Protein specificity

[Aggie]

For the past several years, when creationists have argued that mutations can't result in an increase of information, by "information" they seem to really mean "protein specificity". For example, in this article, Answers in Genesis says:

A loss of specificity is a loss of information and usually not beneficial.

and

If the theory of evolution were true, there should be many examples of new enzymes developing with increasing specificity. So far we know of none. (Their emphasis.)

What are some cases where mutations have been observed to cause an increase in protein specificity? I'm aware of this example from Talk.Origins, but that article is more than a decade old. It would be useful to know about some that have been discovered more recently.

 

[Loudmouth]

For the past several years, when creationists have argued that mutations can't result in an increase of information, by "information" they seem to really mean "protein specificity". For example, in this article, Answers in Genesis says:



and


What are some cases where mutations have been observed to cause an increase in protein specificity? I'm aware of this example from Talk.Origins, but that article is more than a decade old. It would be useful to know about some that have been discovered more recently.

A quick search found this article:

"Because it is difficult to achieve by rational design, tuning substrate specificity is a favorite target for directed evolution. DNA shuffling (an in vitro DNA recombination method in which parent genes are fragmented and reassembled) and selection were used to create an Escherichia coli aminotransferase [4•] that accepted β-branched substrates, which were poorly accepted by the wild type enzyme. Earlier attempts to change substrate specificity by site-directed mutagenesis had resulted in limited success. This aminotransferase activity compensated for a defective host ilvE gene (the defect renders the cells unable to make isoleucine, leucine and valine) and allowed cells to grow in minimal media in the absence of these amino acids. Four rounds of shuffling increased the activity of aspartate aminotranferase for valine and 2-oxovaline by five orders of magnitude, while decreasing by 30-fold the activity towards the natural substrate, aspartate."
http://www.sciencedirect.com/science/article/pii/S1367593199800106

 

[Aggie]

A quick search found this article:

"Because it is difficult to achieve by rational design, tuning substrate specificity is a favorite target for directed evolution. DNA shuffling (an in vitro DNA recombination method in which parent genes are fragmented and reassembled) and selection were used to create an Escherichia coli aminotransferase [4•] that accepted β-branched substrates, which were poorly accepted by the wild type enzyme. Earlier attempts to change substrate specificity by site-directed mutagenesis had resulted in limited success. This aminotransferase activity compensated for a defective host ilvE gene (the defect renders the cells unable to make isoleucine, leucine and valine) and allowed cells to grow in minimal media in the absence of these amino acids. Four rounds of shuffling increased the activity of aspartate aminotranferase for valine and 2-oxovaline by five orders of magnitude, while decreasing by 30-fold the activity towards the natural substrate, aspartate."
http://www.sciencedirect.com/science/article/pii/S1367593199800106

Did that result in a total increase of its specificity? Based on that summary, it sounds like it made the protein able to react with substances it couldn't react with previously, while decreasing its reactivity with the original substrate. That's a change of function, but it isn't clear from that quote whether the new protein is more specific than the original one.

When the function of the protein changes to a large degree, it might difficult to determine whether there was an increase of specificity or not. (Unless there's some widely-accepted metric for comparing specificity between across protein types; I don't know whether there is.) If a metric like that doesn't exist, I think it would be more useful to have an example where the overall function of the protein stayed mostly the same, but the protein became more specific with respect to the same substrate it reacted with originally, as seems to be the case with the Alipoprotein AI example.

 

[sfs]

Not exactly what you're looking for, but somatic mutations routinely increase antibody specificity.

 

[Loudmouth]

Did that result in a total increase of its specificity?

All you can really measure is specificity to one substrate. I know of no way of testing a protein's "total specificity" since it would require testing the protein against billions and billions of potential molecules (tapping into my inner Carl Sagan).

Based on that summary, it sounds like it made the protein able to react with substances it couldn't react with previously, while decreasing its reactivity with the original substrate. That's a change of function, but it isn't clear from that quote whether the new protein is more specific than the original one.

It is an increase in the specificity for a substrate.

For any protein, you can find something that it interacts with, even weakly. I would bet 2 months salary that if you searched long enough you could find something that a protein with a random 400 amino acid sequence would react with at high enough concentrations.

