Clonal haematopoiesis, or CH, arises when somatic mutations in haematopoietic stem cells allow them to outcompete their neighbours and produce expanded populations of mutant blood cells detectable in the peripheral circulation. The condition is remarkably common, present in an estimated 10 to 20 percent of people over the age of 65, and by mid-century the global population over 65 is projected to double, placing hundreds of millions of people at risk of CH-associated complications. Mutations in DNMT3A and TET2 together account for roughly 70 percent of all CH variants, and both have been linked to heightened inflammatory responses in myeloid cells, as well as increased risk of haematologic malignancies and cardiovascular disease. Yet the cell-intrinsic mechanisms connecting these mutations to inflammatory signalling have remained incompletely understood, and clinicians have long struggled to explain why individuals carrying the same mutation can show such different clinical outcomes.

The research team hypothesised that retrotransposable elements, or RTEs, might provide the missing mechanistic link. These genomic parasites, including long interspersed nuclear elements (LINEs), short interspersed nuclear elements (SINEs), and long terminal repeat (LTR) elements also known as human endogenous retroviruses, are normally silenced by DNA methylation and repressive histone modifications. When that silencing breaks down, RTEs can produce RNA and even DNA copies that the cell mistakes for viral invaders, activating innate immune sensors such as cGAS and triggering type-I interferon responses. RTE derepression is increasingly recognised as a hallmark of ageing and has been implicated as a causative factor in cellular senescence, making it a natural suspect in a condition defined by age, mutation, and inflammation.

To test the hypothesis, the researchers analysed peripheral blood mononuclear cell samples from 56 individuals with clonal haematopoiesis and 12 non-CH controls, drawn from a larger population study of 738 otherwise healthy adults over 50 recruited through elective hip replacement surgery at King’s College Hospital in London and The Robert Jones and Agnes Hunt Orthopaedic Hospital in Oswestry. Genomic DNA was sequenced with a customised myeloid panel achieving deep coverage through error-corrected duplex consensus reads, while RNA sequencing without poly(A) selection captured both gene and repetitive element expression, averaging 65.1 million paired-end reads per sample. Participants were stratified into five groups: DNMT3A-mutant high variant allele frequency (VAF above 10 percent, n = 10), DNMT3A-mutant low VAF (n = 30), DNMT3A/TET2 double-mutant (n = 9), TET2-mutant (n = 7), and non-CH controls (n = 12).

The results were unambiguous for the largest expanded clones. High-VAF DNMT3A-mutant clones exhibited widespread derepression of retrotransposable elements, dominated by the LINE:L1 and LTR:ERV1/ERVL families, which are typically repressed by DNA methylation. This pattern fits neatly with prior work showing that DNMT3A loss disrupts de novo methylation and permits repetitive element reactivation in haematopoietic and embryonic stem cells. Interestingly, the high-VAF DNMT3A group was not uniform: the team identified two distinct subgroups, one with markedly elevated RTE expression and another resembling controls, revealing substantial heterogeneity within the same mutation class. The position of the mutation within the protein appeared to matter, with variants affecting the PWWP domain exclusively associated with the RTE-high phenotype, and within the methyltransferase domain most high-VAF mutations showing elevated RTE expression except the recurrent R882H hotspot, which clustered in the RTE-low group. The authors caution that with only ten high-VAF cases these observations require validation in larger cohorts, but they suggest that different DNMT3A mutations may not be biologically equivalent.

Functionally, the RTE-high DNMT3A clones looked dramatically different from their RTE-low counterparts. Gene set enrichment analysis showed that high-VAF DNMT3A clones with elevated RTE expression were enriched for inflammatory signalling pathways, including TNF-alpha/NF-kappaB signalling and broad inflammatory response programmes. At the effector level, these clones expressed significantly higher levels of TNF and the alarmin S100A9, and showed upregulation of multiple interferon regulatory genes, including ISG15, IFI44, IFIT1, IFIT2, and IFIT3, a signature consistent with RTE-derived nucleic acids activating cytosolic sensors and driving type-I interferon responses. The researchers also observed enrichment of pathways involving the Human Silencing Hub (HUSH) and Sirtuin 1 (SIRT1), which they interpret as possible compensatory attempts by alternative epigenetic regulators, including HUSH, Polycomb Repressive Complex 2, and SIRT1, to preserve transcriptional repression in the face of failing DNMT3A-mediated methylation, a coordinated but ultimately failing cellular response rather than random transcriptional noise.

