Friday, May 08, 2015

Ford Doolittle talks about transposons, junk DNA, ENCODE, and how science should work

Here's more from the interview with Ford Doolittle [The Philosophical Approach: An Interview with Ford Doolittle].
Gitschier: I want to close with what you describe as your “latest rant.” How did you get on function?

Doolittle: Well, I’ve always been on that.

Back in 1980, people were talking about transposable elements as if their function was to speed evolution; that they exist because of their future utility. And I’ve never liked that kind of idea. I didn’t like it in terms of introns. And Dawkins had just published The Selfish Gene in 1978.

Carmen Sapienza, a student of mine who now works on eukaryotic imprinting, and I wrote a paper which was rejected by Science after seven referees. But we heard that Leslie Orgel and Francis Crick were working on something like this, so we sent it to them. They said, “If you submit it to Nature, we will tell Nature not to publish ours without publishing yours, and to publish yours first,” etc., which was very nice.

That paper, seemingly now very simplistic, said you don’t need to suppose that transposable elements are there for the purpose of speeding evolution. These are selfish things, and natural selection will favor such elements that can make copies of themselves in genomes and then spread horizontally to other genomes within the species. These are basically parasites. I think many people would now accept this, but it was radical at the time.

People don’t like to think that the human genome has junk in it. This came back when the ENCODE papers came out a few years ago and were touted as spelling the “demise of junk DNA.” That got my dander up.

I wrote a perspective in PNAS, and Dan Graur had a much more vituperative thing in Genome Biology and Evolution. I don’t think the ENCODE people have given up; they had a kind of semi-apology in PNAS, which wasn’t really an apology.

It is the same as the tree of life issue, but until we actually have some agreement about what we mean by words we are going to get into these arguments, and in my mind, there are two devastating things you can say about the ENCODE people.

One is that they completely ignored all that history about junk DNA and selfish DNA. There was a huge body of evidence that excess DNA might serve some structural role in the chromosomes, but not informational. They also ignored what philosophers of biology have spent a lot of time asking: what do you mean by “function?” And you can mean one of two things: we might mean either what natural selection favored, which is what I think most biologists mean, or we might mean what it does. Some people might say, “Well the function of this gene is in the development of cancer,” but they don’t really mean that natural selection put it there so that it would cause cancer. These are not-so-subtle differences.

I think many molecular biologists and genomicists, in particular, think that each and every nucleotide is there for a reason, that we are perfect organisms. It is almost as if we were still theists thinking God doesn’t make junk; we just now think natural selection doesn’t make junk. I think there is a deep issue about the extent to which we are noisy creatures and the extent to which we are finely honed machines. I think the latter view informs much of genomics, and I think it is false.

ENCODE wouldn’t have got funded had they said 80% of the human genome is just junk, transposable elements.

Gitschier: It is justifying itself, post hoc. They are the big players with a lot of money. It’s like a machine—“We can do it, so let’s just do it!”

Doolittle: It’s a juggernaut is what you are saying.

My other objection is that it is false ontology. I think all of our science suffers not only from the big science motivation, but from what I call “positivism.”

A couple of times we submitted papers saying, “Everybody’s doing something this way, and it doesn’t work, and it is wrong to do it this way.” And Nature would write back, “We’re not interested in negative reports like this. What does work?” And we say, “We don’t give a damn what does work, it is important to know that what people are doing now is not working.”

There is no critique in science, very little. You can’t actually say, “This doesn’t mean what people say it means.” You’ve got to be “positive;” you’ve got to be moving the program forward all the time. I don’t think that is right.

Now, and down the road, we’re going to tackle directly relevant questions, like what is the meaning of function in the concept of genomics? There are legitimate evolutionary constructs in which you can address transposable elements, and people have not really explored that. Questions about the tree of life, again, and some of the questions we’ve been through are things that continue to interest me and which have a strong philosophical component as well as a data-related component. That’s what I’m interested in pursuing.


96 comments :

  1. This blog is getting more hilarious by the day...

    Why don-t you just write your book full of new evolutionary insights instead of continuing this hopeless rant against ENCODE.

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    1. You're becoming more idiotic by the day, and it's no longer hilarious. It's pathetic.

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    2. See you contributed to that collection of idiotic, hackneyed old YEC lies - Evolution's Achilles Heels.

      Wonderful...

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  2. Gitschier: But Darwin, did he ever talk about microbes at all?
    Doolittle: No.


    This isn't quite true and particularly ironic given that the microbes Darwin *did* talk about (albeit briefly) were halophiles! From the Voyage:



    In other words, Darwin was observing pigments from halophiles, and correctly concluding that they were of microbial origin ("infusorial animalcula").

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    1. For some reason the quote didn't show up. It was:

      Parts of the lake seen from a short distance appeared of a reddish colour, and this perhaps was owing to some infusorial animalcula.

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    2. Good point Jonathan. I have made the case elsewhere that Darwin's readings on cattle plague provided a basis for his pangenesis ideas: See Rinderpest

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  3. Intriguing quote regarding Doolittle's criticism of ENCODE:

    There was a huge body of evidence that excess DNA might serve some structural role in the chromosomes, but not informational.

    Comments? Clarification?

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  4. Larry Morran,

    For a big fan of the neutral theory of macroevoultion, can you cite a single best piece of evidence for it? Is it not all based on thin air and wishful thinking? (I grant you that it is fine for short term microevolution)

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    1. You should think and review carefully what you write before submitting it. Maybe you could then phrase an intelligible question. For now what you wrote sounds exactly as misinformed and nonsensical as anything written by creationists.

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    2. It is time people focus on science rather than religion or philosophy. If you have actual evidence, by all means tell us. If not, go home and work hard to find some.

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    3. Kimura and Ohta: “Probably the strongest evidence for the theory is the remarkable uniformity for each protein molecule in the rate of mutant substitutions in the course of evolution.” (1). Given the silence so far to my question, I take it that Larry Moran has nothing better to say than Kimura and Ohta. And so, the question now is: is the molecular clock, the universal one of course which was meant by Kimura and Ohta, a reality of Nature? Here, surprise, all sides agree that it is not!!!

      And so, the Neutral theory of macroevolution has zero, zip, zilch, nada evidence for it, period.

      So, Larry, if you still believe in such a base less theory and chase the junk DNA bandwagon, it seems more like a personal idiosyncrasy than a disinterested interest in truth.

      Ref:
      1. Kimura M, Ohta T (1971) Protein polymorphism as a phase of molecular evolution. Nature 229: 467-479.

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    4. Actually, the Neutral theory of macroevolution is not merely waiting for evidence. It is in fact already disproven. The theory predicts a universal molecular clock. (and was in fact an ad hoc invention for explaining a molecular clock, which in turn was a mis-interpretation for the reality of genetic equidistance.) But unfortunately, that prediction is the exact opposite of what is being found as more sequences became known in recent years. Each species has its own specific molecular clock, with simple organisms having faster clock.

