Le raisonnement conditionnel, fondé sur les énoncés de la forme Si P alors Q, est celui qui a reçu le plus d'attention de la part des psychologues. Les arguments principaux du raisonnement conditionnel, comme le Modus Ponens (MP), sont constitués de trois éléments : la prémisse majeure (Si P alors Q), la prémisse mineure (P) et la conclusion (Q). Ces éléments constituent trois étapes de traitement distinctes. Cependant, la dimension temporelle du raisonnement a été en partie négligée dans la littérature. L’objectif central de cette thèse a été d’explorer cette dimension temporelle à l’aide d’une approche novatrice combinant l’utilisation de la mesure du temps de lecture des prémisses, de l’Electroencéphalographie (EEG) et de la Magnétoencéphalographie (MEG). Nous nous sommes donné trois objectifs : 1) Déterminer la séquence des étapes de traitement élémentaire de l’argument MP ; 2) Déterminer comment l’incertitude d’un conditionnel thématique est prise en compte ; 3) Mettre en évidence les différences interindividuelles de traitement d’un énoncé conditionnel, basique ou thématique, en introduisant l’étude de l’argument AC qui permet de dissocier deux populations : les individus qui acceptent la conclusion de AC et les individus qui la rejettent.L’ensemble des données révèle que tous les individus ont une tendance à se focaliser davantage sur P que sur Q lors du traitement du conditionnel, avec des degrés variables selon les individus. Lorsque la prémisse P (ou Q pour les participants qui acceptent AC) est présentée, elle est intégrée à la prémisse majeure afin de générer une conclusion Q encodée et stockée en mémoire de travail avant d’être comparée avec la conclusion présentée.Lorsque le conditionnel est incertain (conditionnel thématique), cette incertitude sur la suffisance de P pour Q (ou de Q pour P) semble être prise en compte par les sujets au niveau de la prémisse majeure et se manifeste par une attente moins prononcée de la conclusion Q une fois que la prémisse P a été présentée. / The conditional reasoning, based on statements of the form If P then Q, is one which has received the most attention from psychologists. The main arguments of conditional reasoning, as the Modus Ponens (MP), consist of three elements: the major premise (If P then Q), the minor premise (P) and conclusion (Q). These elements constitute three separate processing steps. However, the temporal dimension of reasoning has been partly neglected in the literature. The central objective of this thesis was to explore the temporal dimension by using an innovative approach combining the use of the measurement of premises reading time and of the electroencephalography (EEG) and magnetoencephalography ( MEG). We set three objectives: 1) Determine the sequence of processing steps of the basic argument MP 2) Determine how the uncertainty of a conditional theme is taken into account, 3) Highlight the interindividual differences in treatment a conditional statement, or basic theme by introducing the study of the AC argument, which allows to separate two populations: individuals who accept the conclusion of AC and individuals who reject it. The data reveals that all individuals have a tendency to focus more on P and Q in the processing of the conditional, with varying degrees in different individuals. When the premise P (or Q for participants that accept AC) is presented, it is integrated with the major premise to generate a conclusion Q encoded and stored in working memory before being compared with the conclusions presented. When the conditional is uncertain (Thematic conditional), this uncertainty about the sufficiency of P for Q (or Q for P) seems to be taken into account by the subjects at the major premise and is manifested by an less pronounced expectation of Q conclusion when the premise P has been presented.

No description available.

Copy number Variants (CNVs), which comprise deletions, insertions and inversions of genomic sequence, are a main form of genetic variation between individual genomes. CNVs are commonly present in the genomes of human and other species. However, they have not been extensively characterized as their ascertainment is challenging. I reviewed current CNV studies and CNV discovery methods, especially the algorithms which infer CNVs from whole genome Single Nucleotide Polymorphism (SNP) arrays and compared the performance of three analytical tools in order to identify the best method of CNV identification. Then I applied this method to identify CNV events in three European population isolates—the island of Vis in Croatia, the islands of Orkney in Scotland and villages in the South Tyrol in Italy - from Illumina genome-wide array data with more than 300,000 SNPs. I analyzed and compared CNV features across these three populations, including CNV frequencies, genome distribution, gene content, segmental duplication overlap and GC content. With the pedigree information for each population, I investigated the inheritance and segregation of CNVs in families. I also looked at association between CNVs and quantitative traits measured in the study samples. CNVs were widely found in study samples and reference genomes. Discrepancies were found between sets of CNVs called by different analytical tools. I detected 4016 CNVs in 1964 individuals, out of a total of 2789 participants from the three population isolates, which clustered into 743 copy number variable regions (CNVRs). Features of these CVNRs, including frequency and distribution, were compared and were shown to differ significantly between the Orcadian, South Tyrolean and Dalmatian population samples. Consistent with the inference that this indicated population-specific CNVR identity and origin, it was also demonstrated that CNV variation within each population can be used to measure genetic relatedness. Finally, I discovered that individuals who had extreme values of some metabolic traits possessed rare CNVs which overlapped with known genes more often than in individuals with moderate trait values.

