Parasitic protists of genera Trypanosoma and Leishmania are members of Trypanosomatidae family. In our studies, we investigated genetic influence on infections caused by these parasites in a mouse model. These diseases are on genetic level controlled by quantitative trait loci (QTLs), when the resulting phenotype is controlled by set of genes with small individual effect. As a mouse model for mapping of QTLs controlling these infections, we used recombinant congenic strains (RCS). Each RCS carry unique set of 12.5% of the genome from donor parental strain on genetic background of other parental strain. For mapping of QTLs controlling infections caused by Trypanosoma brucei brucei (T. b. brucei) and Leishmania tropica (L. tropica) and eosinophil infiltration into inguinal lymph nodes after Leishmania major (L. major) infection, we used RCS from CcS/Dem series, where STS is donor strain and BALB/cHeA is strain of genetic background. First, it was necessary to find suitable model strains for mapping. In all three studies, we selected RCS, which exceeded range of monitored phenotype parameters in comparison with any other tested RCS or parental strains. Mice of RCS CcS-11 showed shorter survival after T. b. brucei infection and strain CcS-9 exhibited higher eosinophil infiltration after L. major infection. For...

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BACKGROUND: Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with diseases of the colon including inflammatory bowel diseases (IBD) and colorectal cancer (CRC). However, the functional role of many of these SNPs is largely unknown and tissue-specific resources are lacking. Expression quantitative trait loci (eQTL) mapping identifies target genes of disease-associated SNPs. This study provides a comprehensive eQTL map of distal colonic samples obtained from 40 healthy African Americans and demonstrates their relevance for GWAS of colonic diseases. RESULTS: 8.4 million imputed SNPs were tested for their associations with 16,252 expression probes representing 12,363 unique genes. 1,941 significant cis-eQTL, corresponding to 122 independent signals, were identified at a false discovery rate (FDR) of 0.01. Overall, among colon cis-eQTL, there was significant enrichment for GWAS variants for IBD (Crohn's disease [CD] and ulcerative colitis [UC]) and CRC as well as type 2 diabetes and body mass index. ERAP2, ADCY3, INPP5E, UBA7, SFMBT1, NXPE1 and REXO2 were identified as target genes for IBD-associated variants. The CRC-associated eQTL rs3802842 was associated with the expression of C11orf93 (COLCA2). Enrichment of colon eQTL near transcription start sites and for active histone marks was demonstrated, and eQTL with high population differentiation were identified. CONCLUSIONS: Through the comprehensive study of eQTL in the human colon, this study identified novel target genes for IBD- and CRC-associated genetic variants. Moreover, bioinformatic characterization of colon eQTL provides a tissue-specific tool to improve understanding of biological differences in diseases between different ethnic groups.

Female reproductive performance is a critical component of sustainable pig production systems. There is abundant evidence of genetic variation in these traits among pig breeds. The aims of this study were to identify quantitative trait loci (QTL) affecting reproductive traits and to identify and characterise positional candidate gene(s) underlying the QTL. A Large White - Meishan F2 population was scanned for QTL with effects on reproductive traits. This analysis revealed 13 putative QTLs on seven different chromosomes with effects on five different traits: ovulation rate (OR), teat number (TN), prenatal survival (PS), total born alive (TBA) and litter size (LS). QTL for PS and LS on chromosome 8 were fine mapped and Secreted Phosphoprotein 1 (SPP1) confirmed as a candidate gene. A genome-wide association study was performed on a diverse population of different breeds and crosses lines, for reproductive traits including LS, TBA, number of stillborn piglets, and number of mummified piglets. Fourteen SNPs were found significantly associated with reproductive traits. The functional study of SPP1 examined the hypothesis that differences in foetal growth may be associated with the effectiveness of conceptus attachment, as measured by SPP1 expression. Patterns of SPP1 mRNA and protein expression in placental and uterine tissues supplying the smallest and a normal-sized foetus from the same uterus were examined in Large White-Landrace (LW-LR), Large White (LW) and Meishan (MS) females 40 and 45 of pregnancy. The smallest LW-LR foetuses tended to have a higher level of SPP1 mRNA in endometrium tissue compared to the normal-sized foetuses. However, placenta expression was higher in the normal-sized foetuses compared to the smallest ones. SPP1 protein levels in normal sized foetuses were significantly higher than in the smallest litter mates for all the tissues. Significantly higher levels of SPP1 mRNA and protein were found in MS compared to LW. In both breeds, significant differences between sizes were found in some tissues, with similar expression patterns in respect to size, for both mRNA and protein in endometrial tissues when compared to contemporary LW. In placenta, the direction of the expression differed between breeds, with a higher expression of mRNA and protein in the normal-sized MS foetuses and in the smallest sized LW foetuses. The comparison of SPP1 expression between different foetal sizes and different breeds revealed associations between breed, foetal size, and SPP1 protein, factors implicated in PS and LS. These results together with the genetic evidence indicate that the potential role of SPP1 in placental and foetal development merits further investigation.

