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Down Syndrome Abstract
of the Month: April 2000

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Down syndrome: genetic recombination and the origin of the extra chromosome 21.

Hassold T, Sherman S
Clin Genet 2000 Feb;57(2):95-100

Department of Genetics and The Center for Human Genetics, Case Western Reserve University and University Hospitals of Cleveland, OH, USA.

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Despite the clinical importance of trisomy 21, we have been ignorant of the causes of meiotic nondisjunction of chromosome 21. Recently, however, genetic mapping studies of trisomy 21 families have led to the identification of the first molecular correlate of human nondisjunction; i.e. altered levels and positioning of meiotic recombinational events. Specifically, increases in 0 exchange events or in distal-only or pericentromeric exchanges are significantly increased in trisomy 21-generating meioses. These observations have led to the idea that chromosome 21 nondisjunction requires 'two hits': first, the establishment in prophase I of a 'vulnerable' bivalent and second, abnormal processing of the bivalent at metaphase I or II.

My comments:

Some quick background:

The cells in our body have two sets of chromosomes, so they're called diploid cells. The act of a diploid cell producing a cell which only has one set of chromosomes (haploid cell) is called meiosis. Meiosis I is the act of splitting up the chromosomes into two (hopefully) equal halves; Meiosis II is another division but without splitting the number of chromosomes. If the chromosomes don't split equally, the result is called "non-disjunction" and trisomies occur.

"Recombination" is the normal process by which chromosomes exchange genetic material with each other during meiosis. The area where the recombination occurs is an "exchange."

In the egg, the first meiosis (MI) begins in the female fetus. MI is suspended, and is completed only after ovulation of the egg, which is quickly followed by MII. 90% of all cases of trisomy 21 can be traced back to the egg.

Now, for the important points in the paper:

Most, if not all, cases of human trisomies are due to alterations in recombination. Mistakes in recombination seem to increase the risk of nondisjunction. Since recombination occurs prenatally in MI, then this suggests that most, if not all, cases of nondisjunction is initiated at the start of MI, in the fetus.

Studies also indicate that nondisjunction may require a second event, or "hit," involving the degredation of a meiotic process (a protein integral to the meiotic event). This "hit" could occur in MI or MII. If there is an environmental risk to DS, this is where it could have influence.

The increase risk of maternal age could be explained by the length of time between the beginning of MI and the completion of MI, possibly due to age-dependent degradation of meiosis-specific proteins.

And finally, there does appear to be a significant association between maternal smoking at the time of conception in women under 35 years of age and having a child with trisomy 21. This seems to be associated with errors in MII. This has only been found in one study, and is deemed preliminary at this time.

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