Meiosis I Errors Research Articles

The association between maternal occupation and down syndrome: A report from the national Down syndrome project.

Among live births, Down syndrome (DS) due to trisomy 21 is the most commonly occurring autosomal trisomy, typically resulting from meiotic nondisjunction. Currently, advanced maternal age and altered recombination patterns are the only well-known risk factors for nondisjunction. Maternal occupation has not been investigated as a risk factor for maternally-derived cases of trisomy 21. This study explored the association between maternal occupation and chromosome 21 nondisjunction, stratified by the stage of maternal error - either Meiosis I (MI) or Meiosis II (MII). Additionally, we investigated specific toxic agents associated with occupation classes. Using narrative job descriptions from the National Down Syndrome Project (NDSP), a population-based case-control study, occupation was coded using the 2010 Standard Occupational Classification (SOC). Odds ratios were calculated for the association between occupation class and having a child with DS, stratified by meiotic stage. An exposure analysis was performed within occupational classes that were statistically significant predictors of having a child with DS. Odds ratios were calculated to analyze associations between individual exposures and having a child with DS. The odds of MII nondisjunction were increased among Production Workers (OR = 3.15; 95%CI = 1.52,6.55). Women who worked as Life, Physical and Social Scientists or in Food Preparation and Serving-Related Occupations experienced greater likelihood of MI errors (OR = 5.72(1.80,18.20), and OR = 1.87(1.08,3.24), respectively). Exposure to solvents within the Production Worker group was a significant predictor (p < 0.05) for MI nondisjunction. No other environmental agents had a significant association with nondisjunction. Specific maternal occupation classes were associated with MI and MII chromosome 21 nondisjunction. These occupation classes were selected for an exposure analysis, which determined solvents as highly predictive of MI nondisjunction among Production Workers. Findings from this analysis will serve to further explore the relationship between maternal occupation and chromosome 21 nondisjunction.

Incidence and origin of meiotic whole and segmental chromosomal aneuploidies detected by karyomapping.

What is the incidence and origin of meiotic whole and segmental aneuploidies detected by karyomapping at a blastocyst stage in human-derived IVF embryos? What is the distribution of various types of errors, including rare chromosomal abnormalities? The incidence of chromosomal aneuploidies was assessed in 967 trophectoderm biopsies from 180 couples who underwent 215 cycles of IVF with preimplantation genetic testing for monogenetic disease with a known causal mutation with a mean maternal age of 32.7 years. DNA from both parents and a reference sample was genotyped together with the analysed trophectoderm samples by karyomapping (single-nucleotide-polymorphism-based array). Chromosomal abnormalities were detected in 31% of the analysed samples. At least one whole chromosomal aneuploidy was detected in 27.1% of the trophectoderm biopsies, whereas a segmental aneuploidy was detected in 5.1% of the trophectoderm biopsies. Our results reveal that segmental aneuploidies predominantly affect paternally derived chromosomes (70.4%; P < 0.01) compared with whole chromosomal aneuploidies that more frequently affect maternally derived chromosomes (90.1%; P < 0.0001). Also, the frequency of meiosis I (MI) and meiosis II (MII) errors was established in meiotic trisomies; MI errors were observed to be more frequent (n = 102/147 [69.4%]) than MII errors (n = 45/147 [30.6%]). Karyomapping is a robust method that is suitable for preimplantation genetic testing for monogenetic disease and for detecting meiotic aneuploidies, including meiotic segmental aneuploidies, and provides complex information about their parental origin. Our results revealed that segmental aneuploidy more frequently affects paternal chromosomes compared with whole chromosomal aneuploidy in human IVF embryos at the blastocyst stage.

