LAUSR

Epistatic interactions can make the outcomes of evolution unpredictable, but no comprehensive data are available on the extent and temporal dynamics of changes in the effects of mutations as protein sequences evolve. Here, we use phylogenetic deep mutational scanning to measure the functional effect of every possible amino acid mutation in a series of ancestral and extant steroid receptor DNA binding domains. Across 700 million years of evolution, epistatic interactions caused the effects of most mutations to become decorrelated from their initial effects and their windows of evolutionary accessibility to open and close transiently. Most effects changed gradually and without bias at rates that were largely constant across time, indicating a neutral process caused by many weak epistatic interactions. Our findings show that protein sequences drift inexorably into contingency and unpredictability, but that the process is statistically predictable, given sufficient phylogenetic and experimental data. Description Proteins adrift in a sea of mutations In two related proteins, one might expect the same mutation to have the same effect, but whether this is true greatly depends on context. Looking at nine ancestral reconstructions of a DNA-binding domain, Park et al. evaluated the effects of 275 substitutions at predicted evolutionary steps. The effects of mutations were highly contingent on a dense network of epistatic interactions. There were mutations with both short and long memory length, but the average rate of epistatic change was generally constant. The landscape of potential and actual interactions is thus constantly shifting at a rate that can be known, but the direction of the change is contingent on evolutionary history and becomes unpredictable after a time. —MAF The effect and fate of most mutations gradually become unpredictable as proteins evolve.