Department of Exercise Science, Syracuse University, Syracuse, NY 13244;
Universidad Peruana Cayetano Heredia, Lima, Peru.
Proc Natl Acad Sci U S A. 2019 Nov 26;116(48):24006-24011. doi: 10.1073/pnas.1906171116. Epub 2019 Nov 11.
Highland native Andeans have resided at altitude for millennia. They display high aerobic capacity (VOmax) at altitude, which may be a reflection of genetic adaptation to hypoxia. Previous genomewide (GW) scans for natural selection have nominated gene () as a candidate gene. The encoded protein, EGLN1/PHD2, is an O sensor that controls levels of the Hypoxia Inducible Factor-α (HIF-α), which regulates the cellular response to hypoxia. From GW association and analysis of covariance performed on a total sample of 429 Peruvian Quechua and 94 US lowland referents, we identified 5 SNPs associated with higher VOmax (L⋅min and mL⋅min⋅kg) in hypoxia (rs1769793, rs2064766, rs2437150, rs2491403, rs479200). For 4 of these SNPs, Quechua had the highest frequency of the advantageous (high VOmax) allele compared with 25 diverse lowland comparison populations from the 1000 Genomes Project. Genotype effects were substantial, with high versus low VOmax genotype categories differing by ∼11% (e.g., for rs1769793 SNP genotype TT = 34.2 mL⋅min⋅kg vs. CC = 30.5 mL⋅min⋅kg). To guard against spurious association, we controlled for population stratification. Findings were replicated for SNP rs1769793 in an independent Andean sample collected in 2002. These findings contextualize previous reports of natural selection at in Andeans, and support the hypothesis that natural selection has increased the frequency of an causal variant that enhances O delivery or use during exercise at altitude in Peruvian Quechua.
高地安第斯人已经在高海拔地区居住了数千年。他们在高海拔地区表现出很高的有氧能力（VOmax），这可能反映了他们对缺氧的遗传适应。先前针对自然选择的全基因组（GW）扫描已提名 基因（）作为候选基因。编码的蛋白 EGLN1/PHD2 是一种 O 传感器，可控制缺氧诱导因子-α（HIF-α）的水平，从而调节细胞对缺氧的反应。在总共 429 名秘鲁克丘亚人和 94 名美国低地参照者的全样本中，我们进行了 GW 关联和协方差分析，鉴定出 5 个与低氧状态下更高 VOmax（L⋅min 和 mL⋅min⋅kg）相关的 SNPs（rs1769793、rs2064766、rs2437150、rs2491403、rs479200）。对于其中的 4 个 SNPs，与来自 1000 基因组计划的 25 个不同低地对照人群相比，克丘亚人具有最高的有利（高 VOmax）等位基因频率。基因型效应非常显著，高 VOmax 与低 VOmax 基因型类别之间的差异约为 11%（例如，rs1769793 SNP 基因型 TT = 34.2 mL⋅min⋅kg 与 CC = 30.5 mL⋅min⋅kg）。为了防止虚假关联，我们控制了群体分层。在 2002 年收集的一个独立的安第斯人群样本中，对 SNP rs1769793 进行了重复验证。这些发现使先前在安第斯人身上报道的 基因自然选择的报告更加合理，并支持了这样一种假设，即自然选择增加了一个因果变异的频率，该变异在秘鲁克丘亚人在高海拔地区运动时增强了 O 的输送或利用。
