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Author
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Topic: The IHE
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warren_bergerson
Member
Member # 262
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posted 05. January 2003 08:28
Mike,
I would like to clarify and expand a bit on yesterday’s comments. As I stated yesterday, front loading or non-random design or directed design is an important subject. The importance of the subject, however, is not the existence of front loading, but the implications front loading has for scientific analysis and scientific theory construction.
Biological design involves or can be defined or viewed as involving large sets of ‘dynamic and teleological’ causal relationships. Using this approach, there are three dimensions to design- 1)number of components, 2)teleological complexity or improbability, and 3)level of dynamics or rate of change.
Front loading or directed design exists where a biological systems needs to find a complex adaptive solution very fast. If we use RM&NS as the measurement base, then front loading or directed design occurs when the rate of change or level of dynamics required for survival exceeds the expected rate of change that can be produced by a process of random variation and whole organism selection. As I mentioned yesterday, the real issue here is not the existence of front loading(which is fairly obvious) but the appropriate scientific explanation for the phenomena.
The generally accepted convention in scientific theory construction is that 1)the universe is controlled by permanent and universal laws or causal relationships and 2)appropriate or acceptable predictive theories are testable, well defined models of permanent and universal causal relationships. [Stochastic relationships are a form of permanent and universal causal relationships.]
In order to conform to existing conventions, scientific theories in genetics and biology describe biological design processes as physical objects(genetic code) or phenotypes, rather than dynamic and teleological causal relationships and they attempt to define processes producing the changes in terms of permanent and universal processes called random variation and natural or whole organism selection.
Front loading and ‘error correction’ are two of the phenomena which clearly demonstrate that the neo-Darwinian explanations don’t work. Or as Singer and Hickey conclude: "Consequently, their evolutionary dynamics cannot be described in terms of either Darwinian selection or random genetic drift".
The problem, I suggest, is with the incorrect assumption that scientific determinism implies the universe is controlled by permanent and universal laws and that the scientific paradigm can only be used to generate and test theories modeling permanent and universal laws of nature. Biological systems, I propose, are best viewed and analyzed as large sets of ‘dynamic and teleological’ laws or causal relationships which are formed by complex processes made up or controlled in large part by laws or causal relationships which are dynamic and teleological causal relationships.
Contrary to widely accepted conventions, the scientific paradigm is fully as applicable to constructing, testing and applying predictive theories formulated to model dynamic and teleological laws of nature as it is to constructing, testing and applying predictive theories formulated to model permanent and universal laws of nature.
As I stated in my earlier post, demonstrating the existence of front loading is important. But far more important is the issue of how science interprets front loading. As someone pointed out, to suggest that the earliest bacteria were front loaded or preprogrammed to produce a man who would paint the Mona Lisa and another who would write Hamlet is a bit difficult to accept. It is, IMO, much easier to accept that a portion of the laws governing the universe are dynamic and teleological, and that the processes which transforms these dynamic and teleological laws are themselves controlled by laws which are dynamic and teleological.
The view that biological systems are controlled by dynamic and teleological laws is even easier to accept, once it is recognized that the scientific paradigm is fully as effective at analyzing and predicting the results produced by dynamic and teleological laws as it is at analyzing and predicting the results produced by permanent and universal laws.
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Frances
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posted 05. January 2003 19:02
Mike
You seem to dismiss my contributions to how cytosine may have arisen on prebiotic earth suggesting that this was not the question you raised but may I point out that your claims included:
quote:
According to Robert Shapiro, cytosine has not been reported in analyses of meteorites nor is it among the products of electric spark discharge experiments. And because of its predisposition to deaminate, under mild conditions, it was a half life of only about 340 years. Put simply, there is not a convincing case that cytosine would have been among the major players of the prebiotic soup. Furthermore, cytidine is not needed for ribozyme function. Recently, Joyce was able to synthesize a functional ribozyme containing only A,G, and U.
Certainly my references place some doubt on your claims.
I am glad that you mention Joyce because recently they showed how a functional ribozyme could be synthesized using two nucleotides. Surely these examples show that natural selection may have played a role in a hypothetical evolution of a two-base code to a four-base code.
Let's work through a hypothetical example:
Let's assume that the original life evolved in underwater heat vents, cytosine would have a hard time being included but over time land cooled down and cytosine was formed:
quote:
These results demonstrate the validity of prebiotic syntheses under dry beach conditions and concentration by evaporation. Prebiotic syntheses on drying beaches may have served as a source of cytosine and other pyrimidines for the RNA and pre-RNA world.
But wait a minute, drying beaches may also have been the location where microspheres (Fox) could have been generated. Would the microsphere be able to protect cytosine? It's interesting that cytosine encodes for many hydrophobic amino acids found in many membrane proteins. Perhaps cytosine was added to 'solidify' the basis of the membranes of the Fox protocell?
Just a hypothetical example of course.
You also object to me placing the front loading at the time of the big bang. Do you have any data to support the timing of your front loading event? From a scientific and theological perspective the Planck time would make for an excellent place for front loading. Perhaps the laws of this universe were front loaded to guarantee or make very likely the evolution of some form of life, somewhere?
May I also point out that your statement quote:
Since my approach adds nothing novel to scientific inquiry (according to you), you should have no problem anticipating where I will go. So where am I going?
Is a strawman of your own invention. I wondered why the need for what I see to be an extraneous addition of 'intelligence' to the 'front loading'? I did state If not, I would like to understand what the assumption of front loading via ID adds to our understanding as opposed to lets say front loading through natural processes.. You have yet to answer this question which you seem to avoid through your above strawman rethorical question. I am not saying that 'front loading' and ID cannot contribute to novel thought but I would argue that it would not add to scientific inquiry in any significant manner. In fact, ID can be dropped and our knowledge would remain the same.
