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Cascades of genetic instability resulting from compromised break-induced replicationVasan, Soumini January 2013 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Break-induced replication (BIR) is a mechanism to repair double-strand breaks
(DSBs) that possess only a single end that can find homology in the genome. This situation can result from the collapse of replication forks or telomere erosion. BIR frequently produces various genetic instabilities including mutations, loss of heterozygosity, deletions, duplications, and template switching that can result in copy-number variations (CNVs). An important type of genomic rearrangement specifically linked to BIR is half crossovers (HCs), which result from fusions between parts of recombining chromosomes. Because HC formation produces a fused molecule as well as a broken chromosome fragment, these events could be highly destabilizing. Here I demonstrate that HC formation results from the interruption of BIR caused by a defective replisome or premature onset of mitosis. Additionally, I document the existence of half crossover instability cascades (HCC) that resemble cycles of non-reciprocal translocations (NRTs) previously described in human tumors. I postulate that HCs represent a potent source of genetic destabilization with significant consequences that mimic those observed in human diseases, including cancer.
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The development of a therapeutic approach for the treatment of individuals with Prader-Willi syndrome and their primary caregiversSethuntsa, Molelekeng 11 1900 (has links)
Prader-Willi syndrome (PWS) is a genetic disorder resulting from a mutation of chromosome 15. It can manifest in physiological characteristics, cognitive impairment, behavioural problems, and sometimes also psychiatric disturbances. Taking care of an individual with PWS has a detrimental impact on the primary caregiver and also affects others around them. This considered, the current study aimed to learn more about the experiences and challenges of individuals diagnosed with PWS and their primary caregivers, in Gauteng and North-West Provinces, South Africa. Purposive sampling was used to select five families which then participated in the study. Qualitative research was used to conduct the study. As it was also crucial to generate a comprehensive understanding of participant experiences, collective instrumental case studies were used ̶ making use of participatory action research, ethnography and elements of auto-ethnography. Data were gathered by conducting semi-structured interviews, which were then analysed using thematic analysis. The data were organized around certain topics and common themes which emerged in each case study and the findings were then integrated with the literature which had been extensively reviewed. Based on these experiences and challenges, interventions were suggested that addressed the challenges and needs of the PWS individuals, their caregivers and families, and those around them (including school teachers). The main findings confirmed that not all individuals diagnosed with PWS manifest all the physiological characteristics, psychiatric disturbances and behavioural problems which have been documented in the literature. Furthermore, the symptoms vary in severity from one individual to the next. Cognitive impairment was, however, common to all individuals in the study. The findings also suggest that having a child diagnosed with PWS has a significantly negative impact on the primary caregiver, and taking care of PWS children is emotionally overwhelming and time-consuming. The use of a client-centred approach, implementing behaviour therapy techniques and doing psycho-education, all proved to be effective in managing some of these behaviours displayed by the individual patients and the challenges experienced by primary caregivers. / Psychology / Ph. D. (Psychology)
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