Human mutation rate associated with DNA replication timing

Abstract

Eukaryotic DNA replication is highly stratified, with different genomic regions shown to replicate at characteristic times during S phase. Here we observe that mutation rate, as reflected in recent evolutionary divergence and human nucleotide diversity, is markedly increased in later-replicating regions of the human genome. All classes of substitutions are affected, suggesting a generalized mechanism involving replication time-dependent DNA damage. This correlation between mutation rate and regionally stratified replication timing may have substantial evolutionary implications.Evolutionary divergence and inferred mutation rates are known to vary across the human genome [1][2][3] , and it has long been speculated that this is a consequence of covariance with an epigenetic feature1 , 2. In human cells, the time of DNA replication exhibits marked regional variability during an S-phase lasting approximately 10-hours4 ,5 . To parallel the conventional division of S-phase into four sequential temporal states (S1-S4), we used a hidden Markov model6 to perform unbiased four-state partitioning of continuous, highresolution replication timing measurements across 1% of the human genome7. We then determined human-chimpanzee nucleotide divergence rates and the density of SNPs8 at putatively neutrally evolving sites within each temporal state, excluding any bases within annotated exons, repetitive elements, CpG islands, 2kb-regions upstream and downstream of genes, intronic splice sites, and conserved non-coding sequences9 (Supplementary Table S1).We observed a striking trend relating the rate of evolutionary divergence and the density of human SNPs to the progress of DNA replication (Fig. 1). Human-chimpanzee substitutions and human SNP density increase 22% and 53%, respectively, during the temporal course of replication, both of which are highly statistically significant (p < 8.43 × 10 −26 , CochranArmitage; Fig. 1a-c, g-i). To rule out potential confounding by the overall low genomewide rate of human-chimpanzee divergence, we also analyzed human-macaque divergence, with similar results (p < 2.7 × 10 −54 ; Fig. 1d-f). We confirmed the absence of bias due to a sampling or stratification effect across different genomic regions by testing (CochranMantel-Haenszel) for three-way interactions, treating region assignment as controlling variable (p < 7.2 × 10 −12 , p < 0.00026 for human-chimpanzee divergence and human SNPs, NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript respectively). Additionally, we repeated all analyses with an independent set of randomly ascertained SNPs 10 , with nearly identical effect (p < 9.69 × 10 −22 ).Next we examined whether the observed correlation between mutation rate and replication time could be explained by variation in another genomic feature for which replication timing might be acting as a surrogate. Regional variation in G+C content 2,3 and, independently, recombination rate2 , 3 have been invoked as potential causes of human mutation rate variation. We the...

DNA replication timing and selection shape the landscape of nucleotide variation in cancer genomes

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Chk1–cyclin A/Cdk1 axis regulates origin firing programs in mammals

“…Very recently, an interesting observation has been made that the mutation rate, as reflected in recent evolutionary divergence and human nucleotide diversity, is markedly increased in late replicating regions of the human genome (Stamatoyannopoulos et al 2009). Given that all classes of substitutions are affected by replication timing, an increased mutation rate appears to result from replication time-dependent DNA damage.…”

Conservation of replication timing reveals global and local regulation of replication origin activity

“…The late replication of telomeres may be involved in feedback control of telomere length (Bianchi and Shore 2007), and the early replication of centromeres may be important for proper chromosome segregation (Feng et al 2009). Furthermore, the elevated mutation rates observed in late replicating regions might exert a selective pressure for particular regions to replicate at specific times (Stamatoyannopoulos et al 2009;Chen et al 2010;Lang and Murray 2011;Agier and Fischer 2012;Marsolier-Kergoat and Goldar 2012). However, it remains unclear why particular chromosomal zones replicate at particular times during S phase.…”