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A sample implementation of the MEFIT system is provided here for research purposes. If you find MEFIT useful, let us know! For that matter, if you find bugs, have questions, or are interested in source code for MEFIT, let us know that, too. We can be contacted at chuttenh@princeton.edu and ogt@princeton.edu. We are currently able to offer for download:

• The MEFIT README file.
• A Windows version.
• A Linux version.

Each of the following files contains MEFIT's pairwise functional relationship predictions for one biological function. Files are formatted to contain one gene pair and probability of relationship per line. Two prediction sets are available for each biological process, one generated from our test set (with the addition of genes annotated to GO's "biological process unknown") and one generated over the entire yeast genome.

• aging: test, total
• alcohol metabolism: test, total
• aldehyde metabolism: test, total
• amine metabolism: test, total
• amine transport: test, total
• amino acid and derivative metabolism: test, total
• aromatic compound metabolism: test, total
• asexual reproduction: test, total
• autophagy: test, total
• biopolymer biosynthesis: test, total
• boron transport: test, total
• carbohydrate metabolism: test, total
• carbohydrate transport: test, total
• carbon utilization: test, total
• cell adhesion: test, total
• cell death: test, total
• cell division: test, total
• cell redox homeostasis: test, total
• cell surface receptor linked signal transduction: test, total
• cell wall catabolism: test, total
• cell wall organization and biogenesis: test, total
• cellular morphogenesis: test, total
• cellular respiration: test, total
• chitin localization: test, total
• chromosome condensation: test, total
• chromosome organization and biogenesis (sensu Eukaryota): test, total
• chromosome segregation: test, total
• cofactor metabolism: test, total
• cofactor transport: test, total
• conjugation: test, total
• cytoskeleton organization and biogenesis: test, total
• cytoskeleton-dependent intracellular transport: test, total
• detection of external stimulus: test, total
• DNA catabolism: test, total
• DNA ligation: test, total
• DNA packaging: test, total
• DNA recombination: test, total
• DNA replication: test, total
• DNA replication and chromosome cycle: test, total
• DNA topological change: test, total
• drug transport: test, total
• electron transport: test, total
• endosome organization and biogenesis: test, total
• energy reserve metabolism: test, total
• ER organization and biogenesis: test, total
• ER-nuclear signaling pathway: test, total
• establishment of protein localization: test, total
• establishment of RNA localization: test, total
• extracellular transport: test, total
• fermentation: test, total
• filamentous growth: test, total
• fluid transport: test, total
• gene silencing: test, total
• glycerol ether metabolism: test, total
• glycoprotein metabolism: test, total
• Golgi organization and biogenesis: test, total
• heterocycle metabolism: test, total
• hydrogen transport: test, total
• interaction between organisms: test, total
• interphase: test, total
• intracellular mRNA localization: test, total
• ion homeostasis: test, total
• ion transport: test, total
• ketone metabolism: test, total
• lipid metabolism: test, total
• lipid transport: test, total
• lipoprotein metabolism: test, total
• M phase: test, total
• maintenance of protein localization: test, total
• mannoprotein metabolism: test, total
• meiotic cell cycle: test, total
• membrane disassembly: test, total
• membrane fusion: test, total
• metabolic compound salvage: test, total
• microtubule organizing center organization and biogenesis: test, total
• mitochondrial transport: test, total
• mitochondrion organization and biogenesis: test, total
• mitotic cell cycle: test, total
• mRNA metabolism: test, total
• mutagenesis: test, total
• negative regulation of cell organization and biogenesis: test, total
• negative regulation of protein metabolism: test, total
• negative regulation of transcription: test, total
• nitrogen compound metabolism: test, total
• nuclear division: test, total
• nuclear organization and biogenesis: test, total
• nuclear transport: test, total
• nucleobase, nucleoside, nucleotide and nucleic acid transport: test, total
• nucleocytoplasmic transport: test, total
• nucleoside metabolism: test, total
• nucleotide metabolism: test, total
• nucleotide-sugar metabolism: test, total
• one-carbon compound metabolism: test, total
• organelle fission: test, total
• organelle fusion: test, total
• organelle inheritance: test, total
• organic acid metabolism: test, total
• organic acid transport: test, total
• organismal physiological process: test, total
• osmoregulation: test, total
• oxygen and reactive oxygen species metabolism: test, total