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    5. @gnomon
      " The theory predicts a universal molecular clock. "

      What you are criticizing is an idealistic model. Nobody believes f.e. that in reality there are strictly 100% neutral (completely invisible to selection) alleles. The same goes for an ideal circle as a physical object. Both are very useful abstractions. The neutral theory is a very useful abstraction. Got it ? So please stop playing semantic games.

      Nobody sensible believes in a universal molecular clock, which is "ticking" exactly the same in all lines. The consensus opinion is ---as pointed out to you by Larry Moran and others --- that there is an approximate molecular clock nothing more and nothing less. Stop attacking straw men!

      Now, please explain --here on this blog, no self citations please-- how an approximate molecular clock is in contradiction to the neutral and the nearly neutral theory.

      Michael

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    6. 1. The distance between two most distant bacteria is approximately the same as that between one of them and human, which is one example of the reality of genetic equidistance. The approximate molecular clock explains, in a ad hoc way, away the approximate equidistance by claiming bacteria and the line leading to human have approximately the same ticking rate. This is simply not true. Bacteria rates are orders of magnitude faster than any multicellular organisms.

      2. The equidistance phenomenon has another feature which contradicts the clock interpretation, the overlap feature. Details can be found in my papers. Briefly, it shows that independent mutations cluster at certain sites well against random probability. And yet, in contrast to equidistance found for long term macroevolution, short term microevolution has very few such sites, fully predicted by probability theory and the Neutral theory.

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    7. So, no to your straw-man of my view. I am precisely criticizing an approximate model or whatever you think your pet model is. If you are a serious scholar, you should not ignore my papers. Try for a change write a critic of my papers.

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    8. The neutral theory doesn't predict a molecular clock. It predicts only that the substitution rate will be equal to the mutation rate. If mutation rates are equal across all life, you get a single molecular clock. If not, you don't. Do mutation rates vary with complexity? Not that I can see. There is some evidence that they vary with size and/or generation length. Possibly with metabolic rate. Possibly with selectable proofreading efficiency. And within a genome depending on various internal conditions. Site to site differences in mutation rate are not all that relevant to molecular clocks, and I expect you're looking at substitution rate anyway.

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    9. John,
      I don't think you or anyone else in the field for that matter has any habit or experience in taking care of all relevant data in a coherent fashion. This is referring to the fact that you selectively ignored my point 2 above. Also, if the Neutral theory doesn’t predict a molecular clock, why Kimura and Ohta said what they did in terms of evidence for their theory? Along this line, please enlighten us what exactly does the theory predict for long term macroevolution outcomes? Has anyone followed those predictions? If so, what were the results? If not, why not?

      Now if you try to counter, please do so in a coherent fashion accounting for all of my points. If science is about cherry picking, it would be way too easy and any fool can do it.

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    10. Neutral theory predicts a universal molecular clock if and only if there is a universal uniform mutation rate.

      What do you mean by "long term macroevolution outcomes"?

      I also find your point #2 unintelligible. Are you referring to protein sequences, exon DNA sequences, non-coding DNA sequences, or what?

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    11. If you are an actual scientist with a real thirst for puzzle solving, you would just go read my papers on point#2. If not, I would consider it a waste of both our time in any further exchanges here. I never intended to talk to lay people because they are not qualified to understand real laws of biology, just like they would not understand particle physics. If you find the math part of point #2 unintelligible, it is to be expected given that neither Darwin nor Kimura (not to mention their followers) was known to be even a second rate mathematician. (I consider the first rate do number theory, the second rate do applied math but still in math or physics field, and the third rate make a living do statistics in non-math field) I also believe like all renowned physicists and mathematicians that the language of nature, biology included, is math and in turn axioms or common sense intuitions.

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    12. Maybe somebody should contact Shi Huang and let him know that malicious hacker must have broken into his account.

      No way these posts can be for real!

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    13. haha, funny. Now, seriously, who are you? What make you think you know what is real?

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    14. @gnomon

      Because you say:

      " it is to be expected given that neither Darwin nor Kimura (not to mention their followers) was known to be even a second rate mathematician.".

      I'd like to ask: Where -on a scale from 1 to 10- do you rank your mathematical credentials?

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    15. I am willing to spend a limited amount of time an efforton crackpot notions. That willingness does not extend to poorly written papers on the web. If you have an argument to make, make it here, clearly and briefly.

      If it matters, yes, I am an actual scientist. In presenting my research I strive very hard for clarity. And you would be well advised to do the same.

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    16. For anyone interested, this paper caught my eye: Huang, S. (2012) Primate phylogeny: molecular evidence for a pongid clade excluding humans and a prosimian clade containing tarsiers. Sci China Life Sci, 55: 709-725

      If you know anything about phylogenetics, you will be amused at its presumption. Full text here.

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    17. gnomon,

      "It is time people focus on science rather than religion or philosophy."

      You seem quite focused on something quite akin to religion, since you're impervious to reason. You can't even see that your wording takes out any possible meaning to what you pretended to ask evidence for (whatever that was).

      "If you have actual evidence, by all means tell us. If not, go home and work hard to find some."

      Unlike the well-behaved colleagues who have tried to have a conversation with you, I have no reason to translate nonsensical questions into sensical ones, and then answer the sensical ones. After all, it's very hard to know if you had any sensical question in mind. As far as I know, there's no "neutral theory of macroevolution" for example. Creationists love making obscure requests that they take for granted everybody in the "opposite" side must believe. Given that's exactly what you're doing, I request that you read and make sure that you ask some intelligible questions. Otherwise I risk letting you think that I'm truly convinced about whatever you might be asking evidence for. Trying to answer your nonsensical requests can't result but on more and more obscure bullshit on your part, as your exchange with the polite ones demonstrates.

      I suggest you to have some rest and try and gain some self-awareness.

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    18. George Simpson:
      “If the two (micro and macro) proved to be basically different, the innumerable studies on micro-evolution would become relatively unimportant and would have minor value in the study of evolution as a whole.”

      Now you seem to think macro is a buzzword for creationists. Now let's see what you are made of, a bunch of junks for sure which you would even be proud of. Call Simpson a creationist, who FYI happens to be one of the fathers of the new synthesis, just in case the junks in your head got you messed up, ha ha.

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    19. What Simpson is basically saying with regard to your junk like rants is this. If there is no neutral theory of macroevolution, there is no theory of evolution and the neutral or junk bandwagon has no clues about what evolution is.

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    20. John,
      You may be a scientist or know something about phylogenetics but not competent, serious, and disinterested enough for my taste, sorry for being frank. This should not be news to you. Of all branches of natural science, evolution ranks least scientific or the softest.

      Jerry Coyne had openly admitted this: “In science’s pecking order, evolutionary biology lurks somewhere near the bottom, far closer to phrenology than to physics.”

      Could anyone have any confidence on the words or beliefs of a practitioner of the likes of phrenology? Now see why I have no interest in talking to your kind of 'scientists'.

