Balancing noise and plasticity in gene expression

Coupling the control of expression stochasticity (noise) with the capacity to expression change (plasticity) can constrain gene function and limit adaptation. Which factors contribute then to modulate this coupling? Transcription re-initiation is generally associated with coupling and this is commonly related to strong chromatin regulation. We alternatively show how strong regulation can however lead to plasticity uncorrelated to noise. The character of the regulation is also relevant, with plastic but noiseless genes usually subjected to broad expression activation whereas plastic and noisy genes experience targeted repression. This differential action is similarly noticed in how histones influence these genes. In contrast, we find that translational mechanisms are the ones separating noise from plasticity in low-plastic genes, a pattern associated with the simplicity of their expression regulation. Neighboring genome architecture as modifier appears then only effective in highly plastic genes. This poses ultimately an interesting paradox between intergenic distances and modulation, with short intergenic distances both associated and not associated with noise at different plasticity levels. Balancing the coupling among different types of expression variability appears thus as a potential shaping force of genome architecture and regulation

Dynamics of gene expression in the genotype-phenotype map

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Física Teórica de la Materia Condensada. Fecha de lectura: 08 de febrero de 2016Genetic and environmental components can combine in quite complex ways to determine the phenotype of living organisms. Broadly, the goal of this thesis is to understand some of the design principles and constraints driving this assembly. We first study how genetic interaction networks – composed of phenotypically relevant interactions between genes – change in response to perturbation in their elements. Such networks at the genome-scale are progressively contributing to map the molecular circuitry that determines cellular behaviour. To what extent this mapping changes in response to different environmental or genetic conditions is however largely unknown. In Chapter 1 we assembled a genetic network using an in silico model of yeast metabolism to explicitly ask how separate genetic backgrounds alter the overall structure of the network. Backgrounds defined by single deletions induce particularly strong rewiring when the deletion corresponds to a catabolic or central metabolic gene, evidencing compensatory versatility. We found as well that weak interactions and those linking functionally separate genes tend to be more unstable. Overall, these patterns reflect the distributed robustness of core metabolic pathways. We examined as well a second class of evolutionary-motivated background, defined as a neutral mutation accumulation. The observed genetic network instability (predominantly in negative interactions) together with an increase in essential genes reflects a global reduction in buffering. Notably, rewiring of the genetic network is associated as well to a diminished environmental plasticity, what emphasizes a mechanistic integration of genetic and environmental buffering. More generally, this work demonstrates how the specific mechanistic causes of robustness influence the architecture of multiconditional genetic interaction maps. In Chapters 2, 3 and 4, we shift to systems that regulate the expression of genes. The plastic expression of different phenotypes enables organisms to respond to a wide variety of environmental changes, adapting their homeostasis. The dynamics of this plasticity can gen particularly interesting when operating mechanisms involve feedback, for instance when a gene encodes its own activator or repressor. The integration of positive and negative feedbacks can establish intricate patterns such as multistability, pulsing or oscillations. This depends on the specific characteristics of each interlinked feedback. In Chapter 2, we investigate a circuit associated with a dual, positive and negative transcriptional autoregulatory motif derived from the multiple antibiotic resistance system (mar) of Escherichia coli. Our results show that this motif enhances response speedup when it incorporates a linear positive feedback. Linearity also anticipates a homogeneous population phenotype anda higher input sensitivity, which we corroborate experimentally. As the motif is embedded in a broader regulatory network, we also studied how the system integrates additional