Phenotypic variability and gene haploinsufficiency

Most genes are present in two copies. Gene haploinsufficiency is a genetic disease mechanism by which the loss of one gene copy leads to disease. Why one copy of the some genes should be insufficient is unknown. Furthermore, it is common that diseases due to gene haploinsufficiency have a highly variable clinical presentation, with some individuals being very severely affected and others only mildly affected. This is obviously problematic for clinicians because the diagnosis of the disease offers little insight as to its likely outcome. Even identical twins may have different clinical problems. This tells us that non-genetic factors contribute to the variability. What are they? One category is "epigenetic" factors, these are factors, often proteins, that affect the activation of a gene but not its basic structure (DNA). The DNA in a cell has to be highly packaged in order to fit in the cell nucleus. Packaged DNA is called chromatin. When a gene needs to be activated (expressed) it is often necessary to loosen the packaging to allow access to proteins that activate gene expression (transcription factors). There are many proteins involved in changing the conformation of chromatin (chromatin modifiers) so as to expose or hide genes from transcription factors. In this way chromatin modifiers ensure that a gene will be activation at the right time and in the right place. In this study we will investigate how a known disease gene and transcription factor, Tbx1, interacts with chromatin and chromatin modifiers. Understanding this may be key to understanding how and why the loss of one copy of Tbx1 results causes a genetic disease with a variable clinical outcome. If chromatin modifiers are indeed important to the disease process, one can imagine that drugs targeting them may improve clinical outcome. We will test this in mouse models of a genetic disease.