Project

quantitative genetics; natural populations; innate immunity; GWAS

Lead
Lay summary
How do variations at the molecular level in an infected individual affect how well he survives and why do these variations exist in the first place? Addressing those questions directly in humans is hard to achieve, which is why we aim to use the fruit fly Drosophila melanogaster as a model system. A panel of 192 inbred lines of D. melanogaster has recently been introduced to the scientific community. What is special about those lines is that their full genome sequence is known. Add to that the great knowledge we already have about the Drosophila genome in general, the system will allow us to realistically and efficiently tackle questions about immunocompetence in natural populations. The collaboration between a Drosophila immunity laboratory, led by Prof. Bruno Lemaitre, and that of human genomics, led by Prof. Jacques Fellay, aims to decode the variability in the genome related to variation in immunocompetence and to find parallels between the human and Drosophila genomes. By simulating a real population in the lab, could we find universal laws governing how host-pathogen interactions shape the genome of the host at the level of a population? If this is proven true, how can we harvest the power of Drosophila genetics to better understand human variability and perhaps devise better preventive and therapeutic strategies that take into account the variations harbored in different patients and populations?

Direct link to Lay Summary

Last update: 21.02.2013

Communication	Title	Media	Place	Year

Number	Title	Start	Funding scheme

General aims: The study of genetic polymorphisms in natural populations is an important approach to understanding complex traits, both their underlying molecular mechanisms and their evolutionary history. In the post-genomic era supported by next-generation sequencing and genotyping technologies, a plethora of genetic information is available to aid researchers. As useful as this information may be, our understanding of biological complexity increases at a slower rate than our ability to procure raw data.Background and significance: Natural polymorphisms in human populations have been shown to be associated with complex disease risk, infection risk, and other quantitative traits. Consequently, a trend towards personalized medicine in which medicine is prescribed with prior knowledge of the patient’s genetic composition has emerged recently in some academic and pharmaceutical research endeavors. The success of such efforts will revolutionize healthcare and introduce novel strategies to cure disease. The genetic model organism, Drosophila melanogaster, provides opportunities with which to examine the underlying genetic basis of complex traits.Research approach: This project aims to better understand the effect of natural variations in populations on response to infection using the Drosophila melanogaster immune system as a model. Using a genetically tractable model system such as Drosophila has many advantages, the most important of which is the level of knowledge of its genetics and the large number of tools that have been accumulated during decades of research. Recently, a panel of 192 inbred Drosophila lines derived from a natural population, the Drosophila Genetic Reference Panel (DGRP), has been completely sequenced. Substantial polymorphism was found in these lines and they can be thought of as a representative sample of variations within the population. Studies on Drosophila can be performed under controlled conditions, large sample sizes, with reproducible experiments, and defined, stable inbred lines. This would help eliminate experimental and random errors and clarify the contribution of genetic variations to the observed phenotype.Briefly, the approach will involve associating variability in survival to infection with variations in the Drosophila genome, which might lead to the characterization of new candidate genes and functional elements related to survival after infection. A bioinformatics survey of the polymorphisms in immunity-related genes will shed light on the evolutionary history of the different components of the immune system. Finally, genetic variants found to play a role in Drosophila immunocompetence will be tested in human populations: genome-wide genotyping and sequencing data from infectious disease and healthy cohorts will be used to search for similar mutations and to investigate the potential immune-related role of corresponding genes and pathways.This project will benefit from the expertise of the Lemaitre laboratory on insect immunity and the Fellay laboratory on human genomic studies related to infectious diseases. Thus, the selected students will benefit from a solid formation in quantitative genetic both in Drosophila - a model system amenable to experimental studies - and in humans populations, with a potential impact on human health.