Differential and sex-specific relationship of DNA replication timing to different forms of human mutation and variation

Understanding the factors that affect the generation of mutations is important in medical, cancer and evolutionary genetics. DNA replication timing is known to affect the distribution of mutations across the human genome. We generated a high resolution map of the human genome’s replication timing program and analyzed its relationship to different forms of human mutation and genome variation. We show that the replication program profoundly shapes the distribution of substitution mutations, with a stronger influence on transversion relative to transition mutations. In addition, we find distinct relationships between replication timing and different kinds of structural mutations: mutations mediated by non-allelic homologous recombination are enriched in the early replicating parts of the genome, while structural mutations arising from other mechanisms are enriched in late replicating regions. An early-replication bias is also observed for meiotic recombination hotspots. Both recombination and structural mutations show gender differences in their relationships to DNA replication timing, with a stronger early-replication bias observed in females. Together, our results indicate a differential and sex-specific relationship of DNA replication timing to the distribution of different forms of mutation and variation across the human genome.