Capturing the impact of genetic variation contributing to biological diversity remains a daunting challenge in the face of expanding human genome information. To understand the environment sensitive transformation of the genotype to the phenotype that is unique to each one of us, we build population-based landscapes to explore the biologic organization of the protein fold and its function in the context of human biology at atomic resolution. Emergent landscape design elements revealed by sequence changes in human protein misfolding diseases reveal a remarkable level of variation sensitive protein-fold dynamics that impact stability, endomembrane trafficking and function. Population-based landscapes reveal hidden properties of the protein fold tuned by cell and tissue specific interactive communities, providing guidance for application of precision medicine to clinical management of the individual.

Cell surface receptor uptake via clathrin-mediated endocytosis (CME) and subsequent intracellular sorting for degradation or recycling regulates the strength and specificity of downstream signaling. Signaling, in turn, modulates early endocytic trafficking. This reciprocal regulation of signaling and endocytosis provides opportunities for the establishment of feedback loops that allow cancer cells to 'adapt' their endocytic trafficking and alter surface-derived signals to enhance cell survival, migration and proliferation.