US 20060099578A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0099578 A1 Wallace et al. (43) Pub. Date: May 11, 2006

(54) MITOCHONDRIAL BIOLOGY EXPRESSION Publication Classification ARRAYS (51) Int. Cl. CI2O I/68 (2006.01) (76) Inventors: Douglas C Wallace, Irvine, CA (US); CI2M I/34 (2006.01) Shawn Levy, Brentwood, TN (US); (52) U.S. Cl...... 435/6: 435/287.2 Keith Kerstann, Atlanta, GA (US); (57) ABSTRACT Vincent Procaccio, Irvine, CA (US) This invention provides a library of involved in mitochondrial biology, arrays containing probes for genes Correspondence Address: involved in mitochondrial biology, methods for making Such GREENLEE WINNER AND SULLIVAN PC arrays, and methods of using Such arrays. Genes and probe 4875 PEARL EAST CIRCLE sequences involved in mitochondrial biology in humans and SUTE 200 mice are provided. The arrays of this invention are useful for determining mitochondrial biology expression profiles. BOULDER, CO 80301 (US) Mitochondrial biology profiles are useful for determining expression profiles diagnostic of physiologi cal conditions; diagnosing physiological conditions; identi (21) Appl. No.: 10/488,619 fying biochemical pathways, genes, and mutations involved (22) PCT Filed: Aug. 30, 2002 in physiological conditions; identify therapeutic agents use ful for preventing and/or treating such physiological condi (86). PCT No.: PCT/USO2/27886 tions; evaluating and/or monitoring the efficacy of Such therapies, and creating and identifying animal models of (30) Foreign Application Priority Data human physiologic conditions. Arrays containing probes for all genes known to be involved in mitochondrial biology are

Aug. 30, 2001 (US). 6031 6323 provided, as well as arrays containing Subsets of Such Aug. 31, 2001 (CA)...... 2356540 probes. Patent Application Publication May 11, 2006 Sheet 1 of 4 US 2006/0099578A1

Patent Application Publication May 11, 2006 Sheet 2 of 4 US 2006/0099578A1

s

Patent Application Publication May 11, 2006 Sheet 4 of 4 US 2006/0099578 A1

(V

N 2 -O

S. N. F. qeeo y X

1Hi

C-Uee 5-2-1-z el-OJuoo-uON US 2006/0099578 A1 May 11, 2006

MTOCHONORAL BIOLOGY EXPRESSION U.S.A. 91:8334-8338). The creation of cybrid cell lines with ARRAYS identical nuclear backgrounds but different mtDNA geno types allows the comparison of one mtDNA mutant to CROSS-REFERENCE TO RELATED another without the potential interference of nuclear genome APPLICATIONS polymorphisms. These cybrid lines have generally been 0001. This application claims priority to U.S. Patent analyzed using biochemical techniques such as assaying Application Ser. No. 60/316.323 filed Aug. 30, 2001, and to cellular respiration or respiratory complex specific activities Canadian Patent Application Serial No. 2.356,540 filed Aug. by enzymology. Some gene expression studies have been 31, 2001, both of which is hereby incorporated in their performed, but they have generally been done on single or entirety by reference to the extent not inconsistent with the small groups of genes (Heddi, A. et al., “Mitochondrial DNA disclosure herein. expression in mitochondrial myopathies and coordinated expression of nuclear genes involved in ATP 1993 J. BACKGROUND OF THE INVENTION Biological Chemistry 268:12156-12163; Heddi, A. et al., "Coordinate induction of energy gene expression in tissues 0002 Mitochondrial disorders are a complex and poly of mitochondrial disease patients' 1999 J Biol Chem genic group of conditions with the patient’s symptoms 274:22968-76). varying due to differences in energetic threshold effect of various tissues and the stochastic nature of mtDNA segre 0004 Gene expression has been extensively studied. gation. Consequently, most mitochondrial disorders are best Although the regulation of mRNA abundance by changes in classified by their genetic cause rather than a biochemical or transcription or RNA degradation is by no means the only phenotypic profile (Shoffner, J. M., and Wallace, D. C., mechanism that regulates levels in a cell, virtually all (1995) “Oxidative phosphorylation diseases.” In The Meta differences in cell type or state can be correlated to changes bolic and Molecular Basis of Inherited Disease, C. R. in the mRNA abundance of several genes (Alizadeh, A. A. Scriver, A. L. Beaudet, W. S. Sly and D. Valle, eds. (New et al., “Distinct types of diffuse large B-cell lymphoma York: McGraw-Hill), pp. 1535-1609; Wallace, D.C., (1999) identified by gene expression profiling.”2000 Nature "Mitochondrial diseases in man and mouse''Science 403:503-11; DeRisi, J. L. et al., “Exploring the metabolic 283: 1482-1488). Many mitochondrial diseases result from and genetic control of gene expression on a genomic scale, mutations in nuclear genes and a Subset of these are known 1997 Science 278:680-686: Schena, M. et al., “Quantita to act by destabilizing the mitochondrial genome. (Graham, tive monitoring of gene expression patterns with a comple B. et al., “A mouse model for mitochondrial myopathy and mentary DNA microarray'1995 Science 270:467-70; cardiomyopathy resulting from a deficiency in the heart/ Schena, M. et al., “Parallel analysis: isoform of the adenine nucleotide translo microarray-based expression monitoring of 1000 genes' cator,1997 Nature Genetics 16:226-234; Shoffner, J. M., 1996 Proc Natl AcadSci USA 93:10614-9; Wallace D.C., and Wallace, D. C., “Oxidative phosphorylation diseases. grant abstract #2R01N502328-18; Kerstann, K. W. 2000 Disorders of two genomes, 1990 Advances in Human American Society for Human Genetics Abstract #1484; Genetics 19:267-330; Zhu, Z. et al., “SURF1, encoding a Kokoszka, J. E. 2000 American Society of Human Genetics factor involved in the biogenesis of cytochrome c oxidase, Abstract #1618: Levy, S. E. 2001 American Society of is mutated in Leigh's syndrome”1998 Nature Genetics Human Genetics Abstract #1501; Levy, S. E. 2000"Ge 20:33743). netic Alteration of the Mouse Mitochondrial Genome and Effects on Gene Expression.” Ph.D. Thesis, Emory Univer 0003. The analysis of mitochondrial function in cultured sity; Coskun, P. E. 2000 American Society of Human cells using somatic cell genetics has been instrumental in the Genetics Abstract #1616; Sligh, J. E. 2000 American characterization of human mitochondrial disorders. Society for Human Genetics Abstract #53; Murdock, D. G. Ethidium bromide and R-6G treatment have been used to 2000 American Society for Human Genetics Abstract #55; create p0 and mitochondria-less cell lines to analyze the Levy S. E. 2000 Keystone Symposia Abstract 119: Wal maternal inheritance and biochemical phenotypes of many lace, D. C., Ellison Medical Foundation, Senior Scholar human mtDNA mutations (Chomyn, A. et al., “In vitro Award in Aging). genetic transfer of protein synthesis and respiration defects to mitochondrial DNA-less cells with myopathy-patient 0005) DNA microarray analysis has been used to study mitochondria, 1991 Molecular and Cellular Biology diffuse large B-cell lymphoma (DLBCL) where microarrays 11:2236-2244; Jun, A. S. et al., “Use of transrnitochondrial were used to expand the diagnosis of DLBCL (Alizadeh, A. cybrids to assign a complex I defect to the mitochondrial A. et al., “Distinct types of diffuse large B-cell lymphoma DNA-encoded NADH dehydrogenase subunit 6 gene muta identified by gene expression profiling.”2000 Nature tion at nucleotide pair 14459 that causes Leber hereditary 403:503-11). While standard histological and morphological optic neuropathy and dystonia, 1996 Molecular and Cel techniques had defined subsets of DLBCL, array analysis lular Biology 16:771-777: King, M. P. et al., “Defects in revealed two clinically distinct classes. These two newly mitochondrial protein synthesis and respiratory chain activ discovered classes were indistinguishable by standard ity segregate with the tRNA Leu(UUR) mutation associated pathology, but expression analysis showed a differential with mitochondrial myopathy, encephalopathy, lactic acido expression of hundreds of genes. Correlation of these sis, and stroke-like episodes, 1992 Molecular and Cellu molecular differences with differences in the progression of lar Biology 12:480490; Trounce, I. et al., “Cytoplasmic the disease and clinical outcome has revealed that these two transfer of the mtDNA nt 8993 TG ATP6 point mutation classes of DLBCL could be considered separate diseases associated with Leigh's syndrome into mtDNA-less cells (Alizadeh, A. A. et al., “Distinct types of diffuse large B-cell demonstrates cosegregation with a decrease in state III lymphoma identified by gene expression profiling.”2000 respiration and ADP/O ratio, 1994 Proc. Natl. Acad. Sci. Nature 403:503-11). US 2006/0099578 A1 May 11, 2006

0006 Mitochondrial DNA sequences have been associ sample nucleotides, e.g., as described in PCT Publication ated with pathologies as described in U.S. Pat. Nos. 5,670. WO 99/05574, and U.S. Pat. Nos. 5,754,524; 6.228,575: 320, 5,296,349, 5,185,244, and 5,494,794. Publications on 5,593,839; and 5.856,101. Methods for screening for disease the subject of mitochondrial biology include: Scheffler I. E. markers are also known to the art, e.g., as described in U.S. (1999) Mitochondria, Wiley-Liss, New York: Lestienne, P. Pat. Nos. 6,228,586: 6,160,104; 6,083,698; 6,268,398: Ed. (1999) Mitochondrial Diseases. Models and Methods, 6,228,578; and 6,265,174. Springer-Verlag, Berlin; Methods in Enzymology (2000) 322:Section V Mitochondria and Apoptosis, Academic 0009 All references cited herein are incorporated by Press, California; Mitochondria and Cell Death (1999) reference in their entirety to the extent that they are not Princeton University Press, New Jersey; Papa S, Ferrucio inconsistent with the disclosure herein. Citation of the above G, and Tager J Eds. (1999) Frontiers of Cellular Biometics. documents is not an admission that any of them are pertinent Molecular Biology, Biochemistry, and Physiopathology, prior art. Kluwer Academic/Plenum Publishers, New York; Lemasters J and Nieminen A (2001) Mitochondria in Pathogenesis, SUMMARY OF THE INVENTION Kluwer Academic/Plenum Publishers, New York; MITO 0010 This invention provides a library of genes involved MAP. http://www.gen.emory.edu/cgi-gin/MITOMAP: Wal in mitochondrial biology, arrays containing probes for genes lace D. C. (2001) “A mitochondrial paradigm for degenera involved in mitochondrial biology, methods for making Such tive diseases and aging.'Novartis Foundation Symposium arrays, and methods of using Such arrays. Genes and probe 235:247-266: Wallace D C “Mitochondrial DNA in Aging sequences involved in mitochondrial biology in humans and and Disease” (August 1997) Scientific American 277:40-47: mice are provided. The arrays of this invention are useful for Wallace D. C. et al., “Mitochondrial biology, degenerative determining mitochondrial biology gene expression profiles. diseases and aging.” (1998) BioFactors 7:187-190; Heddi, Mitochondrial biology gene expression profiles are useful A. et al., “Coordinate Induction of Energy Gene Expression for determining expression profiles diagnostic of energy in Tissues of Mitochondrial Disease Patients” (1999) JBC metabolism-related physiological conditions; diagnosing 274:22968-22976: Wallace, D. C. “Mitochondrial Diseases Such physiological conditions; identifying biochemical path in Man and Mouse.” (1999) Science 283: 1482-1488; ways, genes, and mutations involved in Such physiological Saraste, M. “Oxidative Phosphorylation at the fin de siecle' conditions; identifying therapeutic agents useful for prevent (1999) Science 283:1488-1493; Kokoszka et al., “Increased ing and/or treating Such physiological conditions; evaluating mitochondrial oxidative stress in the Sod2 (+/-) mouse and/or monitoring the efficacy of Such therapies; and creat results in the age-related decline of mitochondrial function ing and identifying animal models of human energy metabo culminating in increased apoptosis,” (2001) PNAS 98:2278 lism-related physiological conditions. Arrays containing 2283; Wallace, D.C. (2001) Mental Retardation and Devel probes for all genes known to be involved in mitochondrial opmental Disabilities 7:158-166; Wallace D. C. (2001) Am. biology are provided, as well as arrays containing Subsets of J Med. Gen. 106:71-93; and Wallace, D.C. (2001) EuroMit Such probes. The mitochondrial biology expression arrays of 5 Abstract. this invention contain probes of genes not previously rec 0007. The analysis of mitochondrial disorders has tradi ognized to participate in mitochondrial biology. tionally consisted of molecular and biochemical descriptions of the defect (Shoffner, J. M., and Wallace, D. C., (1995) BRIEF DESCRIPTION OF THE DRAWINGS “Oxidative phosphorylation diseases.” In The Metabolic and 0011 FIG. 1 is a diagram of the mammalian mitochon Molecular Basis of Inherited Disease, C. R. Scriver, A. L. drion showing mitochonrial energetics, and the relationship Beaudet, W. S. Sly and D. Valle, eds. (New York: McGraw between energy production, reactive oxygen species (ROS) Hill), pp. 1535-1609). Only a limited number of analyses of generation, and regulation of apoptosis. changes in oxidative phosphorylation (OXPHOS) genes expression have been performed in humans harboring 0012 FIG. 2 is a depiction of a hybridized mouse array mtDNA mutations (Heddi, A. et al., “Coordinate Induction of this invention. The picture of the hybridized array shows of Energy Gene Expression in Tissues of Mitochondrial the image generated when the two channels representing the Disease Patients” (1999) JBC 274:22968-22976). The control or reference and experimental targets are overlaid. advent of mouse models for mitochondrial disease created When viewed in color, the spots appear various shades of by the inactivation of nuclear-encoded OXPHOS subunits red, green and yellow. Red spots indicate a predominance of has provided experimental material to study tissue-specific hybridization to control cDNAs, while green spots indicate expression changes. (Murdock, D. G. et al., "Up-regulation the predominance of hybridization to the experimental target of nuclear and mitochondrial genes in the skeletal muscle of sample. Yellow spots indicate an equal hybridization of both mice lacking the heart/muscle isoform of the adenine nucle samples. Spots that are yellow-green or orange when the otide translocator,1999).J. Biol. Chem. 274: 14429-33.) array is shown in color are depicted as half yellow and green, 0008 Nucleic acid arrays have been described, e.g., in or half red and yellow, respectively. U.S. Pat. No. 5,837,832, U.S. Pat. No. 5,807,522, U.S. Pat. 0013 FIG.3 shows the p() LMEB4 cell line gene expres No. 6,007,987, U.S. Pat. No. 6, 110,426, WO 99/05324, sion scatter plot. The scatter plot shows the distribution of 99/05591, WO 00/58516, WO95/11995, WO95/35505A1, gene expression ratio for the p0 LMEB4 sample. The WO 99/42813, JP10503841T2, GR3030430T3, diagonal dotted line indicates a ratio of 1 between the two ES2134481T3, EP804731B1, DE69509925C0, samples. Any spot above the dotted line is up-regulated or CA2192095AA, AU2862995A1, AU709276B2, AT180570, more abundant in the p0 LMEB4 experimental sample EP 1066506, and AU 2780499. Such arrays can be incor compared to the LM(TK)-control. Any spot below the dotted porated into computerized methods for analyzing hybridiza line is down-regulated or less abundant in the experimental tion results when the arrays are contacted with prepared sample compared to the control. US 2006/0099578 A1 May 11, 2006

0014 FIG. 4 shows NZB heart gene expression scatter have instituted the term “gene cluster to refer to non plot. The scatter plot shows the distribution of gene expres redundant sets of gene clusters. A stretch of DNA may be sion ratio for the NZB heart tissue sample. The diagonal transcribed into several splice variants that share sequences, dotted line indicates a ratio of 1 between the two samples. and these would be designated as belonging to one unigene Any spot above the dotted line is up-regulated or more cluster. As used herein “splice variant” refers to one version abundant in the NZB-mtDNA heart experimental sample of several transcripts that are transcribed from one gene. As compared to the “common mtDNA control heart. Any spot used herein “housekeeping gene' refers to a gene that is below the dotted line is down-regulated or less abundant in expressed at a similar level in almost all cell types. the experimental sample compared to the control. 0019. As used herein “genes involved in mitochondrial DETAILED DESCRIPTION OF THE biology” refers to mitochondrial genes and nuclear genes INVENTION involved in cellular structures and functions such as inter mediary metabolism, OXPHOS, mitochondrial transport, 0015. An approach to examining the complex interaction cellular bioenergetics, cellular biogenesis, cell cycle control, between nuclear and cytoplasmic mitochondrial genes is DNA replication, energy, metabolism, heat shock, stress, through the use of arrays such as DNA arrays. DNA microar cellular matrix, cellular structural , protein synthesis rays provide a means to profile the expression patterns of up and translational control, signal transduction, transcription to thousands of genes simultaneously, and knowing where and transcriptional regulation, chromatin structure, reactive and when a gene is expressed often provides insight into its bXygen species (ROS) biology, and apoptosis. biological function. The pattern of gene expression in a particular tissue or cell type can also provide detailed 0020 “mtDNA” means mitochondrial DNA. “nlDNA” information about its state or condition. means nuclear DNA. 0016 Currently, DNA microarrays are the most efficient 0021. As used herein “mitochondrial biology expression method to monitor correlative changes in gene expression profile’ refers to the expression patterns of genes involved and to investigate complex traits on a molecular level. in mitochondrial biology, such as is detected by probes Expression profiles assembled from multiple interrelated derived from those genes, in a sample. The profile can be experiments are used to determine hierarchical connections said to be of the sample or of the source from which the between gene expression patterns underlying complex bio sample is derived. A profile may be measured independently, logical traits. These patterns are used to further define the but a profile may also measured relative to a standard or molecular basis of complex disorders. control or other sample. A complete mitochondrial biology expression profile includes data on all genes known to be 0017. The mitochondrion is assembled from approxi involved in mitochondrial biology for the species from mately 1000 protein-coding nuclear DNA (nDNA) and which the sample is derived. The mitochondrial biology mitochondrial DNA (mtDNA) genes. Thirteen protein-cod expression profile for a selected physiological condition is at ing mitochondrial genes are known, as shown in Table 1. least the expression pattern of genes determined to have The codon usage table of the mtDNA is known. It differs altered expression diagnostic of that physiological condi slightly from the universal code. For example, UGA codes tion, but the expression pattern of additional genes involved for tryptophan instead of termination, AUA codes for in mitochondrial biology may also be included. methionine instead of isoleucine, and AGA and AGG are terminators instead of coding for arginine. 0022. As used herein “array' refers to an ordered set of isolated nucleic acid molecules or spots consisting of plu TABLE 1. ralities of substantially identical isolated nucleic acid mol ecules. Preferably the molecules are attached to a substrate. Gene Map " Abbreviation Location The spots or molecules are ordered so that the location of NADH dehydrogenase 1 MTND1 ND1 3307 4262 each (on the substrate) is known and the identity of each is NADH dehydrogenase 2 MTND2 ND2 4470-SS11 known. Arrays on a micro scale can be called microarrays. NADH dehydrogenase 3 MTND3 ND3 10059-104.04 Microarrays on Solid Substrates. Such as glass or other NADH dehydrogenase 4L MTND4L ND4L 10470–10766 NADH dehydrogenase 4 MTND4 ND4 10760-12137 ceramic slides, can be called gene chips or chips. NADH dehydrogenase 5 MTND5 ND5 12337-14148 NADH dehydrogenase 6 MTND6 ND6 14149–14673 0023. As used herein, an "isolated nucleic acid is a Cytochrome b MTCYB Cytb 14747 15887 nucleic acid outside of the context in which it is found in Cytochrome c oxidase I MTCO1 COI S904 7445 nature. An isolated nucleic acid is a nucleic acid the structure Cytochrome c oxidase II MTCO2 COII 7586 8269 Cytochrome c oxidase III MTCO3 COIII 92O7. 9990 of which is not identical to that of any naturally occurring ATP synthase 6 MTATP6 ATP6 8527 92O7 nucleic acid molecule. The term covers, for example: (a) a ATP synthase 8 MTATP8 ATP8 8366 8S72 DNA which has the sequence of part of a naturally-occurring "'As defined on Mito Map, http://www.gen.emory.edu/cgi-bin/MITOMAP, genomic DNA molecule but is not flanked by both of the which is numbered relative to the Cambridge Sequence (Genbank acces coding or noncoding sequences that flank that part of the sion no. JO1415 and Andrews et al. (1999), A Reanalysis and Revision of molecule in the genome of the organism in which it naturally the Cambridge Reference Sequence for Human Mitochondrial DNA, occurs; (b) a nucleic acid incorporated into a vector or into Nature Genetics 23: 147. the genomic DNA of a prokaryote or eukaryote in a manner Such that the resulting molecule is not identical to any 0018. As used herein “gene' refers to a unigene cluster, naturally-occurring vector or genomic DNA; (c) a separate an expressed sequence, or a sequence that is transcribed and molecule Such as a cDNA, a genomic fragment, a fragment translated into a protein. Another word used in the art for produced by polymerase chain reaction (PCR), or a restric “gene' is “locus.” The National Institutes of Health (NIH) tion fragment; and (d) a recombinant nucleotide sequence US 2006/0099578 A1 May 11, 2006 that is part of a hybrid gene, i.e., a gene encoding a fusion the appropriate target molecules at the same hybridization protein, or a modified gene having a sequence not found in stringency. As used herein “homology” refers to nucleotide nature. sequence identity to a sequence, a molecule, or its comple 0024. As used herein “probe' refers to an isolated nucleic ment. acid that is suitable for hybridizing to other nucleic acids 0029. As used herein “mouse sample” refers to a sample when placed on a solid substrate. Probes for arrays can be as derived from a mouse or a cell line derived from a mouse. short as 20-30 nucleotides and up to as long as several Similarly, as used herein, "human sample” refers to a sample thousand nucleotides. Probes can be single-stranded or derived from a human or a cell line derived from a human. double Stranded. A probe usually comprises at least a par Samples preferably contain total RNA or messenger RNA tially known sequence that is used to investigate or interro (mRNA). As used herein “total RNA refers to a combina gate the presence, absence, and/or amount of a complement tion of several types of RNA, including MRNA, from a cell ing sequence. On the arrays of this invention, a probe is of or a group of cell. As used herein, “MRNA refers to Such a sequence and the hybridization conditions of Such messenger RNA or RNA that has a 3' poly A tail. As used stringency that each probe hybridizes Substantially to only herein, a “prepared sample' or a “target” refers to a sample one type of nucleic acid per target sample. that has been labeled in preparation for array hybridization. 0025. As used herein, “target' or “target sample” refers to A “prepared sample' or “target' is reverse transcribed and the collection of nucleic acids, e.g., reverse transcribed and fluorescently labeled. As used herein “standard” refers to a labeled cDNA used as a prepared sample for array analysis. sample or a dataset that is commonly used for comparison to The target is interrogated by the probes of the array. A unknown samples so that the unknown samples or datasets “target' or “target sample' may be a mixture of several can be standardized for comparison to each other. As used prepared samples that are combined. For example, an herein, "control sample' and “reference sample” refer to experimental target sample may be combined with a differ samples that are used for comparison against an experimen ently labeled control sample and hybridized to an array, the tal sample. combined samples being referred to as the “target' interro 0030. As used herein, “clone” refers to an isolated nucleic gated by the probes of the array. As used herein, “interro acid molecule that may be stored in an organism Such as E. gated” means tested. Probes, targets, and hybridization con coli. A clone is usually made of a vector and an insert. The ditions are chosen such that the probes are capable of insert usually contains a sequence of interest. interrogating the target, i.e., of hybridizing to complemen 0031. For mitochondrial diseases, the accuracy of current tary sequences in the target sample. biochemical and phenotypic techniques has proven quite 0026. As used herein “physiological condition” refers to limited in distinguishing and diagnosing the various disor a healthy or unhealthy physiological state. As used herein ders. Recent technical and analytical advancements make it “optimize an array for diagnosis' refers to selecting probes practical to analyze and quantitate the expression patterns of for an array Such that only probes from genes necessary for thousands of genes at once using arrays Such as DNA diagnosis of one or more physiological conditions are microarrays. This invention applies these array techniques to included. the study of mitochondrial gene expression, in the design of specialized microarrays containing genes involved in mito 0027. As used herein “printing refers to the process of chondrial biology. The arrays of this invention contain applying probes to a solid Substrate, e.g., or applying arrays probes for genes not previously recognized to participate in of probes to a solid Substrate to make a gene chip. As used herein "glass slide' refers to a small piece of glass of the mitochondrial biology. same dimensions as a standard microscope slide. As used 0032 Genes, or expressed sequences, involved in mito herein, “prepared substrate' refers to a substrate that is chondrial biology are involved in cellular structures and prepared with a substance capable of serving as an attach functions such as intermediary metabolism, OXPHOS, ment medium for attaching the probes to the Substrate. Such transport, cellular bioenergetics, cellular biogenesis, cell as poly Lysine. cycle control, DNA replication, energy, metabolism, heat 0028. As used herein “selective hybridization” refers to shock, stress, cellular matrix, cellular structural proteins, hybridization at moderate to high Stringency Such that only protein synthesis and translational control, signal transduc sequences of an appropriate homology can remain bound. tion, transcription and transcriptional regulation, chromatin Selective hybridization is hybridization performed at strin structure, reactive oxygen species (ROS) biology and apo gency conditions such that probes only hybridize to target ptosis. Alterations in mitochondrial functions are associated sample nucleic acids that they are intended to hybridize with a variety of physiological conditions including degen with. Depending on the sequences of the probes and the erative diseases. These functions are involved in many target, the hybridization conditions are chosen to be appro degenerative diseases. This invention provides a compila priately selective. For example, if human sequences are used tion of sequences involved in human and mouse mitochon as probes for interrogating a human sample, selective drial biology. hybridization could be at high Stringency because, allowing 0033. The genes in the arrays of this invention were for neutral polymorphism in humans, the sequences would identified by a variety of techniques including searching be about 99-100% identical. When applying a chimpanzee databanks for sequences related to genes involved in pro target prepared sample to an array containing human cesses similar to mitochondrial biology Such as homologues sequence probes, selective hybridization would be at a lower of prokaryotic genes, and screening mitochondrial mutant stringency. Since hybridizing a target to an array is per cell lines and animal lines for genes having altered expres formed at one chosen hybridization Stringency, probes are sion patterns. When a relevant gene was identified for one chosen so that they can undergo selective hybridization with species, such as the mouse, the homologue for a second US 2006/0099578 A1 May 11, 2006

