Dissertationen zum Thema „Anomalies génétiques en mosaïque“
Geben Sie eine Quelle nach APA, MLA, Chicago, Harvard und anderen Zitierweisen an
Machen Sie sich mit Top-30 Dissertationen für die Forschung zum Thema "Anomalies génétiques en mosaïque" bekannt.
Neben jedem Werk im Literaturverzeichnis ist die Option "Zur Bibliographie hinzufügen" verfügbar. Nutzen Sie sie, wird Ihre bibliographische Angabe des gewählten Werkes nach der nötigen Zitierweise (APA, MLA, Harvard, Chicago, Vancouver usw.) automatisch gestaltet.
Sie können auch den vollen Text der wissenschaftlichen Publikation im PDF-Format herunterladen und eine Online-Annotation der Arbeit lesen, wenn die relevanten Parameter in den Metadaten verfügbar sind.
Sehen Sie die Dissertationen für verschiedene Spezialgebieten durch und erstellen Sie Ihre Bibliographie auf korrekte Weise.
Engel, Camille. „Description phénotypique de formes rares de trouble du développement intellectuel et caractérisation des mécanismes moléculaires impliqués“. Electronic Thesis or Diss., Bourgogne Franche-Comté, 2024. http://www.theses.fr/2024UBFCE006.
Der volle Inhalt der QuelleThe advent of new sequencing techniques has dramatically increased the diagnostic rate of intellectual disability (ID), and more than 2,000 genes are currently known to be involved. Despite these considerable progresses, interpreting the variants identified by sequencing methods remains challenging, and the natural history of newly described ID is often poorly understood. To better understand these disorders and their underlying mechanisms, we have studied four rare forms of ID with various inheritance patterns from both clinical and genetic perspectives. On one hand, we defined the clinical pictures associated with variations in BRAT1, CNOT3 and MTOR, and we investigated the existence of any phenotype-genotype correlations. On the other hand, we contributed to the design of a functional test to reclassify PQBP1 variants of uncertain significance
Sorlin, Arthur. „Caractérisation génomique des anomalies de la pigmentation cutanée en mosaïque“. Thesis, Bourgogne Franche-Comté, 2019. http://www.theses.fr/2019UBFCI011.
Der volle Inhalt der QuelleIntroduction: Mosaic cutaneous dyschromia is strongly evocative of an underlying genetic mosaicism. These post-zygotic events are challenging for conventional diagnostic tools. Thus, genetic basis of mosaic cutaneous dyschromia still remained poorly understood. Materials and Methods: The M.U.S.T.A.R.D. cohort gathers DNA from skin biopsies of patients with mosaic cutaneous dyschromia. After a specialised phenotype analysis, they are referred to either trio exome sequencing (ES) at 200X, or targeted ultra-deep sequencing (60,000X) of candidate genes. Data are analysed with a tailored pipeline, allowing detection of both low-rate nucleotidic variations or chromosomal events. Results: From 2013 to 2019, 101 patients were included. ES was performed for 56, with identification of mosaic SNV in 12 patients in 7 new genes, including 4 new genes (RHOA, DOCK1, GNA13, TFE3), and mosaic chromosomal anomalies in 17 patients. A targeted sequencing of these genes was performed for 40 more patients, with a confirmed mosaic SNV in 17, and a global diagnostic yield of 55% (46/84). Conclusion: This work highlights the importance of a versatile bioinformatic approach combined to a clinical expertise, to decipher the chromosomal and molecular aetiologies of developmental anomalies with mosaic cutaneous dyschromia. It also pinpoints the role of the Rho GTPase pathway, which will help enhancing our understanding of mosaic cutaneous dyschromia, and may ultimately result in better patients’ care
Montjean, Debbie. „Anomalies génétiques et épigénétiques associées à l'infertilité masculine“. Paris 6, 2011. http://www.theses.fr/2011PA066724.
Der volle Inhalt der QuelleDuchesne-Collardot, Amandine. „Approche moléculaire des anomalies génétiques chez les ruminants“. Versailles-St Quentin en Yvelines, 2006. http://www.theses.fr/2006VERS0031.
