Presented by Zia H Shah MD

Abstract

Viruses have been unwitting engineers of mammalian evolution, leaving behind genetic traces that now serve crucial functions in their hosts. Endogenous retroviruses (ERVs) – viral sequences embedded in germline DNA – make up a significant fraction of mammalian genomes and have been co-opted for myriad beneficial rolespmc.ncbi.nlm.nih.gov. Viral-derived genetic elements have reshaped gene regulatory networks and even contributed new protein-coding genes, leading to innovations in physiology and development. For example, viral long terminal repeat (LTR) sequences now act as enhancers and alternative promoters that control host gene expression in a tissue-specific mannerpmc.ncbi.nlm.nih.gov. The immune system bears marks of ancient viral conflicts: viruses have driven extensive adaptive changes in mammalian proteinselifesciences.org, and some captured viral genes now actively defend against infection. One of the most striking virus–host collaborations is in the placenta – a mammalian innovation whose formation and function were enabled by viral genes (such as syncytin) that mediate placental cell fusion, as well as regulatory elements that rewired placental gene expressionpmc.ncbi.nlm.nih.govjournals.plos.org. Viral remnants have also influenced neurobiology; notably, the Arc gene involved in memory is derived from a retrotransposon and exhibits virus-like behavior in neuronspubmed.ncbi.nlm.nih.govneuroscience.stanford.edu. From enabling live birth to refining immune defenses and neural complexity, viruses have repeatedly transitioned from parasites to symbionts. In sum, mammalian evolution has been profoundly shaped by “domesticated” viral elements that now constitute an integral, positive part of our genetic heritage.

Introduction

Viruses are often viewed solely as pathogens, but evolutionary history tells a more complex story. Mammalian genomes are riddled with the DNA remnants of ancient viral infections, especially from retroviruses capable of integrating into host DNA. These endogenous retroviruses and related mobile elements were once dismissed as genetic “junk.” Today, they are recognized as innovation hotspots that mammals have domesticated over millenniapmc.ncbi.nlm.nih.gov. Viral insertions have supplied raw genetic material for evolution to tinker with – new promoters, enhancers, and even whole proteins – some of which have been co-opted for the host’s benefit. This report explores how viruses, particularly ERVs, have contributed positively to mammalian evolution. We examine their roles in shaping gene regulation and genome structure, bolstering the immune system, driving the evolution of the placenta, and influencing neurobiology and development. Together, these examples highlight an emergent theme in evolution: the symbiotic relationship between viruses and mammals, wherein genomic remnants of past viral invasions have been repurposed as instruments of mammalian adaptation and innovation.

Viral Elements in Gene Regulation and Genome Innovation

Far from mere genomic clutter, viral-derived sequences have become important regulators of mammalian genes and architects of genome complexitypmc.ncbi.nlm.nih.gov. Endogenous retroviruses provide abundant cis-regulatory elements – such as LTRs – that serve as promoters and enhancers influencing host gene expression. It is estimated that up to 75% of human genes have multiple promoters, many derived from transposable elements (including ERVs) and used for tissue- or stage-specific expressionpmc.ncbi.nlm.nih.gov. In other words, mammals have frequently “borrowed” viral promoters to fine-tune when and where genes are active. This has expanded the regulatory repertoire without adding new genes, contributing to the greater complexity of gene control in mammalspmc.ncbi.nlm.nih.gov.

One striking example of viral enhancers in action is found in the interferon (IFN) immune response network. A specific ERV sequence (MER41) in the human genome contains binding sites for the interferon-induced transcription factor STAT1pmc.ncbi.nlm.nih.gov. Upon IFN stimulation, MER41 acts as an enhancer: it becomes marked by active chromatin and boosts the expression of nearby genes such as AIM2, which is important for sensing cytosolic DNA and mounting an immune responsepmc.ncbi.nlm.nih.gov. Experimental deletion of the MER41 element was shown to impair induction of AIM2 and other antiviral genes, demonstrating that an ancient viral insertion has been enlisted to fine-tune the modern innate immune responsepmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov. This is a clear case of an exapted viral element that now regulates host immunity.

Viral integration has also introduced alternative splicing and transcript variants in hosts. In germ cells, for instance, an ERV-derived LTR promoter is used to drive an oocyte-specific isoform of the essential enzyme Dicer. This LTR initiates expression of a truncated Dicer transcript needed during oogenesis, and deleting the LTR abolishes that isoform and causes female sterility in micepmc.ncbi.nlm.nih.gov. Thus, a viral sequence is required for normal fertility, illustrating how deeply entrenched these elements can become in developmental programs.

