Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic noise.. Mus musculus

Inbred individuals reared in controlled environments display considerable variance in many complex traits. The underlying cause of this variability has been an enigma, hence the term intangible variation. Here we show that two modifiers of epigenetic gene silencing play a critical role in the process. Inbred mice heterozygous for a null mutation in DNA methyltransferase 3a (Dnmt3a) or tripartite motif protein 28 (Trim28), show greater coefficients of variance in body weight than their wildtype littermates. Inbred mice carrying a mutation in Trim28 develop metabolic syndrome and abnormal behaviour with incomplete penetrance. These studies provide a molecular explanation of developmental noise in whole organisms and suggest that faithful epigenetic control of transcription is central to suppressing deleterious levels of phenotypic variation. These findings have broad implications for understanding the mechanisms underlying sporadic and complex disease in humans. Overall design: Liver gene expression in Trim28MommeD9 heterozygotes compared to wildtype littermates.