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Title: An investigation of euchromatic cytogenetic imbalances without phenotypic effect
Author: Barber, John C. K.
ISNI:       0000 0001 2440 3304
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2000
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The resolution of the light microscope means that conventional chromosome analysis is limited to the detection of imbalances greater than 2-4 megabases of DNA. Consequently, euchromatic chromosomal imbalances usually involve several megabases of DNA and have significant phenotypic consequences. However, an increasing number of exceptions to this rule have been reported in families in which an imbalance has been transmitted from phenotypically normal parents to phenotypically normal or abnormal children. In this work, molecular cytogenetics has been used to confirm that these rearrangements are unbalanced and to investigate the nature of the unbalanced material. Amplification of paralogous pseudogene cassettes was found to underlie euchromatic variation of 15q11.2 and 16p11.2. By contrast, putative euchromatic variants of the chromosome 16 heterochromatic region were found to be duplications of the proximal long arm. The existence of a novel euchromatic variant of 8p23.1 was established and found to involve extra copies of a domain including defensin and olfactory receptor loci. Unique euchromatic imbalances of chromosomes 2, 6, 11 and 22 were confirmed and found to be free of phenotypic consequences except for paternal duplications of the imprinted region of 6q24 associated with transient neonatal diabetes. These findings provide the means of distinguishing between common types of clinically silent variation and pathogenic rearrangement. They also suggest that regions of the genome subject to recent evolutionary change are liable to further copy number alteration and rearrangement. Finally, by indicating that smaller imbalances are more likely to be compatible with a normal phenotype, these results extend the classical additive concept of the segmental aneuploidy established in other organisms.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Chromosomal; Neonatal diabetes