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Author
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Topic: The GUToB
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Mesk
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Member # 630
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posted 29. April 2003 23:54
Peter,
One would expect a certain number of phylogenetically discordant mutations (e.g. reversions, convergent mutations in separate lineages, etc.) to occur in any sequence which has evolved by random mutation, purely by chance. In order to demonstrate the existence of NRM, it is thus not sufficient to simply point to a few examples of discrepancies - you must demonstrate that the number of such discrepancies is higher than expected by chance under the standard evolutionary model. Have you devised a statistical test for ascertaining this, or do you have any ideas about how one could go about creating such a test?
On a tangential note: you appear to be claiming both (1) that NRMs can give the illusion of common descent, and (2) that the presence of NRMs can be distinguished from the molecular pattern predicted by common descent. It appears to me that these two positions are mutually inconsistent - that is, one cannot claim that NRMs generate molecular patterns similar or identical to those predicted by common descent, while simultaneously claiming that you can readily distinguish between the two phenomena in a given set of sequences! I would be interested to hear how you reconcile this apparent contradiction.
Regarding the alpha-actinins: I have perused most of the posts that you have written on the EvC discussion forum on these proteins. I intend to post a detailed discussion of your claims regarding these proteins, but before I do I would like to ask if you have any further information or arguments on another forum that I could examine before discussing your claims. I would like my response to be as comprehensive as possible. Ideally, you could compose some sort of summary of your claims regarding the alpha-actinins and post it here so I could be sure that I have not neglected any important details.
Thanks,
Mesk.
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Janitor@MIT
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posted 05. May 2003 17:07
I suppose the discussion has moved on, but I still see room in some of the definitions of “redundancy” and “degeneracy” (from some of the literature cited and some that hasn’t been cited) for the existence of a continuum between. Maybe they are more closely related than is apparent?
It might also be interesting to relate or compare “redundancy” and “degeneracy” with previous work in evolutionary thought on “senescence” and “convergence,” respectively.
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Mesk
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posted 06. May 2003 02:34
Since Peter has not responded to my request for further information on his claims about the alpha-actinins, I will post my response to those claims which I am aware of. Peter, feel free to contribute further information if you feel my response is incomplete.
Peter’s claims that the alpha-actinins violate evolutionary theory appear to be based on the following logic (quote below obtained from a post of Peter’s on the EvC forum). I hope the Administrator will indulge me in a little quote-by-quote responding – I do not wish to be omit any aspect of Peter’s arguments or quote them out of context, and I would like to respond to Peter’s quote in considerable detail. This is, after all, my livelihood that Peter is attacking, since I will be spending at least the next three years specifically researching the function and evolutionary history of the human ACTN3 gene.
quote:
What exactly is the problem with the redundant actinins? Let's have a careful look.
According to NDT, duplication gave rise to two alpha-actinin.
A close look at these redundant genes reveals that the differences are the result of point-mutations.
This is not entirely true – the two ACTN genes have also accumulated indels in the highly divergent region at the 5’ end of their coding region (corresponding to the N-terminal region of the two actinin proteins). But for most of their length, the divergence between the two genes is due to point mutations, yes.
quote:
Neutral evolution rate is about 10(exp)-9/nucleotide/year, and recent genome wide studies present evidence that purifying selection worked upon duplicated genes (A. Wagner, mini-review in Genome Biology 2002).
For the sake of argument I’ll accept Peter’s figure for the neutral evolution rate, although it is worth pointing out that this figure can vary widely throughout the genome, over time, and in different populations (it is particularly affected by effective population size, for instance). Of course, it goes without saying that this rate is also utterly inapplicable to regions of the genome which are acted on by natural selection.
I also accept the statement that purifying selection acts on duplicated genes – in fact, to go one better, I will specify that purifying selection has certainly acted on the ACTN3 gene. Analysis of substitution rates during the divergence of mouse and human Actn3 genes revealed evidence of very strong purifying selection, as manifested by very low levels of nonsynonymous (amino acid-changing) mutations compared to synonymous (so-called "silent") mutations.
quote:
The ACTN2 and ACTN3 genes are approximately 3000 bp, and share 85% sequence homology. Moreover, the ACTN3 gene is highly conserved within mammals.
Peter’s sequence homology figures are slightly too high here. Despite relatively high levels of similarity along most of the two genes, the most 5’ regions (corresponding to the N-terminals of the proteins) are so divergent that they cannot be aligned in any meaningful sense. Even when these regions are removed from the calculation, however, the nucleotide sequence similarity between the coding regions of the two human genes is only 76%. Because many of the mutations are silent the encoded proteins are 81% identical and 91% similar or identical.
The Actn3 gene is certainly highly conserved in mammals – human and mouse Actn3 coding regions are 89% identical, while the encoded proteins are 97% identical and 98% similar or identical, so Peter is quite correct there.
Now, Peter’s facts are more or less accurate, with some relatively minor errors. These are the conclusions he draws from them:
quote:
1) These data say that approximately 450 bp changes occurred on neutral positions, i.e. positions not under selective constraint.
2) These data mean that it would take about 10(exp)6 years for 3 random mutations to occur in the duplicated gene. Thus 150 million years for 450 neutral mutations.
3) These data imply that after each point-mutation there was (neutral) purifying selection. So, here we have to introduce neutral purifying selection again. What exactly is selection on neutral genes? Not a single evolution biologist was able to tell me, thus far.
The number of substitutions is actually considerably higher than Peter’s figure – there are 629 differences between the coding regions of two genes even if the divergent region is excluded, and the number if this region is considered is larger and includes a number of indel events as well as point mutations.
