Dissertationen zum Thema „Modélisation des gènes“
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Evlampiev, Kirill. „Modélisation de réseaux biologiques“. Paris 6, 2007. http://www.theses.fr/2007PA066200.
Der volle Inhalt der QuelleRefahi, Yassin. „Modélisation multiéchelle de perturbation de la phyllotaxie d'Arabidopsis thaliana“. Phd thesis, Université Montpellier II - Sciences et Techniques du Languedoc, 2011. http://tel.archives-ouvertes.fr/tel-00859869.
Der volle Inhalt der QuelleHerbach, Ulysse. „Modélisation stochastique de l'expression des gènes et inférence de réseaux de régulation“. Thesis, Lyon, 2018. http://www.theses.fr/2018LYSE1155/document.
Der volle Inhalt der QuelleGene expression in a cell has long been only observable through averaged quantities over cell populations. The recent development of single-cell transcriptomics has enabled gene expression to be measured in individual cells: it turns out that even in an isogenic population, the molecular variability can be very important. In particular, an averaged description is not sufficient to account for cell differentiation. In this thesis, we are interested in the emergence of such cell decision-making from underlying gene regulatory networks, which we would like to infer from data. The starting point is the construction of a stochastic gene network model that is able to explain the data using physical arguments. Genes are then seen as an interacting particle system that happens to be a piecewise-deterministic Markov process, and our aim is to derive a tractable statistical model from its stationary distribution. We present two approaches: the first one is a popular field approximation, for which we obtain a concentration result, and the second one is based on an analytically tractable particular case, which provides a hidden Markov random field with interesting properties
Champion, Magali. „Contribution à la modélisation et l'inférence de réseau de régulation de gènes“. Toulouse 3, 2014. http://thesesups.ups-tlse.fr/2613/.
Der volle Inhalt der QuelleThis manuscript intends to study a theoretical analysis and the use of statistical and optimization methods in the context of gene networks. Such networks are powerful tools to represent and analyse complex biological systems, and enable the modelling of functional relationships between elements of these systems. The first part is dedicated to the study of statistical learning methods to infer networks, from sparse linear regressions, in a high-dimensional setting, and particularly the L2-Boosting algorithms. From a theoretical point of view, some consistency results and support stability results were obtained, assuming conditions on the dimension of the problem. The second part deals with the use of L2-Boosting algorithms to learn Sobol indices in a sensitive analysis setting. The estimation of these indices is based on the decomposition of the model with functional ANOVA. The elements of this decomposition are estimated using a procedure of Hierarchical Orthogonalisation of Gram-Schmidt, devoted to build an approximation of the analytical basis, and then, a L 2 -Boosting algorithm, in order to obtain a sparse approximation of the signal. We show that the obtained estimator is consistant in a noisy setting on the approximation dictionary. The last part concerns the development of optimization methods to estimate relationships in networks. We show that the minimization of the log-likelihood can be written as an optimization problem with two components, which consists in finding the structure of the complete graph (order of variables of the nodes of the graph), and then, in making the graph sparse. We propose to use a Genetic Algorithm, adapted to the particular structure of our problem, to solve it
Audrain, Mickaël. „Modélisation des phases précoces de la maladie d’Alzheimer par transfert de gènes“. Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCB010/document.
Der volle Inhalt der QuelleEvaluation of biomarkers and new innovative therapies for Alzheimer's disease (AD) suffers from a misunderstanding of early phases and lack of appropriate animal models close to the human physiopathology. Most available rodent models reproduce hallmarks of AD such as amyloid plaques and neurofibrillary tangles in a few months, while it takes many years to be achieved in human. My PhD work consisted to develop a new modelling strategy of AD early phases without major overexpression of transgenes. To do so, we used gene transfer of human APPSL and PS1M146L using viral vectors injection in the hippocampus of 8 weeks old mice and rats. We characterized these models and showed peptides production, such as betaCTF and abeta42 from APP processing, similar to what is observed in AD patients hippocampi. We also highlighted a hyperphosphorylation of Tau followed by a synaptic failure characterized by a decrease of PSD-95 and GLT-1 levels and by an increase of the tonic current mediated by glutamate. These changes have been finally associated with behavioral deficits. My results suggest that many events appear well before the formation of amyloid plaques or tangles and lead to the disruption of the synapse and the early onset of behavioral defects. Thus, we now have relevant tools to understand the early stages of AD, which will allow us to test new drug compounds on these models with a wide therapeutic window and discover new early biomarkers in plasma and cerebrospinal fluid
Malherbe, Godefroy. „Modélisation de la diffusion dans le noyau et application à l'activation cellulaire“. Paris 6, 2010. http://www.theses.fr/2010PA066481.
Der volle Inhalt der QuelleAvran, David. „Oncogenèse et modélisation des leucémies aigues lymphoblastiques T“. Paris 7, 2013. http://www.theses.fr/2013PA077254.
Der volle Inhalt der QuelleT-celé acute lymphoblastic leukemia (T-ALL) are malignancies derived from lymphoid thymic precursors arrested in their differentiation. We focused on the deletion of the long arm of chromosome 6 (del6q), the most common caryotypic abnormality in T-ALL, which target(s) are, to date, not known. By using both a whole set of integrative genomics and functional approaches, we identified the role of the combined haploinsufficiency of two contiguous genes at 6q14 (by mimicking in vivo an interstitial microdeletion we identified), namely SYNCRIP (encoding hnRNP-Q) and SNHG5 (a non-protein-coding gene that hosts snoRNAs), involved in mRNA maturation and protein translation. These genes are included in the common deleted region in a subtype of T-ALLs characterized by aberrant expression of the TAL1 transcription factor oncogene. In vivo knockdown models using Talr9/Lmolt9/Notch1-ICNtransduced mouse cells, and xenograft of patient's SIL-TAL, not 6q deleted leukemic cells, showed that the combined silencing of both genes was associated to a gain of malignancy. In a parallel work, we identified in T-ALL, recurrent aberrations of a gene usually involved in myeloid malignancies, TET2. Using microarray-based CGH to screen a cohort of T-ALL, we found a focal heterozygous deletion of this gene in one case belonging to the TAL-related oncogenic sub¬group. Moreover, we found mutations in cases belonging to other oncogenic sub-groups. This genetic study reveals that TET2 can play a role in T leukemogenesis, highlighting the ubiquitous nature of epigenetic alterations linked to TET2
Robert, Philippe A. „Modélisation mathématique de la différenciation précoce des lymphocytes T auxiliaires“. Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT002.
Der volle Inhalt der QuelleT helper cells are required to produce cytokines adapted to the type of infection. Several subsets have been defined, including pro-inflammatory Th1, Th2, Th17; and anti-inflammatory, Foxp3+ iTreg cells. The fate-determining decision of a naive T cell to differentiate into a defined subset was investigated here.Recent findings showed that metabolic constituents impact T cell differentiation, but so far the influence of glutamine on T cell differentiation has been neglected although being the main source of nitrogen. In this study, deprivation of glutamine induced an abnormal expression of Foxp3 under Th1 but not under Th2 condition, while impairing Th1 and Th17 differentiation. Thus, in poor metabolic micro-environments like solid tumours, a lack of glutamine would initiate a detrimental anti-inflammatory response.A mathematical modelling approach using Ordinary Differential Equations was chosen to capture the properties of T cell differentiation, first in normal conditions with glutamine. In order to train the model, kinetics of the master transcription factors and cytokines expression were measured under different T cell differentiation polarizing conditions. The in vitro data revealed major delays in transcription, translation and secretion of cytokines, which shaped the order of fate decision events. The model could successfully reproduce the dynamics of differentiation, confirming that the 'canonical' differentiation in vitro can be explained by a simple regulatory network. However, it only partially reproduced the plastic behaviour of T cells. The mathematical model will be utilized to compare different mechanistic hypotheses linking glutamine sensing to differentiation
Marot, Guillemette. „Modélisation statistique pour la recherche de gènes différentiellement exprimés: modèles de variance-covariance, analyse séquentielle et méta-analyse“. Phd thesis, AgroParisTech, 2009. http://tel.archives-ouvertes.fr/tel-00458988.
