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Thread: Can modern biochemistry falsify current Evo theory?

  1. #1 Can modern biochemistry falsify current Evo theory? 
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    In a now closed post I offered the following potential ways to falsify the current popular evolutionary theory.

    A decent example of something that would put evolutionary theory at severe risk might be the discovery that the search space over which natural selection is postulated to act contains insufficient successful molecular pathways from which to mutate required genes, molecular structures, and developmental control systems needed to generate new functional forms.

    It is also possible that the gaps between successful modifications are significantly greater than the steps that mutation and recombination actually make.

    Another challenge would be that the rate of mutation is found out of step with the actual time that biodiversity occurred.

    Finally, evolutionary theory presupposes that life developed naturally from non-life. If it is determined that chemic processes alone are incapable of generating the minimal components required for self-replicating bio systems, then evolution by unguided processes is likely falsified.
    Later, if the thread progresses, I intend to offer some evidence that one or more of these may be in play, but even if in play, they would have no effect on the theory, it would seem pointless to discuss them. So first, would you agree that these situations have the potential of falsifying our current understanding of evolutionary processes? Since there are many definitions for evolutionary processes, let's agree that for this discussion we mean the known processes of adaptation, mutation, recombination and natural selection.


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    Forum Cosmic Wizard paralith's Avatar
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    I'm not sure why you think there are many definitions of evolution, so for clarity I'd like to state that the definition of biological evolution is a change in the allele frequencies of a population over time. The four mechanisms by which evolutionary change occurs are natural selection (which results in adaptations; they are not separate things), mutation, migration/gene flow, and genetic drift. Recombination does not actually change the frequencies of alleles in a population, it results in new combinations of genes within individuals.

    I would also like to state that abiogenesis is a separate issue from evolution; evolution assumes that life already exists. There are multiple existing threads on abiogenesis in this forum that you can continue if you wish.

    Now please provide evidence that the four mechanisms of evolution in incapable of explaining current diversity on earth. This as far as this thread is going to progress unless you provide that evidence.


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  4. #3 Re: Can modern biochemistry falsify current Evo theory? 
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    Quote Originally Posted by cypress
    Another challenge would be that the rate of mutation is found out of step with the actual time that biodiversity occurred.
    Rates of mutation are fairly constant. Rates of evolution are not, because whether or not a mutation is kept depends on environmental conditions.
    "The major difference between a thing that might go wrong and a thing that cannot possibly go wrong is that when a thing that cannot possibly go wrong goes wrong it usually turns out to be impossible to get at or repair." ~ Douglas Adams
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    I understand and would honor a request to provide evidence to a support a claim I made, but to be asked this early in the discussion to provide evidence for a claim I am not making seems beyond the pale. A simple, "yes those would be good tests" is all that is required and if I have nothing left to offer to continue the thread will die in the thread bone yard.

    In a PM you claimed that I am free to repost fruitful inquiries so long as any claim I make is offered with references. I indicated that I intended to provide some information on these areas if the thread continues to assure you that I will offer support for any future claims.

    The topic of this thread and the post asks if these proposed challenges are potential tests for falsification. It is a simple question with a simple answer. This is clearly a scientific inquiry and I should be provided the same curtsey of a response others get to the opening question before being asked to provide evidence for a claim I have not yet made. In a previous post several suggested that discovery of a precambrian mammal would falsify evolutionary theory. Should we have asked for evidence that such a thing exists before we entertain the merits of that as a test? Of course not.

    Even if I had no evidence to suggest any of these tests have merit, it is still instructive to discuss them as confirmation that molecular biology offers fruitful ways to test and confirm evolutionary theory at the level in which the processes acts.

    Can you agree (with the exception of abiogenesis, which you specifically took exception) or if you disagree, state your objection to these as possible tests of evolutionary processes?
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    Forum Cosmic Wizard paralith's Avatar
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    cypress, I already agreed in the previous thread. I also stated in the previous thread that I am unaware of any empirical data that has born these statements out, or that even suggests these statements are possibly true. The fact that you're spending so much time arguing about what you deserve and not actually defending your points is not helping you. Present some evidence, or have this thread moved to Pseudoscience. Your choice.
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    Well forgive me for missing your acknowledgment.

    MIT biochemist Robert Sauer applied "cassette mutagenesis" to proteins to determine the degree variation among amino acids can be tolerated at any particular site. His results show that for a typical 100-subunit functional protein there are 10^65 nonfunctional variants. Douglas Axe, at Cambridge University developed a refined technique including sequence specificity of enzymes and demonstrated the functional sensitivity at 1 in 10^78.

    J bowie and R Sauer, "Identifying Determinants of Folding And Activity for a Protein of Unknown Sequences: Tolerance to Amino Acid Substitution" and several more articles.

    D. Axe, "Extreme Functional Sensitivity to Conservative Amino Acid Changes on Enzyme Exteriors"

    and several others.

    This research is continuing and is focusing on the search for functional evolutionary pathways. There are emerging indications that these variants hold not only for the range of possible combinations but also the combinatorial probabilities of functional stepwise modification from one protein form to another. Again with rare exception, on par with the probabilities indicated, there are strong indications that the gap between workable proteins is on average 4-6 modifications, any one of which generally effectively breaks current function.

    See C. Braden, and R. Poljak, "Structural features of the reactions between antibodies and protein antigens." and Lo Conte, and C. Chothia "The atomic structure of protein-protein recognition sites." As well as several more I can provide.

    See also D. Axe, "Estimating the prevalence of protein sequence adopting functional enzyme folds."

    This puts the ball in the evolutionary biologists court to demonstrate how evolutionary processes you described navigate from one to another functional protein.

    These examples indicate issues with stepwise mutation of genes from one useful function to another as natural selection predicts.
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    Quote Originally Posted by cypress
    Well forgive me for missing your acknowledgment.

    MIT biochemist Robert Sauer applied "cassette mutagenesis" to proteins to determine the degree variation among amino acids can be tolerated at any particular site. His results show that for a typical 100-subunit functional protein there are 10^65 nonfunctional variants. Douglas Axe, at Cambridge University developed a refined technique including sequence specificity of enzymes and demonstrated the functional sensitivity at 1 in 10^78.

    J bowie and R Sauer, "Identifying Determinants of Folding And Activity for a Protein of Unknown Sequences: Tolerance to Amino Acid Substitution" and several more articles.

    D. Axe, "Extreme Functional Sensitivity to Conservative Amino Acid Changes on Enzyme Exteriors"

    and several others.

    This research is continuing and is focusing on the search for functional evolutionary pathways. There are emerging indications that these variants hold not only for the range of possible combinations but also the combinatorial probabilities of functional stepwise modification from one protein form to another. Again with rare exception, on par with the probabilities indicated, there are strong indications that the gap between workable proteins is on average 4-6 modifications, any one of which generally effectively breaks current function.

    See C. Braden, and R. Poljak, "Structural features of the reactions between antibodies and protein antigens." and Lo Conte, and C. Chothia "The atomic structure of protein-protein recognition sites." As well as several more I can provide.

    See also D. Axe, "Estimating the prevalence of protein sequence adopting functional enzyme folds."

    This puts the ball in the evolutionary biologists court to demonstrate how evolutionary processes you described navigate from one to another functional protein.

    These examples indicate issues with stepwise mutation of genes from one useful function to another as natural selection predicts.
    Breaks current function and supplies possibilities for new functions. I have no argument with the fact that the vast majority of mutations are either harmful or neutral to the current function of the protein, but in a changing environment with changing environmental pressures what was once harmful or neutral can in fact become adaptive. Listed here are a variety of studies which have demonstrated new function from mutations. In different environments these mutations could be selected for and maintained in the population. A great many protein families are produced by gene duplication, wherein the original copy of the gene remains under current selective pressures and the duplicate is able to mutate freely into a wide variety of forms which can eventually serve new functions (Paralogy). Here is an article discussing in detail the evolution of protein families by the process of gene duplication. I have the full text and if you desire to read it please PM me with an email address.
    Man can will nothing unless he has first understood that he must count on no one but himself; that he is alone, abandoned on earth in the midst of his infinite responsibilities, without help, with no other aim than the one he sets himself, with no other destiny than the one he forges for himself on this earth.
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    Quote Originally Posted by paralith
    Breaks current function and supplies possibilities for new functions. I have no argument with the fact that the vast majority of mutations are either harmful or neutral to the current function of the protein, but in a changing environment with changing environmental pressures what was once harmful or neutral can in fact become adaptive.
    Bit of a side point but current estimates are that the mutation rate in humans is something like 100-200 new mutations per generation. So on average, each human is born with some 150 mutations. Our continued existence as a species is pretty surprising if certain folks are right about just how many of those mutations are allegedly "detrimental"... as you say, a lot of neutrals and weak detrimentals in that mix.
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    Quote Originally Posted by TheBiologista
    Quote Originally Posted by paralith
    Breaks current function and supplies possibilities for new functions. I have no argument with the fact that the vast majority of mutations are either harmful or neutral to the current function of the protein, but in a changing environment with changing environmental pressures what was once harmful or neutral can in fact become adaptive.
    Bit of a side point but current estimates are that the mutation rate in humans is something like 100-200 new mutations per generation. So on average, each human is born with some 150 mutations. Our continued existence as a species is pretty surprising if certain folks are right about just how many of those mutations are allegedly "detrimental"... as you say, a lot of neutrals and weak detrimentals in that mix.
    True, but you also have to remember that large stretches of our DNA are structural and don't actually code for protein. If we were to count the number of mutations in protein-coding sequences alone it would probably be closer to 10-20. It's primarily those mutations I had in mind when I said most are detrimental to current function.
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    Quote Originally Posted by paralith
    Quote Originally Posted by TheBiologista
    Quote Originally Posted by paralith
    Breaks current function and supplies possibilities for new functions. I have no argument with the fact that the vast majority of mutations are either harmful or neutral to the current function of the protein, but in a changing environment with changing environmental pressures what was once harmful or neutral can in fact become adaptive.
    Bit of a side point but current estimates are that the mutation rate in humans is something like 100-200 new mutations per generation. So on average, each human is born with some 150 mutations. Our continued existence as a species is pretty surprising if certain folks are right about just how many of those mutations are allegedly "detrimental"... as you say, a lot of neutrals and weak detrimentals in that mix.
    True, but you also have to remember that large stretches of our DNA are structural and don't actually code for protein. If we were to count the number of mutations in protein-coding sequences alone it would probably be closer to 10-20. It's primarily those mutations I had in mind when I said most are detrimental to current function.
    That's a good point. It's still nice to see that life, in general, seems to have the robusticity (where's the devolution guy?) to manage 20-ish coding mutations per generation without causing evolution to grind to a halt. The stock creationist claim that functional variation cannot occur due to mutation because of some imagined immedediate and strong negative selection against most mutations just doesn't gel with the observed reality. On the contrary it's easy to see how plenty of detrimental alleles could persist for long enough to undergo a gain of function mutation or until changes in selective pressures render them beneficial in context.
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    Quote Originally Posted by paralith
    Quote Originally Posted by cypress
    Well forgive me for missing your acknowledgment.

    MIT biochemist Robert Sauer applied "cassette mutagenesis" to proteins to determine the degree variation among amino acids can be tolerated at any particular site. His results show that for a typical 100-subunit functional protein there are 10^65 nonfunctional variants. Douglas Axe, at Cambridge University developed a refined technique including sequence specificity of enzymes and demonstrated the functional sensitivity at 1 in 10^78.

    J bowie and R Sauer, "Identifying Determinants of Folding And Activity for a Protein of Unknown Sequences: Tolerance to Amino Acid Substitution" and several more articles.

    D. Axe, "Extreme Functional Sensitivity to Conservative Amino Acid Changes on Enzyme Exteriors"

    and several others.

    This research is continuing and is focusing on the search for functional evolutionary pathways. There are emerging indications that these variants hold not only for the range of possible combinations but also the combinatorial probabilities of functional stepwise modification from one protein form to another. Again with rare exception, on par with the probabilities indicated, there are strong indications that the gap between workable proteins is on average 4-6 modifications, any one of which generally effectively breaks current function.

