Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA

Abstract

As modern humans migrated out of Africa, they encountered many new environmental conditions, including greater temperature extremes, different pathogens and higher altitudes. These diverse environments are likely to have acted as agents of natural selection and to have led to local adaptations. One of the most celebrated examples in humans is the adaptation of Tibetans to the hypoxic environment of the high-altitude Tibetan plateau. A hypoxia pathway gene, EPAS1, was previously identified as having the most extreme signature of positive selection in Tibetans, and was shown to be associated with differences in haemoglobin concentration at high altitude. Re-sequencing the region around EPAS1 in 40 Tibetan and 40 Han individuals, we find that this gene has a highly unusual haplotype structure that can only be convincingly explained by introgression of DNA from Denisovan or Denisovan-related individuals into humans. Scanning a larger set of worldwide populations, we find that the selected haplotype is only found in Denisovans and in Tibetans, and at very low frequency among Han Chinese. Furthermore, the length of the haplotype, and the fact that it is not found in any other populations, makes it unlikely that the haplotype sharing between Tibetans and Denisovans was caused by incomplete ancestral lineage sorting rather than introgression. Our findings illustrate that admixture with other hominin species has provided genetic variation that helped humans to adapt to new environments.

Figure 1. Genome-wide Fst vs maximal allele frequency

The relationship between genome-wide F_ST (x-axis) computed for each pair of the 26 populations and maximal allele frequency (y-axis), first explored in Coop et al. (19). Maximal allele frequency is defined as the largest frequency difference observed for any SNP between a population pair. The 26 populations are from the Human Genome Diversity Panel (HGDP). The labels highlight genes that harbor SNPs previously identified as having strong local adaptation.

Figure 2. Haplotype pattern in a region defined by SNPs that are at high frequency in Tibet and at low frequency in the Han (see Table S3)

Each column is a polymorphic genomic location (95 in total), each row is a phased haplotype (80 Han and 80 Tibetan haplotypes), and the colored column on the left denotes the population identity of the individuals (Han in orange, Tibetans in pink). The top two rows (in dark green) are the haplotypes of the Denisovan individual. The dark cells represent the presence of the derived allele and the grey space represents the presence of the ancestral allele (see Methods). The first column corresponds to the first positions in Table S3 and the last column corresponds to the last position in Table S3. The red and blue arrows at the top indicate the 32 sites in Table S3. The blue arrows represent a five-SNP haplotype block defined by the first five SNPs in the 32.7kb region. The stars beneath the arrows point to sites where Tibetans share a derived allele with the Denisovan individual.

Figure 3. A haplotype network based on the number of pairwise differences between the 40 most common haplotypes

The haplotypes were defined from all the SNPs present in the combined 1000 Genomes and Tibetan samples: 515 SNPs in total within the 32.7kb EPAS1 region. The Denisovan haplotypes were added to the set of the common haplotypes. The R software package pegas was used to generate the figure, using pairwise differences as distances. Each pie chart represents one unique haplotype, labeled with Roman numerals, and the radius of the pie chart is proportional to the log₂(number of chromosomes with that haplotype) plus a minimum size so that it is easier to see the Denisovan haplotype. The sections in the pie provide the breakdown of the haplotype representation amongst populations. The width of the edges is proportional to the number of pairwise differences between the joined haplotypes; the thinnest edge represents a difference of 1 mutation. The legend shows all the possible haplotypes among these populations (see Methods for definition of population acronyms). The numbers next to an edge in the bottom right are the number of pairwise differences between the corresponding haplotypes. We added an edge afterwards between the Tibetan haplotype XXXIII and its closest non-Denisovan haplotype (XXI) to indicate its divergence from the other modern human groups. Extended Data Fig. 5a contains all the pairwise differences between the haplotypes presented in this figure.