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


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.

Download full-text


Available from: Jonathan Sebat, Dec 30, 2013
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: An antiviral component of the human innate immune system-the APOBEC cytidine deaminases-was recently identified as a prominent source of mutations in cancers. Here, we investigated the distribution of APOBEC-induced mutations across the genomes of 119 breast and 24 lung cancer samples. While the rate of most mutations is known to be elevated in late-replicating regions that are characterized by reduced chromatin accessibility and low gene density, we observed a marked enrichment of APOBEC mutations in early-replicating regions. This unusual mutagenesis profile may be associated with a higher propensity to form single-strand DNA substrates for APOBEC enzymes in early-replicating regions and should be accounted for in statistical analyses of cancer genome mutation catalogs aimed at understanding the mechanisms of carcinogenesis as well as highlighting genes that are significantly mutated in cancer.
    Cell Reports 11/2015; DOI:10.1016/j.celrep.2015.09.077 · 8.36 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cell-fate change involves significant genome reorganization, including changes in replication timing, but how these changes are related to genetic variation has not been examined. To study how a change in replication timing that occurs during reprogramming impacts the copy-number variation (CNV) landscape, we generated genome-wide replication-timing profiles of induced pluripotent stem cells (iPSCs) and their parental fibroblasts. A significant portion of the genome changes replication timing as a result of reprogramming, indicative of overall genome reorganization. We found that early- and late-replicating domains in iPSCs are differentially affected by copy-number gains and losses and that in particular, CNV gains accumulate in regions of the genome that change to earlier replication during the reprogramming process. This differential relationship was present irrespective of reprogramming method. Overall, our findings reveal a functional association between reorganization of replication timing and the CNV landscape that emerges during reprogramming.
    Cell Reports 03/2014; 7(1). DOI:10.1016/j.celrep.2014.03.007 · 8.36 Impact Factor
  • Source
    • "This tendency was not observed for older PDGs, which tend to replicate early even if they are located in CNV regions. These results also suggest that copy number formation in gene coding regions is affected distinctly by two mechanisms recently associated to RT. Accordingly, early replicating CNVs are frequently linked to recombination mechanisms such as NAHR, while late-replicating CNVs are more frequently associated to non-homology (NH) based mechanisms (Koren et al., 2012) generally associated with replication errors (Hastings et al., 2009). Therefore, singletons Fig. 3. Gene duplications, CNVs and RT. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Asynchronous replication of the genome has been associated with different rates of point mutation and copy number variation (CNV) in human populations. Here, our aim was to investigate whether the bias in the generation of CNV that is associated with DNA replication timing might have conditioned the birth of new protein-coding genes during evolution. We show that genes that were duplicated during primate evolution are more commonly found among the human genes located in late-replicating CNV regions. We traced the relationship between replication timing and the evolutionary age of duplicated genes. Strikingly, we found that there is a significant enrichment of evolutionary younger duplicates in late-replicating regions of the human and mouse genome. Indeed, the presence of duplicates in late-replicating regions gradually decreases as the evolutionary time since duplication extends. Our results suggest that the accumulation of recent duplications in late-replicating CNV regions is an active process influencing genome evolution.
    Biology Open 11/2013; 2(12). DOI:10.1242/bio.20136924 · 2.42 Impact Factor
Show more