I don’t say that, I’m just saying a long protein will probably have non-selectable, even deleterious steps on the way to its formation.
“Most amino acid changes in proteins diminish a protein’s function. But about one-third of possible amino acid changes are like switching a k for a c in “cat” or “candy”; they can be accommodated without too much trouble. [14] 14.Axe, D. D. 2004. Estimating the prevalence of protein sequences adopting functional enzyme folds. J. Mol. Biol. 341” (Edge of Evolution, p. 134)
And from Axe’s paper, we read: “Combined with the estimated prevalence of plausible hydropathic patterns (for any fold) and of relevant folds for particular functions, this implies the overall prevalence of sequences performing a specific function by any domain-sized fold may be as low as 1 in 10(77), adding to the body of evidence that functional folds require highly extraordinary sequences.”
They had to be added in a specific order for full activity. This implies that some activity was present in other orders, though two mutations were required for low activity.
Others here are telling me our genome is littered with neutral mutations, implying they can stick around. And chloroquine resistance would tend to practically fix the changes in a population, making it even more difficult for drift to remove them.
That’s like saying evolution ignores all but one. White bases his result on what evolution has done, and Behe deduces from there that two mutations are required.
That’s a further deduction, from the mutations being probably deleterious.
But he doesn’t apply it to every other living thing directly, he argues that a double-CCC event (with four or more deleterious mutations) is beyond the edge of evolution. And you seemed to concur with this…
Because his argument then turns to protein-protein binding sites, requiring a handful of deleterious mutations, regardless of other factors. He then examines HIV and malaria, to see how often protein-protein binding sites have evolved, which leads to confirmation of his estimate.
Well, we are still discussing this.
Well, I can’t quote the whole chapter. Let’s try this:
“We can adapt the lessons of the immune system and shape space to help understand the problems random mutation would face in making new protein-protein binding sites in the cell. The immune system is set up to get around the problem. But what happens when you remove the manufacturer who threw all these shuffled pieces of plastic into the pool? What if new pieces had to be made by rare dents or scrapes to old pieces? The immune system is capable of producing an essentially infinite warehouse of little plastic shapes. Experiments with similar systems in laboratories have enabled scientists to test finite subsets of that warehouse, to see how big it must be in order to handle particular challenges. These experiments yield generalizable parameters for the limits of binding proteins in any context, not just immune systems.” (Edge of Evolution, pp. 130-131)
Behe then examines said experiments.
But you just agreed that a double-CCC was beyond the edge of evolution:
Reality tells us that Axe’s estimation is way off.
In that experiment they got 5 different proteins that displayed beta-lactamase activity out of a total of about 2 x10^9 random peptides. This means Axe is off by 68 orders of magnitude, which isn’t too surprising.
Very good! You now understand something about evolution that Michael Behe doesn’t. This is something scientists have been trying to explain to him for years, and he still hasn’t got it. So well done.
However, I suspect you do not understand how this sinks his argument. But maybe you’ll surprise me, we’ll see!
Pro-tip: Trying to support the ridiculous claims by an Intelligent Design Creationist with more ridiculous claims from another Intelligent Design Creationist is not a winning strategy. I’ll let @Rumraket have first crack at this, if he wishes. He has written a lot about Axe.
Completely besides the point. Evolution of chloroquine resistance does not require any simultaneous mutations. Behe is wrong. Period.
Uh, OK? Right? And? Look, much of what you are writing here is abject nonsense, the above being a good example. Do you really think what you wrote above makes even a modicum of sense? Yes, neutral mutations can stick around. So what does that have to do with whether CR is subject to negative selection? And just how do you think CR will fix any changes in a population that is not being exposed to chloroquine? Please, I’d love to hear about that.
How does he derive that from the frequency with which CR evolves in malaria? Try your best to put together a coherent and logical argument for this, not just parrotting Behe’s talking points.
