University of Maryland LibrariesDigital Repository at the University of Maryland
    • Login
    View Item 
    •   DRUM
    • Theses and Dissertations from UMD
    • UMD Theses and Dissertations
    • View Item
    •   DRUM
    • Theses and Dissertations from UMD
    • UMD Theses and Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Genetic Variation at the N-acetyltransferase (NAT) Genes in Global Human Populations

    Thumbnail
    View/Open
    umi-umd-5627.pdf (7.625Mb)
    No. of downloads: 576

    Date
    2008-07-29
    Author
    Mortensen, Holly M.
    Advisor
    Tishkoff, Sarah A.
    Metadata
    Show full item record
    Abstract
    Currently, studies of the possible role of natural selection in shaping the observed variation at drug metabolizing enzyme (DME) loci remain limited. Functional variability at the N-acetyltransferase (NAT) genes is associated with adverse drug reactions and cancer susceptibility in humans. Previous studies of small sets of ethnic groups have indicated that the NAT genes have high levels of amino acid variation that differ in frequency across ethnic groups. I hypothesize that this functional variation may be adaptive in different environments and is maintained due to natural selection. Presumably, change in dietary patterns has been a strong selective pressure throughout the course of human evolution. The most extreme example of a shift in the dietary patterns of modern humans is most certainly the transition from a primarily hunter-gatherer subsistence to an agriculturalist lifestyle, within the past 10,000 years. Metabolism of grain and/or dairy products likely introduced new and foreign toxins to the human body. Although we can only speculate about the selective forces acting on the NAT genes in the past, it is possible that the observed pattern of phenotypic variation is associated with exposure to environmental, specifically dietary, toxins. The purpose of this study is: 1) to characterize nucleotide variation at the NAT drug-metabolizing genes (NAT1, NAT2) and the pseudo-gene (NATP1) in global human populations, including many previously under-represented African populations and 2) to understand the role that natural selection has played in shaping variation at NAT1 and NAT2 in human populations living in different environmental settings. I have resequenced ~3000 bp for each of the NAT1, NAT2 and NATP1 gene regions, in 182 African individuals and 155 individuals from a representative global panel (HGDP-CEPH), and have identified Single Nucleotide Polymorphisms (SNPs) at each locus (NAT1 (48), NATP1 (55) and NAT2 (46)). I have inferred haplotype phase and characterized patterns of haplotype diversity for each NAT locus. I have characterized nucleotide diversity and linkage disequilibrium for this ethnically diverse population dataset, as well as performed several tests of selective neutrality. This work will contribute to our understanding of how variation at the NAT loci may have been adaptive for dealing with changes in diet and exposure to toxins during human evolution.
    URI
    http://hdl.handle.net/1903/8544
    Collections
    • Biology Theses and Dissertations
    • UMD Theses and Dissertations

    DRUM is brought to you by the University of Maryland Libraries
    University of Maryland, College Park, MD 20742-7011 (301)314-1328.
    Please send us your comments.
    Web Accessibility
     

     

    Browse

    All of DRUMCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects

    My Account

    LoginRegister
    Pages
    About DRUMAbout Download Statistics

    DRUM is brought to you by the University of Maryland Libraries
    University of Maryland, College Park, MD 20742-7011 (301)314-1328.
    Please send us your comments.
    Web Accessibility