Systematic analysis of complex genetic interactions

To systematically explore complex genetic interactions, we constructed ~200,000 yeast triple mutants and scored negative trigenic interactions. We selected double-mutant query genes across a broad spectrum of biological processes, spanning a range of quantitative features of the global digenic inter...

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Published in:	Science (American Association for the Advancement of Science) Vol. 360; no. 6386
Main Authors:	Kuzmin, Elena, VanderSluis, Benjamin, Wang, Wen, Tan, Guihong, Deshpande, Raamesh, Chen, Yiqun, Usaj, Matej, Balint, Attila, Mattiazzi Usaj, Mojca, van Leeuwen, Jolanda, Koch, Elizabeth N, Pons, Carles, Dagilis, Andrius J, Pryszlak, Michael, Wang, Jason Zi Yang, Hanchard, Julia, Riggi, Margot, Xu, Kaicong, Heydari, Hamed, San Luis, Bryan-Joseph, Shuteriqi, Ermira, Zhu, Hongwei, Van Dyk, Nydia, Sharifpoor, Sara, Costanzo, Michael, Loewith, Robbie, Caudy, Amy, Bolnick, Daniel, Brown, Grant W, Andrews, Brenda J, Boone, Charles, Myers, Chad L
Format:	Journal Article
Language:	English
Published:	United States The American Association for the Advancement of Science 20-04-2018
Subjects:	Biological activity Biology Enrichment Fitness Gene Regulatory Networks Genes Genetic analysis Genomes Genotype & phenotype Genotypes Heredity Heritability Human populations Lethality Loci Mutants Mutation Natural populations Networks Oligonucleotide Array Sequence Analysis Phenotypic variations Populations Protein interaction Reproductive fitness Saccharomyces cerevisiae - genetics Saccharomyces cerevisiae Proteins - genetics Speciation Wiring Yeast Zebrafish
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Summary:	To systematically explore complex genetic interactions, we constructed ~200,000 yeast triple mutants and scored negative trigenic interactions. We selected double-mutant query genes across a broad spectrum of biological processes, spanning a range of quantitative features of the global digenic interaction network and tested for a genetic interaction with a third mutation. Trigenic interactions often occurred among functionally related genes, and essential genes were hubs on the trigenic network. Despite their functional enrichment, trigenic interactions tended to link genes in distant bioprocesses and displayed a weaker magnitude than digenic interactions. We estimate that the global trigenic interaction network is ~100 times as large as the global digenic network, highlighting the potential for complex genetic interactions to affect the biology of inheritance, including the genotype-to-phenotype relationship.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Current address: Center for Chromosome Stability, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark Current address: Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Ave des Pins Ouest, Montreal, Quebec, H3A 1A3, Canada Author contributions: Conceptualization: E.K., B.V., B.A., C.B., C.M.; Methodology and Investigation: E.K., B.V., W.W., R.D., Y.C., A.B., M.M.U., J.v.L., E.N.K., C.P., A.J.D., M. P., J.Z.W., J.H., M.R., K.X., H.H., B.S.L., E.S., H.Z.; Formal analysis: E.K., B.V., W.W., M.M.U., E.N.K., C.P., A.J.D., J.H., K.X., H.H., M.C., R.L., A.C., D.B., G.W.B.; Resources: G.T.; Data curation: M.U.; Writing – original draft: E.K., B.V., B.A., C.B., C.M.; Writing – review and editing: E.K., B.V., W.W., R.D., A.B., M.M.U., J.v.L., E.N.K., C.P., M.C., D.B., G.W., B.A., C.B., C.M.; Supervision: B.A., C.B., C.M.; Project administration: N.V.D., S.S.; Funding acquisition: B.A., C.B., C.M.
ISSN:	0036-8075 1095-9203 1095-9203
DOI:	10.1126/science.aao1729