3,664 research outputs found
How to understand the cell by breaking it: network analysis of gene perturbation screens
Modern high-throughput gene perturbation screens are key technologies at the
forefront of genetic research. Combined with rich phenotypic descriptors they
enable researchers to observe detailed cellular reactions to experimental
perturbations on a genome-wide scale. This review surveys the current
state-of-the-art in analyzing perturbation screens from a network point of
view. We describe approaches to make the step from the parts list to the wiring
diagram by using phenotypes for network inference and integrating them with
complementary data sources. The first part of the review describes methods to
analyze one- or low-dimensional phenotypes like viability or reporter activity;
the second part concentrates on high-dimensional phenotypes showing global
changes in cell morphology, transcriptome or proteome.Comment: Review based on ISMB 2009 tutorial; after two rounds of revisio
Associative memory in gene regulation networks
The pattern of gene expression in the phenotype of an organism is determined in part by the dynamical attractors of the organism’s gene regulation network. Changes to the connections in this network over evolutionary time alter the adult gene expression pattern and hence the fitness of the organism. However, the evolution of structure in gene expression networks (potentially reflecting past selective environments) and its affordances and limitations with respect to enhancing evolvability is poorly understood in general. In this paper we model the evolution of a gene regulation network in a controlled scenario. We show that selected changes to connections in the regulation network make the currently selected gene expression pattern more robust to environmental variation. Moreover, such changes to connections are necessarily ‘Hebbian’ – ‘genes that fire together wire together’ – i.e. genes whose expression is selected for in the same selective environments become co-regulated. Accordingly, in a manner formally equivalent to well-understood learning behaviour in artificial neural networks, a gene expression network will therefore develop a generalised associative memory of past selected phenotypes. This theoretical framework helps us to better understand the relationship between homeostasis and evolvability (i.e. selection to reduce variability facilitates structured variability), and shows that, in principle, a gene regulation network has the potential to develop ‘recall’ capabilities normally reserved for cognitive systems
Bridging scales in cancer progression: Mapping genotype to phenotype using neural networks
In this review we summarize our recent efforts in trying to understand the
role of heterogeneity in cancer progression by using neural networks to
characterise different aspects of the mapping from a cancer cells genotype and
environment to its phenotype. Our central premise is that cancer is an evolving
system subject to mutation and selection, and the primary conduit for these
processes to occur is the cancer cell whose behaviour is regulated on multiple
biological scales. The selection pressure is mainly driven by the
microenvironment that the tumour is growing in and this acts directly upon the
cell phenotype. In turn, the phenotype is driven by the intracellular pathways
that are regulated by the genotype. Integrating all of these processes is a
massive undertaking and requires bridging many biological scales (i.e.
genotype, pathway, phenotype and environment) that we will only scratch the
surface of in this review. We will focus on models that use neural networks as
a means of connecting these different biological scales, since they allow us to
easily create heterogeneity for selection to act upon and importantly this
heterogeneity can be implemented at different biological scales. More
specifically, we consider three different neural networks that bridge different
aspects of these scales and the dialogue with the micro-environment, (i) the
impact of the micro-environment on evolutionary dynamics, (ii) the mapping from
genotype to phenotype under drug-induced perturbations and (iii) pathway
activity in both normal and cancer cells under different micro-environmental
conditions
A stochastic and dynamical view of pluripotency in mouse embryonic stem cells
Pluripotent embryonic stem cells are of paramount importance for biomedical
research thanks to their innate ability for self-renewal and differentiation
into all major cell lines. The fateful decision to exit or remain in the
pluripotent state is regulated by complex genetic regulatory network. Latest
advances in transcriptomics have made it possible to infer basic topologies of
pluripotency governing networks. The inferred network topologies, however, only
encode boolean information while remaining silent about the roles of dynamics
and molecular noise in gene expression. These features are widely considered
essential for functional decision making. Herein we developed a framework for
extending the boolean level networks into models accounting for individual
genetic switches and promoter architecture which allows mechanistic
interrogation of the roles of molecular noise, external signaling, and network
topology. We demonstrate the pluripotent state of the network to be a broad
attractor which is robust to variations of gene expression. Dynamics of exiting
the pluripotent state, on the other hand, is significantly influenced by the
molecular noise originating from genetic switching events which makes cells
more responsive to extracellular signals. Lastly we show that steady state
probability landscape can be significantly remodeled by global gene switching
rates alone which can be taken as a proxy for how global epigenetic
modifications exert control over stability of pluripotent states.Comment: 11 pages, 7 figure
A tractable genotype-phenotype map for the self-assembly of protein quaternary structure
The mapping between biological genotypes and phenotypes is central to the
study of biological evolution. Here we introduce a rich, intuitive, and
biologically realistic genotype-phenotype (GP) map, that serves as a model of
self-assembling biological structures, such as protein complexes, and remains
computationally and analytically tractable. Our GP map arises naturally from
the self-assembly of polyomino structures on a 2D lattice and exhibits a number
of properties: (genotypes vastly outnumber phenotypes),
(genotypic redundancy varies greatly between
phenotypes), (phenotypes consist
of disconnected mutational networks) and (most
phenotypes can be reached in a small number of mutations). We also show that
the mutational robustness of phenotypes scales very roughly logarithmically
