Composition of a regulatory locus and the impact on phenotype and disease

Mutations that cause birth defects are increasingly found not in genes themselves, but in the DNA switches that turn genes on and off. For decades, scientists assumed that disease-causing mutations mostly disrupted the protein-coding parts of genes. That view has shifted. It is now clear that the majority of mutations linked to disease and human variation lie outside genes, in regulatory regions called enhancers that control when and where proteins are made. This project focuses on how changes in these enhancers lead to congenital abnormalities. Around 1 in 100 human pregnancies results in a deformity, with some of the most common affecting the skeleton of the arms and legs, and the structure of the head and face. The researchers have already identified mutations in regulatory domains responsible for a range of these deformities, using mouse models. Their goal is to understand the mechanism by which such mutations cause defects. This is fundamental science: it asks how the genome’s control circuitry works during development. A deeper understanding of these regulatory mechanisms could eventually inform prenatal diagnostics or suggest targets for intervention, but the immediate payoff is a clearer picture of how the non-coding genome shapes human health and disease.