Genetic Adaptation of the Hypoxia-Inducible Factor Pathway to Oxygen Pressure among Eurasian Human Populations
Genetic Adaptation of the Hypoxia-Inducible Factor Pathway to Oxygen Pressure among Eurasian Human Populations
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欧亚人群缺氧诱导因子途径对氧压的遗传适应
DOI：
10.1093/molbev/mss144
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发表时间：
2012-11-01
影响因子：
10.7
通讯作者：
Zhang, Ya-ping
中科院分区：
文献类型：
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作者：
Ji, Lin-dan;Qiu, Yu-qing;Zhang, Ya-ping
研究人类对高原低氧环境的适应机制是人类生理学和临床医学领域的重要课题。最近，来自缺氧诱导因子（HIF）途径的基因EGLN 1被鉴定为参与高原安第斯人和西藏人的缺氧适应。高原安第斯人和藏人都已适应了极端低氧的生境，而对生活在海平面常氧条件下和中等海拔轻度低氧环境下的人群关注较少，因此，是否存在一种共同的适应机制来响应大范围居住海拔的环境氧压力的定量变化尚不清楚。在这里，我们首先对来自人类基因组多样性-CEPH小组的35个居住在欧亚大陆海平面至中等海拔（N = 691; 0- 2，500 m）的人群进行了全基因组关联研究，以确定常氧和轻度低氧居民的遗传适应特征。此外，我们将本研究的结果与先前发表的六个安第斯高原人和西藏人的全基因组扫描进行了系统性比较，以识别响应氧气压力定量变化的共享适应信号。对于常氧和轻度缺氧人群，最强的适应性信号来自μ阿片受体编码基因（OPRM 1，2.54 x 10（-9）），该基因与呼吸刺激有关，而在系统调查中，所有研究均确定了EGLN 1-DISC 1基因座。对高原藏族（N = 733）和海平面汉族（N = 748）进行的重复研究证实了海拔与OPRM 1（仅藏族，P < 0.01）和EGLN 1-DISC 1（藏族和汉族，P < 0.01）的SNP等位基因频率之间的关联。总之，OPRM 1基因的鉴定表明心肺适应机制是重要的，应该是未来低氧适应研究的重点。此外，从HIF途径中鉴定出EGLN 1基因表明居住在不同海拔、不同氧压的欧亚人群有一种共同的适应机制。
Research into the mechanisms of human adaptation to the hypoxic environment of high altitude is of great interest to the fields of human physiology and clinical medicine. Recently, the gene EGLN1, from the hypoxia-inducible factor (HIF) pathway, was identified as being involved in the hypoxic adaptation of highland Andeans and Tibetans. Both highland Andeans and Tibetans have adapted to an extremely hypoxic habitat and less attention has been paid to populations living in normoxic conditions at sea level and mild-hypoxic environments of moderate altitude, thus, whether a common adaptive mechanism exists in response to quantitative variations of environmental oxygen pressure over a wide range of residing altitudes is unknown. Here, we first performed a genome-wide association study of 35 populations from the Human Genome Diversity-CEPH Panel who dwell at sea level to moderate altitude in Eurasia (N = 691; 0-2,500 m) to identify the genetic adaptation profile of normoxic and mild-hypoxic inhabitants. In addition, we systematically compared the results from the present study to six previously published genome-wide scans of highland Andeans and Tibetans to identify shared adaptive signals in response to quantitative variations of oxygen pressure. For normoxic and mild-hypoxic populations, the strongest adaptive signal came from the mu opioid receptor-encoding gene (OPRM1, 2.54 x 10(-9)), which has been implicated in the stimulation of respiration, while in the systematic survey the EGLN1-DISC1 locus was identified in all studies. A replication study performed with highland Tibetans (N = 733) and sea level Han Chinese (N = 748) confirmed the association between altitude and SNP allele frequencies in OPRM1 (in Tibetans only, P < 0.01) and in EGLN1-DISC1 (in Tibetans and Han Chinese, P < 0.01). Taken together, identification of the OPRM1 gene suggests that cardiopulmonary adaptation mechanisms are important and should be a focus in future studies of hypoxia adaptation. Furthermore, the identification of the EGLN1 gene from the HIF pathway suggests a common adaptive mechanism for Eurasian human populations residing at different altitudes with different oxygen pressures.