IDENTIFICATION OF GENES CONTROLLING BIOLOGICAL PROCESSES AND PATHWAYS THROUGH STATISTICAL ANALYSIS AND NETWORK RECONSTRUCTION

The developmental processes and functions of an organism are controlled by the genes and the proteins that are derived from these genes. The identification of key genes and the reconstruction of gene networks can provide a model to help us understand the regulatory mechanisms for the initiation and progression of biological processes or functional abnormalities (e.g. diseases) in living organisms. In this dissertation, I have developed statistical methods to identify the genes and transcription factors (TFs) involved in biological processes, constructed their regulatory networks, and also evaluated some existing association methods to find robust methods for coexpression analyses. Two kinds of data sets were used for this work: genotype data and gene expression microarray data. On the basis of these data sets, this dissertation has two major parts, together forming six chapters. The first part deals with developing association methods for rare variants using genotype data (chapter 4 and 5). The second part deals with developing and/or evaluating statistical methods to identify genes and TFs involved in biological processes, and construction of their regulatory networks using gene expression data (chapter 2, 3, and 6). For the first part, I have developed two methods to find the groupwise association of rare variants with given diseases or traits. The first method is based on kernel machine learning and can be applied to both quantitative as well as qualitative traits. Simulation results showed that the proposed method has improved power over the existing weighted sum method (WS) in most settings. The second method uses multiple phenotypes to select a few top significant genes. It then finds the association of each gene with each phenotype while controlling the population stratification by adjusting the data for ancestry using principal components. This method was applied to GAW 17 data and was able to find several disease risk genes. For the second part, I have worked on three problems. First problem involved evaluation of eight gene association methods. A very comprehensive comparison of these methods with further analysis clearly demonstrates the distinct and common performance of these eight gene association methods. For the second problem, an algorithm named the bottom-up graphical Gaussian model was developed to identify the TFs that regulate pathway genes and reconstruct their hierarchical regulatory networks. This algorithm has produced very significant results and it is the first report to produce such hierarchical networks for these pathways. The third problem dealt with developing another algorithm called the top-down graphical Gaussian model that identifies the network governed by a specific TF. The network produced by the algorithm is proven to be of very high accuracy.

MODULARITY BASED FUZZY COMMUNITY DETECTION IN SOCIAL NETWORKS

Fuzzy community detection is to identify fuzzy communities in a network, which are groups of vertices in the network such that the membership of a vertex in one community is in [0,1] and that the sum of memberships of vertices in all communities equals to 1. Fuzzy communities are pervasive in social networks, but only a few works have been done for fuzzy community detection. Recently, a one-step forward extension of Newman’s Modularity, the most popular quality function for disjoint community detection, results into the Generalized Modularity (GM) that demonstrates good performance in finding well-known fuzzy communities. Thus, GMis chosen as the quality function in our research. We first propose a generalized fuzzy t-norm modularity to investigate the effect of different fuzzy intersection operators on fuzzy community detection, since the introduction of a fuzzy intersection operation is made feasible by GM. The experimental results show that the Yager operator with a proper parameter value performs better than the product operator in revealing community structure. Then, we focus on how to find optimal fuzzy communities in a network by directly maximizing GM, which we call it Fuzzy Modularity Maximization (FMM) problem. The effort on FMM problem results into the major contribution of this thesis, an efficient and effective GM-based fuzzy community detection method that could automatically discover a fuzzy partition of a network when it is appropriate, which is much better than fuzzy partitions found by existing fuzzy community detection methods, and a crisp partition of a network when appropriate, which is competitive with partitions resulted from the best disjoint community detections up to now. We address FMM problem by iteratively solving a sub-problem called One-Step Modularity Maximization (OSMM). We present two approaches for solving this iterative procedure: a tree-based global optimizer called Find Best Leaf Node (FBLN) and a heuristic-based local optimizer. The OSMM problem is based on a simplified quadratic knapsack problem that can be solved in linear time; thus, a solution of OSMM can be found in linear time. Since the OSMM algorithm is called within FBLN recursively and the structure of the search tree is non-deterministic, we can see that the FMM/FBLN algorithm runs in a time complexity of at least O (n2). So, we also propose several highly efficient and very effective heuristic algorithms namely FMM/H algorithms. We compared our proposed FMM/H algorithms with two state-of-the-art community detection methods, modified MULTICUT Spectral Fuzzy c-Means (MSFCM) and Genetic Algorithm with a Local Search strategy (GALS), on 10 real-world data sets. The experimental results suggest that the H2 variant of FMM/H is the best performing version. The H2 algorithm is very competitive with GALS in producing maximum modularity partitions and performs much better than MSFCM. On all the 10 data sets, H2 is also 2-3 orders of magnitude faster than GALS. Furthermore, by adopting a simply modified version of the H2 algorithm as a mutation operator, we designed a genetic algorithm for fuzzy community detection, namely GAFCD, where elite selection and early termination are applied. The crossover operator is designed to make GAFCD converge fast and to enhance GAFCD’s ability of jumping out of local minimums. Experimental results on all the data sets show that GAFCD uncovers better community structure than GALS.

DISSECTION OF STRESS RESPONSE NETWORKS REGULATING MULTIPLE STRESSES IN RICE

Important food crops like rice are constantly exposed to various stresses that can have devastating effect on their survival and productivity. Being sessile, these highly evolved organisms have developed elaborate molecular machineries to sense a mixture of stress signals and elicit a precise response to minimize the damage. However, recent discoveries revealed that the interplay of these stress regulatory and signaling molecules is highly complex and remains largely unknown. In this work, we conducted large scale analysis of differential gene expression using advanced computational methods to dissect regulation of stress response which is at the heart of all molecular changes leading to the observed phenotypic susceptibility. One of the most important stress conditions in terms of loss of productivity is drought. We performed genomic and proteomic analysis of epigenetic and miRNA mechanisms in regulation of drought responsive genes in rice and found subsets of genes with striking properties. Overexpressed genesets included higher number of epigenetic marks, miRNA targets and transcription factors which regulate drought tolerance. On the other hand, underexpressed genesets were poor in above features but were rich in number of metabolic genes with multiple co-expression partners contributing majorly towards drought resistance. Identification and characterization of the patterns exhibited by differentially expressed genes hold key to uncover the synergistic and antagonistic components of the cross talk between stress response mechanisms. We performed meta-analysis on drought and bacterial stresses in rice and Arabidopsis, and identified hundreds of shared genes. We found high level of conservation of gene expression between these stresses. Weighted co-expression network analysis detected two tight clusters of genes made up of master transcription factors and signaling genes showing strikingly opposite expression status. To comprehensively identify the shared stress responsive genes between multiple abiotic and biotic stresses in rice, we performed meta-analyses of microarray studies from seven different abiotic and six biotic stresses separately and found more than thirteen hundred shared stress responsive genes. Various machine learning techniques utilizing these genes classified the stresses into two major classes' namely abiotic and biotic stresses and multiple classes of individual stresses with high accuracy and identified the top genes showing distinct patterns of expression. Functional enrichment and co-expression network analysis revealed the different roles of plant hormones, transcription factors in conserved and non-conserved genesets in regulation of stress response.