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Xu Jialin Thesis 2018 GENETIC MODIFIERS OF TELOMERE MAINTENANCE AND THEIR CONTRIBUTIONS TO PHENOTYPIC VARIATIONS IN TELOMERE BIOLOGY DISORDERS by Jialin Xu B.Sc., Fudan University, 2009 M.Sc., Fudan University, 2012 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Pharmaceutical Sciences) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) February 2019 © Jialin Xu, 2019 The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Genetic modifiers of telomere maintenance and their contributions to phenotypic variations in telomere biology disorders. submitted by Jialin Xu in partial fulfillment of the requirements for the degree of Doctor of Philosophy In Pharmaceutical Sciences Examining Committee: Dr. Judy Wong Supervisor Dr. Andrew Sandford Supervisory Committee Member Supervisory Committee Member Dr. Suzanne Vercauteran University Examiner Dr. Louis Lefebvre University Examiner Additional Supervisory Committee Members: Dr. Bruce Carleton Supervisory Committee Member Supervisory Committee Member ii Abstract Telomeres, the protective caps at the end of human chromosomes, are shortened during cellular proliferation in normal aging. Telomere biology disorders (TBDs) refer to a spectrum of tissue degenerative disorders caused by accelerated shortening of telomeres secondary to genetic defects in telomere biology genes. Defects in eleven genes involved in telomere length maintenance have been found to cause TBDs. Accelerated telomere shortening leads to premature aging at the cellular level and regenerative defects at the tissue level. TBD-related genetic defects, in concert with intrinsic tissue turn-over rate and various environmental insults that precipitate telomere shortening, determine the aging process of specific tissues and the clinical presentations of TBDs. The main objective of this dissertation is to investigate the genetic factors that contribute to phenotypic variations of TBDs. The thesis is divided into two sections based on the presentations of TBDs in fast- and slow-turnover tissues. In Chapter 2, using patient-derived cell models and DNA samples, I comprehensively assessed the molecular and cellular phenotypes of X-linked dyskeratosis congenita (X-DC) in female DKC1 mutation carriers. I demonstrated that successful X chromosome inactivation (XCI) in their blood cells led to normal dyskerin expression and function and thus normal telomere length maintenance. These populations should be free of hematopoietic disease manifestations. In contrast, protection from XCI in tissue compartments other than the hematopoietic system may not be complete, and DC manifestations could be observed in a patient-specific manner depending on the sum total of the environmental and inherited telomere lengths as confounding factors. iii Extending from the observation with phenotypic variations in female DKC1 mutation carriers, I further investigated how incomplete genetic perturbations of telomerase activity may impact clinical presentations of a common disease. In Chapter 3, using a combination of cell and clinical disease models, I showed that functional defects in telomerase catalytic activity, caused by selected genetic polymorphisms in TERT, led to suboptimal telomere length maintenance. Rapid progression of chronic obstructive pulmonary diseases is associated with patients’ carrying status of the minor allele of rs61748181. Collectively, my study revealed two genetic modifiers for potential causes of phenotypic variations in TBDs. iv Lay Summary X-linked dyskeratosis congenita (X-DC) is a rare disorder that affects 1 in a million people, whereas chronic obstructive pulmonary disease (COPD) affects more than 1.6 million people in Canada. Despite the different prevalence, patients with both diseases have accelerated telomere shortening. Telomeres are the protective caps found at the end of human chromosomes. In this dissertation, I comprehensively assessed female family members of X-DC patients carrying rare genetic changes. My research suggested that these female subjects were free of bone marrow failure, the severe presentation of X-DC, due to their normal telomere lengths in blood. I also evaluated the effect of common genetic changes in telomere biology genes on telomere lengths in a cell model and in COPD patients. Rapid disease progression in COPD patients is associated with genetic changes in telomere biology genes. This study will help to build individualized models for the prediction of short telomere-associated disease presentations. v Preface Chapter 1 is an introduction of telomere biology and the clinical manifestations of telomere biology disorders. A version of this Chapter will be submitted for an invited review article in 2019. Chapter 2: a version