To Err (Meiotically) is Human:
The Genesis of Human Aneuploidy 

Nature Reviews Genetics v.2, n.4 Apr01

Terry Hassold & Patricia Hunt

Preface

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.

Summary

• 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.

Nature Reviews Genetics 2, 280 -291 (2001); doi:10.1038/35066065