Peter’s calculation of the divergence time for Actn2 and Actn3 is also off by approximately a factor of two. The best estimate for the divergence time, based on phylogenetic models, is closer to 300 million years (Dixson et al. 2003. J Mol Evol 56(1):1-10).
But these are quite trivial errors compared to the erroneous claim that these changes must have occurred "on neutral positions... not under selective constraint." This is entirely false, and this error is (IMO) largely responsible for Peter’s misconceptions regarding the evolution of the actinin gene family.
This is an extremely important point, and warrants emphasis:
Just because a gene is redundant in one species, it does not follow that it has always been redundant.
In other words, even if ACTN3 really were redundant in humans (and it is not, as my lab’s study on genotype frequencies in athletes, discussed above, has shown), this does not mean that it has been evolving without selective constraints – i.e. neutrally – since its inception. Not only is Peter’s claim to the contrary illogical, it is also directly contradicted by the available evidence, e.g. the fact that Actn3 is not redundant in mice, as its expression in skeletal muscle is not overlapped by that of Actn2 (the presumed compensatory factor for ACTN3 deficiency in humans); and humans are the only known mammal suffering from null mutations in Actn3 – all other studied mammals, including chimpanzees, have fully functional actinin-3.
These data suggest that Actn3 has been subjected to purifying selection because it performs an important function in the skeletal muscle of most mammals. It appears likely that this function has only recently changed in humans – likely due to evolutionary changes in skeletal muscle, including the loss of very fast-type (IIb) muscle fibres which are present in smaller mammals – allowing a null allele to spread through the human population.
But as the athlete research performed at my lab has shown, ACTN3 is not redundant even in modern humans – in fact, while functional actinin-3 is required for optimal sprint performance, the null allele appears to have spread through the action of natural selection because it provides an advantage for endurance performance. Thus there is literally no support for the notion that actinin-3 has been undergoing purely neutral evolution, even in modern humans, and there is absolutely no need to postulate "neutral purifying selection." Normal, run-of-the-mill purifying selection to maintain protein function is sufficient.
Peter’s final conclusions are:
quote:
As you see, it is highly doubtful that the mechanism that keeps genes (unchanged) in the genome is by natural selection. [In fact this example is a falsification of natural selection. Thus, I demonstrated that both random mutation (see previous posting) and natural selection (this is not the only example) can be falsified at the molecular level. Conclusion: NDT RIP].
As I have shown, Peter’s claims rest on a fundamental misunderstanding: namely, that apparent (and in this case illusory) redundancy of a gene in one species means that that gene must have been redundant throughout its entire evolutionary history. Once that misconception has been set aside it is clear that there is no need for mysterious forces such as "neutral purifying selection" to explain the conservation of the Actn3 gene throughout mammalian evolution – normal purifying selection maintaining gene function is sufficient. Thus ACTN3 presents no difficulties for standard evolutionary theory, and indeed provides a fascinating example of evolution in action in modern humans.
I hope that this post has been sufficient to clarify any confusion regarding the consistency of ACTN3 with modern evolutionary theory. However if Peter (or anyone else) still has doubts regarding any of the points I have raised I would be more than happy to respond to them. I would also still be very interested in hearing Peter's response to the points I raised in my last post to this thread.
[Edited to correct minor formatting error.]
[ 06. May 2003, 02:36: Message edited by: Mesk ]
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peter borger
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posted 07. May 2003 23:54
Hi Mesk,
In response to your letter dd 29april2003:
You say that one would expect a certain number of phylogenetically discordant mutations to occur in any sequence which has evolved by random mutation, purely by chance. As I pointed out before, I do not claim that such mutations do not exist, since it is a well known fact. But such random mutations will not line up unless a mechanism is involved that introduces the mutations specifically on these spots. Only then, these mutations can give the impression of common descent. To exclude such mutations in a phylogenetic analysis it is not sufficient to only look at known hotspots, since such hotspots are only reveiled upon scrutiny of many (>10) intraspecies genomes. I doubt whether this has been carried out for the published phylogenetic analysis.
And as long as papers are being published that compares hundreds of human mtDNA and in comparison with only one chimp mtDNA to get the data in accord with current theory I am absolutely unconvinced of the validity of such theory. Let alone the methods. (For instance: Ingman et al, Nature 2000, 408:708-713). Apparently the authors need the introduction of a chimpanzee mtDNA sequence to understand the data from an evolutionary view.
You also say that in order to demonstrate the existence of NRM, it is thus not sufficient to simply point to a few examples of discrepancies - you must demonstrate that the number of such discrepancies is higher than expected by chance under the standard evolutionary model. In fact this was already demonstrated for the ZFY region by Rex. But even then it is not a problem. I wonder when do things become a problem for standard theory?
Although you might be right, you can also not exclude the possibility that mutations are often (maybe 'all' the time = NRM1+NRM2) introduced on the same spot since you didn't do such analysis. You simply assume all mutations are random. Some straightforward analysis demonstrating NRM1 were recently published pertaining mutations in the lamin gene: 18/20 mutations in the lamin gene leading to progeria were on exaclty the same 'hotspot', while normally mutations are not common in this gene. (Nature, 25 april 2003). This is of course an easily detectable phenotype, but why wouldn't mutations in a non-detectable phenotype (silent mutations) be on th same spot either? I can't think of a good reason.
You also say that (1) NRMs can give the illusion of common descent, and (2) that the presence of NRMs can be distinguished from the molecular pattern predicted by common descent are mutually inconsistent. It may seem that is inconsistent. However, what I mean that it is probably impossible to distinguish between a shared mechanism that introduces mutations independent of common descent as a result of shared sequence and common biochemistry versus common descent. IMO it requires new analysis methods to discriminate between the mechanisms.