    See C. Braden, and R. Poljak, "Structural features of the reactions between antibodies and protein antigens." and Lo Conte, and C. Chothia "The atomic structure of protein-protein recognition sites." As well as several more I can provide.

    See also D. Axe, "Estimating the prevalence of protein sequence adopting functional enzyme folds."

    This puts the ball in the evolutionary biologists court to demonstrate how evolutionary processes you described navigate from one to another functional protein.

    These examples indicate issues with stepwise mutation of genes from one useful function to another as natural selection predicts.
    Breaks current function and supplies possibilities for new functions. I have no argument with the fact that the vast majority of mutations are either harmful or neutral to the current function of the protein, but in a changing environment with changing environmental pressures what was once harmful or neutral can in fact become adaptive. Listed here are a variety of studies which have demonstrated new function from mutations.
    Please reread my post, and notice that I made a distinction between single alteration variants (I indicated that there are some in keeping with the probabilities noted) that derive new functional proteins and the more typical multiple replacement variants that the research describes. Unless I am mistaken, the papers listed in the link all involve two or fewer steps and are consistent with the probabilities described. Given the number of modifications observed in genome studies, the list of known cases should be very large if current observed processes account for these observations. You have provided only the handful of single step variants I already acknowledged and no cases involving a string of successive changes, just the thing that this research predicts.

    To support your counterargument, provide evidence that new function has actually been derived from a multi-step pathway where 3 or more alterations are required. Remember the research I provided indicates that by many orders of magnitude, functional proteins variants generally differ by greater than 4 in key locations. I strongly suspect you will find no examples, except in the frame shift example of nylase, which, though a special case, as expected, also involves a single step modification. However, if you do, then also provide evidence that demonstrate these multi-step variants actually occur at rates greater than would be predicted by probabilities described by the references I offered.

    In different environments these mutations could be selected for and maintained in the population. A great many protein families are produced by gene duplication, wherein the original copy of the gene remains under current selective pressures and the duplicate is able to mutate freely into a wide variety of forms which can eventually serve new functions (Paralogy). Here is an article discussing in detail the evolution of protein families by the process of gene duplication. I have the full text and if you desire to read it please PM me with an email address.
    The article provides interesting inference based on molecular analysis of gene and genome sequences. Can you provide evidence that gene duplication followed by presumably unconstrained mutation of the copied gene can sweep search space and hit on the one in 10^78 or so functional combinations described in the references I noted? This is one of the points of the research I provided. Namely that the number of functional proteins in search space is too few for processes like gene duplication, mutation of non-conserved, non-coding regions and other similar proposed mechanisms to locate the functional variants in any reasonable time frame. The trouble is that without selection pressure, random mutation is far more likely to make other damaging substitutions than to generate a useful variant.

    For these reasons, it is unlikely that gene duplication can improve the odds, but I await some evidence. I don't see anything in the articles you provided that adequately address these issues.
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    I do not see why you would assume all the studies listed on recording new functions from mutation are only 1 or 2 alterations unless you had read them all and verified the exact number of alterations that were recorded. But in any case, if you had simply given me a chance to give you a full text of the gene duplication paper, you would have had your evidence. I will quote from the paper, and you will have to trust me that I am quoting it accurately if you still do not allow me to give it to you.

    Quote Originally Posted by Zhang 2003
    Duplicated genes are often referred to as paralogous genes, which form gene families. Several authors have tabulated the distribution of gene family size for a few completely sequenced genomes [11,12] and this varies substantially among species and gene families [13]; for instance, the biggest gene family in D. melanogaster is the trypsin family [12], with 111 members, whereas the biggest family in mammals is the olfactory receptor family, with ~1000 members [14,15]. From a genomic sequence analysis of the bacterium Escherichia coli, two yeasts, C. elegans and D. melanogaster, Conant andWagner found that ribosomal proteins and transcription factors generally form smaller gene families than do other proteins, such as those controlling cell cycles and metabolism [16].
    Gene duplication has resulted in a great many distinct proteins, as you can see by the numbers listed above for but two protein families. Here are the references to the statements made above so you can check them directly:

    12 Gu, Z. et al. (2002) Extent of gene duplication in the genomes of Drosophila, nematode, and yeast. Mol. Biol. Evol. 19, 256–262
    13 Lespinet, O. et al. (2002) The role of lineage-specific gene family expansion in the evolution of eukaryotes. Genome Res. 12, 1048–1059
    14 Mombaerts, P. (2001) The human repertoire of odorant receptor genes and pseudogenes. Annu. Rev. Genomics Hum. Genet. 2, 493–510
    15 Zhang, X. and Firestein, S. (2002) The olfactory receptor gene superfamily of the mouse. Nat. Neurosci. 5, 124–133

    As you will see if you click on the above link there is a free full text PDF available for reference 15. This article goes into nice detail on the diversity and evolutionary history of this massive protein family with, and I quote, "diverse ligands and functions."

    Here is a search on mouse olfactory receptors in the NCBI Genbank protein sequence database. You can look at the individual sequences yourself and start counting up some differences. You will quickly grow tired of it, though.

    As to your numbers on functional variants, as I said those are variants that retain the current function, and do not speak to potential new functions in different environments or for different purposes.
    Man can will nothing unless he has first understood that he must count on no one but himself; that he is alone, abandoned on earth in the midst of his infinite responsibilities, without help, with no other aim than the one he sets himself, with no other destiny than the one he forges for himself on this earth.
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    Quote Originally Posted by cypress
    Again with rare exception, on par with the probabilities indicated, there are strong indications that the gap between workable proteins is on average 4-6 modifications, any one of which generally effectively breaks current function.
    Evolutionary theory does not demand any maintenance of "current function". Breaks from "current function" are expected.

    And normally, single point mutations do not "break" from current function. There are some key points, but most of - say - the hemoglobin molecule, can tolerate numerous point changes without losing much of its function.
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    Quote Originally Posted by iceaura
    Quote Originally Posted by cypress
    Again with rare exception, on par with the probabilities indicated, there are strong indications that the gap between workable proteins is on average 4-6 modifications, any one of which generally effectively breaks current function.
    Evolutionary theory does not demand any maintenance of "current function". Breaks from "current function" are expected.

    And normally, single point mutations do not "break" from current function. There are some key points, but most of - say - the hemoglobin molecule, can tolerate numerous point changes without losing much of its function.
    Of course, but perhaps you misunderstood the point.

    Once function is broken, by the first step, selection pressure can no longer act as a fitness function to constrain and other more deleterious modifications from occurring prior to hitting on the three or so additional steps required to locate one of the one in 10^78 functional variants. At this point forward search by random a process is blind.
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    Quote Originally Posted by cypress
    Once function is broken, by the first step, selection pressure can no longer act as a fitness function to constrain and other more deleterious modifications from occurring prior to hitting on the three or so additional steps required to locate one of the one in 10^78 functional variants.
    But function is not often completely broken, by one step - and selection pressure is quite likely increased, during substandard functioning, not to mention secondary functioning possibilities.

    And the actual odds are not as described there - since any number of fucntional variants are possible: we aren't shooting for the one.

    And the nonfunctional changes don't get in the way, check? Big block changes are possible - flips and large deletions/duplications etc.

    And so forth.
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    Quote Originally Posted by paralith
    I do not see why you would assume all the studies listed on recording new functions from mutation are only 1 or 2 alterations unless you had read them all and verified the exact number of alterations that were recorded. But in any case, if you had simply given me a chance to give you a full text of the gene duplication paper, you would have had your evidence. I will quote from the paper, and you will have to trust me that I am quoting it accurately if you still do not allow me to give it to you.

    Quote Originally Posted by Zhang 2003
    Duplicated genes are often referred to as paralogous genes, which form gene families. Several authors have tabulated the distribution of gene family size for a few completely sequenced genomes [11,12] and this varies substantially among species and gene families [13]; for instance, the biggest gene family in D. melanogaster is the trypsin family [12], with 111 members, whereas the biggest family in mammals is the olfactory receptor family, with ~1000 members [14,15]. From a genomic sequence analysis of the bacterium Escherichia coli, two yeasts, C. elegans and D. melanogaster, Conant andWagner found that ribosomal proteins and transcription factors generally form smaller gene families than do other proteins, such as those controlling cell cycles and metabolism [16].
    Gene duplication has resulted in a great many distinct proteins, as you can see by the numbers listed above for but two protein families. Here are the references to the statements made above so you can check them directly:

    12 Gu, Z. et al. (2002) Extent of gene duplication in the genomes of Drosophila, nematode, and yeast. Mol. Biol. Evol. 19, 256–262
    13 Lespinet, O. et al. (2002) The role of lineage-specific gene family expansion in the evolution of eukaryotes. Genome Res. 12, 1048–1059
    14 Mombaerts, P. (2001) The human repertoire of odorant receptor genes and pseudogenes. Annu. Rev. Genomics Hum. Genet. 2, 493–510
    15 Zhang, X. and Firestein, S. (2002) The olfactory receptor gene superfamily of the mouse. Nat. Neurosci. 5, 124–133

    As you will see if you click on the above link there is a free full text PDF available for reference 15. This article goes into nice detail on the diversity and evolutionary history of this massive protein family with, and I quote, "diverse ligands and functions."

    Here is a search on mouse olfactory receptors in the NCBI Genbank protein sequence database. You can look at the individual sequences yourself and start counting up some differences. You will quickly grow tired of it, though.

    As to your numbers on functional variants, as I said those are variants that retain the current function, and do not speak to potential new functions in different environments or for different purposes.
    The articles provide plausible answers to interesting questions to be sure. It's just that they don't answer the questions I asked of you.

    Let me clarify my point. I did not ask for you to provide examples or counts of homologous proteins that likely made reuse of a preexisting gene sequence through gene duplication as one step in the process. I also did not ask for you to provide me with a list of modified genes generated by point mutations involving two or fewer discrete steps since these fall well within the range of probability bounds for random process and frequency of functional variants. I am willing to grant that both of these have been actualized since both have been duplicated in the lab, the first through genetic engineering which is a known process, and the second through knock-out experiments with cultured bacteria.

    What I did ask you to provide evidence for (I will be more clear so we avoid future missteps) is an actual detailed multistep process involving 3 or more required modifications (since this is the focus of the challenge) from the original functional gene that demonstrates how known evolutionary process (which you defined above) actually did overcome the odds of 1/1065 to 1/10^78 presented by the research I referenced.

    There are several ways to dispose of this challenge, I offer a few here.

    1) Demonstrate that the research I offered is in error by providing more accurate research

    2) Demonstrate that a process not previously cataloged exists,is operating today and is capable of making multistep leaps to traverse from one to another functional variant.

    3) Demonstrate how known evolutionary processes are able to efficiently and effectively search the sample space to locate the rare variants many orders of magnitude faster than probability would predict.

    The ultimate point of this thread is to show why we should pursue option two.
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    Quote Originally Posted by iceaura
    Quote Originally Posted by cypress
    Once function is broken, by the first step, selection pressure can no longer act as a fitness function to constrain and other more deleterious modifications from occurring prior to hitting on the three or so additional steps required to locate one of the one in 10^78 functional variants.
    But function is not often completely broken, by one step - and selection pressure is quite likely increased, during substandard functioning, not to mention secondary functioning possibilities.
    The research I referenced argues against your claim. Can you provide evidence to support your statement?

    And the actual odds are not as described there - since any number of fucntional variants are possible: we aren't shooting for the one.
    Please reread my post. The numbers quoted are for any functional variants not a particular variant.

    And the nonfunctional changes don't get in the way, check?
    If I understand your, point I agree that they don't get in the way per say with the exception of what I described previously.

    Big block changes are possible - flips and large deletions/duplications etc.

    And so forth.
    As an individual event, I supposes 1/10^78 is possible in the sense that if you made 10^35 searches per day (the approximate number of organisms on earth) then in about a trillion, trillion, trillion, trillion years you would have even (50/50) odds of finding just one of these functional variants among a set of all possible combinations.

