Dataset Information

Selecting biologically informative genes in co-expression networks with a centrality score.

ABSTRACT:

Background

Measures of node centrality in biological networks are useful to detect genes with critical functional roles. In gene co-expression networks, highly connected genes (i.e., candidate hubs) have been associated with key disease-related pathways. Although different approaches to estimating gene centrality are available, their potential biological relevance in gene co-expression networks deserves further investigation. Moreover, standard measures of gene centrality focus on binary interaction networks, which may not always be suitable in the context of co-expression networks. Here, I also investigate a method that identifies potential biologically meaningful genes based on a weighted connectivity score and indicators of statistical relevance.

Results

The method enables a characterization of the strength and diversity of co-expression associations in the network. It outperformed standard centrality measures by highlighting more biologically informative genes in different gene co-expression networks and biological research domains. As part of the illustration of the gene selection potential of this approach, I present an application case in zebrafish heart regeneration. The proposed technique predicted genes that are significantly implicated in cellular processes required for tissue regeneration after injury.

Conclusions

A method for selecting biologically informative genes from gene co-expression networks is provided, together with free open software.

SUBMITTER: Azuaje FJ

PROVIDER: S-EPMC4079186 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Publications

Selecting biologically informative genes in co-expression networks with a centrality score.

Azuaje Francisco J FJ

Biology direct 20140619

<h4>Background</h4>Measures of node centrality in biological networks are useful to detect genes with critical functional roles. In gene co-expression networks, highly connected genes (i.e., candidate hubs) have been associated with key disease-related pathways. Although different approaches to estimating gene centrality are available, their potential biological relevance in gene co-expression networks deserves further investigation. Moreover, standard measures of gene centrality focus on binary ...[more]

PMID: 24947308

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Project description:BackgroundCo-expression networks are a tool widely used for analysis of "Big Data" in biology that can range from transcriptomes to proteomes, metabolomes and more recently even microbiomes. Several methods were proposed to answer biological questions interrogating these networks. Differential co-expression analysis is a recent approach that measures how gene interactions change when a biological system transitions from one state to another. Although the importance of differentially co-expressed genes to identify dysregulated pathways has been noted, their role in gene regulation is not well studied. Herein we investigated differentially co-expressed genes in a relatively simple mono-causal process (B lymphocyte deficiency) and in a complex multi-causal system (cervical cancer).MethodsCo-expression networks of B cell deficiency (Control and BcKO) were reconstructed using Pearson correlation coefficient for two mus musculus datasets: B10.A strain (12 normal, 12 BcKO) and BALB/c strain (10 normal, 10 BcKO). Co-expression networks of cervical cancer (normal and cancer) were reconstructed using local partial correlation method for five datasets (total of 64 normal, 148 cancer). Differentially correlated pairs were identified along with the location of their genes in BcKO and in cancer networks. Minimum Shortest Path and Bi-partite Betweenness Centrality where statistically evaluated for differentially co-expressed genes in corresponding networks. Results: We show that in B cell deficiency the differentially co-expressed genes are highly enriched with immunoglobulin genes (causal genes). In cancer we found that differentially co-expressed genes act as "bottlenecks" rather than causal drivers with most flows that come from the key driver genes to the peripheral genes passing through differentially co-expressed genes. Using in vitro knockdown experiments for two out of 14 differentially co-expressed genes found in cervical cancer (FGFR2 and CACYBP), we showed that they play regulatory roles in cancer cell growth.ConclusionIdentifying differentially co-expressed genes in co-expression networks is an important tool in detecting regulatory genes involved in alterations of phenotype.

