Abstract

It has been suggested that, due to the structure of the genetic code, nonsynonymous transitions are less likely than transversions to cause radical changes in amino acid physicochemical properties so are on average less deleterious. This view was supported by some but not all mutagenesis experiments. Because laboratory measures of fitness effects have limited sensitivities and relative frequencies of different mutations in mutagenesis studies may not match those in nature, we here revisit this issue using comparative genomics. We extend the standard codon model of sequence evolution by adding the parameter η that quantifies the ratio of the fixation probability of transitional nonsynonymous mutations to that of transversional nonsynonymous mutations. We then estimate η from the concatenated alignment of all protein-coding DNA sequences of two closely related genomes. Surprisingly, η ranges from 0.13 to 2.0 across 90 species pairs sampled from the tree of life, with 51 incidences of η < 1 and 30 incidences of η >1 that are statistically significant. Hence, whether nonsynonymous transversions are overall more deleterious than nonsynonymous transitions is species-dependent. Because the corresponding groups of amino acid replacements differ between nonsynonymous transitions and transversions, η is influenced by the relative exchangeabilities of amino acid pairs. Indeed, an extensive search reveals that the large variation in η is primarily explainable by the recently reported among-species disparity in amino acid exchangeabilities. These findings demonstrate that genome-wide nucleotide substitution patterns in coding sequences have species-specific features and are more variable among evolutionary lineages than are currently thought.

中文翻译：

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非同义转换通常比非同义转换更有害吗？

摘要

有人提出，由于遗传密码的结构，与颠换相比，非同义转换不太可能引起氨基酸理化性质的根本变化，因此平均而言危害较小。这种观点得到了一些但不是所有诱变实验的支持。由于适应性效应的实验室测量具有有限的敏感性，并且诱变研究中不同突变的相对频率可能与自然界不匹配，因此我们在这里使用比较基因组学重新讨论这个问题。我们通过添加量化过渡非同义突变的固定概率与颠换非同义突变的固定概率之比的参数 η 来扩展序列进化的标准密码子模型。然后，我们从两个密切相关的基因组的所有蛋白质编码 DNA 序列的串联比对中估计 η。令人惊讶的是，在从生命之树采样的 90 个物种对中，η 的范围从 0.13 到 2.0，其中 51 次 η < 1 和 30 次 η > 1 具有统计显着性。因此，非同义转换是否总体上比非同义转换更有害取决于物种。由于非同义转换和颠换之间的相应氨基酸置换组不同，因此 η 受氨基酸对的相对交换能力的影响。事实上，广泛的搜索表明 η 的巨大变化主要可以通过最近报道的氨基酸交换性的物种间差异来解释。