Thesis (Ph. D.)--University of Hong Kong, 2010. / Includes bibliographical references (leaves 150-166). Also available in print.

Thesis (Ph. D.)--University of Texas at Austin, 2003. / Vita. Includes bibliographical references. Available also from UMI Company.

Thesis (M.A.). / Written for the Dept. of Philosophy. Title from title page of PDF (viewed 2008/07/28). Includes bibliographical references.

Thesis (Ph. D.)--University of Hong Kong, 2010. / Includes bibliographical references (leaves 150-166). Also available online.

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Mammalian nuclear function depends on the complex interaction of genetic and epi-genetic elements coordinated in space and time. Structure and function overlap to such a degree that they are usually considered as being inextricably linked. In this work I combine an experimental approach with a computational one in order to answer two main questions in the field of mammalian chromosome organization. In the first section of this thesis, I attempted to answer the question, to what extent does chromatin from different chromosome territories share the same space inside the nucleus? This is a relatively open question in the field of chromosome territories. It is well-known and accepted that interphase chromosomes are spatially constrained inside the nucleus and that they occupy their own territory, however, the degree of spatial interaction between neighbouring chromosomes is still under debate. Using labelling methods that directly incorporate halogenated DNA precursors into newly replicated DNA without the need for immuno-detection or in situ hybridization, we show that neighbouring chromosome territories colocalise at very low levels. We also found that the native structure of DNA foci is partially responsible for constraining the interaction of chromosome territories as disruption of the innate architecture of DNA foci by treatment with TSA resulted in increased colocalisation signal between adjacent chromosomes territories. The second major question I attempted to answer concerned the correlation between nuclear function and the banding pattern observed in human mitotic chromosomes. Human mitotic chromosomes display characteristic patterns of light and dark bands when visualized under the light microscope using specific chemical dyes such as Giemsa. Despite the long standing use of the Giemsa banding pattern in human genetics for identifying chromosome abnormalities and mapping genes, little is known about the molecular mechanisms that generate the Giemsa banding pattern or its biological relevance. The recent availability of many genetic and epigenetic features mapped to the human genome permit a high-resolution investigation of the molecular correlates of Giemsa banding. Here I investigate the relationship of more than 50 genomic and epigenomic features with light (R) and dark (G) bands. My results confirm many classical results, such as the low gene density of the most darkly staining G bands and their late replication time, using genome-wide data. Surprisingly, I found that for virtually all features investigated, R bands show intermediate properties between the lightest and darkest G bands, suggesting that many R bands contain G-like sequences within them. To identify R bands that show properties of G bands, I employed an unsupervised learning approach to classify R bands on their genomic and epigenomic properties and show that the smallest R bands show a tendency to have characteristics typical of G bands. I revisit the evidence supporting the boundaries of G and R bands in the current cytogenomic map and conclude that inaccurate placement of weakly supported band boundaries can explain the intermediate pattern of R bands. Finally, I propose an approach based on aggregating data from multiple genomic and epigenomic features to improve the positioning of band boundaries in the human cytogenomic map. My results suggest that contiguous domains showing a high degree of uniformity in the ratio of heterochromatin and euchromatin sub-domains define the Giemsa banding pattern in human chromosomes.

