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Stephanie L Sherma - One of the best experts on this subject based on the ideXlab platform.
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a candidate gene analysis and gwas for genes associated with maternal Nondisjunction of chromosome 21
PLOS Genetics, 2019Co-Authors: Jonatha M Chernus, Terry J Hassold, Eleano Feingold, Emily G Alle, Zhe Zeng, Eva R Hoffma, Stephanie L ShermaAbstract:Human Nondisjunction errors in oocytes are the leading cause of pregnancy loss, and for pregnancies that continue to term, the leading cause of intellectual disabilities and birth defects. For the first time, we have conducted a candidate gene and genome-wide association study to identify genes associated with maternal Nondisjunction of chromosome 21 as a first step to understand predisposing factors. A total of 2,186 study participants were genotyped on the HumanOmniExpressExome-8v1-2 array. These participants included 749 live birth offspring with standard trisomy 21 and 1,437 parents. Genotypes from the parents and child were then used to identify mothers with Nondisjunction errors derived in the oocyte and to establish the type of error (meiosis I or meiosis II). We performed a unique set of subgroup comparisons designed to leverage our previous work suggesting that the etiologies of meiosis I and meiosis II Nondisjunction differ for trisomy 21. For the candidate gene analysis, we selected genes associated with chromosome dynamics early in meiosis and genes associated with human global recombination counts. Several candidate genes showed strong associations with maternal Nondisjunction of chromosome 21, demonstrating that genetic variants associated with normal variation in meiotic processes can be risk factors for Nondisjunction. The genome-wide analysis also suggested several new potentially associated loci, although follow-up studies using independent samples are required.
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association between telomere length and chromosome 21 Nondisjunction in the oocyte
Human Genetics, 2015Co-Authors: Igo Albizua, Emily G Alle, Enjami L Rambomarti, Ashima S Ami, Stephanie L ShermaAbstract:Chromosome 21 Nondisjunction in oocytes is the most common cause of trisomy 21, the primary chromosomal abnormality responsible for Down syndrome (DS). This specific type of error is estimated to account for over 90 % of live births with DS, with maternal age being the best known risk factor for chromosome 21 Nondisjunction. The loss of telomere length and the concomitant shortening of chromosomes are considered a biological marker for aging. Thus, we tested the hypothesis that mothers who had a maternal Nondisjunction error leading to a live birth with DS (n = 404) have shorter telomeres than mothers with live births without DS (n = 42). In effect, our hypothesis suggests that mothers of children with DS will appear “biologically older” as compared to the mothers of euploid children. We applied a quantitative PCR assay to measure the genome-wide relative telomere length to test this hypothesis. The results of our study support the hypothesis that young mothers of DS babies are “biologically older” than mothers of euploid babies in the same age group and supports telomere length as a biomarker of age and hence risk for chromosome Nondisjunction.
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an examination of the relationship between hotspots and recombination associated with chromosome 21 Nondisjunction
PLOS ONE, 2014Co-Authors: Eleano Feingold, Vivian G Cheung, Emily G Alle, Tiffany Renee Olive, Stua W Tinke, Candace D Middlebrooks, Ferdouse Egum, Reshmi Chowdhury, Stephanie L ShermaAbstract:Trisomy 21, resulting in Down Syndrome (DS), is the most common autosomal trisomy among live-born infants and is caused mainly by Nondisjunction of chromosome 21 within oocytes. Risk factors for Nondisjunction depend on the parental origin and type of meiotic error. For errors in the oocyte, increased maternal age and altered patterns of recombination are highly associated with Nondisjunction. Studies of normal meiotic events in humans have shown that recombination clusters in regions referred to as hotspots. In addition, GC content, CpG fraction, Poly(A)/Poly(T) fraction and gene density have been found to be significant predictors of the placement of sex-averaged recombination in the human genome. These observations led us to ask whether the altered patterns of recombination associated with maternal Nondisjunction of chromosome 21 could be explained by differences in the relationship between recombination placement and recombination-related genomic features (i.e., GC content, CpG fraction, Poly(A)/Poly(T) fraction or gene density) on 21q or differential hot-spot usage along the nondisjoined chromosome 21. We found several significant associations between our genomic features of interest and recombination, interestingly, these results were not consistent among recombination types (single and double proximal or distal events). We also found statistically significant relationships between the frequency of hotspots and the distribution of recombination along nondisjoined chromosomes. Collectively, these findings suggest that factors that affect the accessibility of a specific chromosome region to recombination may be altered in at least a proportion of oocytes with MI and MII errors.