with phenotype redundancy and is positively correlated with phenotypic
evolvability. Although our GP map describes the assembly of disconnected
objects, it shares many properties with other popular GP maps for connected
units, such as models for RNA secondary structure or the HP lattice model for
protein tertiary structure. The remarkable fact that these important properties
similarly emerge from such different models suggests the possibility that
universal features underlie a much wider class of biologically realistic GP
maps.Comment: 12 pages, 6 figure
Buffered Qualitative Stability explains the robustness and evolvability of transcriptional networks
The gene regulatory network (GRN) is the central decision‐making module of the cell. We have developed a theory called Buffered Qualitative Stability (BQS) based on the hypothesis that GRNs are organised so that they remain robust in the face of unpredictable environmental and evolutionary changes. BQS makes strong and diverse predictions about the network features that allow stable responses under arbitrary perturbations, including the random addition of new connections. We show that the GRNs of E. coli, M. tuberculosis, P. aeruginosa, yeast, mouse, and human all verify the predictions of BQS. BQS explains many of the small- and large‐scale properties of GRNs, provides conditions for evolvable robustness, and highlights general features of transcriptional response. BQS is severely compromised in a human cancer cell line, suggesting that loss of BQS might underlie the phenotypic plasticity of cancer cells, and highlighting a possible sequence of GRN alterations concomitant with cancer initiation. DOI: http://dx.doi.org/10.7554/eLife.02863.00
Identification of response-modulated genetic interactions by sensitivity-based epistatic analysis
<p>Abstract</p> <p>Background</p> <p>High-throughput genomics has enabled the global mapping of genetic interactions based on the phenotypic impact of combinatorial genetic perturbations. An important next step is to understand how these networks are dynamically remodelled in response to environmental stimuli. Here, we report on the development and testing of a method to identify such interactions. The method was developed from first principles by treating the impact on cellular growth of environmental perturbations equivalently to that of gene deletions. This allowed us to establish a novel neutrality function marking the absence of epistasis in terms of sensitivity phenotypes rather than fitness. We tested the method by identifying fitness- and sensitivity-based interactions involved in the response to drug-induced DNA-damage of budding yeast <it>Saccharomyces cerevisiae </it>using two mutant libraries - one containing transcription factor deletions, and the other containing deletions of DNA repair genes.</p> <p>Results</p> <p>Within the library of transcription factor deletion mutants, we observe significant differences in the sets of genetic interactions identified by the fitness- and sensitivity-based approaches. Notably, among the most likely interactions, only ~50% were identified by both methods. While interactions identified solely by the sensitivity-based approach are modulated in response to drug-induced DNA damage, those identified solely by the fitness-based method remained invariant to the treatment. Comparison of the identified interactions to transcriptional profiles and protein-DNA interaction data indicate that the sensitivity-based method improves the identification of interactions involved in the DNA damage response. Additionally, for the library containing DNA repair mutants, we observe that the sensitivity-based method improves the grouping of functionally related genes, as well as the identification of protein complexes, involved in DNA repair.</p> <p>Conclusion</p> <p>Our results show that the identification of response-modulated genetic interactions can be improved by incorporating the effect of a changing environment directly into the neutrality function marking the absence of epistasis. We expect that this extension of conventional epistatic analysis will facilitate the development of dynamic models of gene networks from quantitative measurements of genetic interactions. While the method was developed for growth phenotype, it should apply equally well for other phenotypes, including the expression of fluorescent reporters.</p
A Developmental Systems Perspective on Epistasis: Computational Exploration of Mutational Interactions in Model Developmental Regulatory Networks
The way in which the information contained in genotypes is translated into complex phenotypic traits (i.e. embryonic expression patterns) depends on its decoding by a multilayered hierarchy of biomolecular systems (regulatory networks). Each layer of this hierarchy displays its own regulatory schemes (i.e. operational rules such as +/− feedback) and associated control parameters, resulting in characteristic variational constraints. This process can be conceptualized as a mapping issue, and in the context of highly-dimensional genotype-phenotype mappings (GPMs) epistatic events have been shown to be ubiquitous, manifested in non-linear correspondences between changes in the genotype and their phenotypic effects. In this study I concentrate on epistatic phenomena pervading levels of biological organization above the genetic material, more specifically the realm of molecular networks. At this level, systems approaches to studying GPMs are specially suitable to shed light on the mechanistic basis of epistatic phenomena. To this aim, I constructed and analyzed ensembles of highly-modular (fully interconnected) networks with distinctive topologies, each displaying dynamic behaviors that were categorized as either arbitrary or functional according to early patterning processes in the Drosophila embryo. Spatio-temporal expression trajectories in virtual syncytial embryos were simulated via reaction-diffusion models. My in silico mutational experiments show that: 1) the average fitness decay tendency to successively accumulated mutations in ensembles of functional networks indicates the prevalence of positive epistasis, whereas in ensembles of arbitrary networks negative epistasis is the dominant tendency; and 2) the evaluation of epistatic coefficients of diverse interaction orders indicates that, both positive and negative epistasis are more prevalent in functional networks than in arbitrary ones. Overall, I conclude that the phenotypic and fitness effects of multiple perturbations are strongly conditioned by both the regulatory architecture (i.e. pattern of coupled feedback structures) and the dynamic nature of the spatio-temporal expression trajectories displayed by the simulated networks
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