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    21. That would equally apply to me too, I think. John Harshman is of course an experienced systematist with much practical experience in molecular systematics, and on these forums almost invariably the voice of clarity and sanity.

      Of course "gnomon" is the biologist famous for propounding the First Axiom of Biology. Until he did, I was unaware that axioms were empirical generalizations, particularly ones that were almost impossible to understand.

      Probably no one else here is on gnomon's level. I hope that he will stop talking to all of us.

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    22. Joe,
      You are way too modest in saying the above. You are a creator or leader of a field where John is merely a follower.

      But regardless, I see you prefer to be blind to facts you don't like or understand. The overlap feature of the genetic equidistance result, on which I had a full peer reviewed paper published by an evolution research institute named after the only biologist who won a Nobel for studying evolution, apparently means nothing to you.

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    23. OK OK, somebody help me out here…

      Epigenetic changes cannot account for evolution over even modest time scales in the absence of incredibly strong and ongoing natural selection.

      But there is no evidence of such strong and ongoing natural selection for the maintenance of epigenetic modification, especially in light of given their tendency to rapid reversion.

      Therefore any intellectual light-weight (with insecurity issues) who hitched their wagon to the evolution of complexity as a direct result of epigenetic complexity would feel more than somewhat miffed Joe’s version of events and would more than likely have a hissy fit when confronted with Larry’s.

      Have I managed to summarize what seems to be going on here? I just wanted clarification before embracing the wisdom of Bodhidharma and moving on:

      A sage is neither concerned nor even distracted by the barking of a dog

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    24. Or am I paraphrasing Confucius? I forget.

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    25. I have read several of gnomon's papers so far, and I would have recommended rejection of each one had I been a reviewer. I can only conclude that the referees failed to understand what he was talking about and took that as a sign of their profundity. Peer review has serious shortcomings if the referees don't take their tasks seriously.

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    26. Epigenetic changes cannot account for evolution over even modest time scales in the absence of incredibly strong and ongoing natural selection.

      I don't see what selection has to do with it. It's the instability of epigenetic inheritance that's relevant. What you are calling selection here is merely the maintenance of whatever environment induces the epigenetic effects anew in each generation, not the differential reproduction of epigenetically affected individuals.

      If you're talking about gnomon here, I have no idea what he's getting at or what he means by "epigenetic complexity".

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    27. What Tom said, but with more curse words.

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    28. Hi John

      Again I learned something from you.

      Again and as always, I remain in your debt.

      best regards

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    29. gnomon,

      Now you seem to think macro is a buzzword for creationists.

      You're missing the point. The problem is not whether actual scientists use the word, but that creationists abuse the word "macroevolution." That's what you're doing. You abuse the word and combine it with neutral theory just out of your ignorance about what neutral theory is about. You build a straw-man, and a fallacy of the complex question, only to then complain that nobody wants to answer your challenges. But your problem is that you have built these nonsensical straw-men of evolutionary concepts either out of ignorance and plain stupidity, or just to try and claim to be some kind of messiah in evolutionary biology. Pure crackpotery. Just like creationists.

      Now let's see what you are made of, a bunch of junks for sure which you would even be proud of. Call Simpson a creationist, who FYI happens to be one of the fathers of the new synthesis, just in case the junks in your head got you messed up, ha ha.

      Now you add to your status as a creationist crapper, by adding "quotes" by perceived authorities to, not only miss the point, but to try and deflect your inadequacies onto me. Sorry. Quotes don't work. You're still in trouble for the very same reasons you were in trouble before. You write nonsense. My request stands: learn and understand well before continuing making such a fool out of yourself.

      What Simpson is basically saying with regard to your junk like rants is this. If there is no neutral theory of macroevolution, there is no theory of evolution and the neutral or junk bandwagon has no clues about what evolution is.

      Nope. That's just your interpretation of what Simpson said. An interpretation that introduces more misunderstandings into the conversation, and thus only comes to show that you have no idea about neutral theory, what it refers to, and what evolutionary biologists, most importantly population geneticists, have come to understand about how it might work.

      So, go, study, make sure that you understand what evolutionary biologists understand when they talk about neutral theory, then withdraw your nonsensical articles and start doing something with both quality, and the humility of understanding that you might be wrong.

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    30. Come on now - crazy old Mae Wan Ho likes Gnomon's stuff! He MUST be 100% correect!

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    31. AND he's published in the YEC-run Jon Wells and John A. Davison-friendly Rivista di Biologica!! You just KNOW he is the world's greatest biologist by that alone...

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  5. This seems the most damning opinion of ENCODE I'ver met:
    "ENCODE wouldn’t have got funded had they said 80% of the human genome is just junk, transposable elements."

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    1. Yup. But I disagree. I doubt that ENCODE was funded to prove either way about junk. I would think that it was funded because it promised a map of gene expression and such shit of the human genome, different tissues, etc.

      Unfortunately, their lack of scholarship got the best of them.

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  6. Joe, you said;"Until he did, I was unaware that axioms were empirical generalizations, particularly ones that were almost impossible to understand."

    All I would like to say is nice try for a straw-man and very disappointing for a scientist of your caliber.

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  7. Joe,
    First axiom: the more complex and ordered the macro state of the system (like a space aircraft), the more precise the building parts (or smaller allowed stdev in parts).

    Example: a junkyard is non orderly and can allow highest possible stdev in its parts. A junk virus can have all of its genome freely mutated without effect on its junk nature and so has the largest genetic diversity in terms of percentage difference in genome identity.

    So, I am truly puzzled and speechless that you or anyone else for that matter can manage to find this self evident intuition impossible to understand.

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    1. So that little nonsensical assumption on top of more assumptions, then topped up with further assumptions, with mistaken and misinformed notions, is what inspires you to conceive those mistaken and misinformed "analyses" that you try to make pass for evolutionary biology?

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  8. Joe: "empirical generalizations" ??? Do you really need experience to formulate the above axiom? It is pure a priori truth, at least to me. The relationship between macrostate complexity/order of a system and the stdev of its building parts can only have 3 possible choices, by a priori reasoning, no, inverse, and positive. It is no drainer that the only sensible choice is inverse.

    The great logician Kurt Godel is absolutely brilliant in saying: 'I don't believe in empirical science. I only believe in a priori truth'.

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    1. There's nothing a priori about your "axiom." It has lots of concepts that require priors.

      "First axiom: the more complex and ordered the macro state of the system (like a space aircraft), the more precise the building parts (or smaller allowed stdev in parts)."

      The concepts "complex" and "ordered" require you to be able to categorize percepts into "simple" and "less simple," etc. They require you to make comparisons, most of which are fuzzy in meaning. Those concepts are so not-a-priori, that they can mean all sorts of different things depending on the context. This problem is one of the fountains of your unsurmountable confusions.

      You're also using a concept of stdev. that departs from what it means for most people in the planet, which adds to the complications and hidden assumptions made in your formulation.

