Mutational Scanning

Proper diagnosis of genetic diseases is very important for patients and their families. Thanks to advances in genome sequencing, doctors are now able to list all the mutations present in a patient’s genome - but the interpretation of these mutations is difficult. In our lab, we use experiments in yeast and human cells to study the consequences of mutations found in human patients. Our experiments are focused on selected genes including PAX6, mutations in which cause eye malformations, and TP53, frequently mutated in cancer. In our previous experiments, we found a surprisingly good agreement between mutations in PAX6 that cause slow growth of yeast, and mutations in the same gene that damage eye development in patients. This allows us to predict the severity for thousands of mutations that were never previously seen in patients. We now aim to move beyond disease prediction and understand why certain mutations are more harmful than others. To study this, we will measure how each mutation influences the collection of all RNA molecules found in cells, known as the transcriptome. We will also analyse thousands of mutated cells under the microscope. Applying artificial intelligence methods to these measurements will help us understand why mutations are harmful, and help find appropriate treatments. Finally we will measure the performance of candidate mRNA therapeutics in human cells, in order to develop protocols and software for the design of new mRNA therapies.