Moses Alan M, Durbin Richard
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Mol Biol Evol. 2009 Mar;26(3):527-36. doi: 10.1093/molbev/msn286. Epub 2008 Dec 18.
Models that explicitly account for the effect of selection on new mutations have been proposed to account for "codon bias" or the excess of "preferred" codons that results from selection for translational efficiency and/or accuracy. In principle, such models can be applied to any mutation that results in a preferred allele, but in most cases, the fitness effect of a specific mutation cannot be predicted. Here we show that it is possible to assign preferred and unpreferred states to amino acid changing mutations that occur in protein domains. We propose that mutations that lead to more common amino acids (at a given position in a domain) can be considered "preferred alleles" just as are synonymous mutations leading to codons for more abundant tRNAs. We use genome-scale polymorphism data to show that alleles for preferred amino acids in protein domains occur at higher frequencies in the population, as has been shown for preferred codons. We show that this effect is quantitative, such that there is a correlation between the shift in frequency of preferred alleles and the predicted fitness effect. As expected, we also observe a reduction in the numbers of polymorphisms and substitutions at more important positions in domains, consistent with stronger selection at those positions. We examine the derived allele frequency distribution and polymorphism to divergence ratios of preferred and unpreferred differences and find evidence for both negative and positive selections acting to maintain protein domains in the human population. Finally, we analyze a model for selection on amino acid preferences in protein domains and find that it is consistent with the quantitative effects that we observe.
已经提出了明确考虑选择对新突变影响的模型，以解释“密码子偏好”或因对翻译效率和/或准确性的选择而导致的“偏好”密码子过量现象。原则上，此类模型可应用于任何导致偏好等位基因的突变，但在大多数情况下，特定突变的适应度效应无法预测。在此我们表明，有可能为蛋白质结构域中发生的氨基酸变化突变赋予偏好和非偏好状态。我们提出，导致更常见氨基酸（在结构域的给定位置）的突变可被视为“偏好等位基因”，就如同导致更丰富tRNA密码子的同义突变一样。我们使用全基因组多态性数据表明，蛋白质结构域中偏好氨基酸的等位基因在群体中出现的频率更高，这与偏好密码子的情况相同。我们表明这种效应是定量的，使得偏好等位基因频率的变化与预测的适应度效应之间存在相关性。正如预期的那样，我们还观察到结构域中更重要位置的多态性和替换数量减少，这与这些位置更强的选择作用一致。我们检查了偏好和非偏好差异的衍生等位基因频率分布以及多态性与分化比率，发现有证据表明正向和负向选择都在维持人类群体中的蛋白质结构域。最后，我们分析了一个关于蛋白质结构域中氨基酸偏好选择的模型，发现它与我们观察到的定量效应一致。
