Regulating the expression of gene drives is key to increasing their invasive potential and the mitigation of resistance

Karlsson, Xenia, Hammond, Andrew, Morianou, Ioanna, Kyrou, Kyros, Beaghton, Andrea, Gribble, Matthew, Kranjc, Nace, Galizi, Roberto, Burt, Austin, Crisanti, Andrea and Nolan, Tony ORCID: https://orcid.org/0000-0002-2982-8333 (2021) 'Regulating the expression of gene drives is key to increasing their invasive potential and the mitigation of resistance'. PLoS Genetics, Vol 17, Issue 1, e1009321.

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Abstract

Homing-based gene drives use a germline source of nuclease to copy themselves at specific target sites in a genome and bias their inheritance. Such gene drives can be designed to spread and deliberately suppress populations of malaria mosquitoes by impairing female fertility. However, strong unintended fitness costs of the drive and a propensity to generate resistant mutations can limit a gene drive’s potential to spread. Alternative germline regulatory sequences in the drive element confer improved fecundity of carrier individuals and reduced propensity for target site resistance. This is explained by reduced rates of end-joining repair of DNA breaks from parentally deposited nuclease in the embryo, which can produce heritable mutations that reduce gene drive penetrance. We tracked the generation and selection of resistant mutations over the course of a gene drive invasion of a population. Improved gene drives show faster invasion dynamics, increased suppressive effect and later onset of target site resistance. Our results show that regulation of nuclease expression is as important as the choice of target site when developing a robust homing-based gene drive for population suppression.

Item Type:	Article
Subjects:	QU Biochemistry > QU 4 General works QU Biochemistry > Genetics > QU 450 General Works QU Biochemistry > Genetics > QU 470 Genetic structures QU Biochemistry > Proteins. Amino Acids. Peptides > QU 58.5 DNA.
Faculty: Department:	Biological Sciences > Vector Biology Department
Digital Object Identifer (DOI):	https://doi.org/10.1371/journal.pgen.1009321
Depositing User:	Mel Finley
Date Deposited:	22 Feb 2021 20:29
Last Modified:	22 Feb 2021 20:29
URI:	https://archive.lstmed.ac.uk/id/eprint/17018

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