Tuesday, September 19, 2006

More on non-coding RNAs   posted by Coffee Mug @ 9/19/2006 10:02:00 PM

If the 24-hour science news cycle hasn't knocked it out of the banks yet, recall that there was some hub-bub about a non-coding RNA (ncRNA) being a candidate for the fastest-evolving human gene. There was some discussion about whether ncRNAs might be something to keep an eye on and why RNAs might be particularly good at evolving quickly. This review from March had some factoids worth mulling.

There are more ncRNAs than you thought:

  • Half of the "full-length long Japan" library of human cDNA clones appear to be non-coding. Anti-jargon: cDNA (complementary DNA) is sequence read off of RNA backwards. This group tried to take a very large scale unbiased picture of the RNAs floating around in human cells and did bioinformatics to guess whether they coded for protein or not.
  • The FANTOM 3 consortium sez that 62% of the mouse genome is transcribed. Half of these transcripts are non-coding.
  • MicroRNAs are a subset of ncRNAs that regulate other RNAs. 70% of microRNAs can be found in the brain. There's a big section in the review on particular brain-specific miRNAs and potential roles in development.
  • There are seven brain-specific small nucleolar RNAs (snoRNAs). These are RNAs that act as enzymes to chemically modify nucleotides in other RNAs. There is a particularly provocative connection between snoRNAs and serotonin receptor subtype processing in Prader-Willi Syndrome, a form of mental retardation arising from deletion of a chunk of chromosome 15.
  • LINE-1 retrotransposons make up 17% of the human genome. These are the so-called "jumping genes". They code for the proteins to reverse transcribe them back into the genome. So it's relatively easy for them to proliferate. Technically they aren't non-coding, but the RNA is used in a nontraditional way in that it serves as a template for reading the gene back into the genome at some point. There is some evidence for a role for active LINE-1s in neural differentiation.
The authors say ncRNAs might evolve more quickly because they can be duplicated with less probability of harm than coding RNAs. I'm not so sure about their argument. I'll buy the first point, that ncRNAs are generally smaller and can be duplicated with greater fidelity. They then state that their small size also decreases their likelihood of disrupting existing genes. It seems to me that size wouldn't matter. If a chunk of DNA gets copied into the middle of some gene, the gene should be disrupted. Maybe the consequences could be worse in the specific case where the duplication occurs between regulatory elements and the transcription start site, so that the gene's regulation is more disrupted the further the promoter is pushed from the gene, but this seems like it would be uncommon.

I stated a while back that one reason for expecting a lot from RNAs over protein is that RNAs used to do the whole job back in the good ole days of the RNA World. Surprisingly, I was not the first brilliant, original thinker to arrive at this conclusion. In fact, these folks end by referencing Sean Eddy, who wrote a whole review about the importance of ncRNAs and how the RNA World isn't over. From his review:

The discovery of RNA catalysis and the "RNA world" hypothesis for the origin of life provide a seductive explanation for why rRNA and tRNA are at the core of the translation machinery: perhaps they are the frozen evolutionary relic of the invention of the ribosome by an RNA-based 'riboorganism'. Other known ncRNAs have also been proposed to be ancient relics of the last riboorganisms123-125. The romantic idea of uncovering molecular fossils of a lost RNA world has motivated searches for new ncRNAs. However, as these searches start to succeed, more and more ncRNAs are being found to have apparently well-adapted, specialized biological roles. The idea that ncRNAs are a small and ragged band of relics looks increasingly untenable. The tiny stRNAs and miRNAs, for example, seem to be highly adapted for a world in which RNAi processing and developmentally regulated mRNA targets exist.

Therefore, consider an alternative idea - the "modern RNA world". Many of the ncRNAs we see in fact have roles in which RNA is a more optimal material than protein. Non-coding RNAs are often (though not always) found to have roles that involve sequence- specific recognition of another nucleic acid. (The choice of examples in Figs 1, 2 and 4 is deliberate, showing how snoRNAs, miRNAs and E. coli riboregulatory RNAs all function by sequence-specific base complementarity.) RNA, by its very nature, is an ideal material for this role. Base complementarity allows a very small RNA to be exquisitely sequence specific. Evolution of a small, specific complementary RNA can be achieved in a single step, just by a partial duplication of a fragment of the target gene into an appropriate context for expression of the new ncRNA.