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Genomic Analysis of Human Spinal Deformity and Characterization of a Zebrafish Disease Model Jillian Gwen Buchan Washington University in St

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Genomic Analysis of Human Spinal Deformity and Characterization of a Zebrafish Disease Model Jillian Gwen Buchan Washington University in St Washington University in St. Louis Washington University Open Scholarship All Theses and Dissertations (ETDs) Spring 4-22-2014 Genomic Analysis of Human Spinal Deformity and Characterization of a Zebrafish Disease Model Jillian Gwen Buchan Washington University in St. Louis Follow this and additional works at: https://openscholarship.wustl.edu/etd Recommended Citation Buchan, Jillian Gwen, "Genomic Analysis of Human Spinal Deformity and Characterization of a Zebrafish Disease Model" (2014). All Theses and Dissertations (ETDs). 1223. https://openscholarship.wustl.edu/etd/1223 This Dissertation is brought to you for free and open access by Washington University Open Scholarship. It has been accepted for inclusion in All Theses and Dissertations (ETDs) by an authorized administrator of Washington University Open Scholarship. For more information, please contact [email protected]. WASHINGTON UNIVERSITY IN ST. LOUIS Division of Biology & Biomedical Sciences Molecular Genetics and Genomics Dissertation Examination Committee: Christina A. Gurnett, Chair Carlos Cruchaga Alison M. Goate Matthew I. Goldsmith Kelly R. Monk Lilianna Solnica-Krezel Genomic Analysis of Human Spinal Deformity and Characterization of a Zebrafish Disease Model by Jillian Gwen Buchan A dissertation presented to the Graduate School of Arts and Sciences of Washington University in partial fulfillment of the requirements for the degree of Doctor of Philosophy May 2014 St. Louis, Missouri TABLE OF CONTENTS List of Figures ….………………………………………………………………………… iv List of Tables ….…………………………………………………………………………. vi Acknowledgements ….…………………………………………………………………… viii Abstract of the Dissertation ….…………………………………………………………… ix Chapter 1: Introduction and Perspective …...………………………………………… 1 Figures and Tables ……………………………………………………………………….. 17 References ………………………………………………………………………………... 24 Chapter 2: Copy Number Variation in Adolescent Idiopathic Scoliosis ……………. 33 Summary …………………………………………………………………………………. 34 Introduction ………………………………………………………………………………. 35 Methods ….……………………………………………………………………………….. 36 Results ……………………………………………………………………………………. 38 Discussion ………………………………………………………………………………... 41 Figures and Tables ……………………………………………………………………….. 46 References ………………………………………………………………………………... 58 Chapter 3: Exome Sequencing Identifies Rare Variants in FBN1 and FBN2 Associated with Severe Adolescent Idiopathic Scoliosis ……………………………… 63 Summary …………………………………………………………………………………. 64 Introduction ………………………………………………………………………………. 65 ii Methods ….……………………………………………………………………………….. 66 Results ……………………………………………………………………………………. 71 Discussion ………………………………………………………………………………... 78 Figures and Tables ……………………………………………………………………….. 84 References ………………………………………………………………………………... 92 Chapter 4: Kinesin Family Member 6 (kif6) is Necessary for Normal Vertebral Development in Zebrafish …………………………………………………... 97 Summary …………………………………………………………………………………. 98 Introduction ………………………………………………………………………………. 99 Methods ….……………………………………………………………………………….. 101 Results ……………………………………………………………………………………. 107 Discussion ………………………………………………………………………………... 113 Figures and Tables ……………………………………………………………………….. 117 References ………………………………………………………………………………... 127 Chapter 5: Conclusions and Future Directions ...…………...………………………… 131 References ………………………………………………………………………………... 141 iii LIST OF FIGURES Chapter 1: Introduction and Perspective Figure 1.1: Scoliosis spinal deformity …………………………………………………… 17 Figure 1.2: Schematic demonstrating the Cobb method of measuring spinal curvature in scoliosis ……………...…………………………………………... 18 Figure 1.3: Prevalence of AIS by severity ……………………………………………….. 19 Figure 1.4: Preoperative and postoperative radiograph of an AIS patient ….……………. 20 Figure 1.5: A proposed genetic model for AIS development ………...………………….. 21 Figure 1.6: Disorganized and reduced fibrillin staining in AIS ………………………….. 22 Chapter 2: Copy Number Variation in Adolescent Idiopathic Scoliosis Figure 2.1: Proximal chromosome 1q21.1 duplications identified in AIS patients ……… 46 Figure 2.2: Segregation of chromosome 1q21.1 duplications …………………………… 47 Chapter 3: Exome Sequencing Identifies Rare Variants in FBN1 and FBN2 Associated with Severe Adolescent Idiopathic Scoliosis Figure 3.1: Rare FBN1 and FBN2 variants identified in AIS patients …………………… 84 Figure 3.2: Segregation of FBN1 and FBN2 variants ……………………………..…....... 85 Figure 3.3: Rare FBN1 and FBN2 variants are associated with curve severity in AIS …... 86 Figure 3.4: Elevated pSMAD2 in AIS patients with rare FBN1 variants ………………... 