Title: Diminishing-returns epistasis among random beneficial mutations; experiments and Fishers geometric model

Abstract:

Epistatic interactions among mutations may affect the dynamics and repeatability of adaptation. However, understanding the importance and implications of epistasis is hampered by the observation of substantial variation in patterns of epistasis across empirical studies. Interestingly, some recent studies report prevailing diminishing-returns epistasis among beneficial mutations, i.e. negative epistasis whose strength increases with the fitness effects of mutations, in unicellular microbes and single genes. Here, we use Fisher's geometric model to generate analytical predictions about the relationship between the effect size of mutations and the extent of epistasis. We then test these predictions using the multicellular fungus Aspergillus nidulans by generating a collection of 108 strains that each carry a beneficial mutation in either a poor or a rich nutrient environment and constructing pairwise combinations using sexual crosses. Our results support the predictions from FGM and indicate negative epistasis among beneficial mutations in both environments, which scale with mutational effect size. Hence, our findings show the importance of diminishing-returns epistasis among beneficial mutations also for a multicellular organism, and suggest that this pattern reflects a generic constraint operating at diverse levels of biological organisation.