCATACACCAGAGTCCTCATCCCTCC CTGTTGCACTGCAGACACCCACACCTGGCATGGTGTCAGGTGCCATGGAGACAACAAG GGTGACTGTGATCTTTGCAGGAAGCCCTAACATCACAGTCTCCTCCCGGTCGCCCCCT GCCCCTCGCTTCCCGCTCATGACCAAGGCTGTGACAGTCCGAGGCCATGGCTCCTTGC CTGTTAGGACGACACCCCCACAGCCCTCCTTGACAGCAAGTCCCTCCTCCAGACCTGT GGCTTCCCCTGGAGCCATCTCCAGGTCCCCCACCTCCTCGGGATCCCACAAGGCTGTG CTGACACCTGCAGTAACTAAGGTCATAAGCAGGACAGGGGTCCCCCAGCCCACCCAGG CCCAGAGTGCTTCAAGTCCCAGCACCCCTCTAACTGTGGCTGGAACAGCAGCAGAACA GGTTCCTGTCAGTCCCCTTGCAACCAGGAGCTTGGAGATAGTGCTATCCACAGAGAAG GGCGAAGCCGGGCACAGCCAGCCCATGGGCTCGCCTGCCTCCCCACAGCCACACCCAC TCCCCTCTGCACCACCCCGCCCAGCCCAGCATACCACCATGGCCACCAGGTCTCCAGC TCTGCCCCCAGAGACCCCAGCTGCCGCCAGCCTGTCAACAGCCACTGATGGGCTGGCA GCCACACCCTTCATGTCCCTTGAGTCAACTCGTCCCTCCCAGCTCCTCTCTGGCCTGC CTCCCGACACCAGCCTGCCCCTGGCCAAGGTGGGCACATCTGCCCCAGTGGCCACACC CGGCCCCAAAGCCTCTGTCATCACCACTCCACTCCAGCCACAGGCCACGACTCTGCCT GCTCAGACACTTAGCCCAGTACTGCCTTTCACTCCAGCAGCAATGACCCAGGCGCACC CACCCACTCACATAGCACCCCCAGCAGCAGGCACAGCTCCAGGCCTGCTGCTGGGAGC CACATTGCCAACCTCTGGAGTCCTGCCTGTGGCTGAGGGCACGGCCTCCATGGTATCT GTTGTCCCACGAAAGAGCACCACAGGGAAGGTGGCCATCCTATCCAAGCAAGTGTCTC TGCCCACTTCCATGTATGGTTCTGCAGAGGGTGGGCCCACAGAGCTCACGCCTGCTAC GAGCCACCCTCTCACGCCCTTGGTGGCTGAGCCCGAGGGAGCCCAGGCAGGCACAGCT CTGCCAGTGCCCACATCCTATGCCCTGAGCCGTGTCTCAGCCAGGACGGCCCCCCAAG ACAGCATGCTGGTTCTGTTGCCTCAGCTGGCTGAGGCCCATGGAACCTCGGCAGGGCC TCACCTGGCAGCAGAGCCGGTGGACGAGGCCACCACAGAACCATCTGGGCGCTCAGCC CCAGCCCTGAGCATCGTAGAGGGTTTGGCGGAGGCTTTGGCAACTACCACTGAGGCCA ATACATCCACCACCTGTGTTCCAATCGCCGAGCAGGACTGCGTCCGCCACATCTGCCT GGAGGGCCAGCTGATTCGCGTGAATCAGTCCCAGCACTGTCCCCAGGGTGCTGCTCCC CCTCGCTGTGGGATCCTGGGCCTCGCCGTGCGGGTGGGTGGGGACCGCTGCTGCCCAC TCTGGGAGTGTGCCTGCCGGTGCTCAATCTTCCCTGACCTGAGCTTCGTGACCTTCGA TGGGAGCCACGTAGCTCTGTTCAAGGAGGCCATCTACATCCTCAGCCAGAGCCCAGAT GAAATGCTCACCGTCCATGTACTGGACTGCAAAAGTGCCAACCTGGGGCACCTGAACT GGCCCCCGTTCTGTCTGGTGATGTTGAACATGACTCACTTGGCCCATCAGGTCACTAT TGATCGCTTCAACCGAAAGGTGACTGTGGACTTGCAGCCTGTGTGGCCACCGGTGAGC AGGTATGGATTCAGAATTGAGGACACAGGCCACATGTACATGATCCTGACTCCCTCAG ACATCCAGATCCAGTGGCTCCACAGCTCAGGACTCATGATCGTGGAGGCCAGCAAAAC CAGCAAGGCCCAGGGCCATGGCCTGTGCGGTATCTGTGATGGAGATGCAGCCAATGAC CTTACCCTGAAGGATGGCTCAGTGGTGGGTGGGGCTGAGGACCCTGCTCCCTTTCTGG ACAGCTGGCAGGTGCCCAGCTCCCTGACCTCAGTGGGCCAGACCCGCTTCCGCCCAGA CAGCTGCGCCACAACTGACTGCTCGCCCTGCCTTCGCATGGTGTCCAACCGCACCTTC AGTGCCTGCCACCGCTTTGTGCCTCCGGAGTCATTCTGTGAGCTGTGGATCCGGGACA CCAAGTACGTGCAGCAGCCCTGCGTGGCCCTGACTGTGTACGTGGCCATGTGCCACAA ATTTCATGTGTGCATCGAGTGGCGGCGCTCTGACTACTGCCCCTTCCTGTGCTCCAGC GACTCCACATACCAGGCATGTGTGACAGCCTGTGAGCCACCCAAGACATGCCAGGATG GGATACTAGGGCCTCTGGACCCAGAGCACTGCCAGGTGCTGGGCGAGGGCTGCGTCTG CTCCGAGGGCACCATCTTACACCGGCGCCACTCTGCACTCTGCATCCCGGAGGCCAAG TGCGCCTGCACTGACAGCATGGGGGTGCCGAGGGCCCTGGGGGAGACCTGGAACAGCT CCCTCAGCGGCTGCTGCCAGCACCAGTGCCAAGCCCCAGACACCATTGTCCCGGTGGA TCTGGGCTGCCCCAGTCCCCGCCCTGAGAGCTGCCTGCGATTCGGGGAGGTGGCCTTG CTCCTACCCACCAAGGACCCCTGCTGCCTGGGGACTGTCTGTGTGTGTAACCAGACTC TGTGTGAGGGTCTCGCCCCCACATGCCGCCCAGGCCACCGCCTCCTCACCCACTTCCA GGAGGACTCCTGCTGCCCCAGCTACAGCTGTGAGTGTGACCCAGATCTCTGTGAGGCA GAGCTGGTCCCCAGCTGCCGACAGGACCAGATCCTGATCACGGGCCGCCTGGGGGACT CCTGCTGCACCTCCTACTTCTGCGCCTGTGGTGACTGTCCAGACTCCATCCCCGAATG TCAAGAAGGGGAGGCGCTCACTGTGCACAGGAATACCACGGAACTCTGCTGCCCTCTG TACCAGTGTGTGTGTGAGAACTTCCGCTGTCCCCAAGTGCAGTGTGGCCTGGGCACTG CCCTGGTGGAGGTGTGGAGCCCCGACCGCTGCTGCCCCTACAAATCCTGTGAATGTGA CTGTGACACAATCCCGGTGCCCCGGTGCCATCTGTGGGAGAAATCCCAGCTGGATGAG GAGTTCATGCACAGCGTGGAGAATGTGTGTGGCTGCGCCAAGTACGAGTGTGTGAAGG CCCCGGTGTGTCTGAGCCGCGAGCTGGGTGTGATGCAGCCCGGCCAGACAGTGGTGGA GCTCTCAGCAGATGGCGTGTGCCACACCTCCCGCTGCACCACCGTGCTCGACCCTCTC ACCAACTTCTACCAGATCAACACCACCTCCGTGCTCTGTGACATCCACTGTGAGGCGA ACCAGGAGTACGAGCACCCGCGGGACCTCGCTGCCTGCTGCGGCTCCTGCAGGAACGT GTCCTGTCTCTTCACCTTCCCCAATGGCACCACCTCCCTGTTCTTGCCCGGGGCATCC TGGATCGCAGACTGCGCCCGCCACCACTGCAGCAGCACGCCCCTGGGTGCCGTGCTGG TCCGCTCTCCCATAAGCTGCCCACCGCTCAATGAGACTGAGTGTGCCAAGGTTGGGGG TTCCGTGGTACCTTCCTTGGAAGGATGCTGCAGGACCTGTAAGGAGGATGGGCGCTCC TGCAAGAAGGTGACCATCCGCATGACCATCCGCAAGAATGAATGCAGGAGCAGCACCC CTGTGAACCTAGTGTCCTGCGATGGGAGGTGCCCATCCGCCAGCATCTACAACTACAA CATCAACACCTATGCCCGATTCTGCAAGTGCTGCCGTGAGGTGGGCCTGCAGCGGCGC TCTGTGCAGCTCTTCTGTGCCACCAATGCCACCTGGGTGCCCTATACAGTGCAGGAGC CCACCGACTGTGCCTGCCAGTGGTCCTGAGGCCTGGGGGCCCGGGCTAGCTGGACCAC CTCTGCCAGCCCCACTTTCTGT

ORF Start: ATG at 43 ORF Stop: TGA at 8785

SEQ ID NO: 82 2914 aa MW at 314011.9kD

NOVl 7a, MGARMPRRCLLLLSCFCLLRVESTAEVQHQASALTWKISAELQQEPAPEPSHTYQEMS CG59295-01 LAVEDVTTVMEGKQAEAPDSVAMSSWERRLHRAKCAPSYLFSCFNGGECVHPAFCDCR RFNATGPRCQMVYNAGPERDSICRAWGQHHVETFDGLYYYLSGKGSYTLVGRHEPEGQ Protein Sequence SFSIQVHNDPQCGSSPYTCSRAVSLFFVGEQEIHLAKEVTHGGMRVQLPHVMGSARLQ QLAGYVIVRHQSAFTLAWDGASAVYIKMSPELLGWTHGLCGNNNADPKDDLVTSSGΞG KLTDDWEFVHSWQEQAPNQPPGPTTSSLPRPPCLQQNPGTMQGVYEQCEALLRPPFD ACHAYVSPLPFTASCTSDLCQSMGDVATWCRALAEYARACAQAGRPLQGWRTQLRQCT VHCKEKAFTYNECIACCPASCHPRASCVDSEIACVDGCYCPNGLIFEDGGCVAPAECP CEFHGTLYPPGSWKEDCNTCTCTSGKWECSTAVCPAECSVTGDIHFTTFDGRRYTFP ATCQYILAKSRSSGTFTVTLQNAPCGLNQDGACVQSVSVILHQDPRRQVTLTQAGDVL LFDQYKIIPPYTDDAFEIRRLSSVFLRVRTNVGVRVLYDREGLRLYLQVDQRWVEDTV GLCGTFNGNTQDDFLSPVGVPESTPQLFGNSWKTLSACSPLVSGSPLDPCDVHLQAAS YSVQACSVLTGE FAPCSAFLSPVPYFEQCRRDACRCGQPCLCATLAHYAHLCRRHGL PVDFRARLPACALSCEASKEYSPCVAPCGRTCQDLASPEACGVDGGDDLSRDECVEGC ACPPDTYLDTQADLCVPRNQCSCHFQGVDYPPGDSDIPSLGHCHCKDGVMSCDSRAPA AACPAGQVFVNCSDLHTDLELSRERTCEQQLLNLSVSARGPCLSGCACPQGLLRHGDA CFLPEECPCTWKGKEYFPGDQVMSPCHTCVCQRGSFQCTLHPCASTCTAYGDRHYRTF DGLPFDFVGACKVHLVKSTSDVSFSVIVENVNCYSSGMICRKFISINVGNSLIVFDDD SGNPSPESFLDDKQEVHTWRVGFFTLVHFPQEHITLLWDQRTTVHVQAGPQWQGQLAG LCGNFDLKTINE RTPENLELTNPQEFGSSWAAVECPDTLDPRDMCVLNPLREPFAKK ECSILLSEVFEICHPWDVTWFYSNCLTDTCGCSQGGDCECFCASVSAYAHQCCQHGV AVDWRTPRLCPYDCDFFNKVLGKGPYQLSSLAAGGALVGMKAVGDDIVLVRTEDVAPA DIVSFLLTAALYKAKAHDPDWSLEAADRPNFFLHVTANGSLELAKWQGRDTFQQHAS FLLHRGTRQAGLVALESLAKPSSFLYVSGAVLALRLYEHTEVFRRGTLFRLLDAKPSG AAYPICEWRYDACASPCFQTCRDPRAASCRDVPRVEGCVPVCPTPQVLDEVTQRCVYL EDCVEPAVWVPTEALGNETLPPSQGLPTPSDEEPQLSQESPRTPTHRPALTPAAPLTT ALNPPVTATEEPWSPGPTQTTLQQPLELTASQLPAGPTESPASKGVTASLLAIPHTP ΞSSSLPVALQTPTPGMVSGA ETTRVTVIFAGSPNITVSSRSPPAPRFPLMTKAVTVR GHGSLPVRTTPPQPSLTASPSSRPVASPGAISRSPTSSGSHKAVLTPAVTKVISRTGV PQPTQAQSASSPSTPLTVAGTAAEQVPVSPLATRSLEIVLSTEKGEAGHSQPMGSPAS PQPHPLPSAPPRPAQHTTMATRSPALPPETPAAASLSTATDGLAATPFMSLESTRPSQ LLSGLPPDTSLPLAKVGTSAPVATPGPKASVITTPLQPQATTLPAQTLSPVLPFTPAA MTQAHPPTHIAPPAAGTAPGLLLGATLPTSGVLPVAEGTASMVSWPRKSTTGKVAIL SKQVSLPTSMYGSAEGGPTELTPATSHPLTPLVAEPEGAQAGTALPVPTSYALSRVSA RTAPQDSMLVLLPQLAEAHGTSAGPHLAAEPVDEATTEPSGRSAPALSIVEGLAEALA TTTEANTSTTCVPIAEQDCVRHICLEGQLIRVNQSQHCPQGAAPPRCGILGLAVRVGG DRCCPLWECACRCSIFPDLSFVTFDGSHVALFKEAIYILSQSPDEMLTVHVLDCKSAN LGHLNWPPFCLVMLNMTHLAHQVTIDRFNRKVTVDLQPVWPPVSRYGFRIEDTGHMYM ILTPSDIQIQWLHSSGLMIVEASKTSKAQGHGLCGICDGDAANDLTLKDGSWGGAED PAPFLDSWQVPSSLTSVGQTRFRPDSCATTDCSPCLRMVSNRTFSACHRFVPPESFCE LWIRDTKYVQQPCVALTVYVAMCHKFHVCIEWRRSDYCPFLCSSDSTYQACVTACEPP KTCQDGILGPLDPEHCQVLGEGCVCSEGTILHRRHSALCIPEAKCACTDSMGVPRALG ETWNSSLSGCCQHQCQAPDTIVPVDLGCPSPRPESCLRFGEVALLLPTKDPCCLGTVC VCNQTLCEGLAPTCRPGHRLLTHFQEDSCCPSYSCECDPDLCEAELVPSCRQDQILIT GRLGDSCCTSYFCACGDCPDSIPECQEGEALTVHRNTTELCCPLYQCVCENFRCPQVQ CGLGTALVEVWSPDRCCPYKSCECDCDTIPVPRCHLWEKSQLDEEFMHSVENVCGCAK YECVKAPVCLSRELGVMQPGQTWELSADGVCHTSRCTTVLDPLTNFYQINTTSVLCD IHCEANQEYEHPRDLAACCGSCRNVSCLFTFPNGTTSLFLPGASWIADCARHHCSSTP LGAVLVRSPISCPPLNETECAKVGGSWPSLEGCCRTCKEDGRSCKKVTIRMTIRKNE CRSSTPVNLVSCDGRCPSASIYNYNINTYARFCKCCREVGLQRRSVQLFCATNATWVP YTVQEPTDCACQWS

Further analysis ofthe NOVl 7a protein yielded the following properties shown in Table 17B.

Table 17B. Protein Sequence Properties NO 17a

PSort 0.4610 probability located in outside; 0.1900 probability located in lysosome analysis: (lumen); 0.1000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 24 and 25 analysis:

A search ofthe NOVl 7a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 17C.

In a BLAST search of public sequence databases, the NOVl 7a protein was found to have homology to the proteins shown in the BLASTP data in Table 17D.

PFam analysis indicates that the NOVl 7a protein contains the domains shown in the Table 17E.

Example 18.

The NOVl 8 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 18A.

Further analysis ofthe NOV18a protein yielded the following properties shown in Table 18B.

Table 18B. Protein Sequence Properties NOV18a

PSort 0.6000 probability located in plasma membrane; 0.4000 probability located in analysis: Golgi body; 0.3142 probability located in mitochondrial inner membrane; 0.3000 probability located in endoplasmic reticulum (membrane)

SignalP Cleavage site between residues 35 and 36 analysis:

A search ofthe NOVl 8a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 18C.

In a BLAST search of public sequence databases, the NOVl 8a protein was found to have homology to the proteins shown in the BLASTP data in Table 18D.

PFam analysis indicates that the NOVl 8a protein contains the domains shown in the Table 18E.

Table 18E. Domain Analysis of NOV18a

Example 19.

The NOVl 9 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 19 A.

Table 19A. NOV19 Sequence Analysis

SEQ ID NO: 85 1802 bp

NOVl 9a, TGGGGGAAACAGGCCCGTTGCCCTGGCCTCTTTGCCCTGGGCCAGCCTTTGTGAAGTG CG59284-01 DNA GGCCCCTCTTCTGGGCCCCTTGAGTAGGTTCCATGGCATTTTCTGAACTCCTGGACCT Sequence CGTGGGTGGCCTGGGCAGGTTCCAGGTTCTCCAGACGATGGCTCTGATGGTCTCCATC ATGTGGCTGTGTACCCAGAGCATGCTGGAGAACTTCTCGGCCGCCGTGCCCAGCCACC GCTGCTGGGCACCCCTCCTGGACAACAGCACGGCTCAGGCCAGCATCCTAGGGAGCTT GAGTCCTGAGGCCCTCCTGGCTATTTCCATCCCGCCGGGCCCCAACCAGAGGCCCCAC CAGTGCCGCCGCTTCCGCCAGCCACAGTGGCAGCTCTTGGACCCCAATGCCACGGCCA CCAGCTGGAGCGAGGCCGACACGGAGCCGTGTGTGGATGGCTGGGTCTATGACCGCAG CATCTTCACCTCCACAATCGTGGCCAAGTGGAACCTCGTGTGTGACTCTCATGCTCTG AAGCCCATGGCCCAGTCCATCTACCTGGCTGGGATTCTGGTGGGAGCTGCTGCGTGCG GCCCTGCCTCAGACAGGTTTGGGCGCAGGCTGGTGCTAACCTGGAGCTACCTTCAGAT GGCTGTGATGGGTACGGCAGCTGCCTTCGCCCCTGCCTTCCCCGTGTACTGCCTGTTC CGCTTCCTGTTGGCCTTTGCCGTGGCAGGCGTCATGATGAACACGGGCACTCTCCTGA TGGAGTGGACGGCGGCACGGGCCCGACCCTTGGTGATGACCTTGAACTCTCTGGGCTT CAGCTTCGGCCATGGCCTGACAGCTGCAGTGGCCTACGGTGTGCGGGACTGGACACTG CTGCAGCTGGTGGTCTCGGTCCCCTTCTTCCTCTGCTTTTTGTACTCCTGGTGGCTGG CAGAGTCGGCACGATGGCTCCTCACCACAGGCAGGCTGGATTGGGGCCTGCAGGAGCT GTGGAGGGTGGCTGCCATCAACGGAAAGGGGGCAGTGCAGGACACCCTGACCCCTGAG GTCTTGCTTTCAGCCATGCGGGAGGAGCTGAGCATGGGCCAGCCTCCTGCCAGCCTGG GCACCCTGCTCCGCATGCCCGGACTGCGCTTCCGGACCTGTATCTCCACGTTGTGCTG GTTCGCCTTTGGCTTCACCTTCTTCGGCCTGGCCCTGGACCTGCAGGCCCTGGGCAGC AACATCTTCCTGCTCCAAATGTTCATTGGTGTCGTGGACATCCCAGCCAAGATGGGCG CCCTGCTGCTGCTGAGCCACCTGGGCCGCCGCCCCACGCTGGCCGCATCCCTGTTGCT GGCGGGGCTCTGCATTCTGGCCAACACGCTGGTGCCCCACGAAATGGGGGCTCTGCGC TCAGCCTTGGCCGTGCTGGGGCTGGGCGGGGTGGGGGCTGCCTTCACCTGCATCACCA TCTACAGCAGCGAGCTCTTCCCCACTGTGCTCAGGATGACGGCAGTGGGCTTGGGCCA GATGGCAGCCCGTGGAGGAGCCATCCTGGGGCCTCTGGTCCGGCTGCTGGGTGTCCAT GGCCCCTGGCTGCCCTTGCTGGTGTATGGGACGGTGCCAGTGCTGAGTGGCCTGGCCG CACTGCTTCTGCCCGAGACCCAGAGCTTGCCGCTGCCCGACACCATCCAAGATGTGCA GAACCAGGCAGTAAAGAAGGCAACACATGGCACGCTGGGGAACTCTGTCCTAAAATCC ACACAGTTTTAGCCTCCTGGGGAACCTGCGATGGGACGGTCAGAGGAAGAGACTTCTT CTGT

ORF Start: ATG at 91 ORF Stop: TAG at 1750

SEQ ID NO: 86 553 aa MW at 59629.4kD

NOVl 9a, MAFSELLDLVGGLGRFQVLQTMALMVSIMWLCTQSMLENFSAAVPSHRCWAPLLDNST CG59284-01 AQASILGSLSPEALLAISIPPGPNQRPHQCRRFRQPQWQLLDPNATATSWSEADTEPC VDGWVYDRSIFTSTIVAKWNLVCDSHALKPMAQSIYLAGILVGAAACGPASDRFGRRL Protein Sequence VLTWSYLQMAVMGTAAAFAPAFPVYCLFRFLLAFAVAGVMMNTGTLLMEWTAARARPL VMTLNSLGFSFGHGLTAAVAYGVRDWTLLQLWSVPFFLCFLYSWWLAESARWLLTTG RLDWGLQELWRVAAINGKGAVQDTLTPΞVLLSAMRΞELSMGQPPASLGTLLRMPGLRF RTCISTLCWFAFGFTFFGLALDLQALGSNIFLLQMFIGWDIPAKMGALLLLSHLGRR PTLAASLLLAGLCILANTLVPHEMGALRSALAVLGLGGVGAAFTCITIYSSELFPTVL RMTAVGLGQMAARGGAILGPLVRLLGVHGPWLPLLVYGTVPVLSGLAALLLPETQSLP LPDTIQDVQNQAVKKATHGTLGNSVLKSTQF

Further analysis ofthe NOVl 9a protein yielded the following properties shown in Table 19B.

Table 19B. Protein Sequence Properties NOV19a

PSort 0.6000 probability located in plasma membrane; 0.4000 probability located in analysis: Golgi body; 0.3000 probability located in endoplasmic reticulum (membrane); 0.3000 probability located in microbody (peroxisome)

SignalP Cleavage site between residues 44 and 45 analysis:

A search ofthe NOVl 9a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 19C.

In a BLAST search of public sequence databases, the NOV19a protein was found to have homology to the proteins shown in the BLASTP data in Table 19D.

PFam analysis indicates that the NOVl 9a protein contains the domains shown in the Table 19E.

Example 20.

The NOV20 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 20A.

Table 20A. NOV20 Sequence Analysis

Further analysis ofthe NOV20a protein yielded the following properties shown in Table 20B.

Table 20B. Protein Sequence Properties NOV20a

PSort 0.6400 probability located in plasma membrane; 0.5000 probability located in analysis: microbody (peroxisome); 0.4600 probability located in Golgi body; 0.3700 probability located in endoplasmic reticulum (membrane)

SignalP Cleavage site between residues 41 and 42 analysis:

A search ofthe NOV20a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 20C.

In a BLAST search of public sequence databases, the NOV20a protein was found to have homology to the proteins shown in the BLASTP data in Table 20D.

PFam analysis indicates that the NOV20a protein contains the domains shown in the Table 20E.

Example 21.

The NOV21 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 21A.

Table 21A. NOV21 Sequence Analysis

SEQ ID NO: 89 793 bp

NOV21a, ACTTACTGCATTTGGTGCTGTGATCCAACTCATCTCCCCATCCCTGCAGAGAAACCTG CG59274-01 DNA TGACCATGAGGAGCAGCCTGACCATGGTGGGAACCCTCTGGGCCTTCCTGTCCCTTGT

TACTGCTGTGACCAGTTCTACCAGTTACTTCCTACCTTACTGGCTCTTTGGATCCCAG Sequence ATGGGGAAGCCAGTGTCATTCAGCACATTCCGGAGGTGCAACTACCCTGTGCGGGGAG AGGGACACAGTCTGATCATGGTGGAAGAATGTGGGCGCTATGCCAGCTTCAATGCCAT CCCAAGCCTGGCCTGGCAGATGTGCACAGTGGTGACAGGTGCCGGCTGTGCTCTGCTG CTCCTGGTGGCACTAGCTGCTGTCCTGGGTTGCTGCATGGAGGAGCTCATCTCCAGAA TGATGGGACGTTGCATGGGAGCAGCGCAGTTTGTTGGAGGGCTGCTGATAAGCTCAGG CTGTGCCTTATACCCTTTAGGATGGAATAGCCCGGAGATAATGCAAACATGTGGGAAT GTCTCCAATCAATTTCAGTTAGGTACCTGTCGGCTTGGCTGGGCCTATTACTGTGCTG GAGGTGGAGCAGCTGCAGCCATGTTGATCTGCACCTGGCTCTCTTGCTTTGCTGGAAG AAACCCCAAGCCTGTCATATTGGTGGAGAGCATCATGAGGAATACCAATTCTTATGCT ATGGAGCTTGACCATTGCCTCAAACCTTGAGCTTTGAAAGAAGATTGGAGAGGGTGGG

AAAGGGGAGGAGGGAGCCCTGAAAAGAGGTACTAAGGAT

ORF Start: ATG at 64 ORF Stop: TGA at 724

SEQ ID NO: 90 220 aa MW at 23776JkD

NOV21a, MRSSLTMVGTLWAFLSLVTAVTSSTSYFLPYWLFGSQMGKPVSFSTFRRCNYPVRGEG CG59274-01 HSLIMVEECGRYASFNAIPSLAWQMCTVVTGAGCALLLLVALAAVLGCCMEELISRMM GRC GAAQFVGGLLISSGCALYPLGWNSPEIMQTCGNVSNQFQLGTCRLGWAYYCAGG Protein Sequence GAAAAMLICTWLSCFAGRNPKPVILVESIMRNTNSYAMELDHCLKP

SEQ ID NO: 91 793 bp

NOV21b, ACTTACTGCATTTGGTGCTGTGATCCAACTCATCTCCCCATCCCTGCAGAGAAACCTG CG59274-02 DNA TGACCATGAGGAGCAGCCTGACCATGGTGGGAACCCTCTGGGCCTTCCTGTCCCTTGT

TACTGCTGTGACCAGTTCTACCAGTTACTTCCTACCTTACTGGCTCTTTGGATCCCAG Sequence ATGGGGAAGCCAGTGTCATTCAGCACATTCCGGAGGTGCAACTACCCTGTGCGGGGAG AGGGACACAGTCTGATCATGGTGGAAGAATGTGGGCGCTATGCCAGCTTCAATGCCAT CCCAAGCCTGGCCTGGCAGATGTGCACAGTGGTGACAGGTGCCGGCTGTGCTCTGCTG CTCCTGGTGGCACTAGCTGCTGTCCTGGGTTGCTGCATGGAGGAGCTCATCTCCAGAA TGATGGGACGTTGCATGGGAGCAGCGCAGTTCGTTGGAGGGCTGCTGATAAGCTCAGG CTGTGCCTTATACCCTTTAGGATGGAATAGCCCGGAGATAATGCAAACATGTGGGAAT GTCTCCAATCAATTTCAGTTAGGTACCTGTCGGCTTGGCTGGGCCTATTACTGTGCTG GAGGTGGAGCAGCTGCAGCCATGTTGATCTGCACCTGGCTCTCTTGCTTTGCTGGAAG AAACCCCAAGCCTGTCATATTGGTGGAGAGCATCATGAGGAATACCAATTCTTATGCT ATGGAGCTTGACCATTGCCTCAAACCTTGAGCTTTGAAAGAAGATTGGAGAGGGTGGG AAAGGGGAGGAGGGAGCCCTGAAAAGAGGTACTAAGGAT

Sequence comparison ofthe above protein sequences yields the following sequence relationships shown in Table 2 IB.

Table 21B. Comparison of NOV21a against NO 21b and NOV21c.

NOV21a Residues/

Protein Sequence Identities/ Match Residues Similarities for the Matched Region

NOV21b 1..220 181/220 (82%) 1..220 181/220 (82%)

Further analysis ofthe NOV2 la protein yielded the following properties shown in Table 21C.

Table 21C. Protein Sequence Properties NOV21a

SignalP Likely cleavage site between residues 21 and 22 analysis:

A search ofthe NOV21a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 2 ID.

In a BLAST search of public sequence databases, the NOV2 la protein was found to have homology to the proteins shown in the BLASTP data in Table 2 IE.

PFam analysis indicates that the NOV21a protein contains the domains shown in the Table 21F.

Table 21F. Domain Analysis of NOV21a

Identities/

Pfam Domain NOV21a Match Region Similarities Expect Value for the Matched Region

No Significant Matches Found

Example 22.

The NOV22 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 22A.

Further analysis ofthe NOV22a protein yielded the following properties shown in Table 22B.

Table 22B. Protein Sequence Properties NOV22a

PSort 0.3000 probability located in microbody (peroxisome); 0.3000 probability analysis: located in nucleus; 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen)

SignalP No Known Signal Sequence Indicated analysis:

A search ofthe NOV22a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 22C.

Table 22C. Geneseq Results for NOV22a

NOV22a Identities/

Geneseq Protein/Organism/Length Residues/ Similarities for j Expect Identifier [Patent #, Date] Match the Matched Value

Residues Region

No Significant Matches Found

In a BLAST search of public sequence databases, the NOV22a protein was found to have homology to the proteins shown in the BLASTP data in Table 22D.

Table 22D. Public BLASTP Results for NOV22a

NOV22a

Protein

Residues/ Identities/ Expect

Accession Protein/Organism/Length Similarities for the

Match Value

Number Residues Matched Portion

No Significant Matches Found PFam analysis indicates that the NOV22a protein contains the domains shown in the Table 22E.

Example 23.

The NOV23" clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 23A.

Table 23A. NOV23 Sequence Analysis

SEQ ID NO: 95 1916 bp

NOV23a, GCCGCTGCCGTCGCCCCTAGCCCCAGCAGCCCTGGTCTCGCAGCCTCCTGCGGCTCTG CG57734-01 DNA GTCGCCCGACCAGCCATGTCTCTCGGCGGAGCCTCCGAGCGCAGCGTCCCGGCCACCA Sequence AGATTGAAATTACCGTGTCCTGCCGGACCTTGATACCTTCTCCAAGTCCGACCCCAGT AGGCGGCTCCAGGACCGGGAGGGGGAACTTGGGGTCTGGGCGCGACTCAGGGGCGGGT GGAGTCGGGGCCAGGGGTGGGAGCCGACCTGACGTCCTTCCCTCCCCGCCCCCACCTG CAGTGGTGGTGCTTTACACGCAGAGCCGGGCCAGCCAGGAGTGGCGGGAGTTCGGACG GACCGAGGTGATTGATAACACGCTGAACCCAGACTTCGTGCGCAAATTCGTCCTCGAC TATTTCTTTGAGGAAAAGCAAAATCTGCGCTTCGATGTGTACAACGTGGACTCCAAAA CCAACATCTCCAAACCGAAGGATTTCCTGGGACAAGCGTTCCTGGCCCTGGGAGAGGT GATTGGAGGCCAGGGCAGCCGAGTAGAGCGAACCCTCACGGGTGTACCAGGCAAGAAG TGTGGGACCATATTGCTGACTGCAGAAGAGCTTAGCAATTGTCGGGACATTGCCACCA TGCAGCTGTGTGCAAACAAGCTGGACAAGAAGGACTTCTTTGGGAAATCAGACCCCTT CCTTGTGTTCTACAGGAGCAATGAGGATGGCACGTTCACCATCTGCCACAAGACAGAG GTTGTGAAAAACACGCTGAATCCTGTGTGGCAGCCCTTCAGCATCCCTGTGCGGGCTC TGTGCAATGGAGACTATGACAGAACGGTGAAGATTGATGTGTACGACTGGGACCGGGA TGGAAGCCACGATTTCATTGGTGAGTTCACCACCAGCTACCGGGAGCTGAGCAAGGCC CAGAACCAGTTCACAGTATATGAGGTGCTTAACCCTCGGAAGAAATGTAAGAAGAAGA AATATGTCAACTCAGGAACTGTGACGCTGCTCTCCTTCTCTGTGGACTCTGAATTCAC TTTTGTTGATTACATCAAGGGAGGGACACAGCTGAACTTCACAGTAGCCATTGACTTC ACGGCTTCCAATGGTAATCCTCTGCAGCCTACCTCCCTGCACTACATGAGTCCCTACC AGCTCAGCGCCTATGCCATGGCCCTCAAGGCAGTGGGAGAGATCATCCAGGACTATGA CAGTGATAAGCTCTTCCCAGCTTATGGCTTTGGGGCCAAGCTGCCCCCAGAGGGACGG ATCTCCCACCAGTTCCCCCTGAACAACAATGATGAGGACCCCAACTGTGCGGGCATCG AGGGTGTGCTGGAGAGCTATTTCCAGAGCCTGCGCACAGTGCAGCTCTATGGGCCCAC CTACTTTGCTCCTGTCATCAACCAAGTGGCCAGGGCTGCAGCCAAGATCTCTGATGGC TCCCAGTACTATGTTCTGCTCATCATCACTGATGGGGTCATCTCTGACATGACGCAGA CCAAGGAGGCCATCGTCAGCGCCTCCTCATTGCCCATGTCTATCATTATCGTCGGTGT AGGACCAGCCATGTTTGAGGCAATGGAAGAGTTGGACGGTGATGATGTGCGCGTGTCC TCTAGGGGACGCTACGCAGAGCGGGACATCGTTCAGTTCGTCCCATTCCGAGACTATG TTGACCGGTCGGGGAACCAGGTGTTGAGCATGGCCCGACTGGCCAAGGATGTGCTGGC CGAGATCCCGGAGCAGCTGCTGTCCTATATGCGCACCAGAGACATCCAGCCTCGGCCC CCACCCCCTGCCAACCCCAGCCCGATCCCAGCTCCAGAGCAGCCCTGAGGATTCCACA TATCCAATGCCTCACAGTCTGCAAGCCTGCTCACCCACTGCTTCTGCTTTAAGCCAGA

Sequence comparison ofthe above protein sequences yields the following sequence relationships shown in Table 23B.

Further analysis ofthe NOV23a protein yielded the following properties shown in Table 23C. Table 23C. Protein Sequence Properties NOV23a

PSort 0.8500 probability located in endoplasmic reticulum (membrane); 0.4400 analysis: probability located in plasma membrane; 0.3388 probability located in microbody (peroxisome); 0.3000 probability located in nucleus

SignalP No Known Signal Sequence Indicated analysis:

A search ofthe NOV23a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 23D.

In a BLAST search of public sequence databases, the NOV23a protein was found to have homology to the proteins shown in the BLASTP data in Table 23E.

Table 23E. Public BLASTP Results for NOV23a

Protein NOV23a Identities/

Expect

Accession Protein/Organism/Length Residues/ Similarities for Value

Number

PFam analysis indicates that the NOV23a protein contains the domains shown in the Table 23F.

Example 24.

The NOV24 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 24A.

Table 24A. NOV24 Sequence Analysis

SEQ ID NO: 101 1904 bp

NOV24a, TTTTTTTTTGACACTGTAAAAGAAGTTTATTTCTTGTTCACATAACTGTCCAAGGCTG CG59389-01 DNA GTGTTCCTGGGCAACTTCCAGTTCTCTTCCATGCAATGATTCAAGGACACAGAGTTCT

TCCATCCTGTGACTCTACCATCCCCTAGAGCCCTCTACTGTAAGAGTTACCTAAAGCA Sequence TCTGTGATGGTCCAGGAGGCTTCTCAGGTGATCGGGCAGTGTCAGTCTTCAGCCACTA

AGCCCAGAAGATCTGGGAAGAAGTCAATCAGAGAGCCTTGGGCCAGAGTTCCAGGGGC

TCTGGGAGTGGCTGCCAGGTGAGCTGGACAGTCTGATTTTCAGTGGGGTCCACACAGA

TGGGACGCGGCTTAGGAGGAATCCTGGGCTGCAGGCATTCCTTGGCCTGGTAGTCAGA

TTTCTGGCACTTGTAGCAAGCTCCTGGGGGAGAAGGTTCTGGAGTAACGCCTGGCCGC

TGCGGTTCAGGCATTTGGAAGTTCTTGTGTGCTGGAGATGTGGCTGGGGTTTGTCTCA

CAGTGGAGGTTACCTAACCAAACTCCTGTAAAACCACACCACCTATGCCTGTGATGGG

GACTATTTGAATCTACAGTGCCCTCGGCATTCTACGATAAGTGTCCAATCGGCATTTT

ATGGGCAAGATTACCAAATGTGTAGTTCCCAGAAGCCTGCCTCCCAGAGGGAAGACAG CTTAACCTGTGTGGCAGCCACCACCTTCCAGAAGGTGCTGGACGAATGCCAGAACCAG CGGGCCTGCCACCTCCTGGTCAATAGCCGTGTTTTTGGACCTGACCTTTGTCCAGGAA GCAGTAAATACCTCCTGGTCTCCTTTAAATGCCAACCTAATGAATTAAAAAACAAAAC CGTGTGTGAAGACCAGGAGCTGAAACTGCACTGCCATGAATCCAAGTTCCTCAACATC TACTCTGCGACCTACGGCAGGAGGACCCAGGAAAGGGACATCTGCTCCTCCAAGGCAG AGCGGCTCCCCCCTTTCGATTGCTTGTCTTACTCAGCTTTGCAAGTCCTATCCCGAAG GTGCTATGGGAAGCAGAGATGCAAAATCATCGTCAACAATCACCATTTTGGAAGCCCC TGTTTGCCAGGCATGAAAAAATACCTCACTGTGACCTACGCATGTGTTCCCAAGAACA TACTCACAGCGATTGATCCAGCCATTGCTAATCTAAAACCTTCTTTGAAGCAGAAAGA TGGTGAATATGGTATAAACTTTGACCCAAGCGGATCGAAGGTTCTGAGGAAAGATGGA ATTCTTGTTAGCAACTCTCTGGCAGCCTTTGCTTACATTAGAGCCCACCCGGAGAGAG CTGCCCTGCTGTTCGTGTCCAGTGTCTGCATCGGCCTGGCCCTCACACTGTGCGCCCT GGTCATCAGAGAGTCCTGTGCCAAGGACTTCCGCGACTTGCAGCTGGGGAGGGAGCAG CTGGTGCCAGGAAGTGACAAGGTCGAGGAGGACAGCGAGGATGAAGAAGAGGAGGAGG ACCCCTCTGAGTCTGATTTCCCAGGGGAACTGTCGGGGTTCTGTAGGACTTCATATCC TATATACAGTTCCATAGAAGCTGCAGAGCTCGCAGAAAGGATTGAGCGCAGGGAGCAA ATCATTCAGGAAATATGGATGAACAGTGGTTTGGACACCTCGCTCCCAAGAAACATGG GCCAGTTCTACTGAAAACCACATGCATCTTGATGCGATCGCACTTTCTGAAGAAGGAA

GGATCCCAAATGCCCCTCCAGTTCTGGTTCACCTGTACCTTCTATGAAGGAGAATTCG

TCATGTCATTCAACACTCGTGAGGCCAGGAAGCTATTAAAGGGATGTTTCAAGCTGTT

TCTAGCACATTCCAAAATAAATGAGGAGGGAAGAAAAAAAAAAAAAAA

ORF Start: ATG at 656 ORF Stop: TGA at 1694

SEQ ID NO: 102 346 aa MW at 38793.6kD

NOV24a, MCSSQKPASQREDSLTCVAATTFQKVLDECQNQRACHLLVNSRVFGPDLCPGSSKYLL CG59389-01 VSFKCQPNELKN TVCEDQELKLHCHESKFLNIYSATYGRRTQERDICSSKAERLPPF DCLSYSALQVLSRRCYGKQRCKIIVNNHHFGSPCLPGMKKYLTVTYACVPKNILTAID Protein Sequence PAIANLKPSLKQKDGEYGINFDPSGS VLRKDGILVSNSLAAFAYIRAHPERAALLFV SSVCIGLALTLCALVIRESCAKDFRDLQLGREQLVPGSDKVEEDSEDEEEEEDPSΞSD FPGELSGFCRTSYPIYSSIEAAELAERIERREQIIQEIWMNSGLDTSLPRNMGQFY

SEQ ID NO: 103 1802 bp

NOV24b, TTTTTTTTTGACACTGTAAAAGAAGTTTATTTCTTGTTCACATAACTGTCCAAGGCTG CG59389-02 DNA GTGTTCCTGGGCAACTTCCAGTTCTCTTCCATGCAATGATTCAAGGACACAGAGTTCT Sequence TCCATCCTGTGACTCTACCATCCCCTAGAGCCCTCTACTGTAAGAGTTACCTAAAGCA

TCTGTGATGGTCCAGGAGGCTTCTCAGGTGATCGGGCAGTGTCAGTCTTCAGCCACTA

AGCCCAGAAGATCTGGGAAGAAGTCAATCAGAGAGCCTTGGGCCAGAGTTCCAGGGGC

TCTGGGAGTGGCTGCCAGGTGAGCTGGACAGTCTGATTTTCAGTGGGGTCCACACAGA

TGGGACGCGGCTTAGGAGGAATCCTGGGCTGCAGGCATTCCTTGGCCTGGTAGTCAGA

TTTCTGGCACTTGTAGCAAGCTCCTGGGGGAGAAGGTTCTGGAGTAACGCCTGGCCGC

TGCGGTTCAGGCATTTGGAAGTTCTTGTGTGCTGGAGATGTGGCTGGGGTTTGTCTCA

CAGTGGAGGTTACCTAACCAAACTCCTGTAAAACCACACCACCTATGCCTGTGATGGG

GACTATTTGAATCTACAGTGCCCTCGGCATTCTACGATAAGTGTCCAATCGGCATTTT

ATGGGCAAGATTACCAAATGTGTAGTTCCCAGAAGCCTGCCTCCCAGAGGGAAGACAG

CTTAACCTGTGTGGCAGCCACCACCTTCCAGAAGGTGCTGGACGAATGCCAGAACCAG CGGGCCTGCCACCTCCTGGTCAATAGCCGTGTTTTTGGACCTGACCTTTGTCCAGGAA GCAGTAAATACCTCCTGGTCTCCTTTAAATGCCAACCTAATGAATTAAAAAACAAAAC CGTGTGTGAAGACCAGGAGCTGAAACTGCACTGCCATGAATCCAAGTTCCTCAACATC TACTCTGCGACCTACGGCAGGAGGACCCAGGAAAGGGACATCTGCTCCTCCAAGGCAG AGCGGCTCCCCCCTTTCGATTGCTTGTCTTACTCAGCTTTGCAAGTCCTATCCCGAAG GTGCTATGGGAAGCAGAGATGCAAAATCATCGTCAACAATCACCATTTTGGAAGCCCC TGTTTGCCAGGCGTGAAAAAATACCTCACTGTGACCTACGCATGTGGTATAAACTTCG ACCCAAGCGGATCGAAGGTTCTGAGGAAAGATGGAATTCTTGTTAGCAACTCTCTGGC AGCCTTTGCTTACATTAGAGCCCACCCGGAGAGAGCTGCCCTGCTGTTCGTGTCCAGT GTCTGCATCGGCCTGGCCCTCACACTGTGCGCCCTGGTCATCAGAGAGTCCTGTGCCA AGGACTTCCGCGACTTGCAGCTGGGGAGGGAGCAGCTGGTGCCAGGAAGTGACAAGGT CGAGGAGGACAGCGAGGATGAAGAAGAGGAGGAGGACCCCTCTGAGTCTGATTTCCCA GGGGAACTGTCGGGGTTCTGTAGGACTTCATATCCTATATACAGTTCCATAGAAGCTG CAGAGCTCGCAGAAAGGATTGAGCGCAGGGAGCAAATCATTCAGGAAATATGGATGAA CAGTGGTTTGGACACCTCGCTCCCAAGAAACATGGGCCAGTTCTACTGAAAACCACAT GCATCTTGATGCGATCGCACTTTCTGAAGAAGGAAGGATCCCAAATGCCCCTCCAGTT CTGGTTCACCTGTACCTTCTATGAAGGAGAATTCGTCATGTCATTCAACACTCGTGAG

Sequence comparison ofthe above protein sequences yields the following sequence relationships shown in Table 24B.

Further analysis ofthe NOV24a protein yielded the following properties shown in Table 24C.

Table 24C. Protein Sequence Properties NOV24a

PSort 0.7419 probability located in mitochondrial inner membrane; 0.4400 probability analysis: located in plasma membrane; 0.2000 probability located in endoplasmic reticulum (membrane); 0.1072 probability located in mitochondrial matrix space

SignalP No Known Signal Sequence Indicated analysis:

A search ofthe NOV24a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 24D.

In a BLAST search of public sequence databases, the NOV24a protein was found to have homology to the proteins shown in the BLASTP data in Table 24E.

PFam analysis indicates that the NOV24a protein contains the domains shown in the Table 24F.

Example 25.

The NOV25 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 25A.

GTTTACCTTGGTGCAGAGGAGCAATGGGGAGTGTAAAGAGGCACTAGCAAAGTCCGAG ATGAATGTGAATATGAAGTATCAGCTTCCCAACTTCACCGCGGAAACACCCATCCAGA ATGTCATTCTACATGAGCATCACATTTTCCTTGGTGCCACTAACTACATTTATGTTTT AAATGAGGAAGACCTTCAGAAGGTTGCTGAGTACAAGACTGGGCCTGTGCTGGAACAC CCAGATTGTTTCCCATGTCAGGACTGCAGCAGCAAAGCCAATTTATCAGGAGGTGTTT GGAAAGATAACATCAACATGGCTCTAGTTGTCGACACCTACTATGATGATCAACTCAT TAGCTGTGGCAGCGTCAACAGAGGGACCTGCCAGCGACATGTCTTTCCCCACAATCAT ACTGCTGACATACAGTCGGAGGTTCACTGCATATTCTCCCCACAGATAGAAGAGCCCA GCCAGTGTCCTGACTGTGTGGTGAGCGCCCTGGGAGCCAAAGTCCTTTCATCTGTAAA GGACCGGTTCATCAACTTCTTTGTAGGCAATACCATAAATTCTTCTTATTTCCCAGAT CATCCATTGCATTCGATATCAGTGAGAAGGCTAAAGGAAACGAAAGATGGTTTTATGT TTTTGACGGACCAGTCCTACATTGATGTTTTACCTGAGTTCAGAGATTCTTACCCCAT TAAGTATGTCCATGCCTTTGAAAGCAACAATTTTATTTACTTCTTGACGGTCCAAAGG GAAACTCTAGATGCTCAGACTTTTCACACAAGAATAATCAGGTTCTGTTCCATAAACT CTGGATTGCATTCCTACATGGAAATGCCTCTGGAGTGTATTCTCACAGAAAAGAGAAA AAAGAGATCCACAAAGAAGGAAGTGTTTAATATACTTCAGGCTGCGTATGTCAGCAAG CCTGGGGCCCAGCTTGCTAGACAAATAGGAGCCAGCCTGAATGATGACATTCTTTTCG GGGTGTTCGCACAAAGCAAGCCAGATTCTGCCGAACCAATGGATCGATCTGCCATGTG TGCATTCCCTATCAAATATGTCAACGACTTCTTCAACAAGATCGTCAACAAAAACAAT GTGAGATGTCTCCAGCATTTTTACGGACCCAATCATGAGCACTGCTTTAATAGGACAC TTCTGAGAAATTCATCAGGCTGTGAAGCGCGCCGTGATGAATATCGAACAGAGTTTAC CACAGCTTTGCAGCGCGTTGACTTATTCATGGGTCAATTCAGCGAAGTCCTCTTAACA TCTATATCCACCTTCATTAAAGGAGACCTCACCATAGCTAATCTTGGGACATCAGAGG GTCGCTTCATGCAGGTTGTGGTTTCTCGATCAGGACCATCAACCCCTCATGTGAATTT TCTCCTGGACTCCCATCCAGTGTCTCCAGAAGTGATTGTGGAGCATACATTAAACCAA AATGGCTACACACTGGTTATCACTGGGAAGAAGATCACGAAGATCCCATTGAATGGCT TGGGCTGCAGACATTTCCAGTCCTGCAGTCAATGCCTCTCTGCCCCACCCTTTGTTCA GTGTGGCTGGTGCCACGACAAATGTGTGCGATCGGAGGAATGCCTGAGCGGGACATGG ACTCAACAGATCTGTCTGCCTGCAATCTACAAGGTTTTCCCAAATAGTGCACCCCTTG AAGGAGGGACAAGGCTGACCATATGTGGCTGGGACTTTGGATTTCGGAGGAATAATAA ATTTGATTTAAAGAAAACTAGAGTTCTCCTTGGAAATGAGAGCTGCACCTTGACTTTA AGTGAGAGCACGATGAATACATTGAAATGCACAGTTGGTCCTGCCATGAATAAGCATT TCAATATGTCCATAATTATTTCAAATGGCCACGGGACAACACAATACAGTACATTCTC CTATGTGGATCCTGTAATAACAAGTATTTCGCCGAAATACGGTCCTATGGCTGGTGGC ACTTTACTTACTTTAACTGGAAATTACCTAAACAGTGGGAATTCTAGACACATTTCAA TTGGTGGAAAAACATGTACTTTAAAAAGTGTGTCAAACAGTATTCTTGAATGTTATAC CCCAGCCCAAACCATTTCAACTGAGTTTGCTGTTAAATTGAAAATTGACTTAGCCAAC CGAGAGACAAGCATCTTCAGTTACCGTGAAGATCCCATTGTCTATGAAATTCATCCAA CCAAATCTTTTATTAGTACTTGGTGGAAAGAACCTCTCAACATTGTCAGTTTTCTATT TTGCTTTGCCAGTGGTGGGAGCACAATAACAGGTGTTGGGAAAAACCTGAATTCAGTT AGTGTCCCGAGAATGGTCATAAATGTGCATGAAGCAGGAAGGAACTTTACAGTGGCAT GTCAACATCGCTCTAATTCAGAGATAATCTGTTGTACCACTCCTTCCCTGCAACAGCT GAATCTGCAACTCCCCCTGAAAACCAAAGCCTTTTTCATGTTAGATGGGATCCTTTCC AAATACTTTGATCTCATTTATGTACATAATCCTGTGTTTAAGCCTTTTGAAAAGCCAG TGATGATCTCAATGGGCAATGAAAATGTACTGGAAATTAAGGGAAATGATATTGACCC TGAAGCAGTTAAAGGTGAAGTGTTAAAAGTTGGAAATAAGAGCTGTGAGAATATACAC TTACATTCTGAAGCCGTTTTATGCACGGTCCCCAATGACCTGCTGAAATTGAACAGCG AGCTAAATATAGAGTGGAAGCAAGCAATTTCTTCAACCGTCCTTGGAAAAGTAATAGT TCAACCAGATCAGAATTTCACAGGATTGATTGCTGGTGTTGTCTCAATATCAACAGCA CTGTTATTACTACTTGGGTTTTTCCTGTGGCTGAAAAAGAGAAAGCAAATTAAAGATC TGGGCAGTGAATTAGTTCGCTACGATGCAAGAGTACACACTCCTCATTTGGATAGGCT TGTAAGTGCCCGAAGTGTAAGCCCAACTACAGAAATGGTTTCAAATGAATCTGTAGAC TACCGAGCTACTTTTCCAGAAGATCAGTTTCCTAATTCATCTCAGAACGGTTCATGCC GACAAGTGCAGTATCCTCTGACAGACATGTCCCCCATCCTAACTAGTGGGGACTCTGA TATATCCAGTCCATTACTGCAAAATACTGTCCACATTGACCTCAGTGCTCTAAATCCA GAGCTGGTCCAGGCAGTGCAGCATGTAGTGATTGGGCCCAGTAGCCTGATTGTGCATT TCAATGAAGTCATAGGAAGAGGGCATTTTGGTTGTGTATATCATGGGACTTTGTTGGA CAATGATGGCAAGAAAATTCACTGTGCTGTGAAATCCTTGAACAGAATCACTGACATA GGAGAAGTTTCCCAATTTCTGACCGAGGGAATCATCATGAAAGATTTTAGTCATCCCA ATGTCCTCTCGCTCCTGGGAATCTGCCTGCGAAGTGAAGGGTCTCCGCTGGTGGTCCT ACCATACATGAAACATGGAGATCTTCGAAATTTCATTCGAAATGAGACTCATAATCCA

Further analysis ofthe NOV25a protein yielded the following properties shown in Table 25B.

Table 25B. Protein Sequence Properties NOV25a

PSort 0.4600 probability located in plasma membrane; 0.1226 probability located in analysis: microbody (peroxisome); 0.1000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 25 and 26 analysis:

A search ofthe NOV25a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 25C.

In a BLAST search of public sequence databases, the NOV25a protein was found to have homology to the proteins shown in the BLASTP data in Table 25D.

PFam analysis indicates that the NOV25a protein contains the domains shown in the Table 25E.

Example 26.

The NOV26 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 26A.

