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UBC Theses and Dissertations

Investigation of meiotic defects in male infertility Ren, He


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. 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.

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