GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-03

AUTHORS

Shengdar Q Tsai, Zongli Zheng, Nhu T Nguyen, Matthew Liebers, Ved V Topkar, Vishal Thapar, Nicolas Wyvekens, Cyd Khayter, A John Iafrate, Long P Le, Martin J Aryee, J Keith Joung

ABSTRACT

CRISPR RNA-guided nucleases (RGNs) are widely used genome-editing reagents, but methods to delineate their genome-wide, off-target cleavage activities have been lacking. Here we describe an approach for global detection of DNA double-stranded breaks (DSBs) introduced by RGNs and potentially other nucleases. This method, called genome-wide, unbiased identification of DSBs enabled by sequencing (GUIDE-seq), relies on capture of double-stranded oligodeoxynucleotides into DSBs. Application of GUIDE-seq to 13 RGNs in two human cell lines revealed wide variability in RGN off-target activities and unappreciated characteristics of off-target sequences. The majority of identified sites were not detected by existing computational methods or chromatin immunoprecipitation sequencing (ChIP-seq). GUIDE-seq also identified RGN-independent genomic breakpoint 'hotspots'. Finally, GUIDE-seq revealed that truncated guide RNAs exhibit substantially reduced RGN-induced, off-target DSBs. Our experiments define the most rigorous framework for genome-wide identification of RGN off-target effects to date and provide a method for evaluating the safety of these nucleases before clinical use. More... »

PAGES

187

References to SciGraph publications

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  • Journal

    TITLE

    Nature Biotechnology

    ISSUE

    2

    VOLUME

    33

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nbt.3117

    DOI

    http://dx.doi.org/10.1038/nbt.3117

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1021849416

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/25513782


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