Omicron

"32 mutations in Omicron, Oh, my!"

alanmc — Wed, 15 Dec 2021 19:11:53 +0000

"32 mutations in Omicron, Oh, my!" alanmc Wed, 12/15/2021 - 11:11 More Blog Posts December 15, 2021

Omicron, aka B.1.1.529, is the latest Covid Variant of Concern (VoC) and carries far more mutations than earlier variants, including 32 mutations in the spike protein gene alone. And this news of large numbers of mutations, combined with the scary forecast of Omicron’s dramatically increased infectivity (see case count graph from South Africa, below) and putative antibody avoidance, is definitely worrisome, if not panic inducing.

Case counts of Omicron in Gauteng, South Africa (black line) compared with case counts of other Variants of Concern. (From: https://yourlocalepidemiologist.substack.com/p/omicron-were-getting-some-answers)

But what’s the significance of the quantity of mutations? Fortunately, the answer is, not much. The number of mutations is immaterial; the effect of each mutation, singly or in combination, is what matters. Unfortunately, several of the mutations do make Omicron more scary.

What is a mutation? A mutation is defined simply as a permanent (heritable) change in the DNA (or, in the case of Coronavirus, RNA) base sequence. A mutation could be a substitution of one base for another (e.g. Adenine (A) to Guanine (G)), a deletion of one or more bases, an insertion of one or more bases, a duplication of one of more bases, an inversion of a block of bases, or just about any other base rearrangement you might imagine. A mutation is manifest when the base sequence in a given gene also changes the amino acid sequence of the corresponding protein. A gene can be thought of as a recipe for a protein, and the presence of that specific protein provides the trait or feature. When the base sequence of the gene changes, that can result in a change in the corresponding amino acid in the protein. The cell machinery responsible for protein synthesis reads the DNA (or RNA) base sequence three letters at a time (called a triplet codon) and constructs a growing chain of amino acids as directed from the three base letter instruction or “code”. There are 20 different amino acids in proteins, so substituting one amino acid for another can (but does not always) result in a change of some feature of the protein.

For example, the DNA ( or RNA) base sequence GAG calls for the amino acid Glutamic Acid, which the cell machinery places into the growing chain. If a mutation changes the first G to A, the resulting triplet sequence, AAG, results in the amino acid Lysine being placed into the protein where the Glutamic Acid was. Depending on the exact location of this amino acid substitution, the resulting protein may be unaffected, or have some feature altered, or even rendered completely non-functional.

Here’s a crucial and often misunderstood fact: Mutations are not directed, but random. That is, the virus has no means of predicting and directing a particular mutation that might improve its infectivity. A mutation occurs randomly and spontaneously in one virus particle in a population of viruses, then life goes on, with the mutation either improving infectivity, reducing infectivity, or having no effect on infectivity of that one virus particle in the surrounding population of virus particles. If the random, spontaneous mutation does improve infectivity, that mutated virus particle enjoys an adaptive advantage over all the other nearby virus that didn’t mutate. As a result of this infectious improvement, the progeny of the “improved” virus will, over time, come to dominate the population of viruses. At this point, scientists might notice the genetically different viral strain and give it a name to distinguish it from the initial strain.

While a large number of mutations may increase the likelihood of carrying at least one which increases pathogenicity, the same probability increases the likelihood of diminished pathogenicity. That is, one specific mutation might result in a spike protein better able to bind to the human host cell ACE-2 protein to facilitate infection, thus increasing pathogenicity. But another specific mutation, perhaps simultaneously, might reduce the spike protein’s affinity for the host cell’s ACE-2 protein, thus reducing pathogenicity. With Omicrons 32 mutations on the spike gene, some could well increase infectivity while others could inhibit infectivity. Most mutations have no discernable clinical impact, however.

Omicron's mutations are shown in the map image below. The Spike gene, in green, has a relatively large number of mutations that result in changes to the amino acid sequence of the final spike protein. For example, the 440th amino acid in the spike protein is mutation N440K, in which the original amino acid Asparagine (abbreviated N) is replaced with Lysine (K). This single amino acid change, also observed in other variant strains, is thought to substantially increase infectivity. A little further along the amino acid chain, at position 484, is mutation E484K (also known as the Eek" mutation). Here, the amino acid Glutamic acid (abbreviated 'E') is replaced by the amino acid Lysine ('K') as the 484th amino acid in the spike protein chain. This particular mutation, also present in some other variant stains, is thought to increase the virus's ability to evade antibodies. Although these mutations, and others, are also present in other SARS-CoV-2 variant strains, the combination of different mutations results in Omicron gaining multiple tools to increase its virulence, ranging from increased infectivity to enhanced ability to evade antibodies or other protective measures the body uses to fight off pathogens.

