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Some fun at Larrys blog

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1 Some fun at Larrys blog on Sat Oct 08, 2016 9:33 pm

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[*]http://sandwalk.blogspot.com.br/2016/10/extending-evolutionary-theory-james.html



[*]ElShamah777Monday, October 03, 2016 6:23:00 PM

Mikkel wrote:

"How does he propose this works, in the sense of, how can such a mechanism possess any "knowledge" about what genetic alteration will be adaptive and, much more importantly, what kind of evidence is there that such a mechanism even exists? " 

Shapiro writes:

"Research dating back to the 1930s has shown that genetic change is the result of cell-mediated processes, not simply accidents or damage to the DNA. This cell-active view of genome change applies to all scales of DNA sequence variation, from point mutations to large-scale genome rearrangements and whole genome duplications (WGDs). This conceptual change to active cell inscriptions controlling RW genome functions has profound implications for all areas of the life sciences."

Remarkably, he is not the only one. 

Evidence of non-random mutation rates suggests an evolutionary risk management strategy

http://www.nature.com/nature/journal/v485/n7396/full/nature10995.html

"Upon comparing 34 Escherichia coli genomes, we observe that the neutral mutation rate varies by more than an order of magnitude across 2,659 genes, with mutational hot and cold spots spanning several kilobases. Importantly, the variation is not random: we detect a lower rate in highly expressed genes and in those undergoing stronger purifying selection. Our observations suggest that the mutation rate has been evolutionarily optimized to reduce the risk of deleterious mutations. Current knowledge of factors influencing the mutation rate—including transcription-coupled repair and context-dependent mutagenesis—do not explain these observations, indicating that additional mechanisms must be involved. The findings have important implications for our understanding of evolution and the control of mutations."

Cool. Didnt know that evolution has the remarkable hability of "evolutionary risk management strategy "

Risk management is something that i usually atribute to highly intelligent bankers, stock portfolio managers etc... LOL 

But thats not the first time that we see proponents of evolution atributing intelligence to a mechanism that should not have this hability, as Professor Richard Watson for example, that sayd 

"new research shows that evolution is ABLE TO LEARN from previous experience, which could provide a better explanation of how evolution by natural selection produces such apparently intelligent designs.

haha. 
Reply

Replies





[*]DiogenesWednesday, October 05, 2016 4:54:00 PM

ElShamah77, your quote is precisely the reason why Shapiro is dishonest, as he is claiming things have been "observed" since the 1930's which have in fact never been observed. I have read Shapiro's papers and his claims. Shapiro has NEVER cited a single observed example of his alleged "Natural Genetic Engineering." On the contrary, Shapiro always backs up his ridiculous claims by casting them as a deduction: 

1. Cells have complex biochemical control mechanisms, which look like they "know what's good for them", 
2. Cells mutate and evolve, therefore 
3. Cell mutation and evolution are directed because the cell "knows" what kind of mutations are good for it.

This is total bullshit. It's a non sequitur. 1 and 2 are correct, but 3 does not logically follow. Just because cells have complex biochemical responses (e.g. if you put them in sugar, they start expressing proteins to digest sugar) this does not prove Shapiro's claim-- that cells create new, complex, non-repetitive genetic structures that the cell "knows" is good for it, before the mutation is filtered through natural selection.This bolded claim of Shapiro's is bullshit, he never cited any observed example of that.

Thus your Shapiro quote, "Research dating back to the 1930s has shown that genetic change is the result of cell-mediated processes, not simply accidents or damage to the DNA. This cell-active view of genome change applies to all scales of DNA sequence variation, from point mutations to large-scale genome rearrangements and whole genome duplications (WGDs). This conceptual change to active cell inscriptions controlling RW genome functions has profound implications for all areas of the life sciences", is simply bullshit. It's Shapiro's hypothesis, not an observation.

Shapiro has every right to hypothesize whatever he wants. This "Natural Genetic Engineering" might be real, who knows? But he's a crackpot because he writes as if it's been observed, and because he has never suggested a way for his hypothesis to be falsified experimentally, even when I demanded repeatedly that he suggest an experiment to falsify. 

Some of you may remember that a couple years back I pointed out Shapiro's bullshit, and on his blog he attacked me personally. I repeatedly demanded that he suggest a means to falsify his hypothesis, and he never did, he just banned me from his blog. Then he denied banning me and his sycophants called me a liar.




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DiogenesWednesday, October 05, 2016 4:56:00 PM

ElShamah, do not respond to my criticism by citing more authorities' opinions (which you quote but don't understand). From now on, I demand you cite observations, experiments which allegedly show Shapiro's Natural Genetic Engineering being observed. Every time I demand this of Shapiro's creationist sychophants, they never cite an observation. They just quote authorities that I have no respect for. I demolished Shapiro in a fair debate before he banned me.




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DiogenesWednesday, October 05, 2016 5:01:00 PM

And ElShamah's second authority quotes, while accurate, does not agree with Shapiro. It makes a different point that is NOT Shapiro's hypothetical Natural Genetic Engineering.

