Genomic insights into adaptation to eco-regional and cultural variables across human populations from North, Central and Southeast Asia

Abstract Natural selection has been extensively studied in humans, providing many examples of how climate, diet, and pathogens can translate into local selective pressures and thus phenotypic diversity across populations. However, most studies have focused either on a global scale, with a limited number of populations per geographic area, or on a very local scale. To complement these approaches, we collected and studied a large genomic dataset at a continental scale covering North, Central, and mainland Southeast Asia, and consisting of 863 individuals from 25 culturally diverse populations. We aimed to decipher the selective pressures across the Asian continent, comparing populations from different geographic areas and having contrasted subsistence strategies, using both intra-populations (iHS) and inter-populations (Fst) statistics. We detected both local and continental-wide signals, with some geographically and culturally complex patterns emerging when being compared to the literature. Interestingly, among the regions detected as significant only in mainland Southeast Asia, we found two of them clearly pointing to selective pressures associated with immunity. The first one, detected with iHS only, contains three peptidoglycan binding genes ( REG1A , REG1B and REG3A ) interacting with bacterial cell walls. The second region, the most significant one when intersecting iHS and Fst, contains PELI1 , previously shown to modulate the immune and inflammatory response and to be under selection in Han Chinese and Oceanians. In addition, in North and Central Asia, we uncovered a region overlapping with PTPRC , a gene associated with viruses recognition, as well as another region including GPHB5 , associated with lipid and carbohydrate metabolism. Interestingly, we further identified a signal on PTPRG , where variants have previously been associated with alcohol flushing in East Asia, not only in farmers but also in herders and hunter-gatherers, challenging the hypothesis that this phenotype was selected for in response to the transition to agriculture. In turn, when focusing on signals specific to given subsistence strategies, we found two genes related to immune functions ( TUBA1B and HERC1 ) exclusively in herders. In conclusion, while many signals of selection likely remain to be uncovered in less studied human groups, deciphering whether they are linked to immune, dietary or climatic factors is challenging, as subsistence strategies often covary with climate, which further influence pathogenic loads.