Guéguen Laurent, Duret Laurent
Laboratoire de Biologie et Biométrie Évolutive, CNRS UMR 5558, Université Claude Bernard Lyon 1-Université de Lyon, Villeurbanne, France.
Mol Biol Evol. 2018 Mar 1;35(3):734-742. doi: 10.1093/molbev/msx308.
The measurement of synonymous and nonsynonymous substitution rates (dS and dN) is useful for assessing selection operating on protein sequences or for investigating mutational processes affecting genomes. In particular, the ratio dNdS is expected to be a good proxy for ω, the ratio of fixation probabilities of nonsynonymous mutations relative to that of neutral mutations. Standard methods for estimating dN, dS, or ω rely on the assumption that the base composition of sequences is at the equilibrium of the evolutionary process. In many clades, this assumption of stationarity is in fact incorrect, and we show here through simulations and analyses of empirical data that nonstationarity biases the estimate of dN, dS, and ω. We show that the bias in the estimate of ω can be fixed by explicitly taking into consideration nonstationarity in the modeling of codon evolution, in a maximum likelihood framework. Moreover, we propose an exact method for estimating dN and dS on branches, based on stochastic mapping, that can take into account nonstationarity. This method can be directly applied to any kind of codon evolution model, as long as neutrality is clearly parameterized.
同义替换率和非同义替换率（dS和dN）的测量对于评估作用于蛋白质序列的选择或研究影响基因组的突变过程很有用。特别地，dN/dS比率有望成为ω的良好替代指标，ω即非同义突变相对于中性突变的固定概率之比。估计dN、dS或ω的标准方法依赖于序列的碱基组成处于进化过程平衡状态这一假设。在许多进化枝中，这种平稳性假设实际上是不正确的，我们通过模拟和实证数据分析表明，非平稳性会使dN、dS和ω的估计产生偏差。我们表明，在最大似然框架下，通过在密码子进化建模中明确考虑非平稳性，可以修正ω估计中的偏差。此外，我们基于随机映射提出了一种在分支上估计dN和dS的精确方法，该方法可以考虑非平稳性。只要中性明确参数化，此方法可直接应用于任何类型的密码子进化模型。
