Michael Eisen’s take on ENCODE — there’s no junk?

Michael Eisen has also weighed in on the ENCODE media blitz, but it’s interesting that he criticizes the hype for a very different reason:

The issues all stem, ultimately, from the press releases issued by the ENCODE team, one of which begins:

The hundreds of researchers working on the ENCODE project have revealed that much of what has been called ‘junk DNA’ in the human genome is actually a massive control panel with millions of switches regulating the activity of our genes. Without these switches, genes would not work – and mutations in these regions might lead to human disease. The new information delivered by ENCODE is so comprehensive and complex that it has given rise to a new publishing model in which electronic documents and datasets are interconnected.

The problems start before the first line ends. As the authors undoubtedly know, nobody actually thinks that non-coding DNA is ‘junk’ any more. It’s an idea that pretty much only appears in the popular press, and then only when someone announces that they have debunked it. Which is fairly often. And has been for at least the past decade. So it is more than just intellectually lazy to start the story of ENCODE this way. It is dishonest – nobody can credibly claim this to be a finding of ENCODE. Indeed it was a clear sense of the importance of non-coding DNA that led to the ENCODE project in the first place. And yet, each of the dozens of news stories I read on this topic parroted this absurd talking point – falsely crediting ENCODE with overturning an idea that didn’t need to be overturned.

Let’s parse this statement, because there are some pretty significant differences here between what Dr. Eisen is saying and what I have said.

1. As the authors undoubtedly know, nobody actually thinks that non-coding DNA is ‘junk’ any more.

I’m not sure, but I think he may be suggesting that everyone already knows that 100% of the genome is functional. If so, then this claim is definitely false — I certainly don’t think it’s all functional and I know many colleagues who would be very unlikely to ascribe function to millions of copies of transposable elements, thousands of pseudogenes, and various other non-coding sequences. Again, onion test.

Update: Michael says “I was not saying that everybody knows that 100% of the genome is functional! I was saying that nobody thinks that 100% of non-coding DNA is non-functional. My point was that it’s dishonest to pretend like they’re the first people to debunk the junk DNA meme.”

Whew!

2. It’s an idea that pretty much only appears in the popular press, and then only when someone announces that they have debunked it.

Not true. I see the same “long dismissed as junk…” trope in peer-reviewed research papers all the time.

3. Which is fairly often. And has been for at least the past decade.

More than that. Stories about the supposed demise of junk DNA have been appearing in major media since the 1990s (New York Times, Science, Nature) and there were plenty of reports about potential functions of non-coding DNA throughout the 1980s.

4. So it is more than just intellectually lazy to start the story of ENCODE this way.

Agreed. But it’s pretty much the standard introduction to papers and media stories on non-coding DNA nowadays.

5. It is dishonest – nobody can credibly claim this to be a finding of ENCODE.

Well, nobody can claim to have refuted the long-held notion that all non-coding DNA is non-functional because there was never any period during which scientists ignored possible functions of non-coding DNA. Functions were contemplated for every new type of non-coding DNA elements upon their discovery, and both the “junk DNA” and “selfish DNA” ideas were met with significant resistance. ENCODE’s specific claim that 80% of the genome is functional is new, though. (As is their definition of “function”).

6. Indeed it was a clear sense of the importance of non-coding DNA that led to the ENCODE project in the first place. And yet, each of the dozens of news stories I read on this topic parroted this absurd talking point – falsely crediting ENCODE with overturning an idea that didn’t need to be overturned.

It’s important to distinguish between the different views that one can have on function of non-coding DNA. The notion that “all non-coding DNA is functionless junk” is a straw man position that no one has ever seriously held. So, yes, there was already an expectation that some non-coding DNA would turn out to have function — and plenty of examples were already well known. This extreme “it’s all junk” idea did not need to be overturned, because no one claimed it and, as noted, other examples that refute it were already known. However, there is another claim that is coming out in these media reports and in quotes from the ENCODE authors — that the evidence indicates that 80% or more of the genome is functional. This is a claim that is based on the flimsiest of definitions of “functional” and is not one that likely to be unconvincing to many experts. So, the claim that “there is little or no non-functional DNA at all” is somewhat unique to ENCODE (John Mattick thinks so too). But it is a problematic claim because the evidence for this assertion is very tenuous.

Somewhere in the middle is what I believe to be the most reasonable view: a significant percentage of the non-coding DNA in the human genome is functional in the sense of being biologically meaningful, but most of it probably is not. This is certainly the view that is most consistent with the evidence, and it is, in fact, the one that the early proponents of the “junk DNA” concept actually held. As I noted in a previous post, the ENCODE authors have to work pretty hard to even get the 80% figure, which would still leave an awful lot of non-functional nucleotides in the genome.


