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A large CRISPR-induced bystander mutation causes immune dysregulation.

ABSTRACT: A persistent concern with CRISPR-Cas9 gene editing has been the potential to generate mutations at off-target genomic sites. While CRISPR-engineering mice to delete a ~360?bp intronic enhancer, here we discovered a founder line that had marked immune dysregulation caused by a 24?kb tandem duplication of the sequence adjacent to the on-target deletion. Our results suggest unintended repair of on-target genomic cuts can cause pathogenic "bystander" mutations that escape detection by routine targeted genotyping assays.

SUBMITTER: Simeonov DR 

PROVIDER: S-EPMC6379443 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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A persistent concern with CRISPR-Cas9 gene editing has been the potential to generate mutations at off-target genomic sites. While CRISPR-engineering mice to delete a ~360 bp intronic enhancer, here we discovered a founder line that had marked immune dysregulation caused by a 24 kb tandem duplication of the sequence adjacent to the on-target deletion. Our results suggest unintended repair of on-target genomic cuts can cause pathogenic "bystander" mutations that escape detection by routine target  ...[more]

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