近日，中国科学院北京基因组研究所曾长青研究组，通过与英国、爱尔兰和美国的研究人员研究合作，发现了藏族人群能够适应高海拔地区低氧环境，并且免于罹患高原疾病的一个重要遗传机制——EPAS1基因的多态性。其相关研究成果已于6月7日在美国《国家科学院院刊》（PNAS）网络版发表。
该项目的策划人之一，文章的通讯作者——中国科学院北京基因组研究所曾长青研究员（代表中国参加国际HapMap计划的主要负责人）表示，HapMap绘制的人群多态性图谱是目前研究人类遗传多态性的最主要数据，占其样品总量六分之一的汉族样品数据是研究中华民族遗传多态性的基础。此次新发现的藏族人群特有的EPAS1基因多态，不但是不同人群高原适应机制遗传研究领域的重要进展，同时也为科研人员进一步研发低海拔人群对于高原低氧敏感性的检测手段提供了基础。
众所周知，青藏高原等高海拔地区被称为“生命的禁区”，其空气中氧气的平均含量约为海平面的60%。所以当生活在低海拔地区的人来到高原地区时，由于空气中氧气含量的不足，通常会引起一系列不良高原反应症状，如果经过一段时期习服，多数人血液中的血红蛋白浓度显著升高。这种高血红蛋白现象还见于生活在南美安第斯山区的人群。然而，青藏高原世居人群的血红蛋白浓度却明显低于生活在同样高度的安第斯人群，而与低海拔人群的血红蛋白水平接近，这表明藏族人群对于高海拔的适应机制与祖先同样来自亚洲的安第斯人群有所不同。正是这一特殊的遗传现象，吸引了众多研究团队的研究和关注。
为了揭示导致藏族人低血红蛋白浓度的遗传变异，科学家们在海拔3200米以上的三个不同地区共收集了200多份藏族世居样品，通过对他们的基因组数据进行分析，并与人类基因组国际单体型图（HapMap）计划中居住在低海拔地区的汉族人群基因组数据进行比较，发现位于2号染色体上“EPAS1基因”的选择信号最为强烈，特别是该基因的多态性与藏族人群的低血红蛋白浓度密切相关。
目前，科学家们还在对EPAS1基因的多态性进行深入研究，但该成果已经引起国内外众多媒体的多方关注，相关研究论文已经被Popular Mechanics和Ann Gibbons of Science等杂志进一步跟踪报道。
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PNAS发表论文摘要（英文）
Published online before print June 7, 2010, doi: 10.1073/pnas.1002443107
Natural selection on EPAS1 (HIF2α) associated with low hemoglobin concentration in Tibetan highlanders
Cynthia M. Bealla,1, Gianpiero L. Cavallerib,1, Libin Dengc,2, Robert C. Elstond, Yang Gaoc, Jo Knighte,f, Chaohua Lic, Jiang Chuan Lig, Yu Liangh, Mark McCormackb, Hugh E. Montgomeryi,1, Hao Panc, Peter A. Robbinsj,1,3, Kevin V. Shiannak, Siu Cheung Taml, Ngodrop Tseringm, Krishna R. Veeramahn, Wei Wangh, Puchung Wangduim, Michael E. Wealee,1, Yaomin Xuo, Zhe Xuc, Ling Yangh, M. Justin Zamanp, Changqing Zengc,1,3, Li Zhango,1, Xianglong Zhangc, Pingcuo Zhaxih,1,4, and Yong Tang Zhengq
Abstract
By impairing both function and survival, the severe reduction in oxygen availability associated with high-altitude environments is likely to act as an agent of natural selection. We used genomic and candidate gene approaches to search for evidence of such genetic selection. First, a genome-wide allelic differentiation scan (GWADS) comparing indigenous highlanders of the Tibetan Plateau (3,200–3,500 m) with closely related lowland Han revealed a genome-wide significant divergence across eight SNPs located near EPAS1. This gene encodes the transcription factor HIF2α, which stimulates production of red blood cells and thus increases the concentration of hemoglobin in blood. Second, in a separate cohort of Tibetans residing at 4,200 m, we identified 31 EPAS1 SNPs in high linkage disequilibrium that correlated significantly with hemoglobin concentration. The sex-adjusted hemoglobin concentration was, on average, 0.8 g/dL lower in the major allele homozygotes compared with the heterozygotes. These findings were replicated in a third cohort of Tibetans residing at 4,300 m. The alleles associating with lower hemoglobin concentrations were correlated with the signal from the GWADS study and were observed at greatly elevated frequencies in the Tibetan cohorts compared with the Han. High hemoglobin concentrations are a cardinal feature of chronic mountain sickness offering one plausible mechanism for selection. Alternatively, as EPAS1 is pleiotropic in its effects, selection may have operated on some other aspect of the phenotype. Whichever of these explanations is correct, the evidence for genetic selection at the EPAS1 locus from the GWADS study is supported by the replicated studies associating function with the allelic variants.
