Tuff P, Darlu P
Institut National de la Santé et de la Recherche Médicale U436, Université Paris 7, Paris, France.
Mol Biol Evol. 2000 Nov;17(11):1753-9. doi: 10.1093/oxfordjournals.molbev.a026273.
The remarkable conservation of protein structure, compared with that of sequences, suggests that in the course of evolution, residue substitutions which tend to destabilize a particular structure must be compensated by other substitutions that confer greater stability on that structure. Several approaches have been designed to detect correlated changes in a set of homologous sequences. However, most of them do not take into account the phylogeny of the sequences, and it has been shown that their detection power is weak. It remains unclear whether coevolution could be a general process at the level of amino acids of proteins. In the present study, we analyze the phylogenetic reconstruction of 15 sets of homologous proteins to assess, under different conditions, whether a significant amount of coevolving sites can be detected. Two criteria are used to detect significantly cosubstituting sites. One criterion corresponds to that of Shindyalov, Kolchanov, and Sander. The second one is based on intensive simulations of evolution of protein sequences along a phylogeny to estimate the significance of the number of observed cosubstitutions for pairs of sites. Our results show an important sensitivity of the detection of cosubstituting sites to the model used for the phylogenetic reconstruction. Not considering the uncertainty associated with the reconstructed data might lead to detecting numerous false-positive pairs of sites. Finally, significant amounts of coevolving pairs could be found only when substitutions affecting the physicochemical properties of the amino acids were considered. Such results suggest evidence of a cosubstitution mechanism in protein evolution. However, the identification of nonambiguous coevolving sites is still unresolved.
与序列相比，蛋白质结构具有显著的保守性，这表明在进化过程中，那些倾向于使特定结构不稳定的残基替换必须由其他能赋予该结构更高稳定性的替换来补偿。已经设计了几种方法来检测一组同源序列中的相关变化。然而，它们中的大多数没有考虑序列的系统发育，并且已经表明它们的检测能力较弱。目前尚不清楚共进化是否可能是蛋白质氨基酸水平上的一个普遍过程。在本研究中，我们分析了15组同源蛋白质的系统发育重建，以评估在不同条件下是否能检测到大量的共进化位点。使用两个标准来检测显著共替换的位点。一个标准对应于申德亚洛夫、科尔恰诺夫和桑德的标准。另一个基于对蛋白质序列沿系统发育的进化进行密集模拟，以估计观察到的位点对共替换数量的显著性。我们的结果表明，共替换位点的检测对用于系统发育重建的模型具有重要的敏感性。不考虑与重建数据相关的不确定性可能会导致检测到大量假阳性的位点对。最后，只有当考虑影响氨基酸物理化学性质的替换时，才能发现大量的共进化对。这些结果表明了蛋白质进化中共替换机制的证据。然而，明确的共进化位点的识别仍然没有解决。