• peptide metabolism: test, total
• peptide or protein carboxyl-terminal blocking: test, total
• peptide transport: test, total
• peptidyl-amino acid modification: test, total
• peroxisome organization and biogenesis: test, total
• phosphorus metabolism: test, total
• plasma membrane organization and biogenesis: test, total
• plasmid maintenance: test, total
• polyol transport: test, total
• positive regulation of transcription: test, total
• protein amino acid acetylation: test, total
• protein amino acid alkylation: test, total
• protein amino acid biotinylation: test, total
• protein amino acid deacetylation: test, total
• protein complex assembly: test, total
• protein deneddylation: test, total
• protein depolymerization: test, total
• protein desumoylation: test, total
• protein folding: test, total
• protein kinase cascade: test, total
• protein neddylation: test, total
• protein polymerization: test, total
• protein processing: test, total
• protein secretion: test, total
• protein stabilization: test, total
• protein sumoylation: test, total
• protein-cofactor linkage: test, total
• protein-tetrapyrrole linkage: test, total
• proteolysis and peptidolysis: test, total
• pseudouridine synthesis: test, total
• regulation of cell cycle: test, total
• regulation of cell differentiation: test, total
• regulation of DNA metabolism: test, total
• regulation of enzyme activity: test, total
• regulation of gene expression, epigenetic: test, total
• regulation of protein biosynthesis: test, total
• regulation of protein catabolism: test, total
• regulation of RNA metabolism: test, total
• regulation of signal transduction: test, total
• regulation of transport: test, total
• response to acid: test, total
• response to antibiotic: test, total
• response to carbohydrate stimulus: test, total
• response to DNA damage stimulus: test, total
• response to ethanol: test, total
• response to inorganic substance: test, total
• response to nutrients: test, total
• response to osmotic stress: test, total
• response to pH: test, total
• response to pheromone: test, total
• response to radiation: test, total
• response to starvation: test, total
• response to temperature: test, total
• response to toxin: test, total
• response to unfolded protein: test, total
• response to water: test, total
• response to xenobiotic stimulus: test, total
• ribosome biogenesis: test, total
• RNA 3'-end processing: test, total
• RNA capping: test, total
• RNA catabolism: test, total
• RNA elongation: test, total
• RNA methylation: test, total
• RNA splicing: test, total
• rRNA metabolism: test, total
• rRNA transcription: test, total
• second-messenger-mediated signaling: test, total
• secondary metabolism: test, total
• sequestering of metal ion: test, total
• sex determination: test, total
• sexual reproduction: test, total
• siderophore transport: test, total
• small GTPase mediated signal transduction: test, total
• snoRNA metabolism: test, total
• snoRNA transcription: test, total
• snRNA metabolism: test, total
• spore germination: test, total
• sporulation: test, total
• sulfur metabolism: test, total
• terpene metabolism: test, total
• transcription from mitochondrial promoter: test, total
• transcription from RNA polymerase I promoter: test, total
• transcription from RNA polymerase II promoter: test, total
• transcription from RNA polymerase III promoter: test, total
• transcription initiation: test, total
• transcription termination: test, total
• translation: test, total
• tRNA metabolism: test, total
• two-component signal transduction system (phosphorelay): test, total
• ubiquitin cycle: test, total
• ultradian rhythm: test, total
• vacuolar protein catabolism: test, total
• vacuolar transport: test, total
• vacuole organization and biogenesis: test, total
• vesicle organization and biogenesis: test, total
• vesicle-mediated transport: test, total
• viral life cycle: test, total
• vitamin metabolism: test, total
• vitamin transport: test, total

• The GO terms voted on by our panel of six biologists can be found here.
• The 200 fully processed GO terms used for our positive gold standard generation and functional evaluation are here.
• The 92 GO terms used to generate negative functional relationships can be found here.

This file represents the gold standard answer file generated from our 200 biological functions. Each line contains a gene pair and a 0 (for unrelated pairs) or a 1 (related pairs). As described in Huttenhower et al. 2006, gene pairs coannotated to any function were considered to be related, and gene pairs not coannotated within a very general set of functions were considered to be unrelated. All other gene pairs were excluded from the answer file.

The MEFIT predictions displayed here (and discussed in our paper) used the following microarray data sets as input.

