Whole Genome Sequencing of the Mutamouse Model Reveals Strain- and Colony-Level Variation, and Genomic Features of the Transgene Integration Site

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.

Chemically induced mutations in a MutaMouse reporter gene inform mechanisms underlying human cancer mutational signatures

“…Studies of over 200 chemicals, including more than 90 carcinogens, have demonstrated that TGR models offer high sensitivity and specificity for identifying mutagenic carcinogens 1,2 . One of the most commonly used TGR models is the MutaMouse whose genome was recently sequenced 3 . The MutaMouse harbors~29 copies of the bacterial lacZ transgene on each copy of chromosome 3 4 .…”