SARS-CoV-2 Mutations

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Ygggdrasil
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Summary:

A general thread to collect the latest research on mutations to the SARS-CoV-2 virus.
Given the seeming increased transmissibility of the new SARS-CoV-2 variants being identified, I thought I'd start a general thread to collect and organize information on the various mutations to the SARS-CoV-2 virus.

B.1.1.7 variant (aka 20B/501Y.V1, VOC 202012/01; originally identified in the UK):
This variant is characterized by 14 lineage-specific amino acid replacements and three deletions. Of most concern are:
  • The N501Y mutation within the receptor binding domain (RBD) of the spike (S) protein, which is thought to increase the binding affinity to human ACE2
  • Deletion of residues 69-70 in the S protein which may be involved in evading the human immune response
  • The P681H mutation in the S protein, which are adjacent to the furin cleavage site
Initial report from COG-UK describing the variant: https://www.cogconsortium.uk/wp-con...-2020_SARS-CoV-2-Mutations_final_updated2.pdf
Pre-print manuscript more fully characterizing the vairant: https://virological.org/t/prelimina...defined-by-a-novel-set-of-spike-mutations/563
Report from Imperial College London with epidemiological data suggesting increased transmissibility of the variant: https://www.imperial.ac.uk/media/im...2020-12-31-COVID19-Report-42-Preprint-VOC.pdf

Pre-print showing that the Pfizer vaccine elicits antibodies that recognize viruses containing the N501Y mutation in the S protein: https://www.biorxiv.org/content/10.1101/2021.01.07.425740v1

Pre-print study characterizing the S protein 69-70 deletion: https://www.medrxiv.org/content/10.1101/2020.12.05.20241927v3

B.1.351 variant (aka 20C/501Y.V2; originally identified in South Africa):
This variant is characterized by eight lineage-defining mutations, including the mutation of three important residues in the S protein RBD (K417N, E484K and N501Y).

Pre-print describing the identification of the variant: https://www.krisp.org.za/publications.php?pubid=315

Pre-print suggesting that the E484K mutation could evade immunity: https://www.biorxiv.org/content/10.1101/2020.12.31.425021v1

D614G mutation:
This mutant was observed early in the pandemic and has since become widespread.
Published, peer-reviewed study identifying the spread of the mutation: https://www.sciencedirect.com/science/article/pii/S0092867420308205?via=ihub

Various published, peer-reviewed studies evaluating the role of D614G mutation in affecting the transmissibility of the virus:
SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo: https://science.sciencemag.org/content/370/6523/1464
Spike mutation D614G alters SARS-CoV-2 fitness: https://www.nature.com/articles/s41586-020-2895-3
Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity: https://www.cell.com/cell/fulltext/S0092-8674(20)31537-3

Other resources:
Nice article in JAMA discussing the mutants: https://jamanetwork.com/journals/jama/fullarticle/2775006
CDC page on emerging SARS-CoV-2 variants: https://www.cdc.gov/coronavirus/201...earch/scientific-brief-emerging-variants.html
 
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Ygggdrasil
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Note that widespread transmission of a new variant does not always mean that the new variant is a more transmissible form of the virus. Often, certain variants could be spread more widely by chance (e.g. they happen to get spread at a superspreader event). Here's a good example of the 20A.EU1 variant that emerged in Spain early in the summer and became widespread across Europe, yet researchers subsequently found no evidence that the variant itself had showed increased transmissibility. Rather, the researchers attribute the success of the variant to it being present in the right place at the right time (emerging just as travel and quarantine restrictions were being lifted in Europe).

Emergence and spread of a SARS-CoV-2 variant through Europe in the summer of 2020
Hodcroft et al. medRxiv. Nov 27, 2020
https://www.medrxiv.org/content/10.1101/2020.10.25.20219063v2

