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

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Title: The creation and selection of mutations resistant to a gene drive over multiple generations in the malaria mosquito.
Authors: Hammond, AM
Kyrou, K
Bruttini, M
North, A
Galizi, R
Karlsson, X
Kranjc, N
Carpi, FM
D'Aurizio, R
Crisanti, A
Nolan, T
Item Type: Journal Article
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 effect on the population. We have recently developed gene drives based on CRISPR nuclease constructs that are 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, 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 observed a gradual decrease in its frequency that was accompanied by the spread of small, nuclease-induced mutations at the target gene that are resistant to further cleavage and restore its functionality. Such mutations showed 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 in future gene drive applications.
Issue Date: 4-Oct-2017
Date of Acceptance: 20-Sep-2017
ISSN: 1553-7390
Publisher: Public Library of Science (PLoS)
Journal / Book Title: PLoS Genetics
Volume: 13
Issue: 10
Copyright Statement: © 2017 Hammond et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: 0604 Genetics
Developmental Biology
Publication Status: Published online
Article Number: e1007039
Appears in Collections:Faculty of Natural Sciences

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