Evolutionary history of Tibetans inferred from whole-genome sequencing

The indigenous people of the Tibetan Plateau have been the subject of much recent interest because of their unique genetic adaptations to high altitude. Recent studies have demonstrated that the Tibetan EPAS1 haplotype is involved in high altitude-adaptation and originated in an archaic Denisovan-related population. We sequenced the whole-genomes of 27 Tibetans and conducted analyses to infer a detailed history of demography and natural selection of this population. We detected evidence of population structure between the ancestral Han and Tibetan subpopulations as early as 44 to 58 thousand years ago, but with high rates of gene flow until approximately 9 thousand years ago. The CMS test ranked EPAS1 and EGLN1 as the top two positive selection candidates, and in addition identified PTGIS, VDR, and KCTD12 as new candidate genes. The advantageous Tibetan EPAS1 haplotype shared many variants with the Denisovan genome, with an ancient gene tree divergence between the Tibetan and Denisovan haplotypes of about 1 million years ago. With the exception of EPAS1, we observed no evidence of positive selection on Denisovan-like haplotypes.青藏高原原住民因对高海拔环境具备独特的遗传适应性，近年来受到学界广泛关注。已有研究证实，藏族人群的EPAS1单倍型参与高海拔适应过程，其起源可追溯至与丹尼索瓦人（Denisovan）相关的古老人群。本研究对27名藏族个体开展全基因组测序，并通过相关分析推演该人群的精细人口演化历史与自然选择特征。研究检测到，早在4.4万至5.8万年前，汉族祖先种群与藏族亚群之间便已出现种群结构分化，但直至约9千年前仍维持较高的基因流速率。通过CMS测试，本研究将EPAS1与EGLN1列为排名前两位的正选择候选基因，同时还鉴定出PTGIS、VDR与KCTD12作为全新的候选基因。携带适应性优势的藏族EPAS1单倍型与丹尼索瓦人基因组共享大量变异位点，藏族单倍型与丹尼索瓦人单倍型之间的古基因树分化时间约为100万年前。除EPAS1外，本研究未观测到其他丹尼索瓦人样单倍型受到正选择的证据。