I have no problem if you want to use the idea of teleology to help you formulate hypotheses that can explain how life evolved, what I want to point out though is that the addition of teleology or ID would be only to help with research directions and has little to do with the actual detection of ID or teleology. In fact history has shown how teleological thinking was helpful in the generation of many a theory.
I would also like to point out that your point (2) How does the non-teleologist explain the relationship I discovered between the most common form of DNA mutation and its functional consequence as mediated by the genetic code? Is this yet another example of something that "just happened?" may need some editing. First the link between mutation and functional consequence may not be novel, secondly it is in most cases trivially easy to look back at certain events and find 'teleological explanations' where there really were none. Thus my question how to differentiate between these apparant and actual forms of teleology?
To give a non-teleogical explanation for cytosine and hydrophobicity, see above. What if cytosine was added to facilitate the formation of hydrophobic proteins found so often in membranes? That is, the inclusion of cytosine could be understand in this context in terms of natural selection.
Warren, your definition of 'front loading' seems to be at odds with Mike and other's when you state
quote:
Front loading or directed design exists where a biological systems needs to find a complex adaptive solution very fast. If we use RM&NS as the measurement base, then front loading or directed design occurs when the rate of change or level of dynamics required for survival exceeds the expected rate of change that can be produced by a process of random variation and whole organism selection.
And yet RM&NS is the mechanism of change proposed so how do we reconcile this with your statement? Additionally your claim that
quote:
Front loading and ‘error correction’ are two of the phenomena which clearly demonstrate that the neo-Darwinian explanations don’t work. Or as Singer and Hickey conclude: "Consequently, their evolutionary dynamics cannot be described in terms of either Darwinian selection or random genetic drift".
shows once again a generalization that is not warranted by the available data. What Hickey et al may show at most is that more mechanisms are at play than just RM&NS. Nothing new there though.
quote:
Peptide nucleic acids rather than RNA may have been the first genetic molecule
Kevin E. Nelson, Matthew Levy*, and Stanley L. Miller
Numerous problems exist with the current thinking of RNA as the first genetic material. No plausible prebiotic processes have yet been demonstrated to produce the nucleosides or nucleotides or for efficient two-way nonenzymatic replication. Peptide nucleic acid (PNA) is a promising precursor to RNA, consisting of N-(2-aminoethyl)glycine (AEG) and the adenine, uracil, guanine, and cytosine-N-acetic acids. However, PNA has not yet been demonstrated to be prebiotic. We show here that AEG is produced directly in electric discharge reactions from CH4, N2, NH3, and H2O. Electric discharges also produce ethylenediamine, as do NH4CN polymerizations. AEG is produced from the robust Strecker synthesis with ethylenediamine. The NH4CN polymerization in the presence of glycine leads to the adenine and guanine-N9-acetic acids, and the cytosine and uracil-N1-acetic acids are produced in high yield from the reaction of cyanoacetaldehyde with hydantoic acid, rather than urea. Preliminary experiments suggest that AEG may polymerize rapidly at 100°C to give the polypeptide backbone of PNA. The ease of synthesis of the components of PNA and possibility of polymerization of AEG reinforce the possibility that PNA may have been the first genetic material.
In my search I ran across this interesting tidbit
Fibonacci Numbers and Genetic Code and Yijing and DNA. Interesting how people can find purpose and patterns in such unexpected ways. This surely seems to have some implications for the design inference and false positives I would imagine.
[ 05. January 2003, 21:57: Message edited by: Frances ]
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warren_bergerson
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Member # 262
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posted 06. January 2003 07:16
It is interesting to note that Frances is taking on the task of reinterpreting Mike’s comments. If Mike thinks that non-random design or directed design is a different phenomena from front loading then he can make the point.
quote WB: Front loading and ‘error correction’ are two of the phenomena which clearly demonstrate that the neo-Darwinian explanations don’t work. Or as Singer and Hickey conclude: "Consequently, their evolutionary dynamics cannot be described in terms of either Darwinian selection or random genetic drift".
Quote Frances: shows once again a generalization that is not warranted by the available data. What Hickey et al may show at most is that more mechanisms are at play than just RM&NS. Nothing new there though.
As usual, your comments completely ignore the argument presented.
1. Scientific theories or at least predictive theories are logical/mathematical models of causal relationships or ‘laws of nature’.
2. Using existing conventions, it is only possible to construct predictive scientific theories of permanent and universal causal relationships or laws of nature.
3. Therefore all existing predictive scientific theories of evolution or design processes are expressions of permanent and universal causal relationships or laws of nature.
4. Front loading and error correction show that evolution and other biological design process can not be expressed as permanent and universal causal relationships or laws of nature.
5. MINOR CONCLUSION: Using current techniques and conventions it is not logically possible to construct a valid predictive scientific theory of evolution or other biological design processes.
6. MAJOR CONCLUSION: In order to construct predictive scientific theories of evolution and biological design processes, science needs techniques and conventions which make it possible to apply the scientific paradigm to the analysis and modeling of dynamic and teleological laws of nature.
Real scientists are very careful to avoid unsupported and insupportable claims that there exist valid predictive scientific theories of evolution. People like Frances seem to have no qualms about intentionally ignoring the limitations of existing sciences and making unsupported claims. I personally have a very difficult time understanding why the scientific academic community seems to both tolerate and accept individuals making insupportable claims for scientific theories.
