Is There an Upper Limit to Coronavirus Mutation?

“There is a limit to how viruses can mutate, but we don’t know why,” said Vincent Lacanello, a professor of microbiology and immunology at Columbia University. “There are more possible genetic mutations than all the atoms in the universe. A large portion of the genome could be replaced.”
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News of Beijing time of sina science and technology on February 23, according to foreign media reports, does the mutation degree of coronavirus have upper limit?
Experts point out that their variation seems to be endless…

Although the world’s scientific research experts are competing to develop novel coronavirus vaccine, but the coronavirus is still in mutation, also in genetic changes.
Include SARS inside, virus itself produces mutation also is normal phenomenon, but does the mutation degree of virus and human pathogenicity have certain limit?
Or will coronaviruses continue to evolve indefinitely?

“There is a limit to virus variation, but we don’t know why,” said Vincent Lacanello, a professor of microbiology and immunology at Columbia University. “There are more possible genetic mutations than all the atoms in the universe. A large portion of the genome could be replaced.”

Coronavirus gene sequence is made up of four different chemical groups on or molecules, length 29881 biochemical letters, these biochemical letters provide 9860 amino acids, these amino acids are an essential part of the viral proteins, when those chemical changes, amino acids also changed accordingly, which affects the shape of a viral proteins, which in turn shape changes will also affect the virus protein function, for example: how the virus together with human cells.

“Previous studies on other RNA viruses, such as the SARS virus that has a single stranded RNA as their genetic material, have found that more than half of the base pairs of these viruses can be altered,” says Lacanello.
Mathematically, this means that if a virus has 10,000 base pairs, there is a possibility of having 4^ 5,000 gene sequences.

Considering the visible universe in 4 ^ 135 atoms, the formula for similar to the SARS virus, then its genetic sequence may have 4 ^ 14941 kinds of combination way, this is just the calculation basis and biochemical changes, a chemical replaces another, Kane said: “there are other mutations in the genome, such as: loss or insert, which will further increase the gene sequence number of possibilities.”

But most of these mutations are irrelevant, and much of this will be eliminated immediately, Kane said: “some of the mutations are fatal, so we have never seen, but many mutations are neutral, they are accumulating, important mutations usually occurs on the spike protein of coronavirus, which it is used to capture human ACE2 cell surface receptors of weapons.
The spikes themselves are made up of 1,273 amino acids, and those amino acids are encoded by 3,831 chemical base pairs, so by the same mathematical logic, there are 4^ 1,916 variations in the coding of spikes, which is almost infinite, but nonetheless, there is a lot of redundancy in these mutations, encoding the same amino acids.”

In addition, not every mutation can be identified as a “mutation,” said John Moore, a professor of microbiology and immunology at Cornell University in the United States. “Some mutations occur quietly, and those that are identified and named often have distinctive characteristics, such as being more likely to be transmitted to humans, or being ineffective against vaccines.”

Powerful monitoring mechanism can help scientists through the random sampling of infected people, scans revealed the change of the virus gene, once they find a potentially important mutations, such as: where are these mutations in the genome, they can insert these mutations and ACE2 spike protein receptor interaction computer model, how to predict the mutation will show, but in the end in order to understand how this mutation change the behavior of the virus, they must do experiment for virus or protein.

Previous mutations

First SARS virus variants were found in the spring of 2020, when the original virus was first detected in wuhan was replaced by a new variant called D614G, according to Moore in the journal of the American medical association mentioned point of view, the new variety may appear in Europe, said Moore, until the end of the summer of 2020, scientists found that the virus mutations could enhance the ability to spread their copy.

While novel coronavirus doesn’t mutate as much as HIV or flu viruses, Moore noted that it can mutate when implanted in 100 million people.
In August 2020, another novel coronavirus variant called B.1.1.7 appeared in the UK, and its spread accelerated in November of the same year.
Early studies showed that the main mutation of novel coronavirus mutation, N501Y, again showed enhanced transmissibility, but antibodies applied to novel coronavirusD614G mutation and other previous coronavirus strains were effective against N501Y.

