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

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 wild-type littermates. Trim28 mutants additionally develop metabolic syndrome and abnormal behavior with incomplete penetrance. Genome-wide gene expression analyses identified 284 significantly dysregulated genes in Trim28 heterozygote mutants compared to wild-type mice, with Mas1, which encodes a G-protein coupled receptor implicated in lipid metabolism, showing the greatest average change in expression (7.8-fold higher in mutants). This gene also showed highly variable expression between mutant individuals.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.Experiments designed to analyze the significance of genes and environment on quantitative traits using laboratory rats and mice have found that 70 to 80% of all variation is of unknown origin [1]. Gartner [2] carried out experiments over a period of 20 years to analyze the significance of different components of random variability in quantitative traits. Reduction of genetic variability, by using inbred strains, and reduction of environmental variability, by standardized husbandry, did not significantly reduce the range of random phenotypic variability. Similarly, moving the animals into the wild to increase environmental variability did not increase random phenotypic variability, hence the term 'intangible variance' [1]. For example, only 20 to 30% of the range of the body weights of inbred mice was estimated to be the result of postnatal environment, with the remaining 70 to 80%, which Gartner termed 'the third component', being of unknown or