Thesis (Ph. D.)--Washington State University, May 2010. / Title from PDF title page (viewed on June 9, 2010). "Department of Chemistry." Includes bibliographical references.

Thesis (Ph. D.)--University of California, Berkeley, 1990. / Includes bibliographical references (leaves 156-169).

Thesis (Ph. D.)--University of Pittsburgh, 1991. / Includes bibliographical references (leaves lxiv-lxix).

Thesis (Ph. D.)--University of Wisconsin, 1967. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (M. Sc.)--University of Alberta, 2010. / Title from pdf file main screen (viewed on July 8, 2010). A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Master of Science in Ecology, Department of Biological Sciences, University of Alberta. Includes bibliographical references.

Made available in DSpace on 2014-10-09T12:25:02Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T13:56:16Z (GMT). No. of bitstreams: 1 00321.pdf: 1033687 bytes, checksum: 312be4825d1fd3951e52d9b6f0049c1c (MD5) / Dissertacao (Mestrado) / IEA/D / Instituto de Química - Universidade de São Paulo - IQ/USP

The genetic architectures of cancer and congenital disorders are heterogeneous and incompletely mapped. Rare and low-frequency variants of incomplete penetrance are emerging as an important class of germline and somatic variation, but their contribution to disease remains poorly characterised. This thesis aims to identify and assess pathogenic mutations in the 1q41q42 microdeletion syndrome, neural tube defects, neuropsychiatric disorders and cancer. Rare microdeletions at the 1q41q42 locus cause a clinically heterogeneous syndrome characterized by developmental delay, characteristic dysmorphic features and brain morphological abnormalities. Examining new and published patients with 1q41q42 microdeletions, we found that TP53BP2, encoding ASPP2, is a strong candidate for being the gene responsible for brain morphological abnormalities of the syndrome. Mice deficient for Trp53bp2 show multiple abnormalities overlapping the features of the 1q41q42 microdeletion syndrome such as dysmorphic lateral ventricles, heart and urogenital abnormalities. ASPP2 deficiency also causes neural tube defects, hopping gait, and male-specific motion hyperactivity in mice. We further identify candidate pathogenic TP53BP2 duplications, implicating TP53BP2 dosage sensitivity in the ganglionic eminences of the developing brain, manifested by structural abnormalities in the striatum and lateral ventricles of both deletion and duplication patients. ASPP2 controls neuroepithelial cell polarity via Par3 and genetic disruption of aPKC-Par3 interaction by rare missense variants was implicated in human neural tube defects. An integrative analysis of cancer genomic data revealed that PPP1R13B, encoding ASPP1, bears many hallmarks of a tumour suppressor gene, despite being mutated at a low absolute frequency. A subset of missense somatic mutations in ASPP genes genetically interact with TP53 mutations, disrupting an autoinhibitory mechanism to modulate p53-dependent transcription. In summary, this work identified novel candidate pathogenic variants in developmental disorders and cancer, and explored the mechanisms underlying their respective genotype-phenotype links.

Thanks to the affordability of DNA sequencing, hundreds of thousands of individuals with rare disorders are undergoing whole-genome sequencing in an effort to reveal novel disease aetiologies, increase our understanding of biological processes and improve patient care. However, the power to discover the genetic causes of many unexplained rare diseases is hindered by a paucity of cases with a shared molecular aetiology. This thesis presents research into statistical and computational methods for determining the genetic causes of rare diseases. Methods described herein treat important aspects of the nature of rare diseases, including genetic and phenotypic heterogeneity, phenotypes involving multiple organ systems, Mendelian modes of inheritance and the incorporation of complex prior information such as model organism phenotypes and evolutionary conservation. The complex nature of rare disease phenotypes and the need to aggregate patient data across many centres has led to the adoption of the Human Phenotype Ontology (HPO) as a means of coding patient phenotypes. The HPO provides a standardised vocabulary and captures relationships between disease features. I developed a suite of software packages dubbed 'ontologyX' in order to simplify analysis and visualisation of such ontologically encoded data, and enable them to be incorporated into complex analysis methods. An important aspect of the analysis of ontological data is quantifying the semantic similarity between ontologically annotated entities, which is implemented in the ontologyX software. We employed this functionality in a phenotypic similarity regression framework, 'SimReg', which models the relationship between ontologically encoded patient phenotypes of individuals and rare variation in a given genomic locus. It does so by evaluating support for a model under which the probability that a person carries rare alleles in a locus depends on the similarity between the person's ontologically encoded phenotype and a latent characteristic phenotype which can be inferred from data. A probability of association is computed by comparison of the two models, allowing prioritisation of candidate loci for involvement in disease with respect to a heterogeneous collection of disease phenotypes. SimReg includes a sophisticated treatment of HPO-coded phenotypic data but dichotomises the genetic data at a locus. Therefore, we developed an additional method, 'BeviMed', standing for Bayesian Evaluation of Variant Involvement in Mendelian Disease, which evaluates the evidence of association between allele configurations across rare variants within a genomic locus and a case/control label. It is capable of inferring the probability of association, and conditional on association, the probability of each mode of inheritance and probability of involvement of each variant. Inference is performed through a Bayesian comparison of multiple models: under a baseline model disease risk is independent of allele configuration at the given rare variant sites and under an alternate model disease risk depends on the configuration of alleles, a latent partition of variants into pathogenic and non-pathogenic groups and a mode of inheritance. The method can be used to analyse a dataset comprising thousands of individuals genotyped at hundreds of rare variant sites in a fraction of a second, making it much faster than competing methods and facilitating genome-wide application.

