Messenger RNA was once regarded as the most interesting type of RNA - insofar as RNA could be said to be interesting at all. At least mRNA had a role in coding for proteins, while transfer and ribosomal RNA were purely elements of the protein translation machinery.
But in the past eight years, it has become increasingly clear that there are many more types of RNA than the classic three, and that most of them do not code for proteins. In fact, those noncoding RNAs currently are the stars of the RNA world, racking up more awards recently than U2 at a Grammy ceremony.
In its Dec. 22, 2006, issue, Science honored Piwi-interacting RNA, or piRNA, as one of the top 10 scientific breakthroughs of the year. The piwi genes as a group probably regulate the development of sperm cells; piRNAs bind to and shut down the expression of those genes. The discovery of the general phenomenon of RNA interference was named breakthrough of the year by Science in 2002, and was awarded the Nobel prize in medicine earlier this year. The piRNAs join microRNAs and small interfering RNAs as major players in RNA interference.
And in the Dec. 15, 2006, issue of Cell, researchers from the Whitehead Institute for Biomedical Research, the Massachusetts Institute of Technology and the Broad Institute of Harvard and MIT, all located in Cambridge, Mass., described 21U RNAs, which are the newest member of what the Science news staff termed the "exclusive club" of noncoding RNAs in its citation of piRNAs.
Each of the 21U RNAs appears to be independently transcribed, while siRNAs and piRNAs usually are cut from one long precursor gene that is transcribed as a unit. MicroRNAs also can be transcribed independently , but they are much less diverse. Consequently, the authors argued in their paper that their discovery of more than 10,000 such 21URNAs in the worm C. elegans "dramatically increased the number of known nematode genes."
Like piRNAs, the discovery of 21U RNAs was dependent on technology that is able to tell the difference between an RNA molecule that is present in low numbers - only a few copies of many piRNAs exist per cell, and many 21Us also were present in low copy numbers - and experimental error. Bartel and his team discovered them while searching the C. elegans genome for new microRNAs.
The 21Us are named for what they have in common - a length of exactly 21 nucleotides (miRNAs and siRNAs can run from 21 to 24, while piRNAs run from 24 to 30), and the fact that their first nucleotide is always a uridine. They also share a motif in the DNA sequence upstream of the coding sequence itself - which, in fact, was central to the scientists' being sufficiently confident that what they had discovered was indeed a class of RNA: "Each time you are cloning a 21U RNA, you are typically cloning a different one," senior author David Bartel, professor at the Whitehead Institute, told BioWorld Today. "What they seem to have in common [is] this motif."
But the important thing about 21Us may not be what they have in common, but rather the opposite: Evolutionary pressure on the 21Us appears to be for maximal sequence diversity.
When Bartel and his colleagues compared the 21U RNAs of C. elegans to another worm, C. briggsae, the upstream motif was highly conserved. But they found "not a single case out of 10,000 [21U RNA sequences] where the sequence itself has been retained," Bartel said.
Indeed, the details of their comparative study suggest that when one sequence is lost through mutation, there is an evolutionary advantage for those worms who manage to replace that sequence within the same broad region of chromosome four. Bartel said that the reason for their location - "dispersed throughout one chromosome, but not throughout the genome" is as yet a mystery, as is the pressure to retain such an enormous range of 21U sequences: "Why would it be so bad if some of them were lost?"
A lot remains to be discovered about 21U RNAs - for one thing, what they're good for; for another, whether an analogue exists in humans. Whether they will turn out to be useful for therapeutic targeting also still is in the stars. But that is yet another characteristic they share with other noncoding RNAs - in October, when Craig Mello and Andrew Fire received the 2006 Nobel Prize in physiology or medicine for their discovery of RNA interference, Mello pointed out in his acceptance speech that his work on RNAi, which now is being pursued by several companies, had started out as completely basic research.