Also, trading one function for another is exactly what evolution does. I have yet to see a creationist argue that terrestrial tetrapods evolving from lobe finned fish is not an example of evolution because the fish lost the ability to swim in water. So why use the same failed creationist argument for proteins?

When the function of the protein changes to a large degree, it might difficult to determine whether there was an increase of specificity or not. (Unless there's some widely-accepted metric for comparing specificity between across protein types; I don't know whether there is.) If a metric like that doesn't exist, I think it would be more useful to have an example where the overall function of the protein stayed mostly the same, but the protein became more specific with respect to the same substrate it reacted with originally, as seems to be the case with the Alipoprotein AI example.

There are a few common metrics that you can use. Most deal with the rate at which the substrate binds and releases from the protein. They include Koff, Kon, Kd (which is just Koff/Kon), and Bmax.

http://www.americanlaboratory.com/9...eptor-Using-a-Platform-for-GPCR-Applications/

From basic chemistry classes, you might recognize these as equilibriums for salts and acids/bases.
http://chemwiki.ucdavis.edu/Physica..._Gases/Meaning_Of_The_Equilibrium_Constant,_K

If you are good with math and want to go down the enzyme kinetics rabbit hole, then you can also look at Michaelis-Menten and Lineweaver-Burke plots, types of inhibition, and tons of other cool interactions between physics, math, and biology that goes in on the world of protein chemistry. There is even a new video game that allows random people on the interwebs to solve crystal structures for proteins.

http://news.sciencemag.org/2010/08/video-game-helps-solve-protein-structures

 

[Loudmouth]

Not exactly what you're looking for, but somatic mutations routinely increase antibody specificity.

That's a really good example.

 

[Aggie]

Also, trading one function for another is exactly what evolution does. I have yet to see a creationist argue that terrestrial tetrapods evolving from lobe finned fish is not an example of evolution because the fish lost the ability to swim in water. So why use the same failed creationist argument for proteins?

I'm looking for a specific rebuttal to their argument in this area. Answers in Genesis claims that a particular thing has never been observed to happen, and I'd like to show that it has, in fact, been observed. In order for it to be a good rebuttal, it should be the exact thing that they claim can't happen.

Not exactly what you're looking for, but somatic mutations routinely increase antibody specificity.

That sounds like an example I'll want to use, since antibodies have only a narrow set of of substrates they interact with, and mutations making them more specific would (I assume) be a health benefit. Could you provide some sources that discuss mutations having this effect?

 

[sfs]

I'm looking for a specific rebuttal to their argument in this area. Answers in Genesis claims that a particular thing has never been observed to happen, and I'd like to show that it has, in fact, been observed. In order for it to be a good rebuttal, it should be the exact thing that they claim can't happen.


That sounds like an example I'll want to use, since antibodies have only a narrow set of of substrates they interact with, and mutations making them more specific would (I assume) be a health benefit. Could you provide some sources that discuss mutations having this effect?

It's at the heart of the adaptive immune system. Look up "somatic hypermutation" and "affinity maturation". As Loudmouth points out, you can't actually know how many arbitrary molecules the antibody can bind, since there are too many possible ligands. What we do know is that the affinity for the relevant antigen increases enormously, as a result of a process of random mutation and selection.

 

[Loudmouth]

I'm looking for a specific rebuttal to their argument in this area. Answers in Genesis claims that a particular thing has never been observed to happen, and I'd like to show that it has, in fact, been observed. In order for it to be a good rebuttal, it should be the exact thing that they claim can't happen.

If they are looking for examples of mutations increasing specificity for a specific substrate, then there are plenty of examples. sfs' mention of mutations in antibodies is a really good one.

If they are arguing that substrate specificities can not change, then they have really argued themselves out of the argument. That claim is irrelevant since evolution does not require such a thing to occur.

That sounds like an example I'll want to use, since antibodies have only a narrow set of of substrates they interact with, and mutations making them more specific would (I assume) be a health benefit. Could you provide some sources that discuss mutations having this effect?

