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In this dissertation, I present population genetic studies of indigenous people of the Tibetan plateau, collectively called “Tibetans”. In Chapter 2, I describe population structure of Tibetans and a demographic model explaining it, by analyzing genome-wide variation data of Tibetan populations, including Sherpa people from Nepal, in conjunction with global populations. Specifically, I provide evidence that Tibetan populations are structured due to varying degree of admixture with lowland East Asian gene pool. Among the sampled Tibetan cohorts, the Sherpa are the least, if any, affected by this admixture, and thus are the best representatives of this “high altitude” East Asian gene pool. Assuming this high altitude ancestry contains variants adaptive to the high altitude, I prioritize genetic loci with high proportion of this ancestry in Tibetans as candidates of adaptively evolving genes. In Chapter 3, I investigate the genetic profile of eight ancient individuals from the Himalayas with their whole genome sequences. I show that all of these individuals, ranging from 2,500 to 1,300 years old, are most closely related to contemporary Tibetans, thus making them the first whole ancient genomes of genetic East Asians. The remarkable stability of genetic composition in this region across time, in contrast to diverse cultural connections with various parts of the outside world, highlights the role of high altitudes as a strong barrier to gene flow. I propose that topographic differences made human migration from East Asia to the Tibetan plateau easier than that from either South or Central Asia. Especially, areas with intermediate altitude in the gradually ascending topography may have provided a base camp for ancestral Tibetans to accumulate genetic and cultural adaptations to cope with the high altitude. I also report that the adaptive Tibetan haplotype in the EPAS1 gene seems to have increased in frequency much later than the EGLN1 haplotype in this region. Considering evidence of early Holocene or late Upper Pleistocene divergence of the Tibetan gene pool from that of lowlanders, it is possible that there may be complicating factors such as population structure, multiple selective pressures or epistatic fitness effect in the evolution of these variants. Lastly, in Chapter 4, I explore the genetic history of the Ainu, an indigenous hunter-gatherer group in northern Japan, inspired by the long-held hypothesis of their sharing of ancestry with Tibetans based on Y haplogroup D-M174. I find that the Ainu represent an even deeper branch of East Asian ancestry, rather than sharing a common ancestry with Tibetans. Also, I find evidence for additional gene flow between the Ainu and lowland East Asians. The Ainu are unique among East Asians in being genetically closer to northeast Siberians than to Central Siberians. This may be due to either gene flow or common ancestry, the latter of which raises the possibility that the Ainu represent an early branch of the first East Asian migrants into Siberia, who eventually became ancestors of Native Americans. Ancient genomes from northeast Asia and Siberia will be invaluable to disentangle the evolutionary history of eastern Eurasia in high resolution. Together, I expect that additional population genomic studies using both contemporary and ancient samples will reveal our evolutionary past in East Asia and help us understand how our ancestors could adapt to such a diverse array of environments, ranging from tropical rainforests to freezing dark winter in the Arctic Circle.


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