Serohijos Adrian W R, Shakhnovich Eugene I
Department of Chemistry and Chemical Biology, Harvard University.
Mol Biol Evol. 2014 Jan;31(1):165-76. doi: 10.1093/molbev/mst189. Epub 2013 Oct 11.
The patterns of polymorphisms in genomes are imprints of the evolutionary forces at play in nature. In particular, polymorphisms have been extensively used to infer the fitness effects of mutations and their dynamics of fixation. However, the role and contribution of molecular biophysics to these observations remain unclear. Here, we couple robust findings from protein biophysics, enzymatic flux theory, the selection against the cytotoxic effects of protein misfolding, and explicit population dynamics simulations in the polyclonal regime. First, we recapitulate results on the dynamics of clonal interference and on the shape of the DFE, thus providing them with a molecular and mechanistic foundation. Second, we predict that if evolution is indeed under the dynamic equilibrium of mutation-selection balance, the fraction of stabilizing and destabilizing mutations is almost equal among single-nucleotide polymorphisms segregating at high allele frequencies. This prediction is proven true for polymorphisms in the human coding region. Overall, our results show how selection for protein folding stability predominantly shapes the patterns of polymorphisms in coding regions.
基因组中的多态性模式是自然界中起作用的进化力量的印记。特别是，多态性已被广泛用于推断突变的适应性效应及其固定动态。然而，分子生物物理学对这些观察结果的作用和贡献仍不清楚。在这里，我们将蛋白质生物物理学、酶通量理论、针对蛋白质错误折叠的细胞毒性效应的选择以及多克隆状态下的明确群体动态模拟等有力发现结合起来。首先，我们概括了关于克隆干扰动态和DFE形状的结果，从而为它们提供了分子和机制基础。其次，我们预测，如果进化确实处于突变-选择平衡的动态平衡之下，那么在高等位基因频率下分离的单核苷酸多态性中，稳定和不稳定突变的比例几乎相等。这一预测在人类编码区的多态性中得到了证实。总体而言，我们的结果表明，对蛋白质折叠稳定性的选择如何主要塑造了编码区的多态性模式。
