High-fidelity CRISPR–Cas9 nucleases with no detectable genome-wide off-target effects View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-01

AUTHORS

Benjamin P. Kleinstiver, Vikram Pattanayak, Michelle S. Prew, Shengdar Q. Tsai, Nhu T. Nguyen, Zongli Zheng, J. Keith Joung

ABSTRACT

CRISPR-Cas9 nucleases are widely used for genome editing but can induce unwanted off-target mutations. Existing strategies for reducing genome-wide off-target effects of the widely used Streptococcus pyogenes Cas9 (SpCas9) are imperfect, possessing only partial or unproven efficacies and other limitations that constrain their use. Here we describe SpCas9-HF1, a high-fidelity variant harbouring alterations designed to reduce non-specific DNA contacts. SpCas9-HF1 retains on-target activities comparable to wild-type SpCas9 with >85% of single-guide RNAs (sgRNAs) tested in human cells. Notably, with sgRNAs targeted to standard non-repetitive sequences, SpCas9-HF1 rendered all or nearly all off-target events undetectable by genome-wide break capture and targeted sequencing methods. Even for atypical, repetitive target sites, the vast majority of off-target mutations induced by wild-type SpCas9 were not detected with SpCas9-HF1. With its exceptional precision, SpCas9-HF1 provides an alternative to wild-type SpCas9 for research and therapeutic applications. More broadly, our results suggest a general strategy for optimizing genome-wide specificities of other CRISPR-RNA-guided nucleases. More... »

PAGES

490

References to SciGraph publications

  • 2015-03. Unbiased detection of off-target cleavage by CRISPR-Cas9 and TALENs using integrase-defective lentiviral vectors in NATURE BIOTECHNOLOGY
  • 2015-04. In vivo genome editing using Staphylococcus aureus Cas9 in NATURE
  • 2013-09. CAS9 transcriptional activators for target specificity screening and paired nickases for cooperative genome engineering in NATURE BIOTECHNOLOGY
  • 2013-09. High-throughput profiling of off-target DNA cleavage reveals RNA-programmed Cas9 nuclease specificity in NATURE BIOTECHNOLOGY
  • 2015-03. GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases in NATURE BIOTECHNOLOGY
  • 2015-12. Broadening the targeting range of Staphylococcus aureus CRISPR-Cas9 by modifying PAM recognition in NATURE BIOTECHNOLOGY
  • 2014-09. Structural basis of PAM-dependent target DNA recognition by the Cas9 endonuclease in NATURE
  • 2014-04. Broad specificity profiling of TALENs results in engineered nucleases with improved DNA-cleavage specificity in NATURE METHODS
  • 2015-06-22. Engineered CRISPR-Cas9 nucleases with altered PAM specificities in NATURE
  • 2015-03. Digenome-seq: genome-wide profiling of CRISPR-Cas9 off-target effects in human cells in NATURE METHODS
  • 2015-11. Conformational control of DNA target cleavage by CRISPR–Cas9 in NATURE
  • 2014-03. DNA interrogation by the CRISPR RNA-guided endonuclease Cas9 in NATURE
  • 2011-03. CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III in NATURE
  • 2014-03. Improving CRISPR-Cas nuclease specificity using truncated guide RNAs in NATURE BIOTECHNOLOGY
  • 2013-11. Orthogonal Cas9 proteins for RNA-guided gene regulation and editing in NATURE METHODS
  • 2014-06. Fusion of catalytically inactive Cas9 to FokI nuclease improves the specificity of genome modification in NATURE BIOTECHNOLOGY
  • 2014-06. Dimeric CRISPR RNA-guided FokI nucleases for highly specific genome editing in NATURE BIOTECHNOLOGY
  • 2014-04. CRISPR-Cas systems for editing, regulating and targeting genomes in NATURE BIOTECHNOLOGY
  • 2013-09. DNA targeting specificity of RNA-guided Cas9 nucleases in NATURE BIOTECHNOLOGY
  • 2013-09. High-frequency off-target mutagenesis induced by CRISPR-Cas nucleases in human cells in NATURE BIOTECHNOLOGY
  • 2012-05. FLASH assembly of TALENs for high-throughput genome editing in NATURE BIOTECHNOLOGY
  • 2013-03. RNA-guided editing of bacterial genomes using CRISPR-Cas systems in NATURE BIOTECHNOLOGY
  • 2015-03. Genome-wide detection of DNA double-stranded breaks induced by engineered nucleases in NATURE BIOTECHNOLOGY
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nature16526

    DOI

    http://dx.doi.org/10.1038/nature16526

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1010800066

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/26735016


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