Table 26A. NOV26 Sequence Analysis

SEQ ID NO: 119 2317 bp

NOV26a, AAAACTCCAGGAGGCGGAGGAGGCTAGTGGCAGTACCTGGGCACCCTGACCCTCCCCA CG93443-01 DNA CAGGCCAGAGCCCACCCTCCTGCTCATGAGGGCAGACAGGCCTTTCCAGGGACACAGT

CCCTCTTCTCCCCAGGACCCCAGGGCCAACTCCCCCTGCCGGCCCTCTGCCATCAAAT Sequence TGGCAGTGGCTCCAGGGGAGTCCCCTGGGGATGGGGGACCACTGTTGGGGACCCCTCT GCGTGCACCCCTGTAGTTGGGGAAGCAGGACAGGGGCCTGGGGAGACGGAAGGGCGCC AGGGGTTGAGAGAGGATGGTGGACGTTGTTGGACTTGAAAGGGAAACAGGCCCTCGGG GAAGCCCCTGGCCAGGCCTGCCTCTCCCCTCCCTGGTGGGCCCAGCGCCCCTGCTCAC TTGTCTCTGCCCACAGTGCCTGTCTGTGGAGGACGCCCTGGGCCTGGGCGAGCCTGAG GGGTCAGGGCTGCCCCCGGGCCCGGTCCTGGAGGCCAGGTACGTCGCCCGCCTCAGTG CCGCCGCCGTCCTGTACCTCAGCAACCCCGAGGGCACCTGTGAGGACGCTCGGGCTGG CCTCTGGGCCTCTCATGCAGACCACCTCCTGGCCCTGCTCGAGAGCCCCAAGGCCCTG ACCCCGGGCCTGAGCTGGCTGCTGCAGAGGATGCAGGCCCGGGCTGCCGGCCAGACCC CCAAGACGGCCTGCGTAGATATCCCTCAGCTGCTGGAGGAGGCGGTGGGGGCGGGGGC TCCGGGCAGTGCTGGCGGCGTCCTGGCTGCCCTGCTGGACCATGTCAGGAGCGGGTCT TGCTTCCACGCCTTGCCGAGCCCTCAGTACTTCGTGGACTTTGTGTTCCAGCAGCACA GCAGCGAGGTCCCTATGACGCTGGCCGAGCTGTCAGCCTTGATGCAGCGCCTGGGGGT GGGCAGGGAGGCCCACAGTGACCACAGTCATCGGCACAGGGGAGCCAGCAGCCGGGAC CCTGTGCCCCTCATCAGCTCCAGCAACAGCTCCAGTGTGTGGGACACGGTATGCCTGA GTGCCAGGGACGTGATGGCTGCATATGGACTGTCGGAACAGGCTGGGGTGACCCCGGA GGCCTGGGCCCAACTGAGCCCTGCCCTGCTCCAACAGCAGCTGAGTGGAGCCTACACC TCCCAGTCCAGGCCCCCCGTCCAGGACCAGCTCAGCCAGTCAGAGAGATATCTGTACG GCTCCCTGGCCACGCTGCTCATCTGCCTCTGCGCGGTCTTTGGCCTCCTGCTGCTGAC CTGCACTGGCTGCAGGGGGGTCGCCCACTACATCCTGCAGACCTTCCTGAGCCTGGCA GTGGGTGCACTCACTGGGGACGCTGTCCTGCATCTGACGCCCAAGGTGCTGGGGCTGC ATACACACAGCGAAGAGGGCCTCAGCCCACAGCCCACCTGGCGCCTCCTGGCTATGCT GGCCGGGCTCTACGCCTTCTTCCTGTTTGAGAACCTCTTCAATCTCCTGCTGCCCAGG GACCCGGAGGACCTGGAGGACGGGCCCTGCGGCCACAGCAGCCATAGCCACGGGGGCC ACAGCCACGGTGTGTCCCTGCAGCTGGCACCCAGCGAGCTCCGGCAGCCCAAGCCCCC CCACGAGGGCTCCCGCGCAGACCTGGTGGCGGAGGAGAGCCCGGAGCTGCTGAACCCT GAGCCCAGGAGACTGAGCCCAGAGTTGAGGCTACTGCCCTATATGATCACTCTGGGCG ACGCCGTGCACAACTTCGCCGACGGGCTGGCCGTGGGCGCCGCCTTCGCGTCCTCCTG GAAGACCGGGCTGGCCACCTCGCTGGCCGTGTTCTGCCACGAGTTGCCACACGAGCTG GGGGACTTCGCCGCCTTGCTGCACGCGGGGCTGTCCGTGCGCCAAGCACTGCTGCTGA ACCTGGCCTCCGCGCTCACGGCCTTCGCTGGTCTTACGTGGCACTCGCGGTTGGAGTC AGCGAGGAGAGCGAGGCCTGGATCCTGGCAGTGGCCACCGGCCTGTTCCTTACGTAGC ACTCTGCGACATGCTCCCGGCGATGTTGAAAGTACGGGACCCGCGGCCCCTGGCTCCT CTTCCTGCTGCACAACGTGGGCCTGCTGGGCGGCTGGACCGTCCTGCTGCTGCTGTCC CTGTACGAGGATGACATCACCTTCTGATACCCTGCCCTAGTCCCCCACCTTTGACTTA

AGATCCCACACCTCACAAACCTACAGCCCAGAAACCCAGAAGCCCCTATAGAGGCCCC

AGTCCCAACTCCAGTAAAGACACTCTTGTCCCTTGGAAAAAAAAAAAAAAAAAAA

ORF Start: ATG at 306 ORF Stop: TAG at 2184

SEQ ID NO: 120 626 aa MW at 66248.5kD

NOV26a, MVDWGLERETGPRGSPWPGLPLPSLVGPAPLLTCLCPQCLSVEDALGLGEPEGSGLP CG93443-01 PGPVLEARYVARLSAAAVLYLSNPEGTCEDARAGLWASHADHLLALLESPKALTPGLS WLLQRMQARAAGQTPKTACVDIPQLLEEAVGAGAPGSAGGVLAALLDHVRSGSCFHAL Protein Sequence PSPQYFVDFVFQQHSSEVPMTLAELSALMQRLGVGREAHSDHSHRHRGASSRDPVPLI SSSNSSSVWDTVCLSARDVMAAYGLSEQAGVTPEAWAQLSPALLQQQLSGAYTSQSRP PVQDQLSQSERYLYGSLATLLICLCAVFGLLLLTCTGCRGVAHYILQTFLSLAVGALT GDAVLHLTPKVLGLHTHSEEGLSPQPTWRLLAMLAGLYAFFLFENLFNLLLPRDPEDL EDGPCGHSSHSHGGHSHGVSLQLAPSELRQPKPPHEGSRADLVAEESPELLNPEPRRL SPELRLLPYMITLGDAVHNFADGLAVGAAFASSWKTGLATSLAVFCHELPHELGDFAA LLHAGLSVRQALLLNLASALTAFAGLTWHSRLESARRARPGSWQWPPACSLRSTLRHA PGDVESTGPAAPGSSSCCTTWACWAAGPSCCCCPCTRMTSPSDTLP

Further analysis ofthe NOV26a protein yielded the following properties shown in Table 26B.

Table 26B. Protein Sequence Properties NOV26a

PSort 0.7000 probability located in plasma membrane; 0.3048 probability located in analysis: microbody (peroxisome); 0.2000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in mitochondrial inner membrane

Cleavage site between residues 43 and 44 analysis:

A search ofthe NOV26a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 26C.

In a BLAST search of public sequence databases, the NOV26a protein was found to have homology to the proteins shown in the BLASTP data in Table 26D.

PFam analysis indicates that the NOV26a protein contains the domains shown in the Table 26E.

Example 27.

The NOV27 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 27A.

Table 27A. NOV27 Sequence Analysis

SEQ ID NO: 121 2852 bp

NOV27a, GTGTGCAGTAAACTGGAATGCTCTCCCTCGCTCACTCCTCAGTGTAGGAGTGATCTGA

CG50838-01 DNA AGCAGGACAAGCTCAGCCTGCAGCTGCCGTGGGCTTTGTGTGGACTGGACGCAGAGCT

TGGGAGACGGGGGAGGGCTATTACTCCAATTCACTGTCAATGGAATTACAGCTATAGC Sequence GGCAGTGTATATAGGATTGCTTTTTCTCGTCTTCCTGGAGATGCTCAGTCCCAGTATA

TTTTAAGGAAGAGAAATATAAAGGAAATTTAGTATGCCTCCTTTTCTTTAAATGAAGA

ATTTAGTTTCCTTTACTTCTTAAAAGAGAATACCTGTTCTTGTATAACGTGACTGCAC

CAGACATTCTGAAAAATCAGCAAGAAGCAAAAGCTGGAAATAGCTATTTCACAGCAGG

GTTCTGAAGTAACGGAAGCTACCTTGTATAAAGACCTCAACACTGCTGACCATGATCA

GCGCAGCCTGGAGCATCTTCCTCATCGGGACTAAAATTGGGCTGTTCCTTCAAGTAGC ACCTCTATCAGTTATGGCTAAATCCTGTCCATCTGTGTGTCGCTGCGATGCGGGTTTC ATTTACTGTAATGATCGCTTTCTGACATCCATTCCAACAGGAATACCAGAGGATGCTA CAACTCTCTACCTTCAGAACAACCAAATAAATAATGCTGGGATTCCTTCAGATTTGAA AAACTTGCTGAAAGTAGAAAGAATATACCTATACCACAACAGTTTAGATGAATTTCCT ACCAACCTCCCAAAGTATGTAAAAGAGTTACATTTGCAAGAAAATAACATAAGGACTA TCACTTATGATTCACTTTCAAAAATTCCCTATCTGGAAGAATTACATTTAGATGACAA CTCTGTCTCTGCAGTTAGCATAGAAGAGGGAGCATTCCGAGACAGCAACTATCTCCGA CTGCTTTTCCTGTCCCGTAATCACCTTAGCACAATTCCCTGGGGTTTGCCCAGGACTA TAGAAGAACTACGCTTGGATGATAATCGCATATCCACTATTTCATCACCATCTCTTCA AGGTCTCACTAGTCTAAAACGCCTGGTTCTAGATGGAAACCTGTTGAACAATCATGGT TTAGGTGACAAAGTTTTCTTCAACCTAGTTAATTTGACAGAGCTGTCCCTGGTGCGGA ATTCCCTGACTGCTGCACCAGTAAACCTTCCAGGCACAAACCTGAGGAAGCTTTATCT TCAAGATAACCACATCAATCGGGTGCCCCCAAATGCTTTTTCTTATCTAAGGCAGCTC TATCGACTGGATATGTCCAATAATAACCTAAGTAATTTACCTCAGGGTATCTTTGATG ATTTGGACAATATAACACAACTGATTCTTCGCAACAATCCCTGGTATTGCGGGTGCAA GATGAAATGGGTACGTGACTGGTTACAATCACTACCTGTGAAGGTCAACGTGCGTGGG CTCATGTGCCAAGCCCCAGAAAAGGTTCGTGGGATGGCTATTAAGGATCTCAATGCAG AACTGTTTGATTGTAAGGACAGTGGGATTGTAAGCACCATTCAGATAACCACTGCAAT ACCCAACACAGTGTATCCTGCCCAAGGACAGTGGCCAGCTCCAGTGACCAAACAGCCA GATATTAAGAACCCCAAGCTCACTAAGGATCAACAAACCACAGGGAGTCCCTCAAGAA AAACAATTACAATTACTGTGAAGTCTGTCACCTCTGATACCATTCATATCTCTTGGAA ACTTGCTCTACCTATGACTGCTTTGAGACTCAGCTGGCTTAAACTGGGCCATAGCCCG GCATTTGGATCTATAACAGAAACAATTGTAACAGGGGAACGCAGTGAGTACTTGGTCA CAGCCCTGGAGCCTGATTCACCCTATAAAGTATGCATGGTTCCCATGGAAACCAGCAA CCTCTACCTATTTGATGAAACTCCTGTTTGTATTGAGACTGAAACTGCACCCCTTCGA ATGTACAACCCTACAACCACCCTCAATCGAGAGCAAGAGAAAGAACCTTACAAAAACC CCAATTTACCTTTGGCTGCCATCATTGGTGGGGCTGTGGCCCTGGTTACCATTGCCCT TCTTGCTTTAGTGTGTTGGTATGTTCATAGGAATGGATCGCTCTTCTCAAGGAACTGT GCATATAGCAAAGGGAGGAGAAGAAAGGATGACTATGCAGAAGCTGGCACTAAGAAGG ACAACTCTATCCTGGAAATCAGGGAAACTTCTTTTCAGATGTTACCAATAAGCAATGA ACCCATCTCGAAGGAGGAGTTTGTAATACACACCATATTTCCTCCTAATGGAATGAAT CTGTACAAAAACAATCACAGTGAAAGCAGTAGTAACCGAAGCTACAGAGACAGTGGTA TTCCAGACTCAGATCACTCACACTCATGATGCTGAAGGACTCACAGCAGACTTGTGTT

TTGGGTTTTTTAAACCTAAGGGAGGTGATGGTAGGAACCCTGTTCTACTGCAAAACAC

TGGAAAAAGAGACTGAAAAAAAGCAATGTACTGTACATTTGCCATATAATTTATATTT

AAGAACTTTTTATTAAAAGTTTCAAATTTCAGGTTACTGCTGCGATTGATGTAGTGGA

GATGCCTGAACACAATTCTATATTTTAGTATTTTTTAGTAATTTGTACTGTATTTTCC

TTGCAAATATTGGAGTTATAAACCATTTACTTTGTGTTCTACTGAGTAAGATGACTTG

TTGACTGTGAAAGTGAATTTTCTTGCTGTGTCGAACAATCAGGACTGCATTCATATGA

GATCCTTGTAGTATAAGCACAGGCCATTTTTCACTTTGGTATTAATAAAATGTAAAAA

AAAAATTGGT

ORF Start: ATG at 458 ORF Stop: TGA at 2405

SEQ ID NO: 122 649 aa MW at 72993.5kD

NOV27a, MISAAWSIFLIGTKIGLFLQVAPLSVMAKSCPSVCRCDAGFIYCNDRFLTSIPTGIPE CG50838-01 DATTLYLQNNQINNAGIPSDL NLLKVERIYLYHNSLDEFPTNLPKYVKELHLQENNI RTITYDSLSKIPYLEELHLDDNSVSAVSIEEGAFRDSNYLRLLFLSRNHLSTIPWGLP Protein Sequence RTIEELRLDDNRISTISSPSLQGLTSLKRLVLDGNLLNNHGLGDKVFFNLVNLTELSL VRNSLTAAPVNLPGTNLRKLYLQDNHINRVPPNAFSYLRQLYRLDMSNNNLSNLPQGI FDDLDNITQLILRNNPWYCGCKMKWVRDWLQSLPVKVNVRGLMCQAPEKVRGMAIKDL NAELFDCKDSGIVSTIQITTAIPNTVYPAQGQWPAPVTKQPDIKNPKLTKDQQTTGSP SRKTITITVKSVTSDTIHISWKLALPMTALRLSWLKLGHSPAFGSITETIVTGERSEY LVTALEPDSPYKVCMVPMETSNLYLFDETPVCIETETAPLRMYNPTTTLNREQEKEPY KNPNLPLAAIIGGAVALVTIALLALVCWYVHRNGSLFSRNCAYSKGRRRKDDYAEAGT KKDNSILEIRETSFQMLPISNEPISKEEFVIHTIFPPNGMNLYKNNHSESSSNRSYRD SGIPDSDHSHS

Further analysis ofthe NON27a protein yielded the following properties shown in Table 27B.

Table 27B. Protein Sequence Properties ΝOV27a

PSort 0.6976 probability located in plasma membrane; 0.6400 probability located in analysis: endoplasmic reticulum (membrane); 0.1900 probability located in Golgi body; 0.1000 probability located in endoplasmic reticulum (lumen)

A search ofthe NOV27a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 27C.

In a BLAST search of public sequence databases, the NOV27a protein was found to have homology to the proteins shown in the BLASTP data in Table 27D.

PFam analysis indicates that the NOV27a protein contains the domains shown in the Table 27E.

Example 28.

The NOV28 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 28A.

Table 28A. NOV28 Sequence Analysis

SEQ ID NO: 123 3373 bp

NOV28a, TTGATTGTCCAAGCCACAGATAAAGGGATGCCCAGGCTTTCTAATACGACTGTAATCA CG58567-01 DNA AGGTACAGGTGACTGATATAAATGACAATGCCCCAGCTTTTCTCCCCTCTGAAGCAGT Sequence GGAAATTACAGAAGTCATGACTATTTCAGAAGATTCTTTGCCTGGTGTAATTGTGACT CATGTGTCAGTTCATGATGTGGATTTGAATTCAGCTTTCATATTCAGTTTTGCCAAAG AGAGTAATCCTGGAACCAAGTTTGCTATTGATCAGAACACTGGAGTGGTGGTGTTGGT GAAAACATTGGATTTTGAAGAAATGACTGAATATGAGCTGCTCATCCAAATTTCTGAT TCAGTGCACTACACAGAGGGAGCACTTGTAGTCCGTGTGCTGGATGTCAATGATAATC CACCAGTGTTTTCTCAAGATTTCTATCAGGTCACAGTTCCTGAATCAATACCTGTGGG GTATTCAGTGCTGACTCTGTCAGCCACAGACTTAGAAAGCAATGAGAACATTTCTTAC AGAATTCTATCCTCTTCTAAGGAATTCTCCATTGATCCTAAGAATGGCACAATATTTA CTATCAGTCCCGTATTACTTCTGGATACAATATCAACAACTCGATTTCTTGTGGAAGC CAGTGATGGTGGAAATCCTGACCCGAGAGCTCTTACTTTAGTGGAGATAGGAATAGAA GATATGAACAATTATGCCCCTGAATTCACAGTCAAATCCTATAATCTTAGCCTAAGTG AGGATGCTCTGGTTGGAAGCACGCTTGTTACATTTTCAAACATCGACCATGACTGGAC CCGTGAAAACACATATGTTGAATATTCCATCATCAGTGGTAATTCACAGAACAATTTT CATGTGGAAACTAAGTTCTTTCATTCAGAATATCCTTATAAGCAAGTCGGTTATCTTG TGTTGCTTCACAGTCTGGACAGAGAAGCAAGTGCTAGCCATGAGCTTGTCATTCTGGC ATCTGACAGTGGCTGCCCTCCATTGAGTTCCACAGCTGTCATATCAATACAAGTACTT GATGTCAATGACAATCCCCCAAACTTCAGCAGCCTGAGCTATCACACCCATGTCAAGG AAAGCACCCCTCTAGGGAGTCACATCACTGTGGTCTCAGCAAATGACCGTGACACAGG GTCACATGCAGAAATCATCTACAACATCATCTCTGGAAATGAGAAGGGACATTTTTAC TTAGAAGAAAACACTGGAGTTCTTTATTTGATTAAACCTCTGGATTATGAAAAAATGA CAAAATTCACCTTAACTGTCCAAGCTTCAGATGCAGAAAAGAAACATTTTTCTTTTGC AGTTGTGTTTGTCAGTGTCCTGGATGATAACGACCATGCACCTCAGTTTATGTTCTCA AGCTTCAGCTGTATTGTTCCAGAAAATCTGCCTATTTCCTCTACCATATGCTCTATAA ATGCTCTGGATTTTGATGCTGGTCCGTATGGAGAATTGACCTATTCTATTGTATCACC CTGTTTTCTCACTCATGGAATGTCTTATGATCATGATCTCTTCCTCATTGACCCTTTG ACAGGGGATATTCATGCTAAGCAAATCCTTGACTATGAAAATGGCAATAAATACTGCC TCACAGTCCAAGCCAAAGACAAAGGTGATGCAACTGCCTCCTTAGTGGTCTGGGTGGA TATTGAAGGGATAGATGAATTTGAGCCCATTTTCACTCAAGATCAGTATTTTTTCACC CTCCCAGAAAAGAATAAAGACAGACAGTTGATTGGCAGAGTGGAAGCCTCAGATGCAG ATGCTGGTATTGATGGAGTCATTCTTTACTCCCTTGGAACCTCATCTCCTTTCTTTTC AGTAAATAGAACCAATGGAAATATTTATTTGATTAGAGCCCTTCCCCTAATAAAAAGT CAACTCAACAAAGAAGACACCTTGGAAATGAAAATAATCGCTCATAGTCCCAAATCAG ATTCCAAGTTTGCATCTTGCACTGTTTTTGTGAATGTGTCTTTCTCCTCTGAAGGAAC ACCCTTGGCAGTGTTCGCCAGCAGCTTTTCAATCAGCCTGGTGGTCTCCTTTTTAGTG TTTCTGATACTCATCTGCATTCTAATTGTAATGATTTTAAGACATAAACAAAAAGACA CAATAAACAATTATGAGGAGAAGAAAACCTCATCTTTAGATGCGGACTTGAGAGTGAC CCGGGATGCCAGTGTGCTCAAAGCCTTCCAGAAAACTGACGACTGCAGTAACGAGGTG GTCCCTGTGGATGCCACTCCGGAATGGTTGAGTTTAATAAGTATCATGGAGAAGGATA TTGTCAATCTGTACAGATACTCAAACTCCAGTGGCCACTGTTCTGTGGAAGGAGAAAC TCAGTTACTGACATCAATGATAACAGGCCCTTCTTCCCCCAGTGTCTCCCTGGAAAGG AGTTACACGTGAAGGTTCTGGAAGGTCAACCAGTAAATATGTTGGTTACAACTGTGTT TGCAAAGGATCCTGATGAAGGAAATAATGCAGAAGTTACATACTCAGTATCTTCAGAA GATAGTTCTGATCACTTTAAGATTGACGCCAACAATGGTGAAATAAGAACAACCACAA TACTTTCGTATGATTATAGACCTTCCTACAGAATGAGTGTCATTGCCACTGACCAGGG AGTGCCTCCTCTTCAAGGACAGGCAGTTGTTAATATTCAGGAACTTGATTATGAGACG ACATCTCATTATCTTTTCAGAGTGATTACTACAGACCATAGCAAAAACCTTTCCCTGA GTAGCACAGTCTTCCTTAGTATCGATGTGGAAGATCAGAATGACCATTCCCCATCTTT CCAGGATGAGCTCATTGTGATCAGTGTAGAGGAGAATGTTCCCATAGGAACCCTGGTG TATGTCTTCAATGCCAAAGATGATGACGGCAGTTTTTTGAACAGTAGAATACAATACT ACATTGAATCCCACAACCCTGGCACGAATCCATTTCTCATCCACCCCTCATTTGGCAC ACTAGTCACTGTGTCCCGTCTTGACAGAGAAAGCATTCCAACTGTCATCCTGACAGTA ACAGCATCTGATCAGGCTGTGAATGTGACAGACCGGCGACTGAGATCACTGACAGCAC AAATAGTGATTTTGGATGTAAATGACCACAACCCCACTTTTATTTCTTTCCCCAATGC CCATGTCAAAGAGGATGTCACAGTGGGCTCCTTGGTCCACCACATAACTGCTCACGAT CCAGACGAAGGAAGGAATGGAAAAGTAACATACAGCATCCTCTCAGGAAATGAAAACA TGACGTTTATGCTAGATGAGTCATCAGGCTTACTAACCACAACCTGTCCTTTGGATTA TGAAATGAAAACTCAGCATATTCTGACTGTTCTGGCACTGGATGATGGCACACCAGCA CTTTCTTCATCCCAGACTTTGACAGTTACTGTTCTTGATGTAAATGATGAAGCTCCAG TATTTAAGCAGCACCTGTATGAAGCCTCAGTGAAAGAAAACCAAAATCCAGGGGAGTT TGTTACCAGGGTTGAAGCTCTGGACAGAGATTCAGTGTTCCTTAATACTAGAGAGCTT AACATGTGTTTTCTAGCATTCTACGATGCAGTTTTTAAAAATGGTGGGCTAAGTGCCC AAGCCTTTGTTCGTGTGGACCTGGAGGACGTGAATGATAATCATCCTGTGTTTAACCC ATCAACCTATGTGACGAGCATCAGTGATGAGACCCAGCCAGGCACCGAGATCATCAAT GTTCTTGCCACTGACCAGGACTCTGGGATATATGGGACAGTGGCTTATGAGCTTATTC CAGGAAACGTGTCGTCCCTTTTTACCATTGACTCCACCACAGGAATTATTTACTTAAC ATTACCTCTTAGTCATTTGGAATCTACCACACTTTCGTTGATGGTCTCTGCTCAAGAC GGTGGTGGGCTCACAGCTGTCATTAATGCCGATGTCACCATACACATTTTCCAGACAA CTCTGGCACCTGCTGAGTTTGAAAGGCCTAAGTACACTTTCTTAGTTTATGAAGATGT GCCTGAAGATAGTCCCATTGGAACAGTGAAAGCAAGAGAGCCCTTGAATCCACCTAGG AGCTCTGTAATACACCTGCAAGTTAGAGTTTTGGATGCCAATGACCACAGTCCTTCTT TTCCCACACTTTATTACCAGTCCTCTGTGAGAGAAGATGCTGAAGTGGGAACAGTGGT TCTTGTGCTTTCAGCTGTGGACAAGGATGAAGGCCTGAATGGGCAAACTGAGTATTTT CTGACTGATGAGGCTTGTGGTGCATTCACCATTGATCCTATGTCAGGCACATTGAAAA CCAGCAACACCCTCGACCGTGAAGCCAGATCTCAGCATACATTTAGTGCTGTGGCCAG AGACTGTAGCATCCAGGGTTCACGAAGCACCACTGTAATTATAAAAGTATATGTCACT GATGTTAATGACAATGATCCAGTTTTGGAACAGAACCCTTTTGATGTGTTTCTTTCCC CCGAGTCGCCTACAAACCAGACAACTGTCATTGTGAGAGCTGATGACCTGGACTTGGG GCCCAATGGAACTGTGGACTCCGATGACTCCCCGCTGCTGGACGACTTCCACGTGCAC CCGGACACCGGCATCATCCGCACTGCGCGGCGCCTGGACCGCGAGCGGCGGGACCACT ACAGCTTCGTCGCCGCCACGCTGCTGGGCGCTGTGGTGCAGGTGGAGATTCGCGTCAA CGACGTGAATGACCACTCGCCCCGCTTTCCCCTCGACTCCCTGCAACTCGACGTCTCC GAGCTCAGCCCGCCAGGGACCGCCTTCCGCCTGCCAGTTGCCCACGATCCGGACGCCG GACTGTTCAGCACTCAGGGCTACACCCTGGTGCAACCGTCCGACCTGCCCAAGGACCC CGCAGGCCCGTTCTTCCAGTTGCGCTACCGGACTCCGGGGCCACTACCGTCACCGCTT TTGCCAGGCTCCTCGTCACCCCTGGAGCCTCTAGATCTGGTGCTGCTGCGGCGCTTGG ACCGAGAGGAGGCGGCGGCGCACCGGCTGCAGATCGAGGCATGGGAGGGCGGCCGACC CCGGCGCACCGGCCTCCTGAGCGTGGAGCTGCGCGTGCTGGATGAGAACGACAACCCG CCGGTCTTTGAGCAGGACGAGTCCCGCGCCGCGGTGCGAGAGCACGCCCAGCCGGGCG CCGAGGTCTGTCGCGTGCGCGCCACCGCCCGCGACGTGGGGCCCAATGGCTTCGTGCG CTACAGCGTCCGCGCCCGGCAAGTGCCTGGGGCGGGTAGCGGCGGCGGGGCACTGGGC GACGCGGCCTACTTCGCGTTGGTGGTGGAGGCCCGCGATGGAGGCGCCGAGCATGAGG TTGCCGCGGTGCGTGTGTCCATCGCCGTGCTGGACGTGAATGACAACCGGCCAGCAAT TCACGTGCTCTTTCTCACAGAGGGAGGTGTCGCCCGTGTCTCTGAAGGCGCCCGCCCG GGCGACTACGTGGCTCGCGTCTCGGTGTCTGACGCGGGCGGTGACTGGGAGAAGGAAG ATGAGGCCACAGGGGAGCTTGGTGTGACAGCCTCTGATGCAGATTCAGGACTCTATGG CTTTATTGAATATTCTCTTTATGATGGATTCCTGAGCTATGAAGCACCTCAGGCATTC CGGATCGACCCTCATGATGGGCAAATCTGTGTTTCTCAAGATATCGACAGGGAAAGGG ATCCAGCTACCTATGATCTCCTGGTGGAAGCTAAGGATGGGTTTGAAATCATGCCAGG TGCTTCATTTGAATTATTCGAGATAAATTCTGACACTGGAGAGGTAGTGACAACCACC ATACTTGACAGAGAAATTCAAGAAGTCTTCACCCTTCGAGTACTAGTACGAGATGGGG GATTCCCTTCATTGTCCAGCACCACAACAATCCTCTGCACTGTTGAAGATGAAAACGA TCACGCACCAGAGTTTATTGTTTCCAGTTATGACATTGAGGTTCTGGAAAACCAGGAA CCAGAGGTTGTCTATACGGTTTTAGCCTCTGATATGGATGCTGGCAATAACAGAGCTG TTGAATATCACATAATTGACTCCTCAGAACCAATCTTTTACAGGATTTCTTCTGGTGA TCTCGGCGGAAAGTTCTCCATTCACCCGCGGCTGGGCACTATTCGCACCCGGAAGCCC CTGGATCACGAGACGCAGCCCGTGGTTGTGCTCACGGTGCAGGCGCAGCTCGGCAGCG CCCCAGCCTGCAGCAGCACCGAGGTCAACATAACAGTCATGGATGTCAATGACAACCA CCCAGCGTTCCTCAGGACCTCGGATGAGATTAGAATATCCCAGACCACGCCCCCTGGC ACAGCCTTGTACCTCGCACGTGCGGAAGACAGAGACAGTGGGCGGAACGGACTCATCC GGTACTCCATCGCCAGCCCGCAGCCAGGCGTCTTTGCCATCGACAGAGCCCTGGGGGT GCTGTTCCTCAACGGCAGCCTGGGCGCGGGCGAGCAGCGGGAGCTCACGCTGACTCTC AGGGCCGAGGACCAAGGCGTGCATCCTCAGGCAGCCCTGCTGGTGCTGACAGTCGTTA TCGAGAAACGCGAACACAGCCCATCCTGGACTTTCGAACATTTGGTCTATCAAGTGGA AGTCAGTACTTCTATTGTGACTGTTAAAGCTTTTGCTCCTGACTCAATTCAGGACAGC ATGAAATATTCAATTTTTAGTGGAAATGAAGATGGAGTTCTTTCCCTGTGCTCTAAGT CAGGTGTGGTGAACTGCCTTGCTTCTCTCAGTCACACAGACTTTCTCTCCCTGAAATT TGAATCTTCGGTGAAGGGACACCAAGACAGAGACAAATTACAGCCAATTCATCTTGAT GACAACAACTCAAAGAAGCTGTGCTTTACATTCCCTAGAGCCACTCAGGCTCTTGTAT TCACTGGGCACTGTCTTTCTGATACATCTCTCCCCGGTTGGGTTTTTGCTACCGACTT GGACAGTGGTTTGAACGGCCTGATTGAGTATTCTATTCTGTCTGGCAACCAAGAAGAA GCATTCCAGATTGATGCACTGAGTGGTGTGATAACAACAAAAGCGATTCTAGATTACG AGCTCACCAGCTCCTACAGCTTGATTGTCCAAGCCACAGATAAAGGGATGCCCAGGCT TTCTAATACGACTGTAATCAAGGTACAGGTGACTGATATAAATGACAATGCCCCAGCT TTTCTCCCCTCTGAAGCAGTGGAAATTACAGAAGTCATGACTATTTCAGAAGATTCTT TGCCTGGTGTAATTGTGACTCATGTGTCAGTTCATGATGTGGATTTGAATTCAGCTTT CATATTCAGTTTTGCCAAAGAGAGTAATCCTGGAACCAAGTTTGCTATTGATCAGAAC ACTGGAGTGGTGGTGTTGGTGAAAACATTGGATTTTGAAGAAATGACTGAATATGAGC TGCTCATCCAAATTTCTGATTCAGTGCACTACACAGAGGGAGCACTTGTAGTCCGTGT GCTGGATGTCAATGATAATCCACCAGTGTTTTCTCAAGATTTCTATCAGGTCACAGTT CCTGAATCAATACCTGTGGGGTATTCAGTGCTGACTCTGTCAGCCACAGACTTAGAAA GCAATGAGAACATTTCTTACAGAATTCTATCCTCTTCTAAGGAATTCTCCATTGATCC TAAGAATGGCACAATATTTACTATCAGTCCCGTATTACTTCTGGATACAATATCAACA ACTCGATTTCTTGTGGAAGCCAGTGATGGTGGAAATCCTGACCCGAGAGCTCTTACTT TAGTGGAGATAGGAATAGAAGATATGAACAATTATGCCCCTGAATTCACAGTCAAATC CTATAATCTTAGCCTAAGTGAGGATGCTCTGGTTGGAAGCACGCTTGTTACATTTTCA AACATCGACCATGACTGGACCCGTGAAAACACATATGTTGAATATTCCATCATCAGTG GTAATTCACAGAACAATTTTCATGTGGAAACTAAGTTCTTTCATTCAGAATATCCTTA TAAGCAAGTCGGTTATCTTGTGTTGCTTCACAGTCTGGACAGAGAAGCAAGTGCTAGC CATGAGCTTGTCATTCTGGCATCTGACAGTGGCTGCCCTCCATTGAGTTCCACAGCTG TCATATCAATACAAGTACTTGATGTCAATGACAATCCCCCAAACTTCAGCAGCCTGAG CTATCACACCCATGTCAAGGAAAGCACCCCTCTAGGGAGTCACATCACTGTGGTCTCA GCAAATGACCGTGACACAGGGTCACATGCAGAAATCATCTACAACATCATCTCTGGAA ATGAGAAGGGACATTTTTACTTAGAAGAAAACACTGGAGTTCTTTATTTGATTAAACC TCTGGATTATGAAAAAATGACAAAATTCACCTTAACTGTCCAAGCTTCAGATGCAGAA AAGAAACATTTTTCTTTTGCAGTTGTGTTTGTCAGTGTCCTGGATGATAACGACCATG CACCTCAGTTTATGTTCTCAAGCTTCAGCTGTATTGTTCCAGAAAATCTGCCTATTTC CTCTACCATATGCTCTATAAATGCTCTGGATTTTGATGCTGGTCCGTATGGAGAATTG ACCTATTCTATTGTATCACCCTGTTTTCTCACTCATGGAATGTCTTATGATCATGATC TCTTCCTCATTGACCCTTTGACAGGGGATATTCATGCTAAGCAAATCCTTGACTATGA AAATGGCAATAAATACTGCCTCACAGTCCAAGCCAAAGACAAAGGTGATGCAACTGCC TCCTTAGTGGTCTGGGTGGATATTGAAGGGATAGATGAATTTGAGCCCATTTTCACTC AAGATCAGTATTTTTTCACCCTCCCAGAAAAGAATAAAGACAGACAGTTGATTGGCAG AGTGGAAGCCTCAGATGCAGATGCTGGTATTGATGGAGTCATTCTTTACTCCCTTGGA ACCTCATCTCCTTTCTTTTCAGTAAATAGAACCAATGGAAATATTTATTTGATTAGAG CCCTTCCCCTAATAAAAAGTCAACTCAACAAAGAAGACACCTTGGAAATGAAAATAAT CGCTCATAGTCCCAAATCAGATTCCAAGTTTGCATCTTGCACTGTTTTTGTGAATGTG TCTTTCTCCTCTGAAGGAACACCCTTGGCAGTGTTCGCCAGCAGCTTTTCAATCAGCC TGGTGGTCTCCTTTTTAGTGTTTCTGATACTCATCTGCATTCTAATTGTAATGATTTT AAGACATAAACAAAAAGACACAATAAACAATTATGAGGAGAAGAAAACCTCATCTTTA GATGCGGACTTGAGAGTGACCCGGGATGCCAGTGTGCTCAAAGCCTTCCAGAAAACTG ACGACTGCAGTAACGAGGTGGTCCCTGTGGATGCCACTCCGGAATGGTTGAGTTTAAT AAGTATCATGGAGAAGGATATTGTCAATCTGTACAGATACTCAAACTCCAGTGGCCAC TGTTCTGTGGAAGGAGAAACTGCAGAAGATAAGGAAATCCAGAGGATAAATGAGCATC CCTACAGAAAGTGCTCAGACTCAGCTCTGAGTGACCACGAGTCCAGGGTGCCAGACTC GGGTATCCCGAGGGACTCAGACCAGCTCTCCTGCCTATCTGGGGAAACTGATGTGATG GTGACTGCCGAAACAGCAGAAGCCAGCCAAACATTTGGGGAAGGAGATCAAGGGGAAG GCTGCAGCACCACCTGTGCTCAAAATAATGTGTTACCCCAGACAGTTCAGAAGAGAGA GGCAAAAGAGAGCATCCTGGCTGACGTTAGAAAAGAGTCTGTCTTTATTTCAGGTGAT CAGGAAGTAAGGTGTGCAGCTCTTTCAACTCAGACGACCTCTGATCATGATGGAAAAG ACAACTATCACTGGAATTATCTTCTTAGTTGGGAGCCCAAATTCCAACCTCTTGCCTC AGTATTTAATGATATTGCAAAACTAAAGGATGAACATTTGCATATGCCTGGCATTCCA AAAGAGAAGAAATCTTTTGTTTTTCCACCCCCTTTGATAACAGCAGTAGCCCAGCCTG GGATTAAAGCAGTCCCACCAAGAATGCCGGCAGTAAACCTGGGGCAGGTGCCTCCGAA ACACCCACGCTCTCCCATCCCCTACCATCTTGGTTCTCTGCCAGAAGGCATGACTCCC AATTTTTCTCCATCTCTTTCCCTATTGACGATGCAGCCTCCTGCCTTGTCTCCACTGT TGAGAGAAGGAGAATTATTAGGAACACACATCAGTGGTACATGCCATGAACTTAAAGC AGAAGATGAAGTTCAAATATGAAACCACTGGGATGCCAAGTACCTGCTCACCATTGGT

CATGAATGAATGAACAAAATGTTTTCAAGCCGGCAACTCGAGATTGGGCTCATTTTTA

TCTAAAAGCAAGTGATGTAATTTAGTTAGAGTTTTTAAAACTTCCCCATTAAAGTTTC

TCCAATTTCAAAAAAAAAAAAAAAAAAAA

ORF Start: ATG at 1 ORF Stop: TGA at 9010

SEQ ID NO: 126 3003 aa MW at 329184.0kD

NOV28b, MEKCGLKEEGSYADIDPVAHDPDAGLFSTQGYTLVQPSDLPKDPAGPFFQLRYRTPGP CG58567-05 LPSPLLPGSSSPLEPLDLVLLRRLDREEAAAHRLQIEA DGGRPRRTGLLSVELRVLD ENDNPPVFEQDEYRAAVREDAQPGAEVCRVRATDRDLGPNGFVRYSVRARQVPGAGSG Protein Sequence GGALGDAAYFAVEELSGWRV RPLDREAQA HQLWEARDGGAEPEVATVRVSIAVL DVNDNRPAIHVLFLTEGGVARVSEGARPGDYVARVSVSDADGVIG ITAIDMDSGKNG QLLYFLLSDGKFFiαtNPNTGELIN VALDREHRGHHEMTVLVTDRGSPPRNATMAVYV SVTDINDNRPFFPQCLPGKELHVKVLEGQPVNMLVTTVFAKDPDEGNNAEVTYSVSSE DSSDHFKIDANNGEIRTTTILSYDYRPSYRMSVIATDQGVPPLQGQAWNIQELDYET TSHYLFRVITTDHSKNLSLSSTVFLSIDVEDQNDHSPSFQDELIVISVEENVPIGTLV YVFNAKDDDGSFLNSRIQYYIESHNPGTNPFLIHPSFGTLVTVSRLDRESIPTVILTV TASDQAVNVTDRRLRSLTAQIVILDVNDHNPTFISFPNAHVKEDVTVGSLVHHITAHD PDEGRNGKVTYSILSGNENMTFMLDESSGLLTTTCPLDYEMKTQHILTVLALDDGTPA LSSSQTLTVTVLDVNDEAPVFKQHLYEASVKENQNPGEFVTRVEALDRDSVFLNTREL NMCFLAFYDAVFKNGGLSAQAFVRVDLEDVNDNHPVFNPSTYVTSISDETQPGTEIIN VLATDQDSGIYGTVAYELIPGNVSSLFTIDSTTGIIYLTLPLSHLESTTLSL VSAQD GGGLTAVINADVTIHIFQTTLAPAEFERPKYTFLVYEDVPEDSPIGTVKAREPLNPPR SSVIHLQVRVLDANDHSPSFPTLYYQSSVREDAEVGTWLVLSAVDKDEGLNGQTE F LTDEACGAFTIDPMSGTLKTSNTLDREARSQHTFSAVARDCSIQGSRSTTVIIKVYVT DVNDNDPVLEQNPFDVFLSPΞSPTNQTTVIVRADDLDLGPNGTVDSDDSPLLDDFHVH PDTGIIRTARRLDRERRDHYSFVAATLLGAWQVEIRVNDVNDHSPRFPLDSLQLDVS ELSPPGTAFRLPVAHDPDAGLFSTQGYTLVQPSDLPKDPAGPFFQLRYRTPGPLPSPL LPGSSSPLEPLDLVLLRRLDREEAAAHRLQIEAWDGGRPRRTGLLSVELRVLDENDNP PVFEQDESRAAVREHAQPGAEVCRVRATARDVGPNGFVRYSVRARQVPGAGSGGGALG DAAYFALWEARDGGAEHEVAAVRVSIAVLDVNDNRPAIHVLFLTEGGVARVSEGARP GDYVARVSVSDAGGD EKEDEATGELGVTASDADSGLYGFIEYSLYDGFLSYEAPQAF RIDPHDGQICVSQDIDRERDPATYDLLVEAKDGFEIMPGASFELFEINSDTGEWTTT ILDREIQEVFTLRVLVRDGGFPSLSSTTTILCTVEDENDHAPEFIVSSYDIEVLENQE PEWYTVLASDMDAGNNRAVEYHIIDSSEPIFYRISSGDLGGKFSIHPRLGTIRTRKP LDHETQPVWLTVQAQLGSAPACSSTEVNITVMDVNDNHPAFLRTSDEIRISQTTPPG TALYLARAEDRDSGRNGLIRYSIASPQPGVFAIDRALGVLFLNGSLGAGEQRELTLTL RAEDQGVHPQAALLVLTWIEKRΞHSPS TFEHLVYQVEVSTSIVTVKAFAPDSIQDS MKYSIFSGNEDGVLSLCSKSGWNCLASLSHTDFLSLKFESSVKGHQDRDKLQPIHLD DNNSKKLCFTFPRATQALVFTGHCLSDTSLPG VFATDLDSGLNGLIEYSILSGNQEE AFQIDALSGVITTKAILDYELTSSYSLIVQATDKGMPRLSNTTVIKVQVTDINDNAPA FLPSEAVEITEVMTISEDSLPGVIVTHVSVHDVDLNSAFIFSFAKESNPGTKFAIDQN_; TGVWLVKTLDFEEMTEYELLIQISDSVHYTEGALWRVLDVNDNPPVFSQDFYQVT PESIPVGYSVLTLSATDLESNENISYRILSSSKEFSIDPKNGTIFTISPVLLLDTIST TRFLVEASDGGNPDPRALTLVEIGIEDMNNYAPEFTVKSYNLSLSEDALVGSTLVTFS NIDHDWTRENTYVEYSIISGNSQNNFHVETKFFHSEYPYKQVGYLVLLHSLDREASAS HELVILASDSGCPPLSSTAVISIQVLDVNDNPPNFSSLSYHTHVKESTPLGSHITWS ANDRDTGSHAEIIYNIISGNEKGHFYLEENTGVLYLIKPLDYEK TKFTLTVQASDAE KKHFSFAWFVSVLDDNDHAPQF FSSFSCIVPENLPISSTICSINALDFDAGPYGEL TYSIVSPCFLTHG SYDHDLFLIDPLTGDIHAKQILDYENGNKYCLTVQAKDKGDATA SLWWVDIEGIDEFEPIFTQDQYFFTLPE NKDRQLIGRVEASDADAGIDGVILYSLG TSSPFFSVNRTNGNIYLIRALPLIKSQLNKEDTLEMKIIAHSPKSDSKFASCTVFVNV SFSSEGTPLAVFASSFSISLWSFLVFLILICILIV ILRHKQKDTINNYEEKKTSSL DADLRVTRDASVLKAFQKTDDCSNEWPVDATPE LSLISIMEKDIVNLYRYSNSSGH CSVEGETAEDKEIQRINEHPYRKCSDSALSDHESRVPDSGIPRDSDQLSCLSGETDVM VTAETAEASQTFGEGDQGEGCSTTCAQNNVLPQTVQKREAKESILADVR ESVFISGD QEVRCAALSTQTTSDHDGKDNYH NYLLS EPKFQPLASVFNDIAKLKDEHLHMPGIP KEKKSFVFPPPLITAVAQPGIKAVPPRMPAVNLGQVPPKHPRSPIPYHLGSLPEGMTP NFSPSLSLLTMQPPALSPLLREGELLGTHISGTCHELKAEDEVQI

SEQ ID NO: 127 10267 bp

NOV28c, ATGGAGAAATGTGGGCTTAAAGAGGAAGGCAGTTACGCGGACATAGATCCAGTTGCCC CG58567-06 DNA ACGATCCGGACGCCGGACTGTTCAGCACTCAGGGCTACACCCTGGTGCAACCGTCCGA CCTGCCCAAGGACCCCGCAGGCCCGTTCTTCCAGTTGCGCTACCGGACTCCGGGGCCA Sequence CTACCGTCACCGCTTTTGCCAGGCTCCTCGTCACCCCTGGAGCCTCTAGATCTGGTGC TGCTGCGGCGCTTGGACCGAGAGGAGGCGGCGGCGCACCGGCTGCAGATCGAGGCATG GGACGGCGGCCGACCCCGGCGCACCGGCCTCCTGAGCGTGGAGCTGCGCGTGCTGGAT GAGAACGACAACCCGCCGGTCTTTGAGCAGGACGAGTACCGCGCCGCGGTGCGCGAGG ACGCCCAGCCGGGCGCCGAGGTCTGTCGCGTGCGCGCCACCGACCGCGACCTGGGGCC CAATGGCTTCGTGCGCTACAGCGTCCGCGCCCGGCAAGTGCCTGGGGCGGGTAGCGGC GGCGGGGCACTGGGCGACGCGGCCTACTTCGCGGTGGAGGAGCTGAGCGGCGTGGTGC GAGTGTGGAGACCTCTGGACCGCGAGGCACAGGCCTGGCACCAGTTGGTGGTGGAGGC CCGCGATGGAGGCGCCGAGCCTGAGGTTGCCACGGTGCGCGTGTCCATCGCCGTGCTG GACGTGAATGACAACCGGCCAGCAATTCACGTGCTCTTTCTCACAGAGGGAGGCGTCG CCCGTGTCTCTGAAGGCGCCCGACCGGGCGACTACGTGGCTCGCGTCTCGGTGTCTGA CGCGGACGGTGACTGGGAGAAGGAAGATGAGGCCACAGGGGAGCTTGGTGTGGGTCTT GGAGACGGGAGCATCTCTCTGTCCTTGGAAGGCGGAGAGGGAGACTTCGCGTTGCTAC CCGGCGGCCCCCCAGGGGTATTTTTCCTTTGCGTGGAGGGGCCCCTGGACAGAGAGAG CCGCGATCTGTATGAGTTACTACTGGTGGCCACGGACGCGGGGTCCCCGCCGCTGAGC ACGGAGGAGACGCTGCTACTCCGGGTCGCTGACCTCAATGACCAACCACCTCTCTTCA GCCAACAGCATTACAAGGCCTCAGTGTCCGAGGCCGCGGCCCCTGGCACTGTAGTCAT GTGGGTCAGCGCCTCCGATGCCGACGAGGCAGGCAGTGATCACGCCTGGCTGCGCTAC ACTGTAGTCCAACTCTCGGCTCCCTGCAATCTCGGCTCCCTGCAATCAAAGATGGTCC ACACCGCAGAGTGTGGACCATCTTTTGCCATTGATTCCGAAAGCGGTGCGATCAGCAC TATCCGGACTCTAGACCGAGAGGTCCAGGAGGCGGTGGAGCTGAAAGTGGTGGCCCAG GACCTCGGAGAGCCCCCACTCTCTGCCACCTGCCTGGTGAGCATCACCGTAGATGATG TGAATGACAATGAGCCCATCTTCTGGAGGCAGGTGTACAATGCCACCATTGCAGAGCA TGCCCCGGTTGGACACTGCTTTCTGCAGCTTATATCTGCTCAAGTTGCCTCTGTCAAA ATCAAACACAAACACAAGGAGATACACGAGAAACACAATCTTGCCTATATTTCCTGTC CAGCAGGCACCATCTATGTCATAACCTGGGCAGATGGTGCTGCTGCCTTTAGTGGGAC AGACTTTGCATTCAGTTCTGATGAACTTCAAGCCTTTGTTCTCAAGTCTCTGTTCTGT GAATTAGGAGAAGGAGAGTTAATCAATTGGGTGGCACTGGATCGTGAGCACCGGGGGC ACCATGAGATGACTGTGCTAGTGACAGACCGCGGCTCCCCACCACGAAACGCCACCAT GGCGGTTTACGTCTCAGTTACTGACATCAATGATAACAGGCCCTTCTTCCCCCAGTGT CTCCCTGGAAAGGAGTTACACGTGAAGGTTCTGGAAGGTCAACCAGTAAATATGTTGG TTACAACTGTGTTTGCAAAGGATCCTGATGAAGGAAATAATGCAGAAGTTACATACTC AGTATCTTCAGAAGATAGTTCTGATCACTTTAAGATTGACGCCAACAATGGTGAAATA AGAACAACCACAATACTTTCGTATGATTATAGACCTTCCTACAGAATGAGTGTCATTG CCACTGACCAGGGAGTGCCTCCTCTTCAAGGACAGGCAGTTGTTAATATTCAGGTGAT CCCACTATCCAAAGGGAGAGCAATCATGTCTCAGAATATTAGACATTTAATTATACCA GAAAATTTGAAGCCCACAAAAATAATGAGCTTGATAAAGTCATCTGATCACCTTCAAC AACATTATAATGGAAAGTTACATTTTAGTATTGTTGCAGATGATAAGGATGGACACTT TGAAATAGACAGCTCAACCGGAGACTTGTTTCTTTCTAAGGAACTTGATTATGAGACG ACATCTCATTATCTTTTCAGAGTGATTACTACAGACCATAGCAAAAACCTTTCCCTGA GTAGCACAGTCTTCCTTAGTATCGATGTGGAAGATCAGAATGACCATTCCCCATCTTT CCAGGATGAGCTCATTGTGATCAGTGTAGAGGAGAATGTTCCCATAGGAACCCTGGTG TATGTCTTCAATGCCAAAGATGATGACGGCAGTTTTTTGAACAGTAGAATACAATACT ACATTGAATCCCACAACCCTGGCACGAATCCATTTCTCATCCACCCCTCATTTGGCAC ACTAGTCACTGTGTCCCGTCTTGACAGAGAAAGCATTCCAACTGTCATCCTGACAGTA ACAGCATCTGATCAGGCTGTGAATGTGACAGACCGGCGACTGAGATCACTGACAGCAC AAATAGTGATTTTGGATGTAAATGACCACAACCCCACTTTTATTTCTTTCCCCAATGC CCATGTCAAAGAGGATGTCACAGTGGGCTCCTTGGTCCACCACATAACTGCTCACGAT CCAGACGAAGGAAGGAATGGAAAAGTAACATACAGCATCCTCTCAGGAAATGAAAACA TGACGTTTATGCTAGATGAGTCATCAGGCTTACTAACCACAACCTGTCCTTTGGATTA TGAAATGAAAACTCAGCATATTCTGACTGTTCTGGCACTGGATGATGGCACACCAGCA CTTTCTTCATCCCAGACTTTGACAGTTACTGTTCTTGATGTAAATGATGAAGCTCCAG TATTTAAGCAGCACCTGTATGAAGCCTCAGTGAAAGAAAACCAAAATCCAGGGGAGTT TGTTACCAGGGTTGAAGCTCTGGACAGAGATTCAGGTATGAGGCTGAATGGAGATCCA GACAGGGAGCTGTGTGCAGGAGGGAACCCTCTTGGAAGCAGGGCCCCTCCTGGAAGCA GGACCCCTCCTGAAGGTGGGCTAAGTGCCCAAGCCTTTGTTCGTGTGGACCTGGAGGA CGTGAATGATAATCATCCTGTGTTTAACCCATCAACCTATGTGACGAGCATCAGTGAT GAGACCCAGCCAGGCACCGAGATCATCAATGTTCTTGCCACTGACCAGGACTCTGGGA TATATGGGACAGTGGCTTATGAGCTTATTCCAGGAAACGTGTCGTCCCTTTTTACCAT TGACTCCACCACAGGAATTATTTACTTAACATTACCTCTTAGTCATTTGGAATCTACC ACACTTTCGTTGATGGTCTCTGCTCAAGACGGTGGTGGGCTCACAGCTGTCATTAATG CCGATGTCACCATACACATTTTCCAGACAACTCTGGCACCTGCTGAGTTTGAAAGGCC TAAGTACACTTTCTTAGTTTATGAAGATGTGCCTGAAGATAGTCCCATTGGAACAGTG AAAGCAAGAGAGCCCTTGAATCCACCTAGGAGCTCTGTAATACACCTGCAAGTTAGAG TTTTGGATGCCAATGACCACAGTCCTTCTTTTCCCACACTTTATTACCAGTCCTCTGT GAGAGAAGATGCTGAAGTGGGAACAGTGGTTCTTGTGCTTTCAGCTGTGGACAAGGAT GAAGGCCTGAATGGGCAAACTGAGTATTTTCTGACTGATGAGGCTTGTGGTGCATTCA CCATTGATCCTATGTCAGGCACATTGAAAACCAGCAACACCCTCGACCGTGAAGCCAG ATCTCAGCATACATTTAGTGCTGTGGCCAGAGACTGTAGCATCCAGGGTTCACGAAGC ACCACTGTAATTATAAAAGTATATGTCACTGATGTTAATGACAATGATCCAGTTTTGG AACAGAACCCTTTTGATGTGTTTCTTTCCCCCGAGTCGCCTACAAACCAGACAACTGT CATTGTGAGAGCTGATGACCTGGACTTGGGGCCCAATGGAACTGTGGACTCCGATGAC TCCCCGCTGCTGGACGACTTCCACGTGCACCCGGACACCGGCATCATCCGCACTGCGC GGCGCCTGGACCGCGAGCGGCGGGACCACTACAGCTTCGTCGCCGCCACGCTGCTGGG CGCTGTGGTGCAGGTGGAGATTCGCGTCAACGACGTGAATGACCACTCGCCCCGCTTT CCCCTCGACTCCCTGCAACTCGACGTCTCCGAGCTCAGCCCGCCAGGGACCGCCTTCC GCCTGCCAGTTGCCCACGATCCGGACGCCGGACTGTTCAGCACTCAGGGCTACACCCT GGTGCAACCGTCCGACCTGCCCAAGGACCCCGCAGGCCCGTTCTTCCAGTTGCGCTAC CGGACTCCGGGGCCACTACCGTCACCGCTTTTGCCAGGCTCCTCGTCACCCCTGGAGC CTCTAGATCTGGTGCTGCTGCGGCGCTTGGACCGAGAGGAGGCGGCGGCGCACCGGCT GCAGATCGAGGCATGGGACGGCGGCCGACCCCGGCGCACCGGCCTCCTGAGCGTGGAG CTGCGCGTGCTGGATGAGAACGACAACCCGCCGGTCTTTGAGCAGGACGAGTCCCGCG CCGCGGTGCGAGAGCACGCCCAGCCGGGCGCCGAGGTCTGTCGCGTGCGCGCCACCGC CCGCGACGTGGGGCCCAATGGCTTCGTGCGCTACAGCGTCCGCGCCCGGCAAGTGCCT GGGGCGGGTAGCGGCGGCGGGGCACTGGGCGACGCGGCCTACTTCGCGTTGGTGGTGG AGGCCCGCGATGGAGGCGCCGAGCATGAGGTTGCCGCGGTGCGTGTGTCCATCGCCGT GCTGGACGTGAATGACAACCGGCCAGCAATTCACGTGCTCTTTCTCACAGAGGGAGGT GTCGCCCGTGTCTCTGAAGGCGCCCGCCCGGGCGACTACGTGGCTCGCGTCTCGGTGT CTGACGCGGGCGGTGACTGGGAGAAGGAAGATGAGGCCACAGGGGAGCTTGGTGTGAC AGCCTCTGATGCAGATTCAGGACTCTATGGCTTTATTGAATATTCTCTTTATGATGGA TTCCTGAGCTATGAAGCACCTCAGGCATTCCGGATCGACCCTCATGATGGGCAAATCT GTGTTTCTCAAGATATCGACAGGGAAAGGGATCCAGCTACCTATGATCTCCTGGTGGA AGCTAAGGATGGGTTTGAAATCATGCCAGGTGCTTCATTTGAATTATTCGAGATAAAT TCTGACACTGGAGAGGTAGTGACAACCACCATACTTGACAGAGAAATTCAAGAAGTCT TCACCCTTCGAGTACTAGTACGAGATGGGGGATTCCCTTCATTGTCCAGCACCACAAC AATCCTCTGCACTGTTGAAGATGAAAACGATCACGCACCAGAGTTTATTGTTTCCAGT TATGACATTGAGGTTCTGGAAAACCAGGAACCAGAGGTTGTCTATACGGTTTTAGCCT CTGATATGGATGCTGGCAATAACAGAGCTGTTGAATATCACATAATTGACTCCTCAGA ACCAATCTTTTACAGGATTTCTTCTGGTGATCTCGGCGGAAAGTTCTCCATTCACCCG CGGCTGGGCACTATTCGCACCCGGAAGCCCCTGGATCACGAGACGCAGCCCGTGGTTG TGCTCACGGTGCAGGCGCAGCTCGGCAGCGCCCCAGCCTGCAGCAGCACCGAGGTCAA CATAACAGTCATGGATGTCAATGACAACCACCCAGCGTTCCTCAGGACCTCGGATGAG ATTAGAATATCCCAGACCACGCCCCCTGGCACAGCCTTGTACCTCGCACGTGCGGAAG ACAGAGACAGTGGGCGGAACGGACTCATCCGGTACTCCATCGCCAGCCCGCAGCCAGG CGTCTTTGCCATCGACAGAGCCCTGGGGGTGCTGTTCCTCAACGGCAGCCTGGGCGCG GGCGAGCAGCGGGAGCTCACGCTGACTCTCAGGGCCGAGGACCAAGGCGTGCATCCTC AGGCAGCCCTGCTGGTGCTGACAGTCGTTATCGAGAAACGCGAACACAGCCCATCCTG GACTTTCGAACATTTGGTCTATCAAGTGGAAGTCAGTACTTCTATTGTGACTGTTAAA GCTTTTGCTCCTGACTCAATTCAGGACAGCATGAAATATTCAATTTTTAGTGGAAATG AAGATGGAGTTCTTTCCCTGTGCTCTAAGTCAGGTGTGGTGAACTGCCTTGCTTCTCT CAGTCACACAGACTTTCTCTCCCTGAAATTTGAATCTTCGGTGAAGGGACACCAAGAC AGAGACAAATTACAGCCAATTCATCTTGATGACAACAACTCAAAGAAGCTGTGCTTTA CATTCCCTAGAGCCACTCAGGCTCTTGTATTCACTGGGCACTGTCTTTCTGATACATC TCTCCCCGGTTGGGTTTTTGCTACCGACTTGGACAGTGGTTTGAACGGCCTGATTGAG TATTCTATTCTGTCTGGCAACCAAGAAGAAGCATTCCAGATTGATGCACTGAGTGGTG TGATAACAACAAAAGCGATTCTAGATTACGAGCTCACCAGCTCCTACAGCTTGATTGT CCAAGCCACAGATAAAGGGATGCCCAGGCTTTCTAATACGACTGTAATCAAGGTACAG GTGACTGATATAAATGACAATGCCCCAGCTTTTCTCCCCTCTGAAGCAGTGGAAATTA CAGAAGTCATGACTATTTCAGAAGATTCTTTGCCTGGTGTAATTGTGACTCATGTGTC AGTTCATGATGTGGATTTGAATTCAGCTTTCATATTCAGTTTTGCCAAAGAGAGTAAT CCTGGAACCAAGTTTGCTATTGATCAGAACACTGGAGTGGTGGTGTTGGTGAAAACAT TGGATTTTGAAGAAATGACTGAATATGAGCTGCTCATCCAAATTTCTGATTCAGTGCA CTACACAGAGGGAGCACTTGTAGTCCGTGTGCTGGATGTCAATGATAATCCACCAGTG TTTTCTCAAGATTTCTATCAGGTCACAGTTCCTGAATCAATACCTGTGGGGTATTCAG TGCTGACTCTGTCAGCCACAGACTTAGAAAGCAATGAGAACATTTCTTACAGAATTCT ATCCTCTTCTAAGGAATTCTCCATTGATCCTAAGAATGGCACAATATTTACTATCAGT CCCGTATTACTTCTGGATACAATATCAACAACTCGATTTCTTGTGGAAGCCAGTGATG GTGGAAATCCTGACCCGAGAGCTCTTACTTTAGTGGAGATAGGAATAGAAGATATGAA CAATTATGCCCCTGAATTCACAGTCAAATCCTATAATCTTAGCCTAAGTGAGGATGCT CTGGTTGGAAGCACGCTTGTTACATTTTCAAACATCGACCATGACTGGACCCGTGAAA ACACATATGTTGAATATTCCATCATCAGTGGTAATTCACAGAACAATTTTCATGTGGA AACTAAGTTCTTTCATTCAGAATATCCTTATAAGCAAGTCGGTTATCTTGTGTTGCTT CACAGTCTGGACAGAGAAGCAAGTGCTAGCCATGAGCTTGTCATTCTGGCATCTGACA GTGGCTGCCCTCCATTGAGTTCCACAGCTGTCATATCAATACAAGTACTTGATGTCAA TGACAATCCCCCAAACTTCAGCAGCCTGAGCTATCACACCCATGTCAAGGAAAGCACC CCTCTAGGGAGTCACATCACTGTGGTCTCAGCAAATGACCGTGACACAGGGTCACATG CAGAAATCATCTACAACATCATCTCTGGAAATGAGAAGGGACATTTTTACTTAGAAGA AAACACTGGAGTTCTTTATTTGATTAAACCTCTGGATTATGAAAAAATGACAAAATTC ACCTTAACTGTCCAAGCTTCAGATGCAGAAAAGAAACATTTTTCTTTTGCAGTTGTGT TTGTCAGTGTCCTGGATGATAACGACCATGCACCTCAGTTTATGTTCTCAAGCTTCAG CTGTATTGTTCCAGAAAATCTGCCTATTTCCTCTACCATATGCTCTATAAATGCTCTG GATTTTGATGCTGGTCCGTATGGAGAATTGACCTATTCTATTGTATCACCCTGTTTTC TCACTCATGGAATGTCTTATGATCATGATCTCTTCCTCATTGACCCTTTGACAGGGGA TATTCATGCTAAGCAAATCCTTGACTATGAAAATGGCAATAAATACTGCCTCACAGTC CAAGCCAAAGACAAAGGTGATGCAACTGCCTCCTTAGTGGTCTGGGTGGATATTGAAG GGATAGATGAATTTGAGCCCATTTTCACTCAAGATCAGTATTTTTTCACCCTCCCAGA AAAGAATAAAGACAGACAGTTGATTGGCAGAGTGGAAGCCTCAGATGCAGATGCTGGT ATTGATGGAGTCATTCTTTACTCCCTTGGAACCTCATCTCCTTTCTTTTCAGTAAATA GAACCAATGGAAATATTTATTTGATTAGAGCCCTTCCCCTAATAAAAAGTCAACTCAA CAAAGAAGACACCTTGGAAATGAAAATAATCGCTCATAGTCCCAAATCAGATTCCAAG TTTGCATCTTGCACTGTTTTTGTGAATGTGTCTTTCTCCTCTGAAGGAACACCCTTGG CAGTGTTCGCCAGCAGCTTTTCAATCAGCCTGGTGGTCTCCTTTTTAGTGTTTCTGAT ACTCATCTGCATTCTAATTGTAATGATTTTAAGACATAAACAAAAAGACACAATAAAC AATTATGAGGAGAAGAAAACCTCATCTTTAGATGCGGACTTGAGAGTGACCCGGGATG CCAGTGTGCTCAAAGCCTTCCAGAAAACTGACGACTGCAGTAACGAGGTGGTCCCTGT GGATGCCACTCCGGAATGGTTGAGTTTAATAAGTATCATGGAGAAGGATATTGTCAAT CTGTACAGATACTCAAACTCCAGTGGCCACTGTTCTGTGGAAGGAGAAACTGCAGAAG ATAAGGAAATCCAGAGGATAAATGAGCATCCCTACAGAAAGTGCTCAGACTCAGCTCT GAGTGACCACGAGTCCAGGGTGCCAGACTCGGGTATCCCGAGGGACTCAGACCAGCTC TCCTGCCTATCTGGGGAAACTGATGTGATGGTGACTGCCGAAACAGCAGAAGCCAGCC AAACATTTGGGGAAGGAGATCAAGGGGAAGGCTGCAGCACCACCTGTGCTCAAAATAA TGTGTTACCCCAGACAGTTCAGAAGAGAGAGGCAAAAGAGAGCATCCTGGCTGACGTT AGAAAAGAGTCTGTCTTTATTTCAGGTGATCAGGAAGTAAGGTGTGCAGCTCTTTCAA CTCAGACGACCTCTGATCATGATGGAAAAGACAACTATCACTGGAATTATCTTCTTAG TTGGGAGCCCAAATTCCAACCTCTTGCCTCAGTATTTAATGATATTGCAAAACTAAAG GATGAACATTTGCATATGCCTGGCATTCCAAAAGAGAAGAAATCTTTTGTTTTTCCAC CCCCTTTGATAACAGCAGTAGCCCAGCCTGGGATTAAAGCAGTCCCACCAAGAATGCC GGCAGTAAACCTGGGGCAGGTGCCTCCGAAACACCCACGCTCTCCCATCCCCTACCAT CTTGGTTCTCTGCCAGAAGGCATGACTCCCAATTTTTCTCCATCTCTTTCCCTATTGA CGATGCAGCCTCCTGCCTTGTCTCCACTGTTGAGAGAAGGAGAATTATTAGGAACACA CATCAGTGGTACATGCCATGAACTTAAAGCAGAAGATGAAGTTCAAATATGAAACCAC

