Thesis (M.A. (Translation Studies and Linguistics)) --University of Limpopo, 2012 / This study analyse given and inherited names among the Northern Sotho speaking people in Moletjie and Sekhukhune. The study indicates that names are some of the most important things in people’s lives. It has been indicated that naming cannot be taken for granted as a name serves as an important identity feature. A person without a name is an incomplete person. The study has revealed that the people in Moletjie and Sekhukhune bestow names to people based on ancestors, totems, marriage and initiation schools.

No description available.

Brittle cornea syndrome (BCS) is an autosomal recessive, multisystemic connective tissue disorder characterised by extreme corneal thinning and fragility. Mutations in transcription factors ZNF469 and PRDM5 cause BCS types 1 and 2, respectively. Both genes are believed to regulate the transcription of extracellular matrix (ECM) components, particularly fibrillar collagens, and are suggested to act on a common pathway. Molecular diagnosis is available for affected patients, and those at risk of being heterozygous carriers. Chapter 3 presents the identification of mutations in ZNF469 in 14 families with BCS, and evidence for the downregulation of ECM-associated transcripts in skin fibroblasts from patients with ZNF469-associated disease by Q-PCR.Chapters 4 and 5 focus on PRDM5-associated disease. Chapter 4 highlights previously undescribed and potentially phenotype-related aspects of PRDM5- associated BCS. In chapter 4, a potential role for PRDM5 in development of Bruch’s membrane is suggested, by the observation of significantly reduced expression of major components of Bruch’s membrane, including collagens types I, III, and IV in patients with PRDM5-associated disease using immunohistochemistry. A first description of PRDM5 expression in the human eye is also presented in chapter 4. In chapter 5, a potential role for PRDM5 in retinal vasculogenesis is suggested. PRDM5-related disease also offers an in vivo opportunity to observe a subset of epigenetic regulatory mechanisms in an inherited eye disease, providing mechanistic insights, presented in chapter 5. Examination of PRDM5 interaction partners by pull-down and mass spectrometry reveals the diminished interaction of a PRDM5 construct carrying a BCS-associated mutation with repressive complexes, and, through studies on fibroblasts and retinal tissue from patients, we suggest a role for dysregulation of the repressive histone mark H3K9 di- methylation in vivo. These findings suggest a role for a molecular network surrounding dysregulated H3K9 di-methylation in PRDM5-associated disease. Finally, chapter 6 expands the study of a rare disease into more common diseases investigating the role of genetic variations in ZNF469 and PRDM5 in keratoconus, an ocular disorder resulting in progressive corneal thinning. I identified enrichment of rare potentially pathogenic alleles in ZNF469 in 12.5% of keratoconus patients, highlighting ZNF469 as the most significant genetic factor responsible for keratoconus identified to date. In conclusion, this study of a rare disease, BCS, has provided translational research insights (chapter 3), functional insights (chapter 4) mechanistic insights (chapter 5) and has expanded into other, less rare, diseases (chapter 6).

Inherited thrombocytopenias, including inherited giant platelet disorders (IGPD) or macro thrombocytopenias are relatively rare, but their prevalence is likely underestimated from complexities of diagnosis and a spectrum of subclinical phenotypes. Harris platelet syndrome (HPS) is the most common IGPD reported from the Indian subcontinent. Of note there are an increased number of hemoglobinopathies reported from the geographic location. We analysed red blood cell and platelet indices of blood donors with HPS from the north eastern part of India and compared them with blood indices of blood donors of south India. We found a statistically significant lower platelet count in blood donors with HPS (median, range) 132 (71-267) vs. 252 (160-478) as compared to donors from south India (P < 0.001). Mean platelet volume (MPV) was higher in donors with HPS 13.1, (range 12-21.9 fl) as compared to donors from south India 7.35 (range 6-9.2 fl) (P < 0.001). This study showed that blood donors with HPS had a low median platelet bio-mass 0.17 (0.10-0.38%) vs. 0.19 (0.13-0.28%) in donors from south India. The platelet distribution width (PDW) was 17.4 (14.9-19.6) in donors with HPS vs. 16.38 (15.2-18.5) in south Indian blood donors (P < 0.001). Thirty-three donors with HPS had a normal platelet count with MPV more than 12 fL. Only donors with HPS had giant platelets and thrombocytopenia on peripheral blood smear examination. None of these donors had Dohle body inclusion in their leukocytes. Compared to donors from south India, donors with HPS had a significantly lower hemoglobin 13.8 (12-16.3 gm/dL) vs. 14.8 (12-18) respectively (P < 0.001) while red distribution width (RDW) was higher in HPS 13.6 (11.5-16.7) vs. 12.8 (11.4-15.1). However we did not find any statistically significant difference in MCV, MCH, MCHC between the two groups. Peripheral blood smear did not show any obvious abnormal red blood cell morphology. In the blood donors with HPS we found a statistically higher MPV, RDW and a lower platelet count and platelet biomass. A population-based study will be helpful in determining the existence of any hemoglobinopathies among subjects with HPS.

