Natural selection and DNA sequence variation in Mus

描述（由申请人提供）：进化遗传学的一个主要目标是了解选择如何形成DNA序列变异的模式，并最终将DNA序列变异与影响适应性的表型联系起来。解决这个问题的一个很有希望的方法是研究最近将其活动范围扩展到新环境的物种，寻找等位基因频率和环境变量的相关变化。这种研究环境适应的方法已经成功地应用于黑腹果蝇（Drosophila melanogaster）中，在广泛的纬度横断面上，可以看到各种不同的分子和表型性状的临床变异。最近对人类的研究也将常见代谢紊乱候选基因中等位基因频率的变化与气候变量联系起来，这表明这种方法也可能使我们能够识别重要的疾病基因。家鼠，小家鼠，为人类研究环境适应提供了一个独特的机会，是最好的哺乳动物模型。这项拟议中的研究将从北美和南美不同纬度和海拔的26个种群的260只野生老鼠中取样。采样设计包括海拔和纬度的成对样条。所有小鼠将使用一种新的Affymetrix SNP芯片进行基因分型，以确定基因组中包含适应不同环境和气候的基因的候选区域。选择的基因组区域将被重新测序，以确定等位变异。小鼠为人类无法进行的功能测试提供了特殊的机会。因此，这项工作还将从极端环境中建立16种新的近交系小鼠，对它们的基因组进行测序，并对它们的表型进行初步描述。这些资源将为未来将特定适应性变异与特定表型联系起来的工作奠定基础，其中许多可能与人类代谢紊乱有关。

DESCRIPTION (provided by applicant): A major goal of evolutionary genetics is to understand how selection shapes patterns of DNA sequence variation, and ultimately, to connect DNA sequence variants to phenotypes that affect fitness. One promising approach to this problem is to study species that have recently expanded their ranges into new environments, to look for correlated changes in allele frequencies and environmental variables. This approach to studying environmental adaptation has been used successfully in Drosophila melanogaster where clinal variation is seen for a variety of different molecular and phenotypic traits across broad latitudinal transects. Recent work on humans has also linked changes in allele frequency to climatic variables in candidate genes for common metabolic disorders, suggesting that this approach may also allow us to identify important disease genes. The house mouse, Mus musculus, provides a unique opportunity to study environmental adaptation in the best mammalian model for humans. The proposed research will sample 260 wild mice representing 26 populations across a range of latitudes and altitudes in both North and South America. The sampling design includes paired transects for both altitude and latitude. All mice will be genotyped using a new Affymetrix SNP chip to identify candidate regions of the genome harboring genes underlying adaptation to different environments and climates. Select genomic regions will then be resequenced to identify allelic variants. Mice offer specific opportunities for functional tests not available in humans. Thus, the proposed work will also establish 16 new inbred strains of mice from extreme environments, sequence their genomes, and provide a preliminary description of their phenotypes. These resources will set the stage for future work linking particular adaptive variants to specific phenotypes, many of which are likely to be relevant for human metabolic disorders. PUBLIC HEALTH RELEVANCE: Genes underlying human metabolic disorders show variation that correlates with climate, suggesting a link between environmental adaptation and disease. Mice are the premier model for humans. Here, we will study environmental adaptation in mice, identify candidate genes, and establish resources for future functional tests of the effects of variants at these genes.