The Coronavirus Is a Master of Mixing Its Genome, Worrying Scientists

In recent weeks, scientists have sounded the alarm about new variants of coronoviruses that carry a handful of small mutations, some of which make vaccines less effective.

But it is not just these small genetic changes that are causing anxiety. Novel coronoviruses have a tendency to merge large portions of their genome when it makes copies of itself. Unlike small mutations, which are like typos in sequence, an event called recombination resembles a major copy-and-paste error in which the second half of a sentence is completely overwritten with a slightly different version.

A flurry of new studies suggests that recombination may allow the virus to shape dangerously. But in the long run, this biological machinery can offer a silver layer, helping researchers find drugs to stop the virus in its tracks.

“There is no question that recombination is happening,” said Nels Alde, an evolutionary geneticist at the University of Ulls. “And in fact, it is perhaps a little discouraging and may also come into play in the emergence of some new forms of anxiety.”

Coronovirus mutations, which most people have heard of, such as in the B1.351 variant that were first detected in South Africa, are changes in the long genetic sequence of the virus or a “letter” of the RNA. Because viruses have a robust system for proofing their RNA codes, these small mutations are relatively rare.

Recombination, in contrast, permeates the coronavirus.

Researchers at Vanderbilt University Medical Center recently led virologist Mark Dennison Studied how things flare up During replication in three coronaviruses, including SARS-CoV-2, which cause covidation. The team found that all three viruses Showed “extensive” recombination when copied separately in the laboratory.

Scientists worry that recombination may allow for different forms of coronavirus to combine into more dangerous versions inside a person’s body. For example, when the version B.1.1.7 was first discovered in Britain, there were over a dozen mutations that suddenly appeared.

Dr. Alde stated that recombination can merge mutations from different types that have co-infected within the same person or with someone over time. For now, he said, the idea is speculative: “It is really hard to see these invisible traces from a recombination event.” And although it is possible to be infected with two variants simultaneously, it is considered rare.

Evolutionary epidemiologist Katrina Lithoghe of the Oxford Big Data Institute in Britain suspects that co-infections occur frequently. “But new forms of anxiety have taught us that rare events can still have a major impact,” she said.

Recombination may also allow two different coronaviruses from the same taxonomic group to swap some of their genes. To examine that risk more closely, Drs. Alde and his colleagues compared genetic sequences of several different coronaviruses, including SARS-CoV-2 and some of its distant relatives known to infect pigs and cattle.

Using specially developed software, scientists highlighted the locations where the sequences of those viruses were aligned and matched – and where they were not. The software suggested that in the past centuries of virus development, many recombination events included segments that make up the spike protein, which helps the virus to enter human cells. This is troubling, scientists said, because it could be a pathway through which one virus essentially infects another.

“Through this recombination, a virus that cannot infect people can recombine with viruses such as SARS-CoV-2 and take a sequence to spike, and be able to infect people. , “Said Stephen Goldstein, an evolutionary virologist who worked with The Study.

The conclusions, which were Posted online on Thursday But not yet published in a scientific journal, new evidence has been introduced that related coronaviruses are quite suitable in terms of recombination with each other. There were also several sequences that were cropped in coronaviruses that seemed to emanate from anywhere.

“In some cases, it almost looks like the sequence is falling from the outer space from the coronavirus, which we don’t know yet,” Dr. Said Alde. Recombination of coronaviruses in completely different groups has not been closely studied, as such experiments would likely undergo government review due to security risks in the United States.

Feng Gao, a virologist at Jinan University in Guangzhou, China, said the unusual software was found in coronavirus from new researchers from Utah, which does not provide evidence for ironclade for recombination. It may just be that they developed that way on their own.

“Diversity, no matter what, does not mean recombination,” Dr. Gao said. “This may well be due to the huge diversity during viral development.”

Scientists have limited knowledge about whether recombination can give rise to new pandemic coronaviruses, said Vincent Munster, a viral ecologist with the National Institute of Allergy and Infectious Diseases who has been studying coronavis for years.

Nevertheless, that evidence is growing. In a study released in July and July Formally published today, Dr. Munster and his colleagues suggested that recombination is likely how both SARS-CoV-2 and the viruses behind the original SARS outbreak in 2003 ended up with a variant of the spike protein that allows them to enter tetragonal cells. The spike protein binds to a particular entry point in human cells called ACE2. That paper calls for greater monitoring of coronaviruses to see if there are people using ACE2 and in this way can pose threats to people.

Some scientists are studying the recombination machinery to not only overcome the next pandemic, but to help fight it.

For example, in his A recent study On the recombination of three coronaviruses, Vanderbilt’s Drs. Denison found that inhibiting an enzyme called nsp14-ExoN in mouse coronoviruses reduces the occurrence of recombination. This suggested that the enzyme is important for the ability of mixtures of coronorvis and their RNA to match as they replicate.

Now, a virologist at the University of Connecticut School of Medicine, Drs. Dennison and Sandra Weller are investigating whether this insight can treat people with Kovid.

Some antiviral drugs such as rhamdasevir fight infection by acting as RNA decoys that gum the viral replication process. But these drugs do not work and some had hoped for coronavirus. One theory is that the nsp14-ExoN enzyme cuts out the errors caused by these drugs, thereby protecting the virus.

Dr. Dennison and Drs. Weller, among others, is looking for drugs that block the activity of nsp14-ExoN, allowing Remedisvir and other antivirals to work more effectively. Dr. Weller compares this approach to cocktail therapy for HIV, which combines 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 in the coronavirus, so a drug that successfully suppresses it may only act against more than SARS-CoV-2. He and Dr. Denison is still in the early stages of drug discovery, testing various molecules in cells.

Other scientists see the potential in this approach, not only to improve drugs like Remedisvir, but to prevent the virus from fixing any of its replication mistakes.

“I think it’s a good idea,” Dr. Goldstein said, “Because you know the virus as ‘error catastrophe’ – basically it will mutate so much that it is fatal to the virus.”

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