Intelligent Design

The Sound of The Neutral Theory Exploding

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KABOOM!
Silent Mutations Are Not Always Silent
“Mutations leading to identical amino acid sequences can change protein folding and function”… 12/21/06

Silent Mutations Speak Up
“Biologists have realized that the genetic code harbours a layer of information that they have largely ignored. Again.” 12/21/06

A mutation in a human gene that does not change the resulting amino acid can nevertheless change a protein’s function, according to an online report from Science. The research marks the first time that the phenomenon has been confirmed in mammals.

This time, the focus is on ‘silent’ mutations, single letter changes that were, as their name suggests, generally thought to have little impact on that gene’s instructions for making protein.

But a study published in Science this week shows that two silent mutations are nothing of the sort1. They seem to change the rate at which a drug-pumping protein folds and may help decide whether certain cancers become drug resistant.

Silent — also called synonymous — mutations arise because of the rules of the genetic code. Three chemical letters of DNA, called a codon, instruct the cell to insert a particular amino acid into the string that makes up a protein. But often several different codons code for the same amino acid.

A silent mutation is one that changes the triplet, but leaves the amino acid unchanged. “We were all educated that silent mutations should be ignored, and people really don’t pay attention to them,” says Chava Kimchi-Sarfaty at the National Cancer Institute in Bethesda, Maryland. But it is becoming clear that proteins made of identical amino acids can nevertheless behave differently.

It should be noted that synonymous (silent) mutations are an important part of the neutral theory of molecular evolution and are also an important part of molecular clock theory. If silent mutations are not so silent this handily explains why molecular clocks are such inconsistent timepieces.

One possible explanation is that ribosomes process codons at different rates when the codons differ only by a redundant nucleotide replacement. Think of the ribosome like a caulk gun producing a bead consisting of amino acid polymers that fold as they come out of the gun. If the rate at which the bead comes out changes then the shape it folds into changes as well. Another possibility is post-processing of the protein product where RNA molecules dependent on specific gene sequences alter the way the protein is processed after the ribosome finishes producing it.

Whatever the mechanism it really makes hash out of neutral theory and molecular clock theory.

Also note I’ve blogged in the past about how a design theoretic view predicts things like this. In this comment I described how the NTSC video signal evolved as intelligent designers added additional ways of encoding information to the carrier without effecting the preexisting ways and said we should look for DNA to have multiple encoding schemes one atop the other.

40 Replies to “The Sound of The Neutral Theory Exploding

  1. 1
    PaV says:

    Glad you posted this. I saw it the other day and have alluded to it on several posts already. But I really like the way you anticipated all of this back in Nov.

    Dave, as a programmer, what does this “code within a code” do to the probabilities of randomness bringing biological diversity about? Is it close to a knockout punch?

  2. 2
    DaveScot says:

    PaV

    Programmers really don’t do this kind of thing. It’s more the bailiwick of electronic design (I’ve done both programming and electronic design work in the past – ED and and especially analog ED being further in the past). Although some examples can be called out in digital signal processing. I wrote either here or to a private listserv in the past about how signals can be dug out of what appears for all practical purposes to be random noise. The Global Positioning System modulates signals on carriers broadcast by satellites where the signal on the receiving antenna is so weak it hardly rises above the thermal noise in the antenna. By performing fast fourier transforms on the signal the intelligence from a dozen satellites at once can be recovered from the random noise. Since much of the DNA molecule in eukaryotes appears to be random junk (noise) one might, from a design theoretic view, expect that there is intelligence somehow riding on that noise. I later found that indeed a few of the more outside-the-box thinkers involved in computational biology have been analyzing junk DNA through FFTs looking for patterns to emerge and found some intriguing results. Next year a book is coming out where some of my engineering insights into computational biology should be appearing.

  3. 3
    Jehu says:

    A mutation in a human gene that does not change the resulting amino acid can nevertheless change a protein’s function, according to an online report from Science.

