Whole-Genome Sequencing Pilot Study of the Central Asian Genetic Diversity Project Reveals Distinct Genetic Histories, Adaptive Processes, and Introgression Events

The underrepresentation of Central Asian genomic data has constrained our understanding of their demographic history and hindered advancements in precision medicine and health equity. Despite the region’s rich historical tapestry, characterized by numerous trans-Eurasian migrations following the advent of agriculture and pastoralism, the genetic contributions of ancient Eurasians to modern Central Asians remain poorly understood. To address this gap, we performed an anthropologically informed Central Asian Genomic Diversity Project and reported the results of pilot whole-genome sequencing work on 166 Central Asians and Afghanistan Hazaras (CAAH) from 20 populations to investigate their demographic history, local adaptation, medical relevance, and archaic introgression. Significant genetic differentiation among CAAH populations was revealed. Tajik, Karluks, Turkmen, and Uzbek individuals exhibited higher proportions of West Eurasian ancestry, whereas the Kyrgyz, Karakalpak, Uyghur, and Hazara populations presented increased ancestry related to ancient Northeast Asians. In contrast, Dungans demonstrated a predominance of East Asian-derived ancestry. Four Turkic-related genetic clusters corresponding to geographic distribution were identified, supporting the “Northeast Asia origin” hypothesis for Turkic groups. Additionally, two Indo-European genetic clines were detected, with Hazaras being notably isolated. Strong genetic affinities were observed between Hazaras and Altaic groups in Siberia and between Dungans and Sino-Tibetan-speaking East Asians, underscoring the impact of ancient long-distance migrations on Eurasian genetic diversity. The recent east-west admixture in CAAH was estimated to have occurred 23-31 generations ago, aligning with the Song and Yuan dynasties and the Mongol Empire period. The mutation spectra of candidate disease-causing variants and pharmacogenomic genes were characterized, indicating that differentiated demographic histories significantly influence the genetic architecture of diseases among different Central Asians. Differential post-admixture adaptation signatures identified in the four genetically distinct groups have substantial effects on immune, metabolic, neural, and physical traits. Shifts in subsistence strategies significantly shaped the genetic architecture of complex traits in Central Asians. Neanderthal-like sequences exhibited varying phenotypic effects across genetically distinct CAAH strains, including susceptibility to immune and psychiatric conditions in West Eurasian-biased CAAH individuals and drug metabolism in East Eurasian-biased CAAH individuals. Denisovan-like segments were primarily linked to type 2 diabetes, etc. This research on Central Asian genomic diversity enhances the understanding of their evolutionary history and admixture events, promoting health equity and advancing precision medicine initiatives.