To initiate an infection, the SARS-CoV-2 virus spike protein is attracted to ACE-2, a protein on the surface of the target host cell. If the ACE-2 protein and the spike protein fit together like a key in a lock, that opens a door to the host cell and the infection proceeds. Once inside the cell, the viral genome hijacks the cell machinery to make more copies of the virus, which eventually distribute to infect other cells and ultimately, other human targets. Mutations in the spike gene can result in a more effective "key" for the ACE-2 "lock", resulting in increased infectivity. This is why it’s so important to limit viral infections as soon as possible, because multiplying the virus leads to both more mutations and more human victims. The most effective way to limit viral infections is through vaccinations, masking in public and social distancing.

Omicron (SARS-CoV-2) mutation map (from https://covdb.stanford.edu/page/mutation-viewer/)

Citations and further reading

Mullen J, Tsueng G, et int., and tCfVSB. “Outbreak.info.” outbreak.info, 2020. - https://covdb.stanford.edu/page/mutation-viewer/#omicronOutbreak.info B.1.1.529 Lineage Reportb-1-1-529_1638019891935.svg, CC BY-SA 4.0,

https://commons.wikimedia.org/w/index.php?curid=112859849

https://covdb.stanford.edu/page/mutation-viewer/

https://en.wikipedia.org/wiki/Variants_of_SARS-CoV-2

https://en.wikipedia.org/wiki/SARS-CoV-2_Omicron_variant

https://yourlocalepidemiologist.substack.com/p/omicron-were-getting-some-answers

https://www.nytimes.com/interactive/2021/health/coronavirus-variant-tracker.html

Omicron, delta, E484K. What do they mean?

alanmc — Tue, 30 Nov 2021 20:28:09 +0000

Omicron, delta, E484K. What do they mean? alanmc Tue, 11/30/2021 - 12:28 More Blog Posts November 30, 2021

Understanding the alphabet soup of Coronavirus SARS-CoV-2 genome. B.1.1.7, Delta, E484K… What do the numbers (and letters) mean?

News reports on Covid and the virus responsible for the infection, SARS-CoV-2, is on the news with plenty of science-speak numbers and acronyms. But because these acronyms are usually not part of the ‘news’ being covered in the story, exactly what those codes mean is rarely explained. For example, former FDA Commissioner Scott Gottlieb recently tweeted:

“UK reported its biggest one-day Covid case increase in 3 months just as the new delta variant AY.4 with the S:Y145H mutation in the spike reaches 8% of UK sequenced cases. We need urgent research to figure out if this delta plus is more transmissible, has partial immune evasion?

Delta, AY.4, S:Y145H from Gottlieb’s tweet are all opaque to most readers, (we presume they know UK refers to United Kingdom…), and clearly, the urgency of this tweet demanded attention be focused on the spread and virulence of the then-new worrisome strain (“Delta Plus”) rather than a mundane explanation of the acronyms. The delta plus strain includes the K417N mutation, which may increase the virus strain’s ability to reinfect survivors of earlier Covid strain infections.

and

“…a delta sublineage newly designated as AY.4.2 is noted to be expanding in England… This sublineage is currently increasing in frequency. It includes spike mutations A222V and Y145H." (https://www.cnbc.com/2021/10/20/uk-doctors-call-for-return-of-covid-restrictions-new-mutation-watched.html)

SARS-CoV-2 genome

The genome of the coronavirus responsible for Covid, technically called SAS-CoV-2, is a ring of RNA almost 30,000 bases long. The bases are like a long string of letters spelling words, but in this case, RNA uses only 4 letters (A,U,C, and G) and the words spelled out by the exact sequence of letters in structural genes are instructions for the infected human cell to make specific kinds of proteins. In the structural gene "coding" portion of the genome, each three RNA bases, called a triplet, is like a word calling for a specific amino acid. For example, if the RNA triplet base sequence is AUG, that calls for the amino acid methionine, which is added to the growing chain of amino acids that eventually becomes a functional protein.

The SARS-CoV-2 genome spells out about two dozen different proteins, many of which are important in the infection process or the severity of the resulting illness.

One example is the “spike” protein, which sticks out of the virus particle like points on a crown (and hence the name ‘coronavirus’). The spike protein is responsible for the virus docking with their target human cells, especially the ACE-2 cells) to start the infection process. The Spike protein is also the target for current mRNA based vaccines.

Mutations are permanent changes to the base sequence of letters in the genome, whether the genome is RNA (like coronavirus and many other viruses) or DNA (like other viruses, and all other living things, including humans). Mutations happen in all living things and can be induced by certain chemicals, environmental conditions, or just spontaneously. Mutations can affect a single base, or several bases, or even very long stretches of bases, and can involve deletion of the base(s), or changing a base from one letter to another, or duplication of the base(s), or inversion, insertion of additional bases, or virtually anything that can go wrong with the genome.

