Tesis sobre el tema "Variation génomique"
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Hallin, Johan Henning. "Élucider les facteurs génétiques à l'origine de la variabilité des populations par phénomique et génomique de masse". Thesis, Université Côte d'Azur (ComUE), 2018. http://www.theses.fr/2018AZUR4010/document.
Texto completoThe phenotypic variation between individuals in a population is of crucial importance. It allows populations to evolve to novel conditions by the natural selection of beneficial traits. Variation in traits can be caused by genetic or environmental factors. This work endeavors to study the genetic factors that underlie phenotypic variation in order to understand how variation can be created from one generation to the next; to know what genetic mechanisms are most prominent; to learn how variation can extend beyond the parents; and finally, to use this in order to predict phenotypes of unknown genetic constellations. We used large scale phenomics and genomics to give an unprecedented decomposition of the phenotypic variation in a large population of diploid Saccharomyces cerevisiae strains. Constructing phased outbred lines by large scale crosses of sequenced haploid strains allowed us to infer the genetic makeup of more than 7,000 colonies. We measured the growth of these strains and decomposed the phenotypic variation into its genetic components. In addition, we mapped additive and nonadditive quantitative trait loci, we investigated the occurrence of heterosis and its genetic basis, and using the same populations we used phenotypic and genetic data to predict traits with near perfect accuracy. By using the phased outbred line approach, we succeeded in giving a conclusive account of what genetic factors define phenotypic variation in a diploid population, and in accurately predicting phenotypes from genetic and phenotypic data. Beyond the phased outbred line project, I am currently investigating the genetic basis of gamete inviability and complex traits in intraspecies yeast hybrids. Using 9,000 sequenced gametes from six different hybrids we aim to characterize their recombination landscape and how the genetic background influences it. Furthermore, we have phenotyped these gametes in nine conditions and will dissect the genetic architecture of these traits across multiple genomic backgrounds
Hallin, Johan Henning. "Élucider les facteurs génétiques à l'origine de la variabilité des populations par phénomique et génomique de masse". Electronic Thesis or Diss., Université Côte d'Azur (ComUE), 2018. http://www.theses.fr/2018AZUR4010.
Texto completoThe phenotypic variation between individuals in a population is of crucial importance. It allows populations to evolve to novel conditions by the natural selection of beneficial traits. Variation in traits can be caused by genetic or environmental factors. This work endeavors to study the genetic factors that underlie phenotypic variation in order to understand how variation can be created from one generation to the next; to know what genetic mechanisms are most prominent; to learn how variation can extend beyond the parents; and finally, to use this in order to predict phenotypes of unknown genetic constellations. We used large scale phenomics and genomics to give an unprecedented decomposition of the phenotypic variation in a large population of diploid Saccharomyces cerevisiae strains. Constructing phased outbred lines by large scale crosses of sequenced haploid strains allowed us to infer the genetic makeup of more than 7,000 colonies. We measured the growth of these strains and decomposed the phenotypic variation into its genetic components. In addition, we mapped additive and nonadditive quantitative trait loci, we investigated the occurrence of heterosis and its genetic basis, and using the same populations we used phenotypic and genetic data to predict traits with near perfect accuracy. By using the phased outbred line approach, we succeeded in giving a conclusive account of what genetic factors define phenotypic variation in a diploid population, and in accurately predicting phenotypes from genetic and phenotypic data. Beyond the phased outbred line project, I am currently investigating the genetic basis of gamete inviability and complex traits in intraspecies yeast hybrids. Using 9,000 sequenced gametes from six different hybrids we aim to characterize their recombination landscape and how the genetic background influences it. Furthermore, we have phenotyped these gametes in nine conditions and will dissect the genetic architecture of these traits across multiple genomic backgrounds
Brachi, Benjamin. "Étude de la variation naturelle de traits phénologiques chez Arabidopsis thaliana par une approche de génomique écologique". Thesis, Lille 1, 2010. http://www.theses.fr/2010LIL10112/document.
Texto completoTwo complementary approaches need to be considered in the study of adaptation. The first approach aims at describing the genetic architectures and the genetic bases of phenotypic variation in order to better understand the adaptive walk followed by natural populations toward a phenotypic optimum. The second approach aims to identify the environmental grain of the ecological factors acting as selective pressures in natural populations. In this work we studied the natural variation of phenological traits in Arabidopsis thaliana. We used a powerful combination of genome wide association (GWA) mapping and traditional QTL mapping to fine map the genetics of phenological traits measured under two environments. This dual mapping strategy revealed a strong environmental dependency of both allelic effect and identity of the genes underlying natural variation, but also that natural A. thaliana populations may have followed different adaptive walks. A. thaliana populations were sampled according a hierarchical geographic pattern and characterized ecologically, phenologically and genetically. This strategy revealed that phenological traits were adaptive to fine-grained environmental conditions defined by both climate and soil conditions. In the study of the adaptive walks followed by A. thaliana natural populations, this two sided approach, combining both genomics and ecology, suggests that the description of the genetic architectures and the identification of causal genes should be performed at different spatial scales, following a hierarchical geographic design, and that phenotypes must be measured in ecologically realistic conditions
Perreault-Payette, Alysse. "Génomique des populations et association génotype-phénotype des écotypes de touladi du Lac Supérieur". Master's thesis, Université Laval, 2016. http://hdl.handle.net/20.500.11794/27107.
Texto completoUnderstanding the emergence and maintenance of sympatric ecotypes adapted to various trophic niches is a central topic in evolutionary biology, and also has implications for conservation and management. Lake Trout (Salvelinus namaycush) is renowned for the occurrence of phenotypically distinct ecotypes linked to resource and habitat use throughout North America. A total of four ecotypes have been described in Lake Superior that differ in terms of habitat, diet, morphology and osteology. The principal objective of this study was to quantify the extent of genetic differentiation among sampling sites and among ecotypes. The secondary objective was to identify markers potentially under divergent selection among the four ecotypes that may underlie local adaptation. To this end, a total of 486 individuals were genotyped at 6822 SNPs (single nucleotide polymorphism). In addition, these analyses were conducted alongside morphometric analyses to characterise the extent of morphological divergence among ecotypes within each sampling site. Results reveal that overall genetic differentiation is weak and is higher among sites than among ecotypes within each site. Moreover, we found evidence for divergent selection among ecotypes, and in some instances in association with morphological variation. These markers represent ecologically important traits linked to ecotype divergence. Results from this study will benefit management and conservation practices, and will guide the choice of source populations for stocking in the Great Lakes.
Petit, Morgane. "Etude des patrons de recombinaison, de leur déterminisme génétique et de leurs impacts en sélection génomique". Thesis, Toulouse, INPT, 2017. http://www.theses.fr/2017INPT0083/document.
Texto completoGenetic recombination is a fundamental biological process, which occurs during the meiosis. It allows the good segregation of the chromosomes and contributes to maintain the genetic diversity. Recombination was already studied in a lot of different species, especially in mammals and in farm animals, such as the pig, the cattle or the sheep. In each case, a variation of the recombination rate between the individuals was observed. This variation was heritable and under genetic determinism. In some species, genetic recombination maps were also created, which allowed to localize the crossovers and to detect really tiny genomic regions where the recombination is huge: the recombination hotspots. In the Lacaune breed sheep, a lot of genotyping data are available thanks to two existing arrays: a first with a medium density of markers (about 54,000 markers) and a second with a high density of markers (about 600,000 markers). Two datasets were thus available: a familial dataset with about 6,000 animals genotyped for the 54,000 markers and a dataset of 70 unrelated Lacaune genotyped for the 600,000 markers. Genetic recombination maps were created for these two datasets. With the 70 unrelated Lacaune, about 50,000 hotspots were detected. The familial dataset allowed to observe the mammals common recombination patterns. Finally, when the two datasets were combined, selection signatures were revealed and a high density recombination map were created. Furthermore, a variation of the recombination rate within the individuals was observed and was associated to 2 main QTLs on the chromosomes 6 and 7. Already known, or not, candidate genes were proposed and sometimes studied: especially RNF212 and HEI10. Finally, a comparison with another sheep breed revealed that the genetic recombination maps were really similar, but the individual recombination rate was under a different genetic determinism. A concrete application of the genetic recombination map in genomic selection was also proposed thanks to the creation of lowdensity SNPs sets, which could be used to impute the animals and thus to improve the genotyping and the genomic selection for lessercosts
Lemor, Mélanie. "Influence de la variation de la concentration intracellulaire des désoxyribonucléotides et rubbonucléotides sur la stabilité génomique chez Pyrococcus abyssi". Thesis, Brest, 2017. http://www.theses.fr/2017BRES0097/document.
