Research
Probing inter- and intra-individual variation
Many diseases display significant interindividual variation in phenotypic penetrance, severity, and treatment response. Within individuals, homogeneous cell types can differ in the abundance or localization of molecules. However, there is a critical gap in our understanding of mechanisms driving both inter- and intra- individual variation, particularly in the human brain. We hypothesize that some brain diseases drive increased variability in molecular expression, not just differential expression, which contributes to observed phenotypes. We are therefore investigating non-genetic sources of variability and their impacts on neural development.
Investigating epigenetic mechanisms
Proper epigenetic regulation is essential for normal brain development, with dysregulation implicated in multiple neurodevelopmental disorders. Down syndrome (DS), caused triplication of human chromosome 21, is associated with a broad spectrum of neurological and non-neurological phenotypes, profound interindividual variation and significant changes in genome-wide gene expression patterns. We hypothesize that epigenetic re-wiring underlies a subset of phenotypes in DS. We are therefore analyzing histone changes across diverse individuals and cell types, testing their molecular reversibility, and assessing connections to core neurobiological phenotypes in DS.
