Contribution of 3D genome topological domains to genetic risk of cancers: a genome-wide computational study.

BACKGROUND: Genome-wide association studies have identified statistical associations between various diseases, including cancers, and a large number of single-nucleotide polymorphisms (SNPs). However, they provide no direct explanation of the mechanisms underlying the association. Based on the recent discovery that changes in three-dimensional genome organization may have functional consequences on gene regulation favoring diseases, we investigated systematically the genome-wide distribution of disease-associated SNPs with respect to a specific feature of 3D genome organization: topologically associating domains (TADs) and their borders. RESULTS: For each of 449 diseases, we tested whether the associated SNPs are present in TAD borders more often than observed by chance, where chance (i.e., the null model in statistical terms) corresponds to the same number of pointwise loci drawn at random either in the entire genome, or in the entire set of disease-associated SNPs listed in the GWAS catalog. Our analysis shows that a fraction of diseases displays such a preferential localization of their risk loci. Moreover, cancers are relatively more frequent among these diseases, and this predominance is generally enhanced when considering only intergenic SNPs. The structure of SNP-based diseasome networks confirms that localization of risk loci in TAD borders differs between cancers and non-cancer diseases. Furthermore, different TAD border enrichments are observed in embryonic stem cells and differentiated cells, consistent with changes in topological domains along embryogenesis and delineating their contribution to disease risk. CONCLUSIONS: Our results suggest that, for certain diseases, part of the genetic risk lies in a local genetic variation affecting the genome partitioning in topologically insulated domains. Investigating this possible contribution to genetic risk is particularly relevant in cancers. This study thus opens a way of interpreting genome-wide association studies, by distinguishing two types of disease-associated SNPs: one with an effect on an individual gene, the other acting in interplay with 3D genome organization.

Reaction-diffusion models in weighted and directed connectomes.

Connectomes represent comprehensive descriptions of neural connections in a nervous system to better understand and model central brain function and peripheral processing of afferent and efferent neural signals. Connectomes can be considered as a distinctive and necessary structural component alongside glial, vascular, neurochemical, and metabolic networks of the nervous systems of higher organisms that are required for the control of body functions and interaction with the environment. They are carriers of functional phenomena such as planning behavior and cognition, which are based on the processing of highly dynamic neural signaling patterns. In this study, we examine more detailed connectomes with edge weighting and orientation properties, in which reciprocal neuronal connections are also considered. Diffusion processes are a further necessary condition for generating dynamic bioelectric patterns in connectomes. Based on our precise connectome data, we investigate different diffusion-reaction models to study the propagation of dynamic concentration patterns in control and lesioned connectomes. Therefore, differential equations for modeling diffusion were combined with well-known reaction terms to allow the use of connection weights, connectivity orientation and spatial distances. Three reaction-diffusion systems Gray-Scott, Gierer-Meinhardt and Mimura-Murray were investigated. For this purpose, implicit solvers were implemented in a numerically stable reaction-diffusion system within the framework of neuroVIISAS. The implemented reaction-diffusion systems were applied to a subconnectome which shapes the mechanosensitive pathway that is strongly affected in the multiple sclerosis demyelination disease. It was found that demyelination modeling by connectivity weight modulation changes the oscillations of the target region, i.e. the primary somatosensory cortex, of the mechanosensitive pathway. In conclusion, a new application of reaction-diffusion systems to weighted and directed connectomes has been realized. Because the implementation was realized in the neuroVIISAS framework many possibilities for the study of dynamic reaction-diffusion processes in empirical connectomes as well as specific randomized network models are available now.

Link-usage asymmetry and collective patterns emerging from rich-club organization of complex networks.

