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Topic: What comes after detecting design?
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Pim van Meurs
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Member # 541
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posted 13. July 2003 16:41
Ben comments "It is my firm belief that random mutations are almost always "bad" in the sense that information is lost because of them. "
Information in what sense? Shannon information? Why would mutations be almost always bad in this sense? In fact, most mutations seem to be quite neutral in that sense due to the degenerate nature of the codon to amino acid mapping. This neutral pathway may be quite relevant for evolution as well.
But back to mutations, I would be interested in hearing more about why you think that mutations seem to lead to loss of information. And how does selection figure into this equation?
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peter borger
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posted 13. July 2003 22:17
Pim, I thought I was quite clear in my previous mail. However let me once more try to explain why the ToE fails to provide a reasonable explanation for the Calmodulin gene family. As pointed out, as soon as a gene has been duplicated we have the situation of redundancy and redundant genes will only be stable in the genome when continuous selection is present to keep them in the genome. As a consequence they will not change. Examples for this situations are adaptive duplications, for instance acquired resistance against antibiotics, chemotherapy, but also the high abundace genes. It also implicates that the genes have to be expressed, since the selection is at the level of the phenotype (that what is expressed). If not expressed the duplicate will degenerate. But which one, the original or the duplicate? We don't know since after duplication we have the situation of genetic uncertainty. This is a common problem for genetic redundancies.
You say that you find my claim fascinating but you believe it to be quite erroneous. if so, could you provide a detailed molecular mechanism how evolutionary theory can account for the observations on the calmodulin genes?
You also say that my problem can be found in my statement that "Even before triplication the genes are free to diverge in different organisms. That's what evolution is about: duplication and divergence." Of course I know that evolution is about variation (which may include duplication) and selection. But if we ponder the claim of microbe to man evolution than it is not merely about variation and selection. We have to include an increase of protein coding and non-protein coding DNA elements. The evolutionary explanation is gene duplication and divergence. Is there another way? (Horizontal tranfer is merely relocation). In addition, multiple duplications will be located next to each other (since the mechanism is unequal crossing over) and the complementary DNA sequences of the duplicates will simply recombine out of the genome. This is an appropriate way to get rid of genetic embellishment and is observed in microorganisms(Unless selection keeps the duplicates in the genome). Theres' another reason why the location of the CALM genes makes design sense: distinct chromosomes to avoid recombinations. It's a general finding for genetic redundancies. And as soon as we are to include duplication as a potential genome increase than we are back at the level of redundacies.
I agree with you that under strong selective pressures genes may remain quite well conserved. The issue is that as far as we know the redundant CALM genes are not under strong selective constraint.
Finally, the etymology for degenerate: 'degenerate' is from Latin 'degenerare' meaning 'to deteriorate'. So, my question still is why was the code coined 'degenerate'. I really don't get it. Why would anybody call the most perfect code degenerate?
degenerate (adj.) - 1494, from L. degeneratus, pp. of degenerare "depart from one's kind, fall from ancestral quality," from phrase de genere, from genus (gen. generis) "birth, descent." The verb is from 1545; the noun is 1555. (ref: http://www.etymonline.com/d2etym.htm)
PB
[ 13. July 2003, 22:46: Message edited by: peter borger ]
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Pim van Meurs
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posted 13. July 2003 23:12
Peter, I am not sure what you are arguing. Gene duplication itself may be a selectable event. In fact there seem to be evidence that multiple genes can have a selective advantage. The question now is, what happenes after the duplication. There are a variety of options, one of them is that the gene becomes a pseudogene, the other one is that the gene takes on a new function.
When correcting Peter's remarks about evolution he responds "The evolutionary explanation is gene duplication and divergence."
Gene duplication and divergence is but one of the mechanisms of evolution but lets for the moment accept Peter's suggestion. Peter suggests that unequal cross over is the only mechanism of gene duplication, is that correct I wonder.
But perhaps Peter can help us understand how he reaches the conclusion that "far as we know the redundant CALM genes are not under strong selective constraint"
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peter borger
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posted 14. July 2003 00:12
Peter, I am not sure what you are arguing. Gene duplication itself may be a selectable event.