    Wow! Excuse me while I pick my jaw up off the floor.

  4. 4
    Jehu says:

    Also confounding neutral drift theory, the December 14th issue of Nature had an article finding that the combined effect of neutral mutations is deleterious. From the abstract,

    Subjecting TEM-1 to random mutational drift and purifying selection (to purge deleterious mutations) produced changes in its fitness landscape indicative of negative epistasis; that is, the combined deleterious effects of mutations were, on average, larger than expected from the multiplication of their individual effects. As observed in computational systems, negative epistasis was tightly associated with higher tolerance to mutations (robustness). Thus, under a low selection pressure, a large fraction of mutations was initially tolerated (high robustness), but as mutations accumulated, their fitness toll increased, resulting in the observed negative epistasis. These findings, supported by FoldX stability computations of the mutational effects, prompt a new model in which the mutational robustness (or neutrality) observed in proteins, and other biological systems, is due primarily to a stability margin, or threshold, that buffers the deleterious physico-chemical effects of mutations on fitness. Threshold robustness is inherently epistatic- once the stability threshold is exhausted, the deleterious effects of mutations become fully pronounced, thereby making proteins far less robust than generally assumed.

    I think all of this leads to the conclusion that genomes will only tolerate a limited amount of deviation from a single starting point. This is what observable genetics and the fossil record have been telling us.

    The link:

    “Robustness-epistasis link shapes the fitness landscape of a randomly drifting protein.”
    http://www.ncbi.nlm.nih.gov/en.....s=17122770

  5. 5
    PaV says:

    DaveScot:

    I’m looking forward to the book coming out!

    As to probabilities, doesn’t strike a devastating blow to OOL scientists? Now they not only have to explain how the code for proteins came about, but how, simultaneously, a code to regulate their transcription rate had to come about at the same time. Although, for now, they’re seeing this in humans, and it could be argued that first the code, then the super-code. Any thoughts along these lines?

    Will be interesting to see how all this plays itself out.

  6. 6
    idnet.com.au says:

    Jehu, I think that “the conclusion that genomes will only tolerate a limited amount of deviation from a single starting point” would constitute strong “scientific” evidence for Design.

    I’m not sure that the “mutational robustness (or neutrality) observed in proteins, and other biological systems, is due primarily to a stability margin” is the same as the neutrality Dave is referring to, but this is a very significant paper for Designinst.

    I predict that Nature will accept Design theory before Science.

  7. 7
    idnet.com.au says:

    The following quote from the abstract in my opinion is a design hypothesis.

    “a new model in which the mutational robustness (or neutrality) observed in proteins, and other biological systems, is due primarily to a stability margin, or threshold, that buffers the deleterious physico-chemical effects of mutations on fitness. Threshold robustness is inherently epistatic-once the stability threshold is exhausted, the deleterious effects of mutations become fully pronounced, thereby making proteins far less robust than generally assumed.”

    It is interesting that this paper explains how mutated organisms can survive, even with damaged DNA. They forgot to mention the wonderful benefits of mutations building upon mutations to produce amazing novelty, that is the bedrock of NDE.

  8. 8
    IDist says:

    When will this theory officially break down?

  9. 9
    Jehu says:

    I’m not sure that the “mutational robustness (or neutrality) observed in proteins, and other biological systems, is due primarily to a stability margin” is the same as the neutrality Dave is referring to, but this is a very significant paper for Designinst.

    I suppose it may not be the same neutrality that Dave is referring but it deals with neutral mutations in general. The point is that during epistasis (when the action of one gene is modified by one or more other genes) what may appear to be a neutral mutation is actually negative. In this way seemingly neutral mutations can accumulate until a threshhold is reached and then “the deleterious effects of [the] mutations become fully pronounced.”