TGGGATGCCAAGTACCTGCTCACCATTGGTCATGAATGAATGAACAAAATGTTTTCAA

GCCGGCAACTCGAGATTGGGCTCATTTTTATCTAAAAGCAAGTGATGTAATTTAGTTA

GAGTTTTTAAAACTTCCCCATTAAAGTTTCTCCAATTTCAAAAAAAAAAAAAAAAAAA

A

ORF Start: ATG at 1 ORF Stop: TGA at 10084

SEQ ID NO: 128 3361 aa IMW at 367309. lkD

NOV28c, MEKCGLKEEGSYADIDPVAHDPDAGLFSTQGYTLVQPSDLPKDPAGPFFQLRYRTPGP CG58567-06 LPSPLLPGSSSPLEPLDLVLLRRLDREEAAAHRLQIEAWDGGRPRRTGLLSVELRVLD Protein Sequence ENDNPPVFEQDEYRAAVREDAQPGAEVCRVRATDRDLGPNGFVRYSVRARQVPGAGSG GGALGDAAYFAVEELSGWRVWRPLDREAQA HQLWEARDGGAEPEVATVRVSIAVL DVNDNRPAIHVLFLTEGGVARVSEGARPGDYVARVSVSDADGD EKEDEATGELGVGL GDGSISLSLEGGEGDFALLPGGPPGVFFLCVEGPLDRESRDLYELLLVATDAGSPPLS TEETLLLRVADLNDQPPLFSQQHYKASVSEAAAPGTWM VSASDADEAGSDHAWLRY TWQLSAPCNLGSLQSKMVHTAECGPSFAIDSESGAISTIRTLDREVQEAVELKWAQ DLGEPPLSATCLVSITVDDVNDNEPIFWRQVYNATIAEHAPVGHCFLQLISAQVASVK IKHKHKEIHEKHNLAYISCPAGTIYVIT ADGAAAFSGTDFAFSSDELQAFVLKSLFC ELGEGELIN VALDREHRGHHEMTVLVTDRGSPPRNAT AVYVSVTDINDNRPFFPQC LPGKELHVKVLEGQPVNMLVTTVFAKDPDEGNNAEVTYSVSSEDSSDHFKIDANNGEI RTTTILSYDYRPSYRMSVIATDQGVPPLQGQAWNIQVIPLSKGRAI SQNIRHLIIP ENLKPTKIMSLIKSSDHLQQHYNGKLHFSIVADDKDGHFEIDSSTGDLFLSKELDYET TSHYLFRVITTDHSKNLSLSSTVFLSIDVEDQNDHSPSFQDELIVISVEENVPIGTLV YVFNAKDDDGSFLNSRIQYYIESHNPGTNPFLIHPSFGTLVTVSRLDRESIPTVILTV TASDQAVNVTDRRLRSLTAQIVILDVNDHNPTFISFPNAHVKEDVTVGSLVHHITAHD PDEGRNGKVTYSILSGNENMTFMLDESSGLLTTTCPLDYE KTQHILTVLALDDGTPA LSSSQTLTVTVLDVNDEAPVFKQHLYEASVKENQNPGEFVTRVEALDRDSGMRLNGDP DRELCAGGNPLGSRAPPGSRTPPEGGLSAQAFVRVDLEDVNDNHPVFNPSTYVTSISD ETQPGTEIINVLATDQDSGIYGTVAYELIPGNVSSLFTIDSTTGIIYLTLPLSHLEST TLSLMVSAQDGGGLTAVINADVTIHIFQTTLAPAEFERPKYTFLVYEDVPEDSPIGTV KAREPLNPPRSSVIHLQVRVLDANDHSPSFPTLYYQSSVREDAEVGTWLVLSAVDKD EGLNGQTEYFLTDEACGAFTIDPMSGTLKTSNTLDREARSQHTFSAVARDCSIQGSRS TTVIIKVYVTDVNDNDPVLEQNPFDVFLSPESPTNQTTVIVRADDLDLGPNGTVDSDD SPLLDDFHVHPDTGIIRTARRLDRERRDHYSFVAATLLGAWQVEIRVNDVNDHSPRF PLDSLQLDVSELSPPGTAFRLPVAHDPDAGLFSTQGYTLVQPSDLPKDPAGPFFQLRY RTPGPLPSPLLPGSSSPLEPLDLVLLRRLDREEAAAHRLQIEAWDGGRPRRTGLLSVE LRVLDENDNPPVFEQDESRAAVREHAQPGAEVCRVRATARDVGPNGFVRYSVRARQVP GAGSGGGALGDAAYFALWEARDGGAEHEVAAVRVSIAVLDVNDNRPAIHVLFLTEGG VARVSEGARPGDYVARVSVSDAGGDWEKEDEATGELGVTASDADSGLYGFIEYSLYDG FLSYEAPQAFRIDPHDGQICVSQDIDRΞRDPATYDLLVEAKDGFEIMPGASFELFEIN SDTGEWTTTILDREIQEVFTLRVLVRDGGFPSLSSTTTILCTVEDENDHAPEFIVSS YDIEVLENQEPEWYTVLASDMDAGNNRAVEYHIIDSSEPIFYRISSGDLGGKFSIHP RLGTIRTRKPLDHETQPWVLTVQAQLGSAPACSSTEVNITVMDVNDNHPAFLRTSDE IRISQTTPPGTALYLARAEDRDSGRNGLIRYSIASPQPGVFAIDRALGVLFLNGSLGA GEQRELTLTLRAEDQGVHPQAALLVLTWIEKREHSPS TFEHLVYQVEVSTSIVTVK AFAPDSIQDSMKYSIFSGNEDGVLSLCSKSGWNCLASLSHTDFLSLKFESSVKGHQD RDKLQPIHLDDNNSKKLCFTFPRATQALVFTGHCLSDTSLPGWVFATDLDSGLNGLIE YSILSGNQEEAFQIDALSGVITTKAILDYELTSSYSLIVQATDKGMPRLSNTTVIKVQ VTDINDNAPAFLPSEAVEITEVMTISEDSLPGVIVTHVSVHDVDLNSAFIFSFAKESN PGTKFAIDQNTGVWLVKTLDFEEMTEYELLIQISDSVHYTEGALWRVLDVNDNPPV FSQDFYQVTVPESIPVGYSVLTLSATDLESNENISYRILSSSKEFSIDPKNGTIFTIS PVLLLDTISTTRFLVEASDGGNPDPRALTLVEIGIED NNYAPEFTVKSYNLSLSEDA LVGSTLVTFSNIDHD TRENTYVEYSIISGNSQNNFHVETKFFHSEYPYKQVGYLVLL HSLDREASASHELVILASDSGCPPLSSTAVISIQVLDVNDNPPNFSSLSYHTHVKEST I

PLGSHITWSANDRDTGSHAE11YNIISGNEKGHFYLEENTGVLYLIKPLDYEK TKF TLTVQASDAEKKHFSFAWFVSVLDDNDHAPQFMFSSFSCIVPENLPISSTICSINAL DFDAGPYGELTYSIVSPCFLTHGMSYDHDLFLIDPLTGDIHAKQILDYENGNKYCLTV QAKDKGDATASLWWVDIEGIDEFEPIFTQDQYFFTLPEKNKDRQLIGRVEASDADAG IDGVILYSLGTSSPFFSVNRTNGNIYLIRALPLIKSQLNKEDTLE KIIAHSPKSDSK FASCTVFVNVSFSSEGTPLAVFASSFSISLWSFLVFLILICILIVMILRHKQKDTIN NYEEKKTSSLDADLRVTRDASVLKAFQKTDDCSNEWPVDATPE LSLISIME DIVN LYRYSNSSGHCSVEGETAEDKEIQRINEHPYRKCSDSALSDHESRVPDSGIPRDSDQL SCLSGETDVMVTAETAEASQTFGEGDQGEGCSTTCAQNNVLPQTVQKREAKESILADV RKESVFISGDQEVRCAALSTQTTSDHDGKDNYHWNYLLS EPKFQPLASVFNDIAKLK DEHLHMPGIPKEKKSFVFPPPLITAVAQPGIKAVPPRMPAVNLGQVPPKHPRSPIPYH LGSLPEGMTPNFSPSLSLLTMQPPALSPLLREGELLGTHISGTCHELKAEDEVQI

Sequence comparison ofthe above protein sequences yields the following sequence relationships shown in Table 28B.

Further analysis ofthe NOV28a protein yielded the following properties shown in Table 28C.

Table 28C. Protein Sequence Properties NOV28a

PSort 0.8000 probability located in mitochondrial inner membrane; 0.7000 probability analysis: located in plasma membrane; 0.3000 probability located in microbody (peroxisome); 0.2000 probability located in endoplasmic reticulum (membrane)

SignalP No Known Signal Sequence Indicated analysis:

A search ofthe NOV28a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 28D.

In a BLAST search of public sequence databases, the NOV28a protein was found to have homology to the proteins shown in the BLASTP data in Table 28E.

PFam analysis indicates that the NOV28a protein contains the domains shown in the Table 28F.

Example 29.

The NOV29 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 29A.

Sequence comparison ofthe above protein sequences yields the following sequence relationships shown in Table 29B.

Table 29B. Comparison of NOV29a against NOV29b through NOV29c.

Protein Sequence NOV29a Residues/ Identities/ Match Residues Similarities for the Matched Region

NOV29b

Further analysis ofthe NOV29a protein yielded the following properties shown in Table 29C.

Table 29C. Protein Sequence Properties NOV29a

PSort 0.7000 probability located in plasma membrane; 0.6400 probability located in analysis: microbody (peroxisome); 0.2000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in mitochondrial inner membrane

SignalP No Known Signal Sequence Indicated analysis:

A search ofthe NOV29a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 29D.

In a BLAST search of public sequence databases, the NOV29a protein was found to have homology to the proteins shown in the BLASTP data in Table 29E.

PFam analysis indicates that the NOV29a protein contains the domains shown in the Table 29F.

Example 30.

The NOV30 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 30A.

GGACTCGCTGGACTGCGGTGGGCGCGGGCTGGCTGCGTTGCCCGGGGACCTGCCCTCC TGGACGCGGAGCCTAAACCTGAGTTACAACAAACTCTCTGAGATTGACCCTGCTGGTT TTGAGGACTTGCCGAACCTACAGGAAGTGTACCTCAATAATAATGAGTTGACAGCGGT ACCATCCCTGGGCGCTGCTTCATCACATGTCGTCTCTCTCTTTCTGCAGCACAACAAG ATTCGCAGCGTGGAGGGGAGCCAGCTGAAGGCCTACCTTTCCTTAGAAGTGTTAGATC TGAGTTTGAACAACATCACGGAAGTGCGGAACACCTGCTTTCCACACGGACCGCCTAT AAAGGAGCTGAACCTGGCAGGCAATCGGATTGGCACCCTGGAGTTGGGAGCATTTGAT GGTCTGTCACGGTCGCTGCTAACTCTTCGCCTGAGCAAAAACAGGATCACCCAGCTTC CTGTAAGAGCATTCAAGCTACCCAGGCTGACACAACTGGACCTCAATCGGAACAGGAT TCGGCTGATAGAGGGCCTCACCTTCCAGGGGCTCAACAGCTTGGAGGTGCTGAAGCTT CAGCGAAACAACATCAGCAAACTGACAGATGGGGCCTTCTGGGGACTGTCCAAGATGC ATGTGCTGCACCTGGAGTACAACAGCCTGGTAGAAGTGAACAGCGGCTCGCTCTACGG CCTCACGGCCCTGCATCAGCTCCACCTCAGCAACAATTCCATCGCTCGCATTCACCGC AAGGGCTGGAGCTTCTGCCAGAAGCTGCATGAGTTGGTCCTGTCCTTCAACAACCTGA CACGGCTGGACGAGGAGAGCCTGGCCGAGCTGAGCAGCCTGAGTGTCCTGCGTCTCAG CCACAATTCCATCAGCCACATTGCGGAGGGTGCCTTCAAGGGACTCAGGAGCCTGCGA GTCTTGGATCTGGACCATAACGAGATTTCGGGCACAATAGAGGACACGAGCGGCGCCT TCTCAGGGCTCGACAGCCTCAGCAAGCTGACTCTGTTTGGAAACAAGATCAAGTCTGT GGCTAAGAGAGCATTCTCGGGGCTGGAAGGCCTGGAGCACCTGAACCTTGGAGGGAAT GCGATCAGATCTGTCCAGTTTGATGCCTTTGTGAAGATGAAGAATCTTAAAGAGCTCC ATATCAGCAGCGACAGCTTCCTGTGTGACTGCCAGCTGAAGTGGCTGCCCCCGTGGCT AATTGGCAGGATGCTGCAGGCCTTTGTGACAGCCACCTGTGCCCACCCAGAATCACTG AAGGGTCAGAGCATTTTCTCTGTGCCACCAGAGAGTTTCGTGTGCGATGACTTCCTGA AGCCACAGATCATCACCCAGCCAGAAACCACCATGGCTATGGTGGGCAAGGACATCCG GTTTACATGCTCAGCAGCCAGCAGCAGCAGCTCCCCCATGACCTTTGCCTGGAAGAAA GACAATGAAGTCCTGACCAATGCAGACATGGAGAACTTTGTCCACGTCCACGCGCAGG ACGGGGAAGTGATGGAGTACACCACCATCCTGCACCTCCGTCAGGTCACTTTCGGGCA CGAGGGCCGCTACCAATGTGTCATCACCAACCACTTTGGCTCCACCTATTCACATAAG GCCAGGCTCACCGTGAATGTGTTGCCATCATTCACCAAAACGCCCCACGACATAACCA TCCGGACCACCACCATGGCCCGCCTCGAATGTGCTGCCACAGGTCACCCAAACCCTCA GATTGCCTGGCAGAAGGATGGAGGCACGGATTTCCCCGCTGCCCGTGAGCGACGCATG CATGTCATGCCGGATGACGACGTGTTTTTCATCACTGATGTGAAAATAGATGACGCAG GGGTTTACAGCTGTACTGCTCAGAACTCAGCCGGTTCTATTTCAGCTAATGCCACCCT GACTGTCCTAGAGACCCCATCCTTGGTGGTCCCCTTGGAAGACCGTGTGGTATCTGTG GGAGAAACAGTGGCCCTCCAATGCAAAGCCACGGGGAACCCTCCGCCCCGCATCACCT GGTTCAAGGGGGACCGCCCGCTGAGCCTCACTGAGCGGCACCACCTGACCCCTGACAA CCAGCTCCTGGTGGTTCAGAACGTGGTGGCAGAGGATGCGGGCCGATATACCTGTGAG ATGTCCAACACCCTGGGCACGGAGCGAGCTCACAGCCAGCTGAGCGTCCTGCCCGCAG CAGGCTGCAGGAAGGATGGGACCACGGTAGGCATCTTCACCATTGCTGTCGTGAGCAG CATCGTCCTGACGTCACTGGTCTGGGTGTGCATCATCTACCAGACCAGGAAGAAGAGT GAAGAGTACAGTGTCACCAACACAGATGAAACCGTCGTGCCACCAGATGTTCCAAGCT ACCTCTCTTCTCAGGGGACCCTTTCTGACCGACAAGAAACCGTGGTCAGGACCGAGGG TGGCCCTCAGGCCAATGGGCACATTGAGAGCAATGGTGTGTGTCCAAGAGATGCAAGC CACTTTCCAGAGCCCGACACTCACAGCGTTGCCTGCAGGCAGCCAAAGCTCTGTGCTG GGTCTGCGTATCACAAAGAGCCGTGGAAAGCGATGGAGAAAGCTGAAGGGACACCTGG GCCACATAAGATGGAACACGGTGGCCGGGTCGTATGCAGTGACTGCAACACCGAAGTG GACTGTTACTCCAGGGGACAAGCCTTCCACCCCCAGCCTGTGTCCAGAGACAGCGCAC AGCCAAGTGCGCCAAATGGCCCGGAGCCGGGTGGGAGTGACCAAGAGCATTCTCCACA TCACCAGTGCAGCAGGACTGCCGCTGGGTCCTGCCCCGAGTGCCAAGGGTCGCTCTAC CCCAGTAACCACGATAGAATGCTGACGGCTGTGAAGAAAAAGCCAATGGCATCTCTAG ATGGGAAAGGGGATTCTTCCTGGACTTTAGCAAGGTTGTATCACCCGGACTCCACAGA GCTACAGCCTGCATCTTCATTAACTTCAGGCAGTCCAGAGCGCGCGGAAGCCCAGTAC TTGCTTGTTTCCAATGGCCACCTCCCCAAAGCATGTGACGCCAGTCCCGAGTCCACGC CACTGACAGGACAGCTCCCCGGGAAACAGAGGGTGCCACTGCTGTTGGCACCAAAAAG CTAGGTTTTGTCTACCTCAGTTCTTGTCATACCAATCTCTACGGGAAAGAGAGGTAGG

AGAGGCTGCGAGGAAGCTTGGGTTCAAGCGTCACTCATCTGTACATAGTTGTAACTCC

CATGTGGAGTATCAGTCGCTCACAGGACTTGGATCTGAAGCACAGTAAACGCAAGAGG

GGATTTGTGTACAAAAGGCAAAAAAAAGTATTTGATATCATTGTACATAAGAGTTTTC

AGAGATTTCATATATATCTTTTACAGAGGCTATTTTAATCTTTAGTGCATGGTTAACA

GAAAAAAATTATACAATTTTGACAATATTATTTTTCGTATCAGGTTGCTGTTTAATTT TGGAGGGGGTGGGGAAATAGTTCTGGTGCCTTAACGCATGGCTGGAATTTATAGAGGC TACAACCACATTTGTTCACAGGAGTTTTTGGTGCGGGGTGGGAAGGATGGAAGGCCTT

GGATTTATATTGCACTTCATAGACCCCTAGGCTGCTGTGCGGTGGGACTCCACATGCG

CCGGAAGGAGCTTCAGGTGAGCACTGCTCATGTGTGGATGCCCCTGCAACAGGCTTCC

CTGTCTGTAGAGCCAGGGGTGCAAGTGCCATCCACACTTGCAGTGAATGGCTTTTCCT

TTTAGGTTTAAGTCCTGTCTGTCTGTAAGGCGTAGAATCTGTCCGTCTGTAAGGCGTA

GAATGAGGGTTGTTAATCCATCACAAGCAAAAGGTCAGAACAGTTAAACACTGCCTTT

CCTCCTCCTCTTATTTTATGATAAAAGCAAATGTGGCCTTCTCAGTATCATTCGATTG

CTATTTGAGACTTTTAAATTAAGGTAAAGGCTGCTGGTGTTGGTACCTGTGGATTTTT

CTATACTGATGTTTTCGTTTTGCCAATATAATGAGTATTACATTGGCCTTGGGGGACA

GAAAGGAGGAAGTTCTGACTTTTCAGGGCTACCTTATTTCTACTAAGGACCCAGAGCA

GGCCTGTCCATGCCATTCCTTCGCACAGATGAAACTGAGCTGGGACTGGAAAGGACAG

CCCTTGACCTGGGTTCTGGGTATAATTTGCACTTTTGAGACTGGTAGCTAACCATCTT

ATGAGTGCCAATGTGTCATTTAGTAAAACTTAAATAGAAACAAGGTCCTTCAAATGTT

CCTTTGGCCAAAAGCTGAAGGGAGTTACTGAGAAAATAGTTAACAATTACTGTCAGGT

GTCATCACTGTTCAAAAGGTAAGCACATTTAGAATTTTGTTCTTGACAGTTAACTGAC

TAATCTTACTTCCACAAAATATGTGAATTTGCTGCTTCTGAGAGGCAATGTGAAAGAG

GGAGTATTACTTTTATGTACAAAGTTATTTATTTATAGAAATTTTGGTACAGTGTACA

TTGAAAACCATGTAAAATATTGAAGTGTCTAACAAATGGCATTGAAGTGTCTTTAATA

AAGGTTCATTTATAAATGTCAGTATAGTTGGTGGTCCTTCTTTTACAAACGCAGTCAT

TCTGCCTTTAATTATCTTCCCCCAAAAΑAGAAAAAAAAAATAGGCGAA.GCAAAATCAC

ATACTGTTTGTTTGCTCCAGGGCAGACAACACTGCTAGATTCCTGACATTTTGTTTTG

AATTTTTCTACACCTGGAGCTTGTTAGTCAAGGTCTAAAATCCCTAAGTGTGGTGACC

TTTCCATTTCATCCTGCCTTTTCAAAGCTGGCCCAGGCCCTCCTTTCAGTCTGACATG

AGAATGGCGAGAATGGCTCACCCACCGTGCCCTCCTGCACGAAGCCAGCTGGGCC

ORF Start: ATG at 77 ORF Stop: TAG at 3308

SEQ ID NO: 136 1077 aa MW at ll7735.2kD

NOV30a, MR DLAVLPRLVLIS AQVILLP PAAACTCAGDSLDCGGRGLAALPGDLPSWTRSLN CG59534-01 LSYNKLSEIDPAGFEDLPNLQEVYLNNNELTAVPSLGAASSHWSLFLQHNKIRSVEG Protein Sequence SQLKAYLSLEVLDLSLNNITEVRNTCFPHGPPIKELNLAGNRIGTLELGAFDGLSRSL LTLRLSKNRITQLPVRAFKLPRLTQLDLNRNRIRLIEGLTFQGLNSLEVLKLQRNNIS KLTDGAFWGLSKMHVLHLEYNSLVEVNSGSLYGLTALHQLHLSNNSIARIHRKGWSFC QKLHELVLSFNNLTRLDEESLAELSSLSVLRLSHNSISHIAEGAFKGLRSLRVLDLDH NΞISGTIEDTSGAFSGLDSLSKLTLFGNKIKSVAKRAFSGLEGLEHLNLGGNAIRSVQ FDAFVKMKNLKELHISSDSFLCDCQLK LPP LIGRMLQAFVTATCAHPESLKGQSIF SVPPESFVCDDFLKPQIITQPETTMAMVGKDIRFTCSAASSSSSPMTFAWKKDNEVLT NADMENFVHVHAQDGEV EYTTILHLRQVTFGHEGRYQCVITNHFGSTYSHKARLTVN VLPSFTKTPHDITIRTTTMARLECAATGHPNPQIAWQKDGGTDFPAARERRMHVMPDD DVFFITDVKIDDAGVYSCTAQNSAGSISANATLTVLETPSLWPLEDRWSVGETVAL QC ATGNPPPRIT FKGDRPLSLTERHHLTPDNQLLWQNWAEDAGRYTCEMSNTLG TERAHSQLSVLPAAGCRKDGTTVGIFTIAWSSIVLTSLV VCIIYQTRKKSEEYSVT NTDETWPPDVPSYLSSQGTLSDRQETWRTEGGPQANGHIESNGVCPRDASHFPEPD THSVACRQPKLCAGSAYHKEPWKAMEKAEGTPGPH MEHGGRWCSDCNTEVDCYSRG QAFHPQPVSRDSAQPSAPNGPEPGGSDQEHSPHHQCSRTAAGSCPECQGSLYPSNHDR MLTAVKKKPMASLDGKGDSS TLARLYHPDSTELQPASSLTSGSPERAEAQYLLVSNG HLPKACDASPESTPLTGQLPGKQRVPLLLAPKS

Further analysis ofthe NOV30a protein yielded the following properties shown in Table 3 OB.

Table 30B. Protein Sequence Properties NOV30a

SignalP Cleavage site between residues 29 and 30 analysis: A search ofthe NOV30a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 30C.

In a BLAST search of public sequence databases, the NOV30a protein was found to have homology to the proteins shown in the BLASTP data in Table 30D.

PFam analysis indicates that the NOV30a protein contains the domains shown in the Table 30E.

Example 31.

The NOV31 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 31A.

GCAGGGCCGACATGTGAGGAAGATGTGGATGAATGCCTGTCGGATCCCTGCCTGCACG GCGGAACCTGCAGTGACACTGTGGCAGGCTATATCTGCAGGTGCCCAGAGACCTGGGG TGGGCGCGACTGTTCTGTGCAGCTCACTGGCTGCCAGGGCCACACCTGCCCGCTGGCT GCCACCTGCATCCCTATCTTCGAGTCTGGGGTCCACAGTTACGTCTGCCACTGCCCAC CTGGTACCCATGGACCGTTCTGTGGCCAGAATACCACCTTCTCTGTGATGGCTGGGAG CCCCATTCAGGCATCAGTGCCAGCTGGTGGCCCCCTGGGTCTGGCACTGAGGTTTCGC ACCACACTGCCCGCTGGGACCTTGGCCACTCGCAATGACACCAAGGAAAGCTTGGAGC TGGCATTGGTGGCAGCCACACTTCAGGCCACACTCTGGAGCTACAGCACCACTGTGCT TGTCCTGAGACTGCCGGACCTGGCCCTAAACGATGGCCATTGGCACCAGGTGGAGGTT GTGCTCCATCTAGCGACCCTGGAGCTACGGCTCTGGCATGAGGGCTGCCCTGCCCGGC TCTGTGTGGCCTCTGGTCCTGTGGCCCTGGCTTCCACGGCTTCGGCAACTCCGCTGCC TGCCGGGATCTCCTCTGCCCAGCTGGGGGACGCGACCTTTGCAGGCTGCCTCCAGGAC GTGCGTGTGGATGGCCACCTCCTGCTGCCTGAGGATCTCGGTGAGAACGTCCTCCTGG GCTGTGAGCGCCGAGAGCAGTGCCGGCCTCTGCCTTGTGTCCACGGAGGGTCCTGTGT GGATCTGTGGACTCATTTCCGTTGCGACTGTGCCCGGCCCCATAGAGGTCCCACGTGC GCTGATGAGATTCCTGCTGCCACCTTTGGCTTGGGAGGCGCCCCAAGCTCTGCCTCCT TTCTGCTCCAAGAGCTGCCAGGTCCCAACCTCACAGTGTCTTTCCTTCTCCGCACTCG GGAGTCCGCTGGCCTGTTGCTCCAGTTTGCCAATGACTCCGCAGCTGGCCTAACAGTA TTCCTGAGTGAGGGTCGGATCCGGGCTGAGGTGCCGGGCAGTCCTGCTGTAGTGCTCC CTGGGCGCTGGGATGATGGGCTCCGTCACCTGGTGATGCTCAGCTTCGGGCCTGACCA GCTGCAGGACCTGGGGCAGCACGTGCACGTGGGTGGGAGGCTCCTTGCTGCCGACAGC CAGCCCTGGGGTGGGCCCTTCCGAGGCTGCCTCCAGGACCTGCGACTCGATGGCTGCC ACCTCCCCTTCTTTCCTCTGCCACTGGATAACTCAAGCCAGCCCAGCGAGCTCGGCGG CAGGCAGTCCTGGAACCTCACTGCGGGCTGCGTCTCCGAGGACATGTGCAGTCCTGAC CCCTGTTTCAATGGTGGGACTTGCCTCGTCACCTGGAATGACTTCCACTGTACCTGCC CTGCCAATTTCACGGGGCCTACGTGTGCCCAGCAGCTGTGGTGTCCCGGCCAGCCCTG TCTCCCACCTGCCACGTGTGAGGAGGTCCCTGATGGCTTTGTGTGTGTGGCGGAGGCC ACGTTCCGCGAGGGTCCCCCCGCCGCGTTCAGCGGGCACAACGCGTCGTCAGGGCGCT TGCTCGGCGGCCTGTCGCTGGCCTTTCGCACGCGCGACTCCGAGGCCTGGCTGCTGCG TGCCGCGGCGGGCGCCCTGGAAGGCGTGTGGCTGGCGGTGCGCAATGGCTCGCTGGCG GGGGGCGTGCGCGGAGGCCATGGCCTGCCCGGCGCTGTGCTGCCCATACCGGGGCCGC GCGTGGCCGATGGTGCCTGGCACCGCGTGCGTCTGGCCATGGAGCGCCCGGCGGCCAC CACCTCGCGCTGGCTGCTGTGGCTGGATGGTGCCGCCACCCCGGTGGCGCTGCGCGGC CTGGCCAGTGACCTGGGCTTCCTGCAGGGCCCGGGTGCTGTGCGCATCCTGCTGGCTG AGAACTTCACCGGCTGCTTGGGCCGCGTGGCGCTGGGCGGCCTGCCCCTGCCCTTGGC GCGGCCCCGGCCCGGCGCGGCCCCTGGCGCCCGAGAGCACTTCGCGTCTTGGCCTGGG ACGCCGGCCCCGATCCTCGGCTGCCGCGGCGCGCCCGTGTGTGCGCCCTCGCCCTGTC TGCACGACGGTGCCTGCCGTGACCTCTTCGACGCCTTTGCCTGCGCCTGCGGCCCGGG GTGGGAAGGCCCGCGCTGCGAAGCCCACGTCGACCCCTGTCACTCCGCCCCCTGCGCC CGTGGCCGCTGTCACACGCACCCCGACGGCCGCTTCGAGTGCCGCTGCCCGCCTGGCT TCGGGGGCCCGCGCTGCAGGTTGCCTGTCCCATCCAAGGAGTGCAGCCTGAATGTCAC CTGCCTCGATGGCAGCCCATGTGAGGGTGGCTCTCCCGCTGCCAACTGCAGCTGCCTG GAGGGTCTTGCTGGCCAGAGGTGTCAGGTCCCCACTCTCCCCTGTGAAGCCAACCCCT GCTTGAATGGGGGCACCTGCCGGGCAGCTGGAGGGGTGTCTGAATGTATCTGCAATGC CAGATTCTCCGGCCAGTTCTGTGAAGTGGCGAAGGGCCTGCCCCTGCCGCTGCCATTC CCACTGCTGGAGGTGGCCGTACCTGCAGCCTGTGCCTGCCTCCTCCTCCTCCTCCTGG GCCTCCTTTCAGGGATCCTGGCAGCCCGAAAGCGCCGCCAGTCTGAGGGCACCTACAG CCCAAGCCAGCAGGAGGTGGCTGGGGCCCGGCTGGAGATGGACAGTGTCCTCAAGGTG CCACCGGAGGAGAGACTCATCTAG

ORF Start: TTC at 19 ORF Stop: GAG at 4183

SEQ ID NO: 138 1388 aa MW at 145607.6kD

NOV31a, MKSALIPLVYRGGKRGPEMASPRARKPQSQC DFTVHCATCLGKVTSLLCLYKTRTD CG59289-01 LTPSAGIRIGRECSERFPTPGGNSLELCSEPKLSRVGQCQAQGRCSVPDSYCCNXGNS LELCSEPKLSRVGQCQAQGTVPSEPPSACASDPCAPGTECQATESGGYTCGPMEPRGC Protein Sequence ATQPCHHGALCVPQGPDPTGFRCYCVPGFQGPRCELDIDECASRPCHHGATCRNLADR YECHCPLGYAGVTCE EVDECASAPCLHGGSCLDGVGSFRCVCAPGYGGTRCQLDLDE CQSQPCAHGGTCHDLVNGFRCDCAGTGYEGTHCEREVLECASAPCEHNASCLEGLGSF RCLC PGYSGELCEVDEDECASSPCQHGGRCLQRSDPALYGGVQAAFPGAFSFRHAAG FLCHCPPGFEGADCGVEVDECASRPCLNGGHCQDLPNGFQCHCPDGYAGPTCEEDVDE CLSDPCLHGGTCSDTVAGYICRCPET GGRDCSVQLTGCQGHTCPLAATCIPIFESGV HSYVCHCPPGTHGPFCGQNTTFSVMAGSPIQASVPAGGPLGLALRFRTTLPAGTLATR NDTKESLELALVAATLQATLWSYSTTVLVLRLPDLALNDGHWHQVEWLHLATLELRL HEGCPARLCVASGPVALASTASATPLPAGISSAQLGDATFAGCLQDVRVDGHLLLPE DLGENVLLGCERREQCRPLPCVHGGSCVDL THFRCDCARPHRGPTCADEIPAATFGL GGAPSSASFLLQELPGPNLTVSFLLRTRESAGLLLQFANDSAAGLTVFLSEGRIRAEV PGSPAWLPGR DDGLRHLVMLSFGPDQLQDLGQHVHVGGRLLAADSQP GGPFRGCL QDLRLDGCHLPFFPLPLDNSSQPSELGGRQSWNLTAGCVSEDMCSPDPCFNGGTCLVT NDFHCTCPANFTGPTCAQQL CPGQPCLPPATCEEVPDGFVCVAEATFREGPPAAFS GHNASSGRLLGGLSLAFRTRDSEA LLRAAAGALEGV LAVRNGSLAGGVRGGHGLPG AVLPIPGPRVADGAWHRVRLA ERPAATTSRWLLWLDGAATPVALRGLASDLGFLQGP GAVRILLAENFTGCLGRVALGGLPLPLARPRPGAAPGAREHFASWPGTPAPILGCRGA PVCAPSPCLHDGACRDLFDAFACACGPG EGPRCEAHVDPCHSAPCARGRCHTHPDGR FECRCPPGFGGPRCRLPVPSKECSLNVTCLDGSPCEGGSPAANCSCLEGLAGQRCQVP TLPCEANPCLNGGTCRAAGGVSECICNARFSGQFCEVAKGLPLPLPFPLLEVAVPAAC ACLLLLLLGLLSGILAARKRRQSEGTYSPSQQEVAGARLEMDSVLKVPPEERLI

SEQ ID NO: 139 4200 bp

NOV31b, TAACGAGGTCTAATTTAATTCTCCCAACAGCCTATGAAGTCAGCTCTGATACCCCTAG CG59289-02 DNA TTTACAGAGGAGGTAAACGAGGCCCAGAGATGGCCAGTCCCAGAGCCAGGAAGCCCCA GAGCCAGTGCTGGGATTTCACAGTACACTGTGCTACTTGCCTAGGCAAAGTCACGTCT Sequence CTTCTCTGTCTCTACAAAACGAGGACAGACTGGCTTACTCCGAGCGCTGGTATAAGGA TTGGAAGAGAATGCAGTGAGCGGTTCCCCACCCCAGGAGGTAACTCCCTGGAACTGTG CTCTGAGCCCAAACTCTCAAGGGTTGGTCAGTGCCAGGCACAGGGTAGGTGCTCCGTC CCTGACAGCTATTGTTGCAATCGAGGTAACTCCCTGGAACTGTGCTCTGAGCCCAAAC TCTCAAGGGTTGGTCAGTGCCAGGCACAGGGGACGGTGCCTTCAGAGCCCCCCAGTGC CTGTGCCTCAGACCCGTGCGCTCCAGGGACCGAGTGCCAGGCTACCGAGAGTGGTGGC TATACCTGTGGGCCCATGGAGCCCCGGGGCTGTGCCACCCAGCCATGCCACCACGGCG CTCTGTGTGTGCCCCAGGGTCCAGATCCCACCGGCTTCCGCTGCTACTGCGTGCCGGG TTTCCAGGGCCCACGCTGCGAGCTGGACATCGATGAGTGTGCATCCCGGCCGTGCCAC CATGGGGCCACCTGCCGCAACCTGGCCGATCGCTACGAGTGCCATCGCCCCCTTGGCT ATGCAGGCGTGACCTGCGAGACGGAGGTGGACGAGTGCGCCTCAGCGCCCTGCCTGCA CGGGGCCTCGTGCCTGGACGGCGTGGGCTCCTTCCGCTGTGTGTGCGCGCCAGGCTAC GGGGGCACCCGTTGCCAGCTGGACCTCGACGAGTGCCAGAGCCAGCCGTGCGCACATG GGGGCACGTGCCACGACCTGGTCAACGGGTTCCGGTGCGACTGCGCGGGCACCGGCTA CGAGGGCACGCACTGCGAGCGGGAGGTGCTGGAGTGCGCATCGGCGCCCTGCGAGCAC AACGCGTCCTGCCTCGAGGGCCTCGGGAGCTTCCGCTGCCTCTGTTGGCCAGGCTACA GCGGCGAGCTGTGCGAGGTGGACGAGGACGAGTGTGCATCGAGCCCCTGCCAGCATGG GGGCCGATGCCTGCAGCGCTCTGACCCGGCCCTCTACGGGGGTGTCCAGGCCGCCTTC CCTGGCGCCTTCAGCTTCCGCCATGCTGCGGGTTTCCTGTGCCACTGCCCTCCTGGCT TTGAGGGAGCCGACTGCGGTGTGGAGGTGGACGAGTGTGCCTCACGGCCATGCCTCAA CGGAGGCCACTGCCAGGACCTGCCCAATGGCTTCCAGTGTCACTGCCCAGATGGCTAC GCAGGGCCGACATGTGAGGAAGATGTGGATGAATGCCTGTCGGATCCCTGCCTGCACG GCGGAACCTGCAGTGACACTGTGGCAGGCTATATCTGCAGGTGCCCAGAGACCTGGGG TGGGCGCGACTGTTCTGTGCAGCTCACTGGCTGCCAGGGCCACACCTGCCCGCTGGCT GCCACCTGCATCCCTATCTTCGAGTCTGGGGTCCACAGTTACGTCTGCCACTGCCCAC CTGGTACCCATGGACCGTTCTGTGGCCAGAATACCACCTTCTCTGTGATGGCTGGGAG CCCCATTCAGGCATCAGTGCCAGCTGGTGGCCCCCTGGGTCTGGCACTGAGGTTTCGC ACCACACTGCCCGCTGGGACCTTGGCCACTCGCAATGACACCAAGGAAAGCTTGGAGC TGGCATTGGTGGCAGCCACACTTCAGGCCACACTCTGGAGCTACAGCACCACTGTGCT TGTCCTGAGACTGCCGGACCTGGCCCTAAACGATGGCCATTGGCACCAGGTGGAGGTT GTGCTCCATCTAGCGACCCTGGAGCTACGGCTCTGGCATGAGGGCTGCCCTGCCCGGC TCTGTGTGGCCTCTGGTCCTGTGGCCCTGGCTTCCACGGCTTCGGCAACTCCGCTGCC TGCCGGGATCTCCTCTGCCCAGCTGGGGGACGCGACCTTTGCAGGCTGCCTCCAGGAC GTGCGTGTGGATGGCCACCTCCTGCTGCCTGAGGATCTCGGTGAGAACGTCCTCCTGG GCTGTGAGCGCCGAGAGCAGTGCCGGCCTCTGCCTTGTGTCCACGGAGGGTCCTGTGT GGATCTGTGGACTCATTTCCGTTGCGACTGTGCCCGGCCCCATAGAGGTCCCACGTGC GCTGATGAGATTCCTGCTGCCACCTTTGGCTTGGGAGGCGCCCCAAGCTCTGCCTCCT TTCTGCTCCAAGAGCTGCCAGGTCCCAACCTCACAGTGTCTTTCCTTCTCCGCACTCG GGAGTCCGCTGGCCTGTTGCTCCAGTTTGCCAATGACTCCGCAGCTGGCCTAACAGTA TTCCTGAGTGAGGGTCGGATCCGGGCTGAGGTGCCGGGCAGTCCTGCTGTAGTGCTCC Sequence comparison ofthe above protein sequences yields the following sequence relationships shown in Table 3 IB.

Table 31B. Comparison of NOV31a against NOV31b and NOV31c.

NOV31a Residues/ Identities/

Protein Sequence Match Residues Similarities for the Matched Region

NOV31b 1..1388 1284/1388 (92%) 1..1388 1284/1388 (92%)

Further analysis ofthe NOV31a protein yielded the following properties shown in Table 31C.

Table 31C. Protein Sequence Properties NOV31a

PSort 0.7000 probability located in plasma membrane; 0.3000 probability located in analysis: microbody (peroxisome); 0.2000 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in mitochondrial inner membrane

SignalP No Known Signal Sequence Indicated analysis:

A search ofthe NOV3 la protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 3 ID.

In a BLAST search of public sequence databases, the NOV3 la protein was found to have homology to the proteins shown in the BLASTP data in Table 3 IE.

PFam analysis indicates that the NOV31a protein contains the domains shown in the Table 31F.

Example 32.

The NOV32 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 32A.

Table 32A. NOV32 Sequence Analysis

SEQ ID NO: 141 2855 bp

NOV32a, GAGGGAATGCGCGCAGCTCACAGGCCCTGGGAGTGAGCTGGTGCCCGGCGACCTGGCA

CG57111-01 DNA CCCGCGCCTGGATATGGGGCGTCTACATCGTCCCAGGAGCAGCACCAGCTACAGGAAC CTGCCGCATCTGTTTCTGTTTTTCCTCTTCGTGGGACCCTTCAGCTGCCTCGGGAGTT

Sequence ACAGCCGGGCCACCGAGCTTCTGTACAGCCTAAACGAGGGACTACCCGCGGGGGTGCT CATCGGCAGCCTGGCCGAGGACCTGCGGCTGCTGCCCAGGTCTGCAGGGAGGCCGGAC CCGCAGTCGCAGCTGCCAGAGCGCACCGGTGCTGAGTGGAACCCCCCTCTCTCCTTCA GCCTGGCCTCCCGGGGACTGAGTGGCCAGTACGTGACCCTAGACAACCGCTCTGGGGA GCTGCACACTTCAGCTCAGGAGATCGACAGGGAGGCCCTGTGTGTTGAAGGGGGTGGA GGGACTGCGTGGAGCGGCAGCGTTTCCATCTCCTCCTCTCCTTCTGACTCTTGTCTTT TGCTGCTGGATGTGCTTGTCCTGCCTCAGGAATACTTCAGGTTTGTGAAGGTGAAGAT CGCCATCAGAGACATCAATGACAACGCCCCGCAGTTCCCTGTTTCCCAGATCTCGGTG TGGGTCCCGGAAAATGCACCTGTAAACACCCGACTGGCCATAGAGCATCCTGCTGTGG ACCCAGATGTTGGCATTAATGGGGTTCAGACCTATCGCTTACTGGACTACCATGGTAT GTTCACCCTGGACGTGGAGGAGAATGAGAATGGGGAGCGCACCCCCTACCTAATTGTC ATGGGTGCTTTGGACAGGGAAACCCAGGACCAGTATGTGAGCATCATCACAGCTGAGG ATGGTGGGTCTCCACCACTTTTGGGCAGTGCCACTCTCACCATTGGCATCAGTGACAT TAATGACAATTGCCCTCTCTTCACAGACTCACAAATCAATGTCACTGTGTATGGGAAT GCTACAGTGGGCACCCCAATTGCAGCTGTCCAGGCTGTGGATAAAGACTTGGGGACCA ATGCTCAAATTACTTATTCTTACAGTCAGAAAGTTCCACAAGCATCTAAGGATTTATT TCACCTGGATGAAAACACTGGAGTCATTAAACTTTTCAGTAAGATTGGAGGAAGTGTT CTGGAGTCCCACAAGCTCACCATCCTTGCTAATGGACCAGGCTGCATCCCTGCTGTAA TCACTGCTCTTGTGTCCATTATTAAAGTTATTTTCAGACCCCCTGAAATTGTCCCTCG TTACATAGCAAACGAGATAGATGGTGTTGTTTATCTGAAAGAACTGGAACCCGTTAAC ACTCCCATTGCGTTTTTCACCATAAGAGATCCAGAAGGTAAATACAAGGTTAACTGCT ACCTGGATGGTGAAGGGCCGTTTAGGTTATCACCTTACAAACCATACAATAATGAATA TTTACTAGAGACCACAAAACCTATGGACTATGAGCTACAGCAGTTCTATGAAGTAGCT GTGGTGGCTTGGAACTCTGAGGGATTTCATGTCAAAAGGGTCATTAAA.GTGCAACTTT TAGATGACAATGATAATGCTCCAATTTTCCTTCAACCCTTAATAGAACTAACCATCGA AGAGAACAACTCACCCAATGCCTTTTTGACTAAGCTGTATGCTACAGATGCCGACAGC GAGGAGAGAGGCCAAGTTTCATATTTTCTGGGACCTGATGCTCCATCATATTTTTCCT TAGACAGTGTCACAGGAATTCTGACAGTTTCTACTCAGCTGGACCGAGAAGAGAAAGA; AAAGTACAGATACACTGTCAGAGCTGTTGACTGTGGGAAGCCACCCAGAGAATCAGTA¹ GCCACTGTGGCCCTCACAGTGTTGGATAAAAATGACAACAGTCCTCGGTTTATCAACA AGGACTTCAGCTTTTTTGTGCCTGAAAACTTTCCAGGCTATGGTGAGATTGGAGTAAT TAGTGTAACAGATGCTGACGCTGGACGAAATGGATGGGTCGCCCTCTCTGTGGTGAAC CAGAGTGATATTTTTGTCATAGATACAGGAAAGGGTATGCTGAGGGCTAAAGTCTCTT TGGACAGAGAGCAGCAAAGCTCCTATACTTTGTGGGTTGAAGCTGTTGATGGGGGTGA GCCTGCCCTCTCCTCTACAGCAAAAATCACAATTCTCCTTCTAGATATCAATGACAAC CCTCCTCTTGTTTTGTTTCCTCAGTCTAATATGTCTTATCTGTTAGTACTGCCTTCTA CTCTGCCAGGCTCCCCGGTTACAGAAGTCTATGCTGTCGACAAAGACACAGGCATGAA TGCTGTCATAGCTTACAGCATCATAGGGAGAAGAGGTCCTAGGCCTGAGTCCTTCAGG ATTGACCCTAAAACTGGCAACATTACTTTGGAAGAGGCATTGCTGCAGACAGATTATG GGCTCCATCGCTTACTGGTGAAAGTGAGTGATCATGGTTATCCCGAGCCTCTCCACTC CACAGTCATGGTGAACCTATTTGTCAATGACACTGTCAGTAATGAGAGTTACATTGAG AGTCTTTTAAGAAAAGAACCAGAGATTAATATAGAGGAGAAAGAACCACAAATCTCAA TAGAACCGACTCATAGGAAGGTAGAATCTGTGTCTTGTATGCCCACCTTAGTAGCTCT GTCTGTAATAAGCTTGGGTTCCATCACACTGGTCACAGGGATGGGCATATACATCTGT TTAAGGAAAGGGGAAAAGCATCCCAGGGAAGATGAAAATTTGGAAGTACAGATTCCAC TGAAAGGAAAAATTGACTTGCATATGCGAGAGAGAAAGCCAATGGATATTTCTAATAT TTGATATTTCATG

Further analysis ofthe NOV32a protein yielded the following properties shown in Table 32B.

Table 32B. Protein Sequence Properties NOV32a

PSort 0.6400 probability located in plasma membrane; 0.4000 probability located in analysis: Golgi body; 0.3000 probability located in endoplasmic reticulum (membrane); 0.0300 probability located in mitochondrial inner membrane

SignalP Cleavage site between residues 57 and 58 analysis:

A search ofthe NOV32a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 32C.

In a BLAST search of public sequence databases, the NOV32a protein was found to have homology to the proteins shown in the BLASTP data in Table 32D.

PFam analysis indicates that the NOV32a protein contains the domains shown in the Table

32E.

Example 33.

The NOV33 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 33A.

LGGLACQTALVFPRALQATHYSLLATLELLGKLLLGTLAGGLADGLGPHPCFLLLLIL SAFPVLYLDLAPSTFL

Sequence comparison ofthe above protein sequences yields the following sequence relationships shown in Table 33B.

Further analysis ofthe NOV33a protein yielded the following properties shown in Table 33C.

Table 33C. Protein Sequence Properties NOV33a

PSort 0.6400 probability located in plasma membrane; 0.4600 probability located in analysis: Golgi body; 0.3700 probability located in endoplasmic reticulum (membrane); 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 63 and 64 analysis:

A search ofthe NOV33a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 33D.

In a BLAST search of public sequence databases, the NOV33a protein was found to have homology to the proteins shown in the BLASTP data in Table 33E.

PFam analysis indicates that the NOV33a protein contains the domains shown in the Table 33F.

Example 34.

The NOV34 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 34A.

Table 34A. NOV34 Sequence Analysis

Further analysis ofthe NOV34a protein yielded the following properties shown in Table 34B.

Table 34B. Protein Sequence Properties NOV34a

PSort 0.4500 probability located in cytoplasm; 0.1626 probability located in lysosome analysis: (lumen); 0.1139 probability located in microbody (peroxisome); 0.1000 probability located in mitochondrial matrix space

SignalP No Known Signal Sequence Indicated analysis:

A search ofthe NOV34a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 34C.

Table 34C. Geneseq Results for NOV34a

NOV34a Identities/

Geneseq Protein/Organism/Length Residues/ Similarities for Expect Identifier [Patent #, Date] Match the Matched Value Residues Region

No Significant Matches Found In a BLAST search of public sequence databases, the NOV34a protein was found to have homology to the proteins shown in the BLASTP data in Table 34D.

Table 34D. Public BLASTP Results for NOV34a

Protein NOV34a Identities/

Accession Residues/ Expect

Protein/Organism/Length Similarities for the

Match

Number Matched Portion Value Residues

No Significant Matches Found

PFam analysis indicates that the NOV34a protein contains the domains shown in the Table 34E.

Example 35.

The NOV35 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 35 A.

CG59525-01 LLLTHNLPHDLIGYN YKGERVEANHHITGYVIGTLITTPGPAHSIQGTIYPNASLLI Protein Sequence QNVTQDTGFYTLHAIKINPEKEEVSGQFHVYE NAPGLPVGAFTGIVTRVLVGVAPVA TLACFLLLVRTGRASGQHDFREQLPGHGPSNNSTYPTSPLSPAQAPLPDPRTAAPIYE ELLNHDTNIYCWVNHKADWS

Further analysis ofthe NOV35a protein yielded the following properties shown in Table 35B.

