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

Mutation is associated with developmental and hereditary disorders, ageing and cancer. While we understand some mutational processes operative in human disease, most remain mysterious. We used C. elegans whole genome sequencing to model mutational signatures, analysing 183 worm populations across 17 DNA repairdeficient backgrounds, propagated for 20 generations or exposed to carcinogens. The baseline mutation rate in C. elegans was ~1/genome/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. AflatoxinB1 induced substitutions of guanines in GpC context, as observed in aflatoxininduced liver cancers. Mutational burden increased with impaired nucleotide excision repair. Cisplatin and mechlorethamine, DNA crosslinking agents, caused doseand 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 interstrand crosslinks may play a pathogenic role in such events. Cisplatin mutagenicity was most pronounced in xpf-1 mutants, suggesting this gene critically protects cells against platinum chemotherapy. Thus, experimental model systems combined with genome sequencing can recapture and mechanistically explain mutational signatures associated with human disease. Cold Spring Harbor Laboratory Press on August 20, 2014 Published by genome.cshlp.org Downloaded from