Grant: Project Grant

Current "personalized medicine" projects are identifying all the mutations in every patient, and we need to know which of those mutations are likely to cause diseases. About 1/5 of known disease mutations occur in enigmatic protein regions known as intrinsically disordered regions. When we discover new mutations in disordered regions, we currently can't tell which are harmful (drivers of disease) and which ones are benign (bystanders). Evolutionary analysis can point to biological function because functional sequences are preferentially preserved during evolution. If mutations in disordered regions disrupt features of disordered regions that have been preserved over evolutionary time, we predict that these are more likely to affect function and cause disease. Based on this principle, we propose to develop new bioinformatics to better predict the impact of mutations in disordered regions. To understand why disrupting the conserved features is harmful, we will test the impact of engineered mutations in yeast cells, because they are simpler and easier to study than human cells. In the end, we hope to develop better methods to predict the impact of mutations in disordered regions, and also understand why the mutations in these regions lead to disease.