Just updated: Hammering nails in the “junk-DNA” coffin with this Cell paper “Orchestrated Intron Retention Regulates Normal Granulocyte Differentiation”
Why ?
1. The junk-DNA discussion, even the scientific one, refuses to die even though it is not a very interesting one, which is interesting in itself.
2. Cool/strange/scary expression in the title of the paper: “Orchestrated Intron Retention” ….
My three favourite junkies (junk-DNA supporters) out there are Professors Dr. Moran, Dr. Gregory and post doc. fellow Dr. White. This week they received a strong argument for their junk-DNA cause, which was this paper on how there appears to have been a lot of noise in some of the larger RNA-studies over recent years. This was covered elegantly in this Sandwalk post by professor Moran.
Now if only the Adaptive Complexity blog written by White would have just jumped on the same solid bandwagon all would have been fine, but no. Instead he attacks a lead author behind some of the above mentioned RNA-papers. Again, this would have been fine had it not been for the argument he uses, an argument which has the quality of third grade primary school science:
Second, John Mattick is clueless, and he should not be quoted. So junk DNA holds the secret to human complexity? Then I supposed it also holds the secret to the incredible complexity of an onion, which has five times more non-coding DNA than humans.
He goes on to give us professor Ryans definition of “The onion test”
The onion test is a simple reality check for anyone who thinks they have come up with a universal function for non-coding DNA1. Whatever your proposed function, ask yourself this question: Can I explain why an onion needs about five times more non-coding DNA for this function than a human?
This “test” I hope everyone sees is utter crap. If you don’t I’ll explain: the assumption is “more DNA = more biological complexity/functions” – which of course is wrong since organisms who apparently have very few functions can have more coding genetic material than more complex organisms (try google the number og genes corals have vs. humans). The assumption is wrong also because the onion may need to meet it’s changing environment with an entirely different genetic arsenal than primates, – the comparison is just way off unless you specify more.
I think the first comment to this Adaptive complexity post is brilliant:
Just out of curiosity tho, what’s the standard explanation for junk DNA? Is it just structural or something? – kerr jac
That question emphasizes what has been my main point all along: Dismissing something as junk is contrary to my idea of science being driven out of curiosity and the need to explore. If you label this DNA as “junk”, how do you answer this question with any confidence ?
First: State that most of our genome is junk.
Second: When more and more promoters, enhancers, repressors and other regulatory elements are discovered, claim that this of course was not included in the definition of “most of the genome”. The perfect excuse because it means you’ll never be wrong.
Last: Complain when the press does not understand that “most of our DNA” actually meant “much of our DNA , but with a lot of exceptions” and that science reporters don’t intuitively know which exceptions these are.
Post written using the zpen in dire agony over extremely poor science communication from the same persons who most eagerly criticize science communication from others.
Paper in question added to junk DNA coffin post.
Update: response from Professor Laurence A. Moran here.
![Reblog this post [with Zemanta]](https://i0.wp.com/img.zemanta.com/reblog_e.png)
Image via Wikipedia
Enough talk (see this previous post and links within), on to the peer-reviewed science. Below you will find a list of references that I hope will contribute to the fall of the term “junk-DNA“, – some of it may (currently) lack a known function, but it is not junk !!!
Disclaimer: This is a list of useful references when arguing against the common overestimation of the amount of “junk”-DNA. By listing these I am not claiming anything beyond what I have already posted on this blog or in a comment somewhere. Also and importantly, I have not myself had the time to review these articles as thoroughly as I would have wanted to, – some have been read carefully, others lightly and yet others just skimmed through. Thus, you are more than welcome to comment on these references if you have opinions on any of them, or find them unsuited for this list.
The list will be continuously expanded, and if you have references you would like to add, please notify me with a comment to the post.
