The Causes of Genetic Variation in Susceptibility to Infectious Disease in Natural Populations

The aim of this project is to understand why some individuals in populations are more susceptible to infectious disease than others. This variation not only determines the impact of disease on human health, crop yields and farm animals, but it is also the raw material on which natural selection acts when populations evolve resistance to infection. Despite its importance, we have a poor understanding of the genes that underlie this variation and the evolutionary reasons why it is maintained in populations are poorly understood.

The first question we will ask is simply whether natural selection is increasing genetic variation in susceptibility to infection. To do this we will test whether host populations that naturally encounter a pathogen show more genetic variation in susceptibility to that pathogen. To do this we will infect six species of fruit flies with six different viruses, and see whether there is more variation when a virus infects its natural host.

The second question we will ask is whether natural selection means that susceptibility to infection has a simple genetic basis, with just a few genes having large effects on the chances of an individual being infected. Using some of the same fly species and viruses, we will sequence the genomes of resistant and susceptible flies, and use this information to identify genes causing resistance. We will then be able to see whether there is a simple genetic basis to resistance only when a virus infects its natural host but not when it infects a different species. We can then go on to use statistical methods to understand how natural selection has acted on these genes.

The final question we will ask is whether hosts become resistant by improving their defences, or preventing parasites from hijacking the host's own molecular machinery for the parasite's benefit. We will answer this by genetically manipulating flies to see if the susceptible form is required for by the virus (the 'hijacking' hypothesis) or the resistant form is harming the virus (the 'improving defences' hypothesis).

The primary aim of this grant is to contribute to our fundamental understanding of disease biology. The main impact of our work will therefore be in informing the work of other researchers (such as those doing disease association studies or running breeding programs), which will in turn have impact on health, the economy or environment. This section is to describe the impact outside the 'investigators immediate professional circle', and we therefore include researchers in different fields, especially those doing applied research with direct consequences for health, the environment or the economy.

Public understanding of science

The determinants of disease susceptibility is an easily accessible topic to the public - people care what determines why they might get ill, or why a mosquito might transmit a disease. This makes it an excellent tool with which to engage the public about evolutionary concepts, and make the case that evolution can affect their lives rather than being an arcane academic discipline. We will exploit this using the approaches described in the 'pathways to impact'.

Variation in disease susceptibility

The majority of research in disease susceptibility is either directly medical research or selective breeding of animal and plants. This work is carried out by both the commercial and public sectors. It is by influencing this work that our research is most likely to have substantive impacts outside of evolutionary biology.

These sectors can benefit both by understanding the fundamental biology of the traits they work on. For example, strategies like marker-assisted selection may be far more successful in selecting for resistance to a naturally occurring pathogen (simple genetics) than a newly introduced pathogen (genes of small effect). Similarly, genetic testing of patients might be more effective for infectious disease than non-communicable disease (again due to simple versus complex genetic basis).

These sectors can also benefit by using the techniques and approaches that we have developed. For example, we will provide rapid and cost-effective ways to identify resistance genes that could be used in selective breeding. Currently selective genotyping of extreme phenotypes followed by pooled sequencing is not widely used in commercial and applied research, so illustrating the power of these approaches and promoting their use will benefit these applications.

Control of vector-borne disease

Mosquito-borne viral diseases are a major cause of mortality and morbidity in the developing world, and a major determinant of their prevalence is the rate at which mosquitoes can transmit disease. Current control approaches based on insecticide spraying and insecticide treated bed nets can fail due to the evolution of insecticide resistance, which has led to increasing interest in 'genetic' control methods. Releases of transgenic mosquitoes have already occurred, illustrating the utility of these approaches.

This work will lead to a greater understanding of why insects vary in viral susceptibility, which will inform efforts to control these diseases and monitor populations of mosquitoes for their vector competence.

One long-term possibility is to use the genetic variants that we discover as the basis of approaches to control vector-borne disease. Gene drive systems could be used to drive resistance genes through populations, preventing mosquitoes from vectoring disease. The identification of genes which naturally prevent viral infection will be promising candidates for this strategy.