Der volle Inhalt der QuelleMarot-Briend, Guillemette. „Modélisation statistique pour la recherche de gènes différentiellement exprimés : modèles de variance-covariance, analyse séquentielle et méta-analyse“. Paris, AgroParisTech, 2009. http://pastel.paristech.org/5473/01/phDreportGMarot.pdf.
Der volle Inhalt der QuelleBessiere, Chloé. „Etude des éléments régulateurs de l'expression des gènes chez l'humain“. Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTT099/document.
Der volle Inhalt der QuelleGenome expression is tightly controlled by different regulatory regions to provide a wide variety of cell types and functions. Identifying these regulatory regions, their characteristics and understand how they interact with each other in a tissue-specific manner is prime importance. This knowledge should help better understand the impact of genomic variants often located in non-coding regions. Besides, cancer development is invariably linked to deregulation of gene expression controls. To pave the way for targeted treatments and precision medicine, it is important to understand how all this machinery is orchestrated.To answer this question, several approaches were developed, most of them based on experimental data of histone modification, methylation and transcription factors (TFs). However, these data are limited to specific samples and cannot be generated for all the regulators and all the patients. First, my thesis research aimed at modeling gene expression based on DNA sequence only. We used a linear model with variable selection, equivalent in term of performances with non-parametric methods and easy to interpret. This model allowed me to compare several types of variables based on the DNA sequence, as TFs binding motifs and nucleotide composition. These variables are computed for various gene regions to estimate their regulatory power and contribution. Strikingly, introns, for which nucleotide composition reflects gene environment, appear to explain an important part of gene expression variation. Furthermore, we demonstrated that the topological domains (TADs), in which interactions are favored, share similar genomic compositions. Our prediction model presumably captures, for every individual, the composition of active TADs.A second aspect of my work studied the regulations occurring in introns. The international FANTOM consortium provided one of the most important transcription start sites (TSSs) atlas and we noticed that the majority of these TSSs are detected into non-coding regions, in particular introns. We thus investigated these intronic TSSs. To determine if these TSSs are functional, we searched for new potential regulatory motifs at the vicinity of these transcription signals. We found that a fraction of them is located 2 bases downstream of a repetition of Ts. Biochemical and genetic evidences suggest that at least part of these signals correspond to sense-intronic long non-coding RNAs, which are expressed in a tissue specific manner. The length of the T repetition also appears to govern the presence of a transcription signal at these loci and indirectly impact on host gene expression. These findings provide one possible molecular explanation for the effect of these short tandem repeats of Ts
Perrière, Guy. „Application d'une représentation par objets des connaissances à la modélisation de certains aspects de l'expression des gènes chez Escherichia coli“. Lyon 1, 1992. http://www.theses.fr/1992LYO10168.
Der volle Inhalt der QuelleChaplais, Emmanuel. „Une approche de modélisation de biologie des systèmes sur la spondylarthrite“. Thesis, Versailles-St Quentin en Yvelines, 2015. http://www.theses.fr/2015VERS035V/document.
Der volle Inhalt der QuelleSpondyloarthritis is a frequent chronic inflammatory rheumatism, with a prevalence of 0.43 % in France. This disease presents axial skeleton injuries, but also on peripheral joints, and can results in a total spinal and sacro-iliac motility loss. Extra-articular features including uveitis, psoriasis and inflammatory bowel disease are frequent. Current SpA treatments are only symptomatic, relieving inflammatory symptoms. SpA etiology is largely multifactorial with a genetic component dominated by the long-known strong association with the HLA-B27 allele. This allele, however, is not sufficient for the disease to occur. This thesis project objective was then to identify other genetic factors in the origin of SpA.My work was mainly divided in two complementary data analyses, in a way to get a systems biology approach. The first one consisted in proceed linking analyses on data from Affymetrix genotyping chips gathered from DNA of 1310 people grouped in 210 families. This study allowed notably to detect a new significantly linked region to SpA : 13q13, with an interval of 1.3 Mb. This part of genome is currently being sequenced to allow a better causal SNP identification.Secondly, an Affymetrix HumanGene 1.0 st transcriptomic chips analysis was performed on MD-DCs extracted from 68 people, stimulated or not by LPS during 6 or 24 hours. This cohort was grouped between 23 patients HLA-B27+, 23 healthy controls HLA-B27+ and 21 healthy controls HLA-B27-. I could notice that HLA-B27 allele is farly enough to considerably affect cell transcriptomic profiles, which encourages to include HLA-B27+ healthy controls. Otherwise, a gene network analysis allowed me to highlight on an inhibition of early steps of cholesterol biosyntthesis
Deville, Alexandra. „Suivi de terrain, expérimentations et modélisation : des approches complémentaires pour l'étude de l'impact des populations de colza hors-champ sur les flux de gènes au sein des agro-écosystèmes“. Paris 11, 2004. http://www.theses.fr/2004PA112304.
Der volle Inhalt der QuelleRisk assessment of (trans)gene persistence and dispersal in space and time requires a good knowledge of the vehicles spreading (trans)genes in agro-ecosystems. Feral populations of oilseed rape, located in field margins can act as relays in (trans)genes dispersal. Three complementary approaches were carried out at an agricultural-area scale (Selommes, Loir-et-Cher) to specify the role of such populations in gene dispersal. First, a field survey of all oilseed rape populations (cultivated, feral, volunteers and fallows) in the studied area was conducted for 4 years using GPS cartography. This survey was completed with (i) phenotypic and genotypic analysis of seeds from these populations and (ii) farmers surveys. Second, we identified key-parameters of the life-cycle of feral populations and studied the effect of road verges management (mowing and herbicide treatment) using a demographic study based on modelling and field surveys. Third, an experimental study was designed to evaluate the adaptation of feral populations to their environment. We demonstrate that feral populations of oilseed rape have a potentially influential impact on gene dispersal. They seem to persist through time via self-recruitment or soil seed bank In addition, hybridizations between plants of different populations appear relatively frequent. These specific data collected on feral populations of oilseed rape at a realistic space and time scale are required to refine the predictions of models of gene dispersal and improve risk assessment of gene dispersal
Casagranda, Stefano. „Modélisation, analyse et réduction des systèmes biologiques“. Thesis, Université Côte d'Azur (ComUE), 2017. http://www.theses.fr/2017AZUR4049/document.
Der volle Inhalt der QuelleThis thesis deals with modeling, analysis and reduction of various biological models, with a focus on gene regulatory networks in the bacterium E. coli. Different mathematical approaches are used. In the first part of the thesis, we model, analyze and reduce, using classical tools, a high-dimensional transcription-translation model of RNA polymerase in E. coli. In the second part, we introduce a novel method called Principal Process Analysis (PPA) that allows the analysis of high-dimensional models, by decomposing them into biologically meaningful processes, whose activity or inactivity is evaluated during the time evolution of the system. Exclusion of processes that are always inactive, and inactive in one or several time windows, allows to reduce the complex dynamics of the model to its core mechanisms. The method is applied to models of circadian clock, endocrine toxicology and signaling pathway; its robustness with respect to variations of the initial conditions and parameter values is also tested. In the third part, we present an ODE model of the gene expression machinery of E. coli cells, whose growth is controlled by an external inducer acting on the synthesis of RNA polymerase. We describe our contribution to the design of the model and analyze with PPA the core mechanisms of the regulatory network. In the last part, we specifically model the response of RNA polymerase to the addition of external inducer and estimate model parameters from single-cell data. We discuss the importance of considering cell-to-cell variability for modeling this process: we show that the mean of single-cell fits represents the observed average data better than an average-cell fit
Haye, Alexandre. „Modélisation de l'évolution temporelle de l'expression des gènes sur la base de données de puces à ADN: application à la drosophile“. Doctoral thesis, Universite Libre de Bruxelles, 2011. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209904.
