Perspective: Sign Epistasis and Genetic Costraint on Evolutionary Trajectories

Abstract

Epistasis for fitness means that the selective effect of a mutation is conditional on the genetic background in which it appears. Although epistasis is widely observed in nature, our understanding of its consequences for evolution by natural selection remains incomplete. In particular, much attention focuses only on its influence on the instantaneous rate of changes in frequency of selected alleles via epistatic contribution to the additive genetic variance for fitness. Thus, in this framework epistasis only has evolutionary importance if the interacting loci are simultaneously segregating in the population. However, the selective accessibility of mutational trajectories to high fitness genotypes may depend on the genetic background in which novel mutations appear, and this effect is independent of population polymorphism at other loci. Here we explore this second influence of epistasis on evolution by natural selection. We show that it is the consequence of a particular form of epistasis, which we designate sign epistasis. Sign epistasis means that the sign of the fitness effect of a mutation is under epistatic control; thus, such a mutation is beneficial on some genetic backgrounds and deleterious on others. Recent experimental innovations in microbial systems now permit assessment of the fitness effects of individual mutations on multiple genetic backgrounds. We review this literature and identify many examples of sign epistasis, and we suggest that the implications of these results may generalize to other organisms. These theoretical and empirical considerations imply that strong genetic constraint on the selective accessibility of trajectories to high fitness genotypes may exist and suggest specific areas of investigation for future research.

Bypass of genetic constraints during mutator evolution to antibiotic resistance

“…Of particular interest is the observation of a special type of epistasis termed 'sign epistasis' [2], according to which mutations are beneficial or deleterious depending on the presence or absence of others [3][4][5][6][7][8]. Under sign epistasis, neighbouring mutation combinations display contrasting fitness values, introducing 'ruggedness' in the surface of the fitness landscape.…”

“…First, it generates mutational pathways whose intermediate steps are no longer arranged in ascending order. Therefore, the number of pathways accessible by natural selection decreases [2] and successful adaptation becomes contingent upon the identity of first-step mutations [7]. A second, more drastic consequence is the emergence of multiple fitness peaks, which requires a particularly extreme form of epistasis known as reciprocal sign epistasis [9].…”

Reciprocal sign epistasis is a necessary condition for multi-peaked fitness landscapes

“…For instance, they may limit the number of trajectories towards a fitness optimum that are selectively accessible, with the latter meaning that each mutational step along the trajectory must be fitness increasing . It has been shown that a necessary and sufficient condition for such a reduced accessibility is the presence of so-called sign-epistatic interactions (Weinreich, Watson 2005). Signepistasis refers to the situation where the fitness effect of a mutation A→a can have a different sign depending on the genetic background B or b (Fig.…”

“…By definition, not a single path is selectively accessible by single-mutation steps between two peaks (i.e., all paths exhibit fitness decreases). Escape from a suboptimal peak may still be possible, but it involves significantly increased waiting times as specific combinations of genetic changes must appear in a population (Phillips 1996;Weissman et al 2009), or requires large population sizes that support many mutant genotypes at a given time (Weinreich, Watson 2005). Entrapment on sub-optima and its relation to landscape ruggedness has principally been studied theoretically, for instance within the mathematical framework of NK landscape models that were pioneered by Kauffman (Kauffman 1993).…”

“…It has long been recognized that interaction between mutations can cause landscape ruggedness (Wright 1932), and the involvement of epistasis in multiple peaks has been discussed (Weinreich, Watson 2005). Here we show that when the landscape harbors multiple peaks, it necessarily contains an epistatic motif that is referred to as reciprocal sign epistasis (Fig.…”