• Angus-Hill ML, Schlichter A, Roberts D, Erdjument-Bromage H, Tempst P, Cairns BR. "A Rsc3/Rsc30 zinc cluster dimer reveals novel roles for the chromatin remodeler RSC in gene expression and cell cycle control." Mol Cell. 2001 Apr;7(4):741-51
• Belli G, Molina MM, Garcia-Martinez J, Perez-Ortin JE, Herrero E. "Saccharomyces cerevisiae glutaredoxin 5-deficient cells subjected to continuous oxidizing conditions are affected in the expression of specific sets of genes." J Biol Chem. 2004 Mar 26;279(13):12386-95
• Bernstein BE, Tong JK, Schreiber SL. "Genomewide studies of histone deacetylase function in yeast." Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13708-13
• Brauer MJ, Saldanha AJ, Dolinski K, Botstein D. "Homeostatic adjustment and metabolic remodeling in glucose-limited yeast cultures." Mol Biol Cell. 2005 May;16(5):2503-17
• Brem RB, Kruglyak L. "The landscape of genetic complexity across 5,700 gene expression traits in yeast." Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1572-7
• Brem RB, Yvert G, Clinton R, Kruglyak L. "Genetic dissection of transcriptional regulation in budding yeast." Science. 2002 Apr 26;296(5568):752-5
• Caba E, Dickinson DA, Warnes GR, Aubrecht J. "Differentiating mechanisms of toxicity using global gene expression analysis in Saccharomyces cerevisiae." Mutat Res. 2005 Aug 4;575(1-2):34-46
• Causton HC, Ren B, Koh SS, Harbison CT, Kanin E, Jennings EG, Lee TI, True HL, Lander ES, Young RA. "Remodeling of yeast genome expression in response to environmental changes." Mol Biol Cell. 2001 Feb;12(2):323-37
• Chu S, DeRisi J, Eisen M, Mulholland J, Botstein D, Brown PO, Herskowitz I. "The transcriptional program of sporulation in budding yeast." Science. 1998 Oct 23;282(5389):699-705
• Cohen BA, Pilpel Y, Mitra RD, Church GM. "Discrimination between paralogs using microarray analysis: application to the Yap1p and Yap2p transcriptional networks." Mol Biol Cell. 2002 May;13(5):1608-14
• Duvel K, Santhanam A, Garrett S, Schneper L, Broach JR. "Multiple roles of Tap42 in mediating rapamycin-induced transcriptional changes in yeast." Mol Cell. 2003 Jun;11(6):1467-78
• Eriksson PR, Mendiratta G, McLaughlin NB, Wolfsberg TG, Marino-Ramirez L, Pompa TA, Jainerin M, Landsman D, Shen CH, Clark DJ. "Global regulation by the yeast Spt10 protein is mediated through chromatin structure and the histone upstream activating sequence elements." Mol Cell Biol. 2005 Oct;25(20):9127-37
• Fleming JA, Lightcap ES, Sadis S, Thoroddsen V, Bulawa CE, Blackman RK. "Complementary whole-genome technologies reveal the cellular response to proteasome inhibition by PS-341." Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1461-6
• Gasch AP, Spellman PT, Kao CM, Carmel-Harel O, Eisen MB, Storz G, Botstein D, Brown PO. "Genomic expression programs in the response of yeast cells to environmental changes." Mol Biol Cell. 2000 Dec;11(12):4241-57
• Hardwick JS, Kuruvilla FG, Tong JK, Shamji AF, Schreiber SL. "Rapamycin-modulated transcription defines the subset of nutrient-sensitive signaling pathways directly controlled by the Tor proteins." Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14866-70
• Ideker T, Thorsson V, Ranish JA, Christmas R, Buhler J, Eng JK, Bumgarner R, Goodlett DR, Aebersold R, Hood L. "Integrated genomic and proteomic analyses of a systematically perturbed metabolic network." Science. 2001 May 4;292(5518):929-34
• Jin YS, Laplaza JM, Jeffries TW. "Saccharomyces cerevisiae engineered for xylose metabolism exhibits a respiratory response." Appl Environ Microbiol. 2004 Nov;70(11):6816-25