TET2-mutant clones told a completely different story. Far from derepressing retroelements, TET2-mutant haematopoiesis showed a trend towards reduced RTE expression relative to controls, and no significant associations between RTE activity and any of four curated inflammatory and ageing signatures: interferon regulatory genes, TNF-NF-kappaB, senescence, and the senescence-associated secretory phenotype (SASP). Instead, pathway analysis revealed that TET2-mutant clones were enriched for oxidative phosphorylation, reactive oxygen species signalling, and mechanistic target of rapamycin complex 1 (mTORC1) signalling, pointing to a metabolically driven, redox-associated inflammatory phenotype rather than a retroelement-driven one. This aligns with recent publications implicating metabolic and inflammasome pathways, rather than transposable element activation, in TET2-mutant inflammation. In regression analyses, RTE family expression was significantly and positively associated with all four signature scores in DNMT3A high-VAF cases, showed more selective associations with interferon and senescence programmes in low-VAF DNMT3A cases, and showed no significant associations in TET2-mutant cases.

The findings held up under independent scrutiny. Single-cell TARGET-seq data from a separate study, covering five DNMT3A-mutant and three TET2-mutant samples, showed that DNMT3A-mutant cases contained more upregulated RTE subfamilies across individual haematopoietic lineages, with the erythroid and megakaryocyte compartments showing the strongest enrichment and ERV1, ERVL, ERVL-MaLR, and L1 families contributing most. An external validation cohort of 92 healthy middle-aged and older adults from a publicly available RNA-seq dataset, in which RNAVAR mutation calling identified seven DNMT3A and six TET2 high-VAF cases, reproduced the core pattern: retroelement expression correlated significantly with interferon, TNF-NF-kappaB, and senescence signatures in DNMT3A high-VAF clones but not in TET2-mutant cases. Double-mutant clones carrying both mutations occupied an intermediate position, with RTE levels higher than TET2-mutants but lower than DNMT3A high-VAF clones, and attenuated TNF-NF-kappaB and interferon programmes, hinting at non-redundant and possibly antagonistic roles for the two epigenetic regulators.

The study has limitations the authors acknowledge candidly. Bulk RNA sequencing of peripheral blood mononuclear cells can be influenced by differences in cellular composition, and although the TARGET-seq analyses supported cell-intrinsic differences in RTE regulation, the small single-cell cohort cannot fully exclude compositional effects. The number of high-VAF cases remains modest, and, critically, the data demonstrate an association between RTE derepression and inflammatory pathway activation rather than a proven causal relationship, since both could arise as parallel consequences of DNMT3A-associated epigenetic dysregulation. Recurrent co-occurring CHIP mutations were found in only 10 percent of DNMT3A-mutant cases and showed no enrichment in the RTE-high or high-VAF groups, making co-mutations an unlikely explanation for the observed heterogeneity.

Even so, the implications are considerable. By showing that inflammation in clonal haematopoiesis is mutation-specific, with retrotransposon reactivation powering the inflammatory programme of DNMT3A-mutant clones while metabolic and redox dysregulation drive TET2-mutant inflammation, the study lays the groundwork for mutation-specific biomarkers and therapies. If future functional and preclinical studies confirm that modulating RTE activity can dampen the inflammatory phenotype of DNMT3A-mutant clonal haematopoiesis, interventions could one day be tailored to the specific molecular mechanism behind each patient’s mutated clone, replacing a one-size-fits-all approach with precision medicine for age-related blood disorders and, potentially, the cardiovascular and neurodegenerative diseases that travel with them.

Subject of Research: Mutation-specific retrotransposable element derepression and inflammatory signalling in DNMT3A- and TET2-mutant clonal haematopoiesis

Article Title: Retrotransposable element derepression distinguishes DNMT3A-mutant from TET2-mutant clonal haematopoiesis

Article References: Hasan, M., Durandeau, S., Thompson, I. R., Roussotte, H., Tsai, Y.-T., Seymen, N., Gerlevik, S., Bianchini, N., Alishah, K., Albuquerque, M. M., Lewis, J., Bonganay, L., Jakobsen, N. A., Zeisig, B., Irshad, S., Vyas, P., So, E. C. W., Iacoangeli, A., Zheng, X., … Karimi, M. M. (2026). Retrotransposable element derepression distinguishes DNMT3A-mutant from TET2-mutant clonal haematopoiesis. GeroScience. https://doi.org/10.1007/s11357-026-02510-6

Image Credits: AI Generated

DOI: 10.1007/s11357-026-02510-6

Keywords: clonal haematopoiesis, DNMT3A, TET2, retrotransposable elements, LINE-1, endogenous retroviruses, inflammation, ageing, DNA methylation, interferon signalling, senescence, haematopoietic stem cells

