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?
2 Likes
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.
1 Like
Recent paper illustrating how SARS-CoV-2 fitness is increasing over time:
From the body of the paper:
1 Like
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.
3 Likes
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.
4 Likes
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.
1 Like
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.
3 Likes
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?
Because it is not even close.
Omicron (B.1.1.529) has about sixty mutations against the original Wuhan strain. Given twelve identified as beneficial, which is likely conservative, that is one in five as opposed to Sanford’s statement of, minimally, a ratio of one good mutation to a thousand bad. And as far as I am aware at this point, it could be that none of the omicron mutations are deleterious.
People listen to Sanford and leave with the impression that mainstream scientists must be idiots or willfully blind for not seeing how mutations are an tsunami of overwhelmingly negative errors. I think it reprehensible that he spreads such misinformation.
Yes, but to acknowledge selection is not to address how it effectively counters GE. For slightly deleterious mutations to accumulate, they must be beneath the threshold of selection population wide.
1 Like
On other recent threads in this forum, much has been made of the supposedly daunting rarity of new binding sites. The majority of those infected by viruses however, recover thanks to their immune system developing neutralizing antibodies, which of course, must bind. ID proponents present a somewhat conflicted take on this; emphasizing the odds against finding a complementary shape space, while extolling the design of the immune system for its ability to do just that. The search for covid monoclonal antibodies has demonstrated that there are many more than one way to pick a lock.
For instance, in the development of Tixagevimab and Cilgavimab, from four recovered donors, covid antibody panels of 321 unique amino acid sequences were present. Two were selected which target distinct, non-overlapping epitopes on the spike protein. These bind to the spike protein with far higher affinity than the actual human ACE2 receptor.
Bebtelovimab is another monoclonal which was screened out for its relatively conserved target and binding which was not brittle to the N439 and N501 mutations of the epitope region.
LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants
Using a high-throughput B cell screening pipeline, we isolated LY-CoV1404 (bebtelovimab), a highly potent SARS-CoV-2 spike glycoprotein receptor binding domain (RBD)-specific antibody. …Structural analysis reveals that the contact residues of the LY-CoV1404 epitope are highly conserved, except for N439 and N501. The binding and neutralizing activity of LY-CoV1404 is unaffected by the most common mutations at these positions (N439K and N501Y).
Another team sorted through candidate antibodies with a focus on avoiding the highly variable regions of the receptor-binding motif altogether. Despite the sequence distance between SARS-CoV-1 and SARS-CoV-2, the parental form of Sotrovimab, S309, was isolated from a patient with SARS-CoV-1, again with the idea of targeting conserved, and presumably essential, viral targets.
Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab
There is an interesting discussion of the development of sotrovimab on this YouTube, where Benjamin Pinsky discusses antibody binding in context. The strength of binding varies widely, but is not necessarily correlated with potency, which also factors in immunodominance, synergistic effects, serum half life and degree of impairment from epitope neutralization. An antibody with sticky note binding is often more effective than one with crazy glue binding.
There is more than a half dozen other unpronuncimabs in various stages of readiness. Relevant to ID and creationism is that each of these came out of assays where dozens or hundreds of distinct antibodies from recovered patients were evaluated as monoclonal candidates, all with various degrees of affinity for SARS proteins. The protein shape space is demonstrably not an insurmountable challenge to binding. The greatest interest has been in the spike, but antibodies have also been found which target the capsid and most other viral proteins.
I doubt there could be a more real world, general result. It is not that there is no edge at all to the immune system search; the disease often outruns the body’s defenses. In general, however, antibody binding reinforces the evidence from viral adaptation itself that novel selectivity in protein binding is a routine feature of nature.
2 Likes
strong text****strong text[quote=“RonSewell, post:36, topic:15113”]
Because it is not even close.
Omicron (B.1.1.529) has about sixty mutations against the original Wuhan strain. Given twelve identified as beneficial, which is likely conservative, that is one in five as opposed to Sanford’s statement of, minimally, a ratio of one good mutation to a thousand bad. And as far as I am aware at this point, it could be that none of the omicron mutations are deleterious.
[/quote]
The beneficial mutations of Omicron are not unexpected under GE for GE acknowledge the existence of a very small class of beneficial mutations that have a large effect on fitness. And it is also expected that at the beginning of a zoonose, when there is plenty of room for adaptation to the new host, this class of rare beneficial mutations will accumulate rapidly. But that doesn’t invalidate GE. Here is an interesting quote from Sanford and Nelson on this issue of beneficial mutations accumulation :
« Beneficial mutation accumulation
Mendel also keeps a tally of how many beneficial mutations have accumulated in each individual. Like deleterious mutations, the number of beneficial mutations per individual tends to increase at a relatively constant rate, except for a very small class of beneficial mutations that have relatively large effects on fitness. Above a certain fitness effect, beneficial mutations are strongly amplified, leading to a period of accelerated mutation accumulation for that set of mutations and any mutations linked to them. The rapid amplification of high-impact beneficial mutations is as would be as expected, but it is striking to see that the large majority of beneficial mutations are too subtle to respond to selection (Sanford et al., 2012). Except for those few high-impact beneficial mutations which are strongly amplified, the ratio of beneficial versus deleterious mutations does not change dramatically in response to selection (see Figures 1 and 3). Since it is well known that deleterious mutations arise much more frequently than do beneficial mutations, this means that many more functional nucleotide sites are being disrupted than are being established, even with intense selection. This suggests there should be a strong natural tendency toward net loss of genetic information over time, even while a limited number of beneficial mutations are being strongly amplified. This represents a second major evolutionary paradox that demands serious attention by researchers. Again, it seems clear that this problem can best be understood by further numerical simulation experiments. » (The Next Step in Understanding Population Dynamics: Comprehensive Numerical Simulation)
https://www.researchgate.net/profile/Chase-Nelson-3/publication/260518577_The_Next_Step_in_Understanding_Population_Dynamics_Comprehensive_Numerical_Simulation/links/0f317531805aeddd4e000000/The-Next-Step-in-Understanding-Population-Dynamics-Comprehensive-Numerical-Simulation.pdf?origin=publication_detail
Let’s also not forget that the binding sites in antibodies were randomly produced through V(D)J recombination while we are still in the womb. They are not constructed in response to an infection. The process involves randomly selecting different chunks of DNA and stitching them together. There can be small differences in each joining meaning that you get diversity in reading frames.
In my own work I have submitted proteins for mouse monoclonal antibody production. I got back dozens of candidates, all different random binding sites that bound to the protein I submitted. And this is just from 2 mice. From what I have seen, nearly every person already has antibodies that are specific to all of the surface proteins on SARS-CoV-2. Again, these are antibodies that people have had since birth and well before exposure to any viruses.
2 Likes
Then what would?
1 Like