Covariation Is a Poor Measure of Molecular Coevolution.
Covariation Is a Poor Measure of Molecular Coevolution.
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DOI：
10.1093/molbev/msv109
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发表时间：
2015-09
影响因子：
10.7
通讯作者：
Whelan S
中科院分区：
文献类型：
--
作者：
Talavera D;Lovell SC;Whelan S
氨基酸共变异分析的最新进展导致蛋白质结构预测、蛋白质设计和相互作用组预测的突破。据推测，所观察到的模式的协变是由分子的共同进化，在一个网站上的取代影响在相邻网站的进化力量。我们的理论和实证结果对这一假设提出了质疑。我们证明，最强的共同进化信号是进化速率的下降，并不可行的长时间需要产生协调的取代。我们发现，共变置换大多发现在不同的分支系统发育树，表明它们是独立的事件，可能会或可能不会归因于共同进化。这些观察破坏了分子协同进化是共变信号的主要原因的假设。相比之下，我们发现具有最强共变信号的残基对往往具有低进化速率，并且正是这种低速率引起了共变信号。缓慢进化的残基对不成比例地位于蛋白质的核心，这解释了协变方法检测三维接近的残基对的能力。这些观察使我们提出了“共同进化悖论”：共同进化的强度需要引起协调的变化，这意味着进化速度如此之低，以至于这种变化极不可能发生。由于现代协变方法可能会导致结构基因组学的突破，因此认识到它们的偏见和局限性至关重要。
Recent developments in the analysis of amino acid covariation are leading to breakthroughs in protein structure prediction, protein design, and prediction of the interactome. It is assumed that observed patterns of covariation are caused by molecular coevolution, where substitutions at one site affect the evolutionary forces acting at neighboring sites. Our theoretical and empirical results cast doubt on this assumption. We demonstrate that the strongest coevolutionary signal is a decrease in evolutionary rate and that unfeasibly long times are required to produce coordinated substitutions. We find that covarying substitutions are mostly found on different branches of the phylogenetic tree, indicating that they are independent events that may or may not be attributable to coevolution. These observations undermine the hypothesis that molecular coevolution is the primary cause of the covariation signal. In contrast, we find that the pairs of residues with the strongest covariation signal tend to have low evolutionary rates, and that it is this low rate that gives rise to the covariation signal. Slowly evolving residue pairs are disproportionately located in the protein’s core, which explains covariation methods’ ability to detect pairs of residues that are close in three dimensions. These observations lead us to propose the “coevolution paradox”: The strength of coevolution required to cause coordinated changes means the evolutionary rate is so low that such changes are highly unlikely to occur. As modern covariation methods may lead to breakthroughs in structural genomics, it is critical to recognize their biases and limitations.