Grant: Project Grant

Rapid advances in genomic technologies have led to discoveries of important genes for many diseases. For example, there are now 100s of genes known to be involved in autism, but for the vast majority of them, we don't understand why mutations in them lead to autism, so we can't design medicines to reverse the problem. We do know that these genes encode proteins, and many of the proteins include floppy parts (referred to as intrinsically disordered regions or IDRs) that don't follow the expected patterns of protein function and evolution. A major breakthrough in the past few years was to realize that the IDRs have molecular properties such as electric charge, solubility in water, repeated amino acids, etc. These molecular properties can be discerned from the amino acid sequences, and we want to test whether these properties determine function by systematically searching for all the important properties, and then making synthetic proteins that have those properties and see if they can carry out normal protein function. We will have to do this for some example intrinsically disordered regions whose functions we do understand. At the same time, we will start to predict the function of disease genes based on these molecular properties, and interpret the effects of disease mutations. This help us understand what is going wrong when these proteins are mutated in disease.