Convergent perturbation of the human domain-resolved interactome by viruses and mutations inducing similar disease phenotypes

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.

系统医学（systems medicine）的一项重要目标，是在人类互作组网络（human interactome network）受到遗传与环境扰动的背景下研究疾病。对于同时兼具遗传与感染诱因的疾病，一项关键假说认为：疾病突变或病原体对人类互作组网络产生的相似扰动，可引发相似的疾病表型。截至目前，该假说仅在少数病毒物种的全蛋白层面得到过验证。本研究拓展了所考察的病毒物种范围，并以蛋白质结构域（protein domains）的更高分辨率层面，更为严谨地验证了这一假说。本研究聚焦同时兼具遗传与病毒诱因的疾病，发现内源性遗传突变与外源性病毒蛋白均可诱导相似的疾病表型，并对人类结构域解析型互作组（domain-resolved interactome）产生显著的趋同扰动。泛癌（pan-cancer）与泛致癌病毒（pan-oncovirus）分析进一步揭示：被致癌病毒（oncoviruses）在物理层面靶向或结构层面模拟的人类癌蛋白结构域，显著富集癌症驱动突变（cancer driver mutations）而非乘客突变（passenger mutations），这提示多种致癌病毒可对癌症驱动通路产生趋同靶向作用。本研究提供了一套高分辨率、基于网络的分析框架，可用于从各类遗传与环境疾病诱因对人类互作组网络的影响层面，开展对比研究。