Nondisjunction and Aneuploidy Origin

Nondisjunction is the failure of chromosomes to separate correctly during cell division; when it occurs in meiosis it produces gametes with a missing or extra chromosome, the origin of most constitutional aneuploidy in humans. This topic traces how, when, and in which parent these errors arise.

Definition

Nondisjunction is the failure of homologous chromosomes (in meiosis I) or sister chromatids (in meiosis II or mitosis) to separate to opposite poles, yielding daughter cells with an abnormal chromosome number; meiotic nondisjunction in a gamete is the principal origin of trisomic and monosomic conceptions.

Scope

The entry covers the meaning of nondisjunction in meiosis I versus meiosis II, the mechanisms that lead to chromosome mis-segregation, how the parental and division-of-origin of an aneuploidy is determined, and the contribution of recombination defects. It is a mechanistic reference on the genesis of aneuploidy, not a clinical or screening guide.

Core questions

• What distinguishes nondisjunction at meiosis I from nondisjunction at meiosis II?
• How is the parental and division-of-origin of a trisomy determined?
• Which recombination and cohesion defects predispose a chromosome to mis-segregate?

Key concepts

• Meiosis I versus meiosis II nondisjunction
• Trisomy and monosomy
• Parent-of-origin and division-of-origin
• Susceptible (absent or suboptimal) crossover configurations
• Premature separation of sister chromatids
• Spindle-assembly checkpoint
• Mosaicism from post-zygotic (mitotic) nondisjunction

Mechanisms

Faithful segregation requires that each chromosome pair be held together by a well-placed crossover and by sister-chromatid cohesion until anaphase, and that bi-orientation on the spindle be monitored. Nondisjunction arises when these safeguards fail: a bivalent lacking an exchange (an achiasmate pair) or carrying a crossover positioned very near the centromere or telomere is prone to mis-segregate, as is a chromosome whose cohesion has weakened so that sister chromatids separate prematurely. Such errors generate gametes with 24 or 22 chromosomes, producing trisomy or monosomy at fertilization. Studying DNA polymorphisms in trisomic individuals and their parents allows the error to be assigned to a parent and to meiosis I or II; this work showed that human aneuploidy arises overwhelmingly in the oocyte, frequently at meiosis I and linked to altered recombination (Hassold & Hunt, 2001; Angell, 1997; Nagaoka et al., 2012; Webster & Schuh, 2017).

Clinical relevance

Meiotic nondisjunction is the origin of the common autosomal trisomies and sex-chromosome aneuploidies and of a large fraction of early pregnancy loss. Knowing the division and parent of origin informs the interpretation of cytogenetic findings and recurrence considerations; the topic explains how aneuploidy arises and is not a basis for individual diagnosis or counselling (Hassold & Hunt, 2001; Nagaoka et al., 2012).

Epidemiology

Aneuploidy is the most common class of chromosome abnormality in humans and a leading cause of miscarriage; molecular origin studies attribute the great majority of autosomal trisomies to maternal meiotic errors, with a substantial share occurring at meiosis I (Hassold & Hunt, 2001; Nagaoka et al., 2012).

History

Once chromosome counting became reliable in the mid-twentieth century, aneuploidies such as trisomy 21 were recognized as common causes of congenital disorders and pregnancy loss. DNA-polymorphism studies then made it possible to assign each trisomy to a parent and to a meiotic division, revealing the predominance of maternal meiosis I errors and their association with abnormal recombination, while single-oocyte analyses documented the events directly (Angell, 1997; Hassold & Hunt, 2001).

Debates

Whole-homologue nondisjunction versus premature separation of sister chromatids

Classic models attribute meiosis I errors to failure of whole homologues to separate, but direct analyses of human oocytes also implicate premature separation of sister chromatids and reverse segregation, suggesting the meiosis I error pathway is more heterogeneous than a single mechanism.

Key figures

• Terry Hassold
• Patricia Hunt
• Renée Angell
• Melina Schuh

Seminal works

• hassold-hunt-2001
• angell-1997
• nagaoka-2012

Frequently asked questions

What is the difference between meiosis I and meiosis II nondisjunction?

In meiosis I nondisjunction whole homologous chromosomes fail to separate; in meiosis II it is the sister chromatids that fail to separate. The distinction can often be inferred from which parental chromosome regions are present in the trisomy.

Why are most human aneuploidies of maternal origin?

The great majority of autosomal trisomies trace to errors in the oocyte rather than the sperm, reflecting features of female meiosis such as the long arrest of oocytes and the gradual loss of chromosome cohesion over time.