In keeping with the request for positive proposals, the observation that front loading is incompatible with ‘permanent and universal’ theories such as RM&NS was only incidental. The substance of my comments, which Frances conveniently ignored, was the suggestion that ‘it may be possible to develop predictive scientific models and theories of front loading if the scientific paradigm can be applied to dynamic and teleological causal relationships or laws of nature".
My suggestion that phenomena such as front loading, evolution. and biological design processes can only be explained by ‘complex causation’ is not new. However, the suggestion that complex causation means something other than permanent and universal causation seems to run into some resistance.
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Moderator
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Member # 1
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posted 06. January 2003 07:19
Warren and Frances,
Please refrain from posting in this thread for at lest three days. I'm surely not going to allow you to hijack this promising topic. Thank you.
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Mike Gene
Member
Member # 149
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posted 06. January 2003 12:15
Frances,
I'm still having a hard time seeing the relevance of your references, as I don't see how they show that cytosine would be a major player among the prebiotic beilstein. And the hypothetical example seems quite weak and ad hoc, at least to me. Since Fox's microspheres do not have lipid membranes, I'm having some difficulty seeing the selective pressure you have in mind. And it is simply not true that "cytosine encodes for many hydrophobic amino acids." What codes for the 11 most hydrophobic amino acids are 31 codons. One can code for Phe, Leu, Ile, Met, Val, Tyr, Cys, and Trp using codons that don't have C at any of the three positions. Remember that what I found was not that cytosine encodes hydrophobic amino acids, but that cytosine deamination channels the codon pool into one that draws exclusively from the most hydrophobic amino acids.
As for question 2), your answers have been a) we don't know; b) the relationship between the mutational effects and function may not be novel (I'm not sure what you mean): and c) I may be reading purpose into the pattern. None of these answers seem sufficient cause for me to give up the design inference. From where I sit, these replies come across as "Just because we don't know how to explain this doesn't mean you have proved your case." But I'm just gathering clues and building on them. You are again raising only caveats.
Furthermore, you are incorrect in asserting that I "object" to you putting the front-loaded state at the Big Bang. Simply read my replies and you'll notice that I said I am open to this and encouraged you to "go for it." I did, after all, really like Mike Denton's most recent book. And I agree that situating front-loading with the Big Bang is attractive from a theological point of view. All I am saying to you as that you should flesh out your views. I offered up these two questions as a good place to start. You seem to be raising your points as a reaction to me, working under the impression that if you raise alternative naturalistic explanations, I am obligated to abandon my tentative design thinking. But just as I have no epistemic right to demand that you employ my alternative, you too have no such standing to demand such things from me. All you have as an explanation void of the "extraneous additions", which is really just setting up the game rules to exclude ID unless I can prove its requirement. So we see things differently.
Look, as I said before, I didn't want to get side-tracked discussing generic topics. Somehow, we've quickly gone from the observation that AT-rich genomes encode proteins enriched with FYMINK to things like theology and the Planck time. What I would suggest is this: There is plenty of elbow room at the design table for various teleological views. Why not start a new thread raising the positive reasons why it is that life as we know it was front-loaded into the initial Big Bang conditions? In this thread, you are using this possibility in a negative way as a spoiler to the views I am raising that ends up distracting from the points I am trying to make. Anyway, I'll start up a new thread in the next couple of days that builds on the OP in this one.
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Frances
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posted 06. January 2003 12:38
Mike
I do not want to sidetrack the discussion any further. It seems that I misunderstood your front loading ideas. I understood them to be attempts to provide evidence of intelligent design but you seem to be using it to generate ideas to understand how natural forces played out. I provided a similarly ad hoc thesis of how cytosine could have been a late player in the genetic code. Details need to be worked out but there are some very interesting directions in which research could contribute to explaining the late entry of cytosine into the genetic code. In fact, Joyce's work has shown how natural selection can move from two bases, to three bases to four bases. So was cytosine added since deamination of it led to codons coding for hydrophobic aminoacids or was cytosine added due to selective advantages or are the two scenarios in some way equivalent? Fox's microspheres did not have lipod membranes, exactly why the addition of cytosine to the bases may have been helpful in coding for hydrophobic and hydrophilic aminoacids (polar/non-polar). The teleological view as well as the non-teleological view can help us understand how natural forces played out in the path of evolution. I agree with you that teleological thinking may be one way of generating interesting ideas as long as we realize that such thinking does not really provide for much evidence of intelligent design itself. In fact as I have stated, teleological approaches in the past have led to interesting theories. ID or teleological approaches are used merely to understand how nature works. I personally like the use of engineering terms such as feedback and other control theory terms to better understand how nature works. I am not asking you to give up your design 'thinking', it seems to have led to similar conclusions that others have made.
I was initially under the impression that you were arguing for Intelligent Design as the explanation. Once you are ready to argue that case many of my objections will become relevant. I am merely pointing out that it is relatively trivial to see purpose when looking backwards in time.
To address the moderator's valid concerns I will not be addressing Warren's comments in this thread and would propose to Warren to move his comments to a new thread about front loading.
[ 06. January 2003, 13:16: Message edited by: Frances ]
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Mike Gene
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posted 06. January 2003 13:15
Frances,
I'm not sure it's simply a matter of working out a few "details" of your ad hoc thesis. But rather than prolonging this sidequest, why don't you just start up a new thread raising your thesis in a positive manner? In fact, most of your first paragraph could remain "as is." You could start it out like this: " Let me provide an admittedly ad hoc thesis of how cytosine could have been a late player in the genetic code. Details need to be worked........"