<p>Our primary goal is to better understand complex diseases using statistically disciplined approaches. As multi-modal data is streaming out of consortium projects like Genotype-Tissue Expression (GTEx) project, which aims at collecting samples from various tissue sites in order to understand tissue-specific gene regulation, new approaches are needed that can efficiently model groups of data with minimal loss of power. For example, GTEx project delivers RNA-Seq, Microarray gene expression and genotype data (SNP Arrays) from a vast number of tissues in a given individual subject. In order to analyze this type of multi-level (hierarchical) multi-modal data, we proposed a series of efficient-score based tests or score tests and leveraged groups of tissues or gene isoforms in order map genomic biomarkers. We model group-specific variability as a random effect within a mixed effects model framework. In one instance, we proposed a score-test based approach to map expression quantitative trait loci (eQTL) across multiple-tissues. In order to do that we jointly model all the tissues and make use of all the information available to maximize the power of eQTL mapping and investigate an overall shift in the gene expression combined with tissue-specific effects due to genetic variants. In the second instance, we showed the flexibility of our model framework by expanding it to include tissue-specific epigenetic data (DNA methylation) and map eQTL by leveraging both tissues and methylation. Finally, we also showed that our methods are applicable on different data type such as whole transcriptome expression data, which is designed to analyze genomic events such alternative gene splicing. In order to accomplish this, we proposed two different models that exploit gene expression data of all available gene-isoforms within a gene to map biomarkers of interest (either genes or gene-sets) in paired early-stage breast tumor samples before and after treatment with external beam radiation. Our efficient score-based approaches have very distinct advantages. They have a computational edge over existing methods because they do not need parameter estimation under the alternative hypothesis. As a result, model parameters only have to be estimated once per genome, significantly decreasing computation time. Also, the efficient score is the locally most powerful test and is guaranteed a theoretical optimality over all other approaches in a neighborhood of the null hypothesis. This theoretical performance is born out in extensive simulation studies which show that our approaches consistently outperform existing methods both in statistical power and computational speed. We applied our methods to publicly available datasets. It is important to note that all of our methods also accommodate the analysis of next-generation sequencing data.</p> / Dissertation

Diverses lésions ostéochondrales peuvent affecter les articulations des jeunes chevaux et réduire leurs futures performances en course. L’objectif de cette thèse est d’identifier les régions du génome, appelées locus à caractère quantitatif (QTL), associées avec des caractères mesurant l’ostéochondrose (OC) enregistrés dans le programme GENEQUIN sur une population de Trotteurs Français. Le génotypage a été réalisé à l’aide de la puce SNP Illumina BeadChip EquineSNP50, qui est dense et permet d’exploiter le déséquilibre de liaison par des analyses d’association. Ces analyses sont sujettes à certains problèmes en présence d’une structure familiale des données. Dans la première partie de la thèse, une comparaison de la puissance et de la robustesse d’un choix restreint de méthodes d’analyses est effectuée. L’originalité de ce travail réside dans la dérivation algébrique des moments des distributions des statistiques de test comparées, donnant ainsi plus de généralité à nos résultats et permettant une meilleure compréhension des différences. Les résultats peuvent notamment servir à l’optimisation du dispositif expérimental. La deuxième partie est consacrée à la cartographie des régions QTL des caractères mesurant l’OC en différents sites articulaires dans une population de 583 Trotteurs Français. Cette étude a permis de mettre en évidence plusieurs régions QTL d’effets