Evolutionary history of Tibetans inferred from whole-genome sequencing

Abstract

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.

De novo assembly of a Tibetan genome and identification of novel structural variants associated with high altitude adaptation

“…Their permanent settlement in the Qinghai-Tibetan plateau was dated as early as 30,000 years ago based on genetic data (Shi, et al 2008;Qi, et al 2013;Lu, et al 2016). Previous genetic studies have identified two key genes (EPAS1 and EGLN1) carrying adaptive alleles that help maintain relatively lower hemoglobin concentration in native Tibetans so that over-production of red cells (polycythemia) at high altitude could be avoided [7][8][9][10][11][12][13][14][15][16][17] . Also, a Tibetanenriched 3.4kb deletion (TED) near EPAS1 was reported 18 .…”

“…module. Then15 we used Picard to mask the PCR duplicates and generated the dedup.bam file. Variants were called by the…”

Deletion of the fih gene encoding an inhibitor of hypoxia-inducible factors increases hypoxia tolerance in zebrafish

“…Over evolutionary time, aerobic organisms have developed sophisticated cellular mechanisms that sense and respond to O 2 gradients, as well as physiological systems that adapt to changes in these gradients (1)(2)(3)(4)(5)(6). As consistent oxygen supply affects evolution, studies of hypoxia adaptation (chronic hypoxia) are common (5,7,8). However, organisms often encounter acute hypoxic conditions in addition to chronic hypoxia (5,(7)(8)(9), yet organis-mal mechanisms of adaptation to chronic hypoxia (i.e.…”

“…As consistent oxygen supply affects evolution, studies of hypoxia adaptation (chronic hypoxia) are common (5,7,8). However, organisms often encounter acute hypoxic conditions in addition to chronic hypoxia (5,(7)(8)(9), yet organis-mal mechanisms of adaptation to chronic hypoxia (i.e. hypoxia tolerance) remain largely unknown.…”

The Effect of Hypoxia on Cardiovascular Disease: Friend or Foe?

“…While some of these genes are known to work in specific pathways, the function of many of these genes is not known. In addition, genome wide association studies have identified variants in a number of genes that may facilitate adaptation to high altitude (Zimmerman et al, 1991;Semenza and Wang, 1992;Melillo et al, 1995;Tuder et al, 1995;Lau et al, 1997;Zaobornyj et al, 2009;Simonson et al, 2010;Hu et al, 2017). This may be of relevance especially in light of the known negative feed-back loop, which results in downregulation of HIF1a mRNA with prolonged hypoxia exposure (Ginouves et al, 2008).…”