Natural selection and DNA sequence variation in Mus

描述(申请人提供)：进化遗传学的一个主要目标是了解选择如何塑造DNA序列变异的模式，并最终将DNA序列变异与影响适应度的表型联系起来。解决这个问题的一个有希望的方法是研究最近将它们的范围扩大到新环境的物种，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在果蝇身上得到了成功的应用，果蝇在广阔的纬度横断面上可以看到各种不同的分子和表型特征的克隆性变异。最近对人类的研究还将等位基因频率的变化与常见代谢紊乱候选基因中的气候变量联系起来，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Mus Musculus为研究人类最好的哺乳动物模型的环境适应提供了一个独特的机会。这项拟议的研究将对来自北美和南美不同纬度和海拔范围的26个种群的260只野生老鼠进行采样。抽样设计包括海拔和纬度的成对横断面。所有小鼠都将使用一种新的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。然后将对选定的基因组区域进行重新测序，以识别等位基因变异。老鼠提供了人类所没有的特定的功能测试机会。因此，这项拟议的工作还将建立16个来自极端环境的新的近交系小鼠，对它们的基因组进行排序，并提供它们的表型的初步描述。这些资源将为未来将特定适应变种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.