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MBE Advance Access published online on October 20, 2009
Molecular Biology and Evolution, doi:10.1093/molbev/msp253
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© 2009 The Authors
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Research Article

Evidence that localised variation in primate sequence divergence arises from an influence of nucleosome placement on DNA repair

Hua Ying1,*, Julian Epps2, Rohan Williams1 and Gavin Huttley1,*

1 — John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
2 — School of Electrical Engineering and Telecommunications, The University of New South Wales, Sydney, NSW Australia

* —Corresponding author: Dr Gavin Huttley, John Curtin School of Medical Research, Building 54, The Australian National University, Canberra ACT 0200 Australia, T: 61 2 6125 7961, F: 61 2 6125 2499, M: 0404 004 919, E-mail: gavin.huttley{at}anu.edu.au

Received for publication August 7, 2009. Revision received October 9, 2009. Accepted for publication October 12, 2009.

Understanding the origins of localised substitution rate heterogeneity has important implications for identifying functional genomic sequences. Outside of gene regions, the origins of rate heterogeneity remain unclear. Experimental studies establish that chromatin compaction affects rates of both DNA lesion formation and repair. A functional association between chromatin status and 5-methyl-cytosine also exists. These suggest that both the total rate and type of substitution will be affected by chromatin status. Regular positioning of nucleosomes, the building block of chromatin, further predicts that substitution rate and type should vary spatially in an oscillating manner. We addressed chromatin's influence on substitution rate and type in primates. Matched numbers of sites were sampled from Dnase I Hypersensitive (DHS) and closed chromatin control flank (Flank). Likelihood ratio tests revealed significant excesses of total and of transition substitutions in Flank compared with matched DHS for both intergenic and intronic samples. An additional excess of CpG transitions was evident for the intergenic, but not intronic, regions. Fluctuation in substitution rate along ~ 1800 primate promoters were measured using phylogenetic footprinting. Significant positive correlations were evident between the substitution rate and a nucleosome score from resting human T-cells, with up to ~ 50% of the variance in substitution rate accounted for. Using signal processing techniques, a dominant oscillation at ~ 200 bp was evident in both the substitution rate and nucleosome score. Our results support a role for differential DNA repair rates between open and closed chromatin in the spatial distribution of rate heterogeneity.

Key Words: Substitution rate heterogeneity • molecular evolution • comparative genomics • chromatin • nucleosome • CpG • 5-methyl-cytosine


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