Der volle Inhalt der QuelleLa présente étude traite de quatre approches moléculaires pour l'étude des anomalies génétiques présentes en race bovine: la pathologie comparée combinée à la cartographie comparée, lorsque les pedigrees à disposition ne sont pas assez informatifs, le balayage du génome à l'aide de marqueurs génétiques afin d'obtenir une primolocalisation de l'anomalie, la cartographie fine d'un intervalle déjà identifié, 4. La génomique fonctionnelle, afin de réaliser le profil d'expression d'une région génomique donnée. L'utilisation de ces méthodes sur quatre anomalies génétiques bovines (l'ataxie progressive et le Syndrome Arthrogrypose-Palais fendu en race Charolaise, le Syndrome d'Hypoplasie Généralisée Capréoliforme en race Montbéliarde et la syndactylie en race Holstein) ouvre de nouvelles perspectives, tant pour la filière bovine, avec la mise au point de tests de dépistage que pour l'étude du développement des membres des mammifères. Enfin, les nouvelles approches de génomique fonctionnelle permettent d'envisager à "avenir un renouveau dans l'étude des caractères génétiques des animaux domestiques, et en particulier des bovins
Thieblemont, Catherine. „Contribution à l'analyse des anomalies génétiques impliquées dans la lymphomagénèse“. Lyon 1, 2000. http://www.theses.fr/2000LYO1T051.
Der volle Inhalt der QuelleFerfouri, Fatma. „Anomalies génétiques et épigénétiques de l’ADN spermatique et infertilité masculine“. Versailles-St Quentin en Yvelines, 2012. http://www.theses.fr/2012VERS0054.
Der volle Inhalt der QuelleThe male infertility seems to increase for several decades. Infertility etiologies are multiple, but the genetic and epigenetic causes are important. Here, we tried to study, the abnormalities carried by spermatozoa and sometimes transmissible in the conceptus. This work contains three parts, in a first time, the infertility linked with abnomalities of constitutionel karyotype by studying the consequences for the chromosomal risk with the risk estimated on all spermatozoa, in a second time, the infertility, with normal constitutionel karyotype, where the genetic origin was sometimes demonstrated and sperm morphology altered with macrocephalic sperm, Globozoospermia and spermatozoa with large or small vacuoles and in fine, DNA methylation abnormalities in various azoospermic aetiologies. These approaches have a triple interest because, it estimate the risks for conceptus and advice patients care, guide the choice of spermatozoa to be injected in the oocyte
Trouillot-Vinciguerra, Christine. „Caractérisation des anomalies génétiques responsables de la thrombasthénie de Glanzmann“. Lyon 1, 1996. http://www.theses.fr/1996LYO1T076.
Der volle Inhalt der QuelleMasliah-Planchon, Julien. „Complexe SWI/SNF et cancer _ Altérations génétiques et anomalies métaboliques“. Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS112/document.
Der volle Inhalt der QuelleNearly 20 years ago, the demonstration of truncated bi-allelic mutations in the SMARCB1 gene in rhabdoid tumors established the first demonstration of alterations in the SWI/SNF chromatin remodeling complex in oncology. Since then, the advent of high-throughput molecular analysis techniques applied to oncology has shown that alterations in other genes of the SWI/SNF complex are present in a wide variety of cancers. Through the presentation of several types of SWI/SNF deficient tumors and our models of rhabdoid tumors, we show that the loss of SMARCB1 is associated with an increase of the serine biosynthesis pathway and the downstream metabolic pathways important for oncogenesis.These results could lead to a therapeutic option for rhabdoid tumors or, more generally, for other models of SWI/SNF-deficient tumors. Finally, the prospect of these metabolic changes with the epigenetic alterations observed in SWI / SNF deficient tumors may be relevant to continue to deepen our knowledge of these tumors
Croullebois, Marie-Laurence. „Bases chromosomiques et génétiques des anomalies observées dans les croisements intraspécifiques chez le Millet : Setaria italica (L.) P. B“. Paris 11, 1987. http://www.theses.fr/1987PA112100.
Der volle Inhalt der QuelleBen, Abdelali Raouf. „Détection des anomalies génétiques dans les LAL-T : de la biologie à la clinique“. Thesis, Paris 11, 2011. http://www.theses.fr/2011PA11T013.