cross-talks. Notably, the presence of an accessory positive regulation scales the response so that the circuit becomes unresponsive to other (metabolic) stress signals. Overall, we found that an antagonistic autoregulatory motif genetically encoded as a bicistron represents a versatile stimulus-response mode of control through the action of the positive-feedback regulation. Beyond precise and specific regulatory systems such as mar, in Chapter 3 we explore the possibility that more broad and “stereotypic” expression programs also exist. We firstly analyzed a genome-scale expression dataset comprising single gene deletions in 25% of Saccharomyces cerevisiae genes. Our analyses suggest that tens of broad expression programs exist that explain more variation in this dataset than expected at random. We further find that these programs seem to be activated also in conditions different to gene deletion, such as environmental perturbation or upon experimental compensatory evolution. These results suggest the possibility that broad, unspecific, “educated guess” gene expression responses have evolved as an adaptation to uncertain environments. Finally, in Chapter 4, we focus on a phenomenon by which the ability of expression change (plasticity) appears coupled to uncontrolled, stochastic expression variation (noise). This coupling can constrain gene function and limit adaptation. We examine the factors that contribute at the molecular level to modulate this coupling. Both transcription re-initiation and strong chromatin regulation are generally associated to coupling. Alternatively we show that strong regulation can lead to plasticity without noise. The nature of this regulation is also relevant, with plastic but noiseless genes subjected to broad expression activation whereas plastic and noisy genes experience targeted repression. This differential action is particularly illustrated in how histones influence these genes. The cost of coupling plasticity to noise seems to be then compensated by a wider regulatory versatility. Contrarily, in genes with low plasticity, translational efficiency is the main determinant of noise, a pattern we found linked to gene length. Genome architecture (particularly, neighboring genes) appear then as a modifier only effective in highly plastic genes. In this class, we confirm bipromoters as a architecture capable to reduce coupling (by reducing noise) but also highlight its limitation (as they could also decrease plasticity). This presents ultimately a paradox between intergenic distances and modulation, with short intergenic distances both associated and disassociated to noise at different plasticity levels. In summary, balancing the coupling among different types of expression variability appears as a potential shaping force of genome architecture and regulation.El fenotipo de los organismos vivos es el resultado de una compleja combinación de componentes genéticos y ambientales. Desde un punto de vista general, esta tesis tiene como objetivo tratar de entender algunos de los principios de diseño y limitaciones de tiene este ensamblaje. En el primero de los trabajos presentados se estudia cómo las redes de interacción genética (compuestas de interacciones fenotípicamente relevantes entre genes) cambian en respuesta a perturbaciones en algunos de sus elementos. Este tipo de redes a escala genómica están contribuyendo de manera creciente a mapear los circuitos moleculares que determinan el comportamiento celular. Hasta qué punto este “mapa” cambia en respuesta a diferentes perturbaciones genéticas o ambientales? Tratando de responder a esta pregunta, en el Capítulo 1 hemos ensamblado este tipo de redes en de manera sistemática diferentes fondos genéticos usando un modelo in silico del metabolismo de la levadura. Los fondos genéticos correspondientes a enzimas del catabolismo o metabolismo central indujeron una reorganización de la red particularmente fuerte, indicando una versatilidad en los mecanismos de compensación. Asímismo, las interacciones más débiles y aquellas entre genes funcionalmente distantes aparecen como las más inestables. Estos patrones reflejan la robustez distribuída de las rutas catabólicas y del metabolismo central. Por otro lado, también hemos examinado un tipo de fondo genético evolutivamente motivado, definido por la acumulación sucesiva de deleciones neutrales. La inestabilidad observada (predominantemente en interacciones negativas), junto con un incremento en el número de genes esenciales, refleja una reducción global en los mecanismos de compensación. De manera particularmente interesante, hemos observado que la