species, such as human, if known, was then included on the other. A prepared reference or control target for comparison list of genes involved in mitochondrial biology for the can also be particularly pertinent to the experiment being second species. Mitochondrial mutant cell lines are cell lines performed. A prepared reference target could be a target that have at least one mutation in a gene involved in sample derived from the same cell type from an animal of mitochondrial biology. the same sex, age, and nuclear background as the experi 0034. The microarrays or gene chips of this invention mental target sample, except for one difference. Such as a comprise probes placed in known positions on a solid different phenotype or treatment. Comparing the results of Substrate. A useful solid Substrate is a specialized glass the experimental target with the results of an appropriate microscope slide. The arrays of this invention include arrays reference target yields a profile associated with the one containing probes that detect Some or all expressed difference being tested. When the hybridization results of a sequences involved in mitochondrial biology in a selected first sample are compared to the hybridization results of a species. second sample, the comparison can occur while the hybrid 0035 Arrays of this invention may contain control probes ization results of the first sample are being measured and as well as probes for genes involved in mitochondrial recorded, or afterwards, by comparing the measured and biology. Controls that can be included on the arrays of this recorded hybridization results of the two samples. invention include hybridization controls and Scanning con trols. The controls can be positive or negative controls. One 0037 Probes on an array may be as short as about 20-30 type of hybridization control is spotting the same probe for nucleotides long or as long as the entire gene or clone from a gene involved in mitochondrial biology several times on which they are derived, which may be up to several kilo one chip, each spot having different amounts of probe. This bases. A probe sequence may be identical (have 100% allows for the amount of probe of a given sequence to be homology) to the portion of the gene it hybridizes to or it optimized. Spotting too little probe may lead to a maximum may be a mutated sequence. Mutated probes have less than hybridization signal resulting in a loss of data. Dimethyl 100% homology, such as about 98% homology, about 95% sulfoxide (DMSO) can be used as a negative hybridization homology, about 90% homology, about 80% homology, or and scanning control. A spot of DMSO should give no about 75% homology, or less, with the portions of the genes signal. If there is any signal at a DMSO spot, the problem to which they hybridize. Arrays are designed such that all could be at hybridization or scanning steps. Plant sequences probes on an array can hybridize to their corresponding having sufficiently low homology with human and mouse genes at about the same hybridization stringency. Probes for sequences can be utilized as negative hybridization and arrays used for interrogating samples usually do not contain scanning controls. Plant sequences should not give any sequences such as repetitive sequences that would hybridize signal. A signal at a plant spot could indicate a problem with substantially with nucleic acids derived from more than one hybridization, i.e. too low a hybridization Stringency was gene, i.e., transcripts or cDNAs. Probes for arrays should be used, or with scanning, i.e., the chip was inserted into the unique at the hybridization stringencies used. Statistically, to scanner at the incorrect orientation. Poly A can be used as a be unique in the total human genome, probes should be at positive hybridization specificity/non specificity control. A least about fifteen nucleotides long. A unique probe is only poly A spot should always give intense hybridization. No able to hybridize with one type of nucleic acid per target. A signal at a poly A spot could be the result of use of too high probe is not unique if at the hybridization stringency used, a hybridization stringency. Cy3 or Cy5 incorporated into a it hybridizes with nucleic acids derived from two different PCR product can be a positive scanning control. A spot on genes, i.e. related genes. The homology of the sequence of an array of a PCR product, or any other nucleic acid, that the probe to the gene and the hybridization stringency used includes fluorescent label, should always give a signal, and help determine whether a probe is unique when testing a if this sequence has no homology with any other sequence selected sample. Probes also may not hybridize with differ in the target, there should only be a signal of the label ent nucleic acids derived from the same gene, i.e., splice included in the nucleic acid. Control probes and probes for variants. The location in the gene of the sequence used for genes involved in mitochondrial biology can be duplicated, the probe also helps determines whether a probe is unique triplicated, etc. on the chip as printing controls. Controls for when testing a selected sample. If the splice variants of a arrays can be purchased from Stratagene (SpotReportTM, La gene are known, ideally several different probes sequences are chosen from that gene for an array, such that each probe Jolla, Calif., USA). can only hybridize to nucleic acid derived from one of the 0.036 Standard targets and reference targets are also splice variants. References for sequences of probes useful useful with the arrays of this invention, as is known in the for arrays of this invention are compiled in Tables 3-5 and art. When a prepared sample target to be interrogated is in the sequence listings. Other equivalent probes derived applied to an array of this invention, the results of the test are from the gene sequences from which the Tables 3-5 probes measured, i.e. by Scanning, and recorded. These results can are derived, are also useful for the arrays of this invention. be compared directly to other test results using a similar Arrays of this invention are used at hybridization conditions array. However, it is much more accurate to include a allowing for selective hybridization. At conditions of selec differently labeled standard target in the hybridization mix tive hybridization, probes hybridize with nucleic acid from with the prepared sample target. The results of the experi only one gene. When an array is simultaneously hybridized mental sample target are then standardized, so that they can with two targets or two prepared samples, each probe may be compared accurately to the results of hybridizations of hybridize with a nucleic acid in each prepared sample or other sample targets. If ten different prepared sample targets target. When these two nucleic acids are from the same are hybridized to arrays of this invention, simultaneously unigene cluster, the probe is said to hybridize with one gene, with the same prepared Standard target, then the results of despite the fact that these nucleic acids may contain different the ten sample targets can be accurately compared to each labels. US 2006/0099578 A1 May 11, 2006

0038 Sequences of genes involved in mitochondrial biol array with a fluorescent scanner and using software to ogy from other species can be used to make probes that are analyze the hybridized array image, it can be determined if, useful in the arrays of this invention as long as they and to what extent, genes are Switched on and off, or whether hybridize at about the same hybridization stringency as other or not sequences are present, by comparing fluorescent probes on an array. Sequences that are only able to hybridize intensities at specific locations on the array. The intensity of at a substantially lower Stringency, such as plant sequences, the signal indicates to what extent a sequence is present. In are useful as negative controls. expression arrays, high fluorescent signals indicate that 0.039 The arrays of this invention can be utilized to many copies of a gene are present in a sample, and lower determine profiles for related species by modifying the fluorescent signal shows a gene is less active. By selecting hybridization Stringency appropriately. appropriate hybridization conditions and probes, this tech between organisms is known in the art. For example, human nique is useful for detecting single nucleotide polymor and chimpanzee sequences are about 98% identical. Conse phisms (SNPs) and for sequencing. Methods of designing quently, human arrays are useful for profiling chimpanzees, and using microarrays are continuously being improved with an appropriate lowering of the hybridization Stringency. (Relogio, A. et al. (2002) Nuc. Acids. Res. 30(1 l):e51; Hybridization stringency can be lowered by modifying Iwasaki, Het al. (2002) DNA Res. 9(2):59-62; and Lindroos, hybridization components such as Salt concentrations and K. et al. (2002) Nuc. Acids. Res. 30(14):E70). hybridization and/or wash temperatures, as is known in the 0044 Arrays of this invention may be made by any array art. synthesis methods known in the art such as spotting tech 0040. The sequences useful for the arrays of this inven nology or solid phase synthesis. Preferably the arrays of this tion are useful for designing arrays for other species as well. invention are synthesized by Solid phase synthesis using a To create an array for a new organism, the known sequences combination of photolithography and combinatorial chem from the new organism, including expressed sequence tags istry. Some of the key elements of probe selection and array (ESTs), are compared, by methods known to the art, with the design are common to the production of all arrays. Strategies sequences known to already be useful for other mitochon to optimize probe hybridization, for example, are invariably drial biology arrays. Sequence comparisons may be per included in the process of probe selection. Hybridization formed at the nucleic acid or polypeptide level. Homologous under particular pH, salt, and temperature conditions can be and analogous sequences from the new organism are thereby optimized by taking into account melting temperatures and identified and selected for the new organisms mitochondrial by using empirical rules that correlate with desired hybrid array. The probes on the arrays of this invention are also ization behaviors. Computer models may be used for pre useful as probes for identifying candidates for the new dicting the intensity and concentration-dependence of probe organisms array using molecular biology techniques that hybridization. are standard in the art such as Screening libraries. 0045 Arrays, also called DNA microarrays or DNA 0041 All sequences given herein are meant to encompass chips, are fabricated by high-speed robotics, generally on the complementary Strand, as well as double-stranded poly glass but sometimes on nylon Substrates, for which probes (Phimister, B. (1999) Nature Genetics 21s: 1-60) with nucleotides comprising the given sequence. known identity are used to determine complementary bind 0.042 Microarrays of this invention can contain as few as ing. An experiment with a single DNA chip can provide two probes to as many as all the probes diagnostic of the researchers information on thousands of genes simulta selected physiological condition to be tested. Microarrays of neously. There are several steps in the design and imple this invention may also contain probes for all genes involved mentation of a DNA array experiment. Many strategies have in mitochondrial biology. The arrays of this invention may been investigated at each of these steps: 1) DNA types; 2) contain probes for at least about five genes, at least about ten Chip fabrication; 3) Sample preparation; 4) Assay; 5) Read genes, at least about twenty-five genes, at least about fifty out; and 6) Software (informatics). genes, at least about 100 genes, at least about 500 genes, or 0046) There are two major application forms for the array at least about 1000 genes. The mouse array may contain technology: 1) Determination of expression level (abun probes for at least about 950 genes and the human array may dance) of genes; and 2) Identification of sequence (gene/ contain probes for at least about 600 genes. Arrays of this gene mutation). There appear to be two variants of the array invention may comprise more than about five spots, more technology, in terms of intellectual property, of arrayed than about ten spots, more than about twenty-five spots, DNA sequence with known identity: Format I consists of more than about one hundred spots, more than about 500 probe cDNA (500-5,000 bases long) immobilized to a solid spots, or more than about 1000 spots. Surface Such as glass using robot spotting and exposed to a 0043. Using microarrays may require amplification of set of targets either separately or in a mixture. This method, target sequences (generation of multiple copies of the same “traditionally called DNA microarray, is widely considered sequence) of sequences of interest, such as by PCR or as having been developed at Stanford University. (R. Ekins reverse transcription. As the nucleic acid is copied, it is and F. W. Chu “Microarrays: their origins and applications, tagged with a fluorescent label that emits light like a light 1999 Trends in Biotechnology, 17:217-218). Format II bulb. The labeled nucleic acid is introduced to the microar consists of an array of oligonucleotide (20-80-mer oligos) ray and allowed to react for a period of time. This nucleic or peptide nucleic acid (PNA) probes synthesized either in acid sticks to, or hybridizes, with the probes on the array situ (on-chip) or by conventional synthesis followed by when the probe is sufficiently complementary to the labeled, on-chip immobilization. The array is exposed to labeled amplified, sample nucleic acid. The extra nucleic acid is sample DNA, hybridized, and the identity/abundance of washed off of the array, leaving behind only the nucleic acid complementary sequences is determined. This method, “his that has bound to the probes. By obtaining an image of the torically called DNA chips, was developed at Affymetrix, US 2006/0099578 A1 May 11, 2006

Inc., which sells its photolithographically fabricated prod partners, as well as their intensity ratios, serve as indicators ucts under the GeneChip(R) trademark. Many companies are of specific target abundance, and consequently of the manufacturing oligonucleotide-based chips using alternative Sequence. in-situ synthesis or depositioning technologies. 0051 Arrays can rely on multiple probes to interrogate 0047 Probes on arrays can be hybridized with fluores individual nucleotides in a sequence. The identity of a target cently-labeled target polynucleotides and the hybridized base can be deduced using four identical probes that vary array can be scanned by means of Scanning fluorescence only in the target position, each containing one of the four microscopy. The fluorescence patterns are then analyzed by possible bases. Alternatively, the presence of a consensus an algorithm that determines the extent of mismatch content, sequence can be tested using one or two probes representing identifies polymorphisms, and provides some general specific alleles. To genotype heterozygous or genetically sequencing information (M. Chee et al., 1996 Science mixed samples, arrays with many probes can be created to 274:610). Selectivity is afforded in this system by low provide redundant information, resulting in unequivocal stringency washes to rinse away non-selectively adsorbed genotyping. materials. Subsequent analysis of relative binding signals from array elements determines where base-pair mismatches 0052 Probes fixed on solid substrates and targets (nucle may exist. This method then relies on conventional chemical otide sequences in the sample) are combined in a hybrid methods to maximize stringency, and automated pattern ization buffer solution and held at an appropriate tempera recognition processing is used to discriminate between fully ture until annealing occurs. Thereafter, the Substrate is complementary and partially complementary binding. washed free of extraneous materials, leaving the nucleic acids on the target bound to the fixed probe molecules 0.048 Devices such as standard nucleic acid microarrays allowing for detection and quantitation by methods known or gene chips, require data processing algorithms and the use in the art such as by autoradiograph, liquid Scintillation of sample redundancy (i.e., many of the same types of array counting, and/or fluorescence. As improvements are made in elements for statistically significant data interpretation and hybridization and detection techniques, they can be readily avoidance of anomalies) to provide semi-quantitative analy applied by one of ordinary skill in the art. As is well known sis of polymorphisms or levels of mismatch between the in the art, if the probe molecules and target molecules target sequence and sequences immobilized on the device hybridize by forming a strong non-covalent bond between surface. Such algorithms and software useful for statistical the two molecules, it can be reasonably assumed that the analysis are known to the art. probe and target nucleic acid are essentially identical, or 0049. Using microarrays first requires amplification (gen almost completely complementary if the annealing and eration of multiple copies of the same gene) of genes of washing steps are carried out under conditions of high interest, such as by reverse transcription. As the nucleic acid stringency. The detectable label provides a means for deter is copied, it is tagged with a fluorescent label that emits light mining whether hybridization has occurred. like a lightbulb. The labeled nucleic acid is introduced to the 0053 When using oligonucleotides or polynucleotides as microarray and allowed to react for a period of time. This hybridization probes, the probes may be labeled. In arrays of nucleic acid sticks to, or hybridizes, with the probes on the this invention, the target may instead be labeled by means array when the probe is sufficiently complementary to the known to the art. Target may be labeled with radioactive or nucleic acid in the prepared sample. The extra nucleic acid non-radioactive labels. Targets preferably contain fluores is washed off of the array, leaving behind only the nucleic cent labels. acid that has bound to the probes. By obtaining an image of the array with a fluorescent scanner and using Software to 0054 Various degrees of stringency of hybridization can analyze the hybridized array image, it can be determined if be employed. The more stringent the conditions are, the and to what extent genes are switched on and off, or whether greater the complementarity that is required for duplex or not sequences are present, by comparing fluorescent formation. Stringency can be controlled by temperature, intensities at specific locations on the array. High fluorescent probe concentration, probe length, ionic strength, time, and signals indicate that many copies of a gene are present in a the like. Hybridization experiments are often conducted prepared sample, and lower fluorescent signal shows a gene under moderate to high Stringency conditions by techniques is less active. Expression levels for various genes under well know in the art, as described, for example in Keller, G. different conditions can be directly compared. Such as for a H., and M. M. Manak (1987) DNA Probes, Stockton Press, cancer cell and a normal cell. Similarly, it can be determined New York, N.Y., pp. 169-170, hereby incorporated by ref what genes are turned on and off in response to certain erence. However, sequencing arrays typically use lower stimuli Such as a drug. Such information is valuable because hybridization stringencies, as is known in the art. it identifies genes in disease pathways and also is predictive of either efficacy or toxicity of drugs. 0055 Moderate to high stringency conditions for hybrid ization are known to the art. An example of high Stringency 0050. Detecting a particular polymorphism can be conditions for a blot are hybridizing at 68°C. in 5xSSC/5x accomplished using two probes. One probe is designed to be Denhardt’s solution/0.1% SDS, and washing in 0.2xSSC/ perfectly complementary to a target sequence, and a partner 0.1% SDS at room temperature. An example of conditions of probe is generated that is identical except for a single base moderate stringency are hybridizing at 680 C in 5xSSC/5x mismatch in its center. In the Affymetrix system, these probe Denhardt’s solution/0.1% SDS and washing at 42° C. in pairs are called the Perfect Match probe (PM) and the 3xSSC. The parameters of temperature and salt concentra Mismatch probe (MM. They allow for the quantitation and tion can be varied to achieve the desired level of sequence Subtraction of signals caused by non-specific cross-hybrid identity between probe and target nucleic acid. See, e.g., ization. The difference in hybridization signals between the Sambrook et al. (1989) vide infra or Ausubel et al. (1995) US 2006/0099578 A1 May 11, 2006

Current Protocols in Molecular Biology, John Wiley & characteristics and determine the utility of the fragments as Sons, New York, N.Y., for further guidance on hybridization taught herein. It is also well known that the mutant conditions. sequences can be easily produced with site-directed mutagenesis. See, for example, Larionov, O. A. and Niki 0056. The melting temperature is described by the fol forov, V. G. (1982) Genetika 18(3):349-59; and Shortle, D. lowing formula (Beltz, G. A. et al., 1983 Methods of et al., (1981) Annu. Rev. Genet. 15:265-94, both incorpo Enzymology, R. Wu, L. Grossman and K. Moldave Eds.) rated herein by reference. The skilled artisan can routinely Academic Press, New York 100:266-285). produce deletion-, insertion-, or Substitution-type mutations 0057 Tm=81.5o C+16.6 Log Na++0.41 (+G+C)- and identify those resulting mutants that contain the desired 0.61 (% formamide)-600/length of duplex in base pairs. characteristics of wild-type sequences, or fragments thereof. 0.058 Washes can typically be carried out as follows: 0061 Thus, mutational, insertional, and deletional vari twice at room temperature for 15 minutes in IxSSPE, 0.1% ants of the disclosed nucleotide sequences can be readily SDS (low stringency wash), and once at TM-20o C for 15 prepared by methods which are well known to those skilled minutes in 0.2xSSPE, 0.1% SDS (moderate stringency in the art. These variants can be used in the same manner as wash). the exemplified primer sequences so long as the variants have Substantial sequence homology with the original 0059) Nucleic acid useful in this invention can be created sequence. As used herein, Substantial sequence homology by Polymerase Chain Reaction (PCR) amplification. PCR refers to homology that is sufficient to enable the variant products can be confirmed by agarose gel electrophoresis. polynucleotide to function in the same capacity as the PCR is a repetitive, enzymatic, primed synthesis of a nucleic polynucleotide from which the probe was derived. Homol acid sequence. This procedure is well known and commonly ogy is greater than 80%, greater than 85%, greater than 90%, used by those skilled in this art (see Mullis, U.S. Pat. Nos. or greater than 95%. The degree of homology or identity 4,683,195, 4,683.202, and 4,800,159; Saiki et al. 1985 needed for the variant to fimction in its intended capacity Science 230:1350-1354). PCR is used to enzymatically depends upon the intended use of the sequence. It is well amplify a DNA fragment of interest that is flanked by two within the skill of a person trained in this art to make oligonucleotide primers that hybridize to opposite strands of mutational, insertional, and deletional mutations that are the target sequence. The primers are oriented with the 3' ends equivalent in function or are designed to improve the pointing towards each other. Repeated cycles of heat dena function of the sequence or otherwise provide a method turation of the template, annealing of the primers to their ological advantage. complementary sequences, and extension of the annealed primers with a DNA polymerase result in the amplification 0062 Percent sequence identity of two nucleic acids may of the segment defined by the 5' ends of the PCR primers. be determined using the algorithm of Karlin and Altschul Since the extension product of each primer can serve as a (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268, modified template for the other primer, each cycle essentially doubles as in Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA the amount of DNA template produced in the previous cycle. 90:5873-5877. Such an algorithm is incorporated into the This results in the exponential accumulation of the specific NBLAST and XBLAST programs of Altschulet al. (1990) target fragment, up to several million-fold in a few hours. By J. Mol. Biol. 215:402-410. BLAST nucleotide searches are using a thermostable DNA polymerase Such as the Taq performed with the NBLAST program, score=100, polymerase, which is isolated from the thermophilic bacte wordlength=12, to obtain nucleotide sequences with the rium Thermus aquaticus, the amplification process can be desired percent sequence identity. To obtain gapped align completely automated. Other that can be used are ments for comparison purposes, Gapped BLAST is used as known to those skilled in the art. described in Altschuletal. (1997) Nucl. Acids. Res. 25:3389 3402. When utilizing BLAST and Gapped BLAST pro 0060 Polynucleotide sequences of the present invention grams, the default parameters of the respective programs can be truncated and/or mutated such that certain of the (NBLAST and XBLAST) are used. See http://www.ncbi.ni resulting fragments and/or mutants of the original full-length h.gov. sequence can retain the desired characteristics of the full length sequence. A wide variety of restriction enzymes that 0063 Standard techniques for cloning, DNA isolation, are Suitable for generating fragments from larger nucleic amplification and purification, for enzymatic reactions acid molecules are well known. In addition, it is well known involving DNA ligase, DNA polymerase, restriction endo that Bal31 exonuclease can be conveniently used for time nucleases and the like, and various separation techniques controlled limited digestion of DNA. See, for example, useful herein are those known and commonly employed by Maniatis (1982) Molecular Cloning: A Laboratory Manual, those skilled in the art. A number of standard techniques are Cold Spring Harbor Laboratory, New York, pages 135-139, described in Sambrook et al. (1989) Molecular Cloning, incorporated herein by reference. See also Wei et al. (1983) Second Edition, Cold Spring Harbor Laboratory, Plainview, J. Biol. Chem. 258:13006-13512. By use of Bal31 exonu New York; Maniatis et al. (1982) Molecular Cloning, Cold clease (commonly referred to as "erase-a-base' procedures), Spring Harbor Laboratory, Plainview, New York; Wu (ed.) the ordinarily skilled artisan can remove nucleotides from (1993) Meth. Enzymol. 218, Part I; Wu (ed.) (1979) Meth. either or both ends of the subject nucleic acids to generate Enzymol. 68; Wu et al. (eds.) (1983) Meth. Enzymol. 100 and a wide spectrum of fragments that are functionally equiva 101: Grossman and Moldave (eds.) Meth. Enzymol. 65; lent to the Subject nucleotide sequences. One of ordinary Miller (ed.) (1972) Experiments in Molecular Genetics, skill in the art can, in this manner, generate hundreds of Cold Spring Harbor Laboratory, Cold Spring Harbor, New fragments of controlled, varying lengths from locations all York: Old and Primrose (1981) Principles of Gene Manipu along the original molecule. The ordinarily skilled artisan lation, University of California Press, Berkeley; Schleif and can routinely test or screen the generated fragments for their Wensink (1982) Practical Methods in Molecular Biology, US 2006/0099578 A1 May 11, 2006