      The best you could do is call it "the gnomon assumption", or even "the gnomon paradigm." But calling it "the first axiom of biology" is just presumptuous and preposterous self-serving kookery.

      You can build whatever edifices into the "raison d'etra " of your research, but you have to acknowledge your limitations and unwarranted assumptions. For example, once you have convinced yourself that you have this "axiom," you go on into assuming that you clearly know which life forms constitute the ones with "the most complex and ordered macro-state (like space crafts)."

      All of your "ideas" so far are just as misguided. Your problems are compounded because small bits of what you think then seems to be confirmed by bits of the cherry-picked data that you take, which leads you to proceed with fallacious affirmations of the consequent. You would never actually take it to the test. Either out of sheer incompetence, or of self-delusion, or dishonesty, or all of the above. So you just get yourself twisted and entangled into a mess that might look like scientific enlightenment to your own eyes, but is pure and unadulterated crap.

      Arrivederci.

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  9. Just in case an extremely low probability event may nonetheless occur in this junkyard party full of junk lovers, I wellcome any outlier professional scientist here to be aware and contribute to a special issue of Genomics with a theme of putting the junk bandwagon to where it rightly belongs to, a junkyard of dead theories. see the call for papers announcement here http://www.journals.elsevier.com/genomics/call-for-papers/special-issue-on-the-functionality-of-genomic-dnas/

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    1. Let' see:


      1) Theoretical foundation for all genome regions to be functional. It will cover both the theory and all major features of genome evolution.

      I am curious what exactly those are?

      And are we going to see a single population genetics equation in that volume?

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    2. Hey, Larry. You should check out that link. You will find much to annoy you. Does Elsevier have any integrity whatsoever, or is that not something that publishers think about?

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  10. BTW, I am the managing editor and Prof. James Shapiro is a coeditor.

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    1. Yup. Two ass-holes as editors. That should go well.

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    2. A lot of great scientists were assholes, the problem here is that they're crackpots, intellectually dishonest, and suppress evidence that they're dead wrong (which is plentiful).

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  11. Gnomon

    Regarding: „junk lovers“

    FTR

    http://sandwalk.blogspot.ca/2015/05/ford-doolittle-talks-about-transposons.html?showComment=1431140566562#c7029574849986339769

    Joe is an important and busy scholar with more important things to do than waste his time indulging you.

    On his behalf and on the behalf of the others present – I will intercede one last time:

    Your vacuous yet condescending insults have made you as welcome as a barking dog. Please go away.

    Final point:

    Imagine some imposter pretending to be a Martial Arts master visiting another master’s dojo. Now imagine that pretender to be thoroughly thrashed by some upstart and inexperienced novice. That just happened. The fact that you do not recognize what just happened, speaks volumes.

    Now please go away.

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    1. And just to be clear here...

      John Harshman is also another Master to whom many (including novices such as myself) owe a great debt of gratitude.

      I hope we understand each other.

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    2. Godel was a mathematician, not a scientist. Scientists have to believe in empiricism. For one thing, many "self-evident" propositions turn out not to be true. It's self-evident that the world is flat and stationary, that the continents don't move, that heavy objects fall faster than light ones. Your "axiom" (and I agree with Joe that you don't know what that word means) is no different. You need to provide real evidence for such a phenomenon, but you need to start by making the claim less incoherent.

      I believe I've been able to figure out what you're trying to say, but it hasn't been easy. You have concentrated entirely on protein sequences and seem to say that the more complex an organism, the more residues in the average protein will be under purifying selection, so that a) within-species polymorphism will be reduced and b) maximum genetic distance within a complex clade will be reduced. You have presented very little evidence, perhaps because you think self-evident propositions don't need any.

      Finally, let me critique just a bit of one paper, the one on primate phylogeny. You are attempting to overturn current wisdom on primate relationships, yet the most recent paper on the subject you cite is from 1969. You claim that phylogenetic analysis relies on a molecular clock, which it does not. Thus, you ignore most of the data and fundamentally misunderstand how those data are analyzed. Big problem.

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    3. Why did you pick that bit to critique the paper. I think the worst part is section 3.2 and the accompanying figure 5. Figure 5 shows a phylogeny ((A,B1),B2), but the caption refers to B (=B1 and B2) as a taxon, when it is clearly paraphyletic. It also refers to A as the sister taxon of "B". In the main text this is discussed with "fish" taking the role of "B" and "amphibians" the role of "A". I wouldn't even start with how atrocious the rest of the paper is, there are major misconceptions about what terms like sistertaxon and clade even mean.

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    4. Why did you pick that bit to critique the paper.

      First thing I noticed, very early in, and the part that I think is the biggest problem. I didn't mean to say that there isn't plenty of other nonsense in it, but I think what you bring up is just peripheral nonsense rather than the central misunderstanding.

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    5. Well, I do think the problem you describe is bad enough to have warranted the rejection of the paper. But the issue I went with is something we let people fail undergrad courses for...
      If I wanted to bring up peripheral nonsense I'd be talking about how he deals with fossil calibrations, because that is basically a check list of every mistake in the book.
      Then again, there are a lot of good candidates for the biggest problem in this paper and reasonable people can disagree about which one of them is the worst.

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    6. Note also Figure 6:

      The shorter vertical distance between an MRCA node and one of the sister taxa indicates that a past member of that taxon was the ancestor of the MRCA. For example, a past member of the gorilla lineage was the ancestor of the MRCA shared by all extant chimpanzees and a fraction of extant gorillas.

      What the heck can it mean if not "Gorillas are paraphyletic with respect to chimpanzees" (according to Huang Shi)? But in Figure 6 the "pongid clade" is marked with this "short vertical distance" versus its hominid "sister taxon". In other words, the figure implies that pongids are paraphyletic with respect to hominids (which is of course correct in general if not in detail). This crank idea of "paraphyletic sisters" is, I think, part of the central misunderstanding. When Huang Shi says that pongids and hominids are sister taxa, he doesn't really mean it. He's using a private lingo nobody else understands.

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    7. More problems: dishonest or incompetent use of references. Here's the case I have in mind, from the paper: "There are ample molecular data supporting the pongid clade. First, chimpanzee is closer to orangutan or gorilla than human is in gene expression patterns [45-47]. Second, the chromosome-banding pattern of humans is more similar to orangutan than to chimpanzee or gorilla [48]."

      Here are the references in question:
      45 Enard W , Khaitovich P , Klose J, et al. Intra- and interspecific
      variation in primate gene expression patterns. Science, 2002, 296:
      340–343
      46 Uddin M, Wildman D E, Liu G, et al. Sister grouping of chimpanzees
      and humans as revealed by genome-wide phylogenetic analysis of brain gene expression profiles. Proc Natl Acad Sci USA, 2004, 101: 2957–2962
      47 Karaman M W, Houck M L, Chemnick L G, et al. Comparative analysis of gene-expression patterns in human and African great ape cultured fibroblasts. Genome Res, 2003, 13: 1619–1630
      48 Yunis J J, Prakash O. The origin of man: a chromosomal pictorial legacy. Science, 1982, 215: 1525–1530

      Of these, 46 and 48 directly contradict gnomon's quoted claims, and 47 never even mentions any primates at all. I can find only the abstract of 45, and it doesn't mention comparative similarity of expression patterns among apes, so it's possible that it supports gnomon's claim, though the abstract also states that chimps are the sister group of humans.