Abstract:
Following its emergence in late 2019, SARS-CoV-2 has caused a global pandemic resulting in unprecedented efforts to reduce transmission and develop therapies and vaccines (WHO Emergency Committee, 2020; Zhu et al., 2020). Rapidly generated viral genome sequences have allowed the spread of the virus to be tracked via phylogenetic analysis (Hadfield et al., 2018; Pybus et al., 2020; Worobey et al., 2020). While the virus spread globally in early 2020 before borders closed, intercontinental travel has since been greatly reduced, allowing continent-specific variants to emerge. However, within Europe travel resumed in the summer of 2020, and the impact of this travel on the epidemic is not well understood. Here we report on a novel SARS-CoV-2 variant, 20A.EU1, that emerged in Spain in early summer, and subsequently spread to multiple locations in Europe, accounting for the majority of sequences by autumn. We find no evidence of increased transmissibility of this variant, but instead demonstrate how rising incidence in Spain, resumption of travel across Europe, and lack of effective screening and containment may explain the variant’s success. Despite travel restrictions and quarantine requirements, we estimate 20A.EU1 was introduced hundreds of times to countries across Europe by summertime travellers, likely undermining local efforts to keep SARS-CoV-2 cases low. Our results demonstrate how genomic surveillance is critical to understanding how travel can impact SARS-CoV-2 transmission, and thus for informing future containment strategies as travel resumes.
 
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Summary:: A general thread to collect the latest research on mutations to the SARS-CoV-2 virus.
I hope it's not a hijack, then. As far as I understand PCR is about multiplying a possibly present target sequence up to a detectable level.

How sensitive this method to different strains? I mean, when the mutation making the strain makes the 'reference' part of viral genome different than the 'target'?
 
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Ygggdrasil
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I hope it's not a hijack, then. As far as I understand PCR is about multiplying a possibly present target sequence up to a detectable level.

How sensitive this method to different strains? I mean, when the mutation making the strain makes the 'reference' part of viral genome different than the 'target'?
Yes, the RT-qPCR tests for COVID-19 rely on detecting specific RNA sequences in the virus' RNA genome, and mutation of those sequences could cause the test to give a false negative. In fact, this does seem to be the case with the B.1.1.7 variant, where the 69-70del of the S gene prevents some RT-qPCR tests from detecting the presence of the S gene.

However, the RT-qPCR tests were designed with the idea that the virus could mutate in mind. All of the RT-qPCR tests look for multiple, independent regions of the virus, so even if mutation interferes with detection of the virus at one site, the test would still be able to detect the other sites of the virus RNA. Indeed, people have been able to track the B.1.1.7 variant by seeing RT-qPCR tests that are positive for two markers (N and Orf1ab), but negative for the third marker (S).

It is possible to design RT-qPCR tests that are specific for certain strains of the virus, and researchers have developed such tests for the B.1.1.7 variant. It is also possible to design new RT-qPCR tests that will detect all common variants (by making use of existing sequencing data on the various common circulating strains of the virus).
 
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Thank you for the answer, it is really informative. I know about some cases where the symptoms were conclusive but multiple (!) PCR tests were negative. This were buggin' me for some time already :woot:
 
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A new strain has been discovered in Japan.
Here's the official report from the Japanese National Institute of Infectious Diseases: https://www.niid.go.jp/niid/en/2019-ncov-e/10108-covid19-33-en.html

Here's a good figure from the report comparing the spike protein mutations found in the B.1.1.248 strain found in Japan to other strains:
covid19-33-en-fig.png


The strain contains the N501Y mutation that is thought to increase the strength of binding of the virus' spike protein to the ACE2 receptor on cells in the body as well as the E484K mutation that could be involved in evading antibody-based immunity.
 
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  • #9
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Here's a report of a new strain from Manaus, Brazil called the P.1 lineage. It has 17 unique amino acid changes, 3 deletions, and 4 synonymous mutations, and one 4nt insertion compared to the next most closely related strain (B.1.1.28):

1610558530681.png

https://virological.org/t/genomic-c...-2-lineage-in-manaus-preliminary-findings/586

Of interest are three mutations in the S protein RBD region that are known to be of importance, E484K, K417T and N501Y. The N501Y mutation is also found in the B.1.1.7 lineage from the UK and the B.1.351 lineage from South Africa and is through to potentially increase the transmissibility of the virus by increasing the affinity of the S protein for human ACE2 receptors. The E484K mutation (also found in the B.1.351 lineage) could be involved in evading antibody-based immunity.

The P.1 lineage is very similar to the B.1.1.248 lineage reported above from Japan, which is expected given that the strain was identified in four individuals who had arrived in Tokyo from Amazonas, Brazil.
 

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