moyens et faibles à un niveau significatif mais pas hautement significatif. Nous montrons que l’OC est un caractère polygénique et qu’aucun QTL, ayant un effet à la fois sur l’OC du jarret et l’OC du boulet, n’est détectable dans ce protocole QTL, ce qui infirme l’hypothèse simple d’une cause génétique commune de la sensibilité à cette maladie sur les différents sites anatomiques. Suite à ces travaux, l’identification des gènes candidats et des mutations causales devrait clarifier la physiopathologie moléculaire de l’OC et ainsi permettre de développer des stratégies efficaces pour l’évaluation des risques. Pendant ce temps, les marqueurs peuvent être utilisés dans un contexte de sélection assistée par marqueurs afin d’améliorer la santé et le bien-être du cheval. / Osteochondral lesions are commonly observed in young horses and may be responsible for reduced performances in racing. The purpose of the PhD thesis was to identify genome regions, called quantitative trait loci (QTL), associated with various traits measuring osteochondrosis (OC) and recorded in the GENEQUIN program in a population of French Trotters horses. Genotyping was performed using the EquineSNP50 Illumina high density chip, which allows to exploit the linkage disequilibrium with genome-wide association studies. These analyses are subject to several problems in presence of family structure. We hence first proposed a comparison of power and robustness of a limited choice of models for this type of analysis. The originality of this work lies in the algebraic derivation of the distribution moments of the test statistics compared, making the outcome of this comparison more general and allowing a better understanding of differences. The results can be used to establish an experimental design. The second part was devoted to the QTL fine mapping of traits that measure OC in different joint sites. This study highlighted several significant QTL with low and medium effects but none of them were highly significant. We showed that OC is a polygenic trait and we were not able to identify QTL affecting both OC on the hock and the fetlock, rejecting the hypothesis of a single genetic determinism of susceptibility to this desease accross anatomical sites. Further studies will now focus on the identification of candidate genes and screening for mutation in an attempt to clarify the molecular physiopathology of OC and develop efficient strategies for risk assessment. Meanwhile, markers could be used in a marker-assisted selection context to improve horse health and welfare.

Parmi les contraintes abiotiques la salinité est considérée comme un problème majeur, qui affecte le fonctionnement des plantes, en particulier leur croissance et leur rendement. Afin d’étudier le contrôle génétique de la tolérance à la salinité chez Medicago truncatula, plante modèle de la famille des légumineuses, deux expérimentations ont été réalisées. La première expérimentation visait à étudier l’effet de la contrainte saline sur différents paramètres morpho-physiologiques pour un panel de génotypes de M. truncatula afin de déterminer les traits de phénotypage pour la tolérance à la salinité. Les génotypes A17, TN1.11, DZA315.16, A20, TN1.12 et F83005.5 ont été sélectionnés parmi des lignées originaires de différents pays méditerranéens, qui ont été déjà séquencées (http://www1.montpellierinra.fr/BRC-MTR/mauguio/mauguio.php). Les génotypes ont été étudiés sous 6 traitements salins (0, 30, 60, 90,120 et 150 mM NaCl) dans un essai factoriel sous forme de blocs complets aléatoires en trois répétitions. L’analyse de la variance montre des différences significatives entre les niveaux de salinité et une interaction entre les génotypes et les traitements salins concernant la plupart des caractères étudiés. Le génotype « DZA315.16 » présente les valeurs les plus importantes concernant les effets principaux pour les caractères morphologiques alors que « TN1.11 » présente les valeurs les plus faibles. La projection verticale de la surface foliaire de la plante (Leaf Area=LA), significativement corrélée à la biomasse des plantes, apparaît comme un trait d’intérêt pour le phénotypage de la tolérance à la salinité. La concentration saline la mieux adaptée pour démontrer