Sequencing of 50 human exomes reveals adaptation to high altitude

Abstract

Residents of the Tibetan Plateau show heritable adaptations to extreme altitude. We sequenced 50 exomes of ethnic Tibetans, encompassing coding sequences of 92% of human genes, with an average coverage of 18x per individual. Genes showing population-specific allele frequency changes, which represent strong candidates for altitude adaptation, were identified. The strongest signal of natural selection came from endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1), a transcription factor involved in response to hypoxia. One single-nucleotide polymorphism (SNP) at EPAS1 shows a 78% frequency difference between Tibetan and Han samples, representing the fastest allele frequency change observed at any human gene to date. This SNP's association with erythrocyte abundance supports the role of EPAS1 in adaptation to hypoxia. Thus, a population genomic survey has revealed a functionally important locus in genetic adaptation to high altitude.

Figure 1

Two-dimensional unfolded site frequency spectrum for SNPs in Tibetan (x-axis) and Han (y-axis) population samples. The number of SNPs detected is colored coded according to the logarithmic scale plotted on the right. Arrows indicate a pair of intronic SNPs from the EPAS1 gene that show strikingly elevated derived allele frequencies in the Tibetan sample compared to the Han.

Figure 2

Population-specific allele frequency change. (A) The distribution of F_ST-based PBS statistics for the Tibetan branches, according to the number of variable sites in each gene. Outlier genes are indicated in red. (B) The signal of selection on EPAS1: Genomic average F_ST-based branch lengths for Tibetan (T), Han (H), and Danish (D) branches (left), and branch lengths for EPAS1, indicating substantial differentiation along the Tibetan lineage (right)