Yes, your impression was faulty. Remember that I already pointed out the context, where I am reacting to the published claim that no engineer would have used cytosine. I am slowly explaining why an engineer might very well have used cytosine, and in the process, uncovering connections not seen before. Is this "evidence" for Intelligent Design? As I have argued over the last few years, the whole question of "evidence" quickly becomes very complicated when it comes to these ambiguous topics (for example, you seem to be under the impression that evidence for ID must be something other than a naturalistic process). Thus, rather than claim evidence, I'll simply leave it to the readers to decide for themselves whether my ID hypothesis or your "naturalistic" hypothesis makes more sense of things. Whether your arguments become relevant or my claims are "trivial" is something readers can also decide for themselves.
So I would again encourage you to start another positive thread that explores the evidence of front-loading at the Big Bang, evidence of your cytosine-hypothesis, and/or an attempt to answer Janitor's question.
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Art
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Member # 179
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posted 08. January 2003 21:33
A few questions or points to ponder:
1. If C deamination isn't the prevalent mode of mutation as has been claimed (and a couple of previous posts I have made indicate that it isn't), then what is the significance of the rest of the IHE?
2. Roughly speaking, half of all codons encode hydrophobic amino acids, and half do not. When we take into account both C->T and G->A mutations (which, as far as I can tell, Mike did not), then I don't think that the relative disposition towards hydrophobicity is very compelling or surprising. After all, an amino acid-changing mutation in a "non-hydrophobic codon" has about a 50-50 chance to yield a hydrophobic "product" anyway. The deviation from 50-50 seen with the collection of C->T/G->A changes is not so far off the scale as to be significant. IMO, at least.
3. Again, IMO, I think it's a stretch to make sweeping generalzations regarding hydrophibicity as it relates to protein structure, stability, and relationships with other proteins. Indeed, I think that, in this post-genomics age, one might be able to make a more focused list of possible changes that have more likely evolutionary impacts - say, the part of sequence space that can readily move towards, or actually adopt, one of several motifs known to be involved in protein-protein interactions. (The accessibility that delta-aminolevulinic acid dehydratase has to the DnaJ domain is sort of the thing I have in mind here.)
4. Finally, to stir a pot that no one here seems to drink from, I would suggest (in what must be for now a very vague way) that possible teleological mechanisms in mutation, as they may affect evolution, are likely going to be grounded firmly in the RNA World.
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Frances
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posted 09. January 2003 00:54
May I also propose the hypothesis proposed by Poole in the paper referenced by Mike?
quote:
Conclusions
The tendency for C to undergo deamination, and the way in which deaminations are repaired, provides a clear example of evolution as tinkering. Viewing evolution in this way sheds light on the likely nature of the selection pressure that drove the UT transition. Examination of both UNG and MUG allows us to hypothesize that U excision-repair arose before thymidylate synthase, and that occasional removal of U opposite A by the proto-UNG/MUG (or 'leaky' MUG) drove the UT replacement. Overall, we suggest the following steps for the UT transition: base-excision repairleaky MUGthymidylate synthasedUTPase.
Replacing U with T provided a means by which to fine-tune repair of CU deaminations, but the problem of C deamination was never eliminated — it re-emerged in the form of 5-meC deamination. Tinkering also makes sense of the evolution of the 5-meC apparatus, which subsequently drove the recruitment of the U-excision apparatus into T excision because of the 'unforeseen' side effect of 5-meCT deamination. All this could have been avoided simply by eliminating C early in the evolution of the genetic material — but how boring life would be if evolution worked by engineering.
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Mike Gene
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posted 10. January 2003 00:43
Hi Art,
Thanks much for the on-topic comments. Let's take a look.
1. If C deamination isn't the prevalent mode of mutation as has been claimed (and a couple of previous posts I have made indicate that it isn't), then what is the significance of the rest of the IHE?
Actually, I think the two cites you provided are quite interesting. Details later.
Yet there is plenty of evidence that indicate C-T transitions are the most common base substitution. In my original essay, I already noted:
quote:
This bias for C-T transitions has also been documented in several studies. For example, 31 spontaneous mutations from the APRT locus from Chinese hamster ovary cells were analyzed [6]. Of these, 27 were single base substitutions, where 22/27 were C-T transitions. A similar bias was also seen in an extensive survey of a bacterial gene, where 86% of the base substitutions among 85 spontaneous mutations in lacI were C-T transitions. [7]
In another paper, we read:
quote:
Deborah A. Kreutzer and John M. Essigmann
Oxidized, deaminated cytosines are a source of C->T transitions in vivo
Vol. 95, Issue 7, 3578-3582, March 31, 1998
The most frequently occurring base substitution mutation observed in aerobic organisms is a GC->AT transition. This substitution is also the most abundant genetic change induced as a consequence of oxidative DNA damage.
I can easily expand such cites, but what caught my interest was the genomic data. Recall Table I from my original essay, which shows the results of a comparison of 16 different pseudogenes. CG->TA transitions clearly were the most common. This theme is seen elsewhere. For example, all the substitution in a micronuclear pseudogene from
the ciliate Euplotes crassus were C-T transitions (Florian V, Klein A. A nascent micronuclear pseudogene in the ciliate Euplotes crassus.Nucleic Acids Res 1996 Aug 15;24(16):3195-200). And then there is this:
quote:
Yokoyama S, Meany A, Wilkens H, Yokoyama R.
Initial mutational steps toward loss of opsin gene function in cavefish.
Mol Biol Evol 1995 Jul;12(4):527-32
The river-dwelling fishes of Astyanax fasciatus and their derivatives from Pachon and Micos caves in Mexico were collected. By comparing red (r007) and green (g103) opsin gene sequences from the three populations, we found a high frequency of C-->T changes in r007 and g103 of the eyed Micos fishes presumably due to spontaneous cytosine methylation or enzymatic deamination of the CG dinucleotide, and a deletion of 12 consecutive nucleotides in g101 of the blind Pachon fishes. Thus, high rates of nucleotide substitution and C-->T transitions, usually found for pseudogenes, may occur even before they become nonfunctional.
