Phenotypic variation among mutant animals is common, with some mutants displaying dramatic phenotypes while their genetically similar siblings seem less affected. Why is this? Here, on p. 4430, Charles Kimmel and colleagues reveal that phenotypic variation, in the case of zebrafish mef2cab1086 mutants, can be caused by a fate-switching event during development. Zebrafish mef2cab1086 mutants express a truncated form of Mef2c – a protein involved in skeletal development – and are known to develop variable ectopic bones in their heads. The researchers now reveal that these bones arise due to a fate-switching event during development, such that cells that are normally destined to be ligament variably turn into bone. Selective breeding demonstrates that the penetrance of the bone phenotype is heritable. The authors further show that the mef2cab1086 transcript is differentially expressed in low and high penetrance strains. Finally, they report that a transposon that resides upstream of the mef2ca locus exhibits differential levels of DNA methylation; in high penetrance strains, which express high levels of the mef2cab1086 transcript, DNA methylation of the transposon is significantly reduced. These findings lead the authors to propose that variable epigenetic silencing of transposons underlies the variable mef2cab1086 phenotypes and could explain other cases of phenotypic variability.