Creationists have no answer to this. They think they can generalize from one example to all of evolution. They think it is disputed that there is some sort of edge to evolution at all, as opposed to the idea that every adaptation is equally restrictive in the ways it can evolve. What is being disputed is the idea that any known attribute of any living organism lies beyond that edge. Creationists can’t seem to find any such attributes that lie beyond the edge of evolution without straightforwardly assuming what they should be trying to prove.
By making question-begging assumptions about intermediates all being strongly deleterious, through assuming multiple mutations must be required simultaneously, to assuming there’s some sort of “target” sequence that has to evolve. None of which has any basis in fact.
In every single instance where an extant adaptation’s historical evolution has been attempted recreated in the laboratory, it turns out there have been hundreds, to thousands, or millions of ways in which it could evolve.
No, it wouldn’t. Why are you repeating experimentally demonstrated falsehoods? Do facts matter to you at all? I have referenced you papers detailing experiments that show many proteins are something on the order of one mutation away from creating highly specific and strong binding spots on their surface, triggering their ability to self-assemble into large quaternary structures.
I have also referenced you papers detailing physically realistic computer modeling experiments that show it is easy, trivial, in fact, to positively select for novel binding spots on a protein surface should such a binding spot happen to be beneficial to the organism. You’ve ignored these posts and references every time.
I must conclude you don’t really care about facts, and you seem to be treating Michael Behe’s utterances as you presumably treat your Bible. Infallible, and to be merely quoted as if the final authority on any matter. Is that actually your position on Behe? Is he up there with Jesus in your life? Do you carry a necklace with Behe’s face on it next to the one with a cross? Behe spoke and it was so?
Can you please point out an attribute of any known organism that is known to only be able to evolve by combining four individual deleterious mutations? I expect references to experiments where the entire sequence space separating ancestor from descendant is probed for it’s fitness effects, and the selection coefficients of all possible mutants and their combinations in that space are elucidated. And through such an exhaustive study it was discovered that all intermediate steps were deleterious and that moving from ancestor to descendant would require at least four deleterious mutations.
To save you some time: there is no such reference that shows such a result.
Yes, lots of things are beyond the “edge of evolution.” I’m quite certain that It is “beyond the edge of evolution” for human beings to evolve, in the space of ten generations, the ability to fly.
Does that mean we were “intelligently designed”? I really don’t see the logic of that argument. What am I missing, in your opinion?
Yeah, well his track record on research like that is not exactly stellar.
Only if your idea of a “discussion” is where you are presented clear evidence that you are wrong, and you plug your ears and go “Nah, nah, nah! What? I can’t hear you!”
We now know how CR evolved thanks to the Summers paper, which was not available when Behe wrote his book. No smultaneous mutations are required. This is an empirical, objective fact. That you refuse to accept this does not mean there is any more “discussion” to be had on the subject.
Uh, OK. Well, you certainly did quote a bunch of words there that Behe wrote in his book. It would have been nice, though, if they even remotely constituted an answer to my question.
Axe’s experiment is logically incapable of attaching a probability to the function as it only probed the immediate sequence-neighborhood of a particular structure-function relationship. Since we know entirely different structures sharing essentially no sequence-similarity to the protein family in question can also catalyze the same reaction(metallo beta lactamases are entirely unrelated but can perform the same function, heck it’s even been shown that you can select for beta lactamase function in antibodies), his experiment can’t inform us of how unlikely it is, a priori, of randomly evolving even the particular function of interest.
But even that is a problematic way of thinking of the issue. First of all proteins aren’t evolving by blindly and randomly shooting into sequence space for a specific function. The serine beta-lactamases(TEM-1 beta-lactamase that Axe did his experiment on) belongs to a much larger family of proteins and evolved from other proteins in that family with other, related functions. That his bacteria fail to produce colonies on his plates because the protein might have lost the function that gives them resistance to the level of antibiotic found in the agar isn’t particularly good evidence that those proteins are nonfunctional.