Premature dyad separation in meiosis II is the major segregation error with maternal age in mouse oocytes

As women get older their oocytes become susceptible to chromosome mis-segregation. This generates aneuploid embryos, leading to increased infertility and birth defects. Here we examined the provenance of aneuploidy by tracking chromosomes and their kinetochores in oocytes from young and aged mice. Changes consistent with chromosome cohesion deterioration were found with age, including increased interkinetochore distance and loss of the centromeric protector of cohesion SGO2 in metaphase II arrested (metII) eggs, as well as a rise in the number of weakly attached bivalents in meiosis I (MI) and lagging chromosomes at anaphase I. However, there were no MI errors in congression or biorientation. Instead, premature separation of dyads in meiosis II was the major segregation defect in aged eggs and these were associated with very low levels of SGO2. These data show that although considerable cohesion loss occurs during MI, its consequences are observed during meiosis II, when centromeric cohesion is needed to maintain dyad integrity.

Evidence for dysregulation of genome-wide recombination in oocytes with nondisjoined chromosomes 21

In oocytes with nondisjoined chromosomes 21 due to a meiosis I (MI) error, recombination is significantly reduced along chromosome 21; several lines of evidence indicate that this contributes to the nondisjunction event. A pilot study found evidence that these oocytes also have reduced recombination genome-wide when compared with controls. This suggests that factors that act globally may be contributing to the reduced recombination on chromosome 21, and hence, the nondisjunction event. To identify the source of these factors, we examined two levels of recombination count regulation in oocytes: (i) regulation at the maternal level that leads to correlation in genome-wide recombination across her oocytes and (ii) regulation at the oocyte level that leads to correlation in recombination count among the chromosomes of an oocyte. We sought to determine whether either of these properties was altered in oocytes with an MI error. As it relates to maternal regulation, we found that both oocytes with an MI error (N = 94) and their siblings (N = 64) had reduced recombination when compared with controls (N = 2723). At the oocyte level, we found that the correlation in recombination count among the chromosomes of an oocyte is reduced in oocytes with MI errors compared with that of their siblings or controls. These results suggest that regulation at the maternal level predisposes MI error oocytes to reduced levels of recombination, but additional oocyte-specific dysregulation contributes to the nondisjunction event.

SNP array intensity analysis of the 1st polar body (PB1) can reliably identify premature separation of sister chromatids (PSSC) in meiosis I (MI): a blinded validation study

PSSC is the predominant mechanism of MI errors contributing to the age-related increase in aneuploidy. Distinguishing PSSC from non-disjunction (ND) is important but requires sequential PB and embryo biopsy. Embryos resulting from oocytes with reciprocal errors of the same chromosome in PB1 and PB2 will be euploid following PSSC but aneuploid after ND. This creates clinical uncertainty and hampers research into the mechanisms of MI errors. This study seeks to determine whether signal intensity analysis from PB1 SNP arrays can predict the nature of MI errors.

Targeted deep sequencing of maternal cohesin genes as putative biomarkers for increased risk of embryonic aneuploidy

The cohesin complex is a family of proteins that maintains chromatid cohesion and regulates chromosome segregation during cell division. Since premature separation of sister chromatids (PSSC) accounts for >90% of meiosis I (MI) errors, it is plausible that cohesin abnormalities may confer an increased risk for embryonic aneuploidy. This study uses a combination of oocyte genome-wide gene expression analysis and targeted maternal next generation sequencing (NGS) to investigate if sequence variations in specific cohesin pathway genes are associated with elevated or reduced risks for MI errors.

Altered patterns of multiple recombinant events are associated with nondisjunction of chromosome 21.

We have previously examined characteristics of maternal chromosomes 21 that exhibited a single recombination on 21q and proposed that certain recombination configurations are risk factors for either meiosis I (MI) or meiosis II (MII) nondisjunction. The primary goal of this analysis was to examine characteristics of maternal chromosomes 21 that exhibited multiple recombinant events on 21q to determine whether additional risk factors or mechanisms are suggested. In order to identify the origin (maternal or paternal) and stage (MI or MII) of the meiotic errors, as well as placement of recombination, we genotyped over 1,500 SNPs on 21q. Our analyses included 785 maternal MI errors, 87 of which exhibited two recombinations on 21q, and 283 maternal MII errors, 81 of which exhibited two recombinations on 21q. Among MI cases, the average location of the distal recombination was proximal to that of normally segregating chromosomes 21 (35.28 vs. 38.86 Mb), a different pattern than that seen for single events and one that suggests an association with genomic features. For MII errors, the most proximal recombination was closer to the centromere than that on normally segregating chromosomes 21 and this proximity was associated with increasing maternal age. This pattern is same as that seen among MII errors that exhibit only one recombination. These findings are important as they help us better understand mechanisms that may underlie both age-related and nonage-related meiotic chromosome mal-segregation.

