Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2012-08-29T21:26:52Z No. of bitstreams: 1 Taisa Manuela Bonfim Machado. Ancestralidade em Salvador - BA.pdf: 1157160 bytes, checksum: b3800dd208ac4ea86750232d8ab8ef3d (MD5) / Made available in DSpace on 2012-08-29T21:26:52Z (GMT). No. of bitstreams: 1 Taisa Manuela Bonfim Machado. Ancestralidade em Salvador - BA.pdf: 1157160 bytes, checksum: b3800dd208ac4ea86750232d8ab8ef3d (MD5) Previous issue date: 2008 / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, Bahia, Brasil / Os ameríndios, africanos e europeus foram identificados como principais formadores da população brasileira e conseqüentemente da população de Salvador. A população brasileira considerada a mais heterogênea do mundo é resultado de 500 anos de miscigenação. Contudo a distribuição dos grupos étnicos ancestrais ao longo do território brasileiro não ocorreu de forma homogênea, diferindo significativamente a depender da região geográfica. Além disso, houve um forte direcionamento entre os casamentos, sendo mais freqüentes as uniões entre homens europeus e mulheres ameríndias e africanas. Dados do IBGE 2000 mostram que em Salvador o percentual de afrodescendentes, por autodenominação é de 79,8%. Para estimarmos a contribuição dos grupos ancestrais nesta população foram analisados 1.286 indivíduos, provenientes da população de Salvador, para os alelos específicos de população AT3-I/D, APO, SB19.3, PV92, FYnull, LPL, CKMM, GC e CYP3A4 que apresentam alto diferencial de freqüência entre os grupos ancestrais. Para estimar a origem africana dos indivíduos também foi avaliada a presença de sobrenome de conotação religiosa. Foram identificados 287 sobrenomes nesta população A freqüência de sobrenomes de conotação religiosa foi de 54,9% na população de Salvador e avaliando as regiões presentes no estudo observamos uma relação inversa entre a classe sócio-econômica e a presença deste tipo de sobrenome. Estes dados foram confirmados por uma maior ancestralidade genômica africana (53,1%) entre indivíduos que apresentam sobrenomes de conotação religiosa. A miscigenação da população de Salvador foi confirmada pela diferença das freqüências desta população com as ancestrais. Assim como pela estimativa de mistura populacional, com contribuição africana de 49,2%; 36,3% européia e 14,5% ameríndia e também pelas análises de heterozigose média (0,397) e estrutura populacional. Foi calculada a estatística F (0,005) que demonstrou que as regiões da cidade de Salvador são diferentes, porém em pequenas proporções. Ao compararmos a estimativa da contribuição africana do IBGE, 2000, por autodenominação com os dados de sobrenome e moleculares deste trabalho concluímos que a autodenominação é um critério impreciso na avaliação da contribuição parental dentro desta população. Este tipo de trabalho pode auxiliar estudos de associação entre fatores de saúde com a heterogeneidade ancestral para melhoria e/ou implantação de programas de saúde pública que considerem a composição parental desta população. / Native American, Africans and Europeans are the major founder populations of Brazil and of Salvador city. Brazilian population is considered as the most heterogeneous in the world, resulting from 5 centuries of miscegenation. However, ethnic ancestral groups were not distributed equally in the different Brazilian regions. In addition, a strong bias occurred originated by more frequent unions among European men and Amerindians and Africans women. Results from IBGE 2000 show that in Salvador the percent of selfclassification afrodescending, is 79.8 %. To estimate the contribution of ancestral groups in these populations we analyzed some population specific alleles: AT3-I/D, APO, SB19.3, PV92, FYnull, LPL, CKMM, GC and CYP3A4 from 1,286 subjects of Salvador that presents large frequency differential among ancestry groups. To estimate the African origin of the subjects we also analyzed the religious connotation surnames. We identified 287 surnames in these populations. In Salvador population, the frequency of religious connotation surnames was 54. 9% and we observed an inverse relation between socioeconomic status and the presence of this type of surname. These data were confirmed for a major African genomic ancestry (53. 1%) between individuals that present religious connotation surname. The miscegenation of Salvador was confirmed by the frequencies differences in this population with the ancestry, such as the population admixture esteemed, with African contribution of 49.2%; 36.3% European and 14.5% Amerindian and also by heterozygosis mediam analyses (0,397) and populational structure. F statistic (0,005) was calculated and showed differences between regions in the city, but in little proportions, confirming the admixture estimated in these regions. When we compared IBGE- 2000 African contribution esteemed, by autodenomination, with the surnames and molecular data of this work we concluded that autodenomination is an inaccurate criterion to evaluate the parental contribution into this population. This kind of work can support association studies among health factors with ancestry heterogeneity to improve and/or to implement public health programs that consider the parental composition of this population.

