How to examine the evolution of proteins

| 16 Comments

In my previous post, I described the misguided approach Gauger and Axe have taken to criticizing evolution, and one of the peculiarities of their criticism is that they cited another paper by a paper by Carroll, Ortlund, and Thornton which traced (successfully) the evolutionary history of a class of proteins. Big mistake. As I pointed out, one of the failings of the Gauger/Axe approach is that they're asking how one protein evolved into a cousin protein, without considering the ancestral history …they make the error of trying to argue that an extant protein couldn't have directly evolved into another extant protein, when no one argues that they did.

The tactical error is that right there in the very first paragraph of their paper, Carroll, Ortlund, and Thornton point out the fallacy of what the creationists were doing.

Direct comparisons among present-day proteins can sometime yield insights into the sequence and structural mechanisms that underlie functional differences. Such "horizontal" comparisons, however, cannot determine which protein features are ancestral and which are derived, so they are not suited to reconstructing the events that produced functional diversity.

They don't mention Gauger and Axe, of course — this paper was written before the creationists wrote theirs — but a methodological flaw is still spelled out plainly, the creationists reference it so I presume they read it, and they still charged ahead and did their flawed study, and then had the gall to claim their work was superior.

Ah, silly creationists. They just assume their target audience won't bother to read the work they're citing, and isn't competent to understand it anyway. And they're usually right.

The crew doing the work in the Carroll paper did not make the same mistakes. They are doing ancestral sequence reconstruction (ASR), so the effort to work backward to trace ancestral states is implicit. The bulk of the paper describes the sequencing of homologous and paralogous genes in more organisms (in this case, especially cartilaginous fishes), and the analysis of synthesized, reconstructed ancestral proteins, so it's built entirely on an empirical foundation. And their answers actually advance our understanding of the base-by-base changes that led to the evolution of the current set of proteins. I think they were courteous and sensible (and probably, the idea didn't even occur to them) in not comparing their work to that of the creationists — it would have been less than gracious to point out how ugly, cheap, and cheesy the stuff coming out of the Biologic Institute looks.

What the real scientists were studying is a class of receptors that respond to mineralocorticoid and/or glucocorticoid hormones. These proteins are similar in sequence and structure to one another, and are clearly paralogous: they arose by an ancient gene duplication event, somewhere around 450 million years ago. The two copies have since diverged to have different roles in hormone physiology.

The two receptors are called MR, for mineralocorticoid receptor, and GR, for glucocorticoid receptor.

MRs are activated by adrenal hormones, aldosterone and deoxycorticosterone, and to a lesser exent, cortisol. The receptors are extremely sensitive to the hormones. These hormones are important in regulating salt balance, and you might well imagine that in our fishy ancestors, as well as ourselves, regulating the concentrations of salts in our blood and tissues is a very important function. Deviations can cause death, after all.

GRs are activated by high doses of cortisol; these receptors are much less sensitive, requiring high doses of the hormone to trigger a response. They are important in regulating stress responses: they adjust the immune system and sugar metabolism. These aren't 'twitchy', fast response functions like maintaining salt balance is; they are long-term, 'last-ditch' reactions to growing stresses, so functionally it makes sense that activation requires high levels of accumulated hormone.

Using ASR techniques — phylogenetic analysis and estimating the most likely sequence of the ancestral protein — the investigators have put together a picture of the receptor before MR and GR diverged. This protein is called AncCR, for Ancestral Corticosteroid Receptor, and it has been synthesized in the lab, so we know about its properties. AncCR is a lot like MR: it's sensitive to low concentrations of hormone, and it responds to low concentrations of a broad spectrum of hormones.

The pedigree of these proteins is illustrated below.

grmr_phylo.gif
(Click for larger image)

Simplified phylogeny of corticosteroid receptors. Ancestral sequences are shown at relevant nodes: AncCR, the last common ancestor of all MRs and GRs; AncGR1, the GR ancestor of cartilaginous fishes and bony vertebrates; AncGR2, the GR ancestor of ray- and lobe-finned fishes (including tetrapods); AncMR1, the MR ancestor of cartilaginous fishes and bony vertebrates. (AncGR1.0 and AncGR1.1 are different reconstructions of node AncGR1, inferred from datasets with different taxon sampling.) Black, high sensitivity receptors; gray, low sensitivity receptors. Single and double gray dashes mark functional shifts towards reduced sensitivity and increased specificity, respectively. Support values are the chi-square statistic (1 - p, where p equals the estimated probability that a node could occur by chance alone) calculated from approximate likelihood ratios. The length of branches from AncCR to AncMR1 and to AncGR1, expressed as the mean number of substitutions per site, are indicated in parentheses.

