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.
Proc Natl Acad Sci U S A. 2018 Apr 24;115(17):4453-4458. doi: 10.1073/pnas.1718133115. Epub 2018 Apr 6.
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 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 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.
蛋白质内突变的相互作用有可能使分子进化具有偶然性和不可逆性，但上位性实际上在多大程度上塑造了历史进化轨迹还不清楚。为了解决这个问题，我们从一个深的真核祖先开始，实验测量了热休克蛋白 90（Hsp90）ATP 酶结构域在其十亿年的进化历史中，历史序列取代的适应度效应是如何变化的。我们发现上位性有普遍的影响。在这条谱系中进化的 98 个衍生氨基酸状态中，大约一半在引入重建的祖先 Hsp90 时会降低适应度。而且，绝大多数祖先状态在引入现存的 Hsp90 时会降低适应度。总的来说，超过 75%的历史取代是偶然的，这是由于允许取代使衍生状态非有害，随后被限制性取代使祖先状态有害，或者两者兼而有之。这种上位性主要是由特定的位点相互作用引起的，而不是对蛋白质对突变的耐受性的一般影响。我们的结果表明，上位性在进化时间尺度上不断地打开和关闭突变机会的窗口，产生的历史和生物状态反映了由蛋白质短暂的序列状态所施加的瞬时内部限制。