Der volle Inhalt der QuelleT-cell acute lymphoblastic leukemia (T-ALL) are lymphoid neoplasms characterized by theproliferation of malignant T lymphoblasts arrested at early stages of maturation. Maturation arrest in TALLmirrors normal lymphopoiesis. Thus we have shown that the myeloid transcription factor CEBPA,expressed only in the most immature thymic precursors (ETP), is commonly repressed byhypermethylation in T-ALL with the exception of the most immature subset. It is now widely acceptedthat T-ALL is a “multi-hits” disease where the type A oncogenes affect the differentiation while type Boncogenes are involved in cell cycle regulation, self-renewal and T-cell commitment. The Notchsignaling pathway, crucial for T cell development, is constitutively activated by the occurrence ofmutations in NOTCH1 and /or FBXW7 (N / F) genes in approximately 60% of T-ALL. The prognosticvalue of these mutations is controversial. In our study, we showed that N/F mutations are morefrequently observed in T-ALL arrested at a cortical stage of maturation and confer a good prognosiswhich seems to be influenced by the therapeutic regimen. In this large cohort of T-ALL we could alsodetermine the frequency of the CALM-AF10 oncogenic abnormality. The latter is very common in TALLdeveloped from ETP wich are of very poor prognosis. We have shown that this is the presence ofCALM-AF10 which confers the poor prognosis in this subtype of T-ALL. Contrary to the litterature wedid not find any prognostic value associated with the overexpression of ERG and BAALC genes. Thestudy of genetic abnormalities in T-ALL provides a better understanding of oncogenesis and identifyabnormalities with prognostic value. The interest of this work is to assist clinicians for an efficienttherapeutic stratification to overcome the poor outcome of T-ALL patients
Mahboub-Roy, Yasmina. „Anomalies génétiques des cancers colorectaux et leur détermination en pratique médicale : étude de faisabilité“. Bordeaux 2, 1998. http://www.theses.fr/1998BOR2M012.
Der volle Inhalt der QuelleRodriguez, Rémy. „Caractérisation de déficits immunitaires humains associés à des anomalies génétiques de la voie PI3K“. Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCB102/document.
Der volle Inhalt der QuelleThe pathway p110 catalytic subunit of phosphatidylinositol-4,5-biphosphate 3-kinase (PI3K) is selectively expressed in leukocytes and has a central role in lymphocytes biology. Gain-of-function dominant germline mutations of PIK3CD (encoding p110 ) have been recently described in patients presenting a heterogeneous combined immunodeficiency associated with respiratory tract infections, lymphadenopathy and high EBV and/or CMV viremia. The heterogeneous clinical presentation suggests the existence of genetic or environmental modifying factors. In my thesis I report two new patients with different genetic defects causing CID. The first patient, born from a consanguineous family, presented a known gain-of- function mutation of PIK3CD. His clinical presentation was partially compatible with the already described patients. By whole exome sequencing, we identified a homozygous nonsense mutation in SEC14L2, a known regulator of PI3K pathway. We further analyzed the phenotype and functions of patient’s lymphocytes, and performed a transcriptome analysis to better characterize the implication of SEC14L2 mutation in the pathology. The second patient was born from consanguineous family and presented recurrent severe respiratory tract infections and a fatal Chronic Active EBV disease (CAEBV). By Whole Exome Sequencing, we identified a homozygous rare missense mutation in PIK3CD. 3D structure modelization showed that the mutated amino acid is located in p110 catalytic domain, in an evolutionarily conserved loop that interacts with alpha-helix of PI3K regulatory subunit p85a, which interaction is lost in mutated p110 . Phenotyping of patient’s circulating lymphocytes showed increased CD8+ T cells and reduced NK and CD4+ T cells. The mutation in PI3KCD resulted in impaired PI3K activity in vitro and in vivo. Moreover, patient’s T cells exhibited reduced activation-induced phosphorylation of AKT and p70-S6K, two indirect targets of p110 , that we restored by expressing wild type p110 . Patient’s T cells also showed a decreased induction of IFN- and TNF-↵ and an increased proliferation and calcium flux after TCR stimulation. By CRISPR CAS9 technology, we generated Jurkat T- cell lines expressing wild type or mutated PI3K. Jurkat cells expressing mutant PI3K showed decreased AKT phosphorylation and increased calcium flux and proliferation after TCR stimulation, confirming the implication of PIK3CD mutation in patient’s cells phenotype. Interestingly, we highlighted the existence of a balance between PI3K and PLC- 1 activity during T cell activation, that may be due to a competition for access to their shared substrate, the PIP2. Finally, we identified in our patient a second deleterious mutation in TNFRSF9 that is shared by his healthy sister, who also presented persistent EBV replication in blood, suggesting that this additional mutation may act as a modifying genetic factor. Taken together, the results presented in this thesis identified the first loss-of-function mutation in PIK3CD causing CID
Gouyer, Valérie. „Étude des anomalies génétiques du gène du rétinoblastome dans les carcinomes bronchiques in vivo“. Université Joseph Fourier (Grenoble ; 1971-2015), 1994. http://www.theses.fr/1994GRE10115.
Der volle Inhalt der QuelleHeide, Solveig. „Anomalies du corps calleux : exploration des causes génétiques, corrélations génotypes-phénotypes et applications en prénatal“. Electronic Thesis or Diss., Sorbonne université, 2023. http://www.theses.fr/2023SORUS443.
