Metastable epialleles and their contribution to epigenetic inheritance in mammals

Many epigenetic differences between individuals are driven by genetic variation. Mammalian metastable epialleles are unusual in that they show variable DNA methylation states between genetically identical individuals. The occurrence of such states across generations has resulted in their consideration by many as strong evidence for epigenetic inheritance in mammals, with the classic A^vy and Axin^Fu mouse models - each products of repeat element insertions - being the most widely accepted examples. Equally, there has been interest in exploring their use as epigenetic biosensors given their susceptibility to environmental compromise. Here we review the classic murine metastable epialleles as well as more recently identified candidates, with the aim of providing a more holistic understanding of their biology. We consider the extent to which epigenetic inheritance occurs at metastable epialleles and explore the limited mechanistic insights into the establishment of their variable epigenetic states. We discuss their environmental modulation and their potential relevance in genome regulation. In light of recent whole-genome screens for novel metastable epialleles, we point out the need to reassess their biological relevance in multi-generational studies and we highlight their value as a model to study repeat element silencing as well as the mechanisms and consequences of mammalian epigenetic stochasticity.