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Genetic mechanisms of nondisjunction in humans Gair, Jane Louise


Missegregation of chromosomes in meiosis, or nondisjunction, occurs relatively frequently in humans, and results in pregnancy loss. There is a correlation with advancing maternal age, but the cause of the dramatic increase of aneuploidy, and specifically trisomy (the presence of three copies of a chromosome rather then two), seen with age remains unknown. There is evidence to suggest that chronological age is less important than biological age for trisomy risk, and that regardless of their chronological age, some women are at a greater risk of having a trisomic pregnancy after having already experienced one. Several features of chromosomes are associated with aging, such as a decrease in telomere length, an increase in replication asynchrony at loci including centromeres, and an increase in somatic cell aneuploidy with increasing age. For some chromosomes (15 and 21) an association has also been observed between maternal age, reduced recombination along the chromosome, and risk for nondisjunction. In this project, I have investigated whether or not some women are predisposed to having a trisomic pregnancy. That is, can we predict who will have recurrent trisomy? After analyzing telomere length for an association, no significant decrease in length was seen for women experiencing recurrent trisomy when compared to control women. There was a trend, however, towards longer telomeres in women with a "good" reproductive history (children after 37 years of age) compared to women with a "poor" reproductive history (trisomy and/or recurrent trisomy). As well, although there was no significant increase in replication asynchrony in mothers of trisomy as a group, the younger mothers (<35 years old) of trisomies had increased replication asynchrony when compared to controls of the same age. The relationship between recombination and nondisjunction has been well established and my studies of chromosome 15 confirmed that decreased recombination is associated with meiosis I errors and increased recombination is associated with meiosis II errors. A family with an apparent inherited predisposition to missegregation of chromosome 21 seemed the ideal family in which to study possible genetic mechanisms of nondisjunction. Although nothing conclusive could be determined to be causing their segregation problems, a cryptic rearrangement involving the centromere of chromosome 21 is the most likely explanation. Finally, telomere length was not found to be shortened in children conceived through intracytoplasmic sperm injection (ICSI).

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