Your quote: "Upon comparing 34 Escherichia coli genomes, we observe that the neutral mutation rate varies by more than an order of magnitude across 2,659 genes, with mutational hot and cold spots spanning several kilobases.

This is not Shapiro's NGE, it is not news to us and not controversial. 

As I stated above, to repeat myself: Suppose that a particular protein causes a higher mutation rate in one region of the genome compared to a different region. That is "directed" in the sense that some regions have higher RANDOM mutation rates than others... but it isn't news, we've known for a long time that mutation rates are lower e.g. in metabolic genes.

But no observed process is ever "directed" and creative, in the sense that 

1. the cell knows ahead of time that some final mutation states are more fit than others-- e.g. the cell knows that mutating T to A is good, but G or C would be bad-- the cell never knows which final state is "better", and 

2. the mutated final state is new, complex, and non-repetitive. I have to add the second condition because telomerase does create new DNA sequence, but it's a repetition of a short ancient sequence.

So Shapiro is full of it. There are no observed examples of NGE, and when I demand observations from Shapiro's sycophants, they never cite observations. They bullshit with some paper about sugar digestion-- duh, we know proteins are expressed in response to environmental changes, that's not a creative mutation-- or they cite authorities they don't understand. 

Enough. I demand you describe experiments, not quote authorities.



[*]ElShamah777Wednesday, October 05, 2016 7:34:00 PM

Diogenes

without error detection and error correction, there would be no life. These mechanisms had to be present from day one, when life began, otherwise the mutation rates would be too high, and cells could never replicate with sufficient accuracy, and they would die. 

In the article published in Nature:

Genetic recombination and adaptation to fluctuating environments: selection for geotaxis in Drosophila melanogaster

we read : 
Heritable variation in fitness is the fuel of adaptive evolution, and sex can generate new adaptive combinations of alleles. If the generation of beneficial combinations drives the evolution of recombination, then the level of recombination should result in changes in the response to selection.

So, genetic recombination was discoverd in 1944 by Barbara McClintock and won the Nobel Prize for her work in 1983. 

Shapiro based his findings on hers. So what happens, is PROGRAMMED MUTATIONS, not random mutations. 

We know that random mutations degenerate the genome.


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DiogenesWednesday, October 05, 2016 10:47:00 PM

Everything you just wrote is factually incorrect, and you didn't answer my question. I demanded an observed example of NGE, not NGE presented as some kind of deduction. You presented no examples of observed NGE. Your reference to recombination is not NGE, not remotely, and is not programmed as you absurdly claim. I already pointed out that crossover experiments show that prob of crossover is proportional to physical distance between genes. Meaning the location of crossover is random. It's not programmed, and your authority quote says nothing about programmed anything.

Shapiro's hypothesis (not "findings", he has no findings) is not based on McClintock's. He's just speculating, and he dishobestly passes off what he thinks as a deduction as observed processes.

You presented no examples of observation of NGE.

Your statement "random mutations degenerate the genome" is ridiculous. Modern research keeps adjusting up the rate of beneficial mutations. A common result is that about 3% of all mutations in E. coli are beneficial. It will depend on species, changes in environment, etc. Lenski's long term E. coil experiment showed that beneficial mutations slow down in a constant environment, but never stop. Genome degeneration never happens unless you turn off natural selection.

I asked for programmed mutations. You cited random mutations. It is ever thus.


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The whole truthThursday, October 06, 2016 6:49:00 AM

ElShamah/Otangelo said:

"without error detection and error correction, there would be no life. These mechanisms had to be present from day one, when life began, otherwise the mutation rates would be too high, and cells could never replicate with sufficient accuracy, and they would die."

Huh? What? The allegedly omnipotent, omniscient, omnipresent, omnibenevolent, perfect sky daddy yahoo-yeshoo-holy-spook designed-created (from day one) all living things (including 'man') with errors that need error detection and error correction? Your sky daddy is apparently incompetent, and errors from day one can't be blamed on 'the fall'. 

Oh, and living things do die. Obviously that error detection and error correction have their own 'errors'. 

"So what happens, is PROGRAMMED MUTATIONS, not random mutations."

So all of the disabling, disease causing, disfiguring, and deadly mutations that have ever occurred "from day one" were/are programmed (designed-created) by yahoo-yeshoo-holy-spook (the imaginary, so-called ' Christian God' that you believe in and worship)? 

"We know that random mutations degenerate the genome."

But didn't you say that mutations are "PROGRAMMED", "not random"? How can random mutations degenerate the genome when random mutations don't exist and have never occurred? 


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Otangelo GrassoThursday, October 06, 2016 7:33:00 AM

Diogenes

In the peer reviewed paper : 

Natural genetic engineering: intelligence & design in evolution?

David W Ussery writes:
Organisms seem 'designed'. When one examines the data from sequenced genomes, the changes appear NOT to be random or accidental, but one observes that whole chunks of the genome come and go. These 'chunks' often contain functional units, encoding sets of genes that together can perform some specific function.

