Department of Bioengineering, McGill University, Montreal, Quebec, Canada.
PLoS Comput Biol. 2019 Feb 13;15(2):e1006762. doi: 10.1371/journal.pcbi.1006762. eCollection 2019 Feb.
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.
系统医学的一个重要目标是在人类相互作用网络的遗传和环境扰动的背景下研究疾病。对于具有遗传和传染性因素的疾病，一个关键假设是，人类相互作用网络的相似扰动，无论是由疾病突变还是病原体引起的，都可能产生相似的疾病后果。到目前为止，这一假设仅在全蛋白水平上针对少数几种病毒物种进行了测试。在这里，我们扩展了所检查的病毒物种的范围，并在更高的蛋白结构域分辨率下更严格地测试了这一假设。我们关注既有遗传因素又有病毒因素的疾病，发现内源性遗传突变和诱导相似疾病表型的外源性病毒蛋白对人类结构域分辨相互作用组的显著趋同扰动。泛癌症、泛致癌病毒分析进一步表明，被致癌病毒物理靶向或结构模拟的人类致癌蛋白结构域富含癌症驱动而不是乘客突变，这表明不同致癌病毒对癌症驱动途径的趋同靶向。我们的研究为基于网络的高分辨率比较各种疾病因素（遗传和环境）对人类相互作用组的影响提供了一个框架。