Texto completoIn the three domains of life that include Bacteria, Eukarya and Archaea, one molecule has the sovereign ability to govern life, and not the least one, the mother of all biological mechanisms, DNA. Maintaining the integrity of genomes is obviously essential for life, and faithful DNA replication and repair are the guarantees. The fidelity of these two processes may vary depending on the availability and levels (balance and ratio) of deoxyribonucleotides (dNTPs) and ribonucleotides (rNTPs) during the cell-cycle. Even if intracellular concentration of nucleotides is largely documented in Eukarya and Bacteria, it remains limited in Archaea. From many years one group of Archaea is of great interest for studying genomic maintenance, because of its ability to survive in extremes environments. Pyrococcus abyssi is one of them that is used as biological model for deciphering the stability of DNA at elevated temperature in LM2E. The present work focuses on genomic integrity and particularly on the functional characterization of the three DNA polymerases: PolD, PolB and the p41/p46 complex. Initially, the nucleotide pool has been evaluated in exponentially growing cells using the highly sensitive method that combined chromatography and mass spectrometry (zicHILIC-MS-MS). The results show that rNTPs content is 20-fold higher than dNTPs. For that reason, fidelities of DNA polymerases are challenged to select the correct dNTP over the most abundant rNTP during DNA synthesis. Despite the fact that some mechanisms allow the exclusion of rNTPs from entry to the Pol active site, recent findings indicate that ribonucleotides are incorporated by different DNA Pols with surprisingly high frequency. In this work, the obtained intracellular balance and ratio of rNTPs and dNTP have been used to analyze their effect on DNA synthesis by P. abyssi DNA Pols and cell-free extracts. Our results clearly demonstrate that rNTP incorporation is detectable with distinct efficiencies among DNA pols. Secondly, the consequences of the presence of rNMPs in a DNA template on DNA polymerisation has been examined and highlights that cell-free extracts are able to bypass a single rNMP as well as replicative DNA polymerases. To strengthen that study, single nucleotide incorporation opposite rNMP or dNMP has been carried out and the results demonstrate that replicative Pyrococcus abyssi DNA Pols can basepair the complementary rNTPs opposite dNMPs, and vice-versa, the complementary dNTPs opposite rNMPs.Furthermore, the preliminary results obtained about the nucleolysis activities of the PolD small subunit, DP1, show that the DNA polymerase D is able to remove rNMPs from a DNA strand, suggesting a first level of protection against ribonucleotide contamination of DNA. Definitely, these data indicate that the presence of transient embedded rNMPs in genomic DNA represents a universally conserved phenomenon across Archaea, Bacteria and Eukarya
Flutre, Timothée. "L'annotation des éléments transposables par la compréhension de leur diversification". Phd thesis, Université Paris-Diderot - Paris VII, 2010. http://tel.archives-ouvertes.fr/tel-00560242.
Texto completoDelahaye-Duriez, Andrée. "Identification de nouveaux gènes impliqués dans des maladies ophtalmologiques rares en utilisant la CGH-array". Paris 7, 2011. http://www.theses.fr/2011PA077066.
Texto completoThe karyotype detects a chromosomal anomaly in 7. 7% to 10% of neonates with ocular birth defect. The introduction of microarray technology showed a very high rate of rearrangements below the resolution of karyotyping. My objectives in this work were to characterize using comparative genome hybridisation-based microarray analysis (array-CGH) chromosomal regions involved in rare ophthalmologic disorders, and then to identify new genes. In the first part of my work, we performed array-CGH in 65 patients presenting syndromal ocular developmental anomalies. A causal or potentially causal anomaly was found for 15% of them. Four had a pathogenic deletion involving a gene known to be involved in ocular anomalies (FOXC1 or OTX2}, while 4 others had a pathogenic deletion not classically associated with ocular malformations: del(17)(pl3. 3p!3. 3), del(10)(pl4p!5. 3) and del(16)(pl 1. 2pl 1. 2). In collaboration with other teams, we gathered patients to study genotype-phenotype correlations for 6p25 and 17pl3. 3 deletions. The second part of my work focused on a candidate gene study: ARHGEF26. Sequencing this gene in other patients with similar phenotype and studying the index patient family segregation, we could not demonstrate the ARHGEF26 involvement in this phenotype. This second part highlights the limits and difficulties of gene identification using array-CGH. These results demonstrate that array-CGH-based chromosomal analysis, beyond its importance for diagnosis and genetic counselling, can help to establish new genotype-phenotype correlations for chromosomal anomalies as well as identify potential new regions involved in rare ophthalmologic disorders
Lalagüe, Hadrien. "Genetic response of tree population to spatial climatic variation : an experimental genomic and simulation approach in Fagus sylvatica populations along altitudinal gradients". Thesis, Montpellier 2, 2013. http://www.theses.fr/2013MON20042/document.
Texto completoA major challenge in population genetics is to understand the local adaptation process in natural population and so to disentangle the various evolution forces contributing to local adaptation. The experimental studies on local adaption generally resort to altitudinal gradients that are characterized by strong environmental changes across short spatial scales. Under such condition, the genetic differentiation of the functional trait (measured by the Qst) as well as the genes coding for trait (measured by Fstq) are expected to be mainly driven by selection and gene flow. Genetic drift and mutation are expected to have minor effect. Theoretic studies showed a decoupling between Qst and Fst under strong gene flow and / or recent selection. In this study, I tested this hypothesis by combining experimental and modelling genomic approach in natural population of Fagus sylvatica separated by ~3 kilometres and under contrasted environments.Sampling was conducted in south-eastern France, a region known to have been recently colonised by F.sylvatica. Four naturally-originated populations were sampled at both high and low elevations along two altitudinal gradients. Populations along the altitudinal gradients are expected to be subjected to contrasting climatic conditions. Fifty eight candidate genes were chosen from a databank of 35,000 ESTs according to their putative functional roles in response to drought, cold stress and leaf phenology and sequenced for 96 individuals from four populations that revealed 581 SNPs. Classical tests of departure of site frequency spectra from expectation and outlier detection tests that accounted for the complex demographic history of the populations were used. In contrast with the mono-locus tests, an approach for detecting selection at the multi-locus scale have been tested.The results from experimental approaches were highly contrasted according the method highlighting the limits of those method for population loosely differentiated and spatially close. The modelling approach confirmed the results from the experimental data but revealed that up to 95% of the SNPs detected as outliers were false positive. The multi-locus approach revealed that the markers coding for the trait are differentially correlated compared to the neutral SNPs. But this approach failed to detect accurately the markers coding for the trait if no a priori knowledge is known about them. The modelling approach revealed that genetic changes may occur across very few generation. But while this genetic adaptation is measurable at the trait level, the available method for detecting genetic adaptation at the molecular level appeared to be greatly inaccurate. However, the multi-locus approach provided much more promise for understanding the genetic basis of local adaptation from standing genetic variation of forest trees in response to climate change
Khaiwal, Sakshi. "Prédire le paysage phénotypique naturel de la levure par machine learning". Electronic Thesis or Diss., Université Côte d'Azur, 2024. http://www.theses.fr/2024COAZ6003.