The core problem is one of identity. Short-read sequencing technologies, which dominate modern transcriptomics, produce fragments of RNA sequence that are typically only 100 to 150 nucleotides long. When those fragments originate from a HERV locus, they often match dozens or hundreds of nearly identical copies scattered across the genome with equal fidelity. Standard alignment algorithms, faced with equally good candidates, either discard the read as ambiguous or assign it arbitrarily, which means that expression signals from individual proviral loci are blurred together or lost entirely. Long-read sequencing platforms can span entire proviruses and resolve their origins, but they remain more expensive, lower throughput, and less commonly available, which limits their use in large clinical cohorts. The result has been a persistent blind spot: researchers know that HERV transcripts are present in a sample, but they frequently cannot say which specific retroviral elements are active, where they sit in the genome, or what regulatory logic controls them.

ERVmancer attacks this ambiguity by borrowing an idea from evolutionary biology. Rather than treating each HERV copy as an isolated entity, the framework organizes the 3,043 HERV loci it tracks into a phylogenetic structure, grouping related proviruses into clades that reflect their shared ancestry. When a short sequencing read cannot be uniquely assigned to a single locus, the method uses the phylogeny to make a principled probabilistic assignment: reads that are ambiguous among closely related copies within a clade contribute to the quantification of that clade, while information that distinguishes individual loci is preserved wherever the sequence allows it. In this way, ERVmancer can report expression at multiple resolutions simultaneously, from the individual proviral locus up through families and entire clades, giving researchers a hierarchical view of retroviral activity that mirrors the evolutionary reality of these elements rather than flattening it.

To find out whether this phylogeny-guided strategy actually works better than existing approaches, the team benchmarked ERVmancer using matched datasets in which the same biological samples had been sequenced with both short-read and long-read technologies. The long-read data served as a ground truth of sorts, since it can resolve individual loci directly. Across these comparisons, ERVmancer outperformed existing methods in both sensitivity, meaning its ability to detect genuine HERV expression, and specificity, meaning its ability to avoid false assignments. The evaluation extended across HERV families, and supplementary analyses using simulated sequencing data further probed how reads were distributed among internal phylogenetic clades, providing a detailed picture of where the method succeeds and where uncertainty remains. The tool has been released as a Bioconda package, a distribution channel widely used in the bioinformatics community, which should make adoption straightforward for laboratories analyzing RNA sequencing data.

The practical value of the framework was demonstrated in two disease contexts with very different biology. The first was multiple sclerosis, an autoimmune disease of the central nervous system in which HERV activity has long been suspected of playing a role, though pinning down which elements are involved has been difficult. The researchers applied ERVmancer to RNA sequencing data from spontaneous lymphoblastoid cell lines derived from patients with multiple sclerosis and from healthy controls, all of whom provided written informed consent under protocols reviewed by institutional review boards at the National Institutes of Health and The Wistar Institute. The analysis reproduced expression patterns that had previously been observed only with long-read sequencing, validating that the short-read approach could recover biologically meaningful signal, and it identified HERV expression patterns specific to the disease context, including variability within the ERV3 clade that the team confirmed independently using quantitative reverse-transcription PCR.

The second application turned to cancer, where the interplay between tumor suppressors and endogenous retroviruses has become an increasingly active frontier. Analyzing breast cancer cell lines from the Cancer Cell Line Encyclopedia, ERVmancer uncovered a striking regulatory relationship: the transcription factor p53, famous as the guardian of the genome for its role in suppressing tumors, appears to actively suppress the expression of the HERVH-LTR7 clade. This finding is significant because HERVH and its LTR7 long terminal repeat are known to be active in embryonic stem cells and in certain tumors, where they help maintain a stem-like, proliferative state. The observation that p53 exerts suppressive control over this clade suggests that one way the cell’s primary tumor suppressor keeps cells from reverting to a primitive, uncontrolled state is by silencing the viral remnants that normally fuel such programs in early development. Genome-wide analysis of p53 binding sites across diverse HERV clades and families, presented in the supplementary data, supports the breadth of this regulatory reach.

