In:
National Science Review, Oxford University Press (OUP), Vol. 6, No. 6 ( 2019-11-01), p. 1201-1222
Abstract:
Human genetic adaptation to high altitudes ( & gt;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 & gt; T; p.Ala83Val), with the T allele derived from archaic ancestry and carried by & gt;94% of Tibetans but absent or in low frequencies ( & lt;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 × 10−5), red blood cell count (p = 5.72 × 10−7) and hematocrit (p = 2.57 × 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.
Type of Medium:
Online Resource
ISSN:
2095-5138
,
2053-714X
Language:
English
Publisher:
Oxford University Press (OUP)
Publication Date:
2019
detail.hit.zdb_id:
2745465-4
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