Glover (Ed.) (1985) DNA Cloning Vol. I and II, IRL Press, ological condition, but otherwise similar, are hybridized to Oxford, UK; Hames and Higgins (Eds.) (1985) Nucleic Acid an array of this invention. The hybridization of the prepared Hybridization, IRL Press, Oxford, UK: Setlow and Hol samples are measured and compared to, if possible, deter laender (1979) Genetic Engineering. Principles and Meth mine a profile associated with the physiological condition. ods, Vols. 14, Plenum Press, New York; and Ausubel et al. The profile may be optimized by statistical analysis, as is (1992) Current Protocols in Molecular Biology, Greene/ known in the art, to only contain profile data on probes Wiley, New York, N.Y. Abbreviations and nomenclature, necessary for diagnosing the physiological condition. where employed, are deemed standard in the field and 0068 The profile associated with a physiological condi commonly used in professional journals such as those cited tion can then be used for diagnosis or evaluation using the herein. arrays of this invention, such as in Example 7. The profile of 0064. The arrays of this invention are useful for defining the physiological condition can be analyzed and the analysis expression signatures or profiles for mitochondrial diseases, used to optimize an array for diagnosis of the physiological as well as distinguishing clinical disorders that result from condition. An optimized array for diagnosis of a physiologi OXPHOS dysfunction, oxidative stress, apoptosis, and cal condition minimally contains at least one probe for the aging. The microarrays of this invention are useful for one or more genes that have altered expression levels in the providing profiles for whole classes of mitochondrial dis context of the physiological condition, and probes for eases that have common underlying pathophysiological enough genes to eliminate other likely diagnoses. Diagnosis mechanisms. The data obtained from using these arrays are involves collecting a sample from an individual who might useful in the identification of pathways involved in these have the physiological condition, and determining the pro diseases and in the design of efficient therapies for treating file of the prepared sample using an array of this invention, these diseases. using an array containing probes for all genes involved in mitochondrial biology or fewer probes with at least as many 0065. The arrays of this invention are useful for deter probes as necessary for an array optimized for diagnosis of mining mitochondrial biology expression profiles and for the physiological condition. The profile of the individual is sample evaluation using those profiles. The arrays of this then compared to the profile of the physiological condition, invention are useful for diagnosis, for identifying pathways, and the comparison is analyzed to determine the likelihood genes, and mutations involved in physiological conditions, that the individual has the physiological condition. Arrays of for creating animal models of human physiological condi this invention can also be used for Screening individuals who tions, and for designing curative and preventative therapies are not suspected of having the particular physiological and evaluating their effectiveness. condition. A sample is collected from Such an individual, prepared, and the mitochondrial biology profile of the indi 0.066 The arrays of this invention are useful for deter vidual is determined using an array of this invention, e.g., an mining mitochondrial biology expression profiles of organ array containing probes for all genes involved in mitochon isms, such as humans, mice, and closely related species; drial biology. The profile of this individual is then compared tissues and organs of Such organisms; cell types of Such to known mitochondrial biology profiles of one or more organisms; and cell lines derived from Such organisms. An physiological conditions that the individual may have, to individual can be tested at any age, including as a fetus, determine if the profile of the individual is indicative of a neonate, infant, child, adolescent, mature adult, senior, and diagnosable physiological condition. As demonstrated in deceased. Using standard targets, the arrays of this invention Example 16, the arrays of this invention are also useful for are useful for comparing mitochondrial biology profiles of detecting profiles indicative of physiological conditions different individuals or cells. before the appearance of other symptoms. 0067. The arrays of this invention are useful for deter mining the profile associated with a physiological condition 0069. The profile of, or associated with, a physiological Such as an energy-metabolism-related physiological condi condition is also useful for identifying biochemical path tion. Physiological conditions can be healthy conditions or ways affected by the physiological condition and genes pathological conditions. Examples of healthy conditions in involved in causation of the physiological condition. If a humans are centenaria and physical fitness. An example of profile of a physiological condition demonstrates alteration a pathological condition in humans is Leigh's syndrome in the expression of a gene, that gene is a candidate for (LS). By determining profiles from individuals, with and sequencing to identify a mutation causing the physiological without Such physiological conditions, and comparing them, condition. If a profile demonstrates alteration of expression the mitochondrial biology profile representative and descrip of several genes, then genes known to regulate those are tive of the physiological condition can be determined. Such candidates for sequencing to identify a mutation causing the as for humans in Examples 4-5. Profiles can similarly be physiological condition. Example 3 describes using the determined for cells lines with phenotypes or genotypes arrays of this invention for the identification of mutations associated with physiological conditions, such as in associated with physiological conditions. Examples 13-15. Profiles can also be determined for non 0070 The profile of a physiological condition is useful human animals, including mouse strains, with physiological for creating and/or identifying animal models of human conditions as in Examples 8-12, 16, and 19. The arrays of physiological conditions. The profile of a physiological this invention are useful for determining the range of normal condition may suggest types of mutations, such as knock variation of expression of genes involved in mitochondrial outs, to create in order to mimic the physiological condition biology, as in Example 20. When the arrays of this invention in an animal. The arrays of this invention are also useful for are used to determine a profile associated with a physiologi screening genetically engineered or other mutated popula cal condition, prepared target samples or pooled prepared tions to identify an individual animal having a similar target samples, of individuals with and without the physi profile, and thus associated with the physiological condition. US 2006/0099578 A1 May 11, 2006

0071. The same individual can be profiled, using arrays listed in these tables. Probes can be generated in vitro by of this invention, repeatedly over time or after exposure to nucleic acid synthesis, PCR, cloning techniques or other various environmental conditions, thereby determining the techniques known in the art. Flanking or vector sequence effects of time or exposure. Equivalent individuals can also may be minimized in the probe. Probes generated from be profiled, using the arrays of this invention, at different Research Genetics clones (ResGen/Invitrogen, Carlsbad, ages or after exposure to different environmental conditions, Calif.) can be amplified by PCR as described in Example 22. thereby determining the effects of time or exposure. For Optionally, control probes are also selected for the arrays of example, a control group of mice of a particular genotype this invention. Examples of clones and sequences for mak and of a particular age can be compared, using the arrays of ing control probes are listed in Table 6, SEQID NOS:3041 this invention, to a group of experimental mice of the same 3044. If housekeeping genes are chosen as positive controls, genotype and age, that has been exposed to a certain usually they are derived from the same species as the environmental hazard, to determine the effects of the envi non-control probes. Housekeeping gene probes are available ronmental hazard. Cell lines, as well as organisms, can be from Stratagene (Spot ReportTM, La Jolla, Calif., USA). profiled after exposure to different environmental condi tions, as in Example 15. Arrays of this invention are also 0076 Examples of housekeeping genes are shown in useful for determining the effects of aging. Examples 8 and Table 2. Housekeeping genes generally have a consistent amount of expression in all cells. Using the arrays of this 19 demonstrate differences in profiles at different ages. invention, the expression of the 25 housekeeping genes 0072 Therapy is an environmental condition, the effects listed in Table 2 were compared in 4 cell lines, LMEB4. of which can be tested using the arrays of this invention. NZB, 501-1, and the LM(TK)-cell line grown in media Identification of the pathways affected in a physiological Supplemented with glucose, pyruvate, and uridine (GUP). condition allows identification of therapies useful to treat Some variability was present between cell lines. Housekeep individuals having the physiological condition. For ing genes were also tested in 6 different mouse tissue example, if profiles are determined for the effects of classes samples (brain, heart, liver, kidney, spleen and muscle) in of therapeutic agents, as new physiological conditions are two strains of mice, CAP and NZB. Variation was again profiled, relevant therapeutic agents can be easily identified. present, but slight. The profile of a physiological condition is useful for testing candidate therapies for treating individuals with the physi TABLE 2 ological condition. Any individual, with or without the physiological condition, an animal model of the physiologi Description Functional Class cal condition in humans, or a cell line representative of an -gamma Structural gene individual with the physiological condition, can be treated A272 Capping protein Structrual gene Glyceraldehyde phosphate dehydrogenase Metabolism-glycolysis with a candidate therapy. A sample for profiling is collected DNA ligase I DNA repairisynthesis after treatment, prepared, the profile is determined using an 3-actin Structural array of this invention, and compared to the profile of the Alkaline Phosphatase Unclassified same individual before treatment or to equivalent individu 40s Ribosomal protein S15 Protein synthesis als or cells without treatment to determine the effect of the HypoZanthine phosphoribosyl transferase Metabolism-nucleotide (HPRT) treatment. Therapies reversing the effects of the physiologi Ribosomal protein L15 Protein synthesis cal condition can thereby be identified. Preventative thera Ribosomal Protein S29 Protein translation pies and therapies causing desired physiological conditions Acient ubiquinating protein Metabolism-protein can similarly be identified. Glyceraldehyde 3-phosphate dehydrogenase Metabolism-glycolysis Actin-C. (skeletal muscle) Structural Murine ornithine decarboxylase Metabolism-amino acid 0073. The arrays of this invention are useful for moni calcium binding protein Cab45 Calcium homeostasis toring the effectiveness of a therapy for a particular indi Ribosomal protein L1A Protein synthesis vidual as well as for a population. The profile of a diagnosed RNA splicing protein RNA processing individual can be determined, the individual given a therapy, Actin-gamma () Structural gene E2F transcription factor Transcriptional regulation and then the profile of the individual determined again, using Ubiquitin Unclassified the arrays of this invention. The therapy can be modified and 1 Structural the profile retested, until a satisfactory treated profile is HPRT Metabolism-nucleotide obtained. Phospholipase A2 (14-3-3 Zeta delta) Signal transduction HPRT Metabolism-nucleotide 0074 Arrays containing probes hybridizing at moderate Ribosomal protein L3 Protein synthesis to high Stringency with human genes involved in mitochon drial biology are used for assaying prepared samples from humans, human cell lines, and prepared samples from 0077 Arrays can be printed on solid substrates, e.g., glass closely related species. Arrays containing probes hybridiz microscope slides. Before printing, slides are prepared to ing at moderate to high Stringency with mouse genes provide a Substrate for binding as in Example 23. Arrays can involved in mitochondrial biology are used for assaying be printed using any printing techniques and machines prepared samples from mice, mouse cell lines, and prepared known in the art. Printing involves placing the probes on the samples from closely related species. Substrate, attaching the probes to the Substrate, and blocking the Substrate to prevent non-specific hybridization, as 0075. The arrays of this invention are made using probes described in Example 24. for genes involved in mitochondrial biology. Probes can be selected and generated from the lists of clones and 0078 Samples useful for analyses using the arrays of this sequences in Tables 3-5, or from sequences and clones invention include total RNA samples and mRNA samples. representing genes involved in mitochondrial biology not RNA samples can be prepared as described in Example 25. US 2006/0099578 A1 May 11, 2006

An RNA sample is reverse transcribed into cDNA and larly informative in demonstrating the specificity and sen simultaneously labeled, i.e. with one member of a two-color sitivity of the arrays of this invention while the mouse tissue fluorescent system, such as Cy3-dCTP/Cy5-dCTP as experiments in Examples 8-12 and 16-17 have shown the described in Example 26. The arrays are hybridized with the consistency of the arrays of this invention. prepared sample and washed at appropriate stringencies 0081 Clones used to generate probes are listed in Tables accounting for the choices of sample and probes of the array. 3-5. Clones range from about 1 kb to about 4 kb. The inserts The hybridization stringency can be higher when the probe of most clones have been sequenced on the 5' and 3' ends. sequence has higher homology with the gene it interrogates Sequences of the 5 and 3' ends of the clones are usually and when the probe is larger. A reference target, standard about 200 nt to about 800 nt and are provided herein. Probes target, or other sample target for direct comparison may be may be generated via several methods. For example, the prepared and hybridized simultaneously to the same array. A clones listed in Tables 3-5 may be obtained commercially, prepared sample will not degrade during hybridization and the inserts purified and used as probes. Alternatively, a 5' or is labeled. Prepared samples are reverse transcribed and 3 sequence given in the sequence listings hereof may be used fluorescently labeled. to design an oligonucleotide which may be synthesized and 0079) Hybridization results can be measured and ana used to probe a library to identify a cDNA or genomic clone lyzed using equipment and software available in the art as that is equivalent to the clone used to generate the original described in Example 27. Before finalizing data, preliminary sequence. This newly identified cDNA or genomic equiva results are preferably normalized by methods known in the lent clone may be used to generate a probe. Alternatively, a art. An example of normalization appears in Example 29. pair of sequences from the sequence listings, representing Analysis includes determination of statistical significance. the 5 and 3' ends of one clone, may be used to design PCR Measurement may include normalization and analysis, primers, which may be used to PCR amplify an isolated including statistical analysis. Resulting data are typically nucleic acid that is quivalent to the insert of the correspond stored in computer files. ing clone from which the 5' and 3' were derived. This 0080 Mitochondrial biology expression microarrays are isolated nucleic acid may be used as a probe. Probes should useful for detecting alterations in gene expression caused by not contain a vector sequence that hybridizes with any alterations in mitochondrial biology. Although commer sequence in a sample. Methods for designing PCR primers cially available total genome expression arrays from com and designing oligonucleotides for Screening libraries are panies such as Incyte Pharmaceuticals or Affymetrix contain known in the art. probes for ten to twenty times as many genes as the arrays EXAMPLES of this invention, the commercially available arrays have limitations. Several genes and probes that have been Example 1 included on the arrays of this invention are not available on the commercial arrays. The commercial arrays are also very Human Mitochondrial Biology Array expensive and the large data sets resulting from them can be 0082. A human mitochondrial biology array is made from rather cumbersome to analyze and manipulate. The Smaller, clones representing 650 expressed sequences involved in more focused arrays of this invention allow the expression mitochondrial biology. The clones used to make probes that patterns of hundreds of mitochondrial genes to be monitored are placed on the array are shown in Table 3 which refer quickly and efficiently. This study shows that a custom ences SEQID NOS: 1-994 provided herein setting forth the designed microarray for mitochondrial biology expression 5' and 3' sequences from these clones. The clones identified studies, including probes for nuclear as well as mitochon in Table 3 are used to make a set of probes called Human drial genes, is an effective tool for the analysis of gene Probe Set #1. Control sequences are also placed this array. expression changes caused by alterations in functions result Controls include, but are not limited to blanks, DMSO, ing from a mutation in a gene involved in mitochondrial probes derived from plant sequences, sequence(s) not biology or other changes in metabolic state. The cell line involved in mitochondrial biology, and poly adenine (40-60 experiments in Examples 13-17 and 20 have been particu nucleotides long).

TABLE 3 SEQ ID ResGen UniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID

1 mtDNA - 12S ribosome Mitochondrial DNA 12S 2 mtDNA - 16S ribosome Mitochondrial DNA 16s 3 mtDNA - ATP6 Mitochondrial DNAATP6 4 mtDNA - ATP8 Mitochondrial DNAATP8 5 mtDNA - COX1 Mitochondrial DNA COX1 6 mtDNA - COX2 Mitochondrial DNA COX2 7 mtDNA - COX3 Mitochondrial DNA COX3 8 mtDNA - CYT B Mitochondrial DNA CYTb 9 mtDNA - ND1 Mitochondrial DNAND1 10 mtDNA - ND2 Mitochondrial DNAND2 11 mtDNA - ND3 Mitochondrial DNAND3 12 mtDNA - ND4 Mitochondrial DNAND4 1 3 mtDNA - ND4L Mitochondrial DNAND4L US 2006/0099578 A1 May 11, 2006 12

TABLE 3-continued SEQ ID ResGen UniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID 14 mtDNA - NDS Mitochondrial DNANDS 15 mtDNA - ND6 Mitochondrial DNAND6 16 213890 DECR1 2,4-dienoyl CoA reductase H72937 HS.81548 17 213890 DECR1 2,4-dienoyl CoA reductase H72938 HS.81548 18 S88911 OAS1 2',5'-oligoadenylate synthetase 1 AA146773 HS.82396 19 S88911 OAS1 2',5'-oligoadenylate synthetase 1 AA146772 HS.82396 2O 1576254 2',5'-oligoadenylate 2',5'-oligoadenylate synthetase 1 AA95488O HS.82396 synthetase 1 21 1057786 OAS2 (splice-variant) 2'-5"oligoadenylate synthetase 2 AA568217 22 2190112 A38234 2-OXOGLUTARATE AI610813 DEHYDROGENASE E1 COMPONENT 23 81.4444 CRSP9 33 kDa transcriptional co-activator AA459244 HS.7558 24 81.4444 CRSP9 33 kDa transcriptional co-activator AA459465 HS.7558 25 896949 HMGCR 3-hydroxy-3-methylglutaryl-Coenzyme A AA7794.17 reductase 26 29O111 HMGCS1 3-hydroxy-3-methylglutaryl-Coenzyme A HS.77910 synthase 1 (soluble) 27 29O111 HMGCS1 3-hydroxy-3-methylglutaryl-Coenzyme A N764.92 HS.77910 synthase 1 (soluble) 28 7S7222 HMGCS2 3-hydroxy-3-methylglutaryl-Coenzyme A AA496.148 synthase 2 (mitochondrial) 29 7S7222 HMGCS2 3-hydroxy-3-methylglutaryl-Coenzyme A AA496.149 synthase 2 (mitochondrial) 30 109310 HAAO 3-hydroxyanthranilate 3,4-dioxygenase T8O846 31 109310 HAAO 3-hydroxyanthranilate 3,4-dioxygenase T80921 32 1635163 HAAO 3-hydroxyanthranilate 3,4-dioxygenase AIOOSO31 33 66564 BDH 3-hydroxybutyrate dehydrogenase (heart, T67057 Hs.76893 mitochondrial) 34 66564 BDH 3-hydroxybutyrate dehydrogenase (heart, T670.58 Hs.76893 mitochondrial) 35 838.366 HMGCL 3-hydroxymethyl-3-methylglutaryl AA458779 HS.831 Coenzyme A lyase (hydroxymethylglutaricaciduria) 36 838.366 HMGCL 3-hydroxymethyl-3-methylglutaryl AA458,172 HS.831 Coenzyme A lyase (hydroxymethylglutaricaciduria) 37 28469 OXCT 3-oxoacid CoA transferase R13381 38 28469 OXCT 3-oxoacid CoA transferase R40897 39 S91540 PHGDH 3-phosphoglycerate dehydrogenase AA15873S 40 S91540 PHGDH 3-phosphoglycerate dehydrogenase AA159852 41 26672O PDPK1 3-phosphoinositide dependent protein N22904 kinase-1 42 26672O PDPK1 3-phosphoinositide dependent protein N31292 kinase-1 43 666169 MTR 5-methyltetrahydrofolate-homocysteine AA233 640 methyltransferase 44 666169 MTR 5-methyltetrahydrofolate-homocysteine AA233650 methyltransferase 45 81476S AKAP1 A kinase anchor protein, 149 kD AA454947 HS.78921 46 81476S AKAP1 A kinase anchor protein, 149 kD AA455326 HS.78921 47 2364633 A32422 A32422 AI744652 48 2308263 A40487 A40487 AI671604 49 2240514 AAP1 AAP1 AI637909 50 2266774 ABF2 ABF2 AIS90841 51 36393 ACAT2 acetyl-Coenzyme A acetyltransferase 2 R2S823 (acetoacetyl Coenzyme A thiolase) 52 36393 ACAT2 acetyl-Coenzyme A acetyltransferase 2 R46821 (acetoacetyl Coenzyme A thiolase) 53 45376 ACAA2 acetyl-Coenzyme A acyltransferase 2 HO7926 HS-32SOO (mitochondrial 3-oxoacyl-Coenzyme A thiolase) S4 45376 ACAA2 acetyl-Coenzyme A acyltransferase 2 HS-32SOO (mitochondrial 3-oxoacyl-Coenzyme A thiolase) 55 262932 ACO2 Aconitase 2, mitochondrial H99699 HS.75900 56 366511 No Data Actin, alpha 1, skeletal muscle AAO26.609 57 366511 No Data Actin, alpha 1, skeletal muscle AAO2672O 58 86,7606 ACTB actin, beta AA780815 59 42821S ACTL6 actin-like 6 AAOO1745 HS.10318O 60 42821S ACTL6 actin-like 6 AAOO1815 HS.10318O 61 896962 ACADS acyl-Coenzyme A dehydrogenase, C-2 to AA676663 HS.127610 C-3 short chain US 2006/0099578 A1 May 11, 2006 13

TABLE 3-continued SEQ ID ResGen OniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID 62 298.155 ACADM Acyl-Coenzyme A dehydrogenase, C-4 to N70794 S.79158 C-12 straight chain 63 14O131 ACADL acyl-Coenzyme A dehydrogenase, long R66OOS S.1209 chain 64 14O131 ACADL acyl-Coenzyme A dehydrogenase, long R66OO6 S.1209 chain 65 2431 OO ACADSB acyl-Coenzyme A dehydrogenase, H95792 S.81934 short branched chain 66 2431 OO ACADSB acyl-Coenzyme A dehydrogenase, H96140 S.81934 short branched chain 67 81 0358 ACADVL Acyl-Coenzyme A dehydrogenase, very AA464163 S.82208 long chain 68 81 0358 ACADVL Acyl-Coenzyme A dehydrogenase, very AA464228 S.82208 long chain 69 854SO ACOX2 acyl-Coenzyme A oxidase 2, branched T71713 chain 70 854SO ACOX2 acyl-Coenzyme A oxidase 2, branched T71782 chain 71 7723O4. ANT2 Adenine nucleotide translocator 2 AA404486 S.79172 (fibroblast) 72 7723O4. ANT2 Adenine nucleotide translocator 2 AA405477 S.79172 (fibroblast) 73 755855 ANT3 enine nucleotide translocator 3 (liver) AA496376 S.16428O 74 755855 ANT3 enine nucleotide translocator 3 (liver) AA496654 S.16428O 75 853570 ANT3 denine nucleotide translocator 3 (liver) AA663439 S.16428O 76 868757 AK1 denylate kinase 1 AA77S325 S.76240 77 2O10933 KAD2 HUMAN DENYLATE KINASE ISOENZYME 2 78 40026 ANT1 DP, ATP CARRIER PROTEIN, S.2043 EARTSKELETAL MUSCLE OFORMT1 79 40026 ANT1 DP, ATP CARRIER PROTEIN, RS3942 S.2043 EARTSKELETAL MUSCLE OFORMT1 46248 DPRT s DP-ribosyltransferase (NAD+: poly HO9923 S.177766 (ADP-ribose) polymerase) 81 46248 DPRT ADP-ribosyltransferase (NAD+: poly HO9924 S.177766 (ADP-ribose) polymerase) 82 589276 AFG3 (ATPase family gene 3, yeast)-like 2 AA14732O S.293.85 83 589276 AFG3 (ATPase family gene 3, yeast)-like 2 AA147413 S.293.85 84 1018253 AIF AAS70483 85 855624 aldehyde dehydrogenase 1, soluble AA6641O1 S.76392 86 47853 aldehyde dehydrogenase 4 (glutamate H11346 S.77448 gamma-semialdehyde dehydrogenase; pyrroline-5-carboxylate dehydrogenase) 87 47853 A. aldehyde dehydrogenase 4 (glutamate H11369 S.77448 gamma-semialdehyde dehydrogenase; pyrroline-5-carboxylate dehydrogenase) 88 197657 ALDHS ALDEHYDE DEHYDROGENASE, R93550 S.169517 MITOCHONDRIAL X PRECURSOR 89 197657 ALDHS ALDEHYDE DEHYDROGENASE, R93551 S.169517 MITOCHONDRIAL X PRECURSOR 90 1917741 AOX1 aldehyde oxidase 1 AI343711 S.81047 91 2154324 AGPS alkylglycerone phosphate synthase A445O3S 92 152O618 GABT HUMAN AMINOBUTYRATE AA910669 AMINOTRANSFERASE 93 813651 ALAS1 aminolevulinate, elta-, synthase 1 AA447761 S.78712 94 813651 ALAS1 aminolevulinate, elta-, synthase 1 AA453691 S.78712 95 753346 ALAS2 aminolevulinate, elta-, synthase 2 AA4O6485 S.79103 (sideroblastic hypochromic anemia) 96 753346 ALAS2 aminolevulinate, elta-, synthase 2 S.79103 (sideroblastic hypochromic anemia) 97 2486.31 AMT aminomethyltrans erase (glycine cleavage N59532 S.102 system protein T) 98 2486.31 AMT aminomethyltrans erase (glycine cleavage N78273 S.102 system protein T) 99 1SS 6306 ANT3 ANT3 AA916851 1OO 471597 APISL1 API5-like 1 AAO3S435 S.2279.13 101 471597 APISL1 API5-like 1 AAO35436 S.2279.13 102 127032 API2 apoptosis inhibitor 2 RO7870 S.127799 103 127032 API2 apoptosis inhibitor 2 RO7927 S.127799 104 2285739 API3 apoptosis inhibitor 3 AI628.066 105 927.606 ARAL-1 ARAL-1 AAS35370 US 2006/0099578 A1 May 11, 2006 14

TABLE 3-continued SEQ D ResGen OniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID 170418O ASPARTATE AMINOTRANSFERASE AIO9661S 360778 A A axia telangiectasia mutated (includes AAO16254 S.194382 complementation groups A, C and D) 360778 ATM A axia telangiectasia mutated (includes AAO16988 S.194382 complementation groups A, C and D) 09 845519 AT ATP SYNTHASE GAMMACHA (N, AA644234 MITOCHONDRIAL PRECURSOR 813712 AT PSF1 ATP synthase, H+ transporting, AA453765 S.1811 O1 itochondrial FO complex, subuni b, isoform 813712 AT PSF1 ATP synthase, H+ transporting, AA453849 S.1811 O1 itochondrial FO complex, subuni isoform 193106 AT ATP synthase, H+ transporting, S.429 itochondrial FO complex, subuni (subunit 9) isoform 3 193106 AT ATP synthase, H+ transporting, H47164 S.429 itochon rial FO complex, subuni (subunit 9) isoform 3 487.373 AT PSG1 ATP synthase, H+ transporting, S.80986 itochon rial FO complex, subuni (subunit 9), isoform 1 487.373 AT PSG1 ATP synthase, H+ transporting, AAO46489 S.80986 itochon rial FO complex, subuni (subunit 9), isoform 1 809876 AT PSG2 ATP synthase, H+ transporting, AA455 126 S.89399 itochondrial FO complex, subuni (subunit 9), isoform 2 809876 AT PSG2 ATP synthase, H+ transporting, AA464312 S.89399 itochondrial FO complex, subuni (subunit 9), isoform 2 825312 AT ATP synthase, H+ transporting, AASO4540 S.73851 itochondrial FO complex, subuni 825312 AT ATP synthase, H+ transporting, AASO4465 S.73851 itochondrial FO complex, subuni 39.2622 AT PSB ATP synthase, H+ transporting, AA708298 S.25 itochondrial F1 complex, beta polypeptide 21 8566SO AT ATP synthase, H+ transporting, AA669314 S.89761 itochondrial F1 complex, delta subunit 22 14721SO AT PSO ATP synthase, H+ transporting, AA873577 S.76572 itochondria complex, O Subunit igomycin sensitivity conferring protein) 23 20985.08 AT A421603 S.89512 24 1753047 AT ATP50 AI184610 25 1173869 AT ATPSA1 AA64.0573 26 9641.21 AT ATP5C1 AASO7388 27 1736058 AT ATP5F1 AI126623 28 307873 AT ATPase, Ca++ transporting, plasma N93024 S.995 embrane 4 29 307873 AT ATPase, Ca++ transporting, plasma W21376 S.995 embrane 4 30 1435103 AT ATPase, Ca++ transporting, ubiquitous AA857542 S.S541 31 266312 AT ATPase, Cu++ transporting, beta N26536 S.84.999 polypeptide (Wilson disease) 32 266312 AT ATPase, Cu++ transporting, beta N35647 S.84.999 polypeptide (Wilson disease) 33 AT ATPase, H+ transporting, lysosomal S.106876 (vacuolar proton pump) 31 kD 34 8251.70 AT ATPase, H+ transporting, lysosomal AASO416O S.2553.52 (vacuolar proton pump), alpha polypeptide, 70 kD, isoform 1 35 8251.70 AT ATPase, H+ transporting, lysosomal AASO4159 S.2553.52 (vacuolar proton pump), alpha polypeptide, 70 kD, isoform 1 36 13232O3 AT ATPase, H+ transporting, lysosomal AA877.194 S.1697 (vacuolar proton pump), beta polypeptide, 56/58 kD, isoform 2 37 461522 ABCB7 ATP-binding cassette, Sub-family B S.125856 (MDR/TAP), member 7 38 1709773 MCX1 ATP-DEPENDENT CLP PROTEASE AI131257 US 2006/0099578 A1 May 11, 2006 15

