Efficient allelic-drive in Drosophila

Nat Commun. 2019 Apr 9;10(1):1640. doi: 10.1038/s41467-019-09694-w.

Abstract

Gene-drive systems developed in several organisms result in super-Mendelian inheritance of transgenic insertions. Here, we generalize this "active genetic" approach to preferentially transmit allelic variants (allelic-drive) resulting from only a single or a few nucleotide alterations. We test two configurations for allelic-drive: one, copy-cutting, in which a non-preferred allele is selectively targeted for Cas9/guide RNA (gRNA) cleavage, and a more general approach, copy-grafting, that permits selective inheritance of a desired allele located in close proximity to the gRNA cut site. We also characterize a phenomenon we refer to as lethal-mosaicism that dominantly eliminates NHEJ-induced mutations and favors inheritance of functional cleavage-resistant alleles. These two efficient allelic-drive methods, enhanced by lethal mosaicism and a trans-generational drive process we refer to as "shadow-drive", have broad practical applications in improving health and agriculture and greatly extend the active genetics toolbox.

Publication types

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

MeSH terms

  • Agriculture / methods
  • Alleles*
  • Animals
  • Animals, Genetically Modified / genetics
  • CRISPR-Cas Systems / genetics
  • DNA End-Joining Repair / genetics*
  • DNA Mutational Analysis
  • Drosophila / genetics*
  • Female
  • Gene Drive Technology / methods*
  • Gene Editing / methods
  • Inheritance Patterns / genetics
  • Male
  • Mosaicism
  • RNA, Guide / genetics

Substances

  • RNA, Guide