Table 35B. Protein Sequence Properties NOV35a

PSort 0.8500 probability located in endoplasmic reticulum (membrane); 0.4400 analysis: probability located in plasma membrane; 0.1358 probability located in microbody (peroxisome); 0.1000 probability located in mitochondrial inner membrane

SignalP Cleavage site between residues 42 and 43 analysis:

A search ofthe NOV35a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 35C.

In a BLAST search of public sequence databases, the NOV35a protein was found to have homology to the proteins shown in the BLASTP data in Table 35D.

PFam analysis indicates that the NOV35a protein contains the domains shown in the Table 35E.

Table 35E. Domain Analysis of NO 35a

Identities/

Pfam Domain NOV35a Match Region Similarities Expect Value for the Matched Region

No Significant Matches Found

Example 36.

The NOV36 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 36A.

TATACTCCTTAGTATCAAAGATATCACCAGACTGGATTAGCTCCATGAGTATTATTCG

ATCCCACCGAACACAAGAGGACACAGTGGTAGCACTCTCGGTGACTGGCATCCTGAAG

GTCTGGATTGTTACCTCGGAAATAAGTGACATGCAGGATACTGAGCCAATATTTGAGG

AGGAATCCAAACCAATTTATTGTCAGAATTGCCAAAGCATCTCTTTTTGTGCATTTAC

ACAAAGGTCACTTTTGGTTGTGTGTTCCAAATATTGGAGGGTATTCGATGCCGGAGAC

TATTCCTTGTTGTGTTCAGGTCCTAGTGAAAATGGACAGACATGGACCGGGGGGGACT

TTGTCTCATCAGATAAAGTCATCATTTGGACAGAAAATGGGCAAAGTTATATTTACAA

ACTACCTGCCAGTTGCCTTCCAGCTAGTGATTCATTCCGCAGTGATGTGGGGAAGGCA

GTTGAAAATTTAATTCCTCCTGTACAACATATCCTCTTGGATCGAAAAGATAAAGAGT

TGCTAATTTGTCCTCCTGTTACTCGGTTCTTCTATGGATGCAGAGAATATTTCCATAA

ACTGTTAATTCAGGGTGATTCTTCTGGAAGGTTGAATATTTGGAACATATCAGACACA

GCTGATAAACAGGGAAGTGAAGAAGGGCTGGCAATGACAACTTCTATTAGTTTGCAAG

AGGCATTTGATAAACTGAATCCTTGTCCTGCTGGAATTATAGATCAGCTGAGTGTGAT

TCCCAATAGTAATGAACCTCTTAAAGTAACTGCAAGTGTGTACATACCAGCACATGGA

CGACTTGTTTGTGGTCGTGAAGATGGAAGCATAGTTATTGTACCTGCCACACAGACGG

CCATAGTACAGCTGTTGCAAGGGGAACACATGCTCAGAAGAGGTTGGCCACCTCACAG

AACACTCCGTGGTCATCGGAACAAAGTCACATGTTTGCTATATCCTCATCAGGTCTCA

GCTCGGTATGATCAAAGATACCTGATATCTGGAGGTGTGGATTTTTCAGTCATAATTT

GGGACATATTTTCTGGAGAAATGAAACATATCTTCTGTGTTCATGGTGGTGAGATTAC

TCAACTTCTAGTTCCACCTGAAAACTGTAGTGCAAGAGTACAGCACTGCATCTGCTCT

GTAGCCAGTGACCACTCAGTAGGACTTCTAAGTTTGCGAGAGAAAAAATGCATAATGT

TGGCATCTCGTCACCTTTTTCCTATTCAAGTAATCAAATGGAGGCCTTCTGATGATTA

CCTGGTGGTGGGGTGTTCAGATGGTTCTGTGTACGTCTGGCAAATGGATACTGGTGCA

TTGGATCGTTGTGTGATGGGGATAACAGCAGTTGAGATTCTAAACGCTTGTGATGAAG

CTGTTCCTGCTGCTGTTGATTCACTTAGTCATCCAGCAGTCAACCTAAAACAAGCTAT

GACGAGACGTAGTCTTGCTGCTCTTAAAAATATGGCCCATCATAAGCTACAAACCCTT

GCAACTAACCTCTTGGCTTCTGAGGCATCTGACAAGGGAAATTTACCTAAATATTCTC

ATAACTCCCTGATGGTTCAAGCAATAAAGACAAACCTAACAGACCCGGACATACATGT

GCTATTCTTTGATGTGGAAGCGTTGATTATTCAACTCCTGACTGAAGAAGCCTCTAGG

CCGAATACTGCTCTTATTTCCCCAGAGAATTTGCAAAAAGCATCTGGCAGTTCAGACA

AAGGGGGCTCTTTTTTAACTGGAAAACGAGCAGCAGTTCTCTTCCAACAAGTGAAAGA

AACGATCAAAGAGAACATCAAGGAACACCTCCTTGATGATGAAGAGGAGGATGAGGAG

ATAATGAGGCAGAGAAGGGAAGAAAGTGATCCTGAATATCGGTCCAGCAAATCAAAGC

CATTGACCCTATTAGAATATAATTTAACTATGGACACTGCAAAGCTGTTTATGTCCTG

CCTTCACGCCTGGGGTTTGAATGAAGTACTGGATGAAGTTTGCCTGGATCGCCTTGGA

ATGCTGAAACCCCACTGCACCGTATCGTTTGGCCTCTTGTCAAGAGGAGGCCATATGT

CACTGATGCTGCCGGGTTATAATCAGCCTGCTTGTAAACTGTCACATGGGAAAACAGA

AGTAGGAAGGAAGCTGCCAGCGTCTGAGGGAGTAGGAAAGGGAACTTACGGAGTGTCC

CGTGCCGTCACCACACAGCATCTCCTGTCTATCATTTCTTTGGCAAATACTTTAATGA

GTATGACCAATGCAACTTTTATTGGTGATCATATGAAGAAGGGTCCTACCAGGCCACC

TAGACCAAGCACCCCAGACCTTTCTAAGGCAAGGGGTTCCCCTCCAACTTCCAGTAAT

ATTGTGCAAGGACAGATTAAACAAGTTGCTGCACCTGTCGTTTCCGCTCGGTCTGATG

CTGATCACTCTGGCTCTGACCCTCCTTCTGCTCCTGCTTTACATACCTGTTTCTTAGT

AAATGAAGGTTGGAGTCAGTTAGCTGCTATGCACTGTGTTATGCTGCCAGACCTACTG

GGATTGGATAAATTTAGGCCTCCCCTTCTGGAGATGCTGGCCCGAAGATGGCAAGATC

GATGCTTGGAGGTAAGAGAAGCCGCGCAGGCCCTGCTTCTGGCGGAACTGAGAAGAAT

TGAGCAGGCAGGCAGGAAGGAAGCCATTGATGCCTGGGCTCCTTACTTACCTCAGTAC

ATAGACCACGTCATATCACGTGGAGTCACATCAGAAGCCGCGCAGACTATCACCACGG

CTCCTGATGCCTCAGGGCCTGAAGCAAAAGTCCAGGAGGAAGAGCATGACCTTGTTGA

CGATGACATCACCACTGGTTGCTTATCAAGTGTCCCACAAATGAAAAAAATTTCTACA

TCTTACGAGGAAAGACGGAAGCAAGCTACCGCTATTGTTTTACTTGGAGTAATAGGAG

CTGAATTTGGTGCTGAAATTGAACCTCCTAAACTATTGACCAGACCTCGAAGCTCTAG

CCAAATTCCTGAGGGATTCGGGTTGACTAGTGGTGGATCCAACTACTCGCTGGCCAGA

CATACTTGCAAGGCACTGACGTTTCTTCTGCTACAGCCTCCAAGCCCCAAACTTCCTC

CACACAGCACTATCCGAAGAACAGCCATTGATCTGATTGGACGTGGGTTCACTGTTTG

GGAGCCTTACATGGATGTGTCCGCTGTTCTGATGGGGCTTCTCGAACTTTGTGCCGAT

GCCGAGAAACAACTTGCCAACATCACAATGGGGTTGCCTCTGAGCCCAGCAGCTGACT

CGGCCCGCTCTGCGAGGCATGCCCTCTCGCTCATTGCCACCGCCAGACCACCCGCCTT

CATCACCACCATAGCCAAAGAGGTACACAGACATACGGCTCTTGCAGCAAATACCCAA

TCACAGCAGAATATGCACACAACAACTCTTGCACGAGCTAAAGGGGAAATTTTGAGAG

TCATTGAAATTCTTATTGAAAAGATGCCCACAGATGTTGTGGATCTTCTCGTGGAGGT

Further analysis ofthe NOV36a protein yielded the following properties shown in Table 36B.

Table 36B. Protein Sequence Properties NO 36a

PSort 0.8110 probability located in plasma membrane; 0.6400 probability located in analysis: endoplasmic reticulum (membrane); 0.3700 probability located in Golgi body; 0.1000 probability located in endoplasmic reticulum (lumen)

SignalP Cleavage site between residues 22 and 23 analysis:

A search ofthe NOV36a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 36C.

Table 36C. Geneseq Results for NOV36a

In a BLAST search of public sequence databases, the NOV36a protein was found to have homology to the proteins shown in the BLASTP data in Table 36D.

PFam analysis indicates that the NOV36a protein contains the domains shown in the Table 36E.

Example 37.

The NOV37 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 37A.

Sequence CAGGACAGAAACTGGTGAGTGACTGCACAGAGTTCACTGAAACGGAATGCCTTCCTTG CGGTGAAAGCGAATTCCTAGACACCTGGAACAGAGAGACACACTGCCACCAGCACAAA TACTGCGACCCCAACCTAGGGCTTCGGGTCCAGCAGAAGGGCACCTCAGAAACAGACA CCATCTGCACCTGTGAAGAAGGCTGGCACTGTACGAGTGAGGCCTGTGAGAGCTGTGT CCTGCACCGCTCATGCTCGCCCGGCTTTGGGGTCAAGCAGATTGGTCCCCAGGATCGG CTGAGAGCCCTGGTGGTGATCCCCATCATCTTCGGGATCCTGTTTGCCATCCTCTTGG TGCTGGTCTTTATCAAAAAGGTGGCCAAGAAGCCAACCAATAAGGCCCCCCACCCCAA GCAGGAACCCCAGGAGATCAATTTTCCCGACGATCTTCCTGGCTCCAACACTGCTGCT CCAGTGCAGGAGACTTTACATGGATGCCAACCGGTCACCCAGGAGGATGGCAAAGAGA GTCGCATCTCAGTGCAGGAGAGACAGTGAGGCTGCACCCACCCAGGAGTGTGGCCACG

TGGGCAAACAGGCAGTTGGCCAGAGAGCCTGGTGCTGCTGCTGCAGGGGTGCAGGCAG

AAGCGGGGAGCTATGCCCAGTCAGTGCCAGCCCCTC

ORF Start: ATG at 48 ORF Stop: TGA at 723

SEQ ID NO: 156 225 aa MW at25098.5kD

NOV37a, MVRLPLQCVL GCLLTAVHPEPPTACREKQYLINSQCCSLCQPGQ LVSDCTEFTETΞ CG57245-02 CLPCGESEFLDT NRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCEEG HCTSEAC ESCVLHRSCSPGFGVKQIGPQDRLRALWIPIIFGILFAILLVLVFIKKVAKKPTNKA Protein Sequence PHPKQEPQEINFPDDLPGSNTAAPVQETLHGCQPVTQEDGKESRISVQERQ

SEQ ID NO: 157 1016 bp

NOV37b, GCCTCGCTCGGGCGCCCAGTGGTCCTGCCGCCTGGTCTCACCTCGCCATGGTTCGTCT CG57245-04 DNA GCCTCTGCAGTGCGTCCTCTGGGGCTGCTTGCTGACCGCTGTCCATCCAGAACCACCC Sequence ACTGCATGCAGAGAAAAACAGTACCTAATAAACAGTCAGTGCTGTTCTTTGTGCCAGC CAGGACAGAAACTGGTGAGTGACTGCACAGAGTTCACTGAAGCGGAATGCCTTCCTTG CGGTGAAAGCGAATTCCTAGACACCTGGAACAGAGAGACACACTGCCACCAGCACAAA TACTGCGACCCCAACCTAGGGCTTCGGGTCCAGCAGAAGGGCACCTCAGAAACAGACA CCATCTGCACCTGTGAAGAAGGCTGGCACTGTACGAGTGAGGCCTGTGAGAGCTGTGT CCTGCACCGCTCATGCTCGCCCGGCTTTGGGGTCAAGCAGATTGCTACAGGGGTTTCT GATACCATCTGCGAGCCCTGCCCAGTCGGCTTCTTCTCCAATGTGTCATCTGCTTTCG AAAAATGCCACCCTTGGACAAGCTGTGAGACCAAAGACCTGGTTGTGCAACAGGCAGG CACAAACAAGACTGATGTTGTCCGTGGTCCCCAGGATCGGCTGAGAGCCCTGGTGGTG ATCCCCATCATCTTCGGGATCCTGTTTGCCATCCTCCTGGTGCTGGTCTTTATCAGTG AGTCCTCAGAAAAGGTGGCCAAGAAGCCAACCAATAAGGCCCCCCACCCCAAGCAGGA ACCCCAGGAGATCAATTTTCCCGACGATCTTCCTGGCTCCAACACTGCTGCTCCAGTG CAGGAGACTTTACATGGATGCCAACCGGTCACCCAGGAGGATGGCAAAGAGAGTCGCA TCTCAGTGCAGGAGAGACAGTGAGGCTGCACCCACCCAGGAGTGTGGCCACGTGGGCA

AACAGGCAGTTGGCCAGAGAGCCTGGTGCTGCTGCTGCAGGGGTGCAGGCAGAAGCGG

GGAGCTATGCCCAGTCAGTGCCAGCCCCTC

ORF Start: ATG at 48 ORF Stop: TGA at 891

SEQ ID NO: 158 281 aa MW at 31033.0kD

NOV37b, MVRLPLQCVLWGCLLTAVHPEPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTEAE CG57245-04 CLPCGESEFLDT NRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCEEG HCTSEAC ESCVLHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHP TSCETKDLW Protein Sequence QQAGTNKTDWRGPQDRLRALWIPIIFGILFAILLVLVFISESSEKVA KPTNKAPH PKQEPQEINFPDDLPGSNTAAPVQETLHGCQPVTQEDGKESRISVQERQ

SEQ ID NO: 159 375 bp

NOV37c, AGATCTGAACCACCCACTGCATGCAGAGAAAAACAGTACCTAATAAACAGTCAGTGCT 174308232 DNA GTTCTTTGTGCCAGCCAGGACAGAAACTGGTGAGTGACTGCACAGAGTTCACTGAAAC GGAATGCCTTCCTTGCGGTGAAAGCGAATTCCTAGACACCTGGAACAGAGAGACACAC Sequence TGCCACCAGCACAAATACTGCGACCCCAACCTAGGGCTTCGGGTCCAGCAGAAGGGCA CCTCAGAAACAGACACCATCTGCACCTGTGAAGAAGGCTGGCACTGTACGAGTGAGGC CTGTGAGAGCTGTGTCCTGCACCGCTCATGCTCGCCCGGCTTTGGGGTCAAGCAGATT GGTCCCCAGGATCGGCTGAGACTCGAG

ORF Start: AGA at 1 ORF Stop: at 376

SEQ ID NO: 160 125 aa MW at l4132.6kD NOV37c, RSEPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTETECLPCGESEFLDT NRETH 174308232 Protein CHQHKYCDPNLGLRVQQKGTSETDTICTCEEG HCTSEACESCVLHRSCSPGFGVKQI GPQDRLRLE Sequence

Sequence comparison ofthe above protein sequences yields the following sequence r reellaattiioonnsshhiinpss s shhoowwnn i inn T Taabbllee 3377BB..

Table 37B. Comparison of NOV37a against NOV37b through NO 37c.

NOV37a Residues/ Identities/

Protein Sequence Match Residues Similarities for the Matched Region

NOV37b 1..225 204/281 (72%) 1..281 205/281 (72%)

NOV37c 21..141 121/121 (100%) 3..123 121/121 (100%)

Further analysis ofthe NOV37a protein yielded the following properties shown in Table 37C.

Table 37C. Protein Sequence Properties NOV37a

SignalP Cleavage site between residues 21 and 22 analysis:

A search ofthe NOV37a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 37D.

In a BLAST search of public sequence databases, the NOV37a protein was found to have homology to the proteins shown in the BLASTP data in Table 37E.

PFam analysis indicates that the NOV37a protein contains the domains shown in the Table 37F.

Example 38.

The NOV38 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 38A.

Table 38A. NOV38 Sequence Analysis

SEQ ID NO: 161 1080 bp

NOV38a, GATTTAATTGGCATTATTGTGTTCCCGACCATGAGTGCAGAGACCATGGAGCTGAAGT CG59454-01 DNA GGGTGAGTTTCCTGGCCTTCCTTCTGCTCAACTTTCGTGTCTGCCTCCTTTTGCTTCA Sequence GCTGCTCATGCCTCACTCAGCTCAGTTTTCTGTGCTTGGACCCTCTGGGCCCATCCTG GCCATGGTGGGTGAAGACGCTGATCTGCCCTGTCACCTGTTCCCGACCATGAGTGCAG AGACCATGGAGCTGAAGTGGGTAAGTTCCAGCCTAAGGCAGGTGGTGAACGTGTATGC AGATGGAAAGGAAGTGGAAGACAGGCAGAGTGCACCGTATCGAGGGAGAACTTCGATT CTGCGGGATGGCATCACTGCGGGGAAGGCTGCTCTCCGAATACACAACGTCACAGCCT CTGACAGTGGAAAGTACTTGTGTTATTTCCAAGATGGTGACTTCTATGAAAAAGCCCT GGTGGAGCTGAAGGTTGCAGCACTGGGTTCTAATCTTCACGTCGAAGTGAAGGGTTAT GAAGATGGAGGGATCCATCTGGAGTGCAGGTCCACCGGCTGGTACCCCCAACCCCAAA TACAGTGGGGCAACGCCAAGGGAGAGAACATCCCAGCTGTGGAAGCACCTGTGGTTGC AGATGGAGTGGGCCTATATGAAGTAGCAGCATCTGTGATCATGAAAAGCGGCTCCGGG GAAGGTGTATCCTGCATCATCAGAAATTCCCTCCTCGGCCTGGAAAAGACAGCCAGCA TTTCCATCGCAGACCCCTTCTTCAGGAGCGCCCAGCCCTGGATCGCAGCCCTGGCAGG GACCCTGCCTATCTTGCTGCTGCTTCTCGCCGGAGCCAGTTACTTCTTGTGGAGACAA CAGAAGGAAATAACTGCTCTGTCCAGTGAGATAGAAAGTGAGCAAGAGATGAAAGAAA TGGGATATGCTGCAACAGAGCGGGAAATAAGCCTAAGAGAGAGCCTCCAGGAGGAACT CAAGAGGAAAAAAATCCAGTACTTGACTCGTGGAGAGGAGTCTTCGTCCGATACCAAT AAGTCAGCCTGATGCTCTAATGGAAAAATGGCCCTC

ORF Start: ATG at 31 ORF Stop: TGA at 1054

SEQ ID NO: 162 341 aa MWat37417.4kD

NOV38a, MSAETMELK VSFLAFLLLNFRVCLLLLQLLMPHSAQFSVLGPSGPILAMVGEDADLP CG59454-01 CHLFPTMSAETMELK VSSSLRQVVNVYADGKEVEDRQSAPYRGRTSILRDGITAGKA ALRIHNVTASDSGKYLCYFQDGDFYEKALVELKVAALGSNLHVEVKGYEDGGIHLECR Protein Sequence STGWYPQPQIQ GNAKGENIPAVEAPWADGVGLYEVAASVIMKSGSGEGVSCIIRNS LLGLEKTASISIADPFFRSAQP IAALAGTLPILLLLLAGASYFL RQQKEITALSSE IESEQEMKEMGYAATEREISLRESLQEELKRKKIQYLTRGEESSSDTNKSA

SEQ ID NO: 163 935 bp

NOV38b, ATTTGCTTTCTCTTTTTCCTTTCTTCCGGATGAGAGGCTAAGCCATAATAGAAAGAAT CG59454-03 DNA GGAGAATTATTGATTGACCGTCTTTATTCTGTGGGCTCTGATTCTCCAATGGGAATAC

CAAGGGATGGTTTTCCATACTGGAACCCAAAGGTAAAGACACTCAAGGACAGACATTT Sequence TTGGCAGAGCATAGATGAAAATGGCAAGTTCCCTGGCTTTCCTTCTGCTCAACTTTCA

TGTCTCCCTCCTCTTGGTCCAGCTGCTCACTCCTTGCTCAGCTCAGTTTTCTGTGCTT GGACCCTCTGGGCCCATCCTGGCCATGGTGGGTGAAGACGCTGATCTGCCCTGTCACC TGTTCCCGACCATGAGTGCAGAGACCATGGAGCTGAAGTGGGTAAGTTCCAGCCTAAG GCAGGTGGTGAATGTGTATGCAGATGGAAAGGAAGTGGAAGACAGGCAGAGTGCACCG TATCGAGGGAGAACTTCGATTCTGCGGGATGGCATCACTGCAGGGAAGGCTGCTCTCC GAATACACAACGTCACAGCCTCTGACAGTGGAAAGTACTTGTGTTATTTCCAAGATGG TGACTTCTATGAAAAAGCCCTGGTGGAGCTGAAGGTTGCAGACCCCTTCTTCAGGAGC GCCCAGCCCTGGATCGCAGCCCTGGCAGGGACCCTGCCTATCTTGCTGCTGCTTCTCG CCGGAGCCAGTTACTTCTTGTGGAGACAACAGAAGGAAATAACTGCTCTGTCCAGTGA GATAGAAAGTGAGCAAGAGATGAAAGAAATGGGATATGCTGCAACAGAGCGGGAAATA AGCCTAAGAGAGAGCCTCCAGGAGGAACTCAAGAGGAAAAAAΆTCCAGTACTTGACTC GTGGAGAGGAGTCTTCGTCCGATACCAATAAGTCAGCCTGATGCTCTAATGGAAAAAT

GGCCCTC

ORF Start: ATG at 189 ORF Stop: TGA at 909

SEQ ID NO: 164 240 aa MW at 26651.2kD

NOV38b, MKMASSLAFLLLNFHVSLLLVQLLTPCSAQFSVLGPSGPILAMVGEDADLPCHLFPTM CG59454-03 SAETMELKVSSSLRQWNVYADGKEVEDRQSAPYRGRTSILRDGITAGKAALRIHNV TASDSGKYLCYFQDGDFYEKALVELKVADPFFRSAQP IAALAGTLPILLLLLAGASY Protein Sequence FLWRQQKEITALSSEIESEQEMKEMGYAATEREISLRESLQEELKRKKIQYLTRGEES SSDTNKSA

SEQ ID NO: 165 1689 bp

NOV38c, ATTTGCTTTCTCTTTTTCCTTTCTTCCGGATGAGAGGCTAAGCCATAATAGAAAGAAT CG59454-04 DNA GGAGAATTATTGATTGACCGTCTTTATTCTGTGGGCTCTGATTCTCCAATGGGAATAC

TGTCTCCCTCCTCTTGGTCCAGCTGCTCACTCCTTGCTCAGCTCAGTTTTCTGTGCTT GGACCCTCTGGGCCCATCCTGGCCATGGTGGGTGAAGACGCTGATCTGCCCTGTCACC CGTTCCCGACCATGAGTGCAGAGACCATGGAGCTGAAGTGGGTAAGTTCCAGCCTAAG GCAGGTGGTGAACGTGTATGCAGATGGAAAGGAAGTGGAAGACAGGCAGAGTGCACCG TATCGAGGGAGAACTTCGATTCTGCGGGATGGCATCACTGCAGGGAAGGCTGCTCTCC GAATACACAACGTCACAGCCTCTGACAGTGGAAAGTACTTGTGTTATTTCCAAGATGG TGACTTCTATGAAAAAGCCCTGGTGGAGCTGAAGGTTGCAGCACTGGGTTCTAATCTT CACGTCGAAGTGAAGGGTTATGAGGATGGAGGGATCCATCTGGAGTGCAGGTCCACCG GCTGGTACCCCCAACCCCAAATACAGTGGAGCAACGCCAAGGGAGAGAACATCCCAGC TGTGGAAGCACCTGTGGTTGCAGATGGAGTGGGCCTATATGAAGTAGCAGCATCTGTG ATCATGAGAGGCGGCTCCGGGGAGGGTGTATCCTGCATCATCAGAAATTCCCTCCTCG GCCTGGAAAAGACAGCCAGCATTTCCATCGCAGAGAGCCTCCAGGAGGAACTCAAGAG GAAAAAATCCAGTACTTGACTCGTGGAGAGGAGTCTTCGTCCGATACCAATAAGTCAG

CCTGATGCTCTAATGGAAAAATGGCCCTCTTCAAGCCTGCAGATGTAATTCTGTATCC

AGACATGGCAAATGCCATCCTCCTTGTTTCTGAGGACCAGAGGAGTGTACAGCGTGCT

GAGGAGCCCCATGACCTACCAGACAACCCTGAGAGATTTGAATGGCGTTACTGTGTGC

TTGGCTGTGAAAGCTTCATGTCAGAGAGACACTACTGGGAGGTGGAAGTGGGGGACAG

AAAAGAGTGGCATATTGGGGTATGTAGTAAGAACGTGGAGAGGAAAAAAGTTTGGGTC

AAAATGACACCGGAGAACGGATACTGGACTATGGGCCTGACTGATGGGAATAAGTATC

GGGCTCTCACTGAGCCCAGAACCAACCTGAAACTTCCTGAGCCTCCTAGGAAAGTGGG

GGTCATCCTGGACTATGAGACTGGACATATCTCGTTCTACAATGCCACGGATGGATCT

CATATCTACACATTTCTGCACGCCTCTTCCTCTGAGCCTCTGTATCCTGTATTCAGAA

TTTTGACCTTGGAGCCCACTGCCCTGACCGTTTGCCCAATACCAAAAGTAGAGAGTTC

CCCCGATCCCGACCTAGTGCCTGATCATTCCCTGGAGATACCACTGACCCCAGGCTTA

GCTAATGAAAGTGGGGAGCCTCAGGCTGAAGTAACATCTCTGCTTCTCCCTGCCCAGC

CTGGAGC

ORF Start: ATG at 189 ORF Stop: TGA at 945

SEQ ID NO: 166 252 aa MW at 27148JkD

NOV38c, M MASSLAFLLLNFHVSLLLVQLLTPCSAQFSVLGPSGPILAMVGEDADLPCHPFPTM CG59454-04 SAETMELK VSSSLRQVVNVYADGKEVEDRQSAPYRGRTSILRDGITAGKAALRIHNV Protein Sequence TASDSGKYLCYFQDGDFYEKALVELKVAALGSNLHVEVKGYEDGGIHLECRSTGWYPQ PQIQWSNAKGENIPAVEAP ADGVGLYEVAASVIMRGGSGEGVSCIIRNSLLGLEKT ASISIAESLQEELKRKKSST

Sequence comparison ofthe above protein sequences yields the following sequence relationships shown in Table 38B. Table 38B. Comparison of NOV38a against NOV38b through NOV38c.

NOV38a Residues/ Identities/

Protein Sequence Match Residues Similarities for the Matched Region

NOV38b 33..151 118/119 (99%) 26..144 118/119 (99%)

NOV38c 33..246 208/214 (97%) 26..239 210/214 (97%)

Further analysis ofthe NOV38a protein yielded the following properties shown in Table 38C.

Table 38C. Protein Sequence Properties NOV38a

SignalP Cleavage site between residues 37 and 38 analysis:

A search ofthe NOV38a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 38D.

In a BLAST search of public sequence databases, the NOV38a protein was found to have homology to the proteins shown in the BLASTP data in Table 38E.

PFam analysis indicates that the NOV38a protein contains the domains shown in the Table 38F.

Example 39.

The NOV39 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 39A.

CAGCCCCGCGGCCACCAGAGGGCCGTCCCTGGCCCGGCTGTGTGCCCTGGTGGACCTG TGTCTGGGCTGCTCCCGCTGCACCCAGCGGCTCAATGAAAGCACCTACGTCCTCCGTA GGGTGGAGCATGACTGCTCCCGCGAGATCCTGCTGGCCCGCTTTAAGCAGGCCACCAA GAGCAAGGTCTGGCGCGTGGTGGGCTGCCGGCCCACCTTCCCAAGGCCCCTGTGCTAC CAAGTCTGCCACTACTACAGCCCTGGGCTCGGCTGCCGGCGCCACCGAAACCGGTGCA CCTTTGCCCGCAGTCGCGAGGAGGCCCTGGTCTGGACCTTCGAGCGTCAGCACAACCT CCAGCGCCTATGGCTGAAGGCGGAGGTGCAGGGCAGCGGGGCCCAGGGAGGGGCAGGC CGGGCGGCCGACGCCATCCTTACGGAGTTTGGCGGCCGCTTCGAGCTGCTTTGCTCCC TCTGCTTCAGGCGCTGTCCCCCATGCATCTGTCGCGTGGACCCCCAGGGGCAGTGCCC TGAGCACGGAGCCTGCCCCTCCCTCCTGGCCCACGTGAGCGCCGAGGGCCGCCGCAAG CAACAGTTTGTGGTGGTGAGGCCGCGGCCCCGGGCCGGCCAGCCTCCTGCCTACTGCA GGTTTGTGGGGCGTGGGCAGCCGTGCTGGCGTGGGGAGTCCCGCTGCCAGTTTGCACA CAGCGCCGTGGAGATGGCTGTGTGGGAGGCCGAGCAGCTGGGTGGCCTCCAGCGGGGG GACCTGCTCACACCCCCTGCCCCTGATGGCGACGGGCGCACGGCCCCCCTTGGCCAGC CCCCTGGGGCCCAGCTGTACTGCCCGGCCTGCTTGGTCACCTGCCACTCTCAGGAGGC CTTCGAGAACCACTGCGCATCCTCGGAGCACGCACAGATGGTGGCCTTCGACCAGGCC CTGCCCTGGGAGCACCGTTCCCCACCCCCGGGACTCTCCAAGTTCGAGCTCTGCCCAA AGCCTGACCTCTGTGAGTATGGGGACGCCTGCACCAAGGCACACTCAGCACAGGAGCT GCAGGAGTGGGTCCGGCGCACGCAGGCTGTGGAGCTGCGGGGGCAGGCGGCCTGGCAG GACGGGCTGGTGCCCTACCAGGAGCGGCTGCTGGCCGAGTACCAGCGCAGCAGCAGTG AGGTCCTTGTGCTGGCAGAGACCCTTGATGGAGTGCGTGTCACCTGCAACCAGCCCCT GATGTACCAGGCCCAGGAGAGGAAGACCCAGTACAGCTGGACGTTTGCCGTCCACTCT GAGGAGCCCCTGCTACACGTGGCCCTGCTGAAGCAGGAGCCAGGAGCCGACTTCTCTC TGGTGGCTCCCGGCCTCCCGCCAGGCCGGCTCTACGCACGGGGTGAGCGCTTCCGTGT GCCCAGCTCCACTGCCGACTTCCAGGTGGGAGTGCGTGTGCAGGCTGCCTCGTTCGGC ACCTTTGAGCAATGGGTGGTCTTCGACTTTGGCCGCCGGCCGGTGCTGCTACAAAAGC TGGGGCTGCAGCTGGGCCAGGGGCGTCGCCCAGGACCCTGCAGGAATCTGGCGCTCGG CCACCCTGAGGAGATGGAGCGCTGGCACACTGGCAACCGCCACGTGGTGCCTGGCGTG GAGCGGACGGCCGAGCAGACGGCCCTGATGGCCAAGTACAAGGGCCCTGCCCTGGCCC TGGAGTTCAACCGCAGCAGCGTGGCCTCGGGCCCCATCTCACCAACCAACTATCGGCA GAGGATGCACCAGTTTCTCTATGAGGAGGAGGCGGCTCAGCAGCAGCTGGTGGCCAAG CTGACCCTGCGGGGCCAGGTGTTCCTGAAGACGGCATTGCAGACGCCAGCGCTGAACA TGCTCTTCGCGCCTCCGGGAGCACTGTACGCAGAGGTCCCCGTCCCCTCCTCCCTGAT GCCAGACACAGACCAGGGCTTCCTGCTGGGCCGGGCGGTCAGCACAGCCCTGGTGGCC CCTGTACCTGCACCCGACAATACGGTGTTCGAGGTGCGGCTGGAGAGGCGGGCCAGCT CAGAGCAGGCGCTGTGGCTGCTGCTTCCGGCCCGCTGCTGCTTGGCCCTGGGGCTGCA GCCTGAGGCCCGCCTGGTCCTGGAGGTGCAGTTCCAGATTGACCCGATGACCTTCCGC CTCTGGCACCAGGCAGTGGACACACTGCCTGAGGAGCAGCTGGTGGTGCCCGACTTGC CCACCTGCGCCCTGCCCAGACCTTGGTCTGTCCCACCCTTGCGGCGTGGCAACCGCAA GCAGGAGCTGGCCGTGGCGCTCATCGCGGGCTGGGGCCCTGGGGATGGGAGGCGTGTC CCCCCGCTACTCATCTATGGCCCCTTTGGCACCGGCAAGACCTACACGCTGGCCATGG CCTCCCTGGAGGTCATCCGGAGGCCTGAAACCAAGGTGCTCATCTGCACACACACCAA CAGTCTACACCGGGCAGGCGGTCACCCCCTGGATGTGCTCCAGTCCTCTGATTCTGCA CTCCCTGTAGCCGACCAGCTTTGGGCTTTGGCTTTATCAGGCCCAGCTCAGGGCACCG AGGGTGGCCGGGTCTGCTGTCAGGAGGGACACCAGTGTTTGCTGCTCACCTCTGACAG CCAGACAAGGGCTGTGCTCAGGGGCAGCTCGGCTGGGCACACAGTAGGTGCTTTAGCG GACAGCACTGAGGCCCCCAGCAAGAAGCCCATGAGCTCCTCCCCCTCCCGCAGTGCCG CCGACATCTACATCCGGGAGTATTTCCACAGCCACGTCAGCGGCGGCCACCCCGAGGC CACTCCTCTCCGTGTGATGTACACGGACCGGCCGCTGAGCCAGACGGACCCAGTCACG CTGCAGTACTGTTGCCTGACCGACGACCGCCAGGCTTTCCGCCCGCCCACACGGGCAG AGCTGGCGCGGCACCGCGTGGTGGTCACCACCACCTCCCAGGCCCGTGAGCTCAGGGT GCCGGTCGGCTTCTTCTCCCACATTCTCATCGATGAGGCGGCCCAGATGCTGGAGTGC GAGGCCCTCACCCCGCTGGCCTATGCCTCGCACGGCACCCGCCTCGTGCTGGCGGGCG ACCACATGCAGGTCACACCCCGGCTGTTCAGTGTGGCCAGGGCCCGGGCGGCCGAGCA CACGCTGCTGCACCGCCTCTTCCTGTGCTACCAGCAGGAGACTCACGAGGTGGCGCGG CAGAGCCGCCTGGTCTTCCACGAGAACTACCGCTGCACGGACGCCATTGTCAGCTTCA TCTCGCGGCACTTCTACGTGGCCAAGGGCAACCCCATCCACGCCAGGGGCAAGGTTCC GCCCCACCCCCGGCACTACCCGCTCATGTTCTGCCACGTGGCGGGCAGCCCAGACCGG GACATGTCCATGGCGTCCTGGCTGAATCTGGCTGAGATTGCGCAGGTCGTCGAGAAGG TGCAGGAGGCCTACAACACCTGGCCCAGCTGCTGGGGCGGCCGCGAGCAGAGGTGCAT CTGTGTCGTTTCCCACGGTGCCCAGGTCAGTGCACTGAGGCAGGAGCTGAGGAGGCGG GACCTAGGCCAGGTGTCTGTCGGCAGTTTTGAGATCCTGCCAGGGCGGCAGTTCCGGG TCGTGGTGCTCAGCACTGTGCACACCTGCCAGAGCCTGCTCAGCCCTGGGGCACTGGC CCCTGAGTTCTTCACCGACGCCCGCGTGCTCAACACCGTCCTGACCCGCGCCCAGTCC CAGCTGGTGGTAGTGGGGGACGCCGTGGCCCTCTGCTCCTTCGGGGCCTGCGGCAAGC TCTGGGAGAGCTTCATCCGTGAGTGCGTGGAGCGGCACAGTGTCTGCCCCGAGGGCCT GTCCATGGAGCAGGTCGAGCAGGGTGTGGCGCAGAGACGGCGCTGGCCTCCCCGAGGC ACACAGGCTGGGGCAGCGGGGAACTGGGAGGCTGCCCCAGAGCCAGTAGGGGACCTGG CCGAGGAGCAGGCGGCTGTGGTGACGGCCATGGTGAAGGCAGAGCCGGGAGATGAGGC TCTGAGCCCAGCATCCCGTGACATCACGGCAACCACAGCGCAGACGGAGGCTGCGGCA GCACCAGCAGGAGACGCAGTGAAGGAAGACGTGGTGCCCGGGGCCTGTGCGGCAGGAG CGGCTGCTGCAGCGGGCGTGGAGTCCACGGAGGCTGAGGATGCAGAGGCTGACTTCTG GCCGTGGGACGGGGAGCTCAACGCTGACGACGCCATCCTACGGGAGCTTCTGGACGAG AGCCAGAAGGTGATGGTGACCGTCGGGGAGGACGGGCTGCTGGACACTGTCGCCAGGC CCGAGTCCCTGCAGCAGGCCCGGCTGTACGAGAACCTGCCCCCGGCTGCGCTACGGAA GCTGCTGCACGCGGAGCCCGAGCGGTACCGCCACTGCTCTTTCGTGCCAGAGACCTTC GAGCGGGCGTCAGCCATCCCGCTGGACGATGCCTCCTCGGGCCCCATCCAGGTCAGGG GCCGCCTGGACTGTGGGATGGCCTTCGCCGGGGATGAGGTGCTGGTGCAGCTCCTTTC GGGAGACAAGGCGCCCGAGGGGCGGCTTCGGGGCCGCGTGCTGGGCGTGCTGAAGAGG AAGAGGCACGAGCTGGCGTTTGTGTGCCGCATGGACACGTGGGACCCGCGCATCATGG TCCCCATCAATGGCTCCGTGACCAAGATCTTCGTGGCCGAGCTGAAGGACCCATCGCA GGTCCCCATCTACAGCCTCCGGAAGGGCCGGCTGCAGCGTGTGGGGCTTGAGAGGCTC ACCGCCGAGGCCCGGCACAGCCGGCTCTTCTGGGTCCAAATTGTCCTGTGGCGGCAAG GCTTCTACTACCCGCTGGGCATCGTCCGGGAGGTGCTGCCTGAGGCCAGCACCTGGGA GCAGGGCCTCCGCATCCTCGGCCTGGAGTACAGCTTGAGGGTGCCCCCGTCGGACCAG GCCACCATCACCAAGGTGCTGCAGAAATACCACACGGAGCTTGGCCGGGTTGCCGGCC GCCGAGAGGACTGCCGCGCCTTCTTGACCTTCACTGTGGACCCCCAGGGCGCCTGCAA CCTCGATGATGCCCTCAGTGTCCGAGACCTGGGTCCCAGGTGCGAGGTGGCTGTGCAC ATCACTGATGTGGCCAGCTTCGTGCCCAGGGACGGGGTGCTGGACGTGGAGGCGCGAA GGCAGGGCGCTGCGTTCTATGCCCCCGGCAGGGAGCCAGTGCCCATGCTGCCGGCCAG CCTCTGCCAGGACGTCCTCAGCCTCCTGCCTGGCCGGGACCGCCTGGCCATCTCCCTG TTCCTCACCATGGAGAAGGCCAGTGGCCAGCTGAAGAGCCTGCGCTTTGCACCCTCCG TGGTCCAGTCTGACCGCCAGCTGTCCTACGAGGAGGCGGAGGAGGTGATCAGGCAGCA CCCGGGTGCCGGCCGTGAGCTGCCGGCCCGCCTGGACTCCGTGGACGCCTGCGTCGTG GCCGCGTGCTACTTCTCTCGGCTGCTGCGCCGGCACCGCCTGCGGTCCGACTGCTTCT ATGAGCAGCCGGACGAGGACGGCACCCTGGGCTTCCGCGCGGCCCACATCATGGTGAA GGAGTACATGATTCAGTTTAATAGGCTCGTGGCTGAGTTCCTGGTGGGCAGCGAGTGC ACGCGGACGGTCACGCCTCTGCGGTGGCAGCCAGCACCCCGCAGCCAGCAGCTCAAGG CCCTGTGTGAGAAGCATGGGGACCGGGTGCCCCTGTCACTGCACCTCGGCCACCACCT GCACGGCGGCGGGGGCAGTCCCCCCGACACGCGGCTGCACCTCCTGGCCTCCCTCTGG AAGCAGGTCCAGTTTGCTGCCCGCACCCAGGACTACGAACAGATGGTGGACTTGGTCA CCACGGACGACATGCACCCATTCCTGGCTCCTGCAGGCCGCGACCTCCGCAAGGCCCT GGAGCGCTCGGCGTTCGGCCGCTGCGCCCGGGGCCACCAGCAGCAGGGCGGCCACTAC TCGCTGCAGGTGGACTGGTACACGTGGGCCACCTCGCCCATCCGCAGGTACCTGGACG TGGTGTTGCAGCGGCAGATCCTGCTGGCGCTGGGCCATGGGGGCTCTGCCTACTCTGC CAGGGACATCGATGGGCTCTGCCAGGCCTTCAGCCTCCAGCACGCACTTGCCCAGAGC TATCAGCGGCGGGCGCGCAGCCTGCACCTGGCCGTGCAGCTCAAGGCCCAGCCTCTGG ACAAGCTGGGCTTCGTGGTGGACGTGGAGGCGGGCTCCCGCTGCTTCCGGCTGCTCTT CCCCAGCAACCGGGAGACGCTGCCTGACCCCTGCCCCGTCCCCTACGGCTCCCTGCAG CTGGCCGAGCACCCCCACGCCCTGGCAGGCCGGCCGGGCCTGCGGCTCCTGTGGCGGC GCCGTGTCTACTCAGCGCAGGGATCCAGCCCGCCCCTGCCACTGCCTGGCACTGTGCC GGACCCACACACCCTGGCCGTGGAGACGGCCCTGTGGAAGCAGCTGCTGGAGCTGGTG GAGCTGCAGCGCTGGCCGGAGGCGGCTGCTCTCATCCAGGAGAAGGGCGAGGCGTCCC AGCGGCGGGAGCTGGTGCAGGTGCAGCGGAGCCACTGTGGCCATTTCCTGGAGGTGGC CCGGGAGCTGGGCAGTGGGGACACCCTGCAGGTGCAGCTCGGCACCAGCCTGCAGCAC GGCTTCCTGGTACCGAGCCCTCAGCTCTGGACGGTGGCACCGGGCTTCAGCCTCTGCC TGGAGCACGTGGAGCGGCCCGGAGACTGCTTCTCAGGCCGTGTGTACCGGGCCCCGAG GGACCGGTACCGCGACGTGGATGAGTACGCCTGCGTGTGGGAACCATTCTGCGCCCTG GAGTCGGCCACCGGCGCGGTTGCCGAGAATGACTCCGTCACACTTCAGCACCTGAGTG TCTCCTGGGAGGCGTCACGGACGCCGCAGGGGCAGCTGCAGGGCGCCTTCCGCCTGGA GGCCGCCTTCCTCGAGGAGAACTGTGCCGACATCAACTTCAGCTGCTGCTACCTCTGC ATCCGGCTCGAGGGGCTGCCGGCTCCCACGGCCAGCCCACGCCCTGGGCCCAGCAGCC TCGGCCCTGGCCTGAATGTTGACCCCGGCACGTATACCTGGGTGGCCCACGGGCAGAC GCAGGACTGGGACCAGGAGCGCCGGGCAGACCGGCAGGAGGCTCCCAGACGGGTGCAC CTCTTCGTCCACCACATGGGCATGGAGAAGGTTCCGGAAGAGGTGCTGAGGCCGGGCA CCCTGTTCACCGTTGAGCTGCTGCCCAAGCAGCTTCCTGATCTCCGCAAGGAGGAAGC CGTGCGTGGACTAGAGGAGGCGTCCCCGCTGGTCACCAGCATCGCACTGGGCCGGCCT GTCCCGCAGCCCCTCTGCAGAGCCCCACCCTGCATGAGTGCTCAGGGAGGCTGCCCCC TCTCAGTGATCCCCAGCAGGTTCCTGGAGCGGCAGACCTACAACATCCCCGGAGGCCG CCACAAGCTGAACCCCAGCCAGAACGTGGCGGTCAGGGAGGCTCTGGAGAAGCCTTTC ACGGTCATTCAGGGCCCACCAGGTACAGGGAAGACGATCGTGGGCCTCCACATCGTAT TCTGGTTTCATAAATCAAACCAGGAGCAGGTGCAGCCCGGAGGCCCCCCCCGTGGGGA GAAGCGGCTGGGGGGTCCCTGCATCTTGTACTGCGGCCCCTCCAACAAGTCGGTGGAT GTCCTGGCAGGACTGCTCCTGAGAAGGATGGAGCTGAAGCCCCTCCGTGTGTACAGTG AGCAGGCTGAGGCCAGCGAGTTCCCAGTGCCGCGTGTGGGCAGCAGGAAGCTGCTCAG GAAGAGCCCCCGGGAGGGGAGGCCGAACCAGAGCCTCAGGAGCATCACCCTGCACCAC CGGATCCGGCAGGCCCCCAACCCTTACTCGTCGGAAATCAAGGCCTTTGACACCCGGC TGCAGAGAGGGGAGCTCTTCTCCAGGGAGGACCTGGTCTGGTACAAGAAGGTCTTGTG GGAGGCTCGGAAGTTCGAGCTGGACCGGCATGAGGTCATCCTCTGCACCTGCTCCTGT GCAGCCTCTGCCAGCCTCAAAATCCTGGACGTGAGGCAGATCCTTGTTGACGAGGCAG GCATGGCCACGGAACCTGAAACCCTCATCCCCCTGGTGCAGTTCCCACAGGCCGAGAA GGTGGTTCTTCTCGGAGACCACAAGCAGCTGCGGCCTGTGGTCAAGAATGAGCGGCTG CAAAACCTGGGTCTGGACCGGTCTCTGTTCGAGCGGTACCACGAGGACGCACATATGC TGGACACTCAGTACCGCATGCATGAGGGCATCTGTGCCTTCCCCTCTGTGGCGTTCTA CAAGAGCAAGCTGAAGACGTGGCAGGGCCTGAGGAGGCCGCCCAGTGTCCTGGGCCAC GCTGGCAAGGAGAGCTGCCCTGTCATCTTTGGCCACGTGCAGGGCCACGAGCGGAGCC TGCTGGTGTCCACGGACGAAGGGAATGAGAACTCCAAGGCCAACCTGGAGGAGGTGGC TGAGGTGGTCCGTATCACCAAGCAGCTGACCCTGGGGAGGACCGTAGAGCCCCAGGAC ATCGCCGTCCTCACGCCCTACAACGCGCAGGCCTCTGAGATCAGCAAGGCCCTTCGGC GAGAGGGCATCGCCGGGGTGGCCGTGTCCTCCATCACCAAGAGCCAGGGGAGCGAGTG GCGCTATGTGCTGGTGAGCACCGTCCGCACCTGTGCCAAGAGCGACCTGGACCAGCGG CCCACCAAGAGCTGGCTCAAGAAGTTTCTGGGCTTCGTTGTGGACCCCAACCAAGTGA ATGTGGCTGTCACGCGGGCCCAGGAGGGGCTCTGCCTGATCGGTGAGGGCGGGGCTGG GCTCTTCCAGGGTGGGAACACAGGAGACCACCTCCTTCTGCGCTGCTGCCCCCTCTGG CGTAGCCTCCTGGACTTCTGCGAGGCTCAGCAGACCCTCGTGCCTGCCGGCCAGGGCC GGTGTCTCCGGCTGCCTGTGTGGGGAGGGGAGGGCCGTGCCTGGTGTGGTGGGGACAA GCCACAGCTCCAGAGCTGCTCCGGTGTCACCAGGCTGGCCAAGTCCAAAGTCCCTGAG GCCACCAGCCTTGACTGTCCTGCTGGTCCCACTTTTAAAGCTGCTCCCCAGGACCCCC TGGCCGCTGTGGACTGGGGTCCCTCCGCACCTGGCCCATTTGTGGCTGCGTCCACAGG GGCTCCTGTGGCCTCCCAGAGCCAGCTCGGGGGTCAGATGGTCGCGGGGGCTATGGTC ACTGTGGGAAAAGAGGTTCTGGGCATCTGTGGAGGGAGGGGTGGAGCATGGAGTCTCC AGGACTGTGGCCCCGTTGGTGTGCTGGACGGGCCCTGCCTTGAAGACCATGTCTATTC TTGGACCGTCATGAAATAA

ORF Start: ATG at 1 ORF Stop: TAA at 9703

SEQ ID NO: 168 3234 aa MW at 355870.4kD

NOV39a, MDPAQRPAPGAAIVEGLPSPRSSNVIGLRRGSLWDGPPSRPPEVADTATAKAST AS CG59307-01 GLRTVANSSSGLRGPVSSGASDASLESQAGVRGSTLLPNSPAATRGPSLARLCALVDL Protein Sequence CLGCSRCTQRLNESTYVLRRVEHDCSREILLARFKQATKSKV RWGCRPTFPRPLCY QVCHYYSPGLGCRRHRNRCTFARSREEALVWTFERQHNLQRLWLKAEVQGSGAQGGAG RAADAILTEFGGRFELLCSLCFRRCPPCICRVDPQGQCPEHGACPSLLAHVSAEGRRK QQFVWRPRPRAGQPPAYCRFVGRGQPCWRGESRCQFAHSAVEMAVWEAEQLGGLQRG DLLTPPAPDGDGRTAPLGQPPGAQLYCPACLVTCHSQEAFENHCASSEHAQMVAFDQA LPWEHRSPPPGLSKFELCPKPDLCEYGDACTKAHSAQELQEWVRRTQAVELRGQAA Q DGLVPYQERLLAEYQRSSSEVLVLAETLDGVRVTCNQPLMYQAQERKTQYSWTFAVHS EEPLLHVALLKQEPGADFSLVAPGLPPGRLYARGERFRVPSSTADFQVGVRVQAASFG TFEQWWFDFGRRPVLLQKLGLQLGQGRRPGPCRNLALGHPEEMERWHTGNRHWPGV ERTAEQTAL AKYKGPALALEFNRSSVASGPISPTNYRQRMHQFLYEEEAAQQQLVAK LTLRGQVFLKTALQTPALNMLFAPPGALYAEVPVPSSLMPDTDQGFLLGRAVSTALVA PVPAPDNTVFEVRLERRASSEQALWLLLPARCCLALGLQPEARLVLEVQFQIDPMTFR L HQAVDTLPEΞQLWPDLPTCALPRP SVPPLRRGNRKQELAVALIAG GPGDGRRV PPLLIYGPFGTGKTYTLAMASLEVIRRPETKVLICTHTNSLHRAGGHPLDVLQSSDSA LPVADQLWALALSGPAQGTEGGRVCCQEGHQCLLLTSDSQTRAVLRGSSAGHTVGALA DSTEAPSKKPMSSSPSRSAADIYIREYFHSHVSGGHPEATPLRVMYTDRPLSQTDPVT LQYCCLTDDRQAFRPPTRAELARHRVWTTTSQARELRVPVGFFSHILIDEAAQ LEC EALTPLAYASHGTRLVLAGDHMQVTPRLFSVARARAAEHTLLHRLFLCYQQETHEVAR QSRLVFHENYRCTDAIVSFISRHFYVAKGNPIHARGKVPPHPRHYPLMFCHVAGSPDR DMSMASWLNLAEIAQWEKVQEAYNT PSC GGREQRCICWSHGAQVSALRQELRRR DLGQVSVGSFEILPGRQFRVWLSTVHTCQSLLSPGALAPEFFTDARVLNTVLTRAQS QLVWGDAVALCSFGACGKL ESFIRECVERHSVCPEGLSMEQVEQGVAQRRRWPPRG TQAGAAGN EAAPEPVGDLAEEQAAWTAMVKAEPGDEALSPASRDITATTAQTEAAA APAGDAVKEDWPGACAAGAAAAAGVESTEAEDAEADFWP DGELNADDAILRELLDE SQ VMVTVGEDGLLDTVARPESLQQARLYENLPPAALRKLLHAEPERYRHCSFVPΞTF ERASAIPLDDASSGPIQVRGRLDCGMAFAGDEVLVQLLSGDKAPEGRLRGRVLGVLKR KRHELAFVCRMDTWDPRIMVPINGSVTKIFVAELKDPSQVPIYSLRKGRLQRVGLERL TAEARHSRLFVJVQIVLWRQGFYYPLGIVREVLPEASTWEQGLRILGLEYSLRVPPSDQ ATITKVLQKYHTELGRVAGRREDCRAFLTFTVDPQGACNLDDALSVRDLGPRCEVAVH ITDVASFVPRDGVLDVEARRQGAAFYAPGREPVPMLPASLCQDVLSLLPGRDRLAISL FLT EKASGQLKSLRFAPSWQSDRQLSYEEAEEVIRQHPGAGRELPARLDSVDACW AACYFSRLLRRHRLRSDCFYEQPDEDGTLGFRAAHIMVKEYMIQFNRLVAEFLVGSEC TRTVTPLR QPAPRSQQLKALCEKHGDRVPLSLHLGHHLHGGGGSPPDTRLHLLASL KQVQFAARTQDYEQMVDLVTTDD HPFLAPAGRDLRKALERSAFGRCARGHQQQGGHY SLQVD YT ATSPIRRYLDWLQRQILLALGHGGSAYSARDIDGLCQAFSLQHALAQS YQRRARSLHLAVQLKAQPLDKLGFWDVEAGSRCFRLLFPSNRETLPDPCPVPYGSLQ LAEHPHALAGRPGLRLL RRRVYSAQGSSPPLPLPGTVPDPHTLAVETALWKQLLELV ELQR PEAAALIQEKGEASQRRELVQVQRSHCGHFLEVARELGSGDTLQVQLGTSLQH GFLVPSPQL TVAPGFSLCLEHVERPGDCFSGRVYRAPRDRYRDVDEYACV EPFCAL ESATGAVAENDSVTLQHLSVSWEASRTPQGQLQGAFRLEAAFLEENCADINFSCCYLC IRLEGLPAPTASPRPGPSSLGPGLNVDPGTYTWVAHGQTQD DQERRADRQEAPRRVH LFVHHMG EKVPEEVLRPGTLFTVELLPKQLPDLRKEEAVRGLEΞASPLVTSIALGRP VPQPLCRAPPCMSAQGGCPLSVIPSRFLERQTYNIPGGRHKLNPSQNVAVREALEKPF TVIQGPPGTGKTIVGLHIVFWFHKSNQEQVQPGGPPRGEKRLGGPCILYCGPSNKSVD VLAGLLLRRMELKPLRVYSEQAEASΞFPVPRVGSRKLLRKSPREGRPNQSLRSITLHH RIRQAPNPYSSΞIKAFDTRLQRGELFSRΞDLV YKKVLWEARKFELDRHEVILCTCSC AASASLKILDVRQILVDEAGMATEPETLIPLVQFPQAEKWLLGDHKQLRPWKNERL QNLGLDRSLFERYHEDAH LDTQYRMHEGICAFPSVAFYKSKLKT QGLRRPPSVLGH AGKESCPVIFGHVQGHERSLLVSTDEGNENSKANLEEVAEWRITKQLTLGRTVEPQD IAVLTPYNAQASEISKALRREGIAGVAVSSITKSQGSE RYVLVSTVRTCAKSDLDQR PTKSWLKKFLGFWDPNQVNVAVTRAQEGLCLIGEGGAGLFQGGNTGDHLLLRCCPLW RSLLDFCEAQQTLVPAGQGRCLRLPV GGEGRA CGGDKPQLQSCSGVTRLA SKVPE ATSLDCPAGPTFKAAPQDPLAAVDWGPSAPGPFVAASTGAPVASQSQLGGQMVAGAMV TVGKEVLGICGGRGGAWSLQDCGPVGVLDGPCLEDHVYS TVMK

Further analysis ofthe NOV39a protein yielded the following properties shown in Table 39B.

