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Genomic mapping, functional analysis and bioinformatics of the Werner syndrome locus (WRN)

University of British Columbia

Werner syndrome is a human genetic disorder exhibiting a phenotype of premature senility with adolescent age of onset. Genetic analysis supported the hypothesis that Werner syndrome is a lesion in a single locus, WRN, assigned to the short arm of human chromosome 8 by genetic linkage to a polymorphic marker, D8S87 (Goto et al, 1992). The primary goal of this thesis was the structural and functional genomic characterization of WRN. The thesis consists of two parts. The first part undertook fine scale refinement of the genetic and physical map of the candidate genome interval from markers D8S87 to D8S137. The second part applied bioinformatics to the functional analysis of WRN through comparative sequence analysis of the DExH DNA helicase gene family. The bioinformatics work exploited software enhancements of the "A Caenorhabditis elegans Database" (ACEDB) genomic database management program that I developed during the thesis project period. The results of the genomic analysis phase of this thesis included the development of three polymorphic genetic markers, including one for LHRH - an important gene involved in human reproduction. One marker, D8S2297, was placed into the WRN candidate region by genetic and long range physical map construction spanning D8S339, a marker with reported linkage to WRN. The positions of three genes - GTF2E2, GSR and PPP2CB - were refined upon this map. The bioinformatics phase of the thesis provided molecular phylogenetic analysis to demonstrate orthology relationships of WRN homologous loci. Multiple sequence alignments of orthologous loci provides a good means of elucidating critical amino acid residue motifs with structural or function roles specific to these genes.

Thesis/Dissertation

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2009-06-29

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http://hdl.handle.net/2429/9836

Medical Genetics

University of British Columbia

UBCV

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