Genetic basis of a spontaneous 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 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.

Incomplete Penetrance and Variable Expressivity: From Clinical Studies to Population Cohorts

“…The “omnigenic” model proposes that due to their interconnected nature, variants in gene-regulatory networks that are expressed in disease-relevant cells or tissues may affect the functioning of “core” disease-related genes due to effects on genes outside of the core pathways ( Boyle et al, 2017 ), suggesting that many unrelated variants contribute to the presentation of a phenotype. Proposed as a factor in the inheritance of complex traits, this polygenic architecture could potentially also affect the presentation of monogenic conditions in a similar way, through non-coding variation that affects overall gene regulation, and many loci have been shown to additively affect expressivity and penetrance of monogenic variants in model organisms ( Schell et al, 2022 ).…”

Genome-scale analysis of interactions between genetic perturbations and natural variation

“…While numerous examples of background effects have been reported [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] , we lack a detailed understanding of interactions between genetic perturbations and genetic backgrounds. For example, we do not yet know what characteristics of perturbations and individuals' genotypes increase the likelihood of interactions, what types of epistasis are most likely to underlie background effects, and the properties of interaction networks between perturbations and loci.…”