Antibodies are a huge library that have specificities for just about anything, with any one antibody lineage being specific to an antigen. Early in embryonic development, your developing B-cells shuffle a set of genes to produce an antibody that is specific to that B-cell. If that B-cell ever binds an antigen, and the other cells say it is ok to produce more of that antibody, the B-cell will begin to rapidly divide and produce a ton of that antibody. During that clonal explosion of B-cells there are mutations occurring in the antibody gene. B-cells with antibody mutations that bind more strongly to the antigen are encouraged to divide even more than it's other clonal cousins. This results in better and better antibodies as time goes by.

 

[Aggie]

It's at the heart of the adaptive immune system. Look up "somatic hypermutation" and "affinity maturation". As Loudmouth points out, you can't actually know how many arbitrary molecules the antibody can bind, since there are too many possible ligands. What we do know is that the affinity for the relevant antigen increases enormously, as a result of a process of random mutation and selection.

Oh, I didn't realize you were referring to something that happens during a normal immunological response. Even though that's a type of mutation, I'm pretty sure what Answers in Genesis was intending to claim is that there are no observed examples of a mutation in a gene increasing the specificity in the protein it produces, against the same substrate it acted on previously. I know that's a pretty narrow set of criteria, but if there are any known examples of that, it would be the best rebuttal to their argument about this.

Does anyone have any other suggestions about examples? It sounds like maybe Alipoprotein AI really is the best one.

Edited to add: If you're wondering why I care about having such a specific rebuttal, the answer is that I'm intending to refute this argument from AiG in the evolution book I'm working on, and I think my rebuttal will be more convincing if it's as direct as possible. I've been intending to use Alipoprotein AI as my counterexample, but I'd like to make sure there isn't a better one I should use instead.

 

[Loudmouth]

Oh, I didn't realize you were referring to something that happens during a normal immunological response. Even though that's a type of mutation, I'm pretty sure what Answers in Genesis was intending to claim is that there are no observed examples of a mutation in a gene increasing the specificity in the protein it produces, against the same substrate it acted on previously.

Antibodies are genes, or at least a heterodimer of two proteins.

There are two genes: one for the heavy chain and one for the light chain. Two of each are used to make a single antibody, and those 4 proteins are glued together by disulfide bridges between the cysteines on each protein. The bottom of the "y" is constant for each isotype so that the immune cells can bind to it. The ends of the "y" bind to the antigen. For example, the tetanus vaccine is nothing more than deactivated bacterial proteins (i.e. toxoids). If a toxoid binds to an antigen on a B-cell, which is protein to protein binding, that B-cell is turned on and starts dividing, evolving, and pumping out antibodies into the serum.

It sounds like maybe Alipoprotein AI really is the best one.

Hall's ebg system would work.

"Evolution of the ebgA encoded Ebg beta-galactosidase for an expanded substrate range, evolution of the ebgR encoded Ebg repressor for sensitivity to an expanded range of inducers, the amino acid replacements responsible for those changes, and the evolutionary potential of the system are discussed."
http://www.ncbi.nlm.nih.gov/pubmed/12868605

If you increased the sugar concentrations high enough, I am very confident that I could show some sort of positive evidence of interaction between any protein and that sugar. When you see a protein go from no detectable interaction and biological concentrations of sugar to measureable activity, that is an increase in specificity for that substrate. Period.

 

[whois]

the following seems to be relevant to this discussion, see upload.

 

[Loudmouth]

the following seems to be relevant to this discussion, see upload.

How so?

 

[whois]

How so?

it seems to me that the article is discussing the concepts of the thread.
if it doesn't, then it doesn't.
i provided it basically for research topics for aggie.
the piece certainly doesn't go in depth of anything.

 

[crjmurray]

the following seems to be relevant to this discussion, see upload.

Weird. That just linked to a bunch of pictures of Richard Nixon's face photoshopped on to Raquel Welch's body.

