Charting the genetic interaction map of a cell.

Genome sequencing projects have revealed a massive catalog of genes and astounding genetic diversity in a variety of organisms. We are now faced with the formidable challenge of assigning functions to thousands of genes, and how to use this information to understand how genes interact and coordinate cell function. Studies indicate that the majority of eukaryotic genes are dispensable, highlighting the extensive buffering of genomes against genetic and environmental perturbations. Such robustness poses a significant challenge to those seeking to understand the wiring diagram of the cell. Genome-scale screens for genetic interactions are an effective means to chart the network that underlies this functional redundancy. A complete atlas of genetic interactions offers the potential to assign functions to most genes identified by whole genome sequencing projects and to delineate a functional wiring diagram of the cell. Perhaps more importantly, mapping genetic networks on a large-scale will shed light on the general principles and rules governing genetic networks and provide valuable information regarding the important but elusive relationship between genotype and phenotype.

[1]  Kalin H. Vetsigian,et al.  Exposing the fitness contribution of duplicated genes , 2008, Nature Genetics.

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

[3]  Joshua M. Stuart,et al.  A global analysis of genetic interactions in Caenorhabditis elegans , 2007, Journal of biology.

[4]  Trey Ideker,et al.  Functional Maps of Protein Complexes from Quantitative Genetic Interaction Data , 2008, PLoS Comput. Biol..

[5]  B. Andrews,et al.  Systematic mapping of genetic interaction networks. , 2009, Annual review of genetics.

[6]  Robert P. St.Onge,et al.  Defining genetic interaction , 2008, Proceedings of the National Academy of Sciences.

[7]  P. Hieter,et al.  Specific synthetic lethal killing of RAD54B-deficient human colorectal cancer cells by FEN1 silencing , 2009, Proceedings of the National Academy of Sciences.

[8]  Lee Hartwell,et al.  Robust Interactions , 2004, Science.

[9]  Zhaolei Zhang,et al.  The extensive and condition-dependent nature of epistasis among whole-genome duplicates in yeast. , 2008, Genome research.

[10]  S. Collins,et al.  Comprehensive Characterization of Genes Required for Protein Folding in the Endoplasmic Reticulum , 2009, Science.

[11]  Paul Shannon,et al.  Derivation of genetic interaction networks from quantitative phenotype data , 2005, Genome Biology.

[12]  Ben Lehner,et al.  Evolutionary plasticity of genetic interaction networks , 2008, Nature Genetics.

[13]  Sean R. Collins,et al.  Functional Organization of the S. cerevisiae Phosphorylation Network , 2009, Cell.

[14]  Sean R. Collins,et al.  A tool-kit for high-throughput, quantitative analyses of genetic interactions in E. coli , 2008, Nature Methods.

[15]  P. Hieter,et al.  Synthetic lethal genetic interactions that decrease somatic cell proliferation in Caenorhabditis elegans identify the alternative RFC CTF18 as a candidate cancer drug target. , 2009, Molecular biology of the cell.

[16]  J. Bader,et al.  A DNA Integrity Network in the Yeast Saccharomyces cerevisiae , 2013, Cell.

[17]  Ezgi O. Booth,et al.  Epistasis analysis with global transcriptional phenotypes , 2005, Nature Genetics.

[18]  A. Rose,et al.  Synthetic Lethal Interactions Identify Phenotypic “Interologs” of the Spindle Assembly Checkpoint Components , 2007, Genetics.

[19]  Huiming Ding,et al.  eSGA: E. coli synthetic genetic array analysis , 2008, Nature Methods.

[20]  Michael J. Emanuele,et al.  A Genome-wide RNAi Screen Identifies Multiple Synthetic Lethal Interactions with the Ras Oncogene , 2009, Cell.

[21]  Yolanda T. Chong,et al.  A picture is worth a thousand words: Genomics to phenomics in the yeast Saccharomyces cerevisiae , 2009, FEBS letters.

[22]  G. Church,et al.  Modular epistasis in yeast metabolism , 2005, Nature Genetics.

[23]  Ron Shamir,et al.  A plasma-membrane E-MAP reveals links of the eisosome with sphingolipid metabolism and endosomal trafficking , 2010, Nature Structural &Molecular Biology.

[24]  Jun Wan,et al.  Protein Acetylation Microarray Reveals that NuA4 Controls Key Metabolic Target Regulating Gluconeogenesis , 2009, Cell.