les différences parmi les lignes étudiées se situe entre 90 et 120 mM NaCl. Le génotype « TN1.11 » contrairement à « DZA315.16 » et à « Jemalong-A17 » présente un maintien de la surface foliaire de la plante en réponse à la salinité. Pour la deuxième expérimentation, une population de cent lignées recombinantes (Recombinant Inbred Lines=RILs) produite par le croisement entre « TN1.11 » et « Jemalong-A17 » a été retenue pour l’analyse du contrôle génétique de la tolérance à la salinité. Les RILs ont été développés par la méthode de descendant mono graines (Single Seed descent= SSD) jusqu’ à la génération F6 à l’INP-ENSAT, France. Le plan d’experimentation est « Spli plots » , sous forme de blocs randomisés avec trois répétitions et deux conditions : traitement salin (100 mM NaCl) et témoin (eau). L’expérience a été menée pour déterminer la variabilité génétique et pour identifier les QTLs contrôlant les caractères morphologiques et physiologiques chez la population des lignées recombinantes (RILs). L’analyse de la variance a montré une large variation génétique et une ségrégation transgressive pour les caractères étudiés. La différence entre la moyenne des RILs et la moyenne de leurs parents n’est pas significative concernant tous les caractères étudiés dans les deux conditions, ce qui montre que les RILs utilisées dans notre expérimentation sont représentatives de toutes les lignées recombinantes possibles du croisement « TN1.11 x Jemalong-A17 ». 21 QTLs ont été détectés dans la condition témoin et 19 QTLs ont été identifiés sous contrainte saline (100 mM NaCl). Le pourcentage de la variance phénotypique expliqué par les QTLs varie entre 4.60% et 23.01%. Certains de ces QTLs sont spécifiques à la condition saline, ce qui démontre l’existence du contrôle génétique de la tolérance à la salinité chez M. truncatula ; tandis que les autres ne sont pas spécifiques et contrôlent un même caractère dans les deux conditions. Des QTLs superposés concernant différents caractères ont été aussi observés. Les résultats fournissent des informations importantes en vue de futures analyses fonctionnelles de la tolérance à la salinité chez M.truncatula et pour d’autres espèces voisines. / Among abiotic stresses salinity is considered as a serious problem affecting plant functions especially growth and yield. In order to study the genetic control of salt stress in the model legume Medicago truncatula, two experiments were performed. The first experiment was conducted to study the effect of salt stress on some morpho-physiological parameters in M. truncatula genotypes and to determine the eventual use of some traits as tolerance criteria. Genotypes including A17, TN1.11, DZA315.16, A20, TN1.12 and F83005.5 are selected through a sequenced lines collection (http://www1.montpellierinra.fr/BRC-MTR/mauguio/mauguio.php) which are originated from different Mediterranean countries. Genotypes were studied under 6 salinity treatments (0, 30, 60, 90,120 and 150 mM NaCl) in a factorial design based on randomized complete blocks with three replications. Analysis of variance show significant differences among genotypes, salinity levels and interaction between genotypes and salt treatments for most of studied traits. “DZA315.16” genotype presents the highest main effect values for morphological traits whereas”TN1.11” has low values. Vertically projected leaf area (LA); show the highest variability through all studied salt concentrations. The best concentration to find differences between parental lines is 90 to 120 mM Nacl. A segregating population of recombinant inbred lines (100 RILs) of M.truncatula derived from a cross between TN1.11 and Jemalong-A17 was used for the second experiment. RILs were developed by single-seed descent until F6 generation at the INP-ENSAT, France. The experiment was undertaken to determine the genetic variability and to identify QTLs controlling several traits related to plant growth and physiology, in the population of recombinant inbred lines (RILs). Analyses of variance showed a large genetic variation and transgressive segregation for the traits studied. The difference between the mean of RILs and the mean of their parents was not significant for all of the traits in both