An extensive SNP analysis showed the same theme:
quote:
Zhao Z, Boerwinkle E.
Neighboring-nucleotide effects on single nucleotide polymorphisms: a study of 2.6 million polymorphisms across the human genome.
Genome Res 2002 Nov;12(11):1679-86
We investigated substitution patterns and neighboring-nucleotide effects for 2,576,903 single nucleotide polymorphisms (SNPs) publicly available through the National Center for Biotechnology Information (NCBI). The proportions of substitutions were A/G, 32.77%; C/T, 32.81%; A/C, 8.98%; G/T, 9.06%; A/T, 7.46%; and C/G, 8.92%.
Nevertheless, it looks as if I once again need to remind people that my stuff is not only tentative, but represents the very first steps of an investigation. I'm certainly not arguing that all of evolution (or even design through evolution) is carried out through cytosine deamination. The IHE, along with the initial states, are merely some of the design components at play. And the effects of cytosine deamination can be explored through many different potential design considerations, such as its temp-dependence, the role of methylation/CpG dinucleotides, RNA editing, the influence of UV light, the influence of NO, regulation of ung, etc. There is great opportunity for all kinds of research here.
2. Roughly speaking, half of all codons encode hydrophobic amino acids, and half do not. When we take into account both C->T and G->A mutations (which, as far as I can tell, Mike did not), then I don't think that the relative disposition towards hydrophobicity is very compelling or surprising. After all, an amino acid-changing mutation in a "non-hydrophobic codon" has about a 50-50 chance to yield a hydrophobic "product" anyway. The deviation from 50-50 seen with the collection of C->T/G->A changes is not so far off the scale as to be significant. IMO, at least.
The G->A mutations appear to reflect the error-proof aspect of the code, as the vast majority of missense mutations involve amino acids that are strongly conserved. The only exception is swapping glycine for positively charged residues. The avg. hydrophobicity value only goes from 0.42 to 0.35. About 50% of the G->A mutations increase hydrophobicity with a weighted avg. difference (in hydrophobicity values) of 0.18. In contrast, 86% of C->T mutations increase hydrophobicity (the Pro-Ser changes are the only exceptions) with a weighted avg. difference of 0.45. If we combine both, 68% of the mutations increased hydrophobicity with a weighted avg. difference of 0.31. It still looks like a bias.
But, don't forget, most interesting was this (from my essay):
quote:
The rate of cytosine deamination in double-stranded DNA is less than 1% of that found in single-stranded DNA [3]. Given that DNA can exist in a transient single-stranded state during transcription, this suggests that the IHE may also be targeted to genes that are actively transcribed. In fact, experimental evidence has shown there is a distinct bias for C-T transitions in the coding strand as a consequence of transcription. [11] Thus, a specified set of amino acids is being thrown at every transcribed gene. It's as if life's proteins are being forced to evolve.
Also:
quote:
M. Pilar Francino and Howard Ochman
Deamination as the Basis of Strand-Asymmetric Evolution in Transcribed Escherichia coli Sequences
Molecular Biology and Evolution 18:1147-1150 (2001)
Analyses of sequence evolution in Escherichia coli and Salmonella enterica have revealed that the pattern of nucleotide substitutions in enterobacterial genes is asymmetric. The incidence of C-T transitions is strongly biased toward the nontranscribed strand of DNA, which accumulates such changes at a two- to threefold higher rate than the complementary transcribed strand.
That is, the IHE effect is seen in the coding strand and it is noteworthy that this is the strand most predisposed to cytosine deamination. The genetic code seems to be plugged into the protein-mediated event known as transcription.
And it may get more interesting, as we might even be able to pull the distinction between lagging and leading strand synthesis into this.
3. Again, IMO, I think it's a stretch to make sweeping generalzations regarding hydrophibicity as it relates to protein structure, stability, and relationships with other proteins. Indeed, I think that, in this post-genomics age, one might be able to make a more focused list of possible changes that have more likely evolutionary impacts - say, the part of sequence space that can readily move towards, or actually adopt, one of several motifs known to be involved in protein-protein interactions. (The accessibility that delta-aminolevulinic acid dehydratase has to the DnaJ domain is sort of the thing I have in mind here.)
I agree on both counts. I am not trying to make any sweeping generalizations about protein evolution. I was speculating about one platform for further ID investigations. In the original hypothesis I raised, I noted that the IHE may simply have worked to unpack secondary designs specifically buried in the original designs. And as I warned,
quote:
However, there is an unfortunate caveat worth mentioning. The ability for C-T transition to unmask front-loaded states may have long ceased to exist. Such a dynamic may have been crucial to some early events in evolution, yet given these states may have dissipated (the proximal objectives were reached), current mutations may no longer reflect any detectable design bias. In such a case, the current predominance of C-T transitions (involved in some disease states) may simply be a [/i]vestige of design. [/i]
Which is why I also just added:
quote:
The Increasing Hydrophobicity Effect can be seen both through the genomic analyses of Singer and Hickey and the RNA Editing study of Giege and Brennicke. It thus clearly has played out in evolution. However, it still remains an open question as to exactly how it has played out. There are at least three possibilities:
1) The IHE works only to tweak and adjust protein function as may be the case with the mitochondrial proteins analyzed by Geige and Brennicke. It would be helpful to biochemically characterize some of these edited proteins and compare their properties to unedited versions.
