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CRISPR-Cas9 induces large structural variants at on-target and off-target sites in vivo that segregate across generations. | LitMetric

AI Article Synopsis

  • CRISPR-Cas9 shows promise for curing diseases but poses risks of unintended mutations, highlighting the need for safe therapies.
  • * In a study involving zebrafish, researchers discovered that editing can lead to structural variants (insertions and deletions) in about 6% of modified larvae, with these mutations observed in both targeted and non-targeted DNA regions.
  • * The findings emphasize the importance of testing for off-target mutations before using CRISPR-Cas9 in patients, as a significant percentage of zebrafish offspring inherited these unintended changes.

Article Abstract

CRISPR-Cas9 genome editing has potential to cure diseases without current treatments, but therapies must be safe. Here we show that CRISPR-Cas9 editing can introduce unintended mutations in vivo, which are passed on to the next generation. By editing fertilized zebrafish eggs using four guide RNAs selected for off-target activity in vitro, followed by long-read sequencing of DNA from >1100 larvae, juvenile and adult fish across two generations, we find that structural variants (SVs), i.e., insertions and deletions ≥50 bp, represent 6% of editing outcomes in founder larvae. These SVs occur both at on-target and off-target sites. Our results also illustrate that adult founder zebrafish are mosaic in their germ cells, and that 26% of their offspring carries an off-target mutation and 9% an SV. Hence, pre-testing for off-target activity and SVs using patient material is advisable in clinical applications, to reduce the risk of unanticipated effects with potentially large implications.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8810904PMC
http://dx.doi.org/10.1038/s41467-022-28244-5DOI Listing

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