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Mutation Protocols: Cut-And-Paste DNA with Built-In Tuning Knobs

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We have been discussing lately the idea that mutations, rather than being haphazard, may actually be directed by cellular machinery. In a recent volume of the Annals of the New York Academy of Sciences, several scientists presented evidence in favor of this view. One of these scientists has a paper on what he calls “mutation protocols” – that is, repeated patterns of mutations whose behavior is not only physical, but also logical. In other words, the pattern that the mutation follows is consistent with the overall architecture of the organism. You might call these design-consistent mutations.

In any case, David King gives us examples of two mutation protocols – cut-and-paste functional segments, and tuning knobs.

Tuning knobs are generally implemented in the cell through short sequences of repetitive DNA (called SSRs) — one of the types of DNA previously thought to be junk. The idea was, if it is the same, short DNA sequence over and over again, how can it be useful? If mutations are likely to increase or decrease copy number, aren’t the copies just the result of random copying errors? But it turns out that these short sequences are actually usable *because* they mutate by adding/removing copies, and because of their special placement. These sequences act as “tuning knobs” for the genome. Adding copies is like turning a volume knob one way, and removing copies is like turning it the other. You can also tell that these are specially placed, because if a mutation creates an SSR where there wasn’t one to begin with, this often leads to diseases and even cancer.

So, by having certain sequences signal to the genome “hey I’m a tuning knob”, the mutation system can easily and fairly safely adjust organismal parameters across generations.

The second mutation protocol discussed by King is the copy-and-paste protocol implemented by Transposable elements. These were previously considered “genomic parasites”, but have recently been shown to play a role in providing robust variation in organisms. In other words, transposons can import necessary functions into new sites.

But, what’s even more amazing, is that the functions that the transposons import may themselves have tuning knobs! So, not only is it importing function, it is importing a function with control knobs!

The author also makes an interesting observation – mutations have historically (and in fact still are) described in textbooks to be copying errors, while sexual recombination – which is in fact a mutation – has not been considered in the category of “mutation” because the organism expends considerable energy to accomplish it, and it is so useful for the longevity of the organism. In other words, it wasn’t considered an “error” since it seems to be a part of the design. Likewise, we are finding more and more mutations to actually be part of the design rather than being “errors”.

Of course, this is why I proposed a second-level classification of mutations. A while ago, I proposed separating mutations out into design-consistent and design-inconsistent mutations, and described how one might be able to classify these empirically. I still think this is a useful road to follow.

