UC Berkeley
It’s baaack! COVID-19 is surging again, but this time, its symptoms are milder. That’s probably because vaccines and previous infections have led to some degree of immunity. And even when symptoms aren’t mild, we now have treatments to help those most at risk of severe disease. However new evidence suggests that one of those treatments, the medication molnupiravir, causes mutations in the virus and that these mutant viruses can be passed from person to person. Should we be worried?
Where's the evolution?
Mutations are simply changes in the genetic material of an organism. They aren’t necessarily good or bad, and they are happening all the time. The virus that causes COVID, SARS-CoV-2, accumulated many mutations on its own as it spread through the human population and evolved into different variants or lineages — and most of these mutations are not linked to molnupiravir.
To understand why the new research is raising some eyebrows, you need to know how genetic variation contributes to evolution. Genetic variation refers to all the genetic differences there are between different individuals in a population or species. For example, human blood types, skin colors, heights, and much more vary from one person to the next and each is at least partly influenced by which gene versions (i.e., alleles) the person carries. That is genetic variation. Genetic variation is the raw material for evolution. Natural selection acts by increasing or decreasing the frequency of certain genetic variants in a population. More genetic variation means more genetic variants that natural selection can act upon.
Molnupiravir fights SARS-CoV-2 by causing the virus’s genetic material RNA to mutate … a lot. It can cause SARS-CoV-2 to accumulate so many mutations that the virus “breaks” and can no longer function to get itself copied. A virus that can’t replicate won’t get you sicker and can’t spread, or so the reasoning went. When molnupiravir was approved for use in the U.S., the manufacturer reported that no virus capable of spreading was detected after a full course of the drug.
Random mutations: The good, the bad, and the neutral
Random mutations almost always have outcomes that either make no difference to the organism that carries them (neutral mutations) or have a negative impact (sometimes called deleterious mutations). Why? The genetic material in an organism (DNA or RNA) is a set of instructions for making something complicated, much like a recipe for chocolate chip cookies. Now imagine “mutating” that recipe by swapping out the butter for another ingredient randomly selected from the kitchen: peas, juice, ground beef, crackers…you get the idea. Not good! Other sorts of changes to the recipe (randomly introducing typos) might have little effect on the outcome at all if the overall instructions can still be read. Very, very few random changes would improve the flavor of the cookie. That’s because the recipe was developed to make a tasty cookie. Similarly, an organism’s genetic material has evolved to allow the organism to survive and reproduce. Most random mutations will not improve on the work of eons of evolution.
But some scientists wondered, what if the mutated viruses weren’t always too broken to spread? The new research (not yet in its final form) investigating this possibility relies on detecting the sorts of mutations that molnupiravir causes.
The genome of SARS-CoV-2 is made up of a long string of chemical bases designated by the letters A, G, C and U. Molnupiravir frequently causes a G-base in the genome to mutate into an A-base (G→A). Since G→A mutations are normally rare in SARS-CoV-2, the researchers studied what happened with these mutations at times and in places that molnupiravir use became more common – and they found a close association. For example, the team searched databases for SARS-CoV-2 sequences with many G→A mutations, and they found that almost all of those were collected after late 2021, when molnupiravir began its roll out. Furthermore, those viruses with many G→A mutations were much more likely to come from countries in which molnupiravir was approved than in countries that did not approve the drug. And the viruses with many G→A mutations were much more likely to come from older patients, the demographic to which molnupiravir was primarily prescribed. In many cases, the G→A mutant strains formed tight clusters of closely related viruses on an evolutionary tree, or phylogeny. Since the viruses in these clusters were collected from different individuals living in the same country, the evidence suggests that one person who took molnupiravir passed a mutated viral strain on to someone else and that this viral strain did not die out but kept spreading.
While this drug helps individual patients with their COVID infections, the new research implies that it also has the potential to increase the genetic variation of the virus as a population. And this genetic variation could serve as raw material that natural selection shapes into adaptations – to spread more easily or evade our immune systems, vaccines, or medicines. At least that’s the theoretical concern.
So far there is no evidence that this has actually happened – that molnupiravir has caused mutations that help the virus. And no molnupiravir-linked variants have taken off and become widespread. Nevertheless, this possibility is something to consider as we monitor the virus and compare different strategies for treating it. Viral evolution is inevitable and long-term strategies for living with COVID-19 must take this evolution into account.
Primary literature:
- Sanderson, T., Hisner, R., Donovan-Banfield, I., Hartman, H., Løchen, A., Peacock, T. P., and Ruis, C. (2023). A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes. Nature. Accelerated article preview. https://doi.org/10.1038/s41586-023-06649-6 Read it »
News articles:
Understanding Evolution resources:
- How does molnupiravir work against SARS-CoV-2?
- In your own words, explain what a mutation is.
- Is a random mutation more likely to be helpful to the organism that carries it, harmful, or make no difference? Explain your answer.
- In your own words, describe what genetic variation is and why it matters for evolution.
- Describe three lines of evidence that suggest that molnupiravir causes G→A mutations.
- Describe the evidence that suggests that viruses carrying molnupiravir-mutated genetic material are sometimes passed from one individual to another.
- Teach about variation and natural selection: This short film and exercise for grades 9-12 reinforce the concepts of variation and natural selection using the rock pocket mouse system.
- Teach about variation and natural selection: In this high school and college-level lab, students measure the amount of variation in a natural population of terrestrial wood lice and then determine which traits are subject to selection by predators by performing a simulated predation experiment.
- Teach about random mutation and variation: This board game for the high school and college-levels simulates natural selection. It is suitable for an introductory biology class and for more advanced classes where you could go into more detail on important principles such as the role of variation and mutation.
- Sanderson, T., Hisner, , Donovan-Banfield, I., Hartman, H., Løchen, A., Peacock, T. P., and Ruis, C. (2023). A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes. Nature. Accelerated article preview. https://doi.org/10.1038/s41586-023-06649-6