These findings illustrate why the ability to resolve HERV expression at the clade and locus level matters. A bulk measurement that lumps all HERVH activity together might obscure the fact that a specific subset of proviruses, defined by their evolutionary lineage and their regulatory sequences, is being selectively repressed or activated. In multiple sclerosis, distinguishing disease-associated expression within particular clades could eventually clarify whether endogenous retroviral transcripts act as drivers of pathology, as biomarkers of immune dysregulation, or as byproducts of inflammation. In oncology, understanding which retroviral elements a tumor reactivates, and which tumor suppressors keep them in check, could inform strategies to exploit viral-like antigens on cancer cells for immunotherapy, an approach that has already attracted considerable interest because HERV expression in tumors can generate targets that distinguish malignant cells from healthy tissue.

The methodological advance also speaks to a broader trend in genomics: the recognition that repetitive regions of the genome, long excluded from analysis or collapsed into consensus sequences, contain biology worth recovering in full. As short-read sequencing remains the workhorse of large-scale studies, including biobank-scale transcriptomics and clinical cohorts, tools that can extract locus-resolved information from inherently ambiguous data multiply the value of existing datasets without requiring new sequencing campaigns. ERVmancer’s hierarchical output means that researchers with different questions can query the same analysis at different resolutions, whether they care about a single provirus with a known regulatory function or about the aggregate behavior of an entire retroviral lineage across hundreds of samples.

The study, which was published open access on 25 September 2026 and led by corresponding authors Andrew Patterson and Noam Auslander, brought together expertise spanning virology, neuroimmunology, and computational biology, including contributions from Steven Jacobson of the NIH Neuroimmunology Branch and Paul Lieberman and Samantha Soldan of The Wistar Institute. It was supported by funding from the W. W. Smith Charitable Trust, the Michelson Medical Research Foundation, the United States Department of Defense, and multiple institutes of the National Institutes of Health. As with any computational method, its conclusions will need to be tested and extended by independent groups, and the authors note that the published version followed full peer review at Genome Biology.

For a field that has spent decades peering at the ghostly traces of ancient viruses through a fog of repetitive sequence, ERVmancer offers something close to a lens correction. By letting the evolutionary relationships among HERVs guide the interpretation of ambiguous reads, the framework turns a longstanding liability of short-read data into a tractable inference problem, and it delivers early biological dividends: confirmation that long-read-quality insight can be recovered from ordinary transcriptomic data, disease-specific expression signatures in multiple sclerosis, and evidence that p53, the cell’s most celebrated tumor suppressor, doubles as a warden of the viral archive within our DNA. As researchers begin applying the tool to other cancers, autoimmune conditions, and developmental systems, the regulatory grammar of the genome’s viral fossils may finally come into focus, revealing how infections from the deep past continue to script human biology today.

Subject of Research: A phylogeny-guided computational method for quantifying human endogenous retrovirus expression and regulation in health and disease

Article Title: ERVmancer: a phylogeny-guided framework for decoding human endogenous retrovirus regulatory mechanisms in health and disease

Article References: Patterson, A., Duong, B., Yoon, L., Foster, M., MacMullen, L., Wickramasinghe, J., Lucas, A., Srivastava, A., Jacobson, S., Murphy, M. E., Soldan, S. S., Lieberman, P. M., & Auslander, N. (2026). ERVmancer: a phylogeny-guided framework for decoding human endogenous retrovirus regulatory mechanisms in health and disease. Genome Biology. https://doi.org/10.1186/s13059-026-04287-5

Image Credits: AI Generated

DOI: 10.1186/s13059-026-04287-5

Keywords: human endogenous retroviruses, HERVs, ERVmancer, phylogenetics, RNA sequencing, short-read mapping, multiple sclerosis, breast cancer, p53, HERVH-LTR7, transposable elements, computational genomics

Viral mimicry was formally described in 2015, when two landmark studies showed that inhibiting DNA methylation in cancer cells could trigger an interferon response without any actual virus being present. The trigger turned out to be endogenous double-stranded RNA derived from endogenous retroviruses and other repeats that had been derepressed by epigenetic drugs. Since then, a large body of work has mapped how this process works at the molecular level. Many transposable elements, including long interspersed nuclear elements such as LINE1 and short interspersed elements such as Alu, retain vestiges of their viral ancestry, including promoter sequences and the capacity to generate RNA species that form double-stranded structures. Pairs of oppositely oriented Alu elements, known as IR-Alus, can fold into intramolecular double-stranded RNA hairpins that are recognized by innate immune sensors such as MDA5, while PKR and ZBP1 provide additional surveillance routes for endogenous double-stranded RNA and Z-form nucleic acids.