Investigation of factors associated with paternal nondisjunction of chromosome 21

Previous studies on relatively small samples of individuals with trisomy 21 caused by paternally derived errors have shown that: (1) advanced paternal age is not a risk factor for chromosome 21 nondisjunction (NDJ), (2) absence of recombination, but not the location of recombination is associated with paternal NDJ and (3) there is an excess of males among live-births with paternally derived trisomy 21. An excess of males is also observed among all individuals with trisomy 21. Using 128 families that had a child with trisomy 21 due to a paternally derived error, we examined: paternal age, recombination and the male/female sex ratio. We genotyped STRs along 21q to identify the origin of the error and the location of recombination on the paternal chromosome. Results showed that 32% of paternal meiotic errors occurred in meiosis I (MI) and 68% in meiosis II (MII). We confirmed the lack of a paternal age association with either type of error (mean paternal age for controls, MI, and MII errors: 31.3 +/- 6.6, 32.2 +/- 6.3, 30.6 +/- 6.5, respectively). However, contrary to previous findings, we did not find altered patterns of recombination among paternal MI or MII errors. We found an increased male/female sex ratio among paternal (1.28, 95% CI: 0.68-1.91) and maternal (1.16, 95% CI: 1.02-1.33) meiotic errors. While the sex ratio among individuals with paternal errors was not statistically significant, these findings suggest that selection against female fetuses with trisomy 21 may contribute to the excess of males observed among all individuals with trisomy 21.

Relationship of recombination patterns and maternal age among non-disjoined chromosomes 21

Advancing maternal age has long been identified as the primary risk factor for human chromosome trisomy. More recently, altered patterns of meiotic recombination have been found to be associated with non-disjunction. We have used trisomy 21 as a model for human non-disjunction that occurs during the formation of oocytes to understand the role of maternal age and recombination. Patterns of recombination that increase the risk for non-disjunction of chromosome 21 include absence of any exchange, an exchange near the centromere or a single, telomeric exchange. Our recent work has shown that different susceptibility patterns are associated with the origin of the meiotic error and maternal age. For MI (meiosis I) errors, the proportion of oocytes with susceptible recombination patterns is highest among young mothers and decreases significantly in the oldest age group. In fact, the pattern of exchanges among the oldest age group mimics the pattern observed among normally disjoining chromosomes 21. These results suggest that oocytes of younger women, with functional meiotic apparatus and/or robust ovarian environment, are able to properly resolve all but the most susceptible exchange patterns. As women age, however, meiotic mechanisms erode, making it difficult to resolve even stable exchange events. Interestingly, our preliminary recombination results on MII errors reveal the opposite relationship with maternal age: susceptible pericentromeric exchanges occur most often in the older age group compared with the younger age group. If confirmed, we will have further evidence for multiple risk factors for non-disjunction that act at different times in the meiotic process.

A comparison of maternal age, sex ratio and associated major anomalies among fetal trisomy 18 cases with different cell division of error