The references are unsorted. Feel free to copy, rearrange and use as desired…
Last updated 5/8-13:
Everyone’s talking about their pet peeves, I thought maybe I should too. Here are three of them
1. Labeling DNA with unknown function as “junk”
2. Scientists in ivory towers and on top of their high horses.
3. Holding back on scientific arguments in fear that someone will use them in an unscientific way.
The two last ones are really about how scientists communicate with the rest of the world, and I’ll get back to that
The post that lets me comment on these issues all at the same time is: Scientists Cynical use of “Junk DNA” at Michael Eisens blog (I know the post is rather old, but it is new to me). Coincidentally his post allows me to sum up my recent “junk” posts and the “creationist terror” post.
Quotes for each peeve
Unfortunately, for initially practical reasons, a disproportionate amount (surely in excess of 90%) of research has focused on protein-coding genes, fostering the faulty impression – amongst scientists as well as science writers – that the ~3% of the human genome that is protein-coding contains > 90% of the function.
This is good…..if it means what I mean: that labeling DNA of unknown function as “junk” by default is wrong. Which it most certainly is. For more on this topic, see my 6 post discussion with Larry Moran (1,2,3,4,5,6).
But, then Eisen starts criticizing the press release for the fact that they used this “junk” term:
They work on non-coding DNA precisely because they know it is NOT junk. So why, when it’s time to make a pitch to the local press officer, do they fall back on this old bromide? It obviously appeals to writers – who love it when they can pitch a story as overturning orthodoxy. It seems minor, but pegging it this way leads to some really attrocious misrepresentations of current biological knowledge.
This is bad, because of two reasons. Firstly, the term is not wrong, it’s used on a piece of DNA with an previously unknown function. A lot of this DNA is currently labeled “junk” by the “junk-people“. The only wrongdoing here is that they didn’t specify that regulatory elements have been known for some time, – that’s hardly a grave error. On the contrary, phrasing it like this in the press release underscores and highlights that much of what we previously labeled as “junk” in fact isn’t. That is really, really good, in fact it’s an excellent way of enlightening the public that non-coding DNA isn’t necessarily “junk”. Secondly, when scientists communicate with the rest of the world it is important to use terms that will not serve to alienate. Only to a certain extent of course, because oversimplification can easily distort the true message. But, this press release is not an example of oversimplification. The critique of these news-pieces constitutes nitpicking, and strengthens the view of scientist as locked inside ivory towers or sitting on top of their high horses. There are plenty of examples of press releases that is misrepresenting science, are inaccurate or just plain wrong. The over-hyping of imminent cures for cancer, diabetes and Alzheimer are good examples of bad science news reporting, and this happens almost daily all over the world. Another example is getting statistics all wrong in reporting on genetic tests (there are however, initiatives to try and fix this situation. You are hereby encouraged to go see HelixGene, I also strongly recommend you to join if you can help, or report bad news coverage of science if you find any).
Towards the end of the post I find my third pet peeve:
A second, and less obvious, problem is that this view has played into the hands of the intelligent design crowd.
and
And every time a new study comes out reporting that “junk DNA” is not junk, the ID’ers jump on it as validation of the predictions of ID. It’s hooey of course, but we needn’t give them the opportunity.
Which shows us Eisen is a victim of creationist-terror (see my previous post on this topic), and it makes me sad that we as scientists do not have the guts to stand up against this terror. We must feel free to express whichever valid scientific argument we find relevant in a given topic or field. That some of us don’t makes me really, really unhappy….
A follow up from this post and an ongoing discussion with Professor Larry Moran over at Sandwalk.
Let me start by saying that even though this has been a lengthy discussion, I do not think we’re disagreeing that much, – on the basic facts that is. And the comments following my first post, his second post, my third, his fourth and this (the fifth) post on the topic hopefully will illuminate this fact.
Secondly I will introduce this post as I did the last, with my c-gamma gene (PRKACG). This gene serves as an example of how introns, retroposons and even alu-elements can contain indicators of function.
