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dc.contributor.authorHuang, Cheng-Han
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 51-05, Section: B, page: 2206.;Advisors: Olga O. Blumenfeld.
dc.description.abstractHuman glycophorins {dollar}\alpha{dollar} and {dollar}\delta{dollar} (glycophorins A and B) are two major species of red cell transmembrane sialoglycoproteins carrying the MNSs blood group antigens. The aim of the thesis was to delineate the molecular basis of inherited variation in MNSs-active glycophorins. Normal {dollar}\alpha{dollar} and {dollar}\delta{dollar} glycophorin genes were cloned and a number of variant alleles characterized. Comparison of their nucleotide sequences and restriction maps revealed that genetic variation occurred predominantly through recombination of the {dollar}\alpha{dollar} and {dollar}\delta{dollar} genes. The extracellular domain exons were found to rearrange in a variety of ways to create novel hybrid sequences that elicit antigenic diversification.;Unequal but homologous crossing-over between the {dollar}\alpha{dollar} and {dollar}\delta{dollar} genes has resulted in three hybrid genes encoding MiV, MiV (J.L.) and St{dollar}\sp{lcub}\rm a{rcub}{dollar} glycophorins. The crossing-over sites of the three genes were all localized in the third intron to a region showing strong local strand asymmetry. MiV and MiV (J.L.) genes are arranged in the same 5{dollar}\sp\prime\alpha{dollar}-{dollar}\delta{dollar}3{dollar}\sp\prime{dollar} frame with a junctional sequence formed between the {dollar}\alpha{dollar} exon 3 and {dollar}\delta{dollar} exon 4 but they differ in the {dollar}\delta{dollar} glycophorin alleles that must have participated in the recombination. The St{dollar}\sp{lcub}\rm a{rcub}{dollar} gene is in a reciprocal 5{dollar}\sp\prime\delta{dollar}-{dollar}\alpha{dollar}3{dollar}\sp\prime{dollar} configuration with a junctional sequence created by joining {dollar}\delta{dollar} exon 2 and {dollar}\alpha{dollar} exon 4.;Segmental gene conversions could have resulted in three {dollar}\delta{dollar}-{dollar}\alpha{dollar}-{dollar}\delta{dollar} hybrid genes encoding MiIII, MiVI and MiIII (F) glycophorins. In these recombination events, a segment of the {dollar}\alpha{dollar} gene retaining a functional 5{dollar}\sp\prime{dollar} splicing signal from exon 3 is transposed to replace a portion of {dollar}\delta{dollar} pseudoexon, forming a composite exon that is expressed. The three hybrid genes differ in the location of proximal and distal breakpoints. In the MiIII and MiVI genes, the conversion originated within a complex palindrome containing multiple overlapping inverted repeats but terminated in intron 3 at different positions. In the MiIII (F) gene, the proximal breakpoint was found to be further upstream from those of MiIII and MiVI genes. These results reveal the use of pseudoexon to generate variant glycophorin genes as a novel mechanism for antigenic diversification in man. They also illustrate the similarities to those rearrangements leading to diversification of trypanosome coat proteins and chicken antibodies.;Dantu is a {dollar}\delta{dollar}-{dollar}\alpha{dollar} hybrid gene whose putative crossing-over site was localized to the fourth intron. It is duplicated and tightly linked to a downstream {dollar}\delta{dollar} gene deletion. This particular haplotype was proposed to arise from two steps of unequal homologous recombination. The prevalence of hybrid forms among the variant glycophorin alleles indicates that during evolution multiple mechanisms may have operated to favor rearrangements leading to exchange of gene domains, thereby increasing divergence among members of the glycophorin family.
dc.publisherProQuest Dissertations & Theses
dc.subjectMolecular biology.
dc.titleMolecular basis of inherited variation in human MNSs blood group system

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