Genetic signatures of high-altitude adaptation in Tibetans

Abstract

Indigenous Tibetan people have lived on the Tibetan Plateau for millennia. There is a long-standing question about the genetic basis of high-altitude adaptation in Tibetans. We conduct a genome-wide study of 7.3 million genotyped and imputed SNPs of 3,008 Tibetans and 7,287 non-Tibetan individuals of Eastern Asian ancestry. Using this large dataset, we detect signals of high-altitude adaptation at nine genomic loci, of which seven are unique. The alleles under natural selection at two of these loci [methylenetetrahydrofolate reductase (MTHFR) and EPAS1] are strongly associated with blood-related phenotypes, such as hemoglobin, homocysteine, and folate in Tibetans. The folate-increasing allele of rs1801133 at the MTHFR locus has an increased frequency in Tibetans more than expected under a drift model, which is probably a consequence of adaptation to high UV radiation. These findings provide important insights into understanding the genomic consequences of high-altitude adaptation in Tibetans.

Keywords: Tibetans; genome-wide association study; high-altitude adaptation; mixed linear model; polygenic selection.

Fig. 1.

PCA of genetic ancestry in Chinese populations using genome-wide SNP data. (A) Result from a PCA in a combined sample of 3,381 genetically confirmed Tibetan and Han from this study and 180 Chinese subjects (multiple ethnic groups) from the HGDP. PC1 and PC2 represent the first two eigenvectors from PCA. Note that one of the Yi subjects from the HGDP seems to be of Tibetan ancestry. (B) Distribution of the ethnic groups in China. The blue circles represent the main distribution areas of the ethnic populations in the HGDP, and the red circle represents the Tibetan population. Note that many of the populations, such as Han, Mongola, Tibetan, and Uygur, are distributed widely in a range of regions rather than the specific areas labeled on the map. The green triangles represent the two areas (Seda and Litang) from which our Tibetan subjects were recruited (SI Appendix, Fig. S1).

Fig. 2.

Genome-wide scan for genetic signatures of adaptation. Shown on the y axis are −log10 of P values from the tests of allele frequency difference between Tibetan Chinese (n = 3,008) and EASs (n = 7,287). The analysis was performed using the MLMA-LOCO method, which tests for difference in allele frequency between populations taking into account the difference caused by random drift. SNPs at the genome-wide significant loci are highlighted in red.