Integrating Physiology and Genomics to Reveal Functional Adaptation in High-Altitude Tibetans

描述（由申请人提供）：生活在海拔4000米以上的大多数人都会出现红细胞增多症，这通常被认为是一种增强O2运输的适应性疾病，因此也是肌肉性能的适应性疾病。因此，令人惊讶的是，许多健康的西藏高海拔地区的当地人没有红细胞增多症。我们最近的研究表明，红细胞增多症的丧失与几个基因的适应性正选择有关，特别是那些与缺氧有关的基因。我们的初步生理学研究表明，增强的运动能力与增加的心输出量和肌肉中氧气的扩散运输有关，尽管精确的遗传基础和选择性事件的顺序尚不清楚。我们假设红细胞增多症是对海拔高度的一种误导性反应，并且西藏高原人除了在高海拔缺氧的生理挑战下成功存在的潜在的澄清反应改变之外，还具有与心脏和肌肉结构/功能相关的进化变化。我们将在生理学和基因组学的背景下测试这些假设，通过确定：1）我们先前在运动能力和O2转运通路电导之间的关联是否与藏族女性和汉族男性的[Hb]相关，以及适应性单倍型是否与这些生理数据相关; 2）心脏结构/功能改变是否与心脏的结构/功能改变相关。 和肌肉与我们在目标1中的生理学发现有关，以及藏族男性和女性的静息低氧和高碳酸血症性反应是否与[Hb]相关; 3）精确的遗传变异是否与上述生理学测量和/或[Hb]相关，并破译在进化时间内发生的选择性事件的顺序。

DESCRIPTION (provided by applicant): Most humans living at altitudes above 4000m develop polycythemia, classically thought of as an adaptation to enhance O2 transport and hence muscular performance. It is thus surprising to find that many healthy Tibetan high altitude natives are not polycythemic. Our recent work has shown that loss of polycythemia is associated with positive selection resulting from adaption in several genes, especially those related to hypoxia. Our preliminary physiological studies have shown that enhanced exercise capacity is associated with increased cardiac output and diffusive transport of oxygen in muscle, although the precise genetic underpinnings and the order of selective events are unknown. We hypothesize that polycythemia is a misguided response to altitude and that native Tibetan highlanders have evolutionary changes related to cardiac and muscle structure/function, in addition to potential alterations in ventilatory responses that have enabled their successful existence despite physiological challenges of high-altitude hypoxia. We will test these hypotheses in both a physiological and genomics context by determining: 1) if our previous associations between exercise capacity and O2 transport pathway conductances are associated with [Hb] in Tibetan females and Han Chinese of both sexes and whether adaptive haplotypes are correlated with these physiological data; 2) whether structural/functional alterations in heart and muscle are related to our physiological findings in Aim 1 and whether resting hypoxic and hypercapnic ventilatory responses are associated with [Hb] in Tibetan men and women; and 3) if precise genetic variants relate to the above physiological measurements and/or [Hb] and decipher the order of selective events that have occurred over evolutionary time.