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Predicting Protein Functions Based on Differential Co-expression and Neighborhood Analysis.

ABSTRACT: Proteins are polypeptides essential in biological processes. Protein physical interactions are complemented by other types of functional relationship data including genetic interactions, knowledge about co-expression, and evolutionary pathways. Existing algorithms integrate protein interaction and gene expression data to retrieve context-specific subnetworks composed of genes/proteins with known and unknown functions. However, most protein function prediction algorithms fail to exploit diverse intrinsic information in feature and label spaces. We develop a novel integrative method based on differential Co-expression analysis and Neighbor-voting algorithm for Protein Function Prediction, namely CNPFP. The method integrates heterogeneous data and exploits intrinsic and latent linkages via global iterative approach and genomic features. CNPFP performs three tasks: clustering, differential co-expression analysis, and predicts protein functions. Our aim is to identify yeast cell cycle-specific proteins linked to differentially expressed proteins in the protein-protein interaction network. To capture intrinsic information, CNPFP selects the most relevant feature subset based on global iterative neighbor-voting algorithm. We identify eight condition-specific modules. The most relevant subnetwork has 87 genes highly enriched with cyclin-dependent kinases, a protein kinase relevant for cell cycle regulation. We present comprehensive annotations for 3538 Saccharomyces cerevisiae proteins. Our method achieves an AUROC of 0.9862, accuracy of 0.9710, and F-score of 0.9691. From the results, we can summarize that exploiting intrinsic nature of protein relationships improves the quality of function prediction. Thus, the proposed method is useful in functional genomics studies.

SUBMITTER: Wekesa JS

PROVIDER: S-EPMC8030663 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundLarge-scale sequencing of entire genomes has ushered in a new age in biology. One of the next grand challenges is to dissect the cellular networks consisting of many individual functional modules. Defining co-expression networks without ambiguity based on genome-wide microarray data is difficult and current methods are not robust and consistent with different data sets. This is particularly problematic for little understood organisms since not much existing biological knowledge can be exploited for determining the threshold to differentiate true correlation from random noise. Random matrix theory (RMT), which has been widely and successfully used in physics, is a powerful approach to distinguish system-specific, non-random properties embedded in complex systems from random noise. Here, we have hypothesized that the universal predictions of RMT are also applicable to biological systems and the correlation threshold can be determined by characterizing the correlation matrix of microarray profiles using random matrix theory.ResultsApplication of random matrix theory to microarray data of S. oneidensis, E. coli, yeast, A. thaliana, Drosophila, mouse and human indicates that there is a sharp transition of nearest neighbour spacing distribution (NNSD) of correlation matrix after gradually removing certain elements insider the matrix. Testing on an in silico modular model has demonstrated that this transition can be used to determine the correlation threshold for revealing modular co-expression networks. The co-expression network derived from yeast cell cycling microarray data is supported by gene annotation. The topological properties of the resulting co-expression network agree well with the general properties of biological networks. Computational evaluations have showed that RMT approach is sensitive and robust. Furthermore, evaluation on sampled expression data of an in silico modular gene system has showed that under-sampled expressions do not affect the recovery of gene co-expression network. Moreover, the cellular roles of 215 functionally unknown genes from yeast, E. coli and S. oneidensis are predicted by the gene co-expression networks using guilt-by-association principle, many of which are supported by existing information or our experimental verification, further demonstrating the reliability of this approach for gene function prediction.ConclusionOur rigorous analysis of gene expression microarray profiles using RMT has showed that the transition of NNSD of correlation matrix of microarray profile provides a profound theoretical criterion to determine the correlation threshold for identifying gene co-expression networks.

Project description:Biological and medical sciences are increasingly acknowledging the significance of gene co-expression-networks for investigating complex-systems, phenotypes or diseases. Typically, complex phenotypes are investigated under varying conditions. While approaches for comparing nodes and links in two networks exist, almost no methods for the comparison of multiple networks are available and-to best of our knowledge-no comparative method allows for whole transcriptomic network analysis. However, it is the aim of many studies to compare networks of different conditions, for example, tissues, diseases, treatments, time points, or species. Here we present a method for the systematic comparison of an unlimited number of networks, with unlimited number of transcripts: Co-expression Differential Network Analysis (CoDiNA). In particular, CoDiNA detects links and nodes that are common, specific or different among the networks. We developed a statistical framework to normalize between these different categories of common or changed network links and nodes, resulting in a comprehensive network analysis method, more sophisticated than simply comparing the presence or absence of network nodes. Applying CoDiNA to a neurogenesis study we identified candidate genes involved in neuronal differentiation. We experimentally validated one candidate, demonstrating that its overexpression resulted in a significant disturbance in the underlying gene regulatory network of neurogenesis. Using clinical studies, we compared whole transcriptome co-expression networks from individuals with or without HIV and active tuberculosis (TB) and detected signature genes specific to HIV. Furthermore, analyzing multiple cancer transcription factor (TF) networks, we identified common and distinct features for particular cancer types. These CoDiNA applications demonstrate the successful detection of genes associated with specific phenotypes. Moreover, CoDiNA can also be used for comparing other types of undirected networks, for example, metabolic, protein-protein interaction, ecological and psychometric networks. CoDiNA is publicly available as an R package in CRAN (https://CRAN.R-project.org/package=CoDiNA).

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Predicting Protein Functions Based on Differential Co-expression and Neighborhood Analysis.

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