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I Chromosomal Complements in Human Immature and Mature Chromosomal Complements in Human Immature and Mature Oocytes in Relation to Maternal Age Wejdan M. Alenezi Department of Human Genetics McGill University Montreal, Quebec, Canada Submitted March 2015 A thesis submitted to McGill University Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of masters in science ©Wejdan M. Alenezi i ACKNOWLEDGMENT Foremost, I dedicate my M.Sc. thesis to my beloved mother and siblings whose overseas, unlimited love and support pushed me to go further on the way of knowledge. Their encouragements and motivations allowed me to undertake this academic study and made my M.Sc. thesis to be possible achieved. I would like to express my sincere gratitude to my supervisor Prof. Asangla Ao for introducing me to the field of preimplantation genetic diagnosis (PGD) and embryology. She took the initiative to teach me the basics of human embryo manipulation and the fundamentals of PGD practice. She generously offered me her valuable time to guide me throughout writing my reports and M.Sc. thesis. She encouraged me to participate in several PGD-related conferences. On the top, she emotionally supported me through my health issues I have had during my studies. Without her unwavering guidance, supervision and patience, this academic accomplishment would not have been possible. Beside my supervisor, I would like to extend my acknowledgments to Dr. Zhange Li and Xiao Yun Zhang for teaching me most important PGD related techniques. Their helpful guidance, endless patience, and encouraging words made this project achieved. I am also indebted to my supervisory committee members Prof. Anna Naumova and Prof. Teruko Taketo for their insightful comments and suggestions, and valuable assistance and guidance (especially in statistics) that made this project to be successfully accomplished. I extend my acknowledgments to all embryologists, nurses, and physicians at McGill Reproductive Center for their assistance and cooperation during these years. I am deeply grateful to all patients who donated the research samples. I would like also to acknowledge the ii scholarship granted from the Department of Applied Medical Sciences at Taibah University, my hometown university. Finally, I would like to express my heartfelt thanks to my long-suffering friends: Maha, Raha, Basma, Ghadeer, Luci and Amal whose endless emotional support allowed me to overcome all obstacles I faced throughout my academic studies. Also, I am deeply thankful to Prof. Idrees Al-Turk who encouraged and motivated me to pursue my graduate studies. His continues support and advice, as well as absolute faith in me allowed me to undertake all difficulties I faced throughout my studies. iii PRESENTATION OF THE CURRENT THESIS This M.Sc. thesis was prepared in accordance to the guidelines for the traditional, monographic thesis style. The table of content, and an abstract in English and in French are included. Chapter one contains a general introduction, which provides an overview of the research scope of the present project including the significance, the rationale, and the objectives of the M.Sc. project. This is followed by a literature review, which provides a comprehensive review of the relevant literatures. Chapter two includes the material and methods were applied in the present research. Chapter three demonstrates the results, followed by chapter four that discuss the results obtained in this project. Last, a summery of the present work and final conclusions, including the future direction are presented in chapter five. This thesis is completed by a list of the references cited within chapter one to five, followed by an appendix includes a list of ethics approval of using all human materials were used in this project. iv ABBREVIATIONS 0PN Zero Pronuclear Zygote 1PN One Pronuclear Zygote 2PN Two Pronuclear Zygote 3PN Three Pronuclear Zygote AI Anaphase I stage aCGH Array Comparative Genomic Hybridization AL Anaphase Lag AFC Antral Follicular Count CGH Comparative Genomic Hybridization Chr Chromosome Cht Chromatid COH Controlled Ovarian Hyperstimulation FISH Fluorescence In Situ Hybridization GV Germinal Vesicle GVBD Germinal Vesicle Break Down ICSI Intracytoplasmic Sperm Injection IVF In Vitro Fertilization IVM In Vitro Maturation MC Miscarriage MF Male Factor MI Metaphase I Stage MII Metaphase II Stage ND Non-Disjunction PCOS Polycystic Ovary Syndrome PD Premature Separation PGD Preimplantation Genetic Diagnosis PRL Repeated Pregnancy Loss PSSC Premature Separation of Sister Chromatids SGD Single Gene Defects SNP Single Nucleotide Polymorphism Array v ABSTRACT Numerical chromosome abnormalities significantly contribute to the high incidence of spontaneous abortions, stillbirths, and live births with congenital defects. The vast majority of these abnormalities are maternally related and attributed to meiotic errors occurring during oogenesis. The clinical relevance of these errors, the contribution to the overall rate of chromosome abnormalities, and the association with advanced maternal age are well documented. Maternally related chromosome abnormalities can also be attributed to errors occurring prior to meiosis. Select studies have estimated the incidence of pre-meiotic mitotic errors, though the prevalence, clinical relevance, and association with maternal age remain unknown. Therefore, we aimed to investigate the incidence of pre-meiotic mitotic errors in human immature and mature oocytes derived from women who underwent controlled ovarian hyperstimulation (COH) treatment cycles in relation to maternal age. FISH-based analysis for chromosomes most frequently involved in pregnancy loss (13, 15, 16, 18, 21, 22, and X) was applied to analyze the chromosomal complements in human oocytes. We pioneered a method in developing and validating the FISH signals scoring criteria of chromosomally normal immature oocytes at different maturation stages (in relation to maternal age) by plotting histograms of FISH signals per tested chromosome. These distributions allowed us to determine the possibility of sample variation, as well as confirmed our FISH signals scoring criteria for chromosomally normal oocytes. The overall rates of chromosomally normal immature oocytes at all different maturation stages were comparable between both maternal age groups, suggesting that pre- meiotic mitotic errors are not maternal-age dependent. We re-analyzed the data to estimate the incidence of chromosomally normal immature oocytes at the different maturation stages (in relation to maternal age) when each patient donated “sibling oocytes” for eliminating patient vi bias. These results confirmed that pre-meiotic mitotic errors are not associated with maternal age. Our findings indicate that the incidence of pre-meiotic mitotic errors in human mature oocytes with the corresponding first polar bodies in relation to maternal age is considerably low compared to first meiotic errors. As previously reported, the overall rate of first meiotic errors is directly related to maternal age. Our data suggest that although the contribution of pre-meiotic mitotic errors to the overall rate of maternally related chromosome abnormalities is relatively low, consequences of these errors have clinical relevance to human fertility, at least in our study population. vii SOMMAIRE Plusieurs anomalies chromosomiques contribuent significativement à l’incidence élevée d’avortements spontanés, de morts à la naissance et de naissances avec défauts congénitaux. La vaste majorité de ces anomalies sont attribuées à des erreurs méiotiques qui prennent place durant l’oogenèse. La pertinence de ces erreurs à la pratique clinique, leur contribution aux taux d’anomalies chromosomiques et leur association avec l’âge maternel avancé sont tous bien documentés. Les anomalies chromosomiques d’origine maternelle peuvent aussi être attribuées aux erreurs qui précèdent la méiose. Quelques études ont tenté d’estimer l’incidence d’erreurs miotiques précédant la méiose, malgré que leur prévalence, leur importance clinique et leur association avec l’âge maternel demeurent inconnus. Par conséquent, nous avons investigué l’incidence d’erreurs mitotiques précédant la méiose en relation à l’âge maternel dans les oocytes humains immatures et matures dérivés de femmes ayant subi des cycles de traitement de stimulation ovarienne. La méthode d’analyse FISH pour les chromosomes les plus souvent impliqués dans la perte de grossesse (13, 15, 16, 18, 21, 22, and X) a été appliqué à l’analyse des compléments chromosomiques des oocytes humains. Nous avons créé une nouvelle méthode pour le développement et la validation des critères de notation pour les signaux FISH provenant des oocytes immatures avec chromosomes normaux à différentes étapes de leur maturation en relation avec l’âge maternel. Pour ce faire, nous produisons des histogrammes des signaux FISH pour chaque chromosome testé. Ces distributions nous ont permis de déterminer la variation de l’échantillon ainsi que de confirmer nos critères de notation des signaux FISH.. Le nombre total d’oocytes immatures avec des chromosomes normaux à toutes les étapes de maturation était comparable entre les deux groupes d’âge maternel, suggérant que les erreurs mitotiques qui précèdent la méiose ne sont pas dépendantes sur l’âge maternel. Pour éliminer le biais de viii sélection, nous avons ré-analysé nos données pour estimer l’incidence de chromosomes normaux dans les oocytes immatures en relation à l’âge maternel lorsque chaque patient a donné des
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