Understanding XY chromosome segregation defects in mammals: new insights from the regulation of expression and function of SPO11 splice isoforms

Autosomal chromosome aneuploidy is mostly incompatible with normal development. However, the consequence of aneuploidy is less severe for sex chromosomes. As an example, chromosome constitution associated with Klinefelter Syndrome (KS) (47, XXY) is the most common chromosome abnormality among live-born individuals. Meiotic recombination is essential to ensure the formation of crossovers, a physical link required for proper segregation of the homologous chromosomes and the sex chromosomes. In KS patients, where the extra sex chromosome is of paternal origin, the absence of a crossover accounts for most of the clinical cases. Meiotic recombination follows the programmed introduction in the genome of double strand breaks (DSBs). The protein responsible for such process is SPO11, a highly conserved protein whose ablation (in mouse) or genetic polymorphism (in humans) has been associated with infertility. The Spo11 gene encodes for at least two splice variants, named SPO11β and SPO11α. We have recently shown that SPO11&beta-generated DSBs are required and sufficient to ensure proper recombination, synapses and segregation of the autosomes in male mice. However, XY chromosomes segregation fails because of the lack of DSB formation. This observation strongly implicates alterations in the Spo11 splicing pattern as a cause of XY non-disjunction defects. The goal of this study is to investigate the potential involvement of SPO11 in XY chromosomes non-disjunction, and to understand the molecular mechanisms that control splicing and function of the SPO11 isoforms. The understanding of these mechanisms might lead to the development of screening protocols and/or therapeutic approaches for the diagnosis and prevention of paternally-derived aneuploid conceptuses such as KS or Turner syndrome.