A Computer Model for the Complex Plasticity of Proteins
Behe MJ, Snoke DW. Simulating evolution by gene duplication of protein features that require multiple amino acid residues. Protein Sci. 2004 Oct;13(10):2651-64.
Abstract in brief:
Excerpts Included for Educational Purposes:
From the Abstract:
“Gene duplication is thought to be a major source of evolutionary innovation because it allows one copy of a gene to mutate and explore genetic space while the other copy continues to fulfill the original function. Models of the process often implicitly assume that a single mutation to the duplicated gene can confer a new selectable property. Yet some protein features, such as disulfide bonds or ligand binding sites, require the participation of two or more amino acid residues, which could require several mutations. Here we model the evolution of such protein features by what we consider to be the conceptually simplest route—point mutation in duplicated genes... We conclude that, in general, to be fixed in 10^8 generations, the production of novel protein features that require the participation of two or more amino acid residues simply by multiple point mutations in duplicated genes would entail population sizes of no less than 10^9.”
Abbreviation: MR, multiresidue.
Excerpts from the Full Text:
From the Introduction:
“Although many scientists assume that Darwinian processes account for the evolution of complex biochemical systems, we are skeptical.”
“Thus, rather than simply assuming the general efficacy of random mutation and selection, we want to examine, to the extent possible, which changes are reasonable to expect from a Darwinian process and which are not.”
“We think the most tractable place to begin is with questions of protein structure. Our approach is to examine pathways that are currently considered to be likely routes of evolutionary development and see what types of changes Darwinian processes may be expected to promote along a particular pathway.”
“In most models of the development of evolutionary novelty by gene duplication, it is implicitly assumed that a single, albeit rare, mutation to the duplicated gene can confer a new selectable property (Ohta 1987; 1988a, b; Walsh 1995). However, we are particularly interested in the question of how novel protein structural features may develop throughout evolution; not all structural features of a protein may be attainable by single mutations. In particular, some protein features require the participation of multiple amino acid residues. Perhaps the simplest example of this is the disulfide bond. In order to produce a novel disulfide bond, a duplicated gene coding for a protein lacking unmatched cysteines would require at least two mutations in separate codons, and perhaps as many as six mutations, depending on the starting codons. We call protein characteristics such as disulfide bonds which require the participation of two or more amino acid residues "multiresidue" (MR) features.”
“A more general example of an MR feature is that of a protein binding site. A ligand bound to a protein interacts with multiple amino acid residues...” [references in article]
“In general, therefore, in order to produce a binding site for a new ligand in a protein originally lacking the ability to bind it, multiple mutational events would be necessary. Li (1997) drew attention to this fact in his textbook Molecular Evolution. Prefacing a discussion of the evolutionary development of the 2,3-diphosphoglycerate binding site of hemoglobin, he wrote, "acquiring a new function may require many mutational steps, and a point that needs emphasis is that the early steps might have been selectively neutral because the new function might not be manifested until a certain number of steps had already occurred"...”
From the Results:
“The basic "task" that the model asks a duplicate gene to perform is to accumulate lambda mutations at the correct nucleotide positions to code for a new selectable feature before suffering a null mutation.”
“Because the model presented here does not include recombination, the results can be considered to be most applicable to a haploid, asexual population. However, as will be discussed, implications can also be made for the evolution of diploid, sexual species.”
“The process we envision for the production of a multiresidue (MR) feature is illustrated in Figure 1, where a duplicate gene coding for a protein is represented as an array of squares that stand for nucleotide positions. A gene coding for a duplicate, redundant protein would contain many nucleotides. The majority of nonneutral point mutations to the gene will yield a null allele (again, by which we mean a gene coding for a nonfunctional protein) because most mutations that alter the amino acid sequence of a protein effectively eliminate function...” [references in original article]
“However, if several point mutations (indicated by a "+" in the figure) accumulate at specific nucleotide positions (indicated by the three squares outlined in blue in the figure) in the gene coding for the protein before a null mutation occurs elsewhere in the gene (indicated by a red "X"), then several amino acid residues will have been altered and the new selectable MR feature will have been successfully built in the protein (indicated by the green-shaded area). By hypothesis, the gene is not selectable for the new feature when an intermediate number of mutations has occurred, but only when all sites are in the correct state.”
