Mutations in malformation and disease. (360G-Wellcome-102731_Z_13_Z)

Mutation - a new change in the DNA sequence - is the fundamental basis of most genetically determined diseases, because the consequence is to alter either the composition, or the levels of, particular proteins in the body. This proposal will study mutation and its effects in two distinct but complementary ways. First, it will search for new genes or mutational mechanisms in one particular group of clinically important malformations affecting the skull and face. This work will provide new diagn oses and genetic counselling for affected families. Second, it will analyse the way that certain mutations arise in men's testes and can become enriched over time, increasing the risk that they will be transmitted to children. These seemingly disparate approaches are unexpectedly linked because the body uses the same signalling mechanisms in the very different contexts of the skull and the reproductive cells. Over the five year period of this proposal, the aim is to broaden the scope of previo us investigations and seek evidence that similar mechanisms may shape the occurrence of mutations in a wider range of diseases, including some cancers and neurodevelopmental conditions such as autism and schizophrenia.