XXXX whole-genome sequencing reveals mutational signatures related to carcinogens and DNA repair deficiency.

@entity1 @entity2199 @entity96 @entity5 @entity900 @entity377 @entity74 @entity4078 @entity11189 @entity3700 @entity902
Mutation is associated with developmental and @entity74 , aging, and @entity5 . While we understand some mutational processes operative in @entity1 disease, most remain mysterious. We used @entity2199 whole-genome sequencing to model mutational signatures, analyzing 183 worm populations across 17 DNA repair-deficient backgrounds propagated for 20 generations or exposed to carcinogens. The baseline mutation rate in @entity2199 was approximately one per genome per generation, not overtly altered across several DNA repair deficiencies over 20 generations. Telomere erosion led to complex chromosomal rearrangements initiated by breakage-fusion-bridge cycles and completed by simultaneously acquired, localized clusters of breakpoints. @entity4078 induced substitutions of guanines in a GpC context, as observed in @entity11189 -induced @entity96 . Mutational burden increased with impaired @entity377 excision repair. @entity900 and @entity3700 , DNA crosslinking agents, caused dose- and genotype-dependent signatures among indels, substitutions, and rearrangements. Strikingly, both agents induced clustered rearrangements resembling "chromoanasynthesis," a replication-based mutational signature seen in constitutional genomic disorders, suggesting that interstrand crosslinks may play a pathogenic role in such events. @entity900 mutagenicity was most pronounced in xpf-1 mutants, suggesting that this gene critically protects cells against @entity902 chemotherapy. Thus, experimental model systems combined with genome sequencing can recapture and mechanistically explain mutational signatures associated with @entity1 disease.
