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To err (meiotically) is human: the genesis of human aneuploidy

Key Points

  • Aneuploidy (trisomy or monosomy) is the most commonly identified chromosome abnormality in humans, occurring in at least 5% of all clinically recognized pregnancies.

  • About 1 in 300 liveborn infants are aneuploid, most commonly with a missing or additional sex chromosome or an additional chromosome 21 (Down syndrome).

  • About 1 in 3 miscarriages are aneuploid, with sex chromosome monosomy (45,X) and trisomy 16 being the most common.

  • Most 45,X conceptions involve loss of the paternal X chromosome; most trisomies arise from errors at maternal meiosis I (MI).

  • Abnormal levels or positioning of meiotic recombinational events (cross-overs) have been implicated in the origin of human trisomies.

  • Reductions in recombination have been observed in maternal MI-derived trisomies 15, 16, 18, and 21 and sex-chromosome trisomies, and in paternal MI-derived XXYs and trisomy 21.

  • Increases in recombination have been observed for maternal meiosis-II (MII)-derived trisomy 21, which indicates that the precipitating event for these cases probably occurred at MI.

  • Abnormally positioned recombinational events (too close to, or too far from, the centromere) have been reported for trisomies 16 and 21.

  • Increasing maternal age is the most important aetiological agent associated with aneuploidy: for women in their 40s, as many as one-third of all clinically recognized pregnancies might be trisomic. The basis of the age effect is unclear, although for certain trisomies it might be associated with abnormal recombination.

  • Genetic and/or environmental contributors to human aneuploidy are unknown, although recent reports indicate a possible association with maternal folate polymorphisms and with maternal smoking habits.

Abstract

Aneuploidy (trisomy or monosomy) is the most commonly identified chromosome abnormality in humans, occurring in at least 5% of all clinically recognized pregnancies. Most aneuploid conceptuses perish in utero, which makes this the leading genetic cause of pregnancy loss. However, some aneuploid fetuses survive to term and, as a class, aneuploidy is the most common known cause of mental retardation. Despite the devastating clinical consequences of aneuploidy, relatively little is known of how trisomy and monosomy originate in humans. However, recent molecular and cytogenetic approaches are now beginning to shed light on the non-disjunctional processes that lead to aneuploidy.

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Figure 1: Meiotic 'timelines' for humans.
Figure 2: Meiotic non-disjunction.
Figure 3: Genetic maps of normal and trisomic meioses.
Figure 4: Recombination and meiosis-II-derived trisomies.
Figure 5: Molecular cytogenetic approaches to studying gametes.
Figure 6: Maternal age and trisomy.

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Acknowledgements

Research conducted in the T. Hassold and P. Hunt laboratories and discussed in this article was supported by the National Institutes of Health.

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DATABASE LINKS

trisomy 21

nod

Axs

Dub

ncd

Klinefelter syndrome

MTHFR

MTRR

SCP3

MLH1

FURTHER INFORMATION

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Patricia Hunt's lab

Glossary

ATRESIA

Apoptotic death of follicles.

POLAR BODY

Oogenesis results in only one functional gamete; the remaining products of MI or MII are the polar bodies, which contain chromosomes but virtually no cytoplasm.

GAMETE INTRA-FALLOPIAN TRANSFER (GIFT).

Assisted reproduction technique in which oocytes and sperm are mixed and placed into the fallopian tubes, where fertilization might occur.

SPECTRAL KARYOTYPING

Fluorescence in situ hybridization technique in which differentially labelled DNA probes to all chromosomes are used, making it possible to identify every chromosome in the complement in a single hybridization.

GENE CONVERSION

Non-reciprocal recombination event, in which genetic information at one allele is copied into the complementary allele.

BIVALENT

Synapsed pair of homologous chromosomes in meiosis I.

SYNAPTONEMAL COMPLEX

A tripartite, meiosis-specific structure that binds the homologous chromosomes together during meiosis I.

ANTRAL FOLLICLE

Final stage in the growth of the oocyte, when the follicle develops a fluid-filled cavity — the antrum.

PERIOVULATORY FOLLICLE

The follicle around the time of ovulation; at this stage, the oocyte, which has been suspended in prophase, will resume and complete meiosis I in response to the preovulatory surge of gonadotrophins ('LH surge').

FOLIC ACID

One of the B-vitamins; folic acid is essential for cellular methylation reactions and for de novo synthesis of nucleotide precursors in DNA synthesis.

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Hassold, T., Hunt, P. To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet 2, 280–291 (2001). https://doi.org/10.1038/35066065

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