Der volle Inhalt der QuelleThe Developmental Anomaly of the Corpus Callosum (DACC) is the most common congenital brain malformation. The clinical spectrum associated with DACC is broad, ranging from normal development to varying degrees of intellectual developmental disorder (IDD). The known causes are predominantly genetic with significant heterogeneity, mostly associated with IDD. Causes of DACC with a favorable prognosis (i.e., without IDD) are rare and less studied. Currently, DACC is most often discovered during pregnancy, through second-trimester screening ultrasound. The primary concern at this point is fetal prognosis, which depends on the underlying etiology. A better understanding of the genetic factors involved in DACC plays a crucial role in diagnosis, genetic counseling, and prenatal information. Currently, highlighting diagnostic and prognostic factors is a major challenge in the field of fetal medicine. The main objectives of my thesis were, on the one hand, to identify new genes responsible for DACC, and on the other hand, to establish genotype-phenotype correlations for the identified genes to improve prognostic information, particularly in prenatal care. To address these objectives, the thesis work focused on three complementary axes, conducted in parallel. The first axis involved the description of a new DACC gene, identified through exome sequencing analysis in a cohort of over 500 patients with DACC, recruited over more than 10 years from the genetics departments of La Pitié Salpêtrière Hospital and the neuropediatrics department of Armand Trousseau Hospital. We identified a new gene responsible for DACC, associated with a favorable neurodevelopmental prognosis, ZEB1, a gene previously known to be involved in corneal dystrophy. Through collaboration, we reported clinical, genetic, and radiological data for 14 patients carrying a pathogenic variant in the ZEB1 gene. The second part of the work involved establishing genotype-phenotype correlations of already known genetic syndromes in DCCA, with a primary focus on the inversion duplication deletion of the short arm of chromosome 8 (invdupdel8p), the most common chromosomal anomaly in the cohort of patients with DACC and IDD. This work helped to refine the critical duplicated region in 8p23 responsible for DACC. We also analyzed data from a cohort of patients with a variant in the ARX gene, located on the X chromosome, well known in DCCA with IDD in boys but with less established phenotypes in females. Through a literature review and the description of 10 new female patients, we showed that 40% of women carrying an ARX variant had IDD or a developmental and epileptic encephalopathy. Among the female carriers who had brain imaging, 66% had DACC, although it was not predictive of the underlying neurodevelopmental phenotype. Finally, the third part focused on the application of this data in the context of prenatal diagnosis, with a feasibility study of exome sequencing in prenatal cases of fetal DACC. Conducted since 2018, this study showed a diagnostic yield of 25% with a median turnaround time of 21 days. Then, with the radiology team at Armand Trousseau Hospital, we conducted a radio-genetic correlation study on prenatal imaging, based on subcategories of DACC, showing that the identification of a pathogenic variant was more common in callosal dysplasia and when DACC was not isolated. This collective and personal work has thus improved knowledge about the genetic causes of DACC, increasing diagnostic efficiency, prognostic information, and significantly altering the management of couples in prenatal care
Gadji, Macoura. „Identification et impacts des anomalies génétiques dans la genèse, l'évolution clinique et le traitement des gliomes“. Thèse, Université de Sherbrooke, 2010. http://savoirs.usherbrooke.ca/handle/11143/4318.
Der volle Inhalt der QuelleFlamein, Florence. „Anomalies génétiques d'ABCA3 dans les détresses respiratoires néonatales sévères et les pathologies alvéolo-interstitielles de l'enfant“. Paris 6, 2011. http://www.theses.fr/2011PA066290.
Der volle Inhalt der QuelleMichot, Pauline. „Utilisation des séquences de génome complet pour l'identification de mutations délétères responsables d'anomalies génétiques récessives chez le bovin“. Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLA011/document.