In models of excitable dynamics on graphs, excitations can travel in both directions of an undirected link. However, as a striking interplay of dynamics and network topology, excitations often establish a directional preference. Some of these cases of "link-usage asymmetry" are local in nature and can be mechanistically understood, for instance, from the degree gradient of a link (i.e., the difference in node degrees at both ends of the link). Other contributions to the link-usage asymmetry are instead, as we show, self-organized in nature, and strictly nonlocal. This is the case for excitation waves, where the preferential propagation of excitations along a link depends on its orientation with respect to a hub acting as a source, even if the link in question is several steps away from the hub itself. Here, we identify and quantify the contribution of such self-organized patterns to link-usage asymmetry and show that they extend to ranges significantly longer than those ascribed to local patterns. We introduce a topological characterization, the hub-set-orientation prevalence of a link, which indicates its average orientation with respect to the hubs of a graph. Our numerical results show that the hub-set-orientation prevalence of a link strongly correlates with the preferential usage of the link in the direction of propagation away from the hub core of the graph. Our methodology is embedding-agnostic and allows for the measurement of wave signals and the sizes of the cores from which they originate.

The attractor structure of functional connectivity in coupled logistic maps.

Stylized models of dynamical processes on graphs allow us to explore the relationships between network architecture and dynamics, a topic of relevance in a range of disciplines. One strategy is to translate dynamical observations into pairwise relationships of nodes, often called functional connectivity (FC), and quantitatively compare them with network architecture or structural connectivity (SC). Here, we start from the observation that for coupled logistic maps, SC/FC relationships vary strongly with coupling strength. Using symbolic encoding, the mapping of the dynamics onto a cellular automaton, and the subsequent analysis of the resulting attractors, we show that this behavior is invariant under these transformations and can be understood from the attractors of the cellular automaton alone. Interestingly, noise enhances SC/FC correlations by creating a more uniform sampling of attractors. On a methodological level, we introduce cellular automata as a data analysis tool, rather than a simulation model of dynamics on graphs.

A system-wide network reconstruction of gene regulation and metabolism in Escherichia coli.

Genome-scale metabolic models have become a fundamental tool for examining metabolic principles. However, metabolism is not solely characterized by the underlying biochemical reactions and catalyzing enzymes, but also affected by regulatory events. Since the pioneering work of Covert and co-workers as well as Shlomi and co-workers it is debated, how regulation and metabolism synergistically characterize a coherent cellular state. The first approaches started from metabolic models, which were extended by the regulation of the encoding genes of the catalyzing enzymes. By now, bioinformatics databases in principle allow addressing the challenge of integrating regulation and metabolism on a system-wide level. Collecting information from several databases we provide a network representation of the integrated gene regulatory and metabolic system for Escherichia coli, including major cellular processes, from metabolic processes via protein modification to a variety of regulatory events. Besides transcriptional regulation, we also take into account regulation of translation, enzyme activities and reactions. Our network model provides novel topological characterizations of system components based on their positions in the network. We show that network characteristics suggest a representation of the integrated system as three network domains (regulatory, metabolic and interface networks) instead of two. This new three-domain representation reveals the structural centrality of components with known high functional relevance. This integrated network can serve as a platform for understanding coherent cellular states as active subnetworks and to elucidate crossover effects between metabolism and gene regulation.

Multi-level assessment of obsessive-compulsive disorder (OCD) reveals relations between neural and neurochemical levels.

BACKGROUND: While considerable progress has been made in exploring the psychological, the neural, and the neurochemical dimensions of OCD separately, their interplay is still an open question, especially their changes during psychotherapy. METHODS: Seventeen patients were assessed at these three levels by psychological questionnaires, fMRI, and venipuncture before and after inpatient psychotherapy. Seventeen controls were scanned at comparable time intervals. First, pre/post treatment changes were investigated for all three levels separately: symptom severity, whole-brain and regional activity, and the concentrations of cortisol, serotonin, dopamine, brain-derived neurotrophic factor (BDNF), and immunological parameters (IL-6, IL-10, TNFα). Second, stepwise linear modeling was used to find relations between the variables of the levels. RESULTS: The obsessive-compulsive, depressive, and overall symptom severity was significantly reduced after psychotherapy. At the neural level, the activity in the anterior cingulate cortex (ACC), in frontal regions, in the precuneus, and in the putamen had significantly decreased. No significant changes were found on the neurochemical level. When connecting the levels, a highly significant model was found that explains the decrease in neural activity of the putamen by increases of the concentrations of cortisol, IL-6, and dopamine. CONCLUSION: Multivariate approaches offer insight on the influences that the different levels of the psychiatric disorder OCD have on each other. More research and adapted models are needed.

