Suzannah Rutherford

An issue of fundamental importance from evolutionary biology to medicine is the stabilization of physiology and development against genetic and environmental variation. A huge amount of molecular variation affecting signal transduction is hidden in phenotypically normal populations. This variation accounts for common heritable differences in disease predisposition and is critical for the evolution of developmental pathways. How do species remain morphologically distinct and constant over time? Conversely, how can they evolve under a changing environment?

We use standard quantitative and molecular genetics combined with emerging genome-wide approaches to study latent genetic variation in Hsp90-dependent signaling networks. Hsp90 is a chaperone for critical cell cycle and developmental regulators, including many tumor suppressors and oncogenes. Polymorphic genes that are buffered by Hsp90 in model organisms are candidate genes for human disease and targets for the evolution of development. When Drosophila Hsp90 is impaired, stunning developmental abnormalities are revealed. These depend on previously cryptic variants specific to different genetic backgrounds, and can be enriched by laboratory selection. Using these lines, we have mapped nearly a dozen determninants of a complex Hsp90-dependent eye trait in Drosophila and we are now cloning the genes involved. In a separate project, we have created a library of genetic variation from wild isolates of budding yeast. We are using these lines to explicitly study the role of Hsp90 in maintaining variation in target kinase pathways, stress responses, and adaptation. By manipulating Hsp90 buffering in model organisms we study polymorphic genes and pathways that are critical for the evolution of development and the progression of disease.