Tuesday, December 04, 2012

Sean Eddy on Junk DNA and ENCODE

Sean Eddy is a bioinformatics expert who runs a lab at the Howard Hughes Medical Institute (HHMI) Janelia Farm Research Campus in Virginia (USA).1 Sean was one of the many scientists who spoke out against the ENCODE misinterpretation of their own results [ENCODE says what?].

Most people now know that ENCODE did not disprove junk DNA (with the possible exception of creationists and a few kooks).

Sean has written a wonderful article for Current Biology where he explains in simple terms why there is abundant evidence for junk (i.e. nonfunctional) DNA [The C-value paradox, junk DNA and ENCODE] [preprint].

Here's a quotation from the article to pique your interest.
Recently, the ENCODE project has concluded that 80% of the human genome is reproducibly transcribed, bound to proteins, or has its chromatin specifically modified. In widespread publicity around the project, some ENCODE leaders claimed that this biochemical activity disproves junk DNA. If there is an alternative hypothesis, it must provide an alternative explanation for the data: for the C-value paradox, for mutational load, and for how a large fraction of eukaryotic genomes is composed of neutrally drifting transposon-derived sequence. ENCODE hasn’t done this, and most of ENCODE’s data don’t bear directly on the question. Transposon‑derived sequence is generally expected to be biochemically active by ENCODE’s definitions — lots of transposon sequences are inserted into transcribed genic regions, mobile transposons are transcribed and regulated, and genomic suppression of transposon activity requires DNA‑binding and chromatin modification.

The question that the ‘junk DNA’ concept addresses is not whether these sequences are biochemically ‘active’, but whether they’re there primarily because they’re useful for the organism.


1. More importantly, he's an alumnus of Talk.origins.

84 comments:

  1. but whether they’re there primarily because they’re useful for the organism

    Usefulness - what a concept!

    Don't know what you call stuff you have lying around the house that isn't useful any more; my wife tends to refer to it as junk.

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    Replies
    1. I'll bet a good bit of it can do something though.

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    2. How much would you like to bet?

      I'm willing to bet $1000 that most (>50%) of our genome is junk (i.e. has no function).

      How will we decide when I've won the bet?

      Delete
    3. "I'll bet a good bit of it can do something though."

      I'm pretty sure a junkyard is full of stuff that can do something. Sometimes the junk even gets re-used or recycled into some new purpose. But that doesn't mean it's still all junk until it does, if ever.

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    4. I'm willing to take you up on that bet.

      Just for starters you may like to have a look at "Junk" DNA Holds Clues to Common Diseases.

      I base my decision on the amount of information required to build a complex object. You should see the huge amount of paper (or pdf) needed to build a jet liner! I extrapolate that a similar amount is required to make a human being with a thinking brain.

      But I think we will have to wait a few years to decide who won because the Darwinian ship, like the Titanic, can't turn on a dime.



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    5. "But that doesn't mean it's still all junk until it does, if ever."

      Correction: this should obviously read:

      "But that doesn't mean it's not junk until it does, if ever."



      "I base my decision on the amount of information required to build a complex object. You should see the huge amount of paper (or pdf) needed to build a jet liner! I extrapolate that a similar amount is required to make a human being with a thinking brain."

      Yeah, I'd like to know what those amebae with 100 times the size of a human genome need all that amount of "paper/pdf" for.

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    6. I'd like to know what those amebae with 100 times the size of a human genome need all that amount of "paper/pdf" for.

      Ah! The onion test.

      Suppose I want a computer to print the numbers 1 to 1000. The programming language I use is very primitive and the only way to accomplish this task is this:

      print 1;
      print 2;
      print 3;
      ...
      print 1000;

      That is a very long program.

      Now I get a more advanced or "evolved" programming language that processes "for" loops and has variables. Now the program looks like this:

      for (int i = 1; i <= 1000; i++) print i;

      That program is a lot shorter for the same task.

      We could apply the same logic to the genome, ameba to human!

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    7. We could apply the same logic to the genome, ameba to human!

      We could, but what would be gained? Your "explanation" would explain any conceivable result, since it's an ad hoc assumption. Now, if you actually look at the genomes and into their functions, there's no sign that any genome is more or less efficient at its task than another, or that "programming languages" differ at all among species. On the other hand, there's good evidence that a great many sequences are evolving neutrally, which argues against their being part of any "program".

      And, speaking of the onion test, you would also have to argue that different species of onion differ radically in their genomic efficiency. How would that happen?

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    8. "We could apply the same logic to the genome, ameba to human!"

      Except that your "logic" fails because that's not how genetics works. Do you have any genetic model to back up your "logic"?

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    9. You also don't seem to realize that you've refuted your own argument, Pepe. Remember, you said:

      I base my decision on the amount of information required to build a complex object. You should see the huge amount of paper (or pdf) needed to build a jet liner!

      But if you're now changing your story and saying the human genome is smaller than the onion genome because humans are more complex and therefore more "advanced", then you've just shot your "jet liner" argument out of the sky.

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    10. What I'm saying is that science is just starting to try to understand how the genome works and probably knows less than 1%. The more we learn about the genome to more complex it gets!

      My example was a metaphor to illustrate that point.

      PS: Did you know that scientists are looking at DNA as a perfect mode of data storage.

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    11. What I'm saying is that science is just starting to try to understand how the genome works and probably knows less than 1%. The more we learn about the genome to more complex it gets!