 

[whois]

i just downloaded it, and although it doesn't display properly, the content is still there.
i'll try to copy/paste the discussion into notepad and reupload it.

okay, i got it to paste.
the upload is sourced from the huffpost, and was posted on 12/04/2012 and updated on 02/03/2013
title"Inconvenient Truths: Why Are Self-Styled Defenders of Evolution so Resistant to Lessons From Molecular Genetics?"
author, James A. Shapiro ( at least this is what appears at the head of the article)
Author, 'Evolution: A View from the 21st Century'; Professor of Microbiology, University of Chicago

i guess i could paste it into this post:
Last week, on his very popular blog, WhyEvolutionIsTrue.wordpress.com, Jerry Coyne ridiculed Nicholas Wade's NYT article discussing the negative consequences resulting from the anti-religious tone of most orthodox defenses of evolution.

Wade's article was far from ideal. He failed to distinguish clearly between the overwhelming empirical evidence for evolution and the inevitably limited theories advanced to explain how it occurs. But Wade was taken to task chiefly for making the eminently reasonable argument that the pro-evolution side would be more effective if it showed greater respect for people with religious beliefs.

In the course of the discussion, Ben Goren posted the following scientific challenge on the blog:

"I am unaware of even a single example of biological complexity which defies explanation within the modern Darwinian framework. Perhaps you could offer up such an example...?"

I decided to respond and provide a few examples of evolutionary change where we have enough molecular evidence to know that they did not occur by the gradual accumulation of random mutations:

1. Multiple antibiotic resistance in bacteria;
2. Origin of the eukaryotic cell;
3. Origin of photosynthetic eukaryotic lineages;
4. The "abominable mystery" of rapid angiosperm evolution.

Ben's reply to my intervention illustrates how little some followers of TheWhyEvolutionIsTrue blog care about the molecular analysis of evolution. He seemed to have no idea that bacterial antibiotic resistance evolves by horizontal transfer of plasmids and the accumulation of multiple resistance determinants by transposition and site-specific recombination. (He did not address any of the other three examples I gave.)

Instead of a reasoned answer, I got the following:

Your list indicates to me that you are suffering from some significant misconceptions and / or a lack of understanding of what the Theory of Evolution by Random Mutation and Natural Selection actually is.



Just addressing your first case, for example... well, antibiotic resistance is a textbook example of evolution in practice, and one that Darwin himself likely would have predicted (and certainly not been surprised by).

The idea of Darwin predicting conjugative plasmids, transposons and integrons was indeed novel to me. All Ben seemed able to envision is random mutation to antibiotic resistance. He was unaware that such mutations are irrelevant to the real world evolution and global spread of multiple antibiotic resistance determinants.

I pointed Ben to two of my blogs on the subject. After reading one of them, his response was as follows:

Jim, I just read your first blog entry. And, I'm sorry, but I don't see any significant difference between you and Behe on this.

Ben ignored the history I outlined of research on the evolutionary case in question. Evidently, it was more important for him to equate me with Intelligent Design advocate Michael Behe. I guess he made that connection because I wrote that we still lack a complete scientific explanation for well-documented evolutionary relationships between bacterial flagella, DNA transfer apparatus, and protein injection complexes used in pathogenesis.

Where did Ben's resistance to considering the theoretical implications of molecular analysis come from?

Why did he find it unacceptable for me to indicate specific unresolved evolution issues, as I did in the superbug blog? To quote Ben:

Again, all you're doing is pointing at something you don't understand and lack the imagination to guess at a reasonable understanding, and throwing up your hands and insisting that everybody else should quit as well and join you in your ignorance.

A second commentator, Torbjörn Larsson, argued that horizontal DNA transfer posed no challenge to the neo-Darwinian theory: "In other words the generic gradualism of Darwin mentioned in the article isn't rejected by the observed degree of horizontal gene transfer."

But Torbjörn's claim does not make sense scientifically. Horizontal transfer is not the gradual Darwinian accumulation of changes. Horizontal transfer episodes rapidly incorporate complex evolved DNA structures into new genomes by coordinated molecular events.

There is no way we can reasonably apply the term "random mutation" to a DNA transfer process that utilizes dedicated surface structures for bringing two cells together, assembles a multi-protein DNA transport pore connecting the cells, and initiates DNA transfer replication at a specific site on plasmid DNA.

The well-established molecular details of horizontal transfer in the evolution of bacterial antibiotic resistance are difficult to reconcile with neo-Darwinism.