Breast cancer is the most frequent malignant disease in the female population worldvide. About 10 % of all cases are of hereditary origin. The inactivation of tumor suppressor gene BRCA1 is the main genetic predisposing factor in breast cancer in the Czech Republic. Primarily, BRCA1 participates in DNA double strand break repair. Depending on cell cycle phase, the damage is repaired by homologous recombination or non-homologous end joining. Alternative splicing variants of BRCA1 are frequently detected during the genetic screening of high risk patients. The clinical significance of these variants is unknown. Understanding of the nature of breast cancer genetics is the critical factor for early diagnosis. Based on earlier studies from the Institute of Biochemistry and Experimental Oncology 1st Faculty of Medicine Charles University, two alternative splicing variants which were repeatedly detected in patients, were chosen for functional analysis. The aim of this work is to investigate the impact of alternative splicing variants BRCA1Δ5 and BRCA1Δ10 on DNA double strand breaks repair. Particular variants were over- expressed in the cells of model system. Activity of homologous recombination (HR) and non-homologous end joining (NHEJ) was scored by in vitro DNA repair assay. The cellular localization of...

Introduction: Amyotrophic lateral sclerosis (ALS) is a deadly, progressive neuromuscular disease that affects individuals all over the world. About 10% of the patients have a familial predisposition (FALS) while the remainder of cases are isolated or sporadic (SALS) and of unknown cause. To date, the principal recognized risk factors for ALS are higher age, male gender, slim figure (BMI<23) and a family history of ALS. In 1993, Rosen et al. observed that some FALS cases were associated with mutations in the gene encoding the CuZn superoxide dismutase enzyme (SOD1). Since then, several mutations in the SOD1 gene have been discovered, and mutations in more than 18 other genes have been associated with causing ALS. The aim of this thesis was to identify new mutations associated with ALS pathogenesis, and by comparing patients from different countries, were we also able to identify population-specific genetic variations. The studies are referred to as I–V. Methods: With written informed consent and adhering to the tenets of the Declaration of Helsinki, through a national network of ALS clinicians´, venous blood samples were collected from ALS patients and healthy subjects in Europe and the USA. The patients were diagnosed according to the El Escorial criteria, and as having FALS according to the criteria of Byrne et al. (2011). The DNA variations were amplified by various PCR techniques. (I, III and IV) The amplicons of ataxin 2 (ATXN2), profilin 1 (PFN1), and vesicle-associated membrane protein type B (VAPB) were characterised by direct sequencing. (II) After quantitative PCR, a genotype-phenotype correlation was performed to assess whether the survival motor neuron gene (SMN) modulates the phenotype of ALS. (V) The amplicons of the 50 base pair deletion in the SOD1 promotor (50 bp) were separated by electrophoresis on agarose. Results: (I) We observed a significant association between CAG expansions in the ATXN2 gene and ALS in a European cohort. (II) Abnormal copy number of the SMN1 gene was identified as a risk factor in France, but not in Sweden. Homozygosity of the SMN2 deletion prolonged survival among Swedish ALS patients, compared to French patients. (III) We identified two mutations in the PFN1 gene, the novel p.Thr109Met mutation and the p.Gln117Gly mutation, in two unrelated FALS patients. (IV) In our cohort, we identified five VAPB mutations p.Asp130Glu, p.Ser160del, p.Asp162Glu, p.Met170Ile, and p.Arg184Trp, two of which are novel. (V) The 50 bp deletion upstream of the SOD1 gene was found in equal frequencies in both the patient and control cohorts. The 50 bp deletion did not affect SOD1 enzymatic activity. Furthermore, we found no differences in age of onset or disease duration in relation to the 50 bp deletion genotype.VI Conclusions: (I) Our findings indicate that ATXN2 plays an important role in the pathogenesis of ALS, and that CAG expansions in ATXN2 are a significant risk factor for the disease. (II) We suggest that abnormal SMN1 gene copynumber cannot be considered a universal genetic susceptibility factor for ALS. We also propose that the effect of abnormal SMN2 gene copy number on ALS phenotype may differ between populations. (III) This work provides evidence that PFN1 mutations can cause ALS as a Mendelian dominant trait. The novel p.Thr109Met mutation also shows that disturbance of actin dynamics can cause motor neuron degeneration. (IV) We find it unlikely that the VAPB mutations cause ALS in our cohorts. (V) We find it unlikely that the 50 bp region contains important regulatory elements for SOD1 expression. This thesis supports the theory that ALS is a multigenetic disease, but there appears to be great genetic variation among apparently identical populations. These studies emphasise the importance of continuous genetic screening, to identify further mutations and genes involved in ALS disease, but it also highlights the importance of cooperation and comparison between countries. / On the aetiology of ALS: A comprehensive genetic study

