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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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Reports

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{dagger} Shinichi Morishita1,7{dagger}

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.

1 Department of Computational Biology, Graduate School of Frontier Sciences, the University of Tokyo, Kashiwa, 277-0882, Japan.
2 Departments of Pathology and Genetics, School of Medicine, Stanford University, Stanford, CA 94305–5324, USA.
3 Department of Biological Sciences, Graduate School of Science, the University of Tokyo, Tokyo, 113-0033, Japan.
4 Department of Molecular Preventive Medicine, School of Medicine, the University of Tokyo, Tokyo, 113-0033, Japan.
5 Department of Medical Genome Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Tokyo, 108-8639, Japan.
6 Center for Genetic Resource Information, National Institute of Genetics, Mishima, 411-8540, Japan.
7 Bioinformatics Research and Development (BIRD), Japan Science and Technology Agency (JST), Tokyo, 102-8666, Japan.

* Present address: Mitsubishi Research Institute, Inc., Tokyo, 100-8141, Japan.

{dagger} To whom correspondence should be addressed. E-mail: afire{at}stanford.edu (A.F.); moris{at}cb.k.u-tokyo.ac.jp (S.M.)

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