Maybe, maybe not. What do you mean? That the mechanisms that underly the duplication are selected for?
In fact there seems to be evidence that multiple genes can have a selective advantage.
Do you mean selection of robustness? Or do you mean that dosage of gene expression is selected for? The higher the dosage the more progeny? It implies selection on reproduction (as a matter of fact that's were selection acts on: reproduction rate).
The question now is, what happenes after the duplication. There are a variety of options, one of them is that the gene becomes a pseudogene, the other one is that the gene takes on a new function.
Duplication and adoptation of new function is yet to be demonstrated. I am not aware of observed examples. Are you?
When correcting Peter's remarks about evolution he responds "The evolutionary explanation is gene duplication and divergence."
How else will a genome grow? Through duplication of preexisting DNA elements and divergence. The 2 rounds of genome duplication has been falsified so many times that we can discard it as an option. Maybe somebody could argue for symbiosis of genomes.
Gene duplication and divergence is but one of the mechanisms of evolution but lets for the moment accept Peter's suggestion.
What else does the EoT have?
Peter suggests that unequal cross over is the only mechanism of gene duplication, is that correct I wonder.
The other known mechanisms do not lead to expression of the gene and will immediately lead to (RNA derived) pseudogenes. You can of course assume that it integrated into another expressed and regulated gene through homologous recombination. But that requires the gene already to be homologous and it will inactivate the gene it invaded.
But perhaps Peter can help us understand how he reaches the conclusion that "far as we know the redundant CALM genes are not under strong selective constraint"
The genes can be knocked out in model cell systems with only minor effects. But let's await the mice/rat knockouts. That will shed more light on this matter.
At this moment, genetic redundancies like CALM genes point in the direction of designed multipurpose genomes.
PB
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John Wendt
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Member # 798
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posted 14. July 2003 09:34
From Peter Borger: quote:
Finally, the etymology for degenerate: 'degenerate' is from Latin 'degenerare' meaning 'to deteriorate'. So, my question still is why was the code coined 'degenerate'. I really don't get it. Why would anybody call the most perfect code degenerate?
From Horace Freeland Judson's wonderful book The Eighth Day of Creation, talking about 1954, when people were trying to figure out what a genetic code might look like: quote:
Furthermore, since 4 X 4 X 4 = 64, as many as forty-four of the possible triplets might code for nothing or be available for punctuation marks... Or, possibly, several different base sequences might signify the same amino acid: [Francis] Crick declared that such codes should be called "degenerate," a usage by which quantum physicists describe multiple states that amount to the same thing, as when a set of electrons can take up several orbital arrangements, all with the same energy. "'Degenerate' I certainly invented. Only a physicist would invent it," Crick said.
Also from Crick, in a slightly different context: quote:
People forget how much we didn't know in those days.
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Pim van Meurs
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Member # 541
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posted 14. July 2003 12:09
Peter remarks "At this moment, genetic redundancies like CALM genes point in the direction of designed multipurpose genomes."
Designed by what remains the question. certainly Peter has not been able to eliminate natural pathways as the 'designer' nor has Peter given any reason to infer intelligent design. So perhaps Peter's claim is best rephrased as "genetic redundancies like CALM genes remain so far not fully explained"
Or Toutenhoofd
quote:
Calmodulin (CaM) is a ubiquitous, highly conserved calcium sensor protein involved in the regulation of a wide variety of cellular events. In vertebrates, an identical CaM protein is encoded by a family of non-allelic genes, raising questions concerning the evolutionary pressure responsible for the maintenance of this apparently redundant family. Here we review the evidence that the control of the spatial and temporal availability of CaM may require multiple regulatory levels to ensure the proper localization, maintenance and size of intracellular CaM pools. Differential transcription of the CaM genes provides one level of regulation to meet tissue-specific, developmental and cell-specific needs for altered CaM levels. Post-transcriptional regulation occurs at the level of mRNA stability, perhaps dependent on alternative polyadenylation and differences in the untranslated sequences of the multiple gene transcripts. Recent evidence indicates that trafficking of specific CaM mRNAs may occur to specialized cellular locales such as the dendrites of neurons. This could allow local CaM synthesis and thereby help generate local pools of CaM. Local CaM activity may be further regulated by post-translational mechanisms such as phosphorylation or storage of CaM in a 'masked' form. The spatial resolution of CaM activity is enhanced by the limited free diffusion of CaM combined with differential affinity for and availability of target proteins. Preserving multiple CaM genes with divergent noncoding sequences may be necessary in complex organisms to ensure that the many CaM-dependent processes occur with the requisite spatial and temporal resolution. Transgenic mouse models and studies on mice carrying single and double gene 'knockouts' promise to shed further light on the role of specificity versus redundancy in the evolutionary maintenance of the vertebrate CaM multigene family.
