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Historical contingency and its biophysical basis in glucocorticoid receptor evolution

机译：糖皮质激素受体进化的历史偶然性及其生物物理基础

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摘要

Understanding how chance historical events shape evolutionary processes is a central goal of evolutionary biology. Direct insights into the extent and causes of evolutionary contingency have been limited to experimental systems, because it is difficult to know what happened in the deep past and to characterize other paths that evolution could have followed. Here we combine ancestral protein reconstruction, directed evolution and biophysical analysis to explore alternative 'might-have-been' trajectories during the ancient evolution of a novel protein function. We previously found that the evolution of cortisol specificity in the ancestral glucocorticoid receptor (GR) was contingent on permissive substitutions, which had no apparent effect on receptor function but were necessary for GR to tolerate the large-effect mutations that caused the shift in specificity. Here we show that alternative mutations that could have permitted the historical function-switching substitutions are extremely rare in the ensemble of genotypes accessible to the ancestral GR. In a library of thousands of variants of the ancestral protein, we recovered historical permissive substitutions but no alternative permissive genotypes. Using biophysical analysis, we found that permissive mutations must satisfy at least three physical requirements-they must stabilize specific local elements of the protein structure, maintain the correct energetic balance between functional conformations, and be compatible with the ancestral and derived structures-thus revealing why permissive mutations are rare. These findings demonstrate that GR evolution depended strongly on improbable, non-deterministic events, and this contingency arose from intrinsic biophysical properties of the protein.
机译：了解机会历史事件如何塑造进化过程是进化生物学的中心目标。对进化偶然性的程度和原因的直接见解仅限于实验系统，因为很难知道过去发生的事情以及描述进化可能遵循的其他路径的特征。在这里，我们结合了祖先的蛋白质重建，定向进化和生物物理分析，以探索在新型蛋白质功能的古代进化过程中可能发生的“可能已经存在”的变化轨迹。我们先前发现，祖先糖皮质激素受体（GR）中皮质醇特异性的演变取决于许可的替代，这对受体功能没有明显影响，但对于GR耐受引起特异性转移的大突变是必需的。在这里，我们显示了可能允许历史功能切换替换的替代突变在祖先GR可获得的基因型集合中极为罕见。在数千种祖先蛋白质变体的文库中，我们检索了历史允许的替代，但没有替代的允许的基因型。使用生物物理分析，我们发现允许的突变必须满足至少三个物理要求-它们必须稳定蛋白质结构的特定局部元素，在功能构象之间保持正确的能量平衡，并与祖先和派生的结构兼容-因此揭示了为什么允许突变是罕见的。这些发现表明，遗传资源的进化很大程度上取决于不可能发生的，不确定的事件，而这种偶然性是由于蛋白质的内在生物物理特性引起的。

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  • 来源
    《Nature》 |2014年第7513期|203-207|共5页
  • 作者

    Michael J. Harms; Joseph W. Thornton;

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    Institute of Molecular Biology and Department of Chemistry & Biochemistry, University of Oregon, Eugene, Oregon 97403, USA,Departments of Human Genetics and Ecology & Evolution, University of Chicago, Chicago, Illinois 60637, USA;

    Departments of Human Genetics and Ecology & Evolution, University of Chicago, Chicago, Illinois 60637, USA,Institute of Ecology and Evolution, University of Oregon, Eugene, Oregon 97403, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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