Table 39B. Protein Sequence Properties NOV39a

PSort 0.7000 probability located in plasma membrane; 0.3500 probability located in analysis: nucleus; 0.3000 probability located in microbody (peroxisome); 0.2000 probability located in endoplasmic reticulum (membrane)

SignalP No Known Signal Sequence Indicated analysis:

A search ofthe NOV39a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 39C.

In a BLAST search of public sequence databases, the NOV39a protein was found to have homology to the proteins shown in the BLASTP data in Table 39D.

PFam analysis indicates that the NOV39a protein contains the domains shown in the Table 39E.

Example 40.

The NOV40 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 40A.

Sequence comparison ofthe above protein sequences yields the following sequence relationships shown in Table 40B.

Table 40B. Comparison of NOV40a against NOV40b and NOV40c.

Protein Sequence NOV40a Residues/ Identities/ Match Residues Similarities for the Matched Region

NOV40b 3..113 91/111 (81%)

Further analysis ofthe NOV40a protein yielded the following properties shown in Table 40C.

Table 40C. Protein Sequence Properties NOV40a

SignalP No Known Signal Sequence Indicated analysis:

A search ofthe NOV40a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 40D.

In a BLAST search of public sequence databases, the NOV40a protein was found to have homology to the proteins shown in the BLASTP data in Table 40E.

Table 40E. Public BLASTP Results for NOV40a

PFam analysis indicates that the NOV40a protein contains the domains shown in the Table 40F.

Table 40F. Domain Analysis of NO 40a

Identities/

Pfam Domain NOV40a Match Region Similarities Expect Value for the Matched Region

No Significant Matches Found

Example 41.

The NOV41 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 41A.

Further analysis ofthe NOV4 la protein yielded the following properties shown in Table 4 IB.

Table 41B. Protein Sequence Properties NOV41a

PSort 0.8586 probability located in mitochondrial inner membrane; 0.6000 probability analysis: located in plasma membrane; 0.4000 probability located in Golgi body; 0.3568 probability located in mitochondrial intermembrane space

SignalP No Known Signal Sequence Indicated analysis:

A search ofthe NOV4 la protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 41 C.

In a BLAST search of public sequence databases, the NOV4 la protein was found to have homology to the proteins shown in the BLASTP data in Table 4 ID.

PFam analysis indicates that the NOV4 la protein contains the domains shown in the Table 41E.

Example 42.

The NOV42 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 42A.

Table 42A. NOV42 Sequence Analysis

Sequence comparison ofthe above protein sequences yields the following sequence relationships shown in Table 42B.

Table 42B. Comparison of NOV42a against NOV42b and NOV42c.

Protein Sequence

Further analysis ofthe NOV42a protein yielded the following properties shown in Table 42C.

Table 42C. Protein Sequence Properties NOV42a

PSort 0.4500 probability located in cytoplasm; 0.4273 probability located in analysis: microbody (peroxisome); 0.2034 probability located in lysosome (lumen); 0.1000 probability located in mitochondrial matrix space

SignalP No Known Signal Sequence Indicated analysis:

A search ofthe NOV42a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 42D.

In a BLAST search of public sequence databases, the NOV42a protein was found to have homology to the proteins shown in the BLASTP data in Table 42E.

PFam analysis indicates that the NOV42a protein contains the domains shown in the Table 42F.

Example 43.

The NOV43 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 43A.

NOV43a, GCGCCCCCCACCCTTCCGGCCCCCCAGAACCCGCGCCATCCCCCGGAGCCTCCCCAGA CG59681-01 DNA GCTGGCCGCGCAGGATGGGCGCCCTCAGGCCCACGCTGCTGCCGCCTTCGCTGCCGCT

GCTGCTGCTCCTAATGCTAGGAATGGGATGCTGGGCCCGGGAGGTGCTGGTCCCCGAG Sequence GGGCCCTTGTACCGCGTGGCTGGCACAGCTGTCTCCATCTCCTGCAATGTGACCGGCT ATGAGGGCCCTGCCCAGCAGAACTTCGAGTGGTTCCTGTATAGGCCCGAGGCCCCAGA TACTGCACTGGGCATTGTCAGTACCAAGGATACCCAGTTCTCCTATGCTGTCTTCAAG TCCCGAGTGGTGGCGGGTGAGGTGCAGGTGCAGCGCCTACAAGGTGATGCCGTGGTGC TCAAGATTGCCCGCCTGCAGGCCCAGGATGCCGGCATTTATGAGTGCCACACCCCCTC CACTGATACCCGCTACCTGGGCAGCTACAGCGGCAAGGTGGAGCTGAGAGTTCTTCCA GATGTCCTCCAGGTGTCTGCTGCCCCCCCAGGGCCCCGAGGCCGCCAGGCCCCAACCT CACCCCCACGCATGACGGTGCATGAGGGGCAGGAGCTGGCACTGGGCTGCCTGGCGAG GACAAGCACACAGAAGCACACACACCTGGCAGTGTCCTTTGGGCGATCTGTGCCCGAG GCACCAGTTGGGCGGTCAACTCTGCAGGAAGTGGTGGGAATCCGGTCAGACTTGGCCG TGGAGGCTGGAGCTCCCTATGCTGAGCGATTGGCTGCAGGGGAGCTTCGTCTGGGCAA GGAAGGGACCGATCGGTACCGCATGGTAGTAGGGGGTGCCCAGGCAGGGGACGCAGGC ACCTACCACTGCACTGCCGCTGAGTGGATTCAGGATCCTGATGGCAGCTGGGCCCAGA TTGCAGAGAAAAGGGCCGTCCTGGCCCACGTGGATGTGCAGGCACTGTCCAGCCAGCT GGCAGTGACAGTGGGGCCTGGTGAACGTCGGATCGGCCCAGGGGAGCCCTTGGAACTG CTGTGCAATGTGTCAGGGGCACTTCCCCCAGCAGGCCGTCATGCTGCATACTCTGTAG GTTGGGAGATGGCACCTGCGGGGGCACCTGGGCCCGGCCGCCTGGTAGCCCAGCTGGA CACAGAGGGTGTGGGCAGCCTGGGCCCTGGCTATGAGGGCCGACACATTGCCATGGAG AAGGTGGCATCCAGAACATACCGGCTACGGCTAGAGGCTGCCAGGCCTGGTGATGCGG GCACCTACCGCTGCCTCGCCAAAGCCTATGTTCGAGGGTCTGGGACCCGGCTTCGTGA AGCAGCCAGTGCCCGTTCCCGGCCTCTCCCTGTACATGTGCGGGAGGAAGGTGTGGTG CTGGAGGCTGTGGCATGGCTAGCAGGAGGCACAGTGTACCGCGGGGAGACTGCCTCCC TGCTGTGCAACATCTCTGTGCGGGGTGGCCCCCCAGGACTGCGGCTGGCCGCCAGCTG GTGGGTGGAGCGACCAGAGGACGGAGAGCTCAGCTCTGTCCCTGCCCAGCTGGTGGGT GGCGTAGGCCAGGATGGTGTGGCAGAGCTGGGAGTCCGGCCTGGAGGAGGCCCTGTCA GCGTAGAGCTGGTGGGGCCCCGAAGCCATCGGCTGAGACTACACAGCTTGGGGCCCGA GGATGAAGGCGTGTACCACTGTGCCCCCAGCGCCTGGGTGCAGCATGCCGACTACAGC TGGTACCAGGCGGGCAGTGCCCGCTCAGGGCCTGTTACAGTCTACCCCTACATGCATG GTGAGTGACACCCCCTCCACCCTCCTCACTCTGCCTTCCTCCTGGCCTCTGCCACTGG

CCTTCCCTTCCCATCTTCTGACCCTCCTGCTACTATCTCTCTCCTCCACATTATGTCA

CATGAAGTCTCAAAAAATCCAACTTCCAGCCCTGCAGTGCCCACCTGCACGGGGTCCT

CTGTGGTTGATGCTGACTTGCATGCTGAGGGTGCATGGTGGGCAGC

ORF Start: ATG at 73 ORF Stop: TGA at 1804

SEQ ID NO: 180 577 aa MW at 61171.8kD

NOV43a, MGALRPTLLPPSLPLLLLLMLGMGC AREVLVPEGPLYRVAGTAVSISCNVTGYEGPA CG59681-01 QQNFEWFLYRPEAPDTALGIVSTKDTQFSYAVFKSRWAGEVQVQRLQGDAWLKIAR Protein Sequence LQAQDAGIYECHTPSTDTRYLGSYSGKVELRVLPDVLQVSAAPPGPRGRQAPTSPPRM TVHEGQELALGCLARTSTQKHTHLAVSFGRSVPEAPVGRSTLQEWGIRSDLAVEAGA PYAERLAAGELRLGKEGTDRYRMWGGAQAGDAGTYHCTAAEWIQDPDGSWAQIAEKR AVLAHVDVQALSSQLAVTVGPGERRIGPGEPLELLCNVSGALPPAGRHAAYSVG EMA PAGAPGPGRLVAQLDTEGVGSLGPGYEGRHIAMEKVASRTYRLRLEAARPGDAGTYRC LAKAYVRGSGTRLREAASARSRPLPVHVREEGWLEAVA LAGGTVYRGETASLLCNI SVRGGPPGLRLAASW VERPEDGELSSVPAQLVGGVGQDGVAELGVRPGGGPVSVELV GPRSHRLRLHSLGPEDEGVYHCAPSA VQHADYS YQAGSARSGPVTVYPY HGE

SEQ ID NO: 181 1662 bp

NOV43b, AGATCTCGGGAGGTGCTGGTCCCCGAGGGGCCCTTGTACCGCGTGGCTGGCACAGCTG 174308213 DNA TCTCCATCTCCTGCAATGTGACCGGCTATGAGGGCCCTGCCCAGCAGAACTTCGAGTG GTTCCTGTATAGGCCCGAGGCCCCAGATACTGCACTGGGCATTGTCAGTACCAAGGAT Sequence ACCCAGTTCTCCTATGCTGTCTTCAAGTCCCGAGTGGTGGCGGGTGAGGTGCAGGTGC AGCGCCTACAAGGTGATGCCGTGGTGCTCAAGATTGCCCGCCTGCAGGCCCAGGATGC CGGCATTTATGAGTGCCACACCCCCTCCACTGATACCCGCTACCTGGGCAGCTACAGC GGCAAGGTGGAGCTGAGAGTTCTTCCAGATGTCCTCCAGGTGTCTGCTGCCCCCCCAG GGCCCCGAGGCCGCCAGGCCCCAACCTCACCCCCACGCATGACGGTGCATGAGGGGCA GGAGCTGGCACTGGGCTGCCTGGCGAGGACAAGCACACAGAAGCACACACACCTGGCA GTGTCCTTTGGGCGATCTGTGCCCGAGGCACCAGTTGGGCGGTCAACTCTGCAGGAAG AWVQHADYS YQAGSARSGPVTVYPYMHGELE

Sequence comparison ofthe above protein sequences yields the following sequence relationships shown in Table 43B.

Further analysis ofthe NOV43a protein yielded the following properties shown in Table 43C.

Table 43C. Protein Sequence Properties NOV43a

PSort 0.8497 probability located in lysosome (lumen); 0.5947 probability located in analysis: outside; 0.1197 probability located in microbody (peroxisome); 0.1000 probability located in endoplasmic reticulum (membrane)

SignalP Cleavage site between residues 28 and 29 analysis:

A search ofthe NOV43a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 43D.

In a BLAST search of public sequence databases, the NOV43a protein was found to have homology to the proteins shown in the BLASTP data in Table 43E.

PFam analysis indicates that the NOV43a protein contains the domains shown in the Table 43F.

Example 44.

The NOV44 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 44A.

Table 44A. NOV44 Sequence Analysis

SEQ ID NO: 187 3201 bp

NOV44a, AGAGTCCTCAGCAGGGTAGCCGAGGCCAGGCCACTTCTGCTGAGGATGGGGCAGGCTG CG59869-01 DNA GGGTGTGGGTGTGGCCTGGGGTGGCTCAGGGCTGGAACTGCTGCCTGATTCCTGTGTG

GGGAGAAGCTCAGTGGCCGTTTGCTGCCACTGACAAGGATTTCACATGCAGAAGAGAA Sequence AAGGCCCCCCTCCACCCCCCGCATTCCCTGCCGAGTGAGAGCCAGTGTTTGCTGCCCT

TGCTGGGGGCGGGTAGGAAACCCTGAGCTTCCTGATGCGGAGTCATGAAGCAGAGTCC

TCGGGAAGGCATCTCCCCAACCTTCCCTCATCTCTGGCGGCCCTCTTGGGCCTCTGAC

CCAGCCCCTCCCCGGGCCAGGCTCACAGAAGCTGGCTTCTGGGACTGTCCTGGGCCCA

AGTGGGCACCTGCGCCAGCCCCACCTGTGCCTGGGCTGTGGCCCCTTCCTACAGGGCG

CTCACCATGGCCCCGCCGCTCCTGCTGCTGCTGCTGGCCAGTGGAGCGGCCGCCTGCC

CGCTGCCCTGCGTCTGCCAGAACCTGTCCGAGTCGCTCAGCACCCTCTGTGCCCACCG AGGCCTGCTGTTTGTGCCGCCCAACGTGGACCGGCGCACAGTGGAGCTGCGGCTGGCT GACAACTTCATCCAGGCCCTGGGGCCCCCTGACTTCCGCAACATGACGGGACTGGTGG ACCTGACACTGTCTCGCAATGCCATCACCCGCATTGGGGCCCGCGCCTTTGGGGACCT CGAGAGCCTGCGTTCCCTCCACCTTGACGGCAACAGGCTGGTGGAGCTGGGCACCGGG AGCCTCCGGGGCCCCGTCAATCTGCAGCACCTCATCCTCAGCGGCAACCAGCTGGGCC GCATCGCGCCGGGAGCCTTCGACGACTTCCTAGAGAGCCTGGAGGACCTGGACCTGTC CTACAACAACCTCCGGCAGGTGCCCTGGGCCGGCATCGGCGCCATGCCTGCCCTGCAC ACCCTCAACCTGGACCATAACCTTATTGACGCACTGCCCCCAGGCGCCTTCGCCCAGC TCGGTCAGCTCTCCCGCCTGGACCTCACCTCCAACCGCCTGGCCACGCTGGCTCCGGA CCCGCTTTTCTCTCGTGGGCGTGATGCAGAGGCCTCTCCCGCCCCCCTGGTGCTGAGC TTTAGCGGGAACCCCCTGCACTGCAACTGTGAGCTGCTGTGGCTGCGGCGGCTGGCGC GGCCGGACGACCTGGAAACGTGCGCCTCCCCGCCCGGCCTGGCCGGCCGCTACTTCTG GGCAGTGCCCGAGGGCGAGTTCTCCTGTGAGCCGCCCCTCATTGCCCGCCACACGCAG CGCCTCTGGGTGCTGGAAGGCCAGCGGGCCACGCTGCGGTGCCGGGCCCTGGGTGACC CCGCGCCTACCATGCACTGGGTCGGTCCTGACGACCGGTTGGTTGGCAACTCCTCCCG AGCCCGGGCTTTCCCCAACGGGACCTTAGAGATTGGGGTGACCGGCGCTGGGGACGCT GGGGGCTACACCTGCATCGCCACCAACCCTGCTGGTGAGGCCACAGCCCGAGTAGAAC TGCGGGTGCTGGCCTTGCCCCATGGTGGGAACAGCAGTGCCGAGGGGGGCCGCCCCGG GCCCTCGGACATCGCCGCCTCCGCTCGCACTGCTGCCGAGGGTGAGGGGACGCTGGAG TCTGAGCCAGCCGTGCAGGTGACGGAGGTGACCGCCACCTCAGGGCTGGTGAGCTGGG GTCCCGGGCGGCCAGCCGACCCAGTGTGGATGTTCCAAATCCAGTACAACAGCAGCGA AGATGAGACCCTCATCTACCGGATTGTCCCAGCCTCCAGCCACCACTTCCTGCTGAAG CACCTCGTCCCCGGCGCTGACTATGACCTCTGCCTGCTGGCCTTGTCACCGGCCGCTG GGCCCTCTGACCTCACGGCCACCAGGCTGCTGGGCTGTGCCCATTTCTCCACGCTGCC GGCCTCGCCCCTGTGCCACGCCCTGCAGGCCCACGTGCTGGGCGGGACCCTGACCGTG GCCGTGGGGGGTGTGCTGGTGGCTGCCTTACTGGTCTTCACTGTGGCCTTGCTGGTTC GGGGCCGGGGGGCCGGAAATGGCCGCCTCCCCCTCAAGCTCAGCCACGTCCAGTCCCA GACCAATGGAGGCCCCAGCCCCACACCCAAGGCCCACCCGCCGCGGGAGCCCCCCGCC CCGGCCGCAGCGCAGCTGCTCTCTGGACCTGGGAGATGCCGGGTGCTACGGTTATGCC AGGCGCCTGGGAGGAGCTTGGGCCCGACGGAGCCACTCTGTGCATGGGGGGCTGCTCG GGGCAGGGTGCCGGGGGGTAGGAGGCAGCGCCGAGCGGCTGGAAGAGAGTGTGGTGTG ATGGACGGGCAGCTTCCTGTGTGCTCCAAGGGATGAGCCTCGTGGGGCAGAGGGCCCG GGGCCGCCGCCTGGCCTGGGAGTCCCTCCCTGGTTTTTATTCTCAGTACCTCAGGCTC

CCCTGTGTACTTGGAGGGGCAGGGAGCCCTTTCCTCGGTTCTGGCCTCCAGACCAGGG

TAAGGGCAGGCCCCTCCAACAGGTGCTCACAGCCACCGAGGCAGGGGCTGCAGCCACC

CACTGGGAGTCTTGTTTTTATTTATAATAAAATTGTTGGGGACACCTCAAAAAAAAAA

AAGCCCACAAATTCCCCGAGGGACAATTACGGTACAGCGTCATGACAAAGGCCCACAG

AGTCAAAACCCAAACCGCGCCCTTACAAGCCAGACGGCACAGTCTCGGTCACGAGACA

CTCTGGATCATCCACACAAGTACCCAGACAAACGAGCGCACCATCGCTCTACCCCCCC

ACCGGGCCCGCGGCCCCACCCACCCACAGGACGCACCCGCGCAGCGCCAGCACCCACA

CCACGCGGCCACCAACGACGACACGCACCACCGACAAGCGACACGCACAGCACCGCCA

CGAACAAGACGGTGGAGCTCCTCCGGCACGCGCCCGCAGGCCCCCCGCCCACACGACC

GCCTCCAACACCGCCGCGCGCGCCCTCCACACGAGGACAACGAAACACAAACCAGGCG

GCACCCCGACGCGCAGCCACCCAGCGCCACCGCACGCACACCCCCCAGCGAGCGACGC

CCCAACGCGCGCAGCACGGCCACAGGAGCGCGCACCCCCACCGAACCTAGTTGGTAGA

TAGCAGGTTGC

ORF Start: ATG at 471 ORF Stop: TGA at 2412

SEQ ID NO: 188 647 aa MW at 68097.9kD

NOV44a, MAPPLLLLLLASGAAACPLPCVCQNLSESLSTLCAHRGLLFVPPNVDRRTVELRLADN CG59869-01 FIQALGPPDFRNMTGLVDLTLSRNAITRIGARAFGDLESLRSLHLDGNRLVELGTGSL Protein Sequence RGPVNLQHLILSGNQLGRIAPGAFDDFLESLEDLDLSYNNLRQVP AGIGAMPALHTL NLDHNLIDALPPGAFAQLGQLSRLDLTSNRLATLAPDPLFSRGRDAEASPAPLVLSFS GNPLHCNCELL LRRLARPDDLETCASPPGLAGRYFWAVPEGEFSCEPPLIARHTQRL WVLEGQRATLRCRALGDPAPT HWVGPDDRLVGNSSRARAFPNGTLEIGVTGAGDAGG YTCIATNPAGEATARVELRVLALPHGGNSSAEGGRPGPSDIAASARTAAEGEGTLESE PAVQVTEVTATSGLVSWGPGRPADPVWMFQIQYNSSEDETLIYRIVPASSHHFLLKHL VPGADYDLCLLALSPAAGPSDLTATRLLGCAHFSTLPASPLCHALQAHVLGGTLTVAV GGVLVAALLVFTVALLVRGRGAGNGRLPLKLSHVQSQTNGGPSPTPKAHPPREPPAPA AAQLLSGPGRCRVLRLCQAPGRSLGPTEPLCAWGAARGRVPGGRRQRRAAGRECGVMD GQLPVCSKG

SEQ ID NO: 189 2451 bp

NOV44b, AGAGTCCTCAGCAGGGTAGCCGAGGCCAGGCCACTTCTGCTGAGGATGGGGCAGGCTG CG59869-02 DNA GGGTGTGGGTGTGGCCTGGGGTGGCTCAGGGCTGGAACTGCTGCCTGATTCCTGTGTG Sequence GGGAGAAGCTCAGTGGCCGTTTGCTGCCACTGACAAGGATTTCACATGCAGAAGAGAA

AAGGCCCCCCTCCACCCCCCGCATTCCCTGCCGAGTGAGAGCCAGTGTTTGCTGCCCT

TGCTGGGGGCGGGTAGGAAACCCTGAGCTTCCTGATGCGGAGTCATGAAGCAGAGTCC

TCGGGAAGGCATCTCCCCAACCTTCCCTCATCTCTGGCGGCCCTCTTGGGCCTCTGAC

CCAGCCCCTCCCCGGGCCAGGCTCACAGAAGCTGGCTTCTGGGACTGTCCTGGGCCCA

AGTGGGCACCTGCGCCAGCCCCACCTGTGCCTGGGCTGTGGCCCCTTCCTACAGGGCG

CTCACCATGGCCCCGCCGCTCCTGCTGCTGCTGCTGGCCAGTGGAGCGGCCGCCTGCC

CGCTGCCCTGCGTCTGCCAGAACCTGTCCGAGTCGCTCAGCACCCTCTGTGCCCACCG AGGCCTGCTGTTTGTGCCGCCCAACGTGGACCGGCGCACAGTGGAGCTGCGGCTGGCT GACAACTTCATCCAGGCCCTGGGGCCCCCTGACTTCCGCAACATGACGGGACTGGTGG ACCTGACACTGTCTCGCAATGCCATCACCCGCATTGGGGCCCGCGCCTTTGGGGACCT CGAGAGCCTGCGTTCCCTCCACCTTGACGGCAACAGGCTGGTGGAGCTGGGCACCGGG AGCCTCCGGGGCCCCGTCAATCTGCAGCACCTCATCCTCAGCGGCAACCAGCTGGGCC GCATCGCGCCGGGAGCCTTCGACGACTTCCTAGAGAGCCTGGAGGACCTGGACCTGTC CTACAACAACCTCCGGCAGGTGCCCTGGGCCGGCATCGGCGCCATGCCTGCCCTGCAC ACCCTCAACCTGGACCATAACCTTATTGACGCACTGCCCCCAGGCGCCTTCGCCCAGC TCGGTCAGCTCTCCCGCCTGGACCTCACCTCCAACCGCCTGGCCACGCTGGCTCCGGA CCCGCTTTTCTCTCGTGGGCGTGATGCAGAGGCCTCTCCCGCCCCCCTGGTGCTGAGC TTTAGCGGGAACCCCCTGCACTGCAACTGTGAGCTGCTGTGGCTGCGGCGGCTGGCGC GGCCGGACGACCTGGAAACGTGCGCCTCCCCGCCCGGCCTGGCCGGCCGCTACTTCTG GGCAGTGCCCGAGGGCGAGTTCTCCTGTGAGCCGCCCCTCATTGCCCGCCACACGCAG CGCCTCTGGGTGCTGGAAGGCCAGCGGGCCACGCTGCGGTGCCGGGCCCTGGGTGACC CCGCGCCTACCATGCACTGGGTCGGTCCTGACGACCGGTTGGTTGGCAACTCCTCCCG AGCCCGGGCTTTCCCCAACGGGACCTTAGAGATTGGGGTGACCGGCGCTGGGGACGCT GGGGGCTACACCTGCATCGCCACCAACCCTGCTGGTGAGGCCACAGCCCGAGTAGAAC TGCGGGTGCTGGCCTTGCCCCATGGTGGGAACAGCAGTGCCGAGGGGGGCCGCCCCGG GCCCTCGGACATCGCCGCCTCCGCTCGCACTGCTGCCGAGGGTGAGGGGACGCTGGAG TCTGAGCCAGCCGTGCAGGTGACGGAGGTGACCGCCACCTCAGGGCTGGTGAGCTGGG GTCCCGGGCGGCCAGCCGACCCAGTGTGGATGTTCCAAATCCAGTACAACAGCAGCGA AGATGAGACCCTCATCTACCGGATTGTCCCAGCCTCCAGCCACCACTTCCTGCTGAAG CACCCCGTCCCCGGCGCTGACTATGACCTCTGCCTGCTGGCCTTGTCACCGGCCGCTG GGCCCTCTGACCTCACGGCCACCAGGCTGCTGGGCTGTGCCCATTTCTCCACGCTGCC GGCCTCGCCCCTGTGCCACGCCCTGCAGGCCCACGTGCTGGGCGGGACCCTGACCGTG GCCGTGGGGGGTGTGCTGGTGGCTGCAGCCCCTGCCTCGGTGGCTGTGAGCACCTGTT GGAGGGGCCTGCCCTTACCCTGGTCTGGAGGCCAGAACCGAGGAAAGGGCTCCCTGCC CCTCCAAGTACACAGGGGAGCCTGAGGTACTGAGAATAAAAACCAGGGAGGGACTCCC

AGGCCAGGCGGCGGCCCCGGGCCCTCTGCCCCACGAGGCTCATCCCTTGGAGCACACA

GGAAGCTGCCCGTCCATCACACCACACTCTCTTCCAGCCGCTCGGCGCTGCCTCCTAC

CCCCCGGCACCCTGCCCCGAGCAGCCCCCCATGCACAGAGTGGCTCCGTCGGGCCCAA

GCTCCTCCCAGGCGCCTGGCATAACCGTAGCACCCGGCATCTCCCAGGTCCAGAGAGC

AGCTGCGCTGCGGCC

ORF Start: ATG at 471 ORF Stop: TGA at 2169

SEQ ID NO: 190 566 aa MW at 59683. lkD

NOV44b, MAPPLLLLLLASGAAACPLPCVCQNLSESLSTLCAHRGLLFVPPNVDRRTVELRLADN CG59869-02 FIQALGPPDFRN TGLVDLTLSRNAITRIGARAFGDLESLRSLHLDGNRLVELGTGSL RGPVNLQHLILSGNQLGRIAPGAFDDFLESLEDLDLSYNNLRQVPWAGIGAMPALHTL Protein Sequence NLDHNLIDALPPGAFAQLGQLSRLDLTSNRLATLAPDPLFSRGRDAEASPAPLVLSFS GNPLHCNCELLWLRRLARPDDLETCASPPGLAGRYF AVPEGEFSCEPPLIARHTQRL WVLEGQRATLRCRALGDPAPTMHWVGPDDRLVGNSSRARAFPNGTLEIGVTGAGDAGG YTCIATNPAGEATARVELRVLALPHGGNSSAEGGRPGPSDIAASARTAAEGEGTLESE PAVQVTEVTATSGLVSWGPGRPADPV MFQIQYNSSEDETLIYRIVPASSHHFLLKHP VPGADYDLCLLALSPAAGPSDLTATRLLGCAHFSTLPASPLCHALQAHVLGGTLTVAV GGVLVAAAPASVAVSTC RGLPLP SGGQNRGKGSLPLQVHRGA

SEQ ID NO: 191 2563 bp

NOV44c, TCCCAATCTGGAGGGGAACGTTGCACCCCAGCCCGAGGAGGCCCTGGCCGTGTGAAGA CG59869-03 DNA GCCAGCCAAGTGGGCACCTGCGCCAGCCCCACCTGTGCCTGGCTGTGGCCCCTTCCTA

CAGGGCGCTCACCATGGCCCCCGCGCTCCTGCTGCTGCTGCTGGCCAGTGGAGCGGCC Sequence GCCTGCCCGCTGCCCTGCGTCTGCCAGAACCTGTCCGAGTCGCTCAGCACCCTCTGTG CCCACCGAGGCCTGCTGTTTGTGCCGCCCAACGTGGACCGGCGCACAGTGGAGCTGCG GCTGGCTGACAACTTCATCCAGGCCCTGGGGCCCCCCGACTTCCGCAACATGACGGGA CTGGTGGACCTGACACTGTCTCGCAATGCCATCACCCGCATTGGGGCCCGCGCCTTTG GGGACCTCGAGAGCCTACGTTCCCTCCACCTTGACGGCAACAGGCTGGTGGAGCTGGG CACCGGGAGCCTCCGGGGCCCCGTCAATCTGCAGCACCTCATCCTCAGCGGCAACCAG CTGGGCCGCATCGCGCCGGGAGCCTTCGACGACTTCCTAGAGAGCCTGGAGGACCTGG ACCTGTCCTACAACAACCTCCGGCAGGTGCCCTGGGCCGGCATCGGCGCCATGCCTGC CCTGCACACCCTCAACCTGGACCATAACCTTATTGACGCACTGCCCCCAGGCGCCTTC GCCCAGCTCGGTCAGCTCTCCCGCCTGGACCTCACCTCCAACCGCCTGGCCACGCTGG CTCCGGACCCGCTTTTCTCTCGTGGGCGTGATGCAGAGGCCTCTCCCGCCCCCCTGGT GCTGAGCTTTAGCGGGAACCCCCTGCACTGCAACTGTGAGCTGCTGTGGCTGCGGCGG CTGGCGCGGCCGGACGACCTGGAAACGTGCGCCTCCCCGCCCGGCCTGGCCGGCCGCT ACTTCTGGGCAGTGCCCGAGGGCGAGTTCTCCTGTGAGCCGCCCCTCATTGCCCGCCA CACGCAGCGCCTCTGGGTGCTGGAAGGCCAGCGGGCCACGCTGCGGTGCCGGGCCCTG GGTGACCCCGCGCCTACCATGCACTGGGTCGGTCCTGACGACCGGTTGGTTGGCAACT CCTCCCGAGCCCGGGCTTTCCCCAACGGGACCTTAGAGATTGGGGTGACCGGCGCTGG GGACGCTGGGGGCTACACCTGCATCGCCACCAACCCTGCTGGTGAGGCCACAGCCCGA GTAGAACTGCGGGTGCTGGCCTTGCCCCATGGTGGGAACAGCAGTGCCGAGGGGGGCC GCCCGGGCCCTCGGACATCGGCCCCATGGTGGGAACAGCAGTGCCGAGGGGGGCCGCC CGGGCCCTCGGACATCGCCGCCTCCGCTCGCACTGCTGCCGAGGGTGAGGGGACGCTG GAGTCTGAGCCAGCCGTGCAGGTGACGGAGGTGACCGCCACCTCAGGGCTGGTGAACT GGGGTCCCCGGCAGCCAGCGACCCACGTGTGGATGTTCCAAATCCAGTACAACAGCAG CGAAGATGAGACCCTCATCTGCCGGATTGTCCCAGCCTCCAGCCACCACTTCCTGCTG AAGCACCTCGTCCCCGGCGCTGACTATGACCTCTGCCTGCTGGCCTTGTCACCGGCCG CTGGGCCCTCTGACCTCACGGCCACCAGGCTGCTGGGCTGTGCCCATTTCTCCACGCT GCCGGCCTCGCCCCTGTGCCACGCCCTGCAGGCCCACGTGCTGGGCGGGACCCTGACC GTGGCCGTGGGGGGTGTGCTGGTGGCTGCCTTACTGGTCTTCACTGTGGCCTTGCTGG TTCGGGGCCGGGGGGCCGGAAATGGCCGCCTCCCCCTCAAGCTCAGCCACGTCCAGTC CCAGACCAATGGAGGCCCCAGCCCCACACCCAAGGCCCACCCGCCGCGGAGCCCCCCG CCCCGGCCGCAGCGCAGCTGCTCTCTGGACCTGGGAGATGCCGGGTGCTACGGTTATG CCAGGCGCCTGGGAGGAGCTTGGGCCCGACGGAGCCACTCTGTGCATGGGGGGCTGCT CGGGGCAGGGTGCCGGGGGGTAGGAAGGGAGCCCTCCTGGAGAAGGCGCGAGTCTTGC TGTGCTGAGGAGCCTGCCGTGGACCGCCTCAGCGCCCCCTACACCACTCTCGCCCTGA GGACCAGCACCCTGAGGAAGCTGCAGGGAGGCAGGTATCAGCTCGGCAGACACAAGAG CTTGCATGGCCAGGGCCCCCACAGTGAAAATGACCCCGAGTTGGGGCAAGCTCCCCAT CAAGGGAGACCGCCGCGGAGCCCCCCGCCCCGGCCGCAGCGCAGCTGCTCTCTGGACC TGGGAGATGCCGGGTGCTACGGTTATGCCAGGCGCCTGGGAGGAGCTTGGGCCCGACG GAGCCACTCTGTGCATGGGGGGCTGCTCGGGGCAGGGTGCCGGGGGGTAGGAGGCAGC GCCGAGCGGCTGGAAGAGAGTGTGGTGTGATGGACGGGCAGCTTCCTGTGTGCTCCAA

GGGATGAGCCTCGTGGGGCAGAGGGCCCGGGGCCGCCGCCTGGCCTGGGAGTCCCTCC

CTGGTTTTTAT

ORF Start: ATG at 130 ORF Stop: TGA at 2464

SEQ ID NO: 192 778 aa MW at 82472.5kD

NOV44c, MAPALLLLLLASGAAACPLPCVCQNLSESLSTLCAHRGLLFVPPNVDRRTVELRLADN CG59869-03 FIQALGPPDFRNMTGLVDLTLSRNAITRIGARAFGDLESLRSLHLDGNRLVELGTGSL RGPVNLQHLILSGNQLGRIAPGAFDDFLESLEDLDLSYNNLRQVP AGIGAMPALHTL Protein Sequence NLDHNLIDALPPGAFAQLGQLSRLDLTSNRLATLAPDPLFSRGRDAEASPAPLVLSFS GNPLHCNCELLWLRRLARPDDLETCASPPGLAGRYFWAVPEGEFSCEPPLIARHTQRL VLEGQRATLRCRALGDPAPTMH VGPDDRLVGNSSRARAFPNGTLEIGVTGAGDAGG YTCIATNPAGEATARVELRVLALPHGGNSSAEGGRPGPRTSAPW EQQCRGGPPGPSD lAASARTAAEGEGTLESEPAVQVTEVTATSGLVN GPRQPATHV MFQIQYNSSEDET LICRIVPASSHHFLLKHLVPGADYDLCLLALSPAAGPSDLTATRLLGCAHFSTLPASP LCHALQAHVLGGTLTVAVGGVLVAALLVFTVALLVRGRGAGNGRLPLKLSHVQSQTNG GPSPTPKAHPPRSPPPRPQRSCSLDLGDAGCYGYARRLGGAARRSHSVHGGLLGAGC RGVGREPSWRRRESCCAEEPAVDRLSAPYTTLALRTSTLRKLQGGRYQLGRH SLHGQ GPHSENDPELGQAPHQGRPPRSPPPRPQRSCSLDLGDAGCYGYARRLGGAARRSHSV HGGLLGAGCRGVGGSAERLEESW

Sequence comparison ofthe above protein sequences yields the following sequence relationships shown in Table 44B.

Further analysis ofthe NOV44a protein yielded the following properties shown in Table 44C.

Table 44C. Protein Sequence Properties NOV44a

SignalP Cleavage site between residues 17 and 18 analysis: A search ofthe NOV44a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 44D.

In a BLAST search of public sequence databases, the NOV44a protein was found to have homology to the proteins shown in the BLASTP data in Table 44E.

PFam analysis indicates that the NOV44a protein contains the domains shown in the Table 44F.

Example 45.

The NOV45 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 45A.

Table 45A. NOV45 Sequence Analysis

Sequence comparison ofthe above protein sequences yields the following sequence relationships shown in Table 45B.

Table 45B. Comparison of NOV45a against NOV45b and NOV45c.

Protein Sequence NOV45a Residues/ Identities/ Match Residues Similarities for the Matched Region

NOV45b 1..196 196/196 (100%) 1..196 196/196 (100%)

Further analysis ofthe NOV45a protein yielded the following properties shown in Table 45C. Table 45C. Protein Sequence Properties NOV45a

SignalP Cleavage site between residues 25 and 26 analysis:

A search ofthe NOV45a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 45D.

In a BLAST search of public sequence databases, the NOV45a protein was found to have homology to the proteins shown in the BLASTP data in Table 45E.

PFam analysis predicts that the NOV45a protein contains the domains shown in the Table 45F.

Table 45F. Domain Analysis of NOV45a

Identities/

Pfam Domain NOV45a Match Region j Similarities j Expect Value for the Matched Region

No Significant Matches Found

Example 46.

The NOV46 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 46A.

CTTCTTAGCCCCTTTGCCTTCACTGTTGGGATGGCCCAGCTTATACATTTGGACTATG ATGTGAATTCTAATGCCCACTTGGATTCTTCACAAAATCCATACCTCATAATAGCTAC TCTTTTCATGTTGGTTTTTGACACCCTTCTGTATTTGGTATTGACATTATATTTTGAC AAAATTTTGCCCGGTGAATATGGACATCGATGTTCTCCCTTGTTTTTCCTGAAATCCT GTTTTTGGTTTCAACACGGAAGGGCTAATCATGTGGTCCTTGAGAATGAAACAGATTC TGATCCTACACCTAATGACTGTTTTGAACCAGTGTCTCCAGAATTCTGTGGGAAAGAA GCCATCAGAATCAAAAATCTTAAAAAAGAATATGCAGGGAAGTGTGAGAGAGTAGAAG CTTTGAAAGGTGTGGTGTTTGACATATATGAAGGCCAGATCACTGCCCTCCTTGGTCA CAGTGGAGCTGGAAAAACTACCCTGTTAAACATACTTAGTGGGTTGTCAGTTCCAACA TCAGGTTCAGTCACTGTCTATAATCACACACTTTCAAGAATGGCTGATATAGAAAATA TCAGCAAGTTCACTGGATTTTGTCCACAATCCAATGTGCAATTTGGATTTCTCACTGT GAAAGAAAACCTCAGGCTGTTTGCTAAAATAAAAGGGATTTTGCCACATGAAGTGGAG AAAGAGGTATTGCTATTGGATGAACCGACTGCTGGATTGGATCCTCTTTCAAGGCACC GAATATGGAATCTCCTGAAAGAGGGGAAATCAGACAGAGTAATTCTCTTCAGCACCCA GTTTATAGATGAGGCTGACATTCTGGCGGACAGGAAGGTGTTCATATCCAATGGGAAG CTGAAGTGTGCAGGCTCTTCTCTGTTCCTTAAGAAGAAATGGGGCATAGGCTACCATT TAAGTTTGCATCTGAATGAAAGGTGTGATCCAGAGAGTATAACATCACTGGTTAAGCA GCACATCTCTGATGCCAAATTGACAGCACAAAGTGAAGAAAAACTTGTATATATTTTG CCTTTGGAAAGGACAAACAAATTTCCAGAACTTTACAGGGATCTTGATAGATGTTCTA ACCAAGGCATTGAGGATTATGGTGTTTCCATAACAACTTTGAATGAGGTGTTTCTGAA ATTAGAAGGAAAATCAACTATTGATGAATCAGATATTGGAATTTGGGGACAATTACAA ACTGATGGGGCAAAAGATATAGGAAGCCTTGTTGAGCTGGAACAAGTTTTGTCTTCCT TCCACGAAACAAGGAAAACAATCAGTGGCGTGGCGCTCTGGAGGCAGCAGGTCTGTGC AATAGCAAAAGTTCGCTTCCTAAAGTTAAAGAAAGAAAGAAAAAGCCTGCTGCATAGA TTATTGCTTTTTGGTATTAGCTTTATCCCTCAACTTTTGGAACATCTATTCTACGAGT CATATCAGAAAAGTTACCCGTGGGAACTGTCTCCAAATACATACTTCCTCTCACCAGG ACAACAACCACAGGATCCTCTGACCCATTTACTGGTCATCAATAAGACAGGTTCAACC ATTGATAACTTTTTACATTCACTGAGGCGACAGAACATAGCTATAGAAGTGGATGCCT TTGGAACTAGAAATGGCACAGATGACCCATCTTACAATGGTGCTATCATTGTGTCAGG TGATGAAAAGGATCACAGATTTTCAATAGCATGTAATACAAAACGGCTGAATTGCTTT CCTGTCCTCCTGGATGTCATTAGCAATGGACTACTTGGAATTTTTAATTCGTCAGAAC ACATTCAGACTGACAGAAGCACATTTTTTGAAGAGCATATGGATTATGAGTATGGGTA CCGAAGTAACACCTTCTTCTGGATACCGATGGCAGCCTCTTTCACTCCATACATTGCA ATGAGCAGCATTGGTGACTACAAAGTAAGAGCTCATTCCCAGCTACGGATTTCAGGCC TCTACCCTTCTGCATACTGGTTTGGCCAAGCACTGGTGGATGTTTCCCTGTACTTTTT GATCCTCCTGCTAATGCAAATAATGGATTATATTTTTAGCCCAGAGGAGATTATATTT ATAATTCAAAACCTGTTAATTCAAGTAAGTGGCAGCAATTTTGAAATGGTTTTATTAG ACTATTTTTTCATGAATGCAGTAATATCATTAATCTTAAACCAAAGAACTTCAAATTA CCTGTGCTATTGCATAGTTTTGGTGGTCATCTTCTCGATAGTTGCTACTGATCTAAAT GAATATGGATTTCTAGGGCTATTTTTTGGCACCATGTTAATACCTCCCTTCACATTGA TTGGCTCTCTATTCATTTTTTCTGAGGTAAGTAGTTCCACTTATAGCTCAAGAAACAA AATTGTCCTTTTACCTTTTATTTGCAAAAGAGTGGGGTACCTTCATTTTCTCATTTTT CTTTTCATTCTGCGATGCCTAGAAATGAACTGCAGGAAGAAACTAATGAGAAAGGATC CTGTGTTCAGAATTTCTCCAAGAAGCAACGCTATTTTTCCAAACCCAGAAGAGCCTGA AGGAGAGGAGGAAGATATCCAGATGGAAAGAATGAGAACAGTGAATGCTATGGCTGTG CGAGACTTTGATGAGACACCCGTCATCATTGCCAGCTGTCTACGGAAGGAATATGCAG GCAAAAAGAAAAATTGCTTTTCTAAAAGGAAGAAAAAAATTGCCACAAGAAATGTCTC TTTTTGTGTTAAAAAAGGTGAAGTTATAGGACTGTTAGGACACAATGGAGCTGGTAAA AGTACAACTATTAAGATGATAACTGGAGACACAAAACCAACTGCAGGACAGGTCATTT TGAAAGGGAGCGGTGGAGGGGAACCCCTGGGCTTCCTGGGGTACTGCCCTCAGGAGAA TGCGCTGTGGCCCAACCTGACAGTGAGGCAGCACCTGGAGGTGTACGCTGCCGTGAAA GGTCTCAGGAAAGGGGACGCAATGATCGCCATCACACGGTTAGTGGATGCGCTCAAGC TGCAGGACCAGCTGAAGGCTCCCGTGAAGACCTTGTCAGAGGGAATAAAGCGAAAGCT GTGCTTTGTGCTGAGCATCCTGGGGAACCCGTCAGTGGTGCTTCTGGATGAGCCGTCG ACCGGGATGGACCCCGAGGGGCAGCAGCAAATGTGGCAGGTGATTCGGGCCACCTTTA GAAACACGGAGAGGGGCGCCCTCCTGACCACCCACTACATGGCAGAGGCTGAGGCGGT GTGTGACCGAGTGGCCATCATGGTGTCAGGAAGGCTGAGGTGTATTGGTTCCATCCAA CACCTGAAAAGCAAATTTGGCAAAGACTACCTGCTGGAGATGAAGCTGAAGAACCTGG CACAAATGGAGCCCCTCCATGCAGAGATCCTGAGGCTTTTCCCCCAGGCTGCTCAGCA GGAAAGGTTCTCCTCCCTGATGGTCTATAAGTTGCCTGTTGAGGATGTGCGACCTTTA TCACAGGCTTTCTTCAAATTAGAGATAGTTAAACAGAGTTTCGACCTGGAGGAGTACA

Further analysis ofthe NOV46a protein yielded the following properties shown in Table 46B.

Table 46B. Protein Sequence Properties NOV46a

PSort 0.8000 probability located in plasma membrane; 0.6281 probability located in analysis: mitochondrial inner membrane; 0.4410 probability located in mitochondrial intermembrane space; 0.4000 probability located in Golgi body

SignalP Cleavage site between residues 54 and 55 analysis:

A search ofthe NOV46a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 46C.

Table 46C. Geneseq Results for NOV46a

NOV46a

Geneseq Identities/ , _ .

Protein/Organism/Length [Patent Residues/ Identifier #, Date] SimUarities for π V?al!ue

In a BLAST search of public sequence databases, the NOV46a protein was found to have homology to the proteins shown in the BLASTP data in Table 46D.

PFam analysis indicates that the NOV46a protein contains the domains shown in the Table 46E.

Example 47.

The NOV47 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 47A.

CATCCCTCTGATGATTATTTTGAACCAGTAGCTCCTGAATTCCAAGGAAAAGAAGCCA TCAGAATCAGAAATGTTAAGAAGGAATATAAAGGAAAATCTGGAAAAGTGGAAGCATT GAAAGGTTTGCTCTTTGACATATATGAAGGTCAAATCACGGCAATCCTGGGTCACAGT GGAGCTGGCAAATCTTCACTGCTAAATATTCTTAATGGATTGTCTGTTCCAACAGAAG GTTCAGTTACCATCTATAATAAAAATCTCTCTGAAATGCAAGACTTGGAGGAAATCAG AAAGATAACTGGCGTCTGTCCTCAATTCAATGTTCAATTTGACATACTCACCGTGAAG GAAAACCTCAGCCTGTTTGCTAAAATAAAAGGGATTCATCTAAAGGAAGTGGAACAAG AGATTTTGCTTTTAGATGAACCAACTACTGGATTGGATCCCTTTTCCAGAGATCAAGT GTGGAGCCTCCTGAGAGAGCGTAGAGCAGATCATGTGATCCTTTTCAGTACCCAGTCC ATGGATGAGGCTGACATCCTGGCTGATAGAAAAGTGATCATGTCCAATGGGAGACTGA AGTGTGCAGGTTCTTCTATGTTTTTGAAAAGAAGGTGGGGTCTTGGATATCACCTAAG TTTACATAGGAATGAAATATGTAACCCAGAACAAATAACATCCTTCATTACTCATCAC ATCCCCGATGCTAAATTAAAAACAGAAAACAAAGAAAAGCTTGTATATACTTTGCCAC TGGAAAGGACAAATACATTTCCAGATCTTTTCAGTGATCTGGATAAGTGTTCTGACCA GGGAGTGACAGGTTATGACATTTCCATGTCAACTCTAAATGAAGTCTTTATGAAACTG GAAGGACAGTCAACTATCGAACAAGGTAAAGCCATTTGTATAATTCACAGACAAGTGG AGATGATAAGAGACTCAGAAAGCCTCAATGAAATGGAGCTGGCTCACTCTTCCTTCTC TGAAATGCAGACAGCTGTGAGTGACATGGGCCTCTGGAGAATGCAAGTCTTTGCCATG GCACGGCTCCGTTTCTTAAAGTTAAAACGTCAAACTAAAGTGTTATTGACCCTGTTAT TGGTATTTGGAATCGCAATATTCCCTTTGATTGTTGAAAATATAATGTATGCTATGTT AAATGAAAAGATCGATTGGGAATTTAAAAACGAATTGTATTTTCTCTCTCCTGGACAA CTTCCCCAGGAACCCCGTACCAGCCTGTTGATCATCAATAACACAGGTTCAAATATTG AAGATTTTATAAAATCACTGAAGCATCAAAATATACTTTTGGAAGTAGATGACTTTGA AAACAGAAATGGTACTGATGGCCTCTCATACAATGGAGCTATCATAGTTTGTTTCTGT TTTAAGGATTATAGATTTTCAGTTGTGTGTAATACCAAGAGATTGCACTGTTTTCCAA TTCTTATGAATATTATCAGCAATGGGCTACTTCAAATGTTTAATCACACACAACATAT TCGAATTGAGTCAAGCCCATTTAGCCACATAGGACTCTGGACTGGGTTGCCGGATGGT TCCTTTTTCTTATTTTTGGTTCTATGTAGCATTTCTCCTTATATCACCATGGGCAGCA TCAGTGATTACAAGGTAAGAGCTAAGTCCCAGCTATGGATTTCAGGCCTCTACACTTC TGCTTACTGGTGTGGGCAGGCACTAGTGGACGTCAGCTTCTTCATTTTAATTCTCCTT TTAATGTATTTAATTTTCTACATAGAAAACATGCAGTACCTTCTTATTACATATTTCT TTTATGCTCAGGTTATAGTTACTCCTGGTTATGCAGCTTCTCTTGTCTTCTTCATATA TATGATATCATTTATTTTTCGCAAAAGGAGAAAAAACAGTGGCCTTTGGTCATTTTAC TTCTTTTTTGCCTCCACCATCATGTTTTCCATCACTTTAATCAATCATTTTGACCTAA GTATATTGATTACCACCATGGTATTGGTTCCTTCATATACCTTGCTTGGATTTAAAAC TTTTTTGGAAGTGAGAGACCAGGAGCACTACAGAGAATTGAGTGCCACTGATTTTCTA GTCTGCTTCATACCCTACTTTCAGACTTTGCTATTCGTTTTTGTTCTAAGATGCATGG AACTAAAATGTGGAAAGAAAAGAATGCGAAAAGATCCTGTTTTCAGGATTTCCCCCCA AAGTAGAGATGCTAAGCCAAATCCAGAAGAACCCATAGATGAAGATGAAGATATTCAA ACAGAAAGAATAAGAACAGCCACTGCTCTGACCACTTCAATCTTAGATGAGAAACCTG TTATAATTGCCAGCTGTCTACACAAAGAATATGCAGGCCAGAAGAAAAGTTGCTTTTC AAAGAGGAAGAAGAAAATAGCAGCAAGAAATATCTCTTTCTGTGTTCAAGAAGGTGAA ATTTTGGGATTGCTAGGACCCAATGGTGCTGGAAAAAGTTCATCTATTAGAATGATAT CTGGGATCACAAAGCCAACTGCTGGAGAGGTAGTGCTGAAAGGCTGCAGTTCAGTTTT GGGCCACCTGGGGTACTGCCCTCAAGAGAACGTGCTGTGGCCCATGCTGACGTTGAGG GAACACCTGGAGGTGTATGCTGCCGTCAAGGGGCTCAGGAAAGCGGACGCGAGGCTCG CCATCGCAAGGAGATTAGTGAGTGCTTTCAAACTGCATGAGCAGCTGAATGTTCCTGT GCAGAAATTAACAGCAGGAATCACGAGAAAGTTGTGTTTTGTGCTGAGCCTCCTGGGA AACTCACCTGTCTTGCTCCTGGATGAACCATCTACGGGCATAGACCCCACAGGGCAGC AGCAAATGTGGCAGGCAATCCAGGCAGTCGTTAAAAACACAGAGAGAGGTGTCCTCCT GACCACCCATAACCTGGCTGAGGCGGAAGCCTTGTGTGACCGTGTGGCCATCATGGTG TCTGGAAGGCTTAGATGCATTGGCTCCATCCAACACCTGAAAAACAAACTTGGCAAGG ATTACATTCTAGAGCTAAAAGTGAAGGAAACGTCTCAAGTGACTTTGGTCCACACTGA GATTCTGAAGCTTTTCCCACAGGCTGCAGGGCAGGAAAGGTATTCCTCTTTGTTAACC TATAAGCTGCCCGTGGCAGACGTTTACCCTCTATCACAGACCTTTCACAAATTAGAAG CAGTGAAGCATAACTTTAACCTGGAAGAATACAGCCTTTCTCAGTGCACACTGGAGAA GGTATTCTTAGAGCTTTCTAAAGAACAGGAAGTAGGAAATTTTGATGAAGAAATTGAT ACAACAATGAGATGGAAACTCCTCCCTCATTCAGATGAACCTTAAAACCTCAAACCTA GTAATTTTTT

ORF Start: ATG at 13 ORF Stop: TAA at 4741

Further analysis ofthe NOV47a protein yielded the following properties shown in Table 47B.

Table 47B. Protein Sequence Properties NOV47a

PSort 0.8000 probability located in plasma membrane; 0.4000 probability located in analysis: Golgi body; 0.3000 probability located in endoplasmic reticulum (membrane); 0.3000 probability located in microbody (peroxisome)

SignalP Cleavage site between residues 51 and 52 analysis:

A search ofthe NOV47a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 47C.

In a BLAST search of public sequence databases, the NOV47a protein was found to have homology to the proteins shown in the BLASTP data in Table 47D.

PFam analysis indicates that the NOV47a protein contains the domains shown in the Table

47E.

Table 47E. Domain Analysis of NOV47a dentities/

Pfam Domain NOV47a Match I Expect Region Value

Example 48.

The NOV48 clone was analyzed, and the nucleotide and polypeptide sequences are shown in Table 48A.

Table 48A. NO 48 Sequence Analysis

SEQ ID NO: 201 1599 bp

NOV48a, CGCAGCAGTTTGTGTTCCCTGATGGAAAATGAAGCCTCATCTACTGACTCTCCCATCC CG59945-01 DNA AAAAAGACTTGAGGGCAAAGGAGGACAAAAGTTCCCACGAGGTGGGCACTGCGGGAAG GAGGCCGACGACCCCGAGATTCTCCGGCGACCCCGGCGGGCCACCCCGGGGCGGTGAG Sequence GGTTCCCGCGGCACGTGTGCGGCGGCGCCGGCCGCTTCCCCCGCCGCCCGGGAAGGTC ACGCCGCCCGGACGCCGAGGCTCTCCCCGTGCCCCGCTCCCTCCGCCCCGCACACTCC CGTGACCAGCGCCATGTCCAGCCAGGTGGTGGGCAGTGAGCCACTACAGTACATCATG GCAGAGCCGGCCAGGCCTGACAGTCCAAAGGGCTCCTCGGAGACAGAGACCGAGCCTC CTGTGGCCCTGGCCCCTGGTCCAGCTCCCACCCACTGCCTCCCAGGCCACAAGGAAGA GGAGGATGGGGAGGGGGCTGGGCCTGGCGAGCAGGGCGGTGGGAAGCTGGTGCTCAGC TCCCTGTCCAAGCGCCTCTGCCTGGTCTGTGGGGACGTGGCCTCCGGCTACCACTGCG GTGTGTCATCCTGTGAGGACTGCAAAGCCTTCTTCAAGAGGACCATCCAGGGGAGTAT GGAGTACAGCTGTCTGGCCTCCAACGAGTGTGAGATCACCAAGCGGAGACGCAAGGCC TGTCAGGCCTGCCGCTTCACCAAGAGCCTGCGGCTTCACCAAGAGCCTGCGGGAGCGC GCCTGGACCGCGTCCGGGGTGGGCGGGAGTACAAGCGGTGCCCAGAGGTGGACCCGCT GCCCTTCCCGGGCGCCTTCCCTGCTGGGCCCCTGGCAGTCGCTGGAGGCCCCCAGACG ACAGGCCCAGTGAATGCACTGGTGTCTCATCTAATGGTGGTTGAGCCTGAGAAGCTCT ATGCCTTGCCCGACCCTGCTGGCCCTGATGGGCACCTTCCAGCCGTGGCTACCCTCTG TGACCTCTTTGACCGAGAGATCGTGGTCACCATCAGCTGGGCCAAGAGCATCCCAGGC TTCTCATCGCTGTCGCTGTCTGACCAGATGTCAGTACTGCAGAGAGTATGGATGGAGG TGCTGGTGCCGGGTGTGGCCCAGCGCTCACTGCCACTGCAGGATGAGTTGGCCTTCGC TGAGGACTTAGTCCTGGATGAAGAGGGGGCACGGGCAGCTGGCCTGGGGGAACTGGGG GCTGCCCTGCTGCAACTGGTGCGGCGGCTGCAGTCCCTGCGGCTGGAGCGAGGGGAGT ACGTTCTACTGAAGGCCCTGGCCCTTGCCAATTCAGACTCTGTGCCCATCGAAGATGC CGAGGCTGTGGAGCAGCTGCCAGAAGCTCCGCACGAGGCCCTGCTGGAGTATGAAGCC GGCCGAGCTGGCACCGGAGGGGGTGCTGAGCGGCGGCGGCCAGGCAGGCTGCTGTTCA CGCTACCGCTCCTCCACCAGACAGCGGGCAAAGTGCTGGCCCATTTCTATGGGGTGAA GCTGGAGGGCAAGGTGCCCATGCACAAGCTGTTCTTGGAGATGCTCGAGGCCATGATG GACTGAGGCGAGGGGTGGGACTGGTGGGGGTTC

ORF Start: ATG at 22 ORF Stop: TGA at 1570

SEQ ID NO: 202 516 aa MW at 54706.5kD NOV48a, MENEASSTDSPIQKDLRAKEDKSSHEVGTAGRRPTTPRFSGDPGGPPRGGEGSRGTCA CG59945-01 AAPAASPAAREGHAARTPRLSPCPAPSAPHTPVTSAMSSQWGSEPLQYI AEPARPD SPKGSSETETEPPVALAPGPAPTHCLPGHKEEEDGEGAGPGEQGGGKLVLSSLSKRLC Protein Sequence LVCGDVASGYHCGVSSCEDCKAFFKRTIQGSMEYSCLASNECEITKRRRKACQACRFT KSLRLHQEPAGARLDRVRGGREYKRCPEVDPLPFPGAFPAGPLAVAGGPQTTGPVAL VSHLMWEPEKLYALPDPAGPDGHLPAVATLCDLFDREIWTIS AKSIPGFSSLSLS DQMSVLQRV MEVLVPGVAQRSLPLQDELAFAEDLVLDEEGARAAGLGELGAALLQLV RRLQSLRLERGEYVLLKALALANSDSVPIEDAEAVEQLPEAPHEALLEYEAGRAGTGG GAERRRPGRLLFTLPLLHQTAG VLAHFYGVKLEGKVPMHKLFLEMLEAMD

Further analysis ofthe NOV48a protein yielded the following properties shown in Table 48B.

