Le présent travail consiste à proposer un modèle de représentation des notions théoriques et pratiques de la terminologie et de leurs relations sous forme de thésaurus. Selon la norme ISO 25964-1, 2011, « un thésaurus est un vocabulaire contrôlé et structuré dans lequel les concepts sont représentés par des termes, ayant été organisés afin de rendre explicites les relations entre les concepts (…) ». Notre objectif est de créer un outil pédagogique à la suite d’une réflexion théorique englobant différentes perspectives notionnelles au sein de cette discipline. Les enjeux soulevés par la classification des concepts de certains champs de savoir (notamment ceux donnant lieu à différentes perspectives) n’ont pas été approfondis suffisamment dans la littérature de la terminologie, ni dans celle portant sur les thésaurus. Comment décrire des concepts qui sont sujets à des dissensions théoriques entre les différentes écoles de pensée? Comment classer les différentes relations entretenues par les concepts théoriques et les applications pratiques d’une discipline? À ces questions s’ajoute celle de la prise en compte de ces difficultés dans un thésaurus. Nous commençons par délimiter et organiser les concepts saillants du domaine. Ensuite, à l’aide d’un corpus comprenant des publications associées à différentes approches de la terminologie, nous étudions les réalisations linguistiques de ces concepts et leurs relations en contexte, dans le but de les décrire, de les classer et de les définir. Puis, nous faisons l’encodage de ces données à l’aide d’un logiciel de gestion de thésaurus, en respectant les normes ISO applicables. La dernière étape consiste à définir la visualisation de ces données afin de la rendre conviviale et compréhensible. Enfin, nous présentons les caractéristiques fondamentales du Thésaurus de la terminologie. Nous avons analysé et représenté un échantillon de 45 concepts et leurs termes reliés. Les différents phénomènes associés à ces descripteurs comme la multidimensionalité, la variation conceptuelle et la variation dénominative sont aussi représentés dans notre thésaurus. / This thesis proposes a model to represent theoretical and practical concepts of terminology as well as their terminological relationships in the form of a thesaurus. According to the ISO 25964-1:2011 standard, “a thesaurus is a controlled and structured vocabulary in which concepts are represented by terms that have been previously arranged in order to show explicitly the relations among concepts (…)”. Our objective is to create a pedagogical tool that is grounded in a theoretical reflection about different theoretical perspectives within this discipline. The issues associated with the classification of concepts in certain fields of knowledge (especially those with different perspectives) require further study in the field of terminology and information science, and in the literature relating to thesauri. Indeed, how does one describe concepts that are subject to theoretical dissent and different schools of thought? How can the different relationships between theoretical concepts and practical applications of a discipline be classified? To these questions is added the additional challenge of reflecting these difficulties in a thesaurus. Our first step consists in delimiting and organizing the main concepts of the field. Then, by means of a corpus containing different publications associated with different approaches in terminology, we study the linguistic realizations of those concepts and their relationships in context, with the objective of describing, classifying and defining them. We then encode this data using thesaurus management software that respects the relevant ISO standards. Finally, we produce visualizations of this data to make it more user friendly and understandable. To conclude, we present the fundamental characteristics of the Thésaurus de la terminologie. We have analyzed and presented a sample of 45 concepts and their related terms. Different phenomena related to these descriptors, such as multidimensionality, conceptual variation and denominative variation, are also represented in our thesaurus.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

An exciting new era has dawned for the prevention and management of CAD utilizing genetic risk variants. The recent identification of over 60 susceptibility loci for coronary artery disease (CAD) confirm not only the importance of established risk factors, but also the existence of many novel causal pathways that are expected to improve our understanding of the genetic basis of CAD and facilitate the development of new therapeutic agents over time. Concurrently, Mendelian randomization studies have provided intriguing insights on the causal relationship between CAD-related traits, and highlight the potential benefits of long-term modifications of risk factors. Lastly, genetic risk scores of CAD may serve not only as prognostic, but also as predictive markers and carry the potential to considerably improve the delivery of established prevention strategies. This review will summarize the evolution and discovery of genetic risk variants for CAD and their current and future clinical applications.