The MRs are similar in function to the AncCR, so they aren't particularly interesting in this context — there's no big question about how the MRs retained similar properties to their ancestor. The interesting questions are all about the GRs: what changed to make GRs different from the ancestral protein? What amino acid changes set AncGR1 apart from AncCR?

The investigators have an answer. The first step was the evolution of reduced hormone sensitivity, so that these receptors only responded to very high concentrations of the hormone, and the second step was a loss of sensitivity to the mineralocorticoids, already handled by the MRs, so that they only respond to high doses of cortisol, which at this point became exclusively a stress hormone. And they know exactly which amino acids changed to confer the reduced sensitivity.

They identified three changes: the conversion of a valine at position 43 into an alanine, called V43A; the conversion of an arginine at position 116 into a histidine, R116H; and the conversion of a cysteine at position 71 into a serine, C71S. They also know the effect of the mutations. V43A and R116H each loosen the structure of the receptor so that it's less sensitive, and when both mutations are present the effect greatly reduces sensitivity about 10,000-fold…too much! They make the mutant hormone too insensitive, and much less insensitive than their reconstructed AncGR1.

The most interesting change is C71S. It basically does nothing to the sensitivity; make the C71S change to AncCR, and you get a receptor protein that is essentially indistinguishable in its response. This is effectively a neutral mutation. It can spread freely through a population with no deleterious or advantageous effect.

C71S does have one significant effect in cooperation with the other two mutations: it buffers both V43A and R116H. When all three mutations are present, the desensitizing effects of V43A and R116H are reduced to produce the level of sensitivity expected for the AncGR1 protein. This means we can reconstruct the order of the amino acid changes in evolution. First came C71S, because it doesn't cause any particular adaptive change, and because if either V43A or R116H came first, the resulting receptor would be generally non-functional. The existence of C71S first means the subsequent V43A/R116H changes produced receptors that are still functional, but simply operate only at higher concentrations of the hormones.

All of these changes are perfectly compatible with an evolutionary model of their origin. No sudden leaps, no deleterious intermediates are required — everything hangs together beautifully and is backed up by solid empirical evidence. In addition, the work explains the mechanics of receptor-hormone interactions, stuff I haven't explained here, but if you're a biochemist, there's much to savor in the paper.

It's an amazing contrast to the Gauger and Axe paper, too. No wonder I'm not a creationist!


Carroll SM, Ortlund EA, Thornton JW (2011) Mechanisms for the evolution of a derived function in the ancestral glucocorticoid receptor. PLoS Genet.7(6):e1002117. Epub 2011 Jun 16.

16 Comments

Well even if they didn’t read this paper, the reviewer for the creationist journal should have. He should have pointed out the glaring errors and saved them the humiliation of a retraction. What? Oh. Never mind.

That’s because reviewing doesn’t actually take place at bio-complexity.

I wouldn’t be surprised all that was done, was a quick skimming to see if it “looks like a real science paper” and concludes evolution can’t happpen, followed by a run through a spell-checker, then they shelf it for a couple of weeks to give off the impression that “it’s being reviewed” and then they just publish it, no questions asked. Axe, Behe and Gauger then high-five each other and go have lunch.

And then when it’s published, they call up David Abel to comment on the paper in the comments section of biocomplexity with “Excellent paper”. This is enough of a pretension to baffle their audience.

Rumraket said:

That’s because reviewing doesn’t actually take place at bio-complexity.

I wouldn’t be surprised all that was done, was a quick skimming to see if it “looks like a real science paper” and concludes evolution can’t happpen, followed by a run through a spell-checker, then they shelf it for a couple of weeks to give off the impression that “it’s being reviewed” and then they just publish it, no questions asked. Axe, Behe and Gauger then high-five each other and go have lunch.

And then when it’s published, they call up David Abel to comment on the paper in the comments section of biocomplexity with “Excellent paper”. This is enough of a pretension to baffle their audience.

I would assume you are correct.

