Global epistasis emerges from a generic model of a complex trait

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 increases during laboratory adaptation. Recent work has found 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 more-fit genetic backgrounds. This global "macroscopic" epistasis is thought to make phenotypic evolution repeatable, even while the genetic basis of this evolution is highly stochastic. However, the mechanistic basis of consistent macroscopic epistasis remains unknown. Here we show, using a generic model of a complex trait, that global diminishing-returns and increasing-costs epistasis arise naturally as a consequence of pervasive microscopic epistasis, emerging simply as a statistical trend due to an imbalance between positive and negative contributions to the fitness. Our model predicts a specific quantitative relationship between the magnitude of global epistasis and the stochastic effects of microscopic epistasis, which we confirm by re-analyzing existing data. We also describe the predictions of this model for the patterns of fitness evolution and for how the distribution of fitness e↵ects shifts as a population adapts, and propose additional experimental tests of these results. ⇤

Emergence and Propagation of Epistasis in Metabolic Networks

“…Yet, how epistasis emerges from the molecular architecture of the cell and how it propagates to higher-level phenotypes, such as fitness, remains largely unknown. Several recent studies made a statistical argument that the structure of the fitness landscape (and, as a consequence, the epistatic interactions between mutations at the level of fitness) may be largely independent of the underlying molecular architecture of the organism (Martin, 2014;Lyons et al, 2020;Reddy and Desai, 2020).…”

“…The reasons for these patterns are currently unclear. Several recent theoretical papers offer possible statistical explanations for them (Martin, 2014;Lyons et al, 2020;Reddy and Desai, 2020). On the other hand, mechanistic predictions for the distribution of epistasis coefficients are not yet available (but see Sanjuán and Nebot, 2008;Macía et al, 2012;Chiu et al, 2012).…”

Non-additive polygenic models improve predictions of fitness traits in three eukaryote model species

“…The evidence for non-addi ve gene c architecture presented here may not be surprising given the growing literature of experiments that require genome-wide epistasis to explain asymmetric responses to ar ficial selec on (33) , line-dependent effects of muta ons in Drosophila (14,34) , or significant quan ta ve trait loci hubs in yeast (35) . This has sparked recent development of various sta s cal approaches to test epistasis more generally, by studying the emergent pa erns of epistasis as its contribu on to variance (36) , or one genotype-to-trait map (24,25,31,37,38) as in this study. Recent systems biology approaches for crea ng massively-parallel muta ons using CRISPR/Cas9 techniques (39) , as recently aimed in yeast experiments (40) , should further enable researchers to test the underlying addi ve or epista c interac ons of muta ons.…”

The Population Genetics of Collateral Resistance and Sensitivity

“…Recently, researchers began to systematically probe how the effects of new individual mutations on fitness in one environment and their distribution (i.e., the DFE) vary among genotypes (Khan et al, 2011;Chou et al, 2011;Kryazhimskiy et al, 2014;Johnson et al, 2019;Wang et al, 2016;Aggeli et al, 2020). These studies suggest that the fitness effects of mutations available to a genotype and its overall DFE in a given environment depend primarily on the fitness of that genotype in that environment, a phenomenon referred to as "global epistasis" (Wiser et al, 2013;Kryazhimskiy et al, 2014;Reddy and Desai, 2020;Husain and Murugan, 2020). Thus, we next sought to understand how such epistasis might affect the pleiotropic outcomes of adaptation.…”