At the level of biomolecules, life boils down to two basic principles: sequence and folding. We know, for example, that the sequence of nucleotides in the DNA contains our genetic blueprint, but the way that our DNA is folded and wrapped up in each chromosome helps determine which genes are easily accessible for copying. Proteins – sequences of amino acids – fold into intricate shapes before assuming their duties. So it is no surprise that the third main molecular sequence in the cell – the RNA, made up of single strands of nucleotides – folds as well. Nucleotides are built to pair up – DNA to its matching strand in the genome, DNA to RNA for copying, RNA to the small RNAs that effect translation to protein. And when it is on its own, that tendency to pair up causes the RNA strand to fold over on itself.
The unique, hairpin curves and bulges in the RNA strands owe their shapes to the fact that certain pairs of nucleotides are more strongly attracted than others. So you could be forgiven for thinking the shape of a folded RNA molecule is a chance artifact of the DNA code. Indeed, the overwhelming mass of research on RNA focuses on its sequence and ignores its shape.
Hence the results of a recent study conducted at the Weizmann Institute and Stanford that mapped the folded landscape of RNA were something of a surprise: They revealed a distinct logic, unique to the RNA, in its curves and loops. When the map – constructed from an analysis of nucleotide pairing from hundreds of millions of RNA fragments – was laid out, its formations suggested a legend and key. Certain larger loops appear to mark spots where activity should take place, for example, starting or stopping protein production. The researchers even noted bumps every three nucleotides that could delineate codons – sequences encoding a single amino acid.
In other words, in an evolutionary twist on the idea that the sequence dictates folding and form, here the folds appear to enhance the sequence, adding “notes” that may possibly help the protein manufacturing machinery decipher the code more efficiently.
How important are those notes? Scientists will have to conduct further research to answer that question. But Prof. Eran Segal, the Weizmann researcher involved in creating the map, thinks they might play a role in key biological processes and diseases. In comparing the folds from three different individuals – two parents and a child – they noted that in around 15% of the regions with SNPs – where the parents’ DNA varied by a single nucleotide – the folding shapes were affected, sometimes significantly. The scientists gave these variations in the RNA landscape the endearing name “RiboSNitches,” and proceeded to locate them on the map. Eventually, they think, these RiboSNitches could become real “snitches” – symbols on the RNA maps that can point to possible misreading of the coded sequence.