A large CRISPR-induced bystander mutation causes immune dysregulation

Communications Biology
Dimitre R SimeonovAlexander Marson

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.

References

Mar 20, 2008·Genome Research·Daniel R Zerbino, Ewan Birney
Jan 5, 2013·Science·Le CongFeng Zhang
Mar 4, 2014·Nature Biotechnology·Jeffry D Sander, J Keith Joung
Dec 3, 2015·Science·Ian M SlaymakerFeng Zhang
Jan 19, 2016·Nature Biotechnology·John G DoenchDavid E Root
Aug 31, 2017·Nature·Dimitre R SimeonovAlexander Marson
Oct 11, 2017·Scientific Reports·Katharina BoroviakAllan Bradley
Oct 21, 2017·Cell·Boyan BonevGiacomo Cavalli

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Citations

May 23, 2019·Human Genetics·Minyoung Lee, Hyongbum Kim
Oct 12, 2020·Trends in Genetics : TIG·Gaëtan Burgio, Lydia Teboul
Nov 26, 2020·Molecular Therapy : the Journal of the American Society of Gene Therapy·Garima SharmaChiranjib Chakraborty
Jun 7, 2020·Molecular Therapy : the Journal of the American Society of Gene Therapy·Diana SchenkweinSeppo Ylä-Herttuala
Aug 19, 2021·American Journal of Medical Genetics. Part a·James R Lupski
Aug 16, 2021·Molecular Genetics and Metabolism·Guillermo Aquino-Jarquin

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Methods Mentioned

BETA
PCR
RNA-seq
genotyping
electrophoresis
fluorescence-activated cell sorting
flow cytometry
DNA

Software Mentioned

fastq
BioRender
Protospacer
Bioconductor Package for R
STAR
Velvet
Picard Software Suite
GATK
EdgeR

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