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On the assessment of statistical significance of three-dimensional colocalization of sets of genomic elements.

Witten DM, Noble WS - Nucleic Acids Res. (2012)

Bottom Line: In support of this hypothesis, several research groups have examined sets of functionally associated genomic loci, with the aim of determining whether those loci are statistically significantly colocalized.We show that these previous analyses rely upon a faulty assumption, and we propose a correct non-parametric resampling approach to the same problem.Applying this approach to the same data set does not support the hypothesis that transcriptionally coregulated genes tend to colocalize, but strongly supports the colocalization of centromeres, and provides some evidence of colocalization of origins of early DNA replication, chromosomal breakpoints and transfer RNAs.

View Article: PubMed Central - PubMed

Affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98109, USA. dwitten@u.washington.edu

ABSTRACT
A growing body of experimental evidence supports the hypothesis that the 3D structure of chromatin in the nucleus is closely linked to important functional processes, including DNA replication and gene regulation. In support of this hypothesis, several research groups have examined sets of functionally associated genomic loci, with the aim of determining whether those loci are statistically significantly colocalized. This work presents a critical assessment of two previously reported analyses, both of which used genome-wide DNA-DNA interaction data from the yeast Saccharomyces cerevisiae, and both of which rely upon a simple notion of the statistical significance of colocalization. We show that these previous analyses rely upon a faulty assumption, and we propose a correct non-parametric resampling approach to the same problem. Applying this approach to the same data set does not support the hypothesis that transcriptionally coregulated genes tend to colocalize, but strongly supports the colocalization of centromeres, and provides some evidence of colocalization of origins of early DNA replication, chromosomal breakpoints and transfer RNAs.

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Based on the yeast interaction data of Duan et al., hypergeometric and resampling-based P-values were computed to assess the extent to which certain functional groups colocalize. The height of each bar indicates enrichment or depletion of observed interchromosomal interactions relative to the percent (black line) of all possible interactions that were observed at a false discovery rate below 0.01. Above each bar, the resampling-based P-value is reported (without correction for multiple testing), and an asterisk indicates that the hypergeometric P-value was below 0.01 after Bonferroni correction. Additional information about the fourteen sets of functional elements can be found in Duan et al. (3).
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gks012-F2: Based on the yeast interaction data of Duan et al., hypergeometric and resampling-based P-values were computed to assess the extent to which certain functional groups colocalize. The height of each bar indicates enrichment or depletion of observed interchromosomal interactions relative to the percent (black line) of all possible interactions that were observed at a false discovery rate below 0.01. Above each bar, the resampling-based P-value is reported (without correction for multiple testing), and an asterisk indicates that the hypergeometric P-value was below 0.01 after Bonferroni correction. Additional information about the fourteen sets of functional elements can be found in Duan et al. (3).

Mentions: In the Duan et al. (3) study, 10 groups of functional elements showed significant evidence of colocalization according to the Bonferroni adjusted hypergeometric test. In our reanalysis (Figure 2), three of these groups are no longer significant after Bonferonni adjustment: the complete set of telomeres, one of the two sets of early-firing origins, and one of the two sets of chromosomal breakpoints. Thus, our results suggest that (i) Duan et al. (3) incorrectly concluded that telomeres exhibit colocalization, and (ii) the evidence for colocalization of early-firing origins and for chromosomal breakpoints is weaker than initially reported.Figure 2.


On the assessment of statistical significance of three-dimensional colocalization of sets of genomic elements.

Witten DM, Noble WS - Nucleic Acids Res. (2012)

Based on the yeast interaction data of Duan et al., hypergeometric and resampling-based P-values were computed to assess the extent to which certain functional groups colocalize. The height of each bar indicates enrichment or depletion of observed interchromosomal interactions relative to the percent (black line) of all possible interactions that were observed at a false discovery rate below 0.01. Above each bar, the resampling-based P-value is reported (without correction for multiple testing), and an asterisk indicates that the hypergeometric P-value was below 0.01 after Bonferroni correction. Additional information about the fourteen sets of functional elements can be found in Duan et al. (3).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3351188&req=5

gks012-F2: Based on the yeast interaction data of Duan et al., hypergeometric and resampling-based P-values were computed to assess the extent to which certain functional groups colocalize. The height of each bar indicates enrichment or depletion of observed interchromosomal interactions relative to the percent (black line) of all possible interactions that were observed at a false discovery rate below 0.01. Above each bar, the resampling-based P-value is reported (without correction for multiple testing), and an asterisk indicates that the hypergeometric P-value was below 0.01 after Bonferroni correction. Additional information about the fourteen sets of functional elements can be found in Duan et al. (3).
Mentions: In the Duan et al. (3) study, 10 groups of functional elements showed significant evidence of colocalization according to the Bonferroni adjusted hypergeometric test. In our reanalysis (Figure 2), three of these groups are no longer significant after Bonferonni adjustment: the complete set of telomeres, one of the two sets of early-firing origins, and one of the two sets of chromosomal breakpoints. Thus, our results suggest that (i) Duan et al. (3) incorrectly concluded that telomeres exhibit colocalization, and (ii) the evidence for colocalization of early-firing origins and for chromosomal breakpoints is weaker than initially reported.Figure 2.

Bottom Line: In support of this hypothesis, several research groups have examined sets of functionally associated genomic loci, with the aim of determining whether those loci are statistically significantly colocalized.We show that these previous analyses rely upon a faulty assumption, and we propose a correct non-parametric resampling approach to the same problem.Applying this approach to the same data set does not support the hypothesis that transcriptionally coregulated genes tend to colocalize, but strongly supports the colocalization of centromeres, and provides some evidence of colocalization of origins of early DNA replication, chromosomal breakpoints and transfer RNAs.

View Article: PubMed Central - PubMed

Affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98109, USA. dwitten@u.washington.edu

ABSTRACT
A growing body of experimental evidence supports the hypothesis that the 3D structure of chromatin in the nucleus is closely linked to important functional processes, including DNA replication and gene regulation. In support of this hypothesis, several research groups have examined sets of functionally associated genomic loci, with the aim of determining whether those loci are statistically significantly colocalized. This work presents a critical assessment of two previously reported analyses, both of which used genome-wide DNA-DNA interaction data from the yeast Saccharomyces cerevisiae, and both of which rely upon a simple notion of the statistical significance of colocalization. We show that these previous analyses rely upon a faulty assumption, and we propose a correct non-parametric resampling approach to the same problem. Applying this approach to the same data set does not support the hypothesis that transcriptionally coregulated genes tend to colocalize, but strongly supports the colocalization of centromeres, and provides some evidence of colocalization of origins of early DNA replication, chromosomal breakpoints and transfer RNAs.

Show MeSH