2) In addition to 1), the IHE may have been coupled to carefully chosen initial states to unlock front-loaded states as previously suggested. [1]
3) In addition to 1) and 2), the IHE has the ability to evolve novel proteins not front-loaded into the initial states. If this is true, how often has it occurred and what frequency of novel protein evolution was dependent on the IHE?
We need to remember that the concept of front-loading I employ does not entail any form of strong determinism nor even that our current biotic state was the actively front-loaded state.
As to looking whether the IHE (or something similar) may be helpful in reaching new motifs, that's yet another area to explore. The IHE concept is only a few weeks old and this fruitful ID perspective keeps biting off more than I can chew. Perhaps you can provide a dozen-or-so delta-aminolevulinic acid dehydratase/ DnaJ domain-type examples. Right now, I'm still hunting down what genes were supposedly crucial in the evolution of multicellularity.
4. Finally, to stir a pot that no one here seems to drink from, I would suggest (in what must be for now a very vague way) that possible teleological mechanisms in mutation, as they may affect evolution, are likely going to be grounded firmly in the RNA World.
That's always one possibility.
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Mike Gene
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posted 10. January 2003 10:47
This also looks interesting:
quote:
Proc Natl Acad Sci U S A 1985 Dec;82(23):8114-8
DNA methylation at asymmetric sites is associated with numerous transition mutations.
Selker EU, Stevens JN.
We describe two unusual 5S RNA regions from Neurospora crassa that are tightly linked. Sequence analysis suggests that these genes or pseudogenes, which we designate zeta (zeta) and eta (eta), arose by a 794-base-pair tandem duplication followed by hundreds of exclusively cytosine to thymine mutations. The duplication was most likely generated by nonhomologous recombination involving a DNA segment having a striking purine-pyrimidine strand asymmetry. Restriction analysis of genomic DNA from tissue grown in the presence or absence of 5-azacytidine indicates that many, and perhaps all, cytosines in the duplicated region are methylated in most cells. This is in contrast to the situation typically observed in eukaryotes, where 5-methylcytosine is found only at positions one or two nucleotides preceding guanine residues. No DNA methylation was detected in the unique DNA flanking the zeta-eta duplication. Thus the "signal" for methylation may be the duplication itself. The numerous transition mutations in this region probably occurred by deamination of 5-methylcytosines. Our results suggest that DNA methylation can have important evolutionary consequences in eukaryotes.
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Mike Gene
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posted 14. January 2003 22:05
Art:
If C deamination isn't the prevalent mode of mutation as has been claimed (and a couple of previous posts I have made indicate that it isn't), then what is the significance of the rest of the IHE?
The study that Art cited (Klapacz J, Bhagwat AS. Transcription-dependent increase in multiple classes of base substitution mutations in Escherichia coli. . J Bacteriol 2002;184:6866-72) does not show this. In fact, it further supports my contention.
Because C-T transitions tend to predominate among base substitutions, Klapacz and Bhagwat designed an assay that specifically excludes them in order to get a better look at the less common mutations. Thus, when they write...
quote:
Sequence analysis of the revertants revealed that the frequency of several different base substitutions increased upon transcription of the bleomycin resistance gene and that G. C-to-T. A transversions dominated the spectrum in cells transcribing the gene.
..one should realize they are scoring substitutions other than C-T transitions. That is, G-T transversions are the most common
non C-T substitution. In fact, in one of their experiments they were able to compare the frequency of C-T transitions to anything-other-than-C-T transitions. And the frequency of C-T transitions was 100-1000-fold higher than all these non-CT mutations.
They also explain:
quote:
Traditionally, mutation spectra have been studied using forward mutation assays involving acquisition of resistance to rifampin or mutations in lacI. The Phl r reversion assay de-scribed here is as convenient as any assay involving antibiotic resistance but has one significant advantage over the other assays for studying spontaneous base substitutions. In most forward mutation assays, insertion and/or deletion mutations or C-to-T substitutions dominate the spectrum. For example, in one study of spontaneous Rif r mutants (17) G _ C-to-A _ T transitions comprised 72% of the obtained mutations. In a study of lacI d mutations (19), 29% of the mutations were insertions or deletions, and of the base substitution mutations 47% were G _ C-to-A _ T changes. Such dominance of frame-shifting mutations and C-to-T mutations in the spectra means other base substitutions such as G _ C to T_ A are rarely seen. In the Rif r and lacI d mutational studies mentioned above, G-to-T transversions were seen in only 6.5 and 5.6%, respectively, of all the mutations (17, 19).
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Art
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posted 14. January 2003 23:35
quote:
Art:
If C deamination isn't the prevalent mode of mutation as has been claimed (and a couple of previous posts I have made indicate that it isn't), then what is the significance of the rest of the IHE?
The study that Art cited (Klapacz J, Bhagwat AS. Transcription-dependent increase in multiple classes of base substitution mutations in Escherichia coli. . J Bacteriol 2002;184:6866-72) does not show this. In fact, it further supports my contention.
Because C-T transitions tend to predominate among base substitutions,
But the review by Maki clearly states that C->T changes do not predominate.
This review takes into account a broad range of studies, and the synthesis that results does not agree with your claims, Mike. You seem to be cherry-picking a few studies and ignoring a whole lot of work that does not jibe with your claims.
This makes you other statements about changes in the transcription bubble somewhat questionable. Moreover, it calls into serious question your refusal to include G->A changes in your analysis.
I think more corrections are needed in your article, as well. For example, reference 6 does not support your claims about the ubiquity and importance of C->T changes. In this study, the large proportion of mutations that were observed occurred at a very small number of sites. Thus, unless you can document that hot-spots in general focus mutation on C's, and that these hot-spots also involve possible hydrophobicity-increasing changes (and the main one in refrence 6 does not), your claims seem to be very questionable.