"The pertinent feature of the model is that multiple changes are required in the gene before the new, selectable feature appears."
Discussion:
The model and its limits
"Some features of proteins, such as disulfide bonds and ligand binding sites, which here we call MR features, are composed of multiple amino acid residues. As Li (1997) points out, the evolutionary origins of such features must have involved multiple mutations that were initially neutral with respect to the MR feature. We have attempted to model such a process. In doing so, one might examine a number of possible routes to an MR feature, for example, looking at a unique gene that is under selective constraints, or looking at mutations caused by insertions and deletions or recombination in a duplicate gene. Our model is restricted to the development of MR features by point mutation in a duplicated gene."
"We strongly emphasize that results bearing on the efficiency of this one pathway as a conduit for Darwinian evolution say little or nothing about the efficiency of other possible pathways. Thus, for example, the present study that examines the evolution of MR protein features by point mutation in duplicate genes does not indicate whether evolution of such features by other processes (such as recombination or insertion/deletion mutations) would be more or less efficient."
"There are several reasons, both practical and theoretical, for examining this limited model."
"First, as mentioned earlier, gene duplication is considered to be a major route to evolutionary novelty (Ohno 1970; Lynch and Conery 2000; Wagner 2001; Chothia et al. 2003) and therefore it is important to explore its potential in regard to MR features."
"Second, a duplicated gene can be considered to be largely free of the effects of purifying selection (but see following) and therefore selective effects, which are difficult to estimate, can be ignored, simplifying the task at hand."
"Third, point mutations are well-defined events, where transitions occur among a limited set of states."
"In contrast, insertions and deletions vary in size and composition, making them difficult to model for our purposes. Thus, we confine our model of the development of MR features to what we consider to be the conceptually simplest and computationally most tractable route, of point mutations in a duplicated gene that is free of purifying selection."
"Is the assumption of the selective neutrality of duplicated genes either a realistic or a useful one?"
"...the assumption appears not to be correct in at least some situations..."
"... the idealized model presented here — where there is no selective effect from duplicate genes or from intermediate states of the gene until the MR feature is completely in place in a gene and where the only mutagenic process considered is point mutations..."
"Because neutral gene duplication and point mutation is often invoked to account for complex features of proteins, it would be useful to have a quantitative understanding for what such scenarios would entail in order to assess their reasonableness."
"... mechanisms in addition to gene duplication and point mutation may be necessary to explain the development of MR features in multicellular organisms."
"Although large uncertainties remain, it nonetheless seems reasonable to conclude that, although gene duplication and point mutation may be an effective mechanism for exploring closely neighboring genetic space for novel functions, where single mutations produce selectable effects, this conceptually simple pathway for developing new functions is problematic when multiple mutations are required. Thus, as a rule, we should look to more complicated pathways, perhaps involving insertion, deletion, recombination, selection of intermediate states, or other mechanisms, to account for most MR protein features."
/////////////////////////
Then, a critic commented:
/////////////////////////
To the critic, Behe and Snoke responded the next, in:
M. J. Behe and D. W. Snoke. A response to Michael Lynch. Protein Sci., September 1, 2005; 14(9): 2226 - 2227.
At ARN, Salvador, IDEA GMU Posted:
Behe and Snoke's Response
/////////////////////////
Some additional comments to the original article by Behe and Snoke can be seen at:
How intelligent design should be handled, by Krauze.
Dr. Dembski declared,
"Caricatures of our arguments are presented and then followed with refutations by ID critics (refutations that seem decisive because our case was misreporesented in the first instance) [i.e., in the July 9th, 2005 issue of the New Scientist, titled “The End of Reason: Intelligent Design’s Ultimate Legacy.”] No indication is given that ID has developed methods of design detection that are now widely being discussed (see my book The Design Inference). The closest thing here is a reference to the probabilistic hurdle faced in evolving irreducibly complex molecular machines, a hurdle known as the interface compability problem. Holmes and his co-author indicate that this problem has been addressed in two papers by ID proponents, but cites no references (the references are M.J. Behe and D.W. Snoke, “Simulating Evolution by Gene Duplication of Protein Features That Require Multiple Amino Acid Residues,” Protein Science, 13 (2004): 2651-2664 and my article “Irreducibly Complexity Revisited” (PDF article)). "
In the same last context, see also:
http://www.livejournal.com/users/pmw/13270.html
Abstract in brief:
"A Computer Model for the probability of a duplicated gene acquiring a new function lead Behe & Snoke to conclude that it was too rare an occurrence to qualify as a general source of information in the genome. Thus challenging the belief that neo-Darwinism is able to explain the complex adaptive features of proteins."
