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Role of Cecr2 and Candidate Modifier Genes of Cecr2 in the Neural Tube Defect Exencephaly

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Role of Cecr2 and Candidate Modifier Genes of Cecr2 in the Neural Tube Defect Exencephaly Role of Cecr2 and Candidate Modifier Genes of Cecr2 in the Neural Tube Defect Exencephaly by Renee Yvonne Marie Leduc A thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Molecular Biology and Genetics Department of Biological Sciences University of Alberta © Renee Yvonne Marie Leduc, 2015 Abstract Neurulation, the early developmental process that forms the rudiment of the brain and spinal cord, relies upon the intricate interplay of hundreds of genes in multiple genetic pathways within the appropriate environmental conditions. Neural tube defects (NTDs), common congenital birth defects in humans, arise when the process of neurulation is disrupted. Human NTDs are multifactorial disorders, which means that combinations of many genetic, epigenetic, and environmental factors interact in order for disease to manifest. Our mouse model of NTDs develops the perinatal lethal cranial NTD exencephaly (the murine equivalent of anencephaly in humans) when homozygous for a loss-of-function mutation in the ATP-dependent chromatin remodeling gene Cecr2. Much like in humans, manifestation of the exencephaly phenotype in Cecr2 mutant mice is dependent on multiple factors. Work in this thesis focused on identifying and characterizing the multifactorial nature of exencephaly in both Cecr2 mutant mice and in humans. A previously established incomplete penetrance of exencephaly in Cecr2 homozygous mutant mouse embryos is indicative of genetic and/or environmental changes that are contributing resistance to exencephaly. An updated penetrance analysis that I performed revealed a reduction in exencephaly penetrance, which demonstrated that genetic and/or environmental factors are changing over time. Previous work in our lab has shown that the penetrance of exencephaly in Cecr2 mutant mice is dependent on mouse strain, as Cecr2 mutant BALB/cCrl mice are susceptible to developing exencephaly but Cecr2 mutant FVB/N mice are resistant. This inter-strain variability suggests the presence of modifier genes, where the BALB/cCrl genetic background harbors susceptibility alleles and FVB/N harbors resistance alleles. Prior studies from the McDermid lab identified a modifier region in mouse chromosome 19 that contains at ii least two modifier loci, which contribute to the difference in exencephaly penetrance seen between Cecr2 mutant BALB/cCrl and FVB/N. I have further characterized the chromosome 19 modifier region and demonstrated that the two modifier loci are not additive, suggesting that the modifiers are involved in the same pathway or process. I then used whole exome sequencing of the two mouse strains to identify candidate modifier genes containing protein-coding variants that differed between the two strains. With this analysis, combined with previously generated data from whole genome microarrays, I produced a list of 26 candidate modifier genes that differ in expression and/or protein code between the two mouse strains. I showed via genetic analysis in the mouse that the top candidate gene, Arhgap19, is most likely not a Cecr2 modifier. The human homologue of CECR2 and the human homologues of the remaining candidate modifier genes were then sequenced in a cranial NTD cohort consisting of 156 probands. This study in humans identified protein-coding variants that were predicted to affect protein function in CECR2 and in 17 of the candidate modifier genes, as well as established DNMBP, MMS19, and TJP2 as top candidate NTD modifier genes. As an independent but related project, I also characterized a gene-environment interaction that resulted in circling behavior, a phenotype unrelated to NTDs, in male mice of a specific genetic cohort in our mouse colony. This study is the first to show that environmental enrichment in the form of running-wheels can induce abnormal behaviors in genetically susceptible mice. Additionally, I sought to characterize phenotypes due to homozygous mutation or knockdown of the Drosophila melanogaster homologue of Cecr2 (dikar) in an effort to produce a more tractable genetic model to study the molecular function of Cecr2. Results indicated that dikar is dispensible for normal fly development with no obvious phenotype due to loss of dikar. iii Overall, I have established the Cecr2 mutant mouse as a valuable model for studying the multifactorial nature of NTDs and have produced several novel candidate NTD genes in mice and humans. Important future work will be directed towards the functional characterization of protein-coding variants identified in the human cranial NTD cohort. In the event that a variant is shown to have a functional impact, expanded sequencing efforts of