Texto completoThe study of complex traits is of central importance in various fields, including evolutionary biology, medicine, agriculture, etc. Understanding the genetic factors involved in controlling these traits can be of paramount significance. For example, most diseases-related traits are complex, and unraveling novel drug targets can lead to new and improved treatment methods. Similarly, in agriculture, the identification of genetic loci associated with traits of interest, such as yield, adaptability, and resistance, can help improve crop productivity and quality. The genetic variation present at the population level can greatly contribute to the variance in phenotypic traits. In this thesis, we study the population-level variation in more than 200 complex traits in a natural Saccharomyces cerevisiae collection comprising of 1,011 strains. The study can be divided into three main parts. In the first part, we describe the global correlation patterns among all 223 phenotypes, highlighting some unexpected correlations between unrelated phenotypes. Furthermore, we quantified the correlation between the genetic and phenotypic distances of the strains and its variations between the different clades. In the second part, we identify genetic markers associated with the 223 phenotypes using genome-wide association studies (GWAS). Moreover, we confirmed that the patterns observed at the phenome level of the population were reflected at the genomic level, with a higher number of significantly associated genetic variants being shared between the more correlated phenotypes and vice versa. Finally, the last part is focused on predicting the phenome from various genomic and phenomic data. We developed a machine learning pipeline (GenPhen) that implements the automatization of the hyperparameters optimization process during model learning to obtain the most optimized model for individual phenotypes. In addition, the pipeline can be used to implement four ML methods capable of learning linear to highly non-linear models. We provide a comparison of the ability of the different ML models to predict phenotypes and also different kinds of input predictors including the pangenome, Single Nucleotide Polymorphisms (SNPs), transcriptomic, proteomics, etc. Finally, we implemented multitarget machine learning models that can predict the entire phenome with overall accuracy comparable to that of individual phenotype predictions. Overall, we showed that predictions vary highly depending on the phenotype and that most of the traits were highly polygenic, i.e., they are controlled by a large number of genetic factors with very small effects. In general, our study provides insight into the usefulness of different machine learning methods for predicting complex phenotypes, comparison of different types of predictors for the prioritization of the experimental data required for predictions, and interpretation of ML models to understand the underlying biological mechanisms controlling a trait
Mella-Flores, Daniella. "Diversité génétique et fonctionnelle des cyanobactéries picoplanctoniques marines et adaptation aux stress environnementaux". Paris 6, 2011. http://www.theses.fr/2011PA066359.
Texto completoSinama, Melthide. "Cinétique spatiale et temporelle de zones hybrides : unicité et diversité au sein du modèle Chondrostomes (Teleostei, Cyprinidés), : application pour la conservation d'espèces d'intérêt patrimonial". Thesis, Aix-Marseille, 2013. http://www.theses.fr/2013AIXM4726.
Texto completoIn the Cyprinidae family (Teleostei), Parachondrostoma toxostoma (the sofie) and Chondrostoma nasus (the nase) are respectively endemic and invasive species which are found in sympatry in the south of France. They form two distinct hybrid zones: the Durance River (a highly fragmented environment) and the Ardèche basin (an unfragmented area). The existence of these two different zones allow us to characterize the respective contributions of exogenous selection (environmental factors) and endogenous selection (genomic compatibility) to explain hybridization patterns between the two species.This PhD thesis highlights the complexity of hybridization phenomena. Each situation is highly dependent of the study context. We showed the resistance of the genome of the endemic species to introgression by the genome of the invasive species in some stations. In other cases, we demonstrated more complex scenarios of admixture that evolve over time. The evolutionary potential generated by hybridization is undeniable, and we recommend to take the hybridization process into account in management programs and conservation of biodiversity
Libourel, Cyril. "Identification des bases génétiques associées à la variation naturelle des interactions plante-plante chez Arabidopsis thaliana". Thesis, Toulouse 3, 2019. http://www.theses.fr/2019TOU30064.
Texto completoBiotic interactions are crucial in the response of plant communities to environmental changes. Among these interactions, plant-plant interactions play an important role in the structure, diversity and dynamics of plant communities. Although it is widely accepted that the identification of genes associated with plant-plant interactions is an important step in predicting and understanding the adaptive dynamics of plant communities, studies on the identification of genetic variants associated with natural variation in plant-plant interactions remain scarce. The main objective of this thesis was to characterize and identify the genetic bases associated with natural variation of competitive response in a local population (TOU-A) of the model species Arabidopsis thaliana interacting with different species. In a first chapter, with a resurrection approach coupled with GWA mapping and a temporal genetic differentiation analysis, I was able to show that the TOU-A population was adapted for the identification of associated adaptive genetic bases underlying monospecific plant-plant interactions. In the second chapter, in order to take into account the complexity of plant-plant interactions observed in nature, I was interested in characterizing the genetic architecture of the competitive response of A. thaliana in different contexts of mono- and multi-specific interactions. I was able to highlight biotic specialization of some accessions in response to certain assemblages, and this, despite observing a similar response of the entire population in response to different interaction treatments. Through an approach of GWA mapping, I was able to highlight that the QTLs of competitive response of A. thaliana were mostly different between the 12 interaction treatments. I have also been able to show that biological processes differ between mono- and multi-specific conditions and, more specifically, that receptor like-kinase play a major role in plant-plant interactions. In a third chapter, I sought to functionally validate a gene underlying a QTL associated with the competitive response of A. thaliana to Poa annua. By phenotyping mutant lines and complemented lines, I was able to identify that the PERK13/RHS10 gene was the causative gene underlying this QTL. This functional validation allowed me to characterize PERK13/RHS10 as a positive regulator of a competition avoidance strategy in response to P. annua but also to wheat (Triticum aestivum). This work is in line with interdisciplinary approaches, which intends to improve our understanding of the genetic determinants that underlie the adaptive natural variation of biotic interactions
Débibakas, Sarah. "Impact de la diversité génétique du Sugarcane yellow leaf virus (SCYLV) sur les déterminismes de résistance de la canne à sucre à la feuille jaune". Thesis, Antilles-Guyane, 2012. http://www.theses.fr/2012AGUY0554.
Texto completoModern varieties of sugarcane have a bispecific origin and a complex genetic structure, aneuploid and highly polyploid, maklng genetic resistance study uneasy to perform. Yellow leaf of sugarcane is a viral disease whose causal agent is the sugarcane yellow leaf virus (scylv). This virus has a wide range of diversity. Only three viral genotypes, distinguishable by rt-pcr, were found in guadeloupe. The objectives of this srudy are to assess: l/the possibility to find markers associated with plant resistance to scylv through a genome wide association study 2 1 the impact of the pathogen diversity on the resistance of sugarcane to scylv. Association studies have been conducted with more than 4000 aflp and dart markers on four types of phenotypic data (virus intensity and density in leaves and canes). Phenotypes were measured on 189 varieties of sugarcane in two successive trials in a three randomized complete block design. From these varieties, 40 were selected and allowed to obtain 10 biparental crosses. The offspring were followed during two trials. The incidence and the diversity of scylv were evaluated in the 40 varieties and the offspring. The narrow sense heritability of the resistance to the scylvs was determined. Six markers of the resistance to the scylv and two genes, with potential contribution in virus resistance, have been identified. The study also shows that the resistance of the plant is variable depending on the scylv genotype and that this resistance is partly transmitted to the offspring. Breeding for scylv resistance is practicable
Peluffo, Alexandre E. "The how and the why of ventral branches evolution between Drosophila santomea and Drosophila yakuba : genetic basis, natural variation and plasticity of a shape difference linked to speciation". Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC100.
Texto completoThe thesis tackles the problem of the evolution of shape through the example of a shape difference in the male ventral branches linked to reproductive isolation in two sister species: Drosophila yakuba and Drosophila santomea. The goal is to identify the genes involved in the evolution of this shape difference and the evolutionary causes of such difference. In a first part, the thesis interrogates the concept of “gene” and its search. Then are scientifically characterized the “how” and “why” questions and their link with the distinction of proximal/ultimate, or evolutionary, causes; these philosophical grounds are then linked to Evo-Devo and the experimental work presented in the thesis. In a second part, through geometric morphometrics and a new high-throughput genotyping method, MSG, we identify a loci of 2.7 mega-bases located on chromosome 3L as involved in the evolution of the shape of ventral branches between D. yakuba and D. santomea. These results are linked to our quantitative analysis of shape variation in multiple natural and laboratory strains and strains reared at different temperatures which bring light into the evolutionary causes of this shape difference
Jaillard, Dancette Magali. "Vers une cartographie fine des polymorphismes liés à la résistance aux antimicrobiens". Thesis, Lyon, 2018. http://www.theses.fr/2018LYSE1282/document.
