Project 444234

Congenital heart defects occur in close to 1% of live births, with heart abnormalities having a severe impact on the health and mortality of children. Like most genetic diseases, well over half of congenital heart diseases do not have a clear genetic explanation. The disruption of genetic elements that control the expression of genes (gene regulatory elements) can lead to congenital heart disease. However, we have a largely incomplete knowledge of the gene regulatory elements needed for heart development. In this study we will take a novel approach and compare active gene regulatory elements between human and zebrafish. Zebrafish embryos are powerful models to study heart function as they allow live and direct visualization of all stages of heart development. We will first identify conserved genetic elements that are active in early zebrafish development using genomics techniques that allow us to assign these gene regulatory elements to specific cell types and genes. We will use computational methods to compare these elements to similar elements found in mammals (human and mouse). We will test these elements for their ability to promote gene expression in different regions of the heart, and use this data to define the rules that control how gene activity in the heart is controlled, and will further determine what happens to zebrafish hearts when we disrupt or remove these genetic elements from the zebrafish genome. We will complement this work via collaboration with the Cardiac Genome Clinic at the Hospital for Sick Children to see if mutations of these gene regulatory elements are associated with congenital heart defects. Altogether, this work will expand the options for diagnosis and treatment available to patients and families affected by congenital heart disease.