      You really need to educate yourself about the evidence for non-functionality of much of the genome. Fortunately, this blog is one of the best places to do that. There is a small portion of the genome that is known to be functional. There is a much larger portion of which it can be said with near-certainty is junk. Then there is a portion where the jury is still out. But at absolute minimum about 40% of the genome is junk.

      Am I right there, Larry? I didn't check the latest numbers.

      My example was a metaphor to illustrate that point.

      So what point are you trying to illustrate? At first it seemed to be that humans must have a very large genome which is functional, because we're so complex. Then you say that because humans are so "advanced" we can get by with a small genome. So which is it?

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    12. Oh, BTW, I overlooked this:

      But I think we will have to wait a few years to decide who won because the Darwinian ship, like the Titanic, can't turn on a dime.

      I'm not sure why you're calling this a "Darwinian" ship. Junk DNA is not at all a Darwinian idea. If anything, because it is invisible to natural selection, junk DNA is a decidedly anti-Darwinian concept. If I understand correctly, the adaptationists that dominated evolutionary thinking at the time were royally cheesed off when the idea of junk DNA was first proposed.

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    13. @Pépé

      Did you know that scientists are looking at DNA as a perfect mode of data storage.

      Yes, let's use an organic molecule that is only stable across a small range of temperatures and with a copy error rate of 10**-8 as data storage.

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    14. ...junk DNA is a decidedly anti-Darwinian concept.

      This statement proves that Darwinism can accommodate all points of view. As we say in French: c'est blanc bonet et bonet blanc!

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    15. Yes, let's use an organic molecule that is only stable across a small range of temperatures and with a copy error rate of 10**-8 as data storage.

      Beaten before trying, aren't you?

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    16. Pépé is the kind of person that really makes me believe that there is no such thing as free-will; it's just to difficult to imagine that someone, given the free-will to make the option, would still choose to be an uninformed idiot by choice.

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    17. Beaten before trying, aren't you?

      Indeed, with hard disk error rates in the 10**-14 range you make a compelling argument.

      And DNA achieves it's maximum storage density in it's coiled state in which of course it can not be sequenced.

      So it you don't mind error rates 6 orders of magnitude higher, read/write times that would make the original IBM 8 inch floppy look like a speed demon and prima donna like environmental restrictions then DNA is the obvious choice.

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    18. This statement proves that Darwinism can accommodate all points of view.

      This in response to a post in which I stated that Darwinism cannot accomodate junk DNA? Are you even trying to make sense>

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    19. I stated that Darwinism cannot accomodate junk DNA

      Other Darwinists say the opposite, including the Grand Master of Darwinism, Richard Dawkins, affirming that junk DNA is a stellar proof of the blind undirected trials and erroes of Darwinian evolution.

      You guys need to play the same tune!



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    20. You guys need to play the same tune!

      You don't seem to understand the technical meaning of terms like Darwinian. Much of the conversation is entirely above your head. You could at least make an honest effort to understand the things you want to criticise. Otherwise you end up making a fool of yourself.

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    21. lutesuite: I stated that Darwinism cannot accomodate junk DNA

      Pepe: Other Darwinists say the opposite, including the Grand Master of Darwinism, Richard Dawkins, affirming that junk DNA is a stellar proof of the blind undirected trials and erroes of Darwinian evolution.

      You guys need to play the same tune!


      You guys need to get up to speed with the concepts of biology. You are confusing adaptationism and common descent. Actually, not you, that's a canard repeated far and wide across the Creationist blogosphere that you've just picked up and parroted.

      Variation in phenotypically irrelevant sequence is supportive of Common Descent. It is not supportive of 'hard-line' adaptationism. If that sequence turns out not to be phenotypically irrelevant, it is still supportive of CD (after all, the first molecular phylogenies were constructed on the decidedly non-junk cytochrome c). But Creationists then tend to turn around and say "Common Design". Which is a stupid argument for various reasons, but seeing the same pattern in dispensible sequence refutes it rather neatly, which is why you will find people like Dawkins pointing to variations in junk and other neutral sequences, which are harder for the likes of yourself to just waft away. So you try to waft away the existence of neutrality itself.

      'Darwinism' hardly requires that dispensible sequence to exist on order to remain the prevailing paradigm. It is virtually absent from most prokaryotes, for example. What junk DNA demonstrates is that the metabolic cost of additional DNA appears to be a weak evolutionary burden at best, insufficient to select against its accumulation by various mechanisms, in one particular group of organisms: the eukaryotes.

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    22. Pépé says,

      Other Darwinists say the opposite, including the Grand Master of Darwinism, Richard Dawkins, affirming that junk DNA is a stellar proof of the blind undirected trials and erroes of Darwinian evolution.

      Richard Dawkins is not a big fan of junk DNA and he has never been an advocate of the idea that most of our genome is junk. Your creationist friends have lied to you.

      On the other hand, he has pointed out that certain pseudogenes (a small bit of junk DNA) provide solid evidence for common descent.

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    23. A large fraction of the DNA is never translated into protein. From the point of view of the individual organism this seems paradoxical. If the ‘purpose’ of DNA is to supervise the building of bodies, it is surprising to find a large quantity of DNA which does no such thing. Biologists are racking their brains trying to think what useful task this apparently surplus DNA is doing. But from the point of view of the selfish genes themselves, there is no paradox. The true ‘purpose’ of DNA is to survive, no more and no less. The simplest way to explain the surplus DNA is to suppose that it is a parasite, or at best a harmless but useless passenger, hitching a ride in the survival machines created by the other DNA.
      (The Selfish Gene, Richard Dawkins)

      I will admit that Dawkins didn't use the word "junk", he use the word "parasite" instead.