Der volle Inhalt der QuellePremièrement, l’observation des données d’expression utilisées nous a conduits à approfondir l’étude des phénomènes survenant lors des changements de stades de développement de la drosophile. Dans ce but, deux méthodes de détection automatique de ces changements ont été développées et appliquées aux données temporelles disponibles sur le développement d’eucaryotes supérieurs. Elles ont également été appliquées à des données temporelles relatives à des perturbations externes de bactéries. Cette étude à montré qu’une formulation mathématique simple permettait de retrouver les instants expérimentaux où une perturbation ou un changement de stade de développement est observé, à partir uniquement des profils d’expression. Par ailleurs, la réponse à une perturbation externe s’avère non distinguable d’une succession de stades de développement, sur la base des seuls profils temporels d’expression.
Deuxièmement, en raison des dimensions du problème constitué par les données d’expression de plusieurs milliers de gènes et de l’impossibilité de distinguer le rôle dans la régulation des gènes qui présentent des profils d’expression similaires, il s’est avéré nécessaire de classifier les gènes selon leurs profils d’expression. En nous basant sur les résultats obtenus lors de la détection des stades de développement, la démarche suivie est de regrouper les gènes qui présentent des profils temporels d’expression aux comportements similaires non seulement au cours de la série temporelle complète, mais également dans chacun des stades de développement. Dans cette optique, trois distances ont été proposées et utilisées dans une classification hiérarchique des données d’expression de la drosophile.
Troisièmement, des structures de modèles linéaires et non linéaires ainsi que des méthodes d’estimation et de réduction paramétriques ont été développées et utilisées pour reproduire les données d’expression du développement de la drosophile. Les résultats de ce travail ont montré qu’avec une structure de modèle linéaire simple, la reproduction des profils expérimentaux était excellente et que, dans ce cas, le réseau de régulation génique de la drosophile pouvait se contenter d’une faible connectivité (en moyenne 3 connexions par classe de gènes) et ce, sans hypothèse a priori. Toutefois, les modèles linéaires ont ensuite sérieusement été remis en question par des analyses de robustesse aux perturbations paramétriques et de stabilité des profils après extrapolation dans le temps. Dès lors, quatre structures de modèles non linéaires et cinq méthodes de réduction paramétrique ont été proposées et utilisées pour concilier les critères de reproduction des données, de robustesse et de stabilité des réseaux identifiés. En outre, ces méthodes de modélisation ont été appliquées à un sous-ensemble de 20 gènes impliqués dans le développement musculaire de la drosophile et pour lesquels 36 interactions ont été validées expérimentalement, ainsi qu’à des profils synthétiques bruités. Nous avons pu constater que plus de la moitié des connexions et non-connexions sont retrouvées par trois modèles non linéaires. Les résultats de cette étude ont permis d’éliminer certaines structures de modèle et méthodes de réduction et ont mis en lumière plusieurs directions futures à suivre dans la démarche de modélisation des réseaux de régulation génique.
Doctorat en Sciences de l'ingénieur
info:eu-repo/semantics/nonPublished
Fischer, Stephan. „Modélisation de l'évolution de la taille des génomes et de leur densité en gènes par mutations locales et grands réarrangements chromosomiques“. Phd thesis, INSA de Lyon, 2013. http://tel.archives-ouvertes.fr/tel-00924831.
Der volle Inhalt der QuelleLopez, Pierre fabrice. „De l'analyse de la régulation transcriptionnelle à la modélisation logique des réseaux géniques“. Aix-Marseille 2, 2009. http://www.theses.fr/2009AIX22064.
Der volle Inhalt der QuelleThis thesis report is about bioinformatic analysis of mechanisms involved in regulation of gene expression, an ubiquitous phenomenon in all life froms, notably at the root of cellular differenciation. The use of genomic large scale datasets motivated the creation of specific algorithms and methods. These approaches led to the development of tools and databases, namely the software BZScan for the quantification of DNA microarray images, the ATD database listing polyadenylation sites in human and mouse genomes, the sofware package TranscriptomeBrowser containing a transcriptional signatures database, and the logical simultaion and modellind software signatures database, and the logical simulation and modelling software GINsim. A modular programming approach allowed us to develop efficient communication between these different tools
Wucher, Valentin. „Modélisation d'un réseau de régulation d'ARN pour prédire des fonctions de gènes impliqués dans le mode de reproduction du puceron du pois“. Thesis, Rennes 1, 2014. http://www.theses.fr/2014REN1S076/document.
Der volle Inhalt der QuelleThis thesis aims to discriminate between embryos development towards either sexual or asexual reproduction types in pea aphids, Acyrthosiphon pisum, at the genomic level. This discrimination involves the creation of a post-transcriptional regulation network between microRNAs and mRNAs whose kinetic expressions change depending on the embryogenesis. It also involves a study of this network's interaction modules using formal concept analysis. To do so, a three-step strategy was set up. First the creation of an interaction network between the pea aphid's microRNAs and mRNAs. The network is then reduced by keeping only microRNAs and mRNAs which possess differential kinetics between the two embryogeneses, these are obtained using high-throughput sequencing data. Finally the remaining network is analysed using formal concept analysis. Analysing the network allowed for the identification of several functions of potential interest such as oogenesis, transcriptional regulation or even neuroendocrine system. In addition to network analysis, formal concept analysis was used to create a new method to repair a bipartite graph based on its topology and a method to visualise a bipartite graph using its formal concepts
Graudens, Esther. „Réseaux fonctionnels associés à la résistance innée du cancer colorectal à la chimiothérapie : analyse du transcriptome, annotation fonctionnelle, modélisation systémique“. Paris 11, 2006. http://www.theses.fr/2006PA112039.
Der volle Inhalt der QuelleColorectal cancer is a major cause of death in western countries. In spite of the use of new molecules, resistance to the treatments is important upon first exposure to chemotherapy. The objective of my thesis was to identify functional networks contributing to innate resistance of the tumours. Expression profiles of tumor and metastasis samples from 13 patients with advanced colorectal cancer were collected using cdna microarrays before exposure of the patients to a combined chemotherapy. Experimental and analytical procedures were established to obtain precise and highly documented data. A careful experimental design allowed limiting falsely positive or negative differential hybridization results. A list of 679 genes differentially expressed in relation with responses to chemotherapy was established. The results have been verified and validated by quantitative rt-pcr on the samples investigated and two novel samples whose phenotype was correctly characterized. Functional annotation of the selected genes made it possible to determine the biological processes and cellular components associated with them. A map of functional networks was constructed using a systems biology language. It allowed formulation of hypotheses on underlying mechanisms. A resistant cell would divide poorly, would rapidly repair damages caused to its dna, and would present an increased drug efflux and a frozen extracellular matrix. Two groups of genes predictors of response to chemotherapy were selected, which will have to be validated on new samples. These results could be used as a basis to facilitate resistance bypass through diagnostics and implementation of novel therapeutic strategies
Yvinec, Romain. „Modélisation probabiliste en biologie moléculaire et cellulaire“. Phd thesis, Université Claude Bernard - Lyon I, 2012. http://tel.archives-ouvertes.fr/tel-00749633.
Der volle Inhalt der QuelleDurot, Maxime. „Elucidation du métabolisme des microorganismes par la modélisation et l'interprétation des données d'essentialité de gènes. Application au métabolisme de la bactérie Acinetobacter baylyi ADP1“. Phd thesis, Université d'Evry-Val d'Essonne, 2009. http://tel.archives-ouvertes.fr/tel-00425212.