      Given that three of the four references I have looked at don't say what he claims they do, while the fourth is undecidable, at the very least the peer review was incompetent.

      Delete
    8. http://gene-quantification.com/science-2002.pdf

      Quote (emphasis added):

      The results (Fig. 1A) show that the variation in gene expression between individuals within the species is substantial, relative to the differences between humans and chimpanzee. For example, one human brain sample differs more from the other human samples than the latter differ from the chimpanzee samples. However, for both the brain and liver samples, the humans, as well as the chimpanzees, fall into two mutually exclusive groups when their gene expression patterns are related to that seen in the orangutan, which is evolutionarily further removed from humans and chimpanzees than these are from each other.

      (See also the distance trees in Figure 1A.)

      Delete
    9. Whoops, #47 does indeed show a dendrogram in which chimp and gorilla expression patterns cluster together, with human expression patterns more distant. Orangutans were not examined. So this kinda sorta supports the claim, though only if you assume that there's an expression pattern clock, which is ironic.

      I was for some reason originally looking at the wrong paper.

      Delete
  12. OK - my next question gets complicated, at least in my head.

    I quote Ford Doolittle:

    There was a huge body of evidence that excess DNA might serve some structural role in the chromosomes, but not informational.

    I apologize for repeating myself.

    The inspiration for this hunch (and I insist it is merely a hunch) would be Peter Fraser’s work on the non-random orientation of the X chromosome where the folding of Chromatin and exposure of different active regions to the “periphery” is dependent on the differentiation status of the cell type which fascinates me. That means, some of the intervening chromatin must serve some nondescript “function” as bits and pieces are either exposed or sequestered.

    http://www.bbsrc.ac.uk/news/health/2013/130925-pr-x-shape-chromosome-structure/

    Let’s grant any such intervening DNA represents a redundancy as far as regulation is concerned. The bulk effects of such intervening bulk DNA would still represent non-informational “function”.

    I just want to clear that up before even broaching the ancillary topic of any version of selection that may or may not be operative here.

    Or am I missing something again?

    ReplyDelete
    Replies
    1. One thing you're missing is a question.

      Delete
    2. Hi John

      Right you are...

      My question would be

      There was a huge body of evidence that excess DNA might serve some structural role in the chromosomes, but not informational.

      True or False? ... regardless of any version of selection that may or may not be operative here.



      Delete
    3. I'm not well acquainted with that evidence. And I can't see how it gets around the c-value paradox, if so.

      Delete
    4. Tom,

      It has been a couple of days since you first brought up Ford Doolittle’s quote from Gitschier’s article “The Philosophical Approach: An Interview with Ford Doolittle” in PLoS Genetics:

      “There was a huge body of evidence that excess DNA might serve some structural role in the chromosomes, but not informational.”

      I did not expect the proponents of ‘junk DNA’ hypothesis here at Sandwalk to comment on Doolittle’s quote for obvious reason: it brings forward the hypothesis that the so called “junk DNA” might play non-informational roles, a hypothesis that was promoted by many scholars in the field of genome evolution, including Cavalier-Smith and Ryan Gregory as previously emphasized by Doolittle:

      “The “selfish DNA” scenarios of 1980 (20–22), in which C-value represents only the outcome of conflicts between upward pressure from reproductively competing TEs and downward-directed energetic restraints, have thus, in subsequent decades, yielded to more nuanced understandings. Cavalier-Smith (13, 20) called DNA’s structural and cell biological roles “nucleoskeletal,” considering C-value to be optimized by organism-level natural selection (13, 20). Gregory, now the principal C-value theorist, embraces a more “pluralistic, hierarchical approach” to what he calls “nucleotypic” function”

      http://www.ncbi.nlm.nih.gov/pubmed/23479647

      Delete
    5. Hi John

      Check out this quote from Peter Fraser:

      Dynamic changes in chromatin, and nuclear structure can regulate patterns of cellular gene expression during differentiation and development, or in response to environmental signals. Our research looks at various levels of chromatin, chromosome and nuclear structure, from individual nucleosome modifications to the dynamic 3D structure of chromosomes and their inter-relationships in the nucleus and how they affect genome functions.

      http://www.babraham.ac.uk/our-research/nuclear-dynamics/peter-fraser

      here are some fast and easy sound-bites:

      http://www.bbsrc.ac.uk/news/health/2013/130925-pr-x-shape-chromosome-structure/

      In other words, crucial bits and pieces of DNA may be down-regulated by sequestration to the interior or up-regulated by exposure to the periphery of some non-random chromosomal super-structure. This chromosomal super-structure therefore requires non-informational nucleic acid "clean fill" (to use Doolittle's phraseology) between the crucial bits that get moved around.

      The c-value paradox is not puzzling when comparing onions to say metazoan lineages; but rather, very very puzzling when comparing some lineages of onions to other lineages of onions.

      I think that intervening non-informational (but still functional) nucleic acid “clean-fill” DNA can occur in +/- multiples within certain parameters such that too much bulk DNA becomes too much of a metabolic burden while too little cannot be stretched to fulfill its function of redundant (but not necessarily superfluous) gene regulation as described by Peter Fraser.

      Ford Doolittle (in personal communication) did in fact suggest something along these lines was happening and also was subject to selection:

      Doolittle: That "excess" DNA (that 40x as much that lungfish have compared to us, for instance) might play a structural role or determine other cellular parameters under selection has long been accepted, even by us "junk" supporters.”

      Let’s leave selection out of the discussion for the interim. First things first.

      I think Peter Fraser presents an interesting case worthy of close consideration.

      Would you agree?

      Delete
    6. Hi Claudiu,

      WOW! Again we posted identical thoughts within 3-4 minutes of each other.

      This is getting weird.

      I really need to publically disagree with your assessment of the majority of posters on this site, John especially (just check out his responses to gnomon)

      John displays far more patience and indulgence than I could ever hope to muster were roles reversed such as when I needed to understand the rooting of a phylogenetic tree (I still cringe in embarrassment) and I remain ever grateful to him just as I also remain ever grateful to you and your patient inercessions!

      Both of you have made me a better teacher.

      What am I attempting here?

      I am hoping to reboot the default setting for rules of engagement here. I think both of you are too quick to dismiss what each other has to offer.

      Unfortunately - it appears to have become personal.

      I more than understand that I am currently displaying the height of presumption by speaking to both of you in such fashion and I have no right to do so.

      I ask both of you to forgive me.

