Abstract
BackgroundDown syndrome incidence in humans increases dramatically with maternal age. This is mainly the result of increased meiotic errors, but factors such as differences in abortion rate may play a role as well. Since the meiotic error rate increases almost exponentially after a certain age, its contribution to the overall incidence aneuploidy may mask the contribution of other processes.ResultsTo focus on such selection mechanisms we investigated transmission in trisomic females, using data from mouse models and from Down syndrome humans. In trisomic females the a-priori probability for trisomy is independent of meiotic errors and thus approximately constant in the early embryo. Despite this, the rate of transmission of the extra chromosome decreases with age in females of the Ts65Dn and, as we show, for the Tc1 mouse models for Down syndrome. Evaluating progeny of 73 Tc1 births and 112 Ts65Dn births from females aged 130 days to 250 days old showed that both models exhibit a 3-fold reduction of the probability to transmit the trisomy with increased maternal ageing. This is concurrent with a 2-fold reduction of litter size with maternal ageing. Furthermore, analysis of previously reported 30 births in Down syndrome women shows a similar tendency with an almost three fold reduction in the probability to have a Down syndrome child between a 20 and 30 years old Down syndrome woman.ConclusionsIn the two types of mice models for Down syndrome that were used for this study, and in human Down syndrome, older females have significantly lower probability to transmit the trisomy to the offspring. Our findings, taken together with previous reports of decreased supportive environment of the older uterus, add support to the notion that an older uterus negatively selects the less fit trisomic embryos.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0412-3) contains supplementary material, which is available to authorized users.
Highlights
Down syndrome incidence in humans increases dramatically with maternal age
They reported that of the trisomies that can survive to birth, trisomy 21 was the most frequent one with a 2.3 % occurrence rate
Our findings suggest that the observation of this phenomenon in trisomic mice is reproducible, mirrors the trend seen in human pregnancies, and can in the future be studied in these two independent mouse models
Summary
Down syndrome incidence in humans increases dramatically with maternal age. This is mainly the result of increased meiotic errors, but factors such as differences in abortion rate may play a role as well. Down Syndrome (DS) is the most abundant nonlethal chromosomal abnormality in humans, in which all or part of chromosome 21 appears in three copies instead of two This gene imbalance results in cognitive impairment as well as in moderate to severe negative impacts on physical health [1, 2]. Most DS embryos will die in the uterus – previous studies report that the incidence of aneuploidy in spontaneous abortions is larger than 35 % [3, 10, 11]. They reported that of the trisomies that can survive to birth, trisomy 21 was the most frequent one with a 2.3 % occurrence rate. The aging of the uterine may be playing a role in this selection process, as indicated by
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