Eukaryotes carry extremely complex splicing mechanisms, upon which genes are rearranged to make novel proteins and organisms. That IS NGE, since the information to carry out the correct splicing, at the right place of the genome, and the right rearranging MUST BE a engeneered , arranged, pre programmed process. So the mere fact that it has been observed to occur, permits to make the logical and rational inference that the process is not random.

As i have more than once challenged Larry, but obviously no answer, the origin of the spliceosome cannot be rationally explained by arguing evolution would be capable of the task. As once more, the whole thing is interdependent. There would be no need , use , and reason for evolution to produce a spliceosome, if there were not the information on the genome in order for for the spliceosome to find out where to cut, and to stick together, in order to get new protein products.

As James Barham wrote:

We are finally beginning to realize, on the basis of irrefutable empirical evidence, as well as more careful analysis of Darwinian theory itself, that purposeful action in living things is an objectively real phenomenon that is presupposed, not explained, by the theory of natural selection.

And finally, you are simply wrong by arguing that Shapiro did not back up his claims. He infact did, as he writes here:

McClintock's idea, she went on to identify the predicted ring chromosomes in the variegating mutants (McClintock 1932). Other mutants induced by X-ray treatment also carried chromosome rearrangements. Sections of chromosomes were deleted, translocated, inverted, and duplicated. All of these rearrangements could result from breaking chromosomes at two sites and then rejoining the broken ends to build brand new chromosome structures. These were quite different from the "gene mutations" imagined by Muller and his colleagues.
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Otangelo GrassoThursday, October 06, 2016 7:51:00 AM

The whole truth wrote:

""We know that random mutations degenerate the genome."

But didn't you say that mutations are "PROGRAMMED", "not random"? How can random mutations degenerate the genome when random mutations don't exist and have never occurred? "

There must be a error detection and repair mechanism right from the beginning. "

Natural selection cannot act without accurate replication, yet the protein machinery for the level of accuracy required is itself built by the very genetic code it is designed to protect. Thats a catch22 situation. It would have been challenging enough to explain accurate transcription and translation alone by natural means, but as consequence of UV radiation, it would have quickly been destroyed through accumulation of errors. So accurate replication and proofreading are required for the origin of life. How on earth could proofreading enzymes emerge, especially with this degree of fidelity, when they depend on the very information that they are designed to protect? Think about it.... This is one more prima facie example of chicken and egg situation. What is the alternative explanation to design ? Proofreading DNA by chance ? And a complex suite of translation machinery without a designer? 

furthermore, we read here:

http://nrc58.nas.edu/RAPLab10/Opportunity/Opportunity.aspx?LabCode=50&ROPCD=506451&RONum=B7083

Since the editing machinery itself requires proper proofreading and editing during its manufacturing, how would the information for the machinery be transmitted accurately before the machinery was in place and working properly? Lest it be argued that the accuracy could be achieved stepwise through selection, note that a high degree of accuracy is needed to prevent ‘error catastrophe’ in the first place—from the accumulation of ‘noise’ in the form of junk proteins specified by the damaged DNA. 

That does not mean, even with the repair mechanisms in place, errors and mutations do not occur. They do, but in a lifepermitting range, but as Pitman puts it:

" Genome stability is continually challenged by a diverse array of mutagenic forces that include errors during DNA replication, environmental factors such as UV radiation, and endogenous mutagens such as oxygen free radicals generated during oxidative metabolism. This damage must also be detected and repaired on a constant basis. Of course, this repair isn't perfect and therefore likely contributes significantly to the actual mutation rate over and above that estimated by the indirect methods"
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lutesuiteThursday, October 06, 2016 8:43:00 AM

@ Otangelo"

In the peer reviewed paper : 

Natural genetic engineering: intelligence & design in evolution?

David W Ussery writes...


Here is the first sentence of the abstract for this "peer-reviewed paper":

There are many things that I like about James Shapiro's new book "Evolution: A View from the 21st Century" (FT Press Science, 2011).

That doesn't sound like scientific paper, so much as it does a book report written by a nine-year-old. Perhaps this explains how this article got published in this (now defunct) "journal":

BioMed Central is retracting 43 papers, following their investigation into 50 papers that raised suspicions of fake peer review, possibly involving third-party companies selling the service.

Hmmm....


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judmarcThursday, October 06, 2016 9:03:00 AM

How on earth could proofreading enzymes emerge, especially with this degree of fidelity, when they depend on the very information that they are designed to protect? Think about it.... This is one more prima facie example of chicken and egg situation.

When water freezes - it makes ice! How could something so hard emerge when it depends on the presence of a liquid? Think about it...this is one more prima facie example of a chicken and egg situation.

Thanks to you Otangelo, we now know only God can make ice.


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Mikkel Rumraket RasmussenFriday, October 07, 2016 3:56:00 AM

"Natural selection cannot act without accurate replication, yet the protein machinery for the level of accuracy required is itself built by the very genetic code it is designed to protect."

