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

Abstract

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.