Reference 7 deals with single-stranded DNA, and notes that the spectrum of changes differs from that seen with double-stranded DNA. Again, this calls into question its relevance to your ideas, which necessarily involve double-stranded genomes.
The citation of methylation-promoting deamination is interesting, but of questionable value if you are not willing to explore mechanisms of C methylation. Because it is these mechanisms, and not deamination per se, that becomes a potential driving force.
There seems to me to be a serious contradiction in your discussion about C->U editing in mitochondria. If you don't catch it first, I'll elaborate later.
I'd add more, but Kyle and Irving are patiently waiting for a reply, and they deserve one.
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Mike Gene
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posted 16. January 2003 10:54
Art: But the review by Maki clearly states that C->T changes do not predominate.
This review takes into account a broad range of studies, and the synthesis that results does not agree with your claims, Mike. You seem to be cherry-picking a few studies and ignoring a whole lot of work that does not jibe with your claims.
Well, it's not "my" claim. If I'm "cherry-picking," so are many others:
high rates of nucleotide substitution and C-->T transitions, usually found for pseudogenes - Yokoyama
et al.
The most frequently occurring base substitution mutation observed in aerobic organisms is a GC->AT transition. This substitution is also the most abundant genetic change induced as a consequence of oxidative DNA damage. - Kreutzer and Essigmann
In most forward mutation assays, insertion and/or deletion mutations or C-to-T substitutions dominate the spectrum. For example, in one study of spontaneous Rif r mutants (17) G _ C-to-A _ T transitions comprised 72% of the obtained mutations. In a study of lacI d mutations (19), 29% of the mutations were insertions or deletions, and of the base substitution mutations 47% were G _ C-to-A _ T changes. Such dominance of frame-shifting mutations and C-to-T mutations in the spectra means other base substitutions such as G _ C to T_ A are rarely seen. - Klapacz Bhagwat (your citation)
And as I mention above, several pseudogene and SNP analyses support this position (which is not merely "my" claim). And as I mentioned also, the data from Klapacz and Bhagwat showed the frequency of C-T transitions was 100-1000-fold higher than all these non-CT mutations.
But yes, I shall retrieve the review. If you are right, things get even more interesting.
This makes you other statements about changes in the transcription bubble somewhat questionable.
From Klapacz and Bhagwat (your cite):
quote:
Transcription is an inherently asymmetric process that separates transiently the two strands of DNA and copies one strand as RNA. One DNA strand (the transcribed or template strand [TS]) is paired with 8 to 9 nucleotides of RNA in the transcription bubble and is enveloped by the RNA polymerase. The other DNA strand (the nontranscribed or nontemplate strand [NTS]) is unpaired and is thought to lie on the outside of the RNA polymerase (9). This asymmetry creates differential sensitivities of the two DNA strands within the bubble for chemical probes such as hydroxyl radicals and permanganate
(8, 11). Beletskii and Bhagwat have shown that there is also asymmetry in the susceptibility of cytosines in the two strands to deamination (3). Cytosines in the NTS are up to 10 times more likely to deaminate to uracil than those in the TS (1, 3), and in a strain of Escherichia coli defective in uracil excision (genotype ung), this causes a strand-dependent increase in C-to-T mutations. We refer to instances of this phenomenon as transcription- induced mutations (TIM). The extent of this susceptibility of cytosines in the NTS to deamination is roughly proportional to the frequency of transcription of the gene (1). This phenomenon has been seen with plasmid-borne as well as chromosomal genes (2) and with genes transcribed by the T7 RNA polymerase (4). Further, the frequency of cytosine deamination is directly related to the length of time the transcription bubble stays open (4).
Moreover, it calls into serious question your refusal to include G->A changes in your analysis.
Not much. I'll explain in an upcoming TeleoLogic essay.
I think more corrections are needed in your article, as well. For example, reference 6 does not support your claims about the ubiquity and importance of C->T changes. In this study, the large proportion of mutations that were observed occurred at a very small number of sites. Thus, unless you can document that hot-spots in general focus mutation on C's, and that these hot-spots also involve possible hydrophobicity-increasing changes (and the main one in refrence 6 does not), your claims seem to be very questionable.
Yes, but this only makes it more interesting as yet another layer of asymmetry exists. This is yet another area of research sparked by this teleological hypothesis. There is one important caveat, however, in that I originally warned that the IHE may represent mostly an example of vestigial design, where originally, it was quite focused but such focus has dissipated over the last few billion years. The only way to address this is through research.
Reference 7 deals with single-stranded DNA, and notes that the spectrum of changes differs from that seen with double-stranded DNA. Again, this calls into question its relevance to your ideas, which necessarily involve double-stranded genomes.
Yes, as with most science, things do get called into question as one gradually develops a model. The fact remains that there is a large body of data that support my ideas (some weakly, some strongly). What is most interesting here, however, is your recognition that my ideas are largely indebted to presupposing double-stranded genomes. This itself should help people to see that, contrary to Frances repeated claims, there are subtle, but very significant, distinctions between my ideas and what he keeps calling 'methodological naturalism.'
The citation of methylation-promoting deamination is interesting, but of questionable value if you are not willing to explore mechanisms of C methylation. Because it is these mechanisms, and not deamination per se, that becomes a potential driving force.
Of course I'm willing to explore. As I noted,
quote:
And the effects of cytosine deamination can be explored through many different potential design considerations, such as its temp-dependence, the role of methylation/CpG dinucleotides, RNA editing, the influence of UV light, the influence of NO, regulation of ung, etc. There is great opportunity for all kinds of research here.
