Willoughby, Claire Louise; (2004) The development of novel tools to study the history of recombination in human populations. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The initial aim of this thesis was to explore the possibility of using genomic mismatch scanning (GMS) to study the history of recombination in human populations. The original method of GMS did appear to have been successful on a number of occasions, but there was still a distinct lack of published experimental results, largely thought to be due to the complex nature of the procedure. Therefore during this study the original method was broken down into its constituent parts and attempts made to optimise each step individually. Although some encouraging positive results were obtained, it was concluded that the original GMS procedure was not robust enough to be applied as an alternative to genotyping based methods. As a result, other GMS-like experimental approaches to achieving the same goal of whole genome linkage disequilibrium mapping without genotyping were explored. In parallel conventional genotyping-based studies were performed to define the history of the ABO region on 9q34, in the hope of creating a test system upon which an optimised GMS procedure could be applied. Construction of a multilocus genetic map and mapping of recombination breakpoints indicated variation in recombination rates across 9q33.3 to 9q34.3, with sex-averaged rates reaching 16.33 cM Mb-1 near the telomere. Patterns of linkage disequilibrium across a 1.5 Mb region of 9q34 revealed a block-like structure, with the longest region of disequilibrium extending 204 Kb from the ABO gene to D9S2135 in two Caucasian populations, however no long-range linkage disequilibrium was detected in this region in an African population. Haplotype analysis indicated that within the 204 Kb region there was a finer resolution block-like structure of linkage disequilibrium, and that five haplotypes accounted for 50% of all the chromosomes. Similar haplotypes were detected in both Caucasian populations, whilst sequencing revealed both rare and novel ABO haplotypes within the African population. Finally, phylogenetic analysis of human and chimpanzee haplotypes suggested a possibly ancestry for the ABO polymorphism and indicated an ancestral recombination breakpoint of just 35 bp between nucleotides 261 and 237 within exon 6 of the ABO gene. This breakpoint coincided with a region of dramatic breakdown of linkage disequilibrium in all three populations.

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