Moreover, endogenous retroviruses are highly and selectively activated during early embryonic stages, where they appear to play critical roles in developmental gene regulation. In cleavage-stage embryos around the time of zygotic genome activation, the ERV-L subfamily is transiently expressed and helps drive totipotency-associated genespmc.ncbi.nlm.nih.gov. Notably, in humans the DUX4 transcription factor binds repetitive HERV-L elements to activate a cascade of embryonic genes at the 2-cell stagepmc.ncbi.nlm.nih.gov. Without this burst of ERV-driven gene expression, the embryo cannot successfully transition from the zygote to a developing blastocyst. Similarly, in pluripotent stem cells, the HERV-H family is abundantly expressed and produces long noncoding RNAs that act as regulatory scaffolds. These HERV-H transcripts recruit transcriptional coactivators (like P300) to nearby genes and maintain stem cell pluripotency; if HERV-H is knocked down, dozens of core pluripotency genes (including NANOG and OCT4) are downregulated and cells begin to differentiatepmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov. In summary, what was once viral “cargo” in our genome is now deeply integrated into the host’s gene regulatory circuits. These exapted viral elements provide binding sites for host transcription factors, serve as alternative promoters, and orchestrate the stage- and tissue-specific expression of host genes – effectively expanding the regulatory architecture of the mammalian genomepmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov.

Viruses as a Force in Immune System Evolution

Throughout evolutionary history, viruses have been one of the dominant drivers of adaptation in mammals. Host populations are in a constant arms race with ever-evolving viruses, and this has left a dramatic imprint on the mammalian genome. A 2016 analysis of mammalian proteomes found that viruses have driven close to 30% of all adaptive amino acid changes in conserved human proteinselifesciences.org. In other words, nearly one-third of the beneficial mutations that spread through our ancestors were likely in response to viral challenges. These adaptations are not limited to classic immune proteins – they span a broad array of virus-interacting proteins involved in many cellular functionselifesciences.org. The innate pattern-recognition receptor PKR, for example, is an antiviral protein that evolved under strong positive selection to detect viral RNA, and many other host proteins show similar signatures of virus-driven evolutionelifesciences.org. Viruses, by forcing hosts to adapt or perish, have shaped the evolution of immune pathways at every turn.

Beyond driving sequence evolution, viruses have also donated genes and gene fragments that bolster the host’s immune defenses. This process of viral gene domestication is exemplified by the co-option of retroviral genes as restriction factors. The best-known case is the Fv1 gene in mice, which originated from the gag capsid gene of an ERV and was repurposed to block retrovirus replicationacademic.oup.com. Fv1 protein binds incoming retroviral capsids and prevents their proper uncoating, thus conferring resistance to murine leukemia viruses. Over ~45 million years of murine evolution, Fv1 and its duplicates have diversified to target different viral strainsacademic.oup.com. Here, an enemy’s gene was turned into a shield – a bona fide antiviral protein derived from an ancient virus itself.

A similar phenomenon has occurred with endogenous retroviral envelope genes. Many mammals carry endogenous env genes (often truncated or altered) that can interfere with infection by related viruses. These viral envelope proteins, embedded in host cells, act as decoys or blockades for virus entry – a mechanism known as receptor interferenceacademic.oup.com. For instance, several ERV-derived Env proteins in mice, cats, and other species bind to cell surface receptors and prevent external retroviruses from using those receptors to enter cellsacademic.oup.com. Some Env variants are produced in a secreted, soluble form and mop up circulating viruses by binding their surface glycoproteins, thereby neutralizing the threatopenwetware.org. By competing for the same binding sites, these domesticated viral proteins essentially vaccinate the host against future infections by their exogenous cousins. Researchers have even observed that HERV-K, one of the more intact human ERVs, expresses a Gag protein in cells that can oligomerize with HIV-1 Gag and disrupt the assembly of infectious HIV particlesen.wikipedia.org. Thus, remnants of ancient retroviruses still present in our genome may actively protect us from modern viruses, turning the tables on what was once a pathogenen.wikipedia.org.

Beyond specific genes, the pervasive presence of ERVs in the genome has had broad effects on immune system function. As mentioned earlier, viral sequences like MER41 have wired themselves into immune gene networks, providing regulatory switches for cytokines and antiviral effectorspmc.ncbi.nlm.nih.gov. ERV transcription can also act as an alarm signal: ERV RNAs and cDNA can be sensed by innate immune receptors, keeping the immune system primed. This “viral mimicry” is thought to play a role in anti-tumor immunity and cellular stress responsesen.wikipedia.org. In essence, the long coevolution of viruses and mammals has blurred the line between self and non-self at the molecular level. Many features of our immune system – from its genetic content to its inducible responses – have been molded by viral influence. What began as an adversarial relationship has, in many cases, transitioned to a form of mutualism: hosts gain new defense tools, while the viral genes gain immortality by being preserved in host genomes.

