molecular genetic proof against random mutation (1)

Dear Taz,you write:
Hi Peter, the largest problem with your statements concerning mutation and randomness appear to me to be a confusion with respect to: 1) randomness with an equal probability of a specific occurance over the range of possibilities, 2) randomness with a non-equal proability of a specific occurance over a range of possibilities, 3) and a non-random occurance of a specific possibility over a range. I am sure that there is a better statistical means of saying this, my stats are self taught although sufficient to compile, analyze and submit clinical and production data through the FDA.NDS deals with the second, not the first as you seem to be indicating.I say:
Let's assume you are right.Next you say:
In fact, every reference that you have pointed out supports this treatment of the results far more than number 3 (your apparent approach).I say:
Could you please expand a bit for the 1G5 gene.
In my opinion, the mutations are introduced in the 1g5 gene independent of histons, since then one would expect them to occur roughly every 200 bp, and they don't. Besides, the mutations are also non-random with respect to NUCLEOTIDE and POSITION. Two non-random phenomena in one gene.You say:
The Science paper on Histones, which I had on hand, is very supportive of this interpretation as well.I say:
What Science paper on histones? Ref?You say:
The higher rate of mutations in actively transcribing genes has been well known for years.I say:
So, mutations are independent from DNA replications? A similar observation has been demonstrated for ZFY in comparison to ZFX regions (Kim et al, J of ? will look it up) So, it is dependent on transcription? Nicely fits in my hypothesis.You say:
The fact that both the primary and secondary structure of genes play a role in the probability of a mutational event at those sites is also well known.I say:
So, actually you say there is a mutation inducing mechanism that involves the structure of genes? That would also nicely fit in my hypothesis. Could you expand a bit on this with references, please?You say:
The mutational frequency that everyone talks about is an average of the much higher probability sites and the much lower probability sites. Your directed mutation seems to me to be nothing more than the increased probability based on structural features and is therefor not in conflict with NDS at all.I say:
God doesn't play dice .best wishes,
Peter

Peter Borger, do you have any response to messages 167 and 168?

wj,Since you alerted me to the GLO/scurvy genes-should-get-turned-back-on argument over on Cre v Evo, I wondered if my asthma was going to get better anytime soon.......Mark------------------
Occam's razor is not for shaving with.

