Engineering a minimal gene drive system for integral replacement in Drosophila melanogaster
File(s)
Author(s)
Nash, Alexander
Type
Thesis
Abstract
Gene drives represent a powerful tool for the control of vector-borne diseases. By suppressing
or replacing vector populations, laboratory studies have highlighted the potential for this
group of tools to make a powerful impact on the burden of zoonotic disease. Current genetic
drive systems have a number of limitations, namely their complexity, susceptibility to genetic
resistance, and a high regulatory threshold. Here we suggest a novel design paradigm for the
creation of replacement gene drives, which we have termed ‘Integral Replacement’. By splitting
drive constructs, and integrating components into endogenous loci, we have aimed to engineer
a minimal drive system, with low fitness cost, higher resilience to resistance alleles, and with
greater flexibility for field testing. In so doing we have generated a model that illustrates increases
in efficacy versus existing drive systems, and expanded on work performed on intronic
gRNA cassettes. We subsequently were able to build prototype Integral Gene Drive (IGD)
components, and demonstrate their efficacy using the model organism Drosophila melanogaster,
providing evidence for an initial proof-of-principle for this novel design paradigm.
or replacing vector populations, laboratory studies have highlighted the potential for this
group of tools to make a powerful impact on the burden of zoonotic disease. Current genetic
drive systems have a number of limitations, namely their complexity, susceptibility to genetic
resistance, and a high regulatory threshold. Here we suggest a novel design paradigm for the
creation of replacement gene drives, which we have termed ‘Integral Replacement’. By splitting
drive constructs, and integrating components into endogenous loci, we have aimed to engineer
a minimal drive system, with low fitness cost, higher resilience to resistance alleles, and with
greater flexibility for field testing. In so doing we have generated a model that illustrates increases
in efficacy versus existing drive systems, and expanded on work performed on intronic
gRNA cassettes. We subsequently were able to build prototype Integral Gene Drive (IGD)
components, and demonstrate their efficacy using the model organism Drosophila melanogaster,
providing evidence for an initial proof-of-principle for this novel design paradigm.
Version
Open Access
Date Issued
2020-04
Date Awarded
2020-06
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Windbichler, Nikolai
Gilestro, Giorgio
Sponsor
Biotechnology and Biological Sciences Research Council (Great Britain)
Grant Number
1655064
Publisher Department
Life Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)