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    24. So exactly what do you think that quote demonstrates, Pepe? Do you think anyone is claiming that Dawkins or other evolutionary biologists on the Darwinian end of the spectrum deny the existence of junk DNA? If so, you are grossly misunderstanding the argument. As Larry points out, junk DNA is part of the evidence for common ancestry, but is evidence against the role of strictly Darwinian processes in the evolution. Hence, neo-Darwinians like Dawkins minimize the portion of the DNA they believe to be junk, while non-Darwinians like Larry have a more generous estimate.

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    25. Pépé quotes Dawkins and says,

      I will admit that Dawkins didn't use the word "junk", he use the word "parasite" instead

      Selfish DNA has a function. It is not junk. Dawkins' point is exactly the opposite of what you claim. I agree with Dawkins that active transposon DNA does not qualify as junk DNA.

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    26. I agree with Dawkins that active transposon DNA does not qualify as junk DNA.
      (Laurence A. Moran)

      I'm willing to bet $1000 that most (>50%) of our genome is junk (i.e. has no function).
      (Laurence A. Moran)

      Does that mean you are conceding defeat already?
      :-)

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    27. @ Pépé: Check up the meaning of "active" in a dictionary.

      Delete
    28. Pépé asks,

      Does that mean you are conceding defeat already?

      Active, functional transposons make up about 0.2% of our genome [What's in Your Genome?]

      Pépé, I realize that you can't learn basic biology in just a few days but you could at least read enough on the internet to keep you from looking stupid all the time.

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    29. Pépé: You should feel good that, at least, you have won your bet, although I doubt that you’ll ever see a dime! Indeed, the so called junk DNA’ (jDNA) is functional, but not the way the ENCODE project has trumpeted.

      Most people, including many scientists, are stacked within the current dogma that in order to be functional, DNA must have an informational role (iDNA). As I discussed in a comment below and many other posts here at Sandwalk and elsewhere, genomic DNA can also have various structural roles (sDNA), including a protective role against insertional mutagenesis.

      For example, in the absence of sDNA, which likely constitutes more than 90% of the human genome, humans would have a very high rate of cancers induced by various inserting elements, particularly retroviruses. Considering that there are other mechanisms that preferentially direct retroviruses to sDNA, we can confidently assume that sDNA reduces the rate of cancer in humans by a tremendous factor, possibly hundreds of times. Again, this is a fact that no reputable scientist can dispute.

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    30. Pépé,

      I agree with Dawkins that active transposon DNA does not qualify as junk DNA.
      (Laurence A. Moran)

      I'm willing to bet $1000 that most (>50%) of our genome is junk (i.e. has no function).
      (Laurence A. Moran)

      Does that mean you are conceding defeat already?
      :-)


      Nope. Even with your smiley, it means that you are an ass-hole. There's no contradiction between those quotes. But I will not explain it to you. Maybe if you try to figure it out yourself you'll learn something. (I doubt that you care though.)

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    31. Claudiu Bandea,

      Not to dispute the scientific validity of your claim, but it seems to me you are making much the same error the ENCODE people have, by equivocating on the meaning of the word "functional". That non-coding DNA might serve "functions" independent of its informational content does not change the fact that, in terms of that informational content as defined by its base sequences, it can still be called "junk". This is the usual context in which the term "junk DNA" is used.

      While I can see the argument for not allowing creationists do dictate the terms of scientific discussion, I believe it is an error to ignore the possible ramifications of making grand eye-catching, but not strictly accurate, claims about having overthrown the paradigm of junk DNA without considering how easily such statements can be exploited by religious propagandists. That is the error ENCODE made, and I fear you are making it as well.

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    32. lutesuite,

      You bring forward a critical issue regarding the concept of “junk DNA” (jDNA), namely : the meaning of the word "functional".

      Fortunately, we have some very knowledgeable members in linguistics here at Sandwalk, including Piotr Gasiorowski and andyboerger, so I hope they will help us here.

      I agree with you that in terms of “informational content as defined by its base sequences”, the structural DNA (sDNA) can be called “junk”. But, I think, you would agree that in terms of structural role, the informational DNA (iDNA) can also be called “junk.”

      However, from a scientific perspective, both sDNA and iDNA have a biological function, and neither is “junk.”

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    33. lutesuite,

      In regard to your second point, I do not think that we should obscure scientific findings and facts because they might “be exploited by religious propagandists.”

      On the contrary, the effort by some scientists and bloggers to circumvent the truth might create a deceiving academic and intellectual framework susceptible to, and encouraging, misleading propaganda and unproductive discussions.

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    34. I don't see where any scientists are "circumventing the truth." Your claim of the structural role for non-coding DNA may well be correct. I won't pretend to be knowledgeable enough of the field to hold an informed opinion. But assuming it is, that is a peripheral issue to the question of the origin and nature of "junk DNA." More specifically, it does not refute the hypothesis that much, if not most, of non-coding DNA consists of remnants of transposons and similar "selfish" genomic elements. If anything, your hypothesis strengthens this claim, by providing a reason that a smaller C-value would not be selected for, and that there might be an advantage in retaining these junk elements, rather than having them eliminated thru deletion.

      So, again, it comes down to the language one chooses. One can present the evidence objectively and accurately, saying this finding expands our understanding of the nature of non-coding DNA but does not overthrow or falsify our current understanding.

