PRJNA412528
Pervasive contingency and entrenchment in a billion years of Hsp90 evolution
Although many potential mutations within proteins modulate each other's effects, the extent to which these epistatic interactions influenced the fitness effects of the sequence changes that actually occurred during historical evolution – and thus made molecular evolution contingent and irreversible – is controversial. We addressed this question directly by precisely measuring the fitness effects in both extant and reconstructed ancestral sequence contexts of all historical amino acid substitutions that occurred during the billion-year evolutionary history of the heat shock protein 90 (Hsp90) ATPase domain beginning from a deep eukaryotic ancestor to modern Saccharomyces cerevisiae. We find a pervasive influence of epistasis on historical sequence evolution: the majority of the 98 derived states that evolved during history were deleterious at times before they happened, and the vast majority also became subsequently entrenched, with the ancestral state becoming deleterious after its substitution. A few of these epistatic interactions were of massive fitness consequence, but the majority were of small but evolutionarily relevant effect size. We find that both the large- and small-effect epistasis were largely caused byspecific interactions among sites rather than a general permissive or restrictive effect. Our results highlight how epistasis continually opens and closes windows of mutational opportunity over evolutionary timescales, producing histories and biological states that reflect, in significant part, the transient internal constraints imposed by a protein's fleeting sequence states.