The calmodulin multigene family as a unique case of genetic redundancy: multiple levels of regulation to provide spatial and temporal control of calmodulin pools? Toutenhoofd SL, Strehler EE.
Unless of course Peter can propose why our ignorance should be evidence of a designed multipurpose genome, and how we can establish who or what was the designer.
So many questions but at least it seems that Peter's claims about ToE not being able to explain CALM are erroneous or at least premature.
One may of course ask why a designer would introduce redundancies which are not under evolutionary pressure, leading inevitably to their disappearance. Surely from that perspective a designed genome seems even less plausible.
Hardy D.O., Bender P.K., Kretsinger R.H.;
"Two calmodulin genes are expressed in Arbacia punctulata. An ancient gene duplication is indicated."; J. Mol. Biol. 199:223-227(1988).
Or from Here'The existence of 3 expressible genes for calmodulin may indicate that one is a housekeeping gene and that the additional copies are differentially regulated to modulate calmodulin function."
quote:
Calmodulin (CaM), the principal mediator of the calcium signal, regulates numerous processes pertinent to neural function. Mammalian CaM is generated from three genes that give rise to five distinct transcripts. To determine the regulation of individual CaM transcripts in neurons, we assessed their abundance during differentiation of human IMR-32 neuroblastoma cells. Northern analysis revealed that the 4.1 kb CALM1 transcript was specifically upregulated about two-fold during differentiation, and that this increase correlated with neurite extension. By contrast, the CALM2 and CALM3 mRNAs as well as the 1.7 kb CALM1 transcript showed an initial increase but then returned to levels close to, or only slightly above, controls. The increase in the 4.1 kb transcript was largely due to its specific stabilization in differentiated cells. However, total cellular CaM levels did not change significantly throughout differentiation. To begin to address whether the 4.1 kb CALM1 transcript might play a unique role in providing local CaM pools, we determined its localization in differentiated IMR-32 cells using in situ hybridization. The 4.1 kb CALM1 transcript localized to the cell body, but was also present within extending neurites. This finding agrees with in vivo studies showing elevated levels of the 4.1 kb CALM1 transcript in adult rat central neurons and the presence of CALM1 transcripts in dendrites, and establishes a human in vitro model system to study individual CaM transcripts with respect to neuronal functions.
Regulation of calmodulin mRNAs in differentiating human IMR-32 neuroblastoma cells. Toutenhoofd SL, Strehler EE Biochim Biophys Acta. 2002 Nov 4;1600(1-2):95-104.
quote:
Abstract The recently identified cyclic nucleotide-gated ion channels (AtCNGCs) from Arabidopsis thaliana have the ability to bind calmodulin. Using two different methods, we mapped the binding site of AtCNGC1 to the last predicted K helix of the cyclic nucleotide binding domain. This is in contrast to CNGCs from animals, where the calmodulin binding site is located in the N-terminus, implying that different mechanisms for CNGC modulation have evolved in animals and plants. Furthermore, we
demonstrate that AtCNGC1 and AtCNGC2 have different calmodulin binding affinities and we provide evidence for target specificities among calmodulin isoforms.
Characterisation of calmodulin binding to cyclic nucleotide-gated ion channels from Arabidopsis thaliana Claudia Koehler, Gunther Neuhaus
Strehler himself reports 'Much excitement in the field stems from recent findings correlating mutations in a specific PMCA isoform with deafness and imbalance in mice. It is likely that at least some forms of human hearing and balance impairment may also involve this PMCA. This leads to new possibilities for studies of the functional properties, mechanism of membrane localization and protein interactions of the PMCAs in the specialized cell types of the inner ear. "
Hearing and balance impairments....
