A biological network is a method of representing systems as complex sets of binary interactions or relations between various biological entities. In general, networks or graphs are used to capture relationships between entities or objects. A network can be represented as an N×N matrix where N is the number of nodes, and whose entries tell you if two nodes share an edge. Typically, this matrix will have entries of 0 or 1 with 1 denoting an edge. We can optionally use a weighted graph by assigning a weight to each edge to show how relevant the connection between two nodes is.
History of networks
As early as 1736 Leonhard Euler analyzed a real-world issue known as the Seven Bridges of Königsberg, which established the foundation of graph theory. From the 1930s-1950s the study of random graphs were developed. During the mid-1990s, it was discovered that many different types of "real" networks have structural properties quite different from random networks. In the late 2000s, scale-free and small-world networks began shaping the emergence of systems biology, network biology, and network medicine. In 2014, graph theoretical methods were used by Frank Emmert-Streib to analyze biological networks.
In the 1980s, researchers started viewing DNA or genomes as the dynamic storage of a language system with precise computable finite states represented as a finite-state machine. Recent complex systems research has also suggested some far-reaching commonality in the organization of information in problems from biology, computer science, and physics.
Networks in biology
Protein–protein interaction networks
Protein-protein interaction networks (PINs) represent the physical relationship among proteins present in a cell, where proteins are nodes, and their interactions are undirected edges. Due to their undirected nature, it is difficult to identify all the proteins involved in an interaction. Protein–protein interactions (PPIs) are essential to the cellular processes and also the most intensely analyzed networks in biology. PPIs could be discovered by various experimental techniques, among which the yeast two-hybrid system is a commonly used technique for the study of binary interactions. Recently, high-throughput studies using mass spectrometry have identified large sets of protein interactions.
Many international efforts have resulted in databases that catalog experimentally determined protein-protein interactions. Some of them are the Human Protein Reference Database, Database of Interacting Proteins, the Molecular Interaction Database (MINT), IntAct, and BioGRID. At the same time, multiple computational approaches have been proposed to predict interactions. FunCoup and STRING are examples of such databases, where protein-protein interactions inferred from multiple evidences are gathered and made available for public usage.
Recent studies have indicated the conservation of molecular networks through deep evolutionary time. Moreover, it has been discovered that proteins with high degrees of connectedness are more likely to be essential for survival than proteins with lesser degrees. This observation suggests that the overall composition of the network (not simply interactions between protein pairs) is vital for an organism's overall functioning.
Gene regulatory networks (DNA–protein interaction networks)
The genome encodes thousands of genes whose products (mRNAs, proteins) are crucial to the various processes of life, such as cell differentiation, cell survival, and metabolism. Genes produce such products through a process called transcription, which is regulated by a class of proteins called transcription factors. For instance, the human genome encodes almost 1,500 DNA-binding transcription factors that regulate the expression of more than 20,000 human genes. The complete set of gene products and the interactions among them constitutes gene regulatory networks (GRN). GRNs regulate the levels of gene products within the cell and in-turn the cellular processes.
GRNs are represented with genes and transcriptional factors as nodes and the relationship between them as edges. These edges are directional, representing the regulatory relationship between the two ends of the edge. For example, the directed edge from gene A to gene B indicates that A regulates the expression of B. Thus, these directional edges can not only represent the promotion of gene regulation but also its inhibition.
GRNs are usually constructed by utilizing the gene regulation knowledge available from databases such as., Reactome and KEGG. High-throughput measurement technologies, such as microarray, RNA-Seq, ChIP-chip, and ChIP-seq, enabled the accumulation of large-scale transcriptomics data, which could help in understanding the complex gene regulation patterns.
Gene co-expression networks (transcript–transcript association networks)
Gene co-expression networks can be perceived as association networks between variables that measure transcript abundances. These networks have been used to provide a system biologic analysis of DNA microarray data, RNA-seq data, miRNA data, etc. weighted gene co-expression network analysis is extensively used to identify co-expression modules and intramodular hub genes. Co-expression modules may correspond to cell types or pathways, while highly connected intramodular hubs can be interpreted as representatives of their respective modules.
