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Impact of chromatin structure on sequence variability in the human genome

Nature Structural & Molecular Biology volume 18, pages 510515 (2011) | Download Citation

Abstract

DNA sequence variations in individual genomes give rise to different phenotypes within the same species. One mechanism in this process is the alteration of chromatin structure due to sequence variation that influences gene regulation. We composed a high-confidence collection of human single-nucleotide polymorphisms and indels based on analysis of publicly available sequencing data and investigated whether the DNA loci associated with stable nucleosome positions are protected against mutations. We addressed how the sequence variation reflects the occupancy profiles of nucleosomes bearing different epigenetic modifications on genome scale. We found that indels are depleted around nucleosome positions of all considered types, whereas single-nucleotide polymorphisms are enriched around the positions of bulk nucleosomes but depleted around the positions of epigenetically modified nucleosomes. These findings indicate an increased level of conservation for the sequences associated with epigenetically modified nucleosomes, highlighting complex organization of the human chromatin.

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Acknowledgements

We thank S. Sunyaev, I. Adzhubei and G. Kryukov for the helpful discussions. This project has been funded in part with federal funds from the US National Institutes of Health (GM082798 and U01HG004258 to P.J.P.; contract no. HHSN261200800001E to R.M.S.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government.

Author information

Affiliations

  1. Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.

    • Michael Y Tolstorukov
    •  & Peter J Park
  2. Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Michael Y Tolstorukov
    •  & Peter J Park
  3. Advanced Biomedical Computing Center, Information Systems Program, SAIC-Frederick, National Cancer Institute at Frederick, Frederick, Maryland, USA.

    • Natalia Volfovsky
    •  & Robert M Stephens
  4. HST Informatics Program at Children's Hospital Boston, Boston, Massachusetts, USA.

    • Peter J Park

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Contributions

M.Y.T. performed all analyses. N.V. and R.M.S. produced the collections of sequence variations. P.J.P. directed the project. M.Y.T. and P.J.P. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Peter J Park.

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DOI

https://doi.org/10.1038/nsmb.2012

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