Genetic adaptations to high altitude

描述（由申请人提供）：缺氧是人类生理的主要压力，它会引起血红蛋白（Hb）浓度增加的适应反应，进而补偿血红蛋白（O2 sat）氧饱和度的降低。矛盾的是，西藏高原地区的 O2 sat 明显较低，但血红蛋白水平的增加相对较小，导致动脉氧含量急剧下降。最近的研究发现了与较低 Hb 水平一致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，尽管取得了这些进展，西藏生理学如何应对如此低的动脉氧含量仍然完全未知。在初步研究中，我们已经表明，藏族基因库是不同程度适应缺氧的祖先群体混合的结果，并且自混合以来选择就增加了适应缺氧的等位基因的频率。这种设置允许使用一组强大的方法来寻找适应群体中具有过多血统的基因组区域。我们将把这些和其他标准绘图方法应用于新收集的超过 1,000 个在尼泊尔收集的藏族妇女的 DNA 样本。重要的是，有大量关于缺氧反应特征和生殖变量的数据。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. 我们将对 1,016 名藏族妇女和 100 个新采集的夏尔巴样本中约 900,000 个 SNP/CNV 进行基因分型。我们将推断藏人的当地血统，以确定具有过度缺氧适应血统的地区。目标 2. 我们将通过测试这些缺氧反应表型与繁殖成功之间的相关性来检验长期以来提出的 Hb 水平和 O2 sat 的变化是否具有适应性的观点。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应性变化的变异。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，并将使用这些数据来模拟藏人和为其基因库做出贡献的祖先群体的人口历史。然后，我们将测试自然选择的特征，并使用推断的人口统计模型来估计不同感兴趣的变体组的选择系数。通过拟议的工作，我们期望获得对缺氧反应的生物学和遗传学的新见解。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.