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

Nadia C Whitelaw12, Suyinn Chong1, Daniel K Morgan12, Colm Nestor34, Timothy J Bruxner1, Alyson Ashe, Eleanore Lambley1, Richard Meehan34 and Emma Whitelaw1*

Author Affiliations

1 Genetics and Population Health, Queensland Institute of Medical Research, 300 Herston Road, Brisbane, Queensland 4006, Australia

2 School of Medicine, University of Queensland, 288 Herston Road, Brisbane, Queensland 4001, Australia

3 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Crewe Road, Edinburgh EH4 2XU, UK

4 Breakthrough Research Unit, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK

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Genome Biology 2010, 11:R111  doi:10.1186/gb-2010-11-11-r111

Published: 19 November 2010



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. 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 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.