The metabolic network coherence of human transcriptomes is associated with genetic variation at the cadherin 18 locus.

Metabolic coherence (MC) is a network-based approach to dimensionality reduction that can be used, for example, to interpret the joint expression of genes linked to human metabolism. Computationally, the derivation of 'transcriptomic' MC involves mapping of an individual gene expression profile onto a gene-centric network derived beforehand from a metabolic network (currently Recon2), followed by the determination of the connectivity of a particular, profile-specific subnetwork. The biological significance of MC has been exemplified previously in the context of human inflammatory bowel disease, among others, but the genetic architecture of this quantitative cellular trait is still unclear. Therefore, we performed a genome-wide association study (GWAS) of MC in the 1000 Genomes/ GEUVADIS data (n = 457) and identified a solitary genome-wide significant association with single nucleotide polymorphisms (SNPs) in the intronic region of the cadherin 18 (CDH18) gene on chromosome 5 (lead SNP: rs11744487, p = 1.2 × 10- 8). Cadherin 18 is a transmembrane protein involved in human neural development and cell-to-cell signaling. Notably, genetic variation at the CDH18 locus has been associated with metabolic syndrome-related traits before. Replication of our genome-wide significant GWAS result was successful in another population study from the Netherlands (BIOS, n = 2661; lead SNP), but failed in two additional studies (KORA, Germany, n = 711; GENOA, USA, n = 411). Besides sample size issues, we surmise that these discrepant findings may be attributable to technical differences. While 1000 Genomes/GEUVADIS and BIOS gene expression profiles were generated by RNA sequencing, the KORA and GENOA data were microarray-based. In addition to providing first evidence for a link between regional genetic variation and a metabolism-related characteristic of human transcriptomes, our findings highlight the benefit of adopting a systems biology-oriented approach to molecular data analysis.

Interdisciplinary approach towards a systems medicine toolbox using the example of inflammatory diseases.

Electronic access to multiple data types, from generic information on biological systems at different functional and cellular levels to high-throughput molecular data from human patients, is a prerequisite of successful systems medicine research. However, scientists often encounter technical and conceptual difficulties that forestall the efficient and effective use of these resources. We summarize and discuss some of these obstacles, and suggest ways to avoid or evade them.The methodological gap between data capturing and data analysis is huge in human medical research. Primary data producers often do not fully apprehend the scientific value of their data, whereas data analysts maybe ignorant of the circumstances under which the data were collected. Therefore, the provision of easy-to-use data access tools not only helps to improve data quality on the part of the data producers but also is likely to foster an informed dialogue with the data analysts.We propose a means to integrate phenotypic data, questionnaire data and microbiome data with a user-friendly Systems Medicine toolbox embedded into i2b2/tranSMART. Our approach is exemplified by the integration of a basic outlier detection tool and a more advanced microbiome analysis (alpha diversity) script. Continuous discussion with clinicians, data managers, biostatisticians and systems medicine experts should serve to enrich even further the functionality of toolboxes like ours, being geared to be used by 'informed non-experts' but at the same time attuned to existing, more sophisticated analysis tools.

Toward a theory of coactivation patterns in excitable neural networks.

The relationship between the structural connectivity (SC) and functional connectivity (FC) of neural systems is of central importance in brain network science. It is an open question, however, how the SC-FC relationship depends on specific topological features of brain networks or the models used for describing neural dynamics. Using a basic but general model of discrete excitable units that follow a susceptible-excited-refractory activity cycle (SER model), we here analyze how the network activity patterns underlying functional connectivity are shaped by the characteristic topological features of the network. We develop an analytical framework for describing the contribution of essential topological elements, such as common inputs and pacemakers, to the coactivation of nodes, and demonstrate the validity of the approach by comparison of the analytical predictions with numerical simulations of various exemplar networks. The present analytic framework may serve as an initial step for the mechanistic understanding of the contributions of brain network topology to brain dynamics.

