Sam Lee, Liu Yang, Li Jianrong, Friedman Carol, Lussier Yves A
Center for Biomedical Informatics and Section of Genetic Medicine, Department of Medicine; The University of Chicago, IL 60637, USA.
Pac Symp Biocomput. 2007:76-87.
The study of protein-protein interactions is essential to define the molecular networks that contribute to maintain homeostasis of an organism's body functions. Disruptions in protein interaction networks have been shown to result in diseases in both humans and animals. Monogenic diseases disrupting biochemical pathways such as hereditary coagulopathies (e.g. hemophilia), provided a deep insight in the biochemical pathways of acquired coagulopathies of complex diseases. Indeed, a variety of complex liver diseases can lead to decreased synthesis of the same set of coagulation factors as in hemophilia. Similarly, more complex diseases such as different cancers have been shown to result from malfunctions of common proteins pathways. In order to discover, in high throughput, the molecular underpinnings of poorly characterized diseases, we present a statistical method to identify shared protein interaction network(s) between diseases. Integrating (i) a protein interaction network with (ii) disease to protein relationships derived from mining Gene Ontology annotations and the biomedical literature with natural language understanding (PhenoGO), we identified protein-protein interactions that were associated with pairs of diseases and calculated the statistical significance of the occurrence of interactions in the protein interaction knowledgebase. Significant correlations between diseases and shared protein networks were identified and evaluated in this study, demonstrating the high precision of the approach and correct non-trivial predictions, signifying the potential for discovery. In conclusion, we demonstrate that the associations between diseases are directly correlated to their underlying protein-protein interaction networks, possibly providing insight into the underlying molecular mechanisms of phenotypes and biological processes disrupted in related diseases.
蛋白质-蛋白质相互作用的研究对于定义有助于维持生物体身体功能稳态的分子网络至关重要。蛋白质相互作用网络的破坏已被证明会导致人类和动物的疾病。单基因疾病破坏生化途径,如遗传性凝血病(如血友病),为深入了解复杂疾病获得性凝血病的生化途径提供了线索。事实上,多种复杂的肝脏疾病可导致与血友病相同的一组凝血因子合成减少。同样,诸如不同癌症等更复杂的疾病已被证明是由常见蛋白质途径的功能障碍引起的。为了高通量地发现特征不明疾病的分子基础,我们提出了一种统计方法来识别疾病之间共享的蛋白质相互作用网络。通过将(i)蛋白质相互作用网络与(ii)从挖掘基因本体注释和利用自然语言理解(PhenoGO)的生物医学文献中得出的疾病与蛋白质关系相结合,我们识别了与疾病对相关的蛋白质-蛋白质相互作用,并计算了蛋白质相互作用知识库中相互作用发生的统计显著性。在本研究中确定并评估了疾病与共享蛋白质网络之间的显著相关性,证明了该方法的高精度和正确的非平凡预测,表明了发现的潜力。总之,我们证明疾病之间的关联与它们潜在的蛋白质-蛋白质相互作用网络直接相关,这可能为深入了解相关疾病中破坏的表型和生物过程的潜在分子机制提供线索。
Pac Symp Biocomput. 2007
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