dear taz,You write:
quote:
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Originally posted by wj:
I am curious as to whether the GLO pseudogene issue, previously mentioned on this thread, was ever resolved.
Is there any evidence that humans synthesise ascorbic acid, either through spontaneous oxidation (message #101) or some undiscovered pathway? Is there any evidence of a population of vitamin C synthesisers such as nomads or eskimos?--------------------------------------------------------------------------------I have been able to find no evidence to back up PB's claims (Peter, I am using PB to differentiate you from the other pro-evolution Peter, hope that you do not mind).I say:
No, I don't.You say:
Peters "source" for the two fold mutation was a comment by a person claiming to be a researcher posting onto a medical questions board.
He essentially claimed that 1) there was also a mutation in a lactonase based activity gene and 2) that the reaction which glo performed occured at low rates in situ. I have been unable to find ANY data suporting assertion number one in any of the medical, biological or biochemical publications and I have associates with access to the most wide ranging databases in the world.I say:
Thanks for your searches. We need this elusive Dr Banschbach, I guess.You say:
I think that assertion number two is in error as the oxidation/reduction event required for the generation of the same intermediate as the GLO gene synthesises occurs under more stringent conditions than are generally found in vivo, namely strong acids and a metallic catalyst (info from Strietweiser, Organic Chemistry).I say:
Has anybody ever attempted to look at these things in vitro? I mean, have hepatocytes been cultured and assessed for vit c production and/or lactonase expression? And has been discriminated between productions and release? (For instance, does addition of a protein synthesis inhibitor block lactonase production, but not the release of vit c?). I am not aware of such studies, but I would really like to know. Otherwise they have to be performed.You say:
The second oxidation/reduction event which actually produces ascorbic acid is spontaneous but it is helped along by its position next to the first and by a resulting partial resonance structure. Finally, the rate of production cited by PB's source is actually the release rate by the liver in dietery scurvy conditions.I say:
The release rate does not say anything about the production rate (if still produced, I mean). If it is stored in the liver how long would it take for the liver to be depleted? Do you know, Taz?
However, there were considerable amounts of survivers during the long overseas voyages in the 15-16 century that could last up to 6-12 months, indicating that this part of the population still had vit c, since they didn't die from scurvy. Was it due to an excellent storage system or due to low productions? Both would make the GLO gene redundant, though.You say:
As to the eskimoes and nomads, the only data that I found dealt with eskimo's and it was discovered that, beofre their diets changed, they ate a lot of raw fish which was rich in ascorbic acid. So much for a sub-population which made ascorbic acid.quote:
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In Peter Borger's scenario of directed (by environmental factors) mutations, wouldn't deprivation of dietary vitamin C be a significant directing environmental factor? If only a single mutation is required to convert the GLO pseudogene back to a functional GLO gene and prevent scurvy, why hasn't this mutation been witnessed in dietary stressed humans?
--------------------------------------------------------------------------------If the vitamin was not present in the diet (a level of 200 - 400 mg/day is easily achieved) then yes, it would be a stresor. As to the mutations, I believe that there have been subsequent, non-shared, mutations in the glo gene since the first primate mutational event long ago. I have been unable to get to the NIH to get the paper so I do not have sequence data here. The final answer is that I do not think that there is data in eukaryotes to support PB's directed mutagenesis claims, in any genes.I say:
The latter is only a matter of opinion. As mentioned in previous letters to this board, there may be two types of mutations: random and non-random. Therefore, it can be speculated from exon X of the GLO gene that both types of mutations play a role in the accumulation of mutations in this gene.
The evolutionary vision is that the shared mutations have been introduced in the ancestor and are inherited afterwards. So you see a nice alignment of mutations on certain spots. Evidence for common descent! Other mutations are not shared and have therefore recently been mutated and are not shared. At least that is the evolutionary claim. However, if both a non-random and a random mechanism are involved, the shared mutations could be due to a mechanism, while the non-shared mutations are due to randomness (= equivalent to the evolutionary explanation). We would also observe alignment of mutations, albeit not due to common descent.
A close look at the 1G5 gene in Drosophila demonstrates that shared mutations can be introduced irrespective of common descent. To be specific, the mutations introduced in the subpopulations found in Italy, Peru and USA III are non-random with respect to position and nucleotide, i.e. same spot, same nucleotide. If the study was carried out in only these three subpopulations the evolutionary conclusion would be that they are all derived from the same ancestor. However, since there are 10 additional subpopulation for comparison, direct common ancestry is highly doubtful (As explained in mail #1 of this thread).
Similar results are found for mutations in subpopulations in Australia III and USA I, and for Japan and Peru. These are the non-random mutations. In addition, one also finds random mutations. The Ig5 gene in D. simulans demonstrates similar, albeit less pronounced, results. Even indel-mutations may be non-random as observed in these sequences.
In conlusion, mutations in the same spot in genes from distinct but related organisms may be the result of a non-random mechanism, while also random mutations exist. Bottomline is, it may be impossible to discriminate between common descent or a common non-random mechanism.Best wishes,
Peter[This message has been edited by peter borger, 10-07-2002]

Dear mark,You ask:
Since you alerted me to the GLO/scurvy genes-should-get-turned-back-on argument over on Cre v Evo, I wondered if my asthma was going to get better anytime soon.......My comments:
Maybe in the next generation? Or the next? It will at least not take millions of years, since asthma recently occurred as a Western society disease and dramatically increased from around 1% in the 1970s to almost 10% in the 1990s. Therefore, it probably involves inheritable (?) (epi)genetic modifications. (And non-random mutations in response to a Western life style?).
Best wishes,
Peter

Dear WI,See mail #184. Any questions, don't hesitate to ask.Peter

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Originally posted by peter borger:
Dear mark,

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You ask:
Since you alerted me to the GLO/scurvy genes-should-get-turned-back-on argument over on Cre v Evo, I wondered if my asthma was going to get better anytime soon.......