      I will say no more along these lines.

      Delete
    7. Tom,

      I don't find sound bites convincing; I would have to look into the actual evidence. And I think the c-value paradox most definitely is relevant even when considering differences between distantly related taxa. If all this chromosomal filler is so important, how do fugu get by with so little of it, and why do lungfish need so much? At the very least, it suggests that any positional regulation doesn't need much extra sequence and can accommodate enormous variations in quantity, from almost none to bazillions.

      Could you cite something that provides evidence for this "spacer" function?

      Delete
    8. Hi John

      I was thinking more along the lines that any positional regulation is very exuberantly redundant.

      To quote Ford Doolittle:

      ...larger-genomed organisms might be regulating the same amount of function as smaller-genomed organisms, just in more (and possibly unnecessarily?) elaborate ways.

      If so, all that intervening non-informational DNA that alternately exposes or sequesters crucial sequences according to the developmental/differential/environmental response status of the cell would in fact be functional.

      re
      Could you cite something that provides evidence for this "spacer" function?

      I did provide you Peter Fraser's lab website above. He appears to be a heavy-weight scientifically speaking, but you better than I can asses that contention.

      best and grateful regards,

      Delete
    9. Hi again John

      Here is a relevant publication in Nature
      http://www.ncbi.nlm.nih.gov/pubmed/24067610

      found here

      http://www.babraham.ac.uk/our-research/nuclear-dynamics/peter-fraser/publications

      Delete
    10. Hi John, one last time tonight

      It took me a while - to persevere and read through what Claudiu had to say here (I really am out of my league on this forum)

      http://www.ncbi.nlm.nih.gov/pubmed/23479647

      I think Claudiu has proven himself simultaneously eloquent and cogent.

      Delete
    11. The Hi-C data do not in any way provide evidence for "spacer" function.

      It may be the case that if one shuffles the positions of the enhancers of a given gene and change the spacing of them, they will not work the same way as before. That does not mean the constraints on the amount of DNA in between them and between each of them and the promoters in the neighborhood are tight, and by no means implies that they have been selected to be these particular values.

      It also has zero relevance to the question of junk DNA as most people understand it because spacer DNA is not sequence-constrained DNA, and when creationists (who are the main crusader against junk DNA) talk about the whole genome being functional, they do not have spacer DNA in mind. ENCODE did not present its results in such a light either - people were talking about "switches", "activity" and "regulation"

      Delete
    12. Hi Georgi

      If this spacer DNA is demonstrating the effects of differential induction of facultative heterochromatin, that story would include CpG islands and Alu sequences (for starters).

      To my way of thinking – this story suggests that what was initially parasitic DNA got co-opted into symbiotic DNA as part and parcel of host gene regulation.

      In other words, the "functional" role of “spacer DNA” would be sequence-constrained, in a manner of speaking but not along the lines (as you confirm) originally envisaged by ENCODE.

      Unless of course, I am again missing something.

      Delete
    13. There is truly parasitic, i.e. transposable elements. Those have been coopted as enhancers on some occasions, but most are indeed just parasites.

      But they do not account for all junk DNA. If the balance of small insertions and deletions is in the direction of insertions, the genome will grow neutrally. That would not be parasitic DNA in the strict sense, because unlike TEs it has no active means of propagating itself. There is a gap between the fraction of the human genome that is derived from TE insertions and the fraction of it that belongs to coding and possibly functional noncoding sequence. That gap consists of TEs that have decayed beyond recognition, but also of at least some DNA derived from such insertions.

      CpG islands have nothing to do with this.

      Alu sequences are pure parasites, they have been globally coopted but not on the sequence level of each of them.

      In general, exaptation of junk DNA happens all the time. But the vast majority of junk DNA remains junk.

      Delete
    14. Hi Georgi

      Forgive my persistent presumption.

      But intuitively my gut tells me what you say about spacer DNA cannot be true if we are to lend any credence to Peter Fraser's results.

      Somehow, all that intervening non-informational DNA is alternately and differentially exposing/sequestering crucial bits of expressed/nonexpressed DNA according to the developmental/differential/environmental response status of the cell.

      That tells me that this spacer DNA has to be functional in some sense of the word, but not as first envisaged by ENCODE. How else can one read the Ford Doolittle quotes I cite?

      And the non-randomness of differential induction of facultative heterochromatin tells me there must be something non-random to that intervening spacer DNA; i.e. it must somehow be sequence-constrained in some sense of the word.

      It has to be, or how would Peter Fraser be getting those amazing results? I am suggesting that Ford Doolittle was very prescient indeed!

      What am I missing?

      Delete
    15. Tom, Is it your contention that transcription regulation in fugu is radically different from transcription regulation in lungfish or humans?

      Delete
    16. Hi John

      Re: Tom, Is it your contention that transcription regulation in fugu is radically different from transcription regulation in lungfish or humans?

      As I suggested just above (as well as Claudiu elsewhere)

      Me: I was thinking more along the lines that any positional regulation is very exuberantly redundant.

      Ford Doolittle in fact did answer your question much better than I just did and with specific reference to lungfish:

      Doolittle: That "excess" DNA (that 40x as much that lungfish have compared to us, for instance) might play a structural role or determine other cellular parameters under selection has long been accepted, even by us "junk" supporters.”

      Myself, I am still unclear on the "selection" as a result of your previous corrective intercessions. I merely suggest that something is happening here that provides pause to ponder.

      Delete
    17. Tom MuellerTuesday, May 12, 2015 10:44:00 AM
      But intuitively my gut tells me what you say about spacer DNA cannot be true if we are to lend any credence to Peter Fraser's results.


      I am not quite sure which of those results make you think so - can you clarify a bit?

      Somehow, all that intervening non-informational DNA is alternately and differentially exposing/sequestering crucial bits of expressed/nonexpressed DNA according to the developmental/differential/environmental response status of the cell.

      1) We are very far from understanding how the 3D organization of DNA influences gene expression, But:

      2) Even if it has to be very finely regulated for gene regulation to be properly carried out, that does not mean the intervening DNA is there for that reason. The null hypothesis is that the complicated mess that the regulation of each gene is is such a complicated mess because it has to work around all that DNA, not that the DNA is there so that this marvelously complexity can be generated and that the complexity is adaptive. I hope you get the distinction, I am not sure I phrased it in the best possible way, but it's very important

      3) There is actually little evidence that spacing is of extreme importance. One of the definitions of an enhancer element has it functioning irrespective of spacing and orientation relative to the promoter, and that's indeed how people study enhancers in functional constructs all the time - they stick the enhancers immediately in front (or sometimes downstream) of a reporter gene and observe its expression. There are hundreds of classic experiments of that sort, and they usually recapitulate the expression of the native gene quite well.

      And the non-randomness of differential induction of facultative heterochromatin tells me there must be something non-random to that intervening spacer DNA; i.e. it must somehow be sequence-constrained in some sense of the word.