Large-scale genomics projects such as the Cancer Genome Atlas (TCGA), and the Encyclopedia of DNA Elements (ENCODE) involve generation of data at an unprecedented scale, requiring new computational techniques for analysis and interpretation. In the three studies I present in this thesis, I utilize these data sources to derive biological insights or created visualization tools that enable others to obtain insights more easily. First, I examine the distribution of the lengths for copy number variations (CNVs) in the cancer genome. This analysis shows that a small number of genes are altered at a greater frequency than expected from a power law distribution, suggesting that a large number of genomes must be sequenced for a given tumor type to a comprehensive discovery of somatic mutations. Second, I investigate germline CNVs in thousands of TCGA samples using single nucleotide polymorphism (SNP) array data to find variants that may confer increased susceptibility to cancer. This CNV-based genome-wide association study resulted in many germline CNVs that potentially increase risk in brain, breast, colorectal, renal, or ovarian cancers. Finally, I apply several visualization techniques to create tools for the TCGA and ENCODE projects in order to help investigators better process and synthesize meaning from large volume of data. Seqeyes combines linear and circular genomic views to explore predicted structural variations to help guide experimental validation. The modEncode browser visualizes chromatin organization by integrating data from a multitude of histone marks and chromosomal proteins. These results present visualization as a useful strategy for rapid identification of salient genomic features from large, heterogeneous genomic datasets.

Die Pierre-Robin-Sequenz ist eine angeborene kraniofaziale Fehlbildung, bei der häufig eine Triade von Symptomen, bestehend aus mandibulärer Mikrognathie/Retrognathie, Glossoptose und einer Gaumenspalte, beobachtet werden kann. Aufgrund der Heterogenität der PRS und der häufigen Vergesellschaftung mit Syndromen, konnten Ätiologie und Pathogenese der PRS bisher nur unzureichend geklärt werden. Für einen Teil der Patienten mit isolierter PRS konnte eine familiäre Häufung von PRS-Fällen nachgewiesen werden, was auf eine erbliche Komponente als krankheitsauslösenden Faktor hinweist. In diesem Zusammenhang konnten bei Patienten mit isolierter PRS gehäuft genetische Veränderungen mit einer Entfernung von über 1Mb zentromerisch (5´) von SOX9 auf dem Chromosom 17 detektiert werden. Es wird vermutet, dass diese genetischen Aberrationen am SOX9 Lokus eine gewebsspezifische Fehlregulation von SOX9 während der Embryonalentwicklung auslösen und somit ursächlich für die Entstehung von PRS sein können. Das Ziel dieser Arbeit war es, eine Würzburger Patientenkohorte mit isolierter PRS zu gewinnen und Informationen über die phänotypischen Merkmale der Studienteilnehmer auszuwerten. Im Anschluss sollte die Patienten-DNS mittels molekulargenetischen Analysemethoden auf potenziell krankheitsauslösende genetische Aberrationen am SOX9 Lokus untersucht werden. Zunächst konnte eine Kohorte mit sieben PRS-Patienten erstellt und Informationen über die phänotypischen Krankheitsmerkmale erfasst und ausgewertet werden. Anschließend wurden bei den Studienteilnehmern eine Array-CGH, eine quantitative Echtzeit-Polymerase-Kettenreaktion und im Bereich von drei konservierten, potenziell regulatorischen Elementen des SOX9 Lokus eine Sanger Sequenzierung durchgeführt. Die Array-CGH ergab zunächst bei einem Patienten zwei große Deletionen im regulativen Umfeld des SOX9 Lokus, welche im Weiteren nicht durch qPCR bestätigt werden konnten. Letztendlich konnten durch die Sanger Sequenzierung 22 Varianten detektiert werden, wovon für drei Einzelnukleotid-Polymorphismen eine prädisponierende Wirkung diskutierbar und für zwei Einzelnukleotid-Varianten eine ursächlich pathogene Wirkung nicht auszuschließen ist. / The Pierre-Robin-Sequence is a congenital craniofacial disorder mostly described as a triade of symptoms, consisting of mandibular micrognathia, glossoptosis and cleft palate. Due to its heterogenity, the aetiology and pathogenesis of PRS is not recognized in every case of the disease. Nevertheless familial accumulation in isolated PRS cases pointed to a possible genetic source of pathology. In this context, genetic analysis in patients with isolated PRS pointed to genetic variations far upstream (more than 1Mb) of the SOX9 gene on chromosome 17 as possibly disease-inducing. These genetic variations at the SOX9 lokus are supected to cause tissue specific misregulation of SOX9 during embryogenesis and thus can be seen as causal for the development of isolated PRS. The objective of this study was to form a group of patients with isolated PRS and to gain information about their phenotype. Subsequently, genetic analysis should be used to find potentially disease inducing genetic variations at the SOX9 lokus. A cohort of 7 patients with isolated PRS was formed and the phenotypes of these patients were registered and evaluated. In addition, array-CGH, real-time quantitative polymerase chain reaction and sanger sequencing was performed for all the participants of this study. Array-CGH resulted in two big deletions within the regulary domain of the SOX9 lokus, which could not be confirmed with qPCR. Eventually, sanger sequencing of three conserved, non coding elements at the SOX9 lokus showed 22 variants, of which three single-nucleotid polymorphisms could potentially prove to have a predisposing effect and two singlenucleotid-variants, for which a pathogenic effect cannot be ruled out.

