Premature Separation of Dyads is the origin for maternal age related aneuploidy in mammalian eggs found from chromosome tracking (#153)
As women get older their oocytes become susceptible to chromosome mis-segregation. This generates aneuploid embryos, leading to increased infertility and birth defects1. Current models suggest that maternal age related aneuploidy is caused by a lowering of the cohesive forces holding chromosomes together, which results in prematurely separated bivalents, termed univalents, that segregate equationally in meiosis I. This idea is supported by several approaches that increase univalent number allowing direct observation of their fate2, 3. However here, using high temporal resolution 4D-CLSM, a different etiology of age-related aneuploidy was found that we define as Premature Separation of Dyads (PSD). Bivalent movement was tracked in maturing oocytes microinjected at the Germinal Vesicle (GV) stage with histone 2B and Cenp-C constructs to label chromosomes and kinetochores respectively. This imaging approach was validated on oocytes with a known segregation defect: non-disjunction in young mice harbouring a deletion of the cell cycle regulator FZR1. These oocytes became aneuploid as a result of persistently non-aligned bivalents which co-segregated, so confirming previous in-vitro knockdown strategies4. In contrast, for aged >12 –month old wild-type mice, where FZR1 levels were not appreciably lower, the most common segregation defect led to single chromatids in metaphase II eggs, a finding consistent with human studies5. Surprisingly, univalents were rarely observed in aged oocytes that became aneuploid. Instead, single chromatids were generated only following anaphase-onset. Our results show that maternal age related aneuploidy is brought about by the premature separation of dyads in meiosis II, not by the equational division of univalents during meiosis I as previously thought.