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）：大多数居住在4000m高度的人类都会发展出多余的高血压，从经典地认为是改善O2运输的适应性，因此是肌肉表现。因此，令人惊讶的是，发现许多健康的藏族高海拔本地人不是多余的。我们最近的工作表明，多性疾病的丧失与几种基因的适应性，尤其是与缺氧相关的基因的阳性选择有关。我们的初步生理学研究表明，增强的运动能力与肌肉中氧气的心脏输出和扩散转运有关，尽管精确的遗传基础和选择性事件的顺序尚不清楚。我们假设多细性心血症是对海拔高度的一种错误的反应，除了潜在的通气反应变化，尽管有生理挑战，但除了潜在的通气反应变化外，藏族高地人还具有与心脏和肌肉结构/功能相关的进化变化。我们将通过确定：1）在生理和基因组学环境中测试这些假设：1）如果我们先前的运动能力和O2传输途径电导之间的关联与性别的藏族女性和中国人的[HB]相关，以及自适应单倍型是否与这些物理数据相关； 2）心脏的结构/功能改变是否肌肉与AIM 1中的生理发现有关，以及藏族男性和女性中静止的低氧和过度通气反应是否与[HB]有关； 3）如果精确的遗传变异与上述生理测量和/或[Hb]有关，并破译了在进化时间内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。