Regarding the alpha-actinins: I will respond soon.
best wishes,
Peter
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Mesk
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posted 12. May 2003 04:49
Hi Peter,
I'll respond to your last post relatively briefly, since I'm primarily interested in hearing your thoughts on the actinins and I don't want to distract you from your response on that topic.
What do you mean exactly when you say that NRMs can "line up" to "give the impression of common descent"? How can you distinguish such NRMs from shared genetic changes due to common descent? What you really need here is a detailed protocol, setting out the steps required to identify NRMs in DNA sequences from a given species or group of species, but I'd settle for a brief run-through of your approach to NRM identification.
I'm unclear on your objection to the use of a single chimpanzee sequence as an outgroup for the analysis of human mtDNA sequence variation. The use of an outgroup is standard practice for phylogenetic analysis, and helps to distinguish ancestral from derived variations and so on. Would you be more comfortable if multiple chimpanzee sequences were used?
Regarding statistical analysis of NRMs: demonstrating that the number of discrepancies is significantly higher than expected by chance is absolutely standard practice for any statistical analysis. You must show that the probability of the observed number of discrepancies occurring by chance under the evolutionary model is less than some threshold - 5% (i.e. a p value < 0.05) is most widely accepted. Rex Kerr did not demonstrate this for ZFY - rather, he showed that there was only a modest increase in "double hit" mutations compared to chance expectations (8 observed vs 5 expected). This is almost certainly not a statistically significant increase, although Rex should feel free to chime in if I am mistaken.
Your reference to the recent Nature article on recurrent lamin mutations sounds intriguing, but I have been unable to access the full text due to a glitch with the Nature website. I will comment on this article when I have been able to get hold of it.
Finally, you say that "it is probably impossible to distinguish between a shared mechanism that introduced mutations independent of common descent as a result of shared sequence and common biochemistry versus common descent." This may well be true (it depends on the precise details of the mechanism in question), but again I am puzzled - if you cannot distinguish between NRMs and identity by descent, then how can you claim to be able to identify specific NRMs from sequence data (as you do in your post on human mtDNA near the bottom of page 5 of this thread)? It appears that you identify the NRMs by looking for sequence changes which are contrary to expectations from common descent (i.e. phylogenetic incongruities). Isn't this in fact utterly incompatible with your assertion that NRMs are "impossible to distinguish" from genetic similarities due to common descent?
Moreover, stating that NRMs may occur independently in two separate organisms due to "shared sequence and common biochemistry" simply begs the question - why do the organisms have "shared sequence and common biochemistry" in the first place, if not common descent? If you are prepared to explain some sequence similarities between organisms as pre-dating the origin of NRMs (as you must be, in order for "shared sequence" to be an explanation for NRMs), then why bother postulating NRMs at all?
It strikes me that you are basically arguing here that organisms have similar DNA sequences because they have similar DNA sequences!
I look forward to your response, both to this post and on the topic of the alpha-actinins.
Mesk.
[ 12. May 2003, 04:53: Message edited by: Mesk ]
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peter borger
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posted 14. May 2003 00:38
hi Pim,
In response to your suggestions:
1. provide us with this common mechanism even wild guesses.
I already provided one possible mechanism: the imperfect hairpin. It has been postulated by Lynn Ripley to explain the muations in T4 virus and is described in detail in Lynn Caporale's book 'Darwin in the Genome', page 38. How common are these mechanims? Nobody knows since nobody did research into the mechanisms (except Lynn Ripley). But such mechanisms must be very common considering the mutations that line up and give the illusion of common descent. Even shared mutations can be expected between distinct genes with a high degree of sequence homology in different species (as observed for the ZFX in gorilla and ZFY in lemur&tamarin. It is unequivocal evidence for NRM).
2. provide us with an example which shows your claims about common descent and common mechanisms.
A common mechanism operable in disctinct species that have related multipurpose genomes and the same biochemistry predicts that such organisms may share positional mutations (=NRM1). That is what we observe for instance between genes from chimp and human.
best wishes
Peter
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Pim van Meurs
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posted 14. May 2003 01:21
Peter:
But such mechanisms must be very common considering the mutations that line up and give the illusion of common descent.
So far you have yet to show that these mutations line up and give the illusion of common descent. May I propose that you spend some effort doing so?
Peter: as observed for the ZFX in gorilla and ZFY in lemur&tamarin. It is unequivocal evidence for NRM
I strongly disagree and would like to point out that beyond the assertion there is nothing to really support this.
Peter: A common mechanism operable in disctinct species that have related multipurpose genomes and the same biochemistry predicts that such organisms may share positional mutations (=NRM1). That is what we observe for instance between genes from chimp and human.
So you claim that there exists some 'mechanism' which gives the impression of common descent? Any evidence of such or just speculation? Remember that common descent is based on more than just some genes lining up.
Certainly Lynn Ripley did not seem to agree with your suggestions so I will see what I can find out about the hairpin.
I found some other attempts of yours to explain your argument
quote:
PB: Random mutations that appear over and over on the same spot are called POSITIONAL NONRANDOM MUTATIONS and will give the illusion of common descent. Hairpins are only formed upon internal complementarity of DNA (=base pairing) and are therefore sequence dependent. So, the mutaions are dependent on DNA sequences (as observed for the nonrandom mutaions in p53). Same 'class' same sequence, same mechanism, same non-random mutation, same shared mutations, NO common descent. Easy as that. Get it?
