Open Access Method

We demonstrate that loss-of-function yeast phenotypes are predictable by guilt-by-association in functional gene networks. Testing 1,102 loss-of-function phenotypes from genome-wide assays of yeast reveals predictability of diverse phenotypes, spanning cellular morphology, growth, metabolism, and quantitative cell shape features. We apply the method to extend a genome-wide screen by predicting, then verifying, genes whose disruption elongates yeast cells, and to predict human disease genes. To facilitate network-guided screens, a web server is available http://www.yeastnet.org.

[1]  R. Borstel,et al.  Spontaneous mutation by mutagenic repair of spontaneous lesions in DNA , 1976, Nature.

[2]  C. Pittenger,et al.  Characterization of a mutant strain of Saccharomyces cerevisiae with a deletion of the RAD27 gene, a structural homolog of the RAD2 nucleotide excision repair gene , 1995, Journal of bacteriology.

[3]  David Botstein,et al.  SGD: Saccharomyces Genome Database , 1998, Nucleic Acids Res..

[4]  D. Eisenberg,et al.  A combined algorithm for genome-wide prediction of protein function , 1999, Nature.

[5]  D. Eisenberg,et al.  Assigning protein functions by comparative genome analysis: protein phylogenetic profiles. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[6]  E. Sprinzak,et al.  Prediction of gene function by genome-scale expression analysis: prostate cancer-associated genes. , 1999, Genome research.

[7]  Ronald W. Davis,et al.  Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. , 1999, Science.

[8]  P. Zipperlen,et al.  Functional genomic analysis of C. elegans chromosome I by systematic RNA interference , 2000, Nature.

[9]  D. Valle,et al.  Online Mendelian Inheritance In Man (OMIM) , 2000, Human mutation.

[10]  B. Wilkinson,et al.  Disruption and functional analysis of six ORFs on chromosome XII of Saccharomyces cerevisiae: YLR124w, YLR125w, YLR126c, YLR127c, YLR128w and YLR129w , 2000, Yeast.

[11]  M. Johnston,et al.  A chemical genomics approach toward understanding the global functions of the target of rapamycin protein (TOR). , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Warren C. Lathe,et al.  Predicting protein function by genomic context: quantitative evaluation and qualitative inferences. , 2000, Genome research.

[13]  B. Schwikowski,et al.  A network of protein–protein interactions in yeast , 2000, Nature Biotechnology.

[14]  D. Eisenberg,et al.  Protein function in the post-genomic era , 2000, Nature.

[15]  Christian E. V. Storm,et al.  Automatic clustering of orthologs and in-paralogs from pairwise species comparisons. , 2001, Journal of molecular biology.

[16]  A. Barabasi,et al.  Lethality and centrality in protein networks , 2001, Nature.

[17]  Ronald W. Davis,et al.  A genome-wide screen in Saccharomyces cerevisiae for genes affecting UV radiation sensitivity , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[18]  M. Snyder,et al.  A genomic study of the bipolar bud site selection pattern in Saccharomyces cerevisiae. , 2001, Molecular biology of the cell.

[19]  M. Resnick,et al.  Genes required for ionizing radiation resistance in yeast , 2001, Nature Genetics.

[20]  J. Bonifacino,et al.  Genomic screen for vacuolar protein sorting genes in Saccharomyces cerevisiae. , 2002, Molecular biology of the cell.

[21]  Seth Sadis,et al.  Complementary whole-genome technologies reveal the cellular response to proteasome inhibition by PS-341 , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Charles Boone,et al.  A genome-wide screen for methyl methanesulfonate-sensitive mutants reveals genes required for S phase progression in the presence of DNA damage , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Mike Tyers,et al.  Systematic Identification of Pathways That Couple Cell Growth and Division in Yeast , 2002, Science.

[24]  Ioannis Xenarios,et al.  DIP, the Database of Interacting Proteins: a research tool for studying cellular networks of protein interactions , 2002, Nucleic Acids Res..

[25]  Ronald W. Davis,et al.  Systematic screen for human disease genes in yeast , 2002, Nature Genetics.

[26]  C. Deane,et al.  Protein Interactions , 2002, Molecular & Cellular Proteomics.

[27]  Mark D. Robinson,et al.  FunSpec: a web-based cluster interpreter for yeast , 2002, BMC Bioinformatics.

[28]  Kara Dolinski,et al.  Saccharomyces Genome Database (SGD) provides secondary gene annotation using the Gene Ontology (GO) , 2002, Nucleic Acids Res..

[29]  P. Roach,et al.  Systematic Identification of the Genes Affecting Glycogen Storage in the Yeast Saccharomyces cerevisiae , 2002, Molecular & Cellular Proteomics.

[30]  Jian Zhang,et al.  Genomic Scale Mutant Hunt Identifies Cell Size Homeostasis Genes in S. cerevisiae , 2002, Current Biology.