      Or, you can engage in hyperbolic claims that all those "evolutionists" who have been "circumventing the truth" have been proven wrong, thereby providing succour to the actual liars who want to create the impression that all DNA was specifically designed for a purpose by God.

      Your choice.

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    35. lutesuite said: "Your claim of the structural role for non-coding DNA may well be correct. I won't pretend to be knowledgeable enough of the field to hold an informed opinion. But assuming it is, that is a peripheral issue to the question of the origin and nature of "junk DNA." More specifically, it does not refute the hypothesis that much, if not most, of non-coding DNA consists of remnants of transposons and similar "selfish" genomic elements. If anything, your hypothesis strengthens this claim, by providing a reason that a smaller C-value would not be selected for, and that there might be an advantage in retaining these junk elements, rather than having them eliminated thru deletion “

      I completely agree with most of what you are saying. Indeed, my model on the evolution of genome size and the function of the so called “junk DNA” (jDNA) as a protective mechanism against insertional mutagenesis is based on the fact that “much, if not most, of non-coding DNA consists of remnants of transposons and similar "selfish" genomic elements”. Probably, you did not have the chance to read the original paper and the numerous comments I posted here and elsewhere, in which I address these issues in more detailed; for links to some of this material, please see my comment below in response to a question by Pedro.

      However, I don't think that the putative protective function of the so called jDNA is a peripheral issue. This function might be key to undestanding the evolution of genome size (in your words, it provide “a reason that a smaller C-value would not be selected for”), which is a very important scientific goal. Moreover, this model might have significant biomedical implications and applications (see my previous discussions).

      Also, I think that most if not all evolutionists are open to truth; I also belive that they will embrace this model if they would get the chance to evaluate it. However, if you read previous discussions here at Sandwalk, you’ll find that some of our colleagues have circumvented the data and the rationale supporting this model based on what I consider ideological (anti-religion in this case) reasons, which are in line with to those articulated by you. My point is that we should not let the truth and science become hostage to ideological pursuits.

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    36. However, if you read previous discussions here at Sandwalk, you’ll find that some of our colleagues have circumvented the data and the rationale supporting this model based on what I consider ideological (anti-religion in this case) reasons, which are in line with to those articulated by you. My point is that we should not let the truth and science become hostage to ideological pursuits.

      And if that's the case, then I have to say with all due respect you may share a large portion of blame. You could be more modest and realistic in the appraisal of your model as being a complement to the understanding of the nature of non-coding DNA. But when you instead present as a revolutionary overturning of the standard scientific understanding of the topic (eg. when you suggest that this means Pepe has won his bet, when in fact it does not), you sound suspiciously like a creationist. And, to be clear, I am not accusing you of being one. But if others are coming to that conclusion, you may have to consider you part in fostering that impression.

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    37. My comments here and elsewhere about the paradigm that the so called “junk DNA” (jDNA) provides a protective mechanism against insertional mutagenesis, which in humans and other species is a common cause of cancer, come more than two decades after I published it.

      For whatever reason, the model I proposed has not been embraced. So, now that we know that this paradigm represents a fact that cannot be disputed (any statistician will confirm that), I decided to re-introduce it. I think that's reasonable, don’t you?

      Obviously, Pépé did not make his argument based on my model. But, it just happen that he won his bet with our host Larry. To his credit, Pépé (if indeed he/she is a real person and not a fictional character invented to spike or discussion on jDNA) has not jumped yet up down demanding his ‘cash’, as he probably realized that he was right but not for the reasons he thought. So, kudos to Pépé!

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    38. What would be the reason an amoeba has 100 times more jDNA than a human? Do amoebas get cancer? Why does a breed of onions have so much jDNA and another onion breed with little genetic differences that can be cultured in the exact same conditions doesn't? How does your model cope with that?

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    39. Pedro: What would be the reason an amoeba has 100 times more jDNA than a human? Do amoebas get cancer? Why does a breed of onions have so much jDNA and another onion breed with little genetic differences that can be cultured in the exact same conditions doesn't? How does your model cope with that?

      These are all great questions and any model on the potential function of the so called ‘junk DNA’ (jDNA) should address them. I don’t know if you had the chance to read my comment entitled ‘Five reasons why my theory on the function of ‘junk DNA’ is better than theirs’ in which I made strong case for this:

      “The Onion Test is so formidable and inconvenient that, to my knowledge, it has yet to make it through the peer review into the conventional scientific literature or textbooks. (http://selab.janelia.org/people/eddys/blog/?p=683)

      When confronted with the ‘Onion Test,’ do you know what the leaders of the ENCODE project, who stated that 80% of the human genome is functional, said? They said that the Onion Test is ‘silly ’ (see: http://www.genomicron.evolverzone.com/2012/09/birney-thinks-onion-test-silly/.

      So, if the leaders of the ENCODE project, which has consumed more than 200 million dollars of our tax money, can get out of addressing inconvenient questions about their conclusion by saying that they are ‘silly’ (or by using an even more efficient strategy of dealing with difficult questions or alternative paradigms which is to pretend that they don’t exist), do you expect me to really address these questions here?

      Don’t you think that reasonable answers to such important questions would be worth a page or two in some of our flagship scientific journals? After all, understanding the evolution of the genome side and the potential role, if any, of the so called jDNA are among the most significant scientific questions in biology, aren’t they? And they are worth investing hundreds of millions of dollars in addressing them, aren’t they? So, how much would reasonable answers to your questions be worth? For goodness sake, even Pepe might end up a thousand bucks richer from this fiasco about jDNA!

