In recent weeks, scientists have raised the alarm about new variants of the coronavirus that carry a handful of small mutations, some of which appear to make vaccines less effective.
But it is not just these small genetic changes that are raising concerns. The new coronavirus has a tendency to mix up large chunks of its genome when making copies of itself. Unlike small mutations, which are like typos in the sequence, a phenomenon called recombination resembles a big copy and paste error in which the second half of a sentence is completely replaced by a slightly different version.
A flurry of new studies suggests that recombination may allow the virus to change in a dangerous way. But in the long run, this biological mechanism may offer a silver lining, helping researchers find drugs to stop the virus on its way.
“There is no doubt that recombination is taking place,” said Nels Elde, an evolutionary geneticist at the University of Utah. “And, in fact, it’s probably a little underestimated and may be at stake even in the appearance of some of the new variants of concern.”
The coronavirus mutations that most people have heard of, such as that of variant B.1.351 first detected in South Africa, are changes in a single “letter” of the long genetic sequence of the virus, or RNA. Because the virus has a robust system for reviewing its RNA code, these small mutations are relatively rare.
Recombination, in contrast, is common in coronaviruses.
Researchers at Vanderbilt University Medical Center led by virologist Mark Denison recently studied how things go wrong during replication in three coronaviruses, including SARS-CoV-2, which causes Covid. The team found that all three viruses showed “extensive” recombination when replicating separately in the laboratory.
Scientists fear that recombination may allow different variants of the coronavirus to combine into more dangerous versions within a person’s body. Variant B.1.1.7 first detected in Britain, for example, had more than a dozen mutations that appeared to appear suddenly.
Dr. Elde said the recombination may have merged mutations of different variants that spontaneously appeared in the same person over time or that co-infected someone simultaneously. For the time being, he said, this idea is speculative: “It is very difficult to see these invisible scars from a recombination event”. And although it is possible to be infected with two variants at the same time, it is believed to be rare.
Katrina Lythgoe, an evolutionary epidemiologist at the Oxford Big Data Institute in Britain, is skeptical that co-infection happens frequently. “But the new variants of concern have taught us that rare events can still have a big impact,” she added.
Recombination can also allow two different coronaviruses from the same taxonomic group to exchange some of their genes. To examine this risk more closely, Dr. Elde and his colleagues compared the genetic sequences of many different coronaviruses, including SARS-CoV-2 and some of their distant relatives known to infect pigs and cattle.
Using specially developed software, the scientists highlighted the places where the sequences of these viruses aligned and matched – and where they did not match. The software suggested that in the past two centuries of virus evolution, many of the recombination events involved segments that formed the spike protein, which helps the virus enter human cells. This is worrying, the scientists said, because it could be a route by which one virus essentially equips another to infect people.
“Through this recombination, a virus that cannot infect people can recombine with a virus like SARS-CoV-2 and take the sequence as a peak, and it can become capable of infecting people,” said Stephen Goldstein, a evolutionary virologist who worked on the study.
The findings, posted online on Thursday but not yet published in a scientific journal, offered new evidence that related coronaviruses are quite promiscuous in terms of recombination with one another. There were also many sequences that appeared in the coronaviruses that seemed to appear out of nowhere.
“In some cases, it almost seems like there is a sequence falling from outer space, from coronavirus that we don’t even know yet,” said Elde. Coronavirus recombination in entirely different groups has not been studied closely, in part because such experiments would have to undergo government review in the United States due to security risks.
Feng Gao, a virologist at Jinan University in Guangzhou, China, said that although the new software from Utah researchers found unusual coronavirus sequences, it does not provide solid evidence for recombination. It may simply be that they evolved that way on their own.
“Diversity, no matter how much, does not mean recombination,” said Dr. Gao. “It may well be caused by great diversification during viral evolution.”
Scientists have limited knowledge about whether recombination can give rise to new pandemic coronaviruses, said Vincent Munster, a viral ecologist at the National Institute of Allergy and Infectious Diseases who has been studying coronaviruses for years.
Still, that evidence is growing. In a study launched in July and formally published today, Dr. Munster and his collaborators suggested that recombination is probably how SARS-CoV-2 and the virus behind the original SARS outbreak in 2003 ended with a version of the spike protein that allows them to skillfully enter human cells. This peak of protein binds to a certain point of entry into human cells called ACE2. That document calls for increased surveillance of coronaviruses to see if there are others who use ACE2 and can therefore pose similar threats to people.
Some scientists are studying the recombination machine not only to prevent the next pandemic, but also to help fight it.
For example, in his recent study on the recombination of three coronaviruses, Dr. Denison de Vanderbilt found that blocking an enzyme known as nsp14-ExoN in a mouse coronavirus caused a sudden drop in recombination events. This suggests that the enzyme is vital to the ability of coronaviruses to mix and match their RNA as they replicate.
Now, Dr. Denison and Sandra Weller, a virologist at the University of Connecticut School of Medicine, are investigating whether this discovery could treat people with Covid.
Certain antiviral drugs, such as remdesivir, fight infections by serving as RNA baits that block the viral replication process. But these drugs do not work as well as some expected for coronaviruses. One theory is that the nsp14-ExoN enzyme eliminates the errors caused by these drugs, thus rescuing the virus.
Dr. Denison and Dr. Weller, among others, are looking for drugs that block nsp14-ExoN activity, allowing remdesivir and other antivirals to work more effectively. Dr. Weller compares this approach to HIV cocktail therapies, which combine molecules that act on different aspects of virus replication. “We need combination therapy for coronavirus,” she said.
Dr. Weller notes that nsp14-ExoN is shared among coronaviruses, so a drug that successfully suppresses it could act against more than just SARS-CoV-2. She and Dr. Denison are still in the early stages of drug discovery, testing different molecules in cells.
Other scientists see potential in this approach, not just to make drugs like remdesivir work better, but to prevent the virus from fixing any of its replication errors.
“I think it’s a good idea,” said Goldstein, “because you would push the virus into what is known as an ‘error catastrophe’ – basically, it would mutate so much that it would be lethal to the virus.”