ArticleNature communications2022
Systematic decomposition of sequence determinants governing CRISPR/Cas9 specificity.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed.
- Article
- Mesoscopic Calculation of Single Mismatches in RNA/DNA Hybrids: Strong Hydrogen Bonds of dTrG Affect CRISPR Off-Target Binding.The journal of physical chemistry. B · 2026Article
- High-throughput evaluation of in vitro CRISPR activities enables optimized large-scale multiplex enrichment of rare variants.Nature biomedical engineering · 2026Article
- Deep learning-driven prediction of on-target activity, off-target risk, and repair outcomes in CRISPR/Cas9: current landscape and multi-scale perspectives.Journal of translational medicine · 2026Review
- Targeting redundant gene families: A multiplexed, tissue-specific CRISPR toolbox for Arabidopsis genetic screens.Cell reports · 2026Article
- CrisprPr: a hybrid-driven framework for CRISPR/Cas9 off-target prediction with analysis of prior-information updates.Briefings in bioinformatics · 2026Article
- ARROW: Allele-Specific Recombined gRNA Design for Reduced Off-Target with Enhanced Specificity.Bioengineering (Basel, Switzerland) · 2025Article
- RNA Polymerase III Promoters Compatible with CRISPR Gene Regulation inACS synthetic biology · 2025Article
- Off-target interactions in the CRISPR-Cas9 Machinery: mechanisms and outcomes.Biochemistry and biophysics reports · 2025Review
- A versatile CRISPR/Cas9 system off-target prediction tool using language model.Communications biology · 2025Article
- Construction of multi-targeted CRISPR libraries in tomato to overcome functional redundancy at genome-scale level.Nature communications · 2025Article
- The Evolution of Nucleic Acid-Based Diagnosis Methods from the (pre-)CRISPR to CRISPR era and the Associated Machine/Deep Learning Approaches in Relevant RNA Design.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Article
- Single-base tiled screen unveils design principles of PspCas13b for potent and off-target-free RNA silencing.Nature structural & molecular biology · 2024Article
- Learning to quantify uncertainty in off-target activity for CRISPR guide RNAs.Nucleic acids research · 2024Article
- Generating, modeling and evaluating a large-scale set of CRISPR/Cas9 off-target sites with bulges.Nucleic acids research · 2024Article
- Sensing the DNA-mismatch tolerance of catalytically inactive Cas9 via barcoded DNA nanostructures in solid-state nanopores.Nature biomedical engineering · 2024Article
- Emerging Gene Therapeutics for Epidermolysis Bullosa under Development.International journal of molecular sciences · 2024Review
- Genome-wide CRISPR off-target prediction and optimization using RNA-DNA interaction fingerprints.Nature communications · 2023Article
- Guide-specific loss of efficiency and off-target reduction with Cas9 variants.Nucleic acids research · 2023Article
Corrections and comments
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Authors and funding
14 authors.
Funding
Abstract
The specificity of CRISPR/Cas9 genome editing is largely determined by the sequences of guide RNA (gRNA) and the targeted DNA, yet the sequence-dependent rules underlying off-target effects are not fully understood. To systematically explore the sequence determinants governing CRISPR/Cas9 specificity, here we describe a dual-target system to measure the relative cleavage rate between off- and on-target sequences (off-on ratios) of 1902 gRNAs on 13,314 synthetic target sequences, and reveal a set of sequence rules involving 2 factors in off-targeting: 1) a guide-intrinsic mismatch tolerance (GMT) independent of the mismatch context; 2) an "epistasis-like" combinatorial effect of multiple mismatches, which are associated with the free-energy landscape in R-loop formation and are explainable by a multi-state kinetic model. These sequence rules lead to the development of MOFF, a model-based predictor of Cas9-mediated off-target effects. Moreover, the "epistasis-like" combinatorial effect suggests a strategy of allele-specific genome editing using mismatched guides. With the aid of MOFF prediction, this strategy significantly improves the selectivity and expands the application domain of Cas9-based allele-specific editing, as tested in a high-throughput allele-editing screen on 18 cancer hotspot mutations.
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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 OpenQuestion graph.