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

English version

Autoři: Andrew Hammond ^aff001; Xenia Karlsson ^aff001; Ioanna Morianou ^aff001; Kyros Kyrou ^aff001; Andrea Beaghton ^aff001; Matthew Gribble ^aff001; Nace Kranjc ^aff001; Roberto Galizi ^aff001; Austin Burt ^aff001; Andrea Crisanti ^aff001; Tony Nolan ^aff004
Působiště autorů: Department of Life Sciences, Imperial College London, London, United Kingdom ^aff001; Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America ^aff002; University of Padova, Padova, Italy ^aff003; Liverpool School of Tropical Medicine, Liverpool, United Kingdom ^aff004
Vyšlo v časopise: Regulating the expression of gene drives is key to increasing their invasive potential and the mitigation of resistance. PLoS Genet 17(1): e1009321. doi:10.1371/journal.pgen.1009321
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009321

Souhrn

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.

Klíčová slova:

Alleles – Eggs – Fecundity – Heterozygosity – Larvae – Mosquitoes – Mutation – Nucleases

Zdroje

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