14 comments to Michael Eisen’s take on ENCODE — there’s no junk?

  • Nick Matzke

    “I’m not sure, but I think he may be suggesting that everyone already knows that 100% of the genome is functional.”
    On Twitter etc. Eisen has been criticizing the 80% functional number, so I suspect what he meant by “As the authors undoubtedly know, nobody actually thinks that non-coding DNA is ‘junk’ any more” is something like “everyone already knows that there are functional bits scattered about in the ‘junk’.”
    I think he may independently also dislike the word “junk”, but then so do you…(the term “junk” actually doesn’t bug me very much, given how much “instinctive functionalism” or “instinctive panadaptationism” or “instinctive nonfunctional=not interesting/not fundable”-ism seems to be playing a role in the public rhetoric over this issue, the emotive word “junk” may be just what we need to get a balanced sense of things.
     

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  • Chris Day

    One problem I have always had with ENCODE is the apparent assumption that transcribed DNA must have a function. Why can’t it just be due to sloppy termination or ‘aberrant’ promoters?

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    • Anything that is transcribed, or to which a protein can bind, or… well, pretty much everything short of being replicated at some point counts as a function to them.

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      • Chris Day

        I’d be much happier if they just said they were mapping the regions of euchromatin/heterochromatin in different cells types. No doubt this is useful information, but at this point not much more than cataloging.  Having said that, I should probably go and read their own words in these new papers.

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  • Ryan. I was not saying that everybody knows that 100% of the genome is functional! I was saying that nobody thinks that 100% of non-coding DNA is non-functional. My point was that it’s dishonest to pretend like they’re the first people to debunk the junk DNA meme. 

    I completely agree with this: “a significant percentage of the non-coding DNA in the human genome is functional in the sense of being biologically meaningful, but most of it probably is not.”

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  • The meme in question is not – “a large fraction of the genome is non-functional” – the meme is “people think that all non-coding DNA is junk but now we’ve discovered that it’s not true”. It’s intellectually dishonest on several levels. 1) It pretends that the conventional wisdom is something (all non-coding DNA is junk) that it is not, and 2) ignores the long history of people who have already argued and then shown in myriad ways that lots of non-coding DNA is not junk. 

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    • John Harshman

      Ah. I misunderstood what you meant. Do you have anything against the term “junk DNA”?

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      • G. Spring

        Yeah, me too.  I got the feeling reading Eisen that you might end up on his hall of shame to merely mention the word “junk”.   I guess the word “junk” is sloppy and probably shouldn’t be in papers, sure, but in a colloquial way the question, “How much of our genome is junk?” strikes me as at least somewhat meaningful.  Clearly the “junk DNA hypothesis”, if there ever was one, that ALL non-protein coding regions are non-functional is false and has conclusively been known to be false for a long time, if not since the word was coined.  But since some of the genome, the large majority most likely, is not functional in the fitness sense, is it unreasonable to call it junk? I guess maybe we should just call that fraction non-functional, or non-adaptive, or even a slightly less loaded word like “filler”.  Or maybe we shouldn’t lump it all together even in casual talk, maybe we should just stick to better defined sub-categories: retroposons, pseudogenes, tandem repeats, and so on? 

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  • Stephen

    Sorry this is not really my field … but doesn’t the proportion of functional regions of DNA have very large knock-on effects on our models of neutral evolution? If it were all “functional” then wouldn’t that upset many of the fundamental assumptions behind the models we use for associations studies, or evolutionary distance etc..

    Is everything just functional or not-functional? Can’t some stuff just be highly effectual or very slightly effectual? And surely under all the textbook explanations I have read “functional” only really means “Functional” with a capital F when in the right conjunction with the right other “functional” elements? Otherwise it’s just you know a putative binding site that is occupied by something above some threshold baseline… 

    On the experimental side…I’m also curious about those baselines if everything is functional… but I probably just need to read that a bit more closely… 

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    • John Harshman

      Of course there’s a continuum between extremes of function and nonfunction. A good place to put the boundary is to suppose that any difference with a selection coefficient unable to counteract drift can be considered nonfunctional. That depends on population size, and if I remember the dividing line is about 1/(4N).

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  • Joe Titus

    I believe the “media hype” about the “junk DNA” actually originates from the director of the NHGRI who is quoted at http://www.genome.gov/27549810 as saying, “During the early debates about the Human Genome Project, researchers had predicted that only a few percent of the human genome sequence encoded proteins, the workhorses of the cell, and that the rest was junk. We now know that this conclusion was wrong,” said Eric D. Green, M.D., Ph.D., director of the National Human Genome Research Institute (NHGRI), a part of the National Institutes of Health. “ENCODE has revealed that most of the human genome is involved in the complex molecular choreography required for converting genetic information into living cells and organisms.”

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