The genetic basis of the different cancer phenotypes has been a continuous and accelerating subject of investigation. Data accumulated thanks to recently introduced genome-wide scanning technologies have revealed that human diversity and diseases susceptibility is also greatly influenced by structural alterations in the human genome, such as DNA copy number variants (CNVs) and copy number alterations (CNAs), which influence gene expression in both healthy and pathological cells. Our research aims to investigate the influence of structural alterations on gene expression in cancer cells using SNP microarray data. Specifically, we focus on analyzing DNA copy number alternations (CNAs), which can significantly influence gene expression in cancer cells. Several cancer-predisposing mutations affect genes that are responsible for maintaining the integrity of the chromosomes during cell division, which can result in translocations, gains or losses of large parts of chromosome. To our knowledge, there have been no publications that link whole-genome copy number alterations in cancer to gene expression variations using the full range of possibilities offered by SNP arrays. The accurate use of SNP arrays in the analysis of cancer has been difficult due to tumour purity, tumour heterogeneity, aneuploidy/polyploidy and complex patterns of CNA and loss-of-heterozygosity (LOH). In our work, we use and further extend a recently developed novel tool for tumour genome profiling called OncoSNP (Yau, Mouradov et al. 2010), in order to resolve some of those problems and accurately estimate copy number alterations (CNA) and loss-of-heterozygosity (LOH) from SNP array data in cancer cell samples. The methods developed in this thesis tackle the problem of cancer genomic investigation by developing and validating an extension (DPS smoothing) of a new method (OncoSNP). This approach is used in the analysis of global expression versus CNA patterns in experimental systems and large clinical datasets. We analyse various cancer SNP and gene expression arrays of increasing complexity and heterogeneity, starting with a dataset of head and neck squamous cell carcinoma (HNSCC) cell lines, followed by leukaemia samples and finally a large breast cancer dataset. The central findings of our research are multifold. In the HNSCC dataset we find that the level of genetic instability is not indicative of the pathological state; i.e. there are premalignant lesions displaying extensive mutations. However some genetic features are typical of certain lesion type; e.g. we consistently observe copy loss in the short arm of chromosome 3 in carcinoma. The pattern of homozygous deletion in the dataset reveals common deletion of cancer related genes, especially CDK4 (pI6). Furthermore we notice a significant positive correlation between the copy number and the expression on a systematic level. In Leukaemia, we do not observe extended uniparental disomy as previously published (Akagi, Shih et al. 2009) and expected. However large alterations (whole arm amplification) are observed in individual patients: copy loss in chromosome 7 (2 patients), copy gain in chromosome 8 (3 patients) as well as common alterations around the centromeres and telomeres. In the breast cancer dataset significantly different level of mutations were observed in the different subtypes in the cohort. Furthermore 499 genes were identified with significant correlation between their gene expression (GE) and underlying genomic alterations (either copy number (CN) or loss-of-heterozygosity (LOH)). Performing hierarchical clustering on the cohort using the 499 correlated genes enabled us to recover the subtypes' separation previously based on gene expression alone.

Arterial variants, defined as atypical presentations of anatomy including aberrant origin, course, and branching pattern, are important to be aware of because of their effects in the clinical setting as well as their possible link to pathology. Much research has already been done focusing on specific arterial variants in a specific region in the body. However, more research is needed to determine if there is a relationship between arterial variants in different regions of the body. The purpose of this study is to examine the whole-body arterial system of body donors in order to assess if there is a relationship between the presence of arterial variants in one region of the body to the other. The entire arterial system of twenty-five formalin fixed body donors was examined for the presence of arterial variants. The data was separated into two main categories, central variants (e.g. arch of the aorta, unpaired abdominal aortic branches) and peripheral variants (e.g. upper and lower extremities). The relationship between the central and peripheral variants was determined using quantitative observation, specifically, by examining the percent frequency of cases where arterial variants were co-occurring. Of the body donors examined, all were found to have at least one arterial variant, with an average of 8.7 variants per body. Arterial variants were most commonly found in the foregut with prevalence of 80%, the midgut (68%), left subclavian (60%), right upper extremity (52%), and the left upper extremity (48%). Of the central arterial variants, a percent frequency of 20% was found for the arch of the aorta, 20% for the coronary artery, 12% for the hindgut, 28% for the right renal, and 28% for the left renal. For the peripheral variants, the percent frequencies were as follows: brain variants were 4%, right carotid 8%, left carotid 0%, right subclavian 28%, left upper extremity 40%, right suprarenal 24%, left suprarenal 12%, right phrenic 24%, left phrenic 12%, gonadal 4%, right iliac 40%, left iliac 32%, and right lower extremity 40%. Examination of the relationship between central variants and peripheral variants reveals that the most common arterial variants to occur in tandem in the sample were those of the variant foregut with variants of the left subclavian artery (52% of cases), the upper and lower extremities (36-44% and 40-44% of cases, respectively), and the right iliac artery (36% of cases). The most common central arterial variants to co-occur were the variants of the foregut and midgut observed in 64% of cases. The frequency of cases involving normal central anatomy and variant peripheral anatomy indicates that vascular variants in the periphery are likely unrelated to variants in the central body cavities. However, it does seem like there are “hot spots” for arterial variants to occur, including the foregut, midgut left subclavian artery, right and left upper extremities, the right iliac artery, and the right and left lower extremities. Although there was no discernable pattern found between vascular variants in the present study, that does not preclude the possibility that there is a significant relationship between certain vascular variants. Either way, the high prevalence of cases with multiple arterial variations suggests that they may be more likely to occur than previously thought.