The review emphasizes that viral mimicry is not an accidental by-product confined to drug treatment. Cancer-associated alterations in DNA methylation, histone modifications, splicing and RNA processing routinely generate immunogenic nucleic acids in precancerous cells. Global DNA hypomethylation, a common feature of tumour genomes, relaxes repression at repetitive loci; loss of histone marks such as H3K9me3, mediated by enzymes like SETDB1, or disruption of Polycomb repressive complexes derepresses endogenous retroviruses. Splicing defects, which are pervasive across cancer transcriptomes, can create retained introns and aberrant junctions that form double-stranded RNA or Z-RNA structures sensed by MDA5, PKR and ZBP1. Even mitochondrial double-stranded RNA and cytoplasmic RNA–DNA hybrids derived from R-loops can contribute to the endogenous pool of alarm signals. In this sense, the review argues, the pro-tumorigenic regulatory chaos of transformation is inseparable from the collateral production of viral-like nucleic acids.

Viewed through this lens, viral mimicry emerges as a tumour-suppressive mechanism that shapes tumour evolution from its earliest stages. Cells that activate these antiviral programmes can undergo apoptosis, necroptosis, pyroptosis or translational shutdown driven by PKR, or they can attract immune cells through type I interferon signalling that enhances antigen presentation and cytotoxic lymphocyte activity. Recent work describing viral mimicry as a bottleneck in early cancer evolution, including evidence that the pathway acts as a tumour suppressor in inflammatory contexts such as colitis, supports the idea that most cells attempting transformation are eliminated precisely because they cannot simultaneously disrupt their epigenome and silence the repeats that become exposed. Only clones that acquire effective escape mechanisms survive this selective filter, which is why the review frames viral mimicry escape as a prerequisite rather than an option for malignant cells.

The mechanisms cancer cells use to escape are diverse and, the authors argue, reveal a fundamental dependency. On the transcriptional side, tumours often impose compensatory epigenetic repression on repetitive elements, re-engaging DNA methyltransferases, SETDB1, the RB–EZH2 complex or KDM5B to re-silence retroelements. At the RNA level, the editing enzyme ADAR1 converts adenosine to inosine within double-stranded RNA, destabilizing the structures that immune sensors require and acting as a master regulator of viral mimicry escape; high ADAR1 activity is a hallmark of many tumours and is exploited in leukaemia relapse and other contexts. RNA modifications add another layer: N6-methyladenosine deposited by METTL3 and related machinery can reshape double-stranded RNA to prevent sensor recognition and control the fate of endogenous retroviruses. RNA decay enzymes provide a further escape route, with the exonuclease XRN1 degrading retroelement transcripts, while proteins such as DHX9 and the LINE1 ORF1 protein — which acts like a viral innate immune evasion factor — can chaperone or sequester problematic nucleic acids.

Beyond eliminating the trigger molecules themselves, tumours can dampen the downstream signalling that would translate them into an immune response. Sensor pathways can be epigenetically silenced, as has been described for STING and RIG-I–MAVS components in various cancers; interferon signalling itself can be attenuated through regulators such as USP18 and STAT2, or through negative feedback that blunts the antiviral state. Oncogenic drivers also contribute: mutant KRAS in colorectal cancer impairs DDX60-mediated double-stranded RNA accumulation and viral mimicry, converting immunologically hot tumours into cold ones, while p53 loss has been shown to create chronic viral mimicry pressure that selected clones must overcome. Chemotherapy-resistant breast cancers can switch epigenetic states to evade viral mimicry, illustrating that escape is a dynamic, evolving process throughout tumour progression rather than a one-time event.

The review also connects escape mechanisms to biomarkers and therapeutic vulnerabilities. LINE1 ORF1 protein circulating in the blood has been developed as an ultrasensitive multicancer biomarker, and genome-wide repeat landscapes measurable in cell-free DNA reflect the extent of repeat deregulation in individual tumours. Ratios of stemness to interferon signalling have been proposed as biomarkers of progression in myeloproliferative neoplasms. More importantly, every escape mechanism creates a dependency: tumours that rely on ADAR1, XRN1, DHX9, SETDB1 or m6A machinery to survive their own endogenous viral alarm are theoretically vulnerable to drugs that disable those factors. Pharmacological reactivation of viral mimicry — through DNA methyltransferase inhibitors, EZH2 inhibitors, LSD1 inhibitors, spliceosome-targeted therapies, PRMT inhibition or METTL3 blockade — has been shown in preclinical models to restore immunogenicity, and several such approaches are now entering clinical testing.

