If so, that leads to sort of a paradoxical argument where SARS-CoV-2 is showing an evolutionary pattern (seismic leaps) that doesn't show in less-well-sampled viral genomes, yet the reason for the pattern is because we still aren't sequencing enough. Specifically, if this is how viruses work, it sure isn't what flu does, which is to buil…
If so, that leads to sort of a paradoxical argument where SARS-CoV-2 is showing an evolutionary pattern (seismic leaps) that doesn't show in less-well-sampled viral genomes, yet the reason for the pattern is because we still aren't sequencing enough. Specifically, if this is how viruses work, it sure isn't what flu does, which is to build incrementally in a very orderly phylogenic pattern that can be reconstructed from archived isolates for both humans and animals without any big gaps, as in the supplemental materials at Smith, et al. https://www.pnas.org/doi/10.1073/pnas.0904991106#supplementary-materials
*edit for further comments: In general, regardless of how well we sequence a given RNA virus, evolution appears faster in close-up than in far away. The reason for this again is stabilizing and purifying selection - most mutations are pruned in the long run (ref here is Simmonds 2019 in this post). So hence why "high dots" should not lead the trend, and indeed they do not. And, SARS-CoV-2 should not be mutating faster in the long term (via seismic leaps) than it is at any point when you follow a given clade in real time.
That's not to rule it out (for example, there are still problems with the "dark age" of flu where it seems like 1918 is an extinct offshoot of the H1 progenitor of both 1918 and the flu that survives going forward to 1933 and beyond), but again the purpose of "Should Variants" is to frame the whole topic in the context where there *is no* precedent for what we are seeing, and yet here we are clearly bringing these expectations "oh of course there will be variants." Well, no, it's not an of course matter.
From that point, begins the argument that the variants should not appear, which has to raise the higher bar of ruling out some kind of unprecedented and likely paradoxical evolutionary pattern.
Agree with your point about weighting mutations for likeliness. The next post will, however, show that the VOCs do not consistently travel to their mutation set by following paths of likely mutations (though it's hardly a clear-cut "synthetic signature" for most).
Flu may also be inherently not representative here. It doesn't have a receptor-binding protein, and hence perhaps doesn't need to make leaps. Similar parainfluenza binds to a sialic acid, not a complex protein.
For RSV family though, it does seem to be stable. But we have very low historical sampling and the strength of RSV is that it can use a wider selection of receptor binding proteins and has been suggested to have decoy mechanisms to have antibodies bind to the wrong things.
And to be fair, we actually are not really sure COVID-19 is unprecedented in the corona family. After all, we barely studied common coronaviruses at this biochemical level. Perhaps they do make leaps too?
So perhaps nature has a few methods to solve the problem of immunity evasion and we should not assume COVID-19 should necessarily follow the same patterns as flu?
Of course, perhaps this is unprecedented. But then also no virus ever in our human history had just under 8 American billion *virgin* hosts to work with. A one in a 10 million chance, can be compensated by throwing simply more hosts at it.
In essence my point is, we should be careful trying to extrapolate based on current knowledge as we really know very little for sure in general, but as you say do assume a lot.
If so, that leads to sort of a paradoxical argument where SARS-CoV-2 is showing an evolutionary pattern (seismic leaps) that doesn't show in less-well-sampled viral genomes, yet the reason for the pattern is because we still aren't sequencing enough. Specifically, if this is how viruses work, it sure isn't what flu does, which is to build incrementally in a very orderly phylogenic pattern that can be reconstructed from archived isolates for both humans and animals without any big gaps, as in the supplemental materials at Smith, et al. https://www.pnas.org/doi/10.1073/pnas.0904991106#supplementary-materials
*edit for further comments: In general, regardless of how well we sequence a given RNA virus, evolution appears faster in close-up than in far away. The reason for this again is stabilizing and purifying selection - most mutations are pruned in the long run (ref here is Simmonds 2019 in this post). So hence why "high dots" should not lead the trend, and indeed they do not. And, SARS-CoV-2 should not be mutating faster in the long term (via seismic leaps) than it is at any point when you follow a given clade in real time.
That's not to rule it out (for example, there are still problems with the "dark age" of flu where it seems like 1918 is an extinct offshoot of the H1 progenitor of both 1918 and the flu that survives going forward to 1933 and beyond), but again the purpose of "Should Variants" is to frame the whole topic in the context where there *is no* precedent for what we are seeing, and yet here we are clearly bringing these expectations "oh of course there will be variants." Well, no, it's not an of course matter.
From that point, begins the argument that the variants should not appear, which has to raise the higher bar of ruling out some kind of unprecedented and likely paradoxical evolutionary pattern.
Agree with your point about weighting mutations for likeliness. The next post will, however, show that the VOCs do not consistently travel to their mutation set by following paths of likely mutations (though it's hardly a clear-cut "synthetic signature" for most).
Good points and I'm looking forward to Pt 4.
Flu may also be inherently not representative here. It doesn't have a receptor-binding protein, and hence perhaps doesn't need to make leaps. Similar parainfluenza binds to a sialic acid, not a complex protein.
For RSV family though, it does seem to be stable. But we have very low historical sampling and the strength of RSV is that it can use a wider selection of receptor binding proteins and has been suggested to have decoy mechanisms to have antibodies bind to the wrong things.
And to be fair, we actually are not really sure COVID-19 is unprecedented in the corona family. After all, we barely studied common coronaviruses at this biochemical level. Perhaps they do make leaps too?
So perhaps nature has a few methods to solve the problem of immunity evasion and we should not assume COVID-19 should necessarily follow the same patterns as flu?
Of course, perhaps this is unprecedented. But then also no virus ever in our human history had just under 8 American billion *virgin* hosts to work with. A one in a 10 million chance, can be compensated by throwing simply more hosts at it.
In essence my point is, we should be careful trying to extrapolate based on current knowledge as we really know very little for sure in general, but as you say do assume a lot.