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My comments:
Maybe in the next generation? Or the next? It will at least not take millions of years, since asthma recently occurred as a Western society disease and dramatically increased from around 1% in the 1970s to almost 10% in the 1990s. Therefore, it probably involves inheritable (?) (epi)genetic modifications. (And non-random mutations in response to a Western life style?).
Best wishes,
Peter

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But why should the non-random mutations be restricted to my sperm?Why can't I have systemic somatic mutations that cure me? Similarly, what good is GLO pseudogene that allows you to get scurvy & doesn't get switched back on?Mark------------------
Occam's razor is not for shaving with.

Dear mark,You write:
quote:
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Originally posted by peter borger:
Dear mark,
You ask:
Since you alerted me to the GLO/scurvy genes-should-get-turned-back-on argument over on Cre v Evo, I wondered if my asthma was going to get better anytime soon.......My comments:
Maybe in the next generation? Or the next? It will at least not take millions of years, since asthma recently occurred as a Western society disease and dramatically increased from around 1% in the 1970s to almost 10% in the 1990s. Therefore, it probably involves inheritable (?) (epi)genetic modifications. (And non-random mutations in response to a Western life style?).
Best wishes,
Peter--------------------------------------------------------------------------------But why should the non-random mutations be restricted to my sperm?Why can't I have systemic somatic mutations that cure me? Similarly, what good is GLO pseudogene that allows you to get scurvy & doesn't get switched back on?My response:
Sometimes, actually in a considerable amount of cases, people 'overgrow' their asthma for no obvious reasons. I do not say that this is due to somatic mutations, but it could be considered as a mechanism. Or maybe it involves compensatory mutations and/or epigenic modifications. At present, nobody knows. Time to scrutinise.best wishes,
Peter

quote:

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Sometimes, actually in a considerable amount of cases, people 'overgrow' their asthma for no obvious reasons. I do not say that this is due to somatic mutations, but it could be considered as a mechanism. Or maybe it involves compensatory mutations and/or epigenic modifications. At present, nobody knows. Time to scrutinise.

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I not unaware of such occurrences, especially in children. But what's the point of such somatic mutations if it doesn't affect everyone?Perhaps you have a basis of that testable hypothesis, now?Make a prediction, feel lucky, punk? Mark------------------
Occam's razor is not for shaving with.[This message has been edited by mark24, 10-09-2002]

