Researchers Sequence Genome of 200,000-Year-Old Denisovan

A research team led by scientists at the Max Planck Institute for Evolutionary Anthropology has generated the high-quality genome assembly of a Denisovan using DNA from an ancient molar found in Denisova Cave. It belonged to a man who lived around 200,000 years ago, more than twice as long as the only Denisovan individual previously sequenced. The new genome is forcing researchers to rethink when and where the first human groups met, mixed and migrated across Asia.

Artist’s impression of a Penghu Denisovan walking under the bright sun during the Pleistocene of Taiwan. Image credit: Cheng-Han Sun.

“The Denisovans, an extinct human group, were first identified based on ancient DNA extracted from Denisova 3, a digital phalanx discovered in Denisova Cave in the Altai Mountains of Siberia in 2008,” said Dr. Stéphane Peyrégne, an evolutionary geneticist at the Max Planck Institute for Evolutionary Anthropology, and colleagues.

“Analysis of this individual’s nuclear genome revealed that the Denisovans were a sister group to the Neanderthals, another group of now-extinct humans who lived in western Eurasia during the mid-to-late Pleistocene.”

“While twelve fragmentary remains and one skull have since been attributed to Denisovans based on DNA or protein analyses, only Denisova 3 provided a high-quality genome.”

Dr Peyrégne and his co-authors recovered the genome of a Denisovan from a molar discovered in Denisova Cave in the Altai Mountains of southern Siberia – the same site where Denisovans were first identified in 2010 through DNA analysis of a finger bone.

The cave has since become a cornerstone of research into human evolution, revealing repeated occupations by Denisovans, Neanderthals and even the children of parents from both groups.

The newly analyzed tooth belonged to a male Denisovan who lived around 200,000 years ago, at a time when modern humans had not yet left Africa.

“In 2020, a complete upper left molar was found in layer 17, one of the lowest cultural layers in the southern chamber of Denisova Cave, dated to 200,000 to 170,000 years ago by optically stimulated luminescence,” the scientists explained.

“Designated Denisova 25, this molar is similar in size to other molars discovered in Denisova Cave, Denisova 4 and Denisova 8, and larger than those of Neanderthals as well as most other mid-Pleistocene and later hominids, suggesting that it potentially belonged to a Denisovan.”

“Two samples of 2.7 and 8.9 mg were collected by drilling a hole at the cemento-enamel junction of the tooth, and twelve subsamples, ranging from 4.5 to 20.2 mg, were obtained by gently scraping the outer layer of one of the roots with a dental bur.”

Thanks to exceptional DNA preservation, the authors were able to reconstruct the genome of Denisova 25 with high coverage, making it comparable in quality to the genome of the 65,000-year-old female Denisova 3.

The Denisovans probably had dark skin, unlike the pale Neanderthals. The photo shows a Neanderthal man. Image credit: Mauro Cutrona.

Comparing the two genomes revealed that the Denisovans were far from a single, stable population.

Instead, at least two distinct Denisovan groups occupied the Altai region at different times, one replacing each other over thousands of years.

The ancient Denisovan also carried more Neanderthal DNA than the later, showing that interbreeding between these archaic humans occurred repeatedly – ​​not as rare accidents, but as a recurring feature of life in glacial Eurasia.

Even more striking, the team found evidence that the Denisovans themselves mixed with an even older, “super-archaic” hominid population that split off from the human family tree before the ancestors of Denisovans, Neanderthals, and modern humans diverged.

“Using this second Denisovan genome showed that there was recurring admixture between Neanderthals and Denisovans in the Altai region, but that these mixed populations were replaced by Denisovans from elsewhere, supporting the idea that Denisovans were widespread and that Altai was perhaps at the edge of their geographic range,” the researchers said.

The Denisova 25 genome also helps resolve a long-standing puzzle regarding Denisova ancestry in people living today.

Modern populations in Oceania, parts of South Asia, and East Asia all carry Denisovan DNA – just not the same type.

By comparing Denisovan gene segments in thousands of current genomes, scientists have identified at least three distinct sources of Denisovan.

One group, closely related to the later Denisovan genome, contributed significantly to its ancestry throughout East Asia and beyond.

A second, more deeply divergent Denisovan population independently contributed DNA to the ancestors of Oceanians and South Asians.

Crucially, East Asians do not carry this deeply divergent Denisovan ancestry, suggesting that their ancestors took a different migration route to Asia – probably from the north – whereas the ancestors of Oceanians crossed into South Asia earlier.

“Neanderthal-like DNA segments are shared among all populations, including Oceanians, consistent with a single event outside Africa, but independent Denisovan gene flow suggests multiple migrations into Asia,” the scientists said.

A portrait of a young female Denisovan based on a skeletal profile reconstructed from ancient DNA methylation maps. Image credit: Maayan Harel.

According to the team, some genetic variants of Denisovan were likely beneficial and became very common in modern humans through natural selection.

Using the two Denisovan genomes, the authors identified dozens of regions in current populations that appear to have been shaped by Denisovan introgression, notably in Oceania and South Asia.

Other Denisovan genetic changes offer tantalizing clues about what these ancient humans may have looked like.

Several Denisovan-specific mutations affect genes related to cranial shape, jaw projection, and facial features – traits that match the limited fossil evidence attributed to Denisovans.

Regulatory change is near FOXP2a gene involved in brain development and speech and language in modern humans, raising new questions about Denisovan cognition – although researchers caution that genetic clues cannot replace direct fossil or archaeological evidence.

“The effects of introgressed Denisovan alleles on modern human phenotypes may also provide some insight into Denisovan biology,” the researchers said.

“Using alleles associated with phenotypes in modern humans, we identified 16 associations with 11 Denisovan alleles, including height, blood pressure, monocyte count, and levels of cholesterol, hemoglobin, and C-reactive protein.”

“We also identified 305 expression quantitative trait loci (QTLs) and 117 alternative splicing QTLs affecting gene expression in modern humans in nineteen tissues; the strongest effects include eQTLs in thyroid, tibial artery, testes and muscle.”

“These molecular effects can be exploited to explore other phenotypes not preserved in the fossil record, and this updated catalog provides a more reliable basis for exploring Denisovan traits, adaptations, and disease susceptibilities, some of which may have been brought to modern-day humans through admixture.”

A preprint of the team’s paper was posted on bioRxiv.org on October 20, 2025.

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Stéphane Peyrégne and others. 2025. A high-coverage genome from a 200,000-year-old Denisovan. bioRxivdoi: 10.1101/2025.10.20.683404