A transcomplementing gene drive provides a flexible platform for laboratory investigation and potential field deployment

Nat Commun. 2020 Jan 17;11(1):352. doi: 10.1038/s41467-019-13977-7.

Abstract

CRISPR-based gene drives can spread through wild populations by biasing their own transmission above the 50% value predicted by Mendelian inheritance. These technologies offer population-engineering solutions for combating vector-borne diseases, managing crop pests, and supporting ecosystem conservation efforts. Current technologies raise safety concerns for unintended gene propagation. Herein, we address such concerns by splitting the drive components, Cas9 and gRNAs, into separate alleles to form a trans-complementing split-gene-drive (tGD) and demonstrate its ability to promote super-Mendelian inheritance of the separate transgenes. This dual-component configuration allows for combinatorial transgene optimization and increases safety by restricting escape concerns to experimentation windows. We employ the tGD and a small-molecule-controlled version to investigate the biology of component inheritance and resistant allele formation, and to study the effects of maternal inheritance and impaired homology on efficiency. Lastly, mathematical modeling of tGD spread within populations reveals potential advantages for improving current gene-drive technologies for field population modification.

Publication types

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

MeSH terms

  • Alleles
  • Animals
  • Animals, Genetically Modified
  • Base Sequence
  • CRISPR-Cas Systems
  • Diptera
  • Ecosystem
  • Female
  • Gene Drive Technology / methods*
  • Gene Editing
  • Genes, X-Linked
  • Genetics, Population / methods*
  • Male
  • Models, Theoretical
  • RNA, Guide / genetics
  • Transgenes

Substances

  • RNA, Guide