Genes adapt to outsmart gene-targeting strategies in mutant mouse strains by skipping exons to reinitiate transcription and translation

Gene disruption in mouse embryonic stem cells or zygotes is a conventional genetics approach to identify gene function in vivo. However, because different gene disruption strategies use different mechanisms to disrupt genes, the strategies can result in diverse phenotypes in the resulting mouse mode...

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Bibliographic Details
Published in:Genome Biology 2020-07, Vol.21 (1), p.168-168, Article 168
Main Authors: Hosur, Vishnu, Low, Benjamin E, Li, Daniel, Stafford, Grace A, Kohar, Vivek, Shultz, Leonard D, Wiles, Michael V
Format: Article
Language:English
Subjects:
Adaptation, Biological
Alleles
Animals
Artificial chromosomes
Brain
Cloning
CRISPR
CRISPR-Cas Systems
CRISPR/Cas9
Definitive-null
Embryo cells
Exon skipping
Exons
Female
Gene disruption
Gene editing
Gene Expression
Gene Targeting - methods
Genes
Genome editing
Genomes
Genotype & phenotype
Heart
Knockout-first
Male
Membrane Proteins - genetics
Mice
Mice, Knockout
Mutants
Mutation
Phenotype
Phenotypes
Pregnancy
Proteins
Rodents
Stem cell transplantation
Stem cells
Transcription
Translation
Zygotes
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Summary:Gene disruption in mouse embryonic stem cells or zygotes is a conventional genetics approach to identify gene function in vivo. However, because different gene disruption strategies use different mechanisms to disrupt genes, the strategies can result in diverse phenotypes in the resulting mouse model. To determine whether different gene disruption strategies affect the phenotype of resulting mutant mice, we characterized Rhbdf1 mouse mutant strains generated by three commonly used strategies-definitive-null, targeted knockout (KO)-first, and CRISPR/Cas9. We find that Rhbdf1 responds differently to distinct KO strategies, for example, by skipping exons and reinitiating translation to potentially yield gain-of-function alleles rather than the expected null or severe hypomorphic alleles. Our analysis also revealed that at least 4% of mice generated using the KO-first strategy show conflicting phenotypes. Exon skipping is a widespread phenomenon occurring across the genome. These findings have significant implications for the application of genome editing in both basic research and clinical practice.
ISSN:1474-760X
1474-7596
1474-760X
DOI:10.1186/s13059-020-02086-0