The purpose of the thesis is to investigate what circumstances supports inherited responsibility to afford reparations. The general arguments for and against inherited obligations are presented and discussed. Hereafter, Denmark and Australia’s forced assimilation policies are examined in order to establish their responsibilities to correct the past injustice. The general arguments are applied when scrutinizing the cases. It is visible that it remains difficult to determine a nation’s responsibilities to correct past injustices, however, once considering the continuance of communities as well as inherited benefits and desert-claims, it seems justified that nations also inherit liabilities. The thesis is argumentative and normative in nature, entailing suggestions both for and against inherited responsibility. Once nations recognize that the purpose is to correct an injustice, and not take responsibility for its occurrence, it becomes clear that nations ought to accept inherited responsibility to afford reparations.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24087号 / 医博第4863号 / 新制||医||1059(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 近藤 尚己, 教授 山本 洋介, 教授 辻川 明孝 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Copy number variation (CNV) is an important polymorphism that is associated with a wide range of traits in human, wild and livestock species. In chicken, an important source of animal protein and a developmental model organism, CNV is associated with several phenotypes and evolutionary footprints. However, identification and characterization of CNV inheritance on chicken genome lacks further investigation. We screened CNVs in chicken using two distinct populations with known pedigree. In 826 broilers we identified 25,819 CNVs (4,299 deletions and 21,520 duplications) of which 21,077 were inherited, 201 showed no inheritance and 4,541 were classified as de novo CNVs. In 514 F2 animals (layer and broiler cross) we identified 21,796 CNVs (2,254 deletions and 19,543 duplications) of which 18,230 were inherited, 587 not inherited and 2,979 were classified as de novo CNVs. After a strict filtering step to remove potential false positives and negative CNVs, only 220 (4.84%) and 430 (14.43%) de novo CNVs remained in the broiler and F2 populations, respectively. A total of 33.11% (50 out of 151) of the inherited CNVs identified in ten animals were validated by sequencing data. From the validated CNVs, 64% had more than 80% of their size (bp) validated. A total of 59% and 48.8% were classified as novel CNVs regions (CNVRs) in the broiler and F2, respectively. Considering the Bonferroni-corrected p-values for multiple testing and statistically significant p-values &le; 0.01, we found two CNV segments significantly associated with breast weight, one with breast weight yield, six with breast meat weight, 18 CNV segments with breast meat yield, four with breast filet weight and two with breast yield. These CNV segments that were significantly associated overlapped with 181 protein-coding genes. The CNVseg 300, that was associated with all traits and encompass six CNVRs, overlapped a total of 26 protein-coding genes. Among these genes, the gene MYL1 (Myosin Light Chain 1) is expressed in the fast skeletal muscle fibers, and the genes MLPH (Melanophilin), PRLH (Prolactin Releasing Hormone) and RAB17 (Member RAS Oncogene Family), that were associated with the lavender phenotype (feather blue-grey color) and regulation of homeothermy and the