• Keller G, Ray E, Brown PO, Winge DR. "Haa1, a protein homologous to the copper-regulated transcription factor Ace1, is a novel transcriptional activator." J Biol Chem. 2001 Oct 19;276(42):38697-702
• Lee A, Henras AK, Chanfreau G. "Multiple RNA surveillance pathways limit aberrant expression of iron uptake mRNAs and prevent iron toxicity in S. cerevisiae." Mol Cell. 2005 Jul 1;19(1):39-51
• Martin DE, Demougin P, Hall MN, Bellis M. "Rank Difference Analysis of Microarrays (RDAM), a novel approach to statistical analysis of microarray expression profiling data." BMC Bioinformatics. 2004 Oct 11;5:148
• Ogawa N, DeRisi J, Brown PO. "New components of a system for phosphate accumulation and polyphosphate metabolism in Saccharomyces cerevisiae revealed by genomic expression analysis." Mol Biol Cell. 2000 Dec;11(12):4309-21
• Orlandi I, Bettiga M, Alberghina L, Vai M. "Transcriptional profiling of ubp10 null mutant reveals altered subtelomeric gene expression and insurgence of oxidative stress response." J Biol Chem. 2004 Feb 20;279(8):6414-25
• Primig M, Williams RM, Winzeler EA, Tevzadze GG, Conway AR, Hwang SY, Davis RW, Esposito RE. "The core meiotic transcriptome in budding yeasts." Nat Genet. 2000 Dec;26(4):415-23
• Roberts CJ, Nelson B, Marton MJ, Stoughton R, Meyer MR, Bennett HA, He YD, Dai H, Walker WL, Hughes TR, Tyers M, Boone C, Friend SH. "Signaling and circuitry of multiple MAPK pathways revealed by a matrix of global gene expression profiles." Science. 2000 Feb 4;287(5454):873-80
• Rudra D, Zhao Y, Warner JR. "Central role of Ifh1p-Fhl1p interaction in the synthesis of yeast ribosomal proteins." EMBO J. 2005 Feb 9;24(3):533-42
• Saldanha AJ, Brauer MJ, Botstein D. "Nutritional homeostasis in batch and steady-state culture of yeast." Mol Biol Cell. 2004 Sep;15(9):4089-104
• Schawalder SB, Kabani M, Howald I, Choudhury U, Werner M, Shore D. "Growth-regulated recruitment of the essential yeast ribosomal protein gene activator Ifh1." Nature. 2004 Dec 23;432(7020):1058-61
• Segal E, Shapira M, Regev A, Pe'er D, Botstein D, Koller D, Friedman N. "Module networks: identifying regulatory modules and their condition-specific regulators from gene expression data." Nat Genet. 2003 Jun;34(2):166-76
• Spellman PT, Sherlock G, Zhang MQ, Iyer VR, Anders K, Eisen MB, Brown PO, Botstein D, Futcher B. "Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization." Mol Biol Cell. 1998 Dec;9(12):3273-97
• Tai SL, Boer VM, Daran-Lapujade P, Walsh MC, de Winde JH, Daran JM, Pronk JT. "Two-dimensional transcriptome analysis in chemostat cultures. Combinatorial effects of oxygen availability and macronutrient limitation in Saccharomyces cerevisiae." J Biol Chem. 2005 Jan 7;280(1):437-47
• Williams RM, Primig M, Washburn BK, Winzeler EA, Bellis M, Sarrauste de Menthiere C, Davis RW, Esposito RE. "The Ume6 regulon coordinates metabolic and meiotic gene expression in yeast." Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13431-6
• Yamamoto A, Mizukami Y, Sakurai H. "Identification of a novel class of target genes and a novel type of binding sequence of heat shock transcription factor in Saccharomyces cerevisiae." J Biol Chem. 2005 Mar 25;280(12):11911-9
• Yoshimoto H, Saltsman K, Gasch AP, Li HX, Ogawa N, Botstein D, Brown PO, Cyert MS. "Genome-wide analysis of gene expression regulated by the calcineurin/Crz1p signaling pathway in Saccharomyces cerevisiae." J Biol Chem. 2002 Aug 23;277(34):31079-88
• Yvert G, Brem RB, Whittle J, Akey JM, Foss E, Smith EN, Mackelprang R, Kruglyak L. "Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors." Nat Genet. 2003 Sep;35(1):57-64

  © 2008 Curtis Huttenhower