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risk factors for Nondisjunction of trisomy 21
Cytogenetic and Genome Research, 2005Co-Authors: Stephanie L Sherma, Emily G Alle, Sallie Freema, Neil E LambAbstract:The leading cause of Down syndrome (DS) is Nondisjunction of chromosome 21 occurring during the formation of gametes. In this review, we discuss the progress made to identify risk factors associated w
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maternal meiosis ii Nondisjunction in trisomy 21 is associated with maternal low socioeconomic status
Genetics in Medicine, 2004Co-Authors: Roberta E Christianso, Stephanie L Sherma, Claudine P TorfsAbstract:Maternal meiosis II Nondisjunction in trisomy 21 is associated with maternal low socioeconomic status
Terry J Hassold - One of the best experts on this subject based on the ideXlab platform.
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a candidate gene analysis and gwas for genes associated with maternal Nondisjunction of chromosome 21
PLOS Genetics, 2019Co-Authors: Jonatha M Chernus, Terry J Hassold, Eleano Feingold, Emily G Alle, Zhe Zeng, Eva R Hoffma, Stephanie L ShermaAbstract:Human Nondisjunction errors in oocytes are the leading cause of pregnancy loss, and for pregnancies that continue to term, the leading cause of intellectual disabilities and birth defects. For the first time, we have conducted a candidate gene and genome-wide association study to identify genes associated with maternal Nondisjunction of chromosome 21 as a first step to understand predisposing factors. A total of 2,186 study participants were genotyped on the HumanOmniExpressExome-8v1-2 array. These participants included 749 live birth offspring with standard trisomy 21 and 1,437 parents. Genotypes from the parents and child were then used to identify mothers with Nondisjunction errors derived in the oocyte and to establish the type of error (meiosis I or meiosis II). We performed a unique set of subgroup comparisons designed to leverage our previous work suggesting that the etiologies of meiosis I and meiosis II Nondisjunction differ for trisomy 21. For the candidate gene analysis, we selected genes associated with chromosome dynamics early in meiosis and genes associated with human global recombination counts. Several candidate genes showed strong associations with maternal Nondisjunction of chromosome 21, demonstrating that genetic variants associated with normal variation in meiotic processes can be risk factors for Nondisjunction. The genome-wide analysis also suggested several new potentially associated loci, although follow-up studies using independent samples are required.
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the origin of trisomy 22 evidence for acrocentric chromosome specific patterns of Nondisjunction
American Journal of Medical Genetics Part A, 2007Co-Authors: Heathe Hall, Urvashi Surti, Eleano Feingold, Lori Hoffne, Sofia Shirley, Terry J HassoldAbstract:Trisomy 22 is one of the most common trisomies in clinically recognized pregnancies, yet relatively little is known about the origin of Nondisjunction for chromosome 22. Accordingly, we initiated studies to investigate the origin of the extra chromosome in 130 trisomy 22 cases. Our results indicate that the majority of trisomy 22 errors (>96%) arise during oogenesis with most of these errors ( approximately 90%) occurring during the first meiotic division. As with other trisomies, failure to recombine contributed to Nondisjunction of chromosome 22. Taken together with data available for other trisomies, our results suggest patterns of Nondisjunction that are shared among the acrocentric, but not all nonacrocentric, chromosomes.
