Design principles of multi-map variation in biological systems.

Complexity in biology is often described using a multi-map hierarchical architecture, where the genotype, representing the encoded information, is mapped to the functional level, known as the phenotype, which is then connected to a latent phenotype we refer to as fitness. This underlying architecture governs the processes driving evolution. Furthermore, natural selection, along with other neutral forces, can, in turn, modify these maps.

The limitations of phenotype prediction in metabolism.

Phenotype prediction is at the center of many questions in biology. Prediction is often achieved by determining statistical associations between genetic and phenotypic variation, ignoring the exact processes that cause the phenotype. Here, we present a framework based on genome-scale metabolic reconstructions to reveal the mechanisms behind the associations.

Tolerance to NADH/NAD imbalance anticipates aging and anti-aging interventions.

Redox couples coordinate cellular function, but the consequences of their imbalances are unclear. This is somewhat associated with the limitations of their experimental quantification. Here we circumvent these difficulties by presenting an approach that characterizes fitness-based tolerance profiles to redox couple imbalances using an representation of metabolism.

Dissecting the Fitness Costs of Complex Mutations.

The fitness cost of complex pleiotropic mutations is generally difficult to assess. On the one hand, it is necessary to identify which molecular properties are directly altered by the mutation. On the other, this alteration modifies the activity of many genetic targets with uncertain consequences.

Suboptimal Global Transcriptional Response Increases the Harmful Effects of Loss-of-Function Mutations.

The fitness impact of loss-of-function mutations is generally assumed to reflect the loss of specific molecular functions associated with the perturbed gene. Here, we propose that rewiring of the transcriptome upon deleterious gene inactivation is frequently nonspecific and mimics stereotypic responses to external environmental change. Consequently, transcriptional response to gene deletion could be suboptimal and incur an extra fitness cost.

Genetic buffering and potentiation in metabolism.

Cells adjust their metabolism in response to mutations, but how this reprogramming depends on the genetic context is not well known. Specifically, the absence of individual enzymes can affect reprogramming, and thus the impact of mutations in cell growth. Here, we examine this issue with an in silico model of Saccharomyces cerevisiae's metabolism.

The Impact of Global Transcriptional Regulation on Bacterial Gene Order.

Bacterial gene expression depends on the allocation of limited transcriptional resources provided a particular growth rate and growth condition. Early studies in a few genes suggested this global regulation to generate a unifying hyperbolic expression pattern. Here, we developed a large-scale method that generalizes these experiments to quantify the response to growth of over 700 genes that a priori do not exhibit any specific control.

High-order interactions distort the functional landscape of microbial consortia.

Understanding the link between community composition and function is a major challenge in microbial population biology, with implications for the management of natural microbiomes and the design of synthetic consortia. Specifically, it is poorly understood whether community functions can be quantitatively predicted from traits of species in monoculture. Inspired by the study of complex genetic interactions, we have examined how the amylolytic rate of combinatorial assemblages of six starch-degrading soil bacteria depend on the separate functional contributions from each species and their interactions.

Complex genetic and epigenetic regulation deviates gene expression from a unifying global transcriptional program.

Environmental or genetic perturbations lead to gene expression changes. While most analyses of these changes emphasize the presence of qualitative differences on just a few genes, we now know that changes are widespread. This large-scale variation has been linked to the exclusive influence of a global transcriptional program determined by the new physiological state of the cell.

Deconstructing a multiple antibiotic resistance regulation through the quantification of its input function.

Many essential bacterial responses present complex transcriptional regulation of gene expression. To what extent can the study of these responses substantiate the logic of their regulation? Here, we show how the input function of the genes constituting the response, i.e.

Eco-evolutionary feedbacks can rescue cooperation in microbial populations.

Bacterial populations whose growth depends on the cooperative production of public goods are usually threatened by the rise of cheaters that do not contribute but just consume the common resource. Minimizing cheater invasions appears then as a necessary mechanism to maintain these populations. However, that invasions result instead in the persistence of cooperation is a prospect that has yet remained largely unexplored.

Antagonistic autoregulation speeds up a homogeneous response in Escherichia coli.

By integrating positive and negative feedback loops, biological systems establish intricate gene expression patterns linked to multistability, pulsing, and oscillations. This depends on the specific characteristics of each interlinked feedback, and thus one would expect additional expression programs to be found. Here, we investigate one such program associated with an antagonistic positive and negative transcriptional autoregulatory motif derived from the multiple antibiotic resistance (mar) system of Escherichia coli.

Genetic Redundancies Enhance Information Transfer in Noisy Regulatory Circuits.

Cellular decision making is based on regulatory circuits that associate signal thresholds to specific physiological actions. This transmission of information is subjected to molecular noise what can decrease its fidelity. Here, we show instead how such intrinsic noise enhances information transfer in the presence of multiple circuit copies.

