It is well recognised that there is a surprising degree of phenotypic variation among inbred individuals even when the environmental influences, in the strict sense of the word, are controlled. Genetic textbooks refer to this as "intangible variation" or "developmental noise". Littermates from inbred mouse colonies do show some genetic differences in repetitive parts of the genome, telomere length, CNVs etc but these have never been thought to have a role in phenotype. We suggest that intangible variation results from the stochastic establishment of epigenetic modifications in early development. Work from a number of laboratories suggests that the establishment of these epigenetic states can be influenced by the environment, raising the possibility that they are involved in the developmental origins of some disease states.
We have carried out a "sensitized" ENU mutagenesis screen in the mouse to identify genes that modify epigenetic state. In most cases they are homozygous lethal, indicating the obligate requirement for the genes that have been hit (Blewitt et al, 2005). So far, we have identified fourteen of the underlying mutations, some of these are novel. We have now screened 5000 F1s and identified 50 MommeDs. This project has the potential to identify many more novel genes involved in epigenetic phenomena, and to produce hypomorphs and hypermorphs of known modifiers of epigenetic state. Mice haploinsufficient for such proteins show a range of subtle phenotypes, including obesity and behavioural abnormalities. These mutant lines are a valuable resource to study the role of epigenetics in gene / environment interactions.