Genetic variation and DNA replication timing, or why is there late replicating DNA?

Mutation rates vary significantly within the genome and across species. Recent studies revealed a long suspected replication-timing effect on mutation rate, but the mechanisms that regulate the increase in mutation rate as the genome is replicated remain unclear. Evidence is emerging, however, that DNA repair systems, in general, are less efficient in late replicating heterochromatic regions compared to early replicating euchromatic regions of the genome. At the same time, mutation rates in both vertebrates and invertebrates have been shown to vary with generation time (GT). GT is correlated with genome size, which suggests a possible nucleotypic effect on species-specific mutation rates. These and other observations all converge on a role for DNA replication checkpoints in modulating generation times and mutation rates during the DNA synthetic phase (S phase) of the cell cycle. The following will examine the potential role of the intra-S checkpoint in regulating cell cycle times (GT) and mutation rates in eukaryotes. This article was published online on August 5, 2011. An error was subsequently identified. This notice is included in the online and print versions to indicate that both have been corrected October 4, 2011.