Article

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

Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 11/2012; 91(6). DOI: 10.1016/j.ajhg.2012.10.018
Source: PubMed

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.

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Available from: Jonathan Sebat, Dec 30, 2013
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    • "We next estimated the preferential direction of the replication fork from the replication timing (RT) data (Koren et al. 2012). The RT is highly conserved between human tissues and cell types (Ryba et al. 2010; Pope et al. 2014); therefore, we utilized the RT data from one cell type (lymphoblastoid cell line) to different cancer types. "
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    • "We speculate that increased DNA fragility in early-replicating regions may produce more ssDNA substrate for APOBEC enzymes . Early-replicating, highly transcribed regions of cancer genomes are known to be associated with changes stemming from chromosome breakage, such as copy-number variation, chromosome rearrangements, fragility, and loss of heterozygosity (Barlow et al., 2013; Koren et al., 2012; Pedersen and De, 2013; Sima and Gilbert, 2014). An increased frequency of DNA breakage would in turn be expected to produce more hypermutable ssDNA as the repair of these breaks often involves formation of ssDNA through either 5 0 /3 0 resection (Mimitou and Symington, 2011; Roberts et al., 2012) or uncoupled Figure 4. "
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    • "In both scenarios, genome reorganization precedes gene expression changes, suggesting a potential causal relationship (Apostolou et al., 2013; Phillips- Cremins et al., 2013; Wei et al., 2013; Zhang et al., 2013). Higher-order genome organization has been shown to significantly influence the distribution of genomic aberrations in both immortalized somatic cells and cancer cells, but the underlying mechanism remains elusive (De and Michor, 2011; Fudenberg et al., 2011; Koren et al., 2012; Schuster-Bö ckler and Lehner, 2012). One method of mapping genomic organization is by segmenting the genome into domains based on replication timing, which occurs in a tightly regulated cell-type-specific manner (Gilbert et al., 2010). "
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