    The researchers I referenced were able to locate many (several hundred and more) functional variants in a few years time using known actual processes (goal driven search routines) that can be precisely defined and described. The question I posed here is how do known evolutionary processes search for and locate these functional variants in a reasonable time in a way that can be precisely defined (for each step) and described?

    I submit that we don't have the answer to this question. Perhaps we don't because they can't, and it is time to begin to propose processes that can and do.
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    Quote Originally Posted by cypress
    Please reread my post. The numbers quoted are for any functional variants not a particular variant.
    Then I guess I don't believe their estimations of "functional".

    For one thing, we all know there are many proteins (hemoglobin, say) that exist right now in several variants, of varied - not present/absent - functionality. I see no allowance for better/worse, slower/faster, etc, functionality.

    For another, I don't think anyone really has much of an idea right now about the functionality of a changed protein in an organism, in general - if any function at all, or possibly even nonfunction, keeps it around.

    For a third, we know of proteins formed by assemblages of slightly varied subunits - all the appearance of an evolutionary history that has beaten those impossible odds, and quite common.

    Fourth, we have seen this kind of evolution in the lab - with antibiotic resistance, etc. So however unlikely a naive calculation declares such events to be, they are relatively common.

    Meanwhile, I don't follow your argument against duplicate genes contributing greatly to a lowering of the odds. Having a tolerated reduced functioning gene in a pair with a functional model seems to me to put considerable pressure on the reduced funstioning gene.

    The whole scene reminds me of the standard creationist bs calculation of the odds of forming a working protein by chance, from random assemblages of amino acids.
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    I would like to consider more closely these constraints you’re talking about. You seem to be echoing a concern that I’ve read about recently that not as many sites on a protein are as selectively neutral as was previously thought. Many protein families, for instance, are characterized by a “functional” sequence towards the middle of the protein that is highly conserved (similar) across all members in the family, but the different members vary much more widely in their exterior sequences. This was thought to be because selective pressures are minimal in these areas, so they are free to accumulate mutation.

    This paper by DePristo et al., in addition to several of the ones you referenced, primarily seek to dispel the notion that large areas of a protein are selectively neutral. They review a variety of evidence that shows these exterior areas of the protein, and indeed all areas of a protein, contribute significantly to the stability of that protein, and stability is directly related to function.

    However, neither changes in stability nor changes in function are characterized by purely on/off patterns. There is a range of stabilities a protein can have that will still allow it to perform its function at a range of efficiencies, and there is a subset of that range that is selectively neutral; in other words, the function of the protein is not altered to a point where the organism experiences a reduction in fitness as a result. And even outside of the neutral range is a range where there is still a degree function that is not a complete loss of function even though it is still selectively disadvantageous. Even this paper by Douglas Axe that you referenced shows this. Some of the mutants created by Axe in his study certainly exhibit a decrease in function but not a complete loss of function. It takes a certain number of concurrent mutations before function is completely lost, and this is the threshold of number of mutations that you are concerned about.

    However, let’s consider what happens when a protein acquires a single mutation that brings its level of functionality low enough to have a negative fitness effect on the organism, but is not a complete loss of function and does allow the organism to survive and reproduce, albeit less successfully than its fellows without that mutation. Some of this unfortunate organism’s progeny may accumulate more function lowering mutations that do bring it to the level of loss of function. Let’s say these progeny suffer enough to die before reproducing themselves. Selection has certainly disfavored them. However, some of the organism’s progeny may also have acquired a new mutation that returns the protein’s functionality to within normal levels. Selection certainly favors this mutation and this individual goes on to reproduce.

    What I’m describing is depicted in Figure 1b and Figure 2 in the paper by DePristo et al. In this manner a given protein-coding gene can explore selective space. Even a single amino acid substitution that alters the actual function of the protein may de-stabilize it to a point that is detrimental to fitness; but any subsequent mutations that restore the stability of the protein will be favored by natural selection. The DePristo et al. paper includes references to studies on these compensatory mutations and the important role they play in protein evolution. Even the paper by Douglas Axe that you provided in support of your position states that evolutionary movement from one function to another is not impossible, but can only happen along certain pathways that maintain at least some degree of function. His main point was simply that protein structure is not as vastly flexible as previous researchers thought, and the roads between functions are narrower than previously assumed – narrower, but still there.

    I quote from the article:
    Quote Originally Posted by Douglas Axe
    If we represent the relationship between protein sequence and function as a seascape (Figure 5), this [previous] understanding of the group of homologues implies that they would all be represented by points near the summit of a single dry mountain.

    The results reported here indicate that the true picture is very different. In the hybrid experiment, a set of sequences that are direct intermediates between the two parent b-lactamase sequences was produced. All of these hybrid sequences, in other words, lie on conceptual paths by which one parent sequence is transformed into the other with a minimum number of substitutions. The fact that they all lack biologically significant function means that the points representing these intermediate sequences in a seascape picture are below sea level. Since all of the direct paths from the TEM-1 enzyme to the P. mirabilis enzyme that were sampled dip below sea level, it is reasonable to conclude that a substantial majority of the possible direct paths do likewise. These two natural enzymes would therefore be best pictured as points on different quasi-islands (dry peaks largely surrounded by water). There must be a dry path connecting these quasi-islands via others if they are descendants of a single enzyme, and there may also be direct connecting paths, but from an aerial view, much more water than land separates them.”
    By moving through the space of possible sequences via steps of mutation, compensatory mutation, mutation, compensatory mutation, etc, a protein sequence can accumulate a great deal of variation compared to its ancestral state without immediately killing the lineages of organisms that contain it. As you already acknowledge single step variants, this logical framework provides a way that single steps of variation can accumulate over time.

    In light of this, you comment here:

    Quote Originally Posted by cypress
    I did not ask for you to provide examples or counts of homologous proteins that likely made reuse of a preexisting gene sequence (emphasis mine – paralith) through gene duplication as one step in the process.
    Confuses me somewhat. Any newly evolved gene is going to be the result of sequences that existed before it. To evolve species B you have to start with the ancestral species A. You said that you have no issue with speciation occurring, so you surely must admit to this. Evolution is, after all, descent with modification – descending from a common ancestor by modifying its original characteristics. Any evidence I could give you of evolving genes will start with an ancestral pre-existing gene from which the new functional variant arose.

    And because of this, I do not understand your issue with the validity of protein families as an example. If you actually looked at a couple of the protein sequences in the database I linked to, you could see for yourself that just within the first 20 amino acids there is considerable variation – much more than just three. And these are certainly not laboratory generated variants.

    Thus I feel I have already provided evidence for your option 3:

    Quote Originally Posted by cypress
    Demonstrate how known evolutionary processes are able to efficiently and effectively search the sample space to locate the rare variants many orders of magnitude faster than probability would predict.
    Except I’m sure you will argue that I have not addressed speed, though if you had actually read any of the articles in the list presented as evidence of new function via mutations, I think you’d see that I have. In particular, this study:

    Boraas, M. E., D. B. Seale, and J. E. Boxhorn. 1998. Phagotrophy by a flagellate selects for colonial prey: A possible origin of multicellularity. Evolutionary Ecology 12: 153-164.

    Here the authors did nothing but confine a unicellular algae species in the same environment as an algal predator. No other human directed processes were at work. And yet in the time period of this study alone, this species of algae exhibited a behavior not seen before – colonial multicellularity. And this characteristic persisted long after the authors removed this new variant from the environment with the predator, showing that it was not simply a plastic response but a dedicated change. (This is another paper for which I was able to download the full text, so again PM me if you'd like to read it for yourself. Though you don't seem very interested in reading what I offer you.)

    For further explanation of why natural selection can move evolution along far speedier than would be predicted by more random processes, Dawkin’s “Climbing Mount Improbable” lecture is a good source.

    http://www.digitaljournal.com/article/267371
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    Quote Originally Posted by iceaura
    Quote Originally Posted by cypress
    Please reread my post. The numbers quoted are for any functional variants not a particular variant.
    Then I guess I don't believe their estimations of "functional".
    Ok, let's explore your skepticism more thoroughly.

    For one thing, we all know there are many proteins (hemoglobin, say) that exist right now in several variants, of varied - not present/absent - functionality. I see no allowance for better/worse, slower/faster, etc, functionality.
    As paralith noted, the articles on this topic do make an effort to address the notion of functionality. Axe also made the following remark in the same paper:

    "Mutagenesis studies and alignments of homologous sequences have demonstrated that protein function typically is compatible with a variety of amino-acid residues at most exterior nonactive-site positions."

    Though I did not state it in the same way Axe did, nor was I as direct as you and paralith, I too acknowledge this fact for many classes of proteins.

    This is because the overall shape and key exterior binding sites determine the protein's functional characteristics. Any substitutions that do not disrupt shape or exterior binding sites won't change function to any degree. Therefore the protein function cannot generally be reduced to a precise amino acid sequence.

    To further acknowledge the point you make in this and your previous post, this article(a) confirms that single substitutions that disrupt function are rare.

    (a) D. Axe, N. Foster, and A. Fersht, "A Search for Single Substitutions That Eliminate Enzymatic Function in a Bacterial Ribonuclease." Biochemistry 7(20).

    However, this line of research also confirms that there are domains of proteins that may be unevolvable by the observed stepwise processes in operation today(b). Some proteins have sequences with particular patterns of interior hydrophobic interactions that serve to stabilize folding (and thus function) that are so specific that they either have the same fold as the functional domain, or don't fold at all. Axe chose TEM-1 B-lactmase because it fit this pattern and it is easy to confirm function by experimental test since it serves to protect certain bacteria's from the effects of penicillin-like antibiotics. For this protein configuration, Axe estimated the domain of folding and therefore functional proteins at one in 10^64. Furthermore he was able to establish a specific definition of function whereby any sequence that folded at all no mater how unstably, was considered functional. Since non-working domains have no fold and therefore no set shape structure they very clearly have no biological significance.

    (b) D. Axe, "Estimating the Prevalence of Protein Sequences Adopting Functional Enzyme Folds", Journal of Molecular Biology 3341 (2004).

    Since modern evolutionary theory postulates that all observed diversity is explained by evolutionary processes in operation today, I don't need to show that this is true for all proteins, it is sufficient to demonstrate that even one or a few protein domains have this characteristic.

    I suggest we focus on this example so we avoid being distracted by counter arguments of plausible cases that cannot easily be confirmed or rejected.

    For another, I don't think anyone really has much of an idea right now about the functionality of a changed protein in an organism, in general - if any function at all, or possibly even nonfunction, keeps it around.
    As indicated above, in the case of some protein domains, we can.

    For a third, we know of proteins formed by assemblages of slightly varied subunits - all the appearance of an evolutionary history that has beaten those impossible odds, and quite common.
    Maybe, but as I said, it is not sufficient to demonstrate a few plausible cases based on similarity, or even some experimentally confirmed cases, instead you must show how the particular domains I described can be actualized by the claimed process.


    Fourth, we have seen this kind of evolution in the lab - with antibiotic resistance, etc. So however unlikely a naive calculation declares such events to be, they are relatively common.
    No sorry we have not. I have acknowledged the kind of evolution of which you speak and have stipulated it as fact. However it fits a domain of proteins entirely different from the example I provided. Specifically it falls into a class that prevents the drug from exploiting the particular molecular pathway but in the process weakens but does not alter original function. Furthermore these examples all involve combinatorial events well within the range of random chance probabilities, indicating that nothing other than pure blind search was required.

    Please take a critical look at the argument here or return to the previous cases where functional differences involve a pathway with 3 or more steps. Help me find a way for evolutionary processes to efficiently search for and locate these solutions.
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    Quote Originally Posted by cypress
    Since non-working domains have no fold and therefore no set shape structure they very clearly have no biological significance.
    That isn't clear.