Endogenous Retroviruses and Placental Evolution

Figure: Viral contributions to the evolution of the placenta. (A) Endogenous retrovirus (ERV) integration installs viral genes (gag, pol, env) flanked by regulatory LTRs into the host genome. (B) Examples of co-opted viral elements in the placenta: A retroviral Env protein (Syncytin-1) is expressed in the outer layer of the placenta, where its fusogenic property drives the formation of the multinucleate syncytiotrophoblast (critical for materno-fetal exchange). Separately, an ERV-derived LTR enhancer has been co-opted to ensure placenta-specific expression of the hormone corticotropin-releasing hormone (CRH), which is involved in timing of parturitionjournals.plos.org. Both the viral protein-coding gene and the regulatory sequence have been repurposed for essential placental functions.

The placenta is a defining feature of eutherian mammals – a complex organ that enabled live birth – and remarkably, its evolution was tightly intertwined with retroviruses. The ancestral mammalian placenta arose over 100 million years ago, and evidence suggests that retroviral infiltrations were catalysts for this innovationpmc.ncbi.nlm.nih.gov. Modern placentas across diverse mammals show a striking enrichment of endogenous retrovirus activity and content, pointing to a deep functional relationshippmc.ncbi.nlm.nih.gov. In fact, one conserved feature of trophoblast cells (the building blocks of the placenta) is their unusually high tolerance for ERV expression, which is otherwise suppressed in most tissuespmc.ncbi.nlm.nih.gov. This tolerance likely evolved because ERVs became integral to placental biology.

A hallmark example is the Syncytin family of proteins. Syncytins are retroviral envelope proteins that have been “domesticated” by mammals to mediate cell fusion in the placenta. During placental development, trophoblast cells fuse to form the syncytiotrophoblast, a continuous multinucleated cell layer that lines the interface with maternal blood. This layer is essential for nutrient/gas exchange and for protecting the fetus from the mother’s immune system. Syncytin-1, derived from an ERV envelope gene (HERV-W in humans), is specifically expressed in the syncytiotrophoblast and is directly responsible for cell-cell fusion of trophoblastspmc.ncbi.nlm.nih.gov. In vitro, expressing Syncytin-1 can induce fusion of cells, and blocking Syncytin-1 with neutralizing antibodies or siRNA prevents trophoblast fusionpmc.ncbi.nlm.nih.gov. Conversely, in mice, the deletion of an equivalent syncytin gene causes lethal defects in placental development, underscoring its necessity. Notably, syncytin genes have independently arisen from different retroviruses in various mammalian lineages – from primates to rodents to even some viviparous reptiles – a striking case of convergent viral domestication for the same vital functionacademic.oup.com. The viral Env protein is supremely suited for this task, as it naturally drives membrane fusion during infection; co-opting it allowed mammals to evolve a novel cell fusion program for placenta formation. In addition to fusogenic activity, some syncytin Env proteins retain an immunosuppressive peptide segment that can locally dampen maternal immune responses, helping the semi-foreign fetus evade rejection. In these ways, a retroviral gene became an indispensable structural and immunological component of mammalian reproductionjournals.plos.org.

Beyond providing a specific protein, retroviruses have fundamentally reorganized the genetic regulatory networks of the placenta. Placental cells exhibit unique gene expression profiles, and a growing body of evidence shows that ERV-derived LTRs act as placenta-specific enhancers and promoters for many genesjournals.plos.org. In humans, an endogenous retroviral LTR insertion (from the HERV family) was recently found to serve as an enhancer for the gene encoding corticotropin-releasing hormone (CRH)journals.plos.org. CRH is produced by the placenta and plays a role in determining the timing of birth. The co-opted LTR provides placenta-specific regulatory elements that ramp up CRH expression during pregnancyjournals.plos.org. Such exaptation of viral DNA has likely occurred repeatedly – one analysis identified hundreds of placental enhancers derived from ERVs, each contributing to the lineage-specific gene expression programs in different mammalsacademic.oup.compmc.ncbi.nlm.nih.gov. For instance, in the mouse placenta, an ERV sequence called RLTR13D5 functions as an enhancer bound by key trophoblast transcription factors (like Cdx2 and Elf5), and is required for normal expression of nearby developmental genespmc.ncbi.nlm.nih.gov. The implication is profound: an ancient retroviral infection may have jump-started the origin of the placenta by wiring a set of existing genes into a new regulatory network via its LTRspmc.ncbi.nlm.nih.gov. Over time, as additional ERVs invaded various mammalian genomes, their regulatory sequences provided a “continuous stream of novelty” to further tweak and diversify placental development in each lineagepmc.ncbi.nlm.nih.gov. This model explains why placentas differ so much between species (in structure and gene expression), despite fulfilling the same basic role – each lineage’s placenta has been shaped by a slightly different palette of viral insertions and domestications.

