Prioritizing natural-selection signals from the deep-sequencing genomic data suggests multi-variant adaptation in Tibetan highlanders.
Prioritizing natural-selection signals from the deep-sequencing genomic data suggests multi-variant adaptation in Tibetan highlanders.
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优先考虑来自深度测序基因组数据的自然选择信号表明西藏高地人的多变适应
DOI：
10.1093/nsr/nwz108
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发表时间：
2019-11
影响因子：
20.6
通讯作者：
Xu S
中科院分区：
文献类型：
--
作者：
Deng L;Zhang C;Yuan K;Gao Y;Pan Y;Ge X;He Y;Yuan Y;Lu Y;Zhang X;Chen H;Lou H;Wang X;Lu D;Liu J;Tian L;Feng Q;Khan A;Yang Y;Jin ZB;Yang J;Lu F;Qu J;Kang L;Su B;Xu S
摘要：人类对高海拔（>2500 m）的遗传适应在过去几年中得到了广泛的研究，但几乎没有发现功能性适应性遗传变异，这很大程度上是由于之前的研究缺乏深度基因组测序数据。在这里，我们建立了一个假定的适应性变体列表，包括 63 个错义变体、7 个功能丧失变体、1,298 个进化保守变体和 509 个表达数量性状位点。值得注意的是，选择的顶部信号位于跨膜蛋白编码基因 TMEM247 中。 TMEM247 的西藏版本含有一种高频 (76.3%) 错义变异 rs116983452 (c.248C > T; p.Ala83Val)，T 等位基因源自古老血统，由 >94% 的藏族人携带，但在非藏族人群中不存在或频率较低 (<3%)。 rs116983452-T 与海拔高度呈强正相关，并与血红蛋白浓度 (p = 5.78 × 10−5)、红细胞计数 (p = 5.72 × 10−7) 和血细胞比容 (p = 2.57 × 10−6) 降低显着相关。特别是，与藏族适应性特征相关的任何 EPAS1 变体相比，TMEM247-rs116983452 显示出更大的效应大小，并能更好地预测表型结果。对 TMEM247-rs116983452 和 EPAS1 变体之间的相互作用进行建模表明，上位效应较弱，但具有统计学意义。我们的研究结果支持多种变异可能共同影响高原藏族人的适应能力，而高原上的藏人需要一个复杂的模型来阐明适应性进化机制。
Abstract 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 × 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.
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影响因子：
12.3
作者：
Castel SE;Levy-Moonshine A;Mohammadi P;Banks E;Lappalainen T
通讯作者：
Lappalainen T
影响因子：
64.5
作者：
Boyle EA;Li YI;Pritchard JK
通讯作者：
Pritchard JK
影响因子：
4
作者：
Dimitroulas, Theodoros;Giannakoulas, Georgios;Settas, Loukas
通讯作者：
Settas, Loukas
DOI：
10.1073/pnas.1002443107
发表时间：
2010-06-22
影响因子：
11.1
作者：
Beall, Cynthia M.;Cavalleri, Gianpiero L.;Zheng, Yong Tang
通讯作者：
Zheng, Yong Tang
影响因子：
64.5
作者：
Astle, William J.;Elding, Heather;Soranzo, Nicole
通讯作者：
Soranzo, Nicole