ArticleProceedings of the National Academy of Sciences of the United States of America2017
Human genetic variation alters CRISPR-Cas9 on- and off-targeting specificity at therapeutically implicated loci.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
67 citing papers in PubMed.
- EXCAVATE-HT: A Bioinformatic Pipeline to Identify Targetable Genomic Variants for Allele-Specific Editing.bioRxiv : the preprint server for biology · 2026Article
- CRISPR-HAWK: Haplotype- and Variant-aware guide design toolkit for CRISPR-Cas.bioRxiv : the preprint server for biology · 2025Article
- Off-target effects in CRISPR-Cas genome editing for human therapeutics: Progress and challenges.Molecular therapy. Nucleic acids · 2025Review
- Establishment of a reverse genetics system for studying human immune functions in mice.Science advances · 2025Article
- Variant-aware Cas-OFFinder: web-based in silico variant-aware potential off-target site identification for genome editing applications.Nucleic acids research · 2025Article
- Enhancing Specificity, Precision, Accessibility, Flexibility, and Safety to Overcome Traditional CRISPR/Cas Editing Challenges and Shape Future Innovations.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- The dawn of a cure for sickle cell disease through CRISPR-based treatment: A critical test of equity in public health genomics.Annals of human genetics · 2025Review
- Linking CRISPR-Cas9 double-strand break profiles to gene editing precision with BreakTag.Nature biotechnology · 2025Article
- CRISPR: fundamental principles and implications for anaesthesia.British journal of anaesthesia · 2025Review
- A bioinformatic analysis of gene editing off-target loci altered by common polymorphisms, using 'PopOff'.Journal of the Royal Society of New Zealand · 2025Article
- Arrayed CRISPR libraries for the genome-wide activation, deletion and silencing of human protein-coding genes.Nature biomedical engineering · 2025Article
- DNA-PK inhibition enhances gene editing efficiency in HSPCs for CRISPR-based treatment of X-linked hyper IgM syndrome.Molecular therapy. Methods & clinical development · 2024Article
- Quantifying allele-specific CRISPR editing activity with CRISPECTOR2.0.Nucleic acids research · 2024Article
- Germline variation contributes to false negatives in CRISPR-based experiments with varying burden across ancestries.Nature communications · 2024Article
- Selection of extended CRISPR RNAs with enhanced targeting and specificity.Communications biology · 2024Article
- Making gene editing accessible in resource limited environments: recommendations to guide a first-time user.Frontiers in genome editing · 2024Review
- From GWAS to signal validation: An approach for estimating genetic effects while preserving genomic context.bioRxiv : the preprint server for biology · 2023Article
- Multimodal CRISPR perturbations of GWAS loci associated with coronary artery disease in vascular endothelial cells.PLoS genetics · 2023Article
- Towards the Clinical Application of Gene Therapy for Genetic Inner Ear Diseases.Journal of clinical medicine · 2023Review
- Human genetic diversity alters off-target outcomes of therapeutic gene editing.Nature genetics · 2023Article
7 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors.
Funding
Abstract
The CRISPR-Cas9 nuclease system holds enormous potential for therapeutic genome editing of a wide spectrum of diseases. Large efforts have been made to further understanding of on- and off-target activity to assist the design of CRISPR-based therapies with optimized efficacy and safety. However, current efforts have largely focused on the reference genome or the genome of cell lines to evaluate guide RNA (gRNA) efficiency, safety, and toxicity. Here, we examine the effect of human genetic variation on both on- and off-target specificity. Specifically, we utilize 7,444 whole-genome sequences to examine the effect of variants on the targeting specificity of ∼3,000 gRNAs across 30 therapeutically implicated loci. We demonstrate that human genetic variation can alter the off-target landscape genome-wide including creating and destroying protospacer adjacent motifs (PAMs). Furthermore, single-nucleotide polymorphisms (SNPs) and insertions/deletions (indels) can result in altered on-target sites and novel potent off-target sites, which can predispose patients to treatment failure and adverse effects, respectively; however, these events are rare. Taken together, these data highlight the importance of considering individual genomes for therapeutic genome-editing applications for the design and evaluation of CRISPR-based therapies to minimize risk of treatment failure and/or adverse outcomes.
Indexed as
Identifiers
What OpenQuestion holds
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 OpenQuestion graph.