Estimating the Rate of Adaptive Molecular Evolution in the Presence of Slightly Deleterious Mutations and Population Size Change
Estimating the Rate of Adaptive Molecular Evolution in the Presence of Slightly Deleterious Mutations and Population Size Change
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DOI：
10.1093/molbev/msp119
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发表时间：
2009-09-01
影响因子：
10.7
通讯作者：
Keightley, Peter D.
中科院分区：
文献类型：
--
作者：
Eyre-Walker, Adam;Keightley, Peter D.
适应性进化相对于遗传漂变的普遍性是分子进化中的一个中心问题。基于McDonald-Kreitman检验，已经开发了估计适应性核苷酸取代（α）的分数的方法，该检验对比选择性和中性进化位点之间的多态性和分歧。然而，如果存在轻微有害的突变，这些方法预计会给出向下偏倚的α估计值，因为这些方法会相对于分歧夸大多态性。在这里，我们估计阿尔法同时估计分布的适应性影响的新突变在选定的网站，从网站的频谱和自适应置换的数量。我们使用模拟测试的方法。如果数据符合分析模型的假设，则即使在很少或没有重组的情况下，α的估计值也几乎没有偏倚。然而，群体大小的差异之间的分歧和多态性阶段可能会导致α被高估或低估的一个可预测的因素，这取决于人口规模的变化和有害突变的影响分布的形状的大小。我们分析了几个数据集的蛋白质编码基因和非编码区从人类和果蝇。在果蝇基因中，我们估计大约50%的氨基酸替换和大约20%的内含子替换是适应性的。在人类的蛋白质编码和非编码数据集中，与猕猴序列的比较揭示了适应性取代的证据很少。然而，在人类编码DNA中适应性替换的真实频率可能高达40%，因为基于当前多态性的估计可能由于沿着人类谱系的有效群体大小沿着减少而强烈向下偏倚。
The prevalence of adaptive evolution relative to genetic drift is a central problem in molecular evolution. Methods to estimate the fraction of adaptive nucleotide substitutions (alpha) have been developed, based on the McDonald-Kreitman test, that contrast polymorphism and divergence between selectively and neutrally evolving sites. However, these methods are expected to give downwardly biased estimates of alpha if there are slightly deleterious mutations, because these inflate polymorphism relative to divergence. Here, we estimate alpha by simultaneously estimating the distribution of fitness effects of new mutations at selected sites from the site frequency spectrum and the number of adaptive substitutions. We test the method using simulations. If data meet the assumptions of the analysis model, estimates of alpha show little bias, even when there is little or no recombination. However, population size differences between the divergence and polymorphism phases may cause alpha to be over or underestimated by a predictable factor that depends on the magnitude of the population size change and the shape of the distribution of effects of deleterious mutations. We analyze several data sets of protein-coding genes and noncoding regions from hominids and Drosophila. In Drosophila genes, we estimate that approximately 50% of amino acid substitutions and approximately 20% of substitutions in introns are adaptive. In protein-coding and noncoding data sets of humans, comparison to macaque sequences reveals little evidence for adaptive substitutions. However, the true frequency of adaptive substitutions in human-coding DNA could be as high as 40%, because estimates based on current polymorphism may be strongly downwardly biased by a decrease in the effective population size along the human lineage.