      Well, unlike in traditional scientific publishing, here in the Blogosphere you ‘answer the questions or perish’! So, I did! I answered the Onion Test challenge. And in doing so, I proposed the Hummingbird Case (you can find a narrative of this paradigm here: http://sandwalk.blogspot.com/2012/09/ewan-birney-genomics-big-talker.html).

      Pedro, I hope I didn't lose you during this rant! Please take a serious look at the Hummingbird Case and see if it silences the Onion Test? Maybe the author and other proponents of the OT might jump in, unless they think that Hummingbird Case is silly!

      In regard specifically to amoeba’s freakish genome, its enormous size might have something to do with their enormous appetite for ingesting tons of other genomes that are full of transposable, inserting elements. What do you think?

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    40. Maybe I'm missing something, but I fail to see how your "Hummingbird Case" even remotely addresses the "Onion Test." You seem be claiming that the reason the hummingbird has an unusually small genome is because of the high metabolic demands its mode of flight imposes. Umm, OK. Any supporting evidence? Is there an overall correlation between metabolic demands and genome size? Do humans have much higher metabolic requirements than, say, salamanders? Of the two types of onions Pedro mentions, does one fly about collecting nectar from flowers while the other just sits quietly in the ground? I can't say I've ever seen a flying onion, but you never know.

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    41. @lutesuite

      Obviously you are “missing something.” And, I’m rather surprised because I though you got the essence of my model on the evolution of genome size and of the so called ‘junk DNA’ (jDNA), when you said:

      “If anything, your hypothesis strengthens this claim, by providing a reason that a smaller C-value would not be selected for, and that there might be an advantage in retaining these junk elements, rather than having them eliminated thru deletion.”

      Apparently, I was wrong about your take, but let’s see what Pedro or the OT fans have to say, if anything!

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    42. "Pedro, I hope I didn't lose you during this rant!"

      No worries. I'm not attacking you at all, just asking questions.

      "Please take a serious look at the Hummingbird Case and see if it silences the Onion Test?"

      In here I have to agree to a certain point with Lutesuite. It's not that your model appears to me as necessarilly wrong, it's that the explanation is seems shaky and needs a lot more testing, including clearly invalidating the null-hyphotesis. Even if the humming-bird case did explain without any doubt that particular case you'd still have to have a coherent explanation to most other cases, including the good old different onions, etc. I don't think it is ready to pass the onion test as it is, unless I'm missing something. As for the amoeba case you say that the enourmous size of its genome "MIGHT HAVE something to do" with lateral transfer of genetic material, but this is far from being a good explanation. It COULD be, but you need a unifying concept that fits most observed cases, and at the moment you don't appear to have that. Therefore it's normal that other people will not see your case as a solid alternative to the present model of jDNA. Maybe it will turn out to be correct eventually, but right now it is not in a form that can overthrow the current models.

      Not sure I was clear in my point. What do you think?

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    43. Some more food for thought: if I remember correctly, most if not all, birds of prey show relatively low amounts of jDNA (someone please confirm). That could help with your idea that metabolic rates could have something to do with it. But what about migratory birds that are under extreme metabolic stress? What about migratory mammals in Africa that spend most of their time under nutrient stress, always traveling from one place to the other in great migrations to find water and food? You would have to analyze all these cases, calculate what the energetic needs would be for all representative species and see if metabolic rates correlate with jDNA content all across the board. Just using the humming-bird case is not enough. It's only a single example. Your theory has to demonstrate the capacity to coherently explain most cases under an unified model. Otherwise it won't convince anyone to abandon the current jDNA model. It seems to me that right now the metabolic explanation for low amounts of jDNA is far from clear. probably it doesn't even correlate across most cases, much less jumping to the conclusion of causation.

      What do you think?

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    44. Hum, my posts are not being posted in real time in the thread. Kind of difficult to have a discussion like this with posts missing.

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    45. Let me make the missing post again:

      If you want to pass the "onion test" you have to show that your model is consistent all across the board, not just with a single example from humming-birds. Does two different breeds of onion have significant different metabolic demands that correlate well with the huge difference in jDNA amount? Does a cheetah, which has high metabolic demands, have correspondingly low amounts of jDNA? We know that birds of prey apparently have relatively low jDNA content, but what about other species with also high metabolic demands? What about grazing animals in Africa, in which thousands of animals die for lack of water and food while migrating all the time? Do they all show lowjDNA content? What about migrating birds that travel from northern latitudes to lower latitudes in extreme metabolic stress?

      Can we see a clear correlation between a representative number of species that show consistent levels of jDNA that are consistent with your model? It seems to me that it can't. I think you are far from passing the "onion test". You have to eliminate the null-hypothesis and also show that low jDNA amounts correlate all across the board with a representative number of high metabolism species. Otherwise you don't have a strong case.

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    46. Pedro said: What do you think?

      Well, I think we are making progress. Indeed, as stated by lutesuite this is “a revolutionary overturning of the standard scientific understanding of the topic”, so it is not going be an easy transition. Although relatively straightforward, this model on the evolution of genome size and of so called junk DNA (jDNA) challenges much of the thinking and dogma in the field, so it should be expected to be met with some reluctance. Moreover, like any major paradigm change, it needs to undergo full validation, and that usually requires many new studies and numerous discussions.

      However, fundamentally, this model solves the C-value and jDNA enigmas: as an adaptive defense mechanism, the amount of protective DNA varies from one species to another based on the insertional mutagenesis activity and evolutionary constrains on genome size.