To compare the maternal age, sex ratio, and associated major anomalies among fetal trisomy 18 cases with different cell division of error. Thirty-one consecutive cases of fetal trisomy 18 detected perinatally during a period of 6 years were studied. Among these, 18 were 47,XY,+18, and 13 were 47,XX,+18. The average gestational age at diagnosis was 19.7 +/- 4.6 weeks, and the maternal age at diagnosis was 34.5 +/- 5.8 years. DNA polymorphism analysis was applied to determine the parental origin, stage of non-disjunctional error and recombination. Twenty-eight cases were of maternal origin. Among these, 20 had major anomalies, 17 had meiosis II (MII) errors, 10 had meiosis I (MI) errors, and one had a postzygotic mitotic (PZM) or non-crossover MII error. Three cases were of paternal origin. Among these, two had major anomalies, two had MI errors, and one had a PZM or non-crossover MII error. For the 17 cases with maternal MII errors, the average maternal age was 34.5 +/- 6.6 years. Of these cases, 12 had major anomalies, 13 were male, and 4 were female, giving a male:female sex ratio of 3.25:1. For the 10 cases with maternal MI errors, the average maternal age was 34.8 +/- 5.7 years. Of these cases, seven had major anomalies, three were male, and seven were female, giving a male:female sex ratio of 0.429:1. In trisomy 18, there is a male preponderance in the fetuses caused by maternal MII errors and a female preponderance in the fetuses caused by maternal MI errors. No significant difference was noted in maternal age or in associated major anomalies between the two groups of maternal MII errors and maternal MI errors. No significant difference was noted in associated major anomalies between the maternal and paternal cases.

Maternal meiosis I non-disjunction of chromosome 15: dependence of the maternal age effect on level of recombination.

Non-disjoined chromosomes 15 from 115 cases of uniparental disomy (ascertained through Prader-Willi syndrome) and 13 cases of trisomy of maternal origin were densely typed for microsatellite loci spanning chromosome 15q. Of these 128 cases a total of 97 meiosis I (MI) errors, 19 meiosis II (MII) errors and 12 mitotic errors were identified. The genetic length of a map created from the MI errors was 101 cM, as compared with a maternal length of 137 cM based on CEPH controls. No significant differences were detected in the distribution of recombination events along the chromosome arm and a reduction was seen for most of the chromosome 15 intervals examined. It was estimated that 21% of tetrads leading to MI non-disjunction were achiasmate, which may account for most or all of the reduction in recombination noted. The mean age of mothers of cases involving MI errors which showed no transitions from heterodisomy to isodisomy was significantly lower (32.7) than cases showing one or more observable transitions (36.3) (P < 0.003, t -test). However, even among chiasmate pairs the highest mean maternal age was seen for multiple exchange tetrads. Chromosome-specific differences in maternal age effects may be related to the normal distribution of exchanges (and their individual susceptibilities) for each chromosome. However, they may also reflect the presence of multiple factors which act to ensure normal segregation, each affected by maternal age in a different way and varying in importance for each chromosome.

Characterization of susceptible chiasma configurations that increase the risk for maternal nondisjunction of chromosome 21.

Recent studies of trisomy 21 have shown that altered levels of recombination are associated with maternal non-disjunction occurring at both meiosis I (MI) and meiosis II (MII). To comprehend better the association of recombination with nondisjunction, an understanding of the pattern of meiotic exchange, i.e. the exchange of genetic material at the four-strand stage during prophase, is required. We examined this underlying exchange pattern to determine if specific meiotic configurations are associated with a higher risk of non-disjunction than others. We examined the crossover frequencies of chromosome 21 for three populations: (i) normal female meiotic events; (ii) meiotic events leading to MI non-disjunction; and (iii) those leading to MII non-disjunction. From these crossover frequencies, we estimated the array of meiotic tetrads that produced the observed crossovers. Using this approach, we found that nearly one-half of MI errors were estimated to be achiasmate. The majority of the remaining MI bivalents had exchanges that clustered at the telomere. In contrast, exchanges occurring among MII cases clustered at the pericentromeric region of the chromosome. Unlike the single exchange distributions, double exchanges from the non-disjoined populations seemed to approximate the distribution in the normal population. These data suggest that the location of certain exchanges makes a tetrad susceptible to non-disjunction. Specifically, this susceptibility is associated with the distance between the centromere and closest exchange. This result challenges the widely held concept that events occurring at MII are largely independent of events occurring at MI, and suggests that all non-disjunction events may be initiated during MI and simply resolved at either of the two meiotic stages.