Investigating genetic barriers to the spread of gene drives designed for mosquito control

Gene drive refers to the ability of a genetic element to bias its inheritance among offspring and is a phenomenon displayed by several ‘selfish’ genetic elements. Synthetic versions of these gene drive elements have been built with the deliberate intention of transforming populations of pests or disease-carrying insects, either so that the population is debilitated as the gene drive spreads or so that it is modified in a way that it no longer vectors disease.

We have built gene drive elements in the malaria mosquito that are capable of rapidly spreading and suppressing populations in the laboratory, suggesting enormous potential as a self-sustaining tool for mosquito control, and thus malaria control, in the wild. Nonetheless, in addition to the regulatory and public acceptance challenges for a new technology of this sort, one of the key issues to address is that of resistance – mosquitoes resistant to the mode of action of the gene drive may be expected to have a significant fitness advantage. The nature of this resistance, and the force of its selection, may vary according to gene drive type.

In the gene drives we have developed, which consist of CRISPR-based constructs that are able to copy themselves in the mosquito germline, the most likely forms of resistance are sequence variation and genetic re-arrangements in and around the CRISPR target site.

This project will look at the effect of genomic context, particularly sequence variation around the target site and chromosomal rearrangements, on the efficiency of gene drives and whether such chromosomal variants can be selected.

Where does the project lie on the Translational Pathway?

T1 (Basic Research)

Expected Outputs

The project will produce high quality REF returnable 3*/4* publications and will provide the evidence base for large scale research council and philanthropic (e.g. Open Philanthropy and Gates Foundation) sources of funding

Training Opportunities

Mosquito transgenesis, embryo microinjection, CRISPR, genome editing, bioinformatics, DNA cloning, DNA sequence analysis, Next generation sequencing

Skills Required

Desirable skills to include:- Bioinformatic and/or quantitative biology; molecular biology; aptitude for DNA cloning; basic molecular genetics; population genetics

Key Publications associated with this project

Kyrou K, Hammond AM, Galizi R, Kranjc N, Burt A, Beaghton AK, Nolan T and Crisanti A A CRISPR-Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes Nature Biotechnology 24 September 2018,

A Hammond, R Galizi, K Kyrou, A Simoni, C Siniscalchi, D Katsanos, M Gribble, D Baker, E Marois, S Russell, A Burt, N Windbichler, A Crisanti and T Nolan. A CRISPR-based Gene Drive System Targeting Female Reproduction in the Malaria Mosquito. Nature Biotechnology 34,78–83 (2016

Champer, J., Buchman, A. & Akbari, O. Cheating evolution: engineering gene drives to manipulate the fate of wild populations. Nat Rev Genet 17, 146–159 (2016)

A Hammond, X Karlsson, I Morianou, K Kyrou, A Beaghton, M Gribble, N Kranjc, R Galizi, A Burt, A Crisanti, T Nolan. Regulation of gene drive expression increases its invasive potential and mitigates resistance BioRXiv 360339 (2020) doi: https://doi.org/10.1101/360339;

Natural diversity of the malaria vector Anopheles gambiae (2017) The Anopheles gambiae 1000 Genomes Consortium.  Nature 552,  96–100 (2017)

Deadline: Thursday 11th February 2021; 12:00 noon GMT

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