Journal
NATIONAL SCIENCE REVIEW
Volume 6, Issue 6, Pages 1201-1222Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nsr/nwz108
Keywords
Tibetan; adaptive genetic variant; high-altitude adaptation; next-generation sequencing (NGS); archaic ancestry; expression quantitative traits loci (eQTL); tissue-specific expression; hemoglobin concentration; hypoxia
Categories
Funding
- Strategic Priority Research Program [XDB13040100]
- Key Research Program of Frontier Sciences [QYZDJ-SSW-SYS009]
- Chinese Academy of Sciences (CAS)
- National Natural Science Foundation of China (NSFC) [91731303, 31525014, 31961130380, 31771388, 31501011, 31771389, 81522014, 31871256, 31601046, 31460286, 31660307, 31260252]
- Program of Shanghai Academic Research Leader [16XD1404700]
- UK Royal Society-Newton Advanced Fellowship [NAF\R1\191094]
- National Key Research and Development Program [2016YFC0906403, 2017YFA0105300, 2016YFF0202301]
- Shanghai Municipal Science and Technology Major Project [2017SHZDZX01]
- Science and Technology Commission of Shanghai Municipality (STCSM) [19YF1455200, 16YF1413900]
- NSFC Research Fund for International Young Scientists [31850410477, 2016 PB036]
- CAS Youth Innovation Promotion Association
- National Program for Top-notch Young Innovative Talents of the `Wanren Jihua' Project
- UK Royal Society-Newton Mobility Grants [IE160943]
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Human genetic adaptation to high altitudes (>2500 m) has been extensively studied over the last few years, but few functional adaptive genetic variants have been identified, largely owing to the lack of deep-genome sequencing data available to previous studies. Here, we build a list of putative adaptive variants, including 63 missense, 7 loss-of-function, 1,298 evolutionarily conserved variants and 509 expression quantitative traits loci. Notably, the top signal of selection is located in TMEM247, a transmembrane protein-coding gene. The Tibetan version of TMEM247 harbors one high-frequency (76.3%) missense variant, rs116983452 (c.248C > T; p.Ala83Val), with the T allele derived from archaic ancestry and carried by >94% of Tibetans but absent or in low frequencies (<3%) in non-Tibetan populations. The rs116983452-T is strongly and positively correlated with altitude and significantly associated with reduced hemoglobin concentration (p = 5.78 x 10(-5)), red blood cell count (p = 5.72 x 10(-7)) and hematocrit (p = 2.57 x 10(-6)). In particular, TMEM247-rs116983452 shows greater effect size and better predicts the phenotypic outcome than any EPAS1 variants in association with adaptive traits in Tibetans. Modeling the interaction between TMEM247-rs116983452 and EPAS1 variants indicates weak but statistically significant epistatic effects. Our results support that multiple variants may jointly deliver the fitness of the Tibetans on the plateau, where a complex model is needed to elucidate the adaptive evolution mechanism.
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