Abstract
BackgroundInbred individuals reared in controlled environments display considerable variance in many complex traits but the underlying cause of this intangible variation has been an enigma. Here we show that two modifiers of epigenetic gene silencing play a critical role in the process.ResultsInbred 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.ConclusionsThese 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.
Highlights
Inbred individuals reared in controlled environments display considerable variance in many complex traits but the underlying cause of this intangible variation has been an enigma
In the experiments described here the colonies were maintained by backcrossing to the inbred congenic strain, in some cases C57BL/6 and in other cases FVB/ NJ, and offspring were weighed at weaning
We show that in the inbred C57BL/6 background, haploinsufficiency for DNA methyltransferase 3a (Dnmt3a) was associated with a trend towards reduced body weight, a larger standard deviation from the mean and a significantly increased coefficient of variance compared to wild-type littermates (Figure 1)
Summary
Inbred individuals reared in controlled environments display considerable variance in many complex traits but the underlying cause of this intangible variation has been an enigma. 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. The studies have been carried out using mice heterozygous for known modifiers of epigenetic reprogramming, one of which (Trim28MommeD9/+) emerged from a dominant screen for modifiers of epigenetic reprogramming. In this screen N-ethyl-N-nitrosourea (ENU) mutagenesis was carried out on inbred
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