The proper interplay between the expression of Spo11 splice isoforms and the structure of the pseudoautosomal region promotes XY chromosomes recombination

XY chromosome missegregation is relatively common in humans and can lead to sterility or the generation of aneuploid spermatozoa. A leading cause of XY missegregation in mammals is the lack of formation of double-strand breaks (DSBs) in the pseudoautosomal region (PAR), a defect that may occur in mice due to faulty expression of Spo11 splice isoforms. Using a knock-in (ki) mouse that expresses only the single Spo11 ss splice isoform, here we demonstrate that by varying the genetic background of mice, the length of chromatin loops extending from the PAR axis and the XY recombination proficiency varies. In spermatocytes of C57(Spo11 ss ki/-) mice, in which loops are relatively short, recombination/synapsis between XY is fairly normal. In contrast, in cells of C57/129(Spo11 ss ki/-) males where PAR loops are relatively long, formation of DSBs in the PAR (more frequently the Y-PAR) and XY synapsis fails at a high rate, and mice produce sperm with sex-chromosomal aneuploidy. However, if the entire set of Spo11 splicing isoforms is expressed by a wild type allele in the C57/129 background, XY recombination and synapsis is recovered. By generating a Spo11aki mouse model, we prove that concomitant expression of SPO11 ss and SPO11a isoforms, boosts DSB formation in the PAR. Based on these findings, we propose that SPO11 splice isoforms cooperate functionally in promoting recombination in the PAR, constraining XY asynapsis defects that may arise due to differences in the conformation of the PAR between mouse strains.

Automated summary

XY chromosome missegregation is common in humans and can lead to sterility or the generation of aneuploid spermatozoa. This study investigates the lack of double-strand breaks (DSBs) in the pseudoautosomal region (PAR) as a leading cause of XY missegregation in mice. The study demonstrates that the genetic background of mice affects the length of chromatin loops in the PAR and the proficiency of XY recombination. The findings suggest that varying expression of Spo11 splice isoforms can recover XY recombination and synapsis.