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Scope and limitations of yeast as a model organism for studying human tissue-specific pathways.

Mohammadi S, Saberidokht B, Subramaniam S, Grama A - BMC Syst Biol (2015)

Bottom Line: Specific biochemical processes and associated biomolecules that differentiate various tissues are not completely understood, neither is the extent to which a unicellular organism, such as yeast, can be used to model these processes within each tissue.While tissue-selective genes are significantly associated with the onset and development of a number of tissue-specific pathologies, we show that the human-specific subset has even higher association.Consequently, they provide excellent candidates as drug targets for therapeutic interventions.

View Article: PubMed Central - PubMed

Affiliation: Department of Computer Sciences, Purdue University, West Lafayette, 47907, USA. mohammadi@purdue.edu.

ABSTRACT

Background: Budding yeast, S. cerevisiae, has been used extensively as a model organism for studying cellular processes in evolutionarily distant species, including humans. However, different human tissues, while inheriting a similar genetic code, exhibit distinct anatomical and physiological properties. Specific biochemical processes and associated biomolecules that differentiate various tissues are not completely understood, neither is the extent to which a unicellular organism, such as yeast, can be used to model these processes within each tissue.

Results: We present a novel framework to systematically quantify the suitability of yeast as a model organism for different human tissues. To this end, we develop a computational method for dissecting the global human interactome into tissue-specific cellular networks. By individually aligning these networks with the yeast interactome, we simultaneously partition the functional space of human genes, and their corresponding pathways, based on their conservation both across species and among different tissues. Finally, we couple our framework with a novel statistical model to assess the conservation of tissue-specific pathways and infer the overall similarity of each tissue with yeast. We further study each of these subspaces in detail, and shed light on their unique biological roles in the human tissues.

Conclusions: Our framework provides a novel tool that can be used to assess the suitability of the yeast model for studying tissue-specific physiology and pathophysiology in humans. Many complex disorders are driven by a coupling of housekeeping (universally expressed in all tissues) and tissue-selective (expressed only in specific tissues) dysregulated pathways. While tissue-selective genes are significantly associated with the onset and development of a number of tissue-specific pathologies, we show that the human-specific subset has even higher association. Consequently, they provide excellent candidates as drug targets for therapeutic interventions.

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Related in: MedlinePlus

Enrichment map of unique brain-selective functions. Each node represents a functional term, and the thickness of edges corresponds to the extent of overlap among terms. Conserved and human-specific set of functions is color-coded by green and red colors, respectively. Color intensity of nodes represents the enrichment of terms. Related terms are marked and annotated in the enrichment map
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Fig9: Enrichment map of unique brain-selective functions. Each node represents a functional term, and the thickness of edges corresponds to the extent of overlap among terms. Conserved and human-specific set of functions is color-coded by green and red colors, respectively. Color intensity of nodes represents the enrichment of terms. Related terms are marked and annotated in the enrichment map

Mentions: We use g:ProfileR on both human-specific and conserved genes to identify their enriched functions. The complete list of enriched functions is available for download as Additional file 7. These two subsets share many common terms, due to the underlying prior of both being subsets of tissue-selective genes. To comparatively analyze these functions and rank them based on their human-specificity, we use the log of p-value ratios between human-specific and conserved genes to filter terms that are at least within 2-fold enrichment. We focus on GO biological processes, KEGG pathways, and CORUM protein complexes and remove all genesets with more than 500 genes to filter for overly generic terms. Finally, to group these terms together and provide a visual representation of the functional space of genes, we use EnrichmentMap (EM) [69], a recent Cytoscape [70] plug-in, to construct a network (map) of the enriched terms. We use the log ratio of p-values to color each node in the graph. Figures 8 and 9 illustrate the final enrichment map of unique human-specific and conserved blood-selective and brain-selective functions, respectively.Fig. 8


Scope and limitations of yeast as a model organism for studying human tissue-specific pathways.

Mohammadi S, Saberidokht B, Subramaniam S, Grama A - BMC Syst Biol (2015)

Enrichment map of unique brain-selective functions. Each node represents a functional term, and the thickness of edges corresponds to the extent of overlap among terms. Conserved and human-specific set of functions is color-coded by green and red colors, respectively. Color intensity of nodes represents the enrichment of terms. Related terms are marked and annotated in the enrichment map
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4696342&req=5

Fig9: Enrichment map of unique brain-selective functions. Each node represents a functional term, and the thickness of edges corresponds to the extent of overlap among terms. Conserved and human-specific set of functions is color-coded by green and red colors, respectively. Color intensity of nodes represents the enrichment of terms. Related terms are marked and annotated in the enrichment map
Mentions: We use g:ProfileR on both human-specific and conserved genes to identify their enriched functions. The complete list of enriched functions is available for download as Additional file 7. These two subsets share many common terms, due to the underlying prior of both being subsets of tissue-selective genes. To comparatively analyze these functions and rank them based on their human-specificity, we use the log of p-value ratios between human-specific and conserved genes to filter terms that are at least within 2-fold enrichment. We focus on GO biological processes, KEGG pathways, and CORUM protein complexes and remove all genesets with more than 500 genes to filter for overly generic terms. Finally, to group these terms together and provide a visual representation of the functional space of genes, we use EnrichmentMap (EM) [69], a recent Cytoscape [70] plug-in, to construct a network (map) of the enriched terms. We use the log ratio of p-values to color each node in the graph. Figures 8 and 9 illustrate the final enrichment map of unique human-specific and conserved blood-selective and brain-selective functions, respectively.Fig. 8

Bottom Line: Specific biochemical processes and associated biomolecules that differentiate various tissues are not completely understood, neither is the extent to which a unicellular organism, such as yeast, can be used to model these processes within each tissue.While tissue-selective genes are significantly associated with the onset and development of a number of tissue-specific pathologies, we show that the human-specific subset has even higher association.Consequently, they provide excellent candidates as drug targets for therapeutic interventions.

View Article: PubMed Central - PubMed

Affiliation: Department of Computer Sciences, Purdue University, West Lafayette, 47907, USA. mohammadi@purdue.edu.

ABSTRACT

Background: Budding yeast, S. cerevisiae, has been used extensively as a model organism for studying cellular processes in evolutionarily distant species, including humans. However, different human tissues, while inheriting a similar genetic code, exhibit distinct anatomical and physiological properties. Specific biochemical processes and associated biomolecules that differentiate various tissues are not completely understood, neither is the extent to which a unicellular organism, such as yeast, can be used to model these processes within each tissue.

Results: We present a novel framework to systematically quantify the suitability of yeast as a model organism for different human tissues. To this end, we develop a computational method for dissecting the global human interactome into tissue-specific cellular networks. By individually aligning these networks with the yeast interactome, we simultaneously partition the functional space of human genes, and their corresponding pathways, based on their conservation both across species and among different tissues. Finally, we couple our framework with a novel statistical model to assess the conservation of tissue-specific pathways and infer the overall similarity of each tissue with yeast. We further study each of these subspaces in detail, and shed light on their unique biological roles in the human tissues.

Conclusions: Our framework provides a novel tool that can be used to assess the suitability of the yeast model for studying tissue-specific physiology and pathophysiology in humans. Many complex disorders are driven by a coupling of housekeeping (universally expressed in all tissues) and tissue-selective (expressed only in specific tissues) dysregulated pathways. While tissue-selective genes are significantly associated with the onset and development of a number of tissue-specific pathologies, we show that the human-specific subset has even higher association. Consequently, they provide excellent candidates as drug targets for therapeutic interventions.

Show MeSH
Related in: MedlinePlus