No description available.

Familial Pancreatic Cancer (FPC) is an autosomal dominant condition with greater then 80% of genetic causes unknown. We hypothesize that an integrative approach employing germline exome sequencing and somatic microarray analysis of FFPE DNA will identify novel tumour suppressor genes (TSGs). 55 FPC and 21 sporadic PDAC tumours were analyzed on the Affymetrix Oncoscan FFPE Express 2.0 SNP microarray and compared to data from 33 germline FPC cases analyzed on the Illumina GAIIx Analyzer. We have demonstrated that FPC is genetically heterogeneous with recurrent loss at CDKN2A/p16, TP53 and SMAD4. Analysis of 2 sisters has shown a shared loss region involving DCLK3 and SERPINF1. By an integrative approach, we have identified ATPAF1-AS1 and MAP3K6 as potential TSGs. Germline variants of these genes have been confirmed by Sanger sequencing and somatic fluorescence in-situ hybridization. Future functional studies will better characterize the importance of these regions and novel putative TSGs in FPC.

Familial Pancreatic Cancer (FPC) is an autosomal dominant condition with greater then 80% of genetic causes unknown. We hypothesize that an integrative approach employing germline exome sequencing and somatic microarray analysis of FFPE DNA will identify novel tumour suppressor genes (TSGs). 55 FPC and 21 sporadic PDAC tumours were analyzed on the Affymetrix Oncoscan FFPE Express 2.0 SNP microarray and compared to data from 33 germline FPC cases analyzed on the Illumina GAIIx Analyzer. We have demonstrated that FPC is genetically heterogeneous with recurrent loss at CDKN2A/p16, TP53 and SMAD4. Analysis of 2 sisters has shown a shared loss region involving DCLK3 and SERPINF1. By an integrative approach, we have identified ATPAF1-AS1 and MAP3K6 as potential TSGs. Germline variants of these genes have been confirmed by Sanger sequencing and somatic fluorescence in-situ hybridization. Future functional studies will better characterize the importance of these regions and novel putative TSGs in FPC.

No description available.

Le macrosatellite RNU2 est constitué de répétitions en tandem d'une unité de 6,1 kb. Largement étudié pendant les années 1980 et 1990, il est maintenant oublié des études pan-génomiques du fait de son absence du génome de référence. J'ai dans un premier temps finement caractérisé ce macrosatellite, en réalisant un assemblage in silico de la région génomique, en développant un code-barres pour la technique de peignage moléculaire et en analysant les données du projet 1000 Génomes. J'ai ainsi validé la localisation du locus RNU2 124 kb en amont de BRCA1, et affiné les données de polymorphisme en montrant que le nombre allélique de copies pouvait varier entre 5 et 82 chez 42 individus. J'ai tiré profit de sa localisation au sein d'un large bloc de déséquilibre de liaison pour définir le taux de mutation de ce macrosatellite à l'origine du nombre important d'allèles identifiables au sein de la population générale. Compte tenu de sa proximité avec BRCA1 et de son fort taux de polymorphisme, j'ai étudié le nombre global de copies du CNV dans 2 cohortes de cas de cancer du sein et témoins associés. J'ai montré que le nombre global de copies est significativement plus élevé chez les cas que chez les témoins. Ce travail suggère que le nombre de copies du macrosatellite RNU2 pourrait être impliqué dans la prédisposition génétique au cancer du sein, impliquant ainsi pour la première fois un CNV dans un mécanisme d'inactivation d'un gène de prédisposition au cancer / The RNU2 macrosatellite is composed by tandem repeats of a 6.1 kb-long unit. Extensively studied during the 1980’s and the 1990’s, this locus is now omitted from genome-wide analysis as a result of its absence from the human reference genome. Firstly, I finely characterized this macrosatellite by performing an in silico assembly of this genomic region, by designing a barcode for the molecular combing technique and by analyzing the 1,000 Genomes data. I thus validated the localization of the RNU2 locus 124 kb upstream of BRCA1, and refined the polymorphism data by showing that the allelic copy number ranged from 5 to 82 in 42 individuals. I took advantage of its localization in a large disequilibrium block to determine the mutation rate of this macrosatellite, responsible for the high number of alleles found in the general population. Considering its close proximity to BRCA1 and its high level of polymorphism, I studied the global copy number in 2 cohorts of breast cancer cases and controls. I thus showed that the RNU2 global copy number is significantly higher in breast cancer cases than in controls. My work suggests that the RNU2 macrosatellite copy number could be involved in breast cancer genetic predisposition. This would provide the first example of one inactivating mechanism of a cancer predisposing gene by a macrosatellite