The causes of epistasis

Abstract

Since Bateson's discovery that genes can suppress the phenotypic effects of other genes, gene interactions-called epistasis-have been the topic of a vast research effort. Systems and developmental biologists study epistasis to understand the genotype-phenotype map, whereas evolutionary biologists recognize the fundamental importance of epistasis for evolution. Depending on its form, epistasis may lead to divergence and speciation, provide evolutionary benefits to sex and affect the robustness and evolvability of organisms. That epistasis can itself be shaped by evolution has only recently been realized. Here, we review the empirical pattern of epistasis, and some of the factors that may affect the form and extent of epistasis. Based on their divergent consequences, we distinguish between interactions with or without mean effect, and those affecting the magnitude of fitness effects or their sign. Empirical work has begun to quantify epistasis in multiple dimensions in the context of metabolic and fitness landscape models. We discuss possible proximate causes (such as protein function and metabolic networks) and ultimate factors (including mutation, recombination, and the importance of natural selection and genetic drift). We conclude that, in general, pleiotropy is an important prerequisite for epistasis, and that epistasis may evolve as an adaptive or intrinsic consequence of changes in genetic robustness and evolvability.

Figure 1.

(a) Unidimensional epistasis. The dashed line indicates the multiplicative null model (no epistasis) for the average fitness of mutants carrying the same number of mutations, here with negative effect; the green and red curved lines are examples of positive and negative epistasis, respectively. (b) Multidimensional epistasis. The cube shows an example of a fitness landscape of three loci, where the nodes are genotypes with mutant (‘1’) or wild-type (‘0’) alleles. The arrows point towards genotypes with higher fitness, and their thickness indicates the size of the fitness increment. In this example, a description of multidimensional epistasis includes the presence of sign epistasis (the same allele having opposite fitness effects in different backgrounds, e.g. apparent from the addition of allele ‘1’ at the third locus in 100⇒101 versus 110⇒111) and two fitness maxima (100 and 111).

Figure 2.

A simple metabolic network showing examples of positive (green line), negative (red line) and no (black line) epistasis between loss-of-function gene mutations (X). The synthesis of biomass (black square) from biomass components (such as amino acids or nucleotides, black circles) requires an optimal allocation of a common nutrient (white square) through intermediate metabolites (white circles). Negative epistasis requires that the two pathways affected are the only two involved in the production of an essential biomass component (leading to ‘synthetic lethality’ if the mutations are knockouts); if alternative pathways exist or when affected pathways are involved in distant parts of the metabolism, then multiplicative effects between the two mutations are to be expected (black line). Adapted from Segrè et al. [39].

Figure 3.

Pleiotropy provides opportunities for epistasis. P₁ and P₂ are two phenotypes with effects on fitness (W) encoded by genes G₁ and G₂. (a) No pleiotropy: genes encoding P₁ or P₂ have no pleiotropic effects and lack opportunities for mutual epistatic interactions (red double arrows), except at the level of fitness. (b) Pleiotropy: owing to pleiotropic effects of G₁ and G₂, additional opportunities for epistatic interactions arise at the level of the phenotype. When P₁ and P₂ are phenotypes that show a fitness trade-off (e.g. survival and reproduction for organisms, or enzyme activity and stability for proteins), pleiotropic effects of G₁ and G₂ allow compensatory (i.e. sign epistatic) mutations to alleviate negative pleiotropic effects of previous mutations with a net beneficial effect.