Der volle Inhalt der QuelleThe reduced genetic size of cattle breeds leads to an increase in inbreeding of nearly 1% per generation and a strong genetic drift. This evolution favors regular emergence of recessive genetic abnormalities in dairy and beef cattle breeds. In France, the National Observatory of Bovine Anomalies (ONAB) was created with the aim to detect and control these new emergences. However, detection by the observatories implies a broad diffusion of the deleterious allele in the population and a phenotype with specific clinical features, allowing reporting to ONAB. Therefore the impact of genetic abnormalities is still largely underestimated. However, development of genotyping and genome sequencing technologies, coupled with all available information, makes possible effective detection of causal mutations. Thus, the aim of this thesis was to use all the available data (phenotypes, genotypes, sequences and functional annotations) to identify and validate deleterious mutations segregating in French dairy and beef cattle breeds. We used homozygosity mapping, and study of haplotypes with deficit in homozygous, two strategies boosted by using whole genome sequence (WGS) data. We also explored alternative reverse genetics strategies, based on data mining of French and 1000 bull genomes consortium WGS data.In these different studies, we identified the causal mutations associated with two described recessive syndromes: epidermolysis bullosa junctional in Charolais race (ITGB4, chr19: g.56488278_56493087del) and idiopathic epilepsy (MTCL1, chr24:g.41661691G>A) recently emerged in the Parthenaise breed. We also demonstrated a strong association between the embryonic lethal mutation MH1 and a polymorphism affecting the PFAS gene (chr19: g.28511199C> T ; p.R1205C) in Montbeliarde cattle. With reverse genetic strategies, we identified another mutation, which affects the CAD gene (chr11: g72399397, p.Y452C), likely responsible for embryonic mortality in Normande cattle, and a frameshift mutation in RP1 (chr14:g.23995411_23995412insA, p. R791KfsX13) responsible for progressive retinal degeneration segregating with a high frequency in the Normande breed but also in other European cattle breeds. These studies, still in progress, provide an inventory of potentially deleterious genetic variants, whose characterization could be explored in the future. At last, identification of mutations responsible for these genetic abnormalities provided or will provide diagnostic tests and allow efficient counter selection of these variants in French beef and dairy cattle populations
Chibon, Frédéric. „Étude des altérations génétiques des sarcomes indifférenciés : mise en relation des anomalies identifiées et de la différenciation tumorale“. Paris 7, 2002. http://www.theses.fr/2002PA077050.
Der volle Inhalt der QuelleFlavigny, Jeanne. „Anomalies génétiques de la cardiomyopathie hypertrophique familiale : de leur identification à l'analyse de leurs conséquences ex vivo et in vitro“. Paris 5, 2001. http://www.theses.fr/2001PA05CD01.
Der volle Inhalt der QuelleSchlegel, Nicole. „Anomalies génétiques de l'intégrine αIIbβ3 et thrombasthénie de Glanzmann : découverte et caractérisation d'une nouvelle mutation dans une population à risque“. Paris 6, 1995. http://www.theses.fr/1995PA066827.
Der volle Inhalt der QuelleGarret, Philippine. „Approches bioinformatiques innovantes pour l’analyse de données de séquençage à haut-débit appliquées à l’étude de pathologies génétiques rares avec anomalies du développement“. Thesis, Bourgogne Franche-Comté, 2020. http://www.theses.fr/2020UBFCK020.
Der volle Inhalt der QuelleIn the last years, the advent of exome sequencing (ES) in diagnosis and in research led to the identification of the genetic bases of many Mendelian disorders, allowing many diagnostic wavering cases to be solved. Nevertheless, ES data analysis only leads to the identification of pathogenic or likely pathogenic variants in 30 to 45 % of the undiagnosed cases. Indeed, some limits exist, both at clinical, molecular and bioinformatic levels. The constant evolution of the clinical knowledge, of the number of genes involved in human diseases, and of the clinical-biological correlations, has a significant impact on data analysis, leading to a progressive improvement in diagnostic research. Limits of the current technologies, especially not covered regions, exist, but have been significantly reduced in the recent years. Although genome sequencing will solve some undiagnosed cases, especially in case of non-coding or structural variants, there is still a lot of information to be extracted and analyzed from ES data. Finally, beyond SNV and CNV analyzes, other genetic events can be involved in rare disorders, requiring a bioinformatic development to optimize results.The aim of the project was therefore to improve bioinformatic approaches of ES data analysis in order to identify new molecular mechanisms involved in rare genetic disorders and reduce diagnostic wavering.Several strategies were established. The first one consisted in reanalysing ES data from 80 undiagnosed patients, who were sequenced by the Laboratoire CERBA (CIFRE thesis). It led to the identification of 2 new candidate genes involved in ID, especially OTUD7A gene (article 1). The second strategy was the development of a bioinformatic pipeline in order to extract mitochondrial DNA data from ES data. The mitochondrial genome is not targeted by exome capture kits but can be extracted from off-target data, giving the opportunity to analyze it from preexisting ES data. From the GAD exomes cohort of undiagnosed patients, 2 causal variations were identified in 2 individuals out of 928, affected with neuro-developmental disorder. It thus solved the diagnostic wavering in 0.2 % of patients without diagnosis (article 2). The third strategy consisted in the development of a bioinformatic pipeline to identify mobile elements insertion within ES data, with the expectation that about 0.03 % of the pathogenic variants originate from de novo mobile element insertion. From the GAD exomes cohort of 3322 undiagnosed patients, this step led to the identification of two Alu element insertions in FERMT1 and GRIN2B gene exons (article 3, in process).This PhD permitted to push out some ES limits. Other perspectives exist, and are explored by the GAD team, in connection with the European Solve-RD project
Zinn-Justin, Anne. „Développement de la méthode non paramétrique d'analyse de liaison génétique WPC pour la prise en compte de l'information héritée par descendance au niveau d'un ou plusieurs marqueurs génétiques : application à des données familiales concernant l'alcoolisme et la bilharziose“. Paris 11, 2000. http://www.theses.fr/2000PA11T024.