The c-gamma gene is transcribed in a species specific manner, (primates only), it’s expression is also tissue specific (testis only). The gene is contained within an intron of another gene, it’s 3′ sequence constitutes an exon of this other gene and lastly, putative regulatory elements where found in and around alu-elements in it’s upstream 5′-region.
Now, you can argue that these are all coincidences, … and refuse to speculate on any function. You may even be right in doing so, which I elaborated upon in my previous post. But, this gene is one of the reasons I refuse to put the label “junk” on everything that has not been ascribed a function. In my opinion, the species and tissue specific transcription, the conserved reading frame and the peculiar positioning of this gene, are all indications that this sequence may hide a function. There are other examples too, especially when it comes to transcription of alleged “junk” which in my mind is enough to warrant further investigation and scientific speculation.
There is, as has become very evident from this discussion, evidence pointing towards much of the genome being “junk”, but there are certainly scientifically viable indications to the contrary too. Listening to the counter-arguments and following links in this two-post series will tell you this.
Then… moving on to answers to Professor Moran’s last 4 points:
…
5. Why is the Fugu genome so much smaller than that of other fish?
and
6. When two similar species differ in genome size by a factor of two—probably due to an ancient polyploidization—is the majority of DNA in both species functional?
His argument is that since the genome size differs between species, much of it must be junk. But, you could easily use the same argument towards a function, by saying that the difference in genome size is a defining (functional) difference between species. We just do not know do we ! And, why does the difference in size not give you reason to speculate on function at least in parts of these regions ? Others have however, speculated far better than me on this topic, and a thorough introduction to such research can be found at junkdna.com and following this link to “The Principle of Recursive Genome Function“.
7. In the human lineage there are over one million Alu sequences. They all look like degenerate versions of 7SL RNA. Are all of these sequences functional? If so, what function could they be doing? And why do the human Alus look so different from the mouse ones?
I am not saying all Alu-elements are functional. On the “what is junk” scale, one extreme is that everything that hasn’t been ascribed a function is junk (Larry Moran’s position !?) and on the other end is “nothing is junk”. My position is somewhere in the middle: Some of the DNA in our genome is possibly junk. A number of individual Alu-elements will undoubtedly end up in the “junk”-category when more is known about our genome. That said, it has been shown that Alu-elements can constitute (parts of) regulatory and functional elements. It’s rather hard to tell which ones are functional by just looking at them. I therefore refuse to call them “junk” by default, – I strongly feel that the “junk”-label is a dismissal of any possible function(s) and should be used with caution if at all, – even for Alu-elements.
8. Most intron sequences do not seem to have a function. Why does the size of introns in the same gene vary so much in related species and why isn’t the sequence conserved in most cases?
This argument is similar to the genome size argument above, and the answers for bullet 5 and 6 are equally valid here. Thus, there may be many reasons for a variation in intron size and this variation is not a very good argument to support the “junk” hypothesis. Also, the intron can contain regulatory elements and the c-gamma example above goes to show that introns can even contain functional (as in transcribed) genetic elements.
…..
My final note is this: A lot of this alleged “junk”-DNA is being transcribed into RNA. If it was just “junk” then why has selection preserved the transcription from these regions when transcription is an energy consuming process ? I think the position of “junk”-DNA may have some persuasive arguments, but it’s exceedingly harder to argue that the transcripts from these regions are also “junk”.
No matter what constitutes junk, and how much of it there is, this discussion has been extremely rewarding for me personally. I need to admit that the “junk”-position is more understandable to me now. I even find myself agreeing with many of the arguments, like the importance of drift over selection.
Conversely, even though I think he will never admit to it, Professor Moran indicates in one of his questions during the discussion, that he too is not completely locked into the “everything is junk” position:
How many of those transcripts are functional, according to your speculation, and what the heck are they doing?
Which I think is a perfect ending quote because it goes to show that we are all wondering about this……and that our disagreement is not as fundamental as some have suggested.