In addition, a more worrying will be coronavirus mutations appear in South Africa, it’s called b. 1.351 or N501Y. V2, within the virus variation and the British b. 1.1.7 is very similar, but it appears in the receptors and the spike protein in combination with regional mutations, the region is the position of the spike protein combined with human cells ACE2, will be coronavirus is the most key mutations E484K, it changed the shape of the receptor binding region (RBD), early enough to identify antibodies are difficult to identify the new variation of strain.

Several previous studies have shown that vaccines from companies like Moderna, Pfizer, Novavax and Johnson & Johnson can still protect against coronavirus mutations, but are not as effective as vaccines that target early viral mutations.

Another strain similar to B.1.351, called P.1, has also appeared in Brazil, worrying scientists because of its similarity to the South African novel coronavirus variant.
So far, scientists have found mutations in some strains of B.1.1.7, and even in E484K.

La Kane says receptor is a possible mutations area, it is composed of 223 amino acids, including 22 amino acids with human ACE2 receptors on cells in contact, any one of these amino acids is subject to change (because the receptor binding region potential gene sequence mutation), and increase its contact with human cells, so as to enhance their ability to invade.

Why do viruses mutate?

Mutations sometimes reflect a “builder effect,” in which the virus mutates and becomes dominant because the virus variant happens to enter a person who spreads the virus widely, but this does not necessarily mean that the mutation has an advantage.

“But sometimes the same or very similar mutations, such as the N501Y mutation, appear in different parts of the world, and that usually means that the mutation gives the virus some advantage,” said Mosan Said, assistant professor of biochemistry at Boston University School of Medicine and a researcher in the National Laboratory of Emerging Infectious Diseases.

‘The coronavirus is already very susceptible to infecting humans, so any advantage it might get from a mutation in the future might not be that big,’ Dr. Said said. ‘That’s the equivalent of having your radio on at 10 decibels. Turning it up to 11 decibels doesn’t make a big difference.’

What will happen when mass vaccination against coronavirus begins soon?
“In this case, the vaccine might stimulate the ‘escape mutation’ of the virus, which would achieve the ability to block the neutralizing antibodies,” said Said.

Future virus mutations

SARS virus in the human transmission time is very short, currently scientists can not based on the simulation or the history of the virus to predict the future of the virus will be what kind of mutation, there is a lot of randomness.

Moore said: “we don’t call the shots, we only respond to the virus, in other words, the virus mutation happened in the wild, scientists are studying infectious and lethal, they and their impact on the vaccine’s escape mutation, though a step ahead before the virus mutates is useful, for example: based on the simulation test, predict whether other mutations may occur, but considering the extent of the virus, it may be impossible.
The interactions between proteins and receptors or antibodies are very flexible, and they can tolerate viral mutations in many different ways, and they end up at the same endpoint, so you can’t predict what’s going to happen next.”

Kane noted, scientists can predict some very obvious virus mutation, change some amino acids such as spike protein affects the antibodies, or spike receptor area changes affect the virus enters human body cell adhesion and invasion ability, although scientists cannot predict which mutations can bring advantages to the virus, but they know, the more the spread of the virus, can appear more mutations.

Strong selection pressure, such as the use of a very effective vaccine, may reduce the chance of the virus replicating and mutating, while very weak selection pressure means that the virus does not have to choose to mutate, so any change provides only a negligible advantage.

The trouble comes when we apply moderate levels of selection pressure to the virus, for example: when you don’t have a strong antibody response, widespread use of a vaccine that has little effect, or extending the time between the first and second doses, can be a “breeding ground for new strains of the virus.”
“We are now aware of that,” Moore said.

So in order to prevent future mutations, we need to make sure that we vaccinate people on time to prevent what are called “escape mutations,” we need to prevent the virus from spreading, which increases the probability that the coronavirus will mutate further.

Moore points out, because we can’t predict what specific mutations occur ahead of time, to be two steps behind the virus mutation, rather than twenty steps, the only way is to greatly strengthen the monitoring of new variants of the virus, so scientists can before the spread of the virus, found in the laboratory and test the impact of the new virus mutation.