Age-related Aneuploidy Research Articles

Reproductive Ageing: Metabolic contribution to age-related chromosome missegregation in mammalian oocytes.

Chromosome missegregation and declining energy metabolism are considered to be unrelated features of oocyte ageing that contribute to poor reproductive outcomes. Given the bioenergetic cost of chromosome segregation, we propose here that altered energy metabolism during ageing may be an underlying cause of age-related chromosome missegregation and aneuploidy. Advanced reproductive age in women is a major cause of infertility, miscarriage and congenital abnormalities. This is principally caused by a decrease in oocyte quality and developmental competence with age. Oocyte ageing is characterised by an increase in chromosome missegregation and aneuploidy. However, the underlying mechanisms of age-related aneuploidy have not been fully elucidated and are still under active investigation. In addition to chromosome missegregation, oocyte ageing is also accompanied by metabolic dysfunction. In this review, we integrate old and new perspectives on oocyte ageing, chromosome segregation and metabolism in mammalian oocytes and make direct links between these processes. We consider age-related alterations to chromosome segregation machinery, including the loss of cohesion, microtubule stability and the integrity of the spindle assembly checkpoint. We focus on how metabolic dysfunction in the ageing oocyte disrupts chromosome segregation machinery to contribute to and exacerbate age-related aneuploidy. More specifically, we discuss how mitochondrial function, ATP production and the generation of free radicals are altered during ageing. We also explore recent developments in oocyte metabolic ageing, including altered redox reactions (NAD+ metabolism) and the interactions between oocytes and their somatic nurse cells. Throughout the review, we integrate the mechanisms by which changes in oocyte metabolism influence age-related chromosome missegregation.

Spindle assembly checkpoint insensitivity allows meiosis-II despite chromosomal defects in agedeggs.

Chromosome segregation errors in mammalian oocyte meiosis lead to developmentally compromised aneuploid embryos and become more common with advancing maternal age. Known contributors include age-related chromosome cohesion loss and spindle assembly checkpoint (SAC) fallibility in meiosis-I. But how effective the SAC is in meiosis-II and how this might contribute to age-related aneuploidy is unknown. Here, we developed genetic and pharmacological approaches to directly address the function of the SAC in meiosis-II. We show that the SAC is insensitive in meiosis-II oocytes and that as a result misaligned chromosomes are randomly segregated. Whilst SAC ineffectiveness in meiosis-II is not age-related, it becomes most prejudicial in oocytes from older females because chromosomes that prematurely separate by age-related cohesion loss become misaligned in meiosis-II. We show that in the absence of a robust SAC in meiosis-II these age-related misaligned chromatids are missegregated and lead to aneuploidy. Our data demonstrate that the SAC fails to prevent cell division in the presence of misaligned chromosomes in oocyte meiosis-II, which explains how age-related cohesion loss can give rise to aneuploid embryos.

P-289 KIDscore and PGT-A: Is there a relationship between the findings?

Abstract Study question Is there a correlation between Preimplantation Genetic Tests (PGT) results and Embryoscope’s KIDscore? Summary answer It seems that the higher the KIDscore, the higher the percentage of euploid embryos. What is known already Time lapse technology is bringing new perspectives in the relationship of embryos' morphokinetics and implantation rates after assisted reproduction techniques. However, it seems that only the embryo morphokinetics could be insufficient to predict euploidy. The KIDscoreTM D5 (KS5) algorithm, thus, is used for improving the implantation rates after a single euploid embryo transfer in its blastocyst stage and is related to higher rates of euploid embryos the higher the KS5, which could lead to higher implantation rates. Study design, size, duration Retrospective, observational study performed at a reproductive medicine center, using data collected between 2019 and 2021. A total of 802 embryos were included for analysis. Participants/materials, setting, methods All the embryos were biopsied for PGT (A, SR, and M), after being cultured for five or six days in an Embryoscope® time-lapse incubator (Vitrolife®, Canada). The embryos were then divided into three groups according to the KS5 evaluation: G1 (1-4), G2 (4.1-7), G3 (7.1-9.9) and the percentage of euploidy was evaluated in each group. For statistical analysis, Chi-square, and ANOVA tests, and Pearson correlation were used, considering p < 0.05. Main results and the role of chance The women’s mean age among groups G1 vs. G2 vs. G3 was, respectively: 39.1±3.5 vs. 38.7±3.3 vs. 37.6±3.8, p < 0.001; the mean KS5 of each group was: 2.9±0.7 vs. 5.4±0.8 vs. 8.0±0.7, p < 0.001 and finally, the euploidy rates comparing the G1 vs. G2 vs. G3 were, respectively: 98/341, 28.7% vs. 124/340, 36.5% vs. 63/121, 52.1%, p < 0.001. A weak correlation between women's age and KIDScore was also observed (-0.173, p < 0.001). Limitations, reasons for caution Although there is a positive correlation between embryomorphokinetics and euploidy, and the euploidy rate increases with higher KIDscore, only 50% of the high score embryos are euploids. Therefore, it is still important to perform embryo biopsy. Wider implications of the findings The findings suggest that better embryo morphokinetics provide greater chances of euploidy. Moreover, a weak negative correlation between women's age and KIDScore, possibly due to age-related aneuploidy, was observed. These results highlight time-lapse technology’s importance and the future perspective of morphokinetics evaluation improving implantation rates through euploidy identification. Trial registration number Not Applicable

