Two Families, Two Meiotic Errors
A genetics clinic karyotypes children with Down syndrome and finds 47 chromosomes with three copies of chromosome 21 in each case. To work out the origin of the extra chromosome, a microsatellite locus close to the centromere of chromosome 21 is typed in two families. In family 1 the mother has alleles 1 and 2, the father has alleles 3 and 3, and the child has alleles 1, 2 and 3. In family 2 the mother has alleles 4 and 5, the father has alleles 6 and 6, and the child has alleles 4, 4 and 6. The locus is close to the centromere, so crossing over between the centromere and the locus is uncommon but not impossible. Both mothers are over 35. The clinic wants to explain the results to the parents and to advise on recurrence.
1. Deduce in which meiotic division nondisjunction occurred in each family, and justify your reasoning.
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The father contributes one chromosome 21 carrying allele 3 or 6, so the extra maternal contribution can be identified by subtraction.
Family 1: the child has 1, 2 and 3. The paternal allele is 3, so the child inherited both maternal alleles, 1 and 2. These are the two different homologues, so they failed to separate at meiosis I. Had the error been at meiosis II, the two maternal copies would be sister chromatids and would carry the same allele.
Family 2: the child has 4, 4 and 6. The paternal allele is 6, so the child inherited two copies of maternal allele 4. Two identical copies are sister chromatids, so nondisjunction occurred at meiosis II, after the homologues had separated.
The caveat is the centromere-proximal marker. A crossover between the centromere and the locus would make a meiosis I error look like a meiosis II error, because the two sister chromatids would then carry different alleles. Because the locus is close to the centromere, this is unlikely but not excluded, so the conclusions are probabilities rather than certainties. A rigorous answer states the assumption and the direction in which it could mislead.
2. Explain why maternal age is associated with an increased risk of trisomy 21, with reference to meiosis.
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Human oocytes begin meiosis before birth and then arrest in prophase I, sometimes for decades. During this arrest the homologues are held together by chiasmata and by cohesin complexes; these structures must remain functional until ovulation, when meiosis resumes. Cohesin and other components deteriorate over time, so homologues are less reliably held and the spindle checkpoint may fail to detect errors. When meiosis I finally resumes in an older oocyte, homologous chromosomes are more likely to segregate incorrectly, producing an egg with an extra chromosome 21.
The effect is specific to the mother because the long arrest occurs in oogenesis; sperm are produced continuously from puberty, so paternal chromosomes do not wait for decades. The correlation is statistical: most children with trisomy 21 are born to younger mothers simply because most births are to younger mothers, and advanced maternal age raises the probability rather than determining the outcome. The answer should avoid claiming a precise molecular mechanism as established fact; the cohesin-decay model is the leading explanation, not the only one.
3. The parents ask whether the condition will recur in a future pregnancy. Explain what information would be needed before a useful answer can be given.
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A recurrence risk cannot be quoted from the trisomy alone. The clinic must distinguish between two situations that look similar on a karyotype but have very different inheritance.
First, most cases of trisomy 21 result from nondisjunction in a gamete, and the recurrence risk is low, typically of the order of one percent, with a modest increase with maternal age. Second, a small proportion of cases result from a Robertsonian translocation, in which chromosome 21 is attached to another acrocentric chromosome. If a parent carries such a translocation, the recurrence risk is much higher and other relatives may also carry it.
To tell them apart, the clinic needs parental karyotypes, not only the child's. If a translocation is found, the carrier parent's relatives should be offered testing. The family should also be told that the marker data identify the meiotic division but do not by themselves give a recurrence figure. The answer should make clear that genetic counselling involves probabilities and uncertainty, and that the advice must be based on the parents' own karyotypes rather than on the child's alone.