Currently, the most widely used in vivo mutation monitoring system in humans is the hypoxanthine-guanine phosphoribosyltransferase (hprt) T-cell clonal assay. This dissertation examines the current state of the hprt monitoring system and the usefulness of hprt mutational spectra in revealing environmental exposures. The nature of spontaneous mutational spectra recovered through the implementation of this system is detailed. An examination of hprt mutation frequencies obtained from a set of monozygotic twins revealed a striking influence of genetic factors. As age increases, the influence of genetic factors controlling mutation frequency appears to be modified by environmental factors. Mutational spectra obtained from Russian individuals living in Moscow were distinct from the spectrum of mutation observed in age-matched Western controls. Analysis of the relationship between mutation frequency and subject age clearly demonstrated the lack of any relationship for subjects after the age of 55. This finding contradicts many previously published reports on the relationship between mutation frequency and age. Finally, the influence of tobacco smoking on mutational frequency is clear, however, no change in the mutational spectrum of smokers was revealed. Changes in mutational spectrum are analyzed in the context of the T-cell biology and reveal that the dynamics of this tissue are likely responsible for the observations made in this dissertation. Although the hprt gene is a highly robust and suitable target for the analysis of mutation, the target has not yet been saturated, and new single base-pair substitutions are still being characterized. The data clearly suggest that the T-cell clonal assay in its current state may not be a suitable mutational monitoring system for human populations. This dissertation concludes that new mutational assays need to be developed for monitoring mutations in human populations. / Graduate
| Identifer | oai:union.ndltd.org:uvic.ca/oai:dspace.library.uvic.ca:1828/8811 |
| Date | 24 November 2017 |
| Creators | Curry, John Duncan |
| Contributors | Glickman, Barry W. |
| Source Sets | University of Victoria |
| Language | English, English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
| Rights | Available to the World Wide Web |
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