title: Quantitative genome-wide genetic interaction screens reveal global epistatic relationships of protein complexes in Escherichia coli.
abstract: Large-scale proteomic analyses in Escherichia coli have documented the composition and physical relationships of multiprotein complexes, but not their functional organization into biological pathways and processes. Conversely, genetic interaction (GI) screens can provide insights into the biological role(s) of individual gene and higher order associations. Combining the information from both approaches should elucidate how complexes and pathways intersect functionally at a systems level. However, such integrative analysis has been hindered due to the lack of relevant GI data. Here we present a systematic, unbiased, and quantitative synthetic genetic array screen in E. coli describing the genetic dependencies and functional cross-talk among over 600,000 digenic mutant combinations. Combining this epistasis information with putative functional modules derived from previous proteomic data and genomic context-based methods revealed unexpected associations, including new components required for the biogenesis of iron-sulphur and ribosome integrity, and the interplay between molecular chaperones and proteases. We find that functionally-linked genes co-conserved among γ-proteobacteria are far more likely to have correlated GI profiles than genes with divergent patterns of evolution. Overall, examining bacterial GIs in the context of protein complexes provides avenues for a deeper mechanistic understanding of core microbial systems.
authors.affiliation: Banting and Best Department of Medical Research, Donnelly Centre, University of Toronto, Toronto, Ontario, Canada ; Department of Biochemistry, Research and Innovation Centre, University of Regina, Regina, Saskatchewan, Canada.
authors.forename: Mohan
authors.initials: M
authors.lastname: Babu
authors.affiliation: Banting and Best Department of Medical Research, Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Roland
authors.initials: R
authors.lastname: Arnold
authors.affiliation: Hospital for Sick Children, Toronto, Ontario, Canada ; Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Cedoljub
authors.initials: C
authors.lastname: Bundalovic-Torma
authors.affiliation: Banting and Best Department of Medical Research, Donnelly Centre, University of Toronto, Toronto, Ontario, Canada ; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Alla
authors.initials: A
authors.lastname: Gagarinova
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Keith S
authors.initials: KS
authors.lastname: Wong
authors.affiliation: Department of Biochemistry, Research and Innovation Centre, University of Regina, Regina, Saskatchewan, Canada.
authors.forename: Ashwani
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Geordie
authors.initials: G
authors.lastname: Stewart
authors.affiliation: Department of Biology and Ottawa Institute of Systems Biology, Carleton University, Ottawa, Ontario, Canada.
authors.forename: Bahram
authors.initials: B
authors.lastname: Samanfar
authors.affiliation: Department of Biochemistry, Research and Innovation Centre, University of Regina, Regina, Saskatchewan, Canada.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aoki
authors.affiliation: Banting and Best Department of Medical Research, Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Omar
authors.initials: O
authors.lastname: Wagih
authors.affiliation: Department of Biochemistry, Research and Innovation Centre, University of Regina, Regina, Saskatchewan, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Vlasblom
authors.affiliation: Banting and Best Department of Medical Research, Donnelly Centre, University of Toronto, Toronto, Ontario, Canada ; Department of Biochemistry, Research and Innovation Centre, University of Regina, Regina, Saskatchewan, Canada.
authors.forename: Sadhna
authors.initials: S
authors.lastname: Phanse
authors.affiliation: Department of Biochemistry, Research and Innovation Centre, University of Regina, Regina, Saskatchewan, Canada.
authors.forename: Krunal
authors.initials: K
authors.lastname: Lad
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Angela
authors.initials: A
authors.lastname: Yeou Hsiung Yu
authors.affiliation: Department of Biochemistry, Research and Innovation Centre, University of Regina, Regina, Saskatchewan, Canada.
authors.forename: Christopher
authors.initials: C
authors.lastname: Graham
authors.affiliation: Banting and Best Department of Medical Research, Donnelly Centre, University of Toronto, Toronto, Ontario, Canada ; Department of Biochemistry, Research and Innovation Centre, University of Regina, Regina, Saskatchewan, Canada.
authors.forename: Ke
authors.initials: K
authors.lastname: Jin
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Brown
authors.affiliation: Department of Biology and Ottawa Institute of Systems Biology, Carleton University, Ottawa, Ontario, Canada.
authors.forename: Ashkan
authors.initials: A
authors.lastname: Golshani
authors.affiliation: Banting and Best Department of Medical Research, Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Philip
authors.initials: P
authors.lastname: Kim
authors.affiliation: Department of Biology, Wilfrid Laurier University, Waterloo, Ontario, Canada.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Moreno-Hagelsieb
authors.affiliation: Banting and Best Department of Medical Research, Donnelly Centre, University of Toronto, Toronto, Ontario, Canada ; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jack
authors.initials: J
authors.lastname: Greenblatt
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Walid A
authors.initials: WA
authors.lastname: Houry
authors.affiliation: Hospital for Sick Children, Toronto, Ontario, Canada ; Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada ; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Parkinson
authors.affiliation: Banting and Best Department of Medical Research, Donnelly Centre, University of Toronto, Toronto, Ontario, Canada ; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Emili
mesh_terms: D003593:Cytoplasm / Q000378:metabolism; D004843:Epistasis, Genetic; D004926:Escherichia coli / Q000235:genetics*; D016680:Genome, Bacterial; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D060066:Protein Interaction Maps; D040901:Proteomics
chemical_list: D018832:Molecular Chaperones; D046912:Multiprotein Complexes