Centromere-proximal crossovers disrupt proper homologous chromosome disjunction during meiosis

Abstract

Centromere-proximal crossovers (C-COs) are repressed during meiosis across all species. Moreover, aberrant C-COs are strongly correlated with meiotic aneuploidy such as in Down syndrome. Despite decades of work in understanding C-CO repression, the molecular basis of how they cause chromosomal mis-segregation is unclear. Here, we show that increased C-COs result in mis-segregation of homologs during meiosis I in Schizosaccharomyces pombe. C-COs cause either nondisjunction events where the entire bivalent moves into the same nucleus at meiosis I or result in biorientation of sister chromatids leading to their premature separation. Since meiosis I segregation appears normal in pericentric cohesion deficient mutants, we rule out centromeric cohesion disruption as the primary driver of segregation defects due to C-COs, as suggested in some other species. In contrast, reduced pericentric cohesion alleviates the meiosis I nondisjunction events, thereby supporting the previously suggested "entanglement model" that proposes physical entwining of the bivalent due to retention of sister-chromatid cohesion at centromeres, a hallmark of anaphase I. This alteration also uncovers biorientation of sister-chromatids in meiosis I suggesting mono-orientation disruption as a parallel way to promote mis-segregation in the presence of C-COs. These molecular insights will improve our understanding of infertility and aneuploidy-associated developmental disorders in humans.