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.

The moose population in Sweden is one of the highest in the world. The population have positive impacts on humans but also cause problems such as browsing damages and collisions with traffic. To manage this population in an adaptive and ecological sound way, the managers need to have as much information as possible. The aim of this study was to improve the description of Sweden’s moose management areas regarding available forage for moose. This is done by describing the heterogeneity of the landscape within the moose management areas, which is done by using different landscape indexes. The heterogeneity indexes is then used to analyze if correlation exists between the variation of the landscape and firstly data that describes the available food, secondly data that indicates the moose population density. Multiple regression analysis were done in order to find a model with the indexes that best explains the variation in available forage and moose population indicators.  The results in this study showed a positive correlation between number of moose shot per 1000 hectares and patch richness awhile a negative correlation was found between number of moose shot per 1000 hectares and edge density. Results also showed a negative correlation between both edge density and the patch richness in the landscape with the presence of rowan, sallow, aspen and oak (RASE). Further developments of indexes that describe landscape heterogeneity is needed, but this study may indicate that knowledge of the variation in the landscape might provide useful information on the prerequisites for the Swedish moose population.

The field of Teaching Arabic as a Foreign Language (TAFL) has seen in recent decades a growing interest in portraying and teaching one of the most salient and intrinsic features of Arabic: language variation. This thesis takes a position in contrast to approaches that portray the two varieties as being distinct and well-defined dichotomic units, in favour of an approach that interprets them as two heterogeneous language varieties within one singular linguistic system. The two language varieties are embodied by Standard and Colloquial Arabic and it is argued here for the teaching of both varieties to students of Arabic as a foreign language. In this light, this thesis sets out to investigate the development of two language skills, vocabulary knowledge and language awareness, in a diglossic learning environment. Moreover, it explores the attitudes and perceptions of the students towards Arabic variation. Two experimental methods based on focus-on-form instruction are used in this research to teach Colloquial Arabic to students of Arabic as a foreign language at higher-education level, and the empirical research is conducted within a semi-embedded research design in which qualitative and quantitative data are collected. Students from three universities participate in this research: the Universities of Exeter, Genoa and Milan. This allows for the comparison of results from students of different mother tongues. The main research question that this thesis sets out to answer is: does focus-on-form instruction lead to vocabulary development in two diglossic varieties, namely Standard and Colloquial Arabic, more effectively when it focuses on the two varieties separately or when it links their forms? Two sub-questions investigate which of the two methods of focus-on-form instruction lead more efficiently to the development of language awareness, and the impact they have on students’ attitudes towards Arabic variation. The last sub-question asks to what extent the development of the diglossic language skills and attitudes is a consequence of the method of instruction received. The results of this study suggest that the answer lies in focusing predominantly on one variety at a time with additional consolidation exercises that compare the forms of the two varieties. The main contributions of this thesis are both theoretical, to the literature of TAFL, and empirical, regarding the development of the language skills and attitudes measured.

All production machinery is designed with an inherent capability to handle slight variations in product. This is initially achieved by simply providing adjustments to allow, for example, changes that occur in pack sizes to be accommodated, through user settings or complete sets of change parts. By the appropriate use of these abilities most variations in product can be handled. However when extreme conditions of setups, major changes in product size and configuration, are considered there is no guarantee that the existing machines are able to cope. The problem is even more difficult to deal with when completely new product families are proposed to be made on an existing product line. Such changes in product range are becoming more common as producers respond to demands for ever increasing customization and product differentiation. An issue exists due to the lack of knowledge on the capabilities of the machines being employed. This often forces the producer to undertake a series of practical product trials. These however can only be undertaken once the product form has been decided and produced in sufficient numbers. There is then little opportunity to make changes that could greatly improve the potential output of the line and reduce waste. There is thus a need for a supportive modelling approach that allows the effect of variation in products to be analyzed together with an understanding of the manufacturing machine capability. Only through their analysis and interaction can the capabilities be fully understood and refined to make production possible. This thesis presents a constraint-based approach that offers a solution to the problems above. While employing this approach it has been shown that, a generic process can be formed to identify the limiting factors (constraints) of variant products to be processed. These identified constraints can be mapped to form the potential limits of performance for the machine. The limits of performance of a system (performance envelopes) can be employed to assess the design capability to cope with product variation. The approach is successfully demonstrated on three industrial case studies.

