The rise of the mammals may be feel like a familiar tale, but there’s a twist you likely don’t know about: If it wasn’t for a virus, it might not have happened at all.
One of the few survivors of the asteroid impact 65 million years ago was a small, furry, shrew-like creature that lived in underground burrows and only ventured out at night, when predators weren’t active. The critter—already the product of some 100 million years of evolution—looked like a modern mammal, with body hair and mammary glands, except for one tiny detail: according to a recent genetic study, it didn’t have a placenta. And its kind might never have evolved one if not for a chance encounter with a retrovirus.
Unlike most viruses, which infect, replicate, and then leave their host, retroviruses elbow their way into their host’s genome where they are copied and passed on to daughter cells for the life of the host. This retrovirus, however, managed to sneak its way into one of our ancestor’s sperm or egg cells, able to be passed on to every cell in every subsequent generation. Virus and host had become one.
The viral DNA used its own genes to copy itself, inserting those copies elsewhere in the host’s genome. These copies could be expressed in different parts of the body at different points in time, a symbiotic relationship that gave the shrew some extra raw materials with which to develop new functions.
“Viral proteins already have functions. It’s much easier to borrow these than to evolve them from scratch,” says Aris Katzourakis, an evolutionary biologist at the University of Oxford.
In that would-be mammal living 160 million years ago, a symbiotic retrovirus enabled it to evolve a placenta over many generations. In order to let a fetus mature inside a mother’s uterus, an animal needed a way to provide oxygen and nutrients while removing waste and keeping both blood supplies separate.
Early mammals used the spare viral parts left in the junk drawers of the genome to use a viral gene to help create the placenta, and other symbiotic viruses help turn us from a ball of cells into a fully-formed squalling infant and protect us from pathogens.
Scientists are discovering that the so-called “junk DNA”—a significant portion of which is from symbiotic viruses—is actually a potent force in the evolution of new species. Although the evolution of pregnancy via the placenta might be some of the most persuasive evidence that viruses stashed deep within the genome can help give rise to new species, it’s not the only proof. New studies revealing the role of endogenous retroviruses in the more recent evolution of humans show that these snippets of DNA are helping to blur the boundary between human and virus. Humans are, in a very real sense, part virus.
“The boundaries between organisms are a bit more merged now, a bit more shadowy. We need to break down those boundaries,” says University of Queensland virologist Paul Young. “The more we look, the more we find overlap,”
Infiltrating the Genome
Viruses can infect all organisms, from the largest blue whales to the tiniest bacteria. To a host, infections can range from unnoticed to deadly. To the virus, however, infection is an opportunity to unleash its incredible genome copying abilities. Within hours, it can make millions or even billions of copies of itself.
Retroviruses, however, use a slower, stealthier approach. After entering the cell, the retrovirus uses an enzyme called reverse transcriptase to turn its RNA into DNA before making its way to the nucleus. Once in the nucleus, it inserts its DNA into the host’s genome.
Most of the time, when a virus integrates its genome with the host’s, the new hybrid genome dies when the cell and its descendants do. Sometimes, however, a virus will infect a sperm or egg cell. If fertilization occurs, the offspring will have a copy of the viral genome in every single one of its cells. It can pass the hybrid genome on to its offspring, creating what scientists call a fully endogenous retrovirus—a fancy term for a virus that comes from within.
The process requires an astonishingly rare set of circumstances be met, Katzourakis says. “Although endogenous retroviruses make up a pretty large proportion of our genome, in terms of the number of times they’ve infiltrated our genome over the past sixty or so million years, it only comes down to about 30 or 40 distinct occasions,” he says.
In humans, even the most recent of these infiltrations happened tens of thousands of years ago. In domestic sheep and koalas, however, retroviruses are currently establishing themselves, which gives researchers the opportunity to watch the process in action. In the 1980s, Queensland veterinarian Jon Hanger noticed something odd in a breeding colony of about 70–80 koalas. Every year, the colony lost around 10% of its members to immunosuppression or cancer, especially leukemias, a cancer of white blood cells.
