Omicron spike protein should be impossible, according to DI's Brian Miller

Rumraket hits on this several comments down, saying Brian Miller “appears to not understand that purifying selection can maintain structural stability of a protein against destabilizing mutations.”

Yes, that is clearly implied by Miller trying to argue against a case of a protein evolving from being able to perform one function, into another similar protein that carries out a different function. He’s being quite clear this is what he is trying to accomplish with this argument. He’s not just trying to argue that to discover a new functional protein de novo is very unlikely, he’s also trying to argue against the idea that, for example the flagellum’s filament protein - flagellin - could have evolved from another protein that was less than 90% similar to it.

By Miller using research on protein stability, where mutations were allowed to accumulate without selection to see how many it would take on average before the protein destabilized, to argue against proteins being able to accumulate mutations over time, he really does appear not to understand the rule of purifying selection in these sorts of random walks in protein sequence space.

Yes, when selection is not included, then after relatively few mutations the protein is pretty much guaranteed to destabilize. Hence mutations without selection can’t just accumulate willy-nilly and indefinitely, and you would, without selection, expect the protein to become nonfunctional long before a new function was found (supposing, just for the sake of argument, that 10% of the sequence has to change to find a new function).

The whole point here is that the very same research indicates that when purifying selection is included, the protein really can continue to accumulate mutations well beyond those 5-10 amino acid substitutions, or 10% of sequence length, or whatever “limit” Brian Miller thinks there is. I make this same point in this post.

But why does Rumraket think Miller is talking about a case of purifying selection? In Rumraket’s second source, Miller even says he’s talking about a case of weak selection: “After only a few random mutations (1-2) under weak selection , around a third of subsequent changes to a protein completely disable it.”

This fellow is confused. I am not arguing that the strength of selection changes the proportion of mutations that are destabilizing versus stabilizing. I am arguing that Miller is ignoring selection when he argues against the long-term accumulation of mutations in protein sequences. When Miller is trying to cast doubt on the possibility that, for example, the flagellum’s filament protein flagellin could have evolved incrementally from another protein that is less than 90% similar, by appealing to research done trying to establish how many mutations it takes, on average, to destabilize a protein.
That research shows it takes only a few without selection (because on average more mutations are destabilizing than stabilizing), but when selection is included, the protein actually doesn’t destabilize because now the destabilizing mutations are either selected against(those mutants have lower fitness because their protein falls apart more often), or being compensated for by the fixation of stabilizing mutations.

This is an absurd misunderstanding of the waiting time problem. The waiting time problem refers to when you need two simultaneous, specific mutations before a fitness gain is realized.

No, it just refers to two(or more) specific mutations. The whole problem with the waiting time argument (I’m now explaining what is wrong with the waiting time problem-argument) is that it asks us to pick out particular combinations of mutations (two or more) and then asks us to calculate the odds that that specific “target” set of mutations would occur. And since it would take a lot longer to wait for two specific mutations, rather than to wait for just any two mutations, any time we find that two sequences are different from each other by some number of mutations we could argue they couldn’t possibly have evolved from each other (or from a common ancestor) in the available time because our calculation shows it would take an inordinate amount of time before that set specific set of differences to have occurred. I have a post that explains the problem with the waiting time-type of arguments here:

No reason to go over the rest of this fellow’s post because he doesn’t seem to know what I’m referring to. Yes, creationists (such as John Sanford) really have argued that to get some specific set of mutations takes a really long time on average, and therefore evolution is false because we find that two things A and B have that many differences, and that is regardless of whether those mutations each confer a selective advantage or not.

And he’s actually right. The math generally checks out. It really would take a really long time to wait for that specific set of 2 or more mutations. It’s just that those aren’t the only possible set there was, it was just the one that occurred.

It doesn’t apply when:

  1. The mutations can happen one at a time with a gain in fitness at each step.

Flat out wrong. It still applies. The math still shows that if you need to wait for two specific mutations, even if each of them carries a fitness benefit, it will take a loooong time for those two specific mutations. And if you pick out three specific mutations, it gets even worse. And so on and so forth. The whole argument here is about specific target sequences vs any sequence that works.

If anyone thinks this is all just “creationist nonesense,” here’s Larry Moran saying the same thing:

  1. “The probability of any single mutation occurring is equal to the mutation rare, which is about 10-10. The probability of an additional specific mutation occurring is also 10-10. The combined probability of any two specific mutations occurring is 10-20… Let’s say that three specific mutations are required to change from a cluster of two needles to a cluster of five needles. One hundred million years ago you could calculate that the probability of three specific mutations is about 10-30. It’s highly improbable, just like the specific bridge hand. When such a triple mutation arises we recognize that it was only one of millions and millions of possible evolutionary outcomes.”

Uhm, yes, exactly. That’s my whole goddamned point. That it makes no sense to pick out specific sets of mutations after the fact and declare them to be a “target sequence” that couldn’t possibly evolve because it would take too long(nor does it make sense to calculate the mean time to establishment of some X number, as that treats them as a target too), exactly because it is just one possible set that evolved out of many others that could. It was never a “target” to begin with. It’s just a contingent outcome of history.