Mining Biological Networks towards Protein complex Detection and Gene-Disease Association

Large amounts of biological data are continuously generated nowadays, thanks to the advancements of high-throughput experimental techniques. Mining valuable knowledge from such data still motivates the design of suitable computational methods, to complement the experimental work which is often bound by considerable time and cost requirements. Protein complexes or groups of interacting proteins, are key players in most cellular events. The identification of complexes not only allows to better understand normal biological processes but also to uncover Disease-triggering malfunctions. Ultimately, findings in this research branch can highly enhance the design of effective medical treatments. The aim of this research is to detect protein complexes in protein-protein interaction networks and to associate the detected entities to diseases. The work is divided into three main objectives: first, develop a suitable method for the identification of protein complexes in static interaction networks; second, model the dynamic aspect of protein interaction networks and detect complexes accordingly; and third, design a learning model to link proteins, and subsequently protein complexes, to diseases. In response to these objectives, we present, ProRank+, a novel complex-detection approach based on a ranking algorithm and a merging procedure. Then, we introduce DyCluster, which uses gene expression data, to model the dynamics of the interaction networks, and we adapt the detection algorithm accordingly. Finally, we integrate network topology attributes and several biological features of proteins to form a classification model for gene-disease association. The reliability of the proposed methods is supported by various experimental studies conducted to compare them with existing approaches. Pro Rank+ detects more protein complexes than other state-of-the-art methods. DyCluster goes a step further and achieves a better performance than similar techniques. Then, our learning model shows that combining topological and biological features can greatly enhance the gene-disease association process. Finally, we present a comprehensive case study of breast cancer in which we pinpoint disease genes using our learning model; subsequently, we detect favorable groupings of those genes in a protein interaction network using the Pro-rank+ algorithm

Topology and weights in a protein domain interaction network – a novel way to predict protein interactions

BACKGROUND: While the analysis of unweighted biological webs as diverse as genetic, protein and metabolic networks allowed spectacular insights in the inner workings of a cell, biological networks are not only determined by their static grid of links. In fact, we expect that the heterogeneity in the utilization of connections has a major impact on the organization of cellular activities as well. RESULTS: We consider a web of interactions between protein domains of the Protein Family database (PFAM), which are weighted by a probability score. We apply metrics that combine the static layout and the weights of the underlying interactions. We observe that unweighted measures as well as their weighted counterparts largely share the same trends in the underlying domain interaction network. However, we only find weak signals that weights and the static grid of interactions are connected entities. Therefore assuming that a protein interaction is governed by a single domain interaction, we observe strong and significant correlations of the highest scoring domain interaction and the confidence of protein interactions in the underlying interactions of yeast and fly. Modeling an interaction between proteins if we find a high scoring protein domain interaction we obtain 1, 428 protein interactions among 361 proteins in the human malaria parasite Plasmodium falciparum. Assessing their quality by a logistic regression method we observe that increasing confidence of predicted interactions is accompanied by high scoring domain interactions and elevated levels of functional similarity and evolutionary conservation. CONCLUSION: Our results indicate that probability scores are randomly distributed, allowing to treat static grid and weights of domain interactions as separate entities. In particular, these finding confirms earlier observations that a protein interaction is a matter of a single interaction event on domain level. As an immediate application, we show a simple way to predict potential protein interactions by utilizing expectation scores of single domain interactions

From condition-specific interactions towards the differential complexome of proteins