Thesis (M.Sc. (Med.))--University of the Witwatersrand, Faculty of Health Sciences, 1998. / The issue of Malagasy ancestry has been controversial, and has still not been completely resolved. The historical, linguistic, archaeological and some genetic evidence points to the fact that modern Malagasy are the descendants of immigrants who arrived on the island over the past 2000 years, from South and Southeast Asia, Africa and the Near East. In more recent centuries, mainly in the twentieth century, there have been significant numbers of Indian, Chinese and French immigrants. In addition, archaeological and historical studies of specific regional populations of Malagasy suggest a complex pattern of internal migration within the island, extending back in time to the first European contacts with the island in the sixteenth century. The 22 Malagasy ethnic groups may be classified as "highland" or "lowland" depending on their geographic distribution on the island. Within the ethnic groups, the founding populations have made different genetic contributions: the highland groups are said to have a greater Indonesian contribution to their ancestry, while the lowlanders have a greater African contribution to their ancestry. Genetic studies on the Malagasy have been limited by small sample sizes, deficiencies in sampling procedures and in the limited number of polymorphisms studied. In light of the paucity of written records, the Department of Human Genetics, SAIMR, has undertaken a large study in Madagascar to reconstruct the biological history of its people, using genetic variation. This thesis forms a part of this study. Variation in the a- and p-globin cluster has been extensively studied in many parts of the world, and has been shown to be population specific, with specific variants having distinct geographical distributions. Thus haemoglobin and its related disorders have been the subject of extensive studies for determining the origin(s) of particular populations. In this study, some of the a- and p-globin variation present in the Malagasy was characterised. Seven RFLPs/HVRs in the a-globin gene cluster and seven RFLPs in the p-globin gene cluster were analysed. The common a- and p-globin gene cluster haplotypes differ between African and Asian populations. Frequencies also vary between populations in a specific geographical regions. The aim of this study was to characterise the haplotypes present in the Malagasy, to provide information on the relative genetic contributions of different populations to the peoples of Madagascar. DNA samples from randomly selected, haematologically normal individuals were analysed. Individuals were chosen from six Malagasy ethnic groups: two “highland” populations (Merina and Betsileo), two “lowland" populations (Antasaka and Tsimiheti) and two populations from the south-west of the island (Mahafaly and Vezo). The groups chosen cover a broad range of Madagascar and thus provide some representation of the Malagasy population as a whole. The number of individuals studied in each ethnic group are as follows: Merina: 88; Betsileo: 78; Antasaka: 67; Tsimiheti: 67; Mahafaly: 26; Vezo: 25. The frequencies of the a- and (B-globin RFLP sites and a-globin HVRs in the Malagasy vere calculated. 5' and 3’ p-globin haplotypes were constructed on the basis of homozygosity. A maximum-likelihood algorithm was used to obtain frequencies of 5’ P-globin haplotypes that could not be assigned on the basis of homozygosity. These data were then subject to statistical analysis. The frequencies of the 5’ p-globin haplotypes (consisting of the five sites Hindi 5' to e, Hindi 11 within Gy and Ay, Hindi within \|/P and 3' to it) were the most informative data set for comparing the Malagasy ethnic groups to each other and to other world populations. Unfortunately, the maximum-likelihood estimates of 5‘ p-globin haplotypes could not be used for comparative analyses due to the lack of similar data in other populations. However the strong correlation between the maximum-likelihood frequencies and the observed frequencies illustrated the ability of the algorithm to determine hapiotype frequencies from otherwise uninformative individuals. 5’ p-globin haplotypes were assigned unambiguously for 248 Malagasy chromosomes. Ten haplotypes were found; of these, nine have been reported previously in other world populations and one has not been reported and hns thus been called “rare” in this study. The frequencies of unambiguous 5’ p-globin haplotypes in the Malagasy and the proposed parental populations were initially analysed with x2 tests. For a more accurate comparison between these populations, genetic distances were calculated and used for the construction of phylogenetic trees, principle component analysis was carried out, and a study of heterozygosity versus distance from the centroid was performed. Admixture estimates of two African populations and one Indonesian population to Malagasy ancestry were calculated. Certain general trends were noted in all the analyses. The results are in agreement with the historical data which provides evidence for both African and Asian contributions to Malagasy ancestry. The highlanders were more closely affiliated to the Indonesian/Polynesian populations, while the south-west groups showed the strongest associations with the African populations. The lowlanders were consistently intermediate in position between the highlanders and the south-west groups, with the Antasaka being slightly more closely related to the African populations than the Tsimiheti. The Malagasy were shown to have high heterozygosities, similar to those of African populations, and this high degree of diversity is probably a reflection of the many sources of ancestry of the Malagasy. The south-west groups were the furthest outliers in the model of heterozygosity versus distance from the centroid, suggesting that these groups are the most genetically admixed of all the Malagasy groups that were studied. Estimates of ancestral population admixture confirmed these trends, with the highlanders having the highest proportional contribution by Indonesians (53%), but the lowest total African contribution (47%), while the south-west groups have the highest Bantu contribution (65%). The Indonesian and African contributions to the lowlanders are intermediate between those to highlanders and south-west groups. Overall the Malagasy subjects included in this study showed a 61% African admixture contribution and a 39% Indonesian admixture contribution. It is hoped that the results obtained in this study will contribute to the larger project concerning the origins of the Malagasy, and that they may be used to shed further light on the much debated issue of Malagasy ancestry.

