• Óscar González-Recio, María de Toro and Miguel Ángel Jiménez Clavero
  • The Conversation*

Mutations in viruses occur from random errors in the replication of their genome as they multiply within the cell. These errors generate the biological diversity necessary for natural selection to act on it.

Viruses do not have the will or control their mutations, but the evolutionary process always results in a better adaptation to the environment. In this case, us.

How does natural selection act on SARS-CoV-2? Basically in two ways: either it removes mutations that are deleterious or harmful or it selects favorable mutations because they have an adaptive value.

Knowing the mutations of the SARS-CoV-2 coronavirus is interesting to carry out genomic surveillance of the pandemic, but also to know the impact that the evolution of the virus may have on it.

Evolution of SARS-CoV-2 throughout the pandemic

Since SARS-CoV-2 made the leap our species has accumulated more than 12,700 mutations. Most have no biological consequences. Others have given rise to new variants. Some of these are called variant of interest (VOI) or variant of concern (VOC).

  • Variant of interest (VOI): variant of SARS-CoV-2 that carries genetic changes that can cause a more severe disease, escape the immune system, affect the diagnosis of the disease or its transmissibility, causing community transmission in several countries, increasing its prevalence with a notable impact on the public health.
  • Variant of concern (VOC): it is a VOI that has demonstrated higher transmissibility, poorer prognosis, higher virulence, or lower efficacy of public health measures, including known treatments and vaccines.

At the beginning of the pandemic (before February 2020), when there was still no control over community transmission of the virus, there was a period of rapid genetic diversification of the virus coinciding with its transmission in each geographic region.

Illustration of antibodies attacking SARS CoV-2.

Starting in March 2020, with the arrival of lockdowns in almost the entire world, a mass extinction and a homogenization of mutations (variants) occurred. The confinements stopped the expansion of some variants.

Following the relaxation of restrictions, there was a new diversification, this time more progressively. This phase of the evolution of the coronavirus had an important geographical component, where the appearance of mutations and variants were grouped by geographical regions.

What would have happened without confinement? We do not know, but it could possibly have caused a greater and more rapid diversification of mutations.

And, therefore, the appearance of a greater number of variants. The evolution of the virus would have accelerated and with it its adaptation to the human being. This would have come at a high cost in lives and loss of health for millions of people.

Convergent selection

To date, more than 100 mutations have appeared that lead to changes in the amino acid sequence of virus proteins.


Something to keep in mind is that some of these mutations have recurrently arisen during the pandemic in different variants or lineages throughout the planet in a completely independent way.

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This indicates that there is a strong selective pressure acting on these positions: this is what is known as evolutionary convergence. The virus repeatedly finds the same solutions (mutations) to better adapt to humans and ensure their survival.

Mutations can also occur that are detrimental to the survival or replication of the virus. This is a purifying selection.

For example, a mutation that is recognized by a certain type of antibody that is very prevalent in a population will cause that variant to disappear in favor of others that do not have it. These cases are difficult to detect without sequencing all cases in the population.

There are three positions in the genome that have undergone key mutations in the evolution of the pandemic to date. The first is the D614G mutation in the spicule protein. The other two are R203K and G204R, which have occurred in the nucleocapsid protein of the virus.

Relevant mutations in the spicule

The spicule of the virus is the key that opens the entrance to the human cell. So it is not surprising that there has been a positive selection at the receptor binding site, favored by those mutations that are more efficient at infection.

The D614G mutation appeared around February 2020. This mutation has been detected in the alpha variant, contributing to its expansion to other geographical areas, mainly European at the beginning. But it also emerged in virtually all variants of interest such as beta and delta.

The D614G mutation is located within the spike protein, which the virus uses to penetrate our cells.

Interestingly, this site is more prone to changes, and the mutation could be due to multiple gains of the amino acid aspartic acid, for a later loss and substitution by glycine.

Some regions of the genome are more susceptible to mutations than others. For example, 31 other mutations have appeared at the spicule binding site.

The different variants are determined based on these mutations. They are a footprint of selection that appear in the different lineages of the virus.

Other spike mutations that have appeared in VOCs include N501Y and E484K, which have been associated with a decreased neutralizing antibody response.

These mutations indicate a rapid adaptation of the virus to humans, remaining those that facilitate contagion between people, and its entry into human cells.

Mutations in the nucleocapsid

If the spicule is the key to entry into the cell, the nucleocapsid is the armor that protects your information inside the cell and ensures its transcription.

The nucleocapsid protein coding region appears to accumulate the highest proportion of positive mutations in the SARS-CoV-2 genome, such as R203K and G204R. Mutations that help protect this genetic material from the virus provide an evolutionary advantage.

Although the nucleocapsid has received less attention than the spike protein, it appears to play a critical role in the evolution of the virus and its adaptation to survive in human cells.

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It is foreseeable that mutations will continue to accumulate in this region of the genome throughout the pandemic. These mutations will result in more efficient replication in our cells.

Future of SARS-CoV-2 evolution

In the year and a half that has passed since the pandemic, SARS-CoV-2 is adapting to humans, as well as different animal species. The main mutations are favoring transmissibility, especially in their rapidity (positive selection). To a lesser extent, they are promoting resistance to immunity (negative selection).


The transmissibility of the virus is high compared to other respiratory viruses, which works in favor of its survival, as well as its relatively wide contagion window in some asymptomatic or presymptomatic infected. Although mortality is relatively low in the global population as a whole, the virus is capable of saturating the health system and having a high mortality rate in groups of advanced ages.

The global fatality rates of the virus are not decisive in the survival of SARS-CoV-2, since the main attack rates occur in less severe stages of the disease. This circumstance means that the evolution of the coronavirus is not determined by what happens after the infection process, in the course of the disease and the subsequent convalescence in the host.

Therefore, it is unlikely that mutations will occur in the virus that involve a drastic change in its lethality (higher or lower). It will be a matter of chance that some mutations end up being more or less lethal.

Yes, it is expected that new mutations will arise that increase the transmission capacity of the virus. Mutations that make the vaccines less effective are also possible. Its success will depend on how quickly a high percentage of the world’s population is immunized.

Cut the chains of contagion with the preventive measures that we know and vaccines continue to be the main measures to end the pandemic.

Though it’s too early to tell can’t be ruled out that the composition of vaccines must be varied in the future to include new variants that can induce a more efficient immune response.

* Óscar González-Recio is a geneticist and Scientific researcher at the INIA-CSIC, National Institute for Agricultural and Food Research and Technology (INIA)

María de Toro is responsible for the Genomics and Bioinformatics Platform, La Rioja Biomedical Research Center (CIBIR)

Miguel Ángel Jiménez Clavero is a virologist and Research Professor, National Institute for Agricultural and Food Research and Technology (INIA)

** This article was published on The Conversation and reproduced here under the Creative Commons license.Click here to read the original version.


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