Origins and impacts of regulatory mutations

We study how alterations to DNA called mutations cause birth defects and cancers, based upon new computational analyses of large DNA sequencing datasets. Overall, the challenge is to find the small minority of mutations among many that affect gene functions and cause disease.
Mutations in sperm, eggs or the early embryo can cause a huge range of rare genetic disorders in children, but the mutations underlying most cases are unknown. We aim to understand the processes that lead to these mutations as parents age, to find the few mutations that really matter, and help clinicians to diagnose cases.
A tumour can accumulate many thousands of mutations in complex overlapping patterns, and we work to understand how combinations of mutations cooperate to drive cancer growth. This helps to match cancer patients to the most effective treatments, and may suggest new treatments in under-studied tumour types.
Our work links diverse researchers, NHS clinical staff and industry in multidisciplinary research that generates important new data as well as extracting new insights from existing data. Our projects are designed to reveal fundamental new knowledge about human disease, but also to open new possibilities in current medical practice.

Mutagenic processes give rise to a diverse array of mutations, from short variants affecting a single base-pair to structural variants altering multi-megabase regions. These processes are often biased to preferentially accumulate mutations in particular regions, including regulatory sites that direct gene expression. We and others have shown that these sites can incur elevated rates of mutation in germline and tumour cells, impacting gene regulation. Human genome structure itself is now known to be surprisingly labile in normal and tumour cells, though the origins and impacts of structural variants remain under studied. However, recent technological and algorithmic developments mean that a full understanding of the interacting roles of all variants underlying a disease state is within reach.
The overarching aim of this programme is to characterise the roles of mutational processes in human development and disease. We study genomic instability in the germline, to understand how mutational processes have shaped human gene regulation and may disrupt development. This complements our development of new algorithms to prioritise de novo mutations as candidate variants underlying developmental disorders. We also study mutation in structurally unstable tumours, such as high grade serous ovarian cancer and glioblastoma, to understand the roles of complex somatic mutation patterns in gene regulation and discover new biomarkers of cancer patient outcomes. Recurring themes include the effects of noncoding variation on gene expression, and the combinatorial effects of mutations on phenotypes. We generate and analyse a wide range of large human cohort sequencing datasets, linking diverse HGU and IGC research groups in multidisciplinary projects, in line with the HGU Genome Interpretation research theme. We form novel hypotheses that are tested with the aid of model systems and established HGU/IGC collaborations, as well as the excellent environment for bioinformatics we have established with others at the HGU. Our strong focus on computational biology provides the HGU with the specialised expertise required for big data handling, analysis based upon high performance computing, clinical data security and statistically rigorous science.