What Is Nondisjunction in Meiosis 2 and Why Does It Matter?

Cells rely on precise chromosome separation during meiosis to ensure proper genetic distribution. When this process goes wrong, it can lead to aneuploidy—an abnormal number of chromosomes—linked to various genetic disorders and developmental issues. One such error, nondisjunction in meiosis II, occurs when sister chromatids fail to separate, leading to gametes with missing or extra chromosomes.

Understanding this mistake is crucial for recognizing its implications for human health.

Mechanism Of Nondisjunction In Meiosis II

The failure of sister chromatids to separate properly in meiosis II results from disruptions in key molecular and structural processes. Factors such as defects in chromatid cohesion, improper spindle alignment, and checkpoint failures contribute to this error, leading to aneuploid gametes.

Disruption Of Sister Chromatid Separation

Normally, sister chromatids are pulled apart and distributed evenly into daughter cells. This separation is driven by the mitotic spindle, a structure composed of microtubules that attach to chromosomes via kinetochores. When nondisjunction occurs, sister chromatids remain attached and migrate together to a single daughter cell, resulting in one gamete with an extra chromosome and another missing one.

Research in Nature Reviews Genetics (2020) highlights that defects in kinetochore-microtubule attachments are a primary cause of nondisjunction. If the spindle fails to generate sufficient tension or microtubules attach improperly, chromosomes may not segregate correctly. Additionally, errors in separase, an enzyme that cleaves cohesion proteins, can prevent chromatid disjunction, contributing to chromosomal imbalances.

Cohesion Proteins And Spindle Alignment

Cohesion between sister chromatids is maintained by cohesins, protein complexes essential for proper segregation. In meiosis II, these cohesins must degrade at the right time for chromatids to separate. A study in Cell Reports (2021) found that mutations or age-related deterioration in cohesins can lead to nondisjunction.

Spindle fibers must also align chromosomes correctly along the metaphase plate. Errors in spindle positioning or attachment can misdirect chromatids. Disruptions in the spindle assembly checkpoint (SAC), which ensures proper attachment before anaphase, can allow division to proceed despite misaligned chromosomes, increasing nondisjunction risk.

Chromosome Segregation Checkpoints

To prevent errors, cells employ checkpoints that monitor meiosis. The spindle assembly checkpoint detects improper kinetochore-microtubule attachments and delays anaphase until corrections occur. If this checkpoint fails, cells may proceed with division despite unresolved attachment errors.

A 2022 study in The EMBO Journal demonstrated that mutations in checkpoint proteins, such as Mad2 and BubR1, impair error detection, increasing segregation failures. Additionally, the anaphase-promoting complex (APC/C), which triggers chromatid separation, must be precisely regulated. Overactivation or premature activation of APC/C can contribute to aneuploidy.

Differences Between Meiosis I And Meiosis II Errors

Errors in meiosis I and II both result in aneuploidy but arise from distinct mechanistic failures. In meiosis I, homologous chromosomes fail to separate, while in meiosis II, sister chromatids do not disjoin properly.

In meiosis I, homologous chromosomes align at the metaphase plate and must be pulled to opposite poles. If nondisjunction occurs, both migrate to the same daughter cell, creating gametes with an extra chromosome or none at all. This means all resulting gametes are abnormal. Studies in Nature Genetics (2021) show that maternal age-related weakening of chromosome cohesion increases meiosis I nondisjunction risk.

In contrast, meiosis II errors occur after homologous chromosomes have segregated correctly. The issue lies in sister chromatid separation. If nondisjunction happens here, one gamete inherits both sister chromatids, while another receives none. However, the other two gametes remain normal. Research in The American Journal of Human Genetics (2022) links meiosis II nondisjunction to spindle defects or cohesion protein malfunctions, particularly in aging oocytes.

Since meiosis I errors affect all resulting gametes, they have a higher likelihood of producing nonviable embryos or conditions like trisomy disorders. Meiosis II errors typically impact only half of the gametes, meaning normal fertilization is still possible. Studies in Genetics in Medicine (2023) indicate that while both meiosis I and II errors contribute to trisomy disorders, meiosis I errors are more prevalent, especially in maternal oocytes.

Role In Trisomy 21

Trisomy 21, the genetic basis of Down syndrome, arises when an individual inherits an extra copy of chromosome 21, disrupting normal gene expression and development. Nondisjunction in meiosis II can lead to this condition when sister chromatids fail to separate, resulting in a gamete with two copies of chromosome 21. If fertilized by a normal gamete, the zygote will have three copies of chromosome 21.

Maternal nondisjunction accounts for approximately 90% of trisomy 21 cases, with meiosis I errors being more common than meiosis II errors. However, when meiosis II nondisjunction occurs, it is often linked to maternal age-related factors, such as weakened cohesion proteins and spindle instability. A study in Human Molecular Genetics (2021) found that age-related deterioration of cellular structures in oocytes increases chromatid missegregation, particularly in women over 35. Paternal nondisjunction in meiosis II is rare but has been documented in defects affecting spermatogenesis.

The extra chromosome 21 disrupts molecular and cellular processes. Overexpression of genes on chromosome 21 affects neurological function, cardiac development, and immune regulation. The gene DYRK1A is implicated in cognitive impairment, while increased APP expression contributes to early-onset Alzheimer’s-like pathology in individuals with trisomy 21.

Consequences For Embryonic Development

Nondisjunction in meiosis II significantly alters embryonic development, often leading to early pregnancy loss or congenital disorders. The impact depends on which chromosome is affected and whether the error results in a viable trisomy or a lethal imbalance. Trisomy 21 can result in a live birth with Down syndrome, while most other trisomies lead to miscarriage.

Aneuploidy disrupts normal cell division and differentiation. The presence of an extra chromosome affects gene dosage, leading to abnormal protein expression that interferes with cellular signaling. Single-cell sequencing studies show that aneuploid embryos often exhibit delayed or arrested development during the blastocyst stage, as misregulated gene expression compromises mitotic spindle formation and metabolism.

In surviving aneuploid embryos, structural and functional abnormalities affect multiple organ systems. The brain, heart, and skeletal system are particularly vulnerable. Research in Developmental Cell found that aneuploid neural progenitor cells exhibit altered differentiation, contributing to intellectual disability in Down syndrome. Similarly, cardiac defects, which affect nearly half of individuals with trisomy 21, arise due to disrupted signaling during heart development.