Genetic adaptations to high altitude

对高海拔的遗传适应

• 批准号: 8823695
• 负责人: Anna Di Rienzo
• 金额: $ 51.93万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8823695
• 关键词: Acclimatization; Admixture; Alleles; Altitude; Asians; Biological; Biology; Collection; Complement; DNA; Data; Data Set; Evolution; Frequencies; Gene Frequency; Gene Pool; Genes; Genetic; Genome; Genomic Segment; Genotype; Haplotypes; Health; Hemoglobin; Hemoglobin concentration result; Human; Hypoxia; Learning; Life; Light; Linear Models; Long-Term Effects; Maps; Modeling; Natural Selections; Nepal; Oxygen; Pathway interactions; Phenotype; Physiological; Physiology; Population; Population Genetics; Process; Recording of previous events; Reproductive History; Research Design; Resolution; Sampling; Shapes; Signal Transduction; Site; Specific qualifier value; Stress; System; Testing; Tibet; Variant; Woman; Work; base; bead chip; coping; fitness; genome sequencing; genome-wide; human disease; insight; interest; novel; reproductive; reproductive success; response; trait

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.

描述（由申请人提供）：缺氧是对人类生理学的重大压力，它引起了适应反应，包括升高血红蛋白（HB）浓度，这又补偿了HB（O2 SAT）的氧饱和度的降低。矛盾的是，藏族高地人的SAT显着较低，但HB水平的增加相对较小，导致动脉氧含量的大幅降低。最近的研究已经确定了与HB水平持续相关的有利等位基因，这表明在西藏有利于抵消适应反应的变体。因此，尽管有这些进步，但如何应对如此低的动脉氧含量来应对藏族生理学仍然是完全未知的。在初步研究中，我们表明，藏基因库是由于对缺氧的适应程度不同的祖先种群的混合而产生的，并且选择以来就起作用以增加掺入低氧型等位基因的频率。这种设置允许一组强大的方法来寻找来自适应人群的过多血统的基因组区域。我们将将这些和其他标准映射方法应用于尼泊尔收集的藏族妇女的新收集的新收藏。重要的是，可用于低氧反应性状和生殖变量的广泛数据。反过来，通过这些分析确定的等位基因将进行详细研究，以了解进化过程的重要参数。为此，我们提出了以下特定目的：目标1。我们将在1,016名藏族妇女和100个新收集的夏尔巴省样本中基因型约900,000个SNP/CNV。我们将推断藏族中的地方血统，以识别具有过量缺氧的祖先的地区。 AIM 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测试长期的建议，即HB水平和O2 SAT的变化具有适应性。此外，我们将使用AIM 1中收集的相同基因型数据来映射HB水平，并根据关联和混合图映射进行O2 SAT。 AIM 3。我们将使用AIM 1中收集的相同基因型数据来绘制有助于生殖适应性变化的变体。我们还将使用生殖数据为AIMS 1和2中发现的变体提供直接估计选择系数。AIM 4。我们将对6个夏尔巴省和6个DAI的基因组进行测序，并将使用这些数据来模拟藏族人的人口统计学历史，以及为其基因池造成基因池的祖先种群的人口统计学历史。然后，我们将测试自然选择的签名，并使用推断的人口统计学模型来估算不同感兴趣的变体集合的选择系数。通过拟议的工作，我们希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，从而使藏族对缺氧的适应性成为一种新的自然选择的新案例。