A research team led by scientists at the Max Planck Institute for Evolutionary Anthropology has created a high-quality assembly of the Denisovan genome using DNA from an ancient molar found in Denisova Cave. It belonged to a man who lived about 200,000 years ago—more than twice as old as the only previously sequenced Denisovan man. The new genome is forcing researchers to rethink when and where the first groups of people met, mixed and migrated across Asia.
Artist's concept of the Denisovan Penghu walking under the bright sun during the Pleistocene of Taiwan. Image credit: Cheng-Han Sun.
Dr. Stefan Peyrenevolutionary geneticist from Max Planck Institute for Evolutionary Anthropologyand his colleagues reconstructed the Denisovan genome from a molar discovered in Denisova Cave in the Altai Mountains in southern Siberia—the same location where Denisovans were first identified in 2010 using DNA analysis of a finger bone.
Since then, the cave has become a cornerstone of human evolutionary research, revealing repeated occupation by Denisovans, Neanderthals and even child of parents from both groups.
“The Denisovans, an extinct group of people, were first identified based on ancient DNA extracted from Denisova 3phalanx of a finger discovered in Denisova Cave in the Altai Mountains in Siberia in 2008,” said Dr. Peiren and co-authors.
“Analysis of this individual's nuclear genome revealed that Denisovans were a sister group to Neanderthals, another group of now extinct humans who lived in western Eurasia during the middle and late Pleistocene.”
“Although twelve fragmentary remains and one skull have since been assigned to Denisovans based on DNA or protein analysis, only Denisova 3 yielded a high-quality genome.”
The newly analyzed tooth belonged to a Denisovan man who lived about 200,000 years ago, at a time before modern humans had left Africa.
“In 2020, in layer 17, one of the lowest cultural layers of the South Chamber of Denisova Cave, an intact left upper molar was discovered, dated by optically stimulated luminescence data to 200,000–170,000 years ago,” the scientists explained.
“This molar, designated Denisova 25, is similar in size to other molars found at Denisova Cave, Denisova 4 and Denisova 8, and larger than those of Neanderthals, as well as most other hominins of the Middle Pleistocene and later generations, suggesting that it was potentially Denisovan.”
“Two samples of 2.7 and 8.9 mg were removed by drilling a single hole at the cemento-enamel junction of the tooth, and twelve subsamples ranging from 4.5 to 20.2 mg were obtained by carefully scratching the outer layer of one of the roots with a dental drill.”
Thanks to the exceptional preservation of DNA, the authors were able to reconstruct the genome of Denisova 25 with a high level of coverage, making it comparable in quality to the genome of the 65,000-year-old woman Denisova 3.
Denisovans were probably dark-skinned, unlike the pale Neanderthals. The picture shows a Neanderthal. Image credit: Mauro Cutrona.
A comparison of the two genomes showed that Denisovans were far from a single, stable population.
Instead, at least two separate groups of Denisovans occupied the Altai region at different times, one succeeding the other over the millennia.
The older Denisovan man also carried more Neanderthal DNA than the later one, showing that interbreeding between these archaic humans occurred repeatedly—not as rare accidents, but as a recurring feature of life in Ice Age Eurasia.
Even more amazingly, the team found evidence that Denisovans themselves mixed with an even older, “superarchaic” population of hominins who split off from the human family tree before the ancestors of Denisovans, Neanderthals and modern humans diverged.
“Use of this second Denisovan genome revealed that there was continuous interbreeding between Neanderthals and Denisovans in the Altai region, but these admixed populations were replaced by Denisovans from other locations, supporting the idea that Denisovans were widespread and that Altaians may have been at the edge of their geographic range,” the researchers said.
The Denisova 25 genome also helps solve a long-standing mystery about Denisovan origin in people living today.
Modern populations in Oceania and parts of South and East Asia carry Denisovan DNA, but not of the same type.
By comparing Denisovan genetic segments in thousands of modern genomes, scientists have identified at least three different Denisovan origins.
One group, closely related to the later Denisovan genome, contributed greatly to its ancestry in East Asia and beyond.
A second, more divergent Denisovan population independently passed on DNA to its ancestors residents of Oceania and so that South Asians.
It is important to note that East Asians do not carry this deeply divergent Denisovan ancestry, suggesting that their ancestors took a different route of migration into Asia—likely from the north—while the ancestors of the Oceanians moved through South Asia earlier.
“Neanderthal-like DNA segments are common to all populations, including Oceanians, consistent with a single event outside Africa, but independent Denisovan gene flows suggest multiple migrations into Asia,” the scientists said.
Portrait of a young Denisovan woman based on a skeletal profile reconstructed from ancient DNA methylation maps. Image credit: Maayan Harel.
According to the team, some Denisovan genetic variants were likely beneficial and became common in modern humans as a result of natural selection.
Using two Denisovan genomes, the authors identified dozens of regions in today's populations that appear to have been shaped by Denisovan introgression, particularly in Oceania and South Asia.
Other Denisovan genetic changes offer tantalizing clues about what these ancient people may have looked like.
Several Denisovan-specific mutations affect genes associated with skull shape, jaw protrusion and facial features—features that are consistent with the limited fossil evidence attributed to Denisovans.
One Regulatory Change Is Near FoxP2gene involved in brain development and speech and language in modern humans raises new questions about the cognitive abilities of Denisovans, although researchers caution that genetic clues cannot replace direct fossil or archaeological evidence.
“The influence of introgressed Denisovan alleles on modern human phenotypes may also provide some clues about Denisovan biology,” the researchers say.
“Using alleles that are associated with phenotypes in modern humans, we identified 16 associations with 11 Denisovan alleles, including height, blood pressure, monocyte counts, and levels of cholesterol, hemoglobin, and C-reactive protein.”
“We also identified 305 expression quantitative trait loci (QTLs) and 117 alternative splicing QTLs influencing gene expression in modern humans across nineteen tissues. The strongest effects include eQTLs in the thyroid, tibial arteriosus, testis, and muscle.”
“These molecular effects can be used to study further phenotypes not preserved in the fossil record, and this updated catalog provides a stronger basis for studying Denisovan traits, adaptations and disease susceptibility, some of which may have been passed on to modern humans through admixture.”
A preprint of the team's report was published on bioRxiv.org October 20, 2025
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Stephane Peyren etc.. 2025. The 200,000-year-old Denisovan genome with high coverage. bioRxivdoi: 10.1101/2025.10.20.683404
