Altered Crossover Distribution and Frequency in Spermatocytes of Infertile Men with Azoospermia

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.

Embryonic exposure to the widely-used herbicide atrazine disrupts meiosis and normal follicle formation in female mice

“…A reduced number of crossovers has been found in infertile men 50, 51 . It was suggested that crossover formation is strictly regulated to avoid aneuploidy 42 .…”

“…Our results similarly demonstrate that exposure to ATZ not only delays meiotic synapsis but also affects the number of crossovers. A reduced number of crossovers has been found in infertile men 50 , 51 . It was suggested that crossover formation is strictly regulated to avoid aneuploidy 42 .…”

Regulation of Crossover Frequency and Distribution during Meiotic Recombination

“…Crossover formation is inhibited near centromeres and telomeres in many species including humans (Fig. 3E) (Ottolini et al 2015; Ren et al 2016). Crossovers at centromeres disrupt cohesion in the pericentric region and affect kinetochore orientation.…”

“…For example, crossover formation is not frequently observed near centromere and telomeres, suggesting they may be repressed in these regions. Crossovers at centromere regions lead to aneuploidy in female meiosis and crossovers at telomeres increase azoospermia (Ottolini et al 2015; Ren et al 2016). However, direct testing of how a crossover positioned near centromeres or telomeres might lead to increased errors in chromosome segregation has been challenging in metazoans.…”

Embryo Grading and Pregnancy Outcome in Women of Patients with Azoospermia Following ICSI

“…(10) ; however we disagree with the finding of other authors that the OA group had better overall quality embryos than the NOA group (11) . (12) , which may explain, at least partly, the lower embryo development rates observed.…”