  10. 10
    jwrennie says:

    Come on Dave. None of this is a problem for Darwinism. You are just failing to see the big picture. All of this is actually predicted by Darwinism. You crazy creationists 😛

    On a more serious note. I was reminded of the way you can work out which OS a machine is running over the internet by sending different sorts of network packets at the machine. In theory they should all be identical implementation of the TCP/IP stack, but they all handle the error cases slightly differently and this gives away heaps of information about the machine.

    Interesting discovery.

  11. 11
    bdelloid says:

    DS,

    For years evolutionary biologists have known that “silent sites” are not neutral. Most advanced models for DNA sequence evolution (the kind that are used for estimating divergence times) already take this fact into account. I don’t understand how this indicates an “explosion” given that it is similar to what we have known for years.

  12. 12
    Atom says:

    If Neutral Theory explodes, what happens to the supposed patch it put on Haldane’s Dilemma? Oops…

  13. 13

    I’m wondering about two things:

    When all is said and done, I wonder how many software design patterns will be found in the genetic mechanism.

    I wonder if we can describe irreducible complexity in terms of pre-existing software design patterns.

  14. 14
    DaveScot says:

    bdelloid

    Most advanced models for DNA sequence evolution (the kind that are used for estimating divergence times) already take this fact into account.

    Really. Perhaps you could point me to a general explanation of which silent mutations result in different folding patterns and which ones do not.

    Make sure to copy the authors of the articles I cited as I’m sure they’ll be quite thrilled to know that protein folding has been solved by molecular clock theorists too.

  15. 15
    GeoMor says:

    bdelloid is correct insofar as it has long been known that some silent sites evolve faster than others. Phylogenetic models have taken this into account by having parameters for spatial rate variation (i.e. variation in how fast the molecular clock ticks in different parts of the sequence), and it’s been shown that these fit the data significantly better than rate-invariant models.

    It has also long been known that very highly expressed genes are biased towards certain supposedly synonymous codons, because this allows faster translation. This is measured with the “Codon Adaptation Index”.

    But the finding that it actually affects the protein fold is new and fascinating. I would agree with bdelloid that it’s not really an “explosion” so much as a really cool explanation for something strange that’s been observed in phylogenetics. But, working in the field, you quickly learn that very few, if any, rules in biology are without exception.

  16. 16
    DaveScot says:

    GeoMor

    In the articles:

    “We were all educated that silent mutations should be ignored, and people really don’t pay attention to them,”

    “The habit we all have of disregarding nucleotide changes that don’t change protein sequence may not be a good one,”

    These make the main point. Widely accepted, widely taught generalities in NDE that are exploding.

    Silent mutations effecting protein folding isn’t new. When researchers started sticking eukaryote genes into bacteria in quests to get cheap sources of useful enzymes they found that often the protein products ended up as insoluble inclusion bodies. They were insoluble because they didn’t fold right. The also found that by modifying the gene so its codon usage was more like the host the proteins folded properly. IOW the prokaryote caulk gun (ribosome) is a bit different than the eukaryote in the way it processes redundant codons.

    The new thing here (new in a way other than an admission that a widely accepted/taught bit of NDE dogma is wrong of course) is that the phenomenon of silent mutations causing proteins to fold differently was found for the first time in a mammal. It should be obvious that a differently folded protein is going to change the selection equation for that gene. No one knows when or how because we can’t predict how proteins will fold. All of a sudden silent mutations which have been largely ignored for having any biological activity as everyone was taught and were in the habit of thinking (see above) are now found to be able to change a gene as much as amino acid changes but just as unpredictably.

  17. 17
    Joseph says:

    Out of the 20 amino acids that can be found in living organisms only 2 have only one corresponding codon(triplet). This is a perfect way to use a limited number of amino acids in many different ways.

    Viva the dsign inference…

  18. 18
    Bob OH says:

    Joseph, can you explain your comment: I’m afraid I can’t follow the inference.

    Bob

  19. 19
    Joseph says:

    Don’t be afraid Bob OH.