Combining viral mimicry induction with immunotherapy is a central translational theme. Because viral mimicry activation enhances antitumour immunity and sensitizes cells to immune checkpoint blockade, epigenetic priming with DNMT inhibitors followed by anti-PD1 therapy has shown promise, including in relapsed or refractory NK/T-cell lymphoma, where one of the first trials demonstrating that triggering viral mimicry could augment checkpoint immunotherapy has now been reported. Similar synergy has been observed with EZH2 inhibition in prostate cancer and glioblastoma models, with ZBP1-driven immunogenicity in HER2-directed combinations, and with strategies that restore cGAS–STING and RIG-I–MAVS signalling. Conversely, the review notes that sustained type I interferon signalling can also mediate resistance to some therapies, underscoring that timing, context and combination design matter when manipulating these pathways in patients.

By gathering this evidence into a single conceptual model, the authors propose a reframing of malignant transformation itself: cancer is not simply uncontrolled growth, but uncontrolled growth that has necessarily survived an internal antiviral insurgency of its own making. This unifying model explains why escape mechanisms are so consistently observed across tumour types, why they map onto established dependencies, and why deliberately reactivating viral mimicry represents a rational strategy to expose tumours to their own genome once again. If the framework holds up under experimental and clinical scrutiny, the ancient viral fossils scattered through human DNA may prove to be one of oncology’s most powerful untapped weapons — an alarm that every successful cancer has had to silence, and that medicine may now learn to ring.

Subject of Research: Viral mimicry escape mechanisms in malignant transformation and cancer immunotherapy

Article Title: Viral mimicry escape as a necessary feature of malignant transformation

Article References: Viral mimicry escape as a necessary feature of malignant transformation. (n.d.). https://doi.org/10.1038/s41568-026-00977-1

Image Credits: AI Generated

DOI: 10.1038/s41568-026-00977-1

Keywords: viral mimicry, transposable elements, malignant transformation, epigenetics, interferon signalling, endogenous retroviruses, ADAR1, immune checkpoint blockade, DNA methylation, cancer immunotherapy, innate immunity, double-stranded RNA

Endogenous retroviruses, or ERVs, are the fossilized remnants of retroviruses that once infected the germ-line cells of ancestral hosts. When a retrovirus inserts its provirus into the DNA of a sperm or egg cell that goes on to contribute to the next generation, the insertion can be inherited vertically, copying itself into every cell of every descendant. Over millions of years these elements accumulate mutations, deletions and recombination events, but their diagnostic architecture, including long terminal repeats flanking the core retroviral genes gag, pol and env, often remains recognizable. Because integration events are effectively permanent and their ages can be estimated, ERVs function as paleontological records of the viruses that circulated in host populations deep in evolutionary time.

To recover these viral fossils from the macaque genome, the researchers employed a homology-based, genome-wide screen designed to detect relatively intact proviruses rather than the far more numerous degraded fragments and solo long terminal repeats that litter mammalian genomes. The survey exploited the current highest-quality chromosome-level assembly available for M. fascicularis, an important practical consideration because fragmented assemblies can obscure proviral structure and misplace insertions. Candidate elements were then subjected to structural annotation and phylogenetic classification, anchoring the new macaque sequences within the broader landscape of vertebrate retroviral diversity.

Classification relied on one of the most conserved regions of the retroviral toolkit: the reverse transcriptase domain of the pol gene. Because this enzyme performs the essential step of copying viral RNA into DNA, its sequence is under strong functional constraint and retains enough phylogenetic signal to place divergent elements into their correct lineages. Building multiple alignments of the recovered reverse transcriptase domains and reconstructing their evolutionary relationships, the team found that the macaque proviruses fall into betaretroviral, gammaretroviral and unclassified lineages, with the beta and gamma groups clearly predominating. This pattern mirrors what has been observed in many other mammalian genomes, where betaretroviruses and gammaretroviruses have historically been prolific colonizers of germ lines.

The compositional result carries evolutionary weight. Betaretroviruses, relatives of modern mouse mammary tumor virus and the simian retrovirus SERV, and gammaretroviruses, relatives of murine leukemia virus, differ in their envelope biology, host receptor usage and genomic preferences. A predominance of both classes suggests that the macaque lineage experienced repeated, independent waves of retroviral germline invasion rather than a single dominant radiation. Consistent with that interpretation, dating based on the divergence between the paired long terminal repeats of each provirus, which are identical at the moment of integration and accumulate mutations thereafter, indicated that the 106 loci span a broad range of integration ages, recording multiple distinct epochs of retroviral activity in the species’ ancestry.

