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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Natural selection on EPAS1 (HIF2α) associated with low hemoglobin concentration in Tibetan highlanders
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Natural selection on EPAS1 (HIF2α) associated with low hemoglobin concentration in Tibetan highlanders

机译：藏族高地人群中与低血红蛋白浓度相关的EPAS1（HIF2α）的自然选择

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摘要

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 ￡PAS1 is pleiotropic in its effects, selection may have operated on some other aspect of the phenoty pe. 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.
机译：通过损害功能和生存，与高海拔环境有关的氧气供应的严重减少很可能会成为自然选择的媒介。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，对青藏高原（3,200-3,500 m）的本土高地居民与密切相关的低地汉族进行比较的全基因组等位基因分化扫描（GWADS）显示，位于EPAS1附近的8个SNP存在全基因组显着差异。该基因编码转录因子HIF2α，该因子刺激红血球的产生，从而增加血液中血红蛋白的浓度。其次，在一个居住在4,200 m处的藏人中，我们在高连锁不平衡中鉴定出31个EPAS1 SNP，它们与血红蛋白浓度显着相关。与杂合子相比，主要等位基因纯合子中经性别调整的血红蛋白浓度平均低0.8 g / dL。这些发现被复制到居住在4,300 m处的第三批藏族中。与较低血红蛋白浓度相关的等位基因与来自GWADS研究的信号相关，与汉族相比，在藏族人群中观察到的频率大大升高。高血红蛋白浓度是慢性山区疾病的主要特征，提供了一种可行的选择机制。另外，由于，PAS1的作用是多效性的，因此选择可能对表型的其他方面起作用。无论哪种解释是正确的，GWADS研究在EPAS1基因座进行遗传选择的证据都得到了将功能与等位基因变异相关联的重复研究的支持。

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    Cynthia M. Beall; Gianpiero L. Cavalleri; Libin Deng; Robert C. Elston; Yang Gao; Jo Knight; Chaohua Li; Jiang Chuan Li; Yu Liang; Mark McCormack; Hugh E. Montgomery; Hao Pan; Peter A. Robbins; Kevin V. Shianna; Siu Cheung Tam; Ngodrop Tsering; Krishna R. Veeramah; Wei Wang; Puchung Wangdui; Michael E. Weale; Yaomin Xu; Zhe Xu; Ling Yang; M. Justin Zaman; Changqing Zeng; Li Zhang; Xianglong Zhang; Pingcuo Zhaxi; Yong Tang Zheng;

  • 作者单位

    Department of Anthropology, Case Western Reserve University, Cleveland, OH 44106-7125;

    rnMolecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland;

    rnBeijing Institute of Genomics, Key Laboratory of Genome Sciences and Information, Chinese Academy of Sciences, Beijing 100029, China Faculty of Basic Medical Science, Nanchang University, Nanchang 330006, China;

    rnDepartment of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106-7281;

    rnBeijing Institute of Genomics, Key Laboratory of Genome Sciences and Information, Chinese Academy of Sciences, Beijing 100029, China;

    rnDepartment of Medical and Molecular Genetics, King's College London, Guy's Hospital, London SE1 9RT, United Kingdom National Institute for Health Research, Biomedical Research Centre, Guy's and St. Thomas' National Health Service Foundation Trust and King's College London, London SE1 7EH, United Kingdom;

    rnBeijing Institute of Genomics, Key Laboratory of Genome Sciences and Information, Chinese Academy of Sciences, Beijing 100029, China;

    rnYunnan Institute of Population and Family Planning Research, Kunming 650021, China;

    rnBeijing Genomics Institute at Shenzhen, Shenzhen 518000, China;

    rnMolecular and Cellular Therapeutics, The Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland;

    rnInstitute for Human Health and Performance, University College London, London N19 5LW, United Kingdom;

    rnBeijing Institute of Genomics, Key Laboratory of Genome Sciences and Information, Chinese Academy of Sciences, Beijing 100029, China;

    rnInstitute for Human Health and Performance, University College London, London N19 5LW, United Kingdom;

    rnlnstitute for Genome Sciences and Policy, Center for Human Genome Variation, Duke University, Durham, NC 27708;

    rnSchool of Biomedical Sciences, Chinese University of Hong Kong, Shatin NT, Hong Kong, China;

    rnTibet Academy of Social Sciences, Lhasa 850000, Tibet Autonomous Region, China;

    rnDepartment of History, The Centre for Society and Genetics and the Novembre Laboratory, University of California, Los Angeles, CA 90095-7221;

    rnBeijing Genomics Institute at Shenzhen, Shenzhen 518000, China;

    rnTibet Academy of Social Sciences, Lhasa 850000, Tibet Autonomous Region, China;

    rnDepartment of Medical and Molecular Genetics, King's College London, Guy's Hospital, London SE1 9RT, United Kingdom;

    rnDepartment of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH 44195;

    rnBeijing Institute of Genomics, Key Laboratory of Genome Sciences and Information, Chinese Academy of Sciences, Beijing 100029, China;

    rnBeijing Genomics Institute at Shenzhen, Shenzhen 518000, China;

    rnDepartment of Epidemiology and Public Health, University College London, London WC1E 6BT, United Kingdom;

    rnBeijing Institute of Genomics, Key Laboratory of Genome Sciences and Information, Chinese Academy of Sciences, Beijing 100029, China;

    rnDepartment of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH 44195;

    rnBeijing Institute of Genomics, Key Laboratory of Genome Sciences and Information, Chinese Academy of Sciences, Beijing 100029, China;

    rnBeijing Genomics Institute at Shenzhen, Shenzhen 518000, China The People's Hospital of the Tibet Autonomous Region, Lhasa, 850000 Tibet Autonomous Region, China;

    rnKunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    chronic mountain sickness; high altitude; human genome variation; hypoxia; hypoxia-inducible factor;

    机译：慢性山病高海拔;人类基因组变异;缺氧缺氧诱导因子;

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