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smc1β deficient female mice provide evidence that cohesins are a missing link in age related Nondisjunction
Nature Genetics, 2005Co-Authors: Craig A Hodges, Ekaterina Revenkova, Rolf Jessberge, Terry J HassoldAbstract:SMC1β-deficient female mice provide evidence that cohesins are a missing link in age-related Nondisjunction
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Nondisjunction of chromosome 21
American Journal of Medical Genetics, 2005Co-Authors: N Takaesu, Patricia A Jacobs, Sallie Freema, Annette E Cockwell, Viola C P Freema, I Uchida, Dwai R Lacksto, Jelica Nuccio, David M Kurni, Terry J HassoldAbstract:Chromosome heteromorphisms and restriction fragment length polymorphisms were used to study the origin of the extra chromosome in 54 trisomy 21 conceptuses. The parental origin was determined in 43 cases, with 39 (91%) being maternally and 4 (9%) parentally derived. Analysis of recombination demonstrated the presence of one or two cross-overs in most cases for which sufficient information was available, suggesting that failure to pair/exchange at meiosis I is relatively unimportant in the genesis of trisomy 21.
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Nondisjunction a view from ringside
The New England Journal of Medicine, 2004Co-Authors: Neil E Lamb, Terry J HassoldAbstract:Chromosome Nondisjunction lands a heavy blow on the chin of humanity. The improper segregation of chromosomes during meiosis leads to chromosomally unbalanced eggs or sperm. If these gametes participate in fertilization, the outcome is an aneuploid embryo, with either trisomy (one chromosome too many) or monosomy (one chromosome too few). Since most such embryos are inviable, one might expect that these errors would be extremely rare. This is true for most organisms, but our own species is a notable exception: aneuploidy is identified in at least 5 percent of all clinically recognized pregnancies, making it the leading known cause of . . .
Stephanie L Sherman - One of the best experts on this subject based on the ideXlab platform.
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maternal age and risk for trisomy 21 assessed by the origin of chromosome Nondisjunction a report from the atlanta and national down syndrome projects
Human Genetics, 2009Co-Authors: Emily G Allen, Sallie B Freeman, Charlotte M Druschel, Charlotte A Hobbs, Leslie A Oleary, Paul A Romitti, Marjorie H Royle, Claudine P Torfs, Stephanie L ShermanAbstract:We examined the association between maternal age and chromosome 21 Nondisjunction by origin of the meiotic error. We analyzed data from two population-based, case–control studies: Atlanta Down Syndrome Project (1989–1999) and National Down Syndrome Project (2001–2004). Cases were live born infants with trisomy 21 and controls were infants without trisomy 21 delivered in the same geographical regions. We enrolled 1,215 of 1,881 eligible case families and 1,375 of 2,293 controls. We report four primary findings. First, the significant association between advanced maternal age and chromosome 21 Nondisjunction was restricted to meiotic errors in the egg; the association was not observed in sperm or in post-zygotic mitotic errors. Second, advanced maternal age was significantly associated with both meiosis I (MI) and meiosis II (MII). For example, compared to mothers of controls, mothers of infants with trisomy 21 due to MI Nondisjunction were 8.5 times more likely to be ≥40 years old than 20–24 years old at the birth of the index case (95% CI = 5.6–12.9). Where Nondisjunction occurred in MII, mothers were 15.1 times more likely to be ≥40 years (95% CI = 8.4–27.3). Third, the ratio of MI to MII errors differed by maternal age. The ratio was lower among women <19 years of age and those ≥40 years (2.1, 2.3, respectively) and higher in the middle age group (3.6). Lastly, we found no effect of grand-maternal age on the risk for maternal Nondisjunction. This study emphasizes the complex association between advanced maternal age and Nondisjunction of chromosome 21 during oogenesis.
