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Improved CRISPR-based suppression gene drives mitigate resistance and impose a large reproductive load on laboratory-contained mosquito populations

Hammond, Andrew M.; Kyrou, Kyros; Gribble, Matthew; Karlsson, Xenia; Morianou, Ioanna; Galizi, Roberto; Beaghton, Andrea; Crisanti, Andrea; Nolan, Tony

Improved CRISPR-based suppression gene drives mitigate resistance and impose a large reproductive load on laboratory-contained mosquito populations Thumbnail


Authors

Andrew M. Hammond

Kyros Kyrou

Matthew Gribble

Xenia Karlsson

Ioanna Morianou

Andrea Beaghton

Andrea Crisanti

Tony Nolan



Abstract

Abstract CRISPR-based genes drives bias their own inheritance and can be used to modify entire populations of insect vectors of disease as a novel form of sustainable disease control. Gene drives designed to interfere with female fertility can suppress populations of the mosquito vector of malaria, however laboratory demonstrations showed strong unintended fitness costs and high levels of resistant mutations that limited the potential of the first generation of gene drives to spread. We describe three new gene drives designed to restrict spatio-temporal nuclease expression by using novel regulatory sequences. Two of the three new designs dramatically improve fitness and mitigate the creation and selection of resistance. We dissect the relative contributions of germline CRISPR activity versus embryonic CRISPR activity resulting from parental deposition, showing that the improved performance of the new designs is due to tighter germline restriction of the nuclease activity and significantly lower rates of end-joining repair in the embryo. Moreover, we demonstrate in laboratory-contained population experiments that these gene drives show remarkably improved invasion dynamics compared to the first generation drives, resulting in greater than 90% suppression of the reproductive output and a delay in the emergence of target site resistance, even at a loosely constrained target sequence. These results illustrate important considerations for gene drive design and will help expedite the development of gene drives designed to control malaria transmission in Africa.

Acceptance Date Jun 15, 2018
Publication Date Jul 1, 2018
Publicly Available Date Mar 29, 2024
Journal BioRxiv
Print ISSN 2692-8205
Publisher Cold Spring Harbor Laboratory Press
Keywords CRISPR-based suppression, resistance, mosquito.

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