News on February 23, Beijing time, according to foreign media reports,Is there an upper limit to the degree of mutation of the coronavirus? Experts point out that their variation seems to be endless…Although scientific experts from all over the world are racing to develop vaccines for the new coronavirus, the coronavirus is still mutating and genetic changes are also taking place. Including SARS, it is normal for the virus itself to mutate, but is there a certain limit to the degree of virus mutation and human pathogenicity? Or will the coronavirus continue to evolve indefinitely?
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Vincent Lacanello, professor of microbiology and immunology at Columbia University in the United States, said: “There is a certain limit to virus mutation, but we don’t know why this is the case. There may be more genetic mutations than all atoms in the universe. , A large part of the genome can be replaced.”
The genetic sequence of coronavirus is composed of 4 different chemical base pairs or molecules, reaching 29881 biochemical letters in length. These biochemical letters provide 9,860 amino acid instructions. These amino acids are the basic components of viral proteins. When these chemical base pairs change At the same time, the amino acids also change accordingly, which affects the shape of the virus protein. In turn, changes in the shape of the protein will also affect the function of the virus, such as how the virus combines with human cells.
Lacanello said: “Previous research on other RNA viruses, for example: SARS virus has a single-stranded RNA as their genetic material, found that more than half of the base pairs of these viruses can be changed.” From a mathematical point of view, this This means that if a virus has 10,000 base pairs, there will be a possibility of 4^5,000 gene sequences.
Considering that there are 4^135 atoms in the visible universe, applying this formula to SARS-like viruses, then its gene sequence may have 4^14941 combinations. This is just a calculation of the basic biochemical letter changes, a chemical substance To replace the other, Racanello said: “There are other mutations in the genome, such as deletions or insertions, which will further increase the number of possible gene sequences.”
But most of these mutations are irrelevant, and a large part of them will be eliminated immediately. Lacanello said: “Some mutations are fatal, so we have never seen them before, but many mutations are neutral. They just keep accumulating. Important mutations usually occur in the spike protein of the coronavirus, which is the weapon it uses to capture the ACE2 receptor on the surface of human cells. The spike itself is composed of 1273 amino acids, and these amino acids are composed of 3,831 chemicals. Base-pair coding, therefore, according to the same mathematical logic, there are 4^1916 variations in the coding of spike proteins, which are almost infinite. Nevertheless, there are many redundancy in these mutations, which encode the same amino acid.”
In addition, John Moore, a professor of microbiology and immunology at Cornell University in the United States, said that not every mutation can be identified as a “mutation.” Some mutations occur quietly. The identified and named mutations usually have significant characteristics. For example: it is easier to transmit to humans, or vaccines are ineffective.
A powerful monitoring mechanism can help scientists find changes in viral genes through random sampling of infected people. Once they find potentially important mutations, for example, where these mutations appear in the genome, they can insert these mutations into the thorn. In the computer model of the interaction between the spike protein and the ACE2 receptor, they can predict how the mutation will behave, but in order to finally understand how this mutation changes the behavior of the virus, they must experiment with the virus or protein.
The first SARS virus variant was discovered in the spring of 2020, when it was first detected in Wuhan that the original virus was replaced by a new variant called D614G. According to the views mentioned in the “Journal of the American Medical Association” written by Moore, the new Variants may appear in Europe, Moore said, until the end of the summer of 2020, scientists discovered that this virus mutation may enhance their ability to replicate and spread.
Although the degree of mutation of the new coronavirus is not as severe as that of HIV or influenza virus, Moore pointed out that the virus will mutate if it is implanted into 100 million people. In August 2020, another variant of the new coronavirus called B.1.1.7 appeared in the UK. In November of the same year, the spread of the virus variant accelerated. Early studies have shown that the main mutation N501Y of the new coronavirus has increased transmission capacity again, but the antibodies applied to the new coronavirus D614G mutation and other previous coronavirus strains are effective against N501Y.
