Global epistasis emerges from a generic model of a complex trait.

Gautam Reddy,Michael M Desai

doi:10.7554/elife.64740

Abstract

Epistasis between mutations can make adaptation contingent on evolutionary history. Yet despite widespread 'microscopic' epistasis between the mutations involved, microbial evolution experiments show consistent patterns of fitness increase between replicate lines. Recent work shows that this consistency is driven in part by global patterns of diminishing-returns and increasing-costs epistasis, which make mutations systematically less beneficial (or more deleterious) on fitter genetic backgrounds. However, the origin of this 'global' epistasis remains unknown. Here, we show that diminishing-returns and increasing-costs epistasis emerge generically as a consequence of pervasive microscopic epistasis. Our model predicts a specific quantitative relationship between the magnitude of global epistasis and the stochastic effects of microscopic epistasis, which we confirm by reanalyzing existing data. We further show that the distribution of fitness effects takes on a universal form when epistasis is widespread and introduce a novel fitness landscape model to show how phenotypic evolution can be repeatable despite sequence-level stochasticity.

Highlights

Despite the idiosyncrasies of epistasis, a number of laboratory microbial evolution experiments show systematic patterns of convergent phenotypic evolution and declining adaptability
The coefficients of terms linear in xi represent the additive contribution of each locus to the fitness, the higher-order terms quantify epistatic interactions of all orders, and y is the average fitness across all possible genotypes
This fitness effect will generally involve a sum over a large number of terms involving the f ’s in Equation (2). While this may suggest that an analysis of fitness effects via Equation (2) is intractable, the analysis simplifies considerably if the locus has a significant number of independent interactions that contribute to the fitness

Summary

Introduction

Despite the idiosyncrasies of epistasis, a number of laboratory microbial evolution experiments show systematic patterns of convergent phenotypic evolution and declining adaptability. While diminishing-returns can be rationalized as the saturation of a trait close to a fitness peak, recent work shows a similar dependence on background fitness even for deleterious mutations, which become more costly on higher fitness backgrounds (Johnson et al, 2019). This suggests that fitter backgrounds are less robust to deleterious effects (Figure 1d), a phenomenon that has been termed increasing-costs epistasis. The origin of the global coupling that results in these effects is unknown

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Conclusion