The viruses that plagued our ancestors millions of years ago aren't ancient history—they're still with us. Remnants of viral genes make up a relatively large part of our modern DNA, and scientists have been mostly uncertain what roles, if any, they play.
Now evidence suggests that during human evolution we've co-opted leftover genetic material from some of these "fossil viruses" to turn the tables and help our immune system fight diseases.
Scientists have known that our DNA is peppered with bits of viruses since the human genome was first sequenced some 15 years ago. Still, “it is surprising to many people,” says study co-author Cedric Feschotte, a geneticist at the University of Utah. “It's almost unsettling.”
The extra genetic code comes specifically from retroviruses, which invade host cells in a unique way. “Among all animal viruses, they are the only ones that integrate their own genetic material into the chromosomes of their host,” Feschotte says.
When ancient retroviruses infected our ancestors, they occasionally infiltrated a human sperm or egg cell. If those cells went on to fertilize an embryo, any viral genes incorporated into them had a ticket to ride from one generation to the next.
Along the way, these invaders' DNA sometimes gave rise to new viruses—but only for a while. Over the generations, genetic mutations gradually altered these viruses and eventually shut down their ability to infect new cells or fully replicate themselves. Today, most of the ancient viral oddities left in the human genome have no obvious function.
“It's important to understand that out of this 8 percent—these hundreds of thousands of bits and pieces of DNA scattered throughout the whole genome—most of that material just sits there and decays,” Feschotte explains. “Our job, and really that of our post-doctoral associate Ed Chuong, who did all this work, was to find the needles in the haystack—to identify some of those few elements that may have been co-opted for cellular innovation in the course of evolution.”
As part of their work, the scientists looked at pieces of ancient retroviruses that sit near genes known to function in immunity. They found that the fossil viruses activate when exposed to signaling proteins called interferons, which are released by white blood cells and other cells during a viral infection. Interferons inhibit viral growth and launch the production of anti-viral proteins in other nearby cells.
The team then looked at three different lines of human cells to see if fossil viruses in their genomes could bind with pro-inflammatory signaling proteins that help to fire up the immune system. They identified 20 families that did so, including one dubbed MER41 that entered our evolutionary tree as a virus some 45 to 60 million years ago.
The team then explored how the immune system functioned without some of these viral components. They used a genome editing tool called CRISPR/Cas9 to remove four pieces of the remnant virus DNA. Each time they did so, it crippled our innate immune system—the cells didn't fully respond to interferons as they had before, the team reports this week in Science.
The researchers speculate that such regulatory switches once ensured that the ancient virus would be able to replicate itself ahead of the immune response, a strategy that has been seen in modern retroviruses, including HIV.
“We were not too surprised to see that 50 million years ago a virus out there might have already been using that strategy for its own selfish purpose,” Feschotte says. "It is ironic that the tables have turned, and that these viral-derived elements have been co-opted to regulate genes that control, among other things, viral infections.”
The study is exiting because it adds to the mounting evidence for the ways genetic material from ancient viruses has been repurposed to our advantage, says University of Oxford medical virologist Gkikas Magiorkinis. For example, a protein called syncytin, which is essential for building the placenta in mammals, is derived from an ancient viral gene that once helped the virus to spread in the body.
“It's only rarely that it happens that some of these viral sequences were landed at the right spot at the right time, but clearly there have been many opportunities, and that's the key,” Feschotte says. “This is likely the tip of the iceberg."
Magiorkinis notes, though, that while viral DNA does seem to give our genes a boost under certain circumstances, it's not necessarily something that was indispensable for our survival. Instead, some viral helpers likely became active because they gave ancient humans an advantage under specific circumstances.
“For example,” he speculates, “a boost of the innate immune responses as described in the paper is likely to have provided a way to fight an ancient epidemic caused by the exogenous form of the retrovirus, or maybe even another one.”
Similar processes could also have produced darker results. Such viral remnants have been linked to numerous ailments, including the neurodegenerative disease ALS. The role these genes may play in this and other ailments remains murky, but Feschotte and his team think their work may offer new clues to the reasons viral remnants become active in our genome and what happens when that process goes awry.
“The reactivation of some of these viral-derived switches could suggest a testable hypothesis as to what could happen when these viral sequences become misregulated, for instance in the context of certain cancer and autoimmune diseases,” he says.