Project description:BACKGROUND:Biological insights into group differences, such as disease status, have been achieved through differential co-expression analysis of microarray data. Additional understanding of group differences may be achieved by integrating the connectivity structure of the differential co-expression network and per-gene differential expression between phenotypic groups. Such a global differential co-expression network strategy may increase sensitivity to detect gene-gene interactions (or expression epistasis) that may act as candidates for rewiring susceptibility co-expression networks. METHODS:We test two methods for inferring Genetic Association Interaction Networks (GAIN) incorporating both differential co-expression effects and differential expression effects: a generalized linear model (GLM) regression method with interaction effects (reGAIN) and a Fisher test method for correlation differences (dcGAIN). We rank the importance of each gene with complete interaction network centrality (CINC), which integrates each gene's differential co-expression effects in the GAIN model along with each gene's individual differential expression measure. We compare these methods with statistical learning methods Relief-F, Random Forests and Lasso. We also develop a mixture model and permutation approach for determining significant importance score thresholds for network centralities, Relief-F and Random Forest. We introduce a novel simulation strategy that generates microarray case-control data with embedded differential co-expression networks and underlying correlation structure based on scale-free or Erdos-Renyi (ER) random networks. RESULTS:Using the network simulation strategy, we find that Relief-F and reGAIN provide the best balance between detecting interactions and main effects, plus reGAIN has the ability to adjust for covariates and model quantitative traits. The dcGAIN approach performs best at finding differential co-expression effects by design but worst for main effects, and it does not adjust for covariates and is limited to dichotomous outcomes. When the underlying network is scale free instead of ER, all interaction network methods have greater power to find differential co-expression effects. We apply these methods to a public microarray study of the differential immune response to influenza vaccine, and we identify effects that suggest a role in influenza vaccine immune response for genes from the PI3K family, which includes genes with known immunodeficiency function, and KLRG1, which is a known marker of senescence.

Project description:A common observation in the analysis of gene expression data is that many genes display similarity in their expression patterns and therefore appear to be co-regulated. However, the variation associated with microarray data and the complexity of the experimental designs make the acquisition of co-expressed genes a challenge. We developed a novel method for Extracting microarray gene expression Patterns and Identifying co-expressed Genes, designated as EPIG. The approach utilizes the underlying structure of gene expression data to extract patterns and identify co-expressed genes that are responsive to experimental conditions.Through evaluation of the correlations among profiles, the magnitude of variation in gene expression profiles, and profile signal-to-noise ratio's, EPIG extracts a set of patterns representing co-expressed genes. The method is shown to work well with a simulated data set and microarray data obtained from time-series studies of dauer recovery and L1 starvation in C. elegans and after ultraviolet (UV) or ionizing radiation (IR)-induced DNA damage in diploid human fibroblasts. With the simulated data set, EPIG extracted the appropriate number of patterns which were more stable and homogeneous than the set of patterns that were determined using the CLICK or CAST clustering algorithms. However, CLICK performed better than EPIG and CAST with respect to the average correlation between clusters/patterns of the simulated data. With real biological data, EPIG extracted more dauer-specific patterns than CLICK. Furthermore, analysis of the IR/UV data revealed 18 unique patterns and 2661 genes out of approximately 17,000 that were identified as significantly expressed and categorized to the patterns by EPIG. The time-dependent patterns displayed similar and dissimilar responses between IR and UV treatments. Gene Ontology analysis applied to each pattern-related subset of co-expressed genes revealed underlying biological processes affected by IR- and/or UV- induced DNA damage.EPIG competed with CLICK and performed better than CAST in extracting patterns from simulated data. EPIG extracted more biological informative patterns and co-expressed genes from both C. elegans and IR/UV-treated human fibroblasts. Using Gene Ontology analysis of the genes in the patterns extracted by EPIG, several key biological categories related to p53-dependent cell cycle control were revealed from the IR/UV data. Among them were mitotic cell cycle, DNA replication, DNA repair, cell cycle checkpoint, and G0-like status transition. EPIG can be applied to data sets from a variety of experimental designs.

Dataset Information

Selecting biologically informative genes in co-expression networks with a centrality score.

Background

Results

Conclusions

Publications

Selecting biologically informative genes in co-expression networks with a centrality score.

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