Texto completoThe emergence and spread of multi-drug resistance has become a major worldwide public health concern, calling for better understanding of the underlying resistance mechanisms. Genome-wide association studies are powerful tools to finely map the genetic polymorphism linked to the phenotypic variability observed in a population. However well documented for eukaryotic genome analysis, these studies were only recently applied to prokaryota.Through this PhD project, I searched how to better adapt these tools to the highly plastic bacterial genomes, mainly by working on the representation of the genetic variations in these genomes. Indeed, because the bacteria have the faculty to acquire genetic material by a means other than direct inheritance from a parent cell, their genomes can differ too much within a species to be aligned against a reference. A representation using sequence fragments of length k - the so-called k-mers - offers the required flexibility but generates redundancy and does not allow for a direct interpretation of the identified associations. The method we set up tests the association of these k-mers with the phenotype, and takes advantage of a De Bruijn graph (DBG) built over all genomes to remove the local redundancy of k-mers, and offer a visualisation of the genomic context of the k-mers identified by the test. This synthetic view as DBG subgraphs informs on the nature of the identified sequence: e.g. local polymorphism in a gene or gene acquired through a plasmid. The type of variant can be predicted correctly in 96% of the cases from descriptors of the subgraphs, providing a tractable framework for k-mer-based association studies
Alirol, Servane. "Etude génétique du complexe synaptique lié au récepteur NMDA et caractérisation de modèles à complexité variable dans l'autisme". Thesis, Tours, 2015. http://www.theses.fr/2015TOUR3303/document.
Texto completoAutism is a developmental disorder of the central nervous system defined by impairments in social interaction and communication, and by restricted and repetitive behavior. Its prevalence is currently estimated at around 1% in the general population. Autism is characterized by a wide heterogeneity at both phenotypic and genetic level. To date, more than 300 candidate genes were characterized either by copy number variations (CNV) and/or nucleotide variations (SNV). Their identification has highlighted a significant contribution of de novo mutations, as well as the involvement of targeted pathophysiological pathways, particularly post-synaptic density (PSD)
Saclier, Nathanaëlle. "Origine des variations de taux d’évolution moléculaire inter-spécifiques : apport d’un modèle génomique en milieu souterrain". Thesis, Lyon, 2019. https://n2t.net/ark:/47881/m69p310z.
Texto completoThe rate at which DNA accumulates substitutions varies widely among species. Rate variations have been imputed to species intrinsic features (metabolic rate, life history traits) or to the environment characteristics (ionizing radiations, selection pressure). The aim of this PhD project was to investigate the main hypotheses explaining variations in the rate of molecular evolution between species. To achieve that, we combined the unique properties of subterranean isopods from the Asellidae family and high-throughput sequencing data from the nuclear and mitochondrial genome. Asellidae species have made multiple independent transitions to subterranean environments where subterranean species have repeatedly evolved a lower metabolic rate, a longer lifespan and a longer generation time. Moreover, because they are poor dispersers, they are exposed to the same environment across many generations, allowing us to compare species with long-term contrasted features in term of life history traits and environmental characteristics. We found that generation time negatively impact the rate of molecular evolution in the nuclear genome whereas the mitochondrial rate remained unchanged. We also found an increase of the mutation rate for species living in naturally highly radioactive environments. Finally, the study of the rate of molecular evolution variation at a global scale brought forward a systematic bias which needs to be taken into account in studying the link between the mutation rate and diversification
Shinde, Jayendra. "Mutational signatures reveal the dynamic interplay of risk factors and cellular process during liver tumorigenesis". Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC324/document.
Texto completoCancer is a disease of the genome. A normal cell goes rogue and is transformed into a cancerous cell due to acquired somatic mutations in its genome. The catalogue of these somatic mutations observed in the cancer genome is the outcome of multiple mutational processes that have been operative over the lifetime of a patient. These mutational processes that have occurred throughout the development of cancer may be infidelity of the DNA replication machinery, impaired DNA repair system, enzymatic modifications of DNA, or exposures to exogenous or endogenous mutagens. Each mutational process leaves a characteristic pattern – a “mutational signature” on the cancer genome. Various genomic features related to genome architecture, including DNA replication and transcription, modulate these mutational processes. During my PhD, I analyzed whole exome and whole genome sequencing data from liver tumors to understand the mutational processes remodeling these tumor genomes, their interaction with risk factors, cellular processes, and driver genes, and their evolution along the tumor histories. For that aim, I used existing statistical methods and I developed innovative computational tools to:- extract mutational and structural variant signatures from next-generation sequencing data- identify risk factors or genetic alterations underlying each process- predict the mutational process at the origin of each somatic mutation- explore correlations between mutation rates and cellular processes like replication and transcription- reconstruct the clonal history of a tumor and the timing of mutational processes and copy-number changes These innovative analytical strategies allowed me to identify 10 mutational signatures: 5 ubiquitous signatures operative in every liver cancer but modulated by risk factors (gender, alcohol, tobacco), and 5 sporadic signatures operative in <5% of HCC and associated with specific known (aflatoxin B1, aristolochic acid) or unknown mutational processes. I also identified 6 structural variant signatures, including striking duplicator or deletor phenotypes in rare tumors. Each mutational process showed a different relationship with replication and transcription. Signatures of bulky DNA adducts (polycyclic aromatic hydrocarbons, aflatoxin B1, aristolochic acid) strongly decreased in highly expressed genes due to transcription-coupled repair, whereas the alcohol-related signature 16 displayed a unique feature of transcription-coupled damage. A striking positive correlation between indel rate and gene expression was observed, leading to recurrent mutations in very highly expressed tissue-specific genes. Finally, reconstructing the clonal history of HCC revealed the evolution of mutational processes along tumor development and identified synchronous chromosome duplications as late events probably leading to fast tumor growth and clinical detection of the tumor. Together, these findings shed new light on the mechanisms generating DNA alterations along the natural history of liver cancers
Jaligot, Estelle. "Méthylation de l'ADN génomique et variations épigénétiques chez les végétaux : le cas de l'anomalie florale "mantled" chez le palmier à huile". Montpellier 2, 2003. http://www.theses.fr/2003MON20009.
Texto completoQuenez, Olivier. "Optimisation de la détection et de l'interpretation des variations génomiques issues de données d'exomes pour les études cas-contrôles". Electronic Thesis or Diss., Normandie, 2023. http://www.theses.fr/2023NORMR071.
Texto completoOver the past 20 years, the evolution of new technologies has revealed the great variability of ourgenome, from simple substitutions to chromosomal rearrangements. High-throughput sequencing hasparticularly improved the identification and interpretation of small variations, while offering theopportunity to explore structural variations with a higher resolution than that available with genome-wide microarray analyses. Nevertheless, the identification of structural variations and more specificallycopy number variations (CNVs) from capture sequencing data, has been under exploited and underevaluated. Our main objective was to develop a read depth based bioinformatics pipeline for CNVidentification, and then apply it to a case-control exome study in Alzheimer’s disease research.Alzheimer’s disease (AD) is the most common neurodegenerative disorder. Individual genetic factorsplay an important role in its determinism, and multiple risk factors have been identified, mainlysubstitutions and small insertions/deletions. However, structural variations have already beenidentified in monogenic forms of AD, such as complete duplication of APP gene. CNVs remain largelyunstudied in AD, we set out to apply a case-control approach using massive exome data to detect CNVscontributing to AD risk.As a first step, we established an analysis strategy based on CANOES software to detect CNVs fromNGS data derived from a capture (gene panels, exomes). This approach was validated using 2 largegene panels and exome datasets, compared with independent targeted techniques. In the first dataset(gene panels), sensitivity and specificity were 100%, and we obtained a sensitivity of 87.25% and apredictive positive value of 88.5% for CNV detection in whole exome sequencing data.We then applied this approach to whole exome data from the ADES (Alzheimer Disease ExomeSequencing) and ADSP (Alzheimer Disease Sequencing Project) consortia, grouping, after extensivequality control developed as part of this work, 22,094 samples divided between 4077 early onset cases,8458 late onset and 9559 controls. We developed transcript-level analyses and applied a statisticalmethod based on dosage applied on early onset cases and controls. We were able to identify severalpotential new risk factors, including the 22q11.21 regions, already implicated in neurodevelopmentaldisorders (p=3,8x10-4). In addition, we identified rare deletions in ABCA1 and ABCA7 genes, whoseloss-of-function variations have recently been identified as risk factors for AD, and carried out a jointanalysis of deletions and small loss-of-function variations.In conclusion, we have shown that CNV detection from exome data is reliable, and we have measuredits performance and limitations before applying it to a large dataset to identify new mechanismscontributing to the development of Alzheimer's disease
Lavenu, Audrey. "Modélisation et analyse de la co-circulation de virus grippaux : diffusion en population, variabilité génomique et impact clinique". Paris 6, 2004. http://www.theses.fr/2004PA066190.
Texto completoCumer, Tristan. "Etude des variants structuraux génomiques pour comprendre les processus démographiques et adaptatifs impliqués dans la domestication des petits ruminants". Thesis, Université Grenoble Alpes (ComUE), 2017. http://www.theses.fr/2017GREAV075/document.
