In humans, errors in meiotic chromosome segregation that produce aneuploid gametes increase dramatically as women age, a phenomenon termed the "maternal age effect." During meiosis, cohesion between sister chromatids keeps recombinant homologs physically attached and premature loss of cohesion can lead to missegregation of homologs during meiosis I. A growing body of evidence suggests that meiotic cohesion deteriorates as oocytes age and contributes to the maternal age effect. One hallmark of aging cells is an increase in oxidative damage caused by reactive oxygen species (ROS). Therefore, increased oxidative damage in older oocytes may be one of the factors that leads to premature loss of cohesion and segregation errors. To test this hypothesis, we used an RNAi strategy to induce oxidative stress in Drosophila oocytes and measured the fidelity of chromosome segregation during meiosis. Knockdown of either the cytoplasmic or mitochondrial ROS scavenger superoxide dismutase (SOD) caused a significant increase in segregation errors, and heterozygosity for an smc1 deletion enhanced this phenotype. FISH analysis indicated that SOD knockdown moderately increased the percentage of oocytes with arm cohesion defects. Consistent with premature loss of arm cohesion and destabilization of chiasmata, the frequency at which recombinant homologs missegregate during meiosis I is significantly greater in SOD knockdown oocytes than in controls. Together these results provide an in vivo demonstration that oxidative stress during meiotic prophase induces chromosome segregation errors and support the model that accelerated loss of cohesion in aging human oocytes is caused, at least in part, by oxidative damage. meiosis | maternal age effect | oxidative damage | reactive oxygen species | superoxide dismutase C hromosome segregation errors during female meiosis are the leading cause of birth defects and miscarriages in humans and their incidence increases dramatically with age (1). Over 90% of Down syndrome cases are the result of an extra copy of chromosome 21 inherited from the mother (2). Although the probability of a meiotic missegregation event is relatively low during a woman's twenties, by the time she reaches her early forties, she has a one in three chance of conceiving an aneuploid fetus (3). Work in the last decade has begun to shed light on the molecular mechanisms that underlie this phenomenon known as the "maternal age effect."Proper chromosome segregation during both mitosis and meiosis requires that physical linkages between sister chromatids (cohesion) be formed, maintained, and released in a regulated manner (4, 5). Sister chromatid cohesion, mediated by the evolutionarily conserved cohesin complex, is established during DNA replication. During meiosis, in addition to holding sister chromatids together, cohesion is required to maintain the physical association of recombinant homologs and is therefore essential for proper segregation during the first as well as the second meiotic division (6-8). Normally, a crossover ...
Objective To evaluate the family psychosocial outcomes of children with Down syndrome and atrioventricular septal defect, and examine the impact of these variables on the child’s neurodevelopmental outcome. Methods This was a cross-sectional study that consisted of 57 children with Down syndrome (20 cases and 37 controls), approximately 12–14 months of age. In both groups, we assessed the development of the child, the quality of the child’s home environment, and parenting stress. Results Compared with the Down syndrome without congenital heart defect group, the atrioventricular septal defect group revealed lower scores in all developmental domains, less optimal home environments, and higher parental stress. Significant differences in development were seen in the areas of cognition (p=0.04), expressive language (p=0.05), and gross motor (p<0.01). The Home Observation for Measurement of the Environment revealed significant differences in emotional and verbal responsiveness of the mother between the two groups. The Parenting Stress Index revealed the Down syndrome with atrioventricular septal defect group had a significantly higher child demandingness subdomain scores compared to the Down syndrome without congenital heart defect group. Conclusions The diagnosis of a congenital heart defect in addition to the diagnosis of Down syndrome may provide additional stress to the child and parents, elevating parental concern and disrupting family dynamics, resulting in further neurodevelopmental deficits. Finding that parental stress and home environment may play a role in the neurodevelopmental outcomes may prompt new family-directed interventions and anticipatory guidance for the families of children with Down syndrome who have a congenital heart defect.
