Sepsis is defined as a dysregulated immune response to infection causing organ dysfunction, and is a major area of unmet clinical need. Although conventionally considered a unified disease with a common pathway to organ failure and death, substantial clinical and molecular heterogeneity is seen, which has limited efforts to understand pathophysiology and improve therapeutic strategies. Sepsis is associated with global changes in gene expression, and genetic variants are known to affect the response to infection. This thesis therefore uses an integrated functional genomics approach to investigate disease mechanisms and variation in the sepsis response. Data are presented for 551 patients admitted to intensive care with sepsis due to community acquired pneumonia (CAP) or faecal peritonitis (FP). The sepsis response is explored using genome-wide gene expression and proteomics data, and molecular quantitative trait loci (QTL) are mapped in the context of disease. Comparisons with cardiac surgery patients are performed to identify shared and specific aspects of the host response. The host transcriptomic response was largely shared across sources of sepsis, although some specificity relating to viral infection and interferon signalling was observed and validated in prospectively recruited patients. Expression-based sepsis response signature (SRS) subgroups previously described in CAP were validated, and were additionally observed in FP. SRS1 is associated with higher early mortality, and shows enrichment of pathways relating to T cell exhaustion, cell death, and endotoxin tolerance. Differences between SRS groups were also observed in the FP plasma proteome. Serial sampling enabled the investigation of temporal changes in gene expression and protein abundance within patients. Lastly, disease-relevant expression QTL were identified, and interactions with source of sepsis and SRS determined, highlighting the potential impact of regulatory variation on the sepsis response. This thesis demonstrates the benefit of an integrative functional genomics approach to explore heterogeneity in sepsis, and highlights opportunities for patient stratification and personalised medicine.

MicroRNAs are short RNA molecules that are central to the regulation of many cellular and developmental pathways. They are processed in several stages from structured precursors in the nucleus, into mature microRNAs in the cytoplasm where they direct protein complexes to regulate gene expression through, often imperfect base-pairing with target messenger RNAs. The broad aim of this project is to better understand how polymorphisms and new mutations can disrupt microRNA processing and targeting, and ultimately define their contributions to human disease. I have taken two approaches towards this. The first approach is to comprehensively identify the microRNA targets by developing and applying a novel computational pipeline to identify microRNA binding events genome-wide in RNA-RNA interaction datasets. I use this to examine the transcriptomic diversity of microRNA binding, finding microRNA binding events along the full length of protein coding transcripts and with a variety of non-coding RNAs. This reveals enrichment for non-canonical microRNA binding at promoters and intronic regions around splice sites, and identifies highly spatially clustered binding sites within transcripts that may be acting as competitive endogenous RNAs to compete for microRNAs, effectively sequestering them. Using statistical models and new cell fractionated RNA-seq data, I rank the features of microRNAs and their binding sites which contribute to the strength and specificity of their interaction to provide a better understanding of the major determinants of microRNA targeting. The second approach is to directly identify DNA sequence changes in microRNA precursors that alter processing efficiency affecting mature microRNA abundance which are routinely overlooked in the search for disease or trait associated causal variants. I have systematically screened public datasets for both rare and common polymorphisms that overlap microRNA precursors and are correlated with mature microRNA levels as measured in short RNA sequencing. I use these eQTL SNPs to examine the most important microRNA precursor regions and sequence motifs. Several of these SNPs have been observed as risk factors in cancer or other clinically relevant traits, and correlated with microRNA processing efficiency. I demonstrate that a specific DNA change which is known to be important in the development of some cancers, is located in a microRNA precursor and affects the balance of its two products, miR-146a-3p and miR-146a-5p, that can be produced from that single precursor providing new insights into the mechanisms of microRNA production and the aspects of genetic mis-regulation that result in cancer. I find further examples of common human polymorphisms that appear to affect microRNA production from their precursors, several of these variants are independently implicated in human immune disease, cancer susceptibility and associated with other complex traits. As they exhibit a molecular phenotype and immediately lead to mechanistic hypotheses of trait causality that can be tested, these variants could provide a route into the frequently intractable problem of mechanistically linking non-coding genetic variation to human phenotypes. Applying similar studies to patient DNA has revealed rare and unique DNA changes that are now candidates for causing human disease that are being subject to follow-up experimental studies. Collectively this work has started to define which sequences changes in microRNAs are likely to disrupt their function and provides a paradigm for the analysis of microRNA sequence variants in human genetic disease.