Texto completoGenomic structural variations (SVs) account for a large part of the polymorphism between individuals, but their impacts on micro-evolutionary processes remain poorly known and large-scale studies are scarce.The first part of this manuscript is a bibliographic study of SVs in domestic animals. This part highlights the importance of SVs in modifying genes or their regulation, impacting a large number of traits selected during domestication and linked to productivity, morphology or behaviour.Based on the study of resequenced data from 500 whole genomes of wild and domestic small ruminants, the second part, targeting three SVs described in the bibliography, allowed (i) to refute the hypothesis of a link between the domestication of sheep and the amplification of endogenous protective copies of the JSRV retrovirus located in the 6q13 region, l, (ii) to identify duplications surrounding and affecting the ASIP gene that could be involved in the coat color changes related to the domestication of small ruminants, as well as (iii) highlight a potential adaptive role to arid climate of an haplotype of beta-globin locus in sheep.In the third part, we conducted a whole genome survey of SVs . Through the development of a SVs detection method and its application, we could detect about 50k and 20k SVs in Ovis and Capra. Of these SVs, 135 and 70 in Ovis and Capra, respectively, appear to be linked with domestication and affect genes involved in improvement, immunity, reproduction or survival. In addition, in Morocco, the distributions of 130 SVs for sheep and 35 SVs for goats covariate with environmental variables. Some of them affect genes involved in morphology, immunity and metabolism.This work highlights that many variants impacting genes might have been targeted during initial domestication and subsequent improvement steps or during the local adaptation of sheep and goats. It demonstrates the importance of considering structural variants in genomic studies to describe the genetic basis of domestication
Périchon, Naour Kim. "Etude de la contribution de CNVs (variations du nombre de copies de gènes) dans les formes sévères de toxidermies". Rouen, 2014. http://www.theses.fr/2014ROUES040.
Texto completoBrion, Christian. "Variations dans les réseaux de régulation chez une levure œnologique et impacts sur les propriétés fermentaires". Thesis, Montpellier, SupAgro, 2013. http://www.theses.fr/2013NSAM0001/document.
Texto completoSaccharomyces cerevisiae strains have a high phenotypic diversity, particularly in terms of fermentation properties among wine strains. The molecular bases underlying these behavior differences and the mechanisms of adaptation to the wine environment are still poorly known. Changes in gene expressions contribute to this phenotypic diversity. However, the regulatory networks and the genes involved are badly described. To address these questions, we developed an integrated “genetics-genomics” approach that combines QTL mapping in alcoholic fermentation and expression analysis of a recombinant population. The search for expression QTL allowed us to detect 1465 eQTL corresponding to local or distant regulations, several of them being grouped into hotspots. We highlighted that a duplication of a chromosomal segment is involved in the control of the fermentation kinetics. Our data showed that the expression disturbances are involved in many metabolic networks. We characterized more precisely the sources of expression variations affecting the detoxification systems, and showed that the changes in regulation of several membrane exporters are linked to mutations in transcription factors. We have also deciphered the variations controlling genes of the thiamine metabolism. We showed that an alteration of the sensor Thi3p tends to favor the expression of genes for the thiamine biosynthesis in wine strain at the expense of a gene encoding a pyruvate decarboxylase. This work allowed us to access some of the molecular bases responsible of the diversity and the strains adaptation to oenological conditions
Doan, Quoc Khanh. "Genetic and genomic variation of resistance to viral nervous necrosis in wild populations of european seabass (Dicentrachus labrax)". Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT094/document.
Texto completoEuropean seabass is one of the most economic species in aquaculture in Mediterranean areas. Viral nervous necrosis (VNN), a disease affecting at least 70 aquatic species, has become the most serious threat to seabass cultured industry. While numerous studies have been performed in order to control this disease, no simple and effective procedures are available. In this thesis, we question genetic variability and the potential of selective breeding as an opportunity to address thwart this threat.After a general introduction (first chapter) and a deep literature review of nodavirus in aquaculture (second chapter), we explore in the third chapter the genetic variability of resistance of different wild populations of European seabass, namely Northern Atlantic (NAT), Western Mediterranean (WEM), Northern-East Mediterranean (NEM) and Southern-East Mediterranean (SEM). To address this question, 2011 fish derived from a full-factorial mating scheme, where 9 WEM dams were crossed with 60 sires originated from NAT, WEM, NEM and SEM (15 sires per population), were reared in “common garden”. At 202 days, 1472 were challenged by nodavirus intraperitoneal injection at a mean body weight of 15.8 g. The rest of fish were kept in a single tank in order to collect performance traits. Strikingly, after pedigree recovery, we reveal a very strong and significant differentiation in VNN resistance among sires’ origin (ranging from 53 to 90%), offspring from East Mediterranean sires being the most resistant (83-90% of survival), offspring from WEM sires being intermediate (62% of survival) and offspring from NAT sires being the most sensitive (53% of survival only). A moderate liability heritability for VNN resistance (0.26±0.11) was estimated and negative correlations between resistance and production traits were shown.In the fourth chapter, a search of Quantitative Trait Loci (QTL) linked to the resistance was performed using a medium linkage map as examined. Therefore, 1717 individuals belonging 397 full-sib families and their parents were genotyped for 2722 SNP markers spotted on a SNPChip. From 1274 significant loci, a 24 linkage groups medium-density linkage map was constructed, as well as sex-specific and Origin-specific linkage maps. From these results, we show a 1.25-fold sex-biased heterochiasmy in favor to female recombination rate. Finally, genome scans for QTLs were performed in different methods, and while no QTLs were identified for both “time to death” or survival, we discuss the effect of the experimental design used.In the fifth chapter, a two-step unweighted then weighted Genome-Wide Association Study (GWAS & wGWAS) was carried out based on linear mixed models using the same SNPs as for QTL mapping. The aim was to determine whether we can detect significant individual SNPs linked to resistance against VNN. After SNPs weight calculation, the wGWAS detected one significant SNP explaining 3.11% of the resistance belonging to LG9. Finally, the potential for genomics prediction for VNN resistance using the different genomic models was performed and extensively presented. However, no significant differences were observed between genomic-based estimated breeding values and pedigree-based estimated breeding values.In conclusion, this study depicts a large genetic variation for VNN resistance in wild seabass populations but with negative genetic correlations with production traits. These latter results are valuable to help to define strategies for genetic improvement of resistance against VNN of European seabass. Moreover, the first assumptions on the location of potential QTLs claim for a fine QTL mapping and an expectable add-value of the use of genomic information in potential marker-assisted selection to VNN resistance in European seabass
Lessard, Marie-Hélène. "Découvrir les variations génomiques entre les souches de Lactococcus lactis ssp. cremoris par hybridation suppressive soustractive et par analyse de séquences multi-locus". Thesis, Université Laval, 2009. http://www.theses.ulaval.ca/2009/25996/25996.pdf.
Texto completoMir, Ashfaq Ali. "Variations structurales du génome et du transcriptome humains induites par les rétrotransposons LINE-1". Thesis, Nice, 2015. http://www.theses.fr/2015NICE4106.
Texto completoRetrotransposons are mobile genetics elements, which form almost half of our genome. Only the L1HS subfamily of the Long Interspersed Element-1 class (LINE-1 or L1) has retained the ability to jump autonomously in humans. Their mobilization in the germline – but also in some somatic tissues – contributes to human genetic diversity and to diseases, such as cancer. L1 reactivation can be directly mutagenic by disrupting genes or regulatory sequences. In addition, L1 sequences themselves contain many regulatory cis-elements. Thus, L1 insertions near a gene or within intronic sequences can also produce more subtle genic alterations. To explore L1-mediated genic alterations in a genome-wide manner, we have developed a dedicated RNA-seq analysis software able to identify L1 chimeric or antisense transcripts and to annotate these novel isoforms with their associated alternative splicing events. During the course of this work, it appeared that understanding the link between L1HS insertion polymorphisms and phenotype or disease requires a comprehensive view of the different L1HS copies present in a given individual or sample. To provide a comprehensive summary of L1HS insertion polymorphisms identified in healthy or pathological human samples and published in peer-reviewed journals, we developed euL1db, the European database of L1HS retrotransposon insertions in humans. This work will help understanding the overall impact of L1 insertions on gene expression, at a genome-wide scale
Redon, Sylvia. "Variations structurales du génome et pathologies humaines : recherche de nouveaux marqueurs génétiques impliqués dans les ischémies cérébrales du sujet jeune". Thesis, Brest, 2012. http://www.theses.fr/2012BRES0006.
