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Haplotype diversity at the CYP2D6 locus: Human demography, evolution and disease susceptibility

Fletcher, Benjamin; (2003) Haplotype diversity at the CYP2D6 locus: Human demography, evolution and disease susceptibility. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Cytochrome P450 2D6 (CYP2D6) is the gene that encodes the drug metabolising enzyme (DME) that is responsible for the debrisoquine/sparteine oxidation polymorphism in humans. CYP2D6 has been characterised both genetically and phenotypically in a wide variety of ethnic groups and has been demonstrated to be involved in the metabolism of more than 30 clinically important drugs. Microsatellites are short tandemly repeated nucleotide motifs of 2-5 bases that are found throughout the genomes of eukaryotes e.g. (CA)n. Many of these loci have been found to be highly polymorphic and so they have proved useful in many types of modern genetic analysis. This thesis describes the construction and optimisation of two multiplex polymerase chain reaction (PCR) 'kits' that leverage the ABI GeneScan® platform to rapidly assay a number of single nucleotide polymorphisms (SNPs) to discriminate common CYP2D6 variants and five closely linked dinucleotide microsatellite markers. Data generated with these kits has been used to address five different research areas: investigating intra-ethnic variation in CYP2D6; examining the effectiveness of statistical techniques to reconstruct haplotypes; establishing the age of common CYP2D6 variants; assessing whether common CYP2D6 variants are under positive selection; and examining the role of CYP2D6 variation in a disease group. Evidence of significant genetic structure in CYP2D6 variation is found within both Armenia and Ethiopia. The effectiveness of statistical techniques to predict haplotypes is consistent with estimates of simulation studies that reconstruction is only effective on markers spaced up to 0.1 cM intervals. Dating analysis suggests that the origin of CYP2D6*4 dates to a time frame consistent with the Neolithic expansion. Selection tests suggest that either CYP2D6*4 or an as of yet unidentified locus in linkage disequilibrium may be under positive selection. Finally, CYP2D6 variation in patients suffering from autoimmune hepatitis suggests that individuals with defective alleles are less susceptible to this disease.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Haplotype diversity at the CYP2D6 locus: Human demography, evolution and disease susceptibility
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Cytochrome P450
URI: https://discovery.ucl.ac.uk/id/eprint/10100817
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