In summary, what was once a pathogenic retrovirus infecting a distant ancestor has been transformed into an enabler of viviparity. The co-option of viral genes like syncytin was pivotal for the emergence of the placenta, and the assimilation of viral regulatory elements gave placental mammals an evolutionary fast-track to develop new traits and adapt their reproductive strategiespmc.ncbi.nlm.nih.gov. The placenta’s very existence may hinge on these long-ago viral invasions; as a PLOS Biology primer mused, human pregnancy might look radically different – or might not exist at all – were it not for “eons of retroviral pandemics” in our ancestorsjournals.plos.org. The once parasitic viruses have become symbiotic partners, deeply embedded in the genetic blueprint of mammalian reproduction.

Viral Influence on Neurobiology and Development

Viruses have also made surprising contributions to mammalian neurobiology and development. Perhaps the most startling discovery in this realm is that a gene crucial for learning and memory in mammals derives from a retrotransposon. The Arc gene (Activity-regulated cytoskeleton-associated protein) is essential for long-term memory formation and synaptic plasticity in the brain. In 2018, it was shown that Arc originated from a vertebrate Ty3/gypsy retrotransposon, making it a distant cousin of retrovirusespubmed.ncbi.nlm.nih.gov. Arc retains domains homologous to retroviral Gag proteins – the viral capsid-forming proteins. In neurons, Arc behaves in an eerily virus-like manner: the Arc protein self-assembles into virus-like capsids that can encapsulate Arc mRNA, and these capsid-RNA complexes are released in extracellular vesicles and taken up by neighboring neuronsneuroscience.stanford.edu. In essence, neurons appear to repurpose Arc to facilitate intercellular communication, sending mRNA messages across synapses in a way that resembles retroviral infection (but without pathogenicity)neuroscience.stanford.edu. This Arc system is thought to be important for synaptic coordination and memory consolidation across neuronal networks. The fact that such a fundamental neurological process – memory storage – is carried out by a repurposed viral element is a stunning illustration of evolutionary creativity. An ancient retroelement invaded the germline, and instead of causing harm, it was domesticated and integrated into the complex machinery of cognition. Arc’s viral origin may even explain its ability to undergo activity-dependent self-oligomerization and vesicle budding, properties not commonly seen in typical host proteins. In the grand scheme, the co-option of Arc highlights how viruses have contributed to the emergence of novel cellular functions in the brain, potentially giving mammals (and other vertebrates) enhanced capacity for neural plasticity and learningpubmed.ncbi.nlm.nih.gov.

Viruses have left their mark on earlier stages of development as well. We have already seen how ERVs like HERV-H and HERV-L are indispensable in embryonic stem cells and 2-cell embryos, acting as regulators of gene expression during totipotency and pluripotency. These viral sequences drive the expression of genes that orchestrate developmental transitions, essentially acting as molecular switches that ensure the embryo proceeds through the correct program. For example, the activation of HERV-L by DUX4 in the human 2-cell embryo is required to kick-start the embryo’s genome after fertilizationpmc.ncbi.nlm.nih.gov. Without this ERV-driven zygotic genome activation, early development fails. As another example, the oocyte-specific LTR promoter mentioned earlier (for Dicer) ensures that the egg has the proper RNA interference machinery in place, which is critical for maturation and early zygotic developmentpmc.ncbi.nlm.nih.gov. These cases demonstrate that viral elements are not idle passengers but active participants in developmental gene regulation from the embryo’s first divisions.