Starbuck - Those are all excellent points, and you are certainly right on the current state of knowledge. I think that my assertions will be shown to be correct in the long run, but you are correct that as of current knowledge, there isn't yet a plurality of known function of SSRs. I probably should have been more tentative in my statements, but my excitement sometimes gets the better of me. However, the deeper question is which is the best and most effective way to generalize in biology? I would argue that the far more effective mode of generalization is that if you find something where form and function are intertwined, that recurs often, and where we have several known instances of function, that the leap to view this as a general functional pattern is well-justified. I don't know of a good justification to think that this is not a generalized pattern - the simple fact that we haven't yet elucidated one yet is simply a Darwin-of-the-gaps reasoning. However, there might be other, better reasons that I am missing. Similarly, we don't know what every gene in every organism does, but I think that we are well-justified in assuming, at least as a default assumption, that they do perform some function, because they match a pattern which is regular within biology and which intertwines form and function. johnnyb
I usually enjoy your posts. But I am particularly uncomfortable with the "factual" tone of your post. This paper argues in favor of a hypothesis (i.e., We shouldn't automatically regard all mutations as haphazard accidents; evolution ought to be able to shape mutational mechanisms, such as "tuning knobs" based on SSRs, which could plausibly facilitate evolvability).  But your post appears to treat the "tuning knob" hypothesis as established fact.   I am also especially uneasy with certain of your phrases: "because of their special placement" and "these are specially placed".  Although in certain places a newly-arising (and expanding) SSR can certainly cause disease (there are good examples in the literature), the word "often" surely exaggerates the probability of this eventuality.  I doubt whether the placement of SSRs is really "special" -- I suspect that that there are so many "safe" places for SSRs in the genome that the location of any particular SSR might not be at all special.  (It's just that SSRs in maladaptive locations should be quickly eliminated by selection.)  I also suspect that only a fraction (of hundreds of thousands) of SSRs in a genome have a current function; many are probably indeed "junk". Starbuck
johnnyb, this may be of interest:
Revisiting the Central Dogma in the 21st Century - James A. Shapiro - 2009 Excerpt (Page 12): Underlying the central dogma and conventional views of genome evolution was the idea that the genome is a stable structure that changes rarely and accidentally by chemical fluctuations (106) or replication errors. This view has had to change with the realization that maintenance of genome stability is an active cellular function and the discovery of numerous dedicated biochemical systems for restructuring DNA molecules.(107–110) Genetic change is almost always the result of cellular action on the genome. These natural processes are analogous to human genetic engineering,,, (Page 14) Genome change arises as a consequence of natural genetic engineering, not from accidents. Replication errors and DNA damage are subject to cell surveillance and correction. When DNA damage correction does produce novel genetic structures, natural genetic engineering functions, such as mutator polymerases and nonhomologous end-joining complexes, are involved. Realizing that DNA change is a biochemical process means that it is subject to regulation like other cellular activities. Thus, we expect to see genome change occurring in response to different stimuli (Table 1) and operating nonrandomly throughout the genome, guided by various types of intermolecular contacts (Table 1 of Ref. 112). http://shapiro.bsd.uchicago.edu/Shapiro2009.AnnNYAcadSciMS.RevisitingCentral%20Dogma.pdf
i.e. now this may be a bit simplistic for what you are trying to accomplish, but if dedicated, and sophisticated, molecular mechanisms are specifically changing portions of DNA, and diligently correcting 'truly random chemical fluctuations and replication errors' to DNA, as Shapiro has noted, then why in the world do Darwinists presuppose that ANY of these directed changes to DNA, that are mediated by these sophisticated molecular mechanisms, are random in the first place? It simply makes no sense for them to mandate that they are 'random' changes! In fact, as Koonin recently noted here, finding direct evidence for mediated changes to the genome, by epigentic mechanisms, are in direct violation of the Central Dogma of the modern synthesis of neo-Darwinism:
Does the central dogma still stand? – Koonin EV. – 23 August 2012 Excerpt: Thus, there is non-negligible flow of information from proteins to the genome in modern cells, in a direct violation of the Central Dogma of molecular biology. The prion-mediated heredity that violates the Central Dogma appears to be a specific, most radical manifestation of the widespread assimilation of protein (epigenetic) variation into genetic variation. The epigenetic variation precedes and facilitates genetic adaptation through a general ‘look-ahead effect’ of phenotypic mutations.,,, http://www.ncbi.nlm.nih.gov/pubmed/22913395
