CRISPR-Cas9 globin editing can induce megabase-scale copy-neutral losses of heterozygosity in hematopoietic cells

J. Boutin, J. Rosier, D. Cappellen, F. Prat, J. Toutain, P. Pennamen, J. Bouron, C. Rooryck, J. P. Merlio, I. Lamrissi-Garcia, G. Cullot, S. Amintas, V. Guyonnet-Duperat, C. Ged, J. M. Blouin, E. Richard, S. Dabernat, F. Moreau-Gaudry () and A. Bedel
Additional contact information
J. Boutin: Bordeaux University
J. Rosier: Bordeaux University
D. Cappellen: Bordeaux University
F. Prat: Bordeaux University
J. Toutain: Bordeaux University, MRGM INSERM U1211, CHU de Bordeaux, Service de Génétique Médicale
P. Pennamen: Bordeaux University, MRGM INSERM U1211, CHU de Bordeaux, Service de Génétique Médicale
J. Bouron: Bordeaux University, MRGM INSERM U1211, CHU de Bordeaux, Service de Génétique Médicale
C. Rooryck: Bordeaux University
J. P. Merlio: Bordeaux University
I. Lamrissi-Garcia: Bordeaux University
G. Cullot: Bordeaux University
S. Amintas: Bordeaux University
V. Guyonnet-Duperat: Bordeaux University
C. Ged: Bordeaux University
J. M. Blouin: Bordeaux University
E. Richard: Bordeaux University
S. Dabernat: Bordeaux University
F. Moreau-Gaudry: Bordeaux University
A. Bedel: Bordeaux University

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract CRISPR-Cas9 is a promising technology for gene therapy. However, the ON-target genotoxicity of CRISPR-Cas9 nuclease due to DNA double-strand breaks has received little attention and is probably underestimated. Here we report that genome editing targeting globin genes induces megabase-scale losses of heterozygosity (LOH) from the globin CRISPR-Cas9 cut-site to the telomere (5.2 Mb). In established lines, CRISPR-Cas9 nuclease induces frequent terminal chromosome 11p truncations and rare copy-neutral LOH. In primary hematopoietic progenitor/stem cells, we detect 1.1% of clones (7/648) with acquired megabase LOH induced by CRISPR-Cas9. In-depth analysis by SNP-array reveals the presence of copy-neutral LOH. This leads to 11p15.5 partial uniparental disomy, comprising two Chr11p15.5 imprinting centers (H19/IGF2:IG-DMR/IC1 and KCNQ1OT1:TSS-DMR/IC2) and impacting H19 and IGF2 expression. While this genotoxicity is a safety concern for CRISPR clinical trials, it is also an opportunity to model copy-neutral-LOH for genetic diseases and cancers.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25190-6

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DOI: 10.1038/s41467-021-25190-6

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