Quantitative Trait Loci (QTL) mapping has been widely used to identify genetic loci attributable to the variation observed in complex traits. In recent years, gene expression phenotypes have emerged as a new type of quantitative trait for which QTL can be mapped. Locating sequence variation that has an effect on gene expression (eQTL) is thought to be a promising way to elucidate the genetic architecture of quantitative traits. This thesis explores a number of methodological aspects of eQTL mapping (also known as “genetical genomics”) and considers some practical strategies for applying this approach to livestock populations. One of the exciting prospects of genetical genomics is that the combination of expression studies with fine mapping of functional trait loci can guide the reconstruction of gene networks. The thesis begins with an analysis in which correlations between gene expression and meat quality traits in pigs are investigated in relation to a pork meat quality QTL previously identified. The influence on power due to factors including sample size and records of matched subjects is discussed. An efficient experimental design for two-colour microarrays is then put forward, and it is shown to be an effective use of microarrays for mapping additive eQTL in outbred crosses under simulation. However, designs optimised for detecting both additive and dominance eQTL are found to be less effective. Data collected from livestock populations usually have a pedigreed structure. Many family-based association mapping methods are rather computationally intensive, hence are time-consuming when analysing very large numbers of traits. The application of a novel family-based association method is demonstrated; it is shown to be fast, accurate and flexible for genetical genomics. Furthermore, the results show that multiple testing correction alone is not sufficient to control type I errors in genetical genomics and that careful data filtering is essential. While it is important to limit false positives, it is desirable not to miss many true signals. A multi-trait analysis based on grouping of functionally related genes is devised to detect some of the signals overlooked by a univariate analysis. Using an inbred rat dataset, 13 loci are identified with significant linkage to gene sets of various functions defined by Gene Ontology. Applying this method to livestock species is possible, but the current level of annotations is a limiting factor. Finally, the thesis concludes with some current opinions on the development of genetical genomics and its impact on livestock genetics research.

Fissura de lábio com ou sem fissura de palato não-sindrômica (FL/P NS) é uma malformação craniofacial frequente, com modelo de herança multifatorial, onde fatores de risco genéticos e ambientais atuam na manifestação da doença. Variações nos níveis de expressão gênica têm sido apontadas como um importante mecanismo de susceptibilidade a doenças complexas, e variantes no DNA que regulam esses níveis de expressão (eQTL) têm sido combinadas a estudos de associação para auxiliar no entendimento da etiologia de algumas doenças. No presente trabalho, integramos eQTLs e estudo de associação para 1) verificar se variantes já associadas com FL/P NS possuem um papel regulatório em células-tronco de músculo orbicular do lábio (OOMMSC, um tecido afetado em FL/P NS), e 2) verificar se eQTLs mapeados em OOMMSC teriam associação com a mesma. Para o primeiro objetivo, verificamos a correlação entre os genótipos das variantes rs642961 e rs590223 e os níveis de expressão de IRF6, e também entre rs987525 e os níveis de expressão de MYC. Não encontramos correlação para nenhuma das três variantes testadas. É possível que essas variantes possuam um papel funcional em algum momento específico da embriogênese, ou mesmo que não tenhamos detectado essa correlação devido ao número amostral analisado (N=46). Para o segundo objetivo, realizamos um estudo de associação do tipo caso-controle dos eQTLs rs5011163, rs1505443, rs4793213, rs4793229 e rs1242500. Não encontramos associação entre nenhuma das cinco variantes e FL/P NS. Uma possível explicação para a associação negativa seria a significância marginal dessas variantes como eQTLs em OOMMSC. Além disso, estudos com baixo poder, como o mapeamento de eQTLs em OOMMSC realizado em outro projeto pelo nosso grupo, geralmente detectam os eQTLs de maior