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new insights into human Nondisjunction of chromosome 21 in oocytes
PLOS Genetics, 2008Co-Authors: Tiffany Renee Oliver, Eleanor Feingold, Kai Yu, Vivian G Cheung, Stuart W Tinker, Maneesha Yadavshah, Nirupama Masse, Stephanie L ShermanAbstract:Nondisjunction of chromosome 21 is the leading cause of Down syndrome. Two risk factors for maternal Nondisjunction of chromosome 21 are increased maternal age and altered recombination. In order to provide further insight on mechanisms underlying Nondisjunction, we examined the association between these two well established risk factors for chromosome 21 Nondisjunction. In our approach, short tandem repeat markers along chromosome 21 were genotyped in DNA collected from individuals with free trisomy 21 and their parents. This information was used to determine the origin of the Nondisjunction error and the maternal recombination profile. We analyzed 615 maternal meiosis I and 253 maternal meiosis II cases stratified by maternal age. The examination of meiosis II errors, the first of its type, suggests that the presence of a single exchange within the pericentromeric region of 21q interacts with maternal age-related risk factors. This observation could be explained in two general ways: 1) a pericentromeric exchange initiates or exacerbates the susceptibility to maternal age risk factors or 2) a pericentromeric exchange protects the bivalent against age-related risk factors allowing proper segregation of homologues at meiosis I, but not segregation of sisters at meiosis II. In contrast, analysis of maternal meiosis I errors indicates that a single telomeric exchange imposes the same risk for Nondisjunction, irrespective of the age of the oocyte. Our results emphasize the fact that human Nondisjunction is a multifactorial trait that must be dissected into its component parts to identify specific associated risk factors.
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association between maternal age and meiotic recombination for trisomy 21
American Journal of Human Genetics, 2005Co-Authors: Neil E Lamb, Eleanor Feingold, Kai Yu, John R Shaffer, Stephanie L ShermanAbstract:Altered genetic recombination has been identified as the first molecular correlate of chromosome Nondisjunction in both humans and model organisms. Little evidence has emerged to link maternal age—long recognized as the primary risk factor for Nondisjunction—with altered recombination, although some studies have provided hints of such a relationship. To determine whether an association does exist, chromosome 21 recombination patterns were examined in 400 trisomy 21 cases of maternal meiosis I origin, grouped by maternal age. These recombination patterns were used to predict the chromosome 21 exchange patterns established during meiosis I. There was no statistically significant association between age and overall rate of exchange. The placement of meiotic exchange, however, differed significantly among the age groups. Susceptible patterns (pericentromeric and telomeric exchanges) accounted for 34% of all exchanges among the youngest class of women but only 10% of those among the oldest class. The pattern of exchanges among the oldest age group mimicked the pattern observed among normally disjoining chromosomes 21. These results suggest that the greatest risk factor for Nondisjunction among younger women is the presence of a susceptible exchange pattern. We hypothesize that environmental and age-related insults accumulate in the ovary as a woman ages, leading to malsegregation of oocytes with stable exchange patterns. It is this risk, due to recombination-independent factors, that would be most influenced by increasing age, leading to the observed maternal age effect.
Rebecca J Oakey - One of the best experts on this subject based on the ideXlab platform.
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Nondisjunction and transmission ratio distortion ofchromosome 2 in a 2 8 robertsonian translocation mouse strain
Mammalian Genome, 2006Co-Authors: Reine Schulz, Lara A Underkoffle, Joelle N Collins, Rebecca J OakeyAbstract:Aneuploidy results from Nondisjunction of chromosomes in meiosis and is the leading cause of developmental disabilities and mental retardation in humans. Therefore, understanding aspects of chromosome segregation in a genetic model is of value. Mice heterozygous for a (2.8) Robertsonian translocation were intercrossed with chromosomally normal mice and Chromosome 2 was genotyped for number and parental origin in 836 individuals at 8.5 dpc. The frequency of Nondisjunction of this Robertsonian chromosome is 1.58%. Trisomy of Chromosome 2 with two maternally derived chromosomes is the most developmentally successful aneuploid karyotype at 8.5 dpc. Trisomy of Chromosome 2 with two paternally derived chromosomes is developmentally delayed and less frequent than the converse. Individuals with maternal or paternal uniparental disomy of Chromosome 2 were not detected at 8.5 dpc. Nondisjunction events were distributed randomly across litters, i.e., no evidence for clustering was found. Transmission ratio distortion is frequently observed in Robertsonian chromosomes and a bias against the transmission of the (2.8) Chromosome was detected. Interestingly, this was observed for female and male transmitting parents.
