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The genetic basis of variation in resistance to pathogens: a genome-wide analysis in Drosophila

Reference	BB/C514623/1
Principal Investigator / Supervisor	Prof. Frank Jiggins
Co-Investigators / Co-Supervisors	Dr Sara Knott
Institution	University of Edinburgh
Department	Inst of Evolutionary Biology
Funding type	Research
Value (£)	224,154
Status	Completed
Type	Research Grant
Start date	15/08/2005
End date	14/08/2008
Duration	36 months

Abstract

All animals depend upon an innate immune response to defend themselves against microbial invasion. Innate immune systems rely on a limited repertoire of germ-like encoded molecules to detect and destroy pathogens. These molecules distinguish self from non-self by recognising molecular structures associated with microbes but absent from the host tissues. It is generally thought that these molecular structures are conserved across a large taxonomic range of microbes. Despite high levels of conservation at the molecular level, individuals within invertebrate populations vary hugely in their susceptibility to disease and their innate immune response. The genetic basis of this variation is of considerable interest. It will determine whether or not pests evolve resistance to biological control agents, and may cause variation in the rates at which vectors transmit vertebrate diseases. The insights gained in invertebrates will also inform research on vertebrate innate immune systems. Furthermore, understanding the genetic basis of this variation will allow us to ask why so much variation exists in populations in the first place. Natural genetic variation also allows for an alternative approach to functional genomics. By screening the genome for natural mutants affecting the immune response, it will be possible to identify immunity genes for further functional characterisation. Quantative genetics may be the only way to identify genes or pathways that only have subtle effects on the immune response and will therefore be missed by conventional genetic screens. The aim of this project is to use the techniques of Drosophila genetics to determine the genetic basis of this variation. We will take a stepwise approach. Initially, we will allow isogenic stocks to recombine, and then construct a panel of recombinant isogenic lines that are each a unique mosaic of the two parental lines. Molecular markers will be used to identify which portions of the genome are derived from the resistant and susceptible parental stocks. These recombinant lines will be used to identify regions of the genome containing quantitative trait loci (QTLs) affecting immune competence. Then, we will refine the location of these QTLs using quantitative deficiency mapping. Finally, we will conduct a complementation test with mutant and wild-type stocks of candidate genes to identify the individual genes involved. The advantage of this approach is that is will provide an unbiased survey of variation across the entire genome. For this reason our experiments have the potential to identify uncharacterised genes involved in the innate immune response. We will measure the immune competence of fly stocks using both fungal and bacterial pathogens, and the flies will be infected either by injection directly into the haemocoel or via a natural route through the gut or cuticle. Therefore, or experiments will include variation contributed both by the well characterised pathways leading antimicrobial peptide production and relatively poorly understood pathways leading to the cellular encapsulation, phagocytosis, melanisation etc.

Summary

unavailable

Committee	Closed Committee - Genes & Developmental Biology (GDB)
Research Topics	Immunology, Microbiology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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