With great fanfare comes great cynicism, and so it should: science is built on a tug-of-war between novel claims and kneejerk skeptism, and the probity that follows. When a sound bite leaked out of last year's ENCODE publications, of which Genome Biology was a participatory journal, that '80% of the human genome has a function', evolutionary biologists were cynical all right, and they took to the journals to say so.
While some of the disagreement hinged on the semantics of the word 'function', a key sticking point was the scientific validity of declaring a stretch of the genome functional when there is no evidence for evolutionary constraint on its constituent DNA sequence. In other words, how much function can a DNA sequence really have when it is liable to change willy nilly, with no fitness penalty to the organism?
Seems like a reasonable argument. But what if it is wrong? What if, in certain circumstances, the make-up of a DNA sequence can change when its function does not?
lncRNAs enter the fray
Researchers in the field of non-coding RNA have for many years contested claims that most long non-coding RNAs (lncRNAs) can be dismissed as junk. Sure, a few lncRNAs might have a specific purpose but, for the most part, those long RNAs that are functional encode proteins, or so the argument goes. To say otherwise would beg the question: of what use could such a large quantity of lncRNAs really be?
And yet, inconveniently, functions for lncRNAs keep being discovered. An increasing number are being identified as competing endogenous RNA, or 'ceRNAs', which means that they are involved in the regulation of microRNA levels. Others still are being found to anchor together various combinations of proteins, RNA and DNA, using their unique ability to combine a specific tertiary structure with intermolecular base pairing.
Of this latter class, a number of lncRNAs have been shown to bind to the genome in order to regulate gene expression, with examples including PINT (and its mouse homolog Pint), which is newly described in a Genome Biology article.
PINT: the covert evolutionary operator
One of the many interesting things about PINT and Pint is that, although the two homologs are conserved at the level of function, an evolutionary analysis based on the conservation of DNA sequence would not detect them as homologs – as is the general pattern for human lncRNAs. But a synteny analysis supports the notion that PINT and Pint truly are homologs.
So when we are dealing with lncRNAs, perhaps evolution cannot be measured on the basis of DNA sequence constraint, even though function is still tied into the idea of evolutionary pressures.
And this is a problem for the ENCODE critics, because a significant portion of the disputed 80% is designated 'functional' on the basis of encoding a lncRNA.
PINT even cures cancer
How better to end a post about hyperbolic statements that overegg scientific studies than with a… hyperbolic statement that overeggs a scientific study? OK, so we don't know yet that PINT cures cancer, but the Genome Biology article does show it to be a candidate tumor suppressor, as a linchpin in a p53-pathway feedback loop. For a digest of PINT and p53, see Ramin Sheikhattar's Research Highlight.
*with apologies to Dan Graur and colleagues
- tRFs and the Argonautes: gene silencing from antiquity - 2nd October 2014
- Keeping up with the Jobses: the role of technology in reproducible research - 26th September 2014
- How to disarm a superbug – a story told by forensic genomics - 23rd June 2014