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

I am interested in the mutational processes that cause malformation and disease, and in relating these to the molecular pathways that are perturbed as a consequence. Using high-throughput sequencing, it is now realistic to obtain an unbiased inventory of mutations relevant to serious human diseases, in a manner that conceptually resembles the saturated mutagen-driven screens undertaken in recent decades in model organisms. The advantage of applying this approach to humans is that it impacts dire ctly on clinical disease, rather than relying on interspecies homology. I will investigate two different but complementary disease contexts, in both of which the contribution of single gene mutations is well established, but the inventory of mutations is incomplete: craniosynostosis, and mutations enriched in normal testes and sperm. Aim 1: The malformation that is the primary focus of this work is craniosynostosis, the premature fusion of the cranial sutures. Our data show that genetic causati on in craniosynostosis is currently undersampled. The five-year goal is to identify all monogenic causes of craniosynostosis that comprise over 0.5% of all affected individuals. The downstream goals will be first, to delineate groupings of gene mutations, in each of which craniosynostosis occurs by perturbing signalling in cranial sutures at similar developmental and tissue timepoints; and second, to explore therapeutic approaches in selected cases. Aim 2: We have delineated a novel disease pr ocess, termed selfish spermatogonial selection, which leads to the enrichment of specific pathogenic mutations in sperm. We wish to obtain a more complete inventory of the mutations subject to this phenomenon, and thereby identify the pathways in the testis that are vulnerable to this process. This work will provide fundamental understanding of an important and newly recognised mechanism contributing to serious human malformations and a platform to investigate its broader relevance to complex di sorders and disease susceptibility.