Inefficient Crossover Maturation Underlies Elevated Aneuploidy in Human Female Meiosis

Meiosis is the cellular program that underlies gamete formation. For this program, crossovers between homologous chromosomes play an essential mechanical role to ensure regular segregation. We present a detailed study of crossover formation in human male and female meiosis, enabled by modeling analysis. Results suggest that recombination in the two sexes proceeds analogously and efficiently through most stages. However, specifically in female (but not male), ∼25% of the intermediates that should mature into crossover products actually fail to do so. Further, this “female-specific crossover maturation inefficiency” is inferred to make major contributions to the high level of chromosome mis-segregation and resultant aneuploidy that uniquely afflicts human female oocytes (e.g., giving Down syndrome). Additionally, crossover levels on different chromosomes in the same nucleus tend to co-vary, an effect attributable to global per-nucleus modulation of chromatin loop size. Maturation inefficiency could potentially reflect an evolutionary advantage of increased aneuploidy for human females. [Display omitted] •Human female meiosis, uniquely, exhibits crossover maturation inefficiency•Maturation inefficiency creates crossover configurations prone to mis-segregation•Maturation inefficiency is synergistic with other features for increased aneuploidy•Global modulation of chromatin loop size underlies crossover level variation Human female meiosis exhibits inefficient maturation of crossovers. This effect, alone and in synergy with other features, promotes high frequencies of aneuploid eggs.