How Viral Variants Arise

The public has had a crash course in virology. But sometimes media coverage spews jargon so fast, often without definitions or descriptions, that I wonder to what degree readers or viewers know what terms like antibody, cytokine, or mRNA actually mean.

“Variant” is especially problematical, when coming after “viral,” because it has a plain language meaning too – variation on a theme, something just a little bit different from what we’re used to. But during an epidemic, a small genetic change can have sweeping consequences, fueling a pandemic.

Mutations Build Variants

Variants of SARS-CoV-2 – the COVID virus – are sets of mutations. A mutation is a specific change in a specific gene.

Different variants have some mutations in common, so it can get confusing. For example, three variants circulating in India each has 6 or 7 mutations, three in common. The first and second variants that were discovered each has a unique mutation, but the third variant is a subset of parts of the first two. Got that?

The mutations and variants of clinical importance in COVID affect the spike protein that the virus uses to latch onto and get into our cells. Because genes are written in the biochemical alphabet of a nucleic acid – A, U, C, and G for the RNA that is SARS-CoV-2’s genetic material – algorithms can align sequences. This enables researchers to identify variants and where they’re emerging and spreading.

Comparing gene sequences also enables researchers to trace viral evolution: which variants begat which others, and in what order. Evolutionary trees are used to depict viral variants, just like elephants and mammoths, or humans and chimps, branch from shared ancestors.

Mutations tend to replace single building blocks, like changing “cat” to “bat.” Another force important in generating viral variants is recombination, which swaps swaths of genetic material – like replacing a word in a sentence rather than a single letter. Cat to pig.

Viruses mutate readily because they can’t repair errors in replication of their genetic material. Most of the changes don’t affect the host, us.

Mutations that do harm us either enable the virus to bind more tenaciously to the receptors on our cells and enter, or alter viral surfaces in ways that hide them. Just like a Romulan warship could seem to vanish to the crew of the starship Enterprise on the original Star Trek, a similar cloaking device thanks to a fortuitous (for the virus) mutation may render it invisible to the roaming cells of the human immune system.

A Sentence Analogy

Viral variants are cropping up more frequently as the virus spreads around the globe and has more opportunities to mutate – only herd immunity can stop that, unless the virus mutates itself into fading away. If that was likely I think it would have happened already, like SARS.

The first mutation of concern in the novel coronavirus appeared in the US in March 2020, coming from Europe. D614G speeds viral replication, upping viral load and accelerating spread. The mutant quickly took over the world and is in the variants that were soon to emerge.

Returning to the three viral variants that originated in India, analogy to a familiar sentence, from The Wizard of Oz, tracks the changes, using CAPS. (With no attempt to maintain the 3-letter language of the genetic code or the one-base mutations. I’m not great at analogies.)

If the original virus in India is:

Toto I have a feeling we’re not in Kansas anymore

Then arrival of D614G might change it to:

Toto I have a feeling we’re not in UTAH anymore

Arrival of Indian variant B.1.617.1 would then change it to:

Toto I have a feeling we’re Hot in UTAH anymore

And Indian B.1.617.2 changes it further to:

Toto I Gave a feeling we’re not in Utah anymore. (Note that this rendition loses one change from its predecessor, the H of hot, but gains the G of Gave)

Then Indian B.1.617.3 arrives as all 3 changes.

Toto I Gave a feeling we’re Hot in UTAH anymore

Thank you, Dorothy.

“Variants of Interest” and “Variants of Concern”

Two complications arise when comparing RNA sequences to follow viral evolution, based on practicalities and the nature of mutation.

Practically speaking, nations very greatly in how intensely they’re looking for variants – that is, sequencing the genomes of viruses. The UK, for example, has done a stellar job; the US, not so much. So some countries have more data to parse than others to identify variants. Perhaps the US lagged in noting the spread of variants simply because we were barely looking, focusing instead, perhaps short-sightedly, on testing.

From a scientific standpoint, mutations can show up in two ways. They can spread from one country to another in their hosts, which is how D614G came to the US from Europe, and how the B.1.617 variants from India came to the UK in March 2021. (See Mutants Come to Saratoga.) In that case, connecting countries depicted on maps with lines of the spread makes sense.

But mutations can simply happen, originating in more than one place, without a new variant having to travel in the nose of an airline passenger.

However mutations arise, they persist if they give the virus an advantage – that’s natural selection in action.

Once new mutations collect themselves into new variants, then organizations such as the WHO and the European CDC declare them “variants of interest” (VOI) or “variants of concern” (VOC). The UK has declared the middle version of the Indian trio – B.1.617.2 – as a VOC because it’s spreading so rapidly there.

Viral variants will continue to arise because mutation and natural selection are the forces of evolutionary change; they’re part of nature. And that’s a powerful reason for universal vaccination – to prevent the viral replication that spawns new mutants that then collect into variants that benefit the enemy.

The vaccines protect against the variants that have emerged so far. But could mutations that they don’t cover, perhaps in genes other than the one encoding the spike protein, arise and persist among the ever-shrinking pockets of unvaccinated individuals? Algorithms predict not, but as we’ve learned with this virus like no other, our predictions don’t always hold. The virus continues to surprise us.

Some nations are now in the “control” phase of humanity vs SARS-CoV-2, as new infections and hospitalizations plunge in the wake of widespread vaccination. But only global vaccination can achieve the widespread herd immunity necessary for eradication. We’ve done it before – with smallpox. Let’s learn from that success.