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

Key Points

  • Aneuploidy is extraordinarily common in humans, occurring in an estimated 20–40% of all conceptions. It is the most common cause of miscarriages and congenital defects in our species and is a leading impediment to the treatment of infertility.

  • Most aneuploidy results from maternal meiotic nondisjunctional errors. However, there is remarkable variation among chromosomes in the way in which these errors originate, indicating that there are multiple mechanisms by which human aneuploidy occurs.

  • Studies of human fetal oocytes indicate a high level of recombination errors, indicating that some oocytes are predisposed to nondisjoin because of events that occurred before birth.

  • Cell cycle control checkpoints that operate in meiotic prophase and at the metaphase–anaphase transition are less stringent in females than in males. Consequently, abnormal cells that are eliminated in spermatogenesis may escape detection in the female, ultimately leading to aneuploid eggs.

  • Studies from mice suggest that loss of cohesin proteins over the reproductive life of the female contribute to the maternal age effect on human trisomy.

  • Exposure to endocrine disruptors (for example, bisphenol A) disrupts oogenesis at multiple stages and predisposes the oocyte to aneuploidy.

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.

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Figure 1: Oogenesis and the female meiotic cycle.
Figure 2: Releasing sisters: normal and premature loss of cohesion.

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Acknowledgements

Research conducted in the Hunt and Hassold laboratories and discussed in this Review was supported by US National Institutes of Health grants HD21341 (to T.J.H.) and ES013527 (to P.A.H.). In addition, the authors would gratefully like to acknowledge the three 'grand dames' of human aneuploidy research who sparked our interest and shaped our thinking: D. Warburton, M. Mikkelsen and, most of all, P. Jacobs.

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Correspondence to Terry J. Hassold or Patricia A. Hunt.

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Glossary

Aneuploidy

A chromosome abnormality in which the chromosome number is not a multiple of the haploid number.

Assisted reproductive technology

(ART). Clinical approaches that are used to help infertile couples achieve a normal pregnancy. These include ovarian stimulation protocols using exogenous hormones, in vitro fertilization, intracytoplasmic sperm injection and preimplantation genetic diagnosis.

Nondisjunction

The failure of chromosomes to segregate normally during cell division. Nondisjunction at meiosis I results in products with additional or missing whole chromosomes; nondisjunction at meiosis II results in products with additional or missing sister chromatids.

Pachytene

The stage of meiotic prophase characterized by complete synapsis of all homologues. Importantly, crossover sites can be visualized in pachytene stage cells using appropriate markers.

Bivalent

Paired homologous chromosomes that are tethered by a crossover (or crossovers).

Synapsis

The intimate pairing of homologous chromosomes that occurs during prophase of meiosis and is essential for meiotic recombination. Synapsis is facilitated by the formation of a meiosis-specific protein scaffold called the synaptonemal complex.

Pseudoautosomal region

(PAR). The small region of homology at the distal ends of the X and Y chromosomes that allows for synapsis and recombination.

Sister chromatid cohesion

Replicated chromosomes, or sister chromatids, are held together by cohesin, which is a protein complex that is loaded onto the chromosomes during S phase. In meiosis, sister chromatid cohesion is sequentially released from the chromosome arms at anaphase I and from sister centromeres at anaphase II, allowing for the orderly segregation of homologues and sister chromatids, respectively.

Univalents

Homologous chromosomes that are not associated with one another (for example, owing to failure to recombine).

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Nagaoka, S., Hassold, T. & Hunt, P. Human aneuploidy: mechanisms and new insights into an age-old problem. Nat Rev Genet 13, 493–504 (2012). https://doi.org/10.1038/nrg3245

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