Epistasis Increases the Rate of Conditionally Neutral Substitution in an Adapting Population
Epistasis Increases the Rate of Conditionally Neutral Substitution in an Adapting Population
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DOI：
10.1534/genetics.110.125997
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发表时间：
2011-04-01
期刊：
影响因子：
3.3
通讯作者：
Plotkin, Joshua B.
中科院分区：
文献类型：
--
作者：
Draghi, Jeremy A.;Parsons, Todd L.;Plotkin, Joshua B.
木村观察到，中性替代率应该等于中性突变率。这一经典结果是我们理解分子进化的核心，它继续影响着系统发生学、基因组学和对进化实验的解释。通过证明中性突变以与种群大小和连锁位点的选择无关的速度替代，木村为分子钟的想法提供了一个有影响力的理由，并强调了遗传漂移在塑造分子进化中的重要性。但是，当许多经验研究表明，位点间的上位性很常见时，中性突变是否会根据木村的预期进行替代？在这里，我们研究模拟的、无性的RNA分子种群，我们观察到条件中性突变。例如，突变不会改变出现突变的个体的适应度，但可能会改变后续突变的适应度效应--在种群适应时，替代的频率比预期要高得多。我们使用一个简单的群体遗传模型来量化这些影响，该模型阐明了条件中性位点的替换率如何依赖于群体大小、突变率、选择强度和上位性流行。我们讨论了这些结果对我们理解分子时钟的意义，以及对实验室和自然种群中分子变异的解释。
Kimura observed that the rate of neutral substitution should equal the neutral mutation rate. This classic result is central to our understanding of molecular evolution, and it continues to influence phylogenetics, genomics, and the interpretation of evolution experiments. By demonstrating that neutral mutations substitute at a rate independent of population size and selection at linked sites, Kimura provided an influential justification for the idea of a molecular clock and emphasized the importance of genetic drift in shaping molecular evolution. But when epistasis among sites is common, as numerous empirical studies suggest, do neutral mutations substitute according to Kimura's expectation? Here we study simulated, asexual populations of RNA molecules, and we observe that conditionally neutral mutationsi. e., mutations that do not alter the fitness of the individual in which they arise, but that may alter the fitness effects of subsequent mutations-substitute much more often than expected while a population is adapting. We quantify these effects using a simple population-genetic model that elucidates how the substitution rate at conditionally neutral sites depends on the population size, mutation rate, strength of selection, and prevalence of epistasis. We discuss the implications of these results for our understanding of the molecular clock, and for the interpretation of molecular variation in laboratory and natural populations.