中文摘要：一种严谨而通用的突变数学方法，尤其是能够提供系统级观点的方法非常宝贵。对于噬菌体-细菌相互作用和噬菌体治疗研究来说，噬菌体抗性的系统级理解也非常必要。在网络科学中，区分具有一组公共或相同节点的两个图并识别其含义的能力相当重要。
    本文提出了一种称为最短路径变换分数（SPAF）的方法来比较任意两个网络的最短路径。当SPAF为1时，它可以识别由至少一条最短路径连接的节点对，这些节点对存在于任一网络中，而不是同时存在于两个网络中。同样，SPAF等于零表示两个网络中节点对之间同时存在的相同最短路径。本文从理论上研究了该方法在五种不同微生物物种中的实用性，以捕捉充分研究过的突变的报告效应，并预测新的突变；还通过对耻垢分枝杆菌mc2155进行理论和实验测试，并通过产生一种对分枝杆菌噬菌体D29具有抗性的突变株mc2155，检验了该方法的有效性。这种对D29具有抗性的mc2155突变体表现出显著的表型改变。全基因组测序能确定突变，却难以解释观察到的表型。利用拓扑度量和微分网络的机制，对突变体和野生型的蛋白质-蛋白质相互作用网络进行详尽的分析，并不能得到清晰的图像。然而，SPAF从网络中数十万条可行的最短路径中一致地识别出了最短路径子集末端的蛋白质对。与蛋白质对相关的功能改变与观察到的表型密切相关。
外文摘要：Motivation: A rigorous yet general mathematical approach to mutagenesis, especially one capable of delivering systems-level perspectives would be invaluable. Such systems-level understanding of phage resistance is also highly desirable for phage-bacteria interactions and phage therapy research. Independently, the ability to distinguish between two graphs with a set of common or identical nodes and identify the implications thereof, is important in network science.
   Results: Herein, we propose a measure called shortest path alteration fraction (SPAF) to compare any two networks by shortest paths, using sets. When SPAF is one, it can identify node pairs connected by at least one shortest path, which are present in either network but not both. Similarly, SPAF equalling zero identifies identical shortest paths, which are simultaneously present between a node pair in both networks. We study the utility of our measure theoretically in five diverse microbial species, to capture reported effects of well-studied mutations and predict new ones. We also scrutinize the effectiveness of our procedure through theoretical and experimental tests on Mycobacterium smegmatismc2155 and by generating a mutant of mc2155, which is resistant to mycobacteriophage D29. This mutant of mc2155, which is resistant to D29 exhibits significant phenotypic alterations. Whole-genome sequencing identifies mutations, which cannot readily explain the observed phenotypes. Exhaustive analyses of protein-protein interaction network of the mutant and wild-type, using the machinery of topological metrics and differential networks does not yield a clear picture. However, SPAF coherently identifies pairs of proteins at the end of a subset of shortest paths, from amongst hundreds of thousands of viable shortest paths in the networks. The altered functions associated with the protein pairs are strongly correlated with the observed phenotypes.
 
外文关键词：RECA PROTEIN；CELL-WALL；BACTERIOPHAGE；TUBERCULOSIS；MUTATIONS； THERAPY；MUTANT
作者：Sinha, S；Samaddar, S；Das Gupta, SK；Roy, S
作者单位：Bose Inst
期刊名称：BIOINFORMATICS
期刊影响因子：5.61
出版年份：2021
出版刊次：2
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