Date of Award

1995

Document Type

Thesis

Publisher

Edith Cowan University

Degree Name

Bachelor of Science Honours

Faculty

Faculty of Science, Technology and Engineering

First Supervisor

Dr Luba Kalaydjieva

Abstract

Localising the gene for a previously undescribed autosomal recessive form of CMT involved the use of a relatively new approach to rapid genome screening based on the identification of segments which are inherited identical by descent (IBD) from common founding ancestors. It is most feasible for populations which have been founded relatively recently (say less than 25 generations) and which have remained relatively isolated either geographically or culturally. The method is not suitable for highly inbred populations, that is with first and second cousin matings, as many segments will be inherited by chance. It appears to be a suitable screening option for a rare disease trait so that the possibility of allelic heterogeneity is reduced. It is also an option for those pedigrees where a significant result cannot be obtained through traditional linkage analysis, that is, where a large nuclear family with many affected individuals is not available. Highly informative polymorphic short tandem repeat markers were run on the DNA from an initial selection of ten individuals whose interrelatedness could be established. In the later stages of the study, DNA from forty-seven members of this randomly inbred Bulgarian Gypsy kindred was used for verification of the IBD finding by led score analysis. In the study population where the chosen members are separated from a common ancestor by an average 9.4 meioses, the approximate probability of finding one random segment (not containing the gene) inherited identical by descent (lBD) from this common ancestor was calculated at 9.47 in 1,000 (over 94 markers at an average distance of 12.6 cM). The overall probability of finding an IBD segment (not containing the gene) in three or more chromosomes decreases to 1.7 in 1 million. This study initially identified a 20 cM region on 8q which was shared by three out of six non-sibling chromosomes. This region was extended by saturating with markers at closer intervals and subsequently a 3 cM segment was found to be common among four of six non-sibling chromosomes. Finally, lod score analysis on the forty-seven members of the kindred supported placement of the candidate gene in this 3 cM segment with a maximum led scores at zero recombination for both marker loci D8S558 and D8S529 being 3.38 and 2.73 respectively. These two markers are mapped at 1 cM apart.

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