Grant: Foundation Grant

Every two individuals are genetically different due to mutations inherited from their parents or new mutations that have accumulated during their lifetime. Most of these mutations have no noticeable consequences. Yet, a small number have strong effects and lead to inherited diseases and somatic ones, such as cancers. Some healthy individuals can tolerate the complete loss of genes, while others develop diseases in response to these mutations. The difference between benign and harmful mutations comes from the organization of the cellular machinery and the interaction between this organization and the thousands of mutations that make everyone unique. For instance, the human genome contains hundreds of genes with multiple copies and having these backup copies could be a strong determinant of the resilience of the cell to otherwise harmful mutations. Here we propose an innovative research program that will elucidate these mechanisms of resilience and sensitivity to mutations of the eukaryotic cell. Our approach will involve cutting edge technologies in genome sequencing, high-throughput screening, genome editing and bioinformatics to determine what are the effects of disease and non-disease mutations directly on the inner organization of the cell. Our discoveries will shed light on the mechanisms of resilience and fragility to mutations in addition to providing mechanistic details on how human disease mutations alter the inner cell machinery. This will lead to more powerful approaches for the prediction of disease susceptibility and outcome from genome sequences, as well as to the development of knowledge-guided drug development.