johnnyb, since you have been specifically studying the different types of mutations for a while, I was wondering if you knew how the following mutation rate of 60, which brought the mutation rate down from 100-300 per generation, was specifically derived? i.e. Exactly what type of mutations are they counting and how did they classify them so as to arrive at their '60' number.
We Are All Mutants: First Direct Whole-Genome Measure of Human Mutation Predicts 60 New Mutations in Each of Us - June 2011 http://www.sciencedaily.com/releases/2011/06/110613012758.htm
Supplemental notes: on repetitive DNA:
Bob Dylan, ENCODE and Evolutionary Theory: The Times They Are A-Changin' - James Shapiro - Sept. 12, 2012 Excerpt: In 2005, I published two articles on the functional importance of repetitive DNA with Rick von Sternberg. The major article was entitled "Why repetitive DNA is essential to genome function." These articles with Rick are important to me (and to this blog) for two reasons. The first is that shortly after we submitted them, Rick became a momentary celebrity of the Intelligent Design movement. Critics have taken my co-authorship with Rick as an excuse for "guilt-by-association" claims that I have some ID or Creationist agenda, an allegation with no basis in anything I have written. The second reason the two articles with Rick are important is because they were, frankly, prescient, anticipating the recent ENCODE results. Our basic idea was that the genome is a highly sophisticated information storage organelle. Just like electronic data storage devices, the genome must be highly formatted by generic (i.e. repeated) signals that make it possible to access the stored information when and where it will be useful. http://www.huffingtonpost.com/james-a-shapiro/bob-dylan-encode-and-evol_b_1873935.html Safeguarding genome integrity through extraordinary DNA repair - April, 2011 Excerpt: Unlike euchromatin, where most of an organism’s genes reside and where most DNA consists of long, unrepetitive sequences of base pairs, DNA in heterochromatin consists mostly of short repeated sequences that don’t code for proteins; indeed, heterochromatin was long regarded as containing mostly “junk” DNA. Heterochromatin is now known to be anything but junk, playing a crucial role in organizing chromosomes and maintaining their integrity during cell division. It is concentrated near centromeres, where chromatids are in closest contact, which are required to transmit chromosomes from one generation to the next. Maintaining heterochromatin structure is necessary to the normal growth and functions of cells and organisms. http://phys.org/news/2011-04-safeguarding-genome-extraordinary-dna.html
recent note on sexual recombination
Sex Is Not About Promoting Genetic Variation, Researchers Argue - (July 7, 2011) Excerpt: Biology textbooks maintain that the main function of sex is to promote genetic diversity. But Henry Heng, Ph.D., associate professor in WSU's Center for Molecular Medicine and Genetics, says that's not the case.,,, ,,,the primary function of sex is not about promoting diversity. Rather, it's about keeping the genome context -- an organism's complete collection of genes arranged by chromosome composition and topology -- as unchanged as possible, thereby maintaining a species' identity. This surprising analysis has been published as a cover article in a recent issue of the journal Evolution.,,, For nearly 130 years, traditional perceptions hold that asexual reproduction generates clone-like offspring and sexual reproduction leads to more diverse offspring. "In reality, however, the relationship is quite the opposite," said Heng.,,, http://www.sciencedaily.com/releases/2011/07/110707161037.htm
As to fixing 'random' mutations once they have arisen, well that is another story altogether
More from Ann Gauger on why humans didn’t happen the way Darwin said - July 2012 Excerpt: Each of these new features probably required multiple mutations. Getting a feature that requires six neutral mutations is the limit of what bacteria can produce. For primates (e.g., monkeys, apes and humans) the limit is much more severe. Because of much smaller effective population sizes (an estimated ten thousand for humans instead of a billion for bacteria) and longer generation times (fifteen to twenty years per generation for humans vs. a thousand generations per year for bacteria), it would take a very long time for even a single beneficial mutation to appear and become fixed in a human population. You don’t have to take my word for it. In 2007, Durrett and Schmidt estimated in the journal Genetics that for a single mutation to occur in a nucleotide-binding site and be fixed in a primate lineage would require a waiting time of six million years. The same authors later estimated it would take 216 million years for the binding site to acquire two mutations, if the first mutation was neutral in its effect. Facing Facts But six million years is the entire time allotted for the transition from our last common ancestor with chimps to us according to the standard evolutionary timescale. Two hundred and sixteen million years takes us back to the Triassic, when the very first mammals appeared. One or two mutations simply aren’t sufficient to produce the necessary changes— sixteen anatomical features—in the time available. At most, a new binding site might affect the regulation of one or two genes. https://uncommondesc.wpengine.com/intelligent-design/more-from-ann-gauger-on-why-humans-didnt-happen-

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