Source
Random mutations that appear on the same spot will give the illusion of common descent? Surely non random mutations need not give the illusion of common descent.
Or as SLPX puts it so nicely " I find it fantastic that this process would produce results that just happen to be largely congruent with phylogenetic hypothesis based on non-molecular data."
Or as PaulK points out "Anyway to deal with your assertions.
1) p37-38 deal with the "hairpin" model. Since such models require that the existing sequence is similar they can only upset phylogenetic analysis at fine resolutions- which you apparently accept, unless you wish to claim each species is a seperate creation (which would then pose the question of why the sequences are similar enough to see such mutations). It poses no threat to the larger scale phylogenies which you seem to object to."
It would be helpful if you were to work your way through an example which supports your claims.
It would also be helpful if you could explain the hairpin model a bit more clearly since I have a hard time finding much relevant references. A single page in a book is not enough for this purpose.
So far I found the following statement by Lynn Helen Caporale
quote:
Certain mutations arise by "correction", to palindromic DNA, of quasipalindromic secondary structures formed on the lagging strand when it becomes single-stranded during nucleic acid replication. Thus, context-dependent effects upon genetic variation include mutations that appear to have been "templated" by neighboring DNA sequences, with specific DNA sequences associated with mutation "hotspots" and other "predictable" genetic alterations (Glickman and Ripley, 1984; Trinh and Sinden, 1991, Rosche et al. 1997) with implications for human genetic disease (Gordenin et al. 1997).
And she concludes the section with
quote:
A variety of enzymatic mechanisms for genetic variation have evolved with qualitatively different effects (Arber 1997); these mechanisms modulate local nucleotide variation, rearrange DNA sequences present in the genome, and enable the acquisition of new DNA sequences through horizontal gene transfer (Kidwell 1993, Hartl 1997). Thus, evolution can work on a far more colorful palette than simple random nucleotide change.
Rosche has a good website on leading/lagging strand mutagenesis
Rosche, W.A., Trinh, T.Q. and R.R. Sinden. (1997) Leading strand specific spontaneous mutation corrects a quasipalindrome by an intermolecular strand switch mechanism. J. Mol. Biol., 269, 176-187.
So far it seems to me that you agree with the data supporting common descent but you claim that there exists another possibility namely common mechanisms. I would like to see your ideas of common mechanisms worked out to explain the data we see and show that common mechanisms would lead to the same data as found. So far you seem to reject common descent and thus insist on interpreting the data as common mechanism but you have failed to show either that common descent has been disproven or that common mechanisms explain the data. In fact you seem to suggest that common descent and common mechanisms are two pathways that would lead to identical data?
It seems quite coincidental thus that the consistent phylogenetic findings and other evidence of common descent all seem to match. So far the evidence that the data match another model seems lacking but I am looking forward to you presenting us some worked out examples beyond the mere assertion. We all agree that non random mutations happen and as I have shown non random mutations are not anti-Darwinian.
[ 14. May 2003, 01:26: Message edited by: Pim van Meurs ]
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Mesk
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posted 14. May 2003 03:46
With respect to the imperfect hairpin mechanism Peter postulates as one possible explanation for his version (perhaps we could call it ICIBINCD for "I Can't Believe It's Not Common Descent!"?) of NRM: as I understand it, such a mechanism would require that the genetic sites in question must be present in one "arm" of a pseudopalindromic region; moreover, the corresponding site in the other "arm" of the pseudopalindrome should contain a nucleotide which is complementary to the derived allele of the putative NRM site, and this pseudopalindromic sequence should be highly conserved between all taxa in which the alleged NRM has occurred.
These are hard predictions of the imperfect hairpin hypothesis, so Peter should be able to confirm or deny the activity of the hairpin mechanism by examining the sequence surrounding putative NRMs for such features. If they are not present, then the probability of this mechanism operating are minimal.
I will point out that the total proportion of any organism's genome that satisfies these conditions is likely to be small, so I find it highly implausible that the hairpin mechanism could explain even a small fraction of the millions of tightly coordinated base substitutions which would presumably had to have occurred to give the illusion of common descent. I would be highly intrigued if Peter could provide data suggesting otherwise.
Mesk.
[ 14. May 2003, 03:57: Message edited by: Mesk ]
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peter borger
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posted 15. May 2003 02:32
Mesk, you are correct that the imperfect hairpin mechanism is only ONE possible explanation for alignment of mutations. I also demonstrated another example of NRM probably not related to imperfect hairpins: the 1g5 gene in Drosophila. IMO this is NOT achieved by an imperfect hairpin, since I could not detect a palindromic sequences in the vicinity of the shared mutations. Therefore, I propose a protein and/or RNA mediated mechanisms for the alignment of shared mutations in this region. In eukaryotes a major part of trancribed RNA is noncoding byt has a regulatory function, so I would not be surprised. It must be something like that since it pertians a neutral region, which excludes selection. (Unless the intron is also subject to selection. IMO this not at all farfetched since introns are likely to be involved in fine tuning of regulation of gene expression. They may even be involved in direction of mutations. Who knows?).
You assert that the total proportion of any organism's genome that satisfies palindromic conditions is likely to be small. However, did you ever consider palindromic interactions of genes with similar (pseudo)genes? DNA has two complementary strands. Plenty of palindromic interactions are imaginable for two almost identical genes, with either strand. To form a hairpin the sequences don't have to be in close proximity either. Plenty of NRM may have their origin in alignment of such sequences during celdivision.
We are only beginning to understand genomes and how they work and they certainly did not arise by a random mechanism as some might think. That can also be concluded from a careful comparison of primate chromosomes (as discussed on the EvC- forum).
