Researchers Quantify Cas9-Caused Off-Target Mutagenesis in Mice; Thoughtful Design of Guide RNAs Can Significantly Limit Off-Target Mutagenesis; Inbred Lines Show Surprising Number of Natural Mutations

Scientists are finding new ways to improve the use of the CRISPR enzyme Cas9 and reduce the chances of off-target mutations in laboratory mice, according to new results from a research collaboration including Lauryl Nutter (photo), PhD, Senior Director, Science and Technology Development at The Centre for Phenogenomics at The Hospital for Sick Children (SickKids) in Toronto, Canada The findings, which help scientists contextualize a common concern related to gene editing and identify new strategies to improve its precision, were presented on October 18, 2019 as a featured plenary abstract at the American Society of Human Genetics (ASHG) 2019 Annual Meeting in Houston (October 15-19). The presentation abstract ( is titled “Whole Genome Sequencing Puts Cas9 Off-Target Mutagenesis into the Context Of Genetic Drift.” Dr. Nutter and her collaborators from the multi-institution Knockout Mouse Phenotyping Project (KOMP2) regularly use Cas9 and gene editing to produce lines of laboratory mice with specific mutations. In this work, they often encounter questions about the likelihood of off-target mutagenesis – unintended genetic mutations introduced by the gene-editing process – in their mouse lines. “We wanted to know: to what extent do we need to worry about off-target mutagenesis?” Dr. Nutter explained. By demonstrating the degree of the problem in mice, the researchers hoped to be better able to evaluate it in human cell lines being studied in the laboratory, as well as generate new ways to improve the precision of Cas9-based gene editing.
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