Abstract
The MutaMouse transgenic rodent model is widely used for assessing in vivo mutagenicity. Here, we report the characterization of MutaMouse’s whole genome sequence and its genetic variants compared to the C57BL/6 reference genome. High coverage (>50X) next-generation sequencing (NGS) of whole genomes from multiple MutaMouse animals from the Health Canada (HC) colony showed ~5 million SNVs per genome, ~20% of which are putatively novel. Sequencing of two animals from a geographically separated colony at Covance indicated that, over the course of 23 years, each colony accumulated 47,847 (HC) and 17,677 (Covance) non-parental homozygous single nucleotide variants. We found no novel nonsense or missense mutations that impair the MutaMouse response to genotoxic agents. Pairing sequencing data with array comparative genomic hybridization (aCGH) improved the accuracy and resolution of copy number variants (CNVs) calls and identified 300 genomic regions with CNVs. We also used long-read sequence technology (PacBio) to show that the transgene integration site involved a large deletion event with multiple inversions and rearrangements near a retrotransposon. The MutaMouse genome gives important genetic context to studies using this model, offers insight on the mechanisms of structural variant formation, and contributes a framework to analyze aCGH results alongside NGS data.
Highlights
The MutaMouse transgenic rodent model is widely used for assessing in vivo mutagenicity
Seven MutaMouse animals, including five males obtained from a breeding colony maintained at Health Canada (HC) in Ottawa, Canada, and one male and one female obtained from a breeding colony at Covance, UK, were sequenced in this study
We generated the whole genome sequence of the MutaMouse model and characterized variants in multiple individuals from two geographically isolated colonies using a high sequence depth combined with array comparative genomic hybridization (aCGH)
Summary
The MutaMouse transgenic rodent model is widely used for assessing in vivo mutagenicity. Beginning in the late 1980s, transgenic rodent (TGR) mutation reporter models[3] provided an unprecedented tool for quantifying mutations in mammalian cells. Since this time, TGR models have become the basis of in vivo mutagenicity assessment, and the use of TGR models to evaluate the safety of chemicals is described in the Organisation for Economic Co-operation and Development test guideline 4884. Given the importance of mutagenicity assessment and the prevalent use of the MutaMouse in such evaluations, the availability of a MutaMouse reference genome can provide a deeper understanding of its genetic traits that may be relevant to mutagenicity, chemical metabolism, and toxicology in general. Annotated and characterized genomes of TGR models can improve the utility of these strains for genetic toxicology research by increasing the understanding of the potential biological consequences of genetic variants, and facilitating integration with modern genomic methods
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