Genetics of oocyte ageing

Abstract

Objectives: Correlations between parental age, aneuploidy in germ cells and recent findings on aetiological factors in mammalian trisomy formation are reviewed. Methods: Data from observations in human oocytes, molecular studies on the origin of extra chromosomes in trisomies, experiments in a mouse model system, and transgenic approaches are shown. Results: Errors in chromosome segregation are most frequent in meiosis I of oogenesis in mammals and predominantly predispose specific chromosomes and susceptible chiasmate configurations to maternal age-related nondisjunction. Studies on spindle structure, cell cycle and chromosome behaviour in oocytes of the CBA/Ca mouse used as a model for the maternal age-effect suggest that hormonal homeostasis and size of the follicle pool influence the quality, maturation competence and spindle size of the mammalian oocyte. Predisposition to errors in chromosome segregation are critically dependent on altered cell cycles. Compromized protein synthesis and mitochondrial function affect maturation kinetics and spindle formation, and cause untimely segregation of chromosomes (predivision), mimicking an aged phenotype. Conclusions: Altered cell cycles and untimely resolution of chiasmata but also nondisjunction of late segregating homologues caused by asynchrony in cytoplasmic and nuclear maturation appear to be causal to errors in chromosome segregation with advanced maternal age. Oocytes appear to lack checkpoints guarding against untimely chromosome segregation. Genes and exposures affecting pool size, hormonal homeostasis and interactions between oocytes and their somatic compartment and thus quality of follicles and oocytes have the potential to critically influence chromosome distribution in female meiosis and affect fertility in humans and other mammals.