Based on the stereotypical hairpin structure, researchers have scanned genomes and found over 38,000 likely precursors; nearly 50,000 mature microRNAs have been discovered by sequencing all the RNA found in cells from a variety of species. While found widely in animals, they’ve also been discovered in plants, raising the possibility that they existed in a single-celled ancestral organism.
While some microRNA genes, including lin-4 and let-7, have dramatic phenotypes when mutated, many have weak or confusing effects. This is likely in part due to the fact that a single microRNA can bind to and regulate a variety of genes and so may have a mix of effects when mutated. In other cases, several different microRNAs may bind to the same messenger RNA, creating a redundancy that makes the loss of a single microRNA difficult to detect.
Nevertheless, there’s plenty of evidence that, collectively, they’re essential for normal development in many organisms and tissues. Knocking out the gene that encodes the Dicer protein, which is needed for forming mature microRNAs, causes early embryonic lethality. Knockouts of the gene in specific cell types cause a variety of defects. For example, B cells never mature if Dicer is lost in that cell lineage, and a knockout in nerve cells causes microcephaly and limiting branching of connections among neurons, leading the animals to die shortly after birth.
This being the Medicine prize, the Nobel Committee also cite a number of human genetic diseases that are caused by mutations in microRNA genes.
Overall, the award highlights just how complex life is at the cellular level. There’s a fair number of genes that have to be made by every cell simply to enable their survival. But as for the rest, they exist embedded in complex regulatory networks that interact to ensure that proteins are made only where and when they’re needed, and often degraded if they somehow get made anyway. And every now and then, fundamental research in an oddball species is still telling us unexpected things about those networks.