But more importantly, evolution isn’t somehow trying to evolve a specific function(much less a specific function in a particular structure), that’s target thinking. Rather anything that is nearby in sequence space and has a function that contributes to reproductive fitness will be selected for. So even on the (provably false) assumption that Axe’s number for for the beta-lactamase fold is correct, that tells us nothing about how rare functional proteins are in protein sequence space.
For a different type of experiment that gives much higher probability numbers than Axe’s, you can read this post:
Intermediates are not all assumed to be strongly deleterious, though, Behe even grants that two mutations (out of 5 or 6 mutations total) are neutral, and get fixed. And if the remainder are deleterious, then they must effectively occur simultaneously.
And Behe does not speak of a target sequence, he speaks of general protein-protein interactions, in his edge of evolution.
Which doesn’t help much in the face of numbers like 1 in 10^40.
Well, in this paper (“Evolution of an ancient protein function involved in organized multicellularity in animals”) this was one ancestral protein, which I believe already had a binding site for a target, that then switched to bind to the same site on a different target.
Well, again, that’s going to gum up the works, if binding sites are so easy to come by.
Well, the point being that four individually deleterious mutations are not expected to occur, so no, there would be no such attribute, would be the conclusion.
No, but were it to happen, then that ability would be due to intelligent design.
Yeah, well his track record on research like that is not exactly stellar.
And Casey Luskin responded to the Panda’s Thumb article: " In other words, Vpu has two different protein domains, each of which performs one of the functions cited by Smith. Thus, neither Vpu protein in the two strains of HIV acquired any new function, for as far as we can tell, both Vpus in both strains of HIV generally perform both tasks."
But they state that two mutations were required on each path they found.
Then why does chloroquine resistance arise in about 1 in 10^20 organisms, whereas atovaquone resistance (which requires 1 mutation) arises in about 1 in 10^12 organisms?
Well, I believe CR is subject to negative selection because the mutations for it are deleterious, in the absence of chloroquine. So your first question doesn’t seem to be addressing what I am saying. And I don’t understand your second question.
Because a double-CCC event would require about 10^40 organisms, which is about the number of organisms in the history of life.
They weren’t random though, right? Antibodies need to avoid targeting the body, for starters. Your results depend on how you sample:
“Studies of these libraries have highlighted the enrichment of functional sequences in the recombinational landscape: SCHEMA-designed libraries contain a significant proportion (20–50%) of functional sequences, despite having a high average mutation level (i.e. average distance of a chimera sequence from its closest parent). For comparison, random mutation libraries with the same number of mutations are estimated to contain 10–20 orders of magnitude fewer functional sequences [13]–[15]. Whereas random mutations cause the probability a sequence remains functional to decrease exponentially, mutation by recombination always moves towards other functional sequences and is therefore significantly more conservative [16]. For this reason, intragenic recombination effectively explores functional ridges through a protein sequence space that is mostly nonfunctional.”
If there are no actual examples in need of an explanation, then what is the point? If everything we actually observe could evolve without ID, then why bring up ID?
Well if it’s only two why did you say four to begin with?
And there’s still no references that shows this entirely hypothetical requirement obtains for any known biological entity.
I wasn’t talking specifically about Behe, but I’ve already referenced papers that show Behe’s apologetics about protein-protein interactions don’t reflect reality.
What does that number have to do with anything I’ve said? 1 in 10^40 what?
A “binding site” is just somewhere on the surface of a protein where there is a matching shape and polarity that makes it stick better to another molecule than it does to the solvent (usually between water-soluble proteins that means binding sites are hydrophobic). Any part of a protein’s surface is a potential binding site to some other molecule that already has a correspondingly matching shape and polarity.
The fact that some part of a protein’s surface is already a “binding site” for some molecule X doesn’t make it a “binding site” for molecule Y if it does not already have a sufficiently matching shape and electrostatic charge profile to yield productive binding activity. Regardless of how well that part of the protein already binds another molecule X. The ancestor did not bind the partner protein, it was an enzyme.
