Higher oxygen content and transport characterize high- altitude ethnic Tibetan women with the highest lifetime reproductive success

• 成果类型: Article
• 署名作者: Ye, Shenghao; Sun, Jiayang; Craig, Sienna R.; Di Rienzo, Anna; Witonsky, David; Yu, James J.; Moya, Esteban A.; Simonson, Tatum S.; Powell, Frank L.; Basnyat, Buddha; Strohl, Kingman P.; Hoit, Brian D.; Beall, Cynthia M.
• 署名单位: George Mason University; Dartmouth College; University of Chicago; University of California System; University of California San Diego; University of Oxford; University System of Ohio; Case Western Reserve University; University System of Ohio; Case Western Reserve University; University Hospitals of Cleveland; University System of Ohio; Case Western Reserve University; University Hospitals of Cleveland; University System of Ohio; Case Western Reserve University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14860
• DOI: 10.1073/pnas.2403309121
• 发表日期: 2024-11-05
• 关键词: hemoglobin concentration; pulmonary-edema; adaptation; pregnancy; association; hypoxia; saturation; fertility; residents; variants

摘要

We chose the natural laboratory provided by highaltitude native ethnic Tibetan women who had completed childbearing to examine the hypothesis that multiple oxygen delivery traits were associated with lifetime reproductive success and had genomic associations. Four hundred seventeen (417) women aged 46 to 86 y residing at >= 3,500 m in Upper Mustang, Nepal, provided information on reproductive histories, sociocultural factors, physiological measurements, and DNA samples for this observational cohort study. Simultaneously assessing multiple traits identified combinations associated with lifetime reproductive success measured as the number of livebirths. Women with the most livebirths had distinctive hematological and cardiovascular traits. A hemoglobin concentration near the sample mode and a high percent of oxygen saturation of hemoglobin raised arterial oxygen concentration without risking elevated blood viscosity. We propose ongoing stabilizing selection on hemoglobin concentration because extreme values predicted fewer livebirths and directional selection favoring higher oxygen saturation because higher values had more predicted livebirths. EPAS1, an oxygen homeostasis locus with strong signals of positive natural selection and a high frequency of variants occurring only among populations indigenous to the Tibetan Plateau, associated with hemoglobin concentration. High blood flow into the lungs, wide left ventricles, and low hypoxic heart rate responses aided effective convective oxygen transport to tissues. Women with physiologies closer to unstressed, low altitude values had the highest lifetime reproductive success. This example of ethnic Tibetan women residing at high altitudes in Nepal links reproductive fitness with trait combinations increasing oxygen delivery under severe hypoxic stress and demonstrates ongoing natural selection.