Evidence that localized variation in primate sequence divergence arises from an influence of nucleosome placement on DNA repair - PubMed (original) (raw)

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

Hua Ying et al. Mol Biol Evol. 2010 Mar.

Abstract

Understanding the origins of localized 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 the 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 approximately 1,800 primate promoters was 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 approximately 50% of the variance in substitution rate accounted for. Using signal processing techniques, a dominant oscillation at approximately 200 bp was evident in both the substitution rate and the nucleosome score. Our results support a role for differential DNA repair rates between open and closed chromatin in the spatial distribution of rate heterogeneity.

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Figures

FIG. 1.

Comparison of the substitution signal estimated using phylogenetic footprinting and a phylo-HMM. Shown in the top row of panels is substitution rate variation from footprinting, measured as the sum of tree branch lengths (K), from the genes C D _X_2 and F G _F_5. The lower panel row shows the posterior probabilities a site was classified as fast (_p_fast), estimated from the phylo-HMM. Each horizontal line indicates a nucleosome inferred from one of seven cell lines where magenta represents one of the four cancer cell lines of A375, T47D, MCF7, and MALME; green represents IMR90 cell line; cyan represents PM cell line; and yellow represents the MEC cell line (Ozsolak et al. 2007). formula image is the estimated Pearson's correlation coefficient of the footprinting and phylo-HMM signals.

FIG. 2.

Comparison of the spatial substitution signal with nucleosome score. Example genes exhibiting a positive correlation are shown in the left column, a negative correlation in the right column. x axis is the alignment position; y axis black label is the nucleosome score (Schones et al. 2008) with data shown as a blue histogram; y axis red label is the estimate of K from footprinting with data shown as the red line. Black, orange, and blue horizontal lines with diamond marks at the end represent CpG islands, DHS sites, and repeat sequences, respectively.

FIG. 3.

Signal analysis of substitution amplitude spectra from DUSP and FZD2 promoters. The plot columns correspond to the indicated loci. The upper plot row shows K, whereas the lower row its DFT-based amplitude spectrum. Periods of the footprinting signal appear as peaks of the amplitude spectrum. The first, second, and third highest peaks are annotated with a corresponding number of +, and their period lengths, and CRB are shown in the tables.

FIG. 4.

Evolutionary distance and raw nucleosome score exhibit a ∼200-bp period in primate promoters. Frequency histograms of the periods classified as main (upper row) and secondary (lower row) after eliminating periods with a CRB > 0.2. The left and right columns show the periods from the substitution spectra (K) and the nucleosome score (Schones et al. 2008), respectively.

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Evidence that localized variation in primate sequence divergence arises from an influence of nucleosome placement on DNA repair - PubMed (original) (raw)