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

Bettina Meier, Susanna L. Cooke, Joerg Weiss, Aymeric P. Bailly, Ludmil B. Alexandrov, John Marshall, Keiran Raine, Mark Maddison, Elizabeth Anderson, Michael R. Stratton, Anton Gartner (Lead / Corresponding author), Peter J. Campbell (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    87 Citations (Scopus)

    Abstract

    Mutation is associated with developmental and hereditary disorders, aging and cancer. While we understand some mutational processes operative in human disease, most remain mysterious. We used Caenorhabditis elegans 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 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 aflatoxin-induced liver cancers. Mutational burden increased with impaired nucleotide excision repair. Cisplatin and mechlorethamine, 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 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.

    Original languageEnglish
    Pages (from-to)1624-1636
    Number of pages14
    JournalGenome Research
    Volume24
    Early online date16 Jul 2014
    DOIs
    Publication statusPublished - Oct 2014

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