While capturing the transcriptomic state of a cell is a comparably simple effort with modern sequencing techniques, mapping protein interactomes and complexomes in a sample-specific manner is currently not feasible on a large scale. To understand crucial biological processes, however, knowledge on the physical interplay between proteins can be more interesting than just their mere expression. In this thesis, we present and demonstrate four software tools that unlock the cellular wiring in a condition-specific manner and promise a deeper understanding of what happens upon cell fate transitions. PPIXpress allows to exploit the abundance of existing expression data to generate specific interactomes, which can even consider alternative splicing events when protein isoforms can be related to the presence of causative protein domain interactions of an underlying model. As an addition to this work, we developed the convenient differential analysis tool PPICompare to determine rewiring events and their causes within the inferred interaction networks between grouped samples. Furthermore, we present a new implementation of the combinatorial protein complex prediction algorithm DACO that features a significantly reduced runtime. This improvement facilitates an application of the method for a large number of samples and the resulting sample-specific complexes can ultimately be assessed quantitatively with our novel differential protein complex analysis tool CompleXChange.Das Transkriptom einer Zelle ist mit modernen Sequenzierungstechniken vergleichsweise einfach zu erfassen. Die Ermittlung von Proteininteraktionen und -komplexen wiederum ist in großem Maßstab derzeit nicht möglich. Um wichtige biologische Prozesse zu verstehen, kann das Zusammenspiel von Proteinen jedoch erheblich interessanter sein als deren reine Expression. In dieser Arbeit stellen wir vier Software-Tools vor, die es ermöglichen solche Interaktionen zustandsbezogen zu betrachten und damit ein tieferes Verständnis darüber versprechen, was in der Zelle bei Veränderungen passiert. PPIXpress ermöglicht es vorhandene Expressionsdaten zu nutzen, um die aktiven Interaktionen in einem biologischen Kontext zu ermitteln. Wenn Proteinvarianten mit Interaktionen von Proteindomänen in Verbindung gebracht werden können, kann hierbei sogar alternatives Spleißen berücksichtigen werden. Als Ergänzung dazu haben wir das komfortable Differenzialanalyse-Tool PPICompare entwickelt, welches Veränderungen des Interaktoms und deren Ursachen zwischen gruppierten Proben bestimmen kann. Darüber hinaus stellen wir eine neue Implementierung des Proteinkomplex-Vorhersagealgorithmus DACO vor, die eine deutlich reduzierte Laufzeit aufweist. Diese Verbesserung ermöglicht die Anwendung der Methode auf eine große Anzahl von Proben. Die damit bestimmten probenspezifischen Komplexe können schließlich mit unserem neuartigen Differenzialanalyse-Tool CompleXChange quantitativ bewertet werden

Dense graph pattern mining and visualization

Ph.DDOCTOR OF PHILOSOPH

Transcriptome-based Gene Networks for Systems-level Analysis of Plant Gene Functions

Present day genomic technologies are evolving at an unprecedented rate, allowing interrogation of cellular activities with increasing breadth and depth. However, we know very little about how the genome functions and what the identified genes do. The lack of functional annotations of genes greatly limits the post-analytical interpretation of new high throughput genomic datasets. For plant biologists, the problem is much severe. Less than 50% of all the identified genes in the model plant Arabidopsis thaliana, and only about 20% of all genes in the crop model Oryza sativa have some aspects of their functions assigned. Therefore, there is an urgent need to develop innovative methods to predict and expand on the currently available functional annotations of plant genes. With open-access catching the ‘pulse’ of modern day molecular research, an integration of the copious amount of transcriptome datasets allows rapid prediction of gene functions in specific biological contexts, which provide added evidence over traditional homology-based functional inference. The main goal of this dissertation was to develop data analysis strategies and tools broadly applicable in systems biology research. Two user friendly interactive web applications are presented: The Rice Regulatory Network (RRN) captures an abiotic-stress conditioned gene regulatory network designed to facilitate the identification of transcription factor targets during induction of various environmental stresses. The Arabidopsis Seed Active Network (SANe) is a transcriptional regulatory network that encapsulates various aspects of seed formation, including embryogenesis, endosperm development and seed-coat formation. Further, an edge-set enrichment analysis algorithm is proposed that uses network density as a parameter to estimate the gain or loss in correlation of pathways between two conditionally independent coexpression networks

