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Application of Genomic Technology in the Study of Human Disease Esperanza Anguiano, Ph.D

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Application of Genomic Technology in the Study of Human Disease Esperanza Anguiano, Ph.D ABSTRACT Application of Genomic Technology in the Study of Human Disease Esperanza Anguiano, Ph.D. Mentor: M. Virginia Pascual, M.D. Genomic technologies are helping advance our understanding of human diseases at a very fast pace, especially in the fields of cancer, auto inflammatory diseases as well as immunodeficiencies. High throughput technology permits to survey the entire genome and assess individual genetic variation. This application has proven successful in identifying causal genes in Mendelian diseases and has provided insights into the genetic etiology of complex diseases. In the past, we have applied blood transcriptional profiling to identify biomarkers and therapeutic targets such as IL-1B for patients with systemic onset juvenile idiopathic arthritis (sJIA), one of the major causes of chronic inflammatory arthritis in children. Indeed, clinical trials to evaluate the effect of blocking IL-1B in this disease have proven successful. This discovery supports that sJIA belongs to the recently described category of autoinflammatory diseases, which share similar clinical phenotypes and respond to IL1 blockade. Most autoinflammatory diseases have been described as Mendelian diseases affecting different genes in the IL-1B pathway. In the work presented here, we investigated a potential genetic basis for sJIA, which is a sporadic disease. We applied high throughput next generation sequencing technology to survey the known coding regions of the human genome, the exome, in 6 sJIA trios (individual patients and parents) and in an additional group of 11 patients. In the analysis of trios we identified several potentially pathogenic variants in genes involved in biological functions associated with IL1; we also found mutations in genes shared by two or more sJIA patients. In addition, a rare variant was found in the S100A12 gene, which encodes a biomarker and potential pathogenic factor in the disease, in one family. Overall, our study revealed potential genetic models of compound heterozygous and/or multigenic inheritance in this complex and heterogeneous disease. Application of Genomics Technology in the Study of Human Disease by Esperanza Anguiano, B.S. A Dissertation Approved by the Institute of Biomedical Studies Robert R. Kane, Ph.D., Chairperson Submitted to the Graduate Faculty of Baylor University in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Approved by the Dissertation Committee M. Virginia Pascual, M.D., Chairperson A. Karolina Palucka, M.D., Ph.D. Venuprasad Poojary, Ph.D. Derek Blankenship, Ph.D. Myeongwoo Lee, Ph.D. Accepted by the Graduate School August 2015 J. Larry Lyon, Ph.D., Dean Page bearing signatures is kept on file in the Graduate School. Copyright © 2015 by Esperanza Anguiano All rights reserved TABLE OF CONTENTS LIST OF FIGURES ......................................................................................................... viii LIST OF TABLES ............................................................................................................... x ACKNOWLEDGMENTS ................................................................................................ xii DEDICATION .................................................................................................................. xiv Chapter One ........................................................................................................................ 1 Introduction to Genomics Technology: Applications, Development and Implementation ....................................................................................................... 1 Background ................................................................................................. 1 Overview of Genomics Technology ........................................................... 3 Application of Genomics Technology to Understand Immune MediatedDisease in a Genetically Defective Background ........................ 10 Development and Validation of Genomics Technology Applications ..... 14 Chapter Two.................................................................................................................... 323 Introduction to Systemic Onset Juvenile Idiopathic Arthritis (sJIA) .................... 32 Background ............................................................................................... 32 Pathogenesis of sJIA ................................................................................. 34 sJIA as an Autoinflammatory Disorder .................................................... 44 Treatment Strategies for sJIA Patients ...................................................... 45 Chapter Three.................................................................................................................... 52 Materials and Methods .......................................................................................... 52 Patient Samples ......................................................................................... 52 Sample Preparation ................................................................................... 52 v Exome Data Processing and Alignment ................................................... 55 Variant Calling and Annotation ................................................................ 56 Selection of Candidate Variants ................................................................ 57 Prioritization of Candidate Variants ......................................................... 63 Validation of candidate variants ............................................................... 65 Chapter Four ..................................................................................................................... 67 Results and Discussion ......................................................................................... 67 Clinical Characteristics of sJIA Cohort .................................................... 67 Overall Filtering Strategy in Individual Trios .......................................... 68 Family 1 .................................................................................................... 68 Family 2 .................................................................................................... 72 Family 3 .................................................................................................... 76 Family 4 .................................................................................................... 80 Family 5 .................................................................................................... 84 Family 6 .................................................................................................... 88 Variants Affecting the Same Gene in Multiple sJIA Patients ................... 91 Chapter Five .................................................................................................................... 102 Functional Implications for S100A12 Deletion Identified in sJIA Proband 1 .... 102 Background ............................................................................................. 102 Introduction to S100 Proteins and Association in sJIA .......................... 102 Characterization of Mutant S100A12 ..................................................... 105 Chapter Six...................................................................................................................... 112 General Conclusions and Future Direction ......................................................... 112 General Conclusions ............................................................................... 112 vi Future Direction ...................................................................................... 115 REFERENCES ............................................................................................................... 117 vii LIST OF FIGURES Figure 1.1 Transcriptional profile of fibroblasts treated with or without Poly(I:C) ......... 13 Figure 1.2 Transcriptional profile of PBMC treated with or without Poly(I:C) for 2- or 8- hours .................................................................................................................................. 14 Figure 1.3 Integrity and Purity of Purified DNA. ............................................................. 26 Figure 1.4 Coverage plot for exome sequence data - Nimblegen ..................................... 27 Figure 3.1 Generalized discrete filtering strategy employed in the selection of candidate variants .............................................................................................................................. 62 Figure 4.1 Family 1 pedigree. ........................................................................................... 69 Figure 4.2 Family 2 pedigree. ........................................................................................... 72 Figure 4.3 Family 3 pedigree. ........................................................................................... 76 Figure 4.4 Family 4 pedigree. ........................................................................................... 80 Figure 4.5 Family 5 Pedigree. ........................................................................................... 84 Figure 4.6 Family 6 pedigree. ........................................................................................... 88 Figure 4.7 Overlap of candidate genes with sJIA exome published data. ........................ 96 Figure 4.8 Canonical pathways
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