Mammalian protein-coding genes exhibit widespread beneficial mutations that are not adaptive

Abstract Mutations can be beneficial by bringing innovation to their bearer, allowing them to adapt to environmental change. However, mutations can also be beneficial because they are reverting previous deleterious changes, simply restoring pre-existing functions. By integrating phylogenomic and population data in mammals, we estimated the contribution of beneficial back-mutations to molecular evolution, which had remained widely overlooked so far. Applying a mutation-selection model, we estimated amino acid fitness landscapes for mammalian protein-coding genes. Assuming these fitness landscapes do not change, any beneficial mutation is necessarily a back-mutation. We confirmed that these beneficial back-mutations are positively selected in extant populations and demonstrated that a substantial part of ongoing positive selection is not driven by adaptation to environmental change.