Engineering a Minimal Drive System for Vector Control in Drosophila melanogaster

The significant burden exerted on global health by vector-borne transmission of human diseases such as malaria, yellow fever, dengue fever and others has dictated the need for novel and effective control methodologies. One such methodology is that of a genetic drive, facilitating population-level modification of common vectors (e.g. mosquitoes, tsetse flies, ticks, etc...). Gene drive permits researchers to repurpose naturally occurring transposable elements as a means to artificially drive the rate of inheritance of desired traits between generations of a population at a greater-than Mendelian rate. In so doing, it is possible to spread effector genes that may offer a means to inhibit disease pathogenesis. This methodology offers notable advantages over existing vector control strategies such as use of chemical pesticides, which are largely temporal and require significant logistical and economical commitment. Gene drive is a self-sustaining alternative that can be implemented to permanently address numerous challenges to human health.

Synthetic gene drive systems have been described with a variety of mechanisms for the proliferation of desirable traits across a population. One such mechanism makes use of genes encoding site-specific endonucleases as a means to rapidly drive inheritance of effector genes. The gene-encoded nuclease generates a double-stranded break in a targeted genomic site, and is subsequently used as a template for homologous repair. This results in heterozygous individuals becoming homozygous for the gene - the gene is inserted into the middle of its own recognition sequence, preventing the newly repaired site from being further targeted. Such nuclease-encoding genes can be engineered to carry a cargo, and in this way frequency of the effector gene can increase and be transmitted to the host organism's progeny. Recent advances in genetic engineering have resulted in new classes of synthetic endonucleases that can be designed to specifically cleave genomic sequences. Examples of synthetic gene drive systems have since been demonstrated using Zinc-finger, TALENs and CRISPR nucleases.

We now want to further optimise this synthetic gene drive in order to engineer a minimal system, offering numerous advantages over existing designs. We aim to undertake this work in Drosophila melanogaster. This model organism has significant genomic conservation to a range of target arthropods, making it a potent platform for evaluating the efficiency of this novel system, and permitting high-throughput experimentation. In this way we aim to design and engineer a novel synthetic gene drive system. Furthermore, by investigating gene drive in D. melanogaster, we will provide an avenue for implementation of this drive in a range of vectors, allowing future work to be targeted to relevant organisms in sectors outside of healthcare, such as agriculture.