Is it possible that Ben, Torbjörn and their friends fear that readers will start to entertain doubts about evolutionary orthodoxy when they learn what molecular genetics and the DNA record have to teach us about the molecular nature of variation? The molecular data show that orthodox neo-Darwinian theory is far from providing realistic explanations for well-documented cases of genome sequence evolution.

In preparing for a public lecture early next year on what DNA teaches us about evolution, I made a list of take-home lessons to use as an introduction:

1. Evolution is complex, not reducible to simple formulas;
2. Evolutionary thinking has a long history full of ongoing discoveries;
3. Cell mergers are an important source of abrupt evolutionary novelty;
4. Horizontal DNA transfer is an important source of rapid evolutionary novelty;
5. Cells actively repair and restructure their genomes (the genome as a RW memory system);
6. Proteins evolve by swapping segments, not by changing one amino acid at a time;
7. Mobile genetic elements can rapidly modify genome function at multiple locations and establish genomic networks;
8. Inter-specific hybridization and whole genome duplications are further sources of rapid evolutionary innovation;
9. Genome restructuring (natural genetic engineering) is regulated and activated by stress, cell fusions and inter-specific hybridization.

I would like to understand where Ben and Tobrjörn find a basis for the certainties they express about what kind of evidence to accept. So, can someone please answer two questions for me?

A. What do my nine take-home statements have to do with supernaturalism outside the bounds of science?
B. Where have these statements been convincingly incorporated into Ben's all-encompassing "Theory of Evolution by Random Mutation and Natural Selection"?

 

[Loudmouth]

it seems to me that the article is discussing the concepts of the thread.

Why would you ever think that?

i provided it basically for research topics for aggie.

It seems that you are randomly spamming threads with your same misunderstandings of HGT and biology, no matter what the topic is.

 

[Loudmouth]

i just downloaded it, and although it doesn't display properly, the content is still there.
i'll try to copy/paste the discussion into notepad and reupload it.

okay, i got it to paste.
the upload is sourced from the huffpost, and was posted on 12/04/2012 and updated on 02/03/2013
title"Inconvenient Truths: Why Are Self-Styled Defenders of Evolution so Resistant to Lessons From Molecular Genetics?"
author, James A. Shapiro ( at least this is what appears at the head of the article)
Author, 'Evolution: A View from the 21st Century'; Professor of Microbiology, University of Chicago

i guess i could paste it into this post:
Last week, on his very popular blog, WhyEvolutionIsTrue.wordpress.com, Jerry Coyne ridiculed Nicholas Wade's NYT article discussing the negative consequences resulting from the anti-religious tone of most orthodox defenses of evolution.

Wade's article was far from ideal. He failed to distinguish clearly between the overwhelming empirical evidence for evolution and the inevitably limited theories advanced to explain how it occurs. But Wade was taken to task chiefly for making the eminently reasonable argument that the pro-evolution side would be more effective if it showed greater respect for people with religious beliefs.

In the course of the discussion, Ben Goren posted the following scientific challenge on the blog:

"I am unaware of even a single example of biological complexity which defies explanation within the modern Darwinian framework. Perhaps you could offer up such an example...?"

I decided to respond and provide a few examples of evolutionary change where we have enough molecular evidence to know that they did not occur by the gradual accumulation of random mutations:

1. Multiple antibiotic resistance in bacteria;
2. Origin of the eukaryotic cell;
3. Origin of photosynthetic eukaryotic lineages;
4. The "abominable mystery" of rapid angiosperm evolution.

Ben's reply to my intervention illustrates how little some followers of TheWhyEvolutionIsTrue blog care about the molecular analysis of evolution. He seemed to have no idea that bacterial antibiotic resistance evolves by horizontal transfer of plasmids and the accumulation of multiple resistance determinants by transposition and site-specific recombination. (He did not address any of the other three examples I gave.)

Instead of a reasoned answer, I got the following:

Your list indicates to me that you are suffering from some significant misconceptions and / or a lack of understanding of what the Theory of Evolution by Random Mutation and Natural Selection actually is.



Just addressing your first case, for example... well, antibiotic resistance is a textbook example of evolution in practice, and one that Darwin himself likely would have predicted (and certainly not been surprised by).