87 iv Chapter 4: Kinesin Family Member 6 (kif6) is Necessary for Normal Vertebral Development in Zebrafish Figure 4.1: Skolios mutants develop recessively-inherited curvature of the body axis ….. 117 Figure 4.2: Spinal curvature in skolios mutants occurs independent of major vertebral abnormalities and progressive through adult stages in males ………………… 118 Figure 4.3: Vertebral fusions and malformations occur at similar frequencies in skolios and WT zebrafish ……………………………………………………... 119 Figure 4.4: Meitoc mapping and whole genome sequencing identifies nonsense mutation in kif6 as candidate for skolios ……………………………………… 120 Figure 4.5: Transient knockdown of kif6 using morpholinos ……………………………. 121 Figure 4.6: Design and efficiency of kif6 TALENs ……………………………………… 122 Figure 4.7: TALEN-induced mutations in kif6 recapitulate the skolios phenotype ……… 123 Figure 4.8: RT-PCR expression of kif6 in WT embryos and adult tissues ………………. 124 Figure 4.9: Cilia structure and function are normal in skolios mutants ………………….. 125 v LIST OF TABLES Chapter 1: Introduction and Perspective Table 1.1: Four broad categories of scoliosis ……………………………………………. 23 Chapter 2: Copy Number Variation in Adolescent Idiopathic Scoliosis Table 2.1: Demographics of 143 AIS probands analyzed for copy number variation …… 48 Table 2.2: Frequency of 45 genomic copy number disorder regions in AIS patients ……. 49 Table 2.3: Clinical information for individuals identified with chromosome 1q21.1 duplications …………………………………………………………………… 50 Table 2.4: Summary of rare CNVs (<1% frequency in DGV) identified in AIS patients …………………………………………………………………… 51 Table 2.5: Rare CNVs identified in AIS cases …………………………………………… 52 Chapter 3: Exome Sequencing Identifies Rare Variants in FBN1 and FBN2 Associated with Severe Adolescent Idiopathic Scoliosis Table 3.1: Rare variant frequencies for FBN1 and FBN2 in AIS cases and controls of European ancestry …………………………………………………………….. 88 Table 3.2: Rare FBN1 and FBN2 variants identified in AIS cases (curve ≥10°) ………… 89 Table 3.3: Clinical characteristics of AIS cases (curve ≥10°) of European ancestry with rare variants in FBN1 and FBN2 ……………………………………………… 90 Table 3.4: Clinical features of AIS patients evaluated for Marfan syndrome …………… 91 vi Chapter 4: Kinesin Family Member 6 (kif6) is Necessary for Normal Vertebral Development in Zebrafish Table 4.1: Identification of candidate gene using low-coverage whole genome sequencing …………………………………………………………………….. 126 vii ACKNOWLEDGEMENTS First and foremost, I’d like to thank my thesis advisor, Dr. Christina Gurnett. Chris was a wonderful mentor who provided me with exceptional guidance, sage advice and unwavering support. I have truly appreciated her patience, encouragement and intelligence throughout my graduate studies. I’d like to thank the current and past members of the Gurnett lab: Dr. David Alvarado, Dr. Kyungsoo Ha, Dr. Gabe Haller, Kevin McCall, Piny Yang and Hyuliya Aferol. Whether it was scientific debates, pondering new techniques or trying to figure out Kevin’s puns, I learned a lot from all of you and thoroughly enjoyed my time in the lab. I hope I provided enough “data” to show my appreciation. I’d especially like to thank David, who not only developed several experimental and computational protocols that made much of this work possible, but also served as an additional mentor who was always willing to teach me new techniques and share ideas. I’d also like to acknowledge the members of my thesis committee: Drs. Alison Goate, Anne Bowcock, Matthew Goldsmith, Kelly Monk and Lila Solnica-Krezel as well as other faculty at Washington University in St. Louis who have given me advice and feedback. Thank you especially to Dr. Matthew Goldsmith for allowing me to collaborate on the skolios project. Thank you to all of my friends back in Seattle, here in St. Louis and abroad who have been an invaluable source of inspiration, motivation and comic relief. Finally, I would have never found the courage or aspiration to pursue a PhD without my family. Thank you to all my extended family: aunts, uncles, cousins and first cousins once- removed. I am especially appreciative of my grandparents and my brother, Matt. Most importantly, I could not have gotten here without the love and encouragement from my wonderful parents. viii ABSTRACT OF THE DISSERTATION Genomic Analysis of Human Spinal Deformity and Characterization of a Zebrafish Disease Model by Jillian Gwen Buchan Doctor of Philosophy in Biology & Biomedical Sciences Molecular Genetics and Genomics Washington University in St. Louis, 2014 Associate Professor Christina Gurnett, Chair Scoliosis is characterized by a lateral curvature of the spine that requires long-term bracing and invasive spinal surgery in cases with progressive deformity. Some individuals develop scoliosis secondary to congenital malformations or syndromic disorders, but most scoliosis is considered idiopathic and has no known cause. Adolescent idiopathic scoliosis (AIS) onsets in late childhood and causes
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