Any alternate scenario would involve the possibility of Behe or Abel rejecting or demanding modifications to a paper by Gauger and Axe. Any such scenario is too absurd to imagine. It’s almost certainly a rubber stamp “review”. What’s the point of having your own fake journal if your own stuff can be rejected by it?

Atheistoclast said:

OK, PZ. Let’s go over what you have just quoted but misunderstood:

C71S does have one significant effect in cooperation with the other two mutations: it buffers both V43A and R116H. When all three mutations are present, the desensitizing effects of V43A and R116H are reduced to produce the level of sensitivity expected for the AncGR1 protein.

Translation: The cysteine-serine (neutral) mutation at residue 71 epistatically compensates for the functional degradation produced by the two subsequent mutations that led to a lower level of sensitivity to the hormone.

This means we can reconstruct the order of the amino acid changes in evolution. First came C71S, because it doesn’t cause any particular adaptive change, and because if either V43A or R116H came first, the resulting receptor would be generally non-functional. The existence of C71S first means the subsequent V43A/R116H changes produced receptors that are still functional, but simply operate only at higher concentrations of the hormones.

Translation: And so the neutral mutation reduced the impact of two mutations that would normally have been disastrous as far as function is concerned. However, the end result is a protein that can only operate at higher concentrations of hormonal secretion.

Is this anything to salivate over? No. As with PZ’s comments on hairless fruit fly larvae, caused by mutations in CRES, this kind of degenerative evolution does not help explain where new information and functionality arises in the genome. Even if both developments are “adaptive” or “beneficial”, with respect to fitness, they don’t represent anything innovative at all. They are just minor tweaks involving the loss of either function or expression. Once again, this kind of research explains just how limited Darwinian evolutionism really is in reality.

Translation: As long as I refuse to call it a new function I can still pretend that no real evolution occurred.

Atheistoclast said:

DS said: Translation: As long as I refuse to call it a new function I can still pretend that no real evolution occurred.

So what is this wonderful new function? Why is decreased sensitivity to a hormone so amazingly innovative? Why does PZ get so excited by these kinds of articles?

From the abstract:

“Prior work showed that GR and its paralog, the mineralocorticoid receptor (MR), duplicated from a common ancestor roughly 450 million years ago; the ancestral functions were largely conserved in the MR lineage, but the functions of GRs — reduced sensitivity to all hormones and increased selectivity for glucocorticoids — are derived.”

Derived mean new Joe. Or didn’t you read the paper? Look dude, I hate to break it to you, but small tweaks as the norm for evolutionary change. Now if you going to design something from scratch, you wouldn’t have such constraints. So I guess what you are complaining about is that there is abundant evidence for how evolution works and no evidence whatsoever for ID. No wonder you have your panties in bunge again.

Oh well, I predict that PZ will banish you to the bathroom wall any second now. Your foolish trolling is quite boring.

A-clast is that annoying sub-species of creationist with a moderate science vocabulary that I meet so often and loath completely. Loudmouth braggarts and bullies when they detect a person who using common sense, and having a deeper faith in facts and science, than in invisible entities, foolishly in their egregious presence say; ‘I accept the fact of evolution.’ I’ve met several of these empty vessels, and the saying is completely true, they make a tremendous amount of noise. My usual response to these temporal farts is to suggest that their time would be better spent trying to convince the biology departments at CalTech, or Erasmus University, than to waste their time on street antics. But of course that is the whole scam, to convince in a most dishonest way (whatever happened to their list of the things god said they couldn’t do?)persons who don’t challenge them. A-clast, you are a liar! How does this usually fit with your faith?

robert van bakel said:

A-clast is that annoying sub-species of creationist with a moderate science vocabulary that I meet so often and loath completely. Loudmouth braggarts and bullies when they detect a person who using common sense, and having a deeper faith in facts and science, than in invisible entities, foolishly in their egregious presence say; ‘I accept the fact of evolution.’

When Atheistoclast isn’t screeching to be worshiped as a God of Science, and exalted as the Sainted Slayer of Evolution, from a very superficial examination, he sounds like he knows what he’s talking about.

Unless of course, you know what he’s talking about, then he sounds like a pompous idiot. But, sadly, very few lay-people have the time, effort, or patience to realize this.

harold said:

Rumraket said:

That’s because reviewing doesn’t actually take place at bio-complexity.

