The development of gene drives for genetic control of the malaria mosquito
File(s)Galizi et al - 2016 - A CRISPR-Cas9 sex-ratio distortion system for genetic control.pdf (523.6 KB)
Associated publication 2 - Galizi & Hammond et al 2016
Author(s)
Hammond, Andrew Marc
Type
Thesis
Abstract
Genetic drive systems have the potential to modify entire insect populations in a few years through the super-Mendelian inheritance of a genetic trait. We describe a novel gene drive system called CRISPRh, which acts as a selfish genetic element in the malaria mosquito Anopheles gambiae. CRISPRh is a synthetic allele containing CRISPR/Cas9 endonuclease designed to specifically target and insert a copy of itself into its homologous chromosome in the germline of heterozygous individuals. Using a gene targeting approach, we identified three genes that confer recessive female sterility upon disruption. By inserting CRISPRh at each of these genes, we achieved super-Mendelian inheritance of CRISPRh alleles, ranging from 91 to 99.6% of the progeny of heterozygotes. Population modelling predicts that these high rates of transmission and a recessive knockout phenotype would enable CRISPRh alleles to spread rapidly through a wild mosquito population, causing population suppression through the generation of sterile females. We tested the potential of one CRISPRh allele to invade a caged population of naïve mosquitoes and observed an average increase from 50-76.4% over six generations, demonstrating the first gene drive designed to spread through a natural vector population. The CRISPRh constructs described here generate strong unintended fertility effects and are highly susceptible to target site resistance, making them unsuitable for malaria control. We expect that simple modifications can solve these issues and allow the development of gene drives for the suppression of mosquito populations to levels that do not support malaria transmission.
Version
Open Access
Date Issued
2016-05
Date Awarded
2017-10
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Crisanti, Andrea
Nolan, Tony
Sponsor
Bill and Melinda Gates Foundation
Publisher Department
Life Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)