Meiosis and Nondisjunction

Meiosis is the specialized cell division that produces haploid gametes from diploid precursor cells. It involves two successive divisions: meiosis I (reductional, separating homologs) and meiosis II (equational, separating sister chromatids). Errors in chromosome segregation (nondisjunction) during either division are the primary cause of aneuploidy in human conceptions.

• Meiosis I (reductional division): Homologous chromosomes pair (synapsis), undergo crossing over (recombination), and then separate. Each daughter cell receives one chromosome from each homologous pair (2n to n). This is the step that generates genetic diversity through independent assortment and recombination.
• Meiosis II (equational division): Sister chromatids separate, similar to mitosis. Each daughter cell receives one chromatid. The result is four haploid cells from one diploid precursor.
• Crossing over: Exchange of genetic material between homologous chromosomes during prophase I. Occurs at chiasmata, produces recombinant chromosomes, and is essential for proper segregation. Failure to form at least one crossover per chromosome arm increases nondisjunction risk.
• Nondisjunction in meiosis I: Homologs fail to separate. Both members of a homologous pair go to one daughter cell. Gametes contain either two copies of a chromosome (both homologs) or none. After fertilization, produces trisomic or monosomic zygotes.
• Nondisjunction in meiosis II: Sister chromatids fail to separate. Produces gametes with two copies of the same chromatid or none. Key difference from meiosis I error: the trisomic zygote has two identical copies (isodisomy) from one parent rather than one of each homolog (heterodisomy).
• Distinguishing MI vs MII errors: using pericentromeric DNA markers, meiosis I nondisjunction produces heterozygosity near the centromere (two different homologs), while meiosis II nondisjunction produces homozygosity (two copies of the same chromatid).
• Maternal age effect: Risk of nondisjunction increases dramatically with maternal age, particularly for meiosis I errors. Oocytes arrest in prophase I from fetal life until ovulation, and decades of arrest may degrade cohesins holding bivalents together.
• Robertsonian translocations: Fusion of two acrocentric chromosomes (13, 14, 15, 21, 22) at their centromeres. Carriers have 45 chromosomes but are phenotypically normal. During meiosis, abnormal segregation can produce gametes with an effective trisomy or monosomy (e.g., rob(14;21) carrier has ~15% risk of trisomy 21 offspring if mother, ~1-2% if father).

• Trisomy 21 (Down syndrome): ~95% from nondisjunction (mostly maternal meiosis I), ~4% from Robertsonian translocation, ~1% mosaic. Risk increases from ~1/1,500 at age 20 to ~1/100 at age 40.
• Trisomy 18 (Edwards syndrome): Predominantly maternal meiosis II error. Severe condition with >95% prenatal lethality. Clenched fists with overlapping fingers, rocker-bottom feet, cardiac defects.
• Trisomy 13 (Patau syndrome): ~75% from nondisjunction, ~20% from Robertsonian translocation (often rob(13;14)). Holoprosencephaly, polydactyly, midline defects.
• Sex chromosome aneuploidies: 47,XXY (Klinefelter) and 45,X (Turner) are the most common. Turner syndrome is unique: ~80% lose the paternal sex chromosome, and 45,X is the most common chromosomal cause of first-trimester miscarriage.