NEW YORK (GenomeWeb) – The gene variant that enabled Tibetans to adapt to living at such high altitudes appears to have come from Denisovans, researchers from the University of California, Berkeley, and BGI-Shenzen reported today in Nature.
This finding indicates that as modern humans moved into new regions, they mixed with other hominins already there, such as the now-extinct Denisovans, and picked up variants allowing them to adapt to these new locales.
"We have very clear evidence that this version of the gene came from Denisovans," Berkeley's Rasmus Nielsen said in a statement. "This shows very clearly and directly that humans evolved and adapted to new environments by getting their genes from another species."
The Tibetan plateau is some 4,000 meters high and has an atmospheric oxygen pressure that is about 40 percent lower than the pressure at sea level. When a person from a lower altitude acclimates to living on the plateau, that person typically has increased blood hemoglobin levels.
Tibetans, however, have a limited increase in hemoglobin level, though they also have lower infant mortality and higher fertility rates than low-altitude women who've acclimated to the plateau. Higher hemoglobin levels, the researchers noted, are linked with increased blood viscosity and risk of cardiac events.
Previous work using a combination of exome sequencing and SNP arrays found an association between a variant in the transcription factor gene EPAS1 and high-altitude adaptation in Tibetans.
In the new study, Nielsen and his colleagues re-sequenced the EPAS1 gene and surrounding sequence in 40 Tibetans and 40 Han Chinese to more than 200x coverage using the Illumina HiSeq2000 platform. They uncovered a total 477 SNPs in a region of approximately 129 kilobases in the combined samples.
The fixation index between Tibetans and Han Chinese is elevated in the EPAS1 region, the researchers found, and the variants located there are more differentiated than would be expected, given the genomic similarity between Tibetans and Han Chinese. The fixation index, the researchers noted, is particularly high for a 32.7-kilobase region that houses the 32 most differentiated SNPs they found.
By phasing the data from this super-differentiated region, the researchers noted that Tibetans carried a high-frequency haplotype that differs from both the minority and common haplotypes. For instance, a five-SNP AGGAA-motif in a 2.5-kilobase region was found only in Tibetans, and none of those SNPs were in the minority Tibetan haplotype.
To determine how such fixed differences could arise in a small DNA expanse within a short period of time, the researchers examined both a model of selection on a de novo mutation and a model of selection on standing variation using a simulated 32.7-kilobase region. The number of fixed differences observed, though, was higher than expected based on either of the simulations.
"In other words, it is unlikely that the high degree of haplotype differentiation could be caused by a single beneficial mutation landing by chance on a background of rare SNPs, which are then brought to high frequency by selection," the researchers said in their paper.
Instead, Nielsen and his colleagues said it was more likely that this region originated through either gene flow or ancestral lineage sorting from a divergent population.
By searching through data from the 1,000 Genomes Project and another dataset that included archaic hominins, the researchers found that the five-SNP AGGAA-motif common in Tibetans was missing from other modern human populations, with the exception of two Han Chinese individuals. The Denisovan haplotype, though, matched that motif exactly.
Based on a haplotype network the researchers built, they concluded that the Tibetan haplotype is much closer to the Denisovan haplotype than to any modern human haplotype for this region.
"We found part of the EPAS1 gene in Tibetans is almost identical to the gene in Denisovans and very different from all other humans," Nielsen said. "We can do a statistical analysis to show that this must have come from Denisovans. There is no other way of explaining the data."
This, Nielsen and his colleagues noted, indicates that some instances of human adaptation could be due to gene flow from archaic hominins into modern humans.
"The finding of Tibetans' selected EPAS1 haplotype in Denisovans not only demonstrates the possibility of ancient gene-flow from Denisovans or [Denisovan]-like population to ancestors of Tibetans, but also shows the importance of such events in local adaptation of modern humans," Asan Ciren, a researcher at BGI, added.