In the emerging information on the new variant of the SARS-CoV-2 coronavirus circulating in the UK, a mutation has been of particular concern. The variant, called VUI 202012/01 and reported to be capable of transmitting faster between people, is defined by up to 14 mutations and three deletions in its genetic material. Of particular concern is a mutation, N501Y. While the potential for the variant to affect test and vaccine results is still being studied, health authorities are largely optimistic that most tests and vaccines will continue to work.
What is a mutation?
A mutation means an alteration in the genetic material. In an RNA virus like SARS-CoV-2, proteins are made up of a sequence of amino acids. This virus contains about 30,000 “base pairs”, which are like bricks placed next to each other to form a structure. An alteration in this base can be a mutation, effectively changing the shape and behavior of the virus.
In the UK variant, a mutation has made the virus more likely to bind to human proteins called receptors. This is called N501Y.
What is N501Y?
In short, the amino acid represented by the letter N, and present in position 501 of the genetic structure of the coronavirus, has been replaced in that position by another amino acid, represented by Y. The position where this alteration has occurred is in the receptor binding domain of the spike protein. (It is the spike protein of the virus that binds to the human receptor.)
Therefore, the mutation has increased the binding affinity of the coronavirus. The mutated virus reportedly accounts for 60% of recent infections in London.
According to the Global Initiative for Avian Influenza Data Sharing (GISAID) database, the same mutation in the receptor-binding domain has been independently reported in several countries, including South Africa and Australia. Sequence analysis has shown that this mutation originated separately in the UK and South Africa.
What about the other coronavirus mutations?
Mutations are common, but most of them do not cause alterations in the structure of the proteins they encode; they are called “synonymous” mutations, as they eventually translate into the same amino acids. Another type is the “not synonymous” mutation, which could result in an amino acid change.
In the variant circulating in the UK, there are six synonymous alterations and fourteen non-synonymous mutations. In addition, there are three ‘deletions’: amino acids removed from the sequence.
According to the World Health Organization (WHO), in addition to N501Y, the mutations that “may influence the transmissibility of the virus in humans” are P681H and HV 69/70.
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And what are P681H and HV 69/70?
P681H: This mutation has occurred at the amino acid present at 681, another position in the receptor-binding domain. Here, the amino acid P has been replaced by H. The US Centers for Disease Control (CDC) has said that this is a site “with high variability in coronavirus”, and this specific mutation has also spontaneously arisen several times. The WHO has said that this mutation is of “biological importance”.
Researchers have previously shown that this mutation can promote entry into respiratory epithelial cells and transmission in animal models.
Recent samples sequenced at the African Center of Excellence for Genomics of Infectious Diseases, Redeemer’s University, Nigeria, showed the P681H sequence there. However, the researchers say that at present, “they have no evidence to indicate that the P681H variant is contributing to further transmission of the virus in Nigeria.”
HV 69/70: This mutation is the result of a deletion of amino acids at positions 69 and 70. These positions are again in the peak protein of the virus. This suppression has also been observed in France and South Africa. The CDC has said: “This double deletion has occurred spontaneously many times and probably leads to a change in the shape of (ie, a conformational change in) the spike protein.”
Researchers on behalf of the COVID-19 Genomics Consortium UK (CoG-UK), which red-flagged the new variant in the UK, have said in their preliminary report that this deletion was also seen in an outbreak associated with mink in Denmark. In humans, this deletion has been associated with another mutation, N439K, which again occurred in the receptor-binding domain.
The WHO has highlighted that this deletion can affect the performance of some RT-PCR tests that detect the new coronavirus.
How can it affect RT-PCR tests?
The WHO has said that deletion at positions 69/70 has been found to affect the performance of some diagnostic PCR assays that use an ‘S target gene’ (in the ‘S’ protein or peak). However, the WHO has also said that “most PCR assays worldwide use multiple targets and therefore the impact of the variant on diagnosis is not expected to be significant.”
The CDC has also said that most commercial PCR tests have multiple targets where they detect the virus, so even if a mutation hits one of the targets, the other PCR targets will still work.
In fact, the infection caused by the new strain in the UK was also detected by the conventional RT-PCR test.
“Laboratories that use in-house PCR assays that target the virus S gene should also be aware of this potential problem. To limit the impact on detection capacities in countries, an approach that uses different assays in parallel or multiple assays targeting different viral genes is also recommended to allow detection of potential emerging variants ”, recommended the WHO.
Will vaccine development impact?
The CDC has said that vaccines approved by the US Food and Drug Administration (FDA) are “polyclonal,” producing antibodies that target various parts of the spike protein.
“The virus would probably need to accumulate multiple mutations in the spike protein to evade immunity induced by vaccines or by natural infection,” he said.
And the WHO has said: “Laboratory studies are being carried out to determine if these virus variants have different biological properties or alter the efficacy of the vaccine. At present, there is not enough information to determine if this variant is associated with any change in the severity of the clinical disease, the antibody response or the efficacy of the vaccine ”.
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