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. 2012 Dec 7;91(6):1033-40.
doi: 10.1016/j.ajhg.2012.10.018. Epub 2012 Nov 21.

Differential Relationship of DNA Replication Timing to Different Forms of Human Mutation and Variation

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Free PMC article

Differential Relationship of DNA Replication Timing to Different Forms of Human Mutation and Variation

Amnon Koren et al. Am J Hum Genet. .
Free PMC article

Abstract

Human genetic variation is distributed nonrandomly across the genome, though the principles governing its distribution are only partially known. DNA replication creates opportunities for mutation, and the timing of DNA replication correlates with the density of SNPs across the human genome. To enable deeper investigation of how DNA replication timing relates to human mutation and variation, we generated a high-resolution map of the human genome's replication timing program and analyzed its relationship to point mutations, copy number variations, and the meiotic recombination hotspots utilized by males and females. DNA replication timing associated with point mutations far more strongly than predicted from earlier analyses and showed a stronger relationship to transversion than transition mutations. Structural mutations arising from recombination-based mechanisms and recombination hotspots used more extensively by females were enriched in early-replicating parts of the genome, though these relationships appeared to relate more strongly to the genomic distribution of causative sequence features. These results indicate differential and sex-specific relationship of DNA replication timing to different forms of mutation and recombination.

Figures

Figure 1
Figure 1
Transition Mutations, and Especially Transversion Mutations, Are Enriched in Late S Phase (A) The replication time of chromosome 5 along with the density of cell line mutations. The density of mutations is shown in reverse scale (i.e., higher mutation rates are shown lower on the plot), as mutation rate per 100 Kb windows (smoothed over 40 windows) in all cell lines combined. (B) Distribution of DNA replication timing for the entire genome (gray; mean set to 0) and for cell line mutation locations (green: transitions; red: transversions): transitions, and especially transversions, show a strong bias toward late S phase. (C) The average replication timing structure in the region extending to 3 megabases of both sides of all mutation locations. In dashed lines are the same plots for 20 sets each of random genomic locations matching in number to the mutation events of the different types.
Figure 2
Figure 2
Hotspots of NAHR-Mediated CNVs Are Enriched in Early S Phase, whereas NH-Mediated CNV Hotspots Are Enriched in Late S Phase (A) Distribution of DNA replication timing for the entire genome (gray) and hotspot locations of NAHR (green)-, and NH (red)-mediated CNVs. All CNV locations of each type were hierarchically clustered with a distance cutoff of 5 Mb (for NAHR) or 1 Mb (NH), and hotspots were defined as clusters with at least five events. (B) The average replication timing structure surrounding CNV hotspot locations (as in Figure 1B). (C) The replication profile of chromosome 7, with the locations of hotspots of NAHR (green)- and NH (red)-mediated events shown. (D) The average replication timing structure surrounding all CNV locations compared to random locations matched for GC content (within a 0.01% range). The association of NH events with DNA replication timing is not due to GC effects. In contrast, when considering GC content, NAHR events occur in later-replicating regions than expected for genomic regions with the same GC content (and not early-replicating regions as suggested when ignoring GC content).
Figure 3
Figure 3
Sex-Specific Associations of Recombination Hotspots and De Novo CNVs with DNA Replication Timing (A) Distribution of DNA replication timing for the entire genome (gray) and locations of hotspots of the sex-differentiated recombination rate, calculated by subtracting male recombination rates from female recombination rates. (B) The average replication timing structure surrounding sex-differentiated recombination hotspots (as in Figure 1B). (C) The replication timing structure surrounding male and female recombination hotspots separately, alongside control regions matched for GC content. When considering GC content, female recombination hotspots occur in later-replicating regions than expected for genomic regions with the same GC content (and not early replicating regions as suggested when ignoring GC content); male recombination hotspots occur in much later replicating regions than expected for regions with similar GC content (and hence do show an association with replication timing, in a negative direction, in contrast to the lack of association suggested when ignoring GC content). (D) Large-scale correlation between male and female recombination and DNA replication timing.
Figure 4
Figure 4
Summary of the Distribution of Various Mutational Events along the Replication Timing Program Shown are the 25th, 50th, and 75th percentile of the replication time distribution of events of the indicated genetic variation type. The timing shown is the replication timing of genomic locations carrying these variation types, but not necessarily the time of occurrence of the relevant events (some of which, particularly meiotic recombination events, occur separately than DNA replication).

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