Sunday, September 09, 2012

The Random Genome Project

Sean Eddy is a old—well not too old—talk.origins fan. (Hi Sean!).

Because he's had all that training in how to think correctly, he gets the difference between junk DNA and functional DNA. Read his post at: ENCODE says what? (C'est what?).

Think about your answer to the Random Genome Project thought experiment.
So a-ha, there’s the real question. The experiment that I’d like to see is the Random Genome Project. Synthesize a hundred million base chromosome of entirely random DNA, and do an ENCODE project on that DNA. Place your bets: will it be transcribed? bound by DNA-binding proteins? chromatin marked?

Of course it will.

The Random Genome Project is the null hypothesis, an essential piece of understanding that would be lovely to have before we all fight about the interpretation of ENCODE data on genomes. For random DNA (not transposon-derived DNA, not coding, not regulatory), what’s our null expectation for all these “functional” ENCODE features, by chance alone, in random DNA?

(Hat tip to The Finch and Pea blog, a great blog that I hadn’t seen before the last few days, where you’ll find essentially the same idea.)


25 comments :

  1. Doesn't seem to prove much to me. All of our DNA was generated that way. It's the selection that makes the difference. Your point, I know, is that although many of the random elements may be chemically active, the aren't visible to selection. But that's a different issue.

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    1. The ENCODE project could have found that in the 80%+ of the genome outside clearly functional loci that there was very little metabolic activity, but that turned out to not be the case. To me that's the big news from the project. Sloppy genomic metabolism gives selection some raw materials with which to operate.

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    2. No, the ENCODE project could NOT have found that unless everything we know about DNA, chromatin, and DNA binding proteins is wrong.

      If they had found no "biochemical activity" at all in junk DNA then THAT would have been big news. That's the point that Sean and the rest of us are making.

      Sloppy metabolism is a consequence of biochemistry and evolution. It's not something that's selected for in order to provide opportunities for evolution.

      It's clear that we have to do a much better job of teaching basic biochemistry concepts to our undergraduate and graduate students. Problem is, the teachers need to be taught first and right now I'm not optimistic about that possibility.

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    3. Anonymous, I've read your comment a couple times, and I don't see you saying 'no biochemical activity', but rather 'very little metabolic activity' so not sure why LM used quotes. Also, I don't see anywhere in what you wrote an indication that you think sloppy genomic metabolism is "selected for' in order to provide opportunities for evolution. Maybe I'll read a couple more times just to be sure. ;)

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    4. No, the ENCODE project could NOT have found that unless everything we know about DNA, chromatin, and DNA binding proteins is wrong.

      Still valuable to have such large-scale experimental confirmation. What does ENCODE say about heterochromatic regions?

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  2. Hehe, this is all part of our plan to have Talk.Origins veterans take over the entire field of biology.

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    1. Good, you're young enough to recognize your error and understand that so called 'junk DNA' is actually a homing device for the Mothership.

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    2. Hey, I'm a lot older than that and I don't need to google to tell me that I'm......

      Oh, oh, maybe I do.

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    3. Cool! That means you published tRNAScan-SE when you were 13? ;-)

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    4. If only there was something just as nice to find 16S rRNA genes ... :(

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  4. Well, you always looked very young to me. Glad to see you are in the club ... the last dozen or so scientists who think there is lots of junk DNA.

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    1. ... in Amphiuma and Allium ursinum, maybe. Surely no-one still thinks there's lots in people? They're special!

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    2. You are special, and undoubtedly have little junk DNA. As for the rest, of us, sadly we have lots of it.

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    3. It's true! I have a minuscule genome! I do suffer from c-value envy, however, since my gametes are worthless...

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  5. Age doesn't matter but Muggins does. Its been my observation that cat-people are smarter than the average. I wonder how many of the ENCODE people are ailurophobic.

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  6. As I already mentioned somewhere else: Wouldn't analyses of bacterial genomes inserted into eukaryotic genomes be enough to counter ENCODE's mostly hyped conclusion? There must be thousands of plasmids residing in the genomes of transgenic animals. There are indeed cases where problems with proper transgene expression may be due to some biochemical function of these vector sequences. But put the same transgen in another location and these effects don't show up (position effect variegation). Thus, it is clear that what one observes is rather an effect of the host genome dependent on the insertion site than a function intrinsic to the DNA. If this isn't enough, what about Drosophila ananassae which carries a complete Wolbachia genome in its chromosomes? This is DNA surely not evolved to fulfill some function in the host species. Still, I guess it is a safe bet to assume that it will be associated with nucleosomes and that it will display some of the reactions ENCODE defines as biochemical functions (e.g. transcription factor binding). IMO, the guys who were involved in publishing the 80% number are lacking some basic understanding of biology or are intellectually dishonest. Thus, why spend time suggesting random DNA experiments.

