Investigating rare genetic disorders to gain insight into human biology Público
Mosley, Trenell (Summer 2021)
Abstract
Discerning how genetic variation contributes to phenotypes is a critical part of understanding biology. Historically, scientists have contributed to our comprehension of variation by observing exceptional phenotypes. In humans, this can translate to the investigation of rare genetic diseases (RGDs), which offer unique insights into human biology. There are over 7,000 defined rare genetic diseases that affect more than 350 million people worldwide. By studying RGDs diseases, we have gained insights into essential biological mechanisms that underlie both rare and common diseases and have led to the development and improvement of interventions for them. The advent of next-generation sequencing (NGS) technologies has increased our ability to detect and interpret the genetic variation that underlies rare genetic diseases and has accelerated essential discoveries. Thus, our continued study of RGDs will only increase our understanding of RGDs and human biology. Through my dissertation work, I sought to improve our understanding of human biology by investigating two classes of rare genetic diseases and their underlying variation: a rare monogenic disorder caused by a single nucleotide variant (SNV) and rare, genomic disorders caused by repeat-mediated copy-number variants (CNVs). First, we ascertained two siblings of Middle Eastern descent presenting with a rare syndrome consisting of short stature and insulin resistance. Then, using whole-genome sequencing (WGS), genetic analysis, and functional testing, I identified the underlying genetic cause as an intronic splicing variant in POC1A, thereby giving insights into the allelic spectrum of POC1A-related primordial dwarfism disorders and insulin resistance. For my genomic disorders project, I used a systematic and comprehensive literature search, single nucleotide polymorphism (SNP) genotyping, and WGS, to determine the parent of origin data for multiple pathogenic CNV loci. I demonstrated a significant association between sex-specific patterns in meiotic recombination and parental origin at these loci, which has implications for assessing risks for forming pathogenic CNVs. Taken together, my dissertation work advances our knowledge of the genetic causes underlying rare genetic diseases, has future implications for prospective interventions and counseling for individuals with rare genetic disorders, and gives insight into essential biological processes in human beings.
Table of Contents
Chapter I. Introduction 1
History of Genetic Diseases and Variation 2
Common Genetic Diseases and the Utility of Genome-wide Association Studies 3
Investigating Rare Genetic Diseases 4
Contributions of Variation to Rare Genetic Diseases 8
Utility of Next-Generation Sequencing in Rare Genetic Diseases 12
References 15
Chapter II. A novel intronic mutation causes aberrant splicing in variant POC1A-related syndrome 24
Introduction 25
Materials and Methods 26
Results 38
Discussion 41
Conclusions 46
Tables 47
Figures 48
Supplemental Tables 53
Supplemental Figures 56
References 58
Chapter III. Sex-specific recombination patterns predict parent of origin for recurrent genomic disorders 67
Introduction 68
Methods 69
Results 73
Discussion 75
Conclusions 79
Tables 81
Figures 85
Supplemental Methods 86
Supplemental Tables 98
Supplemental Figures 108
References 123
Chapter IV. Discussion 142
Summary 143
Future Directions 145
Conclusions 149
References 150
About this Dissertation
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