Gene drives offer the possibility of altering and even suppressing wild populations of countless plant and animal species, and CRISPR technology now provides the technical feasibility of engineering them. However, population-suppression gene drives are prone to select resistance, should it arise. Here, we develop mathematical and computational models to identify conditions under which suppression drives will evade resistance, even if resistance is present initially. Previous models assumed resistance is allelic to the drive. We relax this assumption and show that linkage between the resistance and drive loci is critical to the evolution of resistance and that evolution of resistance requires (negative) linkage disequilibrium between the two loci. When the two loci are unlinked or only partially so, a suppression drive that causes limited inviability can evolve to fixation while causing only a minor increase in resistance frequency. Once fixed, the drive allele no longer selects resistance. Our analyses suggest that among gene drives that cause moderate suppression, toxin-antidote systems are less apt to select for resistance than homing drives. Single drives of moderate effect might cause only moderate population suppression, but multiple drives (perhaps delivered sequentially) would allow arbitrary levels of suppression. The most favorable case for evolution of resistance appears to be with suppression homing drives in which resistance is dominant and fully suppresses transmission distortion; partial suppression by resistance heterozygotes or recessive resistance are less prone to resistance evolution. Given that it is now possible to engineer CRISPR-based gene drives capable of circumventing allelic resistance, this design may allow for the engineering of suppression gene drives that are effectively resistance-proof.
Gene drives offer the possibility of altering and even suppressing wild populations of countless plant and animal species, and CRISPR technology now provides the technical feasibility of engineering them. However, population-suppression gene drives are prone to select resistance, should it arise. Here we develop mathematical and computational models to identify conditions under which suppression drives will evade resistance, even if resistance is present initially. We show that linkage between the resistance and drive loci is critical to the evolution, that evolution of resistance requires (negative) linkage disequilibrium between the two loci. When the two loci are unlinked or only partially so, a suppression drive that causes limited inviability can evolve to fixation while causing only a minor increase in resistance frequency. Once fixed, the drive allele no longer selects resistance. Single drives of this type would achieve only partial population suppression, but multiple drives (perhaps delivered sequentially) would allow arbitrary levels of suppression. Given that it is now possible to engineer CRISPR-based gene drives capable of circumventing allelic resistance, this design may allow for the engineering of suppression gene drives that are effectively resistance-proof.
The Fem family of genes influences sex determination and/or the development of sex-specific characteristics in a wide variety of organisms. Here, we describe the first mutational analysis of the Fem-1 gene of Drosophila melanogaster. The amino acid sequence of the two Drosophila Fem-1 transcripts are moderately conserved compared to that of both Fem-1 in C. elegans and the two Fem-1 transcripts in humans, with multiple ankyrin repeats. Using two transposon-induced mutations of Drosophila Fem-1, we observed striking defects in adult courtship behavior that are attributed to defects in male courting as opposed to female receptivity. Specifically, viable Fem-1 mutant males courted Fem-1 females more vigorously with an increased amount of chasing and singing than pairs of control flies. Nevertheless, Fem-1 males did not copulate at a higher frequency than controls. The above courtship defects persisted when Fem-1 males courted control females, but no phenotypes were observed when control males courted Fem-1 females. These results indicate that Drosophila Fem-1 may interact with other genes involved in courtship and sex determination. Fem-1 mutants also suppressed wing and body growth, consistent with the actions of a homologue in mice. Additional analyses of these Fem-1 alleles will help address the nature of these mutations, deepen our molecular understanding of courtship, and contribute to the evolutionary relationships among this highly conserved gene family.
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