Lessons from the pandemic: A new look at an new virus: patterns of mutation accumulation in SARS-CoV-2 since 2019

So far, so good. But this fulfilled prediction doesn’t at all invalidate GE, for GE proponents heartedly agree that specific adaptive mutations commonly occur, especially at the beginning of a zoonose, when there is plenty of room for adaption in the new host. Here is a quote regarding SARS from Carter that illustrates the point : « I hesitate, however, to make a prediction. I think it will attenuate over time, and I think this will be over the course of a couple of years, but this does not mean that a mutation that makes it more infectious or more deadly cannot arise even as the genome, in general, is wasting away »

GE doesn’t predict that a new virus such as SARS2 would gone exinct in two years.

There are too many unknowns to establish a date of extinction for SARS2. However, based on GE, one can still makes the following predictions:

  • Mutations will accumulate linearly (at a constant rate) and largely uniformly across the genome.
  • continuous erosion over time of codon-specificity, including a shift away from human and bat codon preference patterns.

No, SARS2 has not progressed as a counter-example, for when a new virus such as SARS2 first appears in human, there is room for both accumulation of near neutral deleterious mutations and selection of sets of adaptive mutations. But as time passes, the opportunity for the later phenomenon declines, leaving mostly the former.

How exactly do these predictions flow from GE?

Bonjour Gilbert, it has been a while since we last conversed over GE.

While SARS2 may be novel in humans, it is not a new virus. It has been around for at least 6000 years even in a YEC framework and subject to GE over that time. But to skip past that for the moment…

What is significant is not just that there was not just some general prediction that there would be beneficial mutation, but that it was highly exact, and the particular reasons that mutation would be advantageous were recognized in advance. Contrast this with the accumulation of near neutral deleterious mutations and Carter’s fortune cookie prediction that covid will attenuate over time. What, exactly, makes these mutations neutral enough to avoid selection, yet in aggregate deleterious enough to result in extinction? Predict the mechanism of wimpiness; where does it happen? Is the point of failure at tropism? attachment? entry? intracellular replication? egress? Conventional host population adaptation also predicts that the pandemic will wane, so where do we look for the distinctive for GE? You suggest two.

Well, that is not even close. One, for whatever reasons, omicron has presented with an off the scale mutation rate. Two, the spike protein is far less conserved than nonstructural elements. The S1 subunit of the spike is a hotspot compared to the S2 subunit. Mutation is not uniform across the S1 subunit. This is well known because, as well as general scientific interest, this matters for the development of vaccines that the virus will not quickly adapt to. The search is always on for a conserved target that the virus will not easily alter.

SARS-CoV-2 Mutations and Their Impact on Diagnostics, Therapeutics and Vaccines

Human and bat codon bias are not the same, and that is the basis for much analysis of the origin of the zoonotic pathway. Moreover, how would GE allow a shift towards human codon preferences, which appears to be trending, and then erode codon-specificity away from human codon preferences? That would be largely a restoration to the original pristine state before the virus adapted to humans, would it not?

By the way, there is no evidence that influenza has trended away from human codon bias. There is interest in development of genetically engineered attenuated vaccines which grow well in avian eggs, but are mismatched to human bias, because that is what does not happen naturally and at large.

Viruses are little more than itinerate genes packed in a capsid suitcase. They are a poor candidate for GE as their genomes travel light, are relatively efficient and therefore exposed to selection. Considering that covid has been the central news story of the recent two years, GE advocates seem to saying the very least they can get away with. Even their base following is asking, what is with all these variants?

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This is interesting. Note that when I predict that mutations will accumulate linearly, I have in mind near neutral deleterious mutations, not adaptive mutations. Sorry for the imprecision. Now the question arise as to whether or not the mutations in omicron are adaptive. Do you know the answer?

I agree that some specific regions will be less prone to GE. This is why I used the term «largely » to qualify my claim. Maybe I should have said « by and large » instead.

Something I have been wondering about.
Take some time to appreciate these figures showing the divergences between the variants
(top by time, bottom by mutations).


Maybe this doesn’t mean anything (lack of sampling perhaps), but I am rather startled at how the Omicron branch looks. It looks like it took a lot of mutations and a long time since this lineage diverged before it was finally noticed right when it began to compete for dominance. Almost like it had a long and cryptic period when it wasn’t as competitive as other variants, but nevertheless quietly replicating and accumulating mutations until it acquired the right mutational combo and then BOOM!! It takes over. Could this be an example of evolutionary contingency, similar to what happened in Lenski’s Cit+ E.coli? i.e. involving a period of potentiating mutations, which on their own didn’t contribute to fitness but laid down the genetic background for other mutations to actualize the observed gain in fitness as it took over, and currently we see a period of refinement. Curiously, Omicron exhibit an accelerated mutation rate as well, which also happened in Lenski’s E. coli.

