Weak Regulation of Many Targets Is Cumulatively Powerful—An Evolutionary Perspective on microRNA Functionality

Why do microRNAs (miRNAs) weakly repress so many targets such that most targets do not have phenotypic effects? An increasingly accepted view posits that weak targeting has no biological function and each miRNA effectively has only a few functional targets. Here, we review the evolutionary arguments for this postulate and find these arguments seriously flawed. In contrast, from the systems perspective, the power of broad and weak targeting may reside in the cumulative effects of all repressions, which collectively stabilize gene regulatory networks. This view predicts that miRNAs would show little tendency to downsize their target pools. A survey of "twin-miRs" production indeed validates this prediction.