DNA replication timing and higher-ordernuclear organization determine single-nucleotidesubstitution patterns in cancer genomes

摘要

Single-nucleotide substitutions are a defining characteristic of cancer genomes. Many singlenucleotidesubstitutions in cancer genomes arise because of errors in DNA replication, whichis spatio-temporally stratified. Here we propose that DNA replication patterns help shape themutational landscapes of normal and cancer genomes. Using data on five fully sequencedcancer types and two personal genomes, we determined that the frequency of intergenicsingle-nucleotide substitution is significantly higher in late DNA replication timing regions,even after controlling for a number of genomic features. Furthermore, some substitutionsignatures are more frequent in certain DNA replication timing zones. Finally, integrating dataon higher-order nuclear organization, we found that genomic regions in close spatial proximityto late-replicating domains display similar mutation spectra as the late-replicatingregions themselves. These data suggest that DNA replication timing together with higherordergenomic organization contribute to the patterns of single-nucleotide substitutionin normal and cancer genomes.