Table 48B. Protein Sequence Properties NOV48a

PSort 0.7000 probability located in nucleus; 0.3000 probability located in microbody analysis: (peroxisome); 0.1000 probability located in mitochondrial matrix space; 0.1000 probability located in lysosome (lumen)

SignalP No Known Signal Sequence Indicated analysis:

A search ofthe NOV48a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 48C.

In a BLAST search of public sequence databases, the NO V48a protein was found to have homology to the proteins shown in the BLASTP data in Table 48D.

PFam analysis indicates that the NOV48a protein contains the domains shown in the Table 48E.

Example B: Identification of NOVX clones

The novel NOVX target sequences identified in the present invention may have been subjected to the exon linking process to confirm the sequence. PCR primers were designed by starting at the most upstream sequence available, for the forward primer, and at the most downstream sequence available for the reverse primer. In each case, the sequence was examined, walking inward from the respective termini toward the coding sequence, until a suitable sequence that is either unique or highly selective was encountered, or, in the case of the reverse primer, until the stop codon was reached. Such primers were designed based on in silico predictions for the full length cDNA, part (one or more exons) ofthe DNA or protein sequence ofthe target sequence, or by translated homology ofthe predicted exons to closely related human sequences from other species. These primers were then employed in PCR amplification based on the following pool of human cDNAs: adrenal gland, bone marrow, brain - amygdala, brain - cerebellum, brain - hippocampus, brain - substantia nigra, brain - thalamus, brain -whole, fetal brain, fetal kidney, fetal liver, fetal lung, heart, kidney, lymphoma - Raji, mammary gland, pancreas, pituitary gland, placenta, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testis, thyroid, trachea, uterus.

Usually the resulting amplicons were gel purified, cloned and sequenced to high redundancy. The PCR product derived from exon linking was cloned into the pCR2.1 vector from Invifrogen. The resulting bacterial clone has an insert covering the entire open reading frame cloned into the pCR2.1 vector. The resulting sequences from all clones were assembled with themselves, with other fragments in CuraGen Corporation's database and with public ESTs. Fragments and ESTs were included as components for an assembly when the extent of their identity with another component ofthe assembly was at least 95%> over 50 bp. In addition, sequence traces were evaluated manually and edited for corrections if appropriate. These procedures provide the sequence reported herein.

Example C: Quantitative expression analysis of clones in various cells and tissues The quantitative expression of various clones was assessed using microtiter plates containing RNA samples from a variety of normal and pathology-derived cells, cell lines and tissues using real time quantitative PCR (RTQ PCR). RTQ PCR was performed on an Applied Biosystems ABI PRISM® 7700 or an ABI PRISM® 7900 HT Sequence Detection System. Various collections of samples are assembled on the plates, and referred to as Panel 1 (containing normal tissues and cancer cell lines), Panel 2 (containing samples derived from tissues from normal and cancer sources), Panel 3 (containing cancer cell lines), Panel 4 (containing cells and cell lines from normal tissues and cells related to inflammatory conditions), Panel 5D/5I (containing human tissues and cell lines with an emphasis on metabolic diseases), AI_comprehensive_panel (containing normal tissue and samples from autoimmune diseases), Panel CNSD.01 (containing central nervous system samples from normal and diseased brains) and CNS_neurodegeneration_panel (containing samples from normal and Alzheimer's diseased brains).

RNA integrity from all samples is controlled for quality by visual assessment of agarose gel electiopherograms using 28S and 18S ribosomal RNA staining intensity ratio as a guide (2: 1 to 2.5:1 28s: 18s) and the absence of low molecular weight RNAs that would be indicative of degradation products. Samples are controlled against genomic DNA contamination by RTQ PCR reactions run in the absence of reverse transcriptase using probe and primer sets designed to amplify across the span of a single exon.

First, the RNA samples were normalized to reference nucleic acids such as constitutively expressed genes (for example, β-actin and GAPDH). Normalized RNA (5 ul) was converted to cDNA and analyzed by RTQ-PCR using One Step RT-PCR Master Mix Reagents (Applied Biosystems; Catalog No. 4309169) and gene-specific primers according to the manufacturer's instructions.

In other cases, non-normalized RNA samples were converted to single strand cDNA

(sscDNA) using Superscript II (Invitrogen Corporation; Catalog No. 18064-147) and random hexamers according to the manufacturer's instructions. Reactions containing up to 10 μg of total RNA were performed in a volume of 20 μl and incubated for 60 minutes at 42°C. This reaction can be scaled up to 50 μg of total RNA in a final volume of 100 μl. sscDNA samples are then normalized to reference nucleic acids as described previously, using IX TaqMan® Universal Master mix (Applied Biosystems; catalog No. 4324020), following the manufacturer's instructions.

Probes and primers were designed for each assay according to Applied Biosystems Primer Express Software package (version I for Apple Computer's Macintosh Power PC) or a similar algorithm using the target sequence as input. Default settings were used for reaction conditions and the following parameters were set before selecting primers: primer concentration = 250 nM, primer melting temperature (Tm) range = 58°-60°C, primer optimal Tm = 59°C, maximum primer difference = 2°C, probe does not have 5'G, probe Tm must be 10°C greater than primer Tm, amplicon size 75bp to lOObp. The probes and primers selected (see below) were synthesized by Synthegen (Houston, TX, USA). Probes were double purified by HPLC to remove uncoupled dye and evaluated by mass spectioscopy to verify coupling of reporter and quencher dyes to the 5' and 3' ends ofthe probe, respectively. Their final concentrations were: forward and reverse primers, 900nM each, and probe, 200nM.

PCR conditions: When working with RNA samples, normalized RNA from each tissue and each cell line was spotted in each well of either a 96 well or a 384-well PCR plate (Applied Biosystems). PCR cocktails included either a single gene specific probe and primers set, or two multiplexed probe and primers sets (a set specific for the target clone and another gene-specific set multiplexed with the target probe). PCR reactions were set up using TaqMan® One-Step RT-PCR Master Mix (Applied Biosystems, Catalog No. 4313803) following manufacturer's instructions. Reverse transcription was performed at 48°C for 30 minutes followed by amplification/PCR cycles as follows: 95°C 10 min, then 40 cycles of 95°C for 15 seconds, 60°C for 1 minute. Results were recorded as CT values (cycle at which a given sample crosses a threshold level of fluorescence) using a log scale, with the difference in RNA concentration between a given sample and the sample with the lowest CT value being represented as 2 to the power of delta CT. The percent relative expression is then obtained by taking the reciprocal of this RNA difference and multiplying by 100.

When working with sscDNA samples, normalized sscDNA was used as described previously for RNA samples. PCR reactions containing one or two sets of probe and primers were set up as described previously, using IX TaqMan® Universal Master mix (Applied Biosystems; catalog No. 4324020), following the manufacturer's instructions. PCR amplification was performed as follows: 95°C 10 min, then 40 cycles of 95°C for 15 seconds, 60°C for 1 minute. Results were analyzed and processed as described previously.

Panels 1, 1.1, 1.2, and 1.3D

The plates for Panels 1, 1.1, 1.2 and 1.3D include 2 control wells (genomic DNA control and chemistry control) and 94 wells containing cDNA from various samples. The samples in these panels are broken into 2 classes: samples derived from cultured cell lines and samples derived from primary normal tissues. The cell lines are derived from cancers of the following types: lung cancer, breast cancer, melanoma, colon cancer, prostate cancer, CNS cancer, squamous cell carcinoma, ovarian cancer, liver cancer, renal cancer, gastric cancer and pancreatic cancer. Cell lines used in these panels are widely available through the American Type Culture Collection (ATCC), a repository for cultured cell lines, and were cultured using the conditions recommended by the ATCC. The normal tissues found on these panels are comprised of samples derived from all major organ systems from single adult individuals or fetuses. These samples are derived from the following organs: adult skeletal muscle, fetal skeletal muscle, adult heart, fetal heart, adult kidney, fetal kidney, adult liver, fetal liver, adult lung, fetal lung, various regions ofthe brain, the spleen, bone marrow, lymph node, pancreas, salivary gland, pituitary gland, adrenal gland, spinal cord, thymus, stomach, small intestine, colon, bladder, trachea, breast, ovary, uterus, placenta, prostate, testis and adipose.

In the results for Panels 1, 1.1, 1.2 and 1.3D, the following abbreviations are used: ca. = carcinoma, * = established from metastasis, met = metastasis, s cell var = small cell variant, non-s = non-sm = non-small, squam = squamous, pi. eff = pi effusion = pleural effusion, glio = glioma, astro = astrocytoma, and neuro = neuroblastoma.

General_screening_panel_vl.4 The plates for Panel 1.4 include 2 control wells (genomic DNA control and chemistry control) and 94 wells containing cDNA from various samples. The samples in Panel 1.4 are broken into 2 classes: samples derived from cultured cell lines and samples derived from primary normal tissues. The cell lines are derived from cancers ofthe following types: lung cancer, breast cancer, melanoma, colon cancer, prostate cancer, CNS cancer, squamous cell carcinoma, ovarian cancer, liver cancer, renal cancer, gastric cancer and pancreatic cancer. Cell lines used in Panel 1.4 are widely available through the American Type Culture Collection (ATCC), a repository for cultured cell lines, and were cultured using the conditions recommended by the ATCC. The normal tissues found on Panel 1.4 are comprised of pools of samples derived from all major organ systems from 2 to 5 different adult individuals or fetuses. These samples are derived from the following organs: adult skeletal muscle, fetal skeletal muscle, adult heart, fetal heart, adult kidney, fetal kidney, adult liver, fetal liver, adult lung, fetal lung, various regions ofthe brain, the spleen, bone marrow, lymph node, pancreas, salivary gland, pituitary gland, adrenal gland, spinal cord, thymus, stomach, small intestine, colon, bladder, trachea, breast, ovary, uterus, placenta, prostate, testis and adipose. Abbreviations are as described for Panels 1, 1.1, 1.2, and 1.3D.

Panels 2D and 2.2

The plates for Panels 2D and 2.2 generally include 2 confrol wells and 94 test samples composed of RNA or cDNA isolated from human tissue procured by surgeons working in close cooperation with the National Cancer Institute's Cooperative Human Tissue Network (CHTN) or the National Disease Research Initiative (NDRI). The tissues are derived from human malignancies and in cases where indicated many malignant tissues have "matched margins" obtained from noncancerous tissue just adjacent to the tumor. These are termed normal adjacent tissues and are denoted "NAT" in the results below. The tumor tissue and the "matched margins" are evaluated by two independent pathologists (the surgical pathologists and again by a pathologist at NDRI or CHTN). This analysis provides a gross histopathological assessment of tumor differentiation grade. Moreover, most samples include the original surgical pathology report that provides information regarding the clinical stage of the patient. These matched margins are taken from the tissue surrounding (i.e. immediately proximal) to the zone of surgery (designated "NAT", for normal adjacent tissue, in Table RR). In addition, RNA and cDNA samples were obtained from various human tissues derived from autopsies performed on elderly people or sudden death victims (accidents, etc.). These tissues were ascertained to be free of disease and were purchased from various commercial sources such as Clontech (Palo Alto, CA), Research Genetics, and Invitrogen.

Panel 3D The plates of Panel 3D are comprised of 94 cDNA samples and two control samples.

Specifically, 92 of these samples are derived from cultured human cancer cell lines, 2 samples of human primary cerebellar tissue and 2 controls. The human cell lines are generally obtained from ATCC (American Type Culture Collection), NCI or the German tumor cell bank and fall into the following tissue groups: Squamous cell carcinoma ofthe tongue, breast cancer, prostate cancer, melanoma, epidermoid carcinoma, sarcomas, bladder carcinomas, pancreatic cancers, kidney cancers, leukemias/lymphomas, ovarian/uterine/cervical, gastric, colon, lung and CNS cancer cell lines. In addition, there are two independent samples of cerebellum. These cells are all cultured under standard recommended conditions and RNA extracted using the standard procedures. The cell lines in panel 3D and 1.3D are ofthe most common cell lines used in the scientific literature.

Panels 4D, 4R, and 4.1D Panel 4 includes samples on a 96 well plate (2 control wells, 94 test samples) composed of RNA (Panel 4R) or cDNA (Panels 4D/4.1D) isolated from various human cell lines or tissues related to inflammatory conditions. Total RNA from control normal tissues such as colon and lung (Stratagene, La Jolla, CA) and thymus and kidney (Clontech) was employed. Total RNA from liver tissue from cirrhosis patients and kidney from lupus patients was obtained from BioChain (Biochain Institute, Inc., Hayward, CA). Intestinal tissue for RNA preparation from patients diagnosed as having Crohn's disease and ulcerative colitis was obtained from the National Disease Research Interchange (NDRI) (Philadelphia, PA).

Astrocytes, lung fibroblasts, dermal fibroblasts, coronary artery smooth muscle cells, small airway epithelium, bronchial epithelium, microvascular dermal endothelial cells, microvascular lung endothelial cells, human pulmonary aortic endothelial cells, human umbilical vein endothelial cells were all purchased from Clonetics (Walkersville, MD) and grown in the media supplied for these cell types by Clonetics. These primary cell types were activated with various cytokines or combinations of cytokines for 6 and/or 12-14 hours, as indicated. The following cytokines were used; IL-1 beta at approximately l-5ng/ml, TNF alpha at approximately 5-10ng/ml, IFN gamma at approximately 20-50ng/ml, IL-4 at approximately 5-lOng/ml, IL-9 at approximately 5-10ng/ml, IL-13 at approximately 5- lOng/ml. Endothelial cells were sometimes starved for various times by culture in the basal media from Clonetics with 0.1% serum.

Mononuclear cells were prepared from blood of employees at CuraGen Corporation, using Ficoll. LAK cells were prepared from these cells by culture in DMEM 5%> FCS

(Hyclone), lOOμM non essential amino acids (Gibco/Life Technologies, Rockville, MD), lmM sodium pyruvate (Gibco), mercaptoethanol 5.5xl0^"5M (Gibco), and lOmM Hepes (Gibco) and Interleukin 2 for 4-6 days. Cells were then either activated with 10-20ng/ml PMA and l-2μg/ml ionomycin, IL-12 at 5-10ng/ml, IFN gamma at 20-50ng/ml and IL-18 at 5-10ng/ml for 6 hours. In some cases, mononuclear cells were cultured for 4-5 days in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), lmM sodium pyruvate (Gibco), mercaptoethanol 5.5xl0^"5M (Gibco), and lOmM Hepes (Gibco) with PHA (phytohemagglutinin) or PWM (pokeweed mitogen) at approximately 5 μg/ml. Samples were taken at 24, 48 and 72 hours for RNA preparation. MLR (mixed lymphocyte reaction) samples were obtained by taking blood from two donors, isolating the mononuclear cells using Ficoll and mixing the isolated mononuclear cells 1 : 1 at a final concentration of approximately 2xl0⁶cells/ml in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), lmM sodium pyruvate (Gibco), mercaptoethanol (5.5xlO^"5M) (Gibco), and lOmM Hepes (Gibco). The MLR was cultured and samples taken at various time points ranging from 1- 7 days for RNA preparation.

Monocytes were isolated from mononuclear cells using CD 14 Miltenyi Beads, +ve

VS selection columns and a Vario Magnet according to the manufacturer's instructions. Monocytes were differentiated into dendritic cells by culture in DMEM 5% fetal calf serum (FCS) (Hyclone, Logan, UT), lOOμM non essential amino acids (Gibco), lmM sodium pyruvate (Gibco), mercaptoethanol 5.5xl0^"5M (Gibco), and lOmM Hepes (Gibco), 50ng/ml GMCSF and 5ng/ml IL-4 for 5-7 days. Macrophages were prepared by culture of monocytes for 5-7 days in DMEM 5%> FCS (Hyclone), lOOμM non essential amino acids (Gibco), lmM sodium pyruvate (Gibco), mercaptoethanol 5.5xlO^"5M (Gibco), lOmM Hepes (Gibco) and 10%) AB Human Serum or MCSF at approximately 50ng/ml. Monocytes, macrophages and dendritic cells were stimulated for 6 and 12-14 hours with lipopolysaccharide (LPS) at lOOng/ml. Dendritic cells were also stimulated with anti-CD40 monoclonal antibody (Pharmingen) at lOμg/ml for 6 and 12-14 hours.

CD4 lymphocytes, CD8 lymphocytes and NK cells were also isolated from mononuclear cells using CD4, CD8 and CD56 Miltenyi beads, positive VS selection columns and a Vario Magnet according to the manufacturer's instructions. CD45RA and CD45RO CD4 lymphocytes were isolated by depleting mononuclear cells of CD8, CD56, CD14 and CD19 cells using CD8, CD56, CD14 and CD19 Miltenyi beads and positive selection. CD45RO beads were then used to isolate the CD45RO CD4 lymphocytes with the remaining cells being CD45RA CD4 lymphocytes. CD45RA CD4, CD45RO CD4 and CD8 lymphocytes were placed in DMEM 5%> FCS (Hyclone), lOOμM non essential amino acids (Gibco), lmM sodium pyruvate (Gibco), mercaptoethanol 5.5x10^"5M (Gibco), and lOmM

Hepes (Gibco) and plated at 10⁶cells/ml onto Falcon 6 well tissue culture plates that had been coated overnight with 0.5μg/ml anti-CD28 (Pharmingen) and 3ug/ml anti-CD3 (OKT3, ATCC) in PBS. After 6 and 24 hours, the cells were harvested for RNA preparation. To prepare chronically activated CD8 lymphocytes, we activated the isolated CD8 lymphocytes for 4 days on anti-CD28 and anti-CD3 coated plates and then harvested the cells and expanded them in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), lmM sodium pyruvate (Gibco), mercaptoethanol 5.5xl0^"5M (Gibco), and lOmM Hepes (Gibco) and IL-2. The expanded CD8 cells were then activated again with plate bound anti- CD3 and anti-CD28 for 4 days and expanded as before. RNA was isolated 6 and 24 hours after the second activation and after 4 days ofthe second expansion culture. The isolated NK cells were cultured in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), lmM sodium pyruvate (Gibco), mercaptoethanol 5.5 10^"5M (Gibco), and lOmM Hepes (Gibco) and IL-2 for 4-6 days before RNA was prepared.

To obtain B cells, tonsils were procured from NDRI. The tonsil was cut up with sterile dissecting scissors and then passed through a sieve. Tonsil cells were then spun down and resupended at 10⁶cells/ml in DMEM 5%> FCS (Hyclone), lOOμM non essential amino acids (Gibco), lmM sodium pyruvate (Gibco), mercaptoethanol 5.5 lO^"5M (Gibco), and lOmM Hepes (Gibco). To activate the cells, we used PWM at 5 μg/ml or anti-CD40 (Pharmingen) at approximately lOμg/ml and IL-4 at 5-10ng/ml. Cells were harvested for RNA preparation at 24,48 and 72 hours.

To prepare the primary and secondary Thl/Th2 and Trl cells, six- well Falcon plates were coated overnight with lOμg/ml anti-CD28 (Pharmingen) and 2μg/ml OKT3 (ATCC), and then washed twice with PBS. Umbilical cord blood CD4 lymphocytes (Poietic Systems, German Town, MD) were cultured at 10⁵-10⁶cells/ml in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), lmM sodium pyruvate (Gibco), mercaptoethanol 5.5x10^" ⁵M (Gibco), lOmM Hepes (Gibco) and IL-2 (4ng/ml). IL-12 (5ng/ml) and anti-IL4 (1 μg/ml) were used to direct to Thl , while IL-4 (5ng/ml) and anti-IFN gamma (1 μg/ml) were used to direct to Th2 and IL-10 at 5ng/ml was used to direct to Trl . After 4-5 days, the activated Thl, Th2 and Trl lymphocytes were washed once in DMEM and expanded for 4-7 days in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), lmM sodium pyruvate (Gibco), mercaptoethanol 5.5xlO^"5M (Gibco), lOmM Hepes (Gibco) and IL-2 (lng/ml). Following this, the activated Thl, Th2 and Trl lymphocytes were re-stimulated for 5 days with anti-CD28/OKT3 and cytokines as described above, but with the addition of anti- CD95L (lμg/ml) to prevent apoptosis. After 4-5 days, the Thl, Th2 and Trl lymphocytes were washed and then expanded again with IL-2 for 4-7 days. Activated Thl and Th2 lymphocytes were maintained in this way for a maximum of three cycles. RNA was prepared from primary and secondary Thl, Th2 and Trl after 6 and 24 hours following the second and third activations with plate bound anti-CD3 and anti-CD28 mAbs and 4 days into the second and third expansion cultures in Interleukin 2.

The following leukocyte cells lines were obtained from the ATCC: Ramos, EOL-1, KU-812. EOL cells were further differentiated by culture in O.lmM dbcAMP at 5xl0⁵ cells/ml for 8 days, changing the media every 3 days and adjusting the cell concentration to 5xl0⁵cells/ml. For the culture of these cells, we used DMEM or RPMI (as recommended by the ATCC), with the addition of 5% FCS (Hyclone), 1 OOμM non essential amino acids (Gibco), lmM sodium pyruvate (Gibco), mercaptoethanol 5.5xlO^"5M (Gibco), lOmM Hepes (Gibco). RNA was either prepared from resting cells or cells activated with PMA at lOng/ml and ionomycin at lμg/ml for 6 and 14 hours. Keratinocyte line CCD106 and an airway epithelial tumor line NCI-H292 were also obtained from the ATCC. Both were cultured in DMEM 5% FCS (Hyclone), lOOμM non essential amino acids (Gibco), lmM sodium pyruvate (Gibco), mercaptoethanol 5.5xl0^"5M (Gibco), and lOmM Hepes (Gibco). CCD1106 cells were activated for 6 and 14 hours with approximately 5 ng/ml TNF alpha and lng/ml IL-1 beta, while NCI-H292 cells were activated for 6 and 14 hours with the following cytokines: 5ng/ml IL-4, 5ng/ml IL-9, 5ng/ml IL-13 and 25ng/ml IFN gamma.

For these cell lines and blood cells, RNA was prepared by lysing approximately

10⁷cells/ml using Trizol (Gibco BRL). Briefly, 1/10 volume of bromochloropropane (Molecular Research Corporation) was added to the RNA sample, vortexed and after 10 minutes at room temperature, the tubes were spun at 14,000 rpm in a Sorvall SS34 rotor. The aqueous phase was removed and placed in a 15ml Falcon Tube. An equal volume of isopropanol was added and left at -20°C overnight. The precipitated RNA was spun down at 9,000 rpm for 15 min in a Sorvall SS34 rotor and washed in 70%> ethanol. The pellet was redissolved in 300μl of RNAse-free water and 35μl buffer (Promega) 5μl DTT, 7μl RNAsin and 8μl DNAse were added. The tube was incubated at 37°C for 30 minutes to remove contaminating genomic DNA, extracted once with phenol chloroform and re-precipitated with 1/10 volume of 3M sodium acetate and 2 volumes of 100%> ethanol. The RNA was spun down and placed in RNAse free water. RNA was stored at -80°C.

AI_comprehensive panel vl.O The plates for AI_comprehensive panel_vl .0 include two control wells and 89 test samples comprised of cDNA isolated from surgical and postmortem human tissues obtained from the Backus Hospital and Clinomics (Frederick, MD). Total RNA was extracted from tissue samples from the Backus Hospital in the Facility at CuraGen. Total RNA from other tissues was obtained from Clinomics.

Joint tissues including synovial fluid, synovium, bone and cartilage were obtained from patients undergoing total knee or hip replacement surgery at the Backus Hospital. Tissue samples were immediately snap frozen in liquid nitrogen to ensure that isolated RNA was of optimal quality and not degraded. Additional samples of osteoarthritis and rheumatoid arthritis joint tissues were obtained from Clinomics. Normal control tissues were supplied by Clinomics and were obtained during autopsy of trauma victims.

Surgical specimens of psoriatic tissues and adjacent matched tissues were provided as total RNA by Clinomics. Two male and two female patients were selected between the ages of 25 and 47. None ofthe patients were taking prescription drugs at the time samples were isolated.

Surgical specimens of diseased colon from patients with ulcerative colitis and Crohns disease and adjacent matched tissues were obtained from Clinomics. Bowel tissue from three female and three male Crohn's patients between the ages of 41-69 were used. Two patients were not on prescription medication while the others were taking dexamethasone, phenobarbital, or tylenol. Ulcerative colitis tissue was from three male and four female patients. Four ofthe patients were taking lebvid and two were on phenobarbital.

Total RNA from post mortem lung tissue from trauma victims with no disease or with emphysema, asthma or COPD was purchased from Clinomics. Emphysema patients ranged in age from 40-70 and all were smokers, this age range was chosen to focus on patients with cigarette-linked emphysema and to avoid those patients with alpha- 1 anti-trypsin deficiencies. Asthma patients ranged in age from 36-75, and excluded smokers to prevent those patients that could also have COPD. COPD patients ranged in age from 35-80 and included both smokers and non-smokers. Most patients were taking corticosteroids, and bronchodilators.

In the labels employed to identify tissues in the AI_comprehensive panel_vl.O panel, the following abbreviations are used: Al = Autoimmunity Syn = Synovial Normal = No apparent disease Rep22 /Rep20 = individual patients RA = Rheumatoid arthritis

Backus = From Backus Hospital OA = Osteoarthritis (SS) (BA) (MF) = Individual patients Adj = Adjacent tissue Match control = adjacent tissues

-M = Male -F = Female COPD = Chronic obstructive pulmonary disease

Panels 5D and 51 The plates for Panel 5D and 51 include two control wells and a variety of cDNAs isolated from human tissues and cell lines with an emphasis on metabolic diseases. Metabolic tissues were obtained from patients enrolled in the Gestational Diabetes study. Cells were obtained during different stages in the differentiation of adipocytes from human mesenchymal stem cells. Human pancreatic islets were also obtained.

In the Gestational Diabetes study subjects are young (18 - 40 years), otherwise healthy women with and without gestational diabetes undergoing routine (elective) Caesarean section. After delivery of the infant, when the surgical incisions were being repaired/closed, the obstetrician removed a small sample (<1 cc) of the exposed metabolic tissues during the closure of each surgical level. The biopsy material was rinsed in sterile saline, blotted and fast frozen within 5 minutes from the time of removal. The tissue was then flash frozen in liquid nitiogen and stored, individually, in sterile screw-top tubes and kept on dry ice for shipment to or to be picked up by CuraGen. The metabolic tissues of interest include uterine wall (smooth muscle), visceral adipose, skeletal muscle (rectus) and subcutaneous adipose. Patient descriptions are as follows:

Patient 2 Diabetic Hispanic, overweight, not on insulin

Patient 7-9 Nondiabetic Caucasian and obese (BMI>30)

Patient 10 Diabetic Hispanic, overweight, on insulin

Patient 11 Nondiabetic African American and overweight Patient 12 Diabetic Hispanic on insulin

Adipocyte differentiation was induced in donor progenitor cells obtained from Osirus (a division of Clonetics/BioWhittaker) in triplicate, except for Donor 3U which had only two replicates. Scientists at Clonetics isolated, grew and differentiated human mesenchymal stem cells (HuMSCs) for CuraGen based on the published protocol found in Mark F. Pittenger, et al., Multilineage Potential of Adult Human Mesenchymal Stem Cells Science Apr 2 1999: 143-147. Clonetics provided Trizol lysates or frozen pellets suitable for mRNA isolation and ds cDNA production. A general description of each donor is as follows:

Donor 2 and 3 U: Mesenchymal Stem cells, Undifferentiated Adipose

Donor 2 and 3 AM: Adipose, AdiposeMidway Differentiated Donor 2 and 3 AD: Adipose, Adipose Differentiated

Human cell lines were generally obtained from ATCC (American Type Culture Collection), NCI or the German tumor cell bank and fall into the following tissue groups: kidney proximal convoluted tubule, uterine smooth muscle cells, small intestine, liver HepG2 cancer cells, heart primary stromal cells, and adrenal cortical adenoma cells. These cells are all cultured under standard recommended conditions and RNA extracted using the standard procedures. All samples were processed at CuraGen to produce single stranded cDNA.

Panel 51 contains all samples previously described with the addition of pancreatic islets from a 58 year old female patient obtained from the Diabetes Research Institute at the University of Miami School of Medicine. Islet tissue was processed to total RNA at an outside source and delivered to CuraGen for addition to panel 51.

In the labels employed to identify tissues in the 5D and 51 panels, the following abbreviations are used: GO Adipose = Greater Omentum Adipose

SK= Skeletal Muscle

UT = Uterus

PL = Placenta

AD = Adipose Differentiated AM = Adipose Midway Differentiated

U = Undifferentiated Stem Cells

Panel CNSD.01

The plates for Panel CNSD.01 include two control wells and 94 test samples comprised of cDNA isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center. Brains are removed from calvaria of donors between 4 and 24 hours after death, sectioned by neuroanatomists, and frozen at -80°C in liquid nitrogen vapor. All brains are sectioned and examined by neuropathologists to confirm diagnoses with clear associated neuropathology. Disease diagnoses are taken from patient records. The panel contains two brains from each ofthe following diagnoses: Alzheimer's disease, Parkinson's disease, Huntington's disease, Progressive Supernuclear Palsy, Depression, and "Normal controls". Within each of these brains, the following regions are represented: cingulate gyrus, temporal pole, globus palladus, substantia nigra, Brodman Area 4 (primary motor strip), Brodman Area 7 (parietal cortex), Brodman Area 9 (prefrontal cortex), and Brodman area 17 (occipital cortex). Not all brain regions are represented in all cases; e.g., Huntington's disease is characterized in part by neurodegeneration in the globus palladus, thus this region is impossible to obtain from confirmed Huntington's cases. Likewise Parkinson's disease is characterized by degeneration ofthe substantia nigra making this region more difficult to obtain. Normal control brains were examined for neuropathology and found to be free of any pathology consistent with neurodegeneration.

In the labels employed to identify tissues in the CNS panel, the following abbreviations are used: PSP = Progressive supranuclear palsy

Sub Nigra = Substantia nigra

Glob Palladus= Globus palladus

Temp Pole = Temporal pole

Cing Gyr = Cingulate gyrus BA 4 = Brodman Area 4

Panel CNS_Neurodegeneration_V1.0

The plates for Panel CNS_Neurodegeneration_V1.0 include two control wells and 47 test samples comprised of cDNA isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center (McLean Hospital) and the Human Brain and Spinal Fluid Resource Center (VA Greater Los Angeles Healthcare System). Brains are removed from calvaria of donors between 4 and 24 hours after death, sectioned by neuroanatomists, and frozen at -80°C in liquid nitrogen vapor. All brains are sectioned and examined by neuropathologists to confirm diagnoses with clear associated neuropathology.

Disease diagnoses are taken from patient records. The panel contains six brains from Alzheimer's disease (AD) patients, and eight brains from "Normal controls" who showed no evidence of dementia prior to death. The eight normal confrol brains are divided into two categories: Controls with no dementia and no Alzheimer's like pathology (Controls) and controls with no dementia but evidence of severe Alzheimer's like pathology, (specifically senile plaque load rated as level 3 on a scale of 0-3; 0 = no evidence of plaques, 3 = severe AD senile plaque load). Within each of these brains, the following regions are represented: hippocampus, temporal cortex (Brodman Area 21), parietal cortex (Brodman area 7), and occipital cortex (Brodman area 17). These regions were chosen to encompass all levels of neurodegeneration in AD. The hippocampus is a region of early and severe neuronal loss in AD; the temporal cortex is known to show neurodegeneration in AD after the hippocampus; the parietal cortex shows moderate neuronal death in the late stages ofthe disease; the occipital cortex is spared in AD and therefore acts as a "control" region within AD patients. Not all brain regions are represented in all cases.

In the labels employed to identify tissues in the CNS_Neurodegeneration_Vl .0 panel, the following abbreviations are used:

AD = Alzheimer's disease brain; patient was demented and showed AD-like pathology upon autopsy

Control = Control brains; patient not demented, showing no neuropathology

Control (Path) = Control brains; pateint not demented but showing sever AD-like pathology

SupTemporal Ctx = Superior Temporal Cortex

Inf Temporal Ctx = Inferior Temporal Cortex

A. NOVla (CG58546-01: Adlican) Expression of gene CG58546-01 was assessed using the primer-probe sets Ag2933, Ag3370 and Ag3837, described in Tables AA, AB and AC.

Table AA. Probe Name Ag2933

Table AB. Probe Name Ag3370

Table AC. Probe Name Ag3837

CNS_neurodegeneration_vl.O Summary: Ag2933/Ag3370 Expression ofthe CG58546-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

General_screening_panel_vl.4 Summary: Ag3370/Ag3837 The amp plots suggest that there were experimental difficulties with these runs.

Panel 1.3D Summary: Ag2933 Expression ofthe CG58546-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

B. NOV2a and NOV2b (CG58598-01 and CG58598-02: Brain-specific TM protein)

Expression of genes CG58598-01 and CG58598-02 was assessed using the primer-probe set Ag3383, described in Table BA. Results ofthe RTQ-PCR runs are shown in Tables BB, BC, and BD. Please note that CG58598-02 represents a full-length physical clone of the CG58598-01 gene, validating the prediction ofthe gene sequence.

Table BA. Probe Name Ag3383

Table BB. CNS neurodegeneration vl .0

Table BC. General_screening_panel_vl.4

Tissue Name JRel. Exp.(%) Ag3383,| JRel. Exp.(%) Ag3383, j Run 213496699 | ^{lMS1,e W}"^me j Run 213496699

Adipose | o.o Renal ca. TK-10 j o.o

Melanoma* Hs688(A).T 0.0 Bladder 0.3

Melanoma* Gastric ca. (liver met.) Hs688(B).T 0.0 NCI-N87 0.0

Melanoma* M14 .1 °-° Gastric ca. KATO III j 0.0

Melanoma* 1 °-° Colon ca. SW-948 ] o-o

Table BD. Panel CNS 1

CNS_neurodegeneration_vl.0 Summary: Ag3383 This panel confirms the expression of the CG58598-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. The brain preferential expression of this novel protein in both this panel and panel 1.4 suggests that this protein product may be a drug target for the treatment of neurologic disorders.

General_screeningjpanel_vl.4 Summary: Ag3383 Expression of the CG58598-01 gene appears to be preferential to the brain, with the highest level of expression in the cerebellum (CT=30.2). Please see Panel CNS_neurodegeneration_vl.O for discussion of utility in the central nervous system. There is also expression in the CNS cancer cell line U87-MG

(CT=31.1) but no expression in any other CNS cancer cell line. Therefore, expression of this gene can be used to distinguish between the U87-MG cell line and other CNS cancer cell lines on this panel.

Additionally, there is low to moderate expression of this gene in renal and lung cancer cell lines. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of cancer. Furthermore, therapeutic modulation ofthe expression or function of this gene may be effective in the treatment of these cancers.

Panel 2.2 Summary: Ag3383 - Expression ofthe CG58598-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

Panel 4D Summary: Ag3383 - Expression ofthe CG58598-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

Panel CNS_1 Summary: Ag3383 Expression in this panel confirms expression ofthe CG58598-01 gene in the brain. Please see Panel CNS_neurodegeneration_vl.O for discussion of utility in the central nervous system.

C. NOV3a (CG57833-01: Amino acid transporter )

Expression of gene CG57833-01 was assessed using the primer-probe set Ag3341, described in Table CA. Results ofthe RTQ-PCR runs are shown in Tables CB and CC.

Table CA. Probe Name Ag3341

Table CB. Panel 1.3D

Table CC. Panel 4D

Panel 1.3D Summary: Ag3341 The CG57833-01 gene codes for amino acid transporter HNAT3. Tissue distribution of this gene is similar to the results previously reported (Ref.l) with highest expression of this gene in liver sample (CT=28.2). High expression of this gene is also detected in fetal liver (CT=29). Therefore, expression of this gene can be used to distinguish liver samples from other samples used in this panel. In addition, therapeutic modulation ofthe activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of liver related diseases such as liver cirrhosis.

Low expression of this gene is also seen in ovarian cancer OVCAR-5, colon cancer CaCo-2, astrocytoma SW1783, glio/astro U-118-MG, and pancreatic cancer CAP AN 2 cell lines (CTs=33-34). Therefore, therapeutic modulation ofthe activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of lung cancer or ovarian cancer.

Significant expression of this gene is also detected in skeletal muscle (CT=29.9). Interestingly, this gene is expressed at much higher levels in adult (CT=29.9) when compared to fetal skeletal muscle (CT=36.6). This observation suggests that expression of this gene can be used to distinguish adult from fetal skeletal muscle. Furthermore, therapeutic modulation ofthe amino acid transporter encoded by this gene could be useful in treatment of muscle related diseases. More specifically, treatment of weak or dystrophic muscle with the protein encoded by this gene could restore muscle mass or function.

In addition, moderate expression of this gene is also detected in fetal kidney and bladder (CTs=31-32). Interestingly, this gene is expressed at much higher levels in fetal (CT=32) when compared to adult kidney (CT=35.3). Therefore, expression of this gene can be used to distinguish fetal from adult kidney. Furthermore, therapeutic modulation ofthe amino acid transporter encoded by this gene could be useful in treatment of renal diseases.

References.

1. Gu S, Adan-Rice D, Leach RJ, Jiang JX. (2001) A novel human amino acid transporter, hNAT3: cDNA cloning, chromosomal mapping, genomic structure, expression, and functional characterization. Genomics 74(3):262-72.

Panel 4D Summary: Ag3341 Highest expression of CG57833-01 is seen in liver cirrhosis samples (CT=31.3). The amino acid transporter encoded for by this gene could potentially allow cells within the liver to respond to specific microenvironmental signals. Therefore, therapies designed with the protein encoded for by this gene may potentially modulate liver function and play a role in the identification and treatment of inflammatory or autoimmune diseases which affect the liver including liver cirrhosis and fibrosis.

Significant expression of this gene is also seen in thymus, dermal fibroblast, lung fibroblast, NCI-H292 cell lines, and TNFalpha + IL-lbeta treated bronchial and small airway epithelium samples (CTs=32-34). Interestingly, this gene is expressed at much higher levels in TNFalpha + IL-lbeta treated small airway epithelium (CT=33.4) when compared to untreated cells

(CT=37.9). This observation suggests that expression of this gene can be used to distinguish the cytokine treated from untreated small airway epithelium. Furthermore, modulation ofthe expression or activity ofthe protein encoded by this gene through the application of small molecule therapeutics may be useful in the freatment of asthma, COPD, psoriasis and emphysema.

D. NOV4a, NOV4b, and NOV4c (CG57853-01, CG57853-02, and CG57853-03: ILEAL SODΓUM/BΓLE ACID COTRANSPORTER)

Expression of gene CG57853-01, CG57853-02, and CG57853-03 was assessed using the primer-probe sets Ag3350 and Ag2838, described in Tables DA and DB. Results ofthe RTQ- PCR runs are shown in Tables DC, DD and DE. Please note that CG57853-03 represents a full- length physical clone ofthe CG57853-01 gene, validating the prediction ofthe gene sequence. Table DA. Probe Name Ag3350

Table DB. Probe Name Ag2838

Table DC. CNS_neurodegeneration_vl.O

Table DD. General_screening_panel_vl.4

Table DE. Panel 4D

CNS_neurodegeneration_vl.O Summary: Ag3350 This panel does not show differential expression ofthe CG57853-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.

General_screening_panel_vl.4 Summary: Ag3350 - The CG57853-01 gene encodes a novel ileal sodium-bile acid cotransporter. Ileal sodium-dependent bile acid transporters play a role in the absorption of bile acids, regulating levels of bile acids in the large intestine and preventing accumulation of cytotoxic secondary bile acids in the colon (Ref. 1). The highest expression of this gene is seen in gastric cancer cell line NCI-N87 (CT=29.5). Significant expression of this gene is also associated with CNS, colon, renal, liver, lung, breast, ovarian and prostate cancers as well as melanomas. Thus, expression of this gene could be used as a diagnostic marker for the presence of these cancers. Furthermore, therapeutic inhibition using antibodies or small molecule drugs might be of use in the freatment of these cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancreas, adipose, fetal skeletal muscle, heart, fetal liver and the gastrointestinal tract. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as intestinal bile acid malabsorption (IB AM), hypertriglyceridemia, obesity and diabetes.

Interestingly, this gene is expressed at much higher levels in fetal (CT=30.6) when compared to adult liver (CT=36.5). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver. In addition, modulation of expression of this gene may be useful in the treatment of liver related disease such as liver cirrhosis, and cholestasis.

This gene is also widely expressed in tissues originating in the central nervous system. These tissues include the hippocampus, thalamus, and cerebellum. This transporter gene most likely plays a role in the uptake of nutrients. Blockade of this transporter may decrease the loss of neurons due to excitotoxicity during ischemic stroke. In addition, this gene may play a role in cenfral nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

References.

1. Small DM. (1997) Point mutations in the ileal bile salt transporter cause leaks in the enterohepatic circulation leading to severe chronic diarrhea and malabsorption. J Clin Invest 99(8): 1807-8

2. Montagnani M, Love MW, Rossel P, Dawson PA, Qvist P. Absence of dysfunctional ileal sodium-bile acid cotransporter gene mutations in patients with adult-onset idiopathic bile acid malabsorption. Scand J Gastroenterol 2001 Oct;36(10): 1077-80.

3. Wang W, Xue S, Ingles SA, Chen Q, Diep AT, Frankl HD, Stolz A, Haile RW. An association between genetic polymorphisms in the ileal sodium-dependent bile acid transporter gene and the risk of colorectal adenomas. Cancer Epidemiol Biomarkers Prev 2001 Sep;10(9):931-6.

4. Duane WC, Hartich LA, Bartman AE, Ho SB. Diminished gene expression of ileal apical sodium bile acid transporter explains impaired absorption of bile acid in patients with hypertriglyceridemia. J Lipid Res 2000 Sep;41(9):1384-9. Panel 1.3D Summary: Ag2838 - Results using this primer pair are in very good agreement with the results obtained using Ag3350 on panel 1.4. Please see panel 1.4 for discussion.

Panel 4D Summary: Ag3350 Moderate to low expression ofthe CG57853-01 gene is seen in many samples on this panel, with the highest expression in thymus tissue (CT=29.3). This gene is expressed at low to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members ofthe T-cell, B-cell, endothelial cell, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation ofthe gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement of the symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

Interstingly, high expression of this gene is detected in normal colon (CT=29.5), but expression of this gene is decreased in colon samples from patients with IBD colitis (CT=36.4) and Crohn's disease (CT=34.0). Therefore, therapeutic modulation ofthe activity ofthe transporter encoded by this gene may be useful in the treatment of inflammatory bowel disease.

In addition, expression of this gene is up regulated in PWM/PHA-L-stimulated PBMC (CTs= 32-33.6), compared to resting PBMC cells (CT=37.6). Thus, expression of this gene may be used as a marker for activated PBMC cells.

E. NOV5a and NOV5b (CG57829-01 and CG57829-05: A DISINTEGRIN AND METALLOPROTEINASE WITH THROMBOSPONDIN MOTIFS

1 )

Expression of gene CG57829-01 and CG57829-05 was assessed using the primer-probe sets Ag3340 and Ag554, described in Tables EA and EB. Results ofthe RTQ-PCR runs are shown in Tables EC, ED, EE, EF, EG, EH, El, EJ, EK, EL and EM. Please note that CG57829- 05 represents a full-length physical clone.

Table EA. Probe Name Ag3340

Primers! Sequences Length _ ...

¹ ^ " Position

Forward|5 ' -aatggcactggctacttctatg-3 ' (SEQ ID NO : 224) | 22 1894

ITET-5 ' -acgctgtgctctσctgactccacct -3 ' -TAMRA (SEQ ID

Probe NO:225) 25 1942

Reverse |s ' -cacttgccttggacacaga-3 ' (SEQ ID NO:226) 19 j 1970

Table EB. Probe Name Ag554

Table EC. AI_comprehensive panel_vl.O

Table ED. CNS_neurodegeneration_vl .0

Table EE. General_screening_panel_ l.4

Table EP. Panel 1.1

Table EG. Panel 1.2

Table EH. Panel 1.3D

Table El. Panel 2.1

Table EJ. Panel 2D

8120607 064005

Table EK. Panel 3D

NCI-N87- Gastric SCC-4- Squamous cell

2.2 0.0 carcinoma carcinoma of tongue

OVCAR-5- Ovarian SCC-9- Squamous cell

6.5 0.0 carcinoma carcinoma of tongue

RL95-2- Uterine SCC-15- Squamous cell

0.2 0.7 carcinoma carcinoma of tongue

HelaS3- Cervical CAL 27- Squamous cell

0.9 0.6 adenocarcinoma carcinoma of tongue

Table EL. Panel 4. ID

Table EM. Panel 4D

Macrophages LPS 0.0 0.0 JThymus 16.3 24.7

HUVEC none 0.0 0.0 (Kidney 3.4 3.8

HUVEC starved 0.0 1 0.4

Al_comprehensive panel_vl.O Summary: Ag3340 The transcript is highly expressed in 3 out of 6 ulcerative colitis samples, but not in the matched control samples. Similarly, it is expressed in OA tissue and not in normal control samples. Asthma and emphysema lung samples express the transcript at higher levels than in normal lung. The protein encoded for by CG57829-01 has homology to ADAMTS family of molecules suggesting that it may function as an enzyme. Based on its homology, it may contribute to the tissue destruction and remodeling processes associated with asthma, ulcerative colitis, emphysema and osteoarthritis. Therefore, blocking the function ofthe protein encoded for by CG57829-01 with antagonistic antibody therapeutics or small molecule therapeutics could reduce or inhibit tissue destruction in the lungs, intestine, or joints due to emphysema, allergy, asthma, colitis, or osteoarthritis.

CNS_neurodegeneration_vl.0 Summary: Ag3340 This panel does not show differential expression ofthe CG57829-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.

General_screening_panel_vl.4 Summary: Ag3340 Two experiments with the same probe and primer set are in excellent agreement. Highest expression ofthe CG57829-01 gene is seen in breast cancer MDA-MB-231 cell line (CTs=25). As seen in Panel 1.1 , 1.2, and 1.3, this gene has high expression in ovarian and breast cancer cell lines which is also confirmed in Panels 2.1 and 2D. Therefore, expression of this gene could be used as a diagnostic marker for the presence of these cancers. Furhtermore, therapeutic modulation ofthe activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of breast or ovarian cancer.

Among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, fetal liver and the gastrointestinal tract. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Interestingly, this gene is expressed at much higher levels in fetal (CT=32) when compared to adult liver (CT=36). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver.

In addition, this gene is expressed at low to moderate levels in all regions ofthe central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

This gene encodes a homologue of rat ADAMTS-1. Members belonging to ADAM and ADAMTS family has been found to play a role in various inflammatory processes such as arthritic diseases, as well as, development of cancer cachexia and thrombotic thrombocytopenic purpura (Ref. 1, 2, 3). Therefore, therapeutic modulation ofthe activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of these diseases. References.

1. Martel-Pelletier J, Welsch DJ, Pelletier JP. (2001) Metalloproteases and inhibitors in arthritic diseases. Best Pract Res Clin Rheumatol 15(5):805-29

2. Kuno K, Kanada N, Nakashima E, Fujiki F, Ichimura F, Matsushima K. (1997) Molecular cloning of a gene encoding a new type of metalloproteinase-disintegrin family protein with thrombospondin motifs as an inflammation associated gene. J Biol Chem 272(l):556-62.

3. Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, McGee BM, Yang AY, Siemieniak DR, Stark KR, Gruppo R, Sarode R, Shurin SB, Chandrasekaran V, Stabler SP, Sabio H, Bouhassira EE, Upshaw JD Jr, Ginsburg D, Tsai HM. (2001) Mutations in a member ofthe ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 413(6855):488-94

Panel 1.1 Summary: Ag554 Highest expression ofthe CG57829-01 gene is seen in ovarian cancer OVCAR-3 cell line (CT=22). Expression pattern of this gene in this panel is similar to that of panel 1.4. Please see panel 1.4 for discussion and potential utility of this gene.

Panel 1.2 Summary: Ag554 Highest expression ofthe CG57829-01 gene is seen in fetal kidney (CT=23.8). Interestingly, this gene is expressed at much higher levels in fetal (CT=23.8) when compared to adult kidney (CT=27-31). This observation suggests that expression of this gene can be used to distinguish fetal from adult kidney.

High expression of this gene is also seen in cluster of ovarian cancer, breat cancer, renal cancer, prostate cancer, CNS cancer cell lines, as well as in placenta, mammary glands, liver, trachea, stomach, colorectal, and heart. Please see panel 1.4 for discussion and potential utility of this gene.

Panel 1.3D Summary: Ag554 Highest expression ofthe CG57829-01 gene is seen in breast cancer MDA-MB-231 cell line (CT=27.8). Expression pattern of this gene in this panel is similar to that of panel 1.4. Please see panel 1.4 for discussion and potential utility of this gene.

Panel 2.1 Summary: Ag3340 Highest expression ofthe CG57829-01 gene is seen in breast cancer metastasis sample (CT=28). As seen in panel 1.4, expression of this gene is associated with most cancers. Interestingly, expression of this gene seems to be down-regulated in kidney cancers (OD04340, OD04348, OD04450-01, 8120614) and colon metastasis to lung (OD04451-01) (CTs=35-40) compared to the marginal control samples (CTs=31-33).

Therefore, expression of this gene can be used as potential marker to distinguishing between these cancer and normal tissues.

Please see panel 1.4 for discussion and potential utility of this gene. Panel 2D Summary: Ag554 Highest expression ofthe CG57829-01 gene is seen in breast cancer metastasis (OD04590-03) sample (CT=27). As seen in panel 1.4, expression of this gene is associated with most cancers, with high expression in breast cancer samples. Please see panel 1.4 for discussion and potential utility of this gene. Panel 3D Summary: Ag554 Highest expression ofthe CG57829-01 gene is seen in PANC- 1- Pancreatic epithelioid ductal carcinoma sample (CT=28). As seen in panel 1.4, expression of this gene is associated with most cancers, with high expression in XF-CNS, small cell lung and pancreatic cancers. Please see panel 1.4 for discussion and potential utility of this gene.

Panel 4.1D Summary: Ag3340 CG57829-01 is highly induced in the mucoepidermoid cell line NCI-H292 by IL-4 and IL-13 (CTs=29-30). Expression is also high in lung fibroblasts treated with IL-4 or IL-13 and dermal fibroblasts treated with IL-4 (CTs=28-29). These findings are consistent in 3 separate runs with two sets of primers and probes.

Potential Role(s) of CG57829-01 in Inflammation: The protein encoded for by CG57892-01 has homology to ADAMTS family of molecules suggesting that it may function as an enzyme (see references in panel 1.4). The expression of this transcript by lung fibroblasts, the goblet cell like cell line NCI-H292 and dermal fibroblasts, particularly after exposure to IL-4 and IL-13 is consistent with it participating in diseases such as asthma, psoriasis, emphysema and arthritis (Ref.l, 2). Based on its homology, it may contribute to the tissue destruction and remodeling processes associated with asthma, psoriasis, emphysema and arthritis. Blocking the function ofthe protein encoded for by CG57892-01 with antagonistic antibody therapeutics could reduce or inhibit tissue destruction in the lungs, skin, or joints due to emphysema, allergy, asthma, psoriasis, or arthritis.

References.

1. Laliberte R, Rouabhia M, Bosse M, Chakir J. Decreased capacity of asthmatic bronchial fibroblasts to degrade collagen. Matrix Biol 2001 Jan;19(8):743-53

2. Vankemmelbeke MN, Holen I, Wilson AG, Ilic MZ, Handley CJ, Kelner GS, Clark M, Liu C, Maki RA, Burnett D, Buttle DJ. Expression and activity of ADAMTS-5 in synovium. Eur J Biochem 2001 Mar;268(5): 1259-68 Panel 4D Summary: Ag554/Ag3340 Expression pattern for the CG57829-01 gene is same as seen in panel 4. ID with highest expression in IL-4 stimulated lung fibroblast (CT=26.7). Please see the panel 4. ID for discussion and potential utility of this gene.

F. NOV6a (CG59197-01: TULIP 2 )

Expression of gene CG59197-01 was assessed using the primer-probe set Ag3391, described in Table FA. Results ofthe RTQ-PCR runs are shown in Tables FB, FC and FD.

Table FA. Probe Name Ag3391

[Primers: Sequences (Length, Start

Table FB. CNS_neurodegeneration_vl.O

Table FC. General_screeningjpanel_vl.4

Table FD. Panel 4D

Rel. Exp.(%) Rel. Exp.(%)

Tissue Name Ag3391, Run Tissue Name Ag3391, Run

165296469 165296469

Secondary Thl act 16.2 HUVEC IL-lbeta 8.4

CNS_neurodegeneration_vl.O Summary: Ag3391 This panel confirms the expression of the CG59197-01 gene at significant levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion ofthe potential utility of this gene in treatment of central nervous system disorders.

General_screening_panel_vl.4 Summary: Ag3391 The CG59197-01 gene codes for a homologue of rat tuberin like protein, Tulip 2. Expression of this gene is ubiquitous in this panel, with highest expression in a breast cancer T47D cell line (CT=27). Expression of this gene appears to be higher in samples derived from breast, ovarian, prostate and melanoma cancer cell lines than in normal tissues. The widespread expression suggests that this gene product is involved in cell growth and proliferation. Thus, therapeutic modulation ofthe expression or function of this gene may be useful in the treatment of cancer.

Among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract (CTs=28-34). Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity, and Types 1 and 2 diabetes.

Interestingly, this gene is expressed at much higher levels in fetal (CT = 29.7) when compared to adult liver (CT = 34.5). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver.

In addition, this gene is expressed at high levels in all regions ofthe central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord (CTs=27-29). Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 4D Summary: Ag3391 Highest expression ofthe CG59197-01 gene is seen in ionomycin treated Ramos B cells (CT=27.6). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members ofthe T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl .4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation ofthe gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement ofthe symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

In addition, expression of this gene is up-regulated in TNFalpha + IL-lbeta-treated small airway epithelium, and PWM-treated PBMC (CTs=28) as compared to the untreated counterparts (CTs=31). Thus, expression of this gene may be used to distinguish between cytokine-treated small airway epithelium and PWM-treated PBMC cells from their untreated counterparts.

G. NOV9a (CG58180-01: Prohibitin )

Expression of gene CG58180-01 was assessed using the primer-probe set Ag3515, described in Table GA. Results ofthe RTQ-PCR runs are shown in Tables GB, GC and GD.

Table GA. Probe Name Ag3515

Table GB. CNS_neurodegeneration_vl .0

Table GC. General_screening_panel_vl.4

Table GD. Panel 4D

CNS_neurodegeneration_vl.0 Summary: Ag3515 This panel does not show differential expression ofthe CG58180-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.