      Obviously, there are many issues and specific cases (e.g.amoeba) that need to be further addressed in context of this model. However, one of the major undertakes would be to clarify what biological function means. Like lutesuite mentioned above, the current dogma implies that in order to be considered functional, the DNA must have an informational function. In context of this dogma, only ‘informational DNA’ (iDNA) has a function, so unless we clarify the problem with this dogma, it will continue to obstruct progress.

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    47. I don't think you actually answered any of my questions above.

      "Moreover, like any major paradigm change, it needs to undergo full validation, and that usually requires many new studies and numerous discussions."

      But until those studies show that your model correlates to all the points I made above you don't have a case. You say that your model solves the C-value enigma, and you could very well have a case for the high values of jDNA as being functional by your definition. But until your model passes the "onion test" (see my posts above that you have not commented on) it hasn't solved anything. You have to explain both the high and low levels of jDNA, otherwise your model isn't an alternative to the current paradigm.

      Delete
    48. Petro,

      I think if you review your comments on this post, you’ll see that I answered most of your specific questions and that you thanked me for that several times.

      Obviously, this model on the evolution of genome size and of so called junk DNA (jDNA) needs further studies and discussion. However, this model fundamentally answers the very old C-value enigma (which commonly and metaphorically is expressed as the Onion Test):

      : as an adaptive defense mechanism, the amount of protective DNA varies from one species to another based on the insertional mutagenesis activity and evolutionary constrains on genome size.

      Clearly, the protective function of jDNA against insertional mutagenesis is a fact, and no reputable scientist disputes that.

      Delete
    49. No, I get the "essence of your model" just fine, Claudiu. And I don't think I'm missing anything, now. But I was earlier, when I was treating you as a serious scientist.

      I also don't appreciate being quote mined. I now realize why most of the longterm posters here seem to be simply ignoring you, as I will endeavour to do henceforth.

      A bit of internet sleuthing reveals that your "hypothesis" was not published in a peer-reviewed journal, but in a magazine best known for promoting pseudoscientific ideas like AIDS denialism. Since then, you have spent much of the past two decades trolling internet discussion groups complaining that your idea has not been accepted because of the ideological rigidity of the scientific establishment.

      If you really want your idea to be accepted, you would get back into the lab and produce some evidence worthy of passing the peer-review process, rather than just whining about how your genius is not appreciated by the blinkered scientific elite. Until you do so, you deserve to be treated as nothing more than a crank.

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    50. @lutesuite,

      As I said in an earlier comment, unlike the conventional scientific publishing, where you are protected from ‘unpleasant’ comments, here on Blogosphere, you are fully exposed. The only bad part about that, is that it is usually done by people, such as lutesuite, who hide behind anonymity.

      I suggest that if you respect yourself enough to stand behind your words, and if you respect the other members of this blog, you should reveal who you are.

      Also, I think that the editors and the thousands of scientists and clinicians who have published in one of the oldest scientific medical journal Medical Hypothesis, where I published my hypothesis, are highly offended by your remarks about the journal.

      Moreover, I only joined the Blogosphere less than two years ago, so your assertion about “trolling’’ is incorrect. The fact is that, although I published my model on the evolution of genome size and of so called junk DNA (jDNA) more than two decades ago, I never brought it up until now, which might explain why it is not known.

      Delete
    51. http://en.wikipedia.org/wiki/Medical_Hypotheses

      Delete
    52. Claudiu:

      "Clearly, the protective function of jDNA against insertional mutagenesis is a fact, and no reputable scientist disputes that."

      My problem is not really with the insertional mutagenesis part but with the claim that those with less jDNA are due to metabolic/energetic reasons. If we check a representative number of species for which we have metabolic data, does that map well to jDNA size? You should do that, because right now the model is too vague and without clear confirmation. Things like "evolutionary constrains on genome size" sound good but lack solid evidence that actually confirms it. What constrains are those specifically? Metabolism? Remains to be shown, in my opinion. It's too vague. I think your model may be a good hypothesis, but it is certainly in no state to be a paradigm changer for now unless you come up with strong data to support it. I can't blame people for remaining skeptical for now.

      Anyway, I'm not attacking you. But I'd prefer that you worked on your model instead and delivered the goods. As it is it will not convince anyone. It's just an hypothesis that needs far more data to turn into something solid.

      :)

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    53. Pedro,

      I appreciate the fact that you are keeping our discussion here on scientific issues, rather than turning it into meaningless personal attacks.

      I just want to clarify that the ‘Hummingbird case’ was intended to address the issue whether evolution of the genome size and of the so called ‘junk DNA’ (jDNA) can be under host selective constrains? As discussed in the original paper, the presence of jDNA can be explain simply because its rate of origin is higher than that of its deletion, or because jDNA offers a selective advantage. The hummingbirds are a clear example that even in vertebrates the amount of jDNA can be under selective constrains and that it can be reduced if necessary. Therefore, the fact that many species maintain high level of jDNA, supports the idea that it has a selective advantage.

      So what about the paradigm change associated with my model? As you know, despite ECODES’s conclusion that 80% or our genome is functional, most scientists continue to claim, as they have done for almost half of century, that the vast majority of our DNA is non-functional, or junk. However, the current data and observations clearly show that the so-called jDNA provide a defense mechanism against insertional mutagenesis. This is an indisputable, statistical fact, which no reputable scientist denies. If that is the case, and the so-called jDNA provides a defense mechanism at the genome level (just as the immune system which provides hundreds of defense mechanisms at the organismal level), then it makes sense to consider it functional DNA.

