Natural variants suppress mutations in hundreds of essential genes. Issue 5 (27th May 2021)

• Record Type: Journal Article
• Authors: Parts, Leopold; Batté, Amandine; Lopes, Maykel; Yuen, Michael W; Laver, Meredith; San Luis, Bryan‐Joseph; Yue, Jia‐Xing; Pons, Carles; Eray, Elise; Aloy, Patrick; Liti, Gianni; van Leeuwen, Jolanda
• Is Part Of: Molecular systems biology. Volume 17:Issue 5(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-05-27
• Subjects: compensatory evolution -- genetic interactions -- genetic modifiers -- genetic suppression -- natural variation; Molecular biology -- Periodicals; Systems biology -- Periodicals; 572.8
• DOI: 10.15252/msb.202010138
• Languages: English
• ISSNs: 1744-4292

Abstract

Abstract: The consequence of a mutation can be influenced by the context in which it operates. For example, loss of gene function may be tolerated in one genetic background, and lethal in another. The extent to which mutant phenotypes are malleable, the architecture of modifiers and the identities of causal genes remain largely unknown. Here, we measure the fitness effects of ~ 1, 100 temperature‐sensitive alleles of yeast essential genes in the context of variation from ten different natural genetic backgrounds and map the modifiers for 19 combinations. Altogether, fitness defects for 149 of the 580 tested genes (26%) could be suppressed by genetic variation in at least one yeast strain. Suppression was generally driven by gain‐of‐function of a single, strong modifier gene, and involved both genes encoding complex or pathway partners suppressing specific temperature‐sensitive alleles, as well as general modifiers altering the effect of many alleles. The emerging frequency of suppression and range of possible mechanisms suggest that a substantial fraction of monogenic diseases could be managed by modulating other gene products. Synopsis: A survey of ~ 1, 100 temperature‐sensitive alleles of yeast essential genes in ten diverse strains shows that natural genetic variants frequently suppress deleterious mutations. Genetic mapping and allele replacement identify causal suppressor genes. 149 out of 580 tested genes can be suppressed by natural variants from at least one genetic background. A single strong suppressor allele can independently overcome the temperature sensitivity phenotype in nearly all mapped cases. Identified suppressor genes include members of the same complex or pathway as specific temperature‐sensitive mutants, as well as general modifiers that suppress many mutant alleles. Abstract : A survey of ~ 1, 100 temperature‐sensitive alleles of yeast essential genes in ten diverse strains shows that natural genetic variants frequently suppress deleterious mutations. Genetic mapping and allele replacement identify causal suppressor genes.