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Made available in DSpace on 2014-08-13T14:50:48Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-12-18Bitstream added on 2014-08-13T18:00:29Z : No. of bitstreams: 1 000758930_20150818.pdf: 1212662 bytes, checksum: b031bf1d8704df644dfe9adcd8ac1f68 (MD5) Bitstreams deleted on 2015-08-20T11:58:35Z: 000758930_20150818.pdf,. Added 1 bitstream(s) on 2015-08-20T11:59:12Z : No. of bitstreams: 1 000758930.pdf: 3771682 bytes, checksum: 5c0fc2cb3bf6c39b641b63aa4f2b4bee (MD5) / O câncer de mama (CM) é uma doença heterogênea em relação às alterações moleculares, composição celular e evolução clínica. Pacientes com características clínicas e histopatológicas semelhantes podem apresentar prognósticos distintos. Análises de alterações genômicas em larga escala têm contribuído para identificar regiões e genes associados com os vários estágios da tumorigênese mamária. O presente estudo teve como objetivo avaliar o perfil de alterações no número de cópias genômicas por Hibridação Genômica Comparativa baseada em arrays (aCGH), utilizando a plataforma 4x180K (Agilent Technologies) em 53 carcinomas ductais invasivos (CDI) primários. Os CDI apresentaram 3.849 alterações genômicas, com semelhante proporção de perdas e ganhos genômicos (1.622 e 1.731, respectivamente), 444 ganhos em alto nível (12%) e 52 perdas homozigotas (1%). Foram identificadas 19 alterações genômicas significativamente recorrentes presentes em mais de 20% dos tumores. Foram detectadas perdas em 1p36.32, 8p23.3, 8p23.1, 8p11.23, 11q25, 14q11.1-q11.2, 16q23.3, 16q24.1 e 18q23; e ganhos em 1q21.1, 1q21.2, 1q22, 1q32.1, 1q42.3, 1q44, 8q24.21 e 15q11.2. As alterações mais prevalentes foram ganhos em 8q24.21 (36%) e 1q44 (32%), e a perda em 8p11.23 (28,3%). Ganhos em 1q21.1-1q21.2 foram associados com tumores negativos para o receptor de estrógeno (ER-) (P=0,016). Perda em 8p23.1 foi associada com um maior tempo de sobrevida livre de doença (P=0,027) e perda em 8p23.3 com tumores HER2+ (P= 0,033) e Ki67 alto (P= 0,036). Ganho em 8q24.21 foi associado com menor risco de acometimento de linfonodos (P=0,0199). A perda em 14q11.1-q11.2 associou-se com características de maior agressividade tumoral, como grau III (P=0,0147), Ki67 alto (P=0,0096) e pior evolução clínica, desenvolvimento de metástase (P=0,0375). Perda em 18q23 foi associada com tumores negativos para o receptor de progesterona (PR-) (P=0,0065). A ... / Breast cancer (BC) is a heterogeneous both at molecular and clinical level. Patients with similar clinical and histopathological findings can present different prognosis. Analysis of large scale genomic changes have helped to identify regions and genes associated with the various stages of mammary tumorigenesis. The present study aimed to evaluate the genomic profile by Comparative Genomic Hybridization array-based (aCGH), using the platform 4x180K (Agilent Technologies) in 53 primary invasive ductal carcinomas (IDC). The IDC showed 3849 genomic alterations, with similar proportion of genomic gains and losses (1,622 and 1,731, respectively), 444 alterations were found with high copy number gains (12%) and 52 homozygous losses (1%). We were identified 19 significantly recurrent genomic alterations in more than 20% of tumors. Losses were detected at 1p36.32, 8p23.3, 8p23.1, 8p11.23, 11q25, 14q11.1-q11.2, 16q23.3, 16q24.1 and 18q23, and gains at 1q21.1, 1q21.2, 1q22, 1q32.1, 1q42.3, 1q44, 8q24.21 and 15q11.2. The most frequent alterations were gains at 8q24.21 (36%) and 1q44 (32%), and losses at 8p11.23 (28.3%). Gains in 1q21.1-1q21.2 were associated with negative estrogen receptor (ER-) (P = 0.016) tumors. Loss on 8p23.1 was associated with longer disease-free survival (P = 0.027). Losses on 8p23.3 were associated with HER2 + tumors (P = 0.033) and high level of Ki67 (P = 0.036). Gain at 8q24.21 was associated with lower risk of lymph node involvement (P = 0.0199). Loss at 14q11.1-q11.2 was associated with more aggressive tumor characteristics such as grade III (P = 0.0147), high level of Ki67 (P = 0.0096) and worse clinical outcome, with metastasis development (P = 0.0375). Loss at 18q23 was associated with progesterone receptor negative (PR-) (P = 0.0065) tumors. The comparison of the genomic alterations according to receptor status ER, PR and HER2, lymph node involvement (LN) and development of distant metastases (DM) revealed ...