The natural fidelity of polymerase enzymes is high enough to faithfully replicate tens of thousands of bases without making a single error. So in point of fact, error correction machinery is not strictly required for replication of DNA. All the genes of the replication system can be encoded and replicated by even relatively error-prone DNA-polymerases without them making a single error in these relatively few genes. Enzymes have been deliberately designed to be EIGHTY THOUSAND TIMES more error prone than wild-type variants and they still faithfully replicate almost ONE HUNDRED THOUSAND BASEPAIRS without making a single error. 

You seem to be under the misapprehension that without error correction machinery, the mutation rate would be instantly catastrophic. That is simply not the case. As usual your understanding is abysmal and your ignorance is astounding.


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Otangelo GrassoFriday, October 07, 2016 6:40:00 AM

Mikkel 

"The natural fidelity of polymerase enzymes is high enough to faithfully replicate tens of thousands of bases without making a single error."

Correct. And how does it achieve that feat ?!!

Bruce Alberts explains in : The High Fidelity of DNA Replication Requires Several Proofreading Mechanisms

If the DNA polymerase did nothing special when a mispairing occurred between an incoming deoxyribonucleoside triphosphate and the DNA template, the wrong nucleotide would often be incorporated into the new DNA chain, producing frequent mutations. The high fidelity of DNA replication, however, depends not only on complementary base-pairing but also on several “proofreading” mechanisms that act sequentially to correct any initial mispairing that might have occurred.

3′-to-5′ proofreading exonuclease clips off any unpaired residues at the primer terminus, continuing until enough nucleotides have been removed to regenerate a base-paired 3′-OH terminus that can prime DNA synthesis. In this way, DNA polymerase functions as a “self-correcting” enzyme that removes its own polymerization errors as it moves along the DNA

And afterwards, postreplicative mismatch repair is required as well. 

Resumed: No inbuilt 3'-5' exonuclease in the DNA polymerase holoenzyme, and no postreplication repair (PRR) mechanisms, no life !! 

As usual your understanding is abysmal and your ignorance is astounding. But as a intellectual masochist, you must feel a warm fuzzy feeling right now, Mikkel ??!!
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judmarcFriday, October 07, 2016 6:57:00 AM

Bruce Alberts explains

Otangelo, you mean the very same Bruce Alberts who says:


"[But] intelligent design is not science, it has no testable hypotheses, no proposed methodologies


[*]
Laurence A. MoranFriday, October 07, 2016 7:05:00 AM

Mikkel is perfectly correct, as usual. The error rate of DNA polymerase without proofreading is more than sufficient to copy DNA efficiently in organisms with small genomes such as bacteria. The first cells on Earth had small genomes. Proofreading evolved later. Most modern polymerases still don't have a proofreading mechanism. 

As usual, Otangelo's understanding of basic biochemistry is abysmal and his ignorance is astounding. He is incapable of learning even when you take the time to explain thiings to him.


[*]
EdFriday, October 07, 2016 7:06:00 AM

Otangelo, can you please point to the bit where the author states: "Resumed: No inbuilt 3'-5' exonuclease in the DNA polymerase holoenzyme, and no postreplication repair (PRR) mechanisms, no life !! "

What the author does write though:
"As a result, a great deal is known about the detailed enzymology of DNA replication in eucaryotes, and it is clear that the fundamental features of DNA replication—including replication fork geometry and the use of a multiprotein replication machine—have been conserved during the long evolutionary process that separates bacteria and eucaryotes."

Ahh, the author is describing how DNA replication is NOW, not how it was or how it evolved.

He continues:
"There are more protein components in eucaryotic replication machines than there are in the bacterial analogs, even though the basic functions are the same. Thus, for example, the eucaryotic single-strand binding (SSB) protein is formed from three subunits, whereas only a single subunit is found in bacteria."

So what he's saying, there's a simpeler version of DNA replication in bacteria, compared to the eucaryotic system, but the proteins involved perform the same function. 

In fact you've (again!) just quoted a book which refutes your IC fantasy. Well done!!


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Otangelo GrassoFriday, October 07, 2016 8:03:00 AM

Ho Ho Ho!! 

Papa Larry must come to help out his pupill, Mikkel, from the humiliating situation.

As Koonin writes The Logic of Chance: The Nature and Origin of Biological Evolution : 

Eigen’s theory revealed the existence of the fundamental limit on the fidelity of replication (the Eigen threshold): If the product of the error (mutation) rate and the information capacity (genome size) is below the Eigen threshold, there will be stable inheritance and hence evolution; however, if it is above the threshold, the mutational meltdown and extinction become inevitable (Eigen, 1971). The Eigen threshold lies somewhere between 1 and 10 mutations per round of replication (Tejero, et al., 2011) regardless of the exact value, staying above the threshold fidelity is required for sustainable replication and so is a prerequisite for the start of biological evolution. Indeed, the very origin of the first organisms presents at least an appearance of a paradox because a certain minimum level of complexity is required to make self-replication possible at all; high-fidelity replication requires additional functionalities that need even more information to be encoded (Penny, 2005). The crucial question in the study of the origin of life is how the Darwin-Eigen cycle started—how was the minimum complexity that is required to achieve the minimally acceptable replication fidelity attained? In even the simplest modern systems, such as RNA viruses with the replication fidelity of only about 10^3 and viroids that replicate with the lowest fidelity among the known replicons (about 10^2; Gago, et al., 2009), replication is catalyzed by complex protein polymerases. The replicase itself is produced by translation of the respective mRNA(s), which is mediated by the immensely complex ribosomal apparatus. Hence, the dramatic paradox of the origin of life is that, to attain the minimum complexity required for a biological system to start on the Darwin-Eigen spiral, a system of a far greater complexity appears to be required. How such a system could evolve is a puzzle that defeats conventional evolutionary thinking, all of which is about biological systems moving along the spiral; the solution is bound to be unusual. 