I wouldn’t be surprised all that was done, was a quick skimming to see if it “looks like a real science paper” and concludes evolution can’t happpen, followed by a run through a spell-checker, then they shelf it for a couple of weeks to give off the impression that “it’s being reviewed” and then they just publish it, no questions asked. Axe, Behe and Gauger then high-five each other and go have lunch.

And then when it’s published, they call up David Abel to comment on the paper in the comments section of biocomplexity with “Excellent paper”. This is enough of a pretension to baffle their audience.

I would assume you are correct.

Any alternate scenario would involve the possibility of Behe or Abel rejecting or demanding modifications to a paper by Gauger and Axe. Any such scenario is too absurd to imagine. It’s almost certainly a rubber stamp “review”. What’s the point of having your own fake journal if your own stuff can be rejected by it?

I was agnostic about the nature of this publication until I took a look at the editorial team.

apokryltaros said:

robert van bakel said:

A-clast is that annoying sub-species of creationist with a moderate science vocabulary that I meet so often and loath completely. Loudmouth braggarts and bullies when they detect a person who using common sense, and having a deeper faith in facts and science, than in invisible entities, foolishly in their egregious presence say; ‘I accept the fact of evolution.’

When Atheistoclast isn’t screeching to be worshiped as a God of Science, and exalted as the Sainted Slayer of Evolution, from a very superficial examination, he sounds like he knows what he’s talking about.

Unless of course, you know what he’s talking about, then he sounds like a pompous idiot. But, sadly, very few lay-people have the time, effort, or patience to realize this.

Joseph “Atheistoclast” Bozorgmehr takes the very unusual approach of actually trying to read scientific literature and then convince himself that it supports his own views. His ability to convince himself that all the authors and editors have misinterpreted their own work is a testament to the potential folly of even a seemingly intelligent human mind, when compromised by self-serving bias and emotional issues.

This makes him massively frustrating to people who actually care about science.

It also makes him very unpopular with most of his fellow creationists. Actually reading the relevant scientific literature is a taboo that almost none of them violate. Behe claimed that the immune system couldn’t evolve and then famously admitted that he hadn’t read a single paper discussing the evolution of the immune system.

harold said:

apokryltaros said:

robert van bakel said:

A-clast is that annoying sub-species of creationist with a moderate science vocabulary that I meet so often and loath completely. Loudmouth braggarts and bullies when they detect a person who using common sense, and having a deeper faith in facts and science, than in invisible entities, foolishly in their egregious presence say; ‘I accept the fact of evolution.’

When Atheistoclast isn’t screeching to be worshiped as a God of Science, and exalted as the Sainted Slayer of Evolution, from a very superficial examination, he sounds like he knows what he’s talking about.

Unless of course, you know what he’s talking about, then he sounds like a pompous idiot. But, sadly, very few lay-people have the time, effort, or patience to realize this.

Joseph “Atheistoclast” Bozorgmehr takes the very unusual approach of actually trying to read scientific literature and then convince himself that it supports his own views. His ability to convince himself that all the authors and editors have misinterpreted their own work is a testament to the potential folly of even a seemingly intelligent human mind, when compromised by self-serving bias and emotional issues.

This makes him massively frustrating to people who actually care about science.

It also makes him very unpopular with most of his fellow creationists. Actually reading the relevant scientific literature is a taboo that almost none of them violate. Behe claimed that the immune system couldn’t evolve and then famously admitted that he hadn’t read a single paper discussing the evolution of the immune system.

With a name like Bozo I’d go with a nym too. I did a Google search to see if there was really such a person and it looks like UD has had enough of the guy.

http://www.uncommondescent.com/cult[…]ger-with-us/

If they kick out all the whack jobs will guys like Dembski be allowed to post? Who will be left?

Ron Okimoto -

I assume that Joseph Bozorgmehr is his real name, but Bozorgmehr is both a fairly common Persian surname and the name of a semi-legendary pre-Islamic Persian wise man. Therefore, that, too, could be a pseudonym; it could be the equivalent, for someone familiar with Persian culture, of “Joe Socrates” or some such thing. I also assume that Bozo the Clown’s name is a coincidence, not an ironic reference to an obscure (in Anglophone culture) legendary wise man.

