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Title: DNA instability in the human α-globin gene cluster
Author: Lam, Kwan-Wood Gabriel
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2007
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Ectopic recombination is an essential process that creates gene families, causes copy number variation and generates DNA rearrangements, sometimes leading to genetic disorders. Despite its importance, little is known about the dynamics and processes of aberrant crossover in humans. The human a-globin gene cluster is a classic system for studying ectopic recombination. DNA rearrangements such as single a-globin gene deletions (-a chromosomes) arise from unequal crossover between localised homologous regions, and are most likely favoured by malaria, leading to a +-thalassaemia. The aglobin gene cluster was therefore chosen as a test system for studying how copy number variation arises in the human genome. By developing single-DNA-molecule strategies including size fractionation and single-molecule PCR, de novo -a deletions and aaa duplications were both detected for the first time. These rearrangements occur both in blood and in sperm. Analyses o f these mutants show that they are generated by two distinct mechanisms. The major pathway involves ectopic sister chromatid exchange, the frequencies of which appear to be strongly influenced by mutational mosaicism. These rearrangements were common in both blood and sperm, while meiotic exchanges between homologous chromosomes were restricted to the germ-line and with lower frequencies. There was significant reciprocity of deletion and duplication processes, with respect to ectopic exchange breakpoints, haplotype symmetries and recombination frequencies. This indicates that these mutants were most likely generated by a reciprocal intermolecular recombination pathway. However, there was also evidence for extrachromosomal circles, which might suggest the existence of an additional intramolecular pathway that plays only a minor role in generating deletions. The surprisingly high frequencies of de novo deletion and duplication suggest that significant selective forces must have acted against individuals with -a or aaa chromosomes to maintain a constant and high level o f normal a a chromosomes in most malaria-free populations, and with low frequencies of -a and aaa chromosomes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available