Abstract. The question how genetic variability is translated into phenotypic variability is fundamental in biology and medicine. Powerful genomic technologies now determine variability at a genomic level and at unprecedented speed, accuracy and (low) cost. Concurrently, life style monitoring devices and improved clinical diagnostic and imaging technologies generate phenotypic data at unprecedented volumes and resolution. However, the molecular mechanisms that translate genotypic variability into phenotypes are poorly understood and it has been generally challenging to make phenotypic predictions from genomic information alone.
Most biological processes are catalysed and controlled by proteins. This has led to the notion of “proteogenomics” a term that essentially links genomic variability to proteomic variability. To date, proteogenomic efforts have largely focused on the sequence level, using genomic sequences of a specific cell, tissue or organisms to precisely predict which protein and peptide are expected to be detectable in the specific sample.
In this presentation we extend the notion of proteogenomics from the sequence level to the organization of the proteome into functional modules. We define the term “proteotype” as a particular instance of a proteome in terms of its protein composition and organization of proteins into functional modules. We will discuss recent advances in SWATH/DIA mass spectrometry that support the fast, accurate and reproducible measurement of proteotypes. We will show with specific case studies that i) the proteotype is highly modular, ii) genotypic changes cause complex proteotype changes, particularly at the level of proteotype organization and iii) that altered proteotypes affect phenotypes.
At present the generation of a general model or theory that makes accurate predictions of the effects of genotypic variability on the biochemical state of a cell or organism seems out of reach. We therefore propose that precise proteotype measurement can serve as a close indicator of the biochemical state of a cell that reflects the response of the cell to (genomic) perturbation and is strong determinant of phenotypes.
Short Bio. Ruedi Aebersold is a Swiss and Canadian scientist trained at the Biocenter, University of Basel. He completed his education at Caltech. He is a Professor at ETH Zurich and the University of Zurich. He was on the faculties of the Universities of British Columbia and Washington and co-founded the Institute for Systems Biology in Seattle. He is on the SAB of a number of research organizations and has served as senior editor for Molecular and Cellular Proteomics and Molecular Systems Biology. He has co-founded several companies and holds several public service appointments.
The research focus of his group is the proteome. The group has pioneered several widely used techniques and generated a range of open access/open source software and statistical tools that have contributed to making proteomic research results transparent and accurate. The work has been recognized with numerous awards and prizes. More than 40 trainees of the group have reached faculty status at leading research institutions worldwide.