Generation of diversity at the human beta-defensin copy number

Submicroscopic structural genomic variation includes copy number variation (CNV) that can result changes in DNA dosage, and the impacts can be observed on common disease, metabolism, and heritable traits such as colour vision and rhesus blood group. Human beta-defensins form a cluster of at least seven genes on human chromosome 8p23.1, with a diploid copy number commonly ranging between 2 and 7 copies. They encode small secreted antimicrobial peptides with cytokine-like properties which are found expressed at high levels in psoriasis patients, and copy number at this locus has been found to be associated with inflammatory bowel disease, particularly colonic Crohn’s disease. The focus of this thesis has been divided into two studies; looking for the origin of diversity at the human beta-defensins copy number, and development of a multiplex PRT measurement system for accurately typing the beta-defensin region in large case association study. The origin of diversity at the human beta-defensin copy number has been followed by using segregation in CEPH families. Three out of 416 meiotic transmissions changed the copy number by simple allelic recombination between two distinct loci for these genes. Deducing haplotype copy number from microsatellite and multiallelic length polymorphism have allowed this study to map the beta-defensin repeats in two locations at the original location distally REPD and about 5 Mb away at proximally REPP. We have demonstrated our multiplex PRT system is a powerful technique to determine the association of the beta-defensin genes in Crohn’s disease even though we did not produce any convincing support for associations reported from previous studies