Some say that almost a half of the human DNA is “junk”, I say that the evidence indicating otherwise is strong enough to allow for speculation on (and research into) possible functions. In a recent discussion with Professor Larry Moran over at Sandwalk, on this topic, I received this challenge:
If you enjoy speculation so much then speculate on this [list of 8 questions]…
And I’ll answer each question as thoroughly as I can (please, find the first 4 below) but first, as an introduction, I would like to explain one of the reasons I take interest in the subject of “junk”-DNA. Bear with me, it’s an interesting story….
Back when I did my PhD, most of us PhD-students would get at least two projects to work on. One would be a “safe” project that would be reasonably easy to publish and the other one would be a high risk project where the outcome was more uncertain, but could potentially be published in ha higher impact journal (this is an approach I think all labs should follow !!). My “safe” project was to clone and characterize a gene for an isoform (of cAMP-dependent protein kinase) where the mRNA (cDNA) was already published (yes,believe it or not, this was actually publishable back in the days 10 years ago). So, I cloned and I started sequencing looking out for exon/intron boundaries and intron sequences as was standard procedure. Problem was that I didn’t find any intron sequences. The genomic sequence was identical to the mRNA (cDNA) sequence. At the ends where the cDNA and genomic sequences stopped being homologous, I found direct repeats. These are the hallmarks of a retroposon. A retroposon is an mRNA that has been reverse transcribed and inserted into the genome. To add to this peculiar finding, my gene, the PKA C-gamma gene, it turned out, was a retroposon inserted into the intron of another gene (see illustration).
The common perception is that a retroposon is not functional. But, the circumstances in this case, I believe points towards some kind of function. C-gamma translates into mRNA in vivo (as is the case with a handful of other retroposon’s), and since it has an intact reading frame this mRNA can be translated into protein in vitro and in cell lysates. So is this protein detected in vivo ? ….and what if anything, does the protein do………?
This I’ll answer after returning to speculations on Larry Moran’s list of questions:
…
1. Why do pseudogenes and most of the transposon-related sequences look so much like broken genes?
By a broken gene I guess he means a broken reading frame that seems not to code for a protein product. The genetic sequence may still constitute a regulatory element influencing other genes (as was the case with the finding that led to the original discussion, see here for reference). Also, any trancribed RNA from parts of this DNA may have function either as long RNA molecules, miRNA’s or siRNA’s.
2. Why is the DNA sequence in most of our DNA not conserved?
Shorter segments may be conserved interspersed with unconserved regions. Also there has to be a great deal of non-conserved sequence to allow for evolution. This DNA serves a buffering capacity in that it is a reservoir for evolution (that does not make it “junk” !!, see below). Another point on conservation comes from the fact that miRNA’s function on the basis of their structure rather than a conserved sequence (many different sequences can give rise to similar two/three dimensional RNA structures). Thus conserved DNA sequences may not give any information on the function of such sequences and new approaches are needed to study their function.
3. Why can we delete large segments of mammalian DNA with no observable effect?
If you were an alien scientist examining a modern car you would find essential stuff like wheels, steering and breaks. You would also observe parts that seemed not to have any apparent function like the seat-belts, car-radio, air-conditioning, anti-spin system, ashtray, maybe a fire extinguisher and so on. These parts have a distinct function only under certain conditions and unless you are observing the car the instant these items are used, you might, -if you are of the “junk”-people, think that these parts are “junk”. Your conclusion would be strengthened by the fact that you could remove most of these items and the car would still be performing it’s basic functions (start, forward, reverse, turn, stop). Same could be true for the possible functions of large parts of our DNA.
4. Why is there so much variations in repetitive DNA within a species? Some people have segments that are ten times longer than segments found in other people. Are all of the nucleotides in the longer segments functional?
Repeat variation like STR’s are common variations that sometimes leads to functional differences between people, thus they are not “junk”. Similarly, Copynumber variation is a relatively newly discovered phenomenon that may have profound effects. That there is copynumber variation also in DNA yet to be ascribed a function, comes as no surprise and is not an argument for “junk”.