Exploring the Dynamics and Mutational Landscape of Riboregulation with a Minimal Synthetic Circuit in Living Cells.

The regulation of gene expression, triggered by conformational changes in RNA molecules, is widely observed in cellular systems. Here, we examine this mode of control by means of a model-based design and construction of a fully synthetic riboregulatory device. We present a theoretical framework that rests on a simple energy model to predict the dynamic response of such a system.

Rewiring of genetic networks in response to modification of genetic background.

Genome-scale genetic interaction networks are progressively contributing to map the molecular circuitry that determines cellular behavior. To what extent this mapping changes in response to different environmental or genetic conditions is, however, largely unknown. Here, we assembled a genetic network using an in silico model of metabolism in yeast to explicitly ask how separate genetic backgrounds alter network structure.

Plasticity facilitates sustainable growth in the commons.

In the commons, communities whose growth depends on public good, individuals often rely on surprisingly simple strategies, or heuristics, to decide whether to contribute to the shared resource (at risk of exploitation by free-riders). Although this appears a limitation, we show here how four heuristics lead to sustainable growth when coupled to specific ecological constraints. The two simplest ones-contribute permanently or switch stochastically between contributing or not-are first shown to bring sustainability when the public good efficiently promotes growth.

Balancing noise and plasticity in eukaryotic gene expression.

Background: Coupling the control of expression stochasticity (noise) to the ability of expression change (plasticity) can alter gene function and influence adaptation. A number of factors, such as transcription re-initiation, strong chromatin regulation or genome neighboring organization, underlie this coupling. However, these factors do not necessarily combine in equivalent ways and strengths in all genes.

On the search for design principles in biological systems.

The search for basic concepts and underlying principles was at the core of the systems approach to science and technology. This approach was somehow abandoned in mainstream biology after its initial proposal, due to the rise and success of molecular biology. This situation has changed.

The balance of weak and strong interactions in genetic networks.

Genetic interactions are being quantitatively characterized in a comprehensive way in several model organisms. These data are then globally represented in terms of genetic networks. How are interaction strengths distributed in these networks? And what type of functional organization of the underlying genomic systems is revealed by such distribution patterns? Here, I found that weak interactions are important for the structure of genetic buffering between signaling pathways in Caenorhabditis elegans, and that the strength of the association between two genes correlates with the number of common interactors they exhibit.

Local gene regulation details a recognition code within the LacI transcriptional factor family.

The specific binding of regulatory proteins to DNA sequences exhibits no clear patterns of association between amino acids (AAs) and nucleotides (NTs). This complexity of protein-DNA interactions raises the question of whether a simple set of wide-coverage recognition rules can ever be identified. Here, we analyzed this issue using the extensive LacI family of transcriptional factors (TFs).

Trade-offs and noise tolerance in signal detection by genetic circuits.

Genetic circuits can implement elaborated tasks of amplitude or frequency signal detection. What type of constraints could circuits experience in the performance of these tasks, and how are they affected by molecular noise? Here, we consider a simple detection process-a signal acting on a two-component module-to analyze these issues. We show that the presence of a feedback interaction in the detection module imposes a trade-off on amplitude and frequency detection, whose intensity depends on feedback strength.

Persistent competition among stem cells and their daughters in the Drosophila ovary germline niche.

Cell competition is a short-range cell-cell interaction leading to the proliferation of winner cells at the expense of losers, although either cell type shows normal growth in homotypic environments. Drosophila Myc (dMyc; Dm-FlyBase) is a potent inducer of cell competition in wing epithelia, but its role in the ovary germline stem cell niche is unknown. Here, we show that germline stem cells (GSCs) with relative lower levels of dMyc are replaced by GSCs with higher levels of dMyc.

Multistable decision switches for flexible control of epigenetic differentiation.

It is now recognized that molecular circuits with positive feedback can induce two different gene expression states (bistability) under the very same cellular conditions. Whether, and how, cells make use of the coexistence of a larger number of stable states (multistability) is however largely unknown. Here, we first examine how autoregulation, a common attribute of genetic master regulators, facilitates multistability in two-component circuits.

What determines the assembly of transcriptional network motifs in Escherichia coli?

Transcriptional networks are constituted by a collection of building blocks known as network motifs. Why do motifs appear? An adaptive model of motif emergence was recently questioned in favor of neutralist scenarios. Here, we provide a new picture of motif assembly in Escherichia coli which partially clarifies these contrasting explanations.

The determinants of gene order conservation in yeasts.

Background: Why do some groups of physically linked genes stay linked over long evolutionary periods? Although several factors are associated with the formation of gene clusters in eukaryotic genomes, the particular contribution of each feature to clustering maintenance remains unclear.

Results: We quantify the strength of the proposed factors in a yeast lineage. First we identify the magnitude of each variable to determine linkage conservation by using several comparator species at different distances to Saccharomyces cerevisiae.