Tibetan near-complete pangenome reveals complex variants underlying high-altitude adaptation

Abstract

Genomic diversity in indigenous populations offers critical insights into human evolution and population-specific adaptation. Here, we generated 70 near-complete, fully phased genome assemblies from 35 high-altitude Tibetan trios and identified 4.55 million small variants and 63,031 structural variants (SVs) absent from the current global pangenome reference. Comparative analyses with a 595 globally diverse long-read genome dataset revealed 207 previously uncharacterized Tibetan-enriched SVs spanning 275 genes implicated in high-altitude physiological adaptation. Genotyping these SVs in 1,164 Tibetan and Han individuals with 88 physiological traits reveals five variants significantly associated with cardiopulmonary and hematological phenotypes central to hypoxia adaptation. We further map 2.45 Gb of archaic hominin sequences in Tibetans and uncover 18 previously unrecognized introgressed regions enriched in Tibetans with genes related to hematopoiesis and lung function. These regions harbor five Tibetan-enriched SVs, indicating that archaic introgression contributed SVs relevant to human adaptation. Together, these findings reveal substantial uncharacterized genomic diversity in Tibetans and highlight a previously underappreciated role of SVs and archaic SVs in shaping human evolution and high-altitude adaptation.