“About 60 to 70% of the deaths were from cancer. That’s an unusually high number of cancer deaths in any animal, including ours,” Young says.
Although Hanger was working full-time as a veterinarian, he couldn’t shake his curiosity. The mystery drove him back to school to get a PhD on the topic. By 2000, Hanger and Young had identified the full-length retroviral genome that was causing disease in koalas. The virus, however, wasn’t actively transmitted from koala to koala. Instead, a retrovirus had embedded itself in the koalas’ germline and passed from parent to child.
In other words, the virus that was causing disease was located in the koala genome itself.
“This was the first time anyone had seen this happening in real time. All previous endogenous retroviruses had embedded themselves in host genomes many, many millions of years ago,” Young says.
At the breeding colony that Hanger initially studied in Queensland, he and Young found the retrovirus in the genome of every single koala they tested. As they moved northward, toward the city of Cairns, they found a similar picture: every koala carried the retrovirus. Moving south, however, the number of infected koalas dropped. On Kangaroo Island, off the southern coast of Australia near the center of the continent, only a handful of koalas were infected. Examination of koala pelts from museums showed that the retrovirus has been in koala DNA for at least 200 years, according to a 2012 study in Molecular Biology and Evolution, although they think it was present for a few thousand years—the blink of an eye in evolutionary terms.
“It’s amazing that it would have spread through the germline so quickly,” Young says.
Because the introduction of the retrovirus was still so new, the virus hasn’t accumulated many mutations, and the koala’s genetic machinery still actively turns the viral DNA into active virus. That healthy animals also have this virus continues to stump researchers—what’s making the other koalas sick? Nor can they explain how the retrovirus spread throughout the koala population so quickly, especially when it seems to create deadly problems for a significant number of the animals.
One answer may come from another retrovirus that plagues domestic sheep, creating an infectious form of lung cancer. Unlike the koala retrovirus, the Jaagsiekte sheep retrovirus continues to circulate from sheep to sheep, just like a normal virus, but it has also inserted itself into the sheep’s DNA. Ravinder Kanda, a paleovirologist at the Oxford Brooks University in the U.K., says that those sheep that carry a copy of the retroviral DNA are immune to infection from the circulating retrovirus.
“It blocks the receptors that the virus uses to enter the cell so it can’t get in. It provides an immunity benefit,” Kanda says.
Since every virus is different, Katzourakis says it’s impossible to know whether the endogenous retroviruses that came to infect humans followed a similar path. Following the infections as they happen, as well as having an animal model on which to test hypotheses, will likely help us understand how these symbiotic viruses came to play such a powerful role in our own evolution.
A New Force
The idea that a symbiotic virus or any symbiotic relationship could have such a profound influence on the evolution of a new species is both new and controversial. For more than a century after Charles Darwin published On the Origin of Species, scientists focused on competition as evolution’s chief driving force. Biologist Lynn Margulis wasn’t convinced.
The late University of Massachusetts researcher believed that cooperation also played a role. Her evidence lurked in every cell of every plant and animal. Beginning in the late 1960s, Margulis argued that our cells contained symbiotic bacteria known as mitochondria and chloroplasts, which earned room and board by either supplying energy or producing food from sunlight. Margulis’s idea was ridiculed, and she struggled to find a journal that would publish her hypothesis.
By the 1990s, however, enough genetic evidence had accumulated to show that Margulis was right. Symbiosis was responsible for some of the most significant evolutionary leaps in the history of the planet. Most scientists, however, viewed this event as an anomaly, a once-off freak occurrence that, although significant, didn’t play a role in the ongoing evolution of most species. Margulis, though, saw symbiosis everywhere and believed that this softer, gentler side of evolution was getting short shrift in research. Although most symbiosis research has focused on the role of the microbiome, the viruses tucked into our DNA can play a similar role in splitting apart two populations, turning one species into two. The first wedge scientists discovered was a protein called syncytin.