TABLE 3-continued SEQ D ResGen UniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID 39 1467799 KIAAO705 atrophin-1 interacting protein 1 AA883236 HS.22599 40 852273 AZF1 AA772863 41 2367249 B42665 B42665 AI741963 42 194384 BTF3 Basic transcription factor 3 R83OOO HS101025 43 194384 BTF3 Basic transcription factor 3 R82957 HS101025 44 342181 BCL2 B-cell CLL/lymphoma 2 W63749 HS.79241 45 342181 BCL2 B-cell CLL/lymphoma 2 W61100 HS.79241 46 826182 BCL6 B-cell CLL/lymphoma 6 (zinc finger AAS21434 protein 51) 47 814899 BNIP3L BCL2/adenovirus E1B 19 kD-interacting AA465697 HS.13295S protein 3-like 48 23S938 BAK1 BCL2-antagonist/killer 1 H52672 49 23S938 BAK1 BCL2-antagonist/killer 1 H52673 50 2125819 BCL2-associated X protein AIS6S2O3 51 1916575 BCL2-interacting killer (apoptosis AI347S38 inducing) 52 1568561 BCL2-like 1 AA93182O 53 22971.54 BCS1 AI670836 S4 813444 benzodiazapine receptor (peripheral) AA455945 55 813444 benzodiazapine receptor (peripheral) AA45SSS4 56 627125 BH3 interacting domain death agonist AA1904O1 57 627125 BH3 interacting domain death agonist AA190546 58 1573.108 branched chain alpha-ketoacid AA970731 S.20644 dehydrogenase kinase 59 7S6490 BCAT2 branched chain aminotransferase 2, AA43641O S.1O1408 mitochondrial 60 7S6490 BCAT2 branched chain aminotransferase 2, AA481353 S.1O1408 mitochondrial 61 7408O1 BCKDHA branched chain keto acid dehydrogenase AA477298 E1, alpha polypeptide (maple syrup urine disease) 62 7408O1 BCKDHA branched chain keto acid dehydrogenase AA477297 E1, alpha polypeptide (maple syrup urine disease) 63 770835 BCKDHB Branched chain keto acid dehydrogenase AA427739 HS.1265 E1, beta polypeptide (maple syrup urine disease) 64 770835 BCKDHB Branched chain keto acid dehydrogenase HS.1265 E1, beta polypeptide (maple syrup urine disease) 65 129431 EST BRCA2(?) R11316 S.188591 66 129431 EST BRCA2(?) R11315 S.188591 67 836OS CPS1 carbamoyl-phosphate synthetase 1, T61078 S.SO966 mitochondrial 68 836OS CPS1 carbamoyl-phosphate synthetase 1, T6118O S.SO966 mitochondrial 69 1675.950 CRHUS CARBONIC ANHYDRASEW AIOS2226 PRECURSOR 70 744417 CRAT Carnitine acetyltransferase AA621.218 HS.12O68 71 133565 CPT carnitine palmitoyltransferase I, liver R28631 HS.29331 72 133565 CPT carnitine palmitoyltransferase I, liver R32S61 S.293.31 73 415978 CPT carnitine palmitoyltransferase I, liver W85710 S.293.31 74 415978 CPT carnitine palmitoyltransferase I, liver W86378 S.293.31 75 12O106 CASP 1 caspase 1, apoptosis-related cysteine T95052 protease (interleukin 1, beta, convertase) 76 12O106 CASP1 caspase 1, apoptosis-related cysteine T951.49 protease (interleukin 1, beta, convertase) 77 30170 CASP3 caspase 3, apoptosis-related cysteine R14760 protease 78 30170 CASP3 caspase 3, apoptosis-related cysteine R42S30 protease 79 429574 CASP3 caspase 3, apoptosis-related cysteine AAO11445 protease 8O 429574 CASP3 caspase 3, apoptosis-related cysteine AAO11446 protease 81 74S143 caspase 6, apoptosis-related cysteine AA626710 protease 82 279691 CD2-associated protein N48.329 HS.30490 83 279691 CD2-associated protein N49054 HS.30490 84 1558965 cholinesterase-related cell division AA917769 HS.155266 controller 85 324.885 C11 ORF4 11 open reading frame 4 HS.75859 US 2006/0099578 A1 May 11, 2006 16

TABLE 3-continued SEQ D ResGen UniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID 86 324.885 C11 ORF4 chromosome 11 open reading frame 4 W48700 HS.75859 87 1573778 C11 ORF13 chromosome 11 open reading frame 13 AA970526 Hs.72925 88 110772 C14ORF2 chromosome 14 open reading frame 2 T90621 Hs.109052 89 110772 C14ORF2 chromosome 14 open reading frame 2 T83147 Hs.109052 90 897448 C2ORF1 open reading frame 1 AA489478 HS.14454 91 1060841 CIT1 CITRATE SYNTHASE, AA568724 MITOCHONDRIAL PRECURSOR 92 31 OS 19 F10 COAGULATION FACTORX N98524 HS.47913 PRECURSOR 93 31 OS 19 F10 COAGULATION FACTORX W31088 HS.47913 PRECURSOR 94 436062 CPO coproporphyrinogen oxidase HS.89866 (coproporphyria, harderoporphyria) 95 161476 COQ5 COQ5 H2S6O2 96 161476 COQ5 COQ5 H25.556 97 23381.36 COX111-11.2 COX111-11.2 AI703310 98 1902314 COX15.1 COX15.1 AI301929 99 1318021 COXSA COXSA AA76909S 2OO 2326019 COXSB COXSB AI688757 HS.1342 2O1 23O1230 COXSB COXSB AI6993.18 2O2 2097122 COX6A1 COX6A1 A421088 2O3 986164 COX6A2 COX6A2 AA548887 204 2277616 COX6B COX6B AI690478 205 971.851 COX7A1 COX7A1 AAS15958 2O6 937944 COX7A2 COX7A2 AAS 63616 2O7 2O19469 CKMT1 creatine kinase, mitochondrial 1 AI369378 HS.153998 (ubiquitous) 208 795965 CKMT2 Creatine kinase, mitochondrial 2 HS.80691 (sarcomeric) 209 795965 CKMT2 Creatine kinase, mitochondrial 2 AA461048 HS.80691 (sarcomeric) 210 771327 NIFS cysteine desulfurase AA476245 HS.194692 211 771327 NIFS cysteine desulfurase AA476244 HS.194692 212 196189 CYB5 Cytochrome b-5 R92281 HS-83834 213 196189 CYB5 Cytochrome b-5 R919SO HS-83834 214 840894 COX6A1 CYTOCHROME COXIDASE AA482243 HS.180714 POLYPEPTIDE VIA-LIVER PRECURSOR 215 840894 COX6A1 CYTOCHROME COXIDASE AA482340 HS.180714 POLYPEPTIDE VIA-LIVER PRECURSOR 216 824O68 COXSA cytochrome c oxidase subunit Va. AA49073S 217 824O68 COXSA cytochrome c oxidase subunit Va. AA491224 218 298.96S COX6B Cytochrome c oxidase subunit VIb N71160 S.174.031 219 298.96S COX6B Cytochrome c oxidase subunit VIb W05541 S.174.031 220 1472754 COX6B cytochrome c oxidase subunit VIb AA872391 S.174.031 221 838568 COX6C cytochrome c oxidase subunit VIc AA456931 S.74649 222 838568 COX6C cytochrome c oxidase subunit VIc AA457OO6 S.74649 223 14758O3 COX7A1 cytochrome c oxidase subunit VIIa AA87212S S.114346 polypeptide 1 (muscle) 224 16O1947 COX7A2 cytochrome c oxidase subunit VIIa AIOO2403 S.182684 polypeptide 2 (liver) 225 884S11 COX7B cytochrome c oxidase subunit VIIb AA629999 S.75752 226 88448O COX7C cytochrome c oxidase subunit VIIc AA629719 HS.3462 227 1469230 COX8 cytochrome c oxidase subunit VIII AA862.813 S.81097 228 16O126 COX10 Cytochrome c oxidase subunit X (heme H21868 S. 77513 A: farnesyltransferase 229 16O126 COX10 Cytochrome c oxidase subunit X (heme H21869 S. 77513 A: farnesyltransferase 230 1455394 CYC1 cytochrome c-1 AA865265 HS-697 231 194949 CYP3A7 Cytochrome P450 IIIA7 (P450-HFLa) R91078 HS.172323 232 194949 CYP3A7 Cytochrome P450 IIIA7 (P450-HFLa) R91077 HS.172323 233 1724630 S14367 CYTOCHROME P4SO XLA1 AI183397 234 85561 CYP2A7 cytochrome P450, Subfamily IIA TT3031 HS.252937 (phenobarbital-inducible), polypeptide 7 235 85561 CYP2A7 cytochrome P450, Subfamily IIA T72259 HS.252937 (phenobarbital-inducible), polypeptide 7 236 246619 CYP2C8 Cytochrome P450, Subfamily IIC NS3136 (mephenytoin 4-hydroxylase) 237 246619 CYP2C8 Cytochrome P450, Subfamily IIC NS8566 (mephenytoin 4-hydroxylase) US 2006/0099578 A1 May 11, 2006 17

TABLE 3-continued SEQ ID ResGen OniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID 238 195712 CYP2C9 Cytochrome P450, Subfamily IIC R89492 HS.167529 (mephenytoin 4-hydroxylase), polypeptide 9 239 195712 CYP2C9 Cytochrome P450, Subfamily IIC R894.91 HS.167529 (mephenytoin 4-hydroxylase), polypeptide 9 24O 1467195 CYP11B1 cytochrome P450, Subfamily XIB (steroid AA884709 HS.2610 11-beta-hydroxylase), polypeptide 1 241 1497.37 EST Cytochrome P450, Subfamily XIX HOOS92 Hs.141142 (aromatization of androgens) 242 1497.37 EST Cytochrome P450, Subfamily XIX R82738 S.141142 (aromatization of androgens) 243 28462O EST Cytochrome P450, Subfamily XXI N64794 S.124918 (steroid 21-hydroxylase, congenital adrenal hyperplasia) 244 28462O EST Cytochrome P450, Subfamily XXI N77388 S.124918 (steroid 21-hydroxylase, congenital adrenal hyperplasia) 245 266146 CYP24 cytochrome P450, Subfamily XXIV N21576 S.89663 (vitamin D 24-hydroxylase) 246 266146 CYP24 cytochrome P450, Subfamily XXIV S.89663 (vitamin D 24-hydroxylase) 247 295843 CYP27A1 cytochrome P450, Subfamily XXVIIA N66957 S.82568 (steroid 27-hydroxylase, cerebrotendinous xanthomatosis), polypeptide 248. 2043415 DAPK1 death-associated protein kinase 1 AI371.096 HS.153924 249 2364396 DEHUH2 DEHUH2 AI74O677 250 125722 DGUOK deoxyguanosine kinase RO7560 HS.77494 251 125722 DGUOK deoxyguanosine kinase RO7SO6 HS.77494 2S2 2.096376 S2566S DIHYDROLIPOAMIDE AI419467 ACETYLTRANSFERASE COMPONENT 253 813648 DLD dihydrolipoamide dehydrogenase (E3 AA453 679 component of pyruvate dehydrogenase complex, 2-oxo-glutarate complex, branched chain keto acid dehydrogenase complex) 2S4 813648 DLD dihydrolipoamide dehydrogenase (E3 AA447748 CO O l e int O pyruvate dehydrogenase complex, 2-oxo-glutarate complex, branched chain keto acid dehydrogenase complex) 255 271006 DLAT dihydrolipoamide S-acetyltransferase (E2 N299.01 HS.11528S component of pyruvate dehydrogenase complex) 2S6 271006 DLAT dihydrolipoamidedt S-acetyltransferase (E2 N42953 HS.11528S component of pyruvate dehydrogenase ex) 257 815564 DLST Dihydrolipoamide S-succinyltransferase AA456824 HS.196416 (E2 component of 2-oxo-glutarate complex) 258 815564 DLST Dihydrolipoamide S-succinyltransferase AA456899 HS.196416 (E2 component of 2-oxo-glutarate complex) 259 13O894S DIHYDROLIPOAMIDE DIHYDROLIPOAMIDE AA748401 SUCCINYLTRANSFERASE SUCCINYLTRANSFERASE 26O 13O894S DIHYDROLIPOAMIDE DIHYDROLIPOAMIDE AA746285 SUCCINYLTRANSFERASE SUCCINYLTRANSFERASE 261 417385 Dihydroorotate Dihydroorotate dehydrogenase W88472 HS.125846 dehydrogenase 262 417385 Dihydroorotate Dihydroorotate dehydrogenase W89035 HS.125846 dehydrogenase 263 611027 dihydroorotate dihydroorotate dehydrogenase AA173122 HS.94.925 dehydrogenase 264 611027 dihydroorotate dihydroorotate dehydrogenase AA173225 HS.94.925 dehydrogenase 26S 884539 DKFZPS66D143 DKFZP566D143 protein AA629804 266 630013 MSH2 DNA repair protein MSH2 AA21906O HS.78934 267 630013 MSH2 DNA repair protein MSH2 AA219061 HS.78934 268 66642S PLCG1 DNA topoisomerase I AA232856 HS.317 269 66642S PLCG1 DNA topoisomerase I AA233O29 HS.317 US 2006/0099578 A1 May 11, 2006 18

TABLE 3-continued SEQ ID ResGen UniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID 270 810787 HSPF1 DNA PROTEIN HOMOLOG 1 AA481758 HS.82646 271 810787 HSPF1 DNA PROTEIN HOMOLOG 1 AA481022 HS.82646 272 1914863 DYSF dysferlin, limb girdle AI31 O142 HS143897 2B (autosomal recessive) 273 773.399 DMD (muscular dystrophy, AA425649 HS.169470 Duchenne and Becker types), includes DXS142, DXS164, DXS206, DXS230, DXS239, DXS.268, DXS.269, DXS270, DXS272 274 773.399 DMD dystrophin (muscular dystrophy, AA427831 HS.169470 Duchenne and Becker types), includes DXS142, DXS164, DXS206, DXS230, DXS239, DXS.268, DXS.269, DXS270, DXS272 275 7961.97 DMD Dystrophin (muscular dystrophy, AA461118 HS.169470 Duchenne and Becker types), includes DXS142, DXS164, DXS206, DXS230, DXS239, DXS.268, DXS.269, DXS270, DXS272 276 7961.97 DMD Dystrophin (muscular dystrophy, AA461435 HS.169470 Duchenne and Becker types), includes DXS142, DXS164, DXS206, DXS230, DXS239, DXS.268, DXS.269, DXS270, DXS272 277 781017 EGR2 early growth response 2 (Krox-20 HS.1395 (Drosophila) homolog) 278 781017 EGR2 early growth response 2 (Krox-20 AA4463OO HS.1395 (Drosophila) homolog) 279 180512 ENC1 ectodermal-neural cortex (with BTB-like HS.104925 domain) 28O A31998 ELECTRONTRANSFER AI192719 FLAVOPROTEIN ALPHA-SUBUNIT 281 2274.670 S32482 ELECTRONTRANSFER FLAVOPROTEIN BETA-SUBUNIT 282 2267229 S62767 ELONGATION FACTORTU AI609398 283 745542 ECHS1 enoyl Coenzyme A hydratase, short AA626255 Hs.76394 chain, 1, mitochondrial 284 34.4272 EMP3 epithelial 3 W73810 HS.9999 285 34.4272 EMP3 epithelial membrane protein 3 W73748 HS.9999 286 253725 EST EST N21972 HS.43052 287 287569 EST EST N62122 HS.833.13 288 287569 EST EST N78351 HS.833.13 289 489755 EST EST AAO99554 HS.246174 290 489755 EST EST AA101991 HS.246174 291 609989 No Data EST AA1691.76 292 609989 No Data EST AA169296 293 S11012 AGPS EST - putative alkylglycerone phosphate AA099.787 syntinase 294 S11012 AGPS EST - putative alkylglycerone phosphate AA102257 syntinase 295 4495.04 E S EST, Weakly similar to predicted using AA777928 S.121993 Genefinder C. elegans 296 47005 ESTS HO982S HS.6818 297 47005 EST HO992O HS.6818 298 79655 EST T62655 S.11039 s 299 79655 EST T62.509 S.11039 3OO 126229 EST RO6313 S.77677 301 126229 EST RO6258 S.77677 3O2 129606 EST R16545 S.70333 303 129606 EST R16603 S.70333 3O4 165837 EST R86713 S.87595 305 165837 EST R86712 S.87595 306 248669 EST N59553 HS.8941 307 248669 EST N78295 HS.8941 3O8 2S4OO4 EST N223O2 S.177861 309 2S4OO4 EST N75187 S.177861 310 259462 EST N29545 HS.3569 311 290505 EST N67991 S.3O487 312 290505 EST N80413 S.3O487 313 341901 EST W61374 HS.11317 314 429942 EST AAO34O62 HS.387SO 315 784214 ESTS AA446865 HS14018 US 2006/0099578 A1 May 11, 2006 19

TABLE 3-continued SEQ ID ResGen OniGene NO Clone ID Gene e Gene Name GenBank Cluster ID

316 784214 EST AA446980 S.14O18 317 898.222 EST AAS986O2 S.13434 318 1636,741 ESTS AIO17846 S.169539 319 1132O6 EST 1gn y imi 8 O A. RGINYL T83996 S.15395

O N D R C EC URSOR c S Ceal e visiae 1132O6 EST 1gn y imi 8 O A. RGINYL T83997 S.15395

O N D R A. C R EC URSOR Sc CC c Of yC e S Ce e viSi c e 321 i9. AASO4246 S.64593 S 322 782439 ATPSI ig l s AA431433 S.85539 i. R Cricetitius Olgi C c s(ii 2d S 323 782439 ATPSI ud AA431836 S.85539 i (N, i. R A. Cricetitius Olgi C c ud(ii 2d S 324 434968 S S.177S30 EPSILON CHAIN, DRIAL PRECURSOR Bos 325 82874 EST ighly similar to ATPASE T69273 S.241336 NHIBITOR, MITOCHONDRIAL RSOR Rattus norvegicus 326 82874 EST ighly similar to ATPASE T69348 S.241336 NHIBITOR, MITOCHONDRIAL PRECURSOR Rattus norvegicus 327 290753 CS ESTs, Highly similar to CITRATE N67639 S.239760 SYNTHASE, MITOCHONDRIAL PRECURSORSus scrofa 328 290753 CS ESTs, Highly similar to CITRATE WO1297 S.239760 SYNTHASE, MITOCHONDRIAL PRECURSORSus scrofa 329 73.1308 CS ESTs, Highly similar to CITRATE AA416759 S.239760 S HONDRIAL C rofa 330 73.1308 CS S S. ighly similar to CITRATE AA416746 S.239760 YNTHASE, MITOCHONDRIAL s RSORSus scrofa 331 283943 ighly similar to ELONGATION S.41066 R G, MITOCHONDRIAL C R C RSOR Rattus norvegicus 332 283943 E ighly similar to ELONGATION N55159 S.41066 R G, MITOCHONDRIAL RSOR Rattus norvegicus 333 359723 ighly similar to ELONGATION AAO 11122 S.41066 R G, MITOCHONDRIAL RSOR Rattus norvegicus 334 359723 S S ighly similar to ELONGATION AAO10761 S.41066 A R G, MITOCHONDRIAL C S. RSOR Rattus norvegicus 335 430733 hly similar to AA677960 S.3585 HETICAL 16.5 KD PROTEIN NPAS8-EGT2 INTERGENIC REGION Saccharomyces cerevisiae 336 1114960 ETFDH ighly similar to S.30661 HETICAL 29.2 KD PROTEIN 1-PTM1 INTERGENIC REGION Saccharomyces cerevisiae 337 1030791 ighly similar to AA609009 S.63304 HETICAL 44.9 KD PROTEIN NERG7-NMD2 INTERGENIC REGION Saccharomyces cerevisiae 338 950700 PP ESTs, H ighly similar to INORGANIC AA608572 PYROP HOSPHATASE Bos taurus US 2006/0099578 A1 May 11, 2006 20

TABLE 3-continued SEQ ID ResGen OniGene NO Clone ID Gene Comple e Gene Name GenBank Cluster ID 339 322218 ESTs, H ighly similar O ISOLEUCYL W37993 S.SS609 TRNASYNTHETAS s MITOC HONDRIAL Saccharomyces cerevisiae 340 322218 ESIs, F ighly similar O ISOLEUCYL W37992 S.SS609 TRNASYNTHETAS HONDRIAL Saccharomyces

341 LOCS1264 ESTs. Hi l ilar O W88752 HS.7736 MITOC HONDRIAL 60S RIBOSOMAL ROTE NL2 PRECURSOR Sa ccharomyces cerevisiae 342 LOCS1264 E STS, Hiighly similar W88848 HS.7736 TOC HONDRIAL 60S RIBOSOMAL M. OTE NL2 PRECURSOR Sa ccharomyces cerevisiae 343 7536O2 E STs, Hiighly similar AA479944 HS.42484 TOC HONDRIAL CARRIER ROTE N RIM2 Saccharomyces cerevisiae 344 7536O2 E STS, Hiighly similar O AA478847 S.42484 TOC NDRIAL CARRIER ROTE N RIM2 Saccharomyces cerevisiae 345 629916 TIM17B E STS, Hiighly similar O AA219179 S.19105 TOC HONDRIAL IMPORT INNER EMBRANET RANSLOCASE S UBUNIT TIM17 Saccharomyces cerevisiae 346 629916 TIM17B ESTs, Highly similar to AA219 178 HS.19105 TOC HONDRIAL IMPORT INNER EMBRANET RANSLOCASE SUBUNIT TIM1 7 Saccharomyces cerevisiae 347 191826 ESTs, H ighly similar O S.3440 TOC HONDRIAL RNA SPLICING PROTE NMRS3 Saccharomyces C ei e isiaeSi 348 191826 O S.3440 RIAL RNA SPLICING

349 TSOO82 HS-3440

PROT

350 TSOO19 HS-3440

351 488386 AAO46639 S.3440

352 488386 AAO46778 S.3440 RNA SPLICING R4 Saccharomyces

353 61.1467 NDUFS6 O AA176453 S.497.67 TRIFUNCTONAL A SUBUNIT sapiens 61.1467 NDUFS6 O AA176931 S.497.67 O N D R TRIFUNCTONAL A SUBUNIT sapiens 355 1793.36 SDHA O SUCCINATE HSO345 HS.469 Homo sapiens 356 1793.36 SDHA O SUCCINATE HS.469 Homo sapiens 357 843335 SUCLG1 ighly similar O SUCCNYL AA485965 HS.7043 GASE Rattus norvegicus US 2006/0099578 A1 May 11, 2006 21