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molecular analysis of Nondisjunction in mice heterozygous for a robertsonian translocation
Genetics, 2002Co-Authors: Lara A Underkoffle, Laura E Mitchell, Russell A Localio, Shanno M Marchegiani, Justi Morabito, Joelle N Collins, Rebecca J OakeyAbstract:A Robertsonian translocation results in a metacentric chromosome produced by the fusion of two acrocentric chromosomes. Rb heterozygous mice frequently generate aneuploid gametes and embryos, providing a good model for studying meiotic Nondisjunction. We intercrossed mice heterozygous for a (7.18) Robertsonian translocation and performed molecular genotyping of 1812 embryos from 364 litters with known parental origin, strain, and age. Nondisjunction events were scored and factors influencing the frequency of Nondisjunction involving chromosomes 7 and 18 were examined. We concluded the following: The frequency of Nondisjunction among 1784 embryos (3568 meioses) was 15.9%. Nondisjunction events were distributed nonrandomly among progeny. This was inferred from the distribution of the frequency of trisomics and uniparental disomics (UPDs) among all litters. There was no evidence to show an effect of maternal or paternal age on the frequency of Nondisjunction. Strain background did not play an appreciable role in Nondisjunction frequency. The frequency of Nondisjunction for chromosome 18 was significantly higher than that for chromosome 7 in males. The frequency of Nondisjunction for chromosome 7 was significantly higher in females than in males. These results show that molecular genotyping provides a valuable tool for understanding factors influencing meiotic Nondisjunction in mammals.
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Nondisjunction rates and abnormal embryonic development in a mouse cross between heterozygotes carrying a 7 18 robertsonian translocation chromosome
Genetics, 1995Co-Authors: Rebecca J Oakey, P G Matteso, S Litwi, Shirley M Tilghma, Robe L NussbaumAbstract:Mice bearing Robertsonian translocation chromosomes frequently produce aneuploid gametes. They are therefore excellent tools for studying Nondisjunction in mammals. Genotypic analysis of embryos from a mouse cross between two different strains of mice carrying a (7,18) Robertsonian chromosome enabled us to measure the rate of Nondisjunction for chromosomes 7 and 18. Embryos (429) were harvested from 76 litters of mice and the parental origin of each chromosome 7 and 18 determined. Genotyping these embryos has allowed us to conclude the following: (1) there were 96 embryos in which at least one Nondisjunction event had taken place; (2) the rate of maternal Nondisjunction was greater than paternal Nondisjunction for teh chromosomes sampled in these mice; (3) a bias against chromosome 7 and 18 nullisomic gametes was observed, reflected in a smaller than expected number of uniparental disomic embryos; (4) Nondisjunction events did not seem to occur at random throughout the 76 mouse litters, but were clustered into fewer than would be expected cy chance; and (5) a deficiency of paternal chromosome 18 uniparental disomic embryos was observed along with a higher than normal rate of developmental retardation at 8.5 days post coitum, raising the possibility that this chromosome has at least one imprinted gene.
Sco R Hawley - One of the best experts on this subject based on the ideXlab platform.
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X and 4th chromosome Nondisjunction frequency.
2019Co-Authors: Stacie E. Hughes, Elizabeth Hemenway, Fengli Guo, Sco R HawleyAbstract:X and 4th chromosome Nondisjunction frequency.
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statistical analysis of Nondisjunction assays in drosophila
Genetics, 2010Co-Authors: Yong Zeng, Sco R Hawley, Nicole M Schweppe, William D GillilandAbstract:Many advances in the understanding of meiosis have been made by measuring how often errors in chromosome segregation occur. This process of Nondisjunction can be studied by counting experimental progeny, but direct measurement of Nondisjunction rates is complicated by not all classes of Nondisjunctional progeny being viable. For X chromosome Nondisjunction in Drosophila female meiosis, all of the normal progeny survive, while Nondisjunctional eggs produce viable progeny only if fertilized by sperm that carry the appropriate sex chromosome. The rate of Nondisjunction has traditionally been estimated by assuming a binomial process and doubling the number of observed Nondisjunctional progeny, to account for the inviable classes. However, the correct way to derive statistics (such as confidence intervals or hypothesis testing) by this approach is far from clear. Instead, we use the multinomial-Poisson hierarchy model and demonstrate that the old estimator is in fact the maximum-likelihood estimator (MLE). Under more general assumptions, we derive asymptotic normality of this estimator and construct confidence interval and hypothesis testing formulae. Confidence intervals under this framework are always larger than under the binomial framework, and application to published data shows that use of the multinomial approach can avoid an apparent type 1 error made by use of the binomial assumption. The current study provides guidance for researchers designing genetic experiments on Nondisjunction and improves several methods for the analysis of genetic data.
