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Thursday, October 11, 2007

Junk RNA

There are a lot of studies suggesting that a substantial percentage of the genome is transcribed even though less than 5% is known to be functional. This leads to the idea that it encodes some unknown function. The argument is that these regions would not be transcribed unless they were doing something useful.

One objection to these studies is that the workers are looking at artifacts. The so-called transcripts are just noise from accidental transcription. This ties in with the idea that the EST database is full of examples of "transcripts" that don't make any biological sense.

There's another possibility. The regions of junk DNA could be transcribed regularly but the transcripts are rapidly degraded. They do not have a biological function. They are junk RNA.

Arthur Hunt has just posted an article on Panda's Thinb that supports this idea [Junk to the second power]. He describes the work of Wyers et al. (2005) in yeast cells. They show that there is a large class of junk RNA. The take-home lesson here is that you can't assume that some region of genomic DNA is functional just because it's transcribed. It's a lesson that many people need to keep in mind.

Wyers, F., Rougemaille, M., Badis, G., Rousselle, J.C., Dufour, M.E., Boulay, J., Régnault, B., Devaux, F., Namane, A., Séraphin, B., Libri, D. and Jacquier A. (2005) Cryptic pol II transcripts are degraded by a nuclear quality control pathway involving a new poly(A) polymerase. Cell 121:725-37.


A. Vargas said...

I TOLD you guys we'd soon be using the term "junk RNA". Good!

Peter said...

A third explanation is that these transcripts are a byproduct of something purposeful - perhaps the passage of the transcription enzymes is necessary for chromatin remodelling.

Need to clear out your old histones from a particular region of DNA so you can replace them with some other mark? No problem, just send down a pol molecule to bulldoze them out the way. Let the nonsense-mediated decay take care of the rubbish.

Torbjörn Larsson said...
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Torbjörn Larsson said...

Feedback regulation like ubiquitin for protein is cool since it permits in principle both regulation and quality enhancement.

I wonder if this could be a more ancestral RNA regulation than derived protein reading regulation?

Btw, aren't there some qualitative differences between "junk DNA" and "junk RNA"?

IIRC someone noted that besides Ohno's original picture of non-functionality it is still a sometimes reused resource as it is DNA. So it is also "junk in the garage".

But recyclable RNA isn't junked in evolutionary useful pieces. It is more akin to garbage recycling. So if "junk DNA" then "garbage RNA"?

Larry Moran said...

My personal take on this is that most of the transcription is accidental. It's just random bits of RNA that are produced when the transcription complex makes a mistake and starts when it shouldn't.

Some of the predicted transcription might be a true artifact of EST libraries. We know that some of the so-called "RNA" is really bits of genomic DNA that's been copied when the library is made.

Anonymous said...

Hi Larry,

Thanks for the mention.

You bring up an interesting point, one that may make good thermodynamic sense. After all, one can make a polymerase only so specific, and it is pretty likely that one will find non-specific transcription in cases where non-specific site outnumber specific sites by many orders of magnitude.

The CUTs seen in the Wyers et al. study may not be non-specific initiation events, though. The ones that were mapped carefully had rather precise 5'-ends, or transcription initiation sites. This argues that they have bona-fide polII promoters.

What do we make of this surprising observation? Perhaps CUTs are reflective of, not just non-specific transcription, but also of genes in the process of dying. What I mean is this: large-scale duplications are pretty common, and often generate new copies of expressed genes. These duplicates may diverge and acquire new function, or they may start to drift into oblivion because they are not needed. In the latter case, it may be that the last thing to go, because they are much more nondescript, are the promoters. The time in the course of evolution between first losing a functional coding region and the loss of the promoter is a time when un-needed RNAs are being made. The Trf4/5/Rrp6 system would take care of these. (This might be a way to avoid generating lots of potential siRNAs that could target both copies of the duplicated gene.)

That's one thought. Others probably have better ideas.

Larry Moran said...

art says,

The CUTs seen in the Wyers et al. study may not be non-specific initiation events, though. The ones that were mapped carefully had rather precise 5'-ends, or transcription initiation sites. This argues that they have bona-fide polII promoters.

When I say that transcription is accidental I do not mean that it is non-specific. It may begin at preferred sites that just happen to resemble the normal transcription start site.

Here's what Wyers et al. say about these polII transcripts.

Another group of polyadenylated RNA accumulating in a Δrrp6 strain corresponds to new cryptic Pol II transcripts. These CUT transcripts are present at extremely low concentration in wild-type cells, even though some of these transcripts were apparently detected by SAGE analyses (Velculescu et al., 1997). Nevertheless, they appear to represent bona fide transcripts generated by Pol II, containing a 5′ cap. These intergenic cryptic Pol II transcripts are usually relatively short and do not contain long or conserved reading frames. Thus, while we cannot formally exclude that they have a physiological role, their structure suggests that they result from the presence of adventitious promoters at random genomic locations.

This phenomenon is likely to be much more common in mammals where there's 100x more junk DNA..