P–806 Neogametogenesis via oocyte replication

Abstract Study question Can full preimplantation embryo development be achieved from artificial oocytes created through nuclear transfer of a haploid pseudo-blastomere (HpB) into a recipient ooplast? Summary answer It is feasible to replicate the female genome and generate novel sibling oocytes that can yield full preimplantation embryo development, albeit at a reduced rate. What is known already A limitation of assisted reproduction is the number of available oocytes for embryo creation. It is feasible to utilize a somatic cell nucleus to construct novel oocytes through a process known as haploidization, in which a reverse meiosis occurs after SCNT. Similarly, producing haploid parthenogenetic constructs can generate HpBs, useful for genetic testing at the pre-fertilization level or for reproduction. It is feasible to use a HpB as a nuclear donor since it has already completed homologue segregation. Study design, size, duration This is prospective translational animal model study. Over 6 months, 556 oocytes were manipulated for the experimental group, and 158 control oocytes were employed. B6D2F1 HpBs were used to establish the procedure and acquire expertise. FVB HpBs were subsequently introduced for genetic variance. Experimental and control embryos were cultured in a time-lapse incubator (up to 96h). Cleavage parameters were compared to control. Two-sample T-tests and one-way ANOVA with Bonferroni correction were employed for statistical analysis. Participants/materials, setting, methods A cohort of oocytes was harvested from B6D2F1 or FVB superovulated mice and artificially activated by 8% ethanol. At the 8-cell stage, HpBs were exposed to nocodazole. Another cohort of B6D2F1 oocytes was enucleated for recipient ooplasts. HpBs were individually transferred into the perivitelline space of the ooplasts alongside inactivated Sendai virus. After fusion, reconstructed oocytes with spindle development were fertilized by piezo-actuated ICSI using B6D2F1 spermatozoa. Unmanipulated and fertilized B6D2F1 oocytes served as control. Main results and the role of chance A total of 158 control oocytes underwent ICSI with a 67.7% survival rate; of these, 65.4% developed to the blastocyst stage. For artificial oocyte activation (AOA), up to 10 oocytes were activated for each experiment, yielding 8 HpBs per activated oocyte. For the experimental group, 556 oocytes underwent enucleation with a 96.4% survival rate. Nuclear transfer of HpBs resulted in a 93.2% survival rate, consistent for those derived from BDF and FVB. Reconstructed oocytes showed appropriate development of a novel pseudo-meoitic spindle at a rate of 63.7% for B6D2F1 HpBs and 75.5% for FVB HpBs, and ICSI yielded a 67.1% and 57.7% survival rate, respectively. The fertilization rate for the reconstructed oocytes was 64%. Control oocytes underwent ICSI with a 67.7% survival rate. When evaluating time-lapse parameters, reconstructed embryos created via blastomere nuclear transfer showed asynchrony compared to controls beginning as early as the stage of pronuclear fading. While the majority of reconstructed embryos arrested at the 4-cell stage, of those that progressed, 11.3% of those using BDF HpBs and 14.6% of those using FVB HpBs developed to the fully expanded blastocyst stage. This corresponds to a total of 23 reconstructed embryos that developed to the morula or blastocyst stage. Limitations, reasons for caution While we used single-well embryoscope culture for morphokinetic data collection, group culture is superior to single-embryo culture for mice. Thus, developmental rates may be underestimated by this protocol. Implantation and successful pregnancy are also needed to support the clinical utility of this method in generating gametes. Wider implications of the findings: For women with diminished ovarian reserve, oocyte yield and age-related aneuploidy are limitations to achieving genotyped offspring. Nuclear transfer of HpB can generate sibling oocytes while maintaining genetic information. This model represents a promising path for expanding oocyte yield, allowing genetic assessment of sibling oocytes, and enhancing chances of procreation. Trial registration number