Der volle Inhalt der QuelleDans cette thèse, nous explorerons l'utilisation de ces modèles pour compléter la connaissance des réactions à l'aide d'une catégorie particulière de données d'échelle globale : les essentialités de gènes déterminées en observant les phénotypes de croissance de mutants de délétion. Nous nous appuierons pour cela sur la bactérie Acinetobacter baylyi ADP1 pour laquelle une collection complète de mutants de délétion a été récemment constituée au Genoscope.
Après avoir présenté les étapes clés et les développements que nous avons effectués pour reconstruire un modèle global du métabolisme d'A. baylyi, nous montrerons que la confrontation entre phénotypes observés et phénotypes prédits permet de mettre en évidence des incohérences entre les deux échelles d'observations. Nous montrerons ensuite qu'une interprétation formelle de ces incohérences permet de corriger le modèle et d'améliorer la connaissance du métabolisme. Nous illustrerons ce propos en présentant les corrections que nous avons réalisées à l'aide des phénotypes de mutants d'A. baylyi. Enfin, dans une dernière partie, nous proposerons une méthode permettant d'automatiser la correction des incohérences causées par des erreurs d'association entre gènes et réactions.
Durot, Maxime. „Elucidation du métabolisme des microorganismes par la modélisation et l'interprétation des données d'essentialités de gènes : application au métabolisme de la bactérie Acinetobacter baylyi ADP1“. Thesis, Evry-Val d'Essonne, 2009. http://www.theses.fr/2009EVRY0017/document.
Der volle Inhalt der QuelleMicrobial metabolism has traditionally been investigated at two different scales: the finest involves characterizing individually each reaction occurring in the cell; the largest focuses on global cell physiology. While both scales have recently benefited from technological advances, combining them remains, however, especially complex as the global physiological behavior of a cell results from the coordinated action of a large network of reactions. Mathematical modeling approaches have yet shown recently that genome-scale metabolic models could help in linking both scales. In this thesis, we explore the use of such models to expand the knowledge of reactions with a specific type of high-level data: gene essentiality data, assessed using growth phenotypes of deletion mutants. We will use as model organism the bacterium Acinetobacter baylyi ADP1, for which a genome-wide collection of gene deletion mutants has recently been created. Following a presentation of the key steps and developments that have been required to reconstruct a global metabolic model of A. baylyi, we will show that confronting observed and predicted phenotypes highlight inconsistencies between the two scales. We will then show that a formal interpretation of these inconsistencies can guide model corrections and improvements to the knowledge of metabolism. We will illustrate this claim by presenting model corrections triggered by A. baylyi mutant phenotypes. Finally, we will introduce a method that automates the correction of inconsistencies caused by wrong associations between genes and reactions
Fargue, Agnès. „Maîtrise des flux de gènes chez le colza : Etude ex-ante de l'impact de différentes innovations váriétales“. Paris, Institut national d'agronomie de Paris Grignon, 2002. http://www.theses.fr/2002INAP0049.
Der volle Inhalt der QuelleWillbrand, Karen. „Approches inspirées de la physique statistique et de la théorie de l'information pour l'analyse et la modélisation de données issues des puces à ADN“. Paris 7, 2003. http://www.theses.fr/2003PA077252.
Der volle Inhalt der QuelleThis thesis considers the analysis of gene expression data. The first part dis-cusses some modeling approches: statistical analysis of fluctuations, a boolean model (the Kauffman model), an attempt to reconstruct the gene interaction network in yeast and an investigation of the potential link between architecture and dynamics in a gene regulation network. The second part and main contribution introduces a new approach to gene expression data, called 'Up-Down analysis'. It is distinct from the common clustering method. Up-Down analysis compares profile properties of gene expression and random data: we assume that biologically interesting results are rare events for the random model. An essential point of the choosen model is its independence of the exact type of random background fluctuations. The last chapter shows how this approach can be used to construct a new gene-gene distance measure, which can be integrated into ail types of clustering algorithms
Brandenburg, Jean-Tristan. „Modélisation de l'impact de la sélection naturelle et culturelle sur la diversité génétique : cas de la transmission du succès reproducteur et des réseaux de gènes“. Thesis, Paris 11, 2011. http://www.theses.fr/2011PA112338/document.
Der volle Inhalt der QuelleSelective forces are one of the major determinants of the evolution of phenotypic diversity and genetic diversity, in neutral and coding zones of the genome. Selection can occur on genetically - or culturally - transmitted traits. This thesis considers these two selective processes. First, we studied the effects of intergenerational fertility transmission on neutral genetic diversity. Second, we considered the impact of selection on phenotypes coded by a gene network and on the polymorphism of genes within the network.Fertility transmission is a cultural or genetic phenomenon, which is characterised by a positive correlation between the sibship size of an individual and that of its children. It was observed both in human and animal populations. Using a modelling approach, we show that its effects and the possibility to detect it depend both on the kind of studied data (genetic or genealogical data) and on the different kind of transmission (uniparental, biparental). We show that other phenomena, such as the heterogeneity of reproductive success between individuals, can affect its effects. We develop several tools allowing to infer this phenomenon of fertility transmission on genealogical data, as well as on genetic polymorphism data that follows different mutational models (microsatellites, sequences, SNPs) and different transmission modes (haploid or diploid, sex-linked or not). We applied in particular these tools to three human populations of the Cilento area in Italy (genealogical and mitochondrial DNA data), to Central Asian data (Y chromosome) and to HapMap data (autosomes).The second part of this thesis deals with the modelling of the action of natural selection on traits coded by regulation networks and describes the impact of such selection on the evolution of the phenotype and of the underlying genes. A given phenotype is the result of the interaction between different genes and their products. We show that phenotypic selection will modify the gene network organisation, as well as the level of polymorphism of the genes involved in the network. For example, when the optimal phenotype corresponds to an intermediate level of gene expression, the most regulatory genes will lose much of their diversity. Conversely, if the optimal phenotype corresponds to a very strong expression of the genes, it will be the most regulated genes that will be the most constrained. This analysis allowed us to show the complexity of the relations between selection, regulation networks, phenotypes and the environment
Poilleux-Milhem, Hélène. „Test de validation adaptatif dans un modèle de régression : modélisation et estimation de l'effet d'une discontinuité du couvert végétal sur la dispersion du pollen de colza“. Paris 11, 2002. http://www.theses.fr/2002PA112297.
Der volle Inhalt der QuelleThis thesis framework is the spread of genetically modified organisms in the environment. Several parametric models of the individual pollen dispersal distribution have already been proposed for homogeneous experiments (plants emitting marked pollen surrounded by the same unmarked plants). In order to predict the "genetic pollution" in an agricultural landscape, a discontinuity effect on pollen flows in a cultivated area (e. G. A road crosses a field) has to be taken into account. This effect was modelled and estimated: according to the size of the discontinuity, it may correspond to a significant acceleration of the pollen flow. Graphical diagnosis methods show that the modelling of the individual pollen dispersal distribution and of the discontinuity effect, is best fitting the data when using constant piecewise functions. Prior to using parametric models to predict genetic pollution, goodness-of-fit tools are essential. We therefore propose a goodness-of-fit test in a nonlinear Gaussian regression model, where the errors are independent and identically distributed. This test does not require any knowledge on the regression function and on the variance of the observations. It generalises the linear hypothesis tests proposed by Baraud et al (Ann. Statist. 2003, Vol. 31) to the nonlinear hypothesis. It is asymptotically of level α and a set of functions over which it is asymptotically powerful is characterized. It is rate optimal among adaptive procedures over isotropic and anisotropic Hölder classes of alternatives. It is consistent against directional alternatives that approach the null hypothesis at a rate close to the parametric rate. According to a simulation study, this test is powerful even for fixed sample sizes
Le, Tan. „Intégration de l'inférence abductive et inductive pour la représentation des connaissances dans les réseaux de gènes“. Phd thesis, Université Paul Sabatier - Toulouse III, 2014. http://tel.archives-ouvertes.fr/tel-00996894.