Texto completoThe use of locus-specific array-CGH (Comparative Genomic Hybridization) has allowed us to detect largerearrangements in three pathologies of our laboratory: cystic fibrosis, chronic pancreatitis andhemochromatosis. We successfully observed new pathological CNV (Copy Number Variations) in theCFTR (Cystic Fibrosis Transmembrane conductance Regulator) gene and characterized complex eventsin PRSS1 (Protease Serine 1) and HFE (Hemochromatosis) genes, showing that the use of thistechnique is possible even in regions with high sequence homologies.We also confirmed that hypertension, migraine, tobacco and drugs are high significant risk factors forischemic strokes (IS) in young population (under 40 years) (OR=35, 3.8, 4 and 2.8, respectively). Then,we tried to identify new genetic susceptibility loci using a pangenomic approach. Among the 98 copynumber polymorphisms (CNP) observed, an interstitial NOTCH2 deletion is candidate for a protective rolein IS (OR=0.11 [0.01-0.87] ; p=0.013 before Bonferonni correction). We also observed approximately 400uncommon CNV, two of them being particularly reccurent in patients: a 22q13.31 duplication containingCRELD2 (cysteine-rich with EGF-like domains 2) and AGL12 (asparagine-linked glycosylation 12, alpha-1, 6-mannosyltransferase) genes (p=0.02) and a Xq28 deletion localised in the 5’ region of the VBP1 (vonHippel-Lindau binding protein 1) gene (p=0.04). We also applied a candidate-gene approach onNOTCH2, ALOX5AP (5-lipoxygenase activating protein) and coagulation genes (Factor II, Factor VLeiden and MTHFR). A significant association was found for the C677T in the MTHFR gene (5,10-methyltetrahydrofolate) and young ischemic strokes (OR=2.39, p=0.02 for TT genotype). In conclusion,this study confirmed the implication of environmental and genetic factors in ischemic strokes before 40years and suggests new genetic risk factors for IS
Mir, Ashfaq Ali. "Variations structurales du génome et du transcriptome humains induites par les rétrotransposons LINE-1". Electronic Thesis or Diss., Nice, 2015. http://theses.unice.fr/2015NICE4106.
Texto completoRetrotransposons are mobile genetics elements, which form almost half of our genome. Only the L1HS subfamily of the Long Interspersed Element-1 class (LINE-1 or L1) has retained the ability to jump autonomously in humans. Their mobilization in the germline – but also in some somatic tissues – contributes to human genetic diversity and to diseases, such as cancer. L1 reactivation can be directly mutagenic by disrupting genes or regulatory sequences. In addition, L1 sequences themselves contain many regulatory cis-elements. Thus, L1 insertions near a gene or within intronic sequences can also produce more subtle genic alterations. To explore L1-mediated genic alterations in a genome-wide manner, we have developed a dedicated RNA-seq analysis software able to identify L1 chimeric or antisense transcripts and to annotate these novel isoforms with their associated alternative splicing events. During the course of this work, it appeared that understanding the link between L1HS insertion polymorphisms and phenotype or disease requires a comprehensive view of the different L1HS copies present in a given individual or sample. To provide a comprehensive summary of L1HS insertion polymorphisms identified in healthy or pathological human samples and published in peer-reviewed journals, we developed euL1db, the European database of L1HS retrotransposon insertions in humans. This work will help understanding the overall impact of L1 insertions on gene expression, at a genome-wide scale
Malek, Joël. "Genetic alterations of the metastatic lesions in ovarian carcinoma". Thesis, Paris 11, 2011. http://www.theses.fr/2011PA11T109.
Texto completoOvarian cancer is the most deadly gynecological cancer. The high rate of mortality is due to the large tumor burden with extensive metastatic lesion of the abdominal cavity. There are few studies on genetic alterations and their consequences in peritoneal metastatic tumors when compared to their matched ovarian primary tumors. Our hypothesis is that differences between the metastatic and primary lesions might be the cause of residual disease and, most importantly may have a role in post-chemotherapeutic recurrences. Methods: We conducted integrated genomics analysis on matched primary and metastatic tumors from 9 patients. In the papers presented here we analyze genome-wide Copy Number Variations (CNVs) using SNP Arrays targeting peritoneal metastasis differences, Gene expression differences using Microarrays also targeting peritoneal metastasis differences, and for some patients, Single Nucleotide Polymorphisms (SNPs) in genes through Exome sequencing.Results: Here we show that CNVs vary significantly between primary and metastatic tumors and include genes that have been considered potential chemotherapeutic targets based on primary tumor only data. Gene expression differences, while minor, showed highly statistically significant enrichment of genes in ovarian cancer critical pathways. In agreement with findings in other cancers, exome sequencing data revealed very few SNP differences of which most metastasis enriched SNPs were present at very low levels in the primary tumor. The results presented here should allow better design of therapies to target residual ovarian cancer disease
Uddin, Md Mesbah. "Identification of causal factors for recessive lethals in dairy cattle with special focus on large chromosomal deletions". Thesis, Paris, Institut agronomique, vétérinaire et forestier de France, 2019. http://www.theses.fr/2019IAVF0018/document.
Texto completoThe overall aim of this PhD thesis is to identify causal variants for recessive lethal mutations and select a set of predictive markers that are in high linkage-disequilibrium with the causal variants for female fertility in dairy cattle. We addressed this broad aim under five articles: (i) describes a systematic approach of mapping recessive lethals in French Normande cattle using homozygous haplotype deficiency (HHD). This study shows the influence of sample size, quality of genotypes, quality of (genotype) phasing and imputation, age of haplotype (of interest), and last but not the least, multiple testing corrections, on discovery and replicability of HHD results. It also illustrates the importance of fine-mapping with pedigree and whole-genome sequence (WGS) data, (cross-species) integrative annotation to prioritize candidate mutation, and finally, large-scale genotyping of the candidate mutation, to validate or invalidate initial results. (ii) describes a high-resolution population-scale mapping of large chromosomal deletions from whole-genome sequences of 175 animals from three Nordic dairy breeds. This study employs three different approaches to validate identified deletions. Next, it describes population genetic properties and functional importance of these deletions. (iii) deals with three main issues related to imputation of structural variants, in this case, large chromosomal deletions, e.g. availability of deletion genotypes, size of haplotype reference panel, and finally, imputation itself. To address the first two issues, this study describes a Gaussian mixture model-based approach where read-depth data from the variant call format (VCF) file is used to genotype a known deletion locus, without the need for raw sequence (BAM) file. Finally, it presents a pipeline for joint imputation of WGS variants along with large chromosomal deletions. (iv) describes genome-wide association studies for female fertility in three Nordic dairy cattle breeds using imputed WGS variants including large chromosomal deletions. This study is based on the analyses of eight fertility related traits using single-marker association, conditional and joint analyses. This study illustrates that inflation in association test-statistics could be seen even after correcting for population stratification using (genomic) principal components, and relatedness among the samples using genomic relationship matrices; however, this was known for traits with strong polygenic effects, among other factors. Finally, mapping of several new quantitative trait loci (QTL), along with the previously known ones, are reported in this study. This study also highlights the importance of including (imputed) large deletions for association mapping of fertility traits. (v) describes prediction of genomic breeding values for fertility using SNP array-chip genotypes, selected QTL and large chromosomal deletion. Using genomic best linear unbiased prediction (GBLUP) method with one or several genomic-relationship matrices derived from a set of selected markers, this study reports higher prediction accuracy compared with previous report. This study also highlights the influence of selecting markers with best predictability, especially for a breed with small training population, in accuracy of genomic prediction. The results demonstrate that large deletions in general have a high predictive performance
L'Honneur, Anne-Sophie. "Implication des réarrangements génomiques du polyomavirus JC dans la leucoencéphalopathie multifocale progressive Exploring the role of NCCR variation on JC polyomavirus expression from dual reporter minicircles JCV whole genome analysis reveals hypervariability in PML patiients". Thesis, Sorbonne Paris Cité, 2019. http://www.theses.fr/2019USPCB007.
