But the virus fights back – through natural selection.

That is what British researchers argue after they examined the genome of the virus. Their findings can be read in the journal Molecular Biology and Evolution .

Mutation
To understand exactly what the researchers discovered, we first have to dive into the corona virus. SARS-CoV-2 is an RNA virus. The genome of this virus is made up of four so-called nucleobases: cytosine, guanine, adenine, and uracil, also abbreviated as C, G, A and U. These nucleobases in turn form base pairs, which consist of two nucleobases, for example: cytosine and uracil (abbreviated: CU). In their research, scientists focus on these nucleobases and the base pairs they form.

The scientists examined more than 15,000 samples of the virus collected in different parts of the world. Then they looked at how often the four nucleobases (C, G, A, and U) that make up the viral RNA occurred. It is a remarkable discovery. The researchers encountered a striking number of mutations in which cytosine (C) has been converted into uracil (U).

Base pairs
And that mutation often resulted in the creation of a base pair consisting of uracil and uracil (UU). This shows that the base pairs originally made up of cytosine and uracil (CU or UC) actually mutated. And that got the researchers thinking. Because there is a human protein that can mutate viruses in this way. “It appears that the mutation is not involuntary,” said researcher Laurence Hurst. “Instead, we attack the virus by mutating it.”

APOBEC3
The protein in question is referred to as APOBEC3. “SARS-CoV-2 is an RNA virus,” Hurst explains to Scientias.nl . “Our immune cells express a protein – APOBEC3 – which binds to RNA – recognizes certain sequences – and then acts as an enzyme that converts C to U.” The protein focuses in particular on Cs that are accompanied by a U. “This creates many UU pairs.” And when the modified virus copies itself, those changes are also copied, resulting in a mutated version.

Impact
But what impact does that mutation caused by us have on the virus now? The researchers were naturally also curious about this. And they studied the genome again. “Many U’s make the virus unstable,” Hurst said. “And prone to attack by other proteins in us.”

Natural selection
The idea that the mutation does not do the virus any good is further supported by the discovery that the mutation is not passed on as often and therefore does not occur as often as one would expect based on the work of APOBEC3. It suggests that natural selection – the well-known survival of the fittest – throws a spanner in the works. “We estimate that for every ten mutations we see, there are another six that we never see because these mutated viruses are unable to replicate,” said Hurst. “Viruses that contain too many Us may not survive long enough to reproduce.” And so the virus fights back – through natural selection.

Vaccine
The research may have important implications for vaccine development, Hurst thinks. “There are many different ways you can make a vaccine. This way you can make a version of the virus that doesn’t work very well. Such a modified virus can trigger an immune response, but it cannot spread easily at all. ” Vaccines containing such an adapted virus are also referred to as ‘live attenuated vaccines’. “At the moment there are three research groups (for SARS-CoV-2, ed.) That have gone down this path. The problem is that you have to find out what causes a virus to stop functioning properly. Natural selection can tell us that if natural selection promotes anything, it’s probably good for the virus. So if you want to make a live attenuated virus, you should look at it the other way around. If natural selection strongly opposes the addition of U, build in more U. Previous research indicates that many viruses have few CG base pairs. Another protein from us – Zinc Antiviral Protein, ZAP for short – attacks CG base pairs. SARS-CoV-2 also has few CG pairs. So we now suggest that building in more U and more CG base pairs is promising. The virus is much worse than it is now and if we only modify the areas in the RNA that have no further influence on the proteins that the virus produces, then the immune response (which contains the live attenuated vaccine with such an adapted virus in it , ed.), still relies on the good proteins. ” Previous research indicates that many viruses have few CG base pairs. Another protein from us – Zinc Antiviral Protein, ZAP for short – attacks CG base pairs. SARS-CoV-2 also has few CG pairs. So we now suggest that building in more U and more CG base pairs is promising. The virus is much worse than it is now and if we only modify the areas in the RNA that have no further influence on the proteins that the virus produces, then the immune response (which contains the live attenuated vaccine with such an adapted virus in it , ed.), still relies on the good proteins. ” Previous research indicates that many viruses have few CG base pairs. Another protein from us – Zinc Antiviral Protein, ZAP for short – attacks CG base pairs. SARS-CoV-2 also has few CG pairs. So we now suggest that building in more U and more CG base pairs is promising. The virus is much worse than it is now and if we only modify the areas in the RNA that have no further influence on the proteins that the virus produces, then the immune response (which contains the live attenuated vaccine with such an adapted virus in it , ed.), still relies on the good proteins. ”

But the research has even more implications, which also extend beyond SARS-CoV-2. Hurst then thinks of ‘designer genes’, for example. “When we design better genes (for example for gene therapy or laboratory use) or design attenuated genes, we often assume that what is most common in the sequence is also the best. This study shows that U (in the genome of SARS-CoV-2, ed.) Is sometimes very common, but is actually very bad for the virus. So in some contexts it is not the case that what often occurs is also best. ”

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