Again, just speculation to get people thinking. It would be interesting to see what the mutations that occurred during the “silent” period actually do for Omicron.

Recent paper illustrating how SARS-CoV-2 fitness is increasing over time:

From the body of the paper:

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To my knowledge one of the currently most favored speculations is that the Omicron variant probably evolved in a single person with a compromised immune system. Hence why none of it’s immediate ancestors have been detected.
This person would have had a long-term infection where their immune system couldn’t fully clear their body of the infection (possibly someone with HIV), so there was a prolonged arms-race between host and SARS-Cov2 in this individual, before it eventually managed to spread on from that host, having evolved into what we now recognize as the Omicron variant clade.

An alternative hypothesis is that the virus jumped into another species like mice early on in the pandemic, evolved there for considerable amount of time, before finally jumping back into humans, again explaining why we haven’t detected it’s immediate ancestors.

Current thinking seems to be that it is quite unlikely that the Omicron variant has managed to evolve completely undetected for something like a year in some human subpopulation somewhere. Which makes the hypothesis of extended period of infection in a single immune compromised individual with for example HIV(which after all is comparatively common in Africa and where Omicron was first detected) or something similar, or an intermediate animal reservoir, more attractive.

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Real world data has shown an increase in substitution rates in immunocompromised patients, so the theory does hold some water.

I was a bit skeptical of the idea when it first came out, but I am growing more and more convinced as time goes on.

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Here’s a really frightening paper about how Omicron’s higher fitness includes undermining the immune response:

https://www.science.org/doi/10.1126/science.abq1841

In summary, these studies have shown that the high global prevalence of B.1.1.529 (Omicron) infections and reinfections likely reflects considerable subversion of immune recognition at both the B, T cell, antibody binding and nAb level, although with considerable differential modulation through immune imprinting. Some imprinted combinations, such as infection during the Wuhan Hu-1 and Omicron waves, confer particularly impaired responses.

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Omicron has been successful both in absolute terms and in competition with prior variants.

The emergence and epidemic characteristics of the highly mutated SARS‐CoV‐2 Omicron variant

Adaptive mutation of the SARS‐CoV‐2 genome can change the infectivity, immune evasion, and phenotypic characteristics of the virus. The emergence of the Omicron variant has caused serious concern about the increased infectivity, immune escape ability, and reinfection risk.

Papers presenting results that “these mutations do something” gather more attention than “these mutations do nothing”, so whether a number of incidental mutations are slightly deleterious, neutral, or just a tad beneficial is yet to be characterized, but it is recognized that there are several identified mutations which are markedly beneficial. The proportion of positive mutations is wildly at odds with the parameters proposed for GE. From Sanford Carter Price Responding to supposed refutations of genetic entropy from the ‘experts’

the much more abundant deleterious mutations effectively overwhelm and negate the fitness effects of the extremely rare beneficial mutations. The ratio of bad to good mutations is, minimally, 1000:1. With or without selection, bad mutations will always accumulate much more rapidly that beneficial mutations. We have done thousands of numerical simulations showing this. Even given the most generous parameter settings, the near-neutral bad mutations consistently accumulate about 1000 times faster than the beneficial mutations.

we know for sure that random changes will always lead to a net loss of information, and almost all changes will be deleterious. Waiting for a beneficial mutation, even a near-neutral beneficial mutation, is like waiting to win a lottery.

Browsing recent papers and adding it up, it appears that omicron has won the powerball with a lucky streak of at least a dozen draws [ ΔH69/V70, Δ143-145, K417N, G446S, E484K, S494P, Q498R, N501Y, D614G, H655Y, N679K, P681H ]. Given the success of the strain, it would be reasonable to suspect that adaptation extends beyond those presently identified. There is also evidence that synonymous mutations in omicron tilt adaptive to particular tissues and human codon patterns. Good old classic adaptive and purifying selection appear to be functioning pretty well in the real world. Omicron has been a real time empirical determination of what is a biologically realistic spectrum of fitness effects.

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How can you say that the proportion of positive mutations is at odds with the parameters proposed for GE when, as you’ve rightly noted, the effect of a number of mutations is yet unknown?

Nobody denies this, not even the proponents of GE.

Perhaps because they constitute a minority?