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• W2756373468 abstract "Abstract Interactions among mutations within a protein have the potential to make molecular evolution contingent and irreversible, but the extent to which epistasis actually shaped historical evolutionary trajectories is unclear. We addressed this question by identifying all 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 and then precisely measuring their fitness effects when introduced into both extant and reconstructed ancestral Hsp90 proteins. We find a pervasive influence of epistasis: of 98 derived states that evolved during history, most were deleterious at times before they happened, and the vast majority also became subsequently entrenched, with the ancestral state becoming deleterious after its substitution. This epistasis was primarily caused by specific interactions among sites rather than a general permissive or restrictive effect on the protein’s tolerance to mutation. Our results show that epistasis continually opens and closes windows of mutational opportunity over evolutionary timescales, producing histories and biological states that reflect the transient internal constraints imposed by a protein’s fleeting sequence states. Significance statement When mutations within a protein change each other’s functional effects—a phenomenon called epistasis—the trajectories available to evolution at any moment in time depend on the specific set of changes that previously occurred in the protein. The extent to which epistasis has shaped historical evolutionary trajectories is unknown. Using a high-precision bulk fitness assay and ancestral protein reconstruction, we measured the fitness effects in ancestral and extant sequences of all historical substitutions that occurred during the billion-year trajectory of an essential protein. We found that most historical substitutions were contingent on prior epistatic substitutions and/or entrenched by subsequent changes. These results establish that epistasis caused widespread, consequential shifts in the site-specific fitness constraints that shaped the protein’s historical trajectory." @default.
• W2756373468 created "2017-09-25" @default.
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• W2756373468 date "2017-09-18" @default.
• W2756373468 modified "2023-10-18" @default.
• W2756373468 title "Pervasive contingency and entrenchment in a billion years of Hsp90 evolution" @default.
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• W2756373468 doi "https://doi.org/10.1101/189803" @default.
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