      Let's set aside the reasons why you feel "it must be" sequence-constrained, let's look at whether it actually is. What matters most is that when we actually look at it, it isn't

      It isn't conserved when different species are compared, and it isn't constrained based on population genomics data (if you plot the sequence diversity across the genome, it is the lowest within CDS regions and highest in intergenic regions without any evidence for functional noncoding elements in them).

      Delete
    18. Tom, forget the lungfish. What about the fugu? How does it get along without all that crucial spacer DNA?

      Delete
    19. Seems there are two ways to look at the observation that rearranging junk DNA changes the expression of certain genes. First: The "junk" DNA has a regulatory effect on gene expression. Second: The darn junk DNA interferes with the regulation of gene expression unless it's correctly folded out of the way.

      Distinguishing between those ideas might be difficult; they sort of blend into each other. However, the extremely reduced genomes of fugu and bladderworts lends credence to the second.

      Delete
    20. Hi Georgi

      Re: Even if it has to be very finely regulated for gene regulation to be properly carried out, that does not mean the intervening DNA is there for that reason. The null hypothesis is that the complicated mess that the regulation of each gene is is such a complicated mess because it has to work around all that DNA, not that the DNA is there so that this marvelously complexity can be generated and that the complexity is adaptive. I hope you get the distinction, I am not sure I phrased it in the best possible way, but it's very important

      I think I understand you. Paul McBride said as much on another occasion: something along the lines… while there are possible explanations for bulk DNA that include positive selection, it is more likely that weakened negative selection that allows it to build up instead.

      (Just where is that Kiwi when you need him!? Canucks in a pinch always end up doing the heavy lifting) ;-))))

      I get that – but I remind you that we are discussing Ford Doolittle’s insights, so I direct your attention back to what Ford Doolittle actually said:

      Doolittle: That "excess" DNA (that 40x as much that lungfish have compared to us, for instance) might play a structural role or determine other cellular parameters under selection has long been accepted, even by us "junk" supporters.”

      Re: One of the definitions of an enhancer element has it functioning irrespective of spacing and orientation relative to the promoter…

      I get that too. ...that all said BUT NOT irrespective of DNA topology i.e. negative supercoiling of discrete domains for example.

      Discrete domains? Aren’t we sliding back to some sort of requisition of sequence specificity of nondescript intervening DNA somewhere?

      Re:It isn't conserved when different species are compared, and it isn't constrained based on population genomics data (if you plot the sequence diversity across the genome, it is the lowest within CDS regions and highest in intergenic regions without any evidence for functional noncoding elements in them).

      I addressed this question more than once when speculating whether parasitic DNA can be co-opted into becoming symbiotic DNA in different lineages even when discussing different sequences.

      I was thinking of course of human Alu and murine B1 that do not share sequence conservation but may in fact share domain topologies (as just one speculative for example)

      Delete
    21. Hi John

      Re: Tom, forget the lungfish. What about the fugu? How does it get along without all that crucial spacer DNA?

      I already answered that on

      http://sandwalk.blogspot.ca/2015/05/ford-doolittle-talks-about-transposons.html?showComment=1431386802598#c1078638349645264783

      I remind you this whole thread is dedicated to Ford Doolittle’s prescient insights.

      Ford Doolittle talks about transposons, junk DNA, ENCODE, and how science should work

      With all due respect, I wonder out loud whether some selective reading and just a little misinterpretation may have occurred, is all. Please understand, I intend no offense.

      Meanwhile, I am still trying to wrap my head around Peter Fraser's results and exactly how important these may or may not be.

      Delete
    22. Hi Barb,

      We just cross-posted!

      I love the way your phrased that!

      Seems there are two ways to look at the observation that rearranging junk DNA changes the expression of certain genes. First: The "junk" DNA has a regulatory effect on gene expression. Second: The darn junk DNA interferes with the regulation of gene expression unless it's correctly folded out of the way.

      You said it much more eloquently than my amateur attempt.

      re Distinguishing between those ideas might be difficult; they sort of blend into each other. However, the extremely reduced genomes of fugu and bladderworts lends credence to the second.

      Not to hear Peter Fraser tell it. Mind you, I understand he is "talking his position" as they say in "financial circles".

      Delete
    23. I already answered that on

      Perhaps you could answer it more clearly. I often have great trouble understanding what you're trying to say.

      Are you sure Doolittle is even talking about what you're talking about? He might just be referring to the correlation between genome size and cell size.

      Delete
    24. Doolittle: That "excess" DNA (that 40x as much that lungfish have compared to us, for instance) might play a structural role or determine other cellular parameters under selection has long been accepted, even by us "junk" supporters.”

      Actually I would disagree with the statement that this is accepted. I don't think you can find a famous scientist who has never said anything wrong in his life. This is one of those cases.

      We have discussed this many times, and the math simply does not work - all of the theories that suggest that DNA can have a function related to its bulk fail when one takes into consideration the simple fact that any selective advantage of an insertion would be proportional to its size relative to the genome, but all species with very large genomes have such low effective population sizes that the only insertions that could be visible to selection under these models are considerably larger than the kind of insertions through which genomes actually grow. Thus they can neither be selected for, nor maintained by selection once present.

      The only theory that works as an explanation is the accumulation of junk as a result of inefficient selection in small populations of large-bodied organisms.

      Delete
    25. Georgi Marinov, Tuesday, May 12, 2015 11:58:00 PM:

      "Actually I would disagree with the statement that this is accepted. I don't think you can find a famous scientist who has never said anything wrong in his life. This is one of those cases".

      Georgi,

      I understand that you disagree with Doolittle’s statement that the supporters of so called junk DNA (jDNA) have accepted the presumption that jDNA has a structural role. However, even if what you say is true and indeed most of these supporters don’t believe that, why do you think he believes that jDNA has a structural role?

      Delete
    26. " WHO's a famous scientist"?The one that was more right? Or the one that was more wrong but believed he/she was right and made "sure" of it?

      Delete
    27. Hi Georgi

      I have been distracted by family and work obligations – I apologize for my tardy reply. That and I decided to reread Doolittle’s paper as well as Graur’s paper published about the same time.

      Doolittle suggests that …"excess" DNA (that 40x as much that lungfish have compared to us, for instance) might play a structural role or determine other cellular parameters under selection has long been accepted, even by us "junk" supporters.”

      You suggest that Actually I would disagree with the statement that this is accepted. I don't think you can find a famous scientist who has never said anything wrong in his life. This is one of those cases.

      I disagree.

      Your rebuttal:

      ...all of the theories that suggest that DNA can have a function related to its bulk fail when one takes into consideration the simple fact that any selective advantage of an insertion would be proportional to its size relative to the genome…

      I’ll stop you right there.

      I do not think that premise is correct.

      Allow me to rework one of Doolittle’s metaphors. My computer might be 10 ft from the wall socket, but it only has a 5 ft cord. I can solve the situation by using an extension cord (analogous to “spacer DNA”). Ideally, the extension cord need only be another 5 ft. Bringing in a 10 ft or even a 15 ft extension cord will also do the job.