TABLE 3-continued SEQ ID ResGen OniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID 358 843335 SUCLG1 ESTs, Highly similar to SUCCINYL AA48957S HS.7043 COALIGASE Rattus norvegicus 359 LOCS1017 EST s, Highly similar to CGI-113 protein AASO4139 S.1907 7 H. sapiens 360 LOCS1017 ESTs, Highly similar to CGI-113 protein S.1907 7 H. sapiens 361 814271 ESTs, Highly similar to CGI-116 protein S.18885 H. sapiens 362 814271 ESTs, Highly similar to CGI-116 protein AA459222 S.18885 H. sapiens 363 811062 LOCS1629 ESTs, Highly similar to CGI-69 protein AA485441 S.237.924 H. sapiens 364 811062 LOCS1629 ESTs, Highly simi 8 o CGI-69 protein S.237.924 H. sapiens 365 417803 ESTs, Highly simi o hypothetical W88753 O ein H. sapiens 366 417803 ESTs, Highly simi o hypothetical W888.59 O 367 878316 ESTs, Highly similar to Small Zinc finger S.109571 ike 368 SO4689 ESTs, Moderately similar o 3 AA149172 S.SS781 OXOACYL-ACYL-CARRIER PROTEINSYNTHASE I Escherichia coi 369 SO4689 ESTs, Moderately similar o 3 AA149171 S.SS781 OXOACYL-ACYL-CARRIER PROTEINSYNTHASE I Escherichia coi 370 238,907 ESTs, Moderately similar o ABC1 H67876 S.243960 PROTEIN PRECURSOR Saccharomyces cerevisiae 371 238,907 ESTs, Moderately similar S.243960 PROTEIN PRECURSOR Saccharomyces cerevisiae 372 435314 ESTs, Moderately similar AA699919 S.114018 AMINOLEVULINIC ACID SYNTHASE MIT(OCHONDRIAL PRECURSOR, ERYTHROID-SPECIFIC H. sapiens 373 839.027 ESTs, Modera e y similar o CGI-24 AA487499 O ein H. sapi ens 374 839.027 ESTs, Modera e y similar o CGI-24 AA48771S O ein H. sapiensi 375 321354 ESTs, Moderately similar o MSG1 W32403 S.18349 related protein H. sapiens 376 321354 ESTs, Moderately similar W3298O S.18349 related pro ein H. sapiens 377 824911 ESTs, Weakly similar to prediction AA489022 378 824911 ESTs, Weakly similar to prediction AA489.118 379 85384 ESTs, Weakly similar to anon2A5 TT1965 D. melanogaster 380 85384 ESTs, Weakly similar to anon2A5 TT2105 S.10964 D. melanogaster 381 757265 ESTs, Weakly similar to aralar AA426113 H. Sapiens 382 490753 ESTs, Weakly similar to head-elevated AA133166 HS.6693 expression in 0.9 kb D. melanogaster 383 343555 ESTs, Weakly similar to mitochondrial W693.79 S.62669 inner membrane protease 1 S. cerevisiae 384 343555 ESTs, Weakly similar to mitochondrial W69378 S.62669 inner membrane protease 1 S. cerevisiae 385 1983.12 KIAAO719 ESTs, Weakly similar to R94.191 S.211.98 MIT TOCHONDRIAL PRECURSOR PROTEINS IMPORT RECEPTOR Neurospora crassa 386 1983.12 KIAAO719 ESTs, Weakly similar to R94290 S.211.98 MIT TOCHONDRIAL PRECURSOR PROTEINS IMPORT RECEPTOR Neurospora crassa 387 511257 KIAAO719 ESTs, Weakly similar to AAO88722 HS.21198. MIT TOCHONDRIAL PRECURSOR PROTEINS IMPORT RECEPTOR Neurospora crassa US 2006/0099578 A1 May 11, 2006 22

TABLE 3-continued SEQ ID ResGen OniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID

388 511257 KIAAO719 ESTs, Weakly similar O AAO88799 HS.21198. MITOCHONDRIALP RECURSOR PROTEINS IMPORT RECEPTOR Neurospora crassa 389 3246.51 EST ESTs, Weakly similar O W47099 Hs.19513 MITOCHONDRIAL RESPIRATORY FUNCTION PROTEIN 1 Saccharomyces cerevisiae 390 3246.51 EST ESTs, Weakly similar O W47.223 Hs.19513 MITOCHONDRIAL RESPIRATORY FUNCTION PROTEIN 1 Saccharomyces cerevisiae 391 429222 EST ESTs, Weakly similar O MSF1 AAOO4210 HS.3945 PROTEIN S. cerevisiae 392 429222 EST ESTs, Weakly similar O MSF1 AAOO7411 HS.3945 PROTEIN S. cerevisiae 393 754537 EST ESTs, Weakly similar O myosin beta heavy chain, cardiac and skeletal muscle H. sapiens 394 754537 EST ESTs, Weakly similar O myosin beta AA421979 heavy chain, cardiac and skeletal muscle H. sapiens 395 897557 EST ESTs, Weakly similar O myosin beta AA497024 S.1798.17 heavy chain, cardiac and skeletal muscle H. sapiens 396 897557 EST ESTs, Weakly similar O myosin beta AA489606 S.1798.17 heavy chain, cardiac and skeletal muscle H. sapiens 397 812169 EST ESTs, Weakly similar O PROBABLE HS.7807 MITOCHONDRIAL 4OS RIBOSOMAL PROTEIN S5 (S. cerevisiae 398 2O8531 EST ESTs, Weakly similar O PUTATIVE H61979 S.7994 MITOCHONDRIAL CARRIER YBR291C Saccharomyces cerevisiae 399 2O8531 EST ESTs, Weakly similar O PUTATIVE H61978 S.7994 MITOCHONDRIAL CARRIER YBR291C Saccharomyces cerevisiae 400 435509 tRNAleu ESTs, Weakly similar o similar to eucyl-tRNA synthetase C. elegans 43662 EST ESTs, Weakly similar o similar to HOS645 S.21262 mitochrondrial carrier protein C. elegans 43662 EST ESTs, Weakly similar o similar to HOS644 S.21262 mitochrondrial carrier protein C. elegans 403 53385 EST ESTs, Weakly similar o Similar to R16231 S.106620 NAD(P) transhydrogenase, mitochondrial 404 53385 EST ESTs, Weakly similar o Similar to R16232 S.106620 NAD(P) transhydrogenase, mitochondrial 40S 84880 EST ESTs, Weakly similar O WISC PROTEIN T74882 S.12239 Escherichia coli 84880 EST ESTs, Weakly similar O WISC PROTEIN TT4939 HS.12239 Escherichia coli 407 8454.19 FANCA Fanconi anemia, comp ementation group A AA644129 HS.86.297 4.08 624634 FDX1 erredoxin 1 AA187349 HS.744 409 624634 FDX1 erredoxin 1 AA188427 HS.744 410 365149 FECH errochelatase (protoporphyria) AAO2S142 HS.26 411 365149 FECH errochelatase (protoporphyria) AAO2S157 HS.26 412 14691.38 FGA Fibrinogen, Aalpha polypeptide AA865707 S.90765 413 131839 FOLR1 olate receptor 1 (adult) R24635 S.73769 414 131839 FOLR1 olate receptor 1 (adult) R24530 S.73769 415 1466OS FPRL1 ormyl peptide receptor-like 1 R80041 S.99855 416 1466OS FPRL1 ormyl peptide receptor-like 1 R79948 S.99855 417 4906OO FOSL2 FOS-like antigen 2 AA1O1617 S.155210 418 4906OO FOSL2 FOS-like antigen 2 AA1O1616 S.155210 419 27979O FMR1 Fragile X mental retardation 1 N483SS S.89764 420 27979O FMR1 Fragile X mental retardation 1 N49132 S.89764 421 669419 FRDA Friedreich ataxia AA253413 S.95998 422 669419 FRDA Friedreich ataxia AA253388 S.95998 423 469412 FH Fumarate hydratase AAO26917 S.7S653 424 469412 FH Fumarate hydratase AAO26918 S.7S653 US 2006/0099578 A1 May 11, 2006 23

TABLE 3-continued SEQ ID ResGen UniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID 425 84.2839 FUS fusion, derived from t(12; 16) malignant AA486.284 liposarcoma 426 84.2839 FUS fusion, derived from t(12; 16) malignant AA4893.05 liposarcoma 427 81.289 ACTG2 Gamma-actin, enteric Smooth muscle T6004.8 HS.77443 form 428 288663 GB1 gap junction protein, beta 1, 32 kD N62394 (connexin 32, Charcot-Marie-Tooth neuropathy, X-linked) 429 288663 GB1 gap junction protein, beta 1, 32 kD N79360 (connexin 32, Charcot-Marie-Tooth neuropathy, X-linked) 430 2338827 GCDH HUMAN GCDH HUMAN AI693352 431 66534 GCKR T67007 HS.89771

432 66534 GCKR T67OO6 HS.89771

433 471498 GNS glucosamine (N-acetyl)-6-sulfatase AAO3S347 HS.2703 (Sanfilippo disease IIID) 434 122636 G6PC Glucose-6-phosphatase T98886 HS.242 435 122636 G6PC Glucose-6-phosphatase T98887 HS.242 436 166236 G6PD glucose-6-phosphate dehydrogenase R87497 437 166236 G6PD glucose-6-phosphate dehydrogenase R88192 438 75.3775 GMPR Glucose-6-phosphate dehydrogenase AA406242 HS.1435 439 75.3775 GMPR Glucose-6-phosphate dehydrogenase AA410375 HS.1435 440 361S6S GLUD1 glutamate dehydrogenase 1 AAO18372 HS.77SO8 441 361S6S GLUD1 glutamate dehydrogenase 1 AAO17175 HS.77SO8 442 51702 GOT1 glutamic-Oxaloacetic transaminase 1, H22856 HS.S97 soluble (aspartate aminotransferase 1) 443 51702 GOT1 glutamic-Oxaloacetic transaminase 1, H228SS HS.S97 soluble (aspartate aminotransferase 1) 444 841370 GOT2 Glutamic-oxaloacetic transaminase 2, AA487739 Hs.1701.97 mitochondrial (aspartate aminotransferase 2) 445 841370 GOT2 Glutamic-oxaloacetic transaminase 2, AA487521 Hs.1701.97 mitochondrial (aspartate aminotransferase 2) 446 810999 GPX1 glutathione peroxidase 1 AA485362 HS.76686 447 810999 GPX1 glutathione peroxidase 1 AA485517 HS.76686 448 58.7847 GPX2 Glutathione peroxidase 2, gastrointestinal AA135289 HS.2704 449 58.7847 GPX2 Glutathione peroxidase 2, gastrointestinal AA135152 HS.2704 450 85.5523 GPX3 Glutathione peroxidase 3 (plasma) AA66418O HS.172153 451 1555659 GPX3 glutathione peroxidase 3 (plasma) AI147S34 HS.172153 452 448619 GSR Glutathione reductase AA777289 HS.121524 453 811792 GSS Glutathione synthetase AA463458 HS.82327 454 628418 GPD1 glycerol-3-phosphate dehydrogenase 1 AA192547 HS.255718 (soluble) 455 628418 GPD1 glycerol-3-phosphate dehydrogenase 1 AA1931.16 HS.255718 (soluble) 456 428756 GPD2 glycerol-3-phosphate dehydrogenase 2 AAOOS219 HS.932O1 mitochondrial) 457 428756 GPD2 glycerol-3-phosphate dehydrogenase 2 AAOOS218 HS.932O1 (mitochondrial) 458 42558 GATM glycine amidinotransferase (L- R61229 HS.7S335 arginine:glycine amidinotransferase) 459 42558 GATM glycine amidinotransferase (L- R61228 HS.7S335 arginine:glycine amidinotransferase) 460 134748 GCSEH ycine cleavage system protein H R28294 HS.77631 aminomethyl carrier) 461 134748 GCSEH ycine cleavage system protein H R28O81 HS.77631 aminomethyl carrier) 462 248261 GLDC ycine dehydrogenase (decarboxylating: N78O83 HS.27 ycine decarboxylase, glycine cleavage ystem protein P) 463 248261 GLDC ycine dehydrogenase (decarboxylating: NS8494 HS.27 ycine decarboxylase, glycine cleavage ystem protein P) 464 45632 GYS1 ycogen synthase 1 (muscle) HO8446 HS.772 465 45632 GYS1 ycogen synthase 1 (muscle) HO8732 HS.772 466 245920 GYS2 ycogen synthase 2 (liver) N72934 HS.82614 467 245920 GYS2 : ycogen synthase 2 (liver) NS2282 HS.82614 468 1502027 MGE1 GrpE-like protein cochaperone mRNA AA887.226 US 2006/0099578 A1 May 11, 2006 24

TABLE 3-continued SEQ ID ResGen OniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID 469 22SO688 GT GT AI659294 470 841008 GBP1 Guanylate binding protein 1, interferon AA486849 S.62661 inducible, 67 kD 471 841008 GBP1 Guanylate binding protein 1, interferon AA486850 S.62661 inducible, 67 kD 472 796341 CLCN3 sapiens RNA for CLCN3 AA461332 S.174139 473 796341 CLCN3 sapiens RNA for CLCN3 AA4597SO S.174139 474 30O237 No Data sapiens DAP-3 mRNA N78611 475 30O237 No Data sapiens DAP-3 mRNA WO7332 476 341246 CLPP sapiens mRNA for CLPP W58658 S.74362 477 341246 CLPP sapiens mRNA for CLPP W58337 S.74362 478 10311.85 MCSP sapiens mRNA for mitochondrial AA609976 S.111850 capsule selenoprotein 479 259842 PMPCB H. sapiens mRNA for M-phase N298.44 S.184211 phosphoprotein, mpp 11 480 259842 PMPCB H. sapiens mRNA for M-phase N57262 S.184211 phosphoprotein, mpp 11 481 810942 IDEH3G H. sapiens mRNA for NAD (H)-specific AA45938O S.75253 isocitrate dehydrogenase gamma subunit precursor 482 810942 IDEH3G H. sapiens mRNA for NAD (H)-specific AA459606 S.75253 isocitrate dehydrogenase gamma subunit precursor 483 S30282 DUFA1 H. sapiens mRNA for NADH AA111999 S.74823 dehydrogenase 484 S30282 DUFA1 H. sapiens mRNA for NADH AAO83784 S.74823 dehydrogenase 485 813815 R13 H. sapiens mRNA for orphan nuclear AA447727 S.83623 hormone receptor 486 813815 R13 H. sapiens mRNA for orphan nuclear AA447889 S.83623 hormone receptor 487 810959 RHGDIA H. sapiens mRNA for rho GDP AA4594OO S.15916.1 dissociation Inhibitor 1 488 810959 RHGDIA H. sapiens mRNA for rho GDP AA4596.25 S.15916.1 dissociation Inhibitor 1 489 SO6032 T M 1 7 H. sapiens mRNA for TIM17 preprotein AA708446 translocase 490 814526 H. sapiens seb4D mRNA AA459363 491 814526 H. sapiens seb4D mRNA AA459588 492 81446O H. sapiens SURF-5 mRNA AA459247 493 81446O H. sapiens SURF-5 mRNA AA459472 494 6 harakiri, BCL2-interacting protein AIO83676 (contains only BH3 domain) 495 1417985 heat shock 10 kD protein 1 (chaperonin AA878786 O) 496 1417985 heat shock 10 kD protein 1 (chaperonin AI791.247 O) 497 1870305 PB2 heat shock 27 kD protein 2 AI24.5337 S.78846 498 1354618 PF2 heat shock 40 kD protein 2 AA83O392 S.172847 499 755904 PA1A HEAT SHOCK 70 KD PROTEIN 1 AA496544 S.8997 500 1604342 PA9B heat shock 70 kD protein 9B (mortalin-2) AA987644 S.3069 5O1 884719 PA10 HEAT SHOCK COGNATE 71 KD AA6295.67 S.180414 PROTEIN 502 2S3009 HSPCA HEAT SHOCKPROTEIN HSP 90 H38.540 ALPHA 503 2S3009 HSPCA HEAT SHOCKPROTEIN HSP 90 H38588 ALPHA SO4 824.031 heat shock protein, DNAJ-like 2 AA490946 505 824.031 heat shock protein, DNAJ-like 2 AA491132 SO6 1606894 F4 heat shock transcription factor 4 AA999776 S.75486 507 S62101 hect (homologous to the E6-AP (UBE3A) AA211496 S.2SSS61 carboxyl terminus) domain and RCC1 (CHC1)-like domain (RLD) 1 SO8 S62101 HERC1 hect (homologous to the E6-AP (UBE3A) AA211544 carboxyl terminus) domain and RCC1 (CHC1)-like domain (RLD) 1 509 852.59 HMOX1 heme oxygenase (decycling) 1 T71757 S.2O2833 510 852.59 HMOX1 heme oxygenase (decycling) 1 T71606 S.2O2833 511 74S116 HMOX2 Heme oxygenase (decycling) 2 AA626370 S.83853 512 433307 HNF6A hepatocyte nuclear factor 6, alpha AA699732 S.731.68 513 84O158 HK1 Hexokinase 1 AA485271 S.118.625 S1.4 84O158 HK1 Hexokinase 1 AA485272 S.118.625 US 2006/0099578 A1 May 11, 2006 25

TABLE 3-continued SEQ ID ResGen UniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID 515 1338040 C46157 HEXOKINASE D, LIVER ISOZYMES AA811712 S16 211780 No Data Hexosaminidase B (beta polypeptide) H71868 517 211780 No Data Hexosaminidase B (beta polypeptide) H71081 518 767441 HEXB hexosaminidase B (beta polypeptide) AA417946 S.51043 519 767441 HEXB hexosaminidase B (beta polypeptide) AA418121 S.51043 520 97.0591 HMG1 High-mobility group (non histone AA683O85 S.1895.09 chromosomal) protein 1 521 3631 O3 High-mobility group (non histone AAO19511 S.80684 chromosomal) protein 2 522 3631 O3 High-mobility group (non histone AAO192O3 S.80684 chromosomal) protein 2 523 80924 HO3 histidyl-tRNA synthetase T701.04 S.77798 524 80924 HO3 histidyl-tRNA synthetase T70037 S.77798 525 81.2246 HLCS holocarboxylase synthetase (biotin AA455043 S.79375 proprionyl-Coenzyme A-carboxylase (ATP-hydrolysing) ligase) 526 71.2577 HCCS HOLOCYTOCHROME C-TYPE AA281548 S.88859 SYNTHETASE 527 71.2577 HCCS HOLOCYTOCHROME C-TYPE AA281549 S.88859 SYNTHETASE 528 611075 HOXA1 homeo box A1 AA173231 529 611075 HOXA1 homeo box A1 AA173290 530 244146 APAF1 Homo sapiens apoptotic protease NS1014 S.77579 activating factor 1 (Apaf-1) mRNA, complete cols 531 244146 APAF1 Homo sapiens apoptotic protease N72045 S.77579 activating factor 1 (Apaf-1) mRNA, complete cols 532 288796 BNIP2 Homo sapiens BCL2/adenovirus E1B S.155596 19 kD-interacting protein 2 (BNIP2) mRNA, complete cols 533 43262O NOD1 Homo sapiens caspase recruitment AA699441 domain 4 (NOD1) mRNA 534 85.3506 23956 Mirna Homo sapiens clone 23956 mRNA, AA663549 S.8128 partial cols 535 288888 EST Homo sapiens clone 640 unknown N62617 S.44563 mRNA, complete sequence 536 288888 EST Homo sapiens clone 640 unknown N78388 S.44563 mRNA, complete sequence 537 271102 CCS Homo sapiens copper chaperone for S.SOO2 superoxide dismutase (CCS) mRNA, complete cols 538 4898.23 COX17 Homo sapiens COX17 mRNA, complete AA099855 S.16297 cols 539 4898.23 COX17 Homo sapiens COX17 mRNA, complete AAO9932O S.16297 cols 487.348 DYMPLE Homo sapiens dynamin-like protein AAO4.5529 S.180628 mRNA, complete cols S41 487.348 DYMPLE Homo sapiens dynamin-like protein S.180628 mRNA, complete cols S42 359982 BNIP3 Homo sapiens E1B 19K/Bcl-2-binding AAO 63521 S.79428 protein Nip3 mRNA, nuclear gene encoding mitochondrial protein, complete cols 543 359982 BNIP3 Homo sapiens E1B 19K/Bcl-2-binding AAO35669 S.79428 protein Nip3 mRNA, nuclear gene encoding mitochondrial protein, complete cols 544 HUEL Homo sapiens embryonic lung protein S.44053 (HUEL) mRNA, complete cols 545 1472184 HUEL Homo sapiens embryonic lung protein AA873264 S.44053 (HUEL) mRNA, complete cols S46 129644 Homo sapiens eps8 binding protein e3B1 R16667 S.24752 mRNA, complete cols 547 129644 Homo sapiens eps8 binding protein e3B1 R16666 S.24752 mRNA, complete cols S48 563574 FRG1 Homo sapiens FRG1 mRNA, complete AA113339 cols S49 563574 FRG1 Homo sapiens FRG1 mRNA, complete AA112636 cols 550 83279 TIM23 Homo sapiens inner mitochondrial T68317 S.11866 membrane translocase Tim23 (TIM23) US 2006/0099578 A1 May 11, 2006 26

TABLE 3-continued SEQ ID ResGen UniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID mRNA, nuclear gene encoding mitochondrial protein, complete cols 551 83279 TIM23 Homo sapiens inner mitochondrial T68386 S.11866 membrane translocase Tim23 (TIM23) mRNA, nuclear gene encoding mitochondrial protein, complete cols 552 4SS123 KIAAO429 Homo sapiens KIAA0430 mRNA, AA676805 S.77694 complete cols 553 APACD Homo sapiens mRNA or ATP binding N80741 S.153884 protein, complete cols 554 APACD Homo sapiens mRNA or ATP binding WO7537 S.153884 protein, complete cols 555 129146 COX7RP Homo sapiens mRNA or COX7RP, complete cols 556 129146 COX7RP Homo sapiens mRNA or COX7RP, R10947 complete cols 557 745314 HIRIPS Homo sapiens mRNA or HIRA AA625581 S.17368 interacting protein HIRIP5 558 81.0316 KIAAO631 Homo sapiens mRNA or KIAAO631 HS.75154 protein, partial cols 559 81.0316 KIAAO631 Homo sapiens mRNA or KIAAO631 AA464139 HS.75154 protein, partial cols S60 490778 Homo sapiens mRNA or low molecular AA133191 HS.3709 mass ubiquinone-binding protein, complete cols 561 131653 RPMS 12 Homo sapiens mRNA or mitochondrial R23752 HS.9964 ribosomal protein S12 131653 RPMS 12 Homo sapiens mRNA or mitochondrial R23806 HS.9964 ribosomal protein S12 563 344825 LAS Homo sapiens mRNA or putative lipoic W72965 S.S3531 acid synthetase, partial S64 344825 LAS Homo sapiens mRNA or putative lipoic S.S3531 acid synthetase, partial 565 345621 CXX1 Homo sapiens mRNA or putatively W72596 S.2SSS32 prenylated protein 566 345621 CXX1 Homo sapiens mRNA or putatively W76590 S.2SSS32 prenylated protein 567 SCA7 Homo sapiens mRNA or spinocerebellar AA7042SS S.108447 ataxia 7 568 123474 SCD Homo sapiens mRNA or stearoyl-CoA ROO707 S.119597 desaturase 569 123474 SCD Homo sapiens mRNA or stearoyl-CoA S.119597 desaturase 570 855890 cDNA Homo sapiens mRNA: cDNA HS.255914 DKFZp586C0722 (from clone DKFZp586C0722) 571 77.0043 NDUFV1 Homo sapiens NADH: ubiquinone HS.7744 dehydrogenase 51 kDa subunit (NDUFV1) mRNA, nuclear gene encoding mitochondrial protein, complete cols 572 77.0043 NDUFV1 Homo sapiens NADH: ubiquinone AA427652 HS.7744 dehydrogenase 51 kDa subunit (NDUFV1) mRNA, nuclear gene encoding mitochondrial protein, complete cols 573 IDEH1 Homo sapiens NADP-dependent AA666366 HS.11223 isocitrate dehydrogenase (IDH) mRNA, complete cols 574 124753 ABCD4 Homo sapiens peroxisomal membrane RO21.89 HS.94395 protein 69 (PMP69) mRNA, complete cols 575 2931.04 PHYH Homo sapiens peroxisomal phytanoyl N91990 HS.172887 CoA alpha-hydroxylase (PAHX) mRNA, complete cols 576 2931.04 PHYH Homo sapiens peroxisomal phytanoyl N6384.5 HS.172887 CoA alpha-hydroxylase (PAHX) mRNA, complete cols 577 1629.264 hTIM44 Homo sapiens putative mitochondrial AIOO3393 HS.1231.78 inner membrane protein import receptor (hTIM44) mRNA, nuclear gene encoding mitochondrial protein, complete cols US 2006/0099578 A1 May 11, 2006 27