It took a mutation to turn the part of the ancestral GK-enzyme that binds the enzyme’s substrate molecules (“molecule X”), into an efficient scaffolding protein that interacts with the PINS protein(“molecule Y”). This gave the protein an entirely new function. It gained the ability to bind a protein it did not bind before, and it turned it from an enzyme that catalyzes a chemical reaction into a scaffolding protein who’s function is to give structure and direction to dividing cells. Thus there evolved a protein-protein binding site where before there was none.
The fact that this part of the protein already had a sufficiently matching shape and charge - that a single mutation could turn this part of the protein into an efficient binding surface for the partner protein - just shows that Behe is wrong and that it doesn’t take four mutations, or seven mutations, of which two have to be deleterious middle-men, or anything of the sort, to evolve a protein-protein binding interface. Rather it shows that there are proteins in existence where they are already so closely matching in shape and charge, just by chance, that it just takes one to turn them into effective binding partners.
These fortuitous binding surfaces are not this impossible rarity that takes half a dozen mutations, with half of those being deleterious, to evolve. They’re a ubiquitous and unavoidable consequence of intermolecular forces. It’s not much different than finding two rocks that have roughly matching shapes that make them good for stacking, and with a tiny modification will make them even better matched. That really does occur just by chance.
I already referenced you papers that show the generality of this phenomenon that many proteins are easily turned into efficient binding partners:
Abstract
The self-association of proteins into symmetric complexes is ubiquitous in all kingdoms of life. Symmetric complexes possess unique geometric and functional properties, but their internal symmetry can pose a risk. In sickle-cell disease, the symmetry of haemoglobin exacerbates the effect of a mutation, triggering assembly into harmful fibrils. Here we examine the universality of this mechanism and its relation to protein structure geometry. We introduced point mutations solely designed to increase surface hydrophobicity among 12 distinct symmetric complexes from Escherichia coli. Notably, all responded by forming supramolecular assemblies in vitro, as well as in vivo upon heterologous expression in Saccharomyces cerevisiae. Remarkably, in four cases, micrometre-long fibrils formed in vivo in response to a single point mutation. Biophysical measurements and electron microscopy revealed that mutants self-assembled in their folded states and so were not amyloid-like. Structural examination of 73 mutants identified supramolecular assembly hot spots predictable by geometry. A subsequent structural analysis of 7,471 symmetric complexes showed that geometric hot spots were buffered chemically by hydrophilic residues, suggesting a mechanism preventing mis-assembly of these regions. Thus, point mutations can frequently trigger folded proteins to self-assemble into higher-order structures. This potential is counterbalanced by negative selection and can be exploited to design nanomaterials in living cells.
So basically all proteins have potential protein-protein binding interfaces on their surface that by chance have sufficiently similar and matching surfaces on other proteins, that it is a trivial matter for point mutations to render them able to self-assemble into higher order structures. This phenomenon is so ubiquitous that negative selection usually acts against this inherent propensity of proteins to stick together.
Hence, negative selection. Yes, proteins are some compromise structure between how their residues affect their function, their inherent and unavoidable mutual attractions, their ability to fold, and their stability, and how all of this plays together to yield their effect on the reproduction and survival of the organism. And all of these come in degrees ranging from 0, through barely detectable, to intolerable and lethal.
And residues that negatively affect one attribute might positively affect another, so the result of continued selection and mutation(and recombination, and so on) is that some (from the perspective of organismal fitness) compromise protein sequence evolves. That really is the modern view of how proteins function in the cell from the perspective of biophysics and evolution:
20–50%) of functional sequences, despite having a high average mutation level (i.e. average distance of a chimera sequence from its closest parent). For comparison, random mutation libraries with the same number of mutations are estimated to contain 10–20 orders of magnitude fewer functional sequences