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Denisovan Nuclear, Mitochondrial Sequences Give Glimpse of Genetic Diversity

NEW YORK (GenomeWeb) – Nuclear and mitochondrial DNA sequences from two Denisovan individuals suggest that the ancient hominin population was more diverse genetically than Neanderthals, but not as diverse as modern humans, according to the Max Planck Institute for Evolutionary Anthropology's Svante Pääbo and his colleagues.

Teeth appearing to be from Denisovans, a sister group to Neanderthals, were uncovered in the same Siberian cave in which a finger bone belonging to a female Denisovan was first uncovered. By sequencing DNA obtained from these teeth, Pääbo and his colleagues found that mitochondrial DNA diversity among Denisovans was higher than it was among Neanderthals, though nuclear DNA diversity between the groups was comparable, as they reported today in the Proceedings of the National Academy of Sciences.

Genetic differences among Denisovan mtDNA also hinted that Denisovans might have been present in this stretch of Siberia for thousands of years.

"The mtDNA of one molar has accumulated fewer substitutions than the mtDNAs of the other two specimens, suggesting Denisovans were present in the region over several millennia," Pääbo and his colleagues wrote in their paper.

As the molars came from different soil layers, the researchers noted that one tooth, dubbed Denisova 4, is likely to be younger than the other, called Denisova 8. The finger phalanx, also known as Denisova 3, is also likely to be younger than Denisova 8. The tooth morphology varies from what's been found in Neanderthal and modern humans, the researchers also noted.

Pääbo and his colleagues extracted DNA from the samples and sequenced both the nuclear and mitochondrial genomes of these Denisovans. They mapped the nuclear reads they generated to the human reference genome and the mtDNA reads to the Denisova 3 mitochondrial genome. From this, they garnered average mtDNA coverage of Denisova 4 of 72.1-fold and of Denisova 8 of 118.9-fold.

Based on these mtDNA sequences as well as mtDNA from Denisova 3, seven Neanderthals, and five modern humans, the researchers constructed a phylogenetic tree. These two new molar samples formed a clade with the Denisova 3 finger sample, a grouping that excluded Neanderthals.

The mtDNA of the Denisovans exhibited low levels of diversity, as the researchers calculated it to be 3.5 X 10-3. By comparison, they determined the mtDNA diversity of Neanderthals to be 1.8 X 10-3 and of modern humans as 16.1 X 10-3.

The number of nucleotide differences among the Denisovan mtDNA samples also suggests, the researchers reported, that Denisova 8 mtDNA is more diverged and has accumulated fewer substitutions than the other Denisovan mitochondrial genomes.

As Pääbo and his colleagues reported high levels of contamination among their samples, the researchers restricted their nuclear DNA analyses to fragments carrying thymines at the first or last two residues where the human reference genome has cysteine residues. Even with this restriction, they had 1.0 megabases of Denisova 4 sequences and 24.8 megabases of Denisova 8 sequences for analysis.

By examining these autosomal sequences, the researchers found that the two Denisovan individuals from whom the molars came are as closely related to the Denisova 3 individual — showing divergence of 2.9 percent and 3.4 percent — as the Neanderthals are to the Altai Neanderthal genome, a 2.5 percent divergence. By contrast, the four European modern human genomes showed between 6 percent and 6.4 percent divergence, and the 10 modern human genomes from around the world exhibited between 4.2 percent and 9.5 percent divergence.

This, the researchers said, suggests that nuclear DNA diversity appears to be low among the archaic individuals, especially Neanderthals.

Based on mtDNA mutation rates, the Denisova 8 sample appears to be substantially older than Denisova 3 and Denisova 4, Pääbo and his colleagues reported. This, they added, suggests that Denisovans were in the area of the cave where these samples were found at least twice or were present in southern Siberia for an extended period.

As the Denisova 3 genome was previously reported to carry a component from an unknown hominin that diverged some 1 million to 4 million years ago from the Neanderthal line, the differences between the Denisovan genomes — the Denisova 8 nuclear genome appears more deeply diverged from Denisova 3 than Denisova 4 — also bring up the possibility that this component differs among these individuals, the researchers added.

"In particular, it may be that the older Denisovan population living in the cave carried a larger or different such component," the researchers wrote. "It is also possible that the two diverged mtDNA lineages seen in Denisova 8 on the one hand and Denisova 3 and Denisova 4 on the other were both introduced into the Denisovans from this unknown hominin."