The risk of meiotic segregation errors increases dramatically during a woman’s thirties, a phenomenon known as the maternal age effect. In addition, several lines of evidence indicate that meiotic cohesion deteriorates as oocytes age. One mechanism that may contribute to age-induced loss of cohesion is oxidative damage. In support of this model, we recently reported (Perkins et al. in Proc Natl Acad Sci U S A 113(44):E6823–E6830, 2016) that the knockdown of the reactive oxygen species (ROS)–scavenging enzyme, superoxide dismutase (SOD), during meiotic prophase causes premature loss of arm cohesion and segregation errors in Drosophila oocytes. If age-dependent oxidative damage causes meiotic segregation errors, then the expression of extra SOD1 (cytosolic/nuclear) or SOD2 (mitochondrial) in oocytes may attenuate this effect. To test this hypothesis, we generated flies that contain a UAS-controlled EMPTY, SOD1, or SOD2 cassette and induced expression using a Gal4 driver that turns on during meiotic prophase. We then compared the fidelity of chromosome segregation in aged and non-aged Drosophila oocytes for all three genotypes. As expected, p{EMPTY} oocytes subjected to aging exhibited a significant increase in nondisjunction (NDJ) compared with non-aged oocytes. In contrast, the magnitude of age-dependent NDJ was significantly reduced when expression of extra SOD1 or SOD2 was induced during prophase. Our findings support the hypothesis that a major factor underlying the maternal age effect in humans is age-induced oxidative damage that results in premature loss of meiotic cohesion. Moreover, our work raises the exciting possibility that antioxidant supplementation may provide a preventative strategy to reduce the risk of meiotic segregation errors in older women.Electronic supplementary materialThe online version of this article (10.1007/s00412-019-00702-y) contains supplementary material, which is available to authorized users.
Purpose: To accurately ascertain the frequency of pathogenic germline variants (PGVs) in a pan-cancer patient population with universal genetic testing and to assess the economic impact of receiving genetic testing on healthcare costs. Methods: In this prospective study, germline genetic testing using a 105-gene panel was administered to an unselected pan-cancer patient population irrespective of eligibility by current guidelines. Financial records of subjects were analyzed to assess the effect of PGV detection on cost of care one year from the date of testing. Results: A total of 284 patients participated in this study, of which 44 patients (15%) tested positive for a PGV in 14 different cancer types. Of the patients with PGVs, 23 patients (52%) were ineligible for testing by current guidelines. Identification of a PGV did not increase cost of care. Conclusion: Implementation of universal genetic testing for cancer patients in the clinic, beyond that specified by current guidelines, is necessary to accurately assess and treat hereditary cancer syndromes and does not increase healthcare costs.
In humans, chromosome segregation errors in oocytes are responsible for the majority of miscarriages and birth defects. Moreover, as women age, their risk of conceiving an aneuploid fetus increases dramatically and this phenomenon is known as the maternal age effect. One requirement for accurate chromosome segregation during the meiotic divisions is maintenance of sister chromatid cohesion during the extended prophase period that oocytes experience. Cytological evidence in both humans and model organisms suggests that meiotic cohesion deteriorates during the aging process. In addition, segregation errors in human oocytes are most prevalent during meiosis I, consistent with premature loss of arm cohesion. The use of model organisms is critical for unraveling the mechanisms that underlie age-dependent loss of cohesion. Drosophila melanogaster offers several advantages for studying the regulation of meiotic cohesion in oocytes. However, until recently, only genetic tests were available to assay for loss of arm cohesion in oocytes of different genotypes or under different experimental conditions. Here, a detailed protocol is provided for using fluorescence in situ hybridization (FISH) to directly visualize defects in arm cohesion in prometaphase I and metaphase I arrested Drosophila oocytes. By generating a FISH probe that hybridizes to the distal arm of the X chromosome and collecting confocal Z stacks, a researcher can visualize the number of individual FISH signals in three dimensions and determine whether sister chromatid arms are separated. The procedure outlined makes it possible to quantify arm cohesion defects in hundreds of Drosophila oocytes. As such, this method provides an important tool for investigating the mechanisms that contribute to cohesion maintenance as well as the factors that lead to its demise during the aging process.
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