A high-coverage genome from a 200,000-year-old Denisovan
Posted on: 2 December 2025
Preprint posted on 20 October 2025
A global map for introgressed structural variation and selection in humans
Posted on:
Preprint posted on 24 June 2025
Ancient Denisovan DNA from a 200,000-year-old genome and a new global map of archaic structural variants show that inherited Denisovan segments, including whole centromeres, still shape human diversity and local adaptation today
Selected by Siddharth Singh
Categories: evolutionary biology, genetics, genomics, paleontology
A new high-coverage Denisovan genome, approximately 200,000 years old, and a global map of archaic structural variants reveal that repeated mixing with Denisovans has left DNA from single genes to whole centromeres in our genomes, and that some of these inherited pieces have contributed to human adaptation to their environments.
Why I highlight these preprints
Archaic introgression, the DNA that modern humans inherited from Neandertals and Denisovans, is known to comprise ~2-5% of Eurasian genomes. Yet, much of what we know has focused on single-nucleotide changes. These two preprints tackle the problem from new directions.
The preprint from Peyrégne and team presents a 200,000-year-old Denisovan genome, only the second high-quality Denisovan ever sequenced, shedding light on Denisovan population history and previously unrecognized gene flow events. The preprint by Hsieh and colleagues uses long-read sequencing and assembly to map archaic structural variants in modern humans, revealing that large segments of DNA (including entire centromeres) introgressed from Denisovans/Neandertals and may have been favored by natural selection.
I highlight both these studies because they push the boundaries of ancient DNA and pangenome research, and when combined, show how deeply archaic lineages and structural variation have influenced human adaptation in ways we’re only now beginning to understand.
Second high-coverage Denisovan genome: Peyrégne and team sequenced a Denisovan male (“Denisova 25”) at ~23.6× coverage from a molar dated ~200,000 years before present (BP). His genome reveals a distinct, small Denisovan population that interbred with early Neandertals and was later replaced by Neandertals-admixed Denisovans. Remarkably, Denisova 25 also carries genetic material from an even more divergent hominin lineage (aka “super-archaic” humans) that split off before Denisovans and modern humans diverged. By comparing this genome to the younger Denisova 3 genome (~65k BP), the authors show that at least three distinct Denisovan lineages contributed DNA to present-day humans.
Global archaic SV map: Hsieh and colleagues built an unprecedented map of introgressed structural variation by integrating 4 new high-quality Papuan genomes with 94 diverse human assemblies. They discovered ~3,600 archaic introgressed SVs (≥50 bp), identified by finding SVs embedded in segments of Neanderthal/Denisovan origin. Notably, 44% of these introgressed SVs are located within genes (1,592 SVs), often in medically or functionally important regions. Using population-genomic scans (PBS statistics, coalescent modeling), the study finds 16 introgressed SVs with signatures of positive selection in Papuans. Many of these adaptive SVs involve immune-related genes and are associated with changes in gene expression in Papua New Guinea populations.
Cross-study mechanistic links
Ancient DNA meets pangenomics: These studies address a key challenge: ancient genomes are rich in information but lack long-range structure due to degradation, whereas modern long-read assemblies capture structural variants but require ancient references to recognize their origin. The Denisova 25 genome provides a new archaic reference point, while the SV map leverages modern Papuan genomes to unveil archaic SVs that short-read ancient DNA could not detect.
Together, they demonstrate a synergistic strategy, utilizing high-quality ancient sequences to inform introgression mapping and employing advanced modern assemblies to discover large archaic variants, thereby providing a more comprehensive picture of introgressed diversity than either approach alone.
Oceania as an archaic hotspot: Both preprints converge on Papua New Guinea/Oceania as a focal point of archaic influence. Peyrégne and team show that Oceanians carry a deeply divergent Denisovan lineage (a unique Denisovan ancestry not found in East Asians), consistent with an early southerly admixture event. Hsieh and colleagues accordingly find that Papuans harbor the highest concentration of introgressed SVs among global populations. In fact, many of the 16 adaptive SVs are specific to Papuans, and introgressed centromeres were identified in Papuan genomes but not in other groups.
This alignment suggests that Oceanians not only have the most Denisovan DNA by quantity, but also qualitatively different archaic variants, likely stemming from that extra Denisovan lineage, which have been retained and favored in these populations.