NetCoMi: network construction and comparison for microbiome data in R

MOTIVATION Estimating microbial association networks from high-throughput sequencing data is a common exploratory data analysis approach aiming at understanding the complex interplay of microbial communities in their natural habitat. Statistical network estimation workflows comprise several analysis steps, including methods for zero handling, data normalization and computing microbial associations. Since microbial interactions are likely to change between conditions, e.g. between healthy individuals and patients, identifying network differences between groups is often an integral secondary analysis step. Thus far, however, no unifying computational tool is available that facilitates the whole analysis workflow of constructing, analysing and comparing microbial association networks from high-throughput sequencing data. RESULTS Here, we introduce NetCoMi (Network Construction and comparison for Microbiome data), an R package that integrates existing methods for each analysis step in a single reproducible computational workflow. The package offers functionality for constructing and analysing single microbial association networks as well as quantifying network differences. This enables insights into whether single taxa, groups of taxa or the overall network structure change between groups. NetCoMi also contains functionality for constructing differential networks, thus allowing to assess whether single pairs of taxa are differentially associated between two groups. Furthermore, NetCoMi facilitates the construction and analysis of dissimilarity networks of microbiome samples, enabling a high-level graphical summary of the heterogeneity of an entire microbiome sample collection. We illustrate NetCoMi's wide applicability using data sets from the GABRIELA study to compare microbial associations in settled dust from children's rooms between samples from two study centers (Ulm and Munich). AVAILABILITY R scripts used for producing the examples shown in this manuscript are provided as supplementary data. The NetCoMi package, together with a tutorial, is available at https://github.com/stefpeschel/NetCoMi. CONTACT Tel:+49 89 3187 43258; [email protected]. SUPPLEMENTARY INFORMATION Supplementary data are available at Briefings in Bioinformatics online

Discovering Domain-Domain Interactions toward Genome-Wide Protein Interaction and Function Predictions

To fully understand the underlying mechanisms of living cells, it is essential to delineate the intricate interactions between the cell proteins at a genome scale. Insights into the protein functions will enrich our understanding in human diseases and contribute to future drug developments. My dissertation focuses on the development and optimization of machine learning algorithms to study protein-protein interactions and protein function annotations through discovery of domain-domain interactions. First of all, I developed a novel domain-based random decision forest framework (RDFF) that explored all possible domain module pairs in mediating protein interactions. RDFF achieved higher sensitivity (79.78%) and specificity (64.38%) in interaction predictions of S. cerevisiae proteins compared to the popular Maximum Likelihood Estimation (MLE) approach. RDFF can also infer interactions for both single-domain pairs and domain module pairs. Secondly, I proposed cross-species interacting domain patterns (CSIDOP) approach that not only increased fidelity of existing functional annotations, but also proposed novel annotations for unknown proteins. CSIDOP accurately determined functions for 95.42% of proteins in H. sapiens using 2,972 GO `molecular function' terms. In contrast, most existing methods can only achieve accuracies of 50% to 75% using much smaller number of categories. Additionally, we were able to assign novel annotations to 181 unknown H. sapiens proteins. Finally, I implemented a web-based system, called PINFUN, which enables users to make online protein-protein interaction and protein function predictions based on a large-scale collection of known and putative domain interactions

Modeling of Wnt-mediated tissue patterning in vertebrate embryogenesis

During embryogenesis, morphogens form a concentration gradient in responsive tissue, which is then translated into a spatial cellular pattern. The mechanisms by which morphogens spread through a tissue to establish such a morphogenetic field remain elusive. Here, we investigate by mutually complementary simulations and in vivo experiments how Wnt morphogen transport by cytonemes differs from typically assumed diffusion-based transport for patterning of highly dynamic tissue such as the neural plate in zebrafish. Stochasticity strongly influences fate acquisition at the single cell level and results in fluctuating boundaries between pattern regions. Stable patterning can be achieved by sorting through concentration dependent cell migration and apoptosis, independent of the morphogen transport mechanism. We show that Wnt transport by cytonemes achieves distinct Wnt thresholds for the brain primordia earlier compared with diffusion-based transport. We conclude that a cytoneme-mediated morphogen transport together with directed cell sorting is a potentially favored mechanism to establish morphogen gradients in rapidly expanding developmental systems