隨著海拔的升高,，很多環(huán)境因素將隨之發(fā)生改變,，從而形成了一系列海拔高度特異的生存環(huán)境,。在這些生存環(huán)境中，環(huán)境氧分壓的適應(yīng)是非常重要的自然選擇壓力,。因此,，低氧適應(yīng)是當(dāng)前生物進化研究領(lǐng)域的熱點之一。近期的全基因組掃描發(fā)現(xiàn)缺氧誘導(dǎo)因子通路上的EGLN1基因多態(tài)性與高原世居藏族和安第斯山脈人群的低氧適應(yīng)密切相關(guān),。
但這是極端低氧環(huán)境中人群的適應(yīng)情況,，中低海拔中常氧及輕度缺氧人群對環(huán)境氧分壓變化是否存在適應(yīng)性進化并不清楚，不同海拔人群對環(huán)境氧分壓適應(yīng)機制的異同更屬未知,。在中等海拔,，人體面對環(huán)境氧分壓的改變，外周頸動脈化學(xué)感受器的活動顯著增加,；此外也可以觀察到明顯的低壓低氧性認(rèn)知功能損傷,；新生兒體重也隨著海拔的升高而呈現(xiàn)遞減趨勢,。因此,，對占總?cè)丝?5%以上的中低海拔人群進行研究將有助于系統(tǒng)認(rèn)識氧分壓適應(yīng)機制。
在中科院昆明動物研究所張亞平院士和香港中文大學(xué)化學(xué)病理系鄧亮生教授的共同指導(dǎo)下,，季林丹,、徐進博士等研究人員對CEPH-HGDP歐亞人群進行了海拔全基因組關(guān)聯(lián)研究，篩選常氧和輕度低氧環(huán)境的分子適應(yīng)信號,。進而,，結(jié)合已報道的上述兩個高原世居人群的全基因組研究結(jié)果，尋找不同環(huán)境氧分壓的趨同和趨異信號,，并從整體上分析不同海拔居民環(huán)境氧分壓適應(yīng)機制的異同,。此外，適應(yīng)信號還在漢-藏人群中進行了驗證,。
研究結(jié)果表明缺氧誘導(dǎo)因子通路在不同海拔居民的環(huán)境氧分壓適應(yīng)中均起著重要作用,，而不同環(huán)境氧分壓的適應(yīng)涉及的具體分子機制存在差異：中低海拔常氧和輕度低氧人群以缺氧誘導(dǎo)因子的抑制可能具有選擇優(yōu)勢，而高海拔低氧人群中缺氧誘導(dǎo)因子的激活則更具選擇優(yōu)勢,。上述研究結(jié)果系統(tǒng)地闡釋了人類群體氧分壓適應(yīng)的分子機制,，并為高原病的臨床診療、運動醫(yī)學(xué)以及極端低氧環(huán)境職業(yè)暴露的防治等提供線索,。該工作近期在Molecular Biology and Evolution 雜志在線發(fā)表,。（生物谷Bioon.com）
doi:10.1093/molbev/mss144
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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.