The macaque proviruses are also distributed across all chromosomes, a pattern consistent with the idea that integration sites reflect a combination of retroviral target-site preferences and post-insertion forces such as selection, recombination and random genetic drift. Studies in human and mouse have shown that different retroviral genera favor different genomic neighborhoods, with some elements preferentially accumulating in gene-poor regions while others insert near transcription units. The chromosome-wide coverage reported for M. fascicularis means that the new dataset can support analyses of integration preference in a primate genome at a resolution previously unavailable for this species.

The biomedical significance of the work extends beyond evolutionary curiosity. The crab-eating macaque, also known as the cynomolgus macaque, is one of the most widely used primate models in drug development, infectious disease research and transplantation studies, and its endangered status in the wild makes the genomic record it carries all the more valuable to document. ERVs in macaques are directly relevant to laboratory safety as well: previous work has identified and characterized simian endogenous retroviruses in captive macaque populations in Indonesia, raising questions about how these elements behave in breeding colonies. A curated, high-confidence catalog of intact proviral loci gives researchers a framework for tracking ERV expression, recombination and potential co-option in an animal model whose transcriptomes are routinely interrogated.

The broader context of ERV biology reinforces that relevance. In humans, endogenous retroviral sequences have been co-opted for essential functions, most famously the syncytin genes derived from retroviral envelopes that mediate placental cell fusion, and ERV-derived regulatory sequences now contribute to innate immune gene networks. Deregulated ERV expression has also been implicated in a growing list of pathologies, including systemic lupus erythematosus, Parkinson’s disease, neuronal aging and cancer immunotherapy responses, where translated retroviral products can provoke interferon signaling or serve as tumor-associated antigens. Establishing which proviruses are intact in the macaque genome is therefore a prerequisite for asking whether analogous host-virus co-option and immune interactions operate in this model species.

The authors are careful to delineate the scope of their catalog. Because the screen targeted relatively intact proviruses, the dataset deliberately excludes the vastly more abundant degraded ERV fragments and solo long terminal repeats, which form when recombination between the two LTRs of an integrated provirus excises the internal sequence. Those eroded elements represent older and numerically dominant chapters of the retroviral record, and their omission means the 106 loci described here constitute a conservative, high-confidence floor rather than a complete inventory of retroviral genetic material in the macaque genome. Even so, the team notes that the curated set provides a reference resource for investigating the evolutionary history and genomic impact of preserved proviruses in an endangered primate.

The study also joins a rapidly expanding comparative effort. Recent surveys have uncovered endogenous retroviruses in red pandas, ducks and primitive ruminants, and genome-mining approaches have shown that retroviruses have pervasively invaded vertebrate genomes across the tree of life. By adding a systematic account for a close human relative, the macaque analysis helps triangulate which retroviral lineages circulated in the common ancestors of Old World monkeys and apes, and which invasions were lineage-specific. The genome assembly data underlying the work are publicly available through the National Center for Biotechnology Information, and the researchers suggest their dataset will serve as a durable foundation for exploring how viral inheritance has shaped, and continues to shape, the genome of one of biomedical science’s most important animal models.

Subject of Research: Discovery and evolutionary characterization of endogenous retrovirus proviruses in the genome of the crab-eating macaque (Macaca fascicularis)

Article Title: Discovery and evolution of endogenous retroviruses in the genome of crab-eating macaque (Macaca fascicularis)

Article References: Shi, W., Mao, L., Chen, Y., Alfred, N., Fu, Y., Bao, Y., Wang, X., Liu, Y., Yang, S., Ji, L., Zhou, C., Xu, J., Li, W., Shan, T., Wang, J., Zhang, W., & Shen, Q. (2026). Discovery and evolution of endogenous retroviruses in the genome of crab-eating macaque (Macaca fascicularis). Molecular Genetics and Genomics, 301(1), Article 189. https://doi.org/10.1007/s00438-026-02518-9

Image Credits: AI Generated

DOI: 10.1007/s00438-026-02518-9

Keywords: endogenous retroviruses, crab-eating macaque, Macaca fascicularis, retrovirus, genome evolution, provirus, phylogenetic analysis, long terminal repeats, reverse transcriptase, genomics, non-human primate model, viral fossils

Endogenous retroviruses are remnants of infections that occurred over millions of years of evolution. Unlike viruses that spread from cell to cell, these sequences are inherited as part of the genome and are usually restrained by epigenetic mechanisms, including DNA methylation and repressive chromatin structures. In healthy cells, these molecular locks prevent the viral sequences from being transcribed into RNA or producing viral-like molecules. When that repression weakens, however, the genome can begin to generate nucleic acids that resemble the products of an active infection. The immune system may then interpret these signals as evidence that a virus is present, even when no infectious pathogen has entered the brain.

