The timeline of the COVID-19 pandemic has been marked by a series of catastrophic waves: surging crests of infection spreading around the world, often spearheaded by newly evolved variants of the pathogen, such as Delta and Omicron.
This is simply how viral evolution can play out, of course. But SARS-CoV-2 is an unusually successful and dangerous virus; part of what makes the 'novel coronavirus' so formidable is its ceaseless novelty – the unusually rapid pace at which new variants appear to be spawning.
"What we were seeing with the variants of SARS-CoV-2, particularly the variants of concern, is that they have undergone many more mutations than we would expect under the normal evolutionary pace of similar coronaviruses," explains infectious disease researcher Sebastian Duchene from the Peter Doherty Institute for Infection and Immunity in Australia.
Ordinarily, Duchene notes, viruses tend to mutate at a relatively constant pace, taking perhaps a year or longer for a new viral variant to emerge. But the coronavirus doesn't seem to stick to that calendar.
In a new study, Duchene and fellow researchers sought to investigate where this dramatically accelerated timeframe comes from.
They analyzed SARS-CoV-2 genome sequence data to examine how the emergence of variants of concern (VOCs, the most virulent and harmful lineages) might be linked to changes in the substitution rate of the virus: the rate at which new mutations arise in the pathogen's genetic code.
According to the researchers, the background substitution rate of SARS-CoV-2 suggests the virus accrues approximately two mutations each month.
But VOCs are a different beast, with variants such as Alpha, Beta, Gamma, and Delta acquiring numerous mutations in relatively short timeframes, each of which can alter things like the variants' infectiousness, ability to replicate, level of fitness, and so on.
"The sheer number of mutations observed in these four VOCs is much higher than what would be expected under phylogenetic estimates of the nucleotide evolutionary rate of SARS-CoV-2," the researchers explain in their paper, led by first author John Tay, a bioinformatics researcher at the Doherty Institute.
According to the team, the secret of the VOCs' accelerated mutation is not a constant, ongoing phenomenon, but rather something that appears to happen temporarily in the virus's evolution, taking place shortly before variants emerge.
"We find compelling evidence that episodic, instead of long term, increases in the substitution rate underpin the emergence of VOCs," the team writes.
The increased rate of substitutions is about four times higher than the background phylogenetic rate estimate for SARS-CoV-2, but the analysis suggests the accrual of mutations happens in a compressed burst: perhaps as short as four weeks for the Beta variant, and six weeks for the Delta variant.
Other variants took longer, with the Gamma variant thought to have evolved over the course of 17 weeks, while Alpha required 14 weeks.
That's the how of it, but as for why these mutation bursts occur at all, we're not entirely sure.
The researchers say the emergence of VOCs is probably driven by natural selection. Other relevant factors could include infections in unvaccinated populations – which may enable the virus to spread and evolve more easily – and persistent infections in particular individuals, such as immunocompromised patients, which may also lead to altered viral dynamics.
While there's still much we don't fully understand about what triggers so many rapid mutations in SARS-CoV-2, the fact that we can see and track this happening means ongoing genomic monitoring of the virus is crucial.
Doing so might just give us a chance to stop the next wave – instead of catching it.
"This makes the case for very good genomic surveillance, because we didn't catch the intermediate forms of Omicron, and surely there were a few," Duchene told The Sydney Morning Herald.
"Imagine if you could have detected Omicron in the first few patients – if you could prevent it spreading from there, then we wouldn't be in the situation we are now."
The findings are reported in Molecular Biology and Evolution.