reorganización de la red genética está asociada a una reducción en la plasticidad ambiental. Esto pone de manifiesto que los mecanismos que subyacen a la robustez genética y a la ambiental son esencialmente los mismos. De manera más general, este trabajo muestra cómo los mecanismos específicos de robustez afectan la arquitectura multi-condicional de los mapas de interacción genética. En los capítulos 2, 3, y 4, estudiamos diferentes aspectos de los sistemas que regulan la expresión de los genes. La expresión plástica de diferentes fenotipos hace posible que los organismos puedan responder a un amplio rango de cambios ambientales, adaptando su homeostasis a éstos. Las dinámicas específicas de esta plasticidad son particularmente interesantes cuando el mecanismo implica retroalimentación; por ejemplo, cuando un gen codifica su propio activador o represor. La integración de auto-regulaciones positivas y negativas puede establecer complejos patrones fenotípicos, como multiestabilidad, pulsos de actividad o oscilaciones. Esto depende de las características específicas de cada uno de los sistemas de retroalimentación implicados. En el Capítulo 2, estudiamos un motivo que contiene tanto una autoregulación positiva como una negativa, usando como modelo el operón de resistencia múltiple a antibióticos (mar) de Escherichia coli. Nuestros resultados demuestran que eeste sistema acelera la respuesta al incorporar una retroalimentación positiva lineal. Se demuestra experimentalmente que esta linealidad también produce una respuesta homogénea en la población y una alta sensibilidad. Por otro lado, también estudiamos cómo se integra este “motivo” en la red de regulación mayor. En este sentido, observamos que la presencia de una autoregulación positiva adicional es capaz de desacoplar el sistema de señales metabólicas. Finalmente, examinamos la influencia de posibles arquitecturas alternativas, mostrando cómo codificar la autoregulación dual antagonística en forma de bi-cistrón representa un versátil sistema estímulo-respuesta. Además de sistemas regulatorios específicos y precisos como mar, en el Capítulo 3 exploramos la posible existencia adicional de sistemas regulatorios “estereotípicos”, más generales e inespecíficos. Para ello, analizamos en primer lugar un conjunto de datos experimentales en los que la expresión génica a escala genómica fue medida para deleciones en un único gen, que engloba un 25% de los genes de Saccharomyces cerevisiae. Nuestros análisis sugieren que existen decenas de programas globales e inespecíficos. Además, encontramos evidencia de que estos mismos programas también pueden encontrarse en otros tipos de perturbaciones, como las ambientales y tras evolución experimental compensatoria. Estos resultados indican la posibilidad de una respuesta global e inespecifica como potencial estrategia adaptativa en un ambiente incierto. Finalmente, en el Capítulo 4, transladamos nuestra atención al fenómeno por el que la capacidad de un gen de cambiar su expresión génica en respuesta a cambios ambientales (plasticidad) se correlaciona con una variabilidad incontrolada y estocástica (ruido). Este acoplamiento puede limitar la función génica y la adaptación. Examinamos por tanto los factores a nivel molecular que pueden contribuír a su modulación. Tanto la re-iniciación transcripcional como la regulación a nivel de cromatina se presentan asociados a este acoplamiento. Alternativamente, demostramos cómo una regulación fuerte también puede ser ejercida sin incrementar el ruido. La naturaleza de esta regulación también es relevante; la plasticidad desacoplada del ruido se obtiene mediante mecanismos de activación generales. Mientras tanto, la regulación por represión específica está asociada a ruido, como pone también de manifiesto la influencia de las histonas. Nuestros resultados indican que el coste del ruido se ve compensado por una mayor versatilidad regulatoria. Por el contrario, en genes poco plásticos el ruido viene determinado fundamentalmente por la eficiencia traduccional, un patrón que encontramos asociado a la longitud de los genes. En consecuencia, la arquitectura genómica (particularmente la influencia de genes vecinos) constituye un modificadorsólo en genes plásticos. En estos últimos, confirmamos que los promotores bi-direccionales pueden reducir el ruido, pero también reducen la plasticidad. Constituyen por tanto un mecanismo limitado para desacoplar plasticidad y ruido. En resumen, nuestros resultados sugieren que equilibrar diferentes tipos de variabilidad constituye potencialmente una fuerza modeladora de la arquitectura y regulación de los genomas