TABLE 3-continued SEQ ID ResGen OniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID 578 399.532 RPA40 Homo sapiens RNA polymerase I subunit AA733O38 HS.5409 hRPA39 mRNA, complete cols 579 787938 SLC4A4 Homo sapiens sodium bicarbonate AA452278 HS.5462 cotransporter (HNBC1) mRNA, complete cols S8O 1381.89 WFS1 Homo sapiens transmembrane protein RS3910 HS.26O77 (WFS1) mRNA, complete cods 581 1381.89 WFS1 Homo sapiens transmembrane protein RS3911 HS.26O77 (WFS1) mRNA, complete cods 582 266106 YWHAE Human 14-3-3 epsilon mRNA, complete N21624 HS.79474 cols 583 266106 YWHAE Human 14-3-3 epsilon mRNA, complete N28863 HS.79474 ds S84 45464 AK2 Human adenylate kinase 2 (adk2) mRNA, HO973O HS.171811 omplete cols 585 45464 AK2 Human adenylate kinase 2 (adk2) mRNA, H10488 HS.171811 omplete cols S86 795.543 AOE372 Human antioxidant AOE37-2 AA459663 HS.83383 mRNA, complete cols 587 241481 CASP10 Human apoptotic cysteine protease Mch4 H30712 HS.S353 ( Mch4) mRNA, complete cols 588 241481 CASP10 uman apoptotic cysteine protease Mch4 H3O711 HS.S353 Mch4) mRNA, complete cols 589 89.7774 APRT uman APRT gene for adenine AAS98510 HS.28914 phosphoribosyltransferase 590 810SS2 REA Human B-cell receptor associated protein AA464669 HS.7771 (hBAP) mRNA, partial cds 591 810SS2 REA Human B-cell receptor associated protein AA464567 HS.7771 (hBAP) mRNA, partial cds 592 2326129 BBC3 Human Bcl-2 binding component 3 AI688.112 HS.87246 (bbc3) mRNA, partial cols 593 79.5729 BAD Human Bcl-2 binding component 6 AA46O291 Hs.76366 (bbc6) mRNA, complete cols 594 79.5729 BAD Human Bcl-2 binding component 6 AA461579 Hs.76366 (bbc6) mRNA, complete cols 595 814478 BCL2A1 Human Bcl-2 related (Bfl-1) mRNA, AA459.263 HS.227817 complete cols 596 814478 BCL2A1 Human Bcl-2 related (Bfl-1) mRNA, AA459491 HS.227817 complete cols 597 212198 TP53BP2 Human Bcl2, p53 binding protein H69153 HS.44585 Bbp/53BP2 (BBP/53BP2) mRNA, complete cols 598 212198 TP53BP2 Human Bcl2, p53 binding protein H69077 HS.44585 Bbp/53BP2 (BBP/53BP2) mRNA, complete cols 599 432581 Novel Gene Human BRCA2 region, mRNA sequence AA6993.90 HS.184938 CGO12 600 433111 BAC clone CIT987SK-A- Human Chromosome 16 BAC clone AA680407 HS.47278 73.5G6 CIT987SK-A-73SG-6 6O1 78.263S NDUFAB1 Human Chromosome 16 BAC clone AA447569 HS.SSS6 C IT987SK-A-73SG6 602 78.263S NDUFAB1 uman Chromosome 16 BAC clone AA448553 HS.SSS6 C IT987SK-A-73SG6 603 6694.71. 23589 mRNA uman clone 23589 mRNA sequence AA234889 HS.11506 604 6694.71. 23589 mRNA Human clone 23589 mRNA sequence AA2S3479 HS.11506 60S 771173 23732 mRNA Human clone 23732 mRNA, partial cols AA443497 HS.81281 606 771173 23732 mRNA Human clone 23732 mRNA, partial cols AA4294.83 HS.81281 607 745606 237.59 mRNA Human clone 23759 mRNA, partial cols AA626,336 HS.118666 608 323SOO CASP6 Human cysteine protease Mch2 isoform W45688 HS.328O alpha (Mch2) mRNA, complete cols 609 323SOO CASP6 Human cysteine protease Mch2 isoform W44316 HS.328O pha (Mch2) mRNA, complete cols 610 71420 CYP2C9 uman cytochrome P4502C9 (CYP2C9) T47787 mRNA, clone 65 611 71420 CYP2C9 Human cytochrome P4502C9 (CYP2C9) T47788 mRNA, clone 65 612 754490 SLC25A16 Human GT mitochondrial solute carrier AA411554 HS.180408 protein homologue mRNA, complete cols 613 754490 SLC25A16 Human GT mitochondrial solute carrier AA410572 HS.180408 protein homologue mRNA, complete cols 614 1734348 Go-alpha Human guanine nucleotide-binding AI188097 HS.169647 regulatory protein (Go-alpha) gene US 2006/0099578 A1 May 11, 2006 28

TABLE 3-continued SEQ ID ResGen OniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID 615 826.204 FLII Human homolog of D. melanogaster AAS21453 HS.83849 flightless-I gene product mRNA, partial cols 616 144777 HAX1 Human HS1 binding protein HAX-1 R76263 HS.15318 mRNA, nuclear gene encoding mitochondrial protein , complete cols 617 144777 HAX1 Human HS1 binding protein HAX-1 R76544 HS.15318 mRNA, nuclear gene encoding mitochondrial protein , complete cols 618 261481 CUL3 Human Hs-cul-3 mRNA, partial cols H98621 S.78946 619 261481 CUL3 Human Hs-cul-3 mRNA, partial cols N25142 HS.78946 62O 233581 HIP2 Human huntingtin in eracting protein H78483 S.15548S (HIP2) mRNA, complete cols 621 233581 HIP2 Human huntingtin in eracting protein H78385 S.15548S (HIP2) mRNA, complete cols 622 363O86 CKMT1 Human mitochondria creatine kinase AAO19482 S.153998 (CKMT) gene, comp ete cols 623 363O86 CKMT1 Human mitochondria creatine kinase AAO19332 S.153998 (CKMT) gene, comp ete cols 624 1390S84 MIPEP Human mitochondria intermediate AA843592 HS.68.583 peptidase precursor (MIPEP) mRNA, mitochondrial gene encoding mitochondrial protein , complete cols 625 134269 POLRMT Human mitochondria RNA polymerase R31115 S.15388O mRNA, nuclear gene encoding mitochondrial protein , complete cols 626 134269 POLRMT Human mitochondria RNA polymerase R31,174 S.15388O mRNA, nuclear gene encoding mitochondrial protein , complete cols 627 781050 Human mRNA for c-myc binding protein, AA446453 S.80686 complete cols 628 781050 Human mRNA for c-myc binding protein, S.80686 omplete cols 629 4S1706 POLA Human mRNA for DNA polymerase AA7076SO alpha-Subunit 630 41541 Human mRNA for K AA0017 gene, R52789 S.253023 omplete cols 631 41541 Human mRNA for K AA0017 gene, RS2788 S.253023 complete cols 632 8428.18 KARS Human mRNA for K AA0070 gene, AA486.374 S.31 OO partial cols 633 8428.18 KARS Human mRNA for K AA0070 gene, AA48622O HS-3100 partial cols 634 280496 KIAAO123 Human mRNA for K AA0123 gene, NS1632 S.75353 partial cols 635 859627 KIAAO185 Human mRNA for K AAO185 gene, AA666405 s. 255573 partial cols 636 78.3698 KIAAO188 Human mRNA for K AA0188 gene, AA446822 S.81412 partial cols 637 78.3698 KIAAO188 Human mRNA for K AA0188 gene, AA446821 S.81412 partial cols 638 347031 KIAAO195 Human mRNA for K AAO195 gene, W79511 omplete cols 639 347031 KIAAO195 Human mRNA for K AAO195 gene, W79398 complete cols 640 7S3248 KIAAO381 Human mRNA for K AA0381 gene, AA406231 S.1OO113 partial cols 641 7S3248 KIAAO381 Human mRNA for K AA0381 gene, partial cols 642 108208 HADHB Human mRNA for mitochondrial 3 T69767 S.146812 ketoacyl-CoA thiolase beta-subunit of trifunctional protein, complete cols 643 108208 HADHB Human mRNA for mitochondrial 3 T70752 S.146812 ketoacyl-CoA thiolase beta-subunit of trifunctional protein, complete cols 644 869538 NDUFA4 Human NADH:ubiquinone S.108661 oxidoreductase MLRQ subunit mRNA, complete cols 645 810452 TOM34 Human putative outer mitochondrial AA457.118 S.76927 membrane 34 kDa translocase hTOM34 mRNA, complete cols 646 1271.97 Human Xq28 mRNA, complete cols US 2006/0099578 A1 May 11, 2006 29

TABLE 3-continued SEQ ID ResGen OniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID 647 1271.97 CXORF6 Human Xq28 mRNA, complete cols RO8271 S.2O136 648 811108 TRIP6 Human Zyxin related protein ZRP-1 AA4856,77 S.119498 mRNA, complete cols 649 811108 TRIP6 Human Zyxin related protein ZRP-1 AA485807 S.119498 mRNA, complete cols 6SO 79828 HD Huntingtin (Huntington disease) S.79.391 651 79828 HD Huntingtin (Huntington disease) S.79.391 652 1752540 HIP1 huntingtin interacting protein 1 653 1566230 HYAL3 hyaluronoglucosaminidase 3 S.12991O 654 2095653 GLO4 HYDROXYACYLGLUTATHIONE HYDROLASE 655 141966 hydroxy-delta-5-steroid dehydrogenase, 3 S.38586 eta- and steroid delta-isomerase 1 656 141966 ydroxy-delta-5-steroid dehydrogenase, 3 R68906 S.38586 beta- and steroid delta-isomerase 1 657 126243 HMBS Hydroxymethylbilane synthase RO6321 S.82609 658 126243 HMBS ydroxymethylbilane synthase RO6263 S.82609 659 321163 HSUT 9253 hypothetical protein W53OOO S.S615S 660 321163 HSUT 9253 hypothetical protein W52999 S.S615S 661 280507 HPRT1 Hypoxanthine phosphoribosyltransferase N47312 S.82314 (Lesch-Nyhan syndrome) 662 280507 HPRT1 Hypoxanthine phosphoribosyltransferase N47311 S.82314 (Lesch-Nyhan syndrome) 663 2216141 FM1 FM1 AI654459 664 767034 LVBL ilvB (bacterial acetolactate synthase)-like AA424288 S.7888O 665 767034 LVBL ilvB (bacterial acetolactate synthase)-like AA451741 S.7888O 666 1606837 MPDH2 MP (inosine monophosphate) AA996O28 S.75432 ehydrogenase 2 667 50754 MTIF2 NITIATION FACTORIF-2, S.1498.94 MITOCHONDRIAL PRECURSOR 668 111981 interferon, alpha-inducible protein (clone T84633 S.1799.72 FI-6-16) 669 111981 interferon, alpha-inducible protein (clone T91807 S.1799.72 FI-6-16) 670 491763 interleukin 1, beta AA1SOSO7 S.126256 671 491763 interleukin 1, beta AA156711 S.126256 672 2119594 SOCITRATE DEHYDROGENASE AI399657 673 86.9375 socitrate dehydrogenase 2 (NADP+), AA679907 S.252546 mitochondrial 674 21681.68 ETFB isocitrate dehydrogenase 3 (NAD+) alpha AIS65774 (IDH3A), 675 755474 ARS isoleucine-tRNA synthetase AA410636 676 755474 ARS isoleucine-tRNA synthetase AA419.192 677 81.0325 VD isovaleryl Coenzyme A dehydrogenase AA464149 S.77510 678 81.0325 isovaleryl Coenzyme A dehydrogenase AA464216 S.77510 679 2148SOS JC4913 AI469831 68O 809707 jun B proto-oncogene AA454,711 S.198.951 681 809707 jun B proto-oncogene AA456,366 S.198.951 682 1474284 kangai 1 (Suppression of tumorigenicity AA922.309 S.254.09 6, prostate; CD82 antigen (R2 leukocyte antigen, antigen detected by monoclonal and antibody IA4)) 683 845441 KIAAOO16 KIAAO016 gene product AA6445SO S.75187 684 2241S63 KIHUA3 KIHUA3 AI632351 685 21738 HADHSC L-3-hydroxyacyl-Coenzyme A T65482 S.7153 dehydrogenase, short chain 686 21738 HADHSC L-3-hydroxyacyl-Coenzyme A T654O7 S.7153 dehydrogenase, short chain 687 884644 LAMR1 Laminin receptor (2H5 epitope) AA629897 S.181357 688 704360 LCFA HUMAN LCFA HUMAN AA279565 689 1256792 MAD4 Mad4 homolog AA875977 S.102402 690 1908746 MDH1 MALATE DEHYDROGENASE AI302237 691 1636908 MDH2 malate dehydrogenase 2, NAD AIOOO271 S.111076 (mitochondrial) 692 2010949 ME2 malic enzyme 2, mitochondrial AI361039 S.75342 693 896921 ME3 malic enzyme, NADP+-dependent, AA7794O1 S.2838 mitochondrial 694 81.4211 Mannose-6-phosphate receptor (cation AA465223 S.75709 dependent) 695 81.4211 Mannose-6-phosphate receptor (cation S.75709 dependent) US 2006/0099578 A1 May 11, 2006 30

TABLE 3-continued SEQ ID ResGen UniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID 696 589115 MM P1 matrix metalloproteinase 1 (interstitial AA1432O1 collagenase) 697 589115 MM matrix metalloproteinase 1 (interstitial AA143331 collagenase) 698 1574438 MM P11 matrix metalloproteinase 11 (stromelysin AA954935 HS.155324 3) 699 196612 MM P12 matrix metalloproteinase 12 (macrophage R92994 HS.1695 elastase) 700 196612 MM P12 matrix metalloproteinase 12 (macrophage R93037 HS.1695 elastase) 701 2S1047 MM P17 matrix metalloproteinase 17 (membrane H97792 HS.159581 inserted) 702 784589 MM P15 Matrix metalloproteinase 2 AA4433OO HS.8O343 703 784589 MM P15 Matrix metalloproteinase 2 AA443433 HS.8O343 704 470393 MM matrix metalloproteinase 7 (matrilysin, AAO31513 HS.2256 uterine) 705 470393 MM matrix metalloproteinase 7 (matrilysin, AAO31514 HS.2256 uterine) 706 2213770 CCH Matrix metalloproteinase 7 (matrilysin, uterine) 707 22040 MM matrix metalloproteinase 9 (gelatinase B, TT 2581 92 kD gelatinase, 92 kD type IV collagenase) 708 22040 MM matrix metalloproteinase 9 (gelatinase B, T64837 92 kD gelatinase, 92 kD type IV collagenase) 709 773.266 MM matrix metalloproteinase 9 (gelatinase B, HS.151738 92 kD gelatinase, 92 kD type IV collagenase) 710 773.266 MM matrix metalloproteinase 9 (gelatinase B, HS.151738 92 kD gelatinase, 92 kD type IV collagenase) 7 1 2091860 MM PL1 matrix8. metalloproteinase-like HS.198265 Data unavailable TALLOPROTEINASE INHIBITOR RECURSOR Data unavailable TALLOPROTEINASE INHIBITOR RECURSOR 2165301 DEHUMT methylene tetrahydrofolate AI497794 dehydrogenase (NAD+ dependent), methenyltetrahydrofolate cyclohydrolase 1473S06 MMSA HUMAN METHYLMALONATE AA915881 SEMIALDEHYDE DEHYDROGENASE 209 1562 METHYLMALONYL-COAMUTASE AI377286 PRECURSOR 278.570 MITF Microphthalmia-associated transcription N66.177 HS.166O17 actor 278.570 MITF Microphthalmia-associated transcription N99168 HS.166O17 actor 768443 MGST1 microsomal glutathione S-transferase 1 AA495936 HS.790 768443 MGST1 microsomal glutathione S-transferase 1 AA495935 HS.790 6298.96 MAP1B MICROTUBULE-ASSOCIATED AA219045 HS.103042 PROTEIN 1B 722 1084029 MITOCHONDRIAL 2 AAS94052 OXOGLUTARATEMALATE CARRIER PROTEIN 723 442SS RPML3 MITOCHONDRIAL 60S RIBOSOMAL HO6113 HS.79086 PROTEIN L3 724 442SS RPML3 MITOCHONDRIAL 60S RIBOSOMAL HS.79086 PROTEIN L3 725 433553 CAS Mitochondrial carbonic anhydrase AA6994.69 HS.1774.46 726 1175538 A390 18 MITOCHONDRIAL CARNITINE AA641442 PALMITOYLTRANSFERASE II PRECURSOR 727 3246.18 TSFM MITOCHONDRIAL ELONGATION W47015 HS.3273 FACTORTS PRECURSOR 728 3246.18 TSFM MITOCHONDRIAL ELONGATION W47014 HS.3273 FACTORTS PRECURSOR 729 2O66585 LON-PEN MITOCHONDRIAL LON PROTEASE HOMOLOG 730 133099 MMP1 Precursor MITOCHONDRIAL MATRIX R26234 PROTEIN P1 PRECURSOR US 2006/0099578 A1 May 11, 2006 31

TABLE 3-continued SEQ ID ResGen UniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID 731 133099 MMP1 Precursor MITOCHONDRIAL MATRIX R26235 PROTEIN P1 PRECURSOR 732 4484.91 mrp2 MITOCHONDRIAL RIBOSOMAL AA777627 PROTEIN S14 733 1587031 HSPA9 MITOCHONDRIAL STRESS-70 AA948223 PROTEIN 734 814346 MTIF2 mitochondrial translational initiation AA458825 HS.1498.94 factor 2 735 814346 MTIF2 mitochondrial translational initiation HS.1498.94 factor 2 736 1916771 MTRF1 mitochondrial translational release factor 1 AI347695 HS.80683 737 1880757 MAP3KS mitogen-activated protein kinase kinase AI268273 HS.151988 kinase 5 738 22446.21 MRF1 MRF1 AI65690S 739 645006 MRP4 MRP4 AA197284 740 645006 MRP4 MRP4 AA205815 741 1933.324 MPZ protein zero (Charcot-Marie AI3S1956 S.93883 Tooth neuropathy 1B) 742 302190 MLL myeloid lymphoid or mixed-lineage W16724 S.19916O leukemia (trithorax (Drosophila) homolog) 743 302190 MLL myeloid lymphoid or mixed-lineage N77807 S.19916O leukemia (trithorax (Drosophila) homolog) 744 842989 MYL6 MYOSIN LIGHT CHAINALKALI, AA488.346 S.77385 NON-MUSCLE ISOFORM 745 842989 MYL6 MYOSIN LIGHT CHAINALKALI, AA488477 S.77385 NON-MUSCLE ISOFORM 746 814615 MTHFD2 NAD-dependent methylene AA480995 S.154672 tetrahydrofolate dehydrogenase cyclohydrolase 747 814615 MTHFD2 NAD-dependent methylene AA480994 S.154672 tetrahydrofolate dehydrogenase cyclohydrolase 748 773287 DUFA2 NADH dehydrogenase (ubiquinone) AA425211 S.163867 alpha Subcomplex, 2 (8 kD, B8) 749 773287 DUFA2 NADH dehydrogenase (ubiquinone) AA425534 S.163867 alpha Subcomplex, 2 (8 kD, B8) 750 1635681 DUFA2 NADH dehydrogenase (ubiquinone) AIO17426 S.163867 alpha Subcomplex, 2 (8 kD, B8) 751 950578 DUFAS NADH dehydrogenase (ubiquinone) AA608515 S.83916 alpha Subcomplex, 5 (13 kD, B13) 752 897987 DUFA9 NADH dehydrogenase (ubiquinone) AAS98884 S.75227 alpha Subcomplex, 9 (39 kD) 753 450896 DUFB4 NADH dehydrognase (ubiquinone) 1 AA704675 beta subcomplex, 4 (15 kD, B15) 754 S62409 NADH dehydrogenase (ubiquinone) AA214053 S.80595 (8 S plex, 4 (15 kD, B15) 755 S62409 NADH dehydrogenase (ubiquinone) AA214154 S.80595 (8 S plex, 4 (15 kD, B15) 756 307933 U FB5 NADH dehydrogenase (ubiquinone) N93053 S.19236 (8 S plex, 5 (16 kD, SGDH) 757 307933 DUFB5 NADH dehydrogenase (ubiquinone) W21390 S.19236 (8 S plex, 5 (16 kD, SGDH) 758 470861 DUFB6 NADH dehydrogenase (ubiquinone) AAO34268 S.109646 (8 S plex, 6 (17 kD, B17) 759 470861 DUFB6 NADH bbbbbdehydrogenase CCCCC OOOOO (ubiquinone) S.109646 (8 S plex, 6 (17 kD, B17) 760 771089 DUFB7 NADH dehydrogenase (ubiquinone) S. 661 b e 8. S b C Ol plex, 7 (18 kD, B18) 761 771089 DUFB7 ehydrogenase (ubiquinone) AA429046 S. 661 b e 8. S ubcomplex, 7 (18 kD, B18) 762 796.513 DUFC1 H dehydrogenase (ubiquinone) 1, S.84549 subcomplex unknown, 1 (6 kD, KFYI) 763 796.513 DUFC1 NADH dehydrogenase (ubiquinone) 1, AA463815 S.84549 subcomplex unknown, 1 (6 kD, KFYI) 764 7534.57 NADH dehydrogenase (ubiquinone) Fe–S S.8248 protein 1 (75 kD) (NADH-coenzyme Q reductase) 765 7534.57 NADH dehydrogenase (ubiquinone) Fe–S S.8248 protein 1 (75 kD) (NADH-coenzyme Q reductase) US 2006/0099578 A1 May 11, 2006 32

TABLE 3-continued SEQ ID ResGen OniGene NO Clone ID Complete Gene Name GenBank Cluster ID 766 74381.1 NADH dehydrogenase (ubiquinone) Fe–S AA634381 S.S273 protein 3 (30 kD) (NADH-coenzyme Q reductase) 767 377152 NADH dehydrogenase (ubiquinone) Fe–S AAO55101 S.10758 protein 4 (18 kD) (NADH-coenzyme Q reductase) 768 377152 NADH dehydrogenase (ubiquinone) Fe–S AAOSS102 S.10758 protein 4 (18 kD) (NADH-coenzyme Q reductase) 769 SO2141 NADH dehydrogenase (ubiquinone) Fe–S AA127014 S.90443 protein 8 (23 kD) (NADH-coenzyme Q reductase) 770 SO2141 NADH dehydrogenase (ubiquinone) Fe–S AA128.218 S.90443 protein 8 (23 kD) (NADH-coenzyme Q reductase) 771 48626O NADH dehydrogenase (ubiquinone) AA922326 S.51299 flavoprotein 2 (24 kD) 772 676983 RDHUBS NADH-CYTOCHROME BS AIO76798 R E DU CT TASE 773 632O11 N C 2 etic peptide receptor Biguanylate AA994689 S.78518 ase B (atrionatriuretic peptide C e p or B) 774 9949SO FA10 FA10 AASS5087 775 S88691 FA2 FA2 AA97S360 776 92.9358 FA3 FA3 AA492O39 777 2118546 FA6 FA6 AIS24304 778 270489 FA7 FA7 AA748476 779 171756 EA8 EA8 H18333 78O 171756 EA8 H18364 781 473135 FAB1 FAB1 AA873566 782 998616 FB1 AAS357.62 783 2170527 FB10 FB10 AISF1333 784 881693 FB2 AI290799 785 2103675 FB3 AI4O12OO 786 2266937 FB8 AI608733 787 98.4496 FB9 AAS26O75 788 2.277817 FC2 AI6538O1 789 1O194O1 FS2 AA551149 790 1585499 FS5 DUFS5 AA974058 791 S1826 NNT nicotinamide nucleotide transhydrogenase H22944 S.18136 792 S1826 NNT nicotinamide nucleotide transhydrogenase H24.126 S.18136 793 116O732 NOS2A Nitric oxide synthase 2A (inducible, AA877840 S.193788 hepatocytes) 794 1SO466 EST Nitric oxide synthase 3 (endothelial cell) HO1039 S.237163 795 1SO466 EST Nitric oxide synthase 3 (endothelial cell) HO1788 S.237163 796 146882O NOS3 nitric oxide synthase 3 (endothelial cell) AA884967 S.166373 797 755750 NME2 non-metastatic cells 2, protein (NM23B) AA496.628 S.255790 expressed in 798 755750 NME2 non-metastatic cells 2, protein (NM23B) AA496.512 S.255790 expressed in 799 NFATC3 nuclear factor of activated T-cells, HS9048 S.172674 cytoplasmic 3 800 NFATC3 nuclear factor of activated T-cells, HS9047 S.172674 cytoplasmic 3 8O1 1870.662 A548.68 nuclear respiratory factor 1 (NRF1) AI245773 802 S67414 NFYB nuclear transcription factor Y, beta AA13O846 803 78.3696 OAT ornithine aminotransferase (gyrate AA4468.19 atrophy) 804 78.3696 OAT ornithine aminotransferase (gyrate AA44682O atrophy) 805 796646 ODC1 Ornithine decarboxylase 1 AA46O115 806 796646 ODC1 Ornithine decarboxylase 1 AA461467 S.75212 807 1637751 OXA1L. oxidase (cytochrome c) assembly 1-like AIOO118O S.151134 808 1704170 OXA1EHS oxoglutarate dehydrogenase (lipoamide) AIO96611 809 233479 No Data Oxoglutarate dehydrogenase (lipoamide) H78910 810 233479 No Data Oxoglutarate dehydrogenase (lipoamide) H3O138 811 1371793 OGDH oxoglutarate dehydrogenase (lipoamide) AA856769 S.168669 812 1632231 UQCRC1 P31930 UBIQUINOL-CYTOCHROME AIOOS342 C REDUCTASE COMPLEX CORE PROTEIN IPRECURSOR 813 162775 DDX5 P68 PROTEIN H27564 814 162775 DDX5 P68 PROTEIN H27646 US 2006/0099578 A1 May 11, 2006 33

