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Target-specific precision of CRISPR-mediated genome editing

Anob M. Chakrabarti, Tristan Henser-Brownhill, Josep Monserrat, Anna R. Poetsch, Nicholas M. Luscombe, Paola Scaffidi
doi: https://doi.org/10.1101/387027
Anob M. Chakrabarti
Bioinformatics and Computational Biology Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UKDepartment of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK
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Tristan Henser-Brownhill
Cancer Epigenetics Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK
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Josep Monserrat
Cancer Epigenetics Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK
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Anna R. Poetsch
Bioinformatics and Computational Biology Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UKDepartment of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UKOkinawa Institute of Science and Technology Graduate University, Onna-son, Okinawa, Japan
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  • For correspondence: Paola.Scaffidi@crick.ac.uk Nicholas.Luscombe@crick.ac.uk arpoetsch@gmail.com
Nicholas M. Luscombe
Bioinformatics and Computational Biology Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UKDepartment of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UKOkinawa Institute of Science and Technology Graduate University, Onna-son, Okinawa, Japan
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  • For correspondence: Paola.Scaffidi@crick.ac.uk Nicholas.Luscombe@crick.ac.uk arpoetsch@gmail.com
Paola Scaffidi
Cancer Epigenetics Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UKUCL Cancer Institute, University College London, London WC1E 6DD, UK
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  • For correspondence: Paola.Scaffidi@crick.ac.uk Nicholas.Luscombe@crick.ac.uk arpoetsch@gmail.com
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ABSTRACT

The CRISPR-Cas9 system has successfully been adapted to edit the genome of various organisms. However, our ability to predict editing accuracy, efficacy and outcome at specific sites is limited by an incomplete understanding of how the bacterial system interacts with eukaryotic genomes and DNA repair machineries. Here, we performed the largest comparison of indel profiles to date, examining over one thousand sites in the genome of human cells, and uncovered general principles guiding CRISPR-mediated DNA editing. We find that precision of DNA editing varies considerably among sites, with some targets showing one highly-preferred indel and others displaying a wide range of infrequent indels. Editing precision correlates with editing efficiency, homology-associated end-joining for both insertions and deletions, and a preference for single-nucleotide insertions. Precise targets and the identity of their preferred indel can be predicted based on simple rules that mainly depend on the fourth nucleotide upstream of the PAM sequence. Regardless of precision, site-specific indel profiles are highly robust and depend on both DNA sequence and chromatin features. Our findings have important implications for clinical applications of CRISPR technology and reveal general patterns of broken end-joining that can inform us on DNA repair mechanisms in human cells.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 09, 2018.
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Target-specific precision of CRISPR-mediated genome editing
Anob M. Chakrabarti, Tristan Henser-Brownhill, Josep Monserrat, Anna R. Poetsch, Nicholas M. Luscombe, Paola Scaffidi
bioRxiv 387027; doi: https://doi.org/10.1101/387027
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Target-specific precision of CRISPR-mediated genome editing
Anob M. Chakrabarti, Tristan Henser-Brownhill, Josep Monserrat, Anna R. Poetsch, Nicholas M. Luscombe, Paola Scaffidi
bioRxiv 387027; doi: https://doi.org/10.1101/387027

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