Title: Comparison of Modules of Wild Type and Mutant Huntingtin and TP53 Protein Interaction Networks: Implications in Biological Processes and Functions Show Chinese title

Title: 野生型和突变型猎得蛋白与TP53蛋白相互作用网络的比较：对生物过程和功能的意义

Abstract: Disease-causing mutations usually change the interacting partners of mutant proteins. In this article, we propose that the biological consequences of mutation are directly related to the alteration of corresponding protein protein interaction networks (PPIN). Mutation of Huntingtin (HTT) which causes Huntington's disease (HD) and mutations to TP53 which is associated with different cancers are studied as two example cases. We construct the PPIN of wild type and mutant proteins separately and identify the structural modules of each of the networks. The functional role of these modules are then assessed by Gene Ontology (GO) enrichment analysis for biological processes (BPs). We find that a large number of significantly enriched (p<0.0001) GO terms in mutant PPIN were absent in the wild type PPIN indicating the gain of BPs due to mutation. Similarly some of the GO terms enriched in wild type PPIN cease to exist in the modules of mutant PPIN, representing the loss. GO terms common in modules of mutant and wild type networks indicate both loss and gain of BPs. We further assign relevant biological function(s) to each module by classifying the enriched GO terms associated with it. It turns out that most of these biological functions in HTT networks are already known to be altered in HD and those of TP53 networks are altered in cancers. We argue that gain of BPs, and the corresponding biological functions, are due to new interacting partners acquired by mutant proteins. The methodology we adopt here could be applied to genetic diseases where mutations alter the ability of the protein to interact with other proteins. Show Chinese abstract

Abstract: 致病突变通常会改变突变蛋白的相互作用伙伴。本文提出，突变的生物学后果与相应蛋白质-蛋白质相互作用网络（PPIN）的改变直接相关。我们以亨廷顿病（HD）相关的亨廷顿蛋白（HTT）突变和与不同癌症相关的TP53突变为例，分别研究了这两种情况。我们单独构建野生型和突变型蛋白的PPIN，并识别每个网络的结构模块。然后通过基因本体论（GO）富集分析对这些模块的功能角色进行评估，特别是针对生物过程（BPs）。我们发现，突变PPIN中有大量显著富集（p<0.0001）的GO术语在野生型PPIN中不存在，这表明由于突变导致BP的增加。同样，一些在野生型PPIN中富集的GO术语在突变型PPIN的模块中不再存在，表示BP的减少。在突变型和野生型网络模块中共有的GO术语则表明BP的减少和增加。我们进一步通过分类与其相关的富集GO术语，为每个模块分配相关的生物功能。结果表明，HTT网络中的大多数这些生物功能在HD中已知被改变，而TP53网络中的生物功能在癌症中也被改变。我们认为，BP和相应的生物功能的获得是由于突变蛋白获得了新的相互作用伙伴。我们采用的方法可以应用于那些突变改变蛋白与其他蛋白相互作用能力的遗传疾病。