Unraveling the combined effects of demography and natural selection in shaping the genomic background of Southern Himalayan populations

The populations inhabiting the high-altitude Himalayan valleys and the Tibetan plateau represent an exceptional case of human adaptation to a challenging environment having evolved multifaceted physiological adjustments that allow them to cope with hypobaric hypoxia. Recently, several studies shed new light into the ancestry of populations inhabiting the northern regions of the Tibetan plateau, partially elucidating also the genetic bases of their high-altitude adaptation. Nevertheless, the polygenic nature of such an adaptive phenotype, while being previously hypothesized, has not been formally tested so far. Moreover, less attention has been devoted to the study of populations from the Southern slopes of the Himalayas and to the history of migrations, admixture and/or isolation of the many non-Tibetan trans-Himalayan Tibeto-Burman speaking populations. In the present study, we examined genome-wide variation of previously unsurveyed Tibeto-Burman (i.e. Sherpa and Tamangs) and Indo-Aryan communities from remote Nepalese valleys along with literature data for many South/East Asian populations. Our analyses showed that most of Southern Himalayan Tibeto-Burmans derived their East Asian ancestry not from the Tibetan/Sherpa lineage, but from low-altitude ancestors who plausibly migrated across Northeast India/Myanmar, having experienced extensive admixture that reshuffled the ancestral Tibeto-Burman gene pool. These demographic inferences were also confirmed by the absence in Tamangs of the classical Tibetan/Sherpa “hard sweep” signatures at the high-altitude associated EPAS1 and EGLN1 genes. Finally, by generating a 20X whole genome sequence of a Sherpa individual and by merging it with published whole genome sequence data from Sherpa and Tibetan subjects, we applied an innovative gene network-based pipeline for the detection of signatures of positive selection. This approach enabled us to identify possible signals of polygenic adaptation occurred at the level of gene subnetworks belonging to functional pathways involved in controlling angiogenesis, thus expanding the knowledge about the genetic determinants underlying the complex Tibetan/Sherpa adaptive phenotype.