Mammalian Developmental Genetics
Our lab is interested in the mechanisms responsible for birth defects in humans. For this, we are investigating a genetic condition termed 22q11.2 deletion syndrome (22q11.2DS). Patients have a 3 million base pair deletion of one copy of chromosome 22q11.2. Most patients are affected with intellectual disability, congenital heart disease and other malformations, occurring at varied severity.
To understand the reasons for varied severity, we are analyzing whole genome sequence from human subjects with 22q11.2DS to identify genetic modifiers. We recruited human subjects internationally and also through the new Montefiore-Einstein Regional Center for 22q11.2DS. Our hypothesis is that genes acting in the same genetic pathway as the deleted genes, act as modifiers of phenotypes. We are taking a candidate gene approach in which genes have been chosen from functional studies of mouse models of 22q11.2DS.
We are investigating the function of three genes, TBX1, DGCR8 and CRKL in mouse models. These genes are deleted in the 22q11.2 region. TBX1 encodes a T-box transcription factor, DGCR8 encodes a microRNA processor and CRKL encodes a cytoplasmic adaptor protein. Inactivation of either results in congenital heart defects in mice.
We are taking functional genomic and epigenomic approaches on a single cell level to understand the connections to disease. For TBX1, we identified a progenitor cell population that is required for cell fate transitions in heart development. For DGCR8, we are investigating canonical and non-canonical microRNA functions. For CRKL, we are studying its role in neural crest cells in mediating cell signaling required for heart development.
Finally, we are investigating TBX1, TBX2 and TBX3 in inner ear development in embryogenesis.