Abstract
The question how complex phenotypes arise from the biomolecules that constitute cells and tissues is fundamental to biology and medicine. Seminal research results from the 1940’s indicated that proteins determine phenotypes and that changes in the sequence, structure and organization of proteins in macromolecular complexes result in altered phenotypes, creating the notion of molecular disease.
Recent advances in massively parallel, bottom-up mass spectrometry based techniques, exemplified by SWATH-MS, have created the ability to confidently and routinely identify and quantify thousands of proteins from minute samples. Furthermore, a range of computational and experimental methods, including chemical cross-linking MS (XL-MS), cryoEM, single particle analysis, and correlative analyses of protein quantities across sample sets, are beginning to systematically probe the organization and structure of multi-protein modules and protein networks, thus generating the basis for the correlation of the state of the proteome with complex phenotypes.
In this presentation we will discuss emerging computational and laboratory techniques to determine the state of the proteome across large sample cohorts. Using selected applications involving extensively characterized genetic reference panels and cell line compendia, we will demonstrate how the state of the proteome is determined by genetic and environmental factors and how, in turn, the state of the proteome determines complex phenotypes. Overall, the results will highlight the significance of the organization of the proteins that constitute a proteome in complexes, networks and organelles for complex phenotypes.