Harnessing endogenous repair mechanisms for targeted gene knock-in of bovine embryos

Sci Rep. 2020 Sep 29;10(1):16031. doi: 10.1038/s41598-020-72902-x.

Abstract

Introducing useful traits into livestock breeding programs through gene knock-ins has proven challenging. Typically, targeted insertions have been performed in cell lines, followed by somatic cell nuclear transfer cloning, which can be inefficient. An alternative is to introduce genome editing reagents and a homologous recombination (HR) donor template into embryos to trigger homology directed repair (HDR). However, the HR pathway is primarily restricted to actively dividing cells (S/G2-phase) and its efficiency for the introduction of large DNA sequences in zygotes is low. The homology-mediated end joining (HMEJ) approach has been shown to improve knock-in efficiency in non-dividing cells and to harness HDR after direct injection of embryos. The knock-in efficiency for a 1.8 kb gene was contrasted when combining microinjection of a gRNA/Cas9 ribonucleoprotein complex with a traditional HR donor template or an HMEJ template in bovine zygotes. The HMEJ template resulted in a significantly higher rate of gene knock-in as compared to the HR template (37.0% and 13.8%; P < 0.05). Additionally, more than a third of the knock-in embryos (36.9%) were non-mosaic. This approach will facilitate the one-step introduction of gene constructs at a specific location of the bovine genome and contribute to the next generation of elite cattle.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • CRISPR-Associated Protein 9 / genetics
  • CRISPR-Cas Systems / genetics
  • Cattle
  • DNA End-Joining Repair / physiology
  • DNA Repair / genetics
  • Gene Editing / methods*
  • Gene Knock-In Techniques / methods*
  • Genetic Engineering / methods*
  • Genome / genetics
  • Homologous Recombination / genetics
  • Microinjections / methods
  • RNA, Guide, CRISPR-Cas Systems
  • Recombinational DNA Repair / genetics
  • Zygote / physiology

Substances

  • CRISPR-Associated Protein 9