On BioScience and Life and Such

Hey junk people, I accept your challenge (part I)

In Uncategorized on September 23, 2008 at 1:42 pm

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).

From my C-gamma paper: “genomic mapping of the STM7 gene demonstrated that the C-gamma open reading frame was situated within the intron separating exon 16 and 17 in the STM7 gene. In addition, part of the 3’-untranslated region of C-gamma (nucleotide 1478 to 1538 in fig. 2) constitutes an alternately spliced exon (exon 17) in the STM7 gene. The two genes are transcribed in opposite directions in the human genome, ……”

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….

  1. I think you and Dr. Moran are arguing past each other. He’s arguing that based on current evidence, much/most of our genomes consist of junk. You’re arguing that some of what we currently consider junk probably has a function.

    Both are probably correct. Undoubtedly, some sequences that currently seem to be junk will turn out to have function. At the same time, current evidence does suggest that a lot of DNA really is junk.

    As an aside, I don’t agree that “there has to be a great deal of non-conserved sequence to allow for evolution.” Viruses evolve faster than just about anything we know, yet they have little if any non-conserved sequences.

  2. Qetzal. I think you are right, we’re not really disagreeing on the facts. My issue is with the label “junk”. As was stated in one of the comments (from “Matt”) on Prof. Moran’s blog: “I have a Major issue with labelling DNA one way or another when the evidence is far from irrefutable.”

    Point well taken on the viral genomes, you are probably right there too… 🙂

  3. “My issue is with the label “junk”. As was stated in one of the comments (from “Matt”) on Prof. Moran’s blog: “I have a Major issue with labelling DNA one way or another when the evidence is far from irrefutable.”

    But we still call what happens in the morning “sunrise” even when we know that it is not the sun that is rising.

    I suspect that, unfortunately, the term “junkDNA” lost what it was originally intended to refer to. From my understanding, ‘junk’ does not refer to ‘garbage’, i.e., useless, rather to ‘stuff’ that has no current use but might be used – or not – for other things.

    However, I think the notion that calling it ‘junk’ dissuades research is more of a tall tale than anything else.
    One can do a literature search and find that, in fact, research has been going on in ‘junkDNA’ all along.

  4. […] Hey junk people, I accept your challenge (part I) […]

  5. […] 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). […]

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