Can we predict all the ways in which the SARS-CoV-2 coronavirus could evolve?

At the end of last year, three variants of the SARS-CoV-2 coronavirus (the virus causing the Covid-19 epidemic) spreading rapidly have been identified in the United Kingdom, South Africa and Brazil.

More recently, variants have also emerged in India, in the USA and elsewhere, causing concern. Does the emergence of these variants portend a fight against the pandemic which is likely to be prolonged, or will the coronavirus soon lack room for evolutionary maneuver and become a more benign endemic pathogen?

Predictions regarding the course of SARS-CoV-2, in particular its changes in virulence, will always be uncertain. Even the most discerning of evolutionists cannot claim to be infallible in the face of the challenges posed by random mutations in the RNA molecule, the chaotic routes of transmission and propagation of the virus, or the effects of the forces of natural selection. Nonetheless, the now well-established evolutionary concepts, coupled with the wealth of data collected on the virus itself, can at least provide us with some indication of the most likely developments.

A low margin for innovation

SARS-CoV-2 has passed from an unidentified animal host to humans. In doing so, he entered a new, evolving space filled with obstacles, threats, dead ends and, very occasionally, opportunities. It is difficult to imagine this space or take the measure of it. Indeed, it is annoyingly multidimensional, and its boundaries and topographies can be seen from many points of view.

One way to do this is to start by considering the upper limits of the diversity of the coronavirus genomic sequences, or the limits of its “mutational space”. The SARS-CoV-2 genome has 30 base pairs, in other words 000 sites that can each be occupied by one of the four bases making up RNA (adenine, cytosine, guanine and uracil). There are therefore more than a quintillion (four to the power of 30) of possible genomic sequences, which is roughly equivalent to the width of the Milky Way, expressed in meters.

However, this limit, calculated purely mathematically, does not take into account the biology of the coronavirus. It is therefore totally unnecessary. Indeed, hardly any of these hypothetical genomes could produce a virus capable of functioning properly, that is to say capable of infecting cells and of multiplying there. This fundamental obligation, for the mutations that occur, to keep the viral machinery in perfect working order means that there are evolutionary constraints which limit the speed and efficiency of adaptation of the virus. It's good news.

More good news: the experts are relatively optimistic regarding the threat posed by mutations occurring in the genome of the SARS-CoV-2 coronavirus. This activism reflects the fact that the vast majority of mutations that can occur have minimal or even zero consequences on the functionality of the virus. While this can, in theory, explore immense expanses of mutational space, almost all of them are incapable of giving rise to a functioning virus. And many of those who remain would not be able to change his behavior.

However, if most mutations are harmless, in this mutational space there are also a few microscopic nooks (themselves nested in the heart of microscopic nooks ...) in which genomic changes occurring exceptionally could allow the virus to access innovations. .

How fast does SARS-CoV-2 change?

The sequencing of the SARS-CoV-2 genome has allowed us to observe in great detail the SARS-CoV-2 exploring its mutational space. We now know that its genome acquires a or two transfers per month on average, which, given its size, represents a rate of mutation about four times slower than that of the influenza virus. This result has been widely interpreted as positive. In fact, logic dictates that a more stable genome offers fewer possibilities for the virus to escape vaccines or to engage in other genetic sleight of hand.

In this context, the emergence of the so-called “British” variant (alias “Kent variant”, B.1.1.7 or 20I / 501Y.V1) was remarkable and given food for thought. Sequencing data indeed revealed that he had accumulated 23 mutations (the equivalent of several years of modifications), and apparently all at once. Most of these mutations are of little evolutionary significance, but others are responsible for the increased rate of transmission observed for this variant.

Why and how did it happen? It is during their replication inside a human host that viruses mutate. Some of these mutations can change the way they interact with human cells, including those of the immune system. It is possible that the so-called "British" variant appeared in a single immunocompromised patient, during a long-term infection. We can for example imagine that a convalescent plasma treatment (therefore loaded with antibodies), administered over several weeks, could have enabled the selection of such a variant in such a patient.

Similar "evolutionary spurts" have been observed elsewhere. A “variant of interest” recently appeared in Tanzania, for example, is a carrier of 34 distinct mutations. Examples of recombination, where different genomes of SARS-CoV-2 combine to form a hybrid, were also observed. Although these events are rare, their potential importance for the evolution of the virus should not be minimized. A relatively low average mutation rate does not in fact always correspond to a low evolution rate ...

Many called, but few chosen

The evolutionary pressure resulting from the use of antibody-based therapies (convalescent plasma) was probably the trigger for the emergence of the so-called “British” variant. The most obvious consequence of this development has been the increased propensity of the variant to be transmitted more easily. This reveals that the same set of mutations can give the virus multiple benefits, a phenomenon known as "pleiotropy".

Even though we do not yet fully understand the biological mechanisms involved, we can easily identify the affected mutations from the sequence data, as they have arisen. several times during the pandemic. Indeed, mutations occur "blind", but those which confer an advantage are selected by natural selection, which has already happened several times: this mechanism is called "evolutionary convergence".

A dozen mutations are concerned. They are found, in various combinations, in all variants. They modify the Spike protein - the part of the virus that binds to human cells and allows it to infect them. In doing so, these mutations have led to an increase in the number of infections, and therefore deaths. One can find some comfort, however, in the fact that their number seems to be limited… However, it should also be borne in mind that the properties of SARS-CoV-2 are probably not determined by single mutations, but rather by the interaction of several of them. This combinatorial perspective opens up new areas of potentially fruitful mutational space for the coronavirus ...

Understanding how rare and isolated events can alter the trajectory of the entire pandemic should alert us to the dangers of the uncontrolled spread of SARS-CoV-2. Indeed, just as the chances of winning the lottery increase with the number of tickets purchased, the probability that rare evolutionary events lead to the emergence of new worrying variants increases with the number of infected people ...

Ultimately, while it is difficult to predict how SARS-CoV-2 could evolve, one thing is clear: it is imperative to keep the number of cases as low as possible everywhere in the world, because the new variants do not respect any border.

Ed Feil, Professor of Microbial Evolution at The Milner Center for Evolution, University of Bath

This article is republished from The Conversation under Creative Commons license. Read theoriginal article.

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