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.

sars-cov-2 mutationsImage Credit: joshimerbin / Shutterstock.com

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 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 concern have been found?

B.1.1.7 lineage

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 20B/501Y.V1by the CDC. This strain is of B.1.1.7 lineage.

Since its identification in Britain, the B.1.1.7 strain has been found in over 90 different countries around the world. What is concerning about it is that it is thought to be 30-50% more infectious than original strains, and may be more deadly. However current vaccines still work on the strain.

The B.1.1.7 strain has the following key mutations:

  • N5014
  • P681H
  • H69-V70 and Y144/145 deletions

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.

Evidence suggests that this strain is more transmissible, though it does not appear to lessen vaccine efficacy. Recent studies suggest this strain is more deadly, linked to a higher chance of hospitalization.

B.1.351 lineage

Another strain, B.1.351 (also known as 20C/501Y.V2), also shares the N501Y mutation. This variant was first detected in South Africa, October 2020, and has been found in more than 48 other countries since then.

The strain is not thought to be more deadly but is more transmissible than the original strain of SARS-CoV-2. Whilst more research is needed on the effect of different vaccines on B.1.351, evidence is suggesting some of the current vaccines may have reduced efficacy against this variant.

The B.1.351 strain has the following key mutations:

  • N5014
  • K417N
  • E484K

This strain is concerning, as some of the current vaccines have shown to be less effective against it in clinical trials. Furthermore, antibodies developed in those who have recovered from other SARS-CoV-2 variants may not have an effective response as they cannot latch on to the virus tightly enough.

P.1 lineage

Another strain of note, 20J/501Y.V3, was first described in Japan by the National Institute of Infectious Diseases, thought to have arrived in the country from Brazil on the 6th of January. The variant has been traced back to Manaus, Brazil.

The strain is not thought to be more deadly but is more transmissible than the original strain of SARS-CoV-2.

The P.1 strain has the following key mutations:

  • N5014
  • K417T
  • E484K

The P.1 lineage is a branch of the B.1.1.248 lineage 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). It is a close relative of the B.1.351 strain.

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).

More evidence is needed about the effects of the different vaccines on this variant.

B.1.427/B.1.429 lineage CAL.20C variant

The CAL.20C variant which spans the B.1.427 and B.1.429 lineages is common in California. It is currently thought to be 20 percent more infectious than original strains although does not seem to be spreading as fast as some variants like the B.1.1.7.

More studies are needed on the variant to determine its transmissibility, whether vaccines are affected, and whether the rapid spread of the variant in California is due to the variant’s properties. The variant has now been detected in North America, Europe, Asia and Australia.

This strain has the following key mutations:

  • L452R

B.1.617 lineage

This strain, also known as the “double mutant virus”, has spread rapidly through India.

The strain has been dubbed the “double mutant virus” due to two of the concerning mutations it carries.

These two key mutations are:

  • E484Q
  • L452R

Further studies on the strain are needed to determine its transmissibility, although it is suspected to do so due to its spike protein mutations which are thought to increase immune evasion and receptor binding. Whether vaccine efficacy is affected also needs further research.

sars-cov-2 mutationsImage Credit: Lightspring/Shutterstock.com

Mutations of concern

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.

The current mutations of concern that may be aiding the spread of coronavirus are:

D614G

The D614G mutation is of B.1 lineage. It appeared in early 2020 and quickly spread across the world and became dominant.  

The D614G mutation is a missense mutation in which an altered single DNA base pair causes the substitution of aspartic acid (single-letter code: D) with glycine (single-letter code: G) in the protein that the mutated gene encodes.

N501Y

This mutation is present in several lineages including B.1.345, B.1.17 and P.1. IT may aid the virus in bind to cells more tightly.

N501Y affects the receptor-binding domain (RBD) of the spike protein. An asparagine amino acid is replaced by a tyrosine at position 501.

E484K or “Eek”

This spike protein mutation has been found in several lineages and may aid the virus in avoiding some antibody types. In it, there is an exchange of glutamic acid with lysine at position 484.

E484Q

This spike protein mutation is also mutated at position 484, except the glutamic acid is substituted with a glutamine. This mutation is thought to increase immune evasion and ACE2 binding.

K417

This spike protein mutation has been found in several lineages, including P.1 and B.1.351. It is also thought to help the virus bind to cells more tightly.

This mutation is K417N in the B.1.351 strain, and K417T in the P.1 strain

L452R

The L452R spike protein mutation has appeared in several lineages. In this mutation, there is a leucine to arginine substitution at amino acid 452. The mutation is thought to increase immune evasion and ACE2 binding.

It was observed in both the US and Europe in 2020, before increasing in prevalence in January 2021 as it is notably present in the CAL.20C variant that has become widespread in California, particularly in Los Angeles. It is also notably present in the B.1.617 variant.

Q677

This mutation has not been shown to be more infectious as of yet, however, they are becoming increasingly common in the US.

What causes a virus to change and how to stop stronger Covid-19 variants from emerging

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

Further Reading

Last Updated: Apr 13, 2021

Michael Greenwood

Written by

Michael Greenwood

Michael graduated from Manchester Metropolitan University with a B.Sc. in Chemistry in 2014, where he majored in organic, inorganic, physical and analytical chemistry. He is currently completing a Ph.D. on the design and production of gold nanoparticles able to act as multimodal anticancer agents, being both drug delivery platforms and radiation dose enhancers.

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