[31]  B. Daignan-Fornier,et al.  Screening the Yeast “Disruptome” for Mutants Affecting Resistance to the Immunosuppressive Drug, Mycophenolic Acid* , 2002, The Journal of Biological Chemistry.

[32]  Ronald W. Davis,et al.  Functional profiling of the Saccharomyces cerevisiae genome , 2002, Nature.

[33]  Ronald W Davis,et al.  Parallel phenotypic analysis of sporulation and postgermination growth in Saccharomyces cerevisiae , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Charles DeLisi,et al.  Predictome: a database of putative functional links between proteins , 2002, Nucleic Acids Res..

[35]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[36]  Y. Dong,et al.  Systematic functional analysis of the Caenorhabditis elegans genome using RNAi , 2003, Nature.

[37]  Frederick P. Roth,et al.  Predicting phenotype from patterns of annotation , 2003, ISMB.

[38]  A. Barabasi,et al.  Bioinformatics analysis of experimentally determined protein complexes in the yeast Saccharomyces cerevisiae. , 2003, Genome research.

[39]  S. Avery,et al.  Genome-Wide Screening of Saccharomyces cerevisiae To Identify Genes Required for Antibiotic Insusceptibility of Eukaryotes , 2003, Antimicrobial Agents and Chemotherapy.

[40]  Circe W. Tsui,et al.  Functional genomics reveals relationships between the retrovirus-like Ty1 element and its host Saccharomyces cerevisiae. , 2003, Genetics.

[41]  W. Saunders,et al.  Large-scale functional genomic analysis of sporulation and meiosis in Saccharomyces cerevisiae. , 2003, Genetics.

[42]  Anders Blomberg,et al.  High-resolution yeast phenomics resolves different physiological features in the saline response , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[43]  James R. Knight,et al.  A Protein Interaction Map of Drosophila melanogaster , 2003, Science.

[44]  Brad T. Sherman,et al.  DAVID: Database for Annotation, Visualization, and Integrated Discovery , 2003, Genome Biology.

[45]  Yi Xing,et al.  Novel functions of the phosphatidylinositol metabolic pathway discovered by a chemical genomics screen with wortmannin , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[46]  A. Owen,et al.  A Bayesian framework for combining heterogeneous data sources for gene function prediction (in Saccharomyces cerevisiae) , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[47]  H. Bussey,et al.  A Saccharomyces cerevisiae genome-wide mutant screen for altered sensitivity to K1 killer toxin. , 2003, Genetics.

[48]  Christian von Mering,et al.  STRING: a database of predicted functional associations between proteins , 2003, Nucleic Acids Res..

[49]  A. Nicolas,et al.  A genomewide screen in Saccharomyces cerevisiae for genes that suppress the accumulation of mutations , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[50]  Dmitrij Frishman,et al.  MIPS: analysis and annotation of proteins from whole genomes in 2005 , 2005, Nucleic Acids Res..

[51]  A. Fraser,et al.  A first-draft human protein-interaction map , 2004, Genome Biology.

[52]  G. Sumara,et al.  A Probabilistic Functional Network of Yeast Genes , 2004 .

[53]  J. Downward Use of RNA interference libraries to investigate oncogenic signalling in mammalian cells , 2004, Oncogene.

[54]  Martin Kupiec,et al.  A genome-wide screen for Saccharomyces cerevisiae deletion mutants that affect telomere length. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[55]  Charles Boone,et al.  An interactional network of genes involved in chitin synthesis in Saccharomyces cerevisiae , 2005, BMC Genetics.

[56]  A. Fraser,et al.  Development through the eyes of functional genomics. , 2004, Current opinion in genetics & development.

[57]  M. Johnston,et al.  Large‐scale screening of yeast mutants for sensitivity to the IMP dehydrogenase inhibitor 6‐azauracil , 2004, Yeast.

[58]  S. L. Wong,et al.  A Map of the Interactome Network of the Metazoan C. elegans , 2004, Science.

[59]  Matteo Pellegrini,et al.  Prolinks: a database of protein functional linkages derived from coevolution , 2004, Genome Biology.

[60]  Itamar Shalit,et al.  Genomic Approach to Identification of Mutations Affecting Caspofungin Susceptibility in Saccharomyces cerevisiae , 2004, Antimicrobial Agents and Chemotherapy.

[61]  A. Goffeau,et al.  The uses of genome-wide yeast mutant collections , 2004, Genome Biology.

[62]  Razvan C. Bunescu,et al.  Consolidating the set of known human protein-protein interactions in preparation for large-scale mapping of the human interactome , 2005, Genome Biology.

[63]  M. Peter,et al.  A Genome-Wide Screen in Saccharomyces cerevisiae Reveals Altered Transport As a Mechanism of Resistance to the Anticancer Drug Bleomycin , 2004, Cancer Research.

[64]  Shinichi Morishita,et al.  SCMD: Saccharomyces cerevisiae Morphological Database , 2004, Nucleic Acids Res..

