ArticleNucleic acids research2025
Optimizing gRNA selection for high-penetrance F0 CRISPR screening for interrogating disease gene function.
Article in Nucleic acids research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Cell death analysis of inducible, titratable neurodegenerative disease models in zebrafish and human stem cell-derived retinal organoids.Disease models & mechanisms · 2026Article
- Cross-trait clustering of sub-threshold sleep genetic signals identifies EGR2 as a conserved regulator of sleep.bioRxiv : the preprint server for biology · 2026Article
- Overlapping expression and co-operative function of the zebrafish pcdh15 paralogs.Communications biology · 2026Article
- Unprocessed U1 snRNAs as a biomarker of INTS11- and BRAT1-related neurodevelopmental disorders.Genome medicine · 2026Article
- Bi-allelic ATG12 variants impair autophagy and cause a neurodevelopmental disorder.American journal of human genetics · 2026Article
- Two distinct modes of Vgll4-mediated Tead regulation control organ size in zebrafish.Communications biology · 2026Article
- Uncovering dual molecular diagnoses in families with complex phenotypes through structural and clinical studies of novel COL4A6 variants.QJM : monthly journal of the Association of Physicians · 2026Observational
- Targeted blocking of gene splicing can dysregulate intron-embedded primary microRNAs.Communications biology · 2026Article
- High-efficiency TadA cytosine base editors for precise modelling of human disease variants.Nature biomedical engineering · 2026Article
- Rationally Designed TadA-Derived Cytosine Editors Enable Context-Independent Zebrafish Genome Editing.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- CRISPR-based functional genomics tools in vertebrate models.Experimental & molecular medicine · 2025Review
- AFrontiers in genetics · 2025Article
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Authors and funding
6 authors.
Funding
Abstract
Genes and genetic variants associated with human disease are continually being discovered, but validating their causative roles and mechanisms remains a significant challenge. CRISPR/Cas9 genome editing in model organisms like zebrafish can enable phenotypic characterization of founder generation (F0) knockouts (Crispants), but existing approaches are not amenable to high-throughput genetic screening due to high variability, cost, and low phenotype penetrance. To overcome these challenges, here we provide guide RNA (gRNA) selection rules that enable high phenotypic penetrance of up to three simultaneous knockouts in F0 animals following injection of 1-2 gRNAs per gene. We demonstrate a strong transcriptomic overlap in our F0 knockouts and stable knockout lines that take several months to generate. We systematically evaluated this approach across 324 gRNAs targeting 125 genes and demonstrated its utility in studying epistasis, characterizing paralogous genes, and validating human disease gene phenotypes across multiple tissues. Applying our approach in a high-throughput manner, we screened and identified 10 novel neurodevelopmental disorders and 50 hearing genes not previously studied in zebrafish. Altogether, our approach achieves high phenotypic penetrance using low numbers of gRNAs per gene in F0 zebrafish, offering a robust pipeline for rapidly characterizing candidate human disease genes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.