arXiv subjects

Tijana Milenkovic

Publications and source records attributed to Tijana Milenkovic.

25 records · Page 2Linked to original sources

arXiv2015

Local versus Global Biological Network Alignment

Network alignment (NA) aims to find regions of similarities between molecular networks of different species. There exist two NA categories: local (LNA) or global (GNA). LNA finds small highly conserved network regions and produces a many-to-many node mapping. GNA finds large conserved regions and produces a one-to-one node mapping. Given the different outputs of LNA and GNA, when a new NA method is proposed, it is compared against existing methods from the same category. However, both NA categories have the same goal: to allow for transferring functional knowledge from well- to poorly-studied species between conserved network regions. So, which one to choose, LNA or GNA? To answer this, we introduce the first systematic evaluation of the two NA categories. We introduce new measures of alignment quality that allow for fair comparison of the different LNA and GNA outputs, as such measures do not exist. We provide user-friendly software for efficient alignment evaluation that implements the new and existing measures. We evaluate prominent LNA and GNA methods on synthetic and real-world biological networks. We study the effect on alignment quality of using different interaction types and confidence levels. We find that the superiority of one NA category over the other is context-dependent. Further, when we contrast LNA and GNA in the application of learning novel protein functional knowledge, the two produce very different predictions, indicating their complementarity. Our results and software provide guidelines for future NA method development and evaluation.

q-bio.MN↗

arXiv2014

Exploring the structure and function of temporal networks with dynamic graphlets

With the growing amount of available temporal real-world network data, an important question is how to efficiently study these data. One can simply model a temporal network as either a single aggregate static network, or as a series of time-specific snapshots, each of which is an aggregate static network over the corresponding time window. The advantage of modeling the temporal data in these two ways is that one can use existing well established methods for static network analysis to study the resulting aggregate network(s). Here, we develop a novel approach for studying temporal network data more explicitly. We base our methodology on the well established notion of graphlets (subgraphs), which have been successfully used in numerous contexts in static network research. Here, we take the notion of static graphlets to the next level and develop new theory needed to allow for graphlet-based analysis of temporal networks. Our new notion of dynamic graphlets is quite different than existing approaches for dynamic network analysis that are based on temporal motifs (statistically significant subgraphs). Namely, these approaches suffer from many limitations. For example, they can only deal with subgraph structures of limited complexity. Also, their major drawback is that their results heavily depend on the choice of a null network model that is required to evaluate the significance of a subgraph. However, choosing an appropriate null network model is a non-trivial task. Our dynamic graphlet approach overcomes the limitations of the existing temporal motif-based approaches. At the same time, when we thoroughly evaluate the ability of our new approach to characterize the structure and function of an entire temporal network or of individual nodes, we find that the dynamic graphlet approach outperforms the static graphlet approach, which indicates that accounting for temporal information helps.

cs.SI↗

arXiv2013

Dynamic networks reveal key players in aging

Motivation: Since susceptibility to diseases increases with age, studying aging gains importance. Analyses of gene expression or sequence data, which have been indispensable for investigating aging, have been limited to studying genes and their protein products in isolation, ignoring their connectivities. However, proteins function by interacting with other proteins, and this is exactly what biological networks (BNs) model. Thus, analyzing the proteins' BN topologies could contribute to understanding of aging. Current methods for analyzing systems-level BNs deal with their static representations, even though cells are dynamic. For this reason, and because different data types can give complementary biological insights, we integrate current static BNs with aging-related gene expression data to construct dynamic, age-specific BNs. Then, we apply sensitive measures of topology to the dynamic BNs to study cellular changes with age. Results: While global BN topologies do not significantly change with age, local topologies of a number of genes do. We predict such genes as aging-related. We demonstrate credibility of our predictions by: 1) observing significant overlap between our predicted aging-related genes and "ground truth" aging-related genes; 2) showing that our aging-related predictions group by functions and diseases that are different than functions and diseases of genes that are not predicted as aging-related; 3) observing significant overlap between functions and diseases that are enriched in our aging-related predictions and those that are enriched in "ground truth" aging-related data; 4) providing evidence that diseases which are enriched in our aging-related predictions are linked to human aging; and 5) validating all of our high-scoring novel predictions via manual literature search.

