Why do viruses mutate? Actually, the question we should ask is: how do viruses mutate?
Viruses are not consciously thinking beings that pursue a strategy, they do not decide to mutate or how to mutate, and when this happens, it is the result of the mutation to determine whether it will persist in time, and not the other way around. This is true for all viruses, not only for SARS-CoV-2.
Mutations are random errors that can happen during the replication of the genetic material of either a virus or any other microorganism or cell (including the cells in our body). When it comes to viruses, mutations are more frequent in those with RNA genomes (like the coronaviruses) than in those with a DNA genome.
RNA is a chain of molecules indicated by the letters A, U, C e G. Duringreplication, this sequence is copied by a machinery (enzyme) produced by the virus itself, the RNA polymerase, that although very efficient, can make mistakes introducing the wrong letter (mutation) with a probability of 1 in 1million. This probability would be 100 times greater if the coronavirus enzyme did not have a proofreading activity: it can stop and read what it has just copied and correct possible mistakes. However, some mistakes escape the correction. (As a result, coronaviruses mutate less frequently than other RNA viruses).
This happens every time the virus replicates in our cells (about every 10 hours for each viral particle); considering that each infected person may have billions of viral particles, it is clear that the amount of mutations that can possibly appear during an infection is huge. For this reason, at any given moment during a viral infection, a person hosts many different versions of the same virus, some of them more abundant than others, and not all of them are necessarily identical to those that had started the infection. This assorted population is called viral quasispecies.
Most mutations do not have any effect on the viral activity, while others may represent either an advantage or a disadvantage for the virus or the host, and their future depends on that. If a mutation is a disadvantage for the virus, for example because it impairs replication, that sequence of RNA will be copied lesser and lesser until that specific version of the virus with that mutation will eventually disappear (it is like the mutation will die with the virus).
If a mutation is an advantage for the virus, for example, because it allows it to enter the cells much easier or improves replication, there will be more and more viral particle with that mutation, that in turn will pass it to the next viral generations. In this case, we say that the mutation has been fixed in the genome.
The future of a mutation that does not have any effect often depends on the other mutations present in the same viral particles: if they are linked to beneficial mutations they will have a higher probability to survive in time, on the other hand, if they are in the same sequence with unfavourable mutations, they will most probably disappear.
Natural selection acts on all mutated genomes, in a way that those sequences that allow a better viral performance (better replication, high-temperature resistance, better or faster spreading, resistance to antibodies, adaptation to a new host) will survive (microevolution); indeed, only a small fraction of all mutations will proliferate.
The high mutation frequency and the heterogeneity of viral populations, especially for RNA viruses, can affect the pathogenicity and the control of viral diseases: variants of the same virus can have a different virulence (ability to cause disease). In most cases, however, one single mutation is not enough to alter virulence, and a combination of specific mutations in specific positions must occur to cause a significant effect.
But be aware that a mutation that is favourable for the virus is not necessarily dangerous for humans. Many mutations become fixed in the genome because they allow a better adaptation to the host, meaning that the virus can replicate and spread causing milder disease: in this case the advantage is for both the virus and the host. Don’t forget that viruses are biologically set to replicate and spread, and kill the host is not their function.
In summary, a mutation is a change in a specific position of the sequence, while a variant is a sequence that differs from the reference (the first to be characterized, ore the most abundant) for one or more mutations.
Let’s consider the so-called English variant. Its proper name is B.1.1.7, and it is characterized by 17 mutations, 8 of them in the Spike protein (S). This variant was detected in September 2020 in the South of England, when it was realized that the PCR test was able to recognize only 1 out of 2 portions of the virus sequence in some samples. Following this observation, it was discovered that one of the two target portions was mutated and different from the original sequence used to design the test.
These mutations had probably originated in an immune-compromised patient, in which the virus was able to replicate undisturbed for months, mutating several times and fixing many mutations (including those without a direct favourable effect).
Some mutations in the S protein allow the virus an easier entry into the human cells. This has allowed this variant to rapidly spread in the UK: in January 2021 it was detected in 70% of new infections in London. Other mutations of this variant involve other viral genes and do not confer any clear advantage to the virus.
The initial concern about this variant, was due to the mutation in the Spike protein because there was a fear that it could confer resistance to the antibodies produced after the vaccination (Spike is the target of all vaccines approved so far). However, the results of the studies conducted to date show that all the vaccines currently in use confer some level of protection to all the SARS-CoV-2 variants known at the moment. This is because the antibodies produced after vaccination recognize several portions of S, not only the mutated ones. The vaccines may not confer immunity to all of them, but they will protect from severe forms of the disease. If a new variant able to drastically impair the efficacy of the vaccine would appear, the technology will allow to optimize the vaccine or design a different second dose to overcome the problem.
What can we do to avoid new SARS-CoV-2 variants to emerge? The only strategy is to make it difficult for the virus to spread, this way it will have little chance to replicate and mutate. We already know how to do this: distance, masks, hygiene, and best of all vaccination!
Image: “Coronavirus Close Up Image” by danielfoster437 is licensed with CC BY-NC-SA 2.0.
Bibliography
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Thinking Outside the Triangle: Replication Fidelity of the Largest RNA Viruses, Clinton Smith E. et al., Annual Review of Virology 2014, http://doi.org/10.1146/annurev-virology-031413-085507
SARS-CoV-2 (COVID-19) by the numbers, Bar-On et al., eLife 2020, http://doi.org/10.7554/eLife.57309
Understanding the variants of SARS-CoV-2, Burki T., The Lancet 2021 https://doi.org/10.1016/S0140-6736(21)00298-1
Genetic Variants of SARS-CoV-2—What Do They Mean?, Lauring SA et al., JAMA 2021 https://doi.org/10.1001/jama.2020.27124
https://www.cdc.gov/coronavirus/2019-ncov/transmission/variant.html
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