Grant: Project Grant

Why do people have different risks of getting specific diseases? In part, the answer lies in their genes. We know hundreds of mutations that cause genetic diseases e.g. inheriting mutant forms of the CFTR gene causes cystic fibrosis. However, even in well-known examples, the situation is complex - two people inheriting the exact same mutation can have very different severity of symptoms. At present we do not understand the basic mechanisms underlying this. Our goal in this project is to use the powerful genetic tools available in the nematode worm C. elegans to examine systematically why the same mutation can have different effects on different individuals. We will compare how changing each of ~1400 genes affects 10 different worm strains - these 10 strains are as different as 10 different people. This study will yield the first view of the effect of genetic variation on mutant phenotypes in any species and will tell us how to predict this. We already measured the mutant phenotypes of ~1400 genes in 2 worm isolates in a pilot study. We found that ~20% of genes had different mutant phenotypes in this pair of worm isolates showing that genetic differences between individuals often have a major effect on mutant phenotypes. Crucially, we find that we can predict some of these differences in severity, a major step - this study yielded two high profile publications. We now propose to extend this study to 10 worms - comparing 2 worms was just a start. This will give us much more power to investigate the causes of the differences in severity of mutant phenotypes. It will also give us a large enough dataset to begin to build models that will predict the severity of a mutant phenotype in any individual. Ultimately, uncovering the basic principles that govern why the same mutation can have such different disease outcomes in different people will have a key impact on our understanding of genetic disorders in humans.