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the mechanism of secondary Nondisjunction in drosophila melanogaster females
Genetics, 2006Co-Authors: Youbi Xiang, Sco R HawleyAbstract:Bridges (1916) observed that X chromosome Nondisjunction was much more frequent in XXY females than it was in genetically normal XX females. In addition, virtually all cases of X Nondisjunction in XXY females were due to XX ↔ Y segregational events in oocytes in which the two X chromosomes had failed to undergo crossing over. He referred to these XX ↔ Y segregation events as “secondary Nondisjunction.” Cooper (1948) proposed that secondary Nondisjunction results from the formation of an X-Y-X trivalent, such that the Y chromosome directs the segregation of two achiasmate X chromosomes to opposite poles on the first meiotic spindle. Using in situ hybridization to X and YL chromosomal satellite sequences, we demonstrate that XX ↔ Y segregations are indeed presaged by physical associations of the X and Y chromosomal heterochromatin. The physical colocalization of the three sex chromosomes is observed in virtually all oocytes in early prophase and maintained at high frequency until midprophase in all genotypes examined. Although these XXY associations are usually dissolved by late prophase in oocytes that undergo X chromosomal crossing over, they are maintained throughout prophase in oocytes with nonexchange X chromosomes. The persistence of such XXY associations in the absence of exchange presumably facilitates the segregation of the two X chromosomes and the Y chromosome to opposite poles on the developing meiotic spindle. Moreover, the observation that XXY pairings are dissolved at the end of pachytene in oocytes that do undergo X chromosomal crossing over demonstrates that exchanges can alter heterochromatic (and thus presumably centromeric) associations during meiotic prophase.
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recombination and Nondisjunction in humans and flies
Human Molecular Genetics, 1996Co-Authors: Kara E Koehle, Stephanie L Sherma, Sco R Hawley, Terry J HassoldAbstract:Recent studies of Drosophila and humans indicate that aberrant genetic recombination is an important component of Nondisjunction in both species. In both, a proportion of Nondisjunction is associated with failure to pair and/or recombine and in both, exchanges which are either too distal or too proximal increase the likelihood of malsegregation. In this review we provide two perspectives on these observations: first, a review of exchange and chromosome segregation in model organisms, focusing on Drosophila, and secondly an overview of Nondisjunction in humans. This format allows us to describe the paradigms developed from studies of model organisms and to ask whether these paradigms apply to the human situation.
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separation anxiety the etiology of Nondisjunction in flies and people
Human Molecular Genetics, 1994Co-Authors: Sco R Hawley, Jennife A Frazie, Rebekah S RasoolyAbstract:Two new studies examine the recombinational history of human chromosomes that nondisjoin at the first meiotic division in females. Our analysis of these studies suggests two possible etiologies of Nondisjunction in terms of well-understood properties of chromosome mechanics. For both the X chromosome and for chromosome 21, 60-70% of nondisjoined chromosomes are derived from chiasmate bivalents, many of which display unusual patterns of exchange. The patterns of exchange and Nondisjunction observed for human chromosome 21 parallel those exhibited by a mutation in Drosophila that impairs spindle assembly and function. Based on these similarities, we propose that Nondisjunction of chromosome 21 in human females results from an age-dependent loss of spindle-forming ability. The recombinational histories of nondisjoining human X chromosomes are quite different from those of chromosome 21, but rather parallel those obtained for spontaneous Nondisjunction in Drosophila females. The data for X chromosome disjunction in both species can be explained by a model in which Nondisjunction is the consequence of the age-dependent movement of transposable elements. According to this model, Nondisjunction is explained as the consequence of the repair of transposon-induced breaks in the DNA. Both models provide reasonable alternatives to biologically implausible explanations such as the 'production line hypothesis'.