Many of the world's economic rare earth element (REE) deposits are formed from, or have been subsequently upgraded by, hydrothermal fluids. Some of the most important REE minerals are the light REE (LREE) enriched fluorocarbonates and carbonates, which are commonly found in carbonatites. Textural and mineralogical evidence from these and other sites point towards wall rock composition as a major control on the observed REE mineralisation, with the supply of carbonate, and possibly fluoride, thought to be the limiting factor. Despite theoretical and experimental studies focussed on REE speciation in hydrothermal fluids, and a few on REE mineral solubility, there remains a lack of understanding of the processes occurring at the uid-rock interface during REE carbonate and fluorocarbonate mineralisation. Many of the issues surrounding this topic stem from the difficulty of working at elevated temperatures, low REE concentrations, and with the corrosive fluoride ion. The synthesis of REE carbonates under simple, low temperature conditions is a useful starting point for understanding REE mineralisation, and as such has been the focus of research for decades. Despite this, cross-series trends are rarely assessed together under the same conditions, and multi-REE-bearing systems - useful for assessing REE fractionation - have scarcely been explored. Furthermore, wall rock experiments, whereby REE-rich fluids are reacted directly with carbonate rocks, are absent from the literature. The same is true for systems containing fluoride, necessary for studying the formation of fluorocarbonates. A fuller understanding of REE mineralisation cannot be achieved until empirical experimental results can be compared with theoretical data and field observations. This thesis documents the laboratory synthesis of single- and multiple-REE-bearing carbonates and fluorocarbonates, and compares the findings with a mineralogical and textural study of two REE-bearing carbonatite deposits. The REEs La, Nd, Gd, Er and Yb were investigated as representatives of the entire series. The experiments constituted titrations of REE chloride solutions with sodium carbonate, and `wall rock reactions' of REE chloride with dolomite, or dolomite plus fluorite. Batch and flow-through setups were used, and the experiments were performed, or the products aged, at temperatures ranging from ambient to 200 °C. Products were characterised by techniques such as PXRD and SEM to document their structure and morphology as a function of temperature, and assess the influence of single vs multiple REE on the final material (whether mixed or separate phases formed). Results showed that in titration experiments, the LREEs crystallised easily and at low temperatures (as low as room temperature), HREEs either do not crystallise (in some cases even at 200 °C) or are more diffcult to crystallise, and mixed LREE + HREE precipitates behaved more like HREE-only examples. The HREEs and LREEs + HREEs mostly produced X-ray amorphous materials, identified as carbonates using FTIR. These were analysed by XAS (XANES and EXAFS) to assess whether they possessed the same short-range structure as the crystalline phase into which are known to form, thus adding to the non-classical nucleation pathway argument as previously suggested for these materials. Results suggested the short-range order of most phases analysed were similar to known bulk phases, but that these were probably different to the earlier precipitates formed in solution. Additionally, in the mixed LREE + HREE systems (Nd+Er), REEs were well dispersed (as opposed to Nd- and Er-rich clusters). In contrast to the titration results were those of wall rock reactions, in which excellent crystallisation was observed for almost every REE configuration (single- or up to five- REE mix), or ageing duration. All but three of the phases produced were previously described natural or synthetic minerals. When fluorite was included in batch reactions the results were more varied: REE carbonates, fluorides and fluorocarbonates were all observed, but never together in the same sample (except in one example). A textural and mineralogical assessment of two carbonatite deposits, Bayan Obo, China and Tundulu, Malawi, which were analysed by EMPA, revealed multiple stages of hydrothermal activity, some of which related to REE fluorocarbonate mineralisation. REE fluorocarbonates, identified at both sites, were typically LREE enriched. No REE carbonates or fluorides were observed, despite the presence of fluorite (REE-barren) and carbonates at Bayan Obo, and carbonates (low REE content) at Tundulu. However, at both sites apatite contained considerable REE. The REE fluorocarbonates were not solely associated with carbonate wall rocks, although the Ca-REE fluorocarbonate synchysite was only observed in the significantly more carbonate-rock-rich Tundulu samples. At Bayan Obo, bastnasite and huanghoite (Ba-REE fluorocarbonate) were observed, the latter of which is reportedly replacing earlier Ca-REE fluorocarbonates. The results demonstrate the varying behaviour of REEs during precipitation under different conditions, and highlights the influence of dissolved carbonate supply rate to morphology, structure and crystallinity of the products. The occurrence of only one class of REE mineral (carbonate, fluoride or fluorocarbonate) in the synthetic experiments with fluoride may help explain the lack of natural REE carbonates and fluorides - and predominance of REE fluorocarbonates - in hydrothermal systems, as was observed in the natural samples studied. In addition, the lack (absence?) of naturally occurring HREE carbonates and fluorocarbonates in the studied carbonatites (and the literature) is suggested to result not from factors such as structural constraints, but instead from the relative crustal abundances of the individual REEs. It is shown that HREE carbonates and fluorocarbonates are valid species under certain conditions, but that these are not likely to occur naturally.

Magister Scientiae - MSc (Physics) / Rare-earth intermetallic compounds continue to draw considerable attention, due to their fundamental importance in understanding physical properties and potential applications based on a variety of phenomena. The focus of this project is to employ two family of rare-earth intermetallic compounds: RE2Pt2In (RE = Pr, Nd) and RE8Pd24Ga (RE = Gd, Tb, Dy) ternary intermetallic systems as a model candidate to uncover the underlying ground state properties that result in a strong coupling between the conduction electron and the 4f-electron of the rare-earth ions.