In fact, what I found interesting about the article I cited is the hypothesis about one such mechanism - "Thus the "signal" for methylation may be the duplication itself."
There seems to me to be a serious contradiction in your discussion about C->U editing in mitochondria. If you don't catch it first, I'll elaborate later.
Feel free to elaborate. Hopefully it's clear that this design paradigm is giving me a plate that is flowing over (far too much for a late night hobby to keep up with).
But let me add one more thing.
It is often important to step back from all the details of a debate and survey the big picture.
A commonly stated objection about ID is that it scientifically sterile - that it cannot generate a research program. I have once again demonstrated how thoroughly bogus this claim is. Clearly, my teleological hypothesis suggests all kinds of research. Considering only the disputes in this thread , an ID theorist can:
- Establish the most common form of base substitution.
- Determine how often this form of mutation is tied to change in function (relative to other forms of mutation).
- Explore the factors that can mediate this form of mutation (increase or decrease).
- Explore how these factors might fit into a design paradigm.
Etc.
Once one realizes that it is true that my teleological hypothesis does generate various lines of research, that are likely to be important not just to the topic at hand, but have a wider appeal in trying to understand life, another silly objection about ID is eliminated. This is the objection that ID research could be funded by private donations from religious people (given that mainstream funding is unlikely given the explicit teleological assumptions). But I doubt many people are going to donate money to support research that spends several years to establish, once and for all, that C-T transitions are most common (for example). Research funded by private individuals typically needs to promise sensational discoveries, not the bread-n-butter analyses that an ID research program needs (and that is characteristic of 99.9% of mainstream science).
Okay, enough of the big picture. Let me see if I can get a new essay up on my web page that addresses this exclusion of the G-A transtions (coupled to the C-T transitions).
[ 16. January 2003, 10:55: Message edited by: Mike Gene ]
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Frances
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posted 16. January 2003 12:53
The following paper may be of interest as well
DIMMIC et al "MODELING EVOLUTION AT THE PROTEIN LEVEL USING AN ADJUSTABLE AMINO ACID FITNESS MODEL"
They used an adjustable fitness model for amino acid substitutions and found some interesting characteristics:
quote:
While most correlations with bulk were not strong, several of the site classes showed significant correlation with hydrophobicity (see Figure 1). Site class #3 showed substantial negative correlation with amino acid hydrophobicity (R=-0.68, P LT 0.001), and site class #4 showed some positive correlation (R=0.42, P=0.065).
also the following paper
Soyer et al "USING EVOLUTIONARY METHODS TO STUDY G-PROTEIN COUPLED RECEPTORS"
quote:
The correlation between the posterior assignments into the two site classes and the hydropathy plot show that our model assigns the residues into site classes according to their location. Almost all non-transmembrane residues are assigned to site class 2, while almost all transmembrane residues are assigned to site class 1.
and
quote:
These properties are flexibility and hydrophobicity in one case and polarity in the other. Interpreting these results together with the color strips we see that the fitness values for the site class that holds the non-transmembrane residues show a strong positive correlation to flexibility and negative correlation to hydrophobicity. The fitness values of the site class that is mainly occupied by residues from transmembrane regions show a negative correlation to polarity. These correlations are in agreement with the general expectation of non-transmembrane residues being hydrophilic and transmembrane residues being hydrophobic.
Another one
Wu et al, "Discovering Empirically Conserved Amino Acid Substitution Groups in Databases of Protein Families "
quote:
For substitution groups of size 5, the two databases identified two empirically
conserved groups in common. One group, FILMV, contains what are referred to as the
major hydrophobic amino acids. The other group, FILVY, demonstrates that tyrosine
sometimes acts as a hydrophobic amino acid.
But notice
quote:
Nevertheless, in these larger substitution groups, revealing insights can be
obtained from examining the amino acids that they induce negatively. For instance,
both databases identify substitution groups that negatively induce the hydrophobic
amino acids. These substitution groups differ slightly between the databases, perhaps
reflecting the heterogeneity of hydrophilic environments. In addition, both databases
identify substitution groups that negatively induce tryptophan, cysteine, and sometimes
phenylalanine. These large substitution groups might therefore be defined in a negative
sense, by specifying the absence of certain amino acids.
Another one from Naor et al, "Amino Acid Pair Interchanges at Spatially Conserved Locations"
quote:
The second most conserved residue is Cys. which often contributes to the stability of protein structure through the disulfide brideges it forms. The hydrophobic amino acids which are typically found in the interiorof proteins and are involved in non-specific hydrophobic interactions and the polar (Ser Thr Tyr and Hys) are among the least conserved.
There is a lot of data out there that studies the amino acid substitution patterns. Hydrophobicity/Hydophilicity does seem to play an important role but the trends seem to depend on the type of protein involved (membrane vs non-membrane for instance).
Seems that non-ID scientists have already looked at much of the 'research program' proposed by Mike
quote:
Establish the most common form of base substitution.
Determine how often this form of mutation is tied to change in function (relative to other forms of mutation).
Explore the factors that can mediate this form of mutation (increase or decrease).
Explore how these factors might fit into a design paradigm
Except for the latter one, but what is a 'design paradigm' I would ask. So far teleology does not seem to propose a research program much different from a research program based on methodological naturalism which suggests to me that teleology may be sterile after all. Its not that teleology based on front loading may not be able to generate a research program but this research program seems to match one based on methodological naturalism quite closely. And I argue that it still does not resolve how the initial condition arose, teleologically or non-teleologically.
[ 16. January 2003, 13:23: Message edited by: Frances ]
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