title: C. elegans whole-genome sequencing reveals mutational signatures related to carcinogens and DNA repair deficiency.
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 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. Aflatoxin B1 induced substitutions of guanines in a 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 that interstrand crosslinks may play a pathogenic role in such events. Cisplatin mutagenicity was most pronounced in xpf-1 mutants, suggesting that 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.
authors.affiliation: Centre for Gene Regulation and Expression, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom;
authors.forename: Bettina
authors.initials: B
authors.lastname: Meier
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, United Kingdom;
authors.forename: Susanna L
authors.initials: SL
authors.lastname: Cooke
authors.affiliation: Centre for Gene Regulation and Expression, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom;
authors.forename: Joerg
authors.initials: J
authors.lastname: Weiss
authors.affiliation: Centre for Gene Regulation and Expression, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom; CRBM/CNRS UMR5237, University of Montpellier, Montpellier 34293, France;
authors.forename: Aymeric P
authors.initials: AP
authors.lastname: Bailly
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, United Kingdom;
authors.forename: Ludmil B
authors.initials: LB
authors.lastname: Alexandrov
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, United Kingdom;
authors.forename: John
authors.initials: J
authors.lastname: Marshall
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, United Kingdom;
authors.forename: Keiran
authors.initials: K
authors.lastname: Raine
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, United Kingdom;
authors.forename: Mark
authors.initials: M
authors.lastname: Maddison
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, United Kingdom;
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Anderson
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, United Kingdom;
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.affiliation: Centre for Gene Regulation and Expression, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom; pc8@sanger.ac.uk a.gartner@dundee.ac.uk.
authors.forename: Anton
authors.initials: A
authors.lastname: Gartner
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, United Kingdom; Department of Haematology, University of Cambridge, Cambridge CB2 0XY, United Kingdom; Department of Haematology, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D002273:Carcinogens / Q000494:pharmacology*; D004265:DNA Helicases / Q000235:genetics; D004260:DNA Repair; D016678:Genome; D023421:Models, Animal; D009154:Mutation; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: D029742:Caenorhabditis elegans Proteins; D002273:Carcinogens; C403443:MRT-2 protein, C elegans; C547402:XPF-1 protein, C elegans; D004265:DNA Helicases