Scheme: University Research Fellowship
Organisation: University of Cambridge
Dates: Oct 2011-Sep 2014
Summary: In recent years genome-wide association studies have been widely used to identify genetic variants that affect susceptibility to disease. This work tends to involve non-communicable disease in humans, and often identifies variants of modest effect that explain only a small proportion of the genetic variation in disease susceptibility. We have taken advantage of a panel of inbred fly lines with complete genome sequences to investigate the genetic basis of virus resistance in the fruit fly Drosophila melanogaster. Using viruses that naturally infect this species, we found a high level of genetic variation, much of which is due to a small number of genetic variants which have a large effect on virus resistance. Previous work has shown that two of these variants resulted from recent mutations that increased resistance and have been driven to a high frequency by natural selection. Furthermore, we did not find similar major-effect variants when we infected flies with viruses isolated from other species of insects. Therefore, selection for virus resistance appears to increase genetic variation in susceptibility to viral infection. Understanding the function of the genes we have identified promises to give new insights into the antiviral defences of insects.
Dates: Jan 2007-Sep 2011
Summary: The survival of all animals relies on their ability to defend themselves against a variety of pathogenic viruses and micro-organisms. There are often large genetic differences between individuals of the same species in their ability to resist infection by these pathogens. This project aims to identify the genes that cause these differences. This will allow us to understand both the molecular reasons why some individuals are susceptible to infection, and the evolutionary reasons why natural selection hasn’t eliminated susceptibility genes from the population.
We have found that in the fruit flies, there is an ongoing arms race in which hosts evolve new defences and parasites evolve to overcome these defences. This means that within populations of hosts, old versions of genes that are susceptible to infection are continually being replaced by new resistant versions. However, the parasites tend to be ahead in this evolutionary battle. This is partly because parasites die when they encounter a resistant host, but hosts rarely encounter the parasites, and infection only makes them slightly sick. In other words parasite benefit more from infecting their hosts than the host benefits from being resistant.
We have also identified two new genes that make fruit flies resistant to viruses. These promise to give us new insights into what determines whether a virus can infect a cell, which may give us insights into how mosquitoes interact with the viruses they transmit to humans.
The lab is now extending this research to a mosquito that transmits human pathogens like dengue fever and yellow fever. The ultimate aim of this work will be to develop new strategies to control these deadly diseases.