What Mutations of SARS-CoV-2 are Causing Concern?

As viruses are exposed to environmental selection pressures, they mutate and evolve, generating variants that may possess enhanced virulence.

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The mutation rate of ssRNA viruses is observed to be much higher than organisms that possess ssDNA, and many times more than those with dsDNA. Not all mutations necessarily increase virulence, and in the majority of cases may in fact be deleterious or inconsequential.

Therefore, organisms must find an equilibrium between a high mutation rate that allows them to adapt to changing environmental conditions, and a low one that lessens the incidence of catastrophic mutations. Small DNA viruses may encode for their own DNA repair, and some RNA viruses also share the ability to check for and repair replication errors.

However, while DNA viruses generally rely on the transcription machinery of the host cell, RNA viruses encode for their own transcription machinery, meaning that their replication and mutation rate is more directly related to their own genome and is subject to the same evolutionary pressures.

Vignuzzi & Andino (2012) note that the offspring of RNA viruses, with genomes commonly falling into the size range of 7-12 kb in length, tend to bear one or two distinct mutations per nucleotide site. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome is thought to be around 27-31 kb in length, increasing the overall number of mutations acquired, without necessarily increasing the incidence rate.

The ability to rapidly acquire new genetic characteristics allows viruses to emerge in novel hosts, avoid vaccine-induced immunity, and become more virulent, but can also be a double-edged sword in terms of improving overall genome fitness.

What variants of SARS-CoV-2 have been found?

One new strain with a particularly large number of mutations was first noted in the UK in September 2020, termed VOC 202012/01 (a variant of concern – December 2020), and also known as either 20B/501Y.V1or B.1.1.7 by the CDC.

According to the CDC, as of the 11^th of January 2021, 72 cases of B.1.1.7 have been found so far in the United States. The majority of these variants were found in either California or Florida, likely due to a combination of higher visitation and increased testing rate in these states compared with others.

SARS-CoV-2 interacts with ACE2 receptors in the body using its spike protein. This consists of two subunits, the first of which contains the receptor-binding domain. The B.1.1.7 lineage has a mutation on the receptor-binding domain, specifically with an asparagine amino acid being replaced with tyrosine at position 501, thus the mutation is termed N501Y.

Additionally, the strain often shows a deletion of amino acids 69 and 70, also seen to arise spontaneously in other strains, causing a conformational change of the spike protein. At position 681, a mutation from a proline amino acid to histidine has also been found to arise spontaneously in several strains and is prominent in B.1.1.7, as is a mutation to open reading frame 8, the function of which is not yet fully understood. Some evidence suggests that this strain is more transmissible, though it does not appear to induce more severe symptoms or lessen vaccine efficacy.

Another strain, B.1.351 (also known as 20C/501Y.V2), also shares the N501Y mutation, though specifically does not express the deletion of positions 69 and 70. This variant was first detected in South Africa, October 2020, and has been found in several other countries since then, including Zambia, where it was the predominant strain as of December 2020.

Like B.1.1.7, the mutations of B.1.351 have not been found to impact disease severity. Similarly, the P681H mutation often seen in B.1.1.7 has been noted in a strain originating in Nigeria, B.1.1.207, though none of the other 22 mutations unique to B.1.1.7 are observed.

Yet another strain of note was recently described in Japan by the National Institute of Infectious Diseases, thought to have arrived in the country from Brazil on the 6^th of January. It is termed B.1.1.248, and bears 12 mutations in the spike protein, including the previously mentioned N501Y and an exchange of glutamic acid with lysine at position 484 (E484K).

This same mutation was also reported in a distinct member of the same variant lineage as B.1.1.248 on the same day in Brazil, demonstrating the variability even within only recently identified lineages. The E484K mutation had previously been reported in a different lineage originating in Brazil as early as the summer of 2020 (B.1.1.28).

The apparent spontaneity of the development of some of the key mutations that have been discussed here, N501Y and E484K, suggests that the virus could be experiencing convergent selection pressures around the globe, with the most transmissible forms out-competing their cousins.

Which regions of the SARS-CoV-2 genome mutate the most?

A large meta-study performed by Koyama, Platt & Parida (2020) gathered over 10,000 SARS-CoV-2 genomes worldwide and compared them to detect the most common mutations, identifying nearly 6,000 distinct variants.

The most divergent genome segment was ORF1ab, which is the largest by far as it occupies around a third of the genome. ORF1ab is transcribed into a multiprotein complex that is eventually cleaved into a number of nonstructural proteins that are involved in transcription. Some of these proteins are the target of anti-viral drugs remdesivir and favipiravir, which may be a cause for concern regarding the development of a strain against which these drugs have no effect.

The second most diverse region of the SARS-CoV-2 genome is around the spike protein, which must remain largely conserved in order to interact with ACE2. Some mutations, such as D364Y, have been reported to enhance the structural stability of the spike protein, increasing its affinity for the receptor. However, most are likely to lessen the virulence of the virus to such an extent that the lineage quickly dies off.

References

Vignuzzi, M. & Andino, R. (2012) Closing the gap: the challenges in converging theoretical, computational, experimental and real-life studies in virus evolution. Current Opinion in Virology, 2(5).
https://www.sciencedirect.com/science/article/pii/S1879625712001435?via=ihub
Number of total and positive coronavirus (COVID-19) tests conducted in the U.S. as of January 11, 2021, by state (2021) Statistica.
https://www.statista.com/statistics/1111716/covid19-us-positive-tests-by-state/
Pereira, F. (2020) Evolutionary dynamics of the SARS-CoV-2 ORF8 accessory gene. Infection, Genetics and Evolution, 85.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467077/
Emerging SARS-CoV-2 Variants (2021) Centers for Disease Control and Prevention.
https://www.cdc.gov/coronavirus/2019-ncov/more/science-and-research/scientific-brief-emerging-variants.html#_ftn1
Duffy, S. (2018) Why are RNA virus mutation rates so damn high? PLoS Biology, 16(8).
https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000003
Brief report: New Variant Strain of SARS-CoV-2 Identified in Travelers from Brazil (2021) National Institute of Infectious Diseases.
https://www.niid.go.jp/niid/en/2019-ncov-e/10108-covid19-33-en.html
Koyama, T., Platt, D. & Parida, L. (2020) Variant analysis of SARS-CoV-2 genomes. Bulletin World Health Organization, 98(7).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375210

What Mutations of SARS-CoV-2 are Causing Concern?

What variants of SARS-CoV-2 have been found?

Which regions of the SARS-CoV-2 genome mutate the most?

References

Further Reading

Michael Greenwood