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Mol Biol Evol:张亚平等揭示缺氧诱导因子通路的重要作用

  1. Mol Biol Evol
  2. 张亚平
  3. 揭示
  4. 缺氧诱导因子
  5. 通路
  6. 重要作用

来源:昆明动物所 2012-11-18 09:19

随着海拔的升高,很多环境因素将随之发生改变,从而形成了一系列海拔高度特异的生存环境。在这些生存环境中,环境氧分压的适应是非常重要的自然选择压力。因此,低氧适应是当前生物进化研究领域的热点之一。近期的全基因组扫描发现缺氧诱导因子通路上的EGLN1基因多态性与高原世居藏族和安第斯山脉人群的低氧适应密切相关。

随着海拔的升高,很多环境因素将随之发生改变,从而形成了一系列海拔高度特异的生存环境。在这些生存环境中,环境氧分压的适应是非常重要的自然选择压力。因此,低氧适应是当前生物进化研究领域的热点之一。近期的全基因组扫描发现缺氧诱导因子通路上的EGLN1基因多态性与高原世居藏族和安第斯山脉人群的低氧适应密切相关。

但这是极端低氧环境中人群的适应情况,中低海拔中常氧及轻度缺氧人群对环境氧分压变化是否存在适应性进化并不清楚,不同海拔人群对环境氧分压适应机制的异同更属未知。在中等海拔,人体面对环境氧分压的改变,外周颈动脉化学感受器的活动显著增加;此外也可以观察到明显的低压低氧性认知功能损伤;新生儿体重也随着海拔的升高而呈现递减趋势。因此,对占总人口95%以上的中低海拔人群进行研究将有助于系统认识氧分压适应机制。

在中科院昆明动物研究所张亚平院士和香港中文大学化学病理系邓亮生教授的共同指导下,季林丹、徐进博士等研究人员对CEPH-HGDP欧亚人群进行了海拔全基因组关联研究,筛选常氧和轻度低氧环境的分子适应信号。进而,结合已报道的上述两个高原世居人群的全基因组研究结果,寻找不同环境氧分压的趋同和趋异信号,并从整体上分析不同海拔居民环境氧分压适应机制的异同。此外,适应信号还在汉-藏人群中进行了验证。

研究结果表明缺氧诱导因子通路在不同海拔居民的环境氧分压适应中均起着重要作用,而不同环境氧分压的适应涉及的具体分子机制存在差异:中低海拔常氧和轻度低氧人群以缺氧诱导因子的抑制可能具有选择优势,而高海拔低氧人群中缺氧诱导因子的激活则更具选择优势。上述研究结果系统地阐释了人类群体氧分压适应的分子机制,并为高原病的临床诊疗、运动医学以及极端低氧环境职业暴露的防治等提供线索。该工作近期在Molecular Biology and Evolution 杂志在线发表。(生物谷Bioon.com)

Genetic adaptation of the hypoxia-inducible factor pathway to oxygen pressure among Eurasian human populations

Lin-dan Ji1,2,3, Yu-Qing Qiu2,8, Jin Xu1,2,4, David M. Irwin1,5,6, Siu Cheung Tam7, Nelson L.S. Tang2,8,9,10,* and Ya-ping Zhang1,2,11,*

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 - 2,500m) 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, 2.54×10-9), 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.

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