Many known mutations in SARS-CoV-2 are single base changes, called point mutations. Because the viral genome is short compared to other living things, the mutation of a large number of bases will likely render the virus weak or incompetent, effectively killing it off as a pathogen. Any quickly growing population (not just viruses) will tend to generate more mutations, and the bigger the population, the more mutations will accumulate. At least some of these mutations will likely make the pathogen even more virulent.

While this mutation stuff is fascinating for molecular geneticists like me, most people just want to know how they relate to Covid. Well here it is— each mutation has the potential to increase infectivity, or severity of illness, or evade antibodies, so scientific management of Covid requires knowing each one precisely, which requires providing names. Each new variant or strain carries one or more mutations in the genome. The naming convention started haphazardly, based on the lab which initially identified and characterized each mutation, or the geographic source where the strain was first identified. As identification and documentation of variants increased this practice became unwieldy and prone to ambiguity and misinterpretation, so WHO (World Health Organization) took over to standardize the naming procedure, using Greek letters.

Under WHO, the identity of the first group of “variants of concern” (i.e., those strains with potentially increased pathogenicity, either in infectivity or increased severity of illness potential) went from B.1.1.7 to Alpha, B1.351 to Beta, P.1 to Gamma and B.1.617.2 to Delta, the first four letters of the Greek alphabet. Omicron (also known as B.1.1.529 under the old nomenclature system) is the 5^th “Variant of Concern” and undoubtedly will go well beyond.

Each Greek letter refers to a known variant strain with identified mutations in the genome. Each variant of concern has multiple mutations in their RNA sequence, and specifically in sequences providing the recipes for Spike and other structural proteins involved in pathogenicity. That is, mutations in the gene for the spike protein can lead to a strain with spike proteins better able to dock with human target cells (and thus increase infectivity) or spike proteins less susceptible to mRNA vaccine antibodies that recognize specific parts of the spike protein. Omicron, for example, has over 30 mutations in the spike protein gene alone. Note, however, that the absolute number of mutations does not correlate with altered pathogenicity. A single mutation at a particular location on the gene converting one specific amino acid might have more impact than 50 mutations scattered elsewhere. Omicron carries several mutations, including base substitutions resulting in amino acid substitutions, base deletions, base insertions, and more. Some of these are especially worrisome because they are known to influence pathogenicity.

Scientists need a means to identify those specific mutations within the Greek letter strain designation. The exact amino acid sequence of a given protein is determined by the exact base sequence of the respective gene. If a mutation in the gene's RNA sequence changes, say, converting a G to an A, the resulting protein might have a crucial amino acid change. So, for example. E484K refers to the Spike protein’s 484th amino acid in the protein chain. The amino acid glutamine (abbreviated ‘E’) at that exact location in the ancestral strain is replaced by the amino acid Lysine (abbr. ‘K’). This apparently small difference of one amino acid in the spike protein can have grave consequences, as this mutation seems to help the virus evade immune responses, including the protective effect of vaccines. Importantly, this E484K mutation is found in Beta, Gamma and Delta. Each mutation causing a change in the amino acid sequence of proteins involved in pathogenicity must be carefully scrutinized in each new strain as they arise. The best defense against new, potentially pathogenic mutations is to limit the population of viral particles. That is best achieved by vaccinations, masking and social distancing.

Gene map of common SARS-CoV-2 Variants, with Spike protein gene magnified. Detail from https://www.news-medical.net/news/20211122/Interferon-beta-versus-the-SARS-CoV-2-Delta-variant.aspx

More info:

https://www.newsweek.com/delta-ay-variant-ay4-2-urgent-research-scott-gottlieb-fda-which-us-states-uk-1639842

https://www.ncbi.nlm.nih.gov/gene/43740568

https://www.nytimes.com/interactive/2021/health/coronavirus-variant-tracker.html

https://www.newsweek.com/delta-ay-variant-ay4-2-urgent-research-scott-gottlieb-fda-which-us-states-uk-1639842

https://www.cdc.gov/coronavirus/2019-ncov/variants/delta-variant.html?s_cid=11512:covid%20delta:sem.ga:p:RG:GM:gen:PTN:FY21

https://www.sfchronicle.com/health/article/What-we-know-about-AY-4-2-a-delta-subvariant-16544024.php

https://pubmed.ncbi.nlm.nih.gov/33532796/ (E484K mutation)

https://en.wikipedia.org/wiki/Variants_of_SARS-CoV-2

https://www.bmj.com/content/372/bmj.n359 (E484K variant impact on immune response)

https://www.sciencealert.com/how-concerned-should-you-be-about-ay-4-2-delta-subvariant-an-expert-explains (AY-4-2 variant)

https://www.science.org/doi/10.1126/science.abl9463?fbclid=IwAR3CQnDova5tnhXqkK1BmJJXrfjmHnL4NlC4Q8ckV_T2bF52ECRKIifs8j0

https://www.news-medical.net/news/20211122/Interferon-beta-versus-the-SARS-CoV-2-Delta-variant.aspx (Figure 2)

https://covariants.org/variants/21K.Omicron