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

Ying H, Epps J, Williams R, Huttley G - Mol. Biol. Evol. (2009)

Bottom Line: Likelihood ratio tests revealed significant excesses of total and of transition substitutions in Flank compared with matched DHS for both intergenic and intronic samples.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.

View Article: PubMed Central - PubMed

Affiliation: John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia. hua.ying@anu.edu.au

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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Related in: MedlinePlus

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.
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fig3: 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.

Mentions: We illustrate the factors that affect the estimation of periods with analysis of two loci, DUSP and FZD2 (fig. 3). For our analyses of amplitude spectra, we specified a CRB cutoff of 0.2, excluding estimated periods with a greater CRB. After applying the cutoff, the periods with the greatest and penultimate powers were selected as the main and secondary periods, respectively. (We illustrate the effect of other CRB cutoffs in Supplementary fig. S2, Supplementary Material online.) For FZD2, the largest peak from the DFT had a period of 700 bp with CRB of 0.649. This peak likely derives from the large amplitude peak of K spanning alignment positions ∼700–1000 bp and the peak spanning positions ∼100–300 bp. As one would expect from an alignment of 1,400 bp, where a period of 700 can be measured from only two peaks, the 700-bp period has high CRB and thus the uncertainty in this period estimate is high. The two peaks with the next highest power correspond to periods of 233 and 175 bp, respectively, both of which exhibit a CRB < 0.07. These peaks were then selected as the main and secondary periods, respectively, for FZD2. For the DUSP promoter spectrum, only a single period had CRB < 0.2, the dominant peak at ∼200 bp, so this was selected as the main period.


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

Ying H, Epps J, Williams R, Huttley G - Mol. Biol. Evol. (2009)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2822288&req=5

fig3: 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.
Mentions: We illustrate the factors that affect the estimation of periods with analysis of two loci, DUSP and FZD2 (fig. 3). For our analyses of amplitude spectra, we specified a CRB cutoff of 0.2, excluding estimated periods with a greater CRB. After applying the cutoff, the periods with the greatest and penultimate powers were selected as the main and secondary periods, respectively. (We illustrate the effect of other CRB cutoffs in Supplementary fig. S2, Supplementary Material online.) For FZD2, the largest peak from the DFT had a period of 700 bp with CRB of 0.649. This peak likely derives from the large amplitude peak of K spanning alignment positions ∼700–1000 bp and the peak spanning positions ∼100–300 bp. As one would expect from an alignment of 1,400 bp, where a period of 700 can be measured from only two peaks, the 700-bp period has high CRB and thus the uncertainty in this period estimate is high. The two peaks with the next highest power correspond to periods of 233 and 175 bp, respectively, both of which exhibit a CRB < 0.07. These peaks were then selected as the main and secondary periods, respectively, for FZD2. For the DUSP promoter spectrum, only a single period had CRB < 0.2, the dominant peak at ∼200 bp, so this was selected as the main period.

Bottom Line: Likelihood ratio tests revealed significant excesses of total and of transition substitutions in Flank compared with matched DHS for both intergenic and intronic samples.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.

View Article: PubMed Central - PubMed

Affiliation: John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia. hua.ying@anu.edu.au

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.

Show MeSH
Related in: MedlinePlus