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Present-day Tibetans have adapted both genetically and culturally to the high altitude environment of the Tibetan Plateau, but fundamental questions about their origins remain unanswered. Recent archaeological and genetic research suggests the presence of an early population on the Plateau within the past 40 thousand years, followed by the arrival of subsequent groups within the past 10 thousand years. Here, we obtain new genome-wide data for 33 ancient individuals from high elevation sites on the southern fringe of the Tibetan Plateau in Nepal, who we show are most closely related to present-day Tibetans. They derive most of their ancestry from groups related to Late Neolithic populations at the northeastern edge of the Tibetan Plateau but also harbor a minor genetic component from a distinct and deep Paleolithic Eurasian ancestry. In contrast to their Tibetan neighbors, present-day non-Tibetan Tibeto-Burman speakers living at mid-elevations along the southern and eastern margins of the Plateau form a genetic cline that reflects a distinct genetic history. Finally, a comparison between ancient and present-day highlanders confirms ongoing positive selection of high altitude adaptive alleles.

Here we report the Simons Genome Diversity Project data set: high quality genomes from 300 individuals from 142 diverse populations. These genomes include at least 5.8 million base pairs that are not present in the human reference genome. Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence. We show that the ancestors of some pairs of present-day human populations were substantially separated by 100,000 years ago, well before the archaeologically attested onset of behavioural modernity. We also demonstrate that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans; instead, their modern human ancestry is consistent with coming from the same source as that of other non-Africans.

The high-altitude transverse valleys [>3,000 m above sea level (masl)] of the Himalayan arc from Arunachal Pradesh to Ladahk were among the last habitable places permanently colonized by prehistoric humans due to the challenges of resource scarcity, cold stress, and hypoxia. The modern populations of these valleys, who share cultural and linguistic affinities with peoples found today on the Tibetan plateau, are commonly assumed to be the descendants of the earliest inhabitants of the Himalayan arc. However, this assumption has been challenged by archaeological and osteological evidence suggesting that these valleys may have been originally populated from areas other than the Tibetan plateau, including those at low elevation. To investigate the peopling and early population history of this dynamic high-altitude contact zone, we sequenced the genomes (0.04×-7.25×, mean 2.16×) and mitochondrial genomes (20.8×-1,311.0×, mean 482.1×) of eight individuals dating to three periods with distinct material culture in the Annapurna Conservation Area (ACA) of Nepal, spanning 3,150-1,250 y before present (yBP). We demonstrate that the region is characterized by long-term stability of the population genetic make-up despite marked changes in material culture. The ancient genomes, uniparental haplotypes, and high-altitude adaptive alleles suggest a high-altitude East Asian origin for prehistoric Himalayan populations.

Adaptive evolution in humans has rarely been characterized for its whole set of components, i.e. selective pressure, adaptive phenotype, beneficial alleles and realized fitness differential. We combined approaches for detecting polygenic adaptations and for mapping the genetic bases of physiological and fertility phenotypes in approximately 1000 indigenous ethnically Tibetan women from Nepal, adapted to high altitude. The results of genome-wide association analyses and tests for polygenic adaptations showed evidence of positive selection for alleles associated with more pregnancies and live births and evidence of negative selection for those associated with higher offspring mortality. Lower hemoglobin level did not show clear evidence for polygenic adaptation, despite its strong association with an EPAS1 haplotype carrying selective sweep signals. [ABSTRACT FROM AUTHOR]

Indigenous populations of the Tibetan plateau have attracted much attention for their good performance at extreme high altitude. Most genetic studies of Tibetan adaptations have used genetic variation data at the genome scale, while genetic inferences about their demography and population structure are largely based on uniparental markers. To provide genome-wide information on population structure, we analyzed new and published data of 338 individuals from indigenous populations across the plateau in conjunction with worldwide genetic variation data. We found a clear signal of genetic stratification across the east-west axis within Tibetan samples. Samples from more eastern locations tend to have higher genetic affinity with lowland East Asians, which can be explained by more gene flow from lowland East Asia onto the plateau. Our findings corroborate a previous report of admixture signals in Tibetans, which were based on a subset of the samples analyzed here, but add evidence for isolation by distance in a broader geospatial context. [ABSTRACT FROM AUTHOR]

The active hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is an important modulator of the immune system, inhibiting cellular proliferation and regulating transcription of immune response genes. In order to characterize the genetic basis of variation in the immunomodulatory effects of 1,25D, we mapped quantitative traits of 1,25D response at both the cellular and the transcriptional level. We carried out a genome-wide association scan of percent inhibition of cell proliferation (Imax) induced by 1,25D treatment of peripheral blood mononuclear cells from 88 healthy African-American individuals. Two genome-wide significant variants were identified: rs1893662 in a gene desert on chromosome 18 (p = 2.32 x 10−8) and rs6451692 on chromosome 5 (p = 2.55 x 10−8), which may influence the anti-proliferative activity of 1,25D by regulating the expression of nearby genes such as the chemokine gene, CCL28, and the translation initiation gene, PAIP1. We also identified 8 expression quantitative trait loci at a FDR<0.10 for transcriptional response to 1,25D treatment, which include the transcriptional regulator ets variant 3-like (ETV3L) and EH-domain containing 4 (EHD4). In addition, we identified response eQTLs in vitamin D receptor binding sites near genes differentially expressed in response to 1,25D, such as FERM Domain Containing 6 (FRMD6), which plays a critical role in regulating both cell proliferation and apoptosis. Combining information from the GWAS of Imax and the response eQTL mapping enabled identification of putative Imax-associated candidate genes such as PAIP1 and the transcriptional repressor gene ZNF649. Overall, the variants identified in this study are strong candidates for immune traits and diseases linked to vitamin D, such as multiple sclerosis. [ABSTRACT FROM AUTHOR]