Double Mutants, Triple Mutants: Creating Confusion amid COVID Turmoil

The biochemistry of SARS-CoV-2 is too complicated not only for the general public but even among the scientific community and hence rather than be swayed by the so-called double or triple mutants, emphasis must be on vaccination and wearing of proper mask correctly.


Representational Image (Photo by Viktor Forgacs on Unsplash)

 

Newsreaders and newspapers claim that India had now two homegrown variants which they conveniently call as “double mutant” and “triple mutant” first detected in Maharashtra and West Bengal respectively. In fact, one cute newsreader claims in a short clip circulated in the YouTube that two mutants mixed together to form the triple mutant without understanding that SARS-CoV-2 is a single stranded, positive sense enveloped retrovirus, meaning RNA virus.

Biochemistry and molecular biology may not be rocket science but it is complicated as it deals with complex molecules whose 3D structure is relevant and, without understanding the complexity, to claim otherwise that some experts have said this and that is dangerous, as the lady would not have understood what the experts were saying. Terms like replicase, translation, transcription, sense mutation, nonsense mutation, missense mutation, polypeptide, recombination, codon, etc do not mean exactly what the term means commonly. It cannot be learnt through a crash course of say a week or a month.

In fact, the so-called double mutant now named B.1.617 has a total of 13 mutations, but only three mutations are considered relevant. Many of the variants of interest or variant of concern had more than two or three mutation in the spike protein which is composed of 1273 amino acids. If other proteins produced by SARS-CoV-2 which number 29 is reckoned, some have more than 30 mutations. The proteins are replicase polyprotein, Spike glycoprotein, Envelop proteins, Membrane proteins, Neucleocapsid proteins, accessory proteins and other non-structural proteins.

Mutations are a natural phenomenon and this is what drives evolution. If a mutation is beneficial to the organism it continues for generations but if it is harmful it tends to die off. Mutations are caused by various agencies which are called mutagen which is defined as a physical, biological or chemical agent that permanently changes genetic materials and it can come in many form like alpha rays, x- rays, gamma rays, UV rays, reactive oxygen species (superoxide, hydroxyl radicals, hydrogen peroxide), deaminating agents (nitrous acid), Polycyclic aromatic hydrocarbon, alkylating agents (ethylnitrosourea), aromatic amines (2-acetylaminofluorene), alkaloids, bromine, sodium azide, metals like arsenic, cadmium, chromium, intercalating agents (ethidium bromide, proflavine) benzene, virus, bacteria, transposon, etc. But not all mutations are caused by mutagen; there is the so-called “spontaneous mutations” due to spontaneous hydrolysis, errors in DNA or RNA replication, repair and recombination.

Like all organisms, SARS-CoV-2 has also undergone mutations and in fact the variant causing COVID-19 in the first wave in Europe was found to be slightly different in the genetic makeup from the one from Wuhan which causes the first case. The Wuhan variant is known as the wild strain. Now there are thousands and thousands of variants but all variants are not a cause of worry; in fact, most of them are not relevant. However, every variant is observed and those which have certain ramifications were classified a “variant of interest’. From further study, some may be upgraded as “variant of interest” and still further some may be finally upgraded as “variant of high consequence”. Till now for SARS-CoV-2 there is as yet no variant of high consequence.

Those variant of interest or concern has more than two or three mutations and just calling the one first detected in Maharashtra or West Bengal as double or triple mutation is completely wrong and media who just are not aware of the whole story named it as such for sensationalising. It would be wrong to call either Wuhan strain, or UK strain or South Africa strain or Indian strain, etc. The mutations in the spike proteins are human’s concern as it is the spike protein which assisted the virus genome to enter our cells through the ACE-2 receptors and any mutation which facilitate the entry is more dangerous while those which hinders attachment to the receptor will die.

Table 1 & 2 gives the significant mutations on the Spike proteins that are in the different variant of interest and variant of concern. What are the changes that had occurred in the spike protein is given both in the biochemical code as well as in a more detailed manner for general understanding. E484Q means that at locus 484 of the spike protein, glutamate has been replaced by glutamine. The alphabets are single digit code for the 21 amino acids (There is also a three digit code).

