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  • Höijer, IdaUppsala universitet,Science for Life Laboratory, SciLifeLab,Medicinsk genetik och genomik (author)

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

  • Article/chapterEnglish2022

Publisher, publication year, extent ...

  • 2022-02-02
  • Springer Nature,2022
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:uu-468369
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-468369URI
  • https://doi.org/10.1038/s41467-022-28244-5DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Emmanouilidou, AnastasiaUppsala universitet,Medicinsk genetik och genomik,Science for Life Laboratory, SciLifeLab,Uppsala Univ, Beijer Lab, Uppsala, Sweden.(Swepub:uu)anaem996 (author)
  • Östlund, RebeckaUppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab (author)
  • van Schendel, RobinLeiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. (author)
  • Bozorgpana, SelmaUppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab (author)
  • Tijsterman, MarcelLeiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. (author)
  • Feuk, LarsUppsala universitet,Science for Life Laboratory, SciLifeLab,Medicinsk genetik och genomik(Swepub:uu)larsfeuk (author)
  • Gyllensten, Ulf B.Uppsala universitet,Science for Life Laboratory, SciLifeLab,Medicinsk genetik och genomik(Swepub:uu)ulfgyll (author)
  • den Hoed, Marcel,1980-Uppsala universitet,Science for Life Laboratory, SciLifeLab,Medicinsk genetik och genomik,Uppsala Univ, Beijer Lab, Uppsala, Sweden.(Swepub:uu)marde358 (author)
  • Ameur, AdamUppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)adame789 (author)
  • Uppsala universitetScience for Life Laboratory, SciLifeLab (creator_code:org_t)

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  • In:Nature Communications: Springer Nature132041-1723

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