    Have you ever written any computer code or designed an intricate functioning machine?

    Ya see in oreder for me to splain myself to you I need to know what you are familiar with pertaining to the world of intentional design.

  20. 20
    Joseph says:

    But anyways- versatility, Bob OH. It can be a good thing.

    With nature, operating freely, it is what it is. No planning, no forethought.

    However with ID there was planning and forethought. We see this daily with computer programmers and other design functions.

    IOW this is just another layer of information (just as stated in the article). Add that to alternative gene splicing (yet another layer) and the blind watchmaker shrivels into oblivion.

    Rather, the coding regions of DNA function in much the same way as a software program or machine code, directing operations within a complex material system via highly complex yet specified sequences of characters. As Richard Dawkins has noted, “The machine code of the genes is uncannily computer-like.” Or as software developer Bill Gates noted, “DNA is like a computer program, but far, far more advanced than any software we’ve created.” Just as the specific arrangement of two symbols (0 and 1) in a software program can perform a function within a machine environment, so, too, can the precise sequencing of the four nucleotide bases in DNA perform a function within the cell.–Stephen Meyer in DNA and the Origin of Life: Information, Specification, and Explanation

  21. 21
    Bob OH says:

    Joseph – yes I have written computer code (I’m not a programmer, but I have to do some coding as part of my work).

    Bob

  22. 22
    Joseph says:

    Good. Then you should understand the importance of layering information, being able to ‘plug-n-play’ and not painting yourself in a corner by limiting yourself to one amino acid one function. Just like not limiting youself to one gene one protein.

  23. 23
    Bob OH says:

    Err, yes Joseph. But what does this have to do with whether the system is perfect. Sub-optimal designs could have the same properties.

    And why “Viva the dsign inference…”?

    Bob

  24. 24
    Joseph says:

    Bob OH:
    But what does this have to do with whether the system is perfect.

    LoL! I never said, thought nor implied the system was perfect. What I said was this was a perfect way to use a limited number of amino acids in many diffeent ways.

    You and Larry F should see someone about your defunct inference skills.

    Bob OH:
    And why “Viva the dsign inference…”?

    Why not? We do have direct evidence of designing agencies doing things like this.

    Any data that demonstrates some blind watchmaker-type process can cobble together layers of information?

  25. 25
    Bob OH says:

    LoL! I never said, thought nor implied the system was perfect. What I said was this was a perfect way to use a limited number of amino acids in many diffeent ways.

    OK, I’ll re-phrase more precisely: why should what you wrote in post 22 lead to the “perfect way to use a limited number of amino acids in many diffe[r]ent ways.”

    (a) how do we know it’s perfect?
    (b) how does this lead to a design inference? “Why not?” isn’t good enough. Neither is “Theory X must be right because Theory Y is deficient in this regard” (because I’m not asking about Theory Y).

    Bob

  26. 26
    Joseph says:

    LoL! Is that it Bob OH? You’re stuck on some semantic quibble of the word ‘perfect’?

    Plug in “satisfying all requirements” in my original statement, then get a life. Thanks.

    Also “Why not?” was followed by We do have direct evidence of designing agencies doing things like this.

    Add that to post #20 & #22.

    IOW stop selectively reading my posts. That is a sign of serious problems.

    BTW if there are two possibilities and one is shown to be incorrect…

  27. 27
    Bob OH says:

    Joseph, if you use the word “perfect”, it seems reasonable to expect you to mean “perfect”. It’s not quite the same thing as “adequate”, is it?

    As for direct evidence of agencies “doing things like this”, what evidence do you have for agencies (a) being around when the genetic code came into being, and (b) any agency being able to manipulate proto-life to be able to produce a biochemical gloop (for want of a better word) that can both replicate (imperfectly) and produce proteins.

    You’re obviously aware of evidence for (b), (a) seems to be an additional necessary condition.