The Virus and the Placenta
Boston in the mid-1990s was humming with the activity of the Human Genome Project. Sequencing technologies had advanced to the point where scientists were incorporating gene discovery into even the most basic research. Since the American courts had thus far allowed companies to patent the genes they discovered, companies like the Genetics Institute (now a part of Pfizer) saw a chance to cash in. There, molecular biologist John McCoy was looking for proteins secreted by cells since they seemed good targets for developing potential drugs.
All was going as planned until McCoy’s bioinformatics specialist Steve Howes rushed into his lab in 1997 to show him the sequence of a gene they called syncytin, which their work showed was secreted by placenta tissue.
Before McCoy could go public with his discovery, he needed to figure out exactly what syncytin did, a job he passed to bench scientist Sha Mi, who everyone called Misha. Misha’s experiments seemed to be going as planned until, a few months later, she, too, rushed into McCoy’s lab with findings of her own.
Syncytin is produced only by certain cells in the placenta, and it directs the formation of the cellular boundary between the placenta and maternal tissue. Approximately one week after fertilization, the egg, now a hollow ball of cells called a blastocyst, implants itself into the uterus, stimulating the formation of the placenta, which provides the fetus with oxygen and nutrients while removing carbon dioxide and other wastes. It also serves as a barrier to prevent infection and keep maternal and fetal blood separate. (Mixing the two could cause a fatal autoimmune response.) The cells in the outer layer of the blastocyst form the outer layer of the placenta, and those in direct contact with the uterus are the only ones that made syncytin.
When the scientists looked closer at the DNA sequence of syncytin, they found that it was nearly identical to a viral protein called env that caused the virus to fuse with its host cell. In the placenta, syncytin performed helped the fetus fuse with its mother. At last McCoy, Howe, and Mi knew what syncytin did.
“This was a bona fide retroviral envelope protein that had somehow been captured during evolution and been trained to operate in human biology,” McCoy says.
The two other retroviral genes next to syncytin, gag and pol, were completely non-functional, McCoy says. Only env remained intact. “Everything else about that retrovirus had been trashed,” he says. The team published a paper in Nature in 2000.
“An important step in mammalian evolution was accomplished by capturing this viral envelope gene,” McCoy says. “There’s plenty of examples of viruses picking up human genes, but this is one of the first examples of the reverse.”
Humans aren’t the only species with a placenta, however. All mammals have placentas, including marsupials and egg-laying mammals. Although all of these mammals have a syncytin gene, they don’t all have the same syncytin gene. The syncytin produced by mice is completely different from the two syncytins found in humans and other primates. At numerous points in mammalian evolution, symbiotic retroviruses entered the genome and steered different groups of mammals along different evolutionary paths, according to a 2012 paper in PNAS by virologist Harmit Malik at the Fred Hutchinson Cancer Research Center in Seattle. Nor was syncytin the only driver.
Renee Reijo Pera, a developmental biologist and embryonic stem cell expert then at Stanford University, had spent nearly two decades trying to understand how pluripotent embryonic stem cells—which have the ability to become any cell type—mature into their specialized adult forms. Through hints from other animals, she realized that symbiotic viruses were a perfect candidate for this job. Even tiny shifts to the timing of certain developmental events could create large changes. If this piece of DNA was inserted in the right location in the genome, it could help control the expression of nearby genes, making it a perfect candidate for modulating early human development.
“By turning the rheostat a bit, by changing the timing, you can actually change development dramatically,” Reijo Pera says.
Reijo Pera, now the vice president of research and economic development at Montana State University, along with fellow stem cell scientist Joanna Wysocka, focused on the rapid changes that occur in the first week after fertilization. At various stages of development, Reijo Pera, Wysocka, and their colleagues measured which genes were expressed in each individual cell.
