Increasing knowledge about the organization of proteins into complexes, systems, and pathways has led to a flowering of theoretical approaches for exploiting this knowledge in order to better learn the functions of proteins and their roles underlying phenotypic traits and diseases. Much of this body of theory has been developed and tested in model organisms, relying on their relative simplicity and genetic and biochemical tractability to accelerate the research. In this review, we discuss several of the major approaches for computationally integrating proteomics and genomics observations into integrated protein networks, then applying guilt-by-association in these networks in order to identify genes underlying traits. Recent trends in this field include a rising appreciation of the modular network organization of proteins underlying traits or mutational phenotypes, and how to exploit such protein modularity using computational approaches related to the internet search algorithm PageRank. Many protein network-based predictions have recently been experimentally confirmed in yeast, worms, plants, and mice, and several successful approaches in model organisms have been directly translated to analyze human disease, with notable recent applications to glioma and breast cancer prognosis.
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