Excerpts Included for Educational Purposes:
From the Abstract:
“Gene duplication is thought to be a major source of evolutionary innovation because it allows one copy of a gene to mutate and explore genetic space while the other copy continues to fulfill the original function. Models of the process often implicitly assume that a single mutation to the duplicated gene can confer a new selectable property. Yet some protein features, such as disulfide bonds or ligand binding sites, require the participation of two or more amino acid residues, which could require several mutations. Here we model the evolution of such protein features by what we consider to be the conceptually simplest route—point mutation in duplicated genes... We conclude that, in general, to be fixed in 10^8 generations, the production of novel protein features that require the participation of two or more amino acid residues simply by multiple point mutations in duplicated genes would entail population sizes of no less than 10^9.”
Abbreviation: MR, multiresidue.
Excerpts from the Full Text:
From the Introduction:
“Although many scientists assume that Darwinian processes account for the evolution of complex biochemical systems, we are skeptical.”
“Thus, rather than simply assuming the general efficacy of random mutation and selection, we want to examine, to the extent possible, which changes are reasonable to expect from a Darwinian process and which are not.”
“We think the most tractable place to begin is with questions of protein structure. Our approach is to examine pathways that are currently considered to be likely routes of evolutionary development and see what types of changes Darwinian processes may be expected to promote along a particular pathway.”
“In most models of the development of evolutionary novelty by gene duplication, it is implicitly assumed that a single, albeit rare, mutation to the duplicated gene can confer a new selectable property (Ohta 1987; 1988a, b; Walsh 1995). However, we are particularly interested in the question of how novel protein structural features may develop throughout evolution; not all structural features of a protein may be attainable by single mutations. In particular, some protein features require the participation of multiple amino acid residues. Perhaps the simplest example of this is the disulfide bond. In order to produce a novel disulfide bond, a duplicated gene coding for a protein lacking unmatched cysteines would require at least two mutations in separate codons, and perhaps as many as six mutations, depending on the starting codons. We call protein characteristics such as disulfide bonds which require the participation of two or more amino acid residues "multiresidue" (MR) features.”
“A more general example of an MR feature is that of a protein binding site. A ligand bound to a protein interacts with multiple amino acid residues...” [references in article]
“In general, therefore, in order to produce a binding site for a new ligand in a protein originally lacking the ability to bind it, multiple mutational events would be necessary. Li (1997) drew attention to this fact in his textbook Molecular Evolution. Prefacing a discussion of the evolutionary development of the 2,3-diphosphoglycerate binding site of hemoglobin, he wrote, "acquiring a new function may require many mutational steps, and a point that needs emphasis is that the early steps might have been selectively neutral because the new function might not be manifested until a certain number of steps had already occurred"...”
From the Results:
“The basic "task" that the model asks a duplicate gene to perform is to accumulate lambda mutations at the correct nucleotide positions to code for a new selectable feature before suffering a null mutation.”
“Because the model presented here does not include recombination, the results can be considered to be most applicable to a haploid, asexual population. However, as will be discussed, implications can also be made for the evolution of diploid, sexual species.”
“The process we envision for the production of a multiresidue (MR) feature is illustrated in Figure 1, where a duplicate gene coding for a protein is represented as an array of squares that stand for nucleotide positions. A gene coding for a duplicate, redundant protein would contain many nucleotides. The majority of nonneutral point mutations to the gene will yield a null allele (again, by which we mean a gene coding for a nonfunctional protein) because most mutations that alter the amino acid sequence of a protein effectively eliminate function...” [references in original article]
“However, if several point mutations (indicated by a "+" in the figure) accumulate at specific nucleotide positions (indicated by the three squares outlined in blue in the figure) in the gene coding for the protein before a null mutation occurs elsewhere in the gene (indicated by a red "X"), then several amino acid residues will have been altered and the new selectable MR feature will have been successfully built in the protein (indicated by the green-shaded area). By hypothesis, the gene is not selectable for the new feature when an intermediate number of mutations has occurred, but only when all sites are in the correct state.”
