Small-Molecule Control of Super-Mendelian Inheritance in Gene Drives
Víctor López Del Amo,
Brittany S. Leger,
Kurt J. Cox,
Shubhroz Gill,
Alena L. Bishop,
Garrett D. Scanlon,
James A. Walker,
Valentino M. Gantz,
Amit Choudhary
Affiliations
Víctor López Del Amo
Section of Cell and Developmental Biology, University of California San Diego, La Jolla, CA 92093, USA
Brittany S. Leger
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
Kurt J. Cox
Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Divisions of Renal Medicine and Engineering, Brigham and Women’s Hospital, Boston, MA 02115, USA
Shubhroz Gill
Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Alena L. Bishop
Section of Cell and Developmental Biology, University of California San Diego, La Jolla, CA 92093, USA
Garrett D. Scanlon
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
James A. Walker
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Corresponding author
Valentino M. Gantz
Section of Cell and Developmental Biology, University of California San Diego, La Jolla, CA 92093, USA; Corresponding author
Amit Choudhary
Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Divisions of Renal Medicine and Engineering, Brigham and Women’s Hospital, Boston, MA 02115, USA; Corresponding author
Summary: 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.
