Abstract
The use of pathways and gene interaction networks for the analysis of differential expression experiments has allowed us to highlight the differences in gene expression profiles between samples in a systems biology perspective. The usefulness and accuracy of pathway analysis critically depend on our understanding of how genes interact with one another. That knowledge is continuously improving due to advances in next generation sequencing technologies and in computational methods. While most approaches treat each of them as independent entities, pathways actually coordinate to perform essential functions in a cell. In this work, we propose a methodology based on a sparse regression approach to find genes that act as intermediary to and interact with two pathways. We model each gene in a pathway using a set of predictor genes, and a connection is formed between the pathway gene and a predictor gene if the sparse regression coefficient corresponding to the predictor gene is non-zero. A predictor gene is a shared neighbor gene of two pathways if it is connected to at least one gene in each pathway. We compare the sparse regression approach to Weighted Correlation Network Analysis and a correlation distance based approach using time-course RNA-Seq data for dendritic cell from wild type, MyD88-knockout, and TRIF-knockout mice, and a set of RNA-Seq data from 60 Caucasian individuals. For the sparse regression approach, we found overrepresented functions for shared neighbor genes between TLR-signaling pathway and antigen processing and presentation, apoptosis, and Jak-Stat pathways that are supported by prior research, and compares favorably to Weighted Correlation Network Analysis in cases where the gene association signals are weak.
Highlights
Genes in eukaryotic genomes rarely work alone, rather, they cooperate and interact with other genes to form networks or pathways
After knocking out MyD88 or TRIF in dendritic cells, we expected to observe changes in expressions in genes belonging to the downstream antigen processing and presentation, apoptosis, and Jak-Stat pathways [17, 33, 34]
The discovery of genes that link together the activities of different pathways are crucial to the advance of pathway analysis and systems biology
Summary
Genes in eukaryotic genomes rarely work alone, rather, they cooperate and interact with other genes to form networks or pathways. Gene products can act as activators or repressors to other genes, or bind with each other to form more complicated structures. Many types of pathways or interaction databases have been made available, such as databases for metabolic pathways [1, 2], signal transduction pathways [3, 4], and protein-protein interaction networks [5, 6]. Science and Technology (FIRST Program) for the Comprehensive understanding of immune dynamism: toward manipulation of immune responses (https:// research-er.jp/projects/view/106146). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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