Prioritizing natural-selection signals from the deep-sequencing genomic data suggests multi-variant adaptation in Tibetan highlanders

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.

Characterization of Structural Variation in Tibetans Reveals New Evidence of High-altitude Adaptation and Introgression

“…including TMEM247, ATP6V1E2, RHOQ, PIGF, and CRIPT. Through the discovery of Tibetan-Han stratified SNVs in this region, it has been proved that all these candidate genes were relevant to HAA (Huerta-Sánchez et al 2014;Deng et al 2019). Furthermore, LD-linked eQTL tests also confirmed the relationship between the TED and PIGF ( Fig.…”

“…The adaptation of Tibetan highlanders to the Qinghai-Tibet Plateau with an average elevation of over 4,000 meters is a representative case of anatomically modern human (AMH) conquering new environmental conditions (Huerta-Sánchez et al 2014). Previous studies usually used single nucleotide variants (SNVs) to search for selection evidence in the Tibetan genome and successfully identified two essential genes involved in the HIF-1 (hypoxia-inducible transcription factor 1) pathway, EPAS1 (endothelial PAS domain protein 1) and EGLN1 (egl-9 family hypoxia inducible factor 1) (Xiang et al 2013;Huerta-Sánchez et al 2014;Deng et al 2019). The adaptive alleles of these two genes could help maintain the hemoglobin concentration so that red cells would not be overproduced at high altitude (Hu et al 2017;Yang et al 2017).…”

Peopling of Tibet Plateau and multiple waves of admixture of Tibetans inferred from both modern and ancient genome-wide data

“…Genomic evidence supported that multiple variants may jointly deliver the fitness of the modern Tibetans on the TP, and Denisovan introgression into modern Tibetans and surrounding populations including positively selected haplotypes of HIF-1α prolyl hydroxylase1 (EGLN1) and Endothelial PAS domain protein 1 (EPAS1) is significantly associated with the high-altitude adaptation to hypoxia (Simonson, et al 2010;Xu, et al 2011;Huerta-Sanchez, et al 2014;Gnecchi-Ruscone, et al 2018;Chen, Welker, et al 2019;Deng, et al 2019). Compared to other parts of East Asia (Reich 2018;Ning, et al 2019;Jeong, et al 2020;Ning, et al 2020;Wang, Yeh, et al 2020;, the greatest problem facing researchers is the lack of excavated archaeological sites on the TP, which means that certain types of critical data, such as zooarchaeological and archaeobotanical data for reconstructing the subsistence strategy, ancient DNA (aDNA) for dissecting the genomic correlation between ancient individuals and modern Tibetan-like Highlanders, are in short supply.…”

A review of Denisovans

“…(Eglnine homolog 1)和TMEM247(Transmembrane Protein 247)等基因的适应型突变对高原人群的环境适应 具有重要贡献 [25,67,68] . Lu等人 [69] 认为应对高海拔环境 的适应性基因可能来源于早期探索高原的古人类, 并 在长期自然选择下积累到较高的频率.…”

“…Lu等人 [69] 认为应对高海拔环境 的适应性基因可能来源于早期探索高原的古人类, 并 在长期自然选择下积累到较高的频率. 而在高原人群 中出现的EPAS1和TMEM247等突变型基因均在阿尔 泰山地区的丹人基因组中发现 [25,68] , 反映了丹人基因 的渗入可能帮助现代人适应了高海拔环境. 夏河人的 发现 [23,70] .…”