ABSTRACT The present study examined the distribution of six genetic variants (CYP17A1, CYP3A4, SRD5A2, KLK3, AR) in the androgen biosynthesis and metabolism pathway, in 14 sub-Saharan African populations. These polymorphisms have been implicated in several complex diseases, most notably prostate cancer. In order to elucidate the frequencies of these genetic variants, PCR-RFLP and STR based methodologies were employed. Consistent with previously reported results, the frequency distribution of the gene variants in the examined populations greatly coincided with prostate cancer incidence and geographic origin. Populations of African descent had the highest frequencies of the alleles that are postulated to increase risk to prostate cancer, whilst Asian populations had the lowest. Also, there were evident differences in the frequencies of these variants between populations of different continental origin particularly between African and Eurasian populations. The distribution of these genetic variants was further used to assess the spectrum of variation within Africa. The results were greatly aligned with those previously reported, providing further support to the origin and evolution of modern humans from Africa as well as other historic events.

Ph.D., Faculty of Science, University of the Witwatersrand, 2011 / The ABCB1 gene encodes P-glycoprotein, a transmembrane protein that regulates the efflux of drugs in the cells and may affect the response to antiretroviral drugs. ABCB1 polymorphisms affect the function or expression of P-gp. The 3435T allele has been associated with decreased protein production, but is in linkage disequilibrium with other polymorphisms. HIV is prevalent in Southern Africa, and characterization of ABCB1 variation may provide insight into its role in antiretroviral immune response. The aim was to determine if there was any association between ABCB1 variation, relative mRNA levels and immune response. Seven known polymorphisms were characterized for linkage disequilibrium and haplotype analysis, regions upstream of the gene were sequenced for bioinformatic analysis, the relative amounts of mRNA were determined, and CD4+ and viral load data was analyzed for association. Sequencing revealed six novel variations: T-137G, C-233T and G-298A upstream of exon 1, T108G and G153A in exon 2, and A111G in intron 26. The frequencies of the -129T (0.85), 1236T (0.70), 2677G (0.77), IVS 25+3050G (0.86), IVS 25+5231T (0.51), 3435C (0.88) and IVS 26+80T (0.89) polymorphisms were different and LD was lower compared to other populations. The haplotype frequencies were different to other populations and the genetic structure was probably a result of multiple recombination or mutation events. The viral load counts at the second measurement after baseline (time point 2) were significantly different from baseline for the 2677GG and 2677GA genotypes, and the -129T allele was associated with a lower proportional decrease in viral load at 8 the second measurement. The IVS 25+3050GG, 3435CC and IVS 26+80TT genotypes have been associated with lower mean relative mRNA levels. In conclusion, the genetic structure of the southern African populations is different from other populations and that genetic association and functional studies derived from other populations would be irrelevant in this population. A larger sample size and functional studies would be required to attempt to resolve the molecular mechanisms of the ABCB1 gene and to confirm the findings of association between ABCB1 polymorphisms and immune response.

Accurately distinguishing species in the fossil record is difficult when the extent of osteological variation in many modern animals is unknown. Research into intraspecific variation has been conducted in a number of groups, but has not been conducted for systematics use in most modern artiodactyls. In this dissertation I quantify intraspecific variation of teeth in 14 species of modern artiodactyl, then test how accurately cranial characters diagnose modern, sympatric species of duikers, and use this information to reassess the artiodactyl diversity of a fossil group: the superfamily Merycoidodontoidea in the John Day Fossil Beds. Ultimately, variation is not constant between orders or different size classes, is influenced by morphology, size, and dimorphism, and this variation should be incorporated into fossil diagnoses to avoid both overconfidence of diagnosis and under-recognition of possible intraspecific variation.