Peter
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Rex Kerr
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posted 15. May 2003 19:22
We need not necessarily know the mechanism of non-random mutation in order to detect its presence. The original claim was that nonrandom mutation was fooling phylogeny building to such a degree that we were assuming common descent where there was none. To support this claim, all we need to see is a demonstration that there are high levels of nonrandom mutation, and a demonstration that this nonrandom mutation significantly affects the standard phyolgenies we build.
So far, the ZFY data has been offered, and despite having relatively few mutations to work off of, I have demonstrated that phylogenies constructed off of the two halves of the gene produce essentially the same topology (certainly compatible topologies). So at this point there is absolutely no evidence that phylogenies are in any way mistaken.
Let me point out that simply demonstrating a mutational hotspot or specific type of nonrandom mutation is only evidence that phylogenies are mistaken if it can be demonstrated that the changes occur frequently enough and in a manner such that phylogenies are actually broken. There is ample evidence for mutational hotspots, and occasionally ideas on the mechanisms, but the critical piece that is missing is an impact on phylogenies that is so massive as to generate the illusion of common descent. (Note: the only way that I can think that this could happen is if the NRMs are intentionally and coordinatedly placed across the genome by a mischevous pixie or somesuch, in just such a manner that would happen to correspond with what would be expected from a single pattern of common descent. Anything less should generate wildly different phylogenetic trees when different genes are examined, trees with large numbers of mutations and yet no statistically significant resolvable branching pattern, and so on; none of which is the case.)
In the absence of a clear demonstration of broken phylogenies, it would be exceedingly premature of me to agree that common descent has been called into doubt, or even that phylogenies are substantially messed up. I strongly encourage others to do likewise.
Now, I do think that a discussion of mechanisms of nonrandom mutations is interesting; and finding cases of nonrandomness in timing, position, and nucleotide identity are all valuable in enhancing our understanding of the process of mutation. Unfortunately, this is completely outside my area of expertise, so I'll refrain from commenting in detail. But I did want to call attention to the considerable gap between this and some of the claims that have been made.
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Mesk
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posted 20. May 2003 23:09
Peter,
You propose "protein and/or RNA mediated mechanisms for the alignment of shared mutations" in the 1g5 gene of Drosophila, and cite the existence of transcribed, non-coding regulatory RNA as evidence for this. If the mechanism is DNA modification based on a regulatory RNA template, then again there are ways to test this hypothesis. For example, do a BLAST search against the D. melanogaster genome with the region of the 1g5 gene which you propose has undergone NRM, and search for genomic regions which might correspond to the transcribed RNA template you postulate. This template sequence should correspond to the putative derived allele for the NRMs in question. You should also be able to identify potential RNA polymerase binding sites close to the sequence. The identification of such potential templates would add some plausibility to your claims.
In the second paragraph of your post you describe the process of "palindromic interactions of genes with similar (pseudo)genes" as one other possible mechanism. Strictly speaking such interactions need not be palindromic, and the process you describe is in fact a relatively well-known phenomenon known as gene conversion. Again, this is a hypothesis which can readily be tested using sequence data from your putative examples of NRM - simply search the genome of the organism in question with the "derived allele" sequence of your NRM, and identify any potential candidate templates for gene conversion. I would be interested to see what you find.
You claim to have demonstrated NRM through a "careful comparison of primate chromosomes" on the EvC board. I can only assume you are referring to this thread. I do not have time to go through the entire thread, but certainly in your opening post you gave no real explanation of how you were identifying NRMs from the sequences in question. It appeared that you were identifying them purely by looking for phylogenetically discordant bases - but again, such an approach directly contradicts your claim that NRMs can give a false impression of common descent! If, as you assert, NRMs line up to give the impression of common descent, how can you possibly propose to identify them by looking for mutations which don't line up with the predictions of common descent?!? This is the third time I have asked you to resolve this quite blatant self-contradiction, and so far you have given no coherent response.
Finally, Peter, it has now been a fortnight since you promised a response to my post on the alpha-actinins. Do you intend to continue discussion on that matter, or should I assume that you have now renounced your claims that actinin-3 somehow contradicts modern evolutionary theory?
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peter borger
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posted 22. May 2003 02:08
Hi Mesk,
In response to your mail dd 06-05-03:
I’ve read a bit further into the ACTN genes and whether it is in accord with standard evolutionary theory. A publication you are certainly familiar with can be found in Hum Mol Gen 2001, 10:1335-1346. The authors state that “absence of alpha actinin-3 is not associated with an obvious disease phenotype, suggesting that ACTN3 is redundant in humans”.
According to your new data the ACTN3 gene is NOT redundant in humans as your study on genotype frequencies in athletes has shown. As mentioned before, there still is a double negative population of sprinters, demonstrating that they do not require the gene for their performances. That you can find a statistical significant difference between controls, sprinters and endurance doesn’t say anything about the causal relationship of non-functionality of the ACTN3 gene and performance in this subpopulation. A gene will only spread throughout the entire population when constant selective constraints are present, for instance selection on sprint performance (to out run predators?). Otherwise it will get lost.