of this material has been previously published in Xu J, Khincha PP, Giri N, Alter BP, Savage SA, Wong JMY. Investigation of chromosome X inactivation and clinical phenotypes in female carriers of DKC1 mutations. Am J Hematol 2016; 91(12): 1215-20. All laboratory work was conducted in the Faculty of Pharmaceutical Sciences, UBC. I collected all the in vitro data and contributed to most figures in this manuscript, except for Figure 2.2, Figure 2.3, and Table 2.3: I designed the study, performed the experiments, analyzed data and wrote the first draft of the manuscript. The co-first author Dr. Payal Khincha and her supervisor Dr. Sharon Savage designed the study, evaluated patients, and contributed to Figure 2.2 and Table 2.3. They sent clinical samples to RepeatDx laboratory for telomere length measurement to generate Figure 2.3. They also edited the patient recruitment and clinical evaluation content of the manuscript. Dr. Neelam Giri and Dr. Blanch Alter evaluated patients and edited the manuscript. My supervisor Dr. Judy Wong helped me with the study design, data analysis, and manuscript revision. In this study, I used patient materials collected from an Institutional Review Board-approved longitudinal cohort study at the National Cancer Institute (NCI) entitled “Etiologic Investigation of Cancer Susceptibility in Inherited Bone Marrow Failure Syndromes” (www.marrowfailure.cancer.gov, NCI 02–C–0052, ClinicalTrials.gov identifier: NCT0027274). Copyright permission has been obtained from the journal. The Appendix to Chapter 2 is based upon a previously published research article: Xu J, Gu AY, Thumati NR, Wong JMY. Quantification of pseudouridine levels in cellular RNA pools vi with a modified HPLC-UV assay. Genes 2017; 8(9): 219. I performed 90% of the work in this manuscript. Dr. Naresh Thumati initiated the work by optimizing the HPLC-UV method with the help of Dr. Judy Wong. I optimized the assay, validated the method, conceived the biological application for the method and performed related experiments, analyzed the data and wrote the manuscript. Alice Gu assisted in method validation and manuscript revisions. Dr. Judy Wong assisted in the study design and manuscript revision. Copyright permission has been obtained from the journal. Chapter 3: part of this material is based upon two unpublished research articles: (1) Xu, J, Trudeau, MA, Lee, J, Sin, DD, Sandford, AJ, Wong, JMY. Effects of single nucleotide polymorphisms in telomerase reverse transcriptase gene on progression of chronic obstructive pulmonary disease. (2) Xu, J., Trudeau, MA, Sandford, AJ, Wong, JMY. Evaluations of short telomere risk-associated single nucleotide polymorphisms in telomerase reverse transcriptase gene on telomere length maintenance. Both articles have been submitted for publication and are still under review. The laboratory work was conducted in the Faculty of Pharmaceutical Sciences at UBC and the Centre for Heart Lung Innovation at St Paul’s Hospital. I performed 90% of the work in this manuscript. A previous graduate student in the Wong Lab, Matthew Trudeau, initiated the study by running site-directed mutagenesis for two of the eight selected TERT SNPs. I designed the rest of the study, performed the experiments, analyzed the data and wrote the manuscript. A previous graduate student in the Sandford Lab, Jee Lee, contributed to the telomere length measurement by qPCR in Figure 3.11. Dr. Sandford and Dr. Judy Wong contributed to the study design, data analysis, and manuscript revisions. Dr. Sin contributed to manuscript revisions. In this study, I used patient materials collected from an Institutional Review Board-approved cohort study at the University of British Columbia (Providence Health vii Care Research Ethics Board certificate number H09-02042, ClinicalTrials.gov Identifier: NCT00000568). viii Table of Contents Abstract ......................................................................................................................................... iii Lay Summary .................................................................................................................................v Preface ........................................................................................................................................... vi Table of Contents ......................................................................................................................... ix List of Tables ................................................................................................................................xv List of Figures ...........................................................................................................................
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