Nondisjunction can occur at three distinct points: during the first division of meiosis (meiosis I), during the second division of meiosis (meiosis II), or during mitosis in ordinary body cells. The most common and consequential timing is meiosis I in egg cells, which accounts for the majority of chromosomal abnormalities seen in pregnancies.
During Meiosis I: Homologous Chromosomes Fail to Separate
In a normal first meiotic division, paired chromosomes (one from your mother, one from your father) line up together and then pull apart into two separate cells. Nondisjunction in meiosis I happens when that pair fails to split. Both copies of a chromosome end up in the same cell, meaning one resulting cell gets an extra chromosome and the other gets none.
This is the most significant timing for nondisjunction. Looking at Down syndrome as a well-studied example, 93% of cases trace back to an error in the mother’s cells, and of those maternal errors, 86% occurred specifically during meiosis I. Only 14% happened during meiosis II. The reason meiosis I is so error-prone in eggs comes down to a remarkable quirk of biology: the process gets paused for decades.
Why Eggs Are Especially Vulnerable
A female’s egg cells begin meiosis during fetal development, then freeze partway through the first division in a state called dictyate arrest. They stay suspended there until ovulation, which could be 12 years later or 45 years later. That means the structures holding paired chromosomes together must remain intact for decades with no maintenance or replacement.
The protein complexes responsible for keeping chromosomes linked (called cohesins) are loaded onto chromosomes only once, during fetal development. There is no mechanism to replenish them. Over the years, these proteins gradually degrade. In aged mouse oocytes, the key cohesin component is severely reduced compared to younger ones. As cohesin deteriorates, the physical connections between paired chromosomes weaken and can fall apart prematurely, allowing chromosomes to drift to the wrong cell during division. Oxidative damage over time accelerates this breakdown, creating a feedback loop where weakened protein structures become progressively less stable.
This degradation explains the well-documented relationship between maternal age and chromosomal abnormalities. A Danish study of more than 500,000 pregnancies found that compared to women in their twenties, those aged 35 to 39 had roughly a fourfold increased risk of fetal aneuploidy (an abnormal chromosome count). Women aged 40 to 44 had a 16-fold increase, and women 45 or older had a 36-fold increase.
During Meiosis II: Sister Chromatids Fail to Separate
The second meiotic division is structurally simpler. After meiosis I has split chromosome pairs apart, meiosis II splits each chromosome’s two identical copies (sister chromatids) into separate cells. Nondisjunction at this stage means those identical copies travel to the same cell instead of separating.
Meiosis II errors produce a different pattern of abnormality than meiosis I errors. When meiosis I goes wrong, the resulting egg carries two different versions of a chromosome (one originally from each grandparent). When meiosis II goes wrong, the egg carries two identical copies of the same chromosome. Both scenarios lead to trisomy if that egg is fertilized, but meiosis II errors are less common overall.
During Mitosis: Errors in Body Cells
Nondisjunction doesn’t only happen in reproductive cells. Ordinary body cells divide through mitosis throughout your life, and sister chromatids can fail to separate during this process too. When this happens, it doesn’t affect every cell in the body. Instead, it creates mosaicism: some cells carry the normal chromosome number while others have an extra or missing chromosome.
Mitotic nondisjunction is particularly notable in early embryonic development. Research on mouse embryos has revealed that the cellular safety system designed to prevent division errors, called the spindle assembly checkpoint, can detect misaligned chromosomes but often fails to actually delay cell division in response. In early embryos, roughly 80% of severely misaligned chromosomes at the moment of division still showed active checkpoint signaling, meaning the alarm was sounding but the cell divided anyway. This disconnect helps explain why chromosome segregation errors are relatively common in early mammalian embryos. Only about 2% of Down syndrome cases trace to mitotic errors after fertilization, but mosaic forms of other chromosomal conditions can arise this way.
Nondisjunction in Sperm
Sperm production involves the same two meiotic divisions, and nondisjunction can occur at either stage. However, spermatogenesis has more effective quality control than oogenesis. Sperm cells with an extra chromosome (disomy) are filtered out more efficiently than those missing a chromosome (nullisomy), which is why sperm tend to show more missing-chromosome errors than extra-chromosome errors. About 5% of Down syndrome cases originate from paternal nondisjunction. For Klinefelter syndrome (47,XXY), the split is closer to even: the extra X chromosome comes from the mother in about 56% of cases and the father in the remaining cases.
Unlike eggs, sperm are produced continuously from puberty onward rather than sitting in arrested development for decades. This means sperm don’t face the same cohesin degradation problem, which is a major reason why paternal age has a far smaller effect on nondisjunction rates than maternal age.