[ 14. July 2003, 12:41: Message edited by: Pim van Meurs ]
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peter borger
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posted 14. July 2003 19:23
hi Pim,
Why do you keep mailing abstracts on CALM regulation? I've already read them (it's my field of research). What we are discussing is evolutionary mechanism that are responsible for the existance and maintenance of this family. That's what interests me.
The MPG holds that genomes are expected to have lots of redundacies. And that redundancies are not associated with gene duplication (where do these genes come from than?) and that they do not change faster than essential genes. That's exacly what we observe! Now you can twist and turn EoT, but it doesn't fit in.
Redundancies can be either for fine tuning of regulation, give robustness to organism's regulatory pathways or may be derepressed through shuffling of DNA elements and may thus contribute to adaptive phenotypes. Such rapid afaptation have been observed and can only be explained from preexisting information in the genome that can be activated (for instance the Hawaian Wallabi's). So, evolution is NON-gradual. It is saltating since the information has only to be reshuffled and derepressed (through probably a non-random mechanism). It explains a lot.
That redundancies are in the genome without selective constraint tells me that they are kept stable in the genome through (DNA repair?) mechanisms. If lost- no big deal- their function can be easily taken over by pathways with a similar function. As you can see, all necessities required are preexisting in the genomes. I call it a multipurpose genome (MPG). Initially designed for rapid adaptation to populate all niches of the planet.
PB
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Pim van Meurs
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posted 14. July 2003 22:34
Hi Peter,
I assure you that I am not mailing you any such abstracts. Of course I do refer to such abstracts in my postings. I am aware that CALM is your field of research (I assume you are the P. Borger on several of the papers that have come up in my research?) but this forum is not just to educate you on these issues but also help others understand the issues especially as they relate to your claims. As I see it, these abstracts and references place some doubts on your claims. Especially about the issue of the impact of selection. See for instance "Role of Alternative Splicing in Generating Isoform Diversity Among Plasma Membrane Calcium Pumps by Strehler and Zacharias"
I still fail to see how you reach your conclusions but that might be due to your usage of such acronyms as EoT and MPG. Certainly gene duplication and selection are part of the ToE (is that what you mean by EoT?).
I still fail to see any relevance in your statement about redundancies and Wallabi's so I am urging you to make a more coherent case. I have no idea what you are trying to communicate here. Certainly your statement that evolution is non gradual would benefit from some careful argumentation.
you then continue making two presumptions "That redundancies are in the genome without selective constraint tells me that they are kept stable in the genome through (DNA repair?) mechanisms." First of all the references I quote suggest that there may after all be a selectinve contraint and secondly how are DNA repair mechanisms not part of ToE? Your MPG seems interesting but fails to address the real issues namely why ToE would fail to explain CALM and furthermore, without much more about your MPG I would say that I cannot really comment on the relevance of MPG. Certainly you have made some interesting suggestions and may I encourage you to take them to a level suitable for scientific discussion?
How is your research on the history of the usage of the term degeneracy going btw? I would be interested in hearing more about them.
you quote Toutenhoofd 2000, let me add the abstract and perhaps you can explain the relevance of their paper. Since I do not have access to the original at this moment.
quote:
Calmodulin (CaM) is a ubiquitous, highly conserved calcium sensor protein involved in the regulation of a wide variety of cellular events. In vertebrates, an identical CaM protein is encoded by a family of non-allelic genes, raising questions concerning the evolutionary pressure responsible for the maintenance of this apparently redundant family. Here we review the evidence that the control of the spatial and temporal availability of CaM may require multiple regulatory levels to ensure the proper localization, maintenance and size of intracellular CaM pools. Differential transcription of the CaM genes provides one level of regulation to meet tissue-specific, developmental and cell-specific needs for altered CaM levels. Post-transcriptional regulation occurs at the level of mRNA stability, perhaps dependent on alternative polyadenylation and differences in the untranslated sequences of the multiple gene transcripts. Recent evidence indicates that trafficking of specific CaM mRNAs may occur to specialized cellular locales such as the dendrites of neurons. This could allow local CaM synthesis and thereby help generate local pools of CaM. Local CaM activity may be further regulated by post-translational mechanisms such as phosphorylation or storage of CaM in a 'masked' form. The spatial resolution of CaM activity is enhanced by the limited free diffusion of CaM combined with differential affinity for and availability of target proteins. Preserving multiple CaM genes with divergent noncoding sequences may be necessary in complex organisms to ensure that the many CaM-dependent processes occur with the requisite spatial and temporal resolution. Transgenic mouse models and studies on mice carrying single and double gene 'knockouts' promise to shed further light on the role of specificity versus redundancy in the evolutionary maintenance of the vertebrate CaM multigene family.
