Short tandem repeats in populations of the Qinghai-Tibet Plateau and adjacent regions provide insights into high-altitude adaptation.

Abstract

Short tandem repeats (STRs) confer evolutionary advantages across various species, yet their roles in human high-altitude adaptation remain largely unexplored. In this study, we analyzed over 1.1 million STRs in 7876 whole-genome sequencing samples, including 3808 newly sequenced Tibeto-Burman (TB) speakers and Han Chinese individuals inhabiting the Qinghai-Tibet Plateau and neighboring regions. We characterized more than 570,000 polymorphic STRs across coding/noncoding genomic and functional contexts, revealing distinct STR variation patterns specific to TB speakers. Notably, divergent STRs in TB speakers were predominantly located in high-altitude adaptive genes and frequently associated with gene expression levels. Additionally, we identified over 17,000 STRs strongly associated with environmental conditions on the Qinghai-Tibet Plateau. These STRs exerted multilevel gene regulation through modulating protein coding, fine-tuning cis-regulatory elements, and modulating biological pathways. Furthermore, we observed substantial contributions of functional and adaptive STRs to human phenotypic diversity. Collectively, our findings provide genomic STR resources of TB speakers and genetic insights into their roles in human adaptive evolution.