    Bob

  28. 28
    Joseph says:

    Bob OH:
    Joseph, if you use the word “perfect”, it seems reasonable to expect you to mean “perfect”.

    But “perfect” has several meanings and “satisfying all requirements” is one of them. That is why I asked if you had any design experience.

    Bob OH:
    As for direct evidence of agencies “doing things like this”, what evidence do you have for agencies (a) being around when the genetic code came into being

    You mean besides the genetic code and the laws that govern our physical realm?

    Bob OH:
    and (b) any agency being able to manipulate proto-life to be able to produce a biochemical gloop (for want of a better word) that can both replicate (imperfectly) and produce proteins.

    Do you mean besides the fact that science tells us that only life begets life, ie from cells, cells?

  29. 29
    Joseph says:

    Bob OH:
    As for direct evidence of agencies “doing things like this”, what evidence do you have for agencies (a) being around when the genetic code came into being

    Max Planck, offered this during his Nobel Prize acceptance speech:

    “All matter originates and exists only by virtue of a force which brings the particles of an atom to vibration and holds this minute solar system of the atom together . . . . We must assume behind this force the existence of a conscious and intelligent mind.”

  30. 30
    Bob OH says:

    Bob OH:
    As for direct evidence of agencies “doing things like this”, what evidence do you have for agencies (a) being around when the genetic code came into being

    You mean besides the genetic code and the laws that govern our physical realm?

    Ah, the evidence that an agency was around when something appeared is that something appeared. What if the agency had nothing to do with the appearence?

    Bob OH:
    and (b) any agency being able to manipulate proto-life to be able to produce a biochemical gloop (for want of a better word) that can both replicate (imperfectly) and produce proteins.

    Do you mean besides the fact that science tells us that only life begets life, ie from cells, cells?

    Science doesn’t tell us this: it hasn’t shown that abiogenesis is impossible, and indeed is working on showing how it may have come about.

    Do you have a link to the Max Planck speech? I’d like to see why he argued as he did: otherwise you’re just arguing from authority.

    Bob

  31. 31
    Joseph says:

    Bob OH:
    Ah, the evidence that an agency was around when something appeared is that something appeared.

    That is usually the way it goes. Do you think that detectives look for criminals in a case when there isn’t any sign of a crime?

    Bob OH:
    What if the agency had nothing to do with the appearence?

    Then we should be able to test whether ot not nature, operating freely, could bring about what we are observing.

    Again when you have two possibilities and you rule one out…

    Do you mean besides the fact that science tells us that only life begets life, ie from cells, cells?

    Bob OH:
    Science doesn’t tell us this:

    It has & does Bob. And guess what? No one has been able to demonstrate otherwise.

    Bob OH:
    it hasn’t shown that abiogenesis is impossible, and indeed is working on showing how it may have come about.

    Science doesn’t work like that Bob. Perhaps you should go back to school and learn about science.

    Also science isn’t done via promissory notes.

    And if scientists ever do observe a living organism arising from non-living matter they would have refuted a long-standing scientific truth (what I stated above).

    Bob OH:
    Do you have a link to the Max Planck speech? I’d like to see why he argued as he did: otherwise you’re just arguing from authority.

    I will take argument from authority over your argument from ignorance any and every day.

    What MP stated was based on his years of scientific research. But I could see where you would have a problem with that.

  32. 32
    Bob OH says:

    Again when you have two possibilities and you rule one out…

    This only applies if they are the only two possibilities. I haven’t seen any demonstration that this is the case here: has anyone ruled out all possible options (e.g. some natural process that we don’t yet know about)? Until they do, as a point of elementary logic, you can’t say “not A implies B”.

    Science doesn’t work like that Bob. Perhaps you should go back to school and learn about science.

    A list of my publications in scientific journals. Care to show me your list?

