Genetic adaptations to high altitude

描述（由申请人提供）：缺氧是人体生理上的主要应激，其引起包括血红蛋白（Hb）浓度增加的适应反应，血红蛋白浓度增加反过来补偿Hb氧饱和度（O2 sat）的降低。奇怪的是，藏族高原人目前显着低O2饱和度，但相对较小的增加血红蛋白水平导致动脉血氧含量急剧下降。最近的研究已经确定了与较低的Hb水平相关的有利等位基因，这表明西藏的自然选择有利于抵消适应反应的变异。因此，尽管有这些进步，西藏人的生理学如何应对如此低的动脉血氧含量仍然是完全未知的。在初步研究中，我们已经表明，藏族基因库的结果从混合的祖先群体具有不同程度的适应缺氧和选择的作用，因为混合，以增加频率的缺氧适应等位基因。这种设置允许一组强大的方法，从适应人群中寻找具有过量祖先的基因组区域。我们将把这些和其他标准的作图方法应用于一个新的收集了超过1,000个来自尼泊尔藏族妇女的DNA样本的集合。重要的是，广泛的数据可用于缺氧反应性状和生殖变量。反过来，通过这些分析确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。我们将在1,016名藏族妇女和100名新收集的夏尔巴人样本中对约90万个SNP/CNV进行基因分型。我们将推断西藏人的地方祖先，以确定具有过度缺氧适应祖先的地区。目标二。我们将测试长期以来的建议，血红蛋白水平和O2饱和度的变化是适应性的测试这些缺氧反应表型和繁殖成功之间的相关性。此外，我们将使用目标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。我们将使用目标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2中发现的变异体提供直接估计选择系数。目标4。我们将对6名夏尔巴人和6名傣族人的基因组进行测序，并将利用这些数据来模拟藏人的人口统计学历史，以及对他们的基因库做出贡献的祖先人口的历史。然后，我们将测试自然选择的签名，并使用推断的人口模型来估计不同的感兴趣的变体集的选择系数。通过这项工作，我们希望获得新的见解缺氧反应的生物学和遗传学。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，从而使西藏人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.