cs.CE↗

arXiv2012

Identifying edge clusters in networks via edge graphlet degree vectors (edge-GDVs) and edge-GDV-similarities

Inference of new biological knowledge, e.g., prediction of protein function, from protein-protein interaction (PPI) networks has received attention in the post-genomic era. A popular strategy has been to cluster the network into functionally coherent groups of proteins and predict protein function from the clusters. Traditionally, network research has focused on clustering of nodes. However, why favor nodes over edges, when clustering of edges may be preferred? For example, nodes belong to multiple functional groups, but clustering of nodes typically cannot capture the group overlap, while clustering of edges can. Clustering of adjacent edges that share many neighbors was proposed recently, outperforming different node clustering methods. However, since some biological processes can have characteristic "signatures" throughout the network, not just locally, it may be of interest to consider edges that are not necessarily adjacent. Hence, we design a sensitive measure of the "topological similarity" of edges that can deal with edges that are not necessarily adjacent. We cluster edges that are similar according to our measure in different baker's yeast PPI networks, outperforming existing node and edge clustering approaches.

q-bio.MN↗

arXiv2009

Topological network alignment uncovers biological function and phylogeny

Sequence comparison and alignment has had an enormous impact on our understanding of evolution, biology, and disease. Comparison and alignment of biological networks will likely have a similar impact. Existing network alignments use information external to the networks, such as sequence, because no good algorithm for purely topological alignment has yet been devised. In this paper, we present a novel algorithm based solely on network topology, that can be used to align any two networks. We apply it to biological networks to produce by far the most complete topological alignments of biological networks to date. We demonstrate that both species phylogeny and detailed biological function of individual proteins can be extracted from our alignments. Topology-based alignments have the potential to provide a completely new, independent source of phylogenetic information. Our alignment of the protein-protein interaction networks of two very different species--yeast and human--indicate that even distant species share a surprising amount of network topology with each other, suggesting broad similarities in internal cellular wiring across all life on Earth.

q-bio.MN↗

arXiv2009

An integrative approach to modeling biological networks

Since proteins carry out biological processes by interacting with other proteins, analyzing the structure of protein-protein interaction (PPI) networks could explain complex biological mechanisms, evolution, and disease. Similarly, studying protein structure networks, residue interaction graphs (RIGs), might provide insights into protein folding, stability, and function. The first step towards understanding these networks is finding an adequate network model that closely replicates their structure. Evaluating the fit of a model to the data requires comparing the model with real-world networks. Since network comparisons are computationally infeasible, they rely on heuristics, or "network properties." We show that it is difficult to assess the reliability of the fit of a model with any individual network property. Thus, our approach integrates a variety of network properties and further combines these with a series of probabilistic methods to predict an appropriate network model for biological networks. We find geometric random graphs, that model spatial relationships between objects, to be the best-fitting model for RIGs. This validates the correctness of our method, since RIGs have previously been shown to be geometric. We apply our approach to noisy PPI networks and demonstrate that their structure is also consistent with geometric random graphs.

q-bio.MN↗

arXiv2008

Uncovering Biological Network Function via Graphlet Degree Signatures

Proteins are essential macromolecules of life and thus understanding their function is of great importance. The number of functionally unclassified proteins is large even for simple and well studied organisms such as baker's yeast. Methods for determining protein function have shifted their focus from targeting specific proteins based solely on sequence homology to analyses of the entire proteome based on protein-protein interaction (PPI) networks. Since proteins aggregate to perform a certain function, analyzing structural properties of PPI networks may provide useful clues about the biological function of individual proteins, protein complexes they participate in, and even larger subcellular machines. We design a sensitive graph theoretic method for comparing local structures of node neighborhoods that demonstrates that in PPI networks, biological function of a node and its local network structure are closely related. The method groups topologically similar proteins under this measure in a PPI network and shows that these protein groups belong to the same protein complexes, perform the same biological functions, are localized in the same subcellular compartments, and have the same tissue expressions. Moreover, we apply our technique on a proteome-scale network data and infer biological function of yet unclassified proteins demonstrating that our method can provide valuable guidelines for future experimental research.

q-bio.MN↗