conditions, showing that the RILs used in our experiment are representative of the possible recombinant lines from the cross TN1.11 x A17. A total of 21 QTLs were detected under control and 19 QTLs were identified under 100mM salt stress conditions. The percentage of total phenotypic variance explained by the QTLs ranged from 4.60% to 23.01%. Some of the QTLs were specific for one condition, demonstrating that the genetic control of a traits differed under control and salt stress conditions. Some others are non-specific and control a trait in both conditions. Overlapping QTLs for different traits were also observed. The results provide important information for further functional analysis of salt tolerance in M. truncatula

A partir de uma linha macho de corte e outra de postura, foi desenvolvida uma população experimental F2 com objetivo de mapear locos de características quantitativas (QTLs) para características de interesse comercial. Foi gerado um total de 2.063 animais F2 em 17 incubações que foram criados como frangos de corte até a 6&#170; semana de idade, quando foram avaliadas seis características de desempenho. As famílias utilizadas para o estudo, foram as que obtiveram maior número de marcadores microssatélites informativos em trabalhos anteriores envolvendo os cromossomos 1 a 5 com a mesma população. Vinte marcadores dos cromossomos 19, 23, 24, 26, 27 e 28 foram testados nos indivíduos parentais e F1 das famílias escolhidas para checar se eram ou não informativos. Após a genotipagem das 5 famílias escolhidas, foram construídos os mapas de ligação e realizada a análise de mapeamento de QTL por intervalo para cada cromossomo utilizando o método de regressão e o modelo genético F2. Dois modelos foram testados: um incluindo apenas o efeito aditivo do QTL e outro modelo que incluiu também o efeito de dominância. Caso fosse identificado QTL com nível de significância no mínimo sugestivo no genoma, os modelos foram confrontados para confirmar o efeito de dominância do QTL. Foram conduzidas também análises complementares com o intuito de detectar interação do QTL x sexo e QTL x família. Foram estimados a porcentagem da variância fenotípica e o intervalo de confiança para cada QTL. No cromossomo 26 foi mapeado QTL significativo a 5% no cromossomo para ganho de peso dos 35 aos 41 dias, e no cromossomo 27 foi identificado, para a característica peso vivo aos 35 dias um QTL sugestivo no genoma. Os QTL localizados nos cromossomo 26 e 27 foram localizados a 0.0 e 103.0 cM e explicaram 1,95 e 2,03% da variação fenotípica, respectivamente. / With the objective of mapping quantitative trait loci (QTLs) for economically valuable characteristics, an F2 chicken population was developed by crossing a broiler sire line and a layer dam line. A total of 2.063 F2 chickens from 17 incubations were reared as broilers and slaughtered at 6 week of age, when six performance traits were measured. Five families were chosen for this study based on previous work to determine the most informative families. Twenty markers from chromosomes 19, 23, 24, 26, 27 and 28 were tested in the parental and F1 chickens from the chosen families to select the informative markers. After genotyping parental, F1 and F2 chickens, the linkage maps were constructed and QTL Interval mapping analysis was conducted for each chromosome using regression methods and the F2 genetic model. Two different models were tested: one including only the additive effect of the QTL and another model that also included the dominance effect. If at least a genome-wide suggestive QTL was detected, they were compared through standard F tests to confirm the dominance effect of the QTL. Complementary analyses were conducted to investigate the existence of QTL x sex and QTL x family interactions. The percentage of the phenotypic variance explained by the QTL and the confidence intervals were estimated for each QTL. A 5% chromosome-wide significant QTL for weight gain from 35 to 41 d was mapped to chromosome 26 and a QTL that exceeded the genome-wide suggestive threshold for body weight at 35 d was mapped to chromosome 27. This QTL positioned at 103 cM explained 2.03% of the phenotypic variance of the trait and presented a confidence interval from 0 to 111 cM.