Emergent simplicity in microbial community assembly

Published in final edited form as: Science. 2018 August 03; 361(6401): 469–474. doi:10.1126/science.aat1168.A major unresolved question in microbiome research is whether the complex taxonomic architectures observed in surveys of natural communities can be explained and predicted by fundamental, quantitative principles. Bridging theory and experiment is hampered by the multiplicity of ecological processes that simultaneously affect community assembly in natural ecosystems. We addressed this challenge by monitoring the assembly of hundreds of soil- and plant-derived microbiomes in well-controlled minimal synthetic media. Both the community-level function and the coarse-grained taxonomy of the resulting communities are highly predictable and governed by nutrient availability, despite substantial species variability. By generalizing classical ecological models to include widespread nonspecific cross-feeding, we show that these features are all emergent properties of the assembly of large microbial communities, explaining their ubiquity in natural microbiomes.The funding for this work partly results from a Scialog Program sponsored jointly by the Research Corporation, for Science Advancement and. the Gordon and Betty Moore Foundation through grants to Yale University and Boston University by the Research Corporation and by the Simons Foundation. This work was also supported by a young; investigator award from the Human Frontier Science Program to A.S. (RGY0077/2016) and by NIH NIGMS grant 1R35GM119461 and a Simons Investigator as in the Mathematical Modeling of Living Systems (MMLS) to P.M.; D.S. and J.E.G. additionally acknowledge funding from the Defense Advanced Research Projects Agency (purchase request no. HR0011515303, contract no.. HR0011-15-0-0091), the U.S. Department of Energy (DE-SC0012627), the NIH (T32GM100842, 5R01DE024468, R01GM121950, and Sub_P30DK036836_P&F), the National Science Foundation (1457695), the Human Frontier Science Program (RGP0020/2016) and the Boston University Interdisciplinary Biomedical Research Office. (Research Corporation, for Science Advancement; Gordon and Betty Moore Foundation; Boston University by the Research Corporation; Simons Foundation.; RGY0077/2016 - uman Frontier Science Program; 1R35GM119461 - NIH NIGMS grant; Simons Investigator as in the Mathematical Modeling of Living Systems (MMLS); HR0011515303 - Defense Advanced Research Projects Agency; HR0011-15-0-0091 - Defense Advanced Research Projects Agency; T32GM100842 - NIH; 5R01DE024468 - NIH; R01GM121950 - NIH; ub_P30DK036836 - NIH; 1457695 - National Science Foundation; RGP0020/2016 - Human Frontier Science Program; Boston University Interdisciplinary Biomedical Research Office)Accepted manuscrip

Global epistasis on fitness landscapes

Epistatic interactions between mutations add substantial complexity to adaptive landscapes, and are often thought of as detrimental to our ability to predict evolution. Yet, patterns of global epistasis, in which the fitness effect of a mutation is well-predicted by the fitness of its genetic background, may actually be of help in our efforts to reconstruct fitness landscapes and infer adaptive trajectories. Microscopic interactions between mutations, or inherent nonlinearities in the fitness landscape, may cause global epistasis patterns to emerge. In this brief review, we provide a succinct overview of recent work about global epistasis, with an emphasis on building intuition about why it is often observed. To this end, we reconcile simple geometric reasoning with recent mathematical analyses, using these to explain why different mutations in an empirical landscape may exhibit different global epistasis patterns - ranging from diminishing to increasing returns. Finally, we highlight open questions and research directions.Comment: 20 pages, 4 figure

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Glutathione “Redox Homeostasis” and Its Relation to Cardiovascular Disease

More people die from cardiovascular diseases (CVD) than from any other cause. Cardiovascular complications are thought to arise from enhanced levels of free radicals causing impaired “redox homeostasis,” which represents the interplay between oxidative stress (OS) and reductive stress (RS). In this review, we compile several experimental research findings that show sustained shifts towards OS will alter the homeostatic redox mechanism to cause cardiovascular complications, as well as findings that show a prolonged antioxidant state or RS can similarly lead to such cardiovascular complications. This experimental evidence is specifically focused on the role of glutathione, the most abundant antioxidant in the heart, in a redox homeostatic mechanism that has been shifted towards OS or RS. This may lead to impairment of cellular signaling mechanisms and elevated pools of proteotoxicity associated with cardiac dysfunction