Environmental modulation of global epistasis is governed by effective genetic interactions

AbstractInteractions between mutations (epistasis) can add substantial complexity to genotype-phenotype maps, hampering our ability to predict evolution. Yet, recent studies have shown that the fitness effect of a mutation can often be predicted from the fitness of its genetic background using simple, linear relationships. This phenomenon, termedglobal epistasis, has been leveraged to reconstruct fitness landscapes and infer adaptive trajectories in a wide variety of contexts. However, little attention has been paid to how patterns of global epistasis may be affected by environmental variation — both from external sources or induced by the population itself through eco-evolutionary feedbacks — despite this variation frequently being a major driver of evolution. By analyzing a four-mutation fitness landscape, here we show that patterns of global epistasis can be strongly modulated by the concentration of a drug in the environment. Using previous theoretical results, we demonstrate that this modulation can be explained by how specific gene-by-gene interactions are modified by drug dose. Importantly, our results highlight the need to incorporate potential environmental variation into the global epistasis framework in order to predict adaptation in dynamic environments.