In forensic science one frequently has to deal with unidentified skeletonised remains. When conventional methods of identification have proven unsuccessful, forensic facial reconstruction (FFR) may be used, often as a last resort, to assist the process. FFR relies on the relationships between the facial features, subcutaneous soft tissues and underlying bony structure of the skull. The aim of this study was to develop soft tissue thickness (STT) values for South African black females for application to FFR, to compare these values to existing literature or databases, and to test the accuracy and recognisability of reconstructions using these values. It also established whether population-specific STT values are necessary for FRR. Computerised tomography scanning was used to determine average populationspecific STT values at 28 facial landmarks of 154 black females. The Manchester method of facial reconstruction was employed to build faces, for which antemortem photographs were available, on two skulls that were provided by the South African Police Service’s (SAPS) Forensic Science Laboratory. Different data sets of STT values, namely values from this study, two sets of data from American blacks and a South African mixed ancestry group, were used to build four faces for each of the skulls. Two identification sessions were then held. In the first session, 30 observers were asked to select matches from a random group of 20 photographs of black females which included the two actual images. The identification rates calculated for each photograph revealed that the highest rates of a positive match were for the reconstructions based on South African values. In the second session another group of 30 volunteers were asked to match to each photograph the most similar of the four reconstructions made of that particular individual. The reconstructions with STT values from the current (South African) study were selected more often than the other data sets. Although shortcomings do exist, the identification sessions indicated that FFR can be of value. Furthermore, population-specific STT values are important, since skulls reconstructed using these values were selected or identified statistically significantly more often than the others. AFRIKAANS : In forensiese wetenskap het mens dikwels te doen met ongeïdentifiseerde skeletmateriaal. Wanneer die konvensionele metodes van identifikasie onsuksesvol is, mag forensiese gesigsrekonstruksie (FGR) gebruik word, dikwels as `n laaste uitweg, om die proses te help. FGR is afhanklik van die verhouding tussen die gelaatstrekke, subkutane sagte weefsels en onderliggende benige struktuur van die skedel. Die doel van hierdie studie was om sagte weefsel dikte (SWD) waardes vir Suid-Afrikaanse swart vroue te ontwikkel vir gebruik met FGR, om hierdie waardes te vergelyk met bestaande literatuur of databasisse, en die akkuraatheid en herkenbaarheid van rekonstruksies waar hierdie waardes gebruik was te toets. Dit is gedoen ten einde vas te stel of bevolking-spesifieke SWD waardes nodig is vir FGR. Gerekenariseerde tomografie skandering is gebruik om die gemiddelde bevolkingspesifieke SWD waardes op 28 gesigslandmerke van 154 swart vroue te bepaal. Die Manchester metode van gesigsrekonstruksie is gebruik om twee skedels, waarvan antemortem foto’s beskikbaar was en wat voorsien is deur die Suid Afrikaanse Polisie Diens (SAPD) se Forensiese Wetenskap Laboratorium, op te bou. Verskeie data stelle vir SWD waardes, naamlik waardes verkry in hierdie studie, twee stelle Amerikaanse waardes vir swart vroue en `n Suid Afrikaanse groep van gemengde afkoms, is vir hierdie studie gebruik om vier gesigte van elk van die skedels te bou. Twee identifikasie sessies is gehou. In die eerste sessie is 30 deelnemers gevra om passende foto’s uit `n algemene versameling van 20 foto’s van swart vroue te kies. Dit het die twee ware gesigte ingesluit. Die identifikasie waardes wat bereken is vir elke foto het getoon dat die hoogste waardes vir die werklike foto’s verkry is op rekonstruksies gebasseer op Suid-Afrikaanse waardes. In die tweede sessie was `n ander groep van 30 vrywillgers gevra om die mees soortgelyke van die vier rekonstruksies by die foto van die betrokke individu te pas. Die rekonstruksies met SWD waardes van die huidige (Suid Afrikaanse) studie was meer dikwels gekies as die van ander data stelle. Hoewel verskeie tekortkominge bestaan, het die identifikasie sessies getoon dat FGR van waarde kan wees. Verder is bevolking-spesifieke SWD waardes belangrik, aangesien skedels wat opgebou is met hierdie waardes statisties beduidend meer dikwels gekies of geïdentifiseer is as die ander. / Dissertation (MSc)--University of Pretoria, 2010. / Anatomy / unrestricted

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