Der volle Inhalt der QuelleSester, Mathilde. „Modélisation de l'effet des systèmes de cultures sur les flux de gènes entre culture transgénique et adventice apparentée : cas de la betterave sucrière (Beta vulgaris L.)“. Phd thesis, Université de Bourgogne, 2004. http://tel.archives-ouvertes.fr/tel-00080792.
Der volle Inhalt der QuelleÀ cause des dimensions spatiales et temporelles du flux de gène ainsi que de la large gamme de variabilité des systèmes de culture, il est impossible d'étudier le phénomène exclusivement en expérimentation. Par conséquent, nous avons développé un modèle (GENESYS-BETTERAVE) qui quantifie les effets des systèmes de culture sur ce flux de gènes. Il est centré sur le cycle de développement des betteraves cultivées et adventices dans chaque parcelle basé sur une succession de stades clé (plantules, montées, plantes en fleurs, production semencière, stock semencier). Pour chaque stade est calculée la densité d'individus dans la parcelle ainsi que les proportions génotypiques, principalement celles des individus transgéniques. Les relations entre les stades dépendent des cultures en place dans les parcelles, des techniques utilisées pour gérer ces cultures ainsi que du génotype des betteraves. Pendant la floraison, du pollen est échangé entre les parcelles et l'importance de cette dispersion dépend du parcellaire. Une partie des informations nécessaires à la réalisation du modèle, est tirée de la littérature.
Des expérimentations sont ensuite réalisées pour étudier et quantifier les parties encore peu connues du cycle de développement. Elles ont permis de décrire et de modéliser le devenir des semences enfouies de betteraves adventices, en mesurant la mortalité in situ, les capacités de germination des semences et de croissance pré-levée des plantules en fonction des saisons. D'autres essais ont permis de modéliser toutes les étapes clé du développement des betteraves adventices et des traînantes (dynamique et taux de montaison, dynamique de floraison, production de pollen...) dans les cultures les plus fréquentes de la rotation betteravière.
Après avoir été programmé sous forme de logiciel, le modèle est alors utilisé pour des simulations simples qui montrent qu'il prend bien en compte les éléments caractéristiques des systèmes de cultures, en attendant une validation pour vérifier à plus grande échelle le réalisme de la prédiction.
Le, Tan. „Intégration de l'inférence abductive et inductive pour la représentation des connaissances dans les réseaux de gènes“. Phd thesis, Toulouse 3, 2014. http://thesesups.ups-tlse.fr/2337/.
Der volle Inhalt der QuelleDiagnostic reasoning (abductive) and predictive reasoning (inductive) are two methods of reasoning that enable the discovery of new knowledge. When abductive reasoning is the process of finding the best explanation (hypothesis) for a set of observations (Josephson, 1994), the inductive reasoning is the process of predicting, from a set of observations, to find all possible results. These observations may be symptoms of a patient, experiments on genomic and metabolic networks, etc. In this PhD thesis, we are interested in the representation, analysis and synthesis of genomic signaling networks using hypothetical logic. In fact, this thesis focuses on modeling of signaling pathways in response to the DNA double stranded break. To implement the abduction, we use algorithms of production. Then, the default logic is used to build models of minimum representation. These algorithms are proven knowledge discovery on the map of DNA double-strand break. This map is minimal as biological causality graph and allows integrating bio-molecular data
Bocquet-Muchembled, Béatrice. „La famille Ets chez l'Annélide polychète Hediste (Nereis) diversicolor : étude de l'expression des gènes ets et erg, modélisation moléculaire du domaine de liaison à l'ADN de leurs produits“. Lille 1, 2000. https://pepite-depot.univ-lille.fr/RESTREINT/Th_Num/2000/50376-2000-95.pdf.
Der volle Inhalt der QuelleLoubaton, Rodolphe. „Modélisation des effets d’une intervention dans un programme génique temporel“. Electronic Thesis or Diss., Université de Lorraine, 2023. http://www.theses.fr/2023LORR0322.
Der volle Inhalt der QuelleCancer cells can exhibit abnormalities in the expression of certain genes that alter the normal functioning of cellular programs, causing them to proliferate uncontrollably. These cellular programs are made up of the expression of thousands of genes that activate and interact in a concerted fashion. These interactions can be represented as a gene regulatory network. The general objective of this thesis, which follows on from the work of Vallat et al (2021), is to model a cellular program using temporal gene expression data. The model constructed will make it possible to identify target genes whose reduced expression could reduce cell proliferation for therapeutic purposes. In the first chapter, we review existing gene network models in order to justify the choice of our model, which is detailed in the second chapter. This model (called the LiRE model) is a Gaussian parametric statistical model that allows us to take into account gene expression dynamics using parameters describing, among other things, the interactions between genes. The various theoretical properties of our model have enabled us to develop an iterative algorithm for inferring parameters, combining steps of penalized linear regressions lasso and regressions with positivity constraints and constraints on the sum of coefficients. In this chapter, we also carry out a numerical study of this model to investigate its performance on simulated data. In the third chapter, we describe methods for modeling and predicting the results of biological intervention experiments modifying the expression of certain genes, in order to predict the best target genes whose expression should be decreased in the cellular program to reduce cancer cell proliferation. We give theoretical results on different models including our LiRE model. In the final chapter, we detail our R package MultiRNAflow, which enabled us to perform statistical analyses of dynamic and complex gene expression data in order to characterize the genes selected for inference in our model LiRE
Soularue, Jean-Paul. „Évolution de la phénologie des arbres à l'échelle d'un paysage forestier“. Thesis, Bordeaux 1, 2012. http://www.theses.fr/2012BOR14724/document.
Der volle Inhalt der QuelleTiming of bud burst (TBB) is a key adaptive trait affected by temperature variations. Predicting the evolution of natural forests undergoing environmental variations requires to understand the evolutionary dynamics that have resulted in the strong patterns of differentiation characterized for this trait. It has been shown experimentally that the TBB was strongly correlated with the timing off lowering. This suggests that trees having similar TBB tend to mate preferentially, making assortative mating at TBB the default reproduction regime within tree species. Clinal patterns of genetic differentiation have been mostly interpreted as resulting from divergent selection, however, few studies have considered the peculiar features of timing of bud burst. Through a modelling approach based on quantitative genetics models, we first demonstrate here that the sole interaction between assortative mating at TBB and pollen flow can induce a clinal differentiation among populations without any selection pressure. In a such theoretical context, assortative mating filters pollen flow in presence of environmental gradients and progressively shifts the genetic values of populations. Then, we demonstrate that assortative mating amplifies the adaptive response of populations to co-gradient selection, and constrains it in the case of countergradient selection. Finally, we show that assortative mating differentiates populations even in the case of uniform selection
Dussert, Yann. „Évolution de la durée du cycle et du contrôle de l'architecture lors de la domestication du mil (pennisetum glaucum)“. Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066665.