"The pertinent feature of the model is that multiple changes are required in the gene before the new, selectable feature appears."
Discussion:
The model and its limits
"Some features of proteins, such as disulfide bonds and ligand binding sites, which here we call MR features, are composed of multiple amino acid residues. As Li (1997) points out, the evolutionary origins of such features must have involved multiple mutations that were initially neutral with respect to the MR feature. We have attempted to model such a process. In doing so, one might examine a number of possible routes to an MR feature, for example, looking at a unique gene that is under selective constraints, or looking at mutations caused by insertions and deletions or recombination in a duplicate gene. Our model is restricted to the development of MR features by point mutation in a duplicated gene."
"We strongly emphasize that results bearing on the efficiency of this one pathway as a conduit for Darwinian evolution say little or nothing about the efficiency of other possible pathways. Thus, for example, the present study that examines the evolution of MR protein features by point mutation in duplicate genes does not indicate whether evolution of such features by other processes (such as recombination or insertion/deletion mutations) would be more or less efficient."
"There are several reasons, both practical and theoretical, for examining this limited model."
"First, as mentioned earlier, gene duplication is considered to be a major route to evolutionary novelty (Ohno 1970; Lynch and Conery 2000; Wagner 2001; Chothia et al. 2003) and therefore it is important to explore its potential in regard to MR features."
"Second, a duplicated gene can be considered to be largely free of the effects of purifying selection (but see following) and therefore selective effects, which are difficult to estimate, can be ignored, simplifying the task at hand."
"Third, point mutations are well-defined events, where transitions occur among a limited set of states."
"In contrast, insertions and deletions vary in size and composition, making them difficult to model for our purposes. Thus, we confine our model of the development of MR features to what we consider to be the conceptually simplest and computationally most tractable route, of point mutations in a duplicated gene that is free of purifying selection."
"Is the assumption of the selective neutrality of duplicated genes either a realistic or a useful one?"
"...the assumption appears not to be correct in at least some situations..."
"... the idealized model presented here — where there is no selective effect from duplicate genes or from intermediate states of the gene until the MR feature is completely in place in a gene and where the only mutagenic process considered is point mutations..."
"Because neutral gene duplication and point mutation is often invoked to account for complex features of proteins, it would be useful to have a quantitative understanding for what such scenarios would entail in order to assess their reasonableness."
"... mechanisms in addition to gene duplication and point mutation may be necessary to explain the development of MR features in multicellular organisms."
"Although large uncertainties remain, it nonetheless seems reasonable to conclude that, although gene duplication and point mutation may be an effective mechanism for exploring closely neighboring genetic space for novel functions, where single mutations produce selectable effects, this conceptually simple pathway for developing new functions is problematic when multiple mutations are required. Thus, as a rule, we should look to more complicated pathways, perhaps involving insertion, deletion, recombination, selection of intermediate states, or other mechanisms, to account for most MR protein features."
/////////////////////////
Then, a critic commented:
"A recent paper in this journal has challenged the idea that complex adaptive features of proteins can be explained by known molecular, genetic, and evolutionary mechanisms... [click link to see his full abstraction]"
/////////////////////////
To the critic, Behe and Snoke responded the next, in:
M. J. Behe and D. W. Snoke. A response to Michael Lynch. Protein Sci., September 1, 2005; 14(9): 2226 - 2227.
At ARN, Salvador, IDEA GMU Posted:
Behe and Snoke's Response
1. Experimental studies contradict Lynch’s assumption of complete neutrality as a rule; the majority of amino acid substitutions decrease protein function.
2. Lynch’s and our models are not mutually exclusive. Some evolutionary pathways might involve both deleterious and neutral mutations.
3. Lynch writes in the section “The Model” that we “imply that all amino acid changes lead to nonfunctionalization.” We imply no such thing. Although we assumed that intermediate mutations required for a new feature decreased function, we wrote, “it can be calculated that on average a given position will tolerate about six amino acid residues and still maintain function.” Our estimation of {rho} explicitly takes into account the tolerance of sites for substitution.
