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PLoS Genet. 2014 Feb 20;10(2):e1004120. doi: 10.1371/journal.pgen.1004120. eCollection 2014 Feb.

Quantitative genome-wide genetic interaction screens reveal global epistatic relationships of protein complexes in Escherichia coli.

Author information

1
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.
2
Banting and Best Department of Medical Research, Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
3
Hospital for Sick Children, Toronto, Ontario, Canada ; Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
4
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.
5
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
6
Department of Biochemistry, Research and Innovation Centre, University of Regina, Regina, Saskatchewan, Canada.
7
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
8
Department of Biology and Ottawa Institute of Systems Biology, Carleton University, Ottawa, Ontario, Canada.
9
Department of Biology, Wilfrid Laurier University, Waterloo, Ontario, Canada.
10
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.

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.

PMID:
24586182
PMCID:
PMC3930520
DOI:
10.1371/journal.pgen.1004120
[Indexed for MEDLINE]
Free PMC Article

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