Reinventing dN/dS and the study of natural selection

对遗传变异的自然选择是适应和新物种形成的最终原因。所有 基因组水平上的自然选择研究需要一个对照组：一组变异或替换， 没有被选中。到目前为止，这类变体最广泛用于此目的 是蛋白质编码基因内的同义变化。因为这些变体中 非同义变体，它们是自然对照组。然而，大量证据表明， 变化往往不是严格中性的，这是过去三十年来积累的。在许多情况下， 选择的证据为研究者提供了确定哪些同义变化最有可能 受选择的影响，更有可能是严格中立的。缺少的是将此包括在内的方法 信息，分类同义变化（中性和选择），在定量进化模型 这使得我们能够对选择在何处、何时以及如何起作用进行广泛的推断。拟议 研究是基于一类新的进化模型（多个同义词替代或MSS模型） 包括选择性和中性的同义变化的进化变化的估计。这些模型 可以与同源序列比对拟合，以推断氨基酸置换变化的相对速率， 选择同义变化，严格中性同义变化。这些类型的（dN/dS）分析如下： 追溯到进化遗传学的起源，今天它们仍然是最常用的工具之一。我们 一个假设是，目前关于什么构成中性进化地点的定义是错误的， 它使选择力的估计产生偏差（通过低估中性变化的速率）， 没有这种偏见的估计将提供更好和更准确的了解的行动， 自然选择在进化背景下的广泛应用。我们将开发和测试一种新的替代品 模型，使用多套同义替换（MSS模型），我们将把它们应用到一个不同的 一组从生命王国中取样的分类群。估计MSS模型，使用遗传算法发现 搜索所有可能的MSS模型的空间，将使用内部控制进行验证，基于 中性模型预测替代率速度和恒定性，并使用外部控制，基于 预测群体基因组和功能效应的协变量。我们将修改一系列广泛使用的 比较和群体遗传学技术，以利用MSS模型，并开发新的 方法，寻求确定同义变化的选择。我们的模型将广泛应用于 基因组数据分类范围，并作为流行软件包HyPhy和网络的一部分提供 应用程序Datamonkey。

Natural selection on genetic variation is the ultimate cause of adaptation and the formation of new species. All studies of natural selection at the genomic level require a control group: a set of variants or substitutions that have not been subject to selection. The class of variants that, by far, are the most widely used for this purpose are synonymous changes within protein coding genes. Because these variants are interspersed with nonsynonymous variants, they are a natural control group. However, overwhelming evidence that synonymous changes are often not strictly neutral has accumulated over the past three decades. In many contexts the clear evidence for selection provides investigators with ways to identify which synonymous changes are most likely to be affected by selection and which are more likely to be strictly neutral. What is missing are ways to include this information, on classified synonymous changes (neutral and selected), within quantitative evolutionary models that enable a broad range of inferences about where, when, and on what selection operates. The proposed research is based on a new class of evolutionary models (Multiple Synonymous Substitution or MSS models) that include both selected and neutral synonymous changes in estimates of evolutionary change. These models can be fitted to homologous sequence alignments to infer relative rates of amino-acid replacement changes, and selected synonymous changes, to strictly neutral synonymous changes. These types of (dN/dS) analyses go back to the origins of evolutionary genetics, and today they remain among the most commonly used tools. Our hypothesis is that the current definition of what constitutes neutrally evolving sites is importantly wrong in that it biases the estimation of selective forces (by underestimating the rates of neutral changes), and that improved estimates without that bias will provide significantly better and more accurate understanding of the action of natural selection in a broad array of evolutionary contexts. We will develop and test a new class of substitution model that uses multiple sets of synonymous substitutions (MSS models), and we will apply them to a diverse set of taxa sampled from across life's kingdoms. Estimated MSS models, discovered using a genetic algorithm that searches over the space of all possible MSS models, will be validated using internal controls, based on neutral model predictions of substitution rate speed and constancy, and using external controls, based on predicted covariates of population genomic and functional effects. We will revise an array of widely-used comparative and population genetics techniques to take advantage of MSS models, and develop new approaches that seek to identify selection on synonymous changes. Our models will be applied to a wide taxonomic range of genomic data and made available as a part of popular software package HyPhy and web application Datamonkey.