General_screening_panel_vl.4 Summary: Ag3515 - Highest expression ofthe CG58180- 01 gene is detected in lung cancer NCI-H23 cell line (CT=28.3). Expression of this gene is associated with gastric, pancreatic, brain, colon, renal, lung, breast, ovarian and prostate cancers, as well as, melanomas. This gene is a homologue ofthe human prohibitin (PHB), which has been found to be mutated in hereditary breast cancer (Ref. 1). Thus, expression of this gene could be used as a diagnostic marker for the presence of these cancers. Furthermore, therapeutic modulation ofthe activity of this gene using antibodies or small molecule drugs might be of use in the treatment of these cancers.

In addition, this gene is expressed at significant levels in all regions ofthe central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

This gene product is also expressed in adipose, pancreas, adrenal, thyroid, pituitary, skeletal muscle, heart, and liver. This widespread expression in tissues with metabolic function suggests that this gene product may be important for the pathogenesis, diagnosis, and/or treatment of metabolic and endocrine diseases, including obesity and Types 1 and 2 diabetes. References

1. Sato T, Saito H, Swensen J, Olifant A, Wood C, Danner D, Sakamoto T, Takita K, Kasumi F, Miki Y, et al. The human prohibitin gene located on chromosome 17q21 is mutated in sporadic breast cancer. : Cancer Res 1992 Mar 15;52(6):1643-6. Panel 4D Summary: Ag3515 - The CG58180-01 gene is expressed at low to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members ofthe T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern suggests a role for the gene product in cell survival and proliferation. Therefore, modulation ofthe gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement ofthe symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

H. NOVlla and NOVllb (CG59249-01 and CG59249-02:

METALLAPROTEΓNASE-DISINTEGRΓN BETA ) Expression of gene CG59249-01 and CG59249-02 was assessed using the primer-probe set Agl930, described in Table HA. Results ofthe RTQ-PCR runs are shown in Table HB.

Table HA. Probe Name Agl930

Table HB. Panel 4D

Panel 4D Summary: Agl930 The CGCG59249-01 gene is widely expressed among the samples in this panel, with highest expression of this gene in the kidney and small airway epithelium treated with TNF-alpha and IL-1 beta (CTs=32). Low but significant levels of expression are also seen in both treated and untreated samples derived from the basophil cell line KU-812, the pulmonary mucoepidermoid cell line NCI-H292, LAK cells and eosinophils. This pattern of expression in a variety of cell types of significance in the immune response in health and disease suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. Therefore, modulation ofthe gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement ofthe symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

I. NOV12a (CG58577-01: CASPR4 )

Expression of gene CG58577-01 was assessed using the primer-probe set Ag3377, described in Table IA. Results ofthe RTQ-PCR runs are shown in Tables IB, IC, ID and IE.

Table IA. Probe Name Ag3377

Table IB. CNS_neurodegeneration_vl.O

Table IC. Panel 1.3D

Table ID. Panel 4D

Table IE. Panel CNS 1

CNS_neurodegeneration_vl.O Summary: Ag3377 This panel confirms the expression of the CG58577-01 gene at low levels in the brain in an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.3D for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

Panel 1.3D Summary: Ag3377 Expression ofthe CG58577-01 gene is seen almost exclusively in the brain. The highest level of expression is in the thalamus (CT=31.0), with low to moderate expression in amygdala, substantia nigra, cerebellum, hippocampus and cerebral cortex. This gene encodes a protein homologous to the mouse Caspr4 ptorein. The Caspr proteins are contactin-associated transmembrane receptors that may function with contactin, in the recruitment and activation of neural intracellular signaling pathways. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. There is also low levels of expression in lung cancer cell line SHP-77 and neuroblastoma cancer cell line SK-N-AS (CTs=32). Therefore, therapeutic modulation ofthe activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of lung cancer or neuroblastoma cancer.

References 1. Peles E, Nativ M, Lustig M, Grumet M, Schilling J, Martinez R, Plowman GD, Schlessinger J. (1997) Identification of a novel contactin-associated transmembrane receptor with multiple domains implicated in protein-protein interactions. EMBO J 16(5):978-88.

Panel 4D Summary: Ag3377 Significant expression ofthe CG58577-01 gene is seen only in coronary artery, thymus, and kidney (CTs=33-34.8). Therefore expression of this gene can be used to distinguish between these samples and others on this panel. In addition, therapeutic modulation ofthe activity ofthe CASPR protein encoded by this gene may be useful in the treatment of asthma, restenosis, arthritis, systemic lupus erythematosus and kidney disorders.

Panel CNS_1 Summary: Ag3377 - This panel confirms the expression of this gene at significant levels in the brain in an independent group of individuals. Please see Panel 1.4 for a discussion ofthe potential utility of this gene in treatment of central nervous system disorders.

J. NOV14 (CG58575-01: PHOSPHATDDYLSERTNE SYNTHASE-2 )

Expression of gene CG58575-01 was assessed using the primer-probe set Ag3376, described in Table JA. Results ofthe RTQ-PCR runs are shown in Tables JB, JC, JD and JE.

Table JA. Probe Name Ag3376

Table IB. CNSjneurodegeneration_vl.O

Table JC. Panel 1.3D

Table JD. Panel 4D

Table JE. Panel CNS 1

CNS_neurodegeneration_vl.O Summary: Ag3376 This panel does not show differential expression ofthe CG58575-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.3D for discussion of utility of this gene in the central nervous system. Panel 1.3D Summary: Ag3376 The CG58575-01 gene encodes a putative phosphatidylserine synthase-2. In agreement with published results on the mouse homlogue of this gene, the highest expression of this gene is in testis (CT=29.5).

Expression of this gene is confirmed in all regions ofthe brain. Phosphatidylserine synthase activity was found to be reduced in the mnd/mnd mouse, a model for the human degenerative disease neuronal ceroid lipofuscinosis. Therefore, this gene may play a role in neurodegenerative disorders in which there is an abnormal accumulation of lipids and proteins in cellular storage bodies.

In addition, expression of this gene is higher in breast cancer cell lines when compared to expresson in normal breast tissue. Thus, expression of this gene could be used to differentiate between breast cancer cell lines and other samples on this panel and as a marker for breast cancer. Furthermore, therapeutic modulation ofthe expression or function of this gene may be effective in the treatment of breast cancer.

Among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

References

1. Vance JE, Stone SJ, Faust JRAbnormalities in mitochondria-associated membranes and phospholipid biosynthetic enzymes in the mnd/mnd mouse model of neuronal ceroid lipofuscinosis.Biochim Biophys Acta 1997 Feb 18;1344(3):286-99.

2. Sturbois-Balcerzak B, Stone SJ, Sreenivas A, Vance JE. Structure and expression ofthe murine phosphatidylserine synthase-1 gene. J Biol Chem 2001 Mar 16;276(11):8205-12.

Panel 4D Summary: Ag3376 Highest expression ofthe CG58575-01 gene is seen in the B cell line Ramos treated with ionomycin (CT=29.3). Significant levels of expression are seen in activated and untreated NCI-H292 cells, IL-4, IL-9, IL-13 and IFN gamma activated lung fibroblasts, human pulmonary aortic endothelial cells (treated and untreated), small airway epithelium (treated and untreated), treated bronchial epithelium and lung microvascular endothelial cells (treated and untreated). The expression of this gene in cells derived from or within the lung suggests that this gene may be involved in normal conditions as well as pathological and inflammatory lung disorders that include chronic obstructive pulmonary disease, asthma, allergy and emphysema. Moderate/low expression of this gene is also detected in treated and untreated HUVECs (endothelial cells), coronary artery smooth muscle cells (treated and untreated), treated and untreated astrocytes, treated KU-812 basophils, treated and untreated CCDl 106 keratinocytes, IL-4 treated dermal fibroblasts, and normal tissues that include lung, colon, thymus and kidney. Expression in the various immune cell types (as well as in diseased tissue samples) suggests that therapeutic modulation of this gene product may ameliorate symptoms associated with infectious conditions as well as inflammatory and autoimmune disorders that include psoriasis, allergy, asthma, inflammatory bowel disease, rheumatoid arthritis and osteoarthritis. Panel CNS_1 Summary: AG3376 This panel confirms expression ofthe CG58575-01 gene in the brain. Please see Panel 1.3D for discussion of utility of this gene in the central nervous system.

K. NOV16a (CG59239-01: MHC Class I )

Expression of gene CG59239-01 was assessed using the primer-probe sets Ag3516 and Ag3511, described in Tables KA and KB. Results of the RTQ-PCR runs are shown in Tables KC, KD and KE.

Table KA. Probe Name Ag3516

Table KB. Probe Name Ag3517

Table KC. CNS_neurodegeneration_vl .0

Table KD. General_screening_panel_vl.4

Table KE. Panel 4. ID

CNS_neurodegeneration_vl.O Summary: Ag3516/Ag3517 This panel does not show differential expression ofthe CG59239-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.

General_screening__panel_vl.4 Summary: Ag3516/Ag3517 Two experiments with the same probe and primer set produce results that are in excellent agreement, with highest expression ofthe CG59239-01 gene in a brain cancer cell line (CT=24). This gene encodes a major histocompatibility complex (MHC) class I homologue. MHC Class I genes mediate the recognition of intracellular antigens by cytotoxic T cells and are typically ubiquitously expressed. Significant expression is also seen in clusters of cell lines derived from gastric, colon, lung, breast, ovarian and brain cancers. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation ofthe expression or function of this gene may be effective in the tieatment of gastric, colon, lung, breast, ovarian and brain cancer.

Among tissues with metabolic function, this gene is expressed at moderate levels in adipose, adrenal gland, pancreas, pituitary, thyroid, and adult and fetal skeletal muscle, heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal metabolic and neuroendocrine function and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

In addition, this gene shows moderate expression in all regions ofthe CNS examined. Inflammation has been implicated in many CNS neurodegenerative disorders, including Alzheimer's disease. Therefore, therapeutic modulation ofthe expression or function of this gene may be useful in the treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis.

References:

1. Bauer J, Rauschka H, Lassmann H. Inflammation in the nervous system: the human perspective. Glia 2001 Nov;36(2) :235-43 Panel 4.1D Summary: Ag3516/Ag3517 Two experiments with the same probe and primer set produce results that are in excellent agreement, with highest expression ofthe CG59239- 01 gene in LPS-stimulated monocytes (CT=24). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members ofthe T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl .4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation ofthe gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement ofthe symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

This gene encodes a major histocompatibility complex (MHC) class I homolog. MHC class I- like molecules may have utility in forensics, such as in genotyping criminal suspects, and in settling paternity disputes. These antigens are ubiquitously expressed on all nucleated human cells except neurons and trophoblasts, and participate in antigen presentation of viral antigens in the adaptive immune response.

L. NOV17a (CG59295-01: Otogelin )

Expression of gene CG59295-01 was assessed using the primer-probe set Ag3534, described in Table LA. Results ofthe RTQ-PCR runs are shown in Tables LB, and LC.

Table LA. Probe Name Ag3534

Table LB. General_screening_panel_vl .4

Table LC. Panel 4D

CNS_neurodegeneration_vl.O Summary: Ag3534 Expression ofthe CG59295-01 gene is low/undetectable in all samples on this panel (CTs>35).

General_screening_panel_vl.4 Summary: Ag3534 Highest expression ofthe CG59295-01 gene is seen in a colon cancer cell line (CT=31). Low but significant levels of expression are seen in lung and breast cancer cell lines. Therefore, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker for colon cancer. This gene has been linked to deafness. Thus, therapeutic modulation ofthe expression or function of this gene may be effective in the treatment of deafness.

References: Simmler MC, Cohen-Salmon M, El-Amraoui A, Guillaud L, Benichou JC, Petit C, Panthier JJ.

Panel 4D Summary: Ag3534 Expression ofthe CG59295-01 gene is restricted to a few samples, with highest expression in liver cirrhosis (CT=32.2). Low but significant level of expression are also seen in lung and colon. In addition, expression is undetectable in colon from patients with IBD colitis and Crohn's and in liver on Panel 1.4. Thus, expression of this gene may be used to differentiate between normal and diseased liver and colon tissue. Also, therapeutic modulation ofthe activity ofthe otogelin protein encoded by this gene may be useful in the treatment of inflammatory bowel disease and inflammatory or autoimmune diseases which affect the liver including liver cirrhosis and fibrosis. Panel CNS_1 Summary: Ag3534 Expression ofthe CG59295-01 gene is low/undetectable in all samples on this panel (CTs>35).

M. NOV18a (CG59293-01: Renal organic anion transport protein 1 )

Expression of gene CG59293-01 was assessed using the primer-probe sets Ag3948, Ag3532 and Ag2874, described in Tables MA, MB and MC. Results ofthe RTQ-PCR runs are shown in Tables MD, ME, MF, MG, MH, MI, MJ and MK.

Table MA. Probe Name Ag3948

Table MC. Probe Name Ag2874

Table MD. AI_comprehensive panel_vl .0

Table ME. CNS_neurodegeneration_vl .0

Table MF. General_screening_panel_vl.4

Table MG. Panel 1.3D

Table MH. Panel 2D

Table MI. Panel 3D

Table MJ. Panel 4. ID

Table MK. Panel 4D

AI_comprehensive panel_vl.O Summary: Ag3948 This panel confirms expression ofthe CG59293-01 gene in tissue samples related to the immune and inflammatory response. Please see Panels 4 and 4. ID for discussion of utility of this gene in inflammation.

CNS_neurodegeneration_vl.0 Summary: Ag3948 This panel does not show differential expression ofthe CG59293-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel

General_screening_panel_vl .4 for discussion of utility of this gene in the central nervous system. Ag3532 Expression ofthe CG59293-01 gene is low/undetectable in all samples on this panel (CTs>35). General_screening_panel_vl.4 Summary: Ag3948 The expression ofthe CG59293-01 gene, an organic anion transporter homolog, is highest in a small cell lung cancer line LX-1 (CT= 28.2). This gene is also expressed in some ovarian, breast, CNS, gastric, pancreatic, renal and colon cancer cell lines. Therefore, expression of this gene maybe associated with these forms of cancer and therapeutic modulation of this gene might be of use in the treatment or diagnosis of these cancers.

This gene is also expressed at low levels in the cerebellum and fetal brain. The organic anion transporters are involved in transport across the blood brain barrier. This gene may therefore be of use in drug delivery to the CNS, specifically for compounds such as nerve growth factors protein therapeutics which are believed to have numerous uses in the CNS, but lack a delivery system.

References:

Sugiyama D, Kusuhara H, Shitara Y, Abe T, Meier PJ, Sekine T, Endou H, Suzuki H, Sugiyama Y. Characterization ofthe efflux transport of 17beta-estradiol-D-17beta- glucuronide from the brain across the blood-brain barrier. Panel 1.3D Summary: Ag2874 The expression ofthe CG59293-01 gene was assessed in two independent runs on this panel with reasonable concordance between the runs. The highest expression is seen in a small cell lung cancer line LX-1 (CTs=31-32), consistent with expression in Panel 1.3D. This gene is also expressed in some ovarian, breast, CNS, gastric and colon cancer cell lines. Therefore, expression of this gene might be associated with these forms of cancer and therapeutic modulation of this gene might be of use in the treatment or diagnosis of these cancers.

Panel 2D Summary: Ag2874 The CG59293-01 gene is expressed at low levels in the tissues used for panel 2D. The highest expression is seen in a breast cancer sample (CT=34.2). Significant expression is also seen in single samples of ovarian, bladder, prostate and colon cancers compared with the normal adjacent tissue. This indicates that the expression of this gene might be associated with these forms of cancer and therapeutic modulation of this gene might be of use in the treatment or diagnosis of these cancers.

Panel 3D Summary: Ag2874 Highest expression ofthe CG59293-01 gene is seen in a pancreatic cancer cell line (CT=31.6). Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel. In addition, significant expression of this gene is associated with samples derived from lung cancer cell lines (CTs=32-34), an ovarian cancer, gastric cancer and squamous cell carcinoma of tongue. Therefore, therapeutic modulation ofthe activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of these cancers.

Panel 4.1D Summary: Ag3498 The highest expression ofthe CG59293-01 gene is found in the kidney and in the pulmonary muco-epidermoid cell line NCI-H292 (CTs=31). The expression of this gene, although constitutive in the H292 cell line, is up regulated upon treatment with IL-4, 11-9 and IL-13, cytokines that have been linked to the pathogenesis of asthma and/or COPD.

This gene is also found in small airway epithelium and keratinocytes treated with the inflammatory cytokines TNF-a and IL-lb. Therefore, modulation ofthe expression or activity ofthe protein encoded by this transcript through the application of small molecule therapeutics may be useful in the treatment of asthma, COPD, emphysema, psoriasis and wound healing.

Panel 4D Summary: Ag2874/Ag3532 The expression ofthe CG59293-01 transcript detected by two sets of primers was observed mostly in NCI-H292 (CTs=32-33). Upregulation of this transcript in H292 was found upon treatment with IL-4 (Ag 3532) or IL-9 (Ag 2874), both cytokines are involved in the pathogenesis of asthma and/or COPD. This transcript was also detected in small airway epithelium and keratinocytes. Therefore, modulation ofthe expression or activity ofthe protein encoded by this transcript by small molecules could be useful for the tieatment of asthma, COPD and or emphysema and also for the treatment of skin inflammatory diseases such as psoriasis or wound healing.

N. NOV19a (CG59284-01: SOLUTE CARRIER FAMILY 22 ) Expression of gene CG59284-01 was assessed using the primer-probe set Ag3528, described in Table NA.

Table NA. Probe Name Ag3528

CNS_neurodegeneration_vl.O Summary: Ag3528 Expression ofthe CG59284-01 gene is low/undetectable in all samples on this panel (CTs>35). General_screening_panel_vl.4 Summary: Ag3528 Expression ofthe CG59284-01 gene is low/undetectable in all samples on this panel (CTs>35).

Panel 4.1D Summary: Ag3528 Expression ofthe CG59284-01 gene is low/undetectable in all samples on this panel (CTs>35).

O. NOV20a (CG59278-01: Olfactory receptor P2 )

Expression of gene CG59278-01 was assessed using the primer-probe set Ag3526, described in Table OA. Results ofthe RTQ-PCR runs are shown in Table OB.

Table OA. Probe Name Ag3526

Table OB. Panel 4.1D

CNS_neurodegeneration_vl.O Summary: Ag3526 Expression ofthe CG59278-01 gene is low/undetectable in all samples on this panel (CTs>35).

General_screening__panel_vl.4 Summary: Ag3526 Expression ofthe CG59278-01 gene is low/undetectable in all samples on this panel (CTs>35). (Data not shown). This gene encodes a G protein-coupled receptor (GPCR), a type of cell surface receptor involved in signal transduction. This gene product is most similar to members ofthe odorant receptor subfamily of GPCRs. Based on analogy to other odorant receptor genes, we predict that expression of this gene may be highest in nasal epithelium, a sample not represented on this panel.

Panel 4.1D Summary: Ag3526 Expression ofthe CG59278-01 gene is restricted to a sample derived from resting neutrophils (CT=28.2). Thus, expression of this gene could be used as a marker of these cells. This expression is markedly reduced (CT=36.3) in neutrophils activated by TNF-alpha+LPS. This expression profile suggest that the protein encoded by this gene is produced by resting neutrophils but not by activated neutrophils. Therefore, the gene product may reduce activation of these inflammatory cells and be useful as a protein therapeutic to reduce or eliminate the symptoms in patients with Crohn's disease, ulcerative colitis, multiple sclerosis, chronic obstructive pulmonary disease, asthma, emphysema, rheumatoid arthritis, lupus erythematosus, or psoriasis. In addition, small molecule or antibody antagonists of this gene product may be effective in increasing the immune response in patients with AIDS or other immunodeficiencies. P. NOV21a and NOV21b (CG59274-01 and CG59274-02: Lipoma HMGIC fusion partner)

Expression of gene CG59274-01 and CG59274-02 was assessed using the primer-probe set Ag3525, described in Table PA. Results of the RTQ-PCR runs are shown in Tables PB, PC and PD. Please note that CG59274-02 represents a full-length physical clone of the CG59274-01 gene, validating the prediction ofthe gene sequence.

Table PA. Probe Name Ag3525

Table PB. CNS_neurodegeneration_vl.O

Table PC. General_screening_paneι_vl .4

Table PP. Panel 4D

CNS_neurodegeneration_vl.O Summary: Ag3525 This panel does not show differential expression ofthe CG59274-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system. General_screening__panel_vl.4 Summary: Ag3525 The CG59274-01 gene exhibits highly brain preferential expression, with moderate to low levels of expression seen in all regions of the brain examined in this panel. Thus, therapeutic modulation ofthe expression or function of this gene may be effective in the treatment of neurologic disorders, including Alzheimer's disease, Parkinson's disease, epilepsy, stroke and schizophrenia. Among metabolic tissues, expression of this gene is limited to the thyroid. Thus, this gene product may also be effective in treating thyroidopathies.

Panel 4D Summary: Ag3525 The CG59274-01 gene is expressed in normal kidney, thymus and colon as well as in activated LAK cells(CTs=32-33). The gene is also expressed at lower but still significant levels in primary resting T cells, with highest expression seen in a sample derived from an MLR reaction (CT=32). Thus, the protein encoded by this transcript could be important in the function of LAK cells. LAK cells are important in immuosurveillance against bacterial and viral infected cells, as well as transformed cells. Therapeutics designed with this transcript or the protein encoded by it could be important in the treatment of viral and bacterial diseases and cancer.

Q. NOV23a and NOV23b (CG57734-01 and CG57734-02: Lipid associated protein ) Expression of gene CG57734-01 and CG57734-01 was assessed using the primer-probe set Ag572, described in Table QA. Please note that CG57734-02 represents a full-length physical clone of he CG57734-01 gene, validating the prediction ofthe gene sequence.

Table OA. Probe Name Ag572

Panel 1.1 Summary: Ag5734 Expression ofthe CG57734-01 gene is low/undetectable in all samples on this panel (CTs>35).

R. NOV25a (CG59885-01: HGFR)

Expression of gene CG59885-01 was assessed using the primer-probe set Agl684, described in Table RA. Results ofthe RTQ-PCR runs are shown in Tables RB, RC, RD, RE, RF, and RG.

Table RA. Probe Name Agl684

Table RB. CNS_neurodegeneration_vl.O

Table RC. General_screening_panel_vl .4

Table RD. Panel 1.3D

Table RE. Panel 2D

Table RF. Panel 4D

Table RG. Panel 5 Islet

CNS_neurodegeneration_vl.O Summary: Agl684 This panel does not show differential expression of the CG59885-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.4 for discussion of utility of this gene in the central nervous system.

General_screening_panel_vl.4 Summary: Agl684 Highest expression ofthe CG59885-01 gene is seen in a renal cancer cell line (CT=20). Overall, expression appears to be much higher in cancer cell lines than in samples from normal tissue. Significant levels of expression are also seen in cell lines derived from pacreatic, brain, colon, gastric, lung, breast, ovarian, and melanoma cancers. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of cancer. Furthermore, therapeutic modulation ofthe expression or function of this gene with a human monoclonal antibody is anticipated to limit or block the extent of metastasis and growth in most tumors.

Among tissues with metabolic function, this gene is expressed at moderate to low levels in pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle, heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

In addition, this gene is expressed at high levels in all regions ofthe central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system and may be a target of neurologic diseases such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 1.3D Summary: Agl684 Expression ofthe CG59885-01 gene confirms the results of Panel 1.4. Please see Panel 1.4 for discussion of utility of this gene in cancer, metabolic disease and the central nervous system.

Panel 2D Summary: Agl684 Two experiments with the same probe and primer produce results that are in excellent agreement, with highest expression ofthe CG59885-01 gene in kidney cancer (CTs=24-25). In addition, expression of this gene is higher in gastric, bladder, ovarian, thyroid, kidney and colon cancers when compared to expression in the corresponding normal adjacent tissue. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of cancer. Furthermore, therapeutic modulation ofthe expression or function of this gene may be effective in the treatment of these cancers.

Panel 3D Summary: Agl684 Results from one experiment with the CG59885-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

Panel 4D Summary: Agl684 Highest expression ofthe CG59885-01 gene is seen in the NCI-H292 mucoepidermoid cell line treated with IL-4 (CT=25). Significant levels of expression are also seen in a cluster of treated and untreated NCI-H292 mucoepidermoid cells, IL-4, IL-9, IL-13 and IFN gamma activated lung fibroblasts, human pulmonary aortic endothelial cells (treated and untreated), small airway epithelium (treated and untreated), treated bronchial epithelium and lung microvascular endothelial cells (treated and untieated). The expression of this gene in cells derived from or within the lung suggests that this gene may be involved in normal conditions as well as pathological and inflammatory lung disorders that include chronic obstructive pulmonary disease, asthma, allergy and emphysema.

Moderate levels of expression are also detected in treated and untreated HUVECs (endothelial cells), coronary artery smooth muscle cells (treated and untreated), treated and unteeated astrocytes, KU-812 basophils, keratinocytes, dermal fibroblasts, and normal tissues from lung, colon, thymus and kidney. Expression in these immune cell types and tissues suggests that therapeutic modulation of this gene product may ameliorate symptoms associated with infectious conditions as well as inflammatory and autoimmune disorders that include psoriasis, allergy, asthma, inflammatory bowel disease, rheumatoid arthritis and osteoarthritis.

Interestingly, expression of this gene is stimulated in TNFalpha + IL-lbeta treated small airway epithelium (CT=25) and LPS-treated monocytes (CT=27) as compared to their untieated counterparts (CTs=28-40). Thus, expression of this gene can be used to distinguish these treated cells from their untreated counterparts. This gene codes for a variant of hepatocyte growth factor receptor, HGFR-MET. HGFR-MET is a transmembrane tyrosine kinase proto-oncogene, required for the action of hepatocyte growth factor (HGF) (Ref.l). Recently, it was shown that HGF modulates the function of monocytes in a paracrine/autocrine manner (Ref.2). The expression ofthe HGFR-MET gene in LPS-tieated monocytes, suggests a role for this gene product in initiating inflammatory reactions. Therefore, modulation of the expression or activity of HGFR-MET through the application of monoclonal antibodies may reduce or prevent early stages of inflammation and reduce the severity of inflammatory diseases such as psoriasis, asthma, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis and other lung inflammatory diseases.

References. , 1. Stella MC, Comoglio PM. (1999) HGF: a multifunctional growth factor controlling cell scattering. Int J Biochem Cell Biol 1999 Dec;31(12):1357-62

2. Galimi F, Cottone E, Nigna E, Arena Ν, Boccaccio C, Giordano S, Naldini L, Comoglio PM. (2001) Hepatocyte growth factor is a regulator of monocyte-macrophage function. J Immunol 166(2): 1241-7. Panel 5 Islet Summary: Agl684 Highest expression ofthe CG59885-01 gene is seen in kidney-HRCE samples (CT=29.8). In addition, moderate to low expression is also detected in pancreatic islet cells (patient 1), adipose, mesenchymal stem cells, placenta, skeletal muscle from number of donor and patients. Please see panel 1.4 for the potential utility of this gene.

S. NOV26a (CG93443-01: Novel LIV-1 like gene ) Expression of gene CG93443-01 was assessed using the primer-probe sets Ag2552 and

Ag3855, described in Tables SA and SB. Results ofthe RTQ-PCR runs are shown in Tables SC, SD, SE, SF, SG, and SH.

Table SA. Probe Name Ag2552

Table SB. Probe Name Ag3855

Table SC. AI_comprehensive panel_vl .0

Table SD. Panel 1.3D

Rel. Exp.(%) Rel. Exp.(%) Rel. Exp.(%) Rel. Exp.(%)

Tissue Name Ag2552, Run Ag2552, Run Tissue Name Ag2552, Run Ag2552, Run

161905842 163728051 161905842 163728051

Table SE. Panel 2D

Table SF. Panel 3D

Table SG. Panel 4. ID

Table SH. Panel 4D

AI_comprehensive panel_vl.0 Summary: Ag2552 Highest expression ofthe CG93443-01 gene is detected inl 12756 osteoarthritis bone9 sample (CT=28). Moderate expression of this gene is seen most ofthe samples used in this panel. Please see panel 4D for the potential utility of this gene. Results from a second experiment with this gene suggests that expression of this gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

CNS_neurodegeneration_vl.O Summary: Ag3855 Expression ofthe CG93443-01 gene is low/undetectable (CTs > 35) across all ofthe samples on this panel.

General_screening_panel_vl.4 Summary: Ag3855 Results from one experiment with the CG93443-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

Panel 1.3D Summary: Ag2552 Two experiments with the same probe and primer produce results that are in excellent agreement, with highest expression ofthe CG93443-01 gene in gastric cancer NCI-N87 cell line (CTs=27-28). In addition, significant expression of this gene is seen in renal, ovarian, breast, lung, liver, pancreatic and colon cancer cell lines, as well as in melanomas. Thus, therapeutic modulation ofthe expression or function of this gene may be effective in the treatment of these cancers. Among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancrease, adipose, adrenal gland, thyroid, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

Interestingly, this gene is expressed at much higher levels in fetal (CTs=30) when compared to adult heart (CTs=33.4-34). This observation suggests that expression of this gene can be used to distinguish fetal from adult heart.

In addition, this gene is expressed at moderate levels in all regions ofthe central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 2D Summary: Ag2552 Two experiments with the same probe and primer produce results that are in excellent agreement, with high expression ofthe CG93443-01 gene in colon cancer grade 2 ascend colon (OD03921), colon cancer from Partial hepatectomy (ODO4309) metastasis, and ovarian cancer (CTs=27). In addition, expression of this gene is higher in gastric, bladder, ovarian, and colon cancers when compared to expression in the corresponding normal adjacent tissue. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of cancer. Furthermore, therapeutic modulation ofthe expression or function of this gene may be effective in the tieatment of these cancers.

Panel 3D Summary: Ag2552 Highest expression ofthe CG93443-01 gene is detected in KATO Ill-gastric carcinoma (CT=25.5). In addition, expression of this gene is higher in medulloblastoma, small cell lung cancer, gastric, cervical epidermoid carcinoma, B and T cell leukemia and lymphomas, erythroleukemia, KU-812 myelogenous leukemia, pancreatic, bladder and colon cancers. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of cancer. Furthermore, therapeutic modulation ofthe expression or function of this gene may be effective in the treatment of these cancers.

Panel 4.1D Summary: Ag3855 Highest expression ofthe CG93443-01 gene is detected exclusively in ionomycin treated Ramos B cells (CT=26.8). Furthermore, expression of this gene is low/undetectable in resting Ramos B cells (CT=40). Thus, expression of this gene can be used to distinguish ionomycin treated Ramos cells from the untreated cells and also from other samples used in this panel. Also, expression of this gene in stimulated Ramos B cells suggests that this gene may be involved in rheumatic disease including rheumatoid arthritis, lupus, osteoarthritis, and hyperproliferative B cell disorders.

In addition, low but significant expression of this gene is also seen in colon and kidney (CTs=32). Furthermore, expression of this gene is decreased in colon samples from patients with IBD colitis and Crohn's disease relative to normal colon. Therefore, therapeutic modulation ofthe activity of this gene product may be useful in the treatment of inflammatory bowel disease and kidney related disease such as lupus and glomerulonephritis. Panel 4D Summary: Ag2552 Three experiments with the same probe and primer produce results that are in excellent agreement, with highest expression ofthe CG93443-01 gene in KU-812 (Basophil) cells (CTs=26-27). This gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members ofthe T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation ofthe gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement ofthe symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

T. NOV27a (CG50838-01: Leucine-rich repeat transmembrane protein FLRT3)

Expression of gene CG50838-01 was assessed using the primer-probe sets Ag92, Ag2763 and Ag92b, described in Tables TA, TB and TC. Results ofthe RTQ-PCR runs are shown in Tables TD, TE, TF, TG, TH, TI and TJ.

Table TA. Probe Name Ag92

Table TB. Probe Name Ag2763

Table TC. Probe Name Ag92b

Reverse _|5' -taaggtgattacgggacaggaaa-3 ' (SEQ ID NO: 292) 23 934

Table TD. AI_comprehensive panel_vl.0

Table TE. CNS_neurodegeneration_vl.O

Table TF. Panel 1

Table TG. Panel 1.3D

Table TH. Panel 2D

Rel. Rel. Rel.

Exp.(%) Exp.(%) Exp.(%)

Tissue Ag2763, Tissue

Ag92, Ag92b, Name Name

Run Run Run 162555842 149912056 151275585

Table TI. Panel 3D

Table TJ. Panel 4D

AJ_comprehensive panel_vl.O Summary: Ag92 Highest expression ofthe CG50838-01 gene is found in in rheumatoid arthritis (RA) synovium fluid cells (CT=28). This gene shows higher expression in synovium, cartilage and bone samples from rheumatide arthritis patient (CTs=28-29) as compared to orthoarthritis patients (CTs=31-35). Therefore, therapeutic 5 modulation of the activity of the GPCR encoded by this gene may be useful in the treatment of patients suffereing from rheumatoid arthritis.

In addition, low expression of this gene is seen in almost all the samples derived from normal and diseased patients. Please see panel 4D for potential utility of this gene.

CNS_neurodegeneration_vl.O Summary: Ag92b This panel does not show differential 10 expression ofthe CG50838-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1 and 1.3D for discussion of utility of this gene in the central nervous system. Results from two additional experiments with the probe and primer sets Ag92 and Ag2763 are not included. The amp plot indicates that there were experimental difficulties with these runs.

15 Panel 1 Summary: Ag92/Ag92b Three experiments show highest expression ofthe CG50838-01 gene in the cerebellum (CTs=24-27). In addition, expression is seen in the hippocampus, thalamus and hypothalamus. This gene encodes a fibronectin leucine rich transmembrane protein 3 (FLRT3), a member ofthe leucine rich repeats (LRR) protein family. FLRT proteins may play a role in cell adhesion and/or receptor signaling (Ref. 1).

20 Several of LRR proteins, such as connectin, slit, chaoptin, and Toll have pivotal roles in neuronal development in Drosophila and may play significant but distinct roles in neural development and in the adult nervous system of humans (Ref. 2). In Drosophilia, the LRR region of axon guidance proteins has been shown to be critical for their function (especially in axon repulsion). Since the leucine-rich-repeat protein encoded by this gene shows high

25 expression in the cerebellum, it is an excellent candidate neuronal guidance protein for axons, dendrites and/or growth cones in general. Therefore, therapeutic modulation ofthe levels of this protein, or possible signaling via this protein, may be of utility in enhancing/directing compensatory synaptogenesis and fiber growth in the CNS in response to neuronal death (stroke, head trauma), axon lesion (spinal cord injury), or neurodegeneration (Alzheimer's,

30 Parkinson's, Huntington's, vascular dementia or any neurodegenerative disease).

Among tissues with metabolic function, this gene is expressed at moderate to low levels in pituitary, adrenal gland, pancreas, thyroid, skeletal muscle, heart, and adult and fetal liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes.

In addition, there is expression in cell lines derived from pancreatic, gastric, colon, ovarian and lung cancer cell lines. Thus, based upon this pattern of gene expression, the therapeutic modulation ofthe activity ofthe this gene product might be of use in the tieatment of these cancers.

Reference.

1. Lacy SE, Bonnemann CG, Buzney EA, Kunkel LM. Identification of FLRT1, FLRT2, and FLRT3: a novel family of tiansmembrane leucine-rich repeat proteins. Genomics 1999 Dec

15;62(3):417-26

2. Battye R, Stevens A., Perry R.L., Jacobs J.R. (2001) Repellent signaling by Slit requires the leucine-rich repeats. J. Neurosci. 21: 4290-4298.

Panel 1.3D Summary: Ag2763/Ag92b Two experiments with the different probe and primer sets produce results that are in excellent agreement, with high expression of the

CG50838-01 gene in gastric cancer NCI-N87, colon cancer CoCa2, ovarian cancer OVCAR- 5 (CTs=29-31). Thus, expression of this gene can be used as a marker for detection these cancers. In addition, therapeutic modulation ofthe activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of these cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at high to moderate levels in adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

In addition, this gene is expressed at high levels in all regions ofthe central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 2D Summary: Ag2763/Ag92/Ag92b Three experiments with the different probe and primer sets produce results that are in excellent agreement, with highest expression ofthe CG50838-01 gene in the kidney cancer (OD04450-01) sample (CTs=27). In addition, expression of this gene is much lower in the corresponding control margin sample (CT=29). Significant expression of this gene is also seen in nuclear grade 2 kidney cancer and breast cancers. Therefore, therapeutic modulation ofthe activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of kidney or breast cancer.

Panel 3D Summary: Ag92b Highest expression ofthe CG50838-01 gene is detected in a sample derived from a brain cancer cell line (XF-498) and NCI-H727-lung carcinoid

(CTs=27). Therefore, expression of this gene can be used to distinguish these samples from other samples in this panel. In addition, substantial expression of this gene is also seen in primitive neuroectodermal, medulloblastoma, mucoepidermoid lung carcinoma, small cell lung cancer, gastric cancer, ovarian cancer, pacreatic cancer, osteosarcoma, fibrosarcoma and colon cancer cell lines. Therefore, therapeutic modulation ofthe activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of these cancers.

In addition this panel also confirms expression of this gene in CNS, especially cerebellum. See panel 1 for potential utility of this gene.

Panel 4D Summary: Ag2763, 92a, 92b Three experiments with the different probe and primer sets produce results that are in excellent agreement, with high expression of this gene in untieated CCDl 106 (keratinocytes), thymus, TNFalpha + IL-lbeta treated small airway epithelium, and lung (CTs=27-28). Therefore, expression of this gene can be used to distinguish this sample from other samples in the panel. Interestingly, expression of this gene considerably reduced in untieated small airway epithelium and TNFalpha + IL-lbeta treated keratinocytes. Thus, expression of this gene can be used to distinguish between these tieated versus untieated cells.

In addition, significant expression of this gene is also seen in activated CD45RA CD4 lymphocyte, TNFalpha + ILlbeta treated bronchial epithelium, NCI-H292 cells, lung and dermal fibroblasts, liver cirrhosis, lupus kidney, lung and kidney. This gene codes for a fibronectin leucine rich transmembrane protein 3 (FLRT3) like molecule, a member ofthe fibronectin leucine rich transmembrane protein (FLRT) family. These proteins may play a role in cell adhesion and/or receptor signaling (See Ref. 1 in panel 1). This gene may play a role in maintaining normal integrity of lung, and kidney tissue. Therefore, therapeutic modulation ofthe activity ofthe FLRT3 encoded by this gene may be beneficial for the reduction or elimination of the symptoms caused by inflammation in lung epithelia in chronic obstructive pulmonary disease, and in asthma, allergy, emphysema, kidney related diseases such as lupus and glomerulonephritis and liver cirrhosis.

U. NOV28a (CG58567-01: PROTOCADHERIN )

Expression of gene CG58567-01 was assessed using the primer-probe set Ag2897, described in Table UA. Results ofthe RTQ-PCR runs are shown in Tables UB, UC, UD, UE, UF, UG and UH.

Table UA. Probe Name Ag2897

Table UB. AI_comprehensive panel_vl .0

Tissue Name Rel. Exp.(%) Tissue Name Rel. Exp.(%)

Table UC. CNS_neurodegeneration_vl.O

Table UP. Panel 1.3D

Rel. Exp.(%) Rel. Exp.(%) Rel. Exp.(%) Rel. Exp.(%)

Tissue Name Ag2897, Run Ag2897, Run Tissue Name Ag2897, Run Ag2897, Run

161905860 165518166 161905860 165518166

Table UE. Panel 2D

Table UF. Panel 3D

Table UG. Panel 4D

Table UH. Panel CNS 1

AI_comprehensive panel vl.O Summary: Ag2897 Highest expression ofthe CG58567-01 gene is detected in match control psoriasis sample (CT=30). Furthermore, this expression is down-regulated in the corresponding psoriasis sample (CT=33). Therefore expression of this gene can be used to distinguish between these samples. In addition, the expression of this gene is up-regulated in lung from emphysema and COPD patients, which is consistent with its expression in "stressed" small airway epithelium, lung fibroblasts and lung endothelium (treated with TNF-a and IL-1). Therapeutic modulation ofthe expression of this putative protein and/or signaling via this protein by antibodies, small molecules or protein therapeutics may inhibit inflammation in lung tissue due to asthma, emphysema and other COPD type diseases

CNS_neurodegeneration_vl.O Summary: Ag2897 This panel does not show differential expression ofthe CG58567-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.3D for discussion of utility of this gene in the central nervous system. Panel 1.3D Summary: Ag2897 Two experiments with the same probe and primer show highest expression of this gene, a protocadherin homolog, in the spinal cord and the cerebral cortex (CTs=31.5). Low levels of expression are also seen in other regions of the brain including the amygdala and the hippocampus. The cadherins have been shown to be critical for CNS development, specifically for the guidance of axons, dendrites and/or growth cones in general. Therapeutic modulation ofthe levels of this protein, or possible signaling via this protein may be of utility in enhancing/directing compensatory synaptogenesis and fiber growth in the CNS in response to neuronal death (stroke, head trauma), axon lesion (spinal cord injury), or neurodegeneration (Alzheimer's, Parkinson's, Huntington's, vascular dementia or any neurodegenerative disease). Since protocadherins play an important role in synaptogenesis this gene product may also be involved in depression, schizophrenia, which also involve synaptogeneisis. Because this cadherin shows highest expression in the cerebellum, this is also an excellent candidate for the spinocerebellar ataxias as well.

Significant levels of expression are also seen in cell lines derived from ovarian, renal and brain cancers. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation ofthe expression or function of this gene may be effective in the treatment of ovarian, renal and brain cancers.

References: Hilschmann N, Barnikol HU, Barnikol-Watanabe S, Gotz H, Kratzin H, Thinnes FP. The immunoglobulin-like genetic predetermination ofthe brain: the protocadherins, blueprint of the neuronal network. Naturwissenschaften 2001 Jan;88(l):2-12

Panel 2D Summary: Ag2897 Two experiments with the same probe and primer produce results that are in reasonable agreement, with highest expression ofthe CG58567-01 gene in ovarian and kidney cancers (CTs=30.5). Significant levels of expression are also seen in lung and uterine cancers. In addition, higher levels of expression are seen in these cancers than in the corresponding normal adjacent tissues. Thus, therapeutic targeting of this gene product with a human monoclonal antibody is anticipated to limit or block the extent of tumor cell migration and invasion, preferably in kidney, lung, uterine and ovarian tumor tumors. Panel 3D Summary: Ag2897 Highest expression ofthe CG58567-01 gene is seen in a lung cancer cell line (CT=30.1). Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel. Please see panel 2D for the utility of this gene.

Panel 4D Summary: Ag2897 Two experiments with the same probe and primer produce results that are in reasonable agreement, with the CG58567-01 gene highly up-regulated in small airway epithelium and astrocytes stimulated with TNF-alpha and IL-1 beta (CTs=33- 34). Other tissues in the lung also up regulate the expression of this gene including lung microvascular endothelium and lung fibroblasts in response to TNF alpha or the Th2 elaborated cytokine IL-4. This suggests that this molecule could be expressed as a result of inflammation particularly during asthma since TNFalpha and IL-4 may play important roles in the pathology of this disease. Based on the expression profile of this transcript and the types of cytokines which induce it, antibodies to CG58567-01 may inhibit inflammation in lung tissue due to asthma, emphysema and other COPD type diseases.

Panel CNS_1 Summary: Ag2897 The results of this panel confirm expression ofthe CG58567-01 gene in the brain. Please see Panel 1.3D for discussion of utility of this gene in the central nervous system.

V. NOV28b and NOV28c (CG58567-05, CG58567-06: Protocadherin like)

Expression of gene CG58567-05 and CG58567-06 was assessed using the primer-probe sets Ag2897 and Ag705, described in Tables VA and VB. Results ofthe RTQ-PCR runs are shown in Tables VC, VD, VE, VF, VG, VH, VI' and VJ. Table VA. Probe Name Ag2897

Table VB. Probe Name Ag705

Table VC. AI_comprehensive panel_vl.O

Table VD. CNS_neurodegeneration_vl .0

Table VE. Panel 1.2

Table VF. Panel 1.3D

Table VG. Panel 2D

Table VH. Panel 3D

HelaS3- Cervical CAL 27- Squamous cell

0.0 0.0 adenocarcinoma carcinoma of tongue

Table VI. Panel 4D

Table VJ. Panel CNS 1

AI_comprehensive panel_vl.O Summary: Ag2897 Highest expression ofthe CG58567-01 gene is detected in 112427 match control psoriasis sample-F (CT=30). Furthermore, this expression is down-regulated in the corresponding psoriasis sample (CT=33). Therefore expression of this gene can be used to distinguish between these samples. In addition, the expression of this gene is up-regulated in lung from emphysema and COPD patients, which is consistent with its expression in "stressed" small airway epithelium, lung fibroblasts and lung endothelium (tieated with TNF-a and IL-1). Therapeutic modulation ofthe expression of this putative protein and/or signaling via this protein by antibodies, small moleculesvor protein therapeutics may inhibit inflammation in lung tissue due to asthma, emphysema and other COPD type diseases

CNS_neurodegeneration_vl.O Summary: Ag2897 This panel does not show differential expression ofthe CG58567-01 gene in Alzheimer's disease. However, this expression profile confirms the presence of this gene in the brain. Please see Panel 1.3D for discussion of utility of this gene in the central nervous system. Panel 1.2 Summary: Ag705 Two experiments with the same probe and primer show highest expression ofthe CG58567-05 gene in an ovarian cancer cell line and the cerebral cortex (CTs=25-26). This gene is also expressed in other parts ofthe central nervous system, including the spinal cord, amygdala, and hippocampus. Please see Panel 1.3D for further discussion of utility of this gene in the central nervous system. In addition to expression in the ovarian cancer cell line, this gene is also expressed in a cluster of cell lines derived from ovarian and brain cancers. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation ofthe expression or function of this gene may be effective in the treatment of ovarian and brain cancers.

Panel 1.3D Summary: Ag2897 Two experiments with the same probe and primer show highest expression of this gene, a protocadherin homolog, in the spinal cord and the cerebral cortex (CTs=31.5). Low levels of expression are also seen in other regions ofthe brain including the amygdala and the hippocampus. The cadherins have been shown to be critical for CNS development, specifically for the guidance of axons, dendrites and/or growth cones in general. Therapeutic modulation ofthe levels of this protein, or possible signaling via this protein may be of utility in enhancing/directing compensatory synaptogenesis and fiber growth in the CNS in response to neuronal death (stroke, head trauma), axon lesion (spinal cord injury), or neurodegeneration (Alzheimer's, Parkinson's, Huntington's, vascular dementia or any neurodegenerative disease). Since protocadherins play an important role in synaptogenesis this gene product may also be involved in depression, schizophrenia, which also involve synaptogeneisis. Because this cadherin shows highest expression in the cerebellum, this is also an excellent candidate for the spinocerebellar ataxias as well. Significant levels of expression are also seen in cell lines derived from ovarian, renal and brain cancers. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation ofthe expression or function of this gene may be effective in the tieatment of ovarian, renal and brain cancers. References:

Hilschmann N, Barnikol HU, Barnikol-Watanabe S, Gotz H, Rratzin H, Thirmes FP. The immunoglobulin-like genetic predetermination ofthe brain: the protocadherins, blueprint of the neuronal network. Naturwissenschaften 2001 Jan;88(l):2-12

Panel 2D Summary: Ag2897 Two experiments with the same probe and primer produce results that are in reasonable agreement, with highest expression ofthe CG58567-01 gene in ovarian and kidney cancers (CTs=30.5). Significant levels of expression are also seen in lung and uterine cancers. In addition, higher levels of expression are seen in these cancers than in the corresponding normal adjacent tissues. Thus, therapeutic targeting of this gene product with a human monoclonal antibody is anticipated to limit or block the extent of tumor cell migration and invasion, preferably in kidney, lung, uterine and ovarian tumor tumors.

Panel 3D Summary: Ag2897 Highest expression ofthe CG58567-01 gene is seen in a lung cancer cell line (CT=30.1). Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel. Please see Panel 2D for further discussion of utility of this gene in cancer. Panel 4D Summary: Ag2897 Two experiments with the same probe and primer produce results that are in reasonable agreement, with the CG58567-01 gene highly up-regulated in small airway epithelium and astrocytes stimulated with TNF-alpha and IL-1 beta (CTs=33- 34). Other tissues in the lung also up regulate the expression of this gene including lung microvascular endothelium and lung fibroblasts in response to TNF alpha or the Th2 elaborated cytokine IL-4. This suggests that this molecule could be expressed as a result of inflammation particularly during asthma since TNFalpha and IL-4 may play important roles in the pathology of this disease. Based on the expression profile of this transcript and the types of cytokines which induce it, antibodies to CG58567-01 may inhibit inflammation in lung tissue due to asthma, emphysema and other COPD type diseases. Panel CNS_1 Summary: Ag2897 The results of this panel confirm expression ofthe

CG58567-01 gene in the brain. Please see Panel 1.3D for discussion of utility of this gene in the central nervous system. W. NOV29a and NOV29c (CG59243-01 and CG59243-02: Mitochondrial Carrier Protein )

Expression of gene CG59243-01 and CG59243-02 was assessed using the primer-probe set Ag3415, described in Table WA. Results of the RTQ-PCR runs are shown in Tables WB, WC, WD, and WE. Please note that CG59243-02 represents a full-length physical clone of the CG59243-01 gene, validating the prediction ofthe gene sequence.

Table WA. Probe Name Ag3415

Table WB. CNS_neurodegeneration_vl .0

Table WC. Panel 1.3D

Table WD. Panel 2D

Table WE. Panel 4D

AI_comprehensive panel_vl.O Summary: Ag3415 Results from one experiment with the CG59243-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

CNS_neurodegeneration_vl.O Summary: Ag3415 This panel confirms the expression of the CG59243-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.3D for a discussion ofthe potential utility of this gene in treatment of central nervous system disorders. Panel 1.3D Summary: Ag3415 Highest expression ofthe CG59243-01 gene is seen in a colon cancer cell line (CT=33.2), with significant expression also seen in a lung cancer cell line. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of colon or lung cancer. Furthermore, therapeutic modulation ofthe expression or function of this gene may be effective in the treatment of colon or lung cancer.

In addition, this gene is expressed at low levels in fetal brain and cerebral cortex. Therefore, this gene may play a role in central nervous system development and CNS disorders such as Alzheimer's disease, Parkinson's disease, seizures, epilepsy, multiple sclerosis, schizophrenia and depression. Panel 2D Summary: Ag3415 Highest expression of the CG59243-01 gene is seen in a lung cancer (CT=32.5), consistent with expression in Panel 1.3D. Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel. Please see Panel 1.3D for a discussion ofthe potential utility of this gene in treatment of cancer.

Panel 4D Summary: Ag3415 Highest expression ofthe CG59243-01 gene is seen in the B cell line Ramos, tieated with ionomycin (CT=29.5). Low, but significant levels of expression of this transcript are also seen in activated B cells (B cells tieated with PWM or CD40L + IL4). This transcript is also expressed in PBMC treated with the B cell mitogen, PWM, confirming the importance of this gene's expression in activated B cells. B cells represent a principle component of immunity and contribute to the immune response in a number of important functional roles, including antibody production. For example, production of antibodies against self-antigens is a major component in autoimmune disorders such a systemic lupus erythematosus. Since B cells play an important role in autoimmunity, inflammatory processes and inflammatory cascades, therapeutic modulation of this gene product may reduce or eliminate the symptoms of patients suffering from asthma, allergies, chronic obstructive pulmonary disease, emphysema, Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, osteoarthritis, and other autoimmune disorders including systemic lupus erythematosus.

X. NON30a (CG59534-01: Membrane Glycoprotein )

Expression of gene CG59534-01 was assessed using the primer-probe sets Ag5041 and Ag5043, described in Tables XA and XB. Results ofthe RTQ-PCR runs are shown in Tables XC and XD. Table XA. Probe Name Ag5041

Table XB. Probe Name Ag5043

Table XC. General_screening_panel_vl.5

Table XD. Panel 4. ID

General screening panel vl.5 Summary: Ag5041/Ag5043 Two experiments with two different probe and primer sets show highest expression ofthe CG59534-01 gene, a putative membrane glycoprotein, in cell lines derived from brain cancer and gastric cancer (CTs=24- 29). Significant expression of this gene is also seen in cell lines derived from brain cancer, ovarian cancer, and gastric cancer. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation ofthe expression or function of this gene may be effective in the treatment of colon, ovarian, and brain cancers.

Among tissues with metabolic function, this gene is expressed at moderate to low levels in pituitary, adipose, adrenal gland, pancreas, thyroid, and adult and fetal skeletal muscle, heart, and liver. This widespread expression among these tissues suggests that this gene product may play a role in normal neuroendocrine and metabolic and that disregulated expression of this gene may contribute to neuroendocrine disorders or metabolic diseases, such as obesity and diabetes. In addition, this molecule novel membrane glycoprotein is expressed at moderate to low levels in the CNS and may be a small molecule target for the treatment of neurologic diseases such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 4.1D Summary: Ag5041/Ag5043 Two experiments with two different probe and primer sets show highest expression ofthe CG59534-01 gene, a putative membrane glycoprotein, in IL-9 treated fibroblasts and the B cell line Ramos treated with ionomycin (CTs=29-30). This gene is also gene is expressed at moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members ofthe T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl .5 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation ofthe gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement ofthe symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

Y. NOV31a and NOV31b (CG59289-01 and CG59289-02: Crumbs like)

Expression of gene CG59289-01 and CG59289-02 was assessed using the primer-probe sets Ag3530 and Agl932, described in Tables YA and YB. Results ofthe RTQ-PCR runs are shown in Tables YC, and YD.

Table YA. Probe Name Ag3530

Table YB. Probe Name Agl 932

Table YC. CNS_neurodegeneration_vl.0

Table YD. Panel 4D

CNS_neurodegeneration_vl.O Summary: Ag3530 This panel confirms the expression of CG59289-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. The CG59289-01 gene codes for Drosophila CRUMBl (CRB1) homologue, a protein essential for establishing and maintaining epithelial polarity. In mouse, Crbl was shown to be expressed exclusively in the eye, and the central nervous system (Ref. 1). Therefore, similar to the mouse orthologue, the CG59289-01 gene may be expressed in eye and central nervous system and may play a role in retinal and central nervous system disorders such as retinal dystrophies, Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Reference.

1. den Hollander Al, Ghiani M, de Kok YJ, Wijnholds J, Ballabio A, Cremers FP, Broccoli V. (2002) Isolation of Crbl, a mouse homologue of Drosophila crumbs, and analysis of its expression pattern in eye and brain. Mech Dev 110(l-2):203-7

General_screening__panel_vl.4 Summary: Ag3530 Results from one experiment with the CG59289-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

Panel 4D Summary: Ag3530 Highest expression ofthe CG59289-01 gene is seen in normal colon (CT=31). Therefore, expression of this gene may be used to distinguish colon from the other tissues on this panel. Furthermore, expression of this gene is decreased in colon samples from patients with IBD colitis and Crohn's disease relative to normal colon. Therefore, therapeutic modulation ofthe activity ofthe protein encoded by this gene may be useful in the treatment of inflammatory bowel disease. Significant expression is also seen in dendritic cells (DC) and is upregulated in response to CD40. In addition, expression in colon may also result from dendritic cells present in these tissue. Therefore, therapeutic utilization ofthe protein encoded by this transcript may be important in the treatment of diseases where antigen presentation, a function of mature dendritic cells, plays an important role such as asthma, rheumatoid arthrtis, IBD, and psoriasis.

Results from a second experiment with the probe primer set Agl 932 are not included. The amp plot indicates that there were experimental difficulties with this run.

Z. NOV32a (CG57111-01: Protocadherin )

Expression of gene CG57111-01 was assessed using the primer-probe sets Ag3242, Agl012, Agl 096 and Ag704, described in Tables ZA, ZB, ZC and ZD. Results of the RTQ-PCR runs are shown in Tables ZE, ZF,-ZG, ZH, ZI, ZJ, and ZK. Table ZA. Probe Name Ag3242

Table ZB. Probe Name Agl012

Table ZC. Probe Name Agl096

Table ZD. Probe Name Ag704

Table ZE. AI_comprehensivepanel_vl.0

Table ZF. CNS_neurodegeneration_vl .0

Table ZG. Panel 1.2

Table ZH. Panel 1.3D

Tissue Name Rel. Rel. Rel. Tissue Rel. Rel. Rel.

Table ZI. Panel 2.2

Table ZJ. Panel 4D

Table ZK. Panel CNS 1

AI_comprehensive panel_vl.O Summary: Ag3242 Expression ofthe CG59985-01 gene is ubiquitous in this panel, with high expression in samples derived from patients suffering from ulcerative colitis, Crohns disease and psoriasis (CTs=33). In addition, significant expression is also seen in samples derived from synovium, cartilage and bone of rheumatoid arthritis. Therefore, antibody or small molecule therapies designed with the protein encoded for by this gene may be useful in the tieatment of inflammatory bowel diseases and rheumatoid arthritis.