You say that your data do not mean that ACTN3 has been evolving without selective constraints – i.e. neutrally – since its inception. In protein coding genes the functional constraint is estimated by the ratio of non-synonymous (Ka) and synonymous (neutral) substations (Ks). A look at Ka and Ks values for ACTN3 of 0.016subs/site and 0.045subs/site, respectively, and tells me that the gene is under stringent selective constraint. However, you have to assume purifying selection for every neutral point mutation during evolution of this gene otherwise we would expect many alleles within species. But we don’t: all baboons and chimps are homozygous for the wild-type allele (Mills et al, Human Mol Gen 2001). So, apparently you have to assume purifying selection on such positions. On the other hand, a NRM that inactivates a gene that doesn’t negatively affect fitness will easily spread through the population by genetic drift. (I would like to see all variable positions in the ACTN3 gene, also for the N terminal region, since that would give me better understanding whether or not these are neutral positions. I expect that the value of Ks for the entire gene is determined by this region). Or do you mean purifying selection against mutations in the gene? That would make sense.
I am aware that my claim of neutral selection is illogical -a paradox- but that is how one is to falsify standard theory: demonstrate that selection doesn’t work at the level of the genome through the introduction of a paradox. I already demonstrated that if one is to understand the mutations in Drosophila’s 1G5 genes one also has to introduce neutral selection. And the ACTN3 gene is a likely candidate (see above). Neutral selection is nothing and falsifies evolutionary theory. Unless one is to assume non-random mutations, but that would completely invalidate the neo-Darwinian concept.
Furthermore, apparently there is not only the 577X mutation in the ACTN2 gene but another shared mutation -523R- that occurs in linkage disequilibrium with 577X, suggesting that they have arisen independently in the human population. What I like to see now are all raw data (i.e. the sequences of all tested subjects), since the disequilibrium of the two point mutations in the same gene implicates either selection on exons or -more likely- positional non-random mutations. Sequences demonstrating the double mutants would clearly shed some light in this matter. You have access to the sequences, so could you please let me know?
It should also be mentioned that the 577X mutation is not restricted to only one human subpopulation (as for instance the CF gene in Caucasians only). All human subpopulation have the 577X allele with a relative frequency varying between 0.1(0.05) (=African Bantu) and 0.54(0.05) (=Javanese). According to theory this implicates a very old mutation. The Africans most probably demonstrate the lowest 577X frequency due to selection to out sprint lions? Otherwise much higher frequency would be expected in African populations due to genetic drift of this ancient mutation. But probably the ACTN3 gene simply demonstrates positional NRM similar to the lamin gene.
A strong confirmation of NRM due to identical DNA sequence would have been the same NRM mutations in baboon or chimpanzee (as found in ZFX and ZFY for gorilla and lemur, respectively). The authors analyzed 36 baboons and 33 chimpanzees but could not find the 577X mutation. Therefore the authors suggest that the polymorphism originated after the separation of human and chimp lineages. However, the absence of the mutations doesn’t mean that NRM could not have done the trick since the frequency of 577X in chimp can be very low: the authors analyzed only 33 chimp and >1000 human chromosomes. So, this remains to be elucidated. (Do you know publications/website of the ‘all’ ACTN3 sequences of chimp and human so I can have a look at the raw data?).
Furthermore, the 4 ACTN genes are located on 4 different chromosomes. We do not know of molecular mechanisms that duplicate genes and translocate them to other chromosomes. The genes certainly did not arise through 2 rounds of genome duplication (2R hypothesis). This hypothesis has been rejected over and over, since most gene families demonstrate a (A) (B,C,D) topology, rather than (A,B)(C,D) topology. The (A)(B,C,D) topology also accounts for the ACTN genes (Dixson et al, J Mol Evol 2003). That most genes have the (A)(B,C,D) implicates one round of genome duplication [(A)(B)] followed by two duplications of B to spawn C and D [(A)(B,C,D)]. This is even more evidence for non-random phenomena present during evolution. Apparently, evolution -if extant at all- is a guided process governed by rules and laws. However, as long as there is no association between genetic redundancies and gene duplications I doubt evolution in general.
best wishes,
peter
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peter borger
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posted 02. June 2003 00:24
In response to Pim's mail dd 14 may 2003:
That NRM mechanism are common is also demonstrated here:
http://news.bmn.com/news/story?day=021001&story=2
Against the background of high levels of radiation we always find the same positions in the DNA that mutate. Clearcut evidence for NRM1. Such mutations will of course line up --also in distinct organisms-- since they only depend on the physicochemical properties of the DNA. And considering uniformitarianism I don't see an objection why such mutations are not introduced on the same spot in chimps and gorillas. They have the same sequences and biochemistry anyway.
You are under the impression that I did not yet show that these 'mutations line up and give the illusion of common descent'. In my opinion, I gave several examples that demonstate NRM within species, but you apparently don't agree with my interpretations. Furthermore, I have not seen any evidence for gradual Darwinian evolution. On the contrary, a careful scrutiny of primate chromosomes is clearcut evidence of the opposite, i.e. nongradual (directed) evolution. So what exactly is your point?
You also strongly disagree with me on the NRM positions in the ZFY gene of lemur/tamarin and ZFX of gorilla and you would like to point out that beyond my assertion there is nothing to really support this. Maybe you could point out where these NRM support the evolutionary vision? As long as they do not, I take them as evidence for NRM.
You also say that 'my evidence of mechanism that that give the illusion of common descent is based upon speculation. However, I'd strongly encourage you to read my examples carefully. They show NRM and I take them of justify my claim. And your assertion that common descent is based on more than just some genes is simply not true. All that socalled evidence can easily be explained by the GUToB.
In addition I do not know whether or not Lynn Ripley did not seem to agree with my suggestions, since I never had a chat with her. I had, however, a very interesting chat with Lynn Caporale about NRM and she agreed with me that NRM certainly has implications for phylogenetic analysis. My stance is, however, more extreme.