Adaptive legacy of archaic DNA: A theme across both studies is that archaic admixture wasn’t just a curiosity; it contributed functionally significant variation that persists today. The Denisova 25 preprint identifies multiple introgressed segments that reached high frequency in specific regions, suggesting local adaptive benefits (they identified 38 candidate Denisovan introgressed loci under selection in various populations). The SV preprint directly pinpoints structural variants under selection. Both results underscore that introgressed DNA was not purely deleterious noise diluted over time; instead, specific archaic alleles, whether small nucleotide changes or large SVs, conferred adaptive advantages (immunity, metabolism, perhaps altitude or pathogen resistance) that helped humans thrive in new environments.
This shared finding bolsters the view that admixture with archaic humans provided a creative genetic source for adaptation, enriching our species’ evolutionary toolkit.
Field impact and following experiments
Richer archaic genealogies: Having a second Denisovan genome ~135,000 years older than the first allows researchers to reconstruct a much more detailed Denisovan family tree. This will spur new models of Pleistocene human dispersal and underscore that the “Denisovan” was not a single, homogeneous group.
Beyond SNPs – Introgression of Large Variants: The SV-focused preprint by Hsieh and colleagues expands the scope of introgression research from single-point mutations to structural genome archaeology. It reveals that entire regions, such as centromeres and megabase-scale inversions, can be introgressed and survive in our gene pool. This opens up new questions about genome stability and incompatibility.
Methodological leap for detecting ancient DNA: The integration of long-read genome assemblies from diverse living individuals, as demonstrated here, provides a powerful tool for capturing introgression that traditional short-read analyses often miss. This pangenome approach can be extended: researchers can apply similar pipelines to African populations (to hunt for “ghost” archaic SVs from unknown hominins) or other underrepresented groups. The success of identifying adaptive SVs also encourages the development of new statistics and machine-learning methods tuned for structural introgression signals, analogous to those long used for SNPs.
Functional follow-ups on adaptive introgressions: Both preprints yield concrete targets for experimental biology. We now have specific Denisovan-derived alleles, from a FOXP2 regulatory change to a 55 kb HLA deletion, that can be functionally tested for their effects on gene expression or organismal phenotypes. This paves the way for mechanistic studies of archaic alleles, using CRISPR to recreate archaic variants in cell lines or mice to observe immune responses, or epidemiological studies in humans to see if carriers of certain introgressed SVs have different health outcomes.
The identification of archaic centromeres particularly raises the hypothesis that they might impact fertility or meiotic segregation, a testable idea in model systems. By highlighting these variants, the work generates new hypotheses about how archaic genetics contributed to traits such as immunity, high-altitude adaptation, and even morphology, shifting the field toward a more integrative understanding of human adaptation that links deep evolutionary history with present-day biology.
Author questions
Peyrégne et al. 2025
- Super-archaic admixture: The Denisova 25 analysis reports tentative gene flow from a very ancient hominin lineage, with a high false-positive rate for candidate segments. What specific additional genomes or statistical tests would most clearly confirm or refute super-archaic DNA in Denisovans?
- Deep Denisovan lineage in modern humans: You infer that Oceanians and South Asians carry DNA from a deeply divergent Denisovan population likely isolated in South Asia that is not shared with East Asians. Which specific markers or haplotypes best distinguish this southern Denisovan ancestry from the Denisova 3-like northern ancestry, and how could future Denisovan or South Asian ancient genomes most decisively test this separate southern lineage model?
- Adaptive introgression targets: Your Denisova 25 scan identifies candidate selected segments near ATP6V0A4 and COL4A3 in South Asians that also carry disease-linked annotations. Which concrete functional and population-level analyses do you see as most informative for testing whether these Denisovan-derived variants are genuinely adaptive rather than hitchhiking or mildly deleterious?
Hsieh et al. 2025
- Archaic centromeres and fitness: You report intact archaic-derived centromeres in Papuan genomes with divergence times that match Neandertal and Denisovan splits. What empirical tests or datasets would most directly demonstrate whether these introgressed centromeres affect recombination fertility or missegregation risk, and whether they represent neutral variants, tolerated variants, or targets of selection?
- SV introgression map: Your map is built from phased assemblies for only 49 individuals, which underrepresent Africa, the Americas, and parts of Asia. What are your concrete plans to extend long-read assemblies to these populations and to search for additional introgressed SVs, including possible ghost archaic SVs in sub-Saharan Africa, and how general do you expect the Papuan-based signals of archaic SV adaptation to be once a broader panel is available?
- Integrating Denisova 25 with SV data: Now that the Denisova 25 genome is available, do you plan to cross-reference it with the introgressed SV catalog? Denisova 25 might contain structural variants that were not present in Denisova 3. Have you checked if any of the 16 adaptive SVs identified in Papuans are actually present in Denisova 25’s assembly?
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