In addition, a more worrying mutation of the new coronavirus appeared in South Africa. It is called B.1.351 or N501Y.V2. This virus variant is very similar to B.1.1.7 that appeared in the United Kingdom, but it is in the receptor and spikes. There is a mutation in the protein binding region, which is where the spike protein binds to human cell ACE2. The most critical mutation of the new coronavirus is E484K, which changes the shape of the receptor binding region (RBD), which is enough to make it difficult to identify early antibodies New variant strains identified.
Several previous studies have shown that vaccines developed by Moderna, Pfizer, Novavax and Johnson & Johnson can still protect against coronavirus mutations, but they are not as effective as vaccines against early virus mutations.
Another virus variant similar to B.1.351 is called P.1, which also appeared in Brazil. Because of its similarity with the South African new coronavirus variant, its appearance worries scientists. At present, scientists have discovered that some B.1.1.7 virus variants also have mutations, even E484K has mutations.
Lacanello said that the receptor binding region is a region where mutations may occur. It is composed of 223 amino acids, of which 22 amino acids come into contact with the ACE2 receptor on human cells. Any of these amino acids may occur. Change (due to potential mutations in the gene sequence in the receptor binding region) and increase its contact with human cells, thereby enhancing the ability to invade.
Why does the virus mutate?
Mutations sometimes reflect a kind of “founder effect”. The virus mutates. Because the virus variant happens to enter the body of a widely spreading virus, it gradually has a dominant advantage, but this does not necessarily mean that the mutation has an advantage.
Mosan Said, an assistant professor of biochemistry at Boston University School of Medicine and a researcher at the National Laboratory of Emerging Infectious Diseases, said: “But sometimes the same or very similar mutations, such as N501Y mutations, appear in different parts of the world, which usually means Mutations will bring certain advantages to the virus.”
Sayyid said that the current coronavirus is very easy to infect humans, so it may not gain any advantage from mutations in the future. This is equivalent to your radio has been turned on to 10 decibels. If you turn the volume to 11 decibels Time, there will not be much difference.
In the near future, humans will start to inject large-scale coronavirus vaccines. What will happen? Said said: “In this case, the vaccine may stimulate the virus to produce’escape mutations’, thereby achieving the ability to prevent neutralizing antibodies.”
Viral mutations in the future
The SARS virus has spread in humans for a very short time. At present, scientists cannot predict the future variants of the virus based on simulations or virus history. This is very random.
Moore said: “We are not calling the shots. We are just responding to viruses. In other words, virus mutations occur in the wild. Scientists are studying their infectiousness, lethality, and their escape to vaccines. Mutation’s influence, although it is beneficial to be one step ahead of the virus mutation, for example: based on simulation tests to predict whether other mutations may appear, but considering the degree of virus mutation, this may not be feasible. Proteins and receptors or antibodies The interactions are very flexible. They can tolerate viral mutations in many different ways and ultimately achieve the same end point, so you can’t predict what will happen next.”
Lacanello pointed out that scientists may predict some very obvious virus mutations, such as certain amino acid changes on the spike protein that will affect antibody binding, or changes in the receptor binding area of the spike will affect virus adhesion and invasion of human cells. Ability. Although scientists cannot predict which mutations will give the virus an advantage, they know that the more the virus spreads, the more mutations will appear.
Strong selection pressure, such as the use of very effective vaccines, may reduce the chances of virus replication and mutation. At the same time, very weak selection pressure means that the virus does not have to choose to mutate, so any change provides only a negligible advantage.
Troubles come when we exert a moderate level of selective pressure on the virus. For example, when you do not have a strong antibody response, use vaccines with little effect extensively, or extend the time between the first and second doses of vaccines. It may become “a breeding ground for new variants of the virus.” Moore said: “We are now aware of this.”
Therefore, in order to prevent future virus variants, we need to ensure that people are vaccinated on time to prevent the so-called “escape mutation”. We need to prevent the spread of the virus, which will increase the probability of more mutations in the coronavirus.
Moore pointed out that since we cannot predict in advance which specific mutations will occur, if we want to lag behind the virus mutation by two steps, instead of 20 steps, the only way is to greatly strengthen the monitoring of new variant viruses so that scientists can spread the virus. Previously, the effects of new mutations in the virus were discovered and tested in the laboratory. (Ye Qingcheng)
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