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

描述(申请人提供)：大多数居住在海拔4000米以上的人会患上红细胞增多症，这通常被认为是一种适应，以增强氧气的运输，从而促进肌肉表现。因此，令人惊讶的是，许多健康的西藏高原原住民并不患有红细胞增多症。我们最近的工作表明，红细胞增多症的消失与几个基因的适应导致的正选择有关，特别是那些与低氧有关的基因。我们的初步生理学研究表明，运动能力的增强与心输出量的增加和肌肉中氧气的扩散运输有关，尽管确切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误导反应，西藏高原原住民除了呼吸反应的潜在变化外，还有与心脏和肌肉结构/功能相关的进化变化，这些变化使他们能够在高原低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测试这些假设，确定：1)我们之前在运动能力和O2运输途径电导之间的关联是否与藏族女性和汉族男女的[Hb]相关，以及适应性单倍型是否与这些生理数据相关；2)心脏的结构/功能变化是否 我们在目标1中的生理发现以及静息低氧和高二氧化碳呼吸反应是否与藏族男性和女性的[Hb]相关；以及3)精确的遗传变异是否与上述生理测量和/或[Hb]相关，并破译随着进化时间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.