Microglia are particularly important in this process because they continuously survey the neural environment. Their normal functions include clearing damaged material, responding to injury and supporting neuronal health. Short-lived activation can be protective, but persistent stimulation may transform microglia into a source of inflammatory mediators. The study links endogenous retrovirus derepression to this transition, suggesting that the reactivation of viral genetic material can act as an internal alarm system. Rather than responding to an external infection, microglia respond to a disturbance in the genome’s regulatory landscape, initiating innate immune programs that may become damaging when they remain switched on.

At the molecular level, viral-like RNA and other abnormal nucleic-acid signals can be detected by innate immune sensors. These surveillance systems evolved to recognize invading viruses and activate defensive pathways involving interferons, inflammatory cytokines and chemokines. Such signals can alter the behavior of neighboring cells, recruit additional immune activity and reshape the local environment. In the brain, where neurons are highly sensitive to inflammatory changes, prolonged exposure to these mediators can interfere with communication between cells and place additional stress on neural tissue. The findings therefore point to a mechanism through which an epigenetic failure could be converted into a sustained immune response.

The researchers’ central observation is especially significant because it connects three biological events that are often studied separately: the loss of repression over endogenous retroviruses, microglial activation and cellular senescence. Senescent cells are not simply inactive. Although they no longer progress through the cell cycle in the usual way, they can remain metabolically active and release a mixture of inflammatory proteins, growth factors and tissue-remodeling molecules commonly known as the senescence-associated secretory phenotype. In microglia, this state could create a self-reinforcing loop. Viral-like signals may activate the cells, inflammatory signaling may intensify cellular stress, and senescent microglia may then maintain inflammation even after the original trigger has faded.

This proposed relationship offers a new way to think about brain aging. Age-related changes in DNA methylation, chromatin organization and DNA repair can gradually weaken the systems that keep repetitive and viral-derived sequences silent. Similar losses of genomic control have been associated with aging in other tissues, but the consequences in the brain may be distinct because microglia are long-lived immune cells positioned among neurons and synapses. If they become chronically inflammatory or senescent, their altered behavior could affect the support cells and neural circuits around them. The study does not turn endogenous retroviruses into conventional infectious agents; instead, it highlights how their genetic remnants may influence disease without producing a transmissible virus.

The work also has implications for neurodegenerative disorders, in which inflammatory microglia and senescent cells are frequently observed. Conditions such as Alzheimer’s and Parkinson’s disease involve complex interactions among protein accumulation, neuronal injury, immune activation and changes in the aging brain. Endogenous retrovirus activity could represent one contributor within that network rather than a single universal cause. The importance of the new findings lies in identifying a potentially actionable link: if viral sequences are being released from epigenetic control, interventions might aim either to restore their silencing or to block the immune pathways that detect their products.

That possibility raises difficult therapeutic questions. Broad suppression of microglia would be risky because these cells are essential for defense, repair and the removal of cellular debris. Likewise, epigenetic drugs that silence endogenous retroviruses throughout the body could affect many genes and interfere with normal genome regulation. More selective strategies may be required, such as targeting particular retroviral families, interrupting specific nucleic-acid sensing pathways or eliminating senescent cells while preserving beneficial immune responses. Any treatment would also need to distinguish harmful chronic activation from the short-term microglial responses required to protect the brain after injury or infection.

The study’s broader message is that the genome contains more than a static library of protein-coding instructions. Ancient viral sequences can remain biologically influential long after their infectious ancestors have disappeared, and the balance between repression and expression may change during aging or disease. By showing that derepressed endogenous retroviruses can drive microglial inflammation and cellular senescence, Yan and colleagues add a viral-genomic dimension to the biology of brain aging. The findings suggest that some inflammatory processes may begin not with a new pathogen, but with the gradual loss of control over an old one—and that understanding this hidden viral legacy could open new routes for studying neurodegeneration and age-related decline.

Subject of Research: Endogenous retrovirus derepression, microglial activation, neuroinflammation and cellular senescence.

Article Title: Microglia activation by derepression of endogenous retroviruses drives inflammation and cellular senescence.

Article References: Yan, X., Georgopoulou, C., Lee, HM. et al. Microglia activation by derepression of endogenous retroviruses drives inflammation and cellular senescence. Nature Neuroscience (2026). https://doi.org/10.1038/s41593-026-02404-y

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41593-026-02404-y

Keywords: Endogenous retroviruses, microglia, neuroinflammation, cellular senescence, brain aging, epigenetics, innate immunity, neurodegeneration.