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

整合生理学和基因组学揭示高海拔藏族人的功能适应

基本信息

批准号：
9346112
负责人：
Tatum S Simonson
金额：
$ 24.81万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-17 至 2018-08-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：大多数生活在海拔 4000m 以上的人都会出现红细胞增多症，传统上认为这是为了增强 O2 运输从而增强肌肉性能的一种适应。因此，令人惊讶的是，许多健康的西藏高海拔居民并不是多细胞增多症。我们最近的工作表明，红细胞增多症的消失与多个基因适应产生的正选择有关，特别是那些与缺氧相关的基因。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误导性反应，而本土西藏高地人除了通气反应的潜在改变之外，还具有与心脏和肌肉结构/功能相关的进化变化，这使得他们能够在面临高原缺氧的生理挑战的情况下成功生存。我们将在生理学和基因组学背景下测试这些假设，确定：1）我们之前的运动能力和 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相关有了这些生理数据； 2）心脏结构/功能是否改变和肌肉与我们在目标 1 中的生理学发现相关，以及藏族男性和女性静息低氧和高碳酸血症通气反应是否与 [Hb] 相关； 3) 精确的遗传变异是否与上述生理测量和/或 [Hb] 相关，并破译进化过程中发生的选择性事件的顺序。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reply: To PMID 25172885.

回复：PMID 25172885。

DOI：
10.1113/ep085032
发表时间：
2015
期刊：
Experimental physiology
影响因子：
2.7
作者：
Simonson,TatumS;Wei,Guan;Wagner,HarriethE;Wuren,Tana;Bui,Anh;Fine,JanelleM;Qin,Ga;Beltrami,FernandoG;Yan,Ma;Wagner,PeterD;Ge,Ri-Li
通讯作者：
Ge,Ri-Li

Genetic variants at the EGLN1 locus associated with high-altitude adaptation in Tibetans are absent or found at low frequency in highland Andeans.

DOI：
10.1111/ahg.12299
发表时间：
2019-05
期刊：
Annals of human genetics
影响因子：
1.9
作者：
Heinrich EC;Wu L;Lawrence ES;Cole AM;Anza-Ramirez C;Villafuerte FC;Simonson TS
通讯作者：
Simonson TS

Oxygen transport adaptations to exercise in native highland populations.

原生高地人群锻炼时的氧气运输适应。