Texto completoJC Polyomavirus (JCV) is a ubiquitous human virus which causes asymptomatic persistent infections, and occasional urine shedding. In immune depression conditions, JCV causes a fatal disease, progressive multifocal leukoencephalopathy (PML), by infecting oligodendroglial cells of the central nervous system (CNS). The JCV double-stranded circular 5 kb genome is composed of two opposite coding regions - early and late - transcribed from opposite strands of DNA, and separated by the regulator non-coding control region (NCCR). The hallmark of NCCR prototype sequences recovered from PML brain lesions is the presence of rearrangements (rr) of unknown function, compared with urine archetype (at) NCCR sequences. To analyse the effects of such mutations on early and late expression in tissue-specific cultured cells, we produced bidirectional reporter vectors expressing two distinct fluorescent reporters under control of either rr or at JCV NCCR. We adapted the technology involving DNA circles devoid of bacterial plasmid backbone and generated four expression vector maxicircles, to investigate the effects of a single 66 bp deletion differentiating rr and at NCCR. After transfection of U-87MG (human glioblastoma cell line) and HEK293 (human kidney cell line), fluorescent reporter expressions from at and rr NCCR were analysed by cytometry analysis. In HEK293 cells, early and late expressions from at NCCR were similar, whereas in U-87 MG cells, early expression was 2.1-fold higher than late expression (p <0.001, Welch's t-test). This suggests that late expression from at NCCR is impaired in this glioblastoma cell line. Interestingly, late expression from mutated rr NCCR was similar to early expression in both HEK293 and U-87 MG cells, indicating that the 66 bp deletion restored late expression in the glioblastoma cell line. By using this in vitro model, we evidenced a relevant link between JCV NCCR sequence and cell-type dependent expression. In addition to the inter-compartment variability within patients, we further investigated the previously reported intra-compartment variability. By using a single-molecule real-time (SMRT) sequencing technology (PacBio, Pacific Biosciences) in order to obtain 3 kb amplicon sequences in a single read, we analysed precisely the JCV genomic populations in 23 cerebrospinal fluid (CSF), 1 cerebral biopsy (CB) and 19 urine samples of PML patients and 5 urine samples from non PML patients. JCV full-length genome was amplified in 2 overlapping opposite fragments, each encompassing the NCCR and either the early or the late coding sequence. Phylogenetic analysis revealed distribution of PML strains among 6 distinct genotypes, suggesting absence of specific pathogenic JCV genotype. PML JCV NCCR from cerebral samples displayed various deletions affecting mainly b, d and f sections and insertions of duplicated c and e sections. In 18/23 cerebral samples, intra compartment variability consisted in detection of at least two JCV variants and suggested a chronological emergence relationship between the two rearranged forms. In VP1, previously reported aminoacid substitutions at 7 distinct positions of sialic acid binding regions and antigenic epitopes were observed exclusively in cerebral strains. Apart single nucleotide polymorphisms evidenced over the whole viral genome, we observed, in two distinct PML CSF strains, two novel missense mutations, located in the helicase domain of LTAg sequence (Tyr407Asn) and in the N terminal domain of VP2 coding gene (Pro65Ala) respectively. These mutations could play a role in PML pathogenesis by modifying viral and/or cellular replication and transcription, by changing viral particle conformational structure and by immune response escape. This work supports the role of JCV NCCR rearrangements in PML neuropathogenesis and provides further insights in the genesis of neurotropic strains in PML lesions
Cortijo, Sandra. "Etude des variations épigénétiques liées aux séquences répétées comme source de changements phénotypiques héritables chez Arabidopsis thaliana". Phd thesis, Université Paris Sud - Paris XI, 2012. http://tel.archives-ouvertes.fr/tel-00742834.
Texto completoChateigner, Aurélien. "Influence de l'environnement sur l'évolution des génomes de virus". Thesis, Tours, 2014. http://www.theses.fr/2014TOUR4020.
Texto completoThe purpose of this thesis was to study the influence of the environment on the evolution of baculovirus genomes. We first genetically characterised the AcMNPV natural population by high-throughput sequencing and established the susceptibility of 4 hosts to the virus by bioassays. Then, the AcMNPV natural population was subjected to experimental evolution on the 4 host species for 10 cycles. The 10th generation of the evolved viral lines were then phenotypically and genotypically characterised. This experiment showed a virulence trade-off for each line: to increase their virulence to the host on which they evolved, the lines have lost generalist adaptive potential. Furthermore, intra-population diversity decreased for all the lines regardless of host susceptibility. Lastly, by correlating all these results we found specific genome positions involved in host adaptation
Leconte, Jade. "Analyses de variations génomiques liées à la biogéographie des picoalgues Mamiellales Survey of the green picoalga Bathycoccus genomes in the global ocean Genome Resolved Biogeography of Mamiellales Genomic evidence for global ocean plankton biogeography shaped by large-scale current systems Single-cell genomics of multiple uncultured stramenopiles reveals underestimated functional diversity across oceans". Thesis, université Paris-Saclay, 2020. https://www.biblio.univ-evry.fr/theses/2020/interne/2020UPASE013.pdf.
Texto completoMamiellales are an order of unicellular cosmopolitan green algae with ecologically important species such as Bathycoccus, Micromonas or Ostreococcus, major contributors to the primary production. This thesis uses this phytoplankton group with known reference genomes as a study model in order to better analyze the impact of the environment on plankton using samples from the Tara Oceans expedition.To do this, different analyses were carried out to define their biogeography and ecological preferences, first in temperate waters then in the cold, nutrient-rich waters of the Arctic Ocean. In both cases, temperature was shown to be the main factor distinguishing the environment in which the different genomes were found. We then carried out a more detailed study in particular on Bathycoccus prasinos, a species abundant in these two distinct environments, in order to establish its population structure, which proved to be clearly separated into three groups: southern , arctic and temperate samples, again showing an impact of temperature but not only in view of the genomic distance between the first two basins.Finally, our study was extended with various collaborations, allowing us to observe a group of heterotrophic protists, the stramenopiles, and to perform analyses at the much larger scale of communities. All of these results conclude once again, among other things, on the strong impact of temperature, leading us to contribute to the question about the current context of climate change and its impact on plankton
Mayrand, Paul. "Influence des expansions de territoire sur la capacité des approches en génomique du paysage d’identifier les gènes adaptatifs". Thèse, 2017. http://hdl.handle.net/1866/19132.
Texto completoUnder the actual climate changes and human perturbations global context, many species are altering their geographic range. The identification of putatively adaptive loci in those expanding populations is thus important to better understand evolutionary potential and invasiveness of these species. However, in irruptive species undergoing rapid expansion, such as the mountain pine beetle (MPB), demographic processes such as allele surfing can result in spatial patterns of neutral genetic variation that can mimic those that result from adaptive processes. This phenomenon inflates the false discovery rate of adaptive loci and thus confounds landscape genomics methods. In this thesis, I studied the development of neutral and adaptive genetic structure during a range expansion. I investigated precisely how different demographic conditions influence the rate of neutral loci mimicking the spatial patterns of adaptive loci, doing a literature review and using the mountain pine beetle outbreak system to parametrize a simulation model. I simulated the demographic and population genetic dynamics of mountain pine beetle populations undergoing range expansion using the spatially explicit, individual-based genetic model CDmetaPOP. I examined the consequences of three factors on the false discovery rate: 1) species dispersal capacity; 2) timing of sampling during the course of the expansion; and 3) the strength of selection on adaptive reference loci. I found that a combination of weak dispersal capacity, weak selection, and early sampling during expansion results in the highest rate of false positive, while strong dispersal was responsible for lower rates of false positive. Used under these conditions of dispersal capacity, strength of selection and sampling timing, landscape genomics models risk elevated false discovery rates of adaptive loci and must be interpreted cautiously. Complex demography in the current MPB system (and other irruptive and invasive species) makes identification of adaptive loci challenging. Results from this project clearly demonstrate that there is a need for further method development to include these directional demographic processes in the field of landscape genomics.
Quinlan, Jacklyn. "Genomic architecture of sickle cell disease clinical variation in children from West Africa : a case-control study design". Thèse, 2013. http://hdl.handle.net/1866/11255.
