Duplex sequencing identifies genomic features that determine susceptibility to benzo(a)pyrene-induced in vivo mutations

• Published in: BMC genomics Vol. 23; no. 1; pp. 542 - 15
• Main Authors: LeBlanc, Danielle P. M., Meier, Matthew, Lo, Fang Yin, Schmidt, Elizabeth, Valentine, Charles, Williams, Andrew, Salk, Jesse J., Yauk, Carole L., Marchetti, Francesco
• Format: Journal Article
• Language: English
• Published: England BioMed Central 28.07.2022; BMC
• Subjects: Animals; Benzo(a)pyrene; Benzo(a)pyrene - toxicity; Bioinformatics; Bone marrow; Cancer; Decision making; Error correction; Error-corrected sequencing; Etiology; Exposure; Genes; Genetic disorders; Genetic toxicology; Genomes; Genomics; Health risks; In vivo methods and tests; Male; Mice; Mutagenesis; Mutagens; MutaMouse; Mutation; Mutation spectrum; Mutation susceptibility; Point mutation; Pollutants; Pyrene; Technology assessment; Trinucleotide mutation signature; United States > US; Error-corrected sequencing; Mutation spectrum; Genetic toxicology; MutaMouse; Benzo(a)pyrene; Mutation susceptibility; Trinucleotide mutation signature
• ISSN: 1471-2164; 1471-2164
• DOI: 10.1186/s12864-022-08752-w

Exposure to environmental mutagens increases the risk of cancer and genetic disorders. We used Duplex Sequencing (DS), a high-accuracy error-corrected sequencing technology, to analyze mutation induction across twenty 2.4 kb intergenic and genic targets in the bone marrow of MutaMouse males exposed to benzo(a)pyrene (BaP), a widespread environmental pollutant. DS revealed a linear dose-related induction of mutations across all targets with low intra-group variability. Heterochromatic and intergenic regions exhibited the highest mutation frequencies (MF). C:G > A:T transversions at CCA, CCC and GCC trinucleotides were enriched in BaP-exposed mice consistent with the known etiology of BaP mutagenesis. However, GC-content had no effect on mutation susceptibility. A positive correlation was observed between DS and the “gold-standard” transgenic rodent gene mutation assay. Overall, we demonstrate that DS is a promising approach to study in vivo mutagenesis and yields critical insight into the genomic features governing mutation susceptibility, spectrum, and variability across the genome.