The E. coli transcriptional regulatory network and its spatial embedding.

Usually complex networks are studied as graphs consisting of nodes whose spatial arrangement is of no significance. Several real biological networks are, however, embedded in space. In this paper we study the transcription regulatory network (TRN) of E. coli as a spatially embedded network. The embedding space of this network is the circular E. coli chromosome, i.e. it is practically one dimensional. However, the TRN itself is a high-dimensional network due to the existence of an adequate number of long-range connections. We find that nodes in short topological distance l = 1, 2 tend, on average, to be in shorter spatial distances r indicating an abundance of short-range connections as well. Community analysis of the TRN reveals the interesting fact that highly interconnected subnets consist of nodes that tend to be in spatial proximity on the circular chromosome. We also find indications that for certain transcriptional aspects of the E. coli it is advantageous to treat the circular genome as two line segments starting from the OriC and ending to Ter.

A Nonlinear Dynamic Systems Model of Psychotherapy: First Steps Toward Validation and the Role of External Input.

Mathematical modeling and computer simulations are important means to understand the mechanisms of psychotherapy. The challenge is to design models which not only predict outcome, but simulate the nonlinear trajectories of change. Another challenge is to validate them with empirical data. We proposed a model on change dynamics which integrates five variables (order parameters) (therapeutic progress or success, motivation for change, problem severity, emotions, and insight) and four control parameters (capacity to enter a trustful cooperation and working alliance, cognitive competencies and mindfulness, hopefulness, behavioral resources). The control parameters modulate the nonlinear functions interrelating the variables. The evolution dynamics of the system is determined by a set of nine nonlinear difference equations, one for each variable and parameter. Here we outline how the model can be tested and validated by empirical time series data of the variables, by time series of the therapeutic alliance, and by assessing the input onto the system as it is perceived by the client. The parameters are measured by questionnaires at the beginning and at the end of the treatment. A key element of the validation algorithm is the adjustment of the parameter values as assessed by the questionnaires to model-specific parameter values by which the dynamics can be reproduced (calibration). The validation steps are illustrated by the data of a client who used an internet-based tool for high-frequency therapy monitoring (daily self-ratings). Especially after applying the input vector (interventions as experienced by the client) the similarity between the empirical and the model dynamics becomes evident. The averaged correlation between the empirical and the simulated dynamics across all variables is .41, after applying a short averaging mean window and eliminating an initial transient period, it is .62, varying between .47 and .81, depending on the variable. The discussion opens perspectives on the combination of mathematical modeling with real-time monitoring in order to realize data-driven simulations for short-term predictions and to estimate the effects of interventions before real interventions are applied.

Boolean analysis reveals systematic interactions among low-abundance species in the human gut microbiome.

The analysis of microbiome compositions in the human gut has gained increasing interest due to the broader availability of data and functional databases and substantial progress in data analysis methods, but also due to the high relevance of the microbiome in human health and disease. While most analyses infer interactions among highly abundant species, the large number of low-abundance species has received less attention. Here we present a novel analysis method based on Boolean operations applied to microbial co-occurrence patterns. We calibrate our approach with simulated data based on a dynamical Boolean network model from which we interpret the statistics of attractor states as a theoretical proxy for microbiome composition. We show that for given fractions of synergistic and competitive interactions in the model our Boolean abundance analysis can reliably detect these interactions. Analyzing a novel data set of 822 microbiome compositions of the human gut, we find a large number of highly significant synergistic interactions among these low-abundance species, forming a connected network, and a few isolated competitive interactions.

Uncoupling of mucosal gene regulation, mRNA splicing and adherent microbiota signatures in inflammatory bowel disease.

