Small-Molecule Control of Super-Mendelian Inheritance in Gene Drives

Cell Rep. 2020 Jun 30;31(13):107841. doi: 10.1016/j.celrep.2020.107841.


Synthetic CRISPR-based gene-drive systems have tremendous potential in public health and agriculture, such as for fighting vector-borne diseases or suppressing crop pest populations. These elements can rapidly spread in a population by breaching the inheritance limit of 50% dictated by Mendel's law of gene segregation, making them a promising tool for population engineering. However, current technologies lack control over their propagation capacity, and there are important concerns about potential unchecked spreading. Here, we describe a gene-drive system in Drosophila that generates an analog inheritance output that can be tightly and conditionally controlled to between 50% and 100%. This technology uses a modified SpCas9 that responds to a synthetic, orally available small molecule, fine-tuning the inheritance probability. This system opens a new avenue to feasibility studies for spatial and temporal control of gene drives using small molecules.

Keywords: CRISPR; CopyCat; DHFR; Drosophila; destabilized domain; drug control; gene drive; small molecule; split gene drive; super-Mendelian.

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

  • Animals
  • Animals, Genetically Modified
  • CRISPR-Associated Protein 9 / metabolism
  • Drosophila melanogaster / genetics*
  • Gene Drive Technology*
  • Inheritance Patterns / genetics*
  • Pharmaceutical Preparations
  • Small Molecule Libraries / metabolism*


  • Pharmaceutical Preparations
  • Small Molecule Libraries
  • CRISPR-Associated Protein 9