[65]  T. Hughes,et al.  Exploration of Essential Gene Functions via Titratable Promoter Alleles , 2004, Cell.

[66]  S. Kasif,et al.  Whole-genome annotation by using evidence integration in functional-linkage networks. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[67]  Taro L. Saito,et al.  High-dimensional and large-scale phenotyping of yeast mutants. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[68]  Fulai Jin,et al.  Insights into TOR function and rapamycin response: chemical genomic profiling by using a high-density cell array method. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[69]  M. Daly,et al.  Genome-wide association studies for common diseases and complex traits , 2005, Nature Reviews Genetics.

[70]  Matthew A. Hibbs,et al.  Discovery of biological networks from diverse functional genomic data , 2005, Genome Biology.

[71]  Lincoln Stein,et al.  Reactome: a knowledgebase of biological pathways , 2004, Nucleic Acids Res..

[72]  V. Iyer,et al.  Systematic profiling of cellular phenotypes with spotted cell microarrays reveals mating-pheromone response genes , 2006, Genome Biology.

[73]  H. Lehrach,et al.  A Human Protein-Protein Interaction Network: A Resource for Annotating the Proteome , 2005, Cell.

[74]  D. Kowalski,et al.  Genome-wide screen identifies genes whose inactivation confer resistance to cisplatin in Saccharomyces cerevisiae. , 2005, Cancer research.

[75]  Ronald W. Davis,et al.  Mechanisms of Haploinsufficiency Revealed by Genome-Wide Profiling in Yeast , 2005, Genetics.

[76]  T. Ideker,et al.  Systematic interpretation of genetic interactions using protein networks , 2005, Nature Biotechnology.

[77]  Mark Gerstein,et al.  Biochemical and genetic analysis of the yeast proteome with a movable ORF collection. , 2005, Genes & development.

[78]  Sean R. Collins,et al.  Exploration of the Function and Organization of the Yeast Early Secretory Pathway through an Epistatic Miniarray Profile , 2005, Cell.

[79]  A. Dancis,et al.  Genome-Wide Screen for Genes With Effects on Distinct Iron Uptake Activities in Saccharomyces cerevisiae , 2005, Genetics.

[80]  T. Barrette,et al.  Probabilistic model of the human protein-protein interaction network , 2005, Nature Biotechnology.

[81]  S. L. Wong,et al.  Towards a proteome-scale map of the human protein–protein interaction network , 2005, Nature.

[82]  Insuk Lee,et al.  A high-accuracy consensus map of yeast protein complexes reveals modular nature of gene essentiality , 2007, BMC Bioinformatics.

[83]  T. Hughes,et al.  Mapping pathways and phenotypes by systematic gene overexpression. , 2006, Molecular cell.

[84]  Hans-Werner Mewes,et al.  MPact: the MIPS protein interaction resource on yeast , 2005, Nucleic Acids Res..

[85]  G. von Heijne,et al.  A global topology map of the Saccharomyces cerevisiae membrane proteome. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[86]  C. Wijmenga,et al.  Reconstruction of a functional human gene network, with an application for prioritizing positional candidate genes. , 2006, American journal of human genetics.

[87]  Fulai Jin,et al.  Erratum: Insights into TOR function and rapamycin response: Chemical genomic profiling by using a high-density cell array method (Proceedings of the National Academy of Sciences of the United States of America (May 17, 2005) 102, 20 (7215-7220) DOI:10.1073/pnas.0500297102) , 2006 .

[88]  Dmitrij Frishman,et al.  MIPS: analysis and annotation of proteins from whole genomes in 2005 , 2006, Nucleic Acids Res..

[89]  B. Snel,et al.  Predicting disease genes using protein–protein interactions , 2006, Journal of Medical Genetics.

[90]  Arun K. Ramani,et al.  How complete are current yeast and human protein-interaction networks? , 2006, Genome Biology.

[91]  K. N. Chandrika,et al.  Analysis of the human protein interactome and comparison with yeast, worm and fly interaction datasets , 2006, Nature Genetics.

[92]  Sean R. Collins,et al.  Toward a Comprehensive Atlas of the Physical Interactome of Saccharomyces cerevisiae*S , 2007, Molecular & Cellular Proteomics.

[93]  Pall I. Olason,et al.  A human phenome-interactome network of protein complexes implicated in genetic disorders , 2007, Nature Biotechnology.

[94]  R. Sharan,et al.  Network-based prediction of protein function , 2007, Molecular systems biology.

[95]  Gonçalo R. Abecasis,et al.  Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma , 2007, Nature.

[96]  Patrick J. Killion,et al.  Genetic reconstruction of a functional transcriptional regulatory network , 2007, Nature Genetics.

[97]  E. Marcotte,et al.  An Improved, Bias-Reduced Probabilistic Functional Gene Network of Baker's Yeast, Saccharomyces cerevisiae , 2007, PloS one.