There is, of course, a wide spectrum of effects of both coding and noncoding mutations (Figure 2), and there are exceptions to the rule in both directions. Loss-of-function mutations in some protein-coding genes have mild effects [92], as exemplified by as knockouts of the mammalian genes encoding calbindin D9k [93] and C/EBPdelta [94],[95], and the significant number of yeast genes that show no observable phenotype. Reciprocally, knockouts of some highly conserved miRNAs, many of which have multiple targets, give strong phenotypes [96]–[98], even though very few such genes have been identified in genetic screens in Caenorhabditis elegans and Drosophila, and none have been identified in mice, despite the intensity of such screens (see below). Moreover, to date, no naturally arising mutations have been discovered in the Xist gene in either humans or mice, despite the central role that this ncRNA plays in embryogenesis and in X-chromosome dosage control in females [99], possibly because such mutations are lethal.
