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

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It was assumed that most mutations/variations that cause human diseases would be due to changes in the coding regions of genes affecting the structure of proteins. This view has changed dramatically over recent years and it is now clear that the majority of mutations related to disease predisposition and even variability within the human population occur outside genes. The assumption is that these differences reside in regions of the DNA (known as regulatory domains or enhancers) that control protein production in the cell. Our research focusses on how changes in these regulatory domains can lead to congenital abnormalities. Although development of the human foetus is highly reliable, in approximately 1 in 100 cases deformities occur. Some of the most frequent abnormalities that occur affect the skeleton of the arms and legs and structure of the head and face. We have identified mutations in regulatory domains responsible for a spectrum of deformities in these features of the newborn, by using mammalian model systems such as the mouse and our goals are to investigate the mechanism by which this class of mutations causes congenital defects.