OBJECTIVE: An inadequate host response to the intestinal microbiota likely contributes to the manifestation and progression of human inflammatory bowel disease (IBD). However, molecular approaches to unravelling the nature of the defective crosstalk and its consequences for intestinal metabolic and immunological networks are lacking. We assessed the mucosal transcript levels, splicing architecture and mucosa-attached microbial communities of patients with IBD to obtain a comprehensive view of the underlying, hitherto poorly characterised interactions, and how these are altered in IBD. DESIGN: Mucosal biopsies from Crohn's disease and patients with UC, disease controls and healthy individuals (n=63) were subjected to microbiome, transcriptome and splicing analysis, employing next-generation sequencing. The three data levels were integrated by different bioinformatic approaches, including systems biology-inspired network and pathway analysis. RESULTS: Microbiota, host transcript levels and host splicing patterns were influenced most strongly by tissue differences, followed by the effect of inflammation. Both factors point towards a substantial disease-related alteration of metabolic processes. We also observed a strong enrichment of splicing events in inflamed tissues, accompanied by an alteration of the mucosa-attached bacterial taxa. Finally, we noted a striking uncoupling of the three molecular entities when moving from healthy individuals via disease controls to patients with IBD. CONCLUSIONS: Our results provide strong evidence that the interplay between microbiome and host transcriptome, which normally characterises a state of intestinal homeostasis, is drastically perturbed in Crohn's disease and UC. Consequently, integrating multiple OMICs levels appears to be a promising approach to further disentangle the complexity of IBD.

Modular topology emerges from plasticity in a minimalistic excitable network model.

Topological features play a major role in the emergence of complex brain network dynamics underlying brain function. Specific topological properties of brain networks, such as their modular organization, have been widely studied in recent years and shown to be ubiquitous across spatial scales and species. However, the mechanisms underlying the generation and maintenance of such features are still unclear. Using a minimalistic network model with excitable nodes and discrete deterministic dynamics, we studied the effects of a local Hebbian plasticity rule on global network topology. We found that, despite the simple model set-up, the plasticity rule was able to reorganize the global network topology into a modular structure. The structural reorganization was accompanied by enhanced correlations between structural and functional connectivity, and the final network organization reflected features of the dynamical model. These findings demonstrate the potential of simple plasticity rules for structuring the topology of brain connectivity.

Regulation of Spatiotemporal Patterns by Biological Variability: General Principles and Applications to Dictyostelium discoideum.

Spatiotemporal patterns often emerge from local interactions in a self-organizing fashion. In biology, the resulting patterns are also subject to the influence of the systematic differences between the system's constituents (biological variability). This regulation of spatiotemporal patterns by biological variability is the topic of our review. We discuss several examples of correlations between cell properties and the self-organized spatiotemporal patterns, together with their relevance for biology. Our guiding, illustrative example will be spiral waves of cAMP in a colony of Dictyostelium discoideum cells. Analogous processes take place in diverse situations (such as cardiac tissue, where spiral waves occur in potentially fatal ventricular fibrillation) so a deeper understanding of this additional layer of self-organized pattern formation would be beneficial to a wide range of applications. One of the most striking differences between pattern-forming systems in physics or chemistry and those in biology is the potential importance of variability. In the former, system components are essentially identical with random fluctuations determining the details of the self-organization process and the resulting patterns. In biology, due to variability, the properties of potentially very few cells can have a driving influence on the resulting asymptotic collective state of the colony. Variability is one means of implementing a few-element control on the collective mode. Regulatory architectures, parameters of signaling cascades, and properties of structure formation processes can be "reverse-engineered" from observed spatiotemporal patterns, as different types of regulation and forms of interactions between the constituents can lead to markedly different correlations. The power of this biology-inspired view of pattern formation lies in building a bridge between two scales: the patterns as a collective state of a very large number of cells on the one hand, and the internal parameters of the single cells on the other.

Understanding genetic variation - the value of systems biology.

Pharmacology is currently transformed by the vast amounts of genome-associated information available for system-level interpretation. Here I review the potential of systems biology to facilitate this interpretation, thus paving the way for the emerging field of systems pharmacology. In particular, I will show how gene regulatory and metabolic networks can serve as a framework for interpreting high throughput data and as an interface to detailed dynamical models. In addition to the established connectivity analyses of effective networks, I suggest here to also analyze higher order architectural properties of effective networks.