Der volle Inhalt der QuellePearl millet is a cereal cultivated in the sudano-sahelian area in Africa. Using a data set consisting of 18 microsatellites and 8 nucleotide sequences for 45 domesticated and wild populations, I showed the existence of a high differentiation between two wild genetic pools. Using the model-based Approximate Bayesian Computation (ABC) approach, I tested different domestication scenarios and showed that a single domestication in eastern Sahel is more likely than other models.There are two main types of domesticated pearl millet: early-flowering and late-flowering varieties. My results show a lack of neutral genetic differentiation between these two types, suggesting the existence of recurrent gene flow. I also studied a candidate gene, PgHd3a, belonging to the Hd3a-like family and which could be implicated in the floral transition. No selection footprint has been detected, and it is likely this gene is not involved in the phenotypic difference between early and late-flowering varieties. Expression results casted some doubt about its role during floral transition in pearl millet. I also isolated a new paralog of PgHd3a, PgHd3a-2.Finally, I studied a longitudinal frequency cline at the continental scale for the presence of a Miniature Inverted-repeat Transposable Element (MITE) located in the teosinte branched1 gene, involved in the regulation of the number of tillers in maize. By comparing differentiation levels between the MITE and 13 neutral microsatellites, and by investigating the nucleotide polymorphism in the genomic region surrounding the MITE, I showed the cline was probably caused by neutral processes
Jung, Nicolas. „Modélisation de phénomènes biologiques complexes : application à l'étude de la réponse antigénique de lymphocytes B sains et tumoraux“. Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ067/document.
Der volle Inhalt der QuelleSystem biology is a well-suited context for interdisciplinary. In this thesis, statistical models and theories closely meet biological models and experiments. We focused on a specific complex system model: the chronic B-cell chronic lymphocytic leukemia disease which is a cancer of the blood cells. We started by modeling the genetic program which underlies this disease and we compared it to the healthy one. This conduced us to introduce the concept of cascade networks. We then showed our ability to control this complex system by predicting with our mathematical model the effects of a gene inhibition experiment. This thesis ends with the perspective of oriented modulation, i.e. targeted interventional experiments on genes allowing to “reprogram” the cancerous genetic program toward a healthy normal state
Khimoun, Aurélie. „Histoire évolutive, contexte spatial et écologique de la divergence de deux sous-espèces d'Antirrhinum majus“. Toulouse 3, 2012. http://thesesups.ups-tlse.fr/2280/.
Der volle Inhalt der QuelleThis thesis sought at understanding how evolutionary and ecological processes lead to population divergence and ultimately speciation. To this aim, i integrated the different components of speciation - ecological, spatial and matting isolation - ina temporal framework to gain a better understanding of their dynamicinteraction through time. I studied the ongoing divergence of two snapdragon subspecies of Antirrhiunum majus pseudomajus and A. M striatum. I tested the relative role of historical processes of colonasation (post-glacial colonisation scenario), contemporary barriers to gene flow and local adaptation to explain the current patterns of subspecies distribution and the distribution of their genetic diversity. I also investigated the extent of gene flaw between the two subspecies in the contact zones and the role of environmental factors on the direction of gene flow and the maintenance of disjunct distributions despite gene flow. Finally, i studied the relative roles of neutral processesof dispersal and selective processes in the maintenance of a stable hybrid zone between the two subspecies
Duquenne, Manon. „Incidence de paramètres technologiques sur l'expression de gènes et la production d'entérotoxines de Staphylococcus aureus au cours des 72 h suivant l'empresurage des laits en fabrication fromagère“. Phd thesis, AgroParisTech, 2010. http://pastel.archives-ouvertes.fr/pastel-00569982.
Der volle Inhalt der QuelleRougemont, Quentin. „Évolution de la divergence entre la lamproie fluviatile (Lampetra fluviatilis) et la lamproie deplaner (Lampetra planeri) inférée par approches expérimentales et de génomique des populations“. Thesis, Rennes 1, 2015. http://www.theses.fr/2015REN1S141/document.
Der volle Inhalt der QuelleThis thesis investigates the process of speciation between the European lampreys Lampetra fluviatilis and L. planeri. The two species have drastically different life history strategies: L. fluviatilis is parasitic and anadromous while L. planeri is non-parasitic and strictly freshwater resident. Yet their level of reproductive isolation and history of divergence remain poorly understood. A multidisciplinary approach including experiments, population genomics analyses and historical reconstruction was undertaken to address these issues. Experimental crosses revealed a very low level of reproductive isolation, partially mirrored by variable levels of gene flow in wild populations. Genetic analyses revealed that the two taxa were best described as partially reproductively isolated ecotypes suggesting that endogenous genetic barriers partially reduced effective migration between ecotypes. Genome wide analyses showed the importance of the current and ancient geographical context of speciation. In particular, parapatric L. planeri populations diverged mostly through drift and displayed a reduced genetic diversity . Demographic inferences suggested that divergence have likely emerged in allopatry and then secondary contacts resulted in partial parallelism between replicate population pairs. A strong heterogeneity of divergence across the genome was revealed by sympatric populations suggesting that genomic islands of differentiation were not linked to ongoing ecological divergence. Further investigations showed that the genetic diversity of L. planeri populations was weakly affected by human-induced river fragmentation. Resident populations displayed a higher diversity when gene flow was possible with L. fluviatilis populations in downstream sections of rivers. Overall this thesis showed that parasitic and non-parasitic lamprey ecotypes represent a promising model for studying speciation and notably the genomic architecture of divergence
Angevin, Frédérique. „Modélisation de l'impact des systèmes de culture sur la pollinisation croisée chez le maïs dans le cadre de l'établissement de règles de coexistence“. Phd thesis, AgroParisTech, 2012. http://pastel.archives-ouvertes.fr/pastel-00875332.
Der volle Inhalt der QuelleKnibbe, Carole. „Structuration des génomes par sélection indirecte de la variabilité mutationnelle : une approche de modélisation et de simulation“. Phd thesis, INSA de Lyon, 2006. http://tel.archives-ouvertes.fr/tel-00482375.
Der volle Inhalt der QuelleApra, Caroline. „Etude du développement des méninges & modélisation de tumeurs fibreuses solitaires chez la souris par introduction du gène de fusion NAB2-STAT6 dans les cellules PGDS-positives“. Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL052.
Der volle Inhalt der QuelleMeningeal solitary fibrous tumors (SFT), like somatic SFT, are characterized by the NAB2-STAT6 fusion gene. This fusion induces the nuclear relocation of the STAT6 transcription factor and the activation of EGR transcription, increasing proliferation. Meningeal SFT cells, like meningioma cells, are positive for prostaglandin-D2-Synthase (PGDS), a specific marker of meningeal, especially arachnoid, cells. In Part 1, we showed that benign SFT can transform into malignant TFS - formerly hemangiopericytomas - and we reported the therapeutic efficacy of pazopanib, an inhibitor of vascular endothelial growth factor. Part 2 is devoted to the molecular study of SFT: the comparison of the exome of pairs of SFT, a grade I primary and grade III recurrence, brought out the pathogenic variant of TP53 c.743G> T. The transcriptome of meningeal SFT showed the aggregation of SFT from all localizations, distinct from meningiomas. Part 3 presents the modeling of meningeal SFT in genetically modified mice by the introduction of two NAB2-STAT6 fusion genes (exons 2-16 and 6-17). The RCAS-NAB2-STAT6 retroviruses, injected at birth into the subdural space of PGDS-tva mice, specifically infect arachnoid cells. After more than a year of follow-up, the animals did not develop any SFT. It is likely that, as in many other tumor models, fusion is not sufficient to induce tumor development. In Part 4, we adapted the iDisco method, which usually allows three-dimensional visualization of brain samples, for mouse embryos and whole skulls, and described the expression of PGDS in mice in situ, between the 11th post-conception day and the 7th post-natal day. It is located in the meninges at the skull base in the early stages and at the convexity after birth, and also in the radial glia
Dussert, Yann. „Évolution de la durée du cycle et du contrôle de l'architecture lors de la domestication du mil (pennisetum glaucum)“. Electronic Thesis or Diss., Paris 6, 2014. http://www.theses.fr/2014PA066665.
