Published online before print
December 19, 2005, 10.1101/gr.4362006
Genome Res. 16:157-163, 2006
©2006 by Cold Spring Harbor Laboratory Press; ISSN 1088-9051/06 $5.00
Letter
Large-scale structure of genomic methylation patterns
Robert A. Rollins1,5,
Fatemeh Haghighi1,5,
John R. Edwards2,3,
Rajdeep Das4,
Michael Q. Zhang4,
Jingyue Ju2,3 and
Timothy H. Bestor1,6
1 Department of Genetics and Development, College of Physicians and Surgeons of Columbia University, Columbia University, New York, New York 10032, USA
2 Columbia Genome Center, Columbia University, New York, New York 10032, USA
3 Department of Chemical Engineering, Columbia University, New York, New York 10032, USA
4 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA
The mammalian genome depends on patterns of methylated cytosines for normal function, but the relationship between genomic methylation patterns and the underlying sequence is unclear. We have characterized the methylation landscape of the human genome by global analysis of patterns of CpG depletion and by direct sequencing of 3073 unmethylated domains and 2565 methylated domains from human brain DNA. The genome was found to consist of short (<4 kb) unmethylated domains embedded in a matrix of long methylated domains. Unmethylated domains were enriched in promoters, CpG islands, and first exons, while methylated domains comprised interspersed and tandem-repeated sequences, exons other than first exons, and non-annotated single-copy sequences that are depleted in the CpG dinucleotide. The enrichment of regulatory sequences in the relatively small unmethylated compartment suggests that cytosine methylation constrains the effective size of the genome through the selective exposure of regulatory sequences. This buffers regulatory networks against changes in total genome size and provides an explanation for the C value paradox, which concerns the wide variations in genome size that scale independently of gene number. This suggestion is compatible with the finding that cytosine methylation is universal among large-genome eukaryotes, while many eukaryotes with genome sizes <5 x 108 bp do not methylate their DNA.
Article published online ahead of print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.4362006.
5 These authors contributed equally to this work
6 Corresponding author.
E-mail THB12{at}Columbia.edu; fax (212) 740-0992.
[Supplemental material is available online at www.genome.org.]
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