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Intergenerational genomic DNA methylation patterns in mouse hybrid strains

Luz D Orozco1, Liudmilla Rubbi1, Lisa J Martin2, Fang Fang3, Farhad Hormozdiari4, Nam Che2, Andrew D Smith3, Aldons J Lusis2 and Matteo Pellegrini1*

Author Affiliations

1 Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA

2 Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA

3 Molecular and Computational Biology, University of Southern California, Los Angeles, CA 90089, USA

4 Department of Computer Science, University of California Los Angeles, Los Angeles, CA 90095, USA

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Genome Biology 2014, 15:R68  doi:10.1186/gb-2014-15-5-r68

Published: 16 May 2014

Abstract

Background

DNA methylation is a contributing factor to both rare and common human diseases, and plays a major role in development and gene silencing. While the variation of DNA methylation among individuals has been partially characterized, the degree to which methylation patterns are preserved across generations is still poorly understood. To determine the extent of methylation differences between two generations of mice we examined DNA methylation patterns in the livers of eight parental and F1 mice from C57BL/6J and DBA/2J mouse strains using bisulfite sequencing.

Results

We find a large proportion of reproducible methylation differences between C57BL/6J and DBA/2J chromosomes in CpGs, which are highly heritable between parent and F1 mice. We also find sex differences in methylation levels in 396 genes, and 11% of these are differentially expressed between females and males. Using a recently developed approach to identify allelically methylated regions independently of genotypic differences, we identify 112 novel putative imprinted genes and microRNAs, and validate imprinting at the RNA level in 10 of these genes.

Conclusions

The majority of DNA methylation differences among individuals are associated with genetic differences, and a much smaller proportion of these epigenetic differences are due to sex, imprinting or stochastic intergenerational effects. Epigenetic differences can be a determining factor in heritable traits and should be considered in association studies for molecular and clinical traits, as we observed that methylation differences in the mouse model are highly heritable and can have functional consequences on molecular traits such as gene expression.