As usual, Larrys understanding as University Professor of basic biochemistry is abysmal and his ignorance is astounding. He is incapable of learning even from a laymen as me, even when you take the time to explain thiings to him.

Funny, if it would not be sad.....
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lutesuiteFriday, October 07, 2016 8:52:00 AM

Anyone else smell a quote mine? Koonin's whole book can be found at the link below, with Otangelo's quote(mine) on p.355. You be the judge:

http://evolocus.com/Textbooks/Koonin2011.pdf


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Laurence A. MoranFriday, October 07, 2016 9:14:00 AM

Otangelo Grasso is an expert at shifting goalposts. He first claimed that proofreading and error correction were essential. He said,

... without error detection and error correction, there would be no life. These mechanisms had to be present from day one, when life began, otherwise the mutation rates would be too high, and cells could never replicate with sufficient accuracy, and they would die. 

This is not correct. Error detection and proofreading were not necessary in the beginning. They evolved later when genomes became more complex.

This demonstrates that Otangelo Grasso does not understand anything about biochemistry. However, instead of admitting he was wrong he now shifts the argument to the incorporation accuracy of DNA polymerase itself. This is so typical. It's why I find it impossible to have an intelligent conversation with him. 

It's a good thing I turned off my irony meter before reading this ... 

As usual, Larrys understanding as University Professor of basic biochemistry is abysmal and his ignorance is astounding. He is incapable of learning even from a laymen as me, even when you take the time to explain thiings to him.

Funny, if it would not be sad.....


[*]
judmarcFriday, October 07, 2016 9:33:00 AM

As Koonin writes The Logic of Chance: The Nature and Origin of Biological Evolution

Good book. You might try reading it, or even better, understanding it.

By "understanding," I mean understanding why these scientists you quote support the theory of evolution.


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Otangelo GrassoFriday, October 07, 2016 9:48:00 AM

Larry wrote

"he was wrong he now shifts the argument to the incorporation accuracy of DNA polymerase itself. "

That was the crux of the question, when Mikkel wrote :

"The natural fidelity of polymerase enzymes is high enough to faithfully replicate tens of thousands of bases without making a single error. "

Well, yes, it is, precisely because it INCORPORATES ESSENTIAL REPAIR MECHANISMS, as pointed out above. 

But maybe i am missing something, and it would be kind of your part to back up your claim :

" This is not correct. Error detection and proofreading were not necessary in the beginning. They evolved later when genomes became more complex. "

Any evidence for this ??
Delete


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EdFriday, October 07, 2016 9:50:00 AM

Otangelo, reads scientific literature, like he reads the bible, cherry picking all the way.
He's been caught lying/ quote mining Davies, Bruce Alberts, Koonin, only picking out the bits which confirm his fantasy (ID), ignoring everything which doesn't fit or refutes his own fantasy.

And he also is under the impression god is knitting nucleotides together when you run a PCR.


[*]
Otangelo GrassoFriday, October 07, 2016 9:58:00 AM

Ed wrote

" ignoring everything which doesn't fit or refutes his own fantasy."

What exactly i am ignoring ?!

And if you read my comment above, i am actually eagerly waiting Larry to back up his claims. Be assured that i WILL NOT IGNORE his evidence, and be the first to change my mind, if the eventually new scientific evidence ( which i might not know of yet ) refutes what i learned so far. 

" And he also is under the impression god is knitting nucleotides together when you run a PCR ". 

No, thats actually scientists doing this. Thats why it is a example of INTELLIGENT DESIGN, and invalid to refute what i wrote. 
Delete


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Laurence A. MoranFriday, October 07, 2016 10:17:00 AM

Otangelo Grasso says,

That was the crux of the question, when Mikkel wrote :

"The natural fidelity of polymerase enzymes is high enough to faithfully replicate tens of thousands of bases without making a single error. "

Well, yes, it is, precisely because it INCORPORATES ESSENTIAL REPAIR MECHANISMS, as pointed out above. 


RNA polymerase is an examples of a polymerase that does not have proofreading. The proofreading activity of DNA polymerases can be inactivated by mutation. Their modern nucleotide incorporation error rates are about 10^-6, which means they make a mistake about one time in a million nucleotides incorporated. They don't need additional repair or proofreading mechanisms to accurately copy a genome of about 500,000 bp. (That's enough for hundreds of genes.) 