Predicting attractors from spectral properties of stylized gene regulatory networks.

How the architecture of gene regulatory networks shapes gene expression patterns is an open question, which has been approached from a multitude of angles. The dominant strategy has been to identify nonrandom features in these networks and then argue for the function of these features using mechanistic modeling. Here we establish the foundation of an alternative approach by studying the correlation of network eigenvectors with synthetic gene expression data simulated with a basic and popular model of gene expression dynamics: Boolean threshold dynamics in signed directed graphs. We show that eigenvectors of the network adjacency matrix can predict collective states (attractors). However, the overall predictive power depends on details of the network architecture, namely the fraction of positive 3-cycles, in a predictable fashion. Our results are a set of statistical observations, providing a systematic step towards a further theoretical understanding of the role of network eigenvectors in dynamics on graphs.

Marine ecosystem shifts with deglacial sea-ice loss inferred from ancient DNA shotgun sequencing.

Sea ice is a key factor for the functioning and services provided by polar marine ecosystems. However, ecosystem responses to sea-ice loss are largely unknown because time-series data are lacking. Here, we use shotgun metagenomics of marine sedimentary ancient DNA off Kamchatka (Western Bering Sea) covering the last ~20,000 years. We traced shifts from a sea ice-adapted late-glacial ecosystem, characterized by diatoms, copepods, and codfish to an ice-free Holocene characterized by cyanobacteria, salmon, and herring. By providing information about marine ecosystem dynamics across a broad taxonomic spectrum, our data show that ancient DNA will be an important new tool in identifying long-term ecosystem responses to climate transitions for improvements of ocean and cryosphere risk assessments. We conclude that continuing sea-ice decline on the northern Bering Sea shelf might impact on carbon export and disrupt benthic food supply and could allow for a northward expansion of salmon and Pacific herring.

Local topological features of robust supply networks.

The design of robust supply and distribution systems is one of the fundamental challenges at the interface of network science and logistics. Given the multitude of performance criteria, real-world constraints, and external influences acting upon such a system, even formulating an appropriate research question to address this topic is non-trivial. Here we present an abstraction of a supply and distribution system leading to a minimal model, which only retains stylized facts of the systemic function and, in this way, allows us to investigate the generic properties of robust supply networks. On this level of abstraction, a supply and distribution system is the strategic use of transportation to eliminate mismatches between production patterns (i.e., the amounts of goods produced at each production site of a company) and demand patterns (i.e., the amount of goods consumed at each location). When creating networks based on this paradigm and furthermore requiring the robustness of the system with respect to the loss of transportation routes (edge of the network) we see that robust networks are built from specific sets of subgraphs, while vulnerable networks display a markedly different subgraph composition. Our findings confirm a long-standing hypothesis in the field of network science, namely, that network motifs-statistically over-represented small subgraphs-are informative about the robust functioning of a network. Also, our findings offer a blueprint for enhancing the robustness of real-world supply and distribution systems. Supplementary Information: The online version contains supplementary material available at 10.1007/s41109-022-00470-2.

Inferring missing edges in a graph from observed collective patterns.

Many real-life networks are incomplete. Dynamical observations can allow estimating missing edges. Such procedures, often summarized under the term 'network inference', typically evaluate the statistical correlations among pairs of nodes to determine connectivity. Here, we offer an alternative approach: completing an incomplete network by observing its collective behavior. We illustrate this approach for the case of patterns emerging in reaction-diffusion systems on graphs, where collective behaviors can be associated with eigenvectors of the network's Laplacian matrix. Our method combines a partial spectral decomposition of the network's Laplacian matrix with eigenvalue assignment by matching the patterns to the eigenvectors of the incomplete graph. We show that knowledge of a few collective patterns can allow the prediction of missing edges and that this result holds across a range of network architectures. We present a numerical case study using activator-inhibitor dynamics and we illustrate that the main requirement for the observed patterns is that they are not confined to subsets of nodes, but involve the whole network.