Furthermore, it seems to me that you don't get a grip on NRM and the implications for standard evolutionary theory. What you fail to see is that due to the same original DNA sequences (either for protein or RNA) and the same original biochemistry of similar original MPGs (they only differed from each other w.r.t. shuffled interspaced DNA elements, e.g. the primate karyotypes) mutations can be introduced over and over on the same spot. In the same MPG and natural background it is almost certain that mutations are introduced on the same spots (see ref above). Therefore, they will give the illusion of common descent.
According to you SLPX (Dr Page) puts it so nicely: "I find it fantastic that this process would produce results that just happen to be largely congruent with phylogenetic hypothesis based on non-molecular data."
But I think NRM is not fantastic at all. It is expected from the same physicochemical properties of the sequences plus the same biochemistry. Evolution of all life forms on earth by random mutations followed by selection THAT is fantastic. If evolution plays a role on this planet to generate all life forms, than it is mediated by universal information carriers (creatons) that interact with matter in a biogenic field. That would make much more sense than suggesting a random process. Random mechanisms plus selection to give rise to all life forms is not even backed up by scientific observations.
You also seem to agree with PaulK points out that "they (hairpin model) can only upset phylogenetic analysis at fine resolutions- which you apparently accept, unless you wish to claim each species is a seperate creation (which would then pose the question of why the sequences are similar enough to see such mutations). It poses no threat to the larger scale phylogenies which you seem to object to." However, in a careful analysis of Dr Page's best example of common descent I already pointed out how we can find MPGs according to GUToB. That also addressed PaulK comments. Unfortunately I was not allowed to continue my discussions on GUToB on the EvC forum.
You say that "it would be helpful if you were to work your way through an example which supports your claims." Where exactly do you not understand what I claim about the 1g5 genes, and the ZFY/ZFX genes? Furthermore, what about the genes that do not fit the phylogenetic tree I referred to already? For instance IL-1beta, cytC, but also ADH, and many more? For IL-1beta you first have to assume that it duplicated and than you have to assume that it got lost because it is not present in th genome. But what kind of explanation is that? It is also nothing but speculation, to get the data in accord with standard theory. And standard theory most likely is wrong.
You also quote Lynn Helen Caporale:
quote:
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Certain mutations arise by "correction", to palindromic DNA, of quasipalindromic secondary structures formed on the lagging strand when it becomes single-stranded during nucleic acid replication. Thus, context-dependent effects upon genetic variation include mutations that appear to have been "templated" by neighboring DNA sequences, with specific DNA sequences associated with mutation "hotspots" and other "predictable" genetic alterations (Glickman and Ripley, 1984; Trinh and Sinden, 1991, Rosche et al. 1997) with implications for human genetic disease (Gordenin et al. 1997).
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quote:
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A variety of enzymatic mechanisms for genetic variation have evolved with qualitatively different effects (Arber 1997); these mechanisms modulate local nucleotide variation, rearrange DNA sequences present in the genome, and enable the acquisition of new DNA sequences through horizontal gene transfer (Kidwell 1993, Hartl 1997). Thus, evolution can work on a far more colorful palette than simple random nucleotide change.
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These quotes do not pertain Lynn Ripley's research. They describe just another mechanism that operates in the genome to give rise to NRM. That Dr caporale thinks these mechanism evolved is entirely her opinion. These observations suggest however that all mechanism to induce variation are currently already preexisting in the genome and it is for certain that Darwin made his observations on these mechanism (in his description of his breeding experiments that --by the way-- clearly demonstrated non-random mutations). Not understanding the source of these observations the NDTers assumed them to be random. Apparently they are not.
In addition, you think that "I agree with the data supporting common descent but you claim that there exists another possibility namely common mechanisms." However, I have come to the conclusion that the molecular data presented in literature could equally well be in accordance with common origin due to common sequences and mechanisms, and thus do not advocate common descent. It is up to the evolutionary community to exclude common mechanism as the origin of mutations prior to propaging claims that evolution by random mutations plus selection is a fact. The opposite is more likely to be a fact: NRM & guided nongradual 'evolution'.
And you say that you would like to see your ideas of common mechanisms worked out to explain the data we see and show that common mechanisms would lead to the same data as found. As demonstrated in a previous mail to Rex, shared sequences and mechanisms in conjunction with random mutions can give rise to the illusion of common descent. It was an oversimplification but it clearly demonstrates what I mean. And there is increasing evidence for similar mechanisms (read Caporale's book, she gives a nice overview).
You may also be under the impression that I have failed to show that common descent has been disproven or that common mechanisms explain the data. But in fact I have demonstrated that common descent and common mechanisms are two pathways that may lead to identical data. If one is to advocate the one, the other has to be excluded. A lot of work to do. I already provided several genes that demonstrate NRM (in conjunction with RM). And I didn't even have to search. In all these genes positinal NRM will give the false impression of common descent.
Finally, that it seems quite coincidental that the consistent phylogenetic findings and other evidence of common descent all seem to match is simply not true. There may be many exception that proof the rule, but what they really demonstrate is disproof of common descent. In the eyes of GUToB is is not at all coincidential that such mutations line up, since similar MPG have the same original DNA sequences and biochemistry. As a result the data could be interpreted as common descent, while in fact all they have is a common origin.
