Robust Detection of Hierarchical Communities from Escherichia coli Gene Expression Data

Determining the functional structure of biological networks is a central goal of systems biology. One approach is to analyze gene expression data to infer a network of gene interactions on the basis of their correlated responses to environmental and genetic perturbations. The inferred network can then be analyzed to identify functional communities. However, commonly used algorithms can yield unreliable results due to experimental noise, algorithmic stochasticity, and the influence of arbitrarily chosen parameter values. Furthermore, the results obtained typically provide only a simplistic view of the network partitioned into disjoint communities and provide no information of the relationship between communities. Here, we present methods to robustly detect coregulated and functionally enriched gene communities and demonstrate their application and validity for Escherichia coli gene expression data. Applying a recently developed community detection algorithm to the network of interactions identified with the context likelihood of relatedness (CLR) method, we show that a hierarchy of network communities can be identified. These communities significantly enrich for gene ontology (GO) terms, consistent with them representing biologically meaningful groups. Further, analysis of the most significantly enriched communities identified several candidate new regulatory interactions. The robustness of our methods is demonstrated by showing that a core set of functional communities is reliably found when artificial noise, modeling experimental noise, is added to the data. We find that noise mainly acts conservatively, increasing the relatedness required for a network link to be reliably assigned and decreasing the size of the core communities, rather than causing association of genes into new communities.Comment: Due to appear in PLoS Computational Biology. Supplementary Figure S1 was not uploaded but is available by contacting the author. 27 pages, 5 figures, 15 supplementary file

The evolutionary origins of hierarchy

Hierarchical organization -- the recursive composition of sub-modules -- is ubiquitous in biological networks, including neural, metabolic, ecological, and genetic regulatory networks, and in human-made systems, such as large organizations and the Internet. To date, most research on hierarchy in networks has been limited to quantifying this property. However, an open, important question in evolutionary biology is why hierarchical organization evolves in the first place. It has recently been shown that modularity evolves because of the presence of a cost for network connections. Here we investigate whether such connection costs also tend to cause a hierarchical organization of such modules. In computational simulations, we find that networks without a connection cost do not evolve to be hierarchical, even when the task has a hierarchical structure. However, with a connection cost, networks evolve to be both modular and hierarchical, and these networks exhibit higher overall performance and evolvability (i.e. faster adaptation to new environments). Additional analyses confirm that hierarchy independently improves adaptability after controlling for modularity. Overall, our results suggest that the same force--the cost of connections--promotes the evolution of both hierarchy and modularity, and that these properties are important drivers of network performance and adaptability. In addition to shedding light on the emergence of hierarchy across the many domains in which it appears, these findings will also accelerate future research into evolving more complex, intelligent computational brains in the fields of artificial intelligence and robotics.Comment: 32 page

The Emergence of Canalization and Evolvability in an Open-Ended, Interactive Evolutionary System

Natural evolution has produced a tremendous diversity of functional organisms. Many believe an essential component of this process was the evolution of evolvability, whereby evolution speeds up its ability to innovate by generating a more adaptive pool of offspring. One hypothesized mechanism for evolvability is developmental canalization, wherein certain dimensions of variation become more likely to be traversed and others are prevented from being explored (e.g. offspring tend to have similarly sized legs, and mutations affect the length of both legs, not each leg individually). While ubiquitous in nature, canalization almost never evolves in computational simulations of evolution. Not only does that deprive us of in silico models in which to study the evolution of evolvability, but it also raises the question of which conditions give rise to this form of evolvability. Answering this question would shed light on why such evolvability emerged naturally and could accelerate engineering efforts to harness evolution to solve important engineering challenges. In this paper we reveal a unique system in which canalization did emerge in computational evolution. We document that genomes entrench certain dimensions of variation that were frequently explored during their evolutionary history. The genetic representation of these organisms also evolved to be highly modular and hierarchical, and we show that these organizational properties correlate with increased fitness. Interestingly, the type of computational evolutionary experiment that produced this evolvability was very different from traditional digital evolution in that there was no objective, suggesting that open-ended, divergent evolutionary processes may be necessary for the evolution of evolvability.Comment: SI can be found at: http://www.evolvingai.org/files/SI_0.zi

Investigating modularity and transparency within bioinspired connectionist architectures using genetic and epigenetic models

