NEW YORK (GenomeWeb) – A new analysis hints that Inuit and Native American populations may owe some genetic adaptation to the environment to ancient mixing with an archaic hominin related to the Denisovans.
In a paper scheduled to appear this week in Molecular Biology and Evolution, researchers from the US, Israel, the UK, and Denmark used available genotyping data and genomes sequences from efforts such as the 1000 Genomes Project and the Simons Genome Diversity Project to analyze a chromosome 1 region previously found to be under strong positive selection in Inuit individuals from Greenland.
The team found that the haplotype in this region most closely resembled sequences from the Denisovans, an archaic human species discovered through genomic sequencing of a bone fragment found in a Siberian cave. Based on the present-day distribution and frequency of this haplotype — coupled with proposed brown fat-related functions for a neighboring gene — the group suspects the introgressed archaic sequence may been retained and selected for due to its advantage in cold climes.
"We showed that it wasn't just positive selection. It was positive selection on a variant that was originally introduced from an archaic human population via interbreeding with modern humans," first author Fernando Racimo told GenomeWeb. Racimo is currently a post-doctoral researcher at the New York Genome Center. He was a student in senior author Rasmus Nielsen's integrative biology lab at the University of California at Berkeley when the analysis was done.
In a study published in Science in 2015, members of the same team described diet and cold adaptations, involving the enzyme-coding gene FADS in particular. The highly selected variants were identified using Illumina MetaboChip-based genotyping profiles for 191 individuals from an Inuit population in Greenland.
For their current analysis, Racimo, Nielsen, and their colleagues focused on the part of the genome which showed the second strongest signal of positive selection in the Greenland Inuit population: a stretch of sequence spanning some 40,000 bases on chromosome 1 between the transcription factor gene TBX15 and WARS2, a gene coding for a synthetase enzyme.
With the help of statistical analyses, demographic simulations, haplotype network analyses, and other comparisons tapping available sequence data for populations around the world, the team found that the sequence in this region contained a haplotype that "looks very similar to variants that are in the Denisovan genome, but it's very, very different from other modern human variants," Racimo said.
Similar variants appear to occur at relatively high frequency in Native American and Siberian populations, the researchers reported, particularly those with lower levels of European ancestry. It was relatively rare in Europeans and nearly negligible in African populations, but present at intermediate frequency in Asian populations.
"The geographic distribution, along with the fact that the sequence is so similar to the Denisovan genome, was one of the forms of evidence that this sequence was likely introduced from archaic humans into the modern human genome," Racimo said.
Since it is appears to have been strongly selected in Inuit and Native American populations, the team suspects that the introgressed archaic sequence was advantageous to an ancestral Native American population prior to migrations and dispersal into new sites across North, South, and Central America.
Though the TBX15 gene has several proposed functions, Racimo noted that the gene's role in brown fat development could theoretically have helped in cold adaptation for ancestral groups migrating across Siberia and Beringia into the Americas.
"The strongest hypothesis that we have at the moment is that [it was] TBX15's role in the development of brown fat cells, which can produce heat by lipid oxidation, that historically drove the archaic variant to high frequency," he said, though he cautioned that TBX15 has other functions as well, including reported roles in body fat distribution, craniofacial morphology, and bone development.
The researchers are doing follow-up experiments to try to get a better idea of how the archaic haplotype affects brown fat development, cold adaptation, and/or other processes. Results from the current study suggest the introgressed haplotype and original Denisovan sequence are linked to methylation and expression differences relative to the Altai Neanderthal and other modern humans.
A handful of other studies have found adaptive introgression of sequences originating in archaic hominins, leading to genes with potential ties to immunity, skin pigmentation, and other traits and conditions.
In a study reported in Nature in 2014, for example, Nielsen and colleagues from the US, China, Turkey, Saudi Arabia, and Denmark described adaptations in high-altitude Tibetan populations that seemed to stem from versions of the EPAS1 gene inherited through ancient mixing with Denisovans or a related hominin species.
Although the introgressed sequence in the new study shows the closest sequence ties to the Denisovan region, Racimo noted that the haplotype's distribution in present-day human populations is closer to that expected for sequences stemming from Neanderthal admixture (Denisovan ancestry has been described in Oceanic and East Asian populations, for the most part).
So it's also possible that the introgressed sequence might reflect modern human admixture with a yet-unidentified archaic human species that was related to Denisovans, Racimo explained. "There could have been some other, unsampled, archaic population whose genome we don't have at the moment," he said.
If admixture did occur with Denisovans, the team suspects the modern human ancestors of Native Americans might have encountered Denisovans in Central Asia, though it's tough to know for sure based on the Denisovan material found so far.
"The only place that we know Denisovans have been sampled from is the cave in Siberia, the Denisova Cave," Racimo said. "It is possible that an interbreeding event may have happened somewhere around Central Asia … but at this moment it's hard to point out, especially given the fact that we only have Denisovan genome sequences from one location."