Der volle Inhalt der QuelleLinkage analysis methods search for a familial cotransmission between a phenotype and a genetic marker, in order to loccalize on a chromosornal region a gene influenc!ng the phenotype. The WPC ("Weighted Pairwise Correlation") model-free linkage analysis method, introduced par Commenges in 1994, can be applied to all kind of phenotypes, without any distributional assumption, and is especially suitable for the analysis of large pedigrees. We developed the WPC method to take into account several unlinked marker loci (multi-loci analysis) and to incorporate the ldentical By Descent (IBD) information in the calculation oftlie resemblance at a marker locus (two-point analysis) or in a chromosomal region (multipoint analysis). Simulation studies conducted under various genetic models showed that two-locus tests were more powerful than one-locus tests, and confirmed that the use of the WPC-IBD method leads to a large increase of power, especially in the situation of poorly informative markers. Use of multipoint information in the re-analysis of breast cancer data from the BCLC ("Breast Cancer Linkage Consortium") led to a substantial gain in power as compared to two-point analysis. The use of two-point and multipoint WPC-lBD methods for the analysis of COGA (''Collaborative Study on the Genetic of Alcoholism'') data confinned the involvement of chromosome 4q2l containing Alcohol Dehydrogcnase (ADH) genes in predisposition to alcoholism. Analysis of infection levels by Schistosoma mansoni in schistosomiasis in Brazilian data using WPC-IBD two-point and multipoint one-locus and two-locus methods showed linkage to three chromosomal regions (1p21-q23, 7q135-q36 and 6p21-q21 ), in addition to 5q31-33 where was mapped the SMI gene
Jourdain, Jeanlin. „Détection et caractérisation de variants génétiques affectant la fertilité ou la durée de gestation chez les bovins en valorisant des bases de données populationnelles“. Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPASB028.
Der volle Inhalt der QuelleAbstract: The ability of animals to reproduce is a key factor in herd management, leading to the induction of lactation and the birth of calves for the market or for replacement. Over the past 80 years, cattle fertility has declined sharply as a result of selection that has long focused on production traits. The aim of my thesis was to exploit the large French databases - consisting of 7 million births per year, traceability, and performance information on these animals, supplemented by 2 million genotypes on SNP arrays and the sequences of complete genome of 5,000 bulls - to identify loci influencing different aspects of male and female fertility and gestation length. By developing a mapping method based on the study of linkage disequilibrium between markers from different chromosomes in large families, 12 interchromosomal rearrangements were identified. They affect the fertility of carrier sires, their daughters and various fitness traits. Some twenty recessive loci have also been revealed by conducting case/control approaches on groups of animals with contrasting phenotypes, strongly impacting male or female fertility. Hundreds of thousands of matings between genotyped animals have made it possible to study the interactions of parental genomes on insemination outcomes, and to initiate studies on compatibility between animals. Finally, works on gestation length in 16 French breeds has added to our knowledge on the heritability and variability of this trait, and described the risks associated with selection for shorter gestations. All these results show that cattle can be used as a model for genetic research, thanks to the data routinely generated on the farm. They should also be used in genetic selection to improve animal fertility, a key factor in the sustainability of cattle farming
Mouka, Aurélie. „Analyse des variations du nombre de copies d'ADN dans une cohorte d'hommes infertiles et génération de modèles génétiques d’étude de la méiose à partir de cellules iPS de patients infertiles“. Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS300/document.
