The origin of human aneuploidy: where we have been, where we are going

Abstract

Aneuploidy is the most common chromosome abnormality in humans, and is the leading genetic cause of miscarriage and congenital birth defects. Since the identification of the first human aneuploid conditions nearly a half-century ago, a great deal of information has accrued on its origin and etiology. We know that most aneuploidy derives from errors in maternal meiosis I, that maternal age is a risk factor for most, if not all, human trisomies, and that alterations in recombination are an important contributor to meiotic non-disjunction. In this review, we summarize some of the data that have led to these conclusions, and discuss some of the approaches now being used to address the underlying causes of meiotic non-disjunction in humans.

All dosage compensation is local: Gene-by-gene regulation of sex-biased expression on the chicken Z chromosome

“…In animals with large differences in the gene content between the X and Y, dosage could potentially affect hundreds of genes. In humans, most large aneuploidy and trisomy events are lethal, and of those that can be tolerated by the developing embryo, many produce severe congenital birth defects (FitzPatrick, 2005;Hassold et al, 2007) or sterility (Doswell et al, 2006;Visootsak and Graham, 2006). It is consequently logical that as the degenerative process of the Y chromosome reduces its gene content and makes a larger proportion of X-linked genes subject to gene dosage effects (Charlesworth and Charlesworth, 2000;Charlesworth et al, 2005), some mechanism evolves to balance the dosage of the X chromosome complement in both sexes.…”

Preimplantation genetic diagnosis and screening by array comparative genomic hybridisation: experience of more than 100 cases in a single centre

“…It is well known that chromosomal aneuploidy increases exponentially with increasing maternal age. 21,22 Therefore, patients with advanced age should be counselled accordingly before the initiation of PGS cycles.…”

Recent advance in our understanding of the molecular nature of chromosomal abnormalities

“…63 There has been an anecdotal consensus that a woman with a previous aneuploid conception has an increased recurrence risk for the same or a different aneuploidy. 64,65 Recently, we identified mutations in the SYCP3 gene in two women with a recurrent pregnancy loss at between 6 and 10 weeks, possibly due to a repeated aneuploidy.…”

“…63 The basis for the age-dependent increase in nondisjunction in meiosis I has been a long-standing enigma in this field. The first specific evidence related to this issue was the observation that oocytes from older mice display a decrease in number of chiasmata, which might predispose the germ line cells to non-disjunction in meiosis I.…”