Genetic basis of a spontaneous mutation’s expressivity

• Published in: Genetics (Austin) 2022-03, Vol.220 (3)
• Main Authors: Schell, Rachel, Hale, Joseph J, Mullis, Martin N, Matsui, Takeshi, Foree, Ryan, Ehrenreich, Ian M
• Format: Article
• Language: English
• Subjects: Alleles; Genetic Background; Genetic diversity; Genetic variance; Genetics; Humans; Investigation; Loci; Missense mutation; Mitochondria; Mutation; Phenotype; Yeasts
• ISSN: 1943-2631; 0016-6731; 1943-2631
• DOI: 10.1093/genetics/iyac013

Abstract Genetic background often influences the phenotypic consequences of mutations, resulting in variable expressivity. How standing genetic variants collectively cause this phenomenon is not fully understood. Here, we comprehensively identify loci in a budding yeast cross that impact the growth of individuals carrying a spontaneous missense mutation in the nuclear-encoded mitochondrial ribosomal gene MRP20. Initial results suggested that a single large effect locus influences the mutation’s expressivity, with 1 allele causing inviability in mutants. However, further experiments revealed this simplicity was an illusion. In fact, many additional loci shape the mutation’s expressivity, collectively leading to a wide spectrum of mutational responses. These results exemplify how complex combinations of alleles can produce a diversity of qualitative and quantitative responses to the same mutation. Genetic background effects impact the contributions of mutations to traits of biomedical, evolutionary, and agricultural significance. The main cause of background effects is likely epistasis between mutations and genetic polymorphisms, but the architectures of these genetic interactions are not fully understood. Here, Schell et al. show that a large number of genetic variants interact with a spontaneous mutation in a yeast cross, causing the mutation’s phenotypic effect to range from lethal to near zero.