efeito, sendo esses frequentemente compartilhados entre tecidos, e, assim, podem não ter relevância para a doença em si. Outros eQTLs de OOMMSC, selecionados por critérios diferentes do presente estudo, estão sendo testados para associação com FL/P NS, o que nos permitirá avaliar a relevância dessa abordagem para detectar variantes de susceptibilidade a FL/P NS / Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a frequent craniofacial malformation, with a multifactorial model of inheritance, in which genetic and environmental risk factors act in disease manifestation. Variation of gene expression has been pointed as an important susceptibility mechanism to complex diseases, and DNA variants that regulate expression levels (eQTLs) have been combined with association studies to help elucidate the etiology of some diseases. In the present work, we integrate eQTL and association studies to 1) verify if variants associated with NSCL/P have a regulatory role in orbicularis oris muscle mesenchymal stem cells (OOMMSC, a tissue affected by NSCL/P); and 2) verify if eQTLs mapped in OOMMSC are associated with the disease. For the first goal, we verified the correlation of the rs642961 and rs590223 genotype variants with IRF6 expression levels, and also between the rs987525 genotype and MYC expression levels. We did not find correlation for any of the three variants tested. Possibly, these variants have a functional role in specific moments of embryogenesis, or sample size (N=46) was insufficient to detect correlation. For the second goal, we did a case-control association study for eQTLs rs5011163, rs1505443, rs4793213, rs4793229 and rs1242500. We did not find association between these variants and NSCL/P. The negative association could be explained by the marginal significance of these variants as eQTLs in OOMMSC. Besides, low-power studies, as the OOMMSC eQTL mapping performed in another project by our group, usually detect eQTLs of larger effect, which are frequently shared among tissues; therefore, they may not be relevant for the disease itself. Other eQTLs, selected under different criteria, are currently being tested for association with NSCL/P, which will enable us to evaluate the relevance of this approach to detect susceptibility variants for NSCL/P

Cette thèse a pour objet l'étude du lien génotype-transcriptome et de son influence sur le développement des maladies multifactorielles. Les apports de ce travail sont à la fois méthodologiques et appliqués. Nous étudions d'abord le lien génotype-transcriptome en établissant la liste des eQTL (expression Quantitative Trait Loci) dans le monocyte et nous évaluons l'apport de l'observation des eQTL pour l'interprétation des analyses d'association génome entier (GWAS). Nous proposons ensuite une méthode pour l'identification de variants génétiques affectant des modules de gènesco-régulés que nous appliquons à l'étude des données d'expression de monocytes issus d'une large étude populationnelle (GHS). Nous mettons ainsi en évidence plusieurs loci affectant l'expression de modules de gènes co-régulés, dont plusieurs sont impliqués dans la prédisposition au diabète de type I. Nous montrons également que le processus d'isolation des cellules monocytaires peut engendrer des biais liés à la contamination par des types cellulaires non désirés et nous proposons une approche pour contrôler ce type de biais dans les analyses. / This thesis deals with the study of the relation between genotype and expression and its influence on the development of complex diseases. This work brings both methodological and applied results.First, we study the relation between genotype and transcriptome by establishing a database of eQTL (expression quantitative Trait Loci) in monocytes and we evaluate the contribution of eQTL for the interpretation of results from Genome Wide Association Studies (GWAS).We then provide a methodology for the identi_cation of genetic polymorphisms regulating modules of co-expressed genes that we apply to a large scale populationnal study of the monocyte transcriptome.We thus identify several loci associated with modules of co-regulated genes, several of which are involved in the susceptibility to type I diabetes. We also show that the isolation of monocytes can induce complex bias through contamination from unwanted cell types and we provide a method to control for such bias in the analysis.

