View Program - 2022 Population, Evolutionary, and Quantitative Genetics Conference

Epistatic interactions have the potential to make the course and outcomes of evolution unpredictable, but no comprehensive data are available on the extent, direction, rate, and consequences of changes in the effects of mutations in any protein across evolutionary time. Here we characterize the temporal dynamics of epistasis by measuring changes in the effect of every possible point mutation along a densely sampled, 700-million-year phylogenetic trajectory of reconstructed and extant proteins in the steroid receptor DNA-binding domain. We found that pervasive epistatic interactions caused the functional effects of the majority of mutations to steadily drift from their initial effects and become completely or substantially contingent on the particular set of intervening substitutions that occurred during history. By statistically characterizing each mutation’s effect as an evolving trait on the phylogeny, we found that epistatic change occurred at a rate that was largely constant across time but varied dramatically among mutations; this pervasive drift in the effects of mutations occurred gradually and without bias via many steps of small magnitude, suggesting a neutral evolutionary process and an underlying architecture of dense but weak epistatic interactions. By transiently opening and closing windows of evolutionary accessibility, substitutions that occurred under purifying selection shaped the historical fate not only of those mutations that fixed during history but also the far greater number that never did. Our findings indicate that the process by which protein sequences drift inevitably into contingency and unpredictability is itself predictable, given sufficient phylogenetic and experimental data.

Epistatic drift causes gradual loss of predictability in molecular evolution