Machine learning algorithms allow computers to deal with incomplete data in tasks such as speech recognition and object detection. Some machine learning algorithms take inspiration from biological systems due to useful properties such as robustness, allowing algorithms to be flexible and domain agnostic. This comes at a cost, resulting in difficulty when one attempts to understand the reasoning behind decisions. This is problematic when such models are applied in realworld situations where accountability, legality, and maintenance are of concern. Artificial gene regulatory networks (AGRNs) are a type of connectionist architecture inspired by gene regulatory mechanisms. AGRNs are of interest within this thesis due to their ability to solve tasks in chaotic dynamical systems despite their relatively small size.The overarching aim of this work was to investigate the properties of connectionist architectures to improve the transparency of their execution. Initially, the evolutionary process and internal structure of AGRNs were investigated. Following this, the creation of an external control layer used to improve the transparency of execution of an external connectionist architecture was attempted.When investigating the evolutionary process of AGRNs, pathways were found that when followed, produced more performant networks in a shorter time frame. Evidence that AGRNs are capable of performing well despite internal interference was found when investigating their modularity, where it was also discovered that they do not develop strict modularity consistently. A control layer inspired by epigenetics that selectively deactivates nodes in trained artificial neural networks (ANNs) was developed; the analysis of its behaviour provided an insight into the internal workings of the ANN

Synthetic biology—putting engineering into biology

Synthetic biology is interpreted as the engineering-driven building of increasingly complex biological entities for novel applications. Encouraged by progress in the design of artificial gene networks, de novo DNA synthesis and protein engineering, we review the case for this emerging discipline. Key aspects of an engineering approach are purpose-orientation, deep insight into the underlying scientific principles, a hierarchy of abstraction including suitable interfaces between and within the levels of the hierarchy, standardization and the separation of design and fabrication. Synthetic biology investigates possibilities to implement these requirements into the process of engineering biological systems. This is illustrated on the DNA level by the implementation of engineering-inspired artificial operations such as toggle switching, oscillating or production of spatial patterns. On the protein level, the functionally self-contained domain structure of a number of proteins suggests possibilities for essentially Lego-like recombination which can be exploited for reprogramming DNA binding domain specificities or signaling pathways. Alternatively, computational design emerges to rationally reprogram enzyme function. Finally, the increasing facility of de novo DNA synthesis—synthetic biology’s system fabrication process—supplies the possibility to implement novel designs for ever more complex systems. Some of these elements have merged to realize the first tangible synthetic biology applications in the area of manufacturing of pharmaceutical compounds.

Analysis of heat kernel highlights the strongly modular and heat-preserving structure of proteins

In this paper, we study the structure and dynamical properties of protein contact networks with respect to other biological networks, together with simulated archetypal models acting as probes. We consider both classical topological descriptors, such as the modularity and statistics of the shortest paths, and different interpretations in terms of diffusion provided by the discrete heat kernel, which is elaborated from the normalized graph Laplacians. A principal component analysis shows high discrimination among the network types, either by considering the topological and heat kernel based vector characterizations. Furthermore, a canonical correlation analysis demonstrates the strong agreement among those two characterizations, providing thus an important justification in terms of interpretability for the heat kernel. Finally, and most importantly, the focused analysis of the heat kernel provides a way to yield insights on the fact that proteins have to satisfy specific structural design constraints that the other considered networks do not need to obey. Notably, the heat trace decay of an ensemble of varying-size proteins denotes subdiffusion, a peculiar property of proteins

Detection of regulator genes and eQTLs in gene networks

Genetic differences between individuals associated to quantitative phenotypic traits, including disease states, are usually found in non-coding genomic regions. These genetic variants are often also associated to differences in expression levels of nearby genes (they are "expression quantitative trait loci" or eQTLs for short) and presumably play a gene regulatory role, affecting the status of molecular networks of interacting genes, proteins and metabolites. Computational systems biology approaches to reconstruct causal gene networks from large-scale omics data have therefore become essential to understand the structure of networks controlled by eQTLs together with other regulatory genes, and to generate detailed hypotheses about the molecular mechanisms that lead from genotype to phenotype. Here we review the main analytical methods and softwares to identify eQTLs and their associated genes, to reconstruct co-expression networks and modules, to reconstruct causal Bayesian gene and module networks, and to validate predicted networks in silico.Comment: minor revision with typos corrected; review article; 24 pages, 2 figure

Complex Networks

Introduction to the Special Issue on Complex Networks, Artificial Life journal.Comment: 7 pages, in pres