It seems that we both agree that non random mutations happen and in potency they could be no threat to Darwinian mechanisms of selection. However, these mutaions question the validity of common descent derived from molecular data and that is my primary point. Otherwise I would have stressed that selection is in doubt here (as I did for the 1g5 and ACTN genes). Apparently both pillars of evolutionary theory can be shown to be doubtful at the level of the genome.
best wishes,
Peter
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Mesk
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Member # 630
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posted 02. June 2003 03:16
Peter,
With respect to the "neutral selection" claim, you appear to have wholly ignored what I wrote on that topic and simply repeated your earlier claims. Let me ask you this simple question: If ACTN3 possessed important functions for most of mammalian evolution (as it does, for instance, in mice), and those functions were only lost during the evolution of the human lineage, is there any paradox here for evolutionary theory? I put it to you that there is not; and I suggest (as explained in my previous post) that the evidence supports precisely this scenario. There is absolutely no reason to postulate absurdities such as "neutral selection" - the evolutionary history of ACTN3 is perfectly explicable by standard evolutionary theory.
You ask for sequence data from the ACTN3 gene in order to test for the presence of NRM. It is worth pointing out that all of our published genotype data on the R577X and Q523R polymorphisms were obtained using RFLP techniques, not sequencing. Most of the detailed sequence data from this region of ACTN3 that we have obtained so far are unpublished, so I am unable to release them publicly. However, if you formulate your hypotheses explicitly (i.e. tell me exactly what features should be present in the sequence data if NRM are present) then I can test these hypotheses myself and return the information to you.
You mention that a strong indicator of NRM would have been if the 577X allele had independently been found in non-human primates (although it is worth pointing out that this would also have been perfectly consistent with common descent). I agree that it is possible that the 577X allele is present in chimpanzees at a low frequency, and this would be consistent with our current hypothesis that the 577X allele has been maintained for a long period of time by balancing selection. We will be undertaking further sequence analysis of chimpanzees as soon as we obtain the relevant DNA samples.
You suggest that "we do not know of molecular mechanisms that duplicate genes and translocate them to other chromosomes." This is patently false. Such a result could be achieved in a number of ways by well-understood molecular mechanisms - for instance, intrachromosomal duplication followed by an interchromosomal translocation event, or even by a simple lone chromosomal translocation event during meiosis. The increasingly disputed 2R hypothesis is by no means the only mechanism by which a four-member gene family might have been formed. I fail to see how any of this provides evidence for "non-random phenomena" or supports a view of evolution as "a guided process governed by rules and laws." Modern evolutionary theory is more than capable of explaining the genesis of gene families, and I strongly recommend that you familiarise yourself with the extensive literature on this topic before you make any further claims along this vein.
Finally, you point to the lack of association between genetic redundancies and gene duplications as a reason to "doubt evolution in general." Firstly, there is an association between gene duplication and redundancy - in that recently duplicated genes are more likely to be redundant than other genes - but this fact alone does not explain the high degree of functional redundancy in genomes. It seems that network buffering or functional degeneracy plays a significant role here. I have recently read several excellent reviews on this topic (and there have been some relevant threads on the ARN Intelligent Design forum), and will hunt up the references for you.
All this aside, I am rather puzzled by your remark. Why the reliance on the duplication-redundancy association as an indicator of the validity of evolutionary theory? It seems like a poor marker at best. Surely stronger predictions of evolutionary theory - the congruence of morphological and molecular phylogenies, for instance - would be better targets?
Mesk.
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Pim van Meurs
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Member # 541
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posted 02. June 2003 12:10
Peter: These observations suggest however that all mechanism to induce variation are currently already preexisting in the genome and it is for certain that Darwin made his observations on these mechanism (in his description of his breeding experiments that --by the way-- clearly demonstrated non-random mutations). Not understanding the source of these observations the NDTers assumed them to be random. Apparently they are not.
Ofcourse most of the mechanisms to induce variation are part of the call itself, although there are external factors to be considered such as chemicals/radiation etc.
NDT did not assume them to be random but observed them to be random with respect to fitness. That they are not random wrt location in the genome, or even wrt time does not negate that these changes seem to be random wrt fitness (utility in the present environment).
Peter: You also say that 'my evidence of mechanism that that give the illusion of common descent is based upon speculation. However, I'd strongly encourage you to read my examples carefully. They show NRM and I take them of justify my claim. And your assertion that common descent is based on more than just some genes is simply not true. All that socalled evidence can easily be explained by the GUToB.
Your examples do not show that there is an illusion of common descent. In fact one of the worked out examples showed otherwise. If NRM is refering to mutations non random wrt location or time but not fitness then NRM is purely Darwinian.
Peter: Against the background of high levels of radiation we always find the same positions in the DNA that mutate. Clearcut evidence for NRM1. Such mutations will of course line up --also in distinct organisms-- since they only depend on the physicochemical properties of the DNA. And considering uniformitarianism I don't see an objection why such mutations are not introduced on the same spot in chimps and gorillas. They have the same sequences and biochemistry anyway.
YOu may have misread the article, it is not the same positions but rather in the same areas or hot spots. Further more you have yet to show that such mutations would lead to common descent. All we are asking for is a worked out example.
From the article
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The observation that radiation accelerates point mutations at all is unexpected, at first glance, because radiation was, until recently, thought to generate primarily DNA lesions (1). A potential explanation is provided by our additional observation that these radiation-associated point mutations are also evolutionary hot spots, indicating that the radiation indirectly increases the cell's normal (evolutionary) mutation mechanism
Natural radioactivity and human mitochondrial DNA mutations Lucy Forster, Peter Forster, Sabine Lutz-Bonengel, Horst Willkomm, and Bernd Brinkmann
PNAS October 15, 2002 ,vol. 99, no. 21 pp 13950-13954
And I am interested to find out why common descent infered from DNA seems to match common descent infered from anatomy and fossils?
[ 02. June 2003, 12:24: Message edited by: Pim van Meurs ]
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