Epistatic impacts of <i>cis</i> - and <i>trans</i> -regulatory mutations on the distribution of mutational effects for gene expression in <i>Saccharomyces cerevisiae</i>

Abstract Epistasis can influence evolution by causing the distribution of phenotypic effects for new mutations to vary among genotypes. Here, we investigate how epistatic interactions between new mutations and an existing regulatory mutation might impact the evolution of gene expression using Saccharomyces cerevisiae. We do so by estimating the distribution of mutational effects for expression of a fluorescent reporter protein driven by the S. cerevisiae TDH3 promoter in a reference strain as well as in eight mutant strains. Each of the mutant strains differed from the reference strain by a single mutation affecting expression of the focal gene. We found that two of these regulatory mutations changed the degree of mutational robustness, as measured by the variance of the distribution of mutational effects, with one initial regulatory mutation increasing mutational robustness while another decreased it. We also found that four of our initial regulatory mutants caused a change in the relative frequency and/or effect size of mutations increasing or decreasing expression, as measured by a change in skewness relative to the reference. Strikingly, in all four of these cases, the change in skewness increased the likelihood that new mutations would at least partially compensate for the effects of the initial regulatory mutation. If this form of epistatic impact on the distribution of mutational effects is common, it should increase the fixation probability of compensatory mutations affecting traits under stabilizing selection and could help explain the prevalence of alleles with compensatory effects in natural populations of S. cerevisiae.