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Fitness assessment of insect genetic replacement systems

Reference	BB/G016976/1
Principal Investigator / Supervisor	Professor Steven Sinkins
Co-Investigators / Co-Supervisors	Dr Luke Alphey
Institution	University of Oxford
Department	Peter Medawar Bldg for Pathogen Research
Funding type	Skills
Value (£)	74,410
Status	Completed
Type	Training Grants
Start date	01/10/2009
End date	30/09/2013
Duration	48 months

Abstract

unavailable

Summary

Recent advances in molecular genetics and genomics have provided an unprecedented ability to manipulate the ability of insect vectors to transmit diseases of humans, crops and livestock, which are of enormous economic importance. Multiple research groups are attempting to identify in the laboratory genes and constructs which, if present in a wild population of a disease vector, would eliminate or dramatically reduce disease transmission; meanwhile some natural refractoriness systems are already available for introgression from sibling species. The pace of current research suggests that within a decade, and probably much sooner, many such systems will be available. This research is focused at present on mosquito-borne diseases, but is equally applicable to various diseases of plants and livestock. However, there are very few methods available to introgress these genes into wild populations, in other words to use them. It is likely that any genetic construct, for example one which reduces the capacity of vector species to transmit pathogens, will have a fitness cost associated with it. This means the genetically altered vector will be at a selective disadvantage relative to the wild type that it is intended to replace. Thus, if the refractory strain were simply released into the field it would be selected against, relative to the wild type, and so the desired trait would not spread. While it is possible that the trait itself may confer a selective advantage in the presence of the targeted pathogen, by allowing the engineered vectors to avoid the fitness costs associated with carrying that pathogen, a great majority of individuals will never be exposed to the pathogen. Thus, an engineered refractory construct is highly unlikely to spread through a wild population unaided. Rather, an effective system for genetic replacement of wild vector populations is essential in order to bring the 'refractory insect' strategy to practical utility. It is desirable for regulatory /biosafety reasons that the replacement system is not too invasive, in other words will stay where you put it within definable parameters. Two systems that have been described with this property and are widely applicable to pest species are i) bidirectional cytoplasmic incompatibility (crossing sterility) induced by the inherited bacterium Wolbachia; and ii) the 'engineered underdominance'-based system of Davis et al (2001) involving pairs of mutually suppressing dominant lethal genetic elements. The student will develop the key tools necessary to assess the dynamics of these two gene replacement systems, in particular relative fitness effects. The relative fitness costs (in terms of egg output and mating competitiveness) of mutually incompatible Wolbachia strains and the penetrance of bidirectional CI will be tested in large cages for the mosquito Aedes polynesiensis, a Polynesian disease vector of major medical and veterinary importance (lymphatic filariasis and heartworm respectively). Fitness costs associated with the introgression and selection of filarial refractoriness from a sibling species (already underway in the Sinkins lab) will also be assessed. Fitness costs of underdominant constructs will be tested using the same methodologies for the related dengue vector mosquito Aedes aegypti, based on Oxitec's work on repressible lethal systems for control of agricultural and public health pests and recent studies applying these systems to underdominance. The project will involve only confined laboratory experiments plus theoretical studies of how these parameters would influence the dynamics of genetic replacement. Key references: Davis, S., Bax, N., and Grewe, P. (2001). Engineered underdominance allows efficient and economic introgression of traits into pest populations. J theor Biol 212:83. Sinkins SP, Gould F (2006) Gene drive systems for insect disease vectors. Nature Rev Gen 7:427.

Committee	Not funded via Committee
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	Training Grant - Industrial Case

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