Genetic architecture of a mutation’s expressivity

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 one allele causing inviability in mutants. However, further dissection revealed that 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 loci can produce a diversity of qualitative and quantitative responses to the same mutation. Significance Statement Mutations can show different phenotypic effects depending on the individuals in which they occur (or background effects). These background effects are important to understand because they impact the contributions of mutations to traits of biomedical, evolutionary, and agricultural significance. While it is known that a main cause of background effects is genetic interactions between mutations and pre-existing genetic variants, the architectures of these interactions are not well characterized. Here, we use show that a large number of genetic variants influence the effect of a spontaneous mutation in a cross of two yeast strains. These loci individually tend to have small impacts, but collectively they cause the mutation to show a range of effects that extends from lethal to near zero.