      Again, say goodbye to the concept of ‘junk DNA’!

      Delete
  2. For those without access to the journal, there is a preprint version here:

    http://selab.janelia.org/publications/Eddy12/Eddy12-preprint.pdf

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  3. Most people now know that ENCODE did not disprove junk DNA (with the possible exception of creationists and a few kooks).

    Larry, I applaud your optimism (even if, when we met in Ottawa last July, you towered over me and smirked). It is a charming attribute, but maybe it's overoptimism.

    I worry that it will take ten years to straighten out the public, and scientists in other fields, on this issue. Sean's article is certainly a good first step.

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    1. Joe, I agree with you. It will take many years for the misleading message trumpeted by the ENCODE to fade. We have to realize that the leaders of this project are very smart and ambitious people, who will not let facts stay in their way. That’s why there occupy those positions. But forget about their misleading message, what’s important here is that the project has generated valuable data that can be used to make progress in understanding our genome.

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  4. I spoke too soon. I read the article and ... it isn't just "useful", it's great. The section headings posing questions read as if they were copied from the postings of creationists. (Maybe they were ...)

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    1. I agree, it was informative and a pleasure to read and for a non biologist like myself it was quite accessible.

      I only had to look up a few terms on google.

      A must read for our blinkered troll Pépé.

      This could be a contender for the next edition of The Oxford Book of Modern Science Writing by Richard Dawkins.

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    2. steve, are you always that nice with others?

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    3. Pépé, do creotard trolls start talking about hurt feelings only when they realize that their position is irrational and non-evidence based or is this a pre-emptive strike ?

      Delete
    4. steve, only the weak argues by insulting!

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    5. "steve, only the weak argues by insulting!"

      "steve, are you always that nice with others?"

      Quite ironic comming from someone who started posting in these blogs by posing as the confused layman asking "Is atheism a prerequisite to understand evolution?" and slowly started showing his true colors by misrepresenting what people were telling him, like "Should I conclude that there is a link between correctly understanding evolution and being an atheist?", "It is clear to me now, from the above comments, that evolution, as explained by Darwin, i.e. Darwinism. fosters atheism. If this is so, isn't Darwinism more a philosophy or worldview than science?
      Please correct me if I am wrong."

      Tell me, pepe, do you go to church for courses on deception, lying, misrepresentation, etc? Is "lying for jesus", "playing the jerk for jesus", etc, all fine by you as long as the result is denigration of science and a rise in IDiocy? Do the end justify the means? Do you think jesus is going to congatulate you on your death for beying a troll in life? When did you make the choice of stop thinking for yourself and become an ignoramus?

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    6. Indeed, I was simply shattered after his I'm sorry, I should have realized that atheists can't answer "why" question. rebuttal.

      As well, it was a sobering moment for me as I came to realization that I was helpless in the face of someone who can marshal facts like Pépé and bring them to bear in an overwhelming rhetorical onslaught.

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    7. Just want to add my endorsement, FWIW. This article is very clear and persuasive to a layperson like myself. A must read for anyone interested in the topic.

      Delete
  5. Unfortunately, very few people, even among those who study biology or genetics, realize that genomic DNA can fulfill two categories of functions: (i) informational functions, which are based primarily on their specific sequence, and (ii) structural functions, which are more or less independent of the sequence.

    The ‘informational DNA’ (iDNA) includes sequences that code for proteins, functional RNAs, and regulatory elements, such as promoters, enhancers, and origins of replication. The ‘structural DNA’ (sDNA) can have organizational, mechanical, spacing functions (e.g. DNA in centromeres and in regions located between iDNA sequences), or protective functions against insertional mutagenesis, which, presumably, covers the entire genomic DNA that has been traditionally labeled as “junk DNA” (jDNA). This is classification of genomic DNA is not explicitly presented in textbooks, although most of the authors and scholars in the field would agree with most of this description.

    In exploring hypotheses on the potential functions of the so called jDNA, it is essential to consider its evolutionary origin. Approximately 50% of the human genome is composed of recognizable transposable elements (TEs), including thousands of human endogenous retroviruses. It is very likely, also, that much of the rest of jDNA are remnants of TEs that have lost their TE-sequence signatures. Considering the abundance and the rapid spread of these elements, it is unlikely that most of them acquire functions as iDNA, although some do. Therefore, from an information perspective, this DNA is non-functional.

    However, as discussed at length here and elsewhere, the current evidence indicate that so called jDNA functions as a sink for the integration of proviruses, transposons and other inserting elements, thereby protecting iDNA from inactivation or alteration of its expression. The evolution of alternative protective mechanisms against insertion mutagenesis, such as specific integration sites in species that have little jDNA, (e.g. Bacteria), is strong evidence for this selective pressure. However, this pressure enters a new dimension in humans and other multicellular species, in which the number of integration events in somatic cells (including those by retroviruses) that would lead to cancer would be enormous without a protective mechanism.

    Probably, the best example of the host evolutionary constrains on the genome size, even in complex organisms such as vertebrates, is the Hummingbird Case: the hummingbirds have the smallest genome size, not only among birds but all tetrapods, apparently because of the selective force imposed by their high metabolic demands associated with powered flight.

    In summary, this model is fully consistent with the current data, makes evolutionary sense, and, statistically, is a fact. Expectedly, as an adaptive defense mechanism, the amount of protective DNA varies from one species to another based on the insertional mutagenesis activity and evolutionary constrains on genome size.