    The complexity of determining lack of function for a complex protein in an unknown biological situation is very great. And the study of protein folding - often mediated, we recall - is very new. The study of evolutionary pathways at this level - which are possible, which common, what some of the unusual ones are - is newer yet.
    Quote Originally Posted by cypress
    Axe chose TEM-1 B-lactmase because it fit this pattern and it is easy to confirm function by experimental test since it serves to protect certain bacteria's from the effects of penicillin-like antibiotics. For this protein configuration, Axe estimated the domain of folding and therefore functional proteins at one in 10^64. Furthermore he was able to establish a specific definition of function whereby any sequence that folded at all no mater how unstably, was considered functional.
    Functional as a protector from antibiotics. He cannot test for other functionality in its former evolutionary circumstances. He has no idea what its original, unevolved function might have been, or how arranged.

    Quote Originally Posted by cypress
    Maybe, but as I said, it is not sufficient to demonstrate a few plausible cases based on similarity, or even some experimentally confirmed cases, instead you must show how the particular domains I described can be actualized by the claimed process.
    Not really. You are postulating an entirely new and completely unknown kind of process as necessary, because you cannot imagine how the known processes can have produced a particular small minority of proteins. This is an extraordinary claim, and the ball of proof is in your court - I can't come up with a plausible evolutionary sequence off hand, but experience has taught us that this kind of bafflement is often short lived in the world of the clever.
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    First, just to clarify, I take it that you agree a step-wise exploration of sequence space via mutation, compensatory mutation, etc is viable for many proteins, since you did not raise a specific argument against this point. In proteins where a single mutation merely reduces function and does not totally eradicate it.

    Quote Originally Posted by cypress
    However, this line of research also confirms that there are domains of proteins that may be unevolvable by the observed stepwise processes in operation today(b). Some proteins have sequences with particular patterns of interior hydrophobic interactions that serve to stabilize folding (and thus function) that are so specific that they either have the same fold as the functional domain, or don't fold at all. Axe chose TEM-1 B-lactmase because it fit this pattern and it is easy to confirm function by experimental test since it serves to protect certain bacteria's from the effects of penicillin-like antibiotics. For this protein configuration, Axe estimated the domain of folding and therefore functional proteins at one in 10^64. Furthermore he was able to establish a specific definition of function whereby any sequence that folded at all no mater how unstably, was considered functional. Since non-working domains have no fold and therefore no set shape structure they very clearly have no biological significance.

    (b) D. Axe, "Estimating the Prevalence of Protein Sequences Adopting Functional Enzyme Folds", Journal of Molecular Biology 3341 (2004).

    Since modern evolutionary theory postulates that all observed diversity is explained by evolutionary processes in operation today, I don't need to show that this is true for all proteins, it is sufficient to demonstrate that even one or a few protein domains have this characteristic.
    As iceaura and I have continually pointed out, this is in reference to a break in current function, not in any potentially new function. Right now, in an environment rife with penicillin-like antibiotics provided by our very own species, there is no doubt a high selective pressure to keep this protein in its functioning state. And I have no doubt that we will not see a loss or significant change of this gene in common bacteria anytime soon. But change the environment, remove this risk (humans die out? one too many nuclear bombs...) and the selection pressure to keep this protein functional is released, and it is free to accumulate mutations in organisms that will live to pass them on, and eventually take up a new function.

    Let's look at a quote from the Axe paper you referred to above:
    Quote Originally Posted by Axe 2004
    The focus here will be upon enzymatic function, by which we mean not mere catalytic activity but rather catalysis that is mechanistically enzyme-like, requiring an active site with definite geometry (at least during chemical conversion) by which particular sidechains make specific contributions to the overall
    catalytic process.
    From the start Axe is limiting his definition of functionality to that of one class of protein; he's not even going to consider, let alone test for, functionality as a structural protein. One mutation may turn this protein into a dead-end enzymatically, if it really does prevent the protein from achieving any kind of tertiary structure, but who knows what potential it may have for becoming a structural unit, many of which do their jobs just fine with (relatively) simple secondary structure.


    Secondly, this is where gene duplication becomes very important in the process of protein diversification. The great thing about gene duplication is that one of the duplicates can maintain the essential function that's keeping the organism alive - and the other one can mutate at no risk to the organism. It is released of the selective pressure since the other duplicate can shoulder it by itself. Thus even in an unchanging environment new sequence space can be explored at no cost to the organism.
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    Quote Originally Posted by paralith
    First, just to clarify, I take it that you agree a step-wise exploration of sequence space via mutation, compensatory mutation, etc is viable for many proteins, since you did not raise a specific argument against this point. In proteins where a single mutation merely reduces function and does not totally eradicate it.
    and a related point in a previous post ....

    And because of this, I do not understand your issue with the validity of protein families as an example. If you actually looked at a couple of the protein sequences in the database I linked to, you could see for yourself that just within the first 20 amino acids there is considerable variation – much more than just three. And these are certainly not laboratory generated variants.

    Thus I feel I have already provided evidence for your option 3:
    I am a bit late responding to your questions, I'm sorry that you have had to ask this more than once.

    Here is the challenge and the options to which paralith refers.

    Quote Originally Posted by cypress
    an actual detailed multistep process involving 3 or more required modifications (since this is the focus of the challenge) from the original functional gene that demonstrates how known evolutionary process (which you defined above) actually did overcome the odds of 1/1065 to 1/10^78 presented by the research I referenced.

    There are several ways to dispose of this challenge, I offer a few here.

    1) Demonstrate that the research I offered is in error by providing more accurate research

    2) Demonstrate that a process not previously cataloged exists,is operating today and is capable of making multistep leaps to traverse from one to another functional variant.

    3) Demonstrate how known evolutionary processes are able to efficiently and effectively search the sample space to locate the rare variants many orders of magnitude faster than probability would predict.
    By "required modifications", I meant to exclude the relatively abundant neutral or near neutral modifications that do not contribute to a new function.

    Recognize that there are multiple cases we are discussing.

    One challenge I posed is this case of generating new protein function. We now know that with few exceptions, nearly every major cell process is carried out by protein assemblies of ten or more molecules (a). In order to function, they must not only fit together, they also must self-assemble. They must discriminate between correct and incorrect binding partners (b). To assemble correctly, at a minimum they must stick to their partners in the right orientation. Therefore they require correct shape and and the correct chemical affinity at the binding site. Most binding sites require on the order of 5-6 amino acids in a coherent patch (c). Furthermore many protein structures involve more than one unique binding sites. The challenge therefore is to explain how known evolutionary process account for generation of new binding sites from sequences that lack them.

    As paralith noted, many single step variants are neutral or only diminish function, in fact, studies indicate that his is true for 30-35% of the variants. This reality alone accounts for the variation paralith noted. In a sequence of 20 base pairs it would not be uncommon to see 4 to 6 variations with no appreciable loss of function. However recall that the challenge is not to show variation from one functionally similar protein to another performing the same function as you have done, the challenge is to explain how known processes can generate an new and different functional binding site that in turn supports a new function.

    Therefore to answer your question, No stepwise search has not been shown viable to generate a new binding site and therefore new function. The number of known confirmed cases of known processes generating a new binding site is one, the case of sickle cell trait in humans, but this one is unusual because it only required one point change to generate a strong new binding site, unlike the typical 5-6 according to the research. This does not mean that there are no examples of proteins that are largely similar but do have different binding sites (with the typical 6 or so alterations) and different function. Clearly from genetic studies, there are. The question is not to find these cases (as you have provided perhaps some), rather the challenge is to demonstrate that known processes actually can generate them. I believe they can't and therefore we should be searching for processes that can.

    (a) B. Alberts, "The cell as a collection of protein machines." Cell 92 (1998)
    (b) I. Nooren, and J. Thornton, "Diversity of protein-protein interactions." EMBO Journal 22 (2003)
    (c) L. Lo Conte, C. Chothia, and J. Janin, "The atomic structure of protein-protein recognition sites." J. Mol. Bio. 285 (1999) and also several other studies primarily of immune system antibodies.

    The second case, I introduced later, is of generation of function in an enzyme protein. In this case, rather than addressing the question of generation of new function, we are instead searching for sequences within the protein capable of producing stable folds which then generates consistent structure and therefore a protein capable of any function. The reason for this that proteins require structure in order to consistently interact with other proteins and chemicals. Proteins that form inconsistent blobs are not able to consistently perform and are therefore not biologically significant. This I'll address paralith's and iceaura's response to this challenge in my next post.
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    Cypress - let us consider carefully what you are asking us for.

    Your Challenge #2:
    In this case, rather than addressing the question of generation of new function, we are instead searching for sequences within the protein capable of producing stable folds which then generates consistent structure and therefore a protein capable of any function.
    ....capable of any function? The assumption you are making here is that we know, or are even capable of knowing, ALL possible functions a given sequence of amino acids could possibly have. As I said before even a protein without significant tertiary structure that may be much less likely of having catalytic ability may have potential function as a structural protein. But how are we to reasonably assess all possible function when it is beyond our ability to predict what environments may arise at some unknown point in the future that would give this particular sequence of amino acids a useful purpose? What is a "blob" right now in the current environment could be a functionally useful structure in a different environment. Even if you change the ambient pH or the mean temperature or the other chaperone molecules, a sequence that used to create a useless "blob" may now conform into something useful, without any mutation in the protein itself.

    In essence, you are asking non-falsifiable questions. Do all protein sequences have a potential function? Do some protein sequences have no potential function? How can you falsify that? Just because some protein sequences do not currently have any known functions does not mean they don't have the potential for some new function that no one has ever thought of or seen before. This means you need to re-think your question. Personally I think your Challenge #2 is simply unscientific, and we should stick with your Challenge #1, which is after all your real question.


    Your Challenge #1:
    However recall that the challenge is not to show variation from one functionally similar protein to another performing the same function as you have done, the challenge is to explain how known processes can generate an new and different functional binding site that in turn supports a new function. The number of known confirmed cases of known processes generating a new binding site is one, the case of sickle cell trait in humans,
    I cannot help but return yet again to the mouse olfactory receptor family. I can see that to you, these proteins are all doing the same function; and they are in the sense that they are sending information about whether or not a certain molecule is present in the nasal cavity. But they are very different in their binding sites and what molecule they actually detect; the variety in the shape of all the possible molecules that may waft into the nose of a mouse from a great variety of sources requires just as a great a variety in binding sites in order to recognize each scent and distinguish it from all the others. It requires a great specificity, as great as the specificity you were lauding for the cooperative function of multiple molecules in carrying out cellular processes. This protein family does indeed represent a diversification of proteins that is the result of a diversification in the active binding site itself.

    but this one is unusual because it only required one point change to generate a strong new binding site, unlike the typical 5-6 according to the research.
    The research you quoted only says "5 - 6 amino acids in a coherent patch." If you already have a patch but change just one of the amino acids you may have a new binding site. If you had a patch of 3 and a patch of 2 separated by one amino acid that disrupted potential cooperation between the 3 and the 2 that changed to create a single cooperative patch, you may have a new binding site. I don't think your research implies that you have to have to suddenly generate five to six new mutations in one spot and that's the only way to get a new binding site.

    And as another example of how new function can evolve, here is an excellent summary of the case of the cmsT locus in maize. It is an entirely new protein that is the result of joining two previously separated sequences that did not, alone, even code for a protein. And it even binds specifically to a fungal toxin.

    Another example of a completely new gene that has strong evidence of functionality.

    How common is this cobbling together of new sequences? How common, as you have asked earlier, is gene duplication the result of new functional genes? According to this study, 11% of the genes in drosophila flies are the result of chimerism of non-coding sequences, 30% are the result of chimerism of different coding sequences, and over 40% are the result of duplication. Step-wise exploration of sequence space is not, by far, the only source of new proteins, and some would argue that it may even be the least important source.
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    Quote Originally Posted by paralith
    Cypress - let us consider carefully what you are asking us for.