metabolism. The present study improves our knowledge about CNV in the chicken genome and provides insight in the distribution and of different classes of CNVs, i.e. inherited and de novo CNVs, in two experimental chicken populations. In addition, the genome-wide association analyses were the first performed on broiler population with breast muscle traits, that are important characteristics for poultry production. The GWAS results allow us to understand the probably relationship between some genes and CNVRs that are significantly associated with breast muscle traits. / A variação de número de cópias (CNV) é um polimorfismo importante que está associado a uma ampla gama de características em seres humanos, espécies selvagens e domésticas. Em frango, que é uma importante fonte de proteína e considerado um modelo biológico, CNVs foram associados a vários fenótipos e passos evolutivos. No entanto, nenhum estudo foi realizado para a identificação e caracterização da herança da CNV no genoma da galinha. Identificamos as CNVs no genoma da galinha usando duas populações experimentais e com pedigree conhecido: uma população de frangos de corte e uma F2. Em 826 frangos de corte, identificamos 25.819 CNVs (4.299 deleções e 21.520 duplicações), dos quais 21.077 foram herdados, 201 não foram herdados e 4.541 foram CNVs denominados de novo. Em 514 animais F2, identificamos 21.796 CNVs (2.254 deleções e 19.543 duplicações) das quais 18.230 foram herdadas, 587 não foram herdadas e 2.979 foram de novo CNVs. Após a etapa de filtragem nos de novo CNVs, apenas 220 (4,84%) e 430 (14,43%) permaneceram nas populações de frango de corte e F2, respectivamente. Um total de 33,11% (50 de 151) das CNV identificadas por dados de genotipagem em dez animais foram validados por dados de sequenciamento. Dos validados, 64% tinham mais de 80% do tamanho (pb) validados. Um total de 59% e 48,8% foram classificados como novas regiões de CNVs (CNVRs) nas populações de frango de corte e F2, respectivamente. Considerando os p-values corrigidos por Bonferroni para testes múltiplos e estatisticamente significativos (&le; 0,01), encontramos dois segmentos de CNV significativamente associados ao peso do peito, um ao rendimento de peso de peito, seis ao peso de carne de peito, 18 ao rendimento de carne de peito, quatro ao peso de filé de peito e dois ao rendimento do filé de peito. Esses segmentos de CNV significativamente associados estão sobrepostos com 181 genes codificadores de proteínas. O CNVseg 300, que foi associado a todas as características e abrange seis CNVRs, foram sobrepostos a um total de 26 genes codificadores de proteínas. Entre estes genes, o gene MYL1 (Myosin Light Chain 1) é expresso nas fibras rápidas do músculo esquelético, e os genes MLPH (Melanophilin), PRLH (Prolactin Releasing Hormone) e RAB17 (Member RAS Oncogene Family), que foram anteiromente associados ao fenótipo de cor azul acinzentado de penas e à regulação da homeotermia e do metabolismo. O presente estudo melhora o conhecimento sobre CNVs no genoma de frango, especialmente sobre a distribuição de CNV herdadas, não herdadas e de novo, em duas populações experimentais de frango. Além disso, a associação genômica foi a primeira realizada na população de frangos de corte com características do músculo do peito, que são muito importantes para a avicultura. Os resultados do GWAS nos permitem compreender a provável relação entre alguns genes e CNVRs que foram significativamente associados às características do músculo do peito.