…
Then again, professor Moran might be right, it may all be junk. This may also be true for my C-gamma gene. because, the protein has never been found in vivo and consequently no function is known to date. Many have tried to find the protein (and/or a function) and some have suffered under the lack of results.
And I should mention in all fairness, that for me personally, it was wise to stop working on this and move on to other research projects and ventures.
Thus, I do understand the position of the “junk” people……..but, and here’s where my disagreement with them starts…..
That we haven’t found a function so far, does not mean that there isn’t any. Reports on new functions of DNA sequences are frequent and one of them was the ….. “opposing thumb” regulatory element….
This belief that there’s hidden function to be found, treasures to unearth if you will, is the difference between those advocating these parts of DNA as “junk” and me. In my opinion, It’s not the details of what is junk and what isn’t, ..- and how much, that bothers me…..
It’s the attitude. To dismiss something as junk is contrary to my idea of science being driven out of curiosity and the need to explore. Curiosity may kill a cat every now and then, but I’ll take that risk and continue to praise the scientist who recognize possibilities in the junk rather than dismissing it.
Answers to the last 4 points made by professor Moran to follow….
We and all other organisms are complicated biological structures made from very simple building blocks on an information template of DNA. Individual variations in DNA are rather easy to work out although you do need lots and lots of DNA sequencers, data-storage facilities and data comparison programs. Fact remains, – you basically only need time and money to do this.
We know that the DNA sequence itself is diverse enough to make every individual exclusive while retaining enough common features for speciation. So, DNA explains a lot, but the final functionality including the ability to adopt to changing environments, depends on the next levels of variation…
Take the Necker Cube below. As described by Edge writer Nathan Myhrvold:
This is a perfectly good 2D picture, but we cannot help trying to force into being a 3D object. The 3D reconstruction problem is ill posed—there are two very different solutions, each of which is feasible. So, when you look at it you alternately see one then the other—you can feel it pop in, or pop out. Without a unique solution your brain flips between the possible solutions.
The analogy to biology is as follows:
Strictly speaking, the cube is two-dimensional. But, for all practical purposes it is a three-dimensional object. At the same time it’s three dimensional form shifts from one confirmation to the other.
The analogy to DNA is that while the written DNA-sequence is linear (two-dimensional) the resulting molecular three dimensional structure allows for transcription into RNA and interactions with proteins both at the DNA and RNA level. These interactions in turn can lead to effects that vary depending on the surrounding environment. The Necker cube is made out of 12 identical lines giving rise to two different three dimensional conformations. DNA is made out of four versions of millions of basepairs. Resulting in a vast number of possible final variations of effects.
Biology handles a chaotic and changing environment using simple building blocks to make flexible, hyper variable, intricate and complicated possible solutions. Knowing the DNA-sequence, the transcriptome and the proteome is basically just discovering the two first dimensions in a many-dimensional organism.
New ideas, approaches and tools are needed to explain how this seemingly chaotic system works. Dismissing reasons for the obvious complexity using terms like “junk-DNA” is not going to get us anywhere.
Instead, let’s start by acknowledging that we know very little. All we know is that function comes out of an apparent chaotic mixture of DNA protein and RNA. Let’s speculate that everything is there for a reason. Without reason you loose hope and visions and those are qualities that science is vitally dependent upon.
Illustration taken from http://wisebytes.net/illusions/
From: THE PRODUCTION LINE, Nature news feature
To: All those who advocate “junk” DNA/RNA in any shape or form
The doubters, [John Mattick] says, “keep regressing to the most orthodox explanation [that the long RNAs are junk]. But they can’t just sit on their intellectual backsides and tell us to prove it.”
– John Mattick (..a long-time advocate of non-coding RNA’s importance..), the director of the Centre for Molecular Biology and Biotechnology at the University of Queensland in Brisbane, Australia
I think the term “intellectual backsides” is particularly pertinent.
e! Science news
BIOpinionated 