Der volle Inhalt der QuellePearl millet is a cereal cultivated in the sudano-sahelian area in Africa. Using a data set consisting of 18 microsatellites and 8 nucleotide sequences for 45 domesticated and wild populations, I showed the existence of a high differentiation between two wild genetic pools. Using the model-based Approximate Bayesian Computation (ABC) approach, I tested different domestication scenarios and showed that a single domestication in eastern Sahel is more likely than other models.There are two main types of domesticated pearl millet: early-flowering and late-flowering varieties. My results show a lack of neutral genetic differentiation between these two types, suggesting the existence of recurrent gene flow. I also studied a candidate gene, PgHd3a, belonging to the Hd3a-like family and which could be implicated in the floral transition. No selection footprint has been detected, and it is likely this gene is not involved in the phenotypic difference between early and late-flowering varieties. Expression results casted some doubt about its role during floral transition in pearl millet. I also isolated a new paralog of PgHd3a, PgHd3a-2.Finally, I studied a longitudinal frequency cline at the continental scale for the presence of a Miniature Inverted-repeat Transposable Element (MITE) located in the teosinte branched1 gene, involved in the regulation of the number of tillers in maize. By comparing differentiation levels between the MITE and 13 neutral microsatellites, and by investigating the nucleotide polymorphism in the genomic region surrounding the MITE, I showed the cline was probably caused by neutral processes
Angevin, Frédérique. „Modélisation de l’impact des systèmes de culture sur la pollinisation croisée chez le maïs dans le cadre de l’établissement de règles de coexistence“. Thesis, Paris, AgroParisTech, 2012. http://www.theses.fr/2012AGPT0062/document.
Der volle Inhalt der QuelleConsumer demand for food free of GMOs is growing and if production standards are to be met, food and non-food chains must be separated. Indeed, European Commission regulations 1829/2003 and 1830/2003 stipulate that food and feed thought to be GMO-free but found to be containing more than a 0.9% portion of an adventitious presence of authorized GMOs have to be distinguished, traced and labelled as such. Moreover, to ensure that producers have a choice a choice among differing types of production, the European Commission has issued recommendations that permit the coexistence of non-GM and GM crops. This poses the problem of how to deal with coexistence in an agricultural supply chain dedicated to handling a single crop species. To help in the elaboration of coexistence rules, and then assess their feasibility and their consequences as well as for setting up monitoring and control schemes, specific field experiments, even if necessary, are not sufficient as their predictive value remains restricted to a given context. It is necessary to be able to forecast the fate of GM crops at the landscape level taking into account the various cropping systems and agricultural practices that may occur across Europe. The key to forecasting spread and behaviour of GM plants and seeds as well as their impacts under a wide range of agro-ecosystems is modelling. Models reproduce the functioning of agro-systems and take into account the relevant factors and processes as well as their interactions. They thus make it possible to simulate the behaviour of agro-systems in non-observed situations and on a long term basis.This doctoral thesis establishes a methodological framework for the development of biological flow models thanks to the dynamic interactions of modelling, evaluation and experimentation. In a first phase, the work involved the design of the MAPOD® model developed in relationship to literature and varietal experiments carried out by GEVES. MAPOD® simulates gene flow between maize crops at the landscape scale. It is based on an individual dispersal function which depends on biological and climatic parameters. It calculates the probability of fecundation at a (x, y) point as a function of distance from the pollen emitter (efficient pollination). Its flowering dynamics module makes it possible to take into account of the consequences of flowering time - lags on GM adventitious presence in harvests. MAPOD® evaluates the effect of the spatial distribution of maize plots, varietal characteristics, and climate as well as agricultural practices on cross-pollination. In this investigation, in a second phase the initial version of MAPOD® was evaluated with another dataset provided by GEVES. Ways to improve the algorithm were thereby defined. In a third phase, the predictive quality of MAPOD® was estimated by comparing model outputs to cross-pollination rates which were obtained by monitoring farmers' fields in Catalonia (Spain) over a 5-year period. The relevance of decisions made according to model output was also evaluated.In a fourth phase, MAPOD® was used to simulate different scenarios involving the introduction of GM varieties into European cropping systems. The efficiency of individual coexistence measures was tested. Afterwards, the effect of combining different types of practices was simulated, leading to a set of decision-support tables elaborated according to the cropping context. At the scale of the collecting basin, with the enhanced version of MAPOD®, the efficiency of segregation strategies (spatial or temporal) that could be implemented by collecting and storing organisations was also studied. Lastly, model outputs were used as a basis for the design of a decision-support tool for use by farmers and extension workers
Troisi, Lucie. „Development of a new class of synthetic gene circuits based on protein-protein interactions“. Electronic Thesis or Diss., Sorbonne université, 2023. http://www.theses.fr/2023SORUS728.
Der volle Inhalt der QuelleSynthetic biology, by its engineering approach, promise to revolutionize the way scientists manipulate and analyze living systems. In this project, we propose to develop a new class of synthetic gene circuits whose fine tuning rely on the affinity competition between active and inactive forms of a transcription factor. Modelling, together with an in silico evolutionary approach, will be used to determine molecular parameters and network topologies required for a given functionality. Circuits will be assembled accordingly and their expression in mammalian cells measured to confirm the expected response or correct our model. Using this methodology, we plan to build multi-inputs circuits with tunable response function, as well as new bistable and oscillatory circuits. The new investigated class of circuits will also be extended to multi-cellular networks exhibiting symmetry breaking or oscillating patterns. This fundamental project bridging modelling and experimental validation will promote the development of advanced targeting circuits with promising applications in diagnosis, gene therapy and complex tissue engineering
Parmentier, Frédéric. „Modélisation et prédiction de la dynamique moléculaire de la maladie de Huntington par la théorie des graphes au travers des modèles et des espèces, et priorisation de cibles thérapeutiques“. Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015PA05T030.
Der volle Inhalt der QuelleHuntington’s disease is a hereditary neurodegenerative disease that has become a model to understand physiopathological mechanisms associated to misfolded proteins that ocurs in brain diseases. Despite exciting findings that have uncover pathological mechanisms occurring in this disease and that might also be relevant to Alzheimer’s disease and Parkinson’s disease, we still do not know yet which are the mechanisms and molecular profiles that rule the dynamic of neurodegenerative processes in Huntington’s disease. Also, we do not understand clearly how the brain resist over such a long time to misfolded proteins, which suggest that the toxicity of these proteins is mild, and that the brain have exceptional compensation capacities. My work is based on the hypothesis that integration of ‘omics’ data from models that depicts various stages of the disease might be able to give us clues to answer these questions. Within this framework, the use of network biology and graph theory concepts seems particularly well suited to help us integrate heterogeneous data across models and species. So far, the outcome of my work suggest that early, pre-symptomatic alterations of signaling pathways and cellular maintenance processes, and persistency and worthening of these phenomenon are at the basis of physiopathological processes that lead to neuronal dysfunction and death. These results might allow to prioritize targets and formulate new hypotheses that are interesting to further study and test experimentally. To conclude, this work shall have a fundamental and translational impact to the field of Huntington’s disease, by pinpointing methods and hypotheses that could be valuable in a therapeutic perspective
John, Alphy. „Propriétés subcellulaires et dynamique à l'échelle de l'embryon gouvernant la morphogenèse“. Electronic Thesis or Diss., Université Côte d'Azur, 2021. http://theses.univ-cotedazur.fr/2021COAZ6017.
