Saturday, January 17, 2009

The DNA-encoded nucleosome organization of a eukaryotic genome by Kaplan et al

This paper supports the MGD hypothesis.

Nature advance online publication 17 December 2008 | doi:10.1038/nature07667; Received 2 October 2008; Accepted 26 November 2008; Published online 17 December 2008

The DNA-encoded nucleosome organization of a eukaryotic genome

Noam Kaplan1,9, Irene K. Moore3,9, Yvonne Fondufe-Mittendorf3, Andrea J. Gossett4, Desiree Tillo5, Yair Field1, Emily M. LeProust6, Timothy R. Hughes5,7,8, Jason D. Lieb4, Jonathan Widom3 & Eran Segal1,2

Department of Computer Science and Applied Mathematics,
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, 2153 Sheridan Road, Evanston, Illinois 60208, USA
Department of Biology, Carolina Center for Genome Sciences, and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
Agilent Technologies Inc., Genomics—LSSU, 5301 Stevens Creek Boulevard, MS 3L/MT Santa Clara, California 95051, USA
Terrence Donnelly Centre for Cellular & Biomolecular Research,
Banting and Best Department of Medical Research, 160 College Street, Toronto, Ontario M5S 3E1, Canada
These authors contributed equally to this work.
Correspondence to: Jonathan Widom3Eran Segal1,2 Correspondence and requests for materials should be addressed to J.W. (Email: or E.S. (Email:

Nucleosome organization is critical for gene regulation1. In living cells this organization is determined by multiple factors, including the action of chromatin remodellers2, competition with site-specific DNA-binding proteins3, and the DNA sequence preferences of the nucleosomes themselves4, 5, 6, 7, 8. However, it has been difficult to estimate the relative importance of each of these mechanisms in vivo 7, 9, 10, 11, because in vivo nucleosome maps reflect the combined action of all influencing factors. Here we determine the importance of nucleosome DNA sequence preferences experimentally by measuring the genome-wide occupancy of nucleosomes assembled on purified yeast genomic DNA. The resulting map, in which nucleosome occupancy is governed only by the intrinsic sequence preferences of nucleosomes, is similar to in vivo nucleosome maps generated in three different growth conditions. In vitro, nucleosome depletion is evident at many transcription factor binding sites and around gene start and end sites, indicating that nucleosome depletion at these sites in vivo is partly encoded in the genome. We confirm these results with a micrococcal nuclease-independent experiment that measures the relative affinity of nucleosomes for 40,000 double-stranded 150-base-pair oligonucleotides. Using our in vitro data, we devise a computational model of nucleosome sequence preferences that is significantly correlated with in vivo nucleosome occupancy in Caenorhabditis elegans. Our results indicate that the intrinsic DNA sequence preferences of nucleosomes have a central role in determining the organization of nucleosomes in vivo.

Chromatin-Associated Periodicity in Genetic Variation Downstream of Transcriptional Start Sites by Sasaki et al

The paper by Sasaki et al in Science supports the MGD hypothesis. Indel rate is inversely related to point mutation rate. Indel is more of an epigenetic event.

Originally published in Science Express on 11 December 2008
Science 16 January 2009:
Vol. 323. no. 5912, pp. 401 - 404
DOI: 10.1126/science.1163183
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Chromatin-Associated Periodicity in Genetic Variation Downstream of Transcriptional Start Sites
Shin Sasaki,1* Cecilia C. Mello,2 Atsuko Shimada,3 Yoichiro Nakatani,1 Shin-ichi Hashimoto,4 Masako Ogawa,4 Kouji Matsushima,4 Sam Guoping Gu,2 Masahiro Kasahara,1 Budrul Ahsan,1 Atsushi Sasaki,1 Taro Saito,1 Yutaka Suzuki,5 Sumio Sugano,5 Yuji Kohara,6 Hiroyuki Takeda,3 Andrew Fire,2 Shinichi Morishita1,7

Might DNA sequence variation reflect germline genetic activity and underlying chromatin structure? We investigated this question using medaka (Japanese killifish, Oryzias latipes), by comparing the genomic sequences of two strains (Hd-rR and HNI) and by mapping 37.3 million nucleosome cores from Hd-rR blastulae and 11,654 representative transcription start sites from six embryonic stages. We observed a distinctive 200–base pair (bp) periodic pattern of genetic variation downstream of transcription start sites; the rate of insertions and deletions longer than 1 bp peaked at positions of approximately +200, +400, and +600 bp, whereas the point mutation rate showed corresponding valleys. This 200-bp periodicity was correlated with the chromatin structure, with nucleosome occupancy minimized at positions 0, +200, +400, and +600 bp. These data exemplify the potential for genetic activity (transcription) and chromatin structure to contribute to molding the DNA sequence on an evolutionary time scale.