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DEGAS: de novo discovery of dysregulated pathways in human diseases.

Ulitsky I, Krishnamurthy A, Karp RM, Shamir R - PLoS ONE (2010)

Bottom Line: Recent studies have found that only a small number of the genes in human disease-related pathways show consistent dysregulation in sick individuals.However, those studies found that some pathway genes are affected in most sick individuals, but genes can differ among individuals.We applied DEGAS to seven human diseases and obtained statistically significant results that appear to home in on compact pathways enriched with hallmarks of the diseases.

View Article: PubMed Central - PubMed

Affiliation: Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel. ulitsky@wi.mit.edu

ABSTRACT

Background: Molecular studies of the human disease transcriptome typically involve a search for genes whose expression is significantly dysregulated in sick individuals compared to healthy controls. Recent studies have found that only a small number of the genes in human disease-related pathways show consistent dysregulation in sick individuals. However, those studies found that some pathway genes are affected in most sick individuals, but genes can differ among individuals. While a pathway is usually defined as a set of genes known to share a specific function, pathway boundaries are frequently difficult to assign, and methods that rely on such definition cannot discover novel pathways. Protein interaction networks can potentially be used to overcome these problems.

Methodology/principal findings: We present DEGAS (DysrEgulated Gene set Analysis via Subnetworks), a method for identifying connected gene subnetworks significantly enriched for genes that are dysregulated in specimens of a disease. We applied DEGAS to seven human diseases and obtained statistically significant results that appear to home in on compact pathways enriched with hallmarks of the diseases. In Parkinson's disease, we provide novel evidence for involvement of mRNA splicing, cell proliferation, and the 14-3-3 complex in the disease progression. DEGAS is available as part of the MATISSE software package (http://acgt.cs.tau.ac.il/matisse).

Conclusions/significance: The subnetworks identified by DEGAS can provide a signature of the disease potentially useful for diagnosis, pinpoint possible pathways affected by the disease, and suggest targets for drug intervention.

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Related in: MedlinePlus

A DP of genes up-regulated in Parkinson's disease patients in the Lesnick et al. data.Nodes in common with MORAN-PD-UP are in blue. Triangles are genes involved in RNA splicing (taken from GO). Diamonds are genes involved in regulation of growth (taken from GO).
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pone-0013367-g006: A DP of genes up-regulated in Parkinson's disease patients in the Lesnick et al. data.Nodes in common with MORAN-PD-UP are in blue. Triangles are genes involved in RNA splicing (taken from GO). Diamonds are genes involved in regulation of growth (taken from GO).

Mentions: A recent study has found little overlap in the gene lists reported by different studies of the PD transcriptome [66]. In order to test the consistency of the results in another dataset, we analyzed another PD dataset due to Lesnick et al. [43], in which expression data from 16 PD cases were compared to 9 controls. The most significant subnetwork (LESNICK-PD-UP) was found for k = 25 (p<0.002) (Figure 6). Strikingly, LESNICK-PD-UP indicated the same enrichments (contained parts of the same pathways) as MORAN-PD-UP. It was significantly enriched with RNA splicing (1.42·10−7, FDR<0.1). Consistent with the anti-proliferation trend identified in MORAN-PD-UP, we also found a slight enrichment for “regulation of growth” genes in LESNICK-PD-UP (p = 0.006), with two genes known to be negative regulators of growth – ING1 and BCL6, shared with MORAN-PD-UP.


DEGAS: de novo discovery of dysregulated pathways in human diseases.

Ulitsky I, Krishnamurthy A, Karp RM, Shamir R - PLoS ONE (2010)

A DP of genes up-regulated in Parkinson's disease patients in the Lesnick et al. data.Nodes in common with MORAN-PD-UP are in blue. Triangles are genes involved in RNA splicing (taken from GO). Diamonds are genes involved in regulation of growth (taken from GO).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2957424&req=5

pone-0013367-g006: A DP of genes up-regulated in Parkinson's disease patients in the Lesnick et al. data.Nodes in common with MORAN-PD-UP are in blue. Triangles are genes involved in RNA splicing (taken from GO). Diamonds are genes involved in regulation of growth (taken from GO).
Mentions: A recent study has found little overlap in the gene lists reported by different studies of the PD transcriptome [66]. In order to test the consistency of the results in another dataset, we analyzed another PD dataset due to Lesnick et al. [43], in which expression data from 16 PD cases were compared to 9 controls. The most significant subnetwork (LESNICK-PD-UP) was found for k = 25 (p<0.002) (Figure 6). Strikingly, LESNICK-PD-UP indicated the same enrichments (contained parts of the same pathways) as MORAN-PD-UP. It was significantly enriched with RNA splicing (1.42·10−7, FDR<0.1). Consistent with the anti-proliferation trend identified in MORAN-PD-UP, we also found a slight enrichment for “regulation of growth” genes in LESNICK-PD-UP (p = 0.006), with two genes known to be negative regulators of growth – ING1 and BCL6, shared with MORAN-PD-UP.

Bottom Line: Recent studies have found that only a small number of the genes in human disease-related pathways show consistent dysregulation in sick individuals.However, those studies found that some pathway genes are affected in most sick individuals, but genes can differ among individuals.We applied DEGAS to seven human diseases and obtained statistically significant results that appear to home in on compact pathways enriched with hallmarks of the diseases.

View Article: PubMed Central - PubMed

Affiliation: Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel. ulitsky@wi.mit.edu

ABSTRACT

Background: Molecular studies of the human disease transcriptome typically involve a search for genes whose expression is significantly dysregulated in sick individuals compared to healthy controls. Recent studies have found that only a small number of the genes in human disease-related pathways show consistent dysregulation in sick individuals. However, those studies found that some pathway genes are affected in most sick individuals, but genes can differ among individuals. While a pathway is usually defined as a set of genes known to share a specific function, pathway boundaries are frequently difficult to assign, and methods that rely on such definition cannot discover novel pathways. Protein interaction networks can potentially be used to overcome these problems.

Methodology/principal findings: We present DEGAS (DysrEgulated Gene set Analysis via Subnetworks), a method for identifying connected gene subnetworks significantly enriched for genes that are dysregulated in specimens of a disease. We applied DEGAS to seven human diseases and obtained statistically significant results that appear to home in on compact pathways enriched with hallmarks of the diseases. In Parkinson's disease, we provide novel evidence for involvement of mRNA splicing, cell proliferation, and the 14-3-3 complex in the disease progression. DEGAS is available as part of the MATISSE software package (http://acgt.cs.tau.ac.il/matisse).

Conclusions/significance: The subnetworks identified by DEGAS can provide a signature of the disease potentially useful for diagnosis, pinpoint possible pathways affected by the disease, and suggest targets for drug intervention.

Show MeSH
Related in: MedlinePlus