Table 1 Variant of Interest

Name (first discovered)

Substitution

Detailed substitution

B.1.526 New York

L5F;

T95I;

D253G;

(S477N*);

(E484K*);

D614G;

(A701V*)

Leucine5Phenylalanine; Threonine95Isoleucine

Aspartate253Glycine

Serine477Asparagine

Glutamate484Lysine

Aspartate614Glycine

Alanine701Valine

B.1.525 New York

A67V

H69/V70del

Y144del

E484K

D614G

Q677H

F888L

Alanine67Valine

Histidine69/Valine70deleted

Tyrosine144deleted

Glutamate484Lysine

Aspartate614Glycine

Glutamine677Histidine

Phenylalanine888Lysine

B.1.617 India

N440K

L452R

E484Q

Asparagine440Lysine

Lysine452Arginine

Glutamate484Glutamine

B.1.618 India

Y145del

H416del

E484K

D614G

Tyrosine145deleted

Histidine146deleted

Glutamate484Glutamine

Aspartate614Glycine

P.2 Brazil

E484K

D614G

V1176F

Glutamate484Lysine

Aspartate614Glycine

Valine1176Phenylalanine

*This is not detected in all samples but in few.

Table 2: Variant of Concern

Name (first discovered)

Substitution

Detailed substitution

B.1.1.7 UK Strain

H69/V70del

Y144del

E484K*

S494P*

N501Y

A570D

D614G

P681H

Histidine69/Valine70deleted

Tyrosine144 deleted

Glutamate484Lysine

Serine494Proline

Asparagine501Tyrosine

Alanine570Aspartate

Aspartate614Glycine

Proline681Histidine

P.1 Japan/Brazil

K417N/T

E484K

N501Y

D614G

Lysine417Asparagine/Threonine

Glutamate484Lysine

Asparagine501Tyrosine

Aspartate614Glycine

B.1.351 South Africa

K417N

E484K

N501Y

D614G

Lysine417Asparagine

Glutamate484Lysine

Asparagine501Tyrosine

Aspartate614Glycine

B.1.427 California

L452R

D614G

Lysine452Arginine

Aspartate614Glycine

B.1.429 California

S13I

W152C

L452R

D614G

Serine13Isoleucine

Tryptophan152Cysteine

Lysine452Arginine

Aspartate614Glycine

*This is not detected in all samples but in few.

Even though the classification is still variants of interest and concern with no variant of high consequence, it does not mean that any of the above variants have little or no consequence in the transmission, morbidity and mortality but more data is required. In fact, many of these variants have shown higher transmission rate with claims that B.1.617 is 1.7 times more transmittable than the wild strain while B.1.351 strain is 2.5 times more transmittable than the wild type strain.

The P.1 variant has 17 amino acid changes, 10 of which are in the spike protein including the 4 listed in Table 2. Classification of the variants is a complex system, following what is called the PANGO (Phylogenetic Assignment of Named Global Outbreak Lineages) system. B.1.1.7 which is one of the most studied variant has at least 17 mutations, eight of which are in the spike protein.

The higher mortality in Europe in the first wave may perhaps be due to a variant but not all as Europe has a higher older population and there is even a hypothesis circulating that Asia was visited by a coronavirus epidemic some 25,000 years ago and that is the reason why Asian have adapted resulting to lower mortality. Studies have indicated that smoking and vegetarian diet reduces transmission though the reasons are unknown. In respect of smoking, it was conjectured that frequent coughing delays the virus’s entry into the lungs.

The point which is attempted to bring out is that the biochemistry of SARS-CoV-2 is too complicated not only for the general public but even among the scientific community who are working in biochemistry and molecular biology and hence rather than be swayed by the so-called double or triple mutants, emphasis must be on vaccination and wearing proper mask correctly. This two should be the mantra for the days to come. The Head of the National Covid Task Force had even suggested wearing of mask at home as the cases of whole families falling prey to the disease is very high. Cracking our brain over the mutations will bring no relief; only fear and panic as the implication is not understood and to leave these to the scientists.

(The views expressed are the writer's own)

First Published:April 27, 2021, 11:29 p.m.

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