At any rate, Joseph Bozorgmehr/Atheistoclast has published a couple of extremely low impact but seemingly somewhat valid scientific papers. One is searchable on Pubmed and the other is in a journal called “Bioeconomics” which is not currently Pubmed searchable. These two papers contain no overt creationist claims, of course, otherwise they couldn’t have snuck past the reviewers. Of course, tragically, the reason he went through this rather serious effort (getting any paper, even a very low-impact one, in a peer-reviewed journal, as a pure amateur sole author, must have taken quite a bit of work), was merely to inflate his credentials. He’s also “published” something in the DI house organ “Biocomplexity”; I assume that since he has been banned from UD, that won’t ever happen again.

He’s been banned by at least one pro-science web site, as well as UD.

I’ve recommended several times that his fourth and subsequent comment on any thread here be automatically moved to the Bathroom Wall. His first few comments are often wrong in an interesting and instructive way, but then he begins to repeat himself.

Ah, silly darwinists. They just assume their target audience will not be able to understand what they’re reading, and isn’t competent to understand it anyway. And they’re usually right.

-But not always.

Most of darwinists arguments are logically flawed because the mere description of actual facts is presumed to be a proof of their theory. This happens because they cannot admit from the beginning any other kind of explanation : as only darwinism can be right, obviously everything which happens will be a proof of its validity, as it is supposed to explain everything. This is a classical tautological way of thinking. We could call that the “a posteriori mandatory explanation” : everything can only happen nicely and straightforwardly following Darwinian principles.

But reality is not that simple. In the evolution from ancestral CR (AncCR) to MRs three AminoAcids changed step by step. Every step needs its own mutation (of the gene), which can brings one change in the protein sequence (of Amino Acids). What M. Myers forgets to say is that a mutation can bring any change and not only the one needed for the correct evolution from AncCr to MRs. That means that the specie will have to “check” every new possible combination of the protein changed by the mutation at every new step. Some will not have any consequences, but a lot will be harmfull, even deadly. A wider problem is that changing only one component is not enough, as creating a new hormone means requires a new cellular receptor and a new functional pathway in physiology. It’s impossible to predict how many changes will be required, but certainly a lot of them. All these mutations will have to be synchronized and bring at every step an advantage if you want them retained by selection (we live in a Darwinian world, isn’t it ?). As M. Myers himself says, for example the C71S mutation must appear firstly and the others only after “because if either V43A or R116H came first, the resulting receptor would be generally non-functional.” In other words, these changes cannot be random : they must respect some kind of order, otherwise the result will be bad (sounds very “Intelligent Design”, isn’t it ?) If this is true even for modifying a single aminoacid, which is the least amount of change in physiology, how do you will explain appearance of much more complex features, involving dozens of intertwined components and genes ? You can choose to believe –or not– that this will happen randomly, but a mere description is not an explanation.

Oh, there’s the tell.

I can always spot the biological ignoramus by the way they use “specie” (coins) as the singular of “species”.

Setting aside your rank stupidity for a moment, you’re wrong. All this change required was first that a neutral mutation go to fixation or high frequency, a common result, followed by either of the subsequent mutations in any order. The “specie” does not check anything.

https://www.google.com/accounts/o8/[…]He-C2Q-FE8R8 said:

Ah, silly darwinists. They just assume their target audience will not be able to understand what they’re reading, and isn’t competent to understand it anyway. And they’re usually right.

Actually, Creationists assume this, and like others of your ilk, project this on to “silly darwinists” (sic) After all, it was Creationists, not “silly darwinists” who invented the “Gish Gallop” and there is a reason why Creationists style themselves as snake oil con-artists.

“You can choose to believe –or not– that this will happen randomly, but a mere description is not an explanation.”

And you can choose not to believe it, but that won’t get you anywhere. What you need is a reason why it won’t work. You don’t have one. What you need is an alternative explanation that explains the observations better. Again, you don’t have one. Believe whatever you want, no one cares.

You can choose to believe –or not– that this will happen randomly

This is all you’ve got? The mutations and their order have to be non-random?

A designer that can’t do anything more than tweak molecular probabilities a little bit here and there?

That’s a rather **small** designer, don’t you think?

About this Entry

This page contains a single entry by PZ Myers published on October 20, 2011 2:05 PM.

How not to examine the evolution of proteins was the previous entry in this blog.

The Curious Case of the Designer’s Bad Design is the next entry in this blog.

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