Demographic History and Genomic Targets of Positive Selection in Giant Gough Mice

A key challenge in understanding how natural selection operates is to identify the mutations and genes that make it possible. Positive selection on beneficial mutations distorts linked variation by altering the site frequency spectrum, the configuration of haplotypes, and population differentiation. By comparing patterns of sequence variation to neutral predictions across genomes, the targets of positive selection can be located. We applied this logic to an unusual population of house mice that shows phenotypic and ecological hallmarks of selection. Mice from Gough Island are twice the body size of mainland mice, eat live seabirds, maintain a very high population density, and inhabit an environment without predators or humans. We used massively parallel short-read sequencing to survey the genomes of 14 Gough Island mice. We computed a set of summary statistics to capture diverse aspects of variation across these genome sequences, used approximate Bayesian computation to reconstruct a null demographic model, and then applied machine learning to estimate the posterior probability of positive selection in each region of the genome. We conducted parallel analyses on genome sequences from 8 mice from Germany, treating them as representatives of a mainland reference population. A few thousand 5kb windows show strong evidence for positive selection in Gough Island mice but not in German mice. Genic regions and the X chromosome contain disproportionate shares of these selection windows. Over-represented gene ontologies in selection windows emphasize neurological themes. Inspection of genomic regions harboring many selection windows with high posterior probabilities pointed to genes with known effects on exploratory behavior and body size as potential targets. Some genes in these regions have missense mutations and/or putative regulatory mutations with large differences between Gough Island mice and German/French mice in the frequency of the derived allele; these are candidates for adaptive variants. Our results provide a genomic portrait of adaptation to island conditions and position Gough Island mice as a powerful system for understanding the genetic component of natural selection.

解析自然选择作用机制的核心难题，在于明确其实现所需的突变与基因。对有益突变的正向选择会通过改变位点频率谱（site frequency spectrum）、单倍型构型以及群体分化，对连锁变异造成扭曲。通过将全基因组范围内的序列变异模式与中性进化预测进行比对，即可定位正向选择的靶标区域。我们将这一研究逻辑应用于一个特殊的家鼠种群——该种群展现出与选择相关的表型与生态特征。戈夫岛（Gough Island）家鼠的体型是大陆家鼠的两倍，它们以活的海鸟为食，种群密度极高，且栖息在无捕食者与人类活动的环境中。我们采用大规模平行短读长测序（massively parallel short-read sequencing）技术，对14只戈夫岛家鼠的基因组进行了测序分析。我们计算了一系列汇总统计量，以捕捉这些基因组序列变异的多维度特征；同时借助近似贝叶斯计算（approximate Bayesian computation）构建了零人口统计学模型，随后应用机器学习方法估算基因组每个区域发生正向选择的后验概率。我们针对来自德国的8只家鼠的基因组序列开展了平行分析，将其作为大陆参考种群的代表。数千个5kb的基因组窗口在戈夫岛家鼠中呈现出显著的正向选择信号，而在德国家鼠中则无此特征。编码基因区域与X染色体中，这类受选择窗口的占比显著偏高。受选择窗口中富集的基因本体（gene ontology）术语主要集中于神经系统相关主题。对包含多个高后验概率受选择窗口的基因组区域进行检视后发现，若干已知对探索行为与体型具有调控作用的基因，可作为潜在的选择靶标。这些区域中的部分基因存在错义突变（missense mutation）和/或推定的调控突变，且戈夫岛家鼠与德/法家鼠之间的衍生等位基因频率存在显著差异；这类突变可作为适应性变异的候选对象。本研究结果为解析岛屿环境适应性进化提供了基因组层面的全貌，并将戈夫岛家鼠确立为研究自然选择遗传基础的理想实验体系。