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  7. I'd like someone to really explain how you can be certain that molecular fragments in a cell you don't identify as "functional" today might not turn out to have a decidedly real function at some later time. How do you now that you merely haven't identified that function, yet?

    And why is this particular publishing event of such Earth shaking, scientific importance? The only thing I can see is an ideological sporting match.

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  8. How do you now that you merely haven't identified that function, yet?

    Dr. Moran's gone through that already in multiple posts on this blog. If I can try as a layperson to paraphrase my understanding of these posts:

    A very, very high percentage of junk is actually identifiable as non-functional crap. Even if *all* the stuff not yet identified as non-functional crap turns out to have functions, that would change today's calculus of the functional percentage of human DNA very little.

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    1. That seems to be more an expression of faith in the efficacy of present day methodology than an answer to the question.

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    2. That seems to be more an expression of faith in the efficacy of present day methodology...

      Only if you are ignorant of the amount of evidence that supports the "crap" conclusion.

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  9. Can you write eulogies on top of two decades old eulogies?

    Larry Moran comes out hard on ENCODE’s recent eulogy for junk DNA, and even harder on science writers promoting the paradigm that at least 80% of the human genome is functional. And, he does it for a very good reason: the ENCODE’s data does not show that by any decent stretch of imagination, period! Here are some notes, starting with some points on human nature:

    1. It would be very difficult for science writers, particularly for those who write for major conventional science outlets (and make a living doing it) to go against the message of one of the most massive recent scientific consortium, which includes hundreds of top scientists and science administrators, including the editorial teams of top science journals. Given this reality, I think science writers did a reasonable job, and they are improving on that. The good thing about their hesitation is that it gave the opportunity to some free spirit scientists/writers, like Larry, to shine. And he did!

    2. Another good thing about this suspect paradigm is that it brings the issue of junk DNA at the forefront of scientific debate. Come to think of it, that was admitted even by the promoters of this paradigm, as they made the decision to go with the 80% figure, which would be more impressive and generate more attention than 20% figure, which had some reasonable backup data. With this renewed interest, Larry and other scientists have the opportunity to set things straight on an issue that was hanging low on the scientific interest ladder.

    3. For example, Ryan Gregory, a top scholar in this field, has the opportunity to bring forward his Onion Test, which is so formidable that, to my knowledge, it has yet to pass by the peer review system that guards the upper echelon of science enterprise from inconvenient scientific inquiries. And, that would be likely the case also with the idea behind “The Random Genome Project.” Indeed, as everyone knows, the best way to deal with inconvenient ideas is not to criticize them, which will bring them into discussion, but to pretend they don’t exist.

    4. And, this giant fiasco might give people, who already wrote the eulogy of junk DNA more than two decades ago (see my paper/comments on the function of junk DNA at Larry’s post: A Tribute to Stephen Jay Gould) the chance to ask: can you write eulogies on top of two decades old eulogies?

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  10. Larry,

    Is it possible to obtain a transgenic mouse with a high percentage of "junk" DNA deleted? Has this experiment been done? If yes, was the mouse phenotipically normal?

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    1. @ Ben,

      http://www.ncbi.nlm.nih.gov/pubmed/15496924

      Abstract
      The functional importance of the roughly 98% of mammalian genomes not corresponding to protein coding sequences remains largely undetermined. Here we show that some large-scale deletions of the non-coding DNA referred to as gene deserts can be well tolerated by an organism. We deleted two large non-coding intervals, 1,511 kilobases and 845 kilobases in length, from the mouse genome. Viable mice homozygous for the deletions were generated and were indistinguishable from wild-type littermates with regard to morphology, reproductive fitness, growth, longevity and a variety of parameters assaying general homeostasis. Further detailed analysis of the expression of multiple genes bracketing the deletions revealed only minor expression differences in homozygous deletion and wild-type mice. Together, the two deleted segments harbour 1,243 non-coding sequences conserved between humans and rodents (more than 100 base pairs, 70% identity). Some of the deleted sequences might encode for functions unidentified in our screen; nonetheless, these studies further support the existence of potentially 'disposable DNA' in the genomes of mammals.

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  11. In 100 million bases I wonder how many hairpin loops will be found with a stem length longer than 19? I am guessing none, maybe 1.

    I also wonder how many coding sequences will be found greater than 500 codons in length. I am guessing none.

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