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Proc Natl Acad Sci U S A. 2018 Apr 24;115(17):4453-4458. doi: 10.1073/pnas.1718133115. Epub 2018 Apr 6.

Pervasive contingency and entrenchment in a billion years of Hsp90 evolution.

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Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637.
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605.
Department of Animal Biology, School of Life Sciences, University of Hyderabad, 500046 Hyderabad, India.
Department of Ecology and Evolution, University of Chicago, Chicago, IL 60637;
Department of Human Genetics, University of Chicago, Chicago, IL 60637.


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. To address this question, we experimentally measured how the fitness effects of historical sequence substitutions changed 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 found a pervasive influence of epistasis. Of 98 derived amino acid states that evolved along this lineage, about half compromise fitness when introduced into the reconstructed ancestral Hsp90. And the vast majority of ancestral states reduce fitness when introduced into the extant S. cerevisiae Hsp90. Overall, more than 75% of historical substitutions were contingent on permissive substitutions that rendered the derived state nondeleterious, became entrenched by subsequent restrictive substitutions that made the ancestral state deleterious, or both. This epistasis was primarily caused by specific interactions among sites rather than a general effect on the protein's tolerance to mutation. Our results show that epistasis continually opened and closed windows of mutational opportunity over evolutionary timescales, producing histories and biological states that reflect the transient internal constraints imposed by the protein's fleeting sequence states.


ancestral protein reconstruction; epistasis; heat shock proteins; molecular evolution; protein evolution

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