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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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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 CDX2 and FGF5. The lower panel row shows the posterior probabilities a site was classified as fast (pfast), 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).  is the estimated Pearson's correlation coefficient of the footprinting and phylo-HMM signals.
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fig1: 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 CDX2 and FGF5. The lower panel row shows the posterior probabilities a site was classified as fast (pfast), 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). is the estimated Pearson's correlation coefficient of the footprinting and phylo-HMM signals.

Mentions: Phylogenetic footprinting (hereafter footprinting) was used to assess the spatial distribution of substitutions rather than phylo-HMMs because of the potential sensitivity of the latter to violation of the assumption of spatially homogeneous sequence composition. The footprinting approach has the advantage of assuming compositional homogeneity over a smaller spatial scale, making violation of the assumption less likely. Furthermore, it does not require prior specification of the frequency of fast/slow sites as per the phylo-HMM. We note here that the spatial distribution of K was typically highly correlated with the posterior probabilities classifying a site as “fast” from the phylo-HMM (fig. 1). For loci where the phylo-HMM analysis indicated nominally significant support for clustered substitutions, ∼44% showed strong correlations (ρ > 0.5) between the spatial distribution of K and pfast.


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)

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 CDX2 and FGF5. The lower panel row shows the posterior probabilities a site was classified as fast (pfast), 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).  is the estimated Pearson's correlation coefficient of the footprinting and phylo-HMM signals.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: 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 CDX2 and FGF5. The lower panel row shows the posterior probabilities a site was classified as fast (pfast), 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). is the estimated Pearson's correlation coefficient of the footprinting and phylo-HMM signals.
Mentions: Phylogenetic footprinting (hereafter footprinting) was used to assess the spatial distribution of substitutions rather than phylo-HMMs because of the potential sensitivity of the latter to violation of the assumption of spatially homogeneous sequence composition. The footprinting approach has the advantage of assuming compositional homogeneity over a smaller spatial scale, making violation of the assumption less likely. Furthermore, it does not require prior specification of the frequency of fast/slow sites as per the phylo-HMM. We note here that the spatial distribution of K was typically highly correlated with the posterior probabilities classifying a site as “fast” from the phylo-HMM (fig. 1). For loci where the phylo-HMM analysis indicated nominally significant support for clustered substitutions, ∼44% showed strong correlations (ρ > 0.5) between the spatial distribution of K and pfast.

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