Fissura de lábio com ou sem fissura de palato não-sindrômica (FL/P NS) é uma malformação craniofacial frequente, com modelo de herança multifatorial, onde fatores de risco genéticos e ambientais atuam na manifestação da doença. Variações nos níveis de expressão gênica têm sido apontadas como um importante mecanismo de susceptibilidade a doenças complexas, e variantes no DNA que regulam esses níveis de expressão (eQTL) têm sido combinadas a estudos de associação para auxiliar no entendimento da etiologia de algumas doenças. No presente trabalho, integramos eQTLs e estudo de associação para 1) verificar se variantes já associadas com FL/P NS possuem um papel regulatório em células-tronco de músculo orbicular do lábio (OOMMSC, um tecido afetado em FL/P NS), e 2) verificar se eQTLs mapeados em OOMMSC teriam associação com a mesma. Para o primeiro objetivo, verificamos a correlação entre os genótipos das variantes rs642961 e rs590223 e os níveis de expressão de IRF6, e também entre rs987525 e os níveis de expressão de MYC. Não encontramos correlação para nenhuma das três variantes testadas. É possível que essas variantes possuam um papel funcional em algum momento específico da embriogênese, ou mesmo que não tenhamos detectado essa correlação devido ao número amostral analisado (N=46). Para o segundo objetivo, realizamos um estudo de associação do tipo caso-controle dos eQTLs rs5011163, rs1505443, rs4793213, rs4793229 e rs1242500. Não encontramos associação entre nenhuma das cinco variantes e FL/P NS. Uma possível explicação para a associação negativa seria a significância marginal dessas variantes como eQTLs em OOMMSC. Além disso, estudos com baixo poder, como o mapeamento de eQTLs em OOMMSC realizado em outro projeto pelo nosso grupo, geralmente detectam os eQTLs de maior efeito, sendo esses frequentemente compartilhados entre tecidos, e, assim, podem não ter relevância para a doença em si. Outros eQTLs de OOMMSC, selecionados por critérios diferentes do presente estudo, estão sendo testados para associação com FL/P NS, o que nos permitirá avaliar a relevância dessa abordagem para detectar variantes de susceptibilidade a FL/P NS / Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a frequent craniofacial malformation, with a multifactorial model of inheritance, in which genetic and environmental risk factors act in disease manifestation. Variation of gene expression has been pointed as an important susceptibility mechanism to complex diseases, and DNA variants that regulate expression levels (eQTLs) have been combined with association studies to help elucidate the etiology of some diseases. In the present work, we integrate eQTL and association studies to 1) verify if variants associated with NSCL/P have a regulatory role in orbicularis oris muscle mesenchymal stem cells (OOMMSC, a tissue affected by NSCL/P); and 2) verify if eQTLs mapped in OOMMSC are associated with the disease. For the first goal, we verified the correlation of the rs642961 and rs590223 genotype variants with IRF6 expression levels, and also between the rs987525 genotype and MYC expression levels. We did not find correlation for any of the three variants tested. Possibly, these variants have a functional role in specific moments of embryogenesis, or sample size (N=46) was insufficient to detect correlation. For the second goal, we did a case-control association study for eQTLs rs5011163, rs1505443, rs4793213, rs4793229 and rs1242500. We did not find association between these variants and NSCL/P. The negative association could be explained by the marginal significance of these variants as eQTLs in OOMMSC. Besides, low-power studies, as the OOMMSC eQTL mapping performed in another project by our group, usually detect eQTLs of larger effect, which are frequently shared among tissues; therefore, they may not be relevant for the disease itself. Other eQTLs, selected under different criteria, are currently being tested for association with NSCL/P, which will enable us to evaluate the relevance of this approach to detect susceptibility variants for NSCL/P

Une meilleure compréhension des mécanismes de résistance aux agents pathogènes couplée à une caractérisation de la capacité immune devient un axe de recherche prioritaire en élevage. L’objectif global de la thèse est d’exploiter des informations de phénotypage, de génétique et de génomique pour étudier l’architecture génétique de la capacité immune chez le porc et contribuer à l’identification de marqueurs génétiques et de biomarqueurs sanguins prédictifs de variations de niveaux de paramètres immuns. Le projet s’articule autour de trois axes complémentaires et les résultats obtenus sont basés sur l’exploitation des jeux de données issus des projets IMMOPIG et SUS_FLORA financés par l’ANR, pour lesquels des cohortes de 450 et 560 porcelets ont été prélevés à 60 jours d’âge, trois semaines après une vaccination contre Mycoplasma hyopneumoniae.Nous avons analysé le déterminisme génétique de l’expression des gènes dans le sang par une analyse eGWAS (génotypage 60K SNP et transcriptome du sang pour 242 animaux) validée pour partie par une étude de la régulation spécifique d’allèles (ASE) des transcrits (RNA-Seq sur 38 animaux). Les résultats d’eGWAS mettent en évidence de multiples associations locales (n=2839) et à distance (n=1752) entre des polymorphes SNP