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    1. "The evolution of alternative protective mechanisms against insertion mutagenesis, such as specific integration sites in species that have little jDNA, (e.g. Bacteria), is strong evidence for this selective pressure. However, this pressure enters a new dimension in humans and other multicellular species, in which the number of integration events in somatic cells (including those by retroviruses) that would lead to cancer would be enormous without a protective mechanism."

      Do pufferfishes and hummingbirds have specific integration sites too? If not, how do they cope with cancer/mutational load?

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    2. Although there are many preferred site for the integration of retroviruses and other inserting elements in the genome of multicelluar species (usually within the so called 'junk DNA'), even if we assume a random site for integration, the protective function of this structural DNA is indisputable.

      Say goodbye to the concept of 'junk DNA'!

      Delete
    3. You didn't answer my question. My question is, since a putterfish has very little junk DNA, how does it cope with cancer/mutational load?

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    4. Assuming similar insertion activities by viral and transposable elements in both humans and puffer fish, and neglecting the difference in the number of their somatic cells, the incidence of cancers in some puffer fish species might be ten times higher than in humans. However, I do not know the rate of viral insertions or the rate of cancer in puffer fish.

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    5. Thank you, Claudiu. I'd like to see more discussion on this, since it's not particularly clear to me.

      Delete
    6. Pedro: You can find the original paper on this model on the evolution of genome size and the protective function of the so called “junk DNA” (jDNA) here: http://www.ncbi.nlm.nih.gov/pubmed/2156137

      If you do not have access to the journal, you can find a copy of this short paper (excluding references) right here at Sandwalk: http://sandwalk.blogspot.com/2012/06/tributre-to-stephen-jay-gould.html

      Also, you can find additional comments and discussion, here and elsewise, including Sean Eddy’s blog:
      http://sandwalk.blogspot.com/2012/09/athena-andreadis-writes-for-sceintific.html

      http://selab.janelia.org/people/eddys/blog/?p=683

      http://comments.sciencemag.org/content/10.1126/science.337.6099.1159

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  6. Claudiu: So what you're saying is that species with a lot of insertional activity have a lot of insertional activity as a protection against a lot of insertional activity. I propose we call this the Ouroboros Theory of junk DNA function.

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    1. John: What I’m saying is that insertional mutagenesis is a very strong selective pressure. This selection is so strong that even unicellular organisms such as bacteria, which have huge populations and short life cycle, evolved protective mechanisms against it, in form of specific sites for integration. However, other organisms, such as multicellular species, in which the constraints for a compact genome were more relaxed, took advantage of an alternative protective mechanism based on the ‘structural DNA’ (sDNA) generated by the inserting elements. It’s like fighting fire with fire.

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  7. Pepe says:

    "You should see the huge amount of paper (or pdf) needed to build a jet liner! I extrapolate that a similar amount is required to make a human being with a thinking brain."

    A pretty silly extrapolation, and a pretty good indicator that Pepe has a spectacularly limited understanding of things like genetics and development. Darwin knew about such folk way back when when he wrote:

    "Ignorance more frequently begets confidence than does knowledge: it is those who know little, and not those who know much, who so positively assert that this or that problem will never be solved by science. ":

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  8. Pepe says:

    "You should see the huge amount of paper (or pdf) needed to build a jet liner! I extrapolate that a similar amount is required to make a human being with a thinking brain."

    A pretty silly extrapolation, and a pretty good indicator that Pepe has a spectacularly limited understanding of things like genetics and development. Darwin knew about such folk way back when when he wrote:

    "Ignorance more frequently begets confidence than does knowledge: it is those who know little, and not those who know much, who so positively assert that this or that problem will never be solved by science. ":

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    1. (Is there an echo here?)

      Darwin also said:

      A fair result can be obtained only by fully stating and balancing the facts and arguments on both sides of each question.

      But dogmatists will have none of THAT!



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    2. squatting in between those on the side of reason and evidence and those worshipping superstition and myth is not a better place. It just means you’re halfway to crazy town.

      PZ Meyers

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    3. And speaking of echoes and (I assume) another Sam Harris:

      The fact that Collins, as both a scientist and as an influential apologist for religion, repeatedly emphasizes the silly fiction of Jesus’ singular self-appraisal is one of many embarrassing signs that he has lived too long in the echo chamber of Evangelical Christianity.

      If we are going to be "fully stating and balancing the facts and arguments on both sides of each question" then you need to be honest enough to fully state your position.

      Are you a god soaked IDiot ?

      Are you proposing a supernatural explanation ?

      Do you major premises come from a holy book ?

      What flavour is your invisible friend ?

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    4. Darwin also said:

      A fair result can be obtained only by fully stating and balancing the facts and arguments on both sides of each question.

      But dogmatists will have none of THAT!


      No, they won't. Very true.

      You'll notice you are enjoying full freedom to ask questions and make comments here, as you would be on pretty well any site discussing evolution from a scientifically informed perspective.

      Go try doing that at a creationist website like that of the Discovery Institute, for example, and see how that works.

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  9. Transposon‑derived sequence is generally expected to be biochemically active by ENCODE’s definitions...genomic suppression of transposon activity requires DNA‑binding and chromatin modification.

    That the DNA binding activity these ENCODE papers count as evidence of transposon function is actually all the result of transposon suppression is a huge oversight on ENCODE's part, which I find hard to believe. Has anyone gone through the papers to see if they controlled for this in their analysis?

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