Allelic structures and mechanisms of copy number change at the human DEFA1A3 copy number variable locus

Black, Holly Ann (2014) Allelic structures and mechanisms of copy number change at the human DEFA1A3 copy number variable locus. PhD thesis, University of Nottingham.

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The DEFA1A3 locus on human chromosome 8p23.1 exhibits extensive copy number variation; individuals have between 3-16 copies of DEFA1A3. The region has additional complexity in that each repeat unit contains a gene locus that can be occupied by one of two different genes, DEFA1 or DEFA3. These encode the human neutrophil peptides (HNPs) 1-3, antimicrobial peptides involved in the innate immune response. In order to understand the mutational processes and evolutionary history of a complex locus like DEFA1A3, spatial information is essential. Whilst haplotype DEFA1A3 copy numbers and haplotype ratios of DEFA1 vs. DEFA3 have been determined, little is known about the features shared by, and the structures of, related haplotypes.

In this study, flanking sequence variation has been used to identify five classes of DEFA1A3 haplotype, which are tagged by four SNPs. Haplotypes within each class share similar features, such as DEFA1A3 copy number, but the associations differ between-class and between-population. Emulsion haplotype fusion-PCR has been used to determine the spatial arrangement of the DEFA1 and DEFA3 genes, as well as additional internal variants, across haplotypes of European ancestry. A comparison of the structures of related haplotypes suggests that the predominant mechanism of copy number change at the DEFA1A3 locus is intra-allelic rearrangements (i.e. between haplotypes from the same class), facilitated by the high sequence similarity of repeat units within each class. This explains the preservation of linkage disequilibrium across the DEFA1A3 locus.

The relationship between DEFA1A3 copy number and gene expression is unclear. A comparison between DEFA1A3 haplotype class and HNP1-3 expression in a UK cohort suggests that DEFA1A3 haplotype structure does not influence gene expression. However, the identification of four SNPs which tag DEFA1A3 haplotype class and, in turn, haplotype structure in haplotypes of European ancestry, will aid further studies in this area.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Armour, J.A.
Keywords: Genetic variation, Defensins, Haplotypes, DEFA1A3 locus
Subjects: Q Science > QH Natural history. Biology > QH426 Genetics
QS-QZ Preclinical sciences (NLM Classification) > QU Biochemistry
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID: 27737
Depositing User: Black, Holly
Date Deposited: 13 Feb 2015 14:52
Last Modified: 15 Dec 2017 11:36

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