Upstream eventAltered, Chromosome number
Increase, Aneuploid offspring
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Chemical binding to tubulin in oocytes leading to aneuploid offspring||adjacent||High|
Life Stage Applicability
Key Event Relationship Description
Development of a conceptus from a gamete containing an abnormal number of chromosomes results in an aneuploid offspring. Whether the aneuploid conceptus results in a viable offspring is dependent on the chromosome involved in the aneuploidy. Viable aneuploidies in humans include chromosomes 13, 18 and 21, and the sex chromosomes.
Evidence Supporting this KER
It is well established that in the majority of cases of human offspring with an aneuploid condition, the extra chromosome is inherited from one of the parents. In humans, it is known that aneuploidy occurs more frequently in female germ cells. It has been known for a long time that there is a strong association between increasing maternal age and increasing risk of aneuploid offspring.
Aneuploidy arising during meiosis in germ cells represents the most common chromosomal abnormality at birth and is the leading cause of pregnancy loss in humans. The presence of aneuploid eggs in humans ranges (depending on age), but is approximately 20%. In parallel, approximately 10–30% of human zygotes are aneuploid. 50% of human pregnancies are spontaneously aborted; of these, 50% are due to aneuploidy. Finally, approximately 0.3% of human newborns are aneuploid. These data are summarized in Hassold et al.  and Nagaoka et al. . It is widely accepted that human oocytes are particularly susceptible to chromosome mis-segregation [Hassold et al., 2007; Hunt and Hassold, 2002; Nagaoka et al., 2012]. Trisomy 21 or Down syndrome, with an occurrence of ~1/720 births, is the most common genetic abnormality in newborns [Hassold et al., 2007]. The etiology of human aneuploidy is still not well understood, although there is strong evidence supporting a preferential occurrence during female meiosis I and a positive correlation with maternal age [Hunt and Hassold, 2002; Nagaoka et al., 2012; Webster and Schuh, 2017].
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
There is limited data on the quantitative relationship between aneuploidy in oocytes and aneuploidy in the offspring. It is difficult to compare the frequencies of aneuploid in oocytes with that in offspring because the great majority of aneuploid embryos are eliminated during pregnancy. However, the majority of individuals who are born with aneuploid conditions are constitutionally aneuploid strongly suggesting that this condition was already present at conception. Indeed, experimental data in rodent support a direct relationship. Some of these results deal with chemicals such as griseofulvin [Marchetti et al., 1992; Tiveron et al., 1992] and taxol [Mailhes et al., 1999] that are not included in this AOP because of uncertainty about the MIE (griseofulvin) or because chemical binding results in the stabilization of microtubules rather than depolymerization (taxol). The available data suggest that the frequencies of aneuploidy before and after fertilization are in general agreement with each other. In addition, data with mice deficient in SAC proteins, which have high levels of female germ cell aneuploidy, show little support for selection against aneuploid eggs at fertilization [Leland et al., 2009].
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
This is based on evidence in humans and mice, but is broadly applicable to all eukaryotic species.
Hassold T, Hall H, Hunt P. 2007. The origin of human aneuploidy: Where we have been, where we are going. Hum Mol Genet 16: R203–R208.
Hunt PA, Hassold TJ. 2002. Sex matters in meiosis. Science 296:2181–2183.
Leland S, Nagarajan P, Polyzos A, Thomas S, Samaan G, Donnell R, Marchetti F, Venkatachalam S. 2009. Heterozygosity for a Bub1 mutation causes female-specific germ cell aneuploidy in mice. Proc Natl Acad Sci USA 106:12776-12781.
Mailhes JB, Aardema MJ, Marchetti F. 1990. Cytogenetic analysis of mouse oocytes and one-cell zygotes as a potential assay for heritable germ cell aneuploidy. Mutat Res 242:89-100.
Marchetti F, C Tiveron, B Bassani and F Pacchierotti. 1992. Griseofulvin-induced aneuploidy and meiotic delay in female mouse germ cells, II. Cytogenetic analysis of one-cell zygotes. Mutat Res 266:151-162.
Nagaoka SI, Hassold TJ, Hunt PA. 2012. Human aneuploidy: Mechanisms and new insights into an age-old problem. Nat Rev Genet 13:493–504.
Tiveron C, F Marchetti, B Bassani and F Pacchierotti. 1992. Griseofulvin-induced aneuploidy and meiotic delay in female mouse germ cells, I. Cytogenetic analysis of metaphase II oocytes. Mutat Res 266:143-150.
Webster A, Schuh M. 2017. Mechanisms of aneuploidy in human eggs. Trends Cell Biol 27:55-68.