TABLE 3-continued SEQ ID ResGen UniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID 815 43884 PPIF PEPTIDYL-PROLYL CIS-TRANS HOSS80 HS.17312S SOMERASE, MITOCHONDRIAL PRECURSOR 816 43884 PPIF PEPTIDYL-PROLYL CIS-TRANS HOS115 HS.17312S SOMERASE, MITOCHONDRIAL PRECURSOR 817 774726 PPIF peptidylprolyl isomerase F (cyclophilin AA442081 HS.17312S F) 818 774726 PPIF peptidylprolyl isomerase F (cyclophilin AA442184 HS.17312S F) 819 133273 PMP22 peripheral myelin protein 22 R26960 HS.103724 82O 133273 PMP22 peripheral myelin protein 22 R26732 HS.103724 821 788518 PXMP3 Peroxisomal membrane protein 3 (35 kD, AA452566 Zellweger syndrome) 822 788518 PXMP3 Peroxisomal membrane protein 3 (35 kD, AA452747 Zellweger syndrome) 823 1476157 PXR1 peroxisome receptor 1 AA873073 HS.158O84 824 455263 PET112L PET112 (yeast homolog)-like AA677S72 HS.11127 825 951683 PHC HC AA62998O 826 843109 FARS1 henylalanine-tRNA synthetase AA488691 HSS7969 827 843109 FARS1 henylalanine-tRNA synthetase AA4865O3 HSS7969 828 84.2784 PHC hosphate carrier, mitochondrial AA486.305 HS.78713 829 84.2784 PHC hosphate carrier, mitochondrial AA4862OO HS.78713 830 346009 PFKL hosphofructokinase (liver type) W72140 HS.15545S 831 346009 PFKL hosphofructokinase (liver type) W77881 HS.15545S 832 489626 PFKM hosphofructokinase, muscle AAO991.69 HS.7S160 833 489626 PFKM hosphofructokinase, muscle AA101919 HS.7S160 834 1831.94 hospholipase A2, group IIA (platelets, H44953 vial fluid) 835 1831.94 hospholipase A2, group IIA (platelets, ynovial fluid) 836 7791S PLA2G-2A phospholipase A2, group IIA (platelets, T61323 S.76422 ynovial fluid) 837 7791S PLA2G-2A phospholipase A2, group IIA (platelets, T61271 S.76422 synovial fluid) 838 2367279 PNO673 PNO673 AI741984 839 780947 POLD1 Polymerase (DNA directed), delta 1, AA429661 S.998.90 catalytic subunit (125 kD) 840 780947 POLD1 Polymerase (DNA directed), delta 1, AA446151 S.998.90 catalytic subunit (125 kD) 841 6262O6 POLG polymerase (DNA directed), gamma AA188761 S.80961 842 6262O6 POLG polymerase (DNA directed), gamma AA1886.29 S.80961 843 827129 POLRMT polymerase (RNA) mitochondrial (DNA AAS21239 S.15388O directed) 84.4 2144562 PRAX-1 PRAX-1 AI452994 845 826211 PDCD2 Programmed cell death 2 AAS21466 S.41639 846 814337 PCCB propionyl Coenzyme A carboxylase, beta AA459122 S.63788 polypeptide 847 814337 PCCB propionyl Coenzyme A carboxylase, beta AA459341 S.63788 polypeptide 848 950710 PCCA Propionyl-coA carboxylase alpha chain AA608575 S.8O741 849 824568 KLK3 Prostate specific antigen AA490981 S.171995 8SO 843.134 PBP Prostatic binding protein AA486.514 HS.80423 851 843.134 PBP Prostatic binding protein AA485909 S.80423 852 261971 PRSM1 protease, metallo, 1, 33 kD N27227 S.1831.38 853 261971 PRSM1 protease, metallo, 1, 33 kD H98666 S.1831.38 854 375728 PRSM1 protease, metallo, 1, 33 kD AAO33807 S.1831.38 855 51041 Est protoporphyrinogen oxidase H18633 S.123641 856 51041 Est protoporphyrinogen oxidase H18716 S.123641 857 24716O PPOX protoporphyrinogen oxidase N57891 S.1OOO16 858 504452 PPOX protoporphyrinogen oxidase AA151249 S.1OOO16 859 504452 PPOX protoporphyrinogen oxidase AA151248 S.1OOO16 860 SO1939 HHCMAS6 putative oxidoreductase AA128041 HS.S19 861 SO1939 HHCMAS6 putative oxidoreductase AA128O86 HS.S19 862 108378 PC pyruvate carboxylase T77729 HS.89890 863 108378 PC pyruvate carboxylase T77728 HS.89890 864 8O374 PDHA1 Pyruvate dehydrogenase (lipoamide) T65833 HS.1023 alpha 1 865 8O374 PDHA1 Pyruvate dehydrogenase (lipoamide) T65758 HS.1023 alpha 1 US 2006/0099578 A1 May 11, 2006 34

TABLE 3-continued SEQ ID ResGen OniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID 866 826O77 PDHB pyruvate dehydrogenase (lipoamide) beta HS.979 867 279665 PDX1 Pyruvate dehydrogenase complex, lipoyl S.74642 containing component X; E3-binding protein 868 279665 PDX1 Pyruvate dehydrogenase complex, lipoyl N49046 S.74642 containing component X; E3-binding protein 869 1542260 PDHA2 PYRUVATE DEHYDROGENASE E1 AA9274OO COMPONENT, ALPHA 870 1645668 PDK1 pyruvate dehydrogenase kinase, AIO26814 HS.159477 isoenzyme 1 871 66686 No Data QM PROTEIN T67270 872 66686 No Data QM PROTEIN T67271 873 590727 RENT1 regulator of nonsense transcripts 1 AA156342 874 590727 RENT1 regulator of nonsense transcripts 1 AA156376 875 624627 RRM2 Ribonucleotide reductase M2 polypeptide AA187351 876 624627 RRM2 Ribonucleotide reductase M2 polypeptide AA18843O 877 788334 RPL23L ribosomal protein L23-like AA453O15 878 73O124 RPL7 Ribosomal protein L7 AA412470 879 73O124 RPL7 Ribosomal protein L7 AA412344 880 809578 RPS5 Ribosomal protein S5 AA456616 881 809578 RPS5 Ribosomal protein S5 AA455795 882 214133 FSRG1 RING3 PROTEIN H7252O 883 214133 FSRG1 RING3 PROTEIN H72918 884 110744 SCO2 SCO (cytochrome oxidase deficient, T90560 yeast) homolog 2 885 110744 SCO2 SCO (cytochrome oxidase deficient, T83097 yeast) homolog 2 886 646657 SCO1 SCO1 (yeast homolog) cytochrome AA2O5413 oxidase deficient 1 887 646657 SCO1 SCO1 (yeast homolog) cytochrome AA2OSS79 oxidase deficient 1 888 1074487 SDHD SDHD AAS79646 889 951117 SHMT2 serine hydroxymethyltransferase 2 AA620477 (mitochondrial) 890 2138.479 XNHUSP SERINE--PYRUVATE AIS21720 AMINOTRANSFERASE 891 1251 83 SSBP single-stranded DNA-binding protein ROS693 HS.923 892 1251 83 SSBP single-stranded DNA-binding protein ROS694 HS.923 893 813678 SLC1A3 solute carrier family 1 (glial high affinity AA453823 S.75379 glutamate transporter), member 3 894 813678 SLC1A3 solute carrier family 1 (glial high affinity AA453742 S.75379 glutamate transporter), member 3 895 S86990 SLC11A2 solute carrier family 11 (proton-coupled AA133656 divalent metal ion transporters), member 2 896 S86990 SLC11A2 solute carrier family 11 (proton-coupled AA1336SS divalent metal ion transporters), member 2 897 2029995 SLC12A7 solute carrier family 12 AI492956 S.172613 (potassium chloride transporters), member 7 898 190732 SLC2AS Solute carrier family 2 (facilitated glucose transporter), member 5 899 190732 SLC2AS Solute carrier family 2 (facilitated glucose H38733 transporter), member 5 900 7583O4 SLC25A14 solute carrier family 25 (mitochondrial AA404241 S.1946.86 carrier, brain), member 14 901 7583O4 SLC25A14 solute carrier family 25 (mitochondrial S.1946.86 carrier, brain), member 14 902 897107 SLC25A1 solute carrier family 25 (mitochondrial AA676877 S.111024 carrier; citrate transporter), member 1 903 87841.3 SLC25A11 solute carrier family 25 (mitochondrial AA670357 S.184877 carrier; oxoglutarate carrier), member 11 904 433350 SORD Sorbitol dehydrogenase AA7OO604 HS.878 905 1256737 SPG7 spastic paraplegia 7, paraplegin (pure and AA8761.65 S.78497 complicated autosomal recessive) 906 682S28 SCA1 1 S.74520 (olivopontocerebellar ataxia 1, autosomal dominant, ataxin 1) 907 682S28 SCA1 spinocerebellar ataxia 1 AA256508 S.74520 (olivopontocerebellar ataxia 1, autosomal dominant, ataxin 1) US 2006/0099578 A1 May 11, 2006 35

TABLE 3-continued SEQ ID ResGen UniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID 908 128875 SCA2 Spinocerebellar ataxia 2 R10604 Hs.76253 (olivopontocerebellar ataxia 2, autosomal dominant) 909 128875 SCA2 Spinocerebellar ataxia 2 Hs.76253 (olivopontocerebellar ataxia 2, autosomal dominant) 4471.67 SFRS8 splicing factor, arginine?serine-rich 8 AA702973 HS.84229 (Suppressor-of-white-apricot, Drosophila homolog) 193412S B34181 steroid 11-beta-hydroxylase AI334352 8S9858 STAR Steroidogenic acute regulatory protein AA679454 HS-3132 855395 SCP2 sterol carrier protein 2 AA664009 HS.7S760 82.4699 SUCA HUMAN SUCA HUMAN AA4822O6 80915 SDHA Succinate dehydrogenase 2, flavoprotein TTOO43 (Fp) subunit 9 6 80915 SDHA Succinate dehydrogenase 2, flavoprotein TTO109 (Fp) subunit 797O16 SDHB Succinate dehydrogenase complex, AA463565 HS.64 subunit B, iron Sulfur (Ip) 797O16 SDHB Succinate dehydrogenase complex, AA46351O HS.64 subunit B, iron Sulfur (Ip) 366132 SDHC Succinate dehydrogenase complex, AAO 62805 HS.3577 Subunit C, integral membrane protein, 15 kD 920 SO4145 LSC2 SUCCINATE-COALIGASE AA132OOO 921 SO4145 LSC2 SUCCINATE-COALIGASE AA131817 922 8456.30 SUCLA2 Succinate-CoA ligase, ADP-forming, beta AA644577 S.182217 Subunit 923 1571111 SCOT HUMAN Succinyl CoA: 3-oxoacid CoA transferase AA936982 924 950489 SOD1 Superoxide dismutase 1 (Cu/Zn) AAS991.27 925 15724.67 SOD2 Superoxide dismutase 2 AA934677 926 34.6860 SOD2 Superoxide dismutase 2, mitochondrial W78148 S.177781 927 34.6860 SOD2 Superoxide dismutase 2, mitochondrial W79.913 S.177781 928 84O708 SOD2 Superoxide dismutase 2, mitochondrial AA488O84 HS.177781 929 84O708 SOD2 Superoxide dismutase 2, mitochondrial AA4877SO S.177781 930 1343732 SOD3 Superoxide dismutase 3, extracellular AA72SS64 HS.242O 931 433474 SURF1 Surfeit 1 AA699560 HS.3196 932 21143O2 Surfeit 1 surfeit 1 A417847 HS.3196 933 782797 SMN1 Survival of motor neuron 1, telomeric AA448.194 HS.77306 934 704299 TAZ afazzin (cardiomyopathy, dilated 3A (X- AA27944O S.79021 inked); endocardial fibroelastosis 2: Barth syndrome) 935 7893.76 hioredoxin reductase 1 AA45333S S.13046 936 7893.76 hioredoxin reductase 1 AA464849 S.13046 937 796OOO hiosulfate sulfurtransferase (rhodanese) AA461065 S.74097 938 796OOO hiosulfate sulfurtransferase (rhodanese) AA46O495 S.74097 939 856167 hreonyl-tRNA synthetase AA63O628 S.84131 940 205185 Thrombomodulin HS9861 HS.2O3O 941 205185 Thrombomodulin HS.2O3O 942 2463OO TIA1 cytotoxic granule-associated RNA NS9426 S.182741 binding protein-like 1 943 84.2846 issue inhibitor of metalloproteinase 2 AA48628O S.246948 944 489519 issue inhibitor of metalloproteinase 3 AA099153 S.245188 (Sorsby fundus dystrophy, pseudoinflammatory) 945 489519 TIMP3 issue inhibitor of metalloproteinase 3 AAO99251 S.245188 (Sorsby fundus dystrophy, pseudoinflammatory) 946 754106 TIMP3 issue inhibitor of metalloproteinase 3 AA4792O2 S.245188 (Sorsby fundus dystrophy, pseudoinflammatory) 947 754106 TIMP3 issue inhibitor of metalloproteinase 3 AA478.662 S.245188 (Sorsby fundus dystrophy, pseudoinflammatory) 948 433481 TCF2 transcription factor 2, hepatic; LF-B3; AA699573 S.169853 variant hepatic nuclear factor 949 78584.5 Transcription factor 6-like 1 AA449.118 S.75133 (mitochondrial transcription factor 1-like) 950 78584.5 Transcription factor 6-like 1 AA449551 S.75133 (mitochondrial transcription factor 1-like) 951 841,334 STIP1 TRANSFORMATION-SENSITIVE AA487635 PROTEIN IEF SSP 3521 US 2006/0099578 A1 May 11, 2006 36

TABLE 3-continued SEQ ID ResGen OniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID 952 841,334 TRANSFORMATION-SENSITIVE AA487427 PROTEIN IEF SSP 3521 953 2114841 translocase of inner mitochondrial membrane 8 954 970880 TPM4 4 AA774983 S.102824 955 341328 TPM1 Tropomyosin alpha chain (skeletal W58092 S.77899 muscle) 956 341328 TPM1 Tropomyosin alpha chain (skeletal W58009 S.77899 muscle) 957 32621 WARS2 tryptophanyl tRNA synthetase 2 R43272 S.227274 (mitochondrial) 958 32621 WARS2 tryptophanyl tRNA synthetase 2 R18903 S.227274 (mitochondrial) 959 684582 WARS2 tryptophanyl tRNA synthetase 2 AA251354 S.227274 (mitochondrial) 96.O 684582 WARS2 tryptophanyl tRNA synthetase 2 AA251468 S.227274 (mitochondrial) 961 TID1 tumorous imaginal discs (Drosophila) AA1698.72 S.6216 homolog 962 TID1 tumorous imaginal discs (Drosophila) AA169567 S.6216 homolog 963 1569989 YWHAB tyrosine 3-monooxygenase/tryptophan 5 AA962407 S.182238 monooxygenase activation protein, beta polypeptide 964 1591788 YWHAZ tyrosine 3-monooxygenase/tryptophan 5 AA976477 S.75103 monooxygenase activation protein, Zeta polypeptide 25499 UBIQUINOL-CYTOCHROME C R11 698 S.73818 REDUCTASE COMPLEX 11 KD PROTEIN PRECURSOR 966 25499 UBIQUINOL-CYTOCHROME C R17676 S.73818 REDUCTASE COMPLEX 11 KD PROTEIN PRECURSOR 967 855843 UBIQUINOL-CYTOCHROME C AA664284 S.131255 REDUCTASE COMPLEX 14 KID PROTEIN 968 1160934 UBIQUINOL-CYTOCHROME C AA877.491 REDUCTASE CORE PROTEIN 2 PRECURSOR 969 7828OO UBIQUINOL-CYTOCHROME C AA448.184 HS.3712 REDUCTASE IRON-SULFUR SUBUNIT PRECURSOR 970 1955460 MAS2 UCR1 HUMAN P31930 UBIQUINOL AI365986 CYTOCHROME-C REDUCTASE COMPLEX CORE PROTEIN I 971 236034 UCP2 uncoupling protein 2 (mitochondrial, H61243 S.80658 proton carrier) 972 236034 UCP2 uncoupling protein 2 (mitochondrial, H61242 S.80658 proton carrier) 973 628529 EST uncoupling protein 3 (mitochondrial, AA192SS3 S.76640 proton carrier) 974 628529 EST uncoupling protein 3 (mitochondrial, AA1921.36 S.76640 proton carrier) 975 197932 UQCRB UQCRB R963S2 S.77385 976 197932 UQCRB UQCRB R96395 S.77385 977 494-64 UNG uracil-DNA glycosylase H15111 S.78853 978 494-64 UNG uracil-DNA glycosylase H15112 S.78853 979 76O148 UROD Uroporphyrinogen decarboxylase AA424441 S.786O1 98O 76O148 UROD Uroporphyrinogen decarboxylase AA424344 S.786O1 981 34778 VEGF vascular endothelial growth factor R45059 982 34778 VEGF vascular endothelial growth factor R19956 983 17622OO WDAC1 WDAC AI2O5945 984 1911533 WDAC3 WDAC3 AI268.057 985 486221 WDAC1 Voltage-dependent anion channel 1 AAO44059 S.14915S 986 486221 WDAC1 Voltage-dependent anion channel 1 AAO44113 S.14915S 987 1434908 WDAC2 Voltage-dependent anion channel 2 AA857.093 S.78.902 988 796759 WDAC3 voltage-dependent anion channel 3 AA46O728 S.7381 989 796759 WDAC3 voltage-dependent anion channel 3 AA460900 S.7381 990 815683 WBSCR9 Williams-Beuren syndrome chromosome AA485132 S.194688 region 9 991 815683 WBSCR9 Williams-Beuren syndrome chromosome AA485131 S.194688 region 9 US 2006/0099578 A1 May 11, 2006 37

TABLE 3-continued SEQ ID ResGen UniGene NO Clone ID Gene Complete Gene Name GenBank Cluster ID 992 878676 XRCCS X-ray repair complementing defective AA77S355 HS.84981 repair in Chinese hamster cells 5 (double Strand-break rejoining; Ku autoantigen, 80 kD) 993 269381 ZNF148 Zinc finger protein 148 (pHZ-52) N261.48 994 74SSO3 ZNF9 Zinc finger protein 9 (a cellular retroviral AA625995 HS.2110 nucleic acid binding protein)

Example 2 Table 5. The clones identified in Table 4 are used to make a set of probes called Mouse Probe Set #2. The clones Mouse Mitochondrial Biology Array identified in Table 5 are used to make a set of probes called 0083. A mouse mitochondrial biology array is made from Mouse Probe Set #3. Control sequences are also placed this clones representing expressed sequences. The clones placed array. Controls include, but are not limited to blanks, on the array are shown in Table 4 which references sequence DMSO, probes derived from plant sequences, sequence(s) ID NOS:995-3040 provided herein setting forth the 5' and 3' not involved in mitochondrial biology, and poly adenine sequences from these clones. See Tanaka, T. S. et al., (2000) (40-60 nucleotides long). Sequences used to make probes "Genome-wide expression profiling of mid-gestation pla for the mouse mitochondrial genes can also be found in centa and embryo using 15 k mouse developmental cDNA GenBank Accession No. J01420, which provides the com microarray'Proc. Natl. Acad. Sci. USA 97.9127-9132. plete mouse mitochondrial genome. Preferably, the probes Equivalent clones useful as probes are listed in Table 5. The used for ATP8 and ATP6 do not cross-hybridize with each clones listed in Table 4 are preferable to the clones listed in other. US 2006/0099578 A1 May 11, 2006 38

§§100I’UDIJAN 0090I’ULIWN

ZIJTOO@H

866 666 900 f_00 800 600 US 2006/0099578 A1 May 11, 2006 39

I£900I’UDIJAI

US 2006/0099578 A1 May 11, 2006 42

Z99LI“ULIWN

69969SAAV

90OZ 0IAIZ 0IOiz

Á8 88 68 US 2006/0099578 A1 May 11, 2006 43

90'EIS

IIZ ZIZ ÁIZ 8IZ 6.IZ 0@ US 2006/0099578 A1 May 11, 2006 44

„VNIHULI“(IONIEIH)I(CITH)

ZOV8 80V8 IIV8 8098 9006 IIO6

US 2006/0099578 A1 May 11, 2006 46

0787'ULIWN

ZIV 60O 90HZZ09H US 2006/0099578 A1 May 11, 2006 47

999'ULIWN

80J?ZO?CH US 2006/0099578 A1 May 11, 2006 48

86ISZ’ULTIN 86ISZ’ULTIN

US 2006/0099578 A1 May 11, 2006 50

80(9,09H 6008Z09H 909 L0S 809 60S US 2006/0099578 A1 May 11, 2006 51

969947'ULIWN

9006,09H US 2006/0099578 A1 May 11, 2006 52

ÇOILII’ULIWN

600I909H US 2006/0099578 A1 May 11, 2006 53

99796’ULIWN

99796°ULIWN

US 2006/0099578 A1 May 11, 2006 57

89 69

f_08 808 608 0I8 II3 ZI8 US 2006/0099578 A1 May 11, 2006 58

ZIV@909H

US 2006/0099578 A1 May 11, 2006 63

8969'ULIWN IILII’ULIWN

ÁLTOZ 8TOZ 610,

US 2006/0099578 A1 May 11, 2006 65

ZOLOI’ULIWN 6996]'ULIWN

9u9589SAYIsmpnosnuA,

8090809H ZIVI80€H

Á60€ 960, 860, 660, cal can a can ca, S S S S S (S - S (S can cra (Y (Y (Y (Y cal can cal can a can cal can a can ca, S - ca. US 2006/0099578 A1 May 11, 2006 66

910ÃOII30

98987'ULIWN 99IL'ULIWN IZZI‘ULIWN

Z00980€H 605–1980€H

ca, S - S - S - ca, a cal can cal can a ca S S S - S - cal can a ca S S S - S - S - cal can S S S - S - S - S - US 2006/0099578 A1 May 11, 2006 67

98ISI’UDIJAI 990I’ULIWN

90y680€H 800060€H 80GT IIGI IIZZ ZIZZ ca, S - S - S - a cal can a ca S S S - cal can ra US 2006/0099578 A1 May 11, 2006 68

8.1980I’ULIWN 8896),“ULIWN

IZZZ ZZZZ

US 2006/0099578 A1 May 11, 2006 71

900,0 ZOGIZO 60GIZO II(T90 90H90 60V90

US 2006/0099578 A1 May 11, 2006 73 US 2006/0099578 A1 May 11, 2006 74

ÁLIS”ULIWN US 2006/0099578 A1 May 11, 2006 75

6068Z’ULTIN

0IVOZ Z00IZ US 2006/0099578 A1 May 11, 2006 76

910ÃOII30

698LI“ULIWN 698LI“ULIWN

ZOOT?zz IIGItzz

US 2006/0099578 A1 May 11, 2006 78

ZOGISZ 9006, US 2006/0099578 A1 May 11, 2006 79

ZIV 0IO 90HZ9 US 2006/0099578 A1 May 11, 2006 80

89Itz'ULIWN

LI 0, IL 96

(spo913Iduloo US 2006/0099578 A1 May 11, 2006 81

13

ºu33GIVOTA

80GIÁ9. 60GIÁ9. 60989 US 2006/0099578 A1 May 11, 2006 82

II?I"UITW 0090I’ULIWN

ZOVO? IIOOiz

US 2006/0099578 A1 May 11, 2006 84

ÁSÁL’ULTIN

9008809){ 9908809){

US 2006/0099578 A1 May 11, 2006 87

09.087’ULIWN

80099 †70089 US 2006/0099578 A1 May 11, 2006 88 US 2006/0099578 A1 May 11, 2006 89

0084)

TABLE 5

MAGE Clone Res. Num Gene Genbank Acc. ii D Unigene Cluster Gen. Clone mtDNA-12S rRNA VOO711 in House-Clone mtDNA-16S rRNA VOO711 in House-Clone mtDNA-ATPase 6 VOO711 in House-Clone mtDNA-ATPase 8 VOO711 in House-Clone mtDNA-COX VOO711 in House-Clone mtDNA-COX2 VOO711 in House-Clone mtDNA-COX 3 VOO711 in House-Clone mtDNA-Cyt b VOO711 in House-Clone mtDNA-NADH VOO711 in House-Clone 1 mtDNA-NADH VOO711 in House-Clone mtDNA-NADH VOO711 in House-Clone mtDNA-NADH VOO711 in House-Clone mtDNA-NADH L VOO711 in House-Clone mtDNA-NADH VOO711 in House-Clone mtDNA-NADH VOO711 in House-Clone 2'-5')oligoadenylate synthetase 1 XO4958, AI449562 Mm.14301 577664 M33863 17 14-3-3 protein beta AFOS8797.1 Mm34454 1039350 18 14-3-3 protein epsilon D87663.1 Mm678 670982 19 14-3-3 protein eta US7311 Mm33O8 558,536 2O 14-3-3 protein gamma AFOS8799 Mm.108O2 464892 21 14-3-3 protein theta (tau) US 7312 AA42298O Mm.14722 803843 22 14-3-3 protein zeta U79231 AA671451 Mm3360 1039129 23 25-hydroxyvitamin D3 24-hydroxylase D49438 AA24O836 Mn.6575 657172 precursor 24 25-hydroxyvitamin D3 24-hydroxylase D49438 AI226268 Mn.6575 658678 precursor 25 2-amino-3ketobutyrate-coenzyme Aligase AFO93403 AIO37094 Mm.18618 315143 26 2-oxoglutarate dehydrogenase E1 UO2971 W98443 424,460 component 27 3.2-trans-enoyl-CoA isom, mito precursor Z14049 AI194961 18866S1 28 38g cent. In House-Clone 29 3-beta hydroxy-5-ene steroid M27137 AA274685 766591 dehydrogenase type I 30 3-beta hydroxy-5-ene steroid M75886 AI266804 Mm3O433 1891.212 dehydrogenase type II 31 3-beta hydroxy-5-ene steroid M77015 AA209060 M.335 676577 dehydrogenase type III 32 3-methyl-2-oxobutanoate dehydrogenase L16992 Mm.12819 422840 (lipoamide) 33 41.2a cent. In House-Clone 34 44b cent. In House-Clone 35 45.2b cent. In House-Clone 36 55e cent. In House-Clone 37 5-aminolevulinate synthase precursor M15268 AA189529 Mm.1217 635215 (EST) 38 65c cent. In House-Clone 39 66a cent. In House-Clone 40 67 cent. In House-Clone 41 a-amylase VOO719 AI32S237 M.7074 608852 42 acatyl-CoA acetyltransferase 1 L42293 Mn28099 472233 43 acatyl-CoA acetyltransferase 2 AFO78751 AA239043 694O62 44 Aconitase (iron responsive element) X61147 AA212704 677092 45 Aconitase (iron responsive element) X61147 AA238899 697949 46 Acyl-CoA dehyd, med-chain specific UO7159 AA1041.84 Mm.105.30 5681.49 precursor (MCAD) 47 Acyl-CoA dehyd, short-chain specific L11163 AIOSO239 Min.18759 1379035 precursor 48 Acyl-CoA dehyd, very-long-chain specific U41497 AA2SO410 Mm.1863O 670916 precursor 49 Acyl-CoA dehydrog, long-chain spec. U21489 AA254.905 Mm.2445 71958O precursor (LCAD) 50 adapt In House-Clone 51 Adenine nucleotide translocator 2, AAO33.138.1 fibroblast (Ant2) 52 adenylate kinase isoenzyme 2 (EST) AAO61587 Mm.2946O 483322 53 AdenyloSuccinate synthase AA388461 749837 S4 adenylyl cyclase type VII U12919 W65619 38728O 55 ADP, ATP carrier protein, fibroblast U27316 Mm658 585992 isoform 2 (ant2) 56 ADP, ATP carrier protein, heart isoform T1 U27315 AA717872 Mm.16228 1152250 US 2006/0099578 A1 May 11, 2006 90

