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Thesis (Ph. D.)--University of Hong Kong, 2010. / Includes bibliographical references (leaves 177-189). Also available in print.

published_or_final_version / Psychiatry / Doctoral / Doctor of Philosophy

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After the initiation of the human genome sequencing project and the introduction of the field of ‘bioinformatics’, interest in human genetic diversity studies has been increased. Sequence diversity has helped define differences between genes and genomic regions that were previously unknown or difficult to determine. In this thesis I have undertaken to study sequence diversity in the human genome in three areas; 1) investigated diversity in the MHC as represented by the MICA alleles with respect to the known HLA alleles, 2) investigated the structure and diversity in the intergenic region from an MHC related (paralogous) genomic region and related the structural and diversity findings to the knowledge available on the MHC and the wider genome, and 3) described the identification of three and characterization of five new MHC class I polymorphic markers (Alu) and their polymorphic characteristics in worldwide populations and their associations with skin cancer. 1. Phylogenetic analysis of MICA alpha-domain (extracellular) sequences demonstrated relationships with HLA-B cross-reactive serogroups. The HLA-B and MICA loci are in linkage disequilibrium. The data indicated that MICA and HLA-B have evolved in concert from their common ancestors and that the transmembrane polymorphisms have arisen independently and more recently. 2. Sequence analysis of the CD1 genomic region confirmed the presence of five CD1 genes and revealed that there are four unrelated intergenic regions (IGRs). The IGRs are composed mostly of retroelements including five full-length L1 PA sequences and various pseudogenes. Genomic and phylogenetic analyses support the view that the human CD1 gene copies were duplicated prior to the evolution of primates and the bulk of the HLA class I genes found in humans. 3. Five polymorphic Alu insertions (POALINs) were identified (two from previous studies) and located within the 1.8 megabase of the MHC class I genomic region. All five POALINs are polymorphic, and are positively associated with the HLA-A and HLA-B alleles. The AluyHJ insertion was found most frequently associated with HLA-A1 or A24, AluyHG with HLA-A2, AluyHF with HLA-A2, A-10 or -A26 and AluyTF showed a marginal association with HLA-A29. The AluyMICB insertion was strongly associated with HLA-B17 (HLA-B57, HLA-B58) and HLA-B13. The presence of three Alu insertions (AluyHJ, AluyHG and AluyHF) was found in only one HLA class I haplotype (HLA-A1, -B57, -Cw6) in the 10th IHW cell lines. A novel positive association between the presence of AluyMICB and the ‘MICAdel/MICBnull/HLA-B48’ haplotype was determined. The AluyMICB insertion was also associated with at least three different MICB alleles (*0102, *0107N and *0105) and three different HLA-B alleles (B13, B48 and B57). Based on the analysis of associations between different polymorphic markers within the beta block, the MICB*0102 allele was inferred to be the ancestral form of the MICB*0105 and MICB*0107N alleles. The AluyMICB polymorphism can be used to further investigate haplotype relationship and consequently their lineage origins. Some of the MHC POALINs are haplospecific and associate strongly with certain groups of HLA class I alleles and MHC ancestral haplotypes. The AluyTF frequency was significantly associated with skin cancer (p<0.005). MICA gene diversity is derived from two different evolving paths, therefore one or the other alone cannot reliably mark an ancestral haplotype. The CD1 duplicons originated well before the HLA class I duplicons. The MHC POALINs provide new lineage and linkage markers for the fine mapping study of different haplotypes and variations in linkage groups across 1.8 Mb of the MHC class I region. The POALINs may also prove useful in investigating the origins and history of human populations and in determining the role of human genetic diversity in disease risk.

Thesis (Ph.D.)--Murdoch University, 2005. / Thesis submitted to the Division of Science and Engineering. Bibliography: leaves 220-245.

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The pattern of inactivation in the DXS8237E-UBE1-PCTK1 region is of particular interest, since the mechanisms of X chromosome inactivation and the escape from inactivation are, as yet, not fully understood. The inactivation status of the DXS8237E and PCTKl gene differ: the first undergoes normal inactivation and the second escapes this process. The status of the UBEl gene has been controversial, although it is widely excepted that it does escape X chromosome inactivation. Physical mapping of the region employing YACs and subsequently P ACs has been undertaken, but was restricted in scope by the high frequency of rearrangements occurring. DNA sequences between DXS8237E, UBE1, PCTKl and the distal gene, UHX1, have been investigated with regard to LINEI elements, which are thought to playa role in X-inactivation. The results obtained strongly suggest a link between LINE1 elements and X chromosome inactivation. Sequence analysis results also contributed to the understanding of difficulties with restriction mapping of the region. Further, this work includes the first reported establishment of the UBEl exonintron boundaries. Additionally, genomic sequence analysis showed that only 46kb separate DXS8237E from UHX1, which confirms that this region is extremely gene rich.

No description available.