Abstract
Gene-gene interactions shape complex phenotypes and modify the effects of mutations during development and disease. The effects of statistical gene-gene interactions on phenotypes have been used to assign genes to functional modules. However, directional, epistatic interactions, which reflect regulatory relationships between genes, have been challenging to map at large-scale. Here, we used combinatorial RNA interference and automated single-cell phenotyping to generate a large genetic interaction map for 21 phenotypic features of Drosophila cells. We devised a method that combines genetic interactions on multiple phenotypes to reveal directional relationships. This network reconstructed the sequence of protein activities in mitosis. Moreover, it revealed that the Ras pathway interacts with the SWI/SNF chromatin-remodelling complex, an interaction that we show is conserved in human cancer cells. Our study presents a powerful approach for reconstructing directional regulatory networks and provides a resource for the interpretation of functional consequences of genetic alterations.
Highlights
Genes display epistatic interactions, whereby the presence of one genetic variant can mask, alleviate or amplify the phenotypic effect of other variants (Bateson, 1907)
Systematic screens for genetic interactions have been performed in yeast (Tong et al, 2004; Schuldiner et al, 2005; Costanzo et al, 2010; Ryan et al, 2012), Escherichia coli (Nichols et al, 2011; Babu et al, 2014), Caenorhabditis elegans (Lehner et al, 2006) and metazoan cells (Bakal et al, 2008; Horn et al, 2011; Bassik et al, 2013; Laufer et al, 2013; Roguev et al, 2013)
We generated the largest map of multi-phenotype genetic interaction profiles in metazoan cells to date by co-depleting gene pairs by RNAi in cultured Drosophila S2 cells, high-throughput imaging of
Summary
Genes display epistatic (genetic) interactions, whereby the presence of one genetic variant can mask, alleviate or amplify the phenotypic effect of other variants (Bateson, 1907). Systematic screens for genetic interactions have been performed in yeast (Tong et al, 2004; Schuldiner et al, 2005; Costanzo et al, 2010; Ryan et al, 2012), Escherichia coli (Nichols et al, 2011; Babu et al, 2014), Caenorhabditis elegans (Lehner et al, 2006) and metazoan cells (Bakal et al, 2008; Horn et al, 2011; Bassik et al, 2013; Laufer et al, 2013; Roguev et al, 2013) These approaches have successfully unravelled symmetric relationships, such as pathway and complex co-membership (Baryshnikova et al, 2013).
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