Copy number variation (CNV) is an important polymorphism that is associated with a wide range of traits in human, wild and livestock species. In chicken, an important source of animal protein and a developmental model organism, CNV is associated with several phenotypes and evolutionary footprints. However, identification and characterization of CNV inheritance on chicken genome lacks further investigation. We screened CNVs in chicken using two distinct populations with known pedigree. In 826 broilers we identified 25,819 CNVs (4,299 deletions and 21,520 duplications) of which 21,077 were inherited, 201 showed no inheritance and 4,541 were classified as de novo CNVs. In 514 F2 animals (layer and broiler cross) we identified 21,796 CNVs (2,254 deletions and 19,543 duplications) of which 18,230 were inherited, 587 not inherited and 2,979 were classified as de novo CNVs. After a strict filtering step to remove potential false positives and negative CNVs, only 220 (4.84%) and 430 (14.43%) de novo CNVs remained in the broiler and F2 populations, respectively. A total of 33.11% (50 out of 151) of the inherited CNVs identified in ten animals were validated by sequencing data. From the validated CNVs, 64% had more than 80% of their size (bp) validated. A total of 59% and 48.8% were classified as novel CNVs regions (CNVRs) in the broiler and F2, respectively. Considering the Bonferroni-corrected p-values for multiple testing and statistically significant p-values &le; 0.01, we found two CNV segments significantly associated with breast weight, one with breast weight yield, six with breast meat weight, 18 CNV segments with breast meat yield, four with breast filet weight and two with breast yield. These CNV segments that were significantly associated overlapped with 181 protein-coding genes. The CNVseg 300, that was associated with all traits and encompass six CNVRs, overlapped a total of 26 protein-coding genes. Among these genes, the gene MYL1 (Myosin Light Chain 1) is expressed in the fast skeletal muscle fibers, and the genes MLPH (Melanophilin), PRLH (Prolactin Releasing Hormone) and RAB17 (Member RAS Oncogene Family), that were associated with the lavender phenotype (feather blue-grey color) and regulation of homeothermy and the metabolism. The present study improves our knowledge about CNV in the chicken genome and provides insight in the distribution and of different classes of CNVs, i.e. inherited and de novo CNVs, in two experimental chicken populations. In addition, the genome-wide association analyses were the first performed on broiler population with breast muscle traits, that are important characteristics for poultry production. The GWAS results allow us to understand the probably relationship between some genes and CNVRs that are significantly associated with breast muscle traits. / A variação de número de cópias (CNV) é um polimorfismo importante que está associado a uma ampla gama de características em seres humanos, espécies selvagens e domésticas. Em frango, que é uma importante fonte de proteína e considerado um modelo biológico, CNVs foram associados a vários fenótipos e passos evolutivos. No entanto, nenhum estudo foi realizado para a identificação e caracterização da herança da CNV no genoma da galinha. Identificamos as CNVs no genoma da galinha usando duas populações experimentais e com pedigree conhecido: uma população de frangos de corte e uma F2. Em 826 frangos de corte, identificamos 25.819 CNVs (4.299 deleções e 21.520 duplicações), dos quais 21.077 foram herdados, 201 não foram herdados e 4.541 foram CNVs denominados de novo. Em 514 animais F2, identificamos 21.796 CNVs (2.254 deleções e 19.543 duplicações) das quais 18.230 foram herdadas, 587 não foram herdadas e 2.979 foram de novo CNVs. Após a etapa de filtragem nos de novo CNVs, apenas 220 (4,84%) e 430 (14,43%) permaneceram nas populações de frango de corte e F2, respectivamente. Um total de 33,11% (50 de 151) das CNV identificadas por dados de genotipagem em dez animais foram validados por dados de sequenciamento. Dos validados, 64% tinham mais de 80% do tamanho (pb) validados. Um total de 59% e 48,8% foram classificados como novas regiões de CNVs (CNVRs) nas populações de frango de corte e F2, respectivamente. Considerando os p-values corrigidos por Bonferroni para testes múltiplos e estatisticamente significativos (&le; 0,01), encontramos dois segmentos de CNV significativamente associados ao peso do peito, um ao rendimento de peso de peito, seis ao peso de carne de peito, 18 ao rendimento de carne de peito, quatro ao peso de filé de peito e dois ao rendimento do filé de peito. Esses segmentos de CNV significativamente associados estão sobrepostos com 181 genes codificadores de proteínas. O CNVseg 300, que foi associado a todas as características e abrange seis CNVRs, foram sobrepostos a um total de 26 genes codificadores de proteínas. Entre estes genes, o gene MYL1 (Myosin Light Chain 1) é expresso nas fibras rápidas do músculo esquelético, e os genes MLPH (Melanophilin), PRLH (Prolactin Releasing Hormone) e RAB17 (Member RAS Oncogene Family), que foram anteiromente associados ao fenótipo de cor azul acinzentado de penas e à regulação da homeotermia e do metabolismo. O presente estudo melhora o conhecimento sobre CNVs no genoma de frango, especialmente sobre a distribuição de CNV herdadas, não herdadas e de novo, em duas populações experimentais de frango. Além disso, a associação genômica foi a primeira realizada na população de frangos de corte com características do músculo do peito, que são muito importantes para a avicultura. Os resultados do GWAS nos permitem compreender a provável relação entre alguns genes e CNVRs que foram significativamente associados às características do músculo do peito.

No description available.

Myoclonus-Dystonia (MD) is an inherited, rare, autosomal dominant movement disorder characterized by quick, involuntary muscle jerking or twitching (myoclonus) and involuntary muscle contractions that cause twisting and pulling movements, resulting in abnormal postures (dystonia). The first MD locus was mapped to 7q21-q31 and called DYT11; this locus corresponds to the SGCE gene. Our group previously identified a second MD locus (DYT15) which maps to a 3.18 Mb region on 18p11. Two patients were chosen to undergo next-generation sequencing, which identified 2,292 shared novel variants within the critical region. Analysis of these variants revealed a 3 bp duplication in a transcript referred to as CD108131, which is believed to be a long non-coding RNA. Characterization of this transcript determined that it is 863 bp in size, it is ubiquitously expressed, with high expression in the cerebellum, and it accounts for ~3% of MD cases.