Texto completoBackground: Sickle Cell Disease (SCD) is an important public health issue, particularly in Africa. Phenotypic heterogeneity of SCD is problematic for follow-up and treatment of patients. Little is known about the underlying genomic architecture responsible for this variation. Rationale: Understanding the genetic contribution to the inter-patient variability will help in identifying patients at risk of developing more severe clinical outcomes, as well as help guide future developments for treatment options. Objectives: To characterize genome-wide gene expression patterns associated with SCD clinical severities and to identify genetic regulators of this variation. More specifically, our objectives were to associate gene expression profiles with SCD severity, identify transciptional biomarkers, characterise the genetic control of gene expression variation, and propose drug targets. Methods: A case-control population of 250 SCD patients and 61 unaffected siblings from the National SCD Center in Benin were recruited. Genome-wide gene expression profiles and genotypic data were generated. Results: Genome-wide gene expression patterns associated with SCD clinical variation were enriched in B-lymphocyte development, platelet activation, stress, inflammation and cell proliferation pathways. Transcriptional biomarkers that can discriminate SCD patients with respect to clinical severities were identified. Hundreds of genetic regulators were significantly associated with gene expression variation and potential drug targets are suggested. Conclusion: This work improves our understanding of the biological basis of SCD clinical variation and has the potential to guide development of targeted treatments for SCD patients.
Champagne, Marie-Claude. "Mise au point de techniques moléculaires pour l'étude de l'interaction de Lrp avec la région régulatrice de l'opéron fimbriaire foo (F165₁SBF₎". Thèse, 2006. http://hdl.handle.net/1866/17526.
Texto completoLemieux, Perreault Louis-Philippe. "Approches bio-informatiques appliquées aux technologies émergentes en génomique". Thèse, 2014. http://hdl.handle.net/1866/10884.
Texto completoGenetic studies, such as linkage and association studies, have contributed greatly to a better understanding of the etiology of several diseases. Nonetheless, despite the tens of thousands of genetic studies performed to date, a large part of the heritability of diseases and traits remains unexplained. The last decade experienced unprecedented progress in genomics. For example, the use of microarrays for high-density comparative genomic hybridization has demonstrated the existence of large-scale copy number variations and polymorphisms. These are now detectable using DNA microarray or high-throughput sequencing. In addition, high-throughput sequencing has shown that the majority of variations in the exome are rare or unique to the individual. This has led to the design of a new type of DNA microarray that is enriched for rare variants that can be quickly and inexpensively genotyped in high throughput capacity. In this context, the general objective of this thesis is the development of methodological approaches and bioinformatics tools for the detection at the highest quality standards of copy number polymorphisms and rare single nucleotide variations. It is expected that by doing so, more of the missing heritability of complex traits can then be accounted for, contributing to the advancement of knowledge of the etiology of diseases. We have developed an algorithm for the partition of copy number polymorphisms, making it feasible to use these structural changes in genetic linkage studies with family data. We have also conducted an extensive study in collaboration with the Wellcome Trust Centre for Human Genetics of the University of Oxford to characterize rare copy number definition metrics and their impact on study results with unrelated individuals. We have conducted a thorough comparison of the performance of genotyping algorithms when used with a new DNA microarray composed of a majority of very rare genetic variants. Finally, we have developed a bioinformatics tool for the fast and efficient processing of genetic data to increase quality, reproducibility of results and to reduce spurious associations.
Mhamdi, Zeineb. "Variations génomiques et antigéniques du virus de la grippe porcine (Influenzavirus porcin) sur le territoire québécois". Thèse, 2016. http://hdl.handle.net/1866/18651.
Texto completoData about genomic variability of swine influenza A viruses (SIV) in Quebec herds are scarce. Yet, this information is important for understanding virus evolution in Quebec from until 2015. Different clinical samples were obtained from 24 outbreaks of swine flu in which animals were experiencing respiratory disease. Samples including lung tissues, saliva and nasal swabs were collected and virus isolation was attempted in MDCK cells and embryonated eggs. All eight gene segments of the 18 isolated SIV strains were sequenced and analysed. Antiviral drugs resistance against oseltamivir carboxylate (GS4071), zanamivir (GS167) and amantadine hydrochloride was evaluated by neuraminidase inhibition assays (NAIs) and plaque reduction assay. Two subtypes of SIV, H3N2 and H1N1, were identified in Quebec pig herds. Twelve SIV strains were genetically related to trH3N2 Cluster IV and at least 6 different reassortment profiles were identified. On the other hand, 6 Quebec SIV strains were found to be genetically related to the pandemic virus A(H1N1)pdm09 and from which three reassortment profiles were identified. Overall, the trH3N2 was the most prevalent subtype (66.7%) found in Quebec swine herds. The epitope mapping of HA indicated that the H3 subtype was the most variable with a possibility of 21 amino acids (aa) substitutions within the 5 antigenic sites A(5), B(8), C(5), D(1) and E(2). However, the HA protein of the H1 subtype had only 5 aa substitutions within 3 antigenic sites Sb(1), Ca1(2) and Ca2(2). One H1N1 (1/6 = 16.7%) and one trH3N2 (1/12 = 8.3%) were identified as strains resistant against oseltamivir. In contrast, two H1N1 (2/6 = 33.3%) and two trH3N2 (2/12 = 16.7%) strains were found to be resistant against zanamivir. Overall, the SIV resistance against antiviral neuraminidase inhibitor drugs was (33.3%). All strains were resistant against the M2 inhibitor antiviral drug, amantadine. The presence of antiviral drug resistance in Quebec swine herds and the possible emergence of new SIVs strains are public health concerns supporting the surveillance of SIVs.
D'Amours, Guylaine. "Évaluation du caryotype moléculaire en tant qu’outil diagnostique chez les enfants avec déficience intellectuelle et/ou malformations congénitales". Thèse, 2013. http://hdl.handle.net/1866/10255.
Texto completoMolecular karyotyping identifies a CNV in 10-14% of individuals affected with intellectual disability and/or congenital abnormalities. Therefore, it is now the first-tier analysis for these patients. However, the diagnostic yield is not as clear in the prenatal context, and the risk of pregnancy termination makes the detection of variants of uncertain clinical significance particularly problematic. We tested 49 fetuses with major malformations and a normal karyotype, using a pangenomic CGH array, and obtained a diagnosis in 8.2% of cases. Furthermore, high-resolution microarrays combining molecular karyotyping and SNP genotyping were recently introduced on the market. In addition to identifying CNVs, these platforms detect LOHs, which can indicate the presence of a homozygous mutation or of uniparental disomy. Since these abnormalities can be associated with intellectual disability or congenital abnormalities, their detection is of particular interest for patients whose phenotype remains unexplained. However, the diagnostic yield obtained with these platforms is not confirmed, and the real clinical value of LOH detection is not yet established. We tested 21 children affected with intellectual disability for whom standard genetic analyses failed to provide a diagnosis, and were able to increase the diagnostic yield from 14.3% to 28.6% as a result of the information provided by LOHs. This study shows the clinical usefulness of pangenomic CGH arrays in fetuses with malformation(s), as well as that of SNP arrays in children with intellectual disability.
Girard, Simon L. "Étude sur le rôle des déséquilibres génomiques dans le Syndrome d’Impatiences Musculaires de l’Éveil". Thèse, 2010. http://hdl.handle.net/1866/4115.
Texto completoRestless Legs syndrome (RLS) is a neurological disorder characterized by the urge to move one’s limbs. It is also one of the most frequent causes of insomnia. The prevalence of RLS is estimated to be around 15% in the general population. Complexes disorders like RLS are often the result of the evolution of genetic and environmental components. For RLS, recent Genome Wide Association Study (GWAS) have identified four variants with mild to moderate effects. However, those four variants explain only a small part of the disease heritability and thus, we expect that many new variants are still to be found. The impact of Copy-Number Variation (CNV) in the genetic mechanism of RLS is still unknown. However, many studies have recently position the CNVs as a significant source of genetic variation potentially responsible of phenotypes. In collaboration with a team from Munich, we conducted two genome-wide CNVs studies (Genome Wide SNP chips and Comparative Genomic Hybridization (CGH)) on RLS patients from Germany. Using cases-controls studies, we identified regions with a different occurrence of CNVs for RLS patients, compared to different groups of controls. One of these regions is particularly interesting, as it has already been identified by both linkage and association studies.
"Découvrir les variations génomiques entre les souches de Lactococcus lactis ssp. cremoris par hybridation suppressive soustractive et par analyse de séquences multi-locus". Thesis, Université Laval, 2009. http://www.theses.ulaval.ca/2009/25996/25996.pdf.
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