A groundbreaking research team at the Max Planck Institute for Evolutionary Anthropology has successfully generated a high-quality Denisovan genome assembly using ancient DNA extracted from molar teeth found in the Denisovan Cave. This genome, dating back approximately 200,000 years, significantly predates the only previously sequenced Denisovan specimen. The findings are prompting a reevaluation of when and where early human groups interacted, mixed, and migrated throughout Asia.

Dr. Stéphane Peregne, an evolutionary geneticist from the Max Planck Institute for Evolutionary Anthropology, along with his team, recovered this Denisovan genome from molars excavated in the Denisova Cave, located in the Altai Mountains of southern Siberia. This cave is historically significant as it was the site where Denisovans were first discovered in 2010 through DNA analysis of finger bones.

This cave continues to be pivotal in the study of human evolution, revealing repeated occupations by Denisovans, Neanderthals, and even offspring resulting from the interbreeding of these groups.

“The Denisovans were first identified in 2008 based on ancient DNA sourced from Denisova 3, a phalanx found in the Denisova Cave,” Dr. Peregne and his colleagues noted.

“This analysis confirms that Denisovans are closely related to Neanderthals, an extinct human group that thrived in Western Eurasia during the mid-to-late Pleistocene.”

Since then, twelve fragmentary remains and a single skull have been associated with Denisovans through DNA or protein analysis, with Denisova 3 being the only specimen yielding a high-quality genome.

The newly studied molars, belonging to a Denisovan male who lived approximately 200,000 years ago, are predating modern humans’ migration out of Africa.

“In 2020, a complete upper left molar was found in Layer 17, one of the oldest cultural layers within the southern chamber of the Denisova Cave, dating between 200,000 and 170,000 years old based on photostimulated luminescence,” the scientists elaborated.

“Designated as Denisova 25, this molar resembles others found at Denisova Cave, specifically Denisova 4 and Denisova 8, and exhibits larger dimensions compared to Neanderthal and most post-Middle Pleistocene hominid molars, indicating it likely belonged to a Denisovan.”

“Two samples of 2.7 mg and 8.9 mg were extracted by drilling a hole at the cement-enamel junction of the tooth, with an additional 12 subsamples varying from 4.5 to 20.2 mg collected by carefully scraping the outer root layer using a dental drill.”

Thanks to excellent DNA preservation, researchers successfully reconstructed the genome of Denisova 25 with high coverage, matching the quality of the 65,000-year-old female Denisova 3 genome.

Denisovans likely had dark skin, in contrast to the pale Neanderthals. The image depicts a Neanderthal. Image credit: Mauro Cutrona.

Comparisons between the genomes indicate that Denisovans were not a singular, homogeneous population.

Instead, at least two distinct Denisovan groups inhabited the Altai region at various intervals, with one group gradually replacing the other over millennia.

Earlier Denisovans possessed a greater amount of Neanderthal DNA than later populations, suggesting that interbreeding was a regular event rather than an isolated occurrence in the Ice Age landscape of Eurasia.

Even more intriguing, the study uncovered evidence that Denisovans engaged in interbreeding with “hyperarchaic” hominin groups that diverged from the human lineage before the ancestors of Denisovans, Neanderthals, and modern humans branched off.

“This second Denisovan genome illustrates the recurrent admixture between Neanderthals and Denisovans in the Altai region, suggesting these mixed populations were eventually supplanted by Denisovans from other regions, reinforcing the notion that Denisovans were widespread and that populations in the Altai may have existed at the periphery of their geographic range,” the researchers explained.

The Denisovan 25 genome presents valuable insights into the long-standing mysteries regarding the Denisovan ancestry in contemporary populations.

People in Oceania, parts of South Asia, and East Asia all carry Denisovan DNA, albeit from different Denisovan sources.

Through genetic comparison, scientists have identified at least three separate Denisovan origins, highlighted by their genetic segments found in thousands of modern genomes.

One lineage closely relates to the later Denisovan genome and is linked to widespread ancestry across East Asia and beyond.

A second, more distantly related Denisovan population contributed independently to Oceanian and South Asian ancestry.

Notably, East Asians do not share this highly divergent Denisovan ancestry, implying their ancestors may have taken a different route into Asia, potentially from the north, whereas Oceanian ancestors likely migrated through South Asia.

“Neanderthal-like DNA fragments appear in all populations, including Oceanians, aligning with a singular out-of-Africa migration; however, the distinct Denisovan gene flow points to multiple migrations into Asia,” the researchers stated.

Reconstruction of a young Denisovan woman based on skeletal profiles derived from ancient DNA methylation maps. Image credit: Maayan Harel.

The researchers believe certain Denisovan genetic traits offered advantages that increased their prevalence in modern human populations through the process of natural selection.

By analyzing both Denisovan genomes, the authors pinpointed numerous regions in present-day populations that appear to have originated from Denisovan introgression, particularly in Oceania and South Asia.

Genetic alterations observed in other Denisovans provide intriguing insights into their physical appearances.

Several unique mutations in Denisovans influence genes connected to cranial shape, jaw protrusion, and facial characteristics—attributes that align with the limited fossil record associated with Denisovans.

A shift in regulatory mechanisms is on the horizon. The Fox P2 gene, implicated in brain development and language in modern humans, raises important questions regarding the cognitive capabilities of Denisovans, although researchers emphasize that genetic data cannot replace direct fossil or archaeological evidence.

“The impact of Denisovan alleles on modern human phenotypes might also shed light on Denisovan biology,” the researchers pointed out.

“Examining alleles linked to contemporary human traits, we identified 16 associations with 11 Denisovan alleles, covering aspects like height, blood pressure, cholesterol levels, and C-reactive protein levels.”

“Additionally, we recognized 305 expressed quantitative trait loci (QTL) and 117 alternative splicing QTLs that affect gene expression across 19 tissues in modern humans, with the most significant effects observable in the thyroid, tibial artery, testis, and muscle tissues.”

“These molecular effects can be utilized to explore additional phenotypes that are not retained in the fossil record. This updated catalog provides a more reliable foundation for investigating Denisovan traits, adaptations, and disease susceptibilities, some of which may have influenced modern humans through admixture.”

A Preprint of the team’s research paper was published in bioRxiv.org on October 20, 2025.

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Stephane Peregne et al. 2025. High coverage genome of Denisovans from 200,000 years ago. BioRxiv doi: 10.1101/2025.10.20.683404