Genomic history and forensic characteristics of Sherpa highlanders on the Tibetan Plateau inferred from high-resolution InDel panel and genome-wide SNPs

Abstract

Sherpa people, one of the high-altitude hypoxic adaptive populations, mainly reside in Nepal and the southern Tibet Autonomous Region. The genetic origin and detailed evolutionary profiles of Sherpas remain to be further explored and comprehensively characterized. Here we analyzed the newly-generated InDel genotype data from 628 Dingjie Sherpas by merging with 4222 worldwide InDel profiles and collected genome-wide SNP data (approximately 600K SNPs) from 1612 individuals in 191 modern and ancient populations to explore and reconstruct the fine-scale genetic structure of Sherpas and their relationships with nearby modern and ancient East Asians based on the shared alleles and haplotypes. The forensic parameters of 57 autosomal InDels (A-InDels) included in our used new-generation InDel amplification system showed that this focused InDel panel is informative and polymorphic in Dingjie Sherpas, suggesting that it can be used as the supplementary tool for forensic personal identification and parentage testing in Dingjie Sherpas. Descriptive findings from the PCA, ADMIXTURE, and TreeMix-based phylogenies suggested that studied Nepal Sherpas showed excess allele sharing with neighboring Tibeto-Burman Tibetans. Furthermore, patterns of allele sharing in f-statistics demonstrated that Nepal Sherpas had a different evolutionary history compared with their neighbors from Nepal (Newar and Gurung) but showed genetic similarity with 2700-year-old Chokhopani and modern Tibet Tibetans. QpAdm/qpGraph-based admixture sources and models further showed that Sherpas, core Tibetans, and Chokhopani formed one clade, which could be fitted as having the main ancestry from late Neolithic Qijia millet farmers and other deep ancestries from early Asians. Chromosome painting profiles and shared IBD fragments inferred from fineSTRUCTURE and ChromoPainter not only confirmed the abovementioned genomic affinity patterns but also revealed the fine-scale genetic microstructures among Sino-Tibetan speakers. Finally, natural-selection signals revealed via iHS, nSL and iHH12 showed natural selection signatures associated with disease susceptibility in Sherpas. Generally, we provided the comprehensive landscape of admixture and evolutionary history of Sherpa people based on the shared alleles and haplotypes from the InDel-based genotype data and high-density genome-wide SNP data. The more detailed genetic landscape of Sherpa people should be further confirmed and characterized via ancient genomes or single-molecule real-time sequencing technology.