DNA-DNA chromatin networks
Within a nucleus, DNA is constantly in motion. Perpetual actions such as genome folding and Cohesin extrusion morph the shape of a genome in real time. The spatial location of strands of chromatin relative to each other plays an important role in the activation or suppression of certain genes. DNA-DNA Chromatin Networks help biologists to understand these interactions by analyzing commonalities amongst different loci. The size of a network can vary significantly, from a few genes to several thousand and thus network analysis can provide vital support in understanding relationships among different areas of the genome. As an example, analysis of spatially similar loci within the organization in a nucleus with Genome Architecture Mapping (GAM) can be used to construct a network of loci with edges representing highly linked genomic regions.
In such networks, edge weights often correspond to the frequency or strength of interaction between loci, while network construction may involve filtering or thresholding to retain only strong interactions. Some examples of this may include filtering out certain gene locations, filtering based on quartile of closeness, or by expression as this can serve to reduce noise and highlight biologically meaningful relationships for interpretation.
The first graphic portrays the layout of the Hist1 region of the mm9 mouse genome, a large cluster of genes that encode for replication-dependant histones. The organization of the histone genes in this cluster have been found to be practically identical to that of the human Hist1 region. The data used to develop this network graph was discovered through GAM. Each node on the graph represents a genomic loci within the mouse genome. The edges between the nodes represent a linkage disequilibrium between the connected nodes greater than the average across all 81 genomic windows. The initial locations of the nodes within the graphic were randomly selected but the methodology of choosing edges shaped the graph into a rudimentary graphical representation of the placement of genomic loci throughout the Hist1 region.
Highly connected nodes in such chromatin interaction networks can be interpreted as hubs, and may be used to define communities of loci that interact more frequently with one another. These community structures reflect the modular organization commonly observed in biological and regulatory networks.name="Topology and evolution of regulatory control networks"> In hub-based approaches, nodes are assigned to the community of the hub with which they share the strongest interaction, often with constraints to ensure that each node belongs to only one community.
Such network representations are closely related to heat map visualizations, where interaction data are displayed as a matrix (adjacency matrix) in which each cell represents the interaction strength between two loci. Patterns observed in heat maps, such as dense blocks of high interaction, often correspond to communities identified in the network representation. These approaches enable combination of graph-based and matrix-based analyses of chromatin organization. This type of comparison can be seen in the graphics below where the heat map and network visualizations can be compared in such a manner.
Metabolic networks
Cells break down the food and nutrients into small molecules necessary for cellular processing through a series of biochemical reactions. These biochemical reactions are catalyzed by enzymes. The complete set of all these biochemical reactions in all the pathways represents the metabolic network. Within the metabolic network, the small molecules take the roles of nodes, and they could be either carbohydrates, lipids, or amino acids. The reactions which convert these small molecules from one form to another are represented as edges. It is possible to use network analyses to infer how selection acts on metabolic pathways.
Signaling networks
Signals are transduced within cells or in between cells and thus form complex signaling networks which plays a key role in the tissue structure. For instance, the MAPK/ERK pathway is transduced from the cell surface to the cell nucleus by a series of protein-protein interactions, phosphorylation reactions, and other events. Signaling networks typically integrate protein–protein interaction networks, gene regulatory networks, and metabolic networks. Single cell sequencing technologies allows the extraction of inter-cellular signaling, an example is NicheNet, which allows to modeling intercellular communication by linking ligands to target genes.
Neuronal networks
The complex interactions in the brain make it a perfect candidate to apply network theory. Neurons in the brain are deeply connected with one another, and this results in complex networks being present in the structural and functional aspects of the brain. For instance, small-world network properties have been demonstrated in connections between cortical regions of the primate brain or during swallowing in humans. This suggests that cortical areas of the brain are not directly interacting with each other, but most areas can be reached from all others through only a few interactions.
Food webs
All organisms are connected through feeding interactions. If a species eats or is eaten by another species, they are connected in an intricate food web of predator and prey interactions. The stability of these interactions has been a long-standing question in ecology. That is to say if certain individuals are removed, what happens to the network (i.e., does it collapse or adapt)? Network analysis can be used to explore food web stability and determine if certain network properties result in more stable networks. Moreover, network analysis can be used to determine how selective removals of species will influence the food web as a whole. This is especially important considering the potential species loss due to global climate change.
Network medicine