CNS_neurodegeneration_vl.O Summary: Agl012/Agl096/Ag3242 Three experiments with three different probe and primer sets produce results that are in excellent agreement, with highest expression ofthe CG57448-01 gene in the hippocampus of a patient with Alzheimer's disease. No change is detected in the expression of this gene in the postmortem Alzheimer's diseased brain when compared to controls; however this panel confirms the expression of this gene in the CNS in an independent group of patients. See panel 1.2 for a discussion of utility. A third experiment with the probe and primer set Ag704 shows low/undetectable levels of expression (CTs>35). (Data not shown.) The data suggest that there is a probability of a probe failure.

Panel 1.2 Summary: Agl096/Ag3242 Two experiments with two different probe and primer sets produce results that are in excellent agreement, with highest expression ofthe CG57448-01 gene in cancer cell lines derived from lung cancer and melanoma (CTs=24-25). Significant levels of expression are also seen in a renal cancer cell line, ovarian cancer cell lines and brain cancer cell lines. Thus, expression of this gene could be used to differentiate between these samples and other samples on this panel and as a diagnostic marker for the presence of these cancers. This gene encodes a protein that is homologous to cadherin, a cell- adhesion molecule. Therefore, therapeutic modulation ofthe expression or function of this gene may be effective in the tieatment of lung, renal and melanoma cancers.

Expression ofthe this gene is also high in many regions ofthe brain, including the amygdala, thalamus, cerebellum, and cerebral cortex, with highest expression in the hippocampus. Expression is also detected in the spinal cord. Cadherins can act as axon guidance and cell adhesion proteins, specifically during development and in the response to injury (ref 1). Therefore, manipulation of levels of this protein may be of use in inducing a compensatory synaptogenic response to neuronal death in Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar ataxia, progressive supranuclear palsy, ALS, head trauma, stroke, or any other disease/condition associated with neuronal loss.

Among tissues with metabolic function, this gene is moderately expressed in pituitary gland, adrenal gland, thyroid, pancreas, skeletal muscle, and liver, reflecting the widespread role of cadherins in cell-cell adhesion. This expression suggests that this gene product may play a role in normal metabolic and neuroendocrine function and that dysregulated expression of this gene may contribute to metabolic diseases (such as obesity and diabetes) or neuroendocrine disorders.

References:

Ranscht B. (2000) Cadherins: molecular codes for axon guidance and synapse formation. Int. J. Dev. Neurosci. 18: 643-651. Panel 1.3D Summary: Ag3242 Highest expression ofthe CG57448-01 gene is seen in a renal cancer cell line (CT=31.1). Significant expression is also seen in cell lines derived from ovarian cancer, lung cancer, brain cancer and melanoma. This is in concordance with the results in the previous panel. Please see Panel 1.2 for discussion of utility of this gene in the treatment of cancer. As in the previous panel, this gene is also highly expressed in the central nervous system. Please see Panel 1.2 for a fuller discussion of utility of this gene in the central nervous system.

Results from a second experiment with the probe primer set Ag704 are not included. The amp plot indicates that there is a high probability of a probe failure. Panel 2.2 Summary: Ag3242 Highest expression ofthe CG57448-01 gene is seen in a sample derived from an ocular melanoma metastasis (CT=29). Thus, expression of this gene could be used to differentiate between this sample and other samples on this pane.

Panel 2D Summary: Ag704 Results from one experiment with the CG57448-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run. Panel 3D Summary: Agl012 Results from one experiment with the CG57448-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

Panel 4D Summary: Agl096/Ag3242 Two experiments with two different probe and primer sets produce results that are in excellent agreement, with highest expression ofthe CG57448-01 gene in the basophil cell line (KU-812) treated with PMA/ionomycin (CTs=30- 32). Significant expression is also seen in a cluster of treated and untreated samples derived from the muco-epidermoid cell line NCI-H292. Thus, this gene, which encodes a cadherin homolog, is expressed in both a cell line that is often used as a model of airway epithelium (NCI-H292) and a cell line that is a reasonable model for the inflammatory cells that contribute to various inflammatory lung diseases. This suggests that suggest that therapeutic modulation of this gene prodcut may reduce or eliminate the symptoms of patients suffering from pathological and inflammatory lung disorders, including chronic obstructive pulmonary disease, asthma, allergy and emphysema.

Low but significant levels of expression are also seen in the samples derived from normal colon, kidney, lung and thymus. This suggests that this gene product may play a role in the homeostasis of these tissues. Therefore, therapeutic modulation ofthe expression or function of this gene product may be important for maintaining or restoring normal function to this organs during inflammation.

Results from a third experiment with the probe primer set Ag704 are not included. The amp plot indicates that there is a high probability of a probe failure.

Panel CNS_1 Summary: Agl 012 This panel confirms the expression ofthe CG57448-01 gene at low levels in the brains of an independent group of individuals. Please see Panel 1.2 for a discussion ofthe potential utility of this gene in treatment of central nervous system disorders.

AA. NOV33c (CG59363-03: BAB26184 like)

Expression of gene CG59363-03 was assessed using the primer-probe set Ag5254, described in Table AAA.

Table AAA. Probe Name Ag5254

CNS_neurodegeneration_vl.O Summary: Ag5254 Expression ofthe CG55966-03 gene is low/undetectable in all samples on this panel (CTs>35).

General_screening__panel_vl.5 Summary: Ag5254 Expression ofthe CG55966-03 gene is low/undetectable in all samples on this panel (CTs>35).

Panel 4.1D Summary: Ag5254 Expression ofthe CG55966-03 gene is low/undetectable in all samples on this panel (CTs>35). AB. NOV34a (CG59301-01 : Androgen receptor-like ) Expression of gene CG59301-01 was assessed using the primer-probe set Ag3536, described in Table ABA. Results ofthe RTQ-PCR runs are shown in Tables ABB, ABC, ABD, and ABE.

Table ABA. Probe Name Ag3536

Table ABB. CNS_neurodegeneration_vl.0

Table ABC. General_screening_panel_vl.4

Table ABD. Panel 2.2

Table ABE. Panel 4D

CNS_neurodegeneration_vl.O Summary: Ag3536 This panel confirms the expression of the CG59301-01 gene at low levels in the brain in an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion ofthe potential utility of this gene in treatment of central nervous system disorders.

General_screeningjpanel_vl.4 Summary: Ag3536 Highest expression ofthe CG59301-01 gene is detected in one ofthe lung cancer cell line NCI-H23 (CT=30.8). In addition, high expression of this gene is also detected in a breast cancer cell line T47D and ovarian cancer cell line SK-OV-3 (CTs=31). Therefore, expression of this gene can be use to distinguish these samples from other samples used in this panel and as marker in detection of these cancer. Also, significant expression of this gene is seen in CNS cancer, colon cancer, gastric cancer, lung cancer, breast cancer, renal cancer and prostate cancer cell lines. Therefore, therapeutic modulation ofthe activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of these cancer.

Low expression of this gene is also observed in samples derived from prostate, kidney and bladder. Therefore, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the tieatment of disease associated with these tissues.

This gene is expressed at low to moderate levels in cerebellum, hippocampus, and fetal brain (CTs=32-35). Therefore, this gene may play a role in central nervous system disorders such as, Parkinson's disease, epilepsy, seizure, ataxia, autism, schizophrenia and depression.

Panel 2.2 Summary: Ag3536 Significant expression ofthe CG59301-01 gene is seen in two ofthe breast cancer metastasis samples in this panel (CTs=34-34.5). Therefore, expression of this gene may be used to distinguish breast cancers from the other samples on this panel. Furthermore, therapeutic modulation ofthe activity of this gene product may be beneficial in the tieatment of breast cancer.

Panel 4D Summary: Ag3536 Highest expression of CG59301-01 is detected in colon (CT=30.83). Therefore, expression of this gene may be used to distinguish colon from the other tissues on this panel. Furthermore, expression of this gene is decreased in colon samples from patients with IBD colitis and Crohn's disease (CT>35) relative to normal colon. Therefore, therapeutic modulation of the this gene product may be useful in the tieatment of inflammatory bowel disease.

Low to moderate expression of this gene is also seen samples derived from lung, activated and resting primary Th2, IL-2+IFN gamma treated LAK cells, HUVEC, lung microvascular EC, TNFalpha + ILlbeta treated bronchial epithelium, TNFalpha + ILlbeta treated small airway epithelium, TNFalpha + IL-lbeta treated astrocytes, TNFalpha + IL-lbeta treated CCDl 106 (keratinocytes), lung fibroblast, TNF alpha treated dermal fibroblast CCD 1070 cells and in liver cirrhosis samples. Therefore, therapeutic modulation of this gene or its protein product may be beneficial in the treatment of general autoimmunity, allergies, asthma, psoriasis and emphysema. Panel CNS_1 Summary: Ag3536 Expression of this gene is low/undetectable (CTs > 35) across all ofthe samples on this panel. AC. NOV35a (CG59525-01: CARCINOEMBRYONIC ANTIGEN CGMl

)

Expression of gene CG59525-01 was assessed using the primer-probe set Ag3457, described in Table ACA. Results ofthe RTQ-PCR runs are shown in Tables ACB, and ACC. Table ACA. Probe Name Ag3457

Table ACB. General_screening_panel_vl.4

Renal ca. UO-31 0.0 Pancreas Pool 18.3

Table ACC. Panel 4D

CNS_neurodegeneration_vl.O Summary: Ag3457 Expression of CG59525-01 gene is low/undetectable (CTs > 34.5) across all ofthe samples on this panel.

General_screening panel_vl.4 Summary: Ag3457 Significant expression of CG59525-01 gene is seen exclusively in a colon cancer cell line (CT = 34.02). Therefore, expression of this gene may be used to distinguish colon cancers from the other samples on this panel. Furthermore, therapeutic modulation ofthe activity ofthe protein encoded by this gene may be beneficial in the treatment of colon cancer.

Panel 4D Summary: Ag3457 Low to moderate expression of CG59525-01 gene is detected in both resting and activated, primary and secondary Thl, Th2, Trl samples, activated secondary CD8 lymphocyte and 2ry Thl/Th2/Trl_anti-CD95 CHI 1. In addition, this gene is down-regulated in activated primary Thl cells (CT=35) as compared to resting primary Thl cells (CT=32). Therefore, this gene may be important in regulation of T cell activation or participate in the function(s) of these T cells. Therapeutics designed with the protein encoded for by this transcript could be important in regulating T cell function and treating T cell mediated diseases such as asthma, arthritis, psoriasis, IBD, and systemic lupus erythematosus.

CG59525-01 gene codes for a carcinoembryonic antigen-related cell adhesion molecule (CEACAM). CEACAM1, a related protein, has been shown to regulate early maturation and activation of dentritic cells, thereby facilitating priming and polarization of T cell responses (Ref. 1). Low to moderate expression of this gene is also detected in untreated dendritic cells (CT=34) and anti-CD40 treated cells (CT=33). Thus, the protein encoded by this transcript may be important in dendritic cell differentiation and activation and also, in priming and polarization of T cell responses. Therefore, therapeutics designed with the protein encoded by this transcript could be important for the treatment of asthma, emphysema, inflammatory bowel disease, arthritis and psoriasis.

Expression of this gene is stimulated in IL-2, IL-2+IL12, IL-2+IFN gamma treated LAK cells, PWM/CD40L and IL-4 treated B lymphocytes, anti-CD40 treated dendritic cells, and CCD 1070 TNF alpha tieated dermal fibroblast. Therefore, therapeutic modulation of this gene or its protein product may be beneficial in the treatment of general autoimmunity, psoriasis and emphysema.

References.

1. Kammerer R, Stober D, Singer BB, Obrink B, Reimann J. (2001) Carcinoembryonic antigen-related cell adhesion molecule 1 on murine dendritic cells is a potent regulator of T cell stimulation. J Immunol 2001 Jun l;166(ll):6537-44 AD. NOV36a (CG59484-01 : TGF-BETA RESISTANCE-ASSOCIATED

PROTEIN )

Expression of gene CG59484-01 was assessed using the primer-probe set Ag3448, described in Table ADA. Results ofthe RTQ-PCR runs are shown in Tables ADB, ADC and ADD.

Table ADA. Probe Name Ag3448

Primers Sequences Length Start Position

Forward ' -cagaacactccgtggtcatc-3 ' (SEQ ID NO : 338 ) 20 | 1390 _p , JTET-5 ¹ -tcacatgtttgctatatcctcatcagg-3 ' -TAMRA (SEQ ^ODe JlD NO : 339) 27 1 1419

Reverse _|5 ' -tttgatcataccgagctgaga-3 ' (SEQ ID NO: 340) 21 1446 Table ADB. CNS_neurodegeneration_vl.O

Table ADC. General_screening_panel_vl.4

Table ADD. Panel 4D

CNS_neurodegeneration_vl.0 Summary: Ag3448 This panel confirms the expression of CG59484-01 gene at low levels in the brain in an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion ofthe potential utility of this gene in treatment of central nervous system disorders.

General_screening_panel_vl.4 Summary: Ag3448 Highest expression of CG59484-01 gene is detected in colon (CT=24.9). Therefore, expression of this gene can used to distinguish this sample from other samples in the panel. Furthermore, expression of this gene is decreased in colon cancer tissue and the cell lines (Cts=30-32). Therefore, therapeutic modulation ofthe activity ofthe protein encoded by this gene may be useful in the treatment of colon related diseases such as colon cancers, Crohn's disease, and ulcerative colitis.

Among tissues with metabolic or endocrine function, this gene is expressed at moderate levels (CTs=29-30) in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tiact. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

This gene is expressed at significant (CTs= 27-29) levels throughout the CNS, including in amygdala, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in cential nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. However, moderate levels of expression of this gene are detected in areas outside ofthe central nervous system, suggesting the possibility of a wider role in intercellular signaling.

Panel 4D Summary: Ag3448 Highest expresssion of CG59484-01 gene is detected in resting primary Thl cells. Thus expression of this gene can be used to distinguish this sample from other samples used in this panel. However, moderate levels of expression of this gene are detected in large number of samples used in this panel, suggesting the possibility of a wider role in intercellular signaling.

Interestingly, expression of this gene is decreased in colon samples from patients with IBD colitis (CT=31.22) and Crohn's disease (CT=30.99) relative to normal colon (CT=27.45). Therefore, therapeutic modulation ofthe activity ofthe protein encoded by this gene may be useful in the treatment of inflammatory bowel disease.

AE. NON38a (CG59454-01: Butyrophilin )

Expression of gene CG59454-01 was assessed using the primer-probe set Ag3444, described in Table AEA. Results ofthe RTQ-PCR runs are shown in Tables AEB, and AEC. Table AEA. Probe Name Ag3444

Table AEB. CNS_neurodegeneration_vl .0

Table AEC. Panel 4D

CNS_neurodegeneration_vl.O Summary: Ag3444 This panel confirms the expression of the CG59454-01 gene at low levels in the brain in an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment.

The CG59454-01 gene codes for butyrophilin protein (BTN), a milk protein. Recently it was demonstrated that active immunization ofthe dark Agouti rat with native BTN triggers an inflammatory response in the CNS characterized by the formation of scattered meningeal and perivascular infiltrates of T cells and macrophages (see Ref. 1 in panel 4D).

General_screening_panel_vl.4 Summary: Ag3444 Results from one experiment with the CG59454-01 gene are not included. The amp plot indicates that there were experimental difficulties with this run.

Panel 4D Summary: Ag3444 Highest expression of CG59454-01 is detected in samples derived from two way MLR 3 day and resting primary Thl cells (CTs=25). Thus, expression of this gene can be used to distinguish these two samples from other samples in the panel. In addition, expression of this gene is down-regulated in activated primary Thl cells (CT=29) as compared to resting primary Thl cells (CT=25). Thus, therapeutics designed with the protein encoded for by this transcript could be important in treating T-cell mediated diseases such as asthma, emphysema, psoriasis, IBD, systemic lupus erythematosus, autoimmune encephalomyelitis, and parasitic disease. CG59454-01 gene codes for butyrophilin protein, a milk protein. Recently, butyrophilin has been shown to modulates the encephalitogenic T cell response to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis (Ref.l).

References. 1. Stefferl A, Schubart A, Storch2 M, Amini A, Mather I, Lassmann H, Linington C. (2000) Butyrophilin, a milk protein, modulates the encephalitogenic T cell response to myelin ohgodendrocyte glycoprotein in experimental autoimmune encephalomyelitis. J Immunol 165(5):2859-65

AF. NOV39a (CG59307-01: KIAA1769 )

Expression of gene CG59307-01 was assessed using the primer-probe set Ag3539, described in Table AFA. Results ofthe RTQ-PCR runs are shown in Tables AFB, AFC and AFD.

Table AFA. Probe Name Ag3539

Table AFB. CNS_neurodegeneration_vl .0

Table AFC. General_screening_panel_vl .4

Table AFP. Panel 4D

CNS_neurodegeneration_vl.O Summary: Ag3539 This panel confirms the expression of the CG59307-01 gene at low levels in the brain in an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion ofthe potential utility of this gene in tieatment of cential nervous system disorders.

General_screening_panel_vl.4 Summary: Ag3539 Highest expression of he CG59307-01 gene is detected in a sample derived from one ofthe gastric cancer cell line NCI-N87 (CT=23.9). Thus expression of this gene can be used to distinguish this sample from other samples in the panel. In addition low levels of expression of this gene is also associated with colon cancer, ovarian cancer, breast cancer, and CNS cancer cell lines. Therefore, therapeutic modulation ofthe activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of these cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract (CTs=27-31). Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

In addition, this gene is expressed at low to moderate levels (CTs=31-33) in all regions ofthe central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 4D Summary: Ag3539 Highest expression ofthe CG59307-01 gene is detected in a sample derived from TNFalpha + IL-lbeta tieated CCDl 106 (Keratinocytes) (CT=26.45). Furthermore, expression of this gene is stimulated in activated secondary Thl cells, LAK cells treated with IL-2/IL-2+IFN gamma/IL-2+ IL-12/IL-2+ IL-18, LPS tieated dendritic cells, monocytes, and macrophages, TNF alpha + IFN gamma tieated HUVEC, TNFalpha + IL-lbeta tieated astrocytes, CCDl 106 (Keratinocytes), and lung fibroblasts. Therefore, therapeutics designed with the protein encoded for by this transcript could be important in regulating T cell function and treating T cell mediated diseases such as asthma, arthritis, psoriasis, IBD, cancer cell killing, improvement of host immunity to microbial and viral infections and systemic lupus erythematosus.

AG. NOV40a (CG59713-01: Van Gogh )

Expression of gene CG59713-01 was assessed using the primer-probe set Ag3513, described in Table AGA. Results ofthe RTQ-PCR runs are shown in Tables AGB, AGC and AGD. Table AGA. Probe Name Ag3513

Table AGB. CNS_neurodegeneration_vl.0

Table AGC. General_screening_panel_vl.4

Table AGP. Panel 4D

CNS_neurodegeneration_vl.O Summary: Ag3513 This panel confirms the expression of the CG59713-01 gene at low levels in the brain in an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of cential nervous system disorders.

General_screening_panel_vl.4 Summary: Ag3513 Highest expression ofthe CG59713-01 is detected in sample derived from one ofthe ovarian cancer SK-OV-3(CT=28). Furthermore, significant expression of this gene is associated with number of cancer samples (pancreatic cancer, CNS cancer, colon cancer, gastric cancer, renal cancer, lung cancer, breast cancer, prostate cancer, melanoma cell lines) used in this panel. Therefore, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, or antibodies, might be beneficial in the treatment of all these cancers.

Interestingly, this gene is expressed at much higher levels in fetal (CT=30) when compared to adult liver (CT=34). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver. In addition, the relative overexpression of this gene in fetal liver suggests that the protein product may be required for growth and development ofthe liver in fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation ofthe protein encoded by this gene could be useful in treatment of liver related diseases.

Among tissues with metabolic or endocrine function, this gene is expressed at high to moderate levels (CTs=30-32) in pancreas, adipose, adrenal gland, thyroid, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

In addition, this gene is expressed at low levels (CTs=32-34) in all regions ofthe central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

Panel 4D Summary: Ag3513 Highest expression ofthe CG59713-01 is detected in TNFalpha + IL-lbeta tieated keratinocytes (CT=27.9). Therefore, expression of this gene can be used to distinguish TNFalpha + IL-lbeta treated keratinocytes from other samples used in this panel.

In addition, expression of this gene is stimulated in activated secondary Thl, Th2, and Trl cells, LAK cells treated with IL-2, TNFalpha + IL-lbeta tieated small airway epithelium and NCI-H292 treated with IL-4. Therefore, therapeutic modulation ofthe activity of this gene or its protein product, through the use of small molecule drugs, or antibodies, might be beneficial in the treatment of psoriasis, asthma, emphysema, cancer, microbial and viral infections.

AH. NOV41a (CG59570-01: AQUAPORIN ) Expression of gene CG59570-01 was assessed using the primer-probe set Ag3475, described in Table AHA. Results ofthe RTQ-PCR runs are shown in Tables AHB, and AHC.

Table AHA. Probe Name Ag3475

Table AHB. General_screening_panel_vl .4

Table AHC. Panel 4D

CNS_neurodegeneration_vl.0 Summary: Ag3475 Expression ofthe CG59570-01 gene is low/undetectable (CTs > 34.5) across all ofthe samples on this panel.

General_screening_panel_vl.4 Summary: Ag3475 High expression ofthe CG59570-01 gene is dectected exclusively in adipose tissue sample (CT=27J3). Thus expression of this gene can be used to distinguish adipose sample from other samples in this panel. In addition to adipose tissue, low levels of expression of this gene is also seen in other tissues with metabolic or endocrine function such as pancreas, adrenal gland, thyroid, skeletal muscle, heart, and the gastrointestinal tiact. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

CG59570-01 codes for protein similar to aquaporin 7. Aquaporins are water channels that are usually found in tissues where water movements are abundant and/or physiologically important. In a systematic analysis of genes expressed in human adipose tissue, Kuriyama et al. (Ref. 1) identified AQP7L, a predicted 342-amino acid protein. They showed that this aquaporin participates in glycerol transport in adipocytes. Thus, we predict that protein encoded by this transcript may also play a role in glycerol transport in adipocytes.

Interestingly, this gene is expressed at much higher levels in adult (CT = 30) when compared to fetal heart (CT = 34). This observation suggests that expression of this gene can be used to distinguish fetal from adult heart. Furhtermore, therapeutic modulation ofthe protein encoded by this gene could be useful in treatment of heart related diseases.

In addition, this gene is expressed at significant levels in some regions ofthe central nervous system examined, including amygdala, hippocampus, substantia nigra, and cerebellum (CTs=30-34). Therefore, this gene may play a role in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, seizure, ataxia, autism, schizophrenia and depression.

Reference.

1. Kuriyama, H.; Kawamoto, S.; Ishida, N.; Ohno, I.; Mita, S.; Matsuzawa, Y.; Matsubara, K.; Okubo, K. (1997) Molecular cloning and expression of a novel human aquaporin from adipose tissue with glycerol permeability. Biochem. Biophys. Res. Commun. 241: 53-58.

Panel 4D Summary: Ag3475 High expression ofthe CG59570-01 is detected untreated and TNF alpha + IL-1 beta treated (CTs=30) HPAEC cells. Thus expression of this gene can be used to distinguish these two samples from other samples in this panel. In addition, low levels of expression of this gene is also detected in lung fibroblast, IFN-gamma treated lung fibroblast, IL-9 treated NCI-H292 cells, starved and IFN-gama tieated HUVEC cells, anti- CD95 CHI 1 treated secondary Thl/Th2/Trl cells, and TNFalpha + IL-lbeta treated small airway epithelium. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of lung related diseases such as asthma, allergies, emphysema, COPD.

Interestingly, this gene is expressed at much higher levels in TNFalpha + IL-lbeta tieated (CT=32) as compared to untreated small airway epithelium (CT = 35). Thus, expression of this gene can be used to distinguish TNFalpha + IL-lbeta treated from the untreated small airway epithelium cells.

Expression of this gene is detected at low levels (CT=34.5) in liver cirrhosis, but not in normal liver (no expression in normal liver is detected on Panel 1.4). The protein encoded for by this gene could potentially allow cells within the liver to respond to specific microenvironmental signals. Therefore, therapies designed with the protein encoded for by this gene may potentially modulate liver function and play a role in the identification and treatment of inflammatory or autoimmune diseases which effect the liver including liver cirrhosis and fibrosis.

In addition, moderate expression of this gene is also observed in kidney, thymus and colon. Therefore, antibody or small molecule therapies designed with the protein encoded for by this gene may be important in the treatment of inflammatory or autoimmune diseases that affect these tissues.

Al. NOV42a (CG56162-02: LYSOPHOSPHOLIPASE-LIKE)

Expression of gene CG56162-02 was assessed using the primer-probe set Ag2042, described in Table AIA. Results ofthe RTQ-PCR runs are shown in Tables AIB and AIC. Please note that CG56162-02 represents a full-length physical clone.

Table AIA. Probe Name Ag2042

Table AIB. Panel 1.3D

Table AIC. Panel 4D

Panel 1.3D Summary: Agl906/Ag2042 The expression of CG56162-02 gene was assessed in two independent runs using 2 different probe/primer pairs, with good concordance between the runs. Highest expression in this panel is seen in brain derived tissue, including the cerebral cortex and a brain cancer (CTs=25-27). Thus, the expression of this gene could be used to distinguish these samples from other samples in the panel.

This gene encodes a lysophosphase homolog that also has high levels of expression in many ofthe endocrine/metabolic tissues found on this panel, including adipose, liver, pancreas, pituitary, skeletal muscle and small intestine. Lysophospholipids are detergent-like intermediates in phospholipid metabolism. Lysophospholipases are important enzymes in the regulation of hormone biosynthesis and metabolism, and have been shown to be important in the regulation of insulin secretion (see reference below). Increased lysophospholipids levels have been detected in a variety of diseases including atherosclerosis and hyperlipidemia. In some cases, increased levels of lysophospholipids are hypothesized to result from a dysfunction of lysophospholipids-regulating enzymes including lysophospholipases, which act on biologic membranes to regulate the level of lysophospholipids by hydrolysis. Thus, this gene product may be useful in the tieatment of diseases associated with increased lysophospholipids.

This gene also shows high expression in the brain. Lysophospholipases are critical enzymes that regulate brain membrane phospholipids. Alterations in their activity have been associated with a host of neurological disorders, including schizophrenia, Parkinson's disease, and

Alzheimer's disease. Thus, therapeutic modulation ofthe expression or function of this gene or gene product may be useful in the treatment of these diseases. Please note that results from a third experiment with the probe/primer set Agl 952 are not included. The amp plot indicates that there were experimental difficulties with this run. References:

1. Capito K, Reinsmark R, Thams P. Mechanism of fat-induced attenuation of glucose- induced insulin secretion from mouse pancreatic islets. Acta Diabetol 1999 Dec;36(3): 119-25

2. Ross BM, Turenne S, Moszczynska A, Warsh JJ, Kish SJ.Differential alteration of phospholipase A2 activities in brain of patients with schizophrenia. Brain Res 1999 Mar 13;821(2):407-13

3. Ross BM, Moszczynska A, Erlich J, Kish SJ. Low activity of key phospholipid catabolic and anabolic enzymes in human substantia nigra: possible implications for Parkinson's disease. Neuroscience 1998 Apr; 83 (3): 791-8

4. Ross BM, Moszczynska A, Erlich J, Kish SJ.Phospholipid-metabolizing enzymes in Alzheimer's disease: increased lysophospholipid acyltiansferase activity and decreased phospholipase A2 activity. JNeurochem 1998 Feb;70(2):786-93

Panel 4D Summary: Agl906/Agl952/Ag2042 The expression of CG56162-02 gene was assessed in three independent runs using three different probe/primer pairs, with good concordance between the runs. This gene is expressed at moderate levels in a wide variety of cells including resting macrophages, TNF-alpha-activated dermal fibroblasts, LPS-stimulated dendritic cells, TNF-alpha+IL-1 -beta-activated pulmonary artery endothelial cells, TNF- alpha+IL-1 -beta-activated lung microvascular cells, and TNF-alpha+IFN-gamma-activated umbilical vein endothelial cells (CTs=27-28). Thus, antibodies and small molecules that antagonize the function ofthe CG120803-01 geen product may be useful to reduce or eliminate the symptoms in patients with inflammatory and autoimmune diseases, such as lupus erythernatosus, asthma, emphysema, Crohn's disease, ulcerative colitis, multiple sclerosis, rheumatoid arthritis, osteoarthritis, and psoriasis. AJ. NOV45a and NOV45b (CG59859-01 and CG59859-02: Testis expressed protein 261 (TEG-261) )

Expression of genes CG59859-01 and CG59859-02 was assessed using the primer-probe set Ag3623, described in Table AJA. Results of the RTQ-PCR runs are shown in Tables AJB, AJC and AJD. Please note that CG59859-02 represents a full-length physical clone of the CG59859-01 gene, validating the prediction ofthe gene sequence.

Table AJA. Probe Name Ag3623

Table AJB. CNS_neurodegeneration_vl .0

Table AJC. General_screening_panel_vl.4

Table AID. Panel 4. ID

CNS_neurodegeneration_vl.O Summary: Ag3623 This panel confirms the expression of the CG59859-01 gene at low levels in the brains of an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of central nervous system disorders.

General_screening_panel_vl.4 Summary: Ag3623 Highest expression ofthe CG59859-01 gene is detected in samples derived from gastric cancer KATO III cell line (CT=25). Furthermore, high expression of this gene is seen in samples derived from CNS cancer, colon cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer and melanoma cells. Therefore, expression of this gene can be used to distinguish these samples from other samples in the panel and also as a marker in detection of these cancers. In addition, therapeutic modulation ofthe activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the tieatment of these cancers.

Among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes. Panel 4.1D Summary: Ag3623 Highest expression ofthe CG59859-01 gene is detected in activated secondary Th2 cells (CT=28.8). In high expression of this gene is seen in activated primary and secondary - Thl, Th2 and Trl cells (CTs=29) as compared to corresponding resting cells (CTs=30-31). Therefore expression of this gene can be used to distinguish between these activated versus resting cells.

Also, this gene is expressed at high to moderate levels in a wide range of cell types of significance in the immune response in health and disease. These cells include members of the T-cell, B-cell, endothelial cell, macrophage/monocyte, and peripheral blood mononuclear cell family, as well as epithelial and fibroblast cell types from lung and skin, and normal tissues represented by colon, lung, thymus and kidney. This ubiquitous pattern of expression suggests that this gene product may be involved in homeostatic processes for these and other cell types and tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl .4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation ofthe gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement ofthe symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

Interestingly, expression of this gene is stimulated in PWM/PHA-L treated PBMC cells and PMA/ionomycin tieated KU-812 cells (basophils) (CTs=29) as compared to the corresponding untreated/resting cells (CTs=31). Therefore, expression of this gene can be used to distinguish these treated versus untreated cells. In addition, antibody or small molecule therapies designed with the protein encoded for by this gene could block or inhibit inflammation or tissue damage due to basophil activation or PBMC activation in response to systemic lupus erythematosus, Crohn's disease, ulcerative colitis, multiple sclerosis, chronic obstructive pulmonary disease, asthma, emphysema, rheumatoid arthritis, allergies, hypersensitivity reactions, psoriasis, and viral infections.

AK. NOV46a (CG59913-01: ATP-BINDING CASSETTE TRANSPORTER ) Expression of gene CG59913-01 was assessed using the primer-probe set Ag3631 , described in Table AKA. Results ofthe RTQ-PCR runs are shown in Tables AKB, AKC and AKD.

Table AKA. Probe Name Ag3631

Table AKB. CNS_neurodegeneration_vl.O

Table AKC. General_screening_panel_vl .4

Tissue Name Rel. Exp.(%) Ag3631, Tissue Name |Rel. Exp.(%) Ag3631,

Table AKD. Panel 4. ID

CNS_neurodegeneration_vl.O Summary: Ag3631 This panel confirms the expression of the CG59913-01 gene at low levels in the brain in an independent group of individuals. However, no differential expression of this gene was detected between Alzheimer's diseased postmortem brains and those of non-demented controls in this experiment. Please see Panel 1.4 for a discussion of the potential utility of this gene in treatment of cential nervous system disorders.

General_screening_panel_vl.4 Summary: Ag3631 The expression ofthe CG59913-01 is highest in sample derived from kidney (CT=28.23). Furhtermore, expression of this gene is very low in fetal kidney (CT=33). Thus, expression of this gene can be used in distinguishing the adult kidney from fetal kidney and also from other samples in this panel.

Among tissues with metabolic or endocrine function, this gene is expressed at low to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, fetal liver and the gastrointestinal tiact. Therefore, therapeutic modulation ofthe activity of this gene may prove useful in the tieatment of endocrine/metabolically related diseases, such as obesity and diabetes.

CG59913-01 gene codes for a variant of ATP-binding casette A9 protein, an ATP-binding cassette (ABC) transporter belonging to ABCA sub-family. The ABC superfamily comprises of myriad transmembrane proteins involved in the transport of vitamins, peptides, steroid hormones, ions, sugars, and amino acids (ref. 1). Known genetic diseases resulting from dysfunctional ABC transporters are cystic fibrosis, Zellweger syndrome, adrenoleukodystiophy, multidrug resistance, Stargardt macular dystrophy, Tangier disease (TD) and familial HDL deficiency (FHA) (ref. 2, 3). Recently, it has been shown that functional loss of ABCA1, a transporter belonging to ABCA subfamily, in mice causes severe placental malformation, aberrant lipid distribution, and kidney glomerulonephritis, as well as, high-density lipoprotein cholesterol deficiency (ref 3). CG59913-01 gene is expressed in large number ofthe normal tissue used in this panel. In analogy to ABCAl, this gene may also play a wider role in lipid metabolism, renal inflammation, and cardiovascular disease and CNS disorders.

Refrences. 1. Higgins CF. (1992) ABC transporters: from microorganisms to man. Annu Rev Cell Biol 8:67-113

PMID: 1282354

2. Decottignies A, Goffeau A. (1997) Complete inventory ofthe yeast ABC proteins. Nat Genet 15(2): 137-45. The complete sequence ofthe yeast genome predicts the existence of 29 proteins belonging to the ubiquitous ATP-binding cassette (ABC) superfamily. Using binary comparison, phylogenetic classification and detection of conserved amino acid residues, the yeast ABC proteins have been classified in a total of six clusters, including ten subclusters of distinct predicted topology and presumed distinct function. Study ofthe yeast ABC proteins provides insight into the physiological function and biochemical mechanisms of their human homologues, such as those involved in cystic fibrosis, adrenoleukodystiophy, Zellweger syndrome, multidrug resistance and the antiviral activity of interferons.

P D: 9020838

3. Christiansen-Weber TA, Voland JR, Wu Y, Ngo K, Roland BL, Nguyen S, Peterson PA, Fung-Leung WP.(2000) Functional loss of ABCAl in mice causes severe placental malformation, aberrant lipid distribution, and kidney glomerulonephritis as well as high- density lipoprotein cholesterol deficiency. Am J Pathol 2000 Sep;157(3):1017-29

Tangier disease (TD) and familial HDL deficiency (FHA) have recently been linked to mutations in the human ATP-binding cassette transporter 1 (hABCAl), a member ofthe ABC superfamily. Both diseases are characterized by the lowering or lack of high-density lipoprotein cholesterol (HDL-C) and low serum cholesterol. The murine ABCAl -/- phenotype corroborates the human TD linkage to ABCAl . Similar to TD in humans, HDL-C is virtually absent in ABCAl-/- mice accompanied by a reduction in serum cholesterol and lipid deposition in various tissues. In addition, the placenta of ABCAl-/- mice is malformed, resulting in severe embryo growth retardation, fetal loss, and neonatal death. The basis for these defects appears to be altered steroidogenesis, a direct result ofthe lack of HDL-C. By 6 months of age, ABCAl-/- animals develop membranoproliferative glomerulonephritis due to deposition of immunocomplexes followed by cardiomegaly with ventricular dilation and hypertrophy, ultimately succumbing to congestive heart failure. This murine model of TD will be very useful in the study of lipid metabolism, renal inflammation, and cardiovascular disease and may reveal previously unsuspected relationships between them. PMID: 10980140

Panel 4.1D Summary: Ag3631 The expression ofthe CG59913-01 gene is high in sample derived from HPAEC and coronary artery SMC cell lines(CTs=30). Thus, expression of this gene can be used to distinguish these samples from other samples in this panel. Interestingly, expression of this gene is stimulated on treatment of dermal fibroblast and

HUVEC cells with IFN gama (CTs=31-32). Therefore, therapeutics designed with the protein encoded for by this transcript could be important treating diseases such as asthma, arthritis, psoriasis, IBD, and systemic lupus erythematosus.

Significant expression of this gene is also detected in a liver cirrhosis sample (CT = 32). Furthermore, expression of this gene is low/undetectable in normal liver (CT=35)in Panel 1.4, suggesting that its expression is unique to liver cirrhosis. Therefore, antibodies or small molecule therapeutics could reduce or inhibit fibrosis that occurs in liver cirrhosis.

This gene is expressed at moderate levels in the normal colon, lung, thymus and kidney tissues (CTs=32-33). This ubiquitous pattern of expression in normal tissues suggests that this gene product may be involved in homeostatic processes for these tissues. This pattern is in agreement with the expression profile in General_screening_panel_vl.4 and also suggests a role for the gene product in cell survival and proliferation. Therefore, modulation ofthe gene product with a functional therapeutic may lead to the alteration of functions associated with these cell types and lead to improvement ofthe symptoms of patients suffering from autoimmune and inflammatory diseases such as asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, rheumatoid arthritis, and osteoarthritis.

AL. NOV47a (CG59909-01: ATP-BINDING CASSETTE TRANSPORTER )

Expression of gene CG59909-01 was assessed using the primer-probe set Ag3630, described in Table ALA. Results ofthe RTQ-PCR runs are shown in Tables ALB, ALC and ALD.

Table ALA. Probe Name Ag3630

Table ALB. CNS_neurodegeneration_vl.O

Table ALC. General_screening_panel_ l.4

Table ALP. Panel 4. ID

CNS_neurodegeneration_vl.O Summary: Ag3630 Two experiments with the same probe and primer set produce results that are in excellent agreement. This panel confirms the expression of this gene at low to moderate levels in the brains of an independent group of individuals. Expression of this gene is found to be up-regulated in the temporal cortex of Alzheimer's disease patients. Therefore, blockade of this protein product may be of use in reversing the dementia/memory loss associated with Alzheimer's disease and neuronal death.

General_screening_panel_vl.4 Summary: Ag3630 The CG59909-01 gene is expressed primarily in normal tissue samples, with highest expression in the fetal lung (CT=26.3).

This gene has low-to-moderate expression in adipose, liver, heart, skeletal muscle, adrenal, pituitary and pancreas. By homology, this gene product is a lipid or cholesterol transporter and can be expected to play a critical role in metabolic processes. Therapeutic modulation of ag3630 may be a treatment for endocrine or metabolic disease, including Types 1 and 2 diabetes and obesity.

Interestingly, this gene is expressed at much higher levels in fetal (CT=26.3) when compared to adult liver (CT=30.5). This observation suggests that expression of this gene can be used to distinguish fetal from adult liver.

Panel 4.1D Summary: Ag3630 Highest expression ofthe CG59909-01 gene is detected in TNF alpha + IL-1 beta treated HPAEC (CT=28.5). In addition, this gene is expressed in endothelium, smooth muscle cells and fibroblasts. It is also expressed in normal kidney, lung, colon, and thymus. The transcript was particularly induced by gamma interferon in HUVEC cells. HUVEC cells have been used in many in vitro models to examine leukocyte extiavsation. Gamma interferon treatment induces the expression many proteins in HUVEC cells that induce leukocyte rolling and binding, necessary steps in the movement of leukocytes from the blood into the periphery. The putative transporter encoded for by this tianscript could be important in endothelium mediated leukocyte recruitment and thus be an important target for the treatment of inflammation associated with asthma, emphysema, psoriasis, and arthritis.

Reference.

1. Lidington EA, Moyes DL, McCormack AM, Rose ML. (1999) A comparison of primary endothelial cells and endothelial cell lines for studies of immune interactions. Transpl Immunol 1999 Dec;7(4):239-46

AM. NOV48a (CG59945-01: STERODD HORMONE RECEPTOR )

Expression of gene CG59945-01 was assessed using the primer-probe sets Ag3632 and ag3666, described in Tables AMA and AMB. Results ofthe RTQ-PCR runs are shown in Tables AMC, and AMD. Table AMA. Probe Name Ag3632

Table AMB. Probe Name ag3666

Table AMC. CNS_neurodegeneration_vl .0

Table AMD. General_screening_panel_vl .4

CNS_neurodegeneration_vl.0 Summary: Ag3632 This panel confirms the expression of The CG59945-01 gene at significant levels in the brain in an independent group of individuals. This gene is found to be upregulated in the temporal cortex of Alzheimer's disease patients. Blockade of this receptor may be of use in the treatment of this disease and decrease neuronal death.

The CG59945-01 gene, a steroid hormone receptor homolog. Steroid hormones play a role in brain development and modulating emotion, among other functions. Based on the expression of this gene in the brain and its homology to a steroid hormone receptor, this gene product may play a role in normal neurologic development and function.

Ag3666 Results from one experiment with this gene are not included. The amp plot indicates that there were experimental difficulties with this run.

References:

1. Kawata M, Matsuda K, Nishi M, Ogawa H, Ochiai I. Intracellular dynamics of steroid hormone receptor. Neurosci Res 2001 Jul;40(3): 197-203

General_screening_panel_ l.4 Summary: Ag3632 Expression ofthe CG59945-01 gene is restricted to the testis (CT=33.9). Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel and as a marker of testicular tissue. Furthermore, therapeutic modulation ofthe expression or function of this gene may be useful in the treatment of male infertility or hypogonadism.

General_screening_panel_vl.5 Summary: Ag3666 Expression ofthe CG59945-01 gene is low/undetectable in all samples on this panel (CTs>35).

Panel 4.1D Summary: Ag3632/Ag3666 Expression ofthe CG59945-01 gene is low/undetectable in all samples on this panel (CTs>35). Panel CNS_1 Summary: Ag3666 Expression ofthe CG59945-01 gene is low/undetectable in all samples on this panel (CTs>35). Example D: Identification of Single Nucleotide Polymorphisms in NOVX nucleic acid sequences

Variant sequences are also included in this application. A variant sequence can include a single nucleotide polymorphism (SNP). A SNP can, in some instances, be referred to as a "cSNP" to denote that the nucleotide sequence containing the SNP originates as a cDNA. A SNP can arise in several ways. For example, a SNP may be due to a substitution of one nucleotide for another at the polymorphic site. Such a substitution can be either a transition or a tiansversion. A SNP can also arise from a deletion of a nucleotide or an insertion of a nucleotide, relative to a reference allele. In this case, the polymorphic site is a site at which one allele bears a gap with respect to a particular nucleotide in another allele. SNPs occurring within genes may result in an alteration ofthe amino acid encoded by the gene at the position ofthe SNP. Intiagenic SNPs may also be silent, when a codon including a SNP encodes the same amino acid as a result ofthe redundancy ofthe genetic code. SNPs occurring outside the region of a gene, or in an intron within a gene, do not result in changes in any amino acid sequence of a protein but may result in altered regulation ofthe expression pattern. Examples include alteration in temporal expression, physiological response regulation, cell type expression regulation, intensity of expression, and stability of transcribed message. SeqCalling assemblies produced by the exon linking process were selected and extended using the following criteria. Genomic clones having regions with 98% identity to all or part ofthe initial or extended sequence were identified by BLASTN searches using the relevant sequence to query human genomic databases. The genomic clones that resulted were selected for further analysis because this identity indicates that these clones contain the genomic locus for these SeqCalling assemblies. These sequences were analyzed for putative coding regions as well as for similarity to the known DNA and protein sequences. Programs used for these analyses include Grail, Genscan, BLAST, HMMER, FASTA, Hybrid and other relevant programs.

Some additional genomic regions may have also been identified because selected SeqCalling assemblies map to those regions. Such SeqCalling sequences may have overlapped with regions defined by homology or exon prediction. They may also be included because the location ofthe fragment was in the vicinity of genomic regions identified by similarity or exon prediction that had been included in the original predicted sequence. The sequence so identified was manually assembled and then may have been extended using one or more additional sequences taken from CuraGen Corporation's human SeqCalling database. SeqCalling fragments suitable for inclusion were identified by the CuraTools™ program SeqExtend or by identifying SeqCalling fragments mapping to the appropriate regions ofthe genomic clones analyzed.

The regions defined by the procedures described above were then manually integrated and corrected for apparent inconsistencies that may have arisen, for example, from miscalled bases in the original fragments or from discrepancies between predicted exon junctions, EST locations and regions of sequence similarity, to derive the final sequence disclosed herein. When necessary, the process to identify and analyze SeqCalling assemblies and genomic clones was reiterated to derive the full length sequence (Alderborn et al., Determination of Single Nucleotide Polymorphisms by Real-time Pyrophosphate DNA Sequencing. Genome Research. 10 (8) 1249-1265, 2000).

Variants are reported individually but any combination of all or a select subset of variants are also included as contemplated NOVX embodiments ofthe invention.

RESULTS:

NOV2a SNP Data

One polymorphic variant of NOV2a has been identified and is shown in Table 3 A.

NOV4a SNP Data

Four polymorphic variants of NOV4a have been identified and are shown in Table

3B.

Table 3B

Variant Nucleotides Amino Acids

NOV5a SNP Data

Four polymorphic variants of NOV5a have been identified and are shown in Table C.

NOV7a SNP Data

Two polymorphic variants of NOV7a have been identified and are shown in Table D.

NOVlOa SNP Data Two polymoφhic variants of NOVlOa have been identified and are shown in Table E.

NOVlla SNP Data Seven polymoφhic variants of NOVl la have been identified and are shown in Table F.

NOV15a SNP Data

One polymoφhic variant of NOVl 5a has been identified and is shown in Table 3G.

NOV19a SNP Data

Two polymoφhic variants of NOVl 9a has been identified and are shown in Table H.

NOV21a SNP Data

One polymoφhic variant of NO V2 la has been identified and is shown in Table 31.

NO 23a SNP Data

Eight polymoφhic variants of NOV23a have been identified and are shown in Table J.

NOV24a SNP Data

Six polymoφhic variants of NOV24a have been identified and are shown in Table K.

NOV25a SNP Data

Eight polymoφhic variants of NOV25a have been identified and are shown in Table L.

NOV27a SNP Data

Three polymoφhic variants of NOV27a have been identified and are shown in Table M.

NOV29a SNP Data

Three polymoφhic variants of NOV29a have been identified and are shown in Table N.

NOV 30a SNP Data

Six polymoφhic variants of NOV30a have been identified and are shown in Table

3O.

NOV31a SNP Data

Fifteen polymoφhic variants of NO V3 la have been identified and are shown in Table 3P.

NOV33a SNP Data

Two polymoφhic variants of NO V33a have been identified and are shown in Table 3Q.

NOV36a SNP Data Three polymoφhic variants of NO V36a have been identified and are reported in

Table 3R.

NOV37a SNP Data

Two polymoφhic variants of NO V37a have been identified and are reported in Table S.

NOV39a SNP Data

Two polymoφhic variants of NO V39a have been identified and are shown in Table T.

NO 40a SNP Data

One polymoφhic variant of NOV40a has been identified and is shown in Table 3U.

NOV42a SNP Data

One polymoφhic variant of NOV42a has been identified and is shown in Table 3N.

NON43a SΝP Data

One polymoφhic variant of ΝOV43a has been identified and is shown in Table 3W.

NOV44a SNP Data

Four polymoφhic variants of NOV44a have been identified and are shown in Table X.

NOV45a SNP Data

One polymoφhic variant of NOV45a has been identified and is shown in Table 3Y.

OTHER EMBODIMENTS

Although particular embodiments have been disclosed herein in detail, this has been done by way of example for puφoses of illustration only, and is not intended to be limiting with respect to the scope ofthe appended claims, which follow. In particular, it is contemplated by the inventors that various substitutions, alterations, and modifications may be made to the invention without departing from the spirit and scope ofthe invention as defined by the claims. The choice of nucleic acid starting material, clone of interest, or library type is believed to be a matter of routine for a person of ordinary skill in the art with knowledge of the embodiments described herein. The claims presented are representative ofthe inventions disclosed herein. Other, unclaimed inventions are also contemplated. Applicants reserve the right to pursue such inventions in later claims.

We claim:

Claims

1. An isolated polypeptide comprising an amino acid sequence selected from the group consisting of: a) a mature form ofthe amino acid sequence selected from the group consisting of SEQ ID NO:2«, wherein n is an integer between 1-101; b) a variant of a mature form ofthe amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1-101, wherein any amino acid in the mature form is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed; c) the amino acid sequence selected from the group consisting of SEQ ID NO:2«, wherein n is an integer between 1-101; d) a variant ofthe amino acid sequence selected from the group consisting of SEQ ID NO :2n, wherein n is an integer between 1-101, wherein any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% ofthe amino acid residues in the sequence are so changed; and e) a fragment of any of a) through d).

2. The polypeptide of claim 1 that is a naturally occurring allelic variant ofthe sequence selected from the group consisting of SEQ ID NO:2?t, wherein n is an integer between 1-101.

3. The polypeptide of claim 2, wherein said allelic variant comprises an amino acid sequence that is the translation of a nucleic acid sequence differing by a single nucleotide from a nucleic acid sequence selected from the group consisting of SEQ ID NO:2n-l, wherein n is an integer between 1-101.

4. The polypeptide of claim 1 that is a variant polypeptide described therein, wherein any amino acid specified in the chosen sequence is changed to provide a conservative substitution.

5. A pharmaceutical composition comprising the polypeptide of claim 1 and a pharmaceutically acceptable carrier.

6. A kit comprising in one or more containers, the pharmaceutical composition of claim 5.

7. The use of a therapeutic in the manufacture of a medicament for treating a syndrome associated with a human disease, the disease selected from a pathology associated with the polypeptide of claim 1, wherein said therapeutic is the polypeptide of claim 1.

8. A method for determining the presence or amount of the polypeptide of claim 1 in a sample, the method comprising:

(a) providing said sample; (b) introducing said sample to an antibody that binds immunospecifically to the polypeptide; and (c) determining the presence or amount of antibody bound to said polypeptide, thereby determining the presence or amount of polypeptide in said sample.

9. A method for determining the presence of or predisposition to a disease associated with altered levels ofthe polypeptide of claim 1 in a first mammalian subject, the method comprising: a) measuring the level of expression ofthe polypeptide in a sample from the first mammalian subject; and b) comparing the amount of said polypeptide in the sample of step (a) to the amount ofthe polypeptide present in a control sample from a second mammalian subject known not to have, or not to be predisposed to, said disease, wherein an alteration in the expression level ofthe polypeptide in the first subject as compared to the control sample indicates the presence of or predisposition to said disease.

10. A method for modulating the activity ofthe polypeptide of claim 1, the method comprising introducing a cell sample expressing the polypeptide of said claim with an antibody that binds to said polypeptide in an amount sufficient to modulate the activity ofthe polypeptide.

11. The method of claim 10, wherein said subject is a human.

12. An isolated nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of: a) a mature form ofthe amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1-101; b) a variant of a mature form ofthe amino acid sequence selected from the group consisting of SEQ ID NO:2H, wherein n is an integer between 1-101, wherein any amino acid in the mature form ofthe chosen sequence is changed to a different amino acid, provided that no more than 15% ofthe amino acid residues in the sequence ofthe mature form are so changed; c) the amino acid sequence selected from the group consisting of SEQ ID NO:2«, wherein n is an integer between 1-101; d) a variant ofthe amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1-101, in which any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% ofthe amino acid residues in the sequence are so changed; e) a nucleic acid fragment encoding at least a portion of a polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO:2«, wherein n is an integer between 1-101, or any variant of said polypeptide wherein any amino acid ofthe chosen sequence is changed to a different amino acid, provided that no more than 10% ofthe amino acid residues in the sequence are so changed; and f) the complement of any of said nucleic acid molecules.

13. The nucleic acid molecule of claim 12, wherein the nucleic acid molecule comprises the nucleotide sequence of a naturally occurring allelic nucleic acid variant.

14. The nucleic acid molecule of claim 12 that encodes a variant polypeptide, wherein the variant polypeptide has the polypeptide sequence of a naturally occurring polypeptide variant.

15. The nucleic acid molecule of claim 12, wherein the nucleic acid molecule differs by a single nucleotide from a nucleic acid sequence selected from the group consisting of SEQ ID NO:2«-l, wherein n is an integer between 1-101.

16. The nucleic acid molecule of claim 12, wherein said nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of a) the nucleotide sequence selected from the group consisting of SEQ ID NO:2«- 1, wherein n is an integer between 1-101; b) a nucleotide sequence wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO:2«-l, wherein n is an integer between 1 - 101 , is changed from that selected from the group consisting ofthe chosen sequence to a different nucleotide provided that no more than 15% ofthe nucleotides are so changed; c) a nucleic acid fragment ofthe sequence selected from the group consisting of SEQ ID NO:2n-l, wherein n is an integer between 1-101; and d) a nucleic acid fragment wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO:2«-l, wherein n is an integer between 1-101, is changed from that selected from the group consisting ofthe chosen sequence to a different nucleotide provided that no more than 15% ofthe nucleotides are so changed.

17. The nucleic acid molecule of claim 12, wherein said nucleic acid molecule hybridizes under stringent conditions to the nucleotide sequence selected from the group consisting of SEQ ID NO:2n-l, wherein n is an integer between 1-101, or a complement of said nucleotide sequence.

18. The nucleic acid molecule of claim 12, wherein the nucleic acid molecule comprises a nucleotide sequence in which any nucleotide specified in the coding sequence ofthe chosen nucleotide sequence is changed from that selected from the group consisting ofthe chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides in the chosen coding sequence are so changed, an isolated second polynucleotide that is a complement ofthe first polynucleotide, or a fragment of any of them.

19. A vector comprising the nucleic acid molecule of claim 12.

20. The vector of claim 19, further comprising a promoter operably linked to said nucleic acid molecule.

21. A cell comprising the vector of claim 20.

22. A method for determining the presence or amount ofthe nucleic acid molecule of claim 12 in a sample, the method comprising: (a) providing said sample; (b) introducing said sample to a probe that binds to said nucleic acid molecule; and

(c) determining the presence or amount of said probe bound to said nucleic acid molecule, thereby determining the presence or amount ofthe nucleic acid molecule in said sample.

23. The method of claim 22 wherein presence or amount of the nucleic acid molecule is used as a marker for cell or tissue type.

24. The method of claim 23 wherein the cell or tissue type is cancerous.

25. A method for determining the presence of or predisposition to a disease associated with altered levels ofthe nucleic acid molecule of claim 12 in a first mammalian subject, the method comprising: a) measuring the amount ofthe nucleic acid in a sample from the first mammalian subject; and b) comparing the amount of said nucleic acid in the sample of step (a) to the amount ofthe nucleic acid present in a control sample from a second mammalian subject known not to have or not be predisposed to, the disease; wherein an alteration in the level ofthe nucleic acid in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.

26. An antibody that binds immunospecifically to the polypeptide of claim 1.

5

27. The antibody of claim 26, wherein said antibody is a monoclonal antibody.

28. The antibody of claim 26, wherein the antibody is a humanized antibody.

10 29. The antibody of claim 26, wherein the antibody is a fully human antibody

30. The antibody of claim 26, wherein the dissociation constant for the binding ofthe polypeptide to the antibody is less than 1 x 10^"9 M.

15 31. The antibody of claim 26, wherein the antibody neutralizes an activity of the polypeptide.

32. A pharmaceutical composition comprising the antibody of claim 26 and a pharmaceutically acceptable carrier.

20

33. A kit comprising in one or more containers, the pharmaceutical composition of claim 29.

34. The use of a therapeutic in the manufacture of a medicament for treating a syndrome 25 associated with a human disease, the disease selected from a pathology associated with the polypeptide of claim 1, wherein said therapeutic is a NOVX antibody.

35. A method of treating or preventing a NOVX-associated disorder, said method comprising admimstering to a subject in which such tieatmnet or prevention is desired

30 the antibody of claim 26 in an amount sufficient to treat or prevent said NONx- associated disorder in said subject.

36. A method of treating a pathological state in a mammal, the method comprising administering to the mammal the antibody of claim 26 in an amount sufficient to alleviate the pathological state.

37. A method of treating or preventing a pathology associated with the polypeptide of claim 1, said method comprising administering to a subject in which such treatment or prevention is desired a NOVX antibody in an amount sufficient to treat or prevent said pathology in said subject.

38. The method of claim 37, wherein the subj ect is a human.