The human genome is not entirely human.
Some 8% of our DNA, in fact, originated in viruses, remnants of ancients invasions dating back millions of years. By infecting sperm and eggs, viral DNA found its way into germline DNA—the genetic information passed down to future generations—and stuck around.
Researchers can find these fragments and study what they do. But because the pieces burrowed their way into our DNA so long ago, scientists haven’t been able to watch the process unfold in nature—and see how the genome puts up a fight against such an infiltration.
“It’s a rare event, so basically, it’s never been directly studied, certainly not in a mammal,” said William Theurkauf, a geneticist at University of Massachusetts Medical School.
“And that’s where the koala comes in.”
A koala retrovirus, or KoRV, has been rolling through koala populations in Australia from the north to south. It’s passed among the animals like other types of viruses—what’s called horizontal transmission—but it has also started to wriggle its way into the germline. Koalas are now being born with the virus already integrated into their genomes—vertical transmission.
The virus has left koalas susceptible to infections and types of cancer. But it’s also extended scientists an opportunity to research the transition as a virus goes from exogenous (external) to endogenous (built into the genome), a process that hasn’t played out in humans in hundreds of thousands of years. It’s like a marsupial-enabled time machine.
“The koala provided this ideal system because it is quite a spectacular invasion in the wild, in nature,” said Cedric Feschotte, a professor of molecular biology and genetics at Cornell University. “There are relatively few examples of this.”
In a new paper, Theurkauf and colleagues report what appears to be an initial immune-like response that cells deploy to recognize viruses as foreign and to try to stop them from proliferating. It’s not always effective, given that viruses do make it into the genome. But the system that the researchers described works by distinguishing something foreign as different from the self, and tries to block it.
“We think we’ve stumbled on this innate recognition response,” Theurkauf said.
The study, which was published Thursday in the journal Cell, relied on samples—testis, liver, and brain—from two wild koalas that had KoRV.
Researchers who were not involved with the study said it highlighted an important hypothesis, but that the system described doesn’t fully explain how a cell can differentiate between genes from a virus and genes from itself.
“They brought a new piece to the puzzle,” Feschotte said. “The puzzle is not done yet.”
Retroviruses like KoRV replicate by inserting their genome into the DNA of an infected cell. (HIV is the most well-known example of a retrovirus.) If they infect germ cells, the DNA they’re embedding into is the germline, and the viral DNA can potentially catch a ride into future generations.
Generally, once viral DNA gets settled into an animal’s genome, it develops mutations over time and loses its infectious capabilities.
“It’s almost like carbon dating,” said Zhiping Weng, a computational biologist at UMass Medical School and, along with Theurkauf, a senior author on the paper. “You can tell the sequences are old because they pick up a lot of defective pieces, so they don’t work.”
Even after stretches of viral DNA get passed along and mutate over millions of years, they can sometimes still be expressed and make proteins. They have occasionally played a key role in evolution: Endogenous retroviruses helped drive the development of the placenta in mammals, for example.
Generally, though, the animal genome has tools to suppress the expression of viral genes. If this is a secondary immune response to a viral DNA invasion—one that specifically tamps down certain genes—then the system described in the new paper is like a primary, broader defense, Theurkauf said.
Theurkauf likened it to how the immune system responds when you are infected by a virus—like, say, flu. The body identifies the strain of flu that is making you sick and starts making antibodies designed to wipe out that specific virus—what’s called adaptive immunity.
But there’s an initial, innate response in which the immune system recognizes the virus as something generally foreign—different from the host—and tries to fend it off. It’s not as powerful or precise, but it can help buy time as the adaptive response classifies the particular invader and fortifies the antibodies.
“It turns out the genome basically has the same two-phase system” as a general immune response, Theurkauf said.
This innate genome system kicks in when the virus gives away its presence in a cell, according to the new research. When a gene is expressed, a piece of RNA is made with protein-manufacturing instructions. During this process, genetic pieces that are not required for putting together the protein are cut out, or spliced. A virus, however, makes a piece of unspliced RNA. The new paper suggests it’s like a phone ringing in a game of hide-and-seek: the unspliced sequence alerts the cell to the presence of a target. The cell in turn tries to block the virus from replicating.
John Coffin, a virologist at Tufts University, who was not involved with the study, said he wondered if the germ cells’ response was part of the body’s broader immune reaction to recognizing a pathogen—that the genetic battle was one arm of the body’s effort to fend off infection. That would make more sense from an evolutionary perspective, he said.
And Feschotte noted that some host genes are also left unspliced, or get spliced in alternative ways. This means that the system described in the paper has to have other ways of distinguishing host genes from foreign genes.
“The splicing alone is not enough—there’s got to be something else going on,” he said, adding that the paper “brings us one step closer to figuring out” the full process.
For their future research, Theurkauf and Weng are hoping to learn how cells recognize viral DNA in a more detailed way. They’re also trying to get a better sense of how a virus can evade the immune defenses, and find a new home in our genomes.