    Your Challenge #2:
    In this case, rather than addressing the question of generation of new function, we are instead searching for sequences within the protein capable of producing stable folds which then generates consistent structure and therefore a protein capable of any function.
    ....capable of any function? The assumption you are making here is that we know, or are even capable of knowing, ALL possible functions a given sequence of amino acids could possibly have. As I said before even a protein without significant tertiary structure that may be much less likely of having catalytic ability may have potential function as a structural protein. But how are we to reasonably assess all possible function when it is beyond our ability to predict what environments may arise at some unknown point in the future that would give this particular sequence of amino acids a useful purpose? What is a "blob" right now in the current environment could be a functionally useful structure in a different environment. Even if you change the ambient pH or the mean temperature or the other chaperone molecules, a sequence that used to create a useless "blob" may now conform into something useful, without any mutation in the protein itself.
    As a general statement I agree it is difficult or impossible to predict function based on tertiary structure, however, in this case we are simply looking for configurations that generate a stable tertiary structure at all. Configurations with stable folds in the domain of interest are functional, while those with no stable fold and therefore no stable structure are non-functional. Experimental tests are used to confirm this fact.

    This is not a stretch either since it is known that tertiary structure determines protein function. Proteins that lack a stable tertiary structure are widely recognized as non-functional. I realize you don't need this link paralith, but other readers may benefit from it.

    As to your speculation that another environment might stabilize these blobs, recognize that the nature of fold stability in this study are hydrophobic domains of the secondary structure. Stability is reduced and eliminated by disruption of continuous hydrophobic regions. In this class of protein enzyme, these regions either exist and align or they don't. Given this reality, it is unscientific to speculate that an unstructured "blob" of this kind could, in a different environment contain a stable structure. Instead of speculating, you should provide evidence that this is true. Best current observations and chemistry indicates it is not.


    I believe this addresses iceaura's first line of questions in his most recent post as well.


    In essence, you are asking non-falsifiable questions. Do all protein sequences have a potential function? Do some protein sequences have no potential function? How can you falsify that? Just because some protein sequences do not currently have any known functions does not mean they don't have the potential for some new function that no one has ever thought of or seen before. This means you need to re-think your question. Personally I think your Challenge #2 is simply unscientific, and we should stick with your Challenge #1, which is after all your real question.
    Except you are reframing my argument to make it seem non-falsifiable. Here is my question properly framed:

    Modern evolutionary theory claims to account for all observed diversity by known processes presently in operation. The theory describes these processes and provides experimental and observational support for them. Therefore, if any biological component can be identified that cannot be formed through these observed processes, then the theory is falsified and should be altered. This argument is identically framed to the precambrian mammal example that you agreed was a properly framed test of evolutionary theory.

    I have proposed that TEM(1) B-lactamases fit this profile because, as research shows, the frequency of variations capable of generating the required tertiary structure is rare (1 in 10^64 or less) and the the set of variations that lack this structure are widely recognized as biologically inactive. If this continues to hold true, then natural selection is unable to drive a successful stepwise search and random processes are too slow to account for rarity of this event. The combination described puts this domain of protein enzyme out of reach to our current understanding of the stepwise processes proposed by current observed evolutionary theory, unless you accept dumb luck. I can accept one or two accidents but we would need thousands. It is important to also note that this class of enzyme is known to have existed prior to use of penicillin-like antibiotics.

    Note that I have not claimed that we will never find a functional stepwise pathway to TEM(1) B-lactamase. Just as I suspect you would not claim that we will never find a precambrian mammal fossil. Still, current evidence suggests we will not find such a fossil, just as current evidence indicates we will not find a stepwise solution to TEM(1) B-lactamase structure. So, while the ball is presently in my court to find a precambrian mammal fossil, the ball is now squarely in the court of proponents of stepwise processes to find a solution to this challenge.

    But it is not scientific to merely speculate about some story as to how this might occur, just as it is not proper to appeal to an undetectable supernatural process. Remember the creationist can also claim that someday evidence for their favorite currently undetectable processes will come forth and clearly we do not accept that claim.

    iceaura also asked this question, though slightly differently.

    I will address your response to Challenge 1 in my next post.
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    Quote Originally Posted by cypress
    Configurations with stable folds in the domain of interest are functional, while those with no stable fold and therefore no stable structure are non-functional. Experimental tests are used to confirm this fact.
    You seem to be blatantly ignoring my suggestion that proteins with no significant tertiary structure could have function as structural proteins. You are also ignoring the fact that if natural selection is released on that particular enzyme, it can be free to accumulate several mutations, some of which may remove its function for a time, but as it accumulates more mutations a new function may be found. The key is that if there is no environmental pressure making that protein essential to the survival of the organism, it doesn't matter if it goes enzymatically useless for a few generations.

    As to your speculation that another environment might stabilize these blobs, recognize that the nature of fold stability in this study are hydrophobic domains of the secondary structure. Stability is reduced and eliminated by disruption of continuous hydrophobic regions. In this class of protein enzyme, these regions either exist and align or they don't. Given this reality, it is unscientific to speculate that an unstructured "blob" of this kind could, in a different environment contain a stable structure. Instead of speculating, you should provide evidence that this is true. Best current observations and chemistry indicates it is not.
    Cypress, I saw nothing in the Axe paper on this protein that suggests this at all. First of all, the author describes that there already exist in nature multiple forms of the A beta-lacatmase protein in different Escheria species - multiple functioning forms with different sequences.

    Quote Originally Posted by Axe
    The SCOP structure classification (release 1.63†) lists 13 “species”-level variants of the class A b-lactamase fold. Removal of two of these (the TEM-52 variant being very similar to the TEM-1 variant, and the PER-1 variant showing substantial structural deviation from otherwise conserved features18) leaves a set of 11 natural large-domain variants with close structural similarity (Figure 4)
    and considerable sequence diversity.
    Secondly, the author also found that he could totally obliterate the active site of this protein and the bacteria were still able to survive the presence of ampicillin up to 10 ug/ul, well past the typical 5 ug/ml usually used to distinguish a minimal level of resistance.

    Quote Originally Posted by Axe
    However, when attempts were made to produce a reference sequence using this selection threshold, sequences that passed selection were found to carry mutations that would eliminate function by the known enzymatic mechanism.
    While he proposed that the resistance was related to general properties of the protein and not the active site itself, this just goes to show that in an environment with lower levels of the risk factor, even temporarily so, the protein's active site could mutate to total lack of function and back and the lineages of bacteria holding it would live to carry on that mutated gene.

    Thirdly, he tested his experimental sequences at a variety of temperatures and DID find a resulting variety of function.

    Quote Originally Posted by Axe
    The resulting values (3.5, 4.0, and 4,200 mg/ml, respectively) give a reference sequence activity of 0.01% relative to TEM-1 at 37 degrees C ((4.0–3.5)/(4200–3.5)Z10K4). This is 30-fold lower than the 0.3% value measured at 25 degrees C ((20–5)/ (5200–5)Z0.003), indicating that the reference sequence enzyme undergoes substantial changes with increasing temperature in this range.
    Fourthly, the author did not test for specific beta-lactamase functionality by any fold, but only by the existing fold (the large-domain fold) due to the limitations of his experimental design.

    Quote Originally Posted by Axe
    But, since many other folds might be comparably suitable scaffolds for this enzymatic function, how can we take this into account in our assessment of the overall prevalence of functional sequences? Conceiving this prevalence as a fraction, the numerator would ideally be the number of sequences of large-domain length that provide a working b-lactamase (in the specified biological context) via any fold, and the denominator would be the total number of possible sequences of this length. Realistically, though, the only numerator we can estimate by experiment is the number of sequences of large-domain length that provide a working b-lactamase via the large-domain fold.
    ...
    Since the four randomization experiments provide an upper-bound estimate of the likelihood of solving the local problem for a ten-residue set, the likelihood of the joint solution may be estimated by applying the above per-position mean (0.38) across the domain. The resulting figure, 10^64 (0.38153Z 10K64), is thus an upper-bound estimate of the prevalence of functional sequences among the whole set of signature-compliant large-domain sequences.
    Thus, this number you keep throwing at us is assuming a functional site of only ten amino acids long that forms this particular large-domain fold conformation, not any possible conformation of any number of amino acids that could serve a similar function.

    Except you are reframing my argument to make it seem non-falsifiable. Here is my question properly framed:

    Modern evolutionary theory claims to account for all observed diversity by known processes presently in operation. The theory describes these processes and provides experimental and observational support for them. Therefore, if any biological component can be identified that cannot be formed through these observed processes, then the theory is falsified and should be altered. This argument is identically framed to the precambrian mammal example that you agreed was a properly framed test of evolutionary theory.
    Which means that your supposed second challenge is really just the same as your first challenge, which is why I wanted to simply focus on that and not try to spuriously divide it into two separate tasks.

    I have proposed that TEM(1) B-lactamases fit this profile because, as research shows, the frequency of variations capable of generating the required tertiary structure is rare (1 in 10^64 or less) and the the set of variations that lack this structure are widely recognized as biologically inactive.
    Inactive for penicillin resistance. Inactive in forming that particular fold. That is not the same as completely lacking any possible biological function.

    If this continues to hold true, then natural selection is unable to drive a successful stepwise search and random processes are too slow to account for rarity of this event.The combination described puts this domain of protein enzyme out of reach to our current understanding of the stepwise processes proposed by current observed evolutionary theory, unless you accept dumb luck. I can accept one or two accidents but we would need thousands. It is important to also note that this class of enzyme is known to have existed prior to use of penicillin-like antibiotics.

    Note that I have not claimed that we will never find a functional stepwise pathway to TEM(1) B-lactamase. Just as I suspect you would not claim that we will never find a precambrian mammal fossil. Still, current evidence suggests we will not find such a fossil, just as current evidence indicates we will not find a stepwise solution to TEM(1) B-lactamase structure. So, while the ball is presently in my court to find a precambrian mammal fossil, the ball is now squarely in the court of proponents of stepwise processes to find a solution to this challenge.
    Known mechanisms certainly can account for the evolution of beta lactamases, especially if this protein previously served a different function in bacteria that never experienced greater than 5 ug/ul concentration of pencillins, until one day it did experience a higher concentration and those mutants which had come across this functional conformation were the ones who survived and carried on today. And yes, I saw your note on the human use of penicillin, but remember it was derived from a fungi that evolved this antibiotic itself to protect from bacteria that would attack it. Humans are not the only organisms that have needed to develop immune defenses against bacteria.

    And finally, it's not necessary that we find a stepwise process that arrives at this particular amino acid sequence, because while some new proteins are generated that way, not all of them are. There are a variety of mechanisms by which beta lactamase may have come into existence.

    But it is not scientific to merely speculate about some story as to how this might occur, just as it is not proper to appeal to an undetectable supernatural process. Remember the creationist can also claim that someday evidence for their favorite currently undetectable processes will come forth and clearly we do not accept that claim.
    The processes to which I am referring are not undetectable. We know that there is variation in nature across time and space in the selective pressures on proteins. We know that proteins can mutate, can duplicate, can emerge from the bringing together of previously separated sequences in the genome.

    No, we do not have direct experimental evidence for the evolution of every single protein currently known. By this same logic we do not have direct experimental evidence for the evolution of animals only known through their fossils, because, we only have their fossils. There are two reasons why this does not constitute falsification of evolution. One, biology and science in general does make the assumption of uniformitarianism. The processes that we have observed have gone on in the past and do go on today even if we aren't watching it ourselves. If we don't make that assumption, we may as well all go home because we'll never know anything about things we haven't witnessed with our own eyes, and that's a LOT of things. Two, you have neither shown definitively that it is impossible for known processes to conceivably arrive at certain proteins nor have you offered any alternatives we can test for. We can test for the presence of a rabbit fossil in the Cambrian by keeping an eye out for rabbits whenever we're digging in Cambrian fossil deposits. And so far, it's a no show.

    I am growing increasingly skeptical, cypress, that you will ever find information that shows it impossible for known evolutionary processes to have generated current organic structures. I will wait for your promised next post but I have to say you are running out of ground to stand on.
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    Quote Originally Posted by paralith
    Quote Originally Posted by cypress
    Configurations with stable folds in the domain of interest are functional, while those with no stable fold and therefore no stable structure are non-functional. Experimental tests are used to confirm this fact.
    You seem to be blatantly ignoring my suggestion that proteins with no significant tertiary structure could have function as structural proteins.
    I don't mean to be ignoring you. I am simply waiting for some examples to support the suggestion.