      However, selective advantage in this case is not proportional to the added length of the cord. That is what I meant earlier by +/- multiples within certain parameters such that one lineage of onion may have more bulk DNA than another lineage of onion while doing the same job, as it were.

      I note that Graur (of Genetic Load fame) also seems to agree along these same lines:

      It has been pointed to us that junk DNA, garbage DNA, and functional DNA may not add up to 100% because some parts of the genome may be functional but not under constraint with respect to nucleotide composition. We tentatively call such genomic segments “indifferent DNA.” Indifferent DNA refers to DNA sites that are functional, but show no evidence of selection against point mutations. Deletion of these sites, however, is deleterious, and is subject to purifying selection. Examples of indifferent DNA are spacers and flanking elements whose presence is required but whose sequence is not important.

      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622293/

      You continue:

      …but all species with very large genomes have such low effective population sizes that the only insertions that could be visible to selection under these models are considerably larger than the kind of insertions through which genomes actually grow. Thus they can neither be selected for, nor maintained by selection once present.

      I think my contradiction of your first premise begins to unravel your syllogism. That said; I agree that Mike Lynch’s contention that the amount of bulk DNA scales negatively with effective population size is a valid rebuttal. Maybe weakened negative selection has merely permitted the build of bulk DNA in smaller populations. (Special Thanks to Paul McBride for helping bring me up to speed!!)

      I still think if fair to say that Doolittle and Graur are hedging their bets regarding any non-informational nucleotypic as well as nucleoskeletal advantages meaning your attribution of "wrong" was misplaced.

      At the risk of incurring John’s wrath, I still wonder out loud (forgive my persistence) whether higher hierarchical orders of selection may be at play here.

      Delete
    28. As I said in the other thread, it is never a good idea to argue with analogies.

      The specific details need to be examined.

      When people talk about bulk DNA having function, they usually talk about it controlling nuclear/cell volume, having some sort of buffering/protection role against TE insertions, etc. In all of those cases, any additional DNA will have a selective advantage no larger than the ratio of its size and the size of the genome. L1 elements are the largest TEs in mammalian genomes, and those are 6kb in size. The genome is 3x10^9, i e. 6 orders of magnitude larger. The effective population size is on the order of 10^4. So the largest TEs are way below the size they would have to be to visible to selection.

      This means all such theories fail because there is no mechanism through which a genome could maintain all that DNA through selection. That does not mean all that DNA does not serve those "functions" once it's there, but those are not selected effects, and have no causal relationship to its presence.

      Now the analogy which you are trying to argue - which boils down to an argument that regulatory elements have to be precisely spaced - falls apart too because once again you need to consider the process. There isn't some state of perfection which is known in advance to evolution and it consciously strives to achieve it. The starting position is one in which the gene is being regulated quite fine as it is and then a big bad TE comes and inserts somewhere between its enhancers. If spacing was so critically important as your model requires (for which there is very little evidence), the vast majority of the time this will be highly detrimental, because you are breaking an already working configuration. A small minority of the time you might end up with something better than what you had before, but those would be rare cases and a species that can get rid of TEs would be in much better shape than those that haven't. But this has not happened, because selection is too weak to do that. Thus the neutral model is entirely sufficient to explain the observations and there is no need to complicate things further with unproven models.

      P.S. If someone is willing to fund an ENCODE for all primates, it would actually be interesting to see how much reconfiguring of spacing there has been within closely related species with big genomes and lots of REs.

      Delete
    29. Hi Georgi

      And THANK YOU! I am very grateful for the time and trouble you are dedicating to my inquiries. A few points I am still unclear on:

      I think Ford Doolittle was specifically referring to nucleoskeletal function for bulk DNA in this particular instance.

      The only selection required for initial genome expansion is at the “selfish/parasitic” level as mentioned before.

      Indel events we are discussing can bring in much more intervening DNA than just the TEs themselves.

      My analogy specifically suggests that size of spacing need not be precise.

      A species may not be able to get rid of its TEs, but a species may adapt to shut down its TEs.

      That means facultative heterochromatin (for example) may consequently represent an exaptation for higher level gene control that is “exuberantly” redundant. Topological domains jumps to mind.

      Perhaps higher level species expansion is now at play here.

      The methylation & the heterochromatin status of cancer cells’ DNA running amok would seem to buttress my line of reasoning.

      I wonder, is there any chance Larry can entice Ford Doolittle himself to weigh in?

      And again thank you for helping me out.

      Delete
    30. Hi Georgi

      Quick after-thought.

      Rereading Ford Doolittle’s quote:

      …"excess" DNA (that 40x as much that lungfish have compared to us, for instance) might play a structural role or determine other cellular parameters under selection has long been accepted, even by us "junk" supporters.”

      Two clarifications are in order, of course Doolittle was simultaneously acknowledging the non-informational nucleotypic as well as nucleoskeletal parameters in his quote. I was in fact focusing on the nucleoskeletal in my answer to you. I want to avoid even the appearance of putting words into Ford Doolittle’s mouth.

      I interpret the “selection” (presumably at the organism level) that Ford Doolittle refers to in the quote as subsequent to an already established genome expansion (which could have occurred by selection at the misnamed “selfish” DNA level).


      My own speculation was that the mechanisms employed to shut down TEs represented an exaptation for an exuberant or redundant level of gene control. The p53 story just jumped to mind. Again, I want to avoid even the appearance of putting words into Ford Doolittle’s mouth.

      That all said, I still stand by my contention that higher orders of hierarchical selection may be at play, but I acknowledge that I have crossed the line into hand-waving speculation.

      Delete
    31. @ Georgi - @ Anybody

      Georgi argues there can be no positive selection at the organism/population level for the build up of bulk DNA. I agree, I suggest we only need invoke selection at the level of selfish DNA (for lack of a better term) or as Graur would call it "indifferent DNA". This leaves open the door for exaptation.

      Georgi then rebuts that "If spacing was so critically important as your model requires (for which there is very little evidence), the vast majority of the time this will be highly detrimental, because you are breaking an already working configuration."

      But I argued exactly along contrary lines!

      My "extension cord" analogy specifically suggests that size of spacing need not be precise.

      ITMT, a species may not be able to get rid of its TEs, but a species may adapt to shut down its TEs.

      That means facultative heterochromatin (as just one for example) may consequently represent an exaptation for higher level gene control that is “exuberantly” redundant. Negatively super-coiled topological domains & the P53 story jumps to mind. And sizes of those domains need not be "precise" whatever that was supposed to mean.

      I thought I had managed to address your caveats with this modified proposal.

      What am I getting wrong?

      Delete
  13. clarification -

    of course, I am not presuming "hunches" on Doolittle's behalf.

    I was of course, referring to my own hunches in attempting to make sense of what Doolittle was on about.

    ReplyDelete