Abstract
Understanding the effects of environmental exposures on germline mutation rates has been a decades-long pursuit in genetics. We used next-generation sequencing and comparative genomic hybridization arrays to investigate genome-wide mutations in the offspring of male mice exposed to benzo(a)pyrene (BaP), a common environmental pollutant. We demonstrate that offspring developing from sperm exposed during the mitotic or post-mitotic phases of spermatogenesis have significantly more de novo single nucleotide variants (1.8-fold; P < 0.01) than controls. Both phases of spermatogenesis are susceptible to the induction of heritable mutations, although mutations arising from post-fertilization events are more common after post-mitotic exposure. In addition, the mutation spectra in sperm and offspring of BaP-exposed males are consistent. Finally, we report a significant increase in transmitted copy number duplications (P = 0.001) in BaP-exposed sires. Our study demonstrates that germ cell mutagen exposures induce genome-wide mutations in the offspring that may be associated with adverse health outcomes.
Highlights
Understanding the effects of environmental exposures on germline mutation rates has been a decades-long pursuit in genetics
The two mating points were selected to investigate the induction of mutations during phases of spermatogenesis that differ in DNA repair activity
We found that de novo mutations are elevated in the descendants of BaP-exposed males, consistent with increases in sperm mutation frequencies
Summary
Understanding the effects of environmental exposures on germline mutation rates has been a decades-long pursuit in genetics. Next-generation sequencing (NGS) and comparative genomic hybridization arrays (aCGH), have allowed de novo mutation rates, and spectra to be studied at the genome-wide level[3,4]. More recent evidence suggests that maternal age[7] and dioxin[8] increase the mutational burden in humans These findings emphasize the need to identify both the endogenous and exogenous factors that may be contributing to human germ cell mutagenesis and genetic diseases. Adewoye et al.[11] demonstrated using aCGH and NGS that paternal radiation exposure induces large deletions and clustered mutations (multisite mutations) in the genomes of their offspring This provided proof of principle that whole-genome approaches can be used to investigate the role of environmental exposures in inducing de novo genome-wide mutations through the germline
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