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.