论文标题

可解释的网络传播,并应用于扩大与SARS-COV-2相互作用的人类蛋白质的曲目

Interpretable Network Propagation with Application to Expanding the Repertoire of Human Proteins that Interact with SARS-CoV-2

论文作者

Law, Jeffrey N., Akers, Kyle, Tasnina, Nure, Della Santina, Catherine M., Deutsch, Shay, Kshirsagar, Meghana, Klein-Seetharaman, Judith, Crovella, Mark, Rajagopalan, Padmavathy, Kasif, Simon, Murali, T. M.

论文摘要

背景:网络传播已在将近20年中广泛用于预测基因功能和表型。尽管这种方法很受欢迎,但在这种情况下,很少关注出处追踪问题,例如,确定输入中的任何实验性观察对每个预测的得分有何贡献。 结果:我们设计了一个具有两个新成分的网络传播框架,并将其应用于预测直接或间接与SARS-COV-2蛋白相互作用的人类蛋白质。首先,我们将每个预测的来源追溯到其经过实验验证的来源,在我们的情况下,这是人类蛋白质在实验上确定与病毒蛋白相互作用的。其次,我们设计了一种技术,有助于减少用户对参数的手动调整。我们发现,对于每个顶级预测,对其得分的最高贡献源于人类蛋白质 - 蛋白质相互作用网络中的直接邻居。我们进一步分析了这些结果,以开发有关SARS-COV-2的功能见解,这些洞察力扩展了已知生物学,例如内质网应激,HSPA5和抗封闭剂之间的联系。 结论:我们研究了如何将我们的出处追踪方法推广到一类基于网络的算法。我们为SARS-COV-2社区提供了有用的资源,这意味着许多以前无证件的蛋白质与病毒感染具有假定的功能关系。该资源包括可以在机会上重新定位以靶向这些蛋白质的潜在药物。我们还讨论了如何将我们的整体框架扩展到其他新出现的病毒。

Background: Network propagation has been widely used for nearly 20 years to predict gene functions and phenotypes. Despite the popularity of this approach, little attention has been paid to the question of provenance tracing in this context, e.g., determining how much any experimental observation in the input contributes to the score of every prediction. Results: We design a network propagation framework with two novel components and apply it to predict human proteins that directly or indirectly interact with SARS-CoV-2 proteins. First, we trace the provenance of each prediction to its experimentally validated sources, which in our case are human proteins experimentally determined to interact with viral proteins. Second, we design a technique that helps to reduce the manual adjustment of parameters by users. We find that for every top-ranking prediction, the highest contribution to its score arises from a direct neighbor in a human protein-protein interaction network. We further analyze these results to develop functional insights on SARS-CoV-2 that expand on known biology such as the connection between endoplasmic reticulum stress, HSPA5, and anti-clotting agents. Conclusions: We examine how our provenance tracing method can be generalized to a broad class of network-based algorithms. We provide a useful resource for the SARS-CoV-2 community that implicates many previously undocumented proteins with putative functional relationships to viral infection. This resource includes potential drugs that can be opportunistically repositioned to target these proteins. We also discuss how our overall framework can be extended to other, newly-emerging viruses.

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