Human endogenous retroviruses (HERVs) are remnants of ancient viral infections, representing genetic “fossils” incorporated directly into the human genome. These sequences, related to modern-day retroviruses like HIV, make up a surprisingly large fraction of our total DNA. HERVs constitute between five and eight percent of the entire human genome, significantly more than the portion that codes for proteins. Although largely inactive, these viral relics are not inert junk DNA; they represent a fascinating evolutionary record that has profoundly shaped human biology through evolutionary co-option.
The Viral Past: How HERVs Integrated into the Human Genome
The process by which these viral sequences became permanent parts of our DNA is known as endogenization. This event began when an exogenous retrovirus successfully infected a germline cell, such as a sperm or an egg, in one of our ancient ancestors. Once inside the germ cell, the retrovirus used its specialized enzyme, reverse transcriptase, to convert its RNA genome into a DNA copy, called a provirus, which then integrated itself into the host cell’s chromosomes.
If that infected germ cell went on to participate in fertilization, the integrated provirus was then passed down to the resulting offspring. This mechanism is a form of vertical transmission, following Mendelian inheritance patterns, rather than the horizontal transmission typical of infectious viruses. Over millions of years, these integration events occurred repeatedly, leading to the accumulation of thousands of HERV copies throughout the primate lineage.
Silent Passengers: The Current State and Structure of HERVs
In the modern human genome, the vast majority of HERVs are non-infectious and incapable of producing new viral particles. This inactivation is due to the accumulation of numerous genetic defects over vast evolutionary timescales. These defects include point mutations, insertions, deletions, and premature stop codons within the viral genes, which have rendered the coding sequences defunct.
However, HERV remnants still possess a distinct structure similar to that of active retroviruses, containing the remnants of gag, pol, and env genes flanked by Long Terminal Repeats (LTRs). The LTRs, which originally regulated the virus’s replication, have largely retained their function as powerful regulatory elements. These LTRs are frequently co-opted by the host genome to act as promoters, enhancers, or transcription factor binding sites, influencing the expression of nearby human genes. Approximately 90% of HERV insertions are now found as solitary LTRs, which arose from recombination events that excised the internal viral genes.
Unexpected Utility: Essential Roles of HERVs in Human Biology
The evolutionary repurposing of HERV genes, a process known as molecular domestication, has provided humans with functions that are surprisingly beneficial. The most well-known example involves the formation of the placenta, a defining feature of mammalian reproduction. The genes for two proteins, Syncytin-1 (derived from HERV-W) and Syncytin-2 (derived from HERV-FRD), are of ancient retroviral origin.
These Syncytin proteins are expressed specifically in the trophoblast layer of the placenta, where they facilitate the fusion of individual cells into a continuous, multinucleated layer called the syncytiotrophoblast. This layer is necessary for nutrient and gas exchange between the mother and fetus, and it also forms a physical barrier that protects the fetus from the maternal immune system. Furthermore, HERV-derived LTRs can regulate the expression of host genes during early embryonic development, including those involved in maintaining pluripotency in stem cells.
The Double-Edged Sword: Links Between HERVs and Disease
While some HERVs have been domesticated for beneficial roles, others are associated with various pathologies, acting as a double-edged sword within the genome. This negative link often arises when HERV sequences are reactivated or overexpressed in certain tissues.
One primary mechanism of harm involves the regulatory LTRs mistakenly activating adjacent host genes, leading to dysregulated expression that can promote disease. This insertional mutagenesis or dysregulation has been linked to the development of certain cancers, where HERV LTRs can act as alternative promoters for oncogenes.
In autoimmune and neurodegenerative disorders, the re-expression of viral proteins is a more direct concern. For instance, the envelope protein derived from HERV-W (specifically Syncytin-1) is found at elevated levels in the brains and cerebrospinal fluid of some patients with Multiple Sclerosis (MS). This re-expressed viral protein can trigger neuroinflammation and an aberrant immune response by binding to receptors on immune cells. However, these links are complex associations, and HERVs are generally considered cofactors that contribute to the disease rather than being the sole cause.