[ 14. July 2003, 22:59: Message edited by: Pim van Meurs ]
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nosivad
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posted 16. July 2003 06:32
I find it fascinating how most posts use the present tense when describing evolution. I and others have suggested that evolution is not in progress at the present. Among those was Julian Huxley, the primary spokesperson for the Modern synthesis. About all I see at present is subspeciation and very little of that. If there was ever a time in the history of the planet when natural selection might be expected to be effective it is at present. All we see is extinction.
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Pim van Meurs
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posted 16. July 2003 11:17
Davison:
You are of course entitled to your beliefs but you have been provided with countless examples that place some signficant doubt on your claims that "all we see is extinction". Perhaps it's time to look in the present?
Let me know if you are interested in some examples that show speciation and natural selection in action.
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nosivad
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posted 16. July 2003 13:08
Pim, I have issued my challenge many times just as Goldschmidt did. I quote him from his "Theoretical Genetics" page 488.
"This hypothesis involves, of course, the idea that evolution, except on the lowest intraspecfic level, proceeds by saltations rather than by slow accumulation of small differences."
I also expect that any presumed example of speciation be verified as to mechanism and be subjected to the critical physiological test of hybrid sterility. The latter of course requires that the parent species be identified with certainty, which also seems often to be in question. Until there exists concrete examples of sexually mediated transpecific evolution, I will continue to conclude that a primary effect of obligatory sexual reproduction is to bring macroevolution (speciation) to standstill.
I also request that you refer to my postings with my code name - nosivad. Unlike yourself, I do not choose to remain anonymous, but prefer to play the game by the rules nevertheless. nosivad
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Bob Wheeling
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posted 16. July 2003 20:49
Peter,
You wrote: "As pointed out, as soon as a gene has been duplicated we have the situation of redundancy and redundant genes will only be stable in the genome when continuous selection is present to keep them in the genome. As a consequence they will not change."
The Probability of Duplicate Gene Preservation by Subfunctionalization, available at:
http://www.genetics.org/cgi/reprint/154/1/459.pdf
doesn't agree with you about this. Here is a brief excerpt:
It has often been argued that gene-duplication events are most commonly followed by a mutational event that silences one member of the pair, while on rare occasions both members of the pair are preserved as one acquires a mutation with a beneficial function and the other retains the original function. However, empirical evidence from genome duplication events suggests that gene duplicates are preserved in genomes far more commonly and for periods far in excess of the expectations under this model, and whereas some gene duplicates clearly evolve new functions, there is little evidence that this is the most common mechanism of duplicate-gene preservation. An alternative hypothesis is that gene duplicates are frequently preserved by subfunctionalization, whereby both members of a pair experience degenerative mutations that reduce their joint levels and patterns of activity to that of the single ancestral gene.
In other words, it takes both copies to accomplish the task it used to take only one copy to do. Both genes must be expressed for survival, allowing the disfunctional parts to acquire new functions. It's a pretty interesting paper. I read it, first, after someone on another board, a biologist, posted a link to it.
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Pim van Meurs
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posted 17. July 2003 11:40
Nosivad, I cannot prevent you from holding on to your theory despite the evidence that seems to strongly contradict it.
Your challenge was met, what you do with it is not much of my interest.
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nosivad
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posted 17. July 2003 13:39
Pim, if my challenge was met, where is the published evidence? Where is the evidence contrary to the challenges presented by Goldschmidt, Grasse, Broom and Petrunkevitch all of whom have said the same thing? I have offered specific and reasonable criteria for the assumption of speciation. You have the responsibility now of providing the proof that all five of us are mistaken.
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