this variant or the gene it affects in additional NTD patients will aid in determining the relevance of such a gene in human NTD etiology. iv Preface The research project involving mice, of which this thesis is a part, received research ethics approval from the Animal Care and Use Committee of the University of Alberta, University of Alberta AUP 00000094. The research project involving human samples received research ethics approval from the University of Alberta Research Ethics Board, project name “Sequencing genes in a cohort of humans with a neural tube defect” (MS3_Pro00042452). This project was part of the larger research project at Duke University, which received research ethics approval from the Duke University Health System Institutional Review Board for Clinical Investigations, project name “Hereditary Basis of Neural Tube Defects” (CR5_Pro00016517). Some of the research conducted for this thesis has previously been published and/or has been completed in collaboration. Specific details regarding publication and collaborations for each results chapter are given in the appropriate chapter preface. v Acknowledgements First and foremost, I wish to express my sincere gratitude to my supervisor, Dr. Heather McDermid, for her unrelenting support, expertise, and patience. Her guidance and mentorship provided the foundation for all future successes in my science career. Her enthusiasm is truly contagious; it kept my passion for science alive. I could not have imagined a better mentor or lab environment for my PhD study. I would also like to extend my thanks to the rest of my thesis committee, Dr. Kirst King- Jones and Dr. Fred Berry, for their insightfulness, guidance, and encouragement. They always were quick and gracious with offering their time and expertise, which has been invaluable for my research. Much of the work in this thesis would not have been possible without the many collaborators I have had the privilege to work with. In the four short months I spent at Duke University, Dr. Allison Ashley-Koch integrated me into her lab as though I was one of her own. She was a superior mentor, and I want to thank her for sharing her immense knowledge, support and laboratory space. Dr. Simon Gregory also provided me with his unrelenting support and expertise, for which I am extremely grateful. Drs. Nicholas Katsanis and Erica Davis were so quick to offer their expertise and resources for my research project, which has led to a very fruitful collaboration for both this project and future projects. At the University of Alberta, Dr. John Locke has offered me his expertise, resources, and laboratory space since I was in undergraduate student. I have always felt like a member of his lab. I am eternally grateful for his advice, support, and mentorship. I also extend my thanks to Dr. Glen Baker, who graciously offered his time, expertise and resources as part of a collaboration. I give a special thanks to my labmates, who are also my friends. They offered much advice for my research and immeasurable support for all aspects of my life. My PhD experience would have been a shadow without them. I also extend a very heartfelt thank-you to the rest of my friends and family, who never once stopped offering their support in all my life’s endeavors. I wish to acknowledge the funding provided by the National Science and Engineering Research Council (NSERC), who supported me throughout my PhD, and with their Micheal Smith Foreign Study Scholarship (MSFSS), made my international research possible. Lastly, I offer my sincerest thanks to the patients and their families that have graciously enrolled in the Duke NTD study, without whom much of this research would not have been possible. vi Table of Contents Page # 1: General Introduction 1 1.1: Introduction 2 1.2: Neurulation 2 1.3: Open neural tube defects 8 1.4: Mice as models of neurulation and neural tube defects 17 1.5: Other models of neurulation and neural tube defects 19 1.6: ATP dependent chromatin remodeling 21 1.7: Cecr2 23 1.8: Objectives 26 2: Materials and methods 28 2.1: Mouse husbandry 29 2.2: Embryo collection and exencephaly penetrance analysis 29 2.3: Small inner ear penetrance analysis 30 2.4: DNA extraction 30 2.5: Cecr2GT45bic genotyping 31 2.6: Cecr2tm1.1Hemc genotyping 31 2.7: Sanger sequencing 32 2.8: Whole exome sequencing of BALB/cCrl and FVB/N 33 2.9: Exonic sequencing of 25 candidate NTD genes in 156 human anencephaly samples 35 2.10: LacZ staining 39 2.11: Paraffin embedding and histology of tissue samples 39 2.12: Immunofluorescence of neurulating embryos 40 2.13: Cloning of human CECR2 41 2.14: Site-directed mutagenesis of human CECR2 plasmid constructs 42 2.15: Sub-cloning human CECR2 plasmid constructs 44 2.16: HEK293 cell culture maintenance, harvest, and transfection 45 2.17: Protein extraction and quantification 47 vii Table of Contents Page
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