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

Meier, B. et al. (2014) C. elegans whole-genome sequencing reveals mutational signatures related to carcinogens and DNA repair deficiency. Genome Research, 24(10), pp. 1624-1636. (doi: 10.1101/gr.175547.114) (PMID:25030888) (PMCID:PMC4199376)

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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.

Item Type:Articles
Additional Information:This work was supported by the Wellcome Trust (grant reference 077012/Z/05/Z). P.J.C. and A.G. are personally funded through Wellcome Trust Senior Clinical Research Fellowships and Senior Basic Research Fellowships, respectively, and are members of the Wellcome funded COMSIG consortium.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cooke, Dr Susie
Authors: Meier, B., Cooke, S. L., Weiss, J., Bailly, A. P., Alexandrov, L. B., Marshall, J., Raine, K., Maddison, M., Anderson, E., Stratton, M. R., Gartner, A., and Campbell, P. J.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Genome Research
Publisher:Cold Spring Harbor Laboratory Press
ISSN:1088-9051
ISSN (Online):1549-5469
Published Online:16 July 2014
Copyright Holders:Copyright © 2014 Meier et al.
First Published:First published in Genome Research 24(10):1624-1636
Publisher Policy:Reproduced under a Creative Commons License

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