Mikkel said "tens of thousands," which is a lot less than one million. He was perfectly correct.

I think Otangelo should stop digging.


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Otangelo GrassoFriday, October 07, 2016 10:39:00 AM

Larry wrote:

" Their modern nucleotide incorporation error rates are about 10^-6, which means they make a mistake about one time in a million nucleotides incorporated. They don't need additional repair or proofreading mechanisms to accurately copy a genome of about 500,000 bp. (That's enough for hundreds of genes.) "

Bruce Alberts writes :

https://www.ncbi.nlm.nih.gov/books/NBK26850/

Rare tautomeric forms of the four DNA bases occur transiently in ratios of 1 part to 104 or 105. These forms mispair without a change in helix geometry: the rare tautomeric form of C pairs with A instead of G, for example.

If the DNA polymerase did nothing special when a mispairing occurred between an incoming deoxyribonucleoside triphosphate and the DNA template, the wrong nucleotide would often be incorporated into the new DNA chain, producing frequent mutations. The high fidelity of DNA replication, however, depends not only on complementary base-pairing but also on several “proofreading” mechanisms that act sequentially to correct any initial mispairing that might have occurred.

So, who is right, Larry ??!!

"I think Otangelo should stop digging. "

Why ? You call yourself a " skeptical biochemist "

I am doing precisely this. I am skeptical and critical. I elucidate precisely where the evidence leads, to. 

Are you disconfortable that the evidence does not lead where you want to, Larry ?!
Delete


[*]
lutesuiteFriday, October 07, 2016 10:52:00 AM

And Otangelo just keeps on digging.


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Mikkel Rumraket RasmussenFriday, October 07, 2016 11:18:00 AM

He's still operating on the idea that a DNA polymerase without proofreading would become a catastrophic error machine, rather than the reality that it just ups the error rate from some extremely small rate to one a few orders of magnitude higher yet still entirely feasible for an organism with a small genome. 

He quotemines Koonin talking about the origin of life in the context of a fully living entity with a translation system. 
Koonin gives error rates of some extremely error-prone RNA polymerases from viruses. Even so a replication fidelity of 10^3 would be one error in a thousand basepairs, which is more than enough for a self-replicating enzyme to be able to stay significantly above the Eigen-threshold when it replicates itself. Besides, viral RNA polymerase fidelities are due to natural selection for extremely high mutation rates. 

Koonin writes, "The Eigen threshold lies somewhere between 1 and 10 mutations per round of replication". 

But a typical Ribozyme is only up to a few hundred bases (and so are the quasi-selfreplicators evolved by Joyce et al), so with an error rate of 10^-3 a hypothetical self-replicating Ribozyme could still replicate itself somewhere around five to ten times before a mutation crept in. 

More pertinently, DNA polymerases are much more accurate and even with proofreading disabled will still replicate tens of thousands of basepairs without a single error. Exactly what I wrote to begin with. Notice how not even a single of Otangelo's references challenges this. That's because it's a concrete real-world fact that the people he quotemines are also aware of.

See Otangelo, if you actually bother to do the math, rather than just copy-paste cherry-picked sections from the literature, turns out this isn't actually a problem. Not for DNA, not even for RNA polymerases and a hypothetical minimal living entity without translation or proofreading machinery. 

In point of fact: Real ribozymes suggest a relaxed error threshold

"The error threshold for replication, the critical copying fidelity below which the fittest genotype deterministically disappears, limits the length of the genome that can be maintained by selection. Primordial replication must have been error-prone, and so early replicators are thought to have been necessarily short1. The error threshold also depends on the fitness landscape. In an RNA world2, many neutral and compensatory mutations can raise the threshold, below which the functional phenotype3, rather than a particular sequence, is still present4, 5. Here we show, on the basis of comparative analysis of two extensively mutagenized ribozymes, that with a copying fidelity of 0.999 per digit per replication the phenotypic error threshold rises well above 7,000 nucleotides, which permits the selective maintenance of a functionally rich riboorganism6 with a genome of more than 100 different genes, the size of a tRNA.This requires an order of magnitude of improvement in the accuracy of in vitro-generated polymerase ribozymes7, 8. Incidentally, this genome size coincides with that estimated for a minimal cell achieved by top-down analysis9, omitting the genes dealing with translation."

And now over to Otangelo who will bring up another irrelevancy, either by quotemining more irrelevant material or just plain make shit up. Or well, I concede he can continue the PCR route and just respond "pfff... hahaha" when shown to be wrong for the fiftieth time.


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Mikkel Rumraket RasmussenFriday, October 07, 2016 11:33:00 AM

"Rare tautomeric forms of the four DNA bases occur transiently in ratios of 1 part to 104 or 105."

That's between tenthousand and one hundred thousand.
Let's remind ourselves what I wrote to begin with and what I responded to: 
Otangelo: ""Natural selection cannot act without accurate replication, yet the protein machinery for the level of accuracy required is itself built by the very genetic code it is designed to protect."