et des variations de transcription, réparties sur l’ensemble des chromosomes. Les analyses ASE confirment l’importance du contrôle génétique en cis, avec une régulation allélique trouvée pour 763 gènes. Les fonctions biologiques associées sont notamment reliées au processing des ARN et à l’immunité. La région du complexe majeur d’histocompatibilité a été trouvée particulièrement riche en eQTL et ASE. L’ensemble de ces données a permis d’établir, pour le porc, une première cartographie des eQTL et gènes soumis à ASE dans le sang.Nous avons étudié les co-variations entre des paramètres immunitaires et le transcriptome du sang pour 243 individus. Les paramètres immunitaires incluent la numération formule sanguine, la caractérisation de sous-populations cellulaires par cytomètre de flux, des dosages sériques (protéine C réactive, haptoglobine, anticorps spécifiques anti Mycoplasma hyopneumoniae), des dosages de réponse suite à des stimulations in vitro du sang total (phagocytose, cytokines IL1b, IL2, IL6, IL8, IL10, TNFa, INFg). Nous avons confirmé l’héritabilité de nombreux paramètres immuns et identifié des covariations avec des profils géniques, offrant des hypothèses sur des biomarqueurs candidats.Nous avons également conduit une analyse fonctionnelle sur quatre animaux de 70 jours d’âge pour caractériser et comparer les profils de transcrits du sang et de trois tissus lymphoïdes associés au tube digestif (ganglion mésentérique, plaques de Peyer jéjunales et iléales). Les données RNA-Seq ont mis en évidence des différentiels d’expression entre les tissus, ce nombre étant plus limité entre les deux types de plaques de Peyer. De manière tout à fait intéressante, parmi les fonctions biologiques enrichies par les gènes différentiellement exprimés entre les deux plaques de Peyer, sont identifiées les voies de différenciation lymphocytaires Th1 et Th2, en cohérence avec une surabondance de lymphocytes B dans les plaques de Peyer iléales.L’ensemble de ces résultats apporte des informations nouvelles pour avancer dans la compréhension du déterminisme génétique des variations de paramètres immunitaires chez le porc, la recherche de polymorphismes causaux de ces variations et l’identification de biomarqueurs sanguins pertinents pour phénotyper la compétence immunitaire. / A better understanding of the mechanisms for resistance to pathogens along with the characterization of the immune capacity has become a priority for research in breeding. The overall objective of this PhD project was to use phenotyping, genetic and genomic information to study the genetic architecture of the immune capacity in the pig and to contribute to the identification of genetic markers and blood biomarkers that predict variations of immune parameter levels. The study was focused on three complementary axes and the results obtained were based on the use of data collected as part of the IMMOPIG and SUS_FLORA projects financed by the ANR, for which 450 and 560 piglet cohorts were sampled at 60 days of age, three weeks after vaccination against Mycoplasma hyopneumoniae.We analyzed the genetic determinism of gene expression in the blood using an eGWAS (60K SNP genotyping and blood transcriptome for 242 animals) confirmed in part by an allele specific expression (ASE) of transcripts (RNA-Seq on 38 animals). The eGWAS results showed multiple local (n=2839) and distant associations between the SNP polymorphisms and transcription variations, spread over all the chromosomes. The ASE analyses confirmed the cis genetic control of gene expression, with allele regulation being found for 763 genes. The biological functions associated were notably associated with RNA processing and immunity. The region of the major histocompatibility complex was found particularly rich in eQTL signals and genes with ASE in the blood.We studied the co-variations between immune parameters and blood transcriptomes for 243 individuals. The immune parameters included the blood count, cell subpopulation characterization by flow cytometry, serum assays (reactive C protein, haptoglobin, antibodies specific for Mycoplasma hyopneumoniae), immune response after in vitro stimulation of peripheral blood (phagocytosis, IL1b, IL2, IL6, IL8, IL10, TNFa, INFg cytokines). We confirmed the heritability of numerous immune parameters and identified covariations with gene profiles, providing hypotheses on biomarker candidates.We also led a functional analysis on four animals at 70 days-of-age in order to characterize and compare the transcriptome profiles of peripheral blood and three gut-associated lymphoid tissues (mesenteric lymph nodes, jejunal and ileal Payer’s patches). The RNA-Seq data showed differential expression between tissues; this number was more limited between the two types of Peyer’s patches. Interestingly, among the biological functions enriched by the differentially expressed genes between the Peyer’s patches, we identified the Th1 and Th2 lymphocyte differentiation pathways, which was in agreement with an over-abundance of B lymphocytes in the ileal Peyer’s patches.Together these results provide new information on the understanding of the genetic determinism of immune parameter variations in the pig, the search for causal polymorphisms of these variations and the identification of relevant blood biomarkers for phenotyping immune competence.