Emphases mine:Mol Biol Evol 1999 Nov;16(11):1633-40Is selection responsible for the low level of variation in the last intron of the ZFY locus?Jaruzelska J, Zietkiewicz E, Labuda D.Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska, Poland.DNA variability was investigated in the last intron of the Y-chromosome-specific zinc finger gene, ZFY, and its X homolog on Xp21.3, ZFX. No polymorphisms were found in the 676-bp ZFY segment in a sample of 205 world-wide-distributed Y chromosomes, other than a solitary nucleotide variant in one individual (nucleotide diversity pi = 0.0014%). In contrast, 10 segregating sites (pi = 0.082%) were identified within 1,089 bp of the ZFX sequence in a sample of 336 X chromosomes. Four of these polymorphisms, which contributed most of the diversity, were located within an Alu insert disrupting the ZFY-ZFX homology (pi Alu = 0.24%). The diversity in the homologous portion of the ZFX intron, although higher than that in ZFY, was lower than that found in genomic segments believed to evolve neutrally; interspecies divergence in both segments was also reduced. Although this suggests that the evolution of both ZFY and ZFX homologs may not be entirely neutral, both Tajima and HKA tests did not reject neutrality. The lack of statistical significance may be attributed to a lack of power in these tests (the low divergence and variability values reduce the power of the HKA and Tajima tests, respectively); furthermore, Homo sapiens has recently undergone a rapid population growth, and selection is more difficult to detect in an expanding population. Therefore, the failure to reject neutrality does not necessarily indicate the absence of selection. In this context, the phylogenetic argument was given more weight in out interpretations. The high level of sequence identity in ZFY and ZFX segments, in spite of their separation 80-130 MYA, reflects a lower mutation rate as compared with other segments believed to undergo unconstrained evolution. Thus, the possibility of weak selection contributing to the low level of nucleotide diversity in the last ZFY intron cannot be excluded and should be kept in mind in the population genetics studies based on Y chromosome variability.***************************************************
Mol Cells 2000 Oct 31;10(5):512-8Evolution of the X-linked zinc finger gene and the Y-linked zinc finger gene in primates.Kim HS, Takenaka O.Division of Biological Sciences, College of Natural Sciences, Pusan National University, Korea. khs307@hyowon.cc.pusan.ac.krWe have sequenced the partial exon of the zinc finger genes (ZFX and ZFY) in 5 hominoids, 2 Old World monkeys, 1 New World monkey, and 1 prosimian. Among these primate species, the percentage similarities of the nucleotide sequence of the ZFX gene were 96-100% and 91.2-99.7% for the ZFY gene. Of 397 sites in the ZFX and ZFY gene sequences, 20 for ZFX gene and 42 for ZFY gene were found to be variable. Substitution causes 1 amino acid change in ZFX, and 5 in ZFY, among 132 amino acids. The numbers of synonymous substitutions per site (Ks) between human and the chimpanzee, gorilla and orangutan for ZFY gene were 0.026, 0.033, and 0.085, respectively. *In contrast, the Ks value between human and hominoid primates for the ZFX gene was 0.008 for each comparison. Comparison of the ZFX and ZFY genes revealed that the synonymous substitution levels were higher in hominoids than in other primates. The rates of synonymous substitution per site per year were higher in the ZFY exon than in the SRY exon, and higher in the ZFY exon than in the ZFY intron, in hominoid primates.
***********************************************************Interesting how that mirrors evolutionary hypotheses of descent....Must be just a coincidence, I'm sure....

dear Dr Page,I know these articles. Actually, I got a personal copy from Dr Kim. However, the authors do not show the sequences, only the percentages. I was curious whether or not the muations were introduced at random ar not. It didn't show these data.
Furthermore 0.026 and 0.033 is both 0.03. So what's your point w.r.t common descent?best wishes,
Peter[This message has been edited by peter borger, 10-10-2002]

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Originally posted by peter borger:
Furthermore 0.026 and 0.033 is both 0.03. So what's your point w.r.t common descent?

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Not really, it very much depends on the number of significant digits. Many academics forget about the (pardon the pun) significance of sig. digs.Been without sleep or rest for too long. Bed time.------------------
"Chance favors the prepared mind." L. Pasteur
Taz

Dear Taz,You are right, it happens a lot that data are presented with to many significant digits. I will check this one.Take your rest, and best wishes,
Peter

quote:

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Originally posted by peter borger:
dear Dr Page,

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I know these articles. Actually, I got a personal copy from Dr Kim. However, the authors do not show the sequences, only the percentages. I was curious whether or not the muations were introduced at random ar not. It didn't show these data.
Furthermore 0.026 and 0.033 is both 0.03. So what's your point w.r.t common descent?

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best wishes,
Peter

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[This message has been edited by peter borger, 10-10-2002]

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The genetic distance reflects the evidence-supported hypotheses of descent.Should have been obvious.

see:http://www2.norwich.edu/spage/zfy1a.htmIt took all of about 15 minutes. There was a nucleotide link at Pubmed, I downloaded the Genbank files, and made an alignment in XESEE.All common procedures in molecular biology.Looks pretty random to me - even within species (see Ptr1 and 2, Pan troglodytes).Of course, the 'non-random' distributions are what we call synapomorphies.