Human aneuploidy: mechanisms and new insights into an age-old problem

Abstract

Trisomic and monosomic (aneuploid) embryos account for at least 10% of human pregnancies and, for women nearing the end of their reproductive lifespan, the incidence may exceed 50%. The errors that lead to aneuploidy almost always occur in the oocyte but, despite intensive investigation, the underlying molecular basis has remained elusive. Recent studies of humans and model organisms have shed new light on the complexity of meiotic defects, providing evidence that the age-related increase in errors in the human female is not attributable to a single factor but to an interplay between unique features of oogenesis and a host of endogenous and exogenous factors.

Figure 1. Oogenesis and the female meiotic cycle

a | Meiosis. Female meiosis can be divided into three temporally distinct phases. Prophase: after DNA replication, homologous chromosomes (shown in red and blue) undergo pairing, synapsis and recombination, and arrest at the diplotene (dictyate) stage. Dictyate arrest: oocytes remain in meiotic arrest until the female reaches maturity and the oocyte has completed an extensive period of growth following follicle formation. The divisions: the luteinizing hormone surge that triggers ovulation also causes resumption and completion of the first meiotic division in the periovulatory oocyte. The ovulated egg is arrested at second meiotic metaphase, and anaphase onset and completion of meiosis II only occur if the egg is fertilized. b | Oogenesis. The process of making an egg is complex and involves four distinct developmental phases. First, commitment to meiosis and meiotic initiation, which occurs at 8–10 weeks of gestation in humans. Second, follicle formation, which occurs during the second trimester in humans. Third, oocyte growth, which occurs in the sexually mature female under the control of paracrine and endocrine signals. Oocyte growth is thought to take approximately 85 days in humans and typically culminates in the ovulation of a single egg. Last, fertilization of the ovulated egg results in the completion of the second meiotic division.

Figure 2. Releasing sisters: normal and premature loss of cohesion

a | The normal situation. Cohesion between sister chromatids (shown by the orange rings) is established during pre-meiotic S phase. Following recombination, cohesion distal to the sites of exchanges tethers homologues throughout dictyate arrest. During the first meiotic division, release of cohesion along chromosome arms but retention at sister centromeres allows homologues to segregate while retaining a centromeric connection between sister chromatids. During the second meiotic division, cleavage of the remaining centromeric cohesion allows sister chromatids to segregate. (Note that in this panel, we have followed segregation of only one of the two homologues; that is, the homologue on the right at anaphase I. Similarly, in the following panels only one of the two possible meiosis II configurations is shown.) b | Premature loss of arm cohesion. Loss of cohesion distal to sites of exchange before anaphase I may result in premature homologue separation into two unpaired univalents, which will then segregate independently of one another at meiosis I. If both homologues travel together, the production of unbalanced gametes is almost certain. For example, as shown here, the sisters of each homologue separate at meiosis II, yielding an oocyte (and second polar body) with an extra chromatid. c | Premature loss of centromeric cohesion. Loss of cohesion between sister centromeres can occur at meiosis I (as shown here) or meiosis II, leading to random segregation of sister centromeres.