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SEGMENTAL DUPLICATIONS PROMOTE GENOMIC INSTABILITY IN HUMAN CHROMOSOME 15q11-q13

Locke, Devin Paul
http://rave.ohiolink.edu/etdc/view?acc_num=case1088114861

Abstract Details

2004, Doctor of Philosophy, Case Western Reserve University, Genetics.
The human genome is comprised of a wide spectrum of repetitive sequences. Segmental duplications are a class of repetitive sequence that has been independently associated with human genomic disease and evolutionary rearrangements. I have undertaken a study to test the hypothesis that evolutionary rearrangements and rearrangements within the human genome are linked by genomic instability at sites of segmental duplication. This study has focused on the 15q11-q13 region of the human genome due to the presence of several large clusters of segmental duplications that have been associated with the common deletion breakpoints of Prader-Willi and Angelman syndromes. Using both computational and experimental techniques I have constructed sequence assemblies within these complex regions that provide a substrate for comparative primate studies. Extensive evolutionary variation at sites of segmental duplication, in both the pericentromeric region of 15q11 and within the 15q11-q13 common deletion breakpoints was observed. The scope of variation detected included both large-scale chromosome restructuring events and local re-patterning within clusters of segmental duplications. Sequence analysis of the 15q11-q13 common deletion breakpoint clusters revealed a complex evolutionary history associated with extensive segmental duplication. In addition, I describe a mechanism in which recurrent homogenization of a particular component of the 15q11-q13 breakpoints, the HERC2 duplicon, suggests dynamic restructuring of these regions occurred recently in multiple independent primate lineages. The abundant plasticity observed in the 15q11-q13 region in primates indicates genomic instability is a general property of segmental duplications that is not bound by the barrier of speciation. Also, through the use of the array comparative genomic hybridization technique I have demonstrated the efficacy of the method for detecting genomic imbalance across a wide range of 15q11-q13 genomic rearrangements. Lastly, the application of the array method to primate comparative genomics provided an unprecedented level of resolution for detecting dosage differences among great ape species. In agreement with the other analyses presented here, segmental duplications were found highly enriched at sites of dosage imbalance, demonstrating the genomic plasticity observed within 15q11-q13 is a genome-wide phenomenon. Together, these studies provide a comprehensive and detailed analysis of the role of segmental duplications in genomic rearrangements both within the human population and between humans and our closest living relatives.
Evan Eichler (Advisor)
300 p.
Biology, Genetics
Genomics; Genomic Instability; Prader-Willi/Angelman Syndromes; Evolution; Array Comparative Genomic Hybridization; Chromosome 15

Recommended Citations

Citations

  • Locke, D. P. (2004). SEGMENTAL DUPLICATIONS PROMOTE GENOMIC INSTABILITY IN HUMAN CHROMOSOME 15q11-q13 [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1088114861

    APA Style (7th edition)

  • Locke, Devin. SEGMENTAL DUPLICATIONS PROMOTE GENOMIC INSTABILITY IN HUMAN CHROMOSOME 15q11-q13. 2004. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1088114861.

    MLA Style (8th edition)

  • Locke, Devin. "SEGMENTAL DUPLICATIONS PROMOTE GENOMIC INSTABILITY IN HUMAN CHROMOSOME 15q11-q13." Doctoral dissertation, Case Western Reserve University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=case1088114861

    Chicago Manual of Style (17th edition)

case1088114861
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© 2004, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.