Dataset Information

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 ?-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.

SUBMITTER: Babu M

PROVIDER: S-EPMC3930520 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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

Babu Mohan M Arnold Roland R Bundalovic-Torma Cedoljub C Gagarinova Alla A Wong Keith S KS Kumar Ashwani A Stewart Geordie G Samanfar Bahram B Aoki Hiroyuki H Wagih Omar O Vlasblom James J Phanse Sadhna S Lad Krunal K Yeou Hsiung Yu Angela A Graham Christopher C Jin Ke K Brown Eric E Golshani Ashkan A Kim Philip P Moreno-Hagelsieb Gabriel G Greenblatt Jack J Houry Walid A WA Parkinson John J Emili Andrew A

PLoS genetics 20140220 2

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 ...[more]

PMID: 24586182

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Project description:The treatment of complex diseases often relies on combinatorial therapy, a strategy where drugs are used to target multiple genes simultaneously. Promising candidate genes for combinatorial perturbation often constitute epistatic genes, i.e., genes which contribute to a phenotype in a non-linear fashion. Experimental identification of the full landscape of genetic interactions by perturbing all gene combinations is prohibitive due to the exponential growth of testable hypotheses. Here we present a model for the inference of pairwise epistatic, including synthetic lethal, gene interactions from siRNA-based perturbation screens. The model exploits the combinatorial nature of siRNA-based screens resulting from the high numbers of sequence-dependent off-target effects, where each siRNA apart from its intended target knocks down hundreds of additional genes. We show that conditional and marginal epistasis can be estimated as interaction coefficients of regression models on perturbation data. We compare two methods, namely glinternet and xyz, for selecting non-zero effects in high dimensions as components of the model, and make recommendations for the appropriate use of each. For data simulated from real RNAi screening libraries, we show that glinternet successfully identifies epistatic gene pairs with high accuracy across a wide range of relevant parameters for the signal-to-noise ratio of observed phenotypes, the effect size of epistasis and the number of observations per double knockdown. xyz is also able to identify interactions from lower dimensional data sets (fewer genes), but is less accurate for many dimensions. Higher accuracy of glinternet, however, comes at the cost of longer running time compared to xyz. The general model is widely applicable and allows mining the wealth of publicly available RNAi screening data for the estimation of epistatic interactions between genes. As a proof of concept, we apply the model to search for interactions, and potential targets for treatment, among previously published sets of siRNA perturbation screens on various pathogens. The identified interactions include both known epistatic interactions as well as novel findings.

Dataset Information

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

Publications

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

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