Abstract
An important goal of systems medicine is to study disease in the context of genetic and environmental perturbations to the human interactome network. For diseases with both genetic and infectious contributors, a key postulate is that similar perturbations of the human interactome by either disease mutations or pathogens can have similar disease consequences. This postulate has so far only been tested for a few viral species at the level of whole proteins. Here, we expand the scope of viral species examined, and test this postulate more rigorously at the higher resolution of protein domains. Focusing on diseases with both genetic and viral contributors, we found significant convergent perturbation of the human domain-resolved interactome by endogenous genetic mutations and exogenous viral proteins inducing similar disease phenotypes. Pan-cancer, pan-oncovirus analysis further revealed that domains of human oncoproteins either physically targeted or structurally mimicked by oncoviruses are enriched for cancer driver rather than passenger mutations, suggesting convergent targeting of cancer driver pathways by diverse oncoviruses. Our study provides a framework for high-resolution, network-based comparison of various disease factors, both genetic and environmental, in terms of their impacts on the human interactome.
Highlights
Cellular function and behaviour are driven by highly coordinated biomolecular interaction networks
Recent advances in systems biology have spawned the view of human disease as a manifestation of genetic and environmental perturbations to the human interactome, a key postulate being that similar perturbation patterns lead to similar disease phenotypes
Recent advances in systems biology have spawned the view of human disease as a manifestation of genetic and environmental perturbations to the human interactome, a key postulate being that similar perturbation patterns lead to similar disease phenotypes [5,6,7,8]
Summary
Cellular function and behaviour are driven by highly coordinated biomolecular interaction networks. Gulbahce et al used yeast two-hybrid screens to map binary interactions between Epstein-Barr virus (EBV) and human papillomavirus (HPV) proteins and human proteins, and transcriptionally profiled human cell lines exogenously expressing HPV oncoproteins E6 and E7 [9]. They found that human genes associated with EBV- and HPV-implicated genetic diseases were often either directly targeted by the virus or transcriptionally regulated by viral targets. This finding led to the idea that oncoviral proteins may preferentially target host proto-oncogenes and tumour suppressors, which was experimentally validated in four families of DNA oncoviruses [10]
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