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Investigation of Meiotic Defects in Male Infertility by He Ren B.Sc., The Investigation of Meiotic Defects in Male Infertility by He Ren B.Sc., The University of British Columbia, 2013 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE AND POSTGRADUATE STUDIES (Reproductive and Developmental Sciences) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) August 2016 © He Ren, 2016 ABSTRACT Formation of the synaptonemal complex (synapsis), and crossing over of DNA (recombination) is important for chromosome segregation during meiosis. However, reduced rates of recombination have been observed in infertile men. Our previous study linked decreased recombination on sex chromosomes to increased XY disomy in sperm. This finding elicited our interest in the relationship between autosomal recombination and sperm disomy. We hypothesize that a lack of recombination on smaller chromosomes (21, X and Y) may most likely lead to aneuploid sperm. Using immunofluorescence, and fluorescent in situ hybridization, we examined synaptic errors, recombination, and sperm aneuploidy in infertile, and fertile men. When all infertile men were pooled, the frequency of recombination on sex chromosomes and bivalent 21 negatively correlated to rates of corresponding sperm disomy. Our unprecedented finding suggest that meiotic defects may indeed be leading to infertility, and increasing sperm aneuploidy. Moreover, we previously showed changes in crossover distribution in some infertile men. In this thesis, we examined whether this population display specific crossover distributions that may cause chromosome missegregation. Using FISH, we analyzed chromosome-specific crossover distributions, discovering that some infertile men had increased crossovers in regions where they are normally inhibited, which may disrupt structural proteins involved in segregation. We were also interested in the mechanisms behind meiotic defects, and hence studied telomere homeostasis in infertile men. We found deficiencies in telomere association with telomerase in this population, suggesting that defective telomere function may promote improper synapsis and recombination. ii Lastly, we examined the meiotic behaviour and sperm aneuploidy rate in an infertile man with a mosaic 45,X(50%)/46,XY karyotype. We found that only 25% of spermatocytes were 45,X, suggesting that half of these cells were arrested. We also noted unpaired sex chromosomes in 12% of spermatocytes. The X:Y sperm ratio was increased, indicating that some 45,X cells may give rise to X-bearing sperm. Even though the patient had higher rates of sperm aneuploidy, the vast majority were of normal constitution. Thus, stringent checkpoints appear to ensure the production of sperm with correct chromosomal complement, and extraction of normal sperm for ICSI may be possible in cases of sex chromosomal mosaicism. iii PREFACE This dissertation is based on one of the ongoing research projects at Dr. Sai Ma’s laboratory, and is the subject of a collaboration with past graduate students at the Ma lab. Ethical approval from University of British Columbia (UBC) was obtained prior to initiation of all studies (H06-03490). This study is funded by the Canadian Institutes of Health Research, Ottawa, Canada, grant numbers MOP-93801 and OBM-101387 to S.M. Author contribution, and publications for each chapter are outlined below: Chapter 2 and 3: The experiments in Chapter 2 were conceived by my supervisor, Dr. Sai Ma. The experiments in Chapter 3 were conceived by Dr. Sai Ma and Kyle Ferguson. The majority of the experiments and data analysis was performed by the author, He Ren. Of the twenty infertile men reported in this thesis, Tanya Vinning and Christa Darr performed the immunostaining and fluorescent in situ hybridization (FISH) on spermatocytes in eight men, as well as FISH on sperm in five men. Dr. Victor Chow from the Department of Urology, University of British Columbia (UBC), performed the testicular biopsies. Dr. Peter Moens from York University, Toronto, provided the SCP1 primary antibodies. With the permission of Dr. Sai Ma, previously published data (sixteen infertile men and twelve control men; Ren et al., 2016) were included in this thesis in order to examine the relationship between meiotic defects, and sperm aneuploidy. A version of this chapter was published. Ren, H., Ferguson, K., Kirkpatrick, G., Vinning, T., Chow, V., & Ma, S. (2016). Altered Crossover Distribution and Frequency in Spermatocytes of Infertile Men with Azoospermia. PloS one, 11(6), iv e0156817. All figures were prepared by He Ren, and the manuscript was written by He Ren and Dr. Sai Ma. Chapter 4: The experiments were conceived by Dr. Sai Ma and He Ren. Data collection and analysis was performed by He Ren. All figures were prepared by He Ren, and the manuscript was written by He Ren and Dr. Sai Ma. Chapter 5: The experiments were conceived by Dr. Sai Ma. Christa Darr performed immunostaining and FISH on sperm for the infertile man. The remaining experiments, and all of the data analysis were performed by He Ren. Dr. Victor Chow performed the testicular biopsy on the 45,X/46,XY infertile man. With the permission of Dr. Sai Ma, previously published data (45,X/46,XY infertile men; Ren et al., 2015) were included in order to examine the meiotic behaviour, and sperm aneuploidy in the infertile man. A version of this chapter was published: Ren, H., Chow, V., & Ma, S. (2015). Meiotic behaviour and sperm aneuploidy in an infertile man with a mosaic 45, X/46, XY karyotype. Reproductive biomedicine online, 31(6), 783-789. All figure preparation was performed by He Ren. The manuscript was written by He Ren and Dr. Sai Ma. v TABLE OF CONTENTS ABSTRACT .............................................................................................................................. ii PREFACE ................................................................................................................................ iv TABLE OF CONTENTS ......................................................................................................... vi LIST OF TABLES .................................................................................................................... x LIST OF FIGURES ................................................................................................................. xi LIST OF ABBREVIATIONS ................................................................................................. xii ACKNOWLEDGEMENTS .................................................................................................. xvii CHAPTER 1: INTRODUCTION ............................................................................................. 1 1.1 Spermatogenesis ......................................................................................................... 2 1.1.1 Regulation of spermatogenesis ........................................................................... 9 1.2 Introduction to meiosis ............................................................................................. 10 1.2.1 Meiosis I............................................................................................................ 10 1.2.1.1 Chromosome pairing ................................................................................. 13 1.2.1.2 Synapsis and the synaptonemal complex .................................................. 15 1.2.1.3 Meiotic recombination ............................................................................... 18 1.2.1.3.1 Mechanism of meiotic recombination .................................................... 18 1.2.1.4 Meiotic inactivation of sex chromosomes ................................................. 23 1.2.1.5 Segregation of chromosomes ..................................................................... 26 1.2.2 Meiosis II .......................................................................................................... 29 1.2.3 Meiotic checkpoints .......................................................................................... 30 1.2.4 Sex differences in meiosis ................................................................................ 32 1.2.5 Origin of aneuploidy ......................................................................................... 33 1.2.5.1 Nondisjunction........................................................................................... 38 1.2.5.2 Premature sister chromatid segregation ..................................................... 40 1.3 Male infertility.......................................................................................................... 44 1.3.1 Overview of male infertility.............................................................................. 44 1.3.1.1 Semen analysis parameters ........................................................................ 44 1.3.1.2 Testicular histology ................................................................................... 46 1.3.2 Genetic factors in male infertility ..................................................................... 47 1.3.2.1 Y chromosome microdeletions .................................................................. 48 vi 1.3.2.2 Cystic fibrosis ............................................................................................ 49 1.3.2.3 Chromosomal abnormalities ...................................................................... 50 1.3.2.4 Defects in meiotic genes ...........................................................................
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