4. In “The Model,” Lynch writes, “As in Behe and Snoke (2004), this adaptation is assumed to be acquired at the expense of an essential function of the ancestral protein… .” We made no such assumption. In our model, the final mutation might restore and enhance the original function.
5. In the Discussion, Lynch writes, “It is difficult to pinpoint the source of the difference between the results of Behe and Snoke and those contained herein… .” The differences are largely due to opposing starting presumptions about whether mutations are deleterious.
6. In the Discussion, Lynch writes, “Behe and Snoke assume that the forward and backward point-mutation rates (per amino acid residue) are equal.” We do not. The mutation rate we use is the nucleotide point-mutation rate.
7. In the Discussion, Lynch writes that we assume mutations have “lethal pleiotropic effects.” We did not assume mutations to be either lethal or pleiotropic. We only assumed that they are “strongly selected against.”
8. In the Discussion, Lynch writes, “If the intermediate steps … are entirely neutral after gene duplication, as Behe and Snoke assume, then there is no compelling reason that ‘one-off’ (type-2) alleles should be absent from the population prior to duplication.” The reason for no “one-off” alleles before duplication in our model is that intermediate mutations are assumed to be deleterious in a singlecopy gene.
9. In the Discussion, Lynch writes, “Behe and Snoke failed to realize that a completely linked pair of duplicate genes has a mutational advantage equal to the mutation rate to null alleles...” Such an effect does not hold for a model like ours in which intermediate mutations are postulated to be deleterious.
10. A recent report [Gao LZ, Innan H. Very low gene duplication rate in the yeast genome. Science. 2004 Nov 19;306(5700):1367-70] presents evidence that the gene duplication rate is lower by several orders of magnitude than that assumed both by Lynch and by us based on the work of Lynch and Conery (2000). If so, then both his and our calculations for the population sizes needed to fix a mutation in a duplicated gene are substantial underestimates.
/////////////////////////
Some additional comments to the original article by Behe and Snoke can be seen at:
How intelligent design should be handled, by Krauze.
"Last year, the journal Protein Science published an article by Behe and Snokes, modelling the probability of a duplicated gene acquiring a new function, and arguing that it was too rare an occurrence to qualify as a general source of information in the genome. This month’s issue of the journal contains a response by Michael Lynch, Behe & Snoke’s reply, and an editorial explaining the whole thing without mentioning the Wedge or worrying about the Coming Theocracy. Wrap up and serve steaming hot for an audience of capable researchers and interested laymen.
Pay attention, critics of intelligent design: This is exactly how intelligent design should be handled. Not by harassing the editor. Not by starting petitions against the authors or trying to have their degrees revoked. Not by passing decrees against intelligent design. And no, not by breaking out the steel-toed boots and brass knuckles, and hammering on the lunatics and idiots, either. Just calmly discuss their claims, focusing on the evidence instead of personalities and politics, and allow them to respond to your points. If intelligent design really is as bankrupt as critics say, nothing will bring it down in cinders faster."
Dr. Dembski declared,
"Caricatures of our arguments are presented and then followed with refutations by ID critics (refutations that seem decisive because our case was misreporesented in the first instance) [i.e., in the July 9th, 2005 issue of the New Scientist, titled “The End of Reason: Intelligent Design’s Ultimate Legacy.”] No indication is given that ID has developed methods of design detection that are now widely being discussed (see my book The Design Inference). The closest thing here is a reference to the probabilistic hurdle faced in evolving irreducibly complex molecular machines, a hurdle known as the interface compability problem. Holmes and his co-author indicate that this problem has been addressed in two papers by ID proponents, but cites no references (the references are M.J. Behe and D.W. Snoke, “Simulating Evolution by Gene Duplication of Protein Features That Require Multiple Amino Acid Residues,” Protein Science, 13 (2004): 2651-2664 and my article “Irreducibly Complexity Revisited” (PDF article)). "
In the same last context, see also:
http://www.livejournal.com/users/pmw/13270.html
posted by fdocc | 2:25 PM
0 Comments:
Post a Comment
<< Home