Cette thèse est la continuation d’un travail, qui a pour objectif d’expliquer le phénomène des emprunts et leurs adaptations phonologiques. La recherche se fonde sur la consultation du journal brésilien du XIXème siècle ‘A Gazetinha’, où l’on trouve un grand nombre de mots français. Ainsi, nous partons d’un corpus écrit, ce qui nous a conduit à réfléchir sur le rôle de l’orthographe dans le résultat de l’adaptation. Notre recherche dans la littérature sur les emprunts, nous a permis d’isoler deux aspects : les adaptations phonologiques des mots français en portugais et la frontière entre l’étymologie et les emprunts. Ce travail contribue à la description de la langue portugaise et de sa phonologie à partir des processus d’adaptation d’emprunts français, et, en outre, à la description des vocabulaires du portugais européen et du portugais brésilien à partir de leurs dictionnaires étymologiques et monolingues. Nos hypothèses fondamentales sont que l’orthographe et la connaissance du français ont un rôle dans le processus d’adaptation ; les locuteurs portugais et les brésiliens peuvent adapter différemment des mots français ; les vocabulaires européen et brésilien peuvent présenter des différences en ce qui concerne les mots d’origine française. Notre méthodologie pour vérifier les adaptations phonologiques consiste en l’application d’un test basé sur l’article The influence of orthography on loanword adaptations, de Vendelin et Peperkamp (2006). Le test a été adapté à notre sujet et appliqué aux locuteurs brésiliens ainsi qu’aux portugais afin de comparer les résultats. Nous envisageons dans notre travail six phonèmes français précis. Les résultats du test sur les adaptations phonologiques révèlent qu’il n’y a pas de différence de choix d’adaptation entre les locuteurs européens et les brésiliens au niveau phonologique. Les adaptations sont toujours vers la langue d’accueil, le portugais. Cependant, l’orthographe et la connaissance du français semblent liées comme facteurs agissants dans le processus quand le locuteur en a besoin. Les subtiles différences d’adaptations n’apparaissent qu’au niveau phonétique, en obéissant aux phénomènes de la langue portugaise. A propos du deuxième aspect de cette recherche- la frontière entre l’étymologie et les emprunts-, nous utilisons comme méthode la consultation de dictionnaires étymologiques et monolingues du portugais pour établir un cadre de discussion où sont comparées leurs informations sur l’origine des mots. Après une analyse de donnés, nous vérifions que les informations sont assez contrastées pour empêcher une lecture facile, qu’on soit linguiste ou non. Notre conclusion est que les dictionnaires ne sont pas une ressource de recherche aux informations incontestables et que d’autres études et réflexions sont encore nécessaires. / The main objective of this thesis is to understand the phenomenon of loanwords and their phonological adaptations. The research was based on consulting the Brazilian newspaper of the nineteenth century 'A Gazetinha', whose use of French words is common. Thus, we start with a written corpus, which makes us think about the role of orthography in loanword adaptations. After our research in the literature about loanwords, we focused on two aspects: the phonological adaptation of French words in Portuguese and the link between etymology and loanwords. This work contributes to the description of the Portuguese lexicon and its phonology from the process of adaptation of French loans. In addition, we contribute to the description of Portuguese vocabulary from their etymological dictionaries and monolingual. Our assumptions are that the orthography and knowledge of French play a role in the adaptation process; Portuguese and Brazilian speakers may show differences to adapt the French words; European and Brazilian vocabulary may show differences related with words of French origin. Our methodology for assessing the phonological adaptation involves the application of a test based on the article The influence of orthography on loanwords adaptations of Vendelin & Peperkamp (2006). The test has been adapted to our subject and applied to Brazilian and Portuguese speakers to compare the results. We analyze six French phonemes in this work. The test results on phonological adaptations show that there is no difference in choice of adaptation between European and Brazilian speakers at the phonological level. Adaptations are always to the target language, Portuguese. However, orthography and knowledge of French appear to be related and active factors in the process when the speaker is needed. The subtle differences in adaptation are only on the phonetic level, obeying the phenomena of Portuguese.Concerning the second aspect studied- the relation between etymology and loanwords-, we use as a research method the consultation of etymological and monolingual dictionaries of Portuguese to establish a framework for discussion comparing their information about the origins of words. After a data analysis, we verify that the information is quite contrasting, which prevents easy reading to any reader, not just to linguists. Our conclusion is that dictionaries are not a source of research with compelling information and other studies and discussions are still needed.