Intriguingly, endogenous retroviruses might also play roles in the development and function of the nervous system beyond Arc. ERV expression is dynamically regulated in the developing brain, and there is evidence that transient “burst” activation of certain ERVs in neural precursor cells can influence differentiationpubmed.ncbi.nlm.nih.govpubmed.ncbi.nlm.nih.gov. The host tightly controls ERV activity in the brain through epigenetic mechanisms (e.g., the TRIM28/KAP1 repressor is crucial for silencing ERVs in neural progenitorspubmed.ncbi.nlm.nih.gov). If this repression is lifted at the wrong time, it can lead to neurodevelopmental issues or neurodegeneration. However, some level of ERV expression may be normal – or even beneficial – in the brain. An intriguing finding is that human endogenous retrovirus HERV-K is expressed in response to certain neural stressors and appears to confer resistance to neurotoxic insultspubmed.ncbi.nlm.nih.gov. In cell culture and mouse models, HERV-K activation was associated with protection of neurons against toxic exposures, hinting that an ancient viral element could play a modern neuroprotective rolepubmed.ncbi.nlm.nih.gov. While the mechanisms remain unclear, one possibility is that low-level viral element expression in the brain induces innate immune pathways or stress responses that precondition cells to withstand damage. It would not be the first time a pathogen-associated molecular pattern is co-opted for normal physiology.

Overall, the contributions of viral elements to neurobiology and development underscore a recurring theme: evolutionary novelty often springs from unlikely sources. What started as viral infections became, through gradual adaptation, a source of genetic innovation for the host. From enabling synaptic communication in the brain to controlling gene expression in embryos, viruses have insinuated themselves into the very fabric of mammalian developmental biology. These examples challenge us to rethink the long-held view that foreign DNA is inevitably harmful – in many cases, viruses have been creative partners in evolution, donating their toolkit to enhance the host’s capabilities.

Epilogue: Symbiosis in Evolution – Mammals and Their Viruses

The story of mammals and viruses is often framed as a never-ending conflict, but as we have seen, it is equally a story of cooperation and co-evolution. Viruses have punctuated our evolutionary history with episodes of intense struggle, yet those same episodes have forged new adaptations and even new biological features. The endogenous viral elements sprinkled throughout our genome are like molecular fossils of ancient battles – fossils that have been reshaped into tools for the present. In the tapestry of mammalian evolution, viruses emerge not only as agents of disease, but also as drivers of genetic innovation, introducing sequences that have been repeatedly assimilated for the host’s benefitpolytechnique-insights.com. The relationship is almost poetic: a chance viral insertion, once perhaps deleterious, can become over time an indispensable part of the host organism.

Modern genomics and virology are now revealing just how deeply interwoven our fates are. The very traits that make us mammals – live birth, complex brains, intricate immune systems – carry imprints of viral ancestry. We carry within us genes that came from viruses and now define who we are. Our placenta is, in a sense, a collaborative organ built with viral as well as cellular genes. Our genome regulation is indebted to legions of endogenous retroviruses that collectively expanded our regulatory DNA and gave our cells new ways to control genes. Even our daily thought and memory might hinge on a protein that began as a retroelement’s capsid. These realizations exemplify the concept of endogenous viral symbiosis: once-parasitic elements have become co-opted symbionts, to the point that the host’s survival and fitness may depend on them.

Looking ahead, the symbiotic relationship between viruses and mammals continues to evolve. Human endogenous retroviruses, for example, are typically dormant, but they can be awakened under certain conditions and potentially play roles in aging and disease – reminding us that the line between helpful and harmful is thin and context-dependent. Yet, the very presence of these elements also offers potential therapeutic avenues (such as viral mimicry in cancer therapy or using syncytin’s fusogenic power in biomedical engineering). In essence, the long viral legacy in our genome is a double-edged sword – one that evolution has wielded to great effect.

In reflection, the interplay of viruses and mammals over millions of years reveals evolution not just as a survival of the fittest, but as a creative process—one that recycles and retools genetic information across the tree of life. Mammals are who they are in part because viruses made their home in our ancestors’ DNA and never left. What began as viral infections ended as innovations. As one article aptly noted, we must rethink our view of viruses: they are not only sources of disease, but also sources of genetic novelty and evolutionary opportunitypolytechnique-insights.com. The saga of endogenous viruses teaches a humbling lesson: the foes of the past can become the allies of the future. Mammalian evolution is a testament to this remarkable symbiosis – an ongoing dialogue between viral and host genomes that has written and rewritten the rules of life, ultimately enabling mammals to thrive in a changing world.

References: The contributions and examples discussed above are supported by up-to-date scientific findings from genomics, evolutionary biology, and virology researchpmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.goven.wikipedia.orgjournals.plos.org, among others, as cited throughout the text. These sources collectively illustrate the positive influence of viral genetic elements on mammalian gene regulation, immunity, placental biology, and neurological innovation. The evolving understanding of virus–host co-evolution continues to be enriched by new discoveries, painting an increasingly detailed picture of our intimate and symbiotic history with viruses.

If you would rather read in Microsoft Word file: