Abstract
During meiosis, homologous chromosomes pair to facilitate the exchange of DNA at crossover sites along the chromosomes. The frequency and distribution of crossover formation are tightly regulated to ensure the proper progression of meiosis. Using immunofluorescence techniques, our group and others have studied the meiotic proteins in spermatocytes of infertile men, showing that this population displays a reduced frequency of crossovers compared to fertile men. An insufficient number of crossovers is thought to promote chromosome missegregation, in which case the faulty cell may face meiotic arrest or contribute to the production of aneuploid sperm. Increasing evidence in model organisms has suggested that the distribution of crossovers may also be important for proper chromosome segregation. In normal males, crossovers are shown to be rare near centromeres and telomeres, while frequent in subtelomeric regions. Our study aims to characterize the crossover distribution in infertile men with non-obstructive (NOA) and obstructive azoospermia (OA) along chromosomes 13, 18 and 21. Eight of the 16 NOA men and five of the 21 OA men in our study displayed reduced crossover frequency compared to control fertile men. Seven NOA men and nine OA men showed altered crossover distributions on at least one of the chromosome arms studied compared to controls. We found that although both NOA and OA men displayed altered crossover distributions, NOA men may be at a higher risk of suffering both altered crossover frequencies and distributions compared to OA men. Our data also suggests that infertile men display an increase in crossover formation in regions where they are normally inhibited, specifically near centromeres and telomeres. Finally, we demonstrated a decrease in crossovers near subtelomeres, as well as increased average crossover distance to telomeres in infertile men. As telomere-guided mechanisms are speculated to play a role in crossover formation in subtelomeres, future studies linking crossover distribution with telomere integrity and sperm aneuploidy may provide new insight into the mechanisms underlying male infertility.
Highlights
During the first meiotic division, a protein structure called the synaptonemal complex (SC) forms between the homologous chromosomes to facilitate the exchange of genetic material in a process known as recombination
Eight of the 16 non-obstructive azoospermia (NOA) men and five of the 21 obstructive azoospermia (OA) men in this study displayed a reduced genome-wide recombination rate compared to controls (Tables 1 and 2)
Six NOA and eight OA men showed an increased frequency of synaptic errors compared to controls (Tables 1 and 2)
Summary
During the first meiotic division, a protein structure called the synaptonemal complex (SC) forms between the homologous chromosomes to facilitate the exchange of genetic material in a process known as recombination. Our previous study found an inverse correlation between the frequency of sex chromosome recombination and XY disomy in the sperm [6] These results suggest that increased errors in recombination may explain the elevated levels of aneuploid sperm observed in infertile men [6,8]. We reported two infertile men with normal crossover frequencies, but altered crossover distributions. Only one infertile man was reported to possess a normal recombination rate, but altered crossover positions [11]. These limited studies suggest that infertile men may display altered crossover frequencies, crossover positions or both [5,11]
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