Natural selection on EPAS1 (HIF2α) associated with low hemoglobin concentration in Tibetan highlanders
Natural selection on EPAS1 (HIF2α) associated with low hemoglobin concentration in Tibetan highlanders
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DOI：
10.1073/pnas.1002443107
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发表时间：
2010-06-22
影响因子：
11.1
通讯作者：
Zheng, Yong Tang
中科院分区：
文献类型：
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作者：
Beall, Cynthia M.;Cavalleri, Gianpiero L.;Zheng, Yong Tang
由于高海拔环境中氧气可利用性的严重降低会损害身体机能和生存能力，它很可能是一种自然选择因素。我们运用基因组学和候选基因方法来寻找这种基因选择的证据。首先，一项全基因组等位基因分化扫描（GWADS）将青藏高原（海拔3200 - 3500米）的本土高原居民与亲缘关系密切的低地汉族人群进行比较，结果发现在靠近EPAS1基因的8个单核苷酸多态性（SNP）位点上存在全基因组显著差异。该基因编码转录因子HIF2α，它能刺激红细胞生成，从而提高血液中血红蛋白的浓度。其次，在另一组居住在海拔4200米的藏族人群中，我们确定了31个处于高度连锁不平衡状态的EPAS1基因SNP，它们与血红蛋白浓度显著相关。在性别调整后，纯合子主要等位基因个体的血红蛋白浓度平均比杂合子低0.8克/分升。这些发现在居住在海拔4300米的第三组藏族人群中得到了重复验证。与较低血红蛋白浓度相关的等位基因与GWADS研究的信号相关，并且在藏族人群中的频率相较于汉族人群大幅升高。高血红蛋白浓度是慢性高山病的一个主要特征，这为选择提供了一种合理的机制。或者，由于EPAS1具有多效性，选择可能作用于表型的其他某些方面。无论哪种解释正确，GWADS研究中关于EPAS1基因座的基因选择证据都得到了将功能与等位基因变体相关联的重复研究的支持。
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 HIF2 alpha, 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.