Inheritance of an epigenetic change in the mouse: a new role for RNA

Hereditary epigenetic variation, initially recognized and studied extensively in plants, had not been reported in mammals until recently. We have now identified the Kit locus as the first example of a paramutable gene of the mouse. Kit(+/+) homozygotes born from Kit(tm1Alf)(/+) heterozygotes maintain and transmit to their progeny the white-spotted phenotype characteristic of the mutant heterozygote. Our observation of unusual amounts of RNA in the sperm of the paramutated (Kit*) males had led us to consider the possibility of RNA-mediated inheritance. A role for RNA was supported further by the efficient establishment of the epigenetic modification following microinjection in one-cell embryos of either sperm RNA of the paramutated males or of the Kit-specific microRNAs miR-221 and -222. In this article, we describe the phenotypes associated with the wild-type genome in the Kit* paramutated animals. Paramutation may be considered to be one possibility of epigenetic modification in the case of familial disease predispositions that are not fully accounted for by Mendelian analysis.