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

Gene drives – genetic elements capable of biasing their own inheritance among offspring – have been developed as a new and potentially powerful form of genetic control for mosquito populations, by spreading into a population either traits that affect its reproductive output or traits that affect its ability to harbour the diseases they ordinarily vector. The gene drives developed to date rely on site-specific DNA nucleases that recognise a target sequence that is rare in the genome and are designed to copy into this target sequence during the process of gamete formation, thereby increasing in copy number. As with any suppressive technology, genetic resistance should be expected and mist be prepared for. This project will look at the effect of genomic context, in particular 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 & T2 Human/Clinical 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, philanthropic (e.g. OP and Gates) and industry funding – in particular an industrial partnership award

Training Opportunities

Mosquito transgenesis, embryo microinjection, CRISPR, genome editing, diagnostic PCR design, bioinformatics, DNA cloning

Skills Required

Desirable skills to include:- Setting up and tracking genetic crosses; Bioinformatic and/or quantitative biology; molecular biology; aptitude for DNA cloning; insectary experience; 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

A Hammond, K Kyrou, M Bruttini, A North, R Galizi, X Karlsson, F Carpi, R D’Aurizio, A Crisanti and T Nolan The dynamics of creation and selection of mutations resistant to a gene drive over multiple generations in the malaria mosquito PLoS Genetics 2017, Oct 9

Hammond AM, Kyrou K, Gribble M, Karlsson, Morianou I, Galizi R, Beaghton AK, Crisanti A and Nolan T Improved CRISPR-based suppression gene drives mitigate resistance and impose a large reproductive load on laboratory contained mosquito populations  bioRxiv (2018) 360339;

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

LSTM Themes and Topics – Key Words

Malaria and other vector borne diseases; Resistance research and management