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Nucleic Acids Research Advance Access published online on April 15, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn122
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Methods Online

Inter-individual variation of DNA methylation and its implications for large-scale epigenome mapping

Christoph Bock1,*, Jörn Walter2, Martina Paulsen2 and Thomas Lengauer1

1Max-Planck-Institut für Informatik and 2Universität des Saarlandes, FR 8.3 Biowissenschaften, Genetik/Epigenetik, Saarbrücken, Germany

*To whom correspondence should be addressed. Tel: +49 681 9325 322; Fax: +49 681 9325 399; Email: cbock{at}mpi-inf.mpg.de

Received August 25, 2007. Revised March 2, 2008. Accepted March 4, 2008.

Genomic DNA methylation profiles exhibit substantial variation within the human population, with important functional implications for gene regulation. So far little is known about the characteristics and determinants of DNA methylation variation among healthy individuals. We performed bioinformatic analysis of high-resolution methylation profiles from multiple individuals, uncovering complex patterns of inter-individual variation that are strongly correlated with the local DNA sequence. CpG-rich regions exhibit low and relatively similar levels of DNA methylation in all individuals, but the sequential order of the (few) methylated among the (many) unmethylated CpGs differs randomly across individuals. In contrast, CpG-poor regions exhibit substantially elevated levels of inter-individual variation, but also significant conservation of specific DNA methylation patterns between unrelated individuals. This observation has important implications for experimental analysis of DNA methylation, e.g. in the context of epigenome projects. First, DNA methylation mapping at single-CpG resolution is expected to uncover informative DNA methylation patterns for the CpG-poor bulk of the human genome. Second, for CpG-rich regions it will be sufficient to measure average methylation levels rather than assaying every single CpG. We substantiate these conclusions by an in silico benchmarking study of six widely used methods for DNA methylation mapping. Based on our findings, we propose a cost-optimized two-track strategy for mammalian methylome projects.


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