Der volle Inhalt der QuelleMorphogenesis is the process of reshaping single-cell zygotes to the final form of a developed animal. Embryonic gene patterning systems determine the body axes and lay down the spatiotemporal specification coordinates for cells. Gene patterning systems also affect the organization of cytoskeletal components in order to drive tissue morphogenesis. While much work was done to understand how AP and DV patterning independently control morphogenesis, little is known on how cross-patterning functions. We use the Drosophila embryo as a model system and focus on the process of tissue folding, a process that is vital for the animal since folding defects can impair neurulation in vertebrates and gastrulation in all animals which are organized into the three germ layers. Past work has shown that an actomyosin meshwork spanning the apical-medial side of prospective mesoderm cells and under the control of the embryo DV patterning plays a key role in mesoderm invagination. Nevertheless, both experimental and theoretical pieces of evidence have argued against apical constriction being the sole mechanism driving invagination. In this study, I have uncovered a lateral cell junctional network under the control of both AP and DV patterning. This contractile network generates tension along the apical-basal axis and within the tissue plane, 10-15 μm inside the mesoderm epithelium initiating lateral cell intercalation. Lateral forces in mesoderm cells seem to play a multivalent role in both driving mesoderm extension and invagination. Finally, by implementing 4D multi-view light-sheet imaging, infra-red femtosecond ablation to perturb the cytoskeleton, and optogenetics to synthetically control tissue morphology, this work shines new light on the origin and functions of a novel mechanism responsible for coordinated tissue elongation and folding
Stigliani, Arnaud. „Modélisation de la liaison à l'ADN et des mécanismes d'action de facteurs de transcription floraux Building Transcription Factor Binding Site Models to Understand Gene Regulation in Plants JASPAR 2018: Update of the open-access database of transcription factor binding profiles and its web framework“. Thesis, Université Grenoble Alpes (ComUE), 2019. https://thares.univ-grenoble-alpes.fr/2019GREAV032.pdf.
Der volle Inhalt der QuelleIn angiosperms, the development of flowers takes place in several stages. The meristem, a stem cell reservoir from which all the plant’s aerial organs emerge, first differentiate into an inflorescence meristem. Floral meristems then emerge from the flanks of the inflorescence meristem to give birth to the different organs that compose the flower : the petals, sepals, stamens and carpel. Each of these phases is finely regulated by transcription factors, a family of proteins that bind to DNA to induce gene activation or repression. If this thesis allowed us to contribute to the JASPAR database, which gather transcription factor binding profiles, its main goal is to provide a new perspective on the understanding of the phenomena that control flower development through the study of a handful of key transcription factors in the regulation of floral development. We have tried to explain the parameters that influence the binding of these transcription factors using bioinformatics models associated with genomics experiments.We have analysed the auxin response factors (ARF) through the study of two representatives of this family of 23 proteins : ARF2 and ARF5. The transcription factors of this family are known to bind in dimers and we have shown that ARF2 and ARF5 prefer different spacings between monomeric binding sites on DNA. We have also shown that some configurations seem to favour the activation of bound genes.Then, we have studied LFY, a master transcription factor of floral development. We have improved an existing binding model and have seen that the integration of genomic data of various kinds provides a better understanding of the binding of the transcription factor in vivo.Finally, we have analyzed the preferences of MADS box transcription factors, known to bind the same DNA sequences and whose role is to determine the identity of floral organs. Through the study of the SEP3/AG complex, which controls the formation of the carpel, we have found that the tetramerization domain of these factors confers binding specificity, potentially explaining that groups of MADS box transcription factors regulate the formation of different floral organs by activating distinct genes
Bertaux, François. „Cell-based multi-scale modeling for systems and synthetic biology : from stochastic gene expression in single cells to spatially organized cell populations“. Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066101/document.
Der volle Inhalt der QuelleCell-intrinsic, non-environmental sources of cell-to-cell variability, such as stochastic gene expression, are increasingly recognized to play an important role in the dynamics of tissues, tumors, microbial communities... However, they are usually ignored or oversimplified in theoretical models of cell populations. In this thesis, we propose a cell-based (each cell is represented individually), multi-scale (cellular decisions are controlled by biochemical reaction pathways simulated in each cell) approach to model the dynamics of cell populations. The main novelty compared to traditional approaches is that the fluctuations of protein levels driven by stochastic gene expression are systematically accounted for (i.e., for every protein in the modeled pathways). This enables to investigate the joint effect of cell-intrinsic and environmental sources of cell-to-cell variability on cell population dynamics. Central to our approach is a parsimonious and principled parameterization strategy for stochastic gene expression models. The approach is applied on two case studies. First, it is used to investigate the resistance of HeLa cells to the anti-cancer agent TRAIL, which can induce apoptosis specifically in cancer cells. A single-cell model of TRAIL-induced apoptosis is constructed and compared to existing quantitative, single-cell experimental data. The model explains fractional killing and correctly predicts transient cell fate inheritance and reversible resistance, two observed properties that are out of reach of previous models of TRAIL-induced apoptosis, which do not capture the dynamics of cell-to-cell variability. In a second step, we integrate this model into multi-cellular simulations to study TRAIL resistance in virtual scenarios constructed to help bridging the gap between standard in-vitro assays and the response of in-vivo tumors. More precisely, we consider the long-term response of multi-cellular spheroids to repeated TRAIL treatments. Analysis of model simulations points to an novel, mechanistic explanation for transient resistance acquisition, which involves the targeted degradation of activated proteins and a differential turnover between pro- and anti- apoptotic proteins. Second, we apply our approach to a synthetic spatial patterning system in yeast cells developed by collaborators. Focusing first on a sensing circuit responding to a messenger molecule, we construct a single-cell model that accurately capture the response kinetics of the circuit as observed in flow cytometry data. We then integrate this model into multi-cellular simulations and show that the response of spatially-organized micro-colonies submitted to gradients of messenger molecules is correctly predicted. Finally, we incorporate a model of a killing circuit and compare the predicted patterns of dead or alive cells with experimental data, yielding insights into how the circuit parameters translate into multi-cellular organization phenotypes. Our modeling approach has the potential to accelerate the obtention of more quantitative and predictive models of cell populations that encompass the molecular scale
Sun, Honglu. „Identifying and Analyzing Long-term Dynamical Behaviors of Gene Regulatory Networks with Hybrid Modeling“. Electronic Thesis or Diss., Ecole centrale de Nantes, 2023. http://www.theses.fr/2023ECDN0043.
Der volle Inhalt der QuelleUsing dynamical models to reveal dynamical properties of gene regulatory networks can help us better understand the nature of these biological systems and develop new medical treatments. In this thesis, we focus on a class of hybrid dynamical systems called Hybrid Gene Regulatory Network (HGRN) and aim to analyze long-term dynamical properties. We propose methods to find limit cycles and analyze their stability, and to analyze the reachability in HGRNs. This is followed by a deeper study of some networks of interest for Systems Biology: The repressilators, and we find conditions for the existenceof sustained oscillations in the 3-dimensional canonical repressilator, and conditions, which are described by topological features of the networks, for the existence of a periodic attractor in discrete 4-dimensional repressilators. In summary, this thesis proposes new methods to analyze some properties of HGRNs that were not investigated before, for instance, the stability of N-dimensional limit cycles, the reachability, etc. The results can be further developed in the future to study other large complex networks
Berthoumieux, Sara. „Méthodes pour l’identification des modèles de réseaux biochimiques“. Thesis, Lyon 1, 2012. http://www.theses.fr/2012LYO10073/document.
Der volle Inhalt der QuelleBacteria manage to constantly adapt their molecular composition to respond to environmentalchanges. We focus on systems of both metabolic and gene regulation that enablesuch type of adaptation, notably in the context of diauxic growth of Escherichia coli, when itshifts from glucose to acetate as a carbon source. To model a metabolic network, we use anapproximate kinetic formalism called linlog and address methodological issues encounteredwhen performing parameter estimation. We propose a maximum-likelihood method basedon Expectation Maximization for parameter estimation from incomplete datasets. We then apply it to the linlog model of central carbon metabolism. We also propose a method foridentifiability analysis and reduction of nonidentifiable models that we then apply to bothsimulated and experimental datasets. Moreover, we monitored gene expression patterns for agene network involved in the control of diauxie and highlight, by means of kinetic models developedin this study, the role of the global physiological state of the cell in regulation of geneexpression. By addressing methodological challenges encountered with models of metabolicand gene networks, this thesis contributes to future efforts integrating both types of networksinto quantitative models