Complex diseases often depend on genetic variation that is expressed only in certain genetic and environmental contexts. We attempt to understand this context-dependence by studying the processes by which it arises. This means studying how complex regulatory systems function, how they evolve, and how evolution causes them to become "canalized" or robust. This is achieved through computational simulations of the in silico development and evolution of ensembles of transcriptional networks. Another approach focuses on evolutionary capacitors, often using the yeast prion [PSI] as a model system. Capacitors are molecular mechanisms that store newly-appeared genetic variation, and phenotypically reveal it later. They therefore provide a window onto the nature of cryptic genetic variation. Our lab uses both theoretical population genetic and comparative genomic approaches to study evolutionary capacitance.