Demographic History and Genetic Adaptation in the Himalayan Region Inferred from Genome-Wide SNP Genotypes of 49 Populations

Abstract

We genotyped 738 individuals belonging to 49 populations from Nepal, Bhutan, North India, or Tibet at over 500,000 SNPs, and analyzed the genotypes in the context of available worldwide population data in order to investigate the demographic history of the region and the genetic adaptations to the harsh environment. The Himalayan populations resembled other South and East Asians, but in addition displayed their own specific ancestral component and showed strong population structure and genetic drift. We also found evidence for multiple admixture events involving Himalayan populations and South/East Asians between 200 and 2,000 years ago. In comparisons with available ancient genomes, the Himalayans, like other East and South Asian populations, showed similar genetic affinity to Eurasian hunter-gatherers (a 24,000-year-old Upper Palaeolithic Siberian), and the related Bronze Age Yamnaya. The high-altitude Himalayan populations all shared a specific ancestral component, suggesting that genetic adaptation to life at high altitude originated only once in this region and subsequently spread. Combining four approaches to identifying specific positively selected loci, we confirmed that the strongest signals of high-altitude adaptation were located near the Endothelial PAS domain-containing protein 1 and Egl-9 Family Hypoxia Inducible Factor 1 loci, and discovered eight additional robust signals of high-altitude adaptation, five of which have strong biological functional links to such adaptation. In conclusion, the demographic history of Himalayan populations is complex, with strong local differentiation, reflecting both genetic and cultural factors; these populations also display evidence of multiple genetic adaptations to high-altitude environments.

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

“…In line with this view, based on SNV analysis, MKL1 was recently reported undergone positive selection in the Himalayan populations from Nepal, Bhutan, North India and Tibet 29 . The 163bp-deletion may disrupt an enhancer of MKL1, leading to a reduced MKL1 expression, subsequently attenuating CAM (cell adhesion molecules) and eventually ameliorating hypoxia-induced pulmonary hypertension (Supplementary Figure 16) 30,31 .…”

Fine-scale population structure and demographic history of British Pakistanis

“…We identified multiple variants in the HLA region at significantly altered frequency in the Jatt/Choudry subgroup, which may be due to selection rather than drift. The HLA region has been identified as a target of selection in different human populations and is involved in immunity against pathogens but also implicated in other phenotypes such as high altitude adaptation 73,[81][82][83] . A larger sample size and a populationspecific HLA reference panel would be required to fine-map the most differentiated variants in this region in the Jatt/Choudhry subgroup, which would be a prerequisite of forming hypotheses about which phenotypes might have been the target of selection.…”

High‐altitude adaptations mitigate risk for hypertension and diabetes‐associated anemia

“…For example, although the high‐altitude adaptations that are best understood involve systems that deliver oxygen to tissues, it is likely that aspects of metabolism are involved in adaptation to high altitude as well—possibly as a means to conserve the scarce resource of oxygen, or to divert it differently during exertion (Bigham & Lee, ). Genes involved in metabolism were among those identified as under selective pressure in Himalayan high‐altitude populations (Arciero et al, ; Bigham & Lee, ). This raises the possibility that unique characteristics of diabetes epidemiology, progression, or complications could be identified in high‐altitude‐adapted populations, which could provide clues to ways in which positive selection on metabolism‐related genes (Arciero et al, ; Horscroft et al, ) may have enhanced high‐altitude function.…”

“…Genes involved in metabolism were among those identified as under selective pressure in Himalayan high‐altitude populations (Arciero et al, ; Bigham & Lee, ). This raises the possibility that unique characteristics of diabetes epidemiology, progression, or complications could be identified in high‐altitude‐adapted populations, which could provide clues to ways in which positive selection on metabolism‐related genes (Arciero et al, ; Horscroft et al, ) may have enhanced high‐altitude function.…”

“…We investigated the intersection of high‐altitude adaptation and chronic disease among the Mosuo ethnic group, close relatives of Tibetans (Jeong et al, ; Lu et al, ; Wen et al, ; Yang et al, ) living in the Hengduan Mountains southeast of the Tibetan Plateau, at ~2,600 m altitude. Population‐genetic research suggests that the Mosuo are closely related to a group of Tibetan Plateau peoples who descended from a single ancestral Himalayan population that carried high‐altitude adapted alleles at a suite of key functional genes (Arciero et al, ; Jeong et al, ; Lu et al, ; Wen et al, ; Yang et al, ). Cultural and historical work suggests that the Mosuo have been residing at high elevation for ~1,500 years (Shih, ), suggesting that ancestral variation that was advantageous at altitude would have been maintained.…”