Fitness conferred by the same allele may differ between genotypes, and these differences shape variation and evolution. Changes in amino acid propensities at protein sites over the course of evolution have been inferred from sequence alignments statistically, but the existing methods are data-intensive and aggregate multiple sites. Here, we develop an approach to detect individual amino acids that confer different fitness in different groups of species from combined sequence and phylogenetic data. Using the fact that the probability of a substitution to an amino acid depends on its fitness, our method looks for amino acids such that substitutions to them occur more frequently in one group of lineages than in another. We validate our method using simulated evolution of a protein site under different scenarios and show that it has high specificity for a wide range of assumptions regarding the underlying changes in selection, while its sensitivity differs between scenarios. We apply our method to the env gene of two HIV-1 subtypes, A and B, and to the HA gene of two influenza A subtypes, H1 and H3, and show that the inferred fitness changes are consistent with the fitness differences observed in deep mutational scanning experiments. We find that changes in relative fitness of different amino acid variants within a site do not always trigger episodes of positive selection and therefore may not result in an overall increase in the frequency of substitutions, but can still be detected from changes in relative frequencies of different substitutions.

中文翻译：

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用单位分辨率进行氨基酸倾向变化的系统发育推断

同一等位基因赋予的适应性在基因型之间可能有所不同，这些差异决定了变异和进化。从进化的过程中，已经从统计学上推断出序列中蛋白质位点的氨基酸倾向的变化，但是现有的方法是数据密集型的并且聚集了多个位点。在这里，我们开发了一种从组合序列和系统发育数据中检测赋予不同物种不同适应性的单个氨基酸的方法。利用替换为氨基酸的可能性取决于其适合性这一事实，我们的方法寻找氨基酸，使得在一组谱系中发生替换的可能性比在另一组谱系中发生的频繁。我们使用模拟的蛋白质位点在不同情况下的进化来验证我们的方法，并表明该方法对选择中潜在变化的各种假设具有高度特异性，而其敏感性在不同情况下有所不同。我们将我们的方法应用于两个HIV-1亚型A和B的env基因，以及两个流感A亚型H1和H3的HA基因，并表明推断的适应性变化与在深处观察到的适应性差异一致突变扫描实验。我们发现，一个位点内不同氨基酸变体的相对适应性变化并不总是会触发阳性选择事件，因此可能不会导致替换频率的整体增加，但仍可以从不同氨基酸相对频率的变化中检测到换人。