Chromosome Ageing Occurs at the Primordial Follicle Stage in both Mouse and Human Oocytes

Inherited aneuploidy is one of the most common causes of human genetic disease affecting approximately 20% of all human embryos and is the major cause of non-conception in older women. Inherited aneuploidies typically arise from meiotic chromosome segregation errors and are strongly affected by maternal age. Cohesin, a protein complex that mediates cohesion between sister chromatids, becomes depleted from oocyte chromosomes with age in mice, potentially contributing to the high rate of aneuploidy in older mouse oocytes. However, it remains unclear at which stage of oogenesis ageing affects chromatid cohesion in mice and whether ageing similarly affects cohesin in human oocytes. Here we use fluorescence in situ hybridisation to assess at which stages of oogenesis ageing alters chromatid separation in mice and in humans. We show that chromatid separation increases with age while oocytes remain dormant in primordial follicles in both mice and humans and that this effect of age on chromatid separation is detectable in fertile women of child-bearing age. Furthermore, we show that this age-dependent increase in chromatid separation is accompanied by age-dependent depletion of the acetylated SMC3-marked cohesive subpopulation of cohesin from oocytes at the dormant primordial follicle stage in both mice and humans. These data suggest that ageing impacts on oocyte chromosomes while they remain dormant in primordial follicles, and that this aspect of oocyte chromosome ageing is shared in both mice and humans. Improving our understanding of these pathways may allow strategies to slow or prevent this aspect of oocyte ageing to be developed.