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The creation and selection of mutations resistant to a gene drive over multiple generations in the malaria mosquito

Andrew Hammond, Kyros Kyrou, Marco Bruttini, Ace North, Roberto Galizi, Xenia Karlsson, Francesco M Carpi, Romina D’Aurizio, Andrea Crisanti, Tony Nolan
doi: https://doi.org/10.1101/149005
Andrew Hammond
1Dept. Life Sciences, Imperial College London, UK
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Kyros Kyrou
1Dept. Life Sciences, Imperial College London, UK
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Marco Bruttini
2Polo d’Innovazione Genomica, Genetica e Biologia, Siena, Italy
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Ace North
3Department of Zoology, University of Oxford
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Roberto Galizi
1Dept. Life Sciences, Imperial College London, UK
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Xenia Karlsson
1Dept. Life Sciences, Imperial College London, UK
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Francesco M Carpi
1Dept. Life Sciences, Imperial College London, UK
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Romina D’Aurizio
4Laboratory of Integrative Systems Medicine (LISM), Institute of Informatics and Telematics (IIT), CNR, Pisa, Italy
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Andrea Crisanti
1Dept. Life Sciences, Imperial College London, UK
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  • For correspondence: acrs@imperial.ac.uk t.nolan@imperial.ac.uk
Tony Nolan
1Dept. Life Sciences, Imperial College London, UK
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  • For correspondence: acrs@imperial.ac.uk t.nolan@imperial.ac.uk
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ABSTRACT

Gene drives have enormous potential for the control of insect populations of medical and agricultural relevance. By preferentially biasing their own inheritance gene drives can rapidly introduce genetic traits even if these confer a negative fitness on the population.

We have recently developed gene drives based on a CRISPR nuclease construct that is designed to disrupt key genes essential for female fertility in the malaria mosquito. The construct copies itself and the associated genetic disruption from one homologous chromosome to another during gamete formation, in a process called homing that ensures the majority of offspring inherit the drive. Such drives have the potential to cause long-lasting, sustainable population suppression though they are also expected to impose a large selection pressure for resistance in the mosquito. One of these population suppression gene drives showed rapid invasion of a caged population over 4 generations, establishing proof of principle for this technology. In order to assess the potential for the emergence of resistance to the gene drive in this population we allowed it to run for 25 generations and monitored the frequency of the gene drive over time. Following the initial increase of the gene drive we noticed a gradual decrease in its frequency that was accompanied emergence of small, nuclease-induced mutations at the target gene that are resistant to further cleavage and restore its functionality. Such mutations show rates of increase consistent with positive selection in the face of the gene drive. Our findings represent the first documented example of selection for resistance to a synthetic gene drive and lead to important design recommendations and considerations in order to mitigate for resistance for future gene drive applications.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted June 12, 2017.
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The creation and selection of mutations resistant to a gene drive over multiple generations in the malaria mosquito
Andrew Hammond, Kyros Kyrou, Marco Bruttini, Ace North, Roberto Galizi, Xenia Karlsson, Francesco M Carpi, Romina D’Aurizio, Andrea Crisanti, Tony Nolan
bioRxiv 149005; doi: https://doi.org/10.1101/149005
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The creation and selection of mutations resistant to a gene drive over multiple generations in the malaria mosquito
Andrew Hammond, Kyros Kyrou, Marco Bruttini, Ace North, Roberto Galizi, Xenia Karlsson, Francesco M Carpi, Romina D’Aurizio, Andrea Crisanti, Tony Nolan
bioRxiv 149005; doi: https://doi.org/10.1101/149005

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