Meiosis in oocytes: predisposition to aneuploidy and its increased incidence with age

Abstract

Mammalian oocytes begin meiosis in the fetal ovary, but only complete it when fertilized in the adult reproductive tract. This review examines the cell biology of this protracted process: from entry of primordial germ cells into meiosis to conception. The defining feature of meiosis is two consecutive cell divisions (meiosis I and II) and two cell cycle arrests: at the germinal vesicle (GV), dictyate stage of prophase I and at metaphase II. These arrests are spanned by three key events, the focus of this review: (i) passage from mitosis to GV arrest during fetal life, regulated by retinoic acid; (ii) passage through meiosis I and (iii) completion of meiosis II following fertilization, both meiotic divisions being regulated by cyclin-dependent kinase (CDK1) activity. Meiosis I in human oocytes is associated with an age-related high rate of chromosomal mis-segregation, such as trisomy 21 (Down's syndrome), resulting in aneuploid conceptuses. Although aneuploidy is likely to be multifactorial, oocytes from older women may be predisposed to be becoming aneuploid as a consequence of an age-long decline in the cohesive ties holding chromosomes together. Such loss goes undetected by the oocyte during meiosis I either because its ability to respond and block division also deteriorates with age, or as a consequence of being inherently unable to respond to the types of segregation defects induced by cohesion loss.

Age-related increase in aneuploidy and alteration of gene expression in mouse first polar bodies

“…Despite the long-established association between advanced maternal age and the incidence of aneuploidy, the molecular link between female age and germ line genomic instability has remained elusive. The influence of maternal age on global gene expression has been offered as an explanation for the increase in aneuploidy with age [30]. Hamatani et al found a number of genes involved in cell cycles, DNA stability and chromosome had lower expression with aging [31].…”

Errors in Chromosome Segregation During Oogenesis and Early Embryogenesis

“…Aberrant positioning of chiasmata (more distal or proximal than normal) on the long arm of chromosome 21 has also been detected and identified as a putative causal factor ( 8,9 ). Much effort has gone into explaining why such positioning would increase the risk for non-disjunction at AI ( [8][9][10] ). The mechanism underlying this process remains to be elucidated, however it should be noted that the same distal chiasma site on chromosome 21 is prevalent in human males and is not associated with a high rate of non-disjunction.…”

Oocyte Cryopreservation for Elective Preservation of Reproductive Potential

“…Risk of chromosomal abnormalities, decreased fecundity, and prevalence of comorbid medical illnesses rise with increasing ageall of which may lead to spontaneous abortion (Barron, 1968). Aneuploidy is thought to affect around 20% of human oocytes (Jones, 2008). Some hypothesize that rates of aneuploidy increase with age through a "two-hit" pathway: nondisjunction followed by an inability of the oocyte to detect the chromosomal abnormality.…”

“…Nondisjunction, or inappropriate chromosomal separation during meiosis I, is a leading cause of aneuploidy and increases with maternal age. Oocytes from older women may have decreased cohesive bonds between chromosomes, further predisposing them to meiotic errors (Jones, 2008). Additionally, as oocytes age, they may be unable to detect errors in recombination and sister chromatid separation.…”