Redondo Rodrigo A F, de Vladar Harold P, Włodarski Tomasz, Bollback Jonathan P
IST Austria, Am Campus 1, 3400 Klosterneuburg, Austria.
IST Austria, Am Campus 1, 3400 Klosterneuburg, Austria
J R Soc Interface. 2017 Jan;14(126). doi: 10.1098/rsif.2016.0139.
Viral capsids are structurally constrained by interactions among the amino acids (AAs) of their constituent proteins. Therefore, epistasis is expected to evolve among physically interacting sites and to influence the rates of substitution. To study the evolution of epistasis, we focused on the major structural protein of the ϕX174 phage family by first reconstructing the ancestral protein sequences of 18 species using a Bayesian statistical framework. The inferred ancestral reconstruction differed at eight AAs, for a total of 256 possible ancestral haplotypes. For each ancestral haplotype and the extant species, we estimated, in silico, the distribution of free energies and epistasis of the capsid structure. We found that free energy has not significantly increased but epistasis has. We decomposed epistasis up to fifth order and found that higher-order epistasis sometimes compensates pairwise interactions making the free energy seem additive. The dN/dS ratio is low, suggesting strong purifying selection, and that structure is under stabilizing selection. We synthesized phages carrying ancestral haplotypes of the coat protein gene and measured their fitness experimentally. Our findings indicate that stabilizing mutations can have higher fitness, and that fitness optima do not necessarily coincide with energy minima.
病毒衣壳在结构上受到其组成蛋白氨基酸（AAs）之间相互作用的限制。因此，上位性预计会在物理相互作用位点之间进化，并影响替代率。为了研究上位性的进化，我们聚焦于ϕX174噬菌体家族的主要结构蛋白，首先使用贝叶斯统计框架重建了18个物种的祖先蛋白序列。推断出的祖先重建在8个氨基酸处不同，共有256种可能的祖先单倍型。对于每种祖先单倍型和现存物种，我们在计算机上估计了衣壳结构的自由能分布和上位性。我们发现自由能没有显著增加，但上位性增加了。我们将上位性分解到五阶，发现高阶上位性有时会补偿成对相互作用，使自由能看起来具有加和性。dN/dS比率较低，表明存在强烈的纯化选择，且结构处于稳定选择之下。我们合成了携带衣壳蛋白基因祖先单倍型的噬菌体，并通过实验测量了它们的适应性。我们的研究结果表明，稳定突变可以具有更高的适应性，且适应性最优值不一定与能量最小值一致。
