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Published online on March 21, 2007, 10.1073/pnas.0609746104

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Genetics
Hyperconserved CpG domains underlie Polycomb-binding sites

( comparative genomics | development | DNA methylation | epigenetics | evolution )

Amos Tanay *{dagger}, Anne H. O'Donnell {ddagger}, Marc Damelin {ddagger}, and Timothy H. Bestor {ddagger}

*Center for Studies in Physics and Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10021; and {ddagger}Department of Genetics and Development, College of Physicians and Surgeons of Columbia University, 701 West 168th Street, New York, NY 10032

Edited by David J. Lipman, National Institutes of Health, Bethesda, MD, and approved February 2, 2007 (received for review November 2, 2006)

Comparative genomics of CpG dinucleotides, which are targets of DNA methyltransferases in vertebrate genomes, has been constrained by their evolutionary instability and by the effect of methylation on their mutation rates. We compared the human and chimpanzee genomes to identify DNA sequence signatures correlated with rates of mutation at CpG dinucleotides. The new signatures were used to develop robust comparative genomics of CpG dinucleotides in heterogeneous regions and to identify genomic domains that have anomalous CpG divergence rates. The data showed that there are {approx}200 genomic regions where CpG distributions are far more conserved than predicted. These hyperconserved CpG domains largely coincide with domains bound by Polycomb repressive complex 2 in undifferentiated human embryonic stem cells and are almost exclusively present near genes whose products are involved in the regulation of embryonic development. Several domains were experimentally shown to be unmethylated at different developmental stages. These data indicate that particular evolutionary patterns and distinct sequence properties on scales much larger than standard transcription factor-binding sites may play an important role in Polycomb recruitment and transcriptional regulation of key developmental genes.

Author contributions: A.T. designed research; A.T., A.H.O., M.D., and T.H.B. performed research; A.T. contributed new reagents/analytic tools; A.T. and T.H.B. analyzed data; and A.T. and T.H.B. wrote the paper.

The authors declare no conflict of interest.

{dagger}To whom correspondence should be addressed.

Amos Tanay, E-mail: atanay{at}mail.rockefeller.edu

www.pnas.org/cgi/doi/10.1073/pnas.0609746104
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