Der volle Inhalt der QuelleInfertility represents a major public health problem and concerns 10 to 15% of couples in the general population. A male factor is responsible for the infertility of the couple in about half of all cases. In approximately 30% of them, the etiology remains unexplained.The first working axis concerned the molecular study of a cohort of infertile patients (nonobstructiveazoospermia/ cryptozoospermia and disorder of the sex development or DSD) for whom analyses of standard karyotype and/or microdeletions of AZF regions were not able to explain the phenotype. The impact of copy number variations of DNA (CNVs) detected by comparative genomic hybridization (CGH-array) is poorly documented. A custom design 400K micoarray, genome-wide and enriched on a wide panel of 445 genes linked with infertility and DSD has been achieved. This array allowed the identification of 171 CNVs of interest.These results underline the potential of this design for diagnosis of male infertility. The second objective of this work was the in vitro modelisation of male infertility in a context of genetic abnormality. For that purpose, human induced pluripotent stem cells (hiPSCs) were generated from erythroblasts by means of not integrative Sendaï virus, in two patients carrying genetic abnormalities (complex chromosomal rearrangement and 46,XX-SRY negative karyotype associated with AMH gene mutation). Secondly, functionality of hiPSCs generated was tested by germ cells in vitro differentiation. Primordial germ cell (PGC) stage was successfully obtained. Cells expressed key PGC markers such as SOX17. The perspectives of this work will be to continuethe germinal differentiation towards more mature stages and so to be able studying the meiotic process in a context of genetic abnormality
Hamel, Ginette. „Amniocentèses et anomalies génétiques à l'hôpital de Chicoutimi“. Thèse, 1991. http://constellation.uqac.ca/1507/1/1466947.pdf.
Der volle Inhalt der QuelleLemay, Philippe. „Anomalies du tube neural : mieux comprendre les causes génétiques de cette pathologie complexe“. Thèse, 2017. http://hdl.handle.net/1866/20746.
Der volle Inhalt der QuelleArsenault, Marie-Pier. „Étude de facteurs génétiques prédictifs dans le neuroblastome, en particulier les anomalies du chromosmoe 14q“. Thèse, 2010. http://hdl.handle.net/1866/4867.
Der volle Inhalt der QuelleNeuroblastoma (NB) accounts for 8% of all childhood cancers and is characterized by its clinical heterogeneity. To evaluate its prognostic, many genetic markers are used: MYCN amplification, 1p deletion, 11q gain and 17q gain. Our goals were first to verify if fluorescence in situ hybridization (FISH) allows a complete analysis of these abnormalities and, second, using a global genomic analysis as single nucleotide polymorphism (SNP), to verify the concordance with FISH results and the prognostic potential of 14q abnormalities, especially these of AKT gene. We then established a FISH panel that has been applied on 16 unfixed tumors. After DNA isolation of 36 tumors, we made a genotypic analysis by SNP using « Affymetrix Genome-Wide Human SNP Array 6.0 » containing 945,826 nonpolymorphic probes and 906,000 polymorphic probes. Our results have demonstrated that FISH allows a complete evaluation of the NB’s important genetic abnormalities and that unbalanced abnormalities are detected very precisely by SNP. 14q abnormalities seem to be associated with clinical factors such as tumor grading and evolution, unlike AKT abnormalities. Analysis of 14q abnormalities revealed three genes of interest, MAX, BCL11B and GPHN, which should be analyzed on a larger sample. Thereby, FISH study seems appropriate to detect the NB’s classic genetic abnormalities, while those found in 14q represent potential therapeutic targets for this tumor.
Kharfallah, Fares. „Études génétiques moléculaires du gène de la polarité planaire SCRIBBLE1 chez les anomalies du tube neural“. Thèse, 2012. http://hdl.handle.net/1866/8761.
Der volle Inhalt der QuelleNeural tube defects (NTDs), including anencephaly and spina bifida, represent a group of very common birth defects in humans. These anomalies are caused by a partial or complete failure of neural tube closure during embryogenesis. NTDs have a multifactorial etiology involving environmental and genetic factors. The non-canonical signaling pathway Frizzled (Fz) / Dishevelled (Dvl) controls the planar cell polarity (PCP) and the morphogenetic process called convergent extension (CE) which is essential for gastrulation and neural tube closure. Importantly, mutations in genes of this pathway were strongly associated with NTDs in mice and humans. Scribble is a PCP gene that causes a severe NTD mouse Circletail. Scribble binds to another PCP protein, Stbm / Vang, and they cooperate together for the stability of the PCP pathway. Our study aims at investigating the role of SCRIBBLE1 in human NTDs by sequence analyses of its open reading frame and exon-intron junctions. The cohort included in this study consisted of 396 patients recruited at the Spina Bifida Centre of Gaslini Hospital in Genoa, Italy, and 83 patients recruited at the Spina Bifida Center of the Sainte Justine Hospital, Montreal, Canada. Patients were affected by several forms of NTDs. We identified nine non-synonymous and rare mutations in 10 patients: p.Asp93Ala (c. 435G>A), p.Gly145Arg (c. 278A>C), p.Gly263Ser (c. 786C>A), p.Gly469Ser (c. 1405G>A), p.Pro649His (c. 1946C>A), p.Gln808His (c. 2424G>T), p.Val1066Met (c. 3196G>A), p.Arg1150Gln (c. 3480G>A) and p.Thr1422Met (c. 4266C>T). Five of those mutations, p.Gly263Ser, p.Pro649His, p.Gln808His, p.Arg1150Gln, p.Thr1422Met, were absent in all controls analyzed and were predicted to be pathogenic using bioinformatics. Our study demonstrates that rare mutations in SCRIB1 could predispose to NTDs in a fraction of patients. The identification of genes that predispose to ATN will help us better understand the pathogenic mechanisms involved in these diseases.
