Department of Anthropology, Case Western Reserve University, Cleveland, OH 44106-7125, USA.
Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11459-64. doi: 10.1073/pnas.1002443107. Epub 2010 Jun 7.
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 HIF2alpha, 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.
由于高海拔环境中氧气供应的严重减少会同时影响功能和生存，因此这种氧气供应的减少可能成为自然选择的一个因素。我们使用基因组和候选基因方法来寻找这种遗传选择的证据。首先，我们比较了青藏高原（3200-3500 米）的土著高原居民和近亲汉族的全基因组等位基因分化扫描（GWADS），发现了位于 EPAS1 附近的八个 SNPs 存在全基因组显著差异。该基因编码转录因子 HIF2alpha，它刺激红细胞的产生，从而增加血液中血红蛋白的浓度。其次，在另一个居住在 4200 米的藏族人群中，我们鉴定了 31 个与血红蛋白浓度显著相关的高连锁不平衡的 EPAS1 SNPs。在调整了性别后，主要等位基因纯合子的血红蛋白浓度比杂合子平均低 0.8 g/dL。这些发现被居住在 4300 米的第三个藏族人群所复制。与低血红蛋白浓度相关的等位基因与 GWADS 研究的信号相关，并在藏族人群中观察到与汉族相比大大升高的频率。高血红蛋白浓度是慢性高原病的一个主要特征，为选择提供了一个合理的机制。或者，由于 EPAS1 在其作用中具有多效性，选择可能作用于表型的其他方面。无论哪种解释是正确的，GWADS 研究中 EPAS1 基因座的遗传选择证据都得到了与等位变异相关的功能研究的支持。
