On the origin of trisomy 21 Down syndrome

Background: Down syndrome, characterized by an extra chromosome 21 is the most common genetic cause for congenital malformations and learning disability. It is well known that the extra chromosome 21 most often originates from the mother, the incidence increases with maternal age, there may be aberrant maternal chromosome 21 recombination and there is a higher recurrence in young women. In spite of intensive efforts to understand the underlying reason(s) for these characteristics, the origin still remains unknown. We hypothesize that maternal trisomy 21 ovarian mosaicism might provide the major causative factor. Results: We used fluorescence in situ hybridization (FISH) with two chromosome 21-specific probes to determine the copy number of chromosome 21 in ovarian cells from eight female foetuses at gestational age 14–22 weeks. All eight phenotypically normal female foetuses were found to be mosaics, containing ovarian cells with an extra chromosome 21. Trisomy 21 occurred with about the same frequency in cells that had entered meiosis as in pre-meiotic and ovarian mesenchymal stroma cells. Conclusion: We suggest that most normal female foetuses are trisomy 21 ovarian mosaics and the maternal age effect is caused by differential selection of these cells during foetal and postnatal development until ovulation. The exceptional occurrence of high-grade ovarian mosaicism may explain why some women have a child with Down syndrome already at young age as well as the associated increased incidence at subsequent conceptions. We also propose that our findings may explain the aberrant maternal recombination patterns previously found by family linkage analysis

Altered patterns of meiotic recombination in human fetal oocytes with asynapsis and/or synaptonemal complex fragmentation at pachytene

Meiotic recombination was analysed in human fetal oocytes to determine whether recombination errors are associated with abnormal chromosome synapsis. Immunostaining was used to identify the synaptonemal complex (SC, the meiosis-specific proteinaceous structure that binds homologous chromosomes) and the DNA mismatch repair protein, MLH1, that locates recombination foci. It was found that 57.1-74.2% of zygotene oocytes showed fragmentation and/or defective chromosome synapsis. Fewer such abnormal cells occurred at pachytene (15.8-28.9%). MLH1 foci were present from zygotene to diplotene in both normal and abnormal oocytes. However, the proportions of oocytes having MLH1 foci, and mean numbers of foci per oocyte, were both lower in abnormal oocytes. Oocytes with fragmented SC had more foci than those with synaptic anomalies. Analysis of chromosomes 13, 18, 21 and X by fluorescence in-situ hybridization (FISH) did not implicate particular chromosomes in recombination deficiency. These observations indicate that recombination is disturbed in oocytes with SC fragmentation and/or synaptic abnormalities during meiotic prophase I. Such disturbances might be a risk factor for selection of fetal oocytes for atresia, as occurs for homologous chromosome pairing. Recombination errors may potentially increase the risk of abnormal chromosome segregation in oocytes that survive and contribute to the reserve in the mature ovary

Trisomy21, Down Syndrome and the origin of Alzheimer's disease

Previously we have shown that foetal ovarian levels of T21 mosaicism may explain the origin of Down syndrome (DS) and the associated maternal age effect. DS individuals reaching ~40 years of age will develop AD, T21 leading to increased amyloidosis. Importantly, normal women, who have had a DS child at a young age, develop AD at an earlier age than other women. Alzheimer’s disease (AD) has two types: early-onset and late-onset. Both types have genetic links. For early-onset the identification of the genes involved have provided good evidence for the amyloid cascade hypothesis. The majority of AD however is sporadic and a number of susceptibility loci have been identified (notably ApoEε4). While more will be uncovered through genome wide association scans, brain aneuploidy may also have a role. Recently a dramatic demonstration of increased chromosome 21 aneuploidy in AD brains ((6–15% versus 0.8–1.8% in control) has demonstrated that this may well contribute to disease pathology. We are currently determining whether the level of T21 mosaicism seen in foetal brain correlates with that seen in foetal ovaries. We hope to ascertain whether T21 mosaicism is likely to play a major role for the origin of sporadic AD