The body is made up of trillions of somatic cells with the capacity to divide into identical daughter cells facilitating organismal growth, repair, and response to the changing environment. This process is called “mitosis.” In the gametes, a different form of cell division occurs called “meiosis.” The outcome of meiosis is the creation of daughter cells, either sperm or egg cells, through reduction division which results in a haploid complement of chromosomes so that on joining with another sex cell at fertilization a new diploid chromosomal complement is restored in the fertilized egg. During anaphase of the cell cycle, chromosomes are separated to opposite ends of the cell to create two daughter cells. Nondisjunction describes the failure of the chromosomes to separate.
The genome is encoded by the chemical sequence of DNA nucleotides within our cells. DNA is condensed by proteins to create “chromatin,” a complex of DNA and proteins. Somatic human cells contain 23 paired chromosomes or 46 total chromosomes. Forty-six is considered the “diploid” number (2n), while 23 is considered the “haploid” number (1n) or half the diploid number. “Aneuploidy” refers to the presence of an abnormal number of chromosomes. Monosomy means the lack of a chromosome or 45 total chromosomes. Trisomy means the presence of an extra chromosome or 47 total chromosomes.
There are 2 parts to the cell cycle: interphase and mitosis/meiosis. Interphase can be further subdivided into growth 1 (G1), synthesis (S), and growth 2 (G2). During the G phases, the cell grows by producing various proteins, and during the S phase, the DNA is replicated so that each chromosome contains 2 identical sister chromatids (c).
Mitosis contains 4 phases: prophase, metaphase, anaphase, and telophase. In prophase, the nuclear envelope breaks down, and chromatin condenses into chromosomes. In metaphase, the chromosomes line up along the metaphase plate, and microtubules attach to the kinetochores of each chromosome. In anaphase, the chromatids separate and are pulled by the microtubules to opposite ends of the cell. Finally, in telophase, the nuclear envelopes reappear, the chromosomes unwind into chromatin, and the cell undergoes cytokinesis, which splits the cell into 2 identical daughter cells.
Meiosis goes through all 5 phases of mitosis twice, with modified mechanisms that ultimately create haploid cells instead of diploid. One modification is in meiosis I. Homologous chromosomes are separated instead of sister chromatids, creating haploid cells. It is during this process where we see crossing over and independent assortment leading to the increased genetic diversity of the progeny. Meiosis II progresses the same way as mitosis, but with the haploid number of chromosomes, ultimately creating 4 daughter cells all genetically distinct from the original cell.
Nondisjunction can occur during anaphase of mitosis, meiosis I, or meiosis II. During anaphase, sister chromatids (or homologous chromosomes for meiosis I), will separate and move to opposite poles of the cell, pulled by microtubules. In nondisjunction, the separation fails to occur.
Mitotic nondisjunction can occur with the inactivation of either topoisomerase II, condensin, or separase. This will result in 2 diploid daughter cells, one with 2n+1 and the other with 2n-1.
If nondisjunction occurs during meiosis I, it is the result of the failure of the tetrads to separate during anaphase I. At the end of meiosis I, there will be 2 haploid daughter cells, one with n+1 and the other with n-1. Both of these daughter cells will then go on to divide once more in meiosis 2, producing 4 daughter cells, 2 with n+1 and 2 with n-1.
Nondisjunction in meiosis II results from the failure of the sister chromatids to separate during anaphase II. Since meiosis I proceeded without error, 2 of the 4 daughter cells will have the normal haploid number. The other 2 daughter cells will be aneuploid, one with n+1 and the other with n-1.
In-utero, the only way to definitively diagnose a fetal chromosomal aneuploidy is by performing cytogenetic analysis of fetal cells, typically obtained through either amniocentesis or chorionic villus sampling. The fetal chromosomal complement is analyzed by performing a karyotype, a chromosome count and analysis under light microscopy, on fetal cells looking for abnormalities of chromosomal number or structure. Many prenatal screening tests exist to help provide an age-adjusted risk of fetal chromosomal aneuploidy through analysis of various markers or cell-free fetal DNA in maternal serum.
With in vitro fertilization (IVF), testing can also be performed prior to implantation through preimplantation genetic diagnosis (PGD), polar body diagnosis (PBD), or blastomere biopsy. PGD is a technique used to identify normal embryos that will be implanted into the mother, though technologically demanding and with additional expense over prenatal diagnosis. PBD can detect maternally derived aneuploidies and is relatively quick to perform when compared to PGD. Lastly, a blastomere biopsy can be performed prior to implantation to allow for genetic analysis however at greater risk to the developing embryo and therefore not currently recommended as standard of practice.
Mitotic nondisjunction can cause somatic mosaicism, with the chromosome imbalance only reflected in the direct offspring of the original cell where the nondisjunction occurred. This can be a cause some forms of cancer, including retinoblastoma.
Meiotic nondisjunction is of greater clinical significance since most aneuploidies are incompatible with life. However, some will result in viable offspring with a spectrum of developmental disorders.
Patau syndrome: Trisomy of chromosome 13
Edwards syndrome: Trisomy of chromosome 18
Down syndrome: Trisomy of chromosome 21 *most common viable aneuploidy
Sex Chromosome Trisomies
Klinefelter Syndrome: An extra X chromosome in a male (XXY)
Triple X syndrome: An extra X chromosome in a female (XXX)
XYY syndrome: An extra Y chromosome in a male
Sex Chromosome Monosomies
Turner Syndrome: Monosomy of X chromosome in a female (X) *the only chromosomal monosomy that is compatible with life.