    Bob

  33. 33
    DaveScot says:

    Impressive list of publications, Bob OH. That and civility is why you can comment here without moderation. I still can’t figure out why you were never able to understand (or concede) that just about every non-specialized cell in a mycelial colony is capable of evolving asexually and spawning new colonies. What’s up with that?

  34. 34
    Joseph says:

    Again when you have two possibilities and you rule one out…

    Bob OH:
    This only applies if they are the only two possibilities.

    That is obvious.

    Bob OH:
    I haven’t seen any demonstration that this is the case here: has anyone ruled out all possible options (e.g. some natural process that we don’t yet know about)?

    This debate doesn’t concern “natural” processes as both design and intelligence are natural.

    Can natural processes account for the origin of nature seeing that they only exist in nature?

    Bob OH:
    Until they do, as a point of elementary logic, you can’t say “not A implies B”.

    Just what do you think the materialistic alternatives are?

    Bob OH:
    it [science] hasn’t shown that abiogenesis is impossible, and indeed is working on showing how it may have come about.

    Science doesn’t work like that Bob. Perhaps you should go back to school and learn about science.

    Regardless of your publications you should know that science does not set out to say that something is impossible. And you should also know that it doesn’t matter who is working on what- if someone starts looking for unicorns and mermaids are they conducting a scientific investigation, just because they are looking?

    IOW a list isn’t needed- just a little common-sense.

  35. 35
    Patrick says:

    has anyone ruled out all possible options

    Personally I find this demand ridiculous since it amounts to arbitrarily raising the requirements for defeating Darwinism. Back in November I had this to say: “This reminds me of the demand that every single conceivable indirect Darwinian pathway must be investigated before Darwinism can be rejected.” So why does this demand keep getting repeated?

  36. 36
    Bob OH says:

    Patrick – I think you’re slightly mis-reading my argument. My point here is that there could be a third alternative, other than evolutionary biology or ID. If so, then you can’t prove ID by dis-proving evolutionary biology. I was just trying to show that Joseph’s logic was faulty.

    As for disproving evolutionary biology (as a research field), you don’t need to go through and disprove every step. I think Kuhn’s model of scientific revolutions is a good (if not perfect) model: it suffices to show that there are several unsolved problems, and that they are not solved despite a lot of effort. Then a rival paradigm can take the original paradigm’s place. Obviously it needs to be a useful paradigm, i.e. it explains most of the same things as the original, and it provides interesting and fruitful avenues of research.

    Joseph – I don’t think we’re going to get anything productive in this discussion, I don’t think you’ve appreciated the points I’m trying to make, and I don’t want to get into a discussion over who has a better idea about how science is done.

    Bob

  37. 37
    Joseph says:

    Just about any argument can be pruned down to two choices- A or not A…

  38. 38
    Patrick says:

    Bob, I got your main point but I thought you were extending it to include the position that every conceivable Indirect Darwinian pathway must be researched before a design inference could be made. My bad.

    Personally I’m open to a third alternative (do you have a specific naturalistic mechanism in mind, such as the acquisition and fusion of genomes, or are you positing a rhetorical device?). In a designed system of sufficient minimum complexity where the plasticity of the language allows for some variance (chaotic systems) I would not be surprised if under certain limited conditions there could be additional emergent complexity. Doesn’t get rid of the design inference entirely and I’m sure many ID proponents would disagree with me. But it’s not like that has ever been observed…I’m just saying I wouldn’t be surprised if that turns out to be the case. So that’d be a sort of ID/Darwinism hybrid as another option.

  39. 39

    […] The theme of silent mutations that are not so silent has been addressed here at UD before (e.g., go here). Here’s a piece that elaborates on the significance of this recent finding: Silent No Longer: Researchers unearth another stratum of meaning in the genetic code By Ivan Amato […]

  40. 40

    […] Uncommon Descent | The Sound of The Neutral Theory ExplodingDec 23, 2006 … It should be noted that synonymous (silent) mutations are an important part of the neutral theory of molecular evolution and are also an … […]

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