Me: The natural fidelity of polymerase enzymes is high enough to faithfully replicate tens of thousands of bases without making a single error. So in point of fact, error correction machinery is not strictly required for replication of DNA. All the genes of the replication system can be encoded and replicated by even relatively error-prone DNA-polymerases without them making a single error in these relatively few genes. Enzymes have been deliberately designed to be EIGHTY THOUSAND TIMES more error prone than wild-type variants and they still faithfully replicate almost ONE HUNDRED THOUSAND BASEPAIRS without making a single error. 

So I'm still correct and you're still wrong. You complete dolt. 

Keep digging Otangelo, keep digging.


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Otangelo GrassoFriday, October 07, 2016 12:21:00 PM

Mikkel wrote

" He's still operating on the idea that a DNA polymerase without proofreading would become a catastrophic error machine, rather than the reality that it just ups the error rate from some extremely small rate to one a few orders of magnitude higher yet still entirely feasible for an organism with a small genome. "

If DNA replication would be sufficient error prone to not cause cancer , aging, and cell death, why at all would cells produce a array of various repair mechanisms, that is :

A proofreading system that catches almost all errors
A mismatch repair system to back up the proofreading system
Photoreactivation (light repair)
Removal of methyl or ethyl groups by O6 – methylguanine methyltransferase
Base excision repair
Nucleotide excision repair
Double-strand DNA break repair
Recombination repair
Error-prone bypass

??? 

Take a peace of paper, write a sentence and insert a number of mispelled grammatical errors. Now ask someone that only understands chinese to find your errors. Could he without understanding english ? How could error be detected without a preceeding program and convention of what is correct ? Furthermore, the whole machinery to produce proteins would have to be in place to produce the error correction enzymes. 

James Shapiro points out that:

all cells from bacteria to man possess a truly astonishing array of repair systems which serve to remove accidental and stochastic sources of mutation. Multiple levels of proofreading mechanisms recognize and remove errors that inevitably occur during DNA replication. … cells protect themselves against precisely the kinds of accidental genetic change that, according to conventional theory, are the sources of evolutionary variability. By virtue of their proofreading and repair systems, living cells are not passive victims of the random forces of chemistry and physics. They devote large resources to suppressing random genetic variation and have the capacity to set the level of background localized mutability by adjusting the activity of their repair systems
Delete


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judmarcFriday, October 07, 2016 12:26:00 PM

Keep digging Otangelo, keep digging.

If it leads to more interesting stuff from you, Mikkel, I'd encourage it as well. ;-)

Thanks.


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Mikkel Rumraket RasmussenFriday, October 07, 2016 1:46:00 PM

"If DNA replication would be sufficient error prone to not cause cancer , aging, and cell death, why at all would cells produce a array of various repair mechanisms, that is :"

First of all, a single-celled organism can't die to age or cancer, those are uniquely problems that multicellular organisms suffer from. 

So why would higher replication fidelity evolve? 
Because on average, less errors mean higher fitness. More errors do not mean instant death, it usually means more deleterious mutations, not instant lethality. That's also why higher replication fidelity can evolve from non-correcting enzymes. They still work even without error correction and don't cause the death of the carrier organism, so if they mutate and increase their accuracy, the carrier will have children with fewer deleterious mutations. If you could actaully think all this would be immediatelyapparent to you. 

You are stuck in the black-and-white thinking of a fundamentalist. You think it has to be fully the way it is now, or else it could not work at all. 

If you read a book with a spelling error in 1 out of every 100 words, YOU CAN STILL READ IT. It's annoying, maybe some of the meaning is ambiguous and in rare cases, lost. But it's readable. But a book with 1 spelling error in every 1000 words is even easier to read. Maybe no meaning is lost there at all, and there are only cases of ambiguity in the details. And a book with 1 error in every 5000 words is even better and so on and so forth. 

Notice how it doesn't have to be ENTIRELY GIBBERISH vs COMPLETELY ERROR FREE. There is a spectrum between the two extremes. 
At a basic level, the base-pairing of ribonucleotides is itself a level of error correction. The system is intrinsically accurate. It is simply not possible under normal physiological conditions for the error-rate to be on the order of total gibberish.


[*]
Laurence A. MoranFriday, October 07, 2016 2:02:00 PM

Otangelo Grasso writes,

So, who is right, Larry ??!!

Both of us are right. That shouldn't come as a big surprise since I did my Ph.D. thesis with Bruce Alberts working on DNA replication.

He and I both know that the error rate of the polymerization reaction, without proofreading, is several orders of magnitude less than the reaction with proofreading. However, we both know that the polymerization reaction, by itself, is still accurate enough to replicate lots of DNA without making any mistakes. 

And we both know that a study of modern polymerases strongly suggests that the primitive enzymes did not have a proofreading mechanism. 


[*]
Mikkel Rumraket RasmussenFriday, October 07, 2016 2:55:00 PM

"Both of us are right. That shouldn't come as a big surprise since I did my Ph.D. thesis with Bruce Alberts working on DNA replication."

This is poetic irony. I think I've chuckled at this for a good 5 minutes now.


