A central objective in biology is to link adaptive evolution in a gene to structural and/or functional phenotypic novelties. Yet most analytic methods make inferences mainly from either phenotypic data or genetic data alone. A small number of models have been developed to infer correlations between the rate of molecular evolution and changes in a discrete or continuous life history trait. But such correlations are not necessarily evidence of adaptation. Here we present a novel approach called the phenotype-genotype branch-site model (PG-BSM) designed to detect evidence of adaptive codon evolution associated with discrete-state phenotype evolution. An episode of adaptation is inferred under standard codon substitution models when there is evidence of positive selection in the form of an elevation in the nonsynonymous-to-synonymous rate ratio ω to a value ω > 1. As it is becoming increasingly clear that ω > 1 can occur without adaptation, the PG-BSM was formulated to infer an instance of adaptive evolution without appealing to evidence of positive selection. The null model makes use of a covarion-like component to account for general heterotachy (i.e., random changes in the evolutionary rate at a site over time). The alternative model employs samples of the phenotypic evolutionary history to test for phenomenological patterns of heterotachy consistent with specific mechanisms of molecular adaptation. These include (i) a persistent increase/decrease in ω at a site following a change in phenotype (the pattern) consistent with an increase/decrease in the functional importance of the site (the mechanism); and (ii) a transient increase in ω at a site along a branch over which the phenotype changed (the pattern) consistent with a change in the site's optimal amino acid (the mechanism). Rejection of the null is followed by post hoc analyses to identify sites with strongest evidence for adaptation in association with changes in the phenotype as well as the most likely evolutionary history of the phenotype. Simulation studies based on a novel method for generating mechanistically realistic signatures of molecular adaptation show that the PG-BSM has good statistical properties. Analyses of three real alignments show that site patterns identified post hoc are consistent with the specific mechanisms of adaptation included in the alternate model. Further simulation studies show that the covarion-like component of the PG-BSM plays a crucial role in mitigating recently discovered statistical pathologies associated with confounding by accounting for heterotachy-by-any-means.

中文翻译：

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用于检测适应性进化的表型-基因型密码子模型

生物学的一个中心目标是将基因的适应性进化与结构和/或功能表型新奇联系起来。然而，大多数分析方法主要仅根据表型数据或遗传数据进行推断。已经开发了少量模型来推断分子进化速度与离散或连续生活史特征变化之间的相关性。但这种相关性不一定是适应的证据。在这里，我们提出了一种称为表型-基因型分支位点模型 (PG-BSM) 的新方法，旨在检测与离散状态表型进化相关的适应性密码子进化的证据。在标准密码子替换模型下，当有证据表明非同义与同义比率 ω 升高到值 ω > 1 时，可以推断出正选择的发生。随着越来越清楚的是 ω > 1 可以在没有适应的情况下发生，PG-BSM 的制定是为了推断适应性进化的实例，而无需求助于积极选择的证据。空模型使用类似协变的组件来解释一般的异性（即，一个位点的进化速率随时间的随机变化）。替代模型采用表型进化历史样本来测试与特定分子适应机制一致的异性现象模式。这些包括 (i) 在表型（模式）发生变化后，某个位点的 ω 持续增加/减少，与该位点功能重要性的增加/减少（机制）一致；(ii) 沿着分支的某个位点 ω 的瞬时增加，表型改变（模式）与该位点的最佳氨基酸（机制）的变化一致。拒绝无效之后是事后分析，以确定具有最强适应证据的位点，与表型的变化以及最可能的表型进化历史相关。基于用于生成分子适应的机械现实特征的新方法的模拟研究表明 PG-BSM 具有良好的统计特性。对三个真实对齐的分析表明，事后确定的站点模式与替代模型中包含的特定适应机制一致。进一步的模拟研究表明，PG-BSM 的 covariion-like 组件在减轻最近发现的与混杂相关的统计病理方面起着至关重要的作用，因为它可以解释任何方式的异质性。