The team identified genes derived from the human endogenous retrovirus HERV-K that were active around the time when the embryo was just eight cells. Of the many known edogenous retroviruses in humans, HERV-K is the newest—it inserted itself as recently as 200,000 years ago. It’s so new that several of its copies in the human genome can still produce viral protein. To prevent this, adults keep a tight control on HERV-K by switching it off, though this isn’t the case in very young embryos, Reijo Pera and Wysocka found. But far from being detrimental, HERV-K activates key genes that help transform a single cell into a fully-formed infant. These HERV-K viral particles and proteins also help protect the tiny ball of cells from being infected by other viruses, the researchers showed in a 2015 Nature paper.
A follow-up study in Nature Genetics, published in early 2016, found another, HERV-H, which produced RNA molecules that also switch other genes on and off. The 13 HERV-H switches identified by Reijo Pera and Wysocka’s team help keep the early embryonic cells pluripotent, ready for any job as an adult cell. When the researchers blocked the production of HERV-H’s RNA molecules, they stopped embryo development in its tracks. Further experiments showed that HERVH-derived RNAs are also required to turn adult cells back into pluripotent stem cells.
“This DNA, what we used to think of as junk DNA, is actually modulating our development,” Reijo Pera says.
This pair of studies followed on the heels of a 2015 paper in Cell Stem Cell that showed researchers could identify the specific stage of development of an embryonic cell based on which set of endogenous retroviruses were active. When the embryo had just one or two cells, it had the most endogenous retroviruses active, says Jonathan Göke, a computational biologist at the Genome Institute of Singapore and first author of the 2015 study. As the embryo got larger, viral activity dropped dramatically, though it still continued in specific groups of cells as the fetus developed.
“We know that they’re active. We know that they’re important, but we still don’t know exactly what they do,” he says.
The work is still preliminary, says virologist John Coffin at Tufts University, who has spent much of his long career studying retroviruses, including endogenous retroviruses. “You can clearly see the pattern of expression of these genes, but their actual role still remains to be established,” he says.
Blurry Boundary
HERV-K may also have played an important role in separating some of the first humans from their primate ancestors by making small adjustments in when certain genes were switched on or off, according to Reijo Pera’s research. But with tens of thousands of viruses embedded in our genomes, scientists have only just begun to explore their potential effects. In a recent paper in Science, University of Utah geneticist Cedric Feschotte found that these viruses played a key role in the evolution of the mammalian immune system and, even now, continue to tell certain immune system genes when to turn on and off.
“These viruses put us on the fast track to evolve all the bells and whistles needed to evade other viruses,” Feschotte says. “These viruses are already equipped with all kind of weapons to evade our immune systems that now can be recycled.”
Although one of the viruses in question, Mer41, infiltrated the genome 45 to 60 million years ago, one of the proteins it controls is only found in humans. Still, because infectious diseases are so deadly, improving an organism’s ability to survive pathogens (even if this protection is derived from a virus) can cause rapid evolutionary changes. It suggests, Feschotte says, that endogenous retroviruses almost certainly played a role in the evolution of humans and are continuing to affect us today.
“They are still evolving, just as we are,” Feschotte says.
The effects of retroviruses, however, aren’t always beneficial. Originally, many probably caused disease in the organisms they infected. Look no further than Australia’s koalas. But in the case of our endogenous retroviruses, we’re far removed from that time. The genetic results we see today are the silver linings to what otherwise might have been a deadly epidemic, Feschotte says.
Katzourakis and Reijo Pera both believe that endogenous retroviruses are blurring the line between virus and human.
“It’s changing how we think of ourselves as a species. Such an intimate interaction between ourselves and these viruses, and exchanging DNA that’s useful for us, has really molded how we’re now thinking of ourselves as a dynamic soup of DNA that’s now infiltrated by viruses,” Kazourakis says.
Haig puts it more succinctly. “Are these viruses a part of us? They definitely are.”
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