27,048 research outputs found
Inferring Gene-Phenotype Associations via Global Protein Complex Network Propagation
BACKGROUND: Phenotypically similar diseases have been found to be caused by functionally related genes, suggesting a modular organization of the genetic landscape of human diseases that mirrors the modularity observed in biological interaction networks. Protein complexes, as molecular machines that integrate multiple gene products to perform biological functions, express the underlying modular organization of protein-protein interaction networks. As such, protein complexes can be useful for interrogating the networks of phenome and interactome to elucidate gene-phenotype associations of diseases. METHODOLOGY/PRINCIPAL FINDINGS: We proposed a technique called RWPCN (Random Walker on Protein Complex Network) for predicting and prioritizing disease genes. The basis of RWPCN is a protein complex network constructed using existing human protein complexes and protein interaction network. To prioritize candidate disease genes for the query disease phenotypes, we compute the associations between the protein complexes and the query phenotypes in their respective protein complex and phenotype networks. We tested RWPCN on predicting gene-phenotype associations using leave-one-out cross-validation; our method was observed to outperform existing approaches. We also applied RWPCN to predict novel disease genes for two representative diseases, namely, Breast Cancer and Diabetes. CONCLUSIONS/SIGNIFICANCE: Guilt-by-association prediction and prioritization of disease genes can be enhanced by fully exploiting the underlying modular organizations of both the disease phenome and the protein interactome. Our RWPCN uses a novel protein complex network as a basis for interrogating the human phenome-interactome network. As the protein complex network can capture the underlying modularity in the biological interaction networks better than simple protein interaction networks, RWPCN was found to be able to detect and prioritize disease genes better than traditional approaches that used only protein-phenotype associations
Chaperones as integrators of cellular networks: Changes of cellular integrity in stress and diseases
Cellular networks undergo rearrangements during stress and diseases. In
un-stressed state the yeast protein-protein interaction network (interactome)
is highly compact, and the centrally organized modules have a large overlap.
During stress several original modules became more separated, and a number of
novel modules also appear. A few basic functions, such as the proteasome
preserve their central position. However, several functions with high energy
demand, such the cell-cycle regulation loose their original centrality during
stress. A number of key stress-dependent protein complexes, such as the
disaggregation-specific chaperone, Hsp104, gain centrality in the stressed
yeast interactome. Molecular chaperones, heat shock, or stress proteins form
complex interaction networks (the chaperome) with each other and their
partners. Here we show that the human chaperome recovers the segregation of
protein synthesis-coupled and stress-related chaperones observed in yeast
recently. Examination of yeast and human interactomes shows that (1) chaperones
are inter-modular integrators of protein-protein interaction networks, which
(2) often bridge hubs and (3) are favorite candidates for extensive
phosphorylation. Moreover, chaperones (4) become more central in the
organization of the isolated modules of the stressed yeast protein-protein
interaction network, which highlights their importance in the de-coupling and
re-coupling of network modules during and after stress. Chaperone-mediated
evolvability of cellular networks may play a key role in cellular adaptation
during stress and various polygenic and chronic diseases, such as cancer,
diabetes or neurodegeneration.Comment: 13 pages, 3 figures, 1 glossar
Modular decomposition of protein-protein interaction networks
We introduce an algorithmic method, termed modular decomposition, that defines the organization of protein-interaction networks as a hierarchy of nested modules. Modular decomposition derives the logical rules of how to combine proteins into the actual functional complexes by identifying groups of proteins acting as a single unit (sub-complexes) and those that can be alternatively exchanged in a set of similar complexes. The method is applied to experimental data on the pro-inflammatory tumor necrosis factor-α (TNF-α)/NFκB transcription factor pathway
How biologically relevant are interaction-based modules in protein networks?
By applying a graph-based algorithm to yeast protein-interaction networks we have extracted modular structures and show that they can be validated using information from the phylogenetic conservation of the network components. We show that the module cores, the parts with the highest intramodular connectivity, are biologically relevant components of the networks. These constituents correlate only weakly with other levels of organization. We also discuss how such structures could be used for finding targets for antimicrobial drugs
High-Betweenness Proteins in the Yeast Protein Interaction Network
Structural features found in biomolecular networks that are absent in random networks produced by simple algorithms can provide insight into the function and evolution of cell regulatory networks. Here we analyze “betweenness” of network nodes, a graph theoretical centrality measure, in the yeast protein interaction network. Proteins that have high betweenness, but low connectivity (degree), were found to be abundant in the yeast proteome. This finding is not explained by algorithms proposed to explain the scale-free property of protein interaction networks, where low-connectivity proteins also have low betweenness. These data suggest the existence of some modular organization of the network, and that the high-betweenness, low-connectivity proteins may act as important links between these modules. We found that proteins with high betweenness are more likely to be essential and that evolutionary age of proteins is positively correlated with betweenness. By comparing different models of genome evolution that generate scale-free networks, we show that rewiring of interactions via mutation is an important factor in the production of such proteins. The evolutionary and functional significance of these observations are discussed
Uncovering the overlapping community structure of complex networks in nature and society
Many complex systems in nature and society can be described in terms of
networks capturing the intricate web of connections among the units they are
made of. A key question is how to interpret the global organization of such
networks as the coexistence of their structural subunits (communities)
associated with more highly interconnected parts. Identifying these a priori
unknown building blocks (such as functionally related proteins, industrial
sectors and groups of people) is crucial to the understanding of the structural
and functional properties of networks. The existing deterministic methods used
for large networks find separated communities, whereas most of the actual
networks are made of highly overlapping cohesive groups of nodes. Here we
introduce an approach to analysing the main statistical features of the
interwoven sets of overlapping communities that makes a step towards uncovering
the modular structure of complex systems. After defining a set of new
characteristic quantities for the statistics of communities, we apply an
efficient technique for exploring overlapping communities on a large scale. We
find that overlaps are significant, and the distributions we introduce reveal
universal features of networks. Our studies of collaboration, word-association
and protein interaction graphs show that the web of communities has non-trivial
correlations and specific scaling properties.Comment: The free academic research software, CFinder, used for the
publication is available at the website of the publication:
http://angel.elte.hu/clusterin
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