Allache, Redouane. „Études génétiques moléculaires des gènes de la polarité planaire cellulaire dans les anomalies du tube neural chez l’Homme“. Thèse, 2014. http://hdl.handle.net/1866/12084.
Der volle Inhalt der QuelleNeural tube defects (NTDs) are among the most common congenital malformations in humans affecting 1–2 infants per 1000 births. NTDs are caused by failure of the neural tube to close during embryogenesis. The most common forms of NTDs in humans are anencephaly and spina bifida. Their etiology is complex implicating environmental and genetic factors. Wnt signaling has been classified as canonical Wnt/ β-catenin dependent or non-canonical planar cell polarity (PCP) pathway. Misregulation of either pathway is linked mainly to cancer or neural tube defects (NTDs) respectively. Both pathwaysseem to antagonize each other. In this study, we investigate the role of Lrp6andANKRD6 as molecular switches between both Wnt pathways as well as CELSR1 as PCP member, in a novel ENU mouse mutant of Lrp6 (Skax26m1Jus) and in human NTDs. For Lrp6, we demonstrate that Skax26m1Jus represents a hypermorphic allele of Lrp6 with increased Wnt canonical and abolished PCP-induced JNK activities. We also show that Lrp6Skax26m1Jusgenetically interacts with a PCP mutant (Vangl2Lp) where double heterozygotes showed an increased frequency of NTDs and defects in cochlear hair cells’ polarity. Importantly, our study also demonstrates the association of rare and novel missense mutations in LRP6 that is an inhibitor rather than an activator of the PCP pathway with human NTDs. We show that three LRP6 mutations in NTDs led to a reduced Wnt canonical activity and enhanced PCP signaling. For ANKRD6: We identified four rare missense mutations in 0.8% of the NTD patients and 2 rare missense mutations in 1.3% of the controls. Notably, when all 6 mutations were validated, only two mutations identified in NTD patients, p.Pro548Leu, p.Arg632His, significantly altered DIVERSIN activity in Wnt signaling assays in a hypomorphic fashion. For CELSR1: We identified one nonsense mutation in exon 1 of CELSR1 that truncates the majority of the protein in one NTD patient and one in-frame 12 bp deletion that removes a putative PKC phosphorylation“SSR” motif in one caudal agenesis patient. We also detected a total of 13 novel missense variants in 12 patients (11 NTDs and 1 caudal agenesis) that were predicted to be pathogenic in silico. Our data confirm an inhibitory role of Lrp6 in PCP signaling in neurulation and indicate that rare missense mutations in LRP6 and ANKRD6 could affect a balanced reciprocal and a highly dosage sensitive antagonism between both Wnt pathways in neurulation and act as predisposing factors to NTDs in a subset of patients. Also, our findings implicate CELSR1 as a risk factor for NTDs or caudal agenesis. Our findings provide additional evidence for a pathogenic role of PCP signaling in thesemalformations and an important tool for better understanding their molecular mechanisms.
Roy-Tourangeau, Mélanie. „Stratégie de détection des anomalies chromosomiques dans les leucémies aiguës pédiatriques“. Thèse, 2013. http://hdl.handle.net/1866/10571.
Der volle Inhalt der QuelleAnalysis of recurrent genomic abnormalities is important for the diagnosis, prognosis and therapeutic choices in paediatric acute leukemia. The aim of our study is to establish a strategy optimizing the detection of cytogenetic abnormalities in childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). To do so, we have characterized childhood AML and ALL cases received in cytogenetic laboratory of CHU Sainte-Justine (Montreal, Canada) between 2005 and 2011. Overall, 253 de novo cases have been analyzed (186 B-ALL, 27 T-ALL and 40 AML) by karyotyping, fluorescence in situ hybridization (FISH) panels, RT-PCR and DNA index. Chromosomal abnormalities detection rates achieved 93,5% in B-ALL (174/186), 66,7% in T-ALL (18/27) and 90% in AML (36/40). Our results suggest the analysis of both molecular and cytogenetic tests to optimize the detection of genomic abnormalities in new cases of childhood AML and ALL.