RA is a chronic and disabling disease with no known cure. The disease has a strong genetic component and modern genetic studies have successfully identified over 100 loci associated with the onset of RA. Despite the number of associations identified, the full genetic component of RA is not known, and for the majority of the loci the causal variant remains unknown. The overall aim of this study was to utilise well-powered genetic data, in order to identify novel loci, refine genetic associations, and generate robust evidence for the causal SNP and causal gene at a selected RA locus. An initial analysis was undertaken utilising 3870 RA cases and 8430 controls from the UK-ImmunoChip, a study designed for comprehensive fine-mapping of confirmed RA susceptibility loci. Analysis of the UK-ImmunoChip data identified a novel finding with the TYK2 locus, and proved informative to refining association signals, illustrating the utility of fine-mapping and implicated SNPs with putative regulatory function. The UK-ImmunoChip was subsequently expanded to incorporate samples from five additional cohorts in a study led by Dr. Stephen Eyre. In additional to novel loci discovery, this study provided evidence for SNPs putatively associated with RA (P smaller or equal to5E-05 < 5E-08). In a combined meta-analysis of 17,581 cases and 20,160 controls, convincing evidence was obtained for two novel RA loci, BACH2 and RAD51B.The newly identified genes implicate two novel pathways in RA (B-cell differentiation and DNA repair) and add to the growing number of loci associated with multiple AIDs. These findings are important to aid comprehensive pathway analysis and add to the knowledge of RA risk genes. The third most associated RA locus in both serological subtypes of disease, with an uncharacterised protein, ANKRD55, was subsequently selected for in-depth characterisation. Utilising genetic and haplotypic analysis the association at this locus was refined to a single signal, with four SNPs in strong LD (r2 > 0.8). Through bioinformatic analysis, two SNPs rs6859219 and rs10065637 showed evidence for functional activity, with evidence of being located in an enhancer element, supported by histone marks, DNAse hypersensitivity, evidence of transcription factor binding and eQTL. The use of RNA and ChIP experiments have established a testable hypothesis that the presence of the putative causal variants rs6859219 and rs10065637, act to weaken the strength of the enhancer element in which they are located, (evidenced by diminished H3k4me1 modification), which in turn down-regulates the transcriptional output of the target gene ANKRD55 (evidenced by eQTL in both whole blood and CD4+ T cells).In summary this study has led to the identification of three novel loci, highlighted the importance of fine-mapping and developed a successful systemic strategy for the characterisation of the 5q11 risk locus associated with RA.

Traditionally, autosomal genes, when expressed, are assumed to express both alleles equally. Exceptions to this tenet include genes for which a specific genotypic polymorphism controls expression level, as well as genes for which monoallelic expression is epigenetically dictated. In this work, we discovered and characterized allele-specific gene expression in a variety of tissues using multiple techniques. We used cell lines and fresh tissue from reciprocal crosses of F1 heterozygous mice and the homozygous parental strains. We relied on a variety of high-throughput genomic techniques including RNA-Seq and DNA SNP-arrays to examine multiple types of allele-specific expression. We searched for novel examples of random autosomal monoallelic expression (RMAE) by using DNA SNP-arrays and cDNA from lymphoblast and fibroblast clonal cell lines of heterozygous mice. We found that of the approximately 1,350 autosomal genes we assessed, over 10% showed evidence of RMAE in at least one cell type. This allele-specific expression was stable over long periods in cell culture and encompassed a variety of gene types, some of which also exhibit RMAE in human clonal lines. Additionally, for a subset of RMAE genes, there seemed to be preferential inactivation of one allele; this monoallelic expression was still considered random, as from clone to clone the gene could be expressed either monoallelically or biallelically. In a second set of experiments we developed an analysis pipeline to examine RNASeq data for allele-specific expression. Using a pilot data set, we assessed the murine liver for parent-of-origin monoallelic expression, examining both known and candidate novel imprinted genes. We observed imprinted monoallelic expression in the adult liver for some, but not all, imprinted genes that have been reported in studies of embryonic tissue. The results suggest that there are few, if any, novel imprinted genes to be discovered in the mouse liver. This pilot data set also allowed examination of the genetic basis of allele specific gene expression. In keeping with recent reports, we found evidence for genetically based allele-specific expression, ranging from mild to greater than 4-fold allelic imbalance. We examined the extent to which this allelic imbalance correlated with total expression levels in the parental strains.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18847号 / 医博第3958号 / 新制||医||1007(附属図書館) / 31798 / 京都大学大学院医学研究科医学専攻 / (主査)教授 小川 誠司, 教授 小泉 昭夫, 教授 藤渕 航 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM