Genetic adaptations to high altitude

描述（由申请人提供）：缺氧是人体生理上的主要压力，它引发了一种适应反应，包括血红蛋白（Hb）浓度的增加，这反过来补偿了血红蛋白（O2 sat）氧饱和度的降低。矛盾的是，西藏高原人表现出明显的低氧饱和度，但相对较少的Hb水平增加导致动脉氧含量急剧减少。最近的研究已经确定了与较低Hb水平相关的有利等位基因，这表明西藏的自然选择倾向于抵消适应反应的变异。因此，尽管取得了这些进展，西藏人的生理机能如何应对如此低的动脉氧含量仍然是完全未知的。在初步研究中，我们已经表明，西藏基因库是具有不同程度低氧适应的祖先群体混合的结果，并且选择在混合后增加了低氧适应等位基因的频率。这种设置允许一套强大的方法，从适应人群中寻找具有多余祖先的基因组区域。我们将把这些和其他标准测绘方法应用于在尼泊尔收集的1000个藏族妇女的DNA样本。重要的是，大量的数据可用于缺氧反应特征和生殖变量。反过来，通过这些分析鉴定的等位基因将被详细研究，以了解进化过程的重要参数。为此，我们提出以下具体目标：目标1。我们将对1016名藏族妇女和100份新采集的夏尔巴人样本进行约90万个snp /CNVs基因型分析。目标2。我们将通过测试这些缺氧反应表型与生殖成功之间的相关性来验证Hb水平和O2 sat的变化是适应性的这一长期建议。此外，我们将使用Aim 1中收集的相同基因型数据，通过关联和混合作图来绘制Hb水平和O2 sat。目标3。我们将使用Aim 1中收集的相同基因型数据来绘制导致生殖适合度变化的变异。我们还将使用生殖数据为目标1和目标2中发现的变异提供直接估计选择系数。目标4。然后，我们将测试自然选择的特征，并使用推断的人口统计学模型来估计不同兴趣变量集的选择系数。通过这项工作，我们期望对缺氧反应的生物学和遗传学有新的认识。此外，生殖数据将使我们能够以前所未有的分辨率阐明适应过程，从而使西藏对缺氧的适应成为一个新的彻底理解的自然选择案例。

DESCRIPTION (provided by applicant): Hypoxia is a major stress on human physiology, which elicits an acclimatization response consisting in an increase in hemoglobin (Hb) concentration, which in turn compensates for the decrease in oxygen saturation of Hb (O2 sat). Paradoxically, Tibetan highlanders present markedly low O2 sat, but relatively little increase in Hb levels resulting in a dramatic reduction of arterial oxygen content. Recent studies have identified advantageous alleles that are consistently associated with lower Hb levels, suggesting that natural selection in Tibet favored variants that counteract the acclimatization response. Therefore, despite these advances, how Tibetan physiology copes with such low arterial oxygen content remains entirely unknown. In preliminary studies, we have shown that the Tibetan gene pool results from the admixture of ancestral populations with different degrees of adaptation to hypoxia and that selection acted since admixture to increase the frequency of hypoxia-adapted alleles. This setting allows a set of powerful approaches that look for genomic regions with excess ancestry from the adapted population. We will apply these and other standard mapping approaches to a new collection of >1,000 DNA samples from Tibetan women collected in Nepal. Importantly, extensive data are available for hypoxia-response traits and reproductive variables. In turn, the alleles identified through these analyses will be investigated in detail to learn abou important parameters of the evolutionary process. To this end, we propose the following specific aims: Aim 1. We will genotype ~900,000 SNPs/CNVs in 1,016 Tibetan women and 100 newly collected Sherpa samples. We will infer local ancestry in the Tibetans to identify regions with excess hypoxia-adapted ancestry. Aim 2. We will test the long-standing proposal that variation in Hb levels and O2 sat is adaptive by testing the correlation between these hypoxia-response phenotypes and reproductive success. In addition, we will use the same genotype data collected in Aim 1 to map Hb levels and O2 sat by association and admixture mapping. Aim 3. We will use the same genotype data collected in Aim 1 to map variants contributing to variation in reproductive fitness. We will also use the reproductive data to provide direct estimates selection coefficients for the variants discovered in Aims 1 and 2. Aim 4. We will sequence the genome of 6 Sherpa and 6 Dai and will use these data to model the demographic history of Tibetans and of the ancestral populations contributing to their gene pool. We will then test for signatures of natural selection and use the inferred demographic model to estimate selection coefficients for different sets of variants of interest. Through the proposed work, we expect to gain new insights into the biology and genetics of hypoxia response. In addition, the reproductive data will allow us to elucidate the adaptation process with unprecedented resolution, thus making Tibetan adaptations to hypoxia a new thoroughly understood case of natural selection.