[25]  R. Korona,et al.  Epistatic buffering of fitness loss in yeast double deletion strains , 2007, Nature Genetics.

[26]  Gary D Bader,et al.  The Genetic Landscape of a Cell , 2010, Science.

[27]  Andrew Emili,et al.  eSGA: E. coli Synthetic Genetic Array analysis , 2008 .

[28]  B. Garvik,et al.  Principles for the buffering of genetic variation. , 2001 .

[29]  T. Hughes,et al.  Two-color cell array screen reveals interdependent roles for histone chaperones and a chromatin boundary regulator in histone gene repression. , 2009, Molecular cell.

[30]  B. Garvik,et al.  Principles for the Buffering of Genetic Variation , 2001, Science.

[31]  N. Katsanis,et al.  Human genetics and disease: Beyond Mendel: an evolving view of human genetic disease transmission , 2002, Nature Reviews Genetics.

[32]  Bin Zhang,et al.  A systems biology approach to drug discovery. , 2008, Advances in genetics.

[33]  Ivan Bratko,et al.  GenePath: a system for automated construction of genetic networks from mutant data , 2003, Bioinform..

[34]  Gary D Bader,et al.  Global Mapping of the Yeast Genetic Interaction Network , 2004, Science.

[35]  Gary D Bader,et al.  Quantitative analysis of fitness and genetic interactions in yeast on a genome scale , 2010, Nature Methods.

[36]  Dmitri A. Petrov,et al.  Pervasive and Persistent Redundancy among Duplicated Genes in Yeast , 2008, PLoS genetics.

[37]  J. Bader,et al.  A robust toolkit for functional profiling of the yeast genome. , 2004, Molecular cell.

[38]  Sean R. Collins,et al.  A genetic interaction map of RNA-processing factors reveals links between Sem1/Dss1-containing complexes and mRNA export and splicing. , 2008, Molecular cell.

[39]  Mike Tyers,et al.  CDK Activity Antagonizes Whi5, an Inhibitor of G1/S Transcription in Yeast , 2004, Cell.

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

[41]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Sean R. Collins,et al.  A strategy for extracting and analyzing large-scale quantitative epistatic interaction data , 2006, Genome Biology.

[43]  Gary D Bader,et al.  Systematic Genetic Analysis with Ordered Arrays of Yeast Deletion Mutants , 2001, Science.

[44]  Timothy B. Stockwell,et al.  The Diploid Genome Sequence of an Individual Human , 2007, PLoS biology.

[45]  D. Durocher,et al.  Significant conservation of synthetic lethal genetic interaction networks between distantly related eukaryotes , 2008, Proceedings of the National Academy of Sciences.

[46]  C. Waddington The strategy of the genes , 1957 .

[47]  Franco J. Vizeacoumar,et al.  Integrating high-throughput genetic interaction mapping and high-content screening to explore yeast spindle morphogenesis , 2010, The Journal of cell biology.

[48]  Ronald W. Davis,et al.  Systematic pathway analysis using high-resolution fitness profiling of combinatorial gene deletions , 2007, Nature Genetics.

[49]  Sridhar Ramaswamy,et al.  Synthetic Lethal Interaction between Oncogenic KRAS Dependency and STK33 Suppression in Human Cancer Cells , 2009, Cell.

[50]  A. Barabasi,et al.  Network biology: understanding the cell's functional organization , 2004, Nature Reviews Genetics.

[51]  Sean R. Collins,et al.  A comprehensive strategy enabling high-resolution functional analysis of the yeast genome , 2008, Nature Methods.

[52]  A. Fraser,et al.  Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling pathways , 2006, Nature Genetics.

[53]  M. Fromont-Racine,et al.  Linking functionally related genes by sensitive and quantitative characterization of genetic interaction profiles , 2008, Proceedings of the National Academy of Sciences.

[54]  H. Bussey,et al.  Exploring genetic interactions and networks with yeast , 2007, Nature Reviews Genetics.

[55]  Martin N. Rossor,et al.  Advanced online publication. , 2005, Nature structural biology.

[56]  R. Shamir,et al.  From E-MAPs to module maps: dissecting quantitative genetic interactions using physical interactions , 2008, Molecular Systems Biology.

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

[58]  Grant W. Brown,et al.  Functional dissection of protein complexes involved in yeast chromosome biology using a genetic interaction map , 2007, Nature.

[59]  Sean R. Collins,et al.  Conservation and Rewiring of Functional Modules Revealed by an Epistasis Map in Fission Yeast , 2008, Science.

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