Integrating physiology and genomics to reveal functional adaptation in high-altit

描述（由申请人提供）：大多数生活在海拔4000米以上的人类会患上红细胞增多症，传统上认为这是一种适应，可以增强氧气运输，从而提高肌肉性能。因此，令人惊讶的是，许多健康的高海拔藏族居民并没有红细胞增多症。我们最近的工作表明，红细胞增多症的丧失与几个基因适应的积极选择有关，特别是那些与缺氧有关的基因。我们的初步生理研究表明，运动能力的增强与心输出量的增加和肌肉中氧气的弥漫性运输有关，尽管精确的遗传基础和选择事件的顺序尚不清楚。我们假设红细胞增多症是一种对海拔的错误反应，西藏高原原住民在心脏和肌肉结构/功能方面有进化变化，此外还有通气反应的潜在改变，这些变化使他们能够在高海拔缺氧的生理挑战下成功生存。我们将在生理学和基因组学的背景下检验这些假设，通过确定：1)我们之前在藏族女性和汉族男女中运动能力和氧运输途径传导之间的关联是否与[Hb]相关，以及适应性单倍型是否与这些生理数据相关；2)心脏是否发生结构/功能改变

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.