Genetic adaptations to high altitude

描述(申请人提供)：低氧是人类生理的主要压力，它引起一种适应反应，包括增加血红蛋白(Hb)浓度，这反过来又补偿Hb(O2 Sat)氧饱和度的下降。矛盾的是，西藏高原人表现出明显的低O2 Sat，但Hb水平相对较小的增加导致动脉血氧含量的显著下降。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驯化反应的变异。因此，尽管取得了这些进展，西藏的生理学如何应对如此低的动脉含氧量仍然是完全未知的。在初步研究中，我们已经证明西藏基因库是由对低氧适应程度不同的祖先群体混合而成的，而且从混合开始的选择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，从适应的种群中寻找具有过剩祖先的基因组区域。我们将把这些方法和其他标准作图方法应用于新收集的1000份来自尼泊尔藏族妇女的DNA样本。重要的是，关于低氧反应特征和生殖变量的大量数据是可用的。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，我们提出了以下具体目标：目的1.对1016名藏族妇女和100名新采集的夏尔巴人样本进行SNPs/CNV基因分型。我们将推断藏族人的当地祖先，以确定具有过度低氧适应祖先的地区。目的2.我们将通过测试这些低氧反应表型与生殖成功之间的相关性来检验Hb水平和O2-Sat的变化是适应性的这一长期观点。此外，我们将使用目标1中收集的相同基因数据，通过关联和混合作图来绘制Hb水平和O2 Sat。目的3.我们将使用在目标1中收集的相同的基因数据来定位导致生殖适合度变异的变异。我们还将使用繁殖数据为AIMS 1和AIMS 2中发现的变异体提供直接估计选择系数。我们将对6个夏尔巴人和6个DAI人的基因组进行测序，并将使用这些数据来模拟藏族人和构成其基因库的祖先种群的人口学历史。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变种集的选择系数。通过这项拟议的工作，我们希望对缺氧反应的生物学和遗传学有新的见解。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，从而使西藏人对低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.