Evolution requires the generation and optimization of new traits ("adaptation") and involves the selection of mutations that improve cellular function. These mutations were assumed to arise by selection of neutral mutations present at all times in the population. Here we review recent evidence that indicates that deleterious mutations are more frequent in the population than previously recognized and that these mutations play a significant role in protein evolution through continuous positive selection. Positively selected mutations include adaptive mutations, i.e. mutations that directly affect enzymatic function, and compensatory mutations, which suppress the pleiotropic effects of adaptive mutations. Compensatory mutations are by far the most frequent of the two and would allow potentially adaptive but deleterious mutations to persist long enough in the population to be positively selected during episodes of adaptation. Compensatory mutations are, by definition, context-dependent and thus constrain the paths available for evolution. This provides a mechanistic basis for the examples of highly constrained evolutionary landscapes and parallel evolution reported in natural and experimental populations. The present review article describes these recent advances in the field of protein evolution and discusses their implications for understanding the genetic basis of disease and for protein engineering in vitro.

中文翻译：

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蛋白质进化的遗传限制。

进化需要新特征的产生和优化（“适应”），并涉及改善细胞功能的突变的选择。假设这些突变是通过选择种群中始终存在的中性突变而产生的。在这里，我们回顾了最近的证据，这些证据表明群体中的有害突变比以前认识到的更频繁，并且这些突变通过持续的正选择在蛋白质进化中发挥着重要作用。积极选择的突变包括适应性突变，即直接影响酶功能的突变，以及抑制适应性突变的多效性的补偿性突变。补偿性突变是目前这两种突变中最常见的，并且可以让潜在的适应性但有害的突变在群体中持续足够长的时间，以便在适应阶段被积极选择。根据定义，补偿性突变依赖于上下文，因此限制了可用于进化的路径。这为在自然和实验种群中报告的高度受限的进化景观和平行进化的例子提供了机械基础。本综述文章描述了蛋白质进化领域的这些最新进展，并讨论了它们对理解疾病的遗传基础和体外蛋白质工程的意义。上下文相关，从而限制了可用于进化的路径。这为在自然和实验种群中报告的高度受限的进化景观和平行进化的例子提供了机械基础。本综述文章描述了蛋白质进化领域的这些最新进展，并讨论了它们对理解疾病的遗传基础和体外蛋白质工程的意义。上下文相关，从而限制了可用于进化的路径。这为在自然和实验种群中报告的高度受限的进化景观和平行进化的例子提供了机械基础。本综述文章描述了蛋白质进化领域的这些最新进展，并讨论了它们对理解疾病的遗传基础和体外蛋白质工程的意义。