Our Genome’s Viral Graveyard
Just when you thought your body couldn’t get any more microbial, it’s time to meet the ancient viruses buried in your genetic code.
With an estimated 10^31 viruses on earth, it’s perhaps unsurprising that they’ve infiltrated every corner of existence — including between the base pairs of our own DNA. Look closely and you’ll find that viral genes make up a significant proportion of the human genome. This may sound alarming when we consider that the most common contexts in which we discuss viruses involve lethal diseases and global pandemics— but these viral elements are little more than fossils of their infectious ancestors.
But while these so-called endogenous retroviruses are no longer threatening from an infectious standpoint, they are not completely innocuous. As with any disruption to our genetic instructions, the insertion of viral elements into the human genome has had consequences both good and bad. And if not for our viral stowaways, human evolution might have taken a very different course through time.
One step back, two steps forward
Retroviruses as a group have earned a bit of a bad rap — understandably so. Some of the most infamous retroviruses include HIV and human T-cell lymphotrophic virus. But as a group, retroviruses aren’t necessarily nasty. They’re the sleeper agents of the viral world, blending their genetic information in with that of their hosts in the ultimate act of assimilation.
Human cells carry genetic instructions in DNA, which is ultimately transcribed into RNA and translated into proteins, which carry out functions in the cell. Retroviruses carry their genetic information as RNA. Once they enter host cells, they convert the viral RNA into DNA that integrates into the host genome, thus becoming indistinguishable from human DNA. It’s because of this unusual backwards flow of information that retroviruses earn the “retro-” prefix.
Infectious retroviruses con our cells into following these alien instructions to manufacture and assemble new viral particles that can go on to infect new hosts. But if any of these retroviruses integrate into cells that eventually produce eggs or sperm, the viral information may be passed onto future generations alongside our own genes. Such offspring now carry endogenous retroviruses in every single one of their cells.
As unusual as this process sounds, all vertebrate genomes studied so far contain endogenous retroviruses. Humans, of course, are not immune, and these integration events are theorized to have happened 30 or 40 times over the course of our history, until 8 percent of the human genome was purely viral. Eight percent sounds trivial — until you consider that only 1.5 percent of our genome actually codes for proteins, the functioning units of a cell.
However, there’s little to fear in the way of endogenous retroviruses reactivating to create new infectious virus. In the generations since their unceremonious arrival, the vast majority of retroviral elements in our DNA have accumulated mutations and degraded to the point of total loss of function. And much like feral animals turned tame companions in human homes, the wildest parts of the viruses nestled in our DNA have been neutralized as well.
But in our genome’s viral graveyard, a few zombies stir. A small handful of endogenous retroviruses — typically the most recent ones to have hopped into the genome — still harbor residual activity, and are capable of exerting influence on how our own genes are controlled and expressed.
With friends like these, who needs enemies?
At first pass, the insertion of retroviral regulatory elements into the human genome may sound like a frightful genetic experiment resulting in human-virus hybrid monsters. But retroviral relics tend to exert their most common and interesting effects by ramping human gene expression up or down, often with far-reaching consequences on our health.
Less than 2 percent of our DNA codes for proteins. A large percentage of the remainder is regulatory — that is, it controls when our genes are turned on, and, when they are turned on, to what extent. When viruses hop into these genetic control panels, they can disrupt on/off switches that keep cellular growth in check. Such changes can have consequences as disastrous as cancer, a disease that often stems from uncontrolled cellular multiplication.
Furthermore, because endogenous retroviruses are, well, viruses, residual expression of foreign viral proteins from our genome can trick the body into thinking it’s under attack. Even if the viral sequences are degraded to the point that they no longer threaten the creation of active viral particles, even partial expression of viral proteins can still inappropriately trigger our immune system to react. If this occurs to a great enough extent, the ultimate collateral damage may result in autoimmune disease. Such links have been theorized to play a role in lupus, arthritis, and neurological diseases such as multiple sclerosis and ALS.
The genome strikes back
Given that the endogenous retrovirus modus operandi involves haphazard hopping into the genome, it’s unsurprising that their presence can add some unwanted genetic baggage. But retroviral villainy may be the exception rather than the norm. As it turns out, the power of endogenous retroviruses is all about location — and over the course of human evolution, we have managed to co-opt this genetic ammunition for our own purposes as well.
For one, life would literally be less sweet without endogenous retroviruses. Hold a bite of bread or rice in your mouth for a few extra seconds and it’ll start to taste sweet. This is due to the activity of salivary amylase, an enzyme that breaks down starches into simple sugars. Amylase is also produced in the small intestine — and that would be its only domain, if not for a retroviral insertion that transplanted amylase into the mouth.
Even more strikingly, retroviruses appear to be partially responsible for the evolution of placental mammals. An integral part of the viral arsenal involves the machinery required for a virus particle to fuse with human cells, allowing the virus to dump its contents into its new host. This fusion process is strikingly similar to the cellular fusion that occurs in a developing placenta, forming a stable barrier called a syncytium between mother and fetus during pregnancy. The very same viral proteins once used to break and enter into human cells have been repurposed to ensure proper development in utero. Plagued by retroviruses, our mammalian ancestors perservered, ultimately turning the tides and usurping some of their enemies’ most powerful weapons. Incredibly, different lineages of mammals appear to carry different variants of these syncytium proteins — all for the same purpose. Syncytia were so nice, we stole them at least twice.
Finally, the same qualities that can make endogenous retroviruses aggravate certain diseases may also be our most useful tools for combating them. For instance, when cells become cancerous, they often drive up expression of genetic information — including any retroviral elements masquerading as human. In other words, tumors may overproduce endogenous retroviral material. Similarly, HIV, another retrovirus, may awaken endogenous retroviral genes from dormancy in infected cells. These extreme behaviors in sick and infected cells may alert the immune system that something is amiss, and these cells can be subsequently dispatched. Thus, endogenous retroviruses may yet serve as an important homing signal for several targeted therapies of the future.
As we turn our gaze inward to study our body’s microbes, bacteria tend to dominate most media coverage. But as close as our relationship with our gut microbiome is, even this intimacy is dwarfed by viruses, which have not only colonized all the same human surfaces as their bacterial brethren, but also sneaked into our genetic material. And while a few of the consequences of this have been negative, overwhelming evidence points to the idea that viruses have substantially and positively shaped the rise of humans. Evolution, it turns out, was the first to go viral.
Katherine Wu is a PhD candidate at Harvard University, where she studies tuberculosis, a highly prevalent and often antibiotic-resistant bacterial infection. She is Co-Director Emeritus of Science in the News, a graduate student organization that trains scientists to better communicate with the general public, and a 2018 AAAS Mass Media Fellow at Smithsonian magazine.
I Contain Multitudes is a multi-part video series dedicated to exploring the wonderful, hidden world of the microbiome.