Epistasis between Beneficial Mutations and the Phenotype-to-Fitness Map for a ssDNA Virus

Abstract

Epistatic interactions between genes and individual mutations are major determinants of the evolutionary properties of genetic systems and have therefore been well documented, but few quantitative data exist on epistatic interactions between beneficial mutations, presumably because such mutations are so much rarer than deleterious ones. We explored epistasis for beneficial mutations by constructing genotypes with pairs of mutations that had been previously identified as beneficial to the ssDNA bacteriophage ID11 and by measuring the effects of these mutations alone and in combination. We constructed 18 of the 36 possible double mutants for the nine available beneficial mutations. We found that epistatic interactions between beneficial mutations were all antagonistic—the effects of the double mutations were less than the sums of the effects of their component single mutations. We found a number of cases of decompensatory interactions, an extreme form of antagonistic epistasis in which the second mutation is actually deleterious in the presence of the first. In the vast majority of cases, recombination uniting two beneficial mutations into the same genome would not be favored by selection, as the recombinant could not outcompete its constituent single mutations. In an attempt to understand these results, we developed a simple model in which the phenotypic effects of mutations are completely additive and epistatic interactions arise as a result of the form of the phenotype-to-fitness mapping. We found that a model with an intermediate phenotypic optimum and additive phenotypic effects provided a good explanation for our data and the observed patterns of epistatic interactions.

Genetic background affects epistatic interactions between two beneficial mutations

“…In addition, we found that the effect of epistasis between the topA and pykF mutations was negatively correlated with the growth rate of the strain containing the mutations, which is consistent with previous studies [8,9,23]. This result suggests that our focal mutations may affect a common saturating physiological process, which is related to growth rate.…”

Benefit of transferred mutations is better predicted by the fitness of recipients than by their ecological or genetic relatedness

“…Recent studies have found that epistatic interactions between beneficial mutations and their genetic backgrounds tend to become increasingly negative as the fitness of the genetic background increases (11)(12)(13)(14)(15)(16). If this relationship also holds across diverse recipient strains, we predict a negative relationship between the absolute fitness of a strain (measured as growth rate) and the benefit conferred by addition of a mutation.…”

“…Epistasis plays a key role in many aspects of biology, including theories of speciation (2,3), the evolution and maintenance of sex (4,5), adaptation (6)(7)(8), and evolutionary contingency (9,10). Whereas early experimental studies focused on interactions between deletion or other knockout mutations, advances in genomic technologies now allow direct tests of interactions between spontaneously occurring beneficial mutations (11)(12)(13)(14)(15)(16). Studies that manipulate beneficial mutations have the potential to identify general patterns that may underlie some degree of predictability in adaptive evolutionary outcomes.…”

“…Studies that manipulate beneficial mutations have the potential to identify general patterns that may underlie some degree of predictability in adaptive evolutionary outcomes. For example, interactions between beneficial mutations often follow a pattern of diminishing returns epistasis, such that the marginal benefit of additional mutations declines with the fitness of the recipient genotype (11)(12)(13)(14)(15)(16). Diminishing returns epistasis reflects a global interaction between mutations that interact at the level of fitness (16).…”

“…Most studies that have examined interactions that affect beneficial mutations have focused on interactions between mutations arising in a single population or in replicate populations evolved from a common ancestor (11,12,14,23,24). In these cases, there are relatively few mutational differences separating different genotypes, limiting our ability to extrapolate findings to an understanding of the influence of mutation interactions on adaptive evolution in genetically diverse natural populations.…”