Oocyte development, meiosis and aneuploidy

Abstract

Meiosis is one of the defining events in gametogenesis. Male and female germ cells both undergo one round of meiotic cell division during their development in order to reduce the ploidy of the gametes, and thereby maintain the ploidy of the species after fertilisation. However, there are some aspects of meiosis in the female germline, such as the prolonged arrest in dictyate, that appear to predispose oocytes to missegregate their chromosomes and transmit aneuploidies to the next generation. These maternally-derived aneuploidies are particularly problematic in humans where they are major contributors to miscarriage, age-related infertility, and the high incidence of Down's syndrome in human conceptions. This review will discuss how events that occur in foetal oocyte development and during the oocytes' prolonged dictyate arrest can influence meiotic chromosome segregation and the incidence of aneuploidy in adult oocytes.

Keywords: Aneuploidy; Cohesion; Meiosis; Oocyte; Recombination; Trisomy.

Fig. 1

Meiotic oocyte progression from foetus to adult. Schematic diagram showing how events that occur during foetal development influence meiosis I chromosome segregation in adult oocytes. Two homologous chromosomes (blue, orange), each comprising two sister chromatids, centromeres (light blue, light orange), sister chromatid cohesion (black circles), synaptonemal complex (green lines) and meiotic spindles (grey lines) are indicated. Sister chromatid cohesion and crossover exchanges/chiasmata established during foetal development provide a physical link between homologous chromosomes that persists after the synaptonemal complex disassembles and throughout dictyate. Chiasmata and sister chromatid cohesion facilitate bi-orientation of bivalent chromosomes on the meiotic spindle during metaphase I in adult oocytes. Removal of arm cohesion and resolution of chiasmata allows homologous chromosomes to segregate to opposite spindle poles in anaphase I, whilst centromeric cohesion continues to hold sister chromatids together at this stage. Removal of centromeric cohesion allows separation of sister chromatids in anaphase II. Both meiotic divisions are asymmetric and segregate one set of chromosomes into the oocyte, and the other into small polar bodies that degenerate during pre-implantation development.

Fig. 2

Potential mechanisms contributing to chromosome missegregation in mammalian oocytes. Schematic diagram showing normal meiotic chromosome segregation (A), and some abnormal meiotic chromosome segregation patterns that can generate oocyte aneuploidy (B–E). Two homologous chromosomes (blue, orange), each comprising two sister chromatids, centromeres (light blue, light orange), and meiotic spindles (grey lines) are indicated. Failure to generate crossovers during foetal development (B), or loss of chiasmata caused by age-dependent weakening of arm cohesion (C), can cause missegregation due to bi-orientation of univalents on the MI spindle, and premature sister chromatid separation during MI. Age-dependent weakening of centromeric cohesion (D), possibly exacerbated by peri-centromeric crossovers (E), can cause missegregation due to bi-orientation of sister chromatids on the meiosis I spindle (D) and/or premature separation of sister chromatids during meiosis I (E). Weakening of centromeric cohesion could potentially affect one (D) or both (E) homologous chromosomes in the same division. A number of additional meiotic chromosome segregation errors are possible which, for clarity, are not depicted here. Any of the abnormal segregation patterns that involve bi-orientation of sister centromeres and premature segregation of sister chromatids at meiosis I can still generate normal haploid oocytes if homologous chromatids partition to different cells in meiosis II (F).