The idea of Darwin predicting conjugative plasmids, transposons and integrons was indeed novel to me. All Ben seemed able to envision is random mutation to antibiotic resistance. He was unaware that such mutations are irrelevant to the real world evolution and global spread of multiple antibiotic resistance determinants.

I pointed Ben to two of my blogs on the subject. After reading one of them, his response was as follows:

Jim, I just read your first blog entry. And, I'm sorry, but I don't see any significant difference between you and Behe on this.

Ben ignored the history I outlined of research on the evolutionary case in question. Evidently, it was more important for him to equate me with Intelligent Design advocate Michael Behe. I guess he made that connection because I wrote that we still lack a complete scientific explanation for well-documented evolutionary relationships between bacterial flagella, DNA transfer apparatus, and protein injection complexes used in pathogenesis.

Where did Ben's resistance to considering the theoretical implications of molecular analysis come from?

Why did he find it unacceptable for me to indicate specific unresolved evolution issues, as I did in the superbug blog? To quote Ben:

Again, all you're doing is pointing at something you don't understand and lack the imagination to guess at a reasonable understanding, and throwing up your hands and insisting that everybody else should quit as well and join you in your ignorance.

A second commentator, Torbjörn Larsson, argued that horizontal DNA transfer posed no challenge to the neo-Darwinian theory: "In other words the generic gradualism of Darwin mentioned in the article isn't rejected by the observed degree of horizontal gene transfer."

But Torbjörn's claim does not make sense scientifically. Horizontal transfer is not the gradual Darwinian accumulation of changes. Horizontal transfer episodes rapidly incorporate complex evolved DNA structures into new genomes by coordinated molecular events.

There is no way we can reasonably apply the term "random mutation" to a DNA transfer process that utilizes dedicated surface structures for bringing two cells together, assembles a multi-protein DNA transport pore connecting the cells, and initiates DNA transfer replication at a specific site on plasmid DNA.

The well-established molecular details of horizontal transfer in the evolution of bacterial antibiotic resistance are difficult to reconcile with neo-Darwinism.

Is it possible that Ben, Torbjörn and their friends fear that readers will start to entertain doubts about evolutionary orthodoxy when they learn what molecular genetics and the DNA record have to teach us about the molecular nature of variation? The molecular data show that orthodox neo-Darwinian theory is far from providing realistic explanations for well-documented cases of genome sequence evolution.

In preparing for a public lecture early next year on what DNA teaches us about evolution, I made a list of take-home lessons to use as an introduction:

1. Evolution is complex, not reducible to simple formulas;
2. Evolutionary thinking has a long history full of ongoing discoveries;
3. Cell mergers are an important source of abrupt evolutionary novelty;
4. Horizontal DNA transfer is an important source of rapid evolutionary novelty;
5. Cells actively repair and restructure their genomes (the genome as a RW memory system);
6. Proteins evolve by swapping segments, not by changing one amino acid at a time;
7. Mobile genetic elements can rapidly modify genome function at multiple locations and establish genomic networks;
8. Inter-specific hybridization and whole genome duplications are further sources of rapid evolutionary innovation;
9. Genome restructuring (natural genetic engineering) is regulated and activated by stress, cell fusions and inter-specific hybridization.

I would like to understand where Ben and Tobrjörn find a basis for the certainties they express about what kind of evidence to accept. So, can someone please answer two questions for me?

A. What do my nine take-home statements have to do with supernaturalism outside the bounds of science?
B. Where have these statements been convincingly incorporated into Ben's all-encompassing "Theory of Evolution by Random Mutation and Natural Selection"?

What does any of this have to do with whether or not mutations can increase substrate specificity in proteins?

 

[whois]

loudmouth,
why are you replying to my posts?
the post and uploads i made were for aggies benefit and research.
only aggie can say whether or not they were useful, okay?

 

[Aggie]

loudmouth,
why are you replying to my posts?
the post and uploads i made were for aggies benefit and research.
only aggie can say whether or not they were useful, okay?

I couldn't get the .zip file to open.

Instead of posting that long summary of the discussion at HuffPo, it would've been more useful for you to just link to it so I could read it myself.