Missegregation refers to the incorrect distribution of chromosomes into daughter cells during cell division. This fundamental biological error can have profound implications for an organism’s development and health. Understanding missegregation is thus important for comprehending various conditions and diseases.
Understanding Errors in Cell Division
Cell division is a fundamental process for growth, repair, and reproduction. During this process, chromosomes, which carry genetic information, must be accurately segregated to ensure each new cell receives a complete and correct set. Missegregation occurs when this distribution is unequal.
One common mechanism of missegregation is non-disjunction, where homologous chromosomes fail to separate during meiosis I, or sister chromatids fail to separate during meiosis II or mitosis. In such cases, one daughter cell receives an extra chromosome, while the other receives one less. Another mechanism is anaphase lag, where a chromosome or chromatid fails to migrate properly to either pole during anaphase and is subsequently lost or excluded from the main nuclei. These errors can happen in both mitotic divisions, which produce somatic cells for growth and repair, and meiotic divisions, which produce gametes for reproduction.
Health Impacts of Chromosome Errors
Missegregation leads to aneuploidy, a condition characterized by an abnormal number of chromosomes in a cell. This imbalance in genetic material can have health consequences. Aneuploidy is a significant cause of various genetic disorders and is frequently observed in human cancers.
Aneuploidy resulting from meiotic missegregation is a cause of developmental disorders. Down syndrome, or Trisomy 21, is a well-known example, caused by an extra copy of chromosome 21. Individuals with this condition often experience developmental delays and distinct facial features. Other examples include Edwards syndrome (Trisomy 18) and Patau syndrome (Trisomy 13), both involving an extra copy of chromosomes 18 and 13. Turner syndrome (Monosomy X), where females are missing one X chromosome, results in short stature and infertility.
Beyond developmental disorders, missegregation significantly contributes to infertility and miscarriage. Many aneuploid embryos are not viable and result in early embryonic lethality, accounting for a substantial percentage of miscarriages. For instance, an estimated 50-70% of first-trimester miscarriages are attributed to chromosomal abnormalities.
There is a strong connection between mitotic missegregation and cancer development. Cancer cells frequently exhibit widespread aneuploidy, a state often referred to as chromosomal instability (CIN). This chromosomal instability can drive tumor growth, promote metastasis, and contribute to drug resistance.
Factors Contributing to Missegregation
Several factors, both internal and external, can increase the likelihood of missegregation during cell division. One well-established link is maternal age, with advanced maternal age correlating with higher rates of meiotic missegregation in oocytes. This increased risk is partly due to the gradual weakening of centromeric cohesion, which helps hold sister chromatids together.
Environmental factors can also influence chromosome stability and lead to missegregation. Exposure to certain chemicals, such as spindle poisons, radiation, or toxins, can disrupt the delicate machinery of cell division. These disruptions can interfere with centromere-kinetochore interactions or spindle formation, increasing the chances of errors.
Genetic predispositions play a role as well, with rare genetic conditions or variations making individuals more susceptible to missegregation events. Defects in specific genes involved in chromosome segregation can increase the frequency of errors.
Errors in cellular machinery, such as defects in spindle fibers, centromeres, or cohesin proteins, are direct causes of missegregation. Spindle fibers are responsible for pulling chromosomes apart, while centromeres are the regions on chromosomes where these fibers attach. Cohesin proteins act like molecular glue, holding sister chromatids together until they are ready to separate. Problems with any of these components can result in chromosomes not segregating correctly.
Cellular Controls for Accurate Chromosome Segregation
Cells possess internal surveillance systems designed to prevent missegregation and ensure accurate chromosome distribution. These mechanisms act as “checkpoints” to monitor the progression of cell division.
The Spindle Assembly Checkpoint (SAC) that halts cell division if any chromosomes are not properly attached to the spindle microtubules. The SAC ensures that each chromosome is correctly oriented and attached to microtubules from opposite poles before allowing the cell to proceed to anaphase, the stage where sister chromatids separate. This checkpoint prevents premature separation of chromosomes, which would lead to an uneven distribution.
The cohesin complex is a ring-shaped protein structure that plays a central role in holding newly duplicated sister chromatids together from the S phase until their separation in anaphase. This cohesion resists the pulling forces of the spindle microtubules, ensuring proper alignment and attachment. Once all chromosomes are correctly attached and the cell is ready to divide, cohesin is abruptly destroyed, allowing the sister chromatids to segregate.
Proper centrosome duplication is also important for accurate spindle formation. Centrosomes are the primary microtubule-organizing centers in animal cells, and they must duplicate precisely before cell division. Each daughter cell needs to inherit a single centrosome to form a bipolar spindle, which is necessary for the equal distribution of chromosomes. Abnormal centrosome numbers are frequently observed in human cancers and contribute to improper chromosome distribution.