Epistasis and natural selection shape the mutational architecture of complex traits.

The evolutionary trajectories of complex traits are constrained by levels of genetic variation as well as genetic correlations among traits. As the ultimate source of all genetic variation is mutation, the distribution of mutations entering populations profoundly affects standing variation and genetic correlations. Here we use an individual-based simulation model to investigate how natural selection and gene interactions (that is, epistasis) shape the evolution of mutational processes affecting complex traits. We find that the presence of epistasis allows natural selection to mould the distribution of mutations, such that mutational effects align with the selection surface. Consequently, novel mutations tend to be more compatible with the current forces of selection acting on the population. These results suggest that in many cases mutational effects should be seen as an outcome of natural selection rather than as an unbiased source of genetic variation that is independent of other evolutionary processes.