TABLE 5-continued

IMAGE Clone Res. Num Gene Genbank Acc. ii ID Unigene Cluster Gen. Clone 57 adrenodoxin precursor L29123 AA461849 Mm.1061 851558 58 Alcohol dehydrogenase 5 AA183.192 6362O7 59 Alcohol dehydrogenase I 69.5105 60 Aldehyde dehydrogenase UO7235 579570 61 aldehyde dehydrogenase (NAD+) 2 UO7235 Mm.2621 1001020 precursor 62 Alpha-1 protease inhibitor U38477 AA212578 Mm.16672 676745 63 1 In House-Clone 64 ioxidant protein 1 M28723 W91307 423832 65 ioxidant protein 1 M28723 Mm.298.21 599017 66 ioxidant protein-2 (AO2) 243957 Mm6587 694.088 67 poptosis inhibitor 2 44490 597715 68 poptosis inhibitor 3 O97958 550702 69 apoptosis regulator BAX, membrane L22472 AI323S21 Mm19904 557643 isoform alpha 70 Apoptosis-inducing factor AF100927 AA866777 1434.491 71 ASC In House-Clone 72 ATP synth lipid-binding protein P1 L19737 A481739 Mm258 888863 precursor (subunit 9) 73 ATP synthase A Channel AA1064O6 AA1064.06 Mm.5293 S19329 74 ATP synthase FO component L19737 AA139793 S80898 75 ATP synthase FO component 735887 76 ATP/GTP binding protein 642977 77 ATPase, Ca++ transporting, cardiac W34.420.1 3.18735 muscle, fast twitch 1 78 ATPase, Ca2+ transporting, heart 3.18735 79 ATPase-like vacule proton channel AA276.030 776055 8O ATP-binding cassette transporter 7 U43892 AUO19072 Mm.4739 1920872 81 Bcl-2 protein U10102 AAO51441 478.723 82 Branched chain alpha ketoacid dehydrog. Mm.8903 578018 Kinase 83 branched chain alpha-ketoacid dehyd chain L47335 314098 E1-alpha 84 Branched-chain a-ketoacid dehydrog. E1b AAOSOS86 476,163 85 Branched-chain amino transferase I AAOO3372 426976 86 BZP In House-Clone 87 C II 3 In House-Clone 88 C IV is In House-Clone 89 Calcium channel, voltage-dependent, L AAS.11037.1 89.0932 type, alpha 2 delta Subunit 90 calm 1 In House-Clone 91 3 AA10904.1.1 571789 92 carbonate dehydratase, hepatic X51971 AI2S6540 Mn3SS38 18894.15 93 Carbonic Anhydrase IV U37091 AA71129 Mm.1614 116.7078 94 carbonyl reductase (NADPH) - mouse XO7411, W11423 Mm...214.54 317572 D26123 95 carnitine O-acetyltransferase (carnitine X85983 AI528757 Mn2O396 acetylase) 96 carnitine O-palmitoyltransferase II UO1163 Mm.294.99 precursor 97 Carnitine palmitoyltransferase 2 Mm.294.99 S8O316 98 Caspase 2 AA20O808 639403 99 Caspase I AAO98.139 550766 OO Catalase AA239490 Mm 4215 678773 O1 CCAAT?enhancer binding protein AA271223.1 738.252 C/EBP), alpha O2 CEBP In House-Clone O3 Cellular apoptosis succep. Protein AA471761 874.148 O4 chaperonin-10 UO9659 Mm.12970 422572 05 CI 1.8K In House-Clone O6 CIB8 In House-Clone O7 col1 In House-Clone O8 col 3 In House-Clone 09 coproporphyrinogen III oxidase precursor D16333 W71884 Mm3582O 3904.87 10 coproporphyrinogen oxidase D16333 AA108600 570602 11 coproporphyrinogen oxidase D16333 AA259342 734795 12 coproporphyrinogen oxidase D16333 W53951 367358 13 Core binding factor beta AA146442.1 596,552 14 creatine kinase Z13968, AA690010 1167886 Z13969 15 Creatine Kinase, muscle XO3233 AA166212 M.2375 608246 16 Creatine kinase-complete M74149 AA27O310 Mm.16831 736251 17 Creatine kinase-mitochondrial Z13968 AIS28837 Mm.97O 6O7301 US 2006/0099578 A1 May 11, 2006 91

TABLE 5-continued

IMAGE Clone Res. Num Gene Genbank Acc. ii ID Unigene Cluster Gen. Clone 18 cyt C oxydase polypeptide VIIa XS8486 Mm...2151 1248366 liver?heart precursor 19 cyto C oxydase polypeptide VIa-heart UO8439 AA415934 Mm21 OSO 846138 precursor cyto C oxydase polypeptide VIa-liver LO 6465 Mm.19094 S33628 precursor 21 cytochrome c oxidase chain IV precursor X54691, Mm...2136 746S46 M37829 22 cytochrome c oxidase chain Va. precursor X15963 AI131665 Mm360 1884978 23 cytochrome c oxidase chain Vb precursor X53157 AIO3S3O2 Mm.16769 1432845 24 cytochrome c oxidase chain VIb NM OO1863 AISO3861 991287 (HUMAN) 25 cytochrome c oxidase chain VIc M2O153 AAO62417 S16889 26 cytochrome c oxidase chain VIIc X52940 AAO31250 Mm.14831 464966 27 cytochrome c oxidase chain VIII U37721 Mm.14022 481408 28 Cytochrome C oxidase Sub VII AAOSO684 47618O 29 cytochrome C oxydase polypeptide VIII-H U15541 AI323348 Mm3841 463967 precursor 30 cytochrome C, somatic XO1756 AA221965 Mn3S389 658678 31 cytochrome C-type heme lyase (CCHL) U36778 Mm3988 400735 32 cytochrome-b5 reductase (HUMAN) NM OOO398 AA816039 112O651 33 CYTOSOLIC BRANCH CHAIN AA286063 776036 AMINOTRANSFERASE 34 D 43 House-Clone 35 D 47 House-Clone 36 D 48 House-Clone 37 D 53 House-Clone 38 D 64 House-Clone 39 D 68 House-Clone 40 D 69 House-Clone 41 D 73 House-Clone 42 D 83 House-Clone 43 D 84 House-Clone 44 House-Clone 45 House-Clone 46 D14 House-Clone 47 House-Clone 48 House-Clone 49 House-Clone 50 House-Clone 51 House-Clone 52 House-Clone 53 House-Clone S4 House-Clone 55 House-Clone 56 House-Clone 57 D39 House-Clone 58 House-Clone 59 D7a House-Clone 60 defender against cell death 1 AAO33006 464622 61 DiGeorge syndrome chromosome region 6 WS4234.1 356181 62 dihydrolipoamide dehydrogenase (E3) JO3490 AA548.170 Hs.7463S 9948.25 (HUMAN) 63 dihydrolipoamide transacylase precursor L42996 AA254971 Mm36.36 719973 64 Dimethyl glycine dehydrogenase AA288418 748958 65 DNA polymerase gamma U53584 Mm3616 575332 66 Dynamin AA266438 317587 67 Dynamin 2 W13111 457445 68 E1B 19k/Bcls-binding prot. Homolog AA105295 571367 (NIP3) 69 ERV In House-Clone 70 ERV-1 U40494 A413376 Mm.28,124 367232 71 EST highly similar to S-100 prota-chain AA466432 872869 72 ESTS AA2S3853.1 660997 73 ESTS AA2684O2.1 721970 74 ESTS W141421 329863 75 ESTs, Highly similar to CREATINE AAO38.095.1 472860 KINASE, SARCOMERIC MITO. PRECUR. 76 ESTs, Highly similar to CREATINE AI322288.1 336085 KINASE, SARCOMERIC MITO. PRECUR. US 2006/0099578 A1 May 11, 2006 92

TABLE 5-continued

IMAGE Clone Res. Num Gene Genbank Acc. ii ID Unigene Cluster Gen. Clone 77 ESTs, Highly similar to W13931.1 330218 DERMATOPONTIN Bos taurus 78 ESTs, Highly similar to MATERNAL AA104976.1 S33314 EFFECT PROTEINSTAUFEN 79 ESTs, Highly similar to NADH AA288040.1 748891 UBIQUINONE OXIDOREDUCTASE 13 KD-B SUB ESTs, Highly similar to NADH AA222463.1 671212 UBIQUINONE OXIDOREDUCTASE SGDHSUB PREC. 81 ESTs, Highly similar to NUCLEAR AAO60802.1 482952 FACTOR NF-KAPPA-BP1OO SUBUNIT 82 ESTs, Highly similar to PINCH AA28928O1 790449 83 ESTs, Highly similar to PTERIN-4- W14332.1 331 681 ALPHA-CARBINOLAMINE DEHYDRATASE 84 ESTs, Highly similar to PUTATIVE W66757.1 387449 REGULATORY PROTEINTSC-22 85 ESTs, Highly similar to SUCCINATE AA108475.1 572339 DEHYDROGENASE 86 ESTs, Highly similar to (define not AA190123.1 642467 available 4588044) 87 ESTs, Highly similar to putative AA184876.1 642977 ATP/GTP-binding protein 88 ESTs, Weakly similar to (define not AA467585.1 833 160 available 366.8141) H. sapiens 89 ESTs, Weakly similar to Survival motor AAS384.19.1 93.2748 neuron M. musculus 90 ESTs, Weakly similar to vesicle membrane AA259674.1 7351.86 protein 91 Excitatory amino acid transporter 3 D43797 AAO6SSO2 Mn24741 524046 92 erredoxin-NADP+ reductase precursor D4992O AA879949 Mm.4719 1230740 93 errochelatase precursor MS9288 Mm.1070 635652 94 Friedreich ataxia S75712 AA93O748 11 SO363 95 Fructose 1–6 bis-phosphate AI3856O2 Mm.2974 336727 96 Fructose bis-phosphate aldolase AISS3136 M.7729 902910 97 Fructose Bisphosphate aldolase A AAS18639 903419 98 Fuzzy Onion homolog (mouse) AA674474 10930O2 99 GAMMA-ADAPTIN AA238435.1 693837 2OO GAPD In House-Clone 2O1 GILZ In House-Clone 2O2 Gluamate receptor, ionotropic, kainate 5 AA261334 Mn2879 733368 (gamma 2) Gluamate receptor, ionotropic, NMDA1 W44130 Mm3292 354244 (Zeta 1) 204 Gluamate receptor, ionotropic, NMDA2C Mm39090 1852361 epsilon 3) 205 Glucose dependent insulinotropic U34295 AA871367 Mm.5115 1096156 polypeptide 2O6 Glucose Phospahate Isomerase I complex M14220 AA276216 776210 2O7 Glucose Phospahate Isomerase I complex M14220 W29397 337413 208 Glucose-6-phosphate isomerase LO9104 AI32718O Mm.589 437357 209 glutamate dehydrogenase (NAD(P)+) XS7024 AAS43797 Mm.106OO 9490OS precursor 210 glutamate oxaloacetate transaminase-2 XO6917, Mm.18916 617490 JO2622 211 Glutaryl-CoA dehydrogenase precursor U18992 Mn2475 573351 (GCD) 212 Glutathione peroxidase-3 (plasma Gpx) U13705 AAO97557 M7156 552393 213 Glutathione peroxidase-4 (phospholipid AAO34666 Mn24OO 466963 Gpx) 214 Glutathione peroxidase-heart isoform AFO45769.1 Mn2400 42O345 (Gpx4) 215 Glutathione peroxidase-plasma isoform U13705.1 AIO42912 1432410 216 Glyceraldehyde 3-phosphate AA122891 579715 dehydrogenase 217 Glycerol 3-phosphate acyltransferase M77003 AA2O9041 676437 218 Glycerophosphate dehydrogenase A414O23 Mm.10669 3O3389 219 Glycogen Phosphorylase (RAT) AA24O684 656882 220 GP4 In House-Clone 221 Gpx In House-Clone 222 GTP2 In House-Clone US 2006/0099578 A1 May 11, 2006 93

TABLE 5-continued

IMAGE Clone Res. Num Gene Genbank Acc. ii ID Unigene Cluster Gen. Clone 223 GTP-binding protein AASO956S 89.0444 224 H+-transporting ATP synthase chain alpha LO1062 AIST3940 Mn4O69 192O315 225 H+-transporting ATP synthase chain beta AFO30559 AI452208 Mm.17869 576.006 226 H+-transporting ATP synthase chain delta AA940343 AA896697 Mn22514 1279053 (EST) 227 H+-transporting ATP synthase chain e U59283 AI115240 188S128 228 H+-transporting ATP synthase chain e U59283 M481625 876416 229 H+-transporting ATP synthase chain U438.93 AA210528 64O931 gamma 230 heat shock protein 60 precursor X55023, AA154729 M.1777 XS3584 231 heat shock protein 70 precursor D11089 AI132204 Mm.2849 1481709 232 heat shock protein, 70 K (hsp68) M12573 AA647374 Mm6388 1108.306 (fragment) 233 Heat shock protein, 84 kDa 1 M1818.6 Mm218O 538585 234 Hexokinase W11571 318642 235 Hexokinase W74835 389.177 236 hexokinase I (3'-seq) JO5277 AI661880 Mm.5290 717383 237 hexokinase I (5'-seq) JO5277 AA197916 Mm.5290 654873 238 high mobility group protein homolog AAO48831.1 478865 HMG4 (Hmg4) mRNA, complete cols 239 HK-40s Ribosomal protein S15 AAO33398 466295 240 HK-40s Ribosomal protein S4 AAOOOO82 42S352 241 HK-A111Acient ubiquinating protein W82989 405768 242 HK-A16060s Ribosomal protein L15 AAO 68842 532,770 243 HK-A17360s Ribosomal protein L3 AA1083.63 570533 244 HK-A21060s Ribosomal protein L1A AA17O607 619006 245 HK-A216RNA splicing protein AA183061 636766 246 HK-A262E2F transcription factor AA3961.23 751755 247 HK-A272Capping protein AA414612 779754 248 HK-A316Actin-gamma (Smooth muscle) M26689 AA71O883 Mm.16562 11668SS 249 HK-A97HypoZanthine phosphoribosyl JOO423 W481.68 Min.18675 3SS084 transferase 250 HK-Actin-alpha (skeletal muscle) M12347 AIO3S279 Mm.4581 1480709 251 HK-Actin-gamma M21495 AI314957 Mm.29913 1928S9 252 HK-Akaline Phosphatase AAO32457 46SOS2 253 HK-b-actin XO3672 AAO79937 Mm.297 536615 2S4 HK-calcium binding protein Cab45 U45977 AI266799 Mm3O149 18912O2 255 HK-DNA ligase I W66.626 388245 2S6 HK-Glyceraldehyde 3-phosphate W14827 AA119563 Mm.5289 S38210 dehydrogenase (G3PDH) 257 HK-Glyceraldehyde phosphate M32599 AA4666.18 Mm.5289 817984 d ehydrogenase 258 K-HPRT In House-Clone 259 HK-HypoZanthine phosphoribosyl JOO423 AI256193 Min.18675 1890233 transferase 260 HK-Murine ornithine decarboxylase M10624 AI32S192 M.15259 608003 261 HK-Myosin 1 LOO923 AIO98.184 Mm3390 14.81939 262 HK-Phospholipase A2 (14-3-3 Zeta delta) D78647 AA171.4341 Mm3360 617315 263 HK-Ribosomal Protein S29 L31609 AAO32465 Mm35816 465138 264 HK-Ubiquitin X51703 AI181949 Mm.235 1451597 26S House mouse; Musculius domesticus W82212.1 403728 mRNA for LN1, complete cols 266 Huntingtin AI876894 AI876894 1922O60 267 hydroxymethylglutaryl-CoA lyase S6SO36 AA838,929 1261134 268 hydroxymethylglutaryl-CoA synthase, U12790, Mm.10633 S18481 mitochondrial U12791 269 GALPHACHAIN C REGION AAO98196.1 551003 270 MAGE EST AAOO9059.1 441176 271 MAGE EST AAO28.306 464O99 272 MAG EST AAO35899.1 468817 273 MAG EST AAO51664.1 479709 274 MAG EST AA118290 574435

275 MAG EST AA2OO984.1 63921.2 276 EST AA2O3878 64O734 277 EST AA215024 6522O7 278 MAG EST AA221250 670393 279 MAG EST AA245545 69928O 28O MAG EST AA250652 697537 281 EST AA266097.1 716941 282 EST AA275684 775722 283 MAG EST AA388512 790857 284 MAG EST AA466O26.1 809016 US 2006/0099578 A1 May 11, 2006 94

TABLE 5-continued

IMAGE Clone Res. Num Gene Genbank Acc. ii ID Unigene Cluster Gen. Clone 28S IMAG AAS 19027.1 904900 286 IMAG WO8090.1 331768 287 IMA WO9924 315773 288 IMA WO9924.1 315773 289 IMAG W15031 33OSO2 290 IMAG W41309.1 351420 291 IMAG W89418.1 42OSS3 292 IMAGE EST-CCAAT enhancer binding AA271223 738.252 protein 293 IMAGE EST-Glucocorticoid-induced W66757 387449 eucine Zipper GILZ protein 294 IMAGE EST-homolog of Unc33 WO8090 331768 (C. Elegans), Collaspin reponse mediated

brot. 2 295 IMAGE EST-sarcoplasmic creatine kinase W18057 336085 296 IMA EST-Sim to gamma W41309 351420 297 IMAGE EST-yeast bile transporter AA473.289 8O3488 298 Interferon gamma receptor AAS41842.1 92O516 299 Interleukin 1 receptor-associated kinase AA276835.1 777580 300 isocitrate dehydrogenase (NADP) US1167 Mm.2966 S71468 301 Kin 17 In House-Clone 302 Lactate Dehydrogenase- M27554 AA88O398 1277670 303 Lactate Dehydrogenase-A4 M17516 AISO 6641 Mm.26504 1024774 304 Lactate Dehydrogenase-sperm specific M17587, AA110449 Mm.16563 S16582 L10389 305 M. musculius mRNA for fibromodulin W63981.1 306 M. musculus mRNA for GTP-binding AAO2O462.1 protein 307 MAD homolog 4 (Drosophila) AAO3O901.1 466SS1 308 Malate dehydrogenase (cyto) W13686 31.8346 309 Malate dehydrogenase (mito) M16229 AA266087 717095 310 malate dehydrogenase precursor, XO7295, Mm21743 4O7143 mitochondrial M16229 311 MAPKINASE PHOSPHATASE-1 AA125367.1 575665 312 Maternal embryonic message 3 AA388,122.1 77.5464 313 MCK In House-Clone 314 DP 6 In House-Clone 315 metal response element DNA-binding AAS456O7.1 945218 protein M96 mRNA, complete cols 316 methylenetetrahydrofolate dehydrogenase JO4627 Mm.443 440345 (NAD+) 317 methylmalonyl-CoA mutase alpha chain XS1941 Mm.4299 571282 precursor 318 Microtubule-associated protein 4 AAOO3769.1 437523 319 Mito matrix prot P1 precursor (hsp60) AA184322 633625 320 Mitochondrial LON protease AAO61310 AAO61310 S14859 321 mitochondrial transcription factor A - U57939 Mm.276 S39693 OSC 322 mitochondrial uncoupling protein M21247 AI13.1780 Mn4177 1498,957 323 monoamine oxidase A - mouse S78615 AI64318.5 864.614 324 Mouse breast heat shock 73 prot (hsc73) M19141 Mm.2944 S38418 325 Mouse calcineurin catalytic subunit AA245461.1 699236 mRNA, complete cols 326 Mouse Circadian output locomotor cycles AFOOO998 AI156715 1494O23 kaput 327 Mouse heatshock protein 27 UO3S 60.1 AA596.241 Mm.13849 10521.88 328 Mouse heatshock protein 86 JO4633 AI649.095 1970.053 329 Mouse med. Chain acyl-CoA UO7159 AAO 61679 48.3333 dehydrogenase 330 Mouse mHox protein LO 6502 W17990 Mm3869 335936 331 Mouse Skd3 mRNA UO9874 Mm3990 6O2340 332 mRNA for sarco/endoplasmic reticulum AA222567.1 695695 Ca2+-ATPase (SERCA2) 333 TF 1 In House-Clone 334 Mus musculus Balbic zinc finger protein W11161.1 316427 PZF (Pzf) mRNA, complete cols 335 Mits miscuits calcium-binding protein AA466432.1 872869 S100A1 mRNA, complete cols 336 Mus musculus cytoplasmic protein Ndr1 AA473269.1 8O3416 (Ndr1) mRNA, complete cols 337 Mus musculus FGF-binding protein (FGF- AA403432.1 717457 BP) mRNA, complete cols US 2006/0099578 A1 May 11, 2006 95

TABLE 5-continued

IMAGE Clone Res. Gene Genbank Acc. ii ID Unigene Cluster Gen. Clone 338 Mus musculus GTP binding protein AASO9565. 89.0444 (GTP2) mRNA, complete cols 339 Mits miscuits hemin-sensitive initiation AAO36546. 466971 factor 2 alpha kinase mRNA, complete cols 340 Mus musculus mRNA for glutamate AIO43222 1431493 receptor channel alpha 4 subunit 341 Mus musculus mRNA for GM3 synthase, AA274576. 748275 complete cols 342 Mus musculus PAF acetylhydrolase AI324436.1 S36464 mRNA, complete cols 343 Mits miscuits pantophysin gene, complete AA271 SOS. 737944 cols 344 Mus musculius rab6frab5-associated W7771.1.1 4O1958 protein (rab6) mRNA, partial cols 345 Mus musculius skeletal muscle LIM AAO47966. protein (FLH1) mRNA, complete cds 346 Mus musculus Stra13 mRNA, complete AAO64241. 48O896 cols 347 WS3 In House-Clone 348 Myeloid cell leukemia sequence 1 U35623, AA38.7843 Mm.1639 761106 AFO63886 349 Myostatin AA052179. 418993 350 NAD(P)+ transhydrogenase (B-specific) Z49204 AI323702 Mm3842 580717 precursor 351 NADH dehydrogenase mwife 404499 352 NADH-ubiquinone oxidoreductase 13 kDa L38438 S99804 Subunit 353 NADH-ubiquinone oxidoreductase 13 kDa U59509 468848 Subunit 3S4 NADP transhydrogenase Z49204 AI323702 Mm3842 580717 355 Nitric Oxide Synthase-2 AAS12708 Mn2893 9222SO 356 Nitric Oxide Synthase-3 AA177240 Min12837 62O940 357 Nuclear respiratory factor-1 AFO980.77 AIS94316 1OO6311 358 Nuclear respiratory factor-2 U20532 Mm.1025 63SS41 359 ornithine carbamoyltransferase precursor XO7092 AI266937 Mm.2611 1891345 360 ornithine-oxo-acid transaminase precursor X64837 AI1964.10 Mm.13694 1887672 361 63a. In House-Clone 362 PACD In House-Clone 363 PEBP2 In House-Clone 364 Peripheral myelin protein, 22 kDa AA416246.1 846.064 365 peripheral-type benzodiazepine receptor 1 U12419 AAO68577 524.463 366 Perox. Proliferator receptor (PPAR) UO1841 W34083 317536 Gamma 367 Peroxisomal/Mitochondrial dienoyl-CoA 338088 isomerase 368 Phosphofructokinase 1 JO3928, AI480449 Mm.1166 862787 AF123533 369 phospholipase A2, platelet, Synovial fluid X74266 AA871S47 Mm.4675 10962S1 370 phosphoprotein phosphatase M81475 AI449151 M.1567 619279 371 PMP 35 L27842 AI573377 Mm.16453 5341.71 372 probable aconitate hydratase, AI385870 AA275929 Mm3OO65 775753 mitochondrial (EST) 373 Procollagen Type 1 AAO73604 536306 374 Procollagen, type I, alpha 1 AAO73604.1 536306 375 Procollagen, type III, alpha 1 W89883.1 42O322 376 Procollagen, type VI, alpha 1 W33786.1 352450 377 Protein Phosphatase inhibitor 2 (IPP2) AAO41826 AAO41826 Mm.296.17 4754O7 378 protoporphyrinogen oxidase U25114, Mm.473O 482868 D4S185 379 pyruvate carboxylase L09192 AI3O3529 Mm.1845 1888741 380 Pyruvate decarboxylase AA3O8254 473778 381 Pyruvate dehydrogenase M76727 AA423301 82O4.09 382 pyruvate dehydrogenase (lipoamide) M76728 AI323722 Mm.4223 S13684 383 pyruvate dehydrogenase (lipoamide) M76727 AA466268 M.34775 888.842 384 Pyruvate dehydrogenase E1 a subunit L13318 AA238899 888.842 (human) 385 pyruvate kinase D383.79 AIO3S313 Mm2635 1432851 386 Pyruvate kinase D63764 AI195164 Mm.8359 1886895 387 Pyruvate kinase AA475,121 873690 388 Pyruvate kinase-like protein W17814 334876 389 RAB1 In House-Clone 390 RAB1, member RAS oncogene family AA17SS.10.1 6195O1 391 Rat NRBF1 AA259674 7351.86