Abstract
A functioning gene drive system could fundamentally change our strategies for the control of vector-borne diseases by facilitating rapid dissemination of transgenes that prevent pathogen transmission or reduce vector capacity. CRISPR/Cas9 gene drive promises such a mechanism, which works by converting cells that are heterozygous for the drive construct into homozygotes, thereby enabling super-Mendelian inheritance. Although CRISPR gene drive activity has already been demonstrated, a key obstacle for current systems is their propensity to generate resistance alleles, which cannot be converted to drive alleles. In this study, we developed two CRISPR gene drive constructs based on the nanos and vasa promoters that allowed us to illuminate the different mechanisms by which resistance alleles are formed in the model organism Drosophila melanogaster. We observed resistance allele formation at high rates both prior to fertilization in the germline and post-fertilization in the embryo due to maternally deposited Cas9. Assessment of drive activity in genetically diverse backgrounds further revealed substantial differences in conversion efficiency and resistance rates. Our results demonstrate that the evolution of resistance will likely impose a severe limitation to the effectiveness of current CRISPR gene drive approaches, especially when applied to diverse natural populations.
Highlights
Gene drive systems promise a mechanism for rapidly spreading alleles in a population through super-Mendelian inheritance [1,2,3,4,5]
We developed two CRISPR gene drive constructs based on the nanos and vasa promoters that allowed us to illuminate the different mechanisms by which resistance alleles are formed in the model organism Drosophila melanogaster
Gene drive systems provide a wide array of potential applications, including new strategies for the control of vector-borne diseases
Summary
Gene drive systems promise a mechanism for rapidly spreading alleles in a population through super-Mendelian inheritance [1,2,3,4,5]. A heterozygote for the drive allele can thereby be converted into a homozygote, resulting in most of its progeny inheriting the drive allele In principle, this allows for the rapid spread of such an allele in the population, even if it carries a fitness cost to the organism [6,7,8,9]. This allows for the rapid spread of such an allele in the population, even if it carries a fitness cost to the organism [6,7,8,9] With this mechanism, a genetic payload could be rapidly disseminated throughout an entire population [6,7,8,9,10,11], presenting a variety of potential applications. Other proposed applications range from spreading genetically engineered antiviral effector genes against dengue [18], to suppressing the populations of invasive crop pests such as Drosophila suzukii [19]
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