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lutesuiteFriday, October 07, 2016 3:29:00 PM

A genuine Marshal Mcluhan/Annie Hall moment. Priceless! I bet Ontangelo doesn't even know what just hit him.


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John HarshmanFriday, October 07, 2016 4:01:00 PM

the error rate of the polymerization reaction, without proofreading, is several orders of magnitude more than the reaction with proofreading.

Fixed. You know what he meant.


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Laurence A. MoranFriday, October 07, 2016 6:18:00 PM

Thanks John. "More" is correct. My bad.


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Otangelo GrassoFriday, October 07, 2016 6:59:00 PM

Larry asserts that

" we both know that the polymerization reaction, by itself, is still accurate enough to replicate lots of DNA without making any mistakes."

In contrast, Alberts writes:

" The high fidelity of DNA replication, however, DEPENDS not only on complementary base-pairing but also on SEVERAL "PROOFREADING" MECHANISMS that act sequentially to correct any initial mispairing that might have occurred. " 

So Alberts does NOT agree with you, Larry. 

Furthermore, following paper : DNA Damage, DNA Repair, and Nanomaterial Toxicity states:

DNA repair is regarded as one of the essential events in ALL life forms.
Delete


[*]
Otangelo GrassoFriday, October 07, 2016 7:43:00 PM


Mikkel wrote

" That's also why higher replication fidelity can evolve from non-correcting enzymes. They still work even without error correction and don't cause the death of the carrier organism, so if they mutate and increase their accuracy, the carrier will have children with fewer deleterious mutations. If you could actaully think all this would be immediately apparent to you. "

You just sucked that out of your finger ? No, you just had a sudden burst of fantasious imagination , Mikkel ? Anyway, you provide a very nice example of what i call PSEUDO - SCIENCE. That is, when someone makes up a superficial scientific story without any evidence whatsoever to back up the claim. But you are not alone, Mikkel. It happens all the time in scientific papers.... LOL. 

Let us digg deeper, shall we ??!!

Do you have a idea about the complexity of the three steps that give rise to High-Fidelity DNA synthesis ?? 

5ʹ → 3ʹ polymerization 1 in 10^5
3ʹ → 5ʹ exonucleolytic proofreading 1 in 10^2
Strand-directed mismatch repair 1 in 10^3
Combined 1 in 10^10
Delete


[*]
Otangelo GrassoFriday, October 07, 2016 7:51:00 PM

This comment has been removed by a blog administrator.

View user profile http://elshamah.heavenforum.com

2 Re: Some fun at Larrys blog on Sat Oct 08, 2016 9:36 pm

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lutesuiteFriday, October 07, 2016 8:33:00 PM

ROTFLMAO! Keep it up, Otangelo. You have no idea how amusing it is to watch you keep spinning your wheels after you claim has been demonstrated to be wrong by direct empirical observation. That claim, you seem to have forgotten is: "Natural selection cannot act without accurate replication, yet the protein machinery for the level of accuracy required is itself built by the very genetic code it is designed to protect." The evidence that demonstrates that to be false has been presented to you, yet you refuse to accept it. And your posts above do not address this.

IDiot.


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EdSaturday, October 08, 2016 5:35:00 AM

Luitesuite, are you sure? I mean Otangelo did write this a few posts above:

"And if you read my comment above, i am actually eagerly waiting Larry to back up his claims. Be assured that i WILL NOT IGNORE his evidence, and be the first to change my mind, if the eventually new scientific evidence ( which i might not know of yet ) refutes what i learned so far. "

He can't have lied, I mean he's a devout christian, they can't lie... right??


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Mikkel Rumraket RasmussenSaturday, October 08, 2016 5:35:00 AM

"Let us digg deeper, shall we ??!!"

Yes, let's do that. Keep going. XD


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Mikkel Rumraket RasmussenSaturday, October 08, 2016 7:05:00 AM

As a committed trooper of God, doing God's work on Earth, not only can Otangelo not lie, and it can't be the case that there is something he doesn't understand, he literally can't be wrong. It's impossible. The chosen one, a prophet send to us by God Himself! Us lowly nonbelievers just can't keep up with this glorious oracle of scientific facts. 

It's been good boys but now is time to buy sandals and prayer mats and PRAISE THE LORD!


[*]
Otangelo GrassoSaturday, October 08, 2016 8:06:00 AM

kkkk.... lick your wounds, Mikkel.... the situation is terrible.
Delete


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photosynthesisSaturday, October 08, 2016 1:06:00 PM

Otangelo,

I don't expect honesty from you, but prove me wrong. Where in your quote does Alberts deny what Larry said. Remember that Larry was very specific in what he said:

"is still accurate enough to replicate lots of DNA without making any mistakes"

Alberts is talking about high fidelity, but he's not saying that the polymerase alone cannot replicate lots of DNA without making any mistakes.

Do you understand that at all? Show us that honesty you were claiming. Show that you understand your mistake.

I won't expect much from you, so I call you an illiterate imbecile right now. I know you won't admit that you neither can know what high-fidelity means in that quote, nor whether or not that quote contradicts Larry's point.

You're an illiterate imbecile.

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