    You are also ignoring the fact that if natural selection is released on that particular enzyme, it can be free to accumulate several mutations, some of which may remove its function for a time, but as it accumulates more mutations a new function may be found. The key is that if there is no environmental pressure making that protein essential to the survival of the organism, it doesn't matter if it goes enzymatically useless for a few generations.
    I agree with this and I cover it by noting the long odds of hitting a functional combination without aid of selection pressure.

    Cypress, I saw nothing in the Axe paper on this protein that suggests this at all. First of all, the author describes that there already exist in nature multiple forms of the A beta-lacatmase protein in different Escheria species - multiple functioning forms with different sequences.
    Right, Axe does not discuss possibilities for non-functional variants and variants that don't produce the folds he studied. However, it is generally known that tertiary structure is required for protein activation. I certainly accept that there are multiple variants within the domain studied that are active. Given that the domain size was on the order of 150 residues this would imply 2*10^195 possibilities with 1 in 10^64 functional or about 10^130 functional combinations, so we might expect to find multiple variants in the environment. Remember I am not disputing that variations exist, I am asking how these variants came to exist.

    So two points of agreement.

    Secondly, the author also found that he could totally obliterate the active site of this protein and the bacteria were still able to survive the presence of ampicillin up to 10 ug/ul, well past the typical 5 ug/ml usually used to distinguish a minimal level of resistance.
    This I consider a significant argument in your favor. I missed this before and it provides a opening and a weakness on my part, suggesting that more research is warranted. Thanks for pointing this out, this is the kind of thing I have been looking for.

    Thirdly, he tested his experimental sequences at a variety of temperatures and DID find a resulting variety of function.
    Sure among other reasons, for the purposes of delimitating where the break between folding and non-folding occurs.

    Fourthly, the author did not test for specific beta-lactamase functionality by any fold, but only by the existing fold (the large-domain fold) due to the limitations of his experimental design.

    Quote Originally Posted by Axe
    But, since many other folds might be comparably suitable scaffolds for this enzymatic function, how can we take this into account in our assessment of the overall prevalence of functional sequences? Conceiving this prevalence as a fraction, the numerator would ideally be the number of sequences of large-domain length that provide a working b-lactamase (in the specified biological context) via any fold, and the denominator would be the total number of possible sequences of this length. Realistically, though, the only numerator we can estimate by experiment is the number of sequences of large-domain length that provide a working b-lactamase via the large-domain fold.
    ...
    Since the four randomization experiments provide an upper-bound estimate of the likelihood of solving the local problem for a ten-residue set, the likelihood of the joint solution may be estimated by applying the above per-position mean (0.38) across the domain. The resulting figure, 10^64 (0.38153Z 10K64), is thus an upper-bound estimate of the prevalence of functional sequences among the whole set of signature-compliant large-domain sequences.
    Thus, this number you keep throwing at us is assuming a functional site of only ten amino acids long that forms this particular large-domain fold conformation, not any possible conformation of any number of amino acids that could serve a similar function.
    Fair point, but I should point out again that the domain included 150 residues not just 10, though generally 10 generally make up the affinity region (consistent with the 5-6 figure I offered previously). However, as I read the article, he argues that it is reasonable to extend his estimate to the other fold domains as an upper bound. This too is a weakness in the research but I find it far less of a concern than the one you offered above.

    Inactive for penicillin resistance. Inactive in forming that particular fold. That is not the same as completely lacking any possible biological function.
    Yes, I may have to concede this point, however as Axe argues, his estimate applies to other domains as well, and though not confirmed directly, offers the same challenge except for the point about weak activity above.

    Known mechanisms certainly can account for the evolution of beta lactamases, especially if this protein previously served a different function in bacteria that never experienced greater than 5 ug/ul concentration of pencillins, until one day it did experience a higher concentration and those mutants which had come across this functional conformation were the ones who survived and carried on today.
    It's a big stretch to say known mechanisms account for B lactamases, but it offers an opening for it, if not simply an argument against my challenge. Well done! My argument needs to do a bit more work in order to close this opening. I'll do a bit more looking but I doubt I have any way of answering this at this time.

    And finally, it's not necessary that we find a stepwise process that arrives at this particular amino acid sequence, because while some new proteins are generated that way, not all of them are. There are a variety of mechanisms by which beta lactamase may have come into existence.
    But once again you traipse into speculation.

    No, we do not have direct experimental evidence for the evolution of every single protein currently known. By this same logic we do not have direct experimental evidence for the evolution of animals only known through their fossils, because, we only have their fossils. There are two reasons why this does not constitute falsification of evolution. One, biology and science in general does make the assumption of uniformitarianism. The processes that we have observed have gone on in the past and do go on today even if we aren't watching it ourselves. If we don't make that assumption, we may as well all go home because we'll never know anything about things we haven't witnessed with our own eyes, and that's a LOT of things.
    Agreed, but by this argument you should be able to demonstrate how the process can accomplish challenges such as these.

    Two, you have neither shown definitively that it is impossible for known processes to conceivably arrive at certain proteins nor have you offered any alternatives we can test for.
    We can't test for alternatives if we don't pursue them. I do agree that there is no sense pursuing alternatives if present explanations work. This is why I am looking critically at the present ones.

    I am growing increasingly skeptical, cypress, that you will ever find information that shows it impossible for known evolutionary processes to have generated current organic structures. I will wait for your promised next post but I have to say you are running out of ground to stand on.
    Again, I agree you have provided an opening in Challenge two, perhaps I'll do better with the original one. Forgive me if I don't get back to it right away.
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    I missed this before and it provides a opening and a weakness on my part, suggesting that more research is warranted.
    In both the threads you are in involved in I get the impression that you have a preexisting point that you are attempting to prove. Am I wrong about that?
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    Quote Originally Posted by cypress
    I don't mean to be ignoring you. I am simply waiting for some examples to support the suggestion.
    It's very easy to look up. As described here, there are many structural proteins, with one example being keratin in our hair and nails. Each individual protein has simple secondary structure of alpha helices, and this is more than sufficient to create structural fibrils.

    I agree with this and I cover it by noting the long odds of hitting a functional combination without aid of selection pressure.
    I'm not sure what you're trying to say here; certainly, who knows how many potentially useful mutations have arisen in the past that don't exist today, but the point is that they can arise. The fact that the selection pressures aren't always exactly right to maintain those mutations in the populations and bring them to a higher frequency is, I think, besides the point. Selection will maintain the best of the possible options available, and if something new and better arrives that will then be selected for.

    Thirdly, he tested his experimental sequences at a variety of temperatures and DID find a resulting variety of function.
    Sure among other reasons, for the purposes of delimitating where the break between folding and non-folding occurs.
    But you do agree that changing ambient environments can alter the conformation of a given amino acid sequence? That is after all how temperature affects function in this case. You previously said that this protein either functions or it doesn't regardless of altering other aspects of the environment like temperature and I think this clearly shows that simply isn't true.

    Thus, this number you keep throwing at us is assuming a functional site of only ten amino acids long that forms this particular large-domain fold conformation, not any possible conformation of any number of amino acids that could serve a similar function.
    Fair point, but I should point out again that the domain included 150 residues not just 10, though generally 10 generally make up the affinity region (consistent with the 5-6 figure I offered previously). However, as I read the article, he argues that it is reasonable to extend his estimate to the other fold domains as an upper bound. This too is a weakness in the research but I find it far less of a concern than the one you offered above.
    If by domain you mean the entire protein, yes; but the functional site itself, on which you have been focusing, and that which that number is referring to, is only in reference to ten amino acids in the active site, as shown in Figure 8. And his estimations are also limited to domains of this size:

    Quote Originally Posted by Axe
    We can adjust the figure to obtain arough estimate of the prevalence of functional largedomainsequences among all sequences of this size (signature-compliant or not).
    Inactive for penicillin resistance. Inactive in forming that particular fold. That is not the same as completely lacking any possible biological function.
    Yes, I may have to concede this point, however as Axe argues, his estimate applies to other domains as well, and though not confirmed directly, offers the same challenge except for the point about weak activity above.
    Other domains of similar size and similar function and similar fold. His study is very specific to the current function, and current mechanism of function, of beta lactamase. You cannot extrapolate from this to say that therefore, the likelihood of anything that resembles beta lactamase but is not exactly beta lactamase has NO biological significance of any kind in any context.

    It's a big stretch to say known mechanisms account for B lactamases, but it offers an opening for it, if not simply an argument against my challenge. Well done! My argument needs to do a bit more work in order to close this opening. I'll do a bit more looking but I doubt I have any way of answering this at this time.
    ....
    But once again you traipse into speculation.
    ...
    Agreed, but by this argument you should be able to demonstrate how the process can accomplish challenges such as these.
    It has been demonstrated, by numerous cases of documented new proteins with new functions. All the processes (mutation, duplication, frameshift, sequence cobbling) have been validated in a variety of other studies. As I said before, I certainly concede that we do not know the exact process by which every single protein came to exist, but that does not constitute evidence against evolution.

    But apparently, we do have evidence of step-wise evolution of beta lactamases. Sadly I cannot access the full text of this article but a quick google scholar search on the evolution of beta lactamases reveals a lot of research on the diversification and evolution of this family, including documentation of novel beta lactamases. It also appears that you are not the only concerned with beta lactamase evolution, but naturally existing intermediaries between becta lactamases and their purported ancestors have been found.

    Two, you have neither shown definitively that it is impossible for known processes to conceivably arrive at certain proteins nor have you offered any alternatives we can test for.
    We can't test for alternatives if we don't pursue them. I do agree that there is no sense pursuing alternatives if present explanations work. This is why I am looking critically at the present ones.
    We can't pursue alternatives if there aren't any! What is to pursue and test for if all you have to offer is "something else"? And again, you most certainly have not provided me with any evidence that really challenges the workings of known processes. Take your time with your next post, but as I said before, your argument is wearing thin.
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    Quote Originally Posted by paralith
    Quote Originally Posted by cypress
    I don't mean to be ignoring you. I am simply waiting for some examples to support the suggestion.
    It's very easy to look up. As described here, there are many structural proteins, with one example being keratin in our hair and nails. Each individual protein has simple secondary structure of alpha helices, and this is more than sufficient to create structural fibrils.
    Fibers are a special case where secondary and tertiary structure coincide.

    I'm not sure what you're trying to say here; certainly, who knows how many potentially useful mutations have arisen in the past that don't exist today, but the point is that they can arise. The fact that the selection pressures aren't always exactly right to maintain those mutations in the populations and bring them to a higher frequency is, I think, besides the point. Selection will maintain the best of the possible options available, and if something new and better arrives that will then be selected for.
    You describe stepwise mutation with each step beneficial. My challenges are of cases with multiple steps where intermediate steps are neutral or harmful. There are now multiple examples of experimental observations involving two steps with neutral or harmful intermediate steps. Empirical results indicate they occur with frequencies of about 10^13 to 10^20 organisms consistent with statistical analysis. (a)

    If by domain you mean the entire protein, yes; but the functional site itself, on which you have been focusing, and that which that number is referring to, is only in reference to ten amino acids in the active site, as shown in Figure 8. And his estimations are also limited to domains of this size:

    Quote Originally Posted by Axe
    We can adjust the figure to obtain arough estimate of the prevalence of functional largedomainsequences among all sequences of this size (signature-compliant or not).
    Sorry, no. If the study only involved a domain of 10 residues then the total number of permutations would have been 20^10 far too few to generate a result of fewer than 1 in 10^64.

    Other domains of similar size and similar function and similar fold. His study is very specific to the current function, and current mechanism of function, of beta lactamase. You cannot extrapolate from this to say that therefore, the likelihood of anything that resembles beta lactamase but is not exactly beta lactamase has NO biological significance of any kind in any context
    .

    Regardless, even if we stick to the direct result, and suppose that in distant history, enzyme activity does exist for a precursor enzyme that lacks the studied fold domain as you uncovered previously, this is really only a minor issue. Note that in order to obtain this fold, random mutation and natural selection would have had to navigate the described odds involving what appears to be multiple steps (up to 10) several of which are apparently neutral with respect to the studied function (until enough of them accumulate).

    It has been demonstrated, by numerous cases of documented new proteins with new functions. All the processes (mutation, duplication, frameshift, sequence cobbling) have been validated in a variety of other studies. As I said before, I certainly concede that we do not know the exact process by which every single protein came to exist, but that does not constitute evidence against evolution.
    No it has not. While single step mutations and in rare cases two step mutations where the intermediate step is neutral or deleterious have been documented (a) and are consistent with results one would obtain based on random chance, the challenges I offer here have not been demonstrated by observed processes. Studies that show similarities do not tell us anything about how they happen. They are interesting, but I accept that the changes from one to the other occurred, I want to know how.

    (a) C. Borland, and R. Lenski. "Historical contingency and the evolution of a key innovation in an experimental population of Escherichia coli." Proc. Natl. Acad. Sci. 105 (2008)

    B. Hall, "Chromosomal mutation for citrate utilization by Escherichia coli K-12." J. Bacteriol. 151 (1982)

    N. White, "Antimalarial drug resistance.", J. Clin. Invest. 113 (2004)

    But apparently, we do have evidence of step-wise evolution of beta lactamases. Sadly I cannot access the full text of this article but a quick google scholar search on the evolution of beta lactamases reveals a lot of research on the diversification and evolution of this family, including documentation of novel beta lactamases. It also appears that you are not the only concerned with beta lactamase evolution, but naturally existing intermediaries between becta lactamases and their purported ancestors have been found.
    More examples of what has happened, but they don't shed any light on how.

    We can't pursue alternatives if there aren't any! What is to pursue and test for if all you have to offer is "something else"?
    Correct me if I am wrong, but falsification tests don't require alternative explanations.

    And again, you most certainly have not provided me with any evidence that really challenges the workings of known processes. Take your time with your next post, but as I said before, your argument is wearing thin.
    But I have. Any modestly critical analyst will see they have a problem if their theory can't explain how something happened except with a just-so story and similarity studies that confirm the event but not the process. That alone is sufficient to raise a concern. In addition the research provides examples of protein features that require multiple steps (more than 3) where the intermediate steps are at least neutral. The protein-protein binding sites and the B-lactamase folds are examples. The odds in these cases are out of reach to random chance, and we have no observed cases and no description of how currently observed process are able to navigate those steps in a reasonable timeframe.

    If life's diversity contains many cases similar to the ones described, it becomes implausible that current processes account for this in the time we have available. The challenge for the proponent of evolution by observed processes is to account for these cases as they come forward in terms a series of mostly single functional steps and zero gaps in functional steps greater than three. the research provided has offered a few that appear to be greater than three.
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    Quote Originally Posted by cypress
    But I have. Any modestly critical analyst will see they have a problem if their theory can't explain how something happened except with a just-so story and similarity studies that confirm the event but not the process. That alone is sufficient to raise a concern. In addition the research provides examples of protein features that require multiple steps (more than 3) where the intermediate steps are at least neutral. The protein-protein binding sites and the B-lactamase folds are examples. The odds in these cases are out of reach to random chance, and we have no observed cases and no description of how currently observed process are able to navigate those steps in a reasonable timeframe.
    I have two questions for you:
    1)How small must odds be in order to be "out of reach" of random chance?
    2)What's a reasonable timeframe?

    More importantly, is a reasonable timeframe to human observation the same as to developing proteins? Do these two things coincide or are they mutually independent(human observation makes no reservations on the process of the organic world)? Is it not possible that random chance acted faster in this case than in others? This paragraph was more my musing on your statements than questions I'd like you to answer, just fyi
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    Quote Originally Posted by cypress
    Fibers are a special case where secondary and tertiary structure coincide.
    ....but the individual units do not have tertiary structure. That's the point.

    You describe stepwise mutation with each step beneficial.
    I most certainly do not propose any such thing. Read again my previous post discussing step-wise exploration of sequence space and my reference to the paper discussing it, assuming that mutation does not render the function completely inoperable AND that the function is under strong selective constraint. A mutation this is deletrious and that brings the protein into a selectively disadvantageous step can then be recovered by a compensatory mutation that brings it back into the zone of selectively neutral variation. This isn't even addressing the fact that what was in beneficial in one environment for one function can become entirely neutral or disadvantageous if the environment changes.

    Sorry, no. If the study only involved a domain of 10 residues then the total number of permutations would have been 20^10 far too few to generate a result of fewer than 1 in 10^64.
    I see. It looks like I mis-read the passage I quoted; however, the estimate over the whole sequence is based on data that was itself only the result of a sequence 10 amino acids long. Even your supporting references use extrapolation from limited known data sets.

    Quote Originally Posted by Axe
    Since the four randomization experiments provide an upper-bound estimate of the likelihood of solving the local problem for a ten-residue set, the likelihood of the joint solution may be estimated by applying the above per-position mean (0.38) across the domain. The resulting figure, 10K64 (0.38153Z 10^64), is thus an upper-bound estimate of the prevalence of functional sequences among the whole set of signature-compliant large-domain sequences.
    Let's consider bacterial evolution. Let's consider a single bacteria growing on an agar plate into a colony. It divides every thirty minutes. After 3 days (72 hours) this single bacteria has turned into a colony containing 2.23x10^ 43 individual bacteria. That's 1.11x10^43 replications during which mutations can accumulate. Given mutation rates in E. coli there will be one mutation for every 1200 replications. That means there will have occurred 9.29x10^39 mutations in this one colony of bacteria. My calculator gives me an overload error if I try to calculate this for a week. Now imagine how many colonies I could generate at once, and let multiply for a week. Suddenly your 1 in every 10^64 alterations doesn't seem so unlikely anymore. Perhaps laboratory studies are unrealistic in providing unlimited resources to allow for maximal replication rate, but put this bacteria on earth for billion years and I don't see much of a problem.

    Regardless, even if we stick to the direct result, and suppose that in distant history, enzyme activity does exist for a precursor enzyme that lacks the studied fold domain as you uncovered previously, this is really only a minor issue. Note that in order to obtain this fold, random mutation and natural selection would have had to navigate the described odds involving what appears to be multiple steps (up to 10) several of which are apparently neutral with respect to the studied function (until enough of them accumulate).
    And this is no longer a valid point since I clearly never stated that EVERY step in a step-wise search of sequence space is beneficial at every single step. Neutral meandering through sequence space across the genome happens every time reproduction happens.

    No it has not. While single step mutations and in rare cases two step mutations where the intermediate step is neutral or deleterious have been documented (a) and are consistent with results one would obtain based on random chance, the challenges I offer here have not been demonstrated by observed processes. Studies that show similarities do not tell us anything about how they happen. They are interesting, but I accept that the changes from one to the other occurred, I want to know how.
    Did you even read the references I provided in an earlier post on the generation of new proteins? Two of them weren't even articles but easily readable commentaries on the studies in question. (Though they contained references to the articles, of course.)

    What are you looking for, really? A study where every member of every generation of a species in the wild was sequenced so that every time a new change arose, we knew exactly when it arose and who it arose in? I know that if I provide you studies of evolution in laboratories where that kind of close scrutiny is actually possible you would tell me this doesn't mean it's possible naturally, even though that's exactly what it means when all the researchers are doing are allowing natural processes to take place in an observable environment.

    More examples of what has happened, but they don't shed any light on how.
    I will do my best to get the full text of the paper that describes documented changes in sequence. But I do think it's rather odd of you to assume outright that the evidence it claims to have will not be there at all.

    Correct me if I am wrong, but falsification tests don't require alternative explanations.
    Of course it does. It requires that you come up with a variety of possible explanations that could yield the same pattern and one by one you test them all in an attempt to falsify them. If you falsify them all you come up with more and try to falsify them. When you are left with but one explanation that after multiple and varied attempts to falsify it still stands, chances are good that you're on the right track.

    But I have. Any modestly critical analyst will see they have a problem if their theory can't explain how something happened except with a just-so story and similarity studies that confirm the event but not the process. That alone is sufficient to raise a concern. In addition the research provides examples of protein features that require multiple steps (more than 3) where the intermediate steps are at least neutral. The protein-protein binding sites and the B-lactamase folds are examples. The odds in these cases are out of reach to random chance, and we have no observed cases and no description of how currently observed process are able to navigate those steps in a reasonable timeframe.

    If life's diversity contains many cases similar to the ones described, it becomes implausible that current processes account for this in the time we have available. The challenge for the proponent of evolution by observed processes is to account for these cases as they come forward in terms a series of mostly single functional steps and zero gaps in functional steps greater than three. the research provided has offered a few that appear to be greater than three.
    cypress, it is becoming clear to me that you will not accept anything short of us watching the process in action for every single case that you decide we need to know. And that simply isn't going to happen. You need to accept the assumption of uniformitarianism if you are going to continue to hold a discussion here. You also need to stop referring to typical ID tactics, for example saying that EVERY single evolutionary change needs to be beneficial, for example describing evolution as random chance when the addition of natural selection results in a process that is far from random but does act to keep those beneficial mutations when they arise. You have yet to state whether or not you are a proponent of ID or creationism yet you are using all their approaches.

    At this point I'm giving you one last chance. But given your track record in this and other threads I am not very hopeful.
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    Quote Originally Posted by paralith
    I most certainly do not propose any such thing. Read again my previous post discussing step-wise exploration of sequence space and my reference to the paper discussing it, assuming that mutation does not render the function completely inoperable AND that the function is under strong selective constraint. A mutation this is deletrious and that brings the protein into a selectively disadvantageous step can then be recovered by a compensatory mutation that brings it back into the zone of selectively neutral variation. This isn't even addressing the fact that what was in beneficial in one environment for one function can become entirely neutral or disadvantageous if the environment changes.
    We may be talking over each other and missing the point each is attempting to make. I fully understand the article and I think I understand the point you are trying to make. I fully accept conceptually the description as well. What I think you miss is the number of organisms we would expect to require for events with neutral and deleterious intermediate events. This paper puts some numbers on such a scenario. Except for a couple errors that make some of their estimates off by a couple orders of magnitude, it provides a reasonable idea of what we are talking about. In short for typical mutation rates, two required changes, the first being neutral they get 10^12 organisms required. In humans, that would be 216 million years about 50 times longer than humans are thought to have existed. I find even these numbers to be too slow to account for observed diversity. Contrast this to two beneficial mutations which would take about a billion organisms. Imagine what happens when the requirement is 4 or 5 neutral intermediate steps for one beneficial change.

    In summary I accept the concept, I am simply having difficulty reconciling it to the numbers and to empirical data (see the research references I provided). In the end, models and descriptions must match empirical results or they are not very useful in my opinion.

    Let's consider bacterial evolution. Let's consider a single bacteria growing on an agar plate into a colony. It divides every thirty minutes. After 3 days (72 hours) this single bacteria has turned into a colony containing 2.23x10^ 43 individual bacteria. That's 1.11x10^43 replications during which mutations can accumulate. Given mutation rates in E. coli there will be one mutation for every 1200 replications. That means there will have occurred 9.29x10^39 mutations in this one colony of bacteria. My calculator gives me an overload error if I try to calculate this for a week. Now imagine how many colonies I could generate at once, and let multiply for a week. Suddenly your 1 in every 10^64 alterations doesn't seem so unlikely anymore. Perhaps laboratory studies are unrealistic in providing unlimited resources to allow for maximal replication rate, but put this bacteria on earth for billion years and I don't see much of a problem.
    As you mention, the problem with this analysis is that bacteria life span was not considered and you ignored the difficulty of feeding all the friends you are culturing. With no deaths, your culture would weigh 2.2*10^28 kg. in just three days. The number of bacteria that has ever lived on earth is estimated at 10^40 by the way. With 10^40 organisms in 3.5 or so billion years we indeed have a problem. I do however appreciate that you are reasoning through the numbers finally.

    What are you looking for, really? A study where every member of every generation of a species in the wild was sequenced so that every time a new change arose, we knew exactly when it arose and who it arose in?
    No, this is unrealistic.

    I know that if I provide you studies of evolution in laboratories where that kind of close scrutiny is actually possible you would tell me this doesn't mean it's possible naturally, even though that's exactly what it means when all the researchers are doing are allowing natural processes to take place in an observable environment.
    Actually this would be ideal. Models would also suffice if they match empirical results for the conditions they model. Except for the minor errors, the model provided in the paper I mentioned above is very good.

    I will do my best to get the full text of the paper that describes documented changes in sequence. But I do think it's rather odd of you to assume outright that the evidence it claims to have will not be there at all.
    No, I'm fine with the studies of recent mutations. I don't need the text, I accept it as is. I must not have stated my intent correctly. I was referring to the origination of the ancient B-lactamase later in the paragraph.

    cypress, it is becoming clear to me that you will not accept anything short of us watching the process in action for every single case that you decide we need to know. And that simply isn't going to happen.
    Then you misunderstand. I believe science requires observation and repetition. I understand that historical sciences are a bit trickier, but the basic processes must still in play and therefore we must be able to test them and confirm they are capable of explaining the historical observations. This is all I ask here. If I haven't seemed consistent on this point, I am sorry for that.

    You need to accept the assumption of uniformitarianism if you are going to continue to hold a discussion here.
    I accept it and have made the case that only process in operation today should be considered.

    You also need to stop referring to typical ID tactics, for example saying that EVERY single evolutionary change needs to be beneficial,
    See above, I don't believe this is true. See also the reference I provided that included direct empirical observation of cases that involved neutral and deleterious steps. What I have said is that in many cases where RM/NS is the claimed mode, in order to account for the event in the timeframe allotted, every step would have to be beneficial. Since I don't believe they all are beneficial, in effect I favor the alternative that other process may be in play. I do not know what these processes might be but several have been proposed in recent years. I don't have a favorite.

    I have not mentioned ID or creationism, and I have provided peer reviewed references.

    for example describing evolution as random chance when the addition of natural selection results in a process that is far from random but does act to keep those beneficial mutations when they arise.
    I accept the role natural selection has and have only mentioned pure chance when selection seems out of play.

    At this point I'm giving you one last chance. But given your track record in this and other threads I am not very hopeful.
    I'm not certain what more you expect of me. I have been fair, respectful and I have honored the site rules in this thread. I have provided evidence and references. I have made a mistake or two. I have accidently misstated some things. I have tried to answer questions posed though I admit my prose is far from perfect.
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    Quote Originally Posted by Arcane_Mathematician
    Quote Originally Posted by cypress
    But I have. Any modestly critical analyst will see they have a problem if their theory can't explain how something happened except with a just-so story and similarity studies that confirm the event but not the process. That alone is sufficient to raise a concern. In addition the research provides examples of protein features that require multiple steps (more than 3) where the intermediate steps are at least neutral. The protein-protein binding sites and the B-lactamase folds are examples. The odds in these cases are out of reach to random chance, and we have no observed cases and no description of how currently observed process are able to navigate those steps in a reasonable timeframe.
    I have two questions for you:
    1)How small must odds be in order to be "out of reach" of random chance?
    2)What's a reasonable timeframe?
    The limits would depend on the number of organisms for mutation to act, the mutation rate, the degree to which intermediates are beneficial or deleterious, and therefore relative survival rates, the mode that mutations are transferred to descendants, and the timeframe under which the event is postulated to have occurred.

    More importantly, is a reasonable timeframe to human observation the same as to developing proteins? Do these two things coincide or are they mutually independent(human observation makes no reservations on the process of the organic world)?
    I'm not certain any of that matters. I would think that the timeframe should coincide with the time that the event was likely to have occurred.

    Is it not possible that random chance acted faster in this case than in others? This paragraph was more my musing on your statements than questions I'd like you to answer, just fyi
    I don't understand.
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    Quote Originally Posted by cypress
    Quote Originally Posted by Arcane_Mathematician
    Quote Originally Posted by cypress
    But I have. Any modestly critical analyst will see they have a problem if their theory can't explain how something happened except with a just-so story and similarity studies that confirm the event but not the process. That alone is sufficient to raise a concern. In addition the research provides examples of protein features that require multiple steps (more than 3) where the intermediate steps are at least neutral. The protein-protein binding sites and the B-lactamase folds are examples. The odds in these cases are out of reach to random chance, and we have no observed cases and no description of how currently observed process are able to navigate those steps in a reasonable timeframe.
    I have two questions for you:
    1)How small must odds be in order to be "out of reach" of random chance?
    2)What's a reasonable timeframe?
    The limits would depend on the number of organisms for mutation to act, the mutation rate, the degree to which intermediates are beneficial or deleterious, and therefore relative survival rates, the mode that mutations are transferred to descendants, and the timeframe under which the event is postulated to have occurred.
    mathematically, it's irrelevant. it does not matter what the odds are nor the time frame. Astronomically low, on the order of 1/10^10000 is still possible to occur by random chance on day 1. There is no such thing as odds so low as to be "out of reach" of random chance.

    Quote Originally Posted by cypress
    More importantly, is a reasonable timeframe to human observation the same as to developing proteins? Do these two things coincide or are they mutually independent(human observation makes no reservations on the process of the organic world)?
    I'm not certain any of that matters. I would think that the timeframe should coincide with the time that the event was likely to have occurred.
    Case in point.

    Quote Originally Posted by cypress
    Is it not possible that random chance acted faster in this case than in others? This paragraph was more my musing on your statements than questions I'd like you to answer, just fyi
    I don't understand.
    as expected.
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    Quote Originally Posted by cypress
    We may be talking over each other and missing the point each is attempting to make. I fully understand the article and I think I understand the point you are trying to make. I fully accept conceptually the description as well. What I think you miss is the number of organisms we would expect to require for events with neutral and deleterious intermediate events. This paper puts some numbers on such a scenario. Except for a couple errors that make some of their estimates off by a couple orders of magnitude, it provides a reasonable idea of what we are talking about. In short for typical mutation rates, two required changes, the first being neutral they get 10^12 organisms required. In humans, that would be 216 million years about 50 times longer than humans are thought to have existed. I find even these numbers to be too slow to account for observed diversity. Contrast this to two beneficial mutations which would take about a billion organisms. Imagine what happens when the requirement is 4 or 5 neutral intermediate steps for one beneficial change.

    In summary I accept the concept, I am simply having difficulty reconciling it to the numbers and to empirical data (see the research references I provided). In the end, models and descriptions must match empirical results or they are not very useful in my opinion.
    And I can see now that you are directly quoting Behe. Whatever you may say about not being an IDer or not, you are continually being faithful to their tactics and their main proponents. From the response to Behe's numbers (not the numbers that are actually from the paper you quoted, which is more than a little dishonest):

    Finally, Behe notes that for one prespecified pair of mutations in one gene in humans with the first one neutral, we obtain a “prohibitively long waiting time” of 216 million years. However, there are at least 20,000 genes in the human genome and for each gene tens if not hundreds of pairs of mutations that can occur in each one. Our results show that the waiting time for one pair of mutations is well approximated by an exponential distribution. If there are k nonoverlapping possibilities for double mutations, then by an elementary result in probability, the waiting time for the first occurrence is the minimum of k independent exponentials and hence has an exponential distribution with a mean that is divided by k. From this we see that, in the case in which the first mutant is neutral or mildy deleterious, double mutations can easily have caused a large number of changes in the human genome since our divergence from chimpanzees. Of course, if the first mutant already confers an advantage, then such changes are easier.
    As you mention, the problem with this analysis is that bacteria life span was not considered and you ignored the difficulty of feeding all the friends you are culturing. With no deaths, your culture would weigh 2.2*10^28 kg. in just three days. The number of bacteria that has ever lived on earth is estimated at 10^40 by the way. With 10^40 organisms in 3.5 or so billion years we indeed have a problem. I do however appreciate that you are reasoning through the numbers finally.
    I easily admit I'm not good with the numbers in these cases. Yet in a study you yourself quoted in an earlier post, discussed here, an E. coli population evolving for 20 years was able to naturally accomplish a 3 step change, with the intervening steps being largely neutral.

    I know that if I provide you studies of evolution in laboratories where that kind of close scrutiny is actually possible you would tell me this doesn't mean it's possible naturally, even though that's exactly what it means when all the researchers are doing are allowing natural processes to take place in an observable environment.
    Actually this would be ideal. Models would also suffice if they match empirical results for the conditions they model. Except for the minor errors, the model provided in the paper I mentioned above is very good.
    Among the others I have already given you, as I state above you already provided one yourself that I didn't even have to look for. And this is only an example of stepwise mutation which, as I have tried to explain before but has been completely overlooked by you, is but ONE way by which new proteins and protein functions can arise. And it may even be the least common, by certain estimates.

    See above, I don't believe this is true. See also the reference I provided that included direct empirical observation of cases that involved neutral and deleterious steps. What I have said is that in many cases where RM/NS is the claimed mode, in order to account for the event in the timeframe allotted, every step would have to be beneficial. Since I don't believe they all are beneficial, in effect I favor the alternative that other process may be in play. I do not know what these processes might be but several have been proposed in recent years. I don't have a favorite.

    I have not mentioned ID or creationism, and I have provided peer reviewed references.

    I'm not certain what more you expect of me. I have been fair, respectful and I have honored the site rules in this thread. I have provided evidence and references. I have made a mistake or two. I have accidently misstated some things. I have tried to answer questions posed though I admit my prose is far from perfect.
    Like I said, you have been very careful not to espouse any particular agenda, but your behavior is very consistent with a particular one. It is clear you are reading a lot of Behe, and as my final input into this I'd like to link to this article:
    Probability, Statistics, Evolution and Intelligent Design

    I wash my hands, and the Biology forum, of this.
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    Quote Originally Posted by paralith

    And I can see now that you are directly quoting Behe. Whatever you may say about not being an IDer or not, you are continually being faithful to their tactics and their main proponents. From the response to Behe's numbers (not the numbers that are actually from the paper you quoted, which is more than a little dishonest):
    The abstract says >100 million years. The formula when applied gives about 10^12 organisms. Behe's name is mentioned in the abstract and they did not object to his conversion to years, so I see nothing wrong with using his conversion rather than doing it myself. I would have used one from the paper but I couldn't find a direct result. His reply and their response are both linked on the site. He is a published peer reviewed biochemist teaching and doing research. Clearly they don't see eye to eye but the authors did not object to his number as a calculation of their model results using the formula and estimating population. That is not dishonest since the two adversaries seem to agree on the result, but apparently not the meaning of it.

    Do you find the article I linked incorrect? Do you have a better one?

    Like I said, you have been very careful not to espouse any particular agenda, but your behavior is very consistent with a particular one. It is clear you are reading a lot of Behe,
    I do admit that I did read all of his comments on the research I provided, but so too did you read his notes. Shame on us.
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    What does 10^12 organisms mean? that's how many could be expected to have come into existence in 10^8 years?
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    If it is determined that chemic processes alone are incapable of generating the minimal components required for self-replicating bio systems, then evolution by unguided processes is likely falsified.
    good luck with proving a negative.
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    Quote Originally Posted by cypress
    Imagine what happens when the requirement is 4 or 5 neutral intermediate steps for one beneficial change.
    Apparently, we are to assume the intervening steps are all neutral in all possible circumstances, the steps are not mediated somehow or correlated or increased in frequency by circumstance but are purely random occurrences completely independent of each other, and all of your assumptions about functionality apply to all possible circumstances and contingencies.

    The argument fro those assumptions appears to be that you cannot imagine things otherwise.

    That is, because you cannot imagine a stepwise series of beneficial or neutral or compensated mutations, or any other related means of accomplishing the change (such as two pairs of beneficial mutations, or some other complexity with the correct four in it, being joined in sexual recombination), we are to presume none is likely to exist.

    That's not very persuasive, as arguments go. Your inability to imagine something says very little about its potential for existence. You are overrating your imagination. Nature is much more complex than your imagination is.
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