Mechanisms of Incomplete Penetrance

About This Grant

Project Summary Incomplete penetrance is a common but poorly understood biological phenomenon in which one person with a genetic mutation develops a disease, while another person with the same mutation does not. This project outlines a trajectory from using zebrafish to model incomplete penetrance in my dissertation work to using patient derived models to study incomplete penetrance in my postdoctoral work. The overall goal of this project is to identify conserved mechanisms of incomplete penetrance that span multiple biological systems and genetic disorders. Specifically, this project focuses on paralogous compensation and DNA methylation of paralogs as shared mechanisms of incomplete penetrance. Paralogous compensation describes a phenomenon in which closely related genes can function in place of each other when one is lost. DNA methylation is a biochemical modification in that controls gene expression. Compensation by paralogs and differences in DNA methylation states have been identified as putative mechanisms of incomplete penetrance in both human diseases and in my system. In this work, both a zebrafish model system and patient-derived induced pluripotent stem cells (iPSCs) will be used to test whether altering paralog expression can be used to rescue a deleterious mutation. One genetic disorder displaying incomplete penetrance is MEF2C haploinsufficiency syndrome. Zebrafish mef2ca mutants can be used to model this disorder and display incomplete penetrance. In my dissertation work I seek to test the hypothesis that heritable changes in DNA methylation and paralog expression underlie incomplete penetrance. Aim 1.1 will use selective breeding to drive high or low phenotype penetrance and evaluate differences in the genome, transcriptome, and methylome that segregate with penetrance. Aim 1.2 will functionally test whether mef2 paralogs can compensate for mef2ca loss using zebrafish transgenic lines. These experiments will elucidate whether paralogs can functionally rescue gene loss, and whether paralog expression is the engine of selection when breeding for incomplete penetrance. To build upon this work and test whether the same mechanisms are conserved across systems, my postdoctoral work will be performed in iPSCs from patients and incompletely penetrant mutation carriers. This work will test the hypothesis that carriers of disease-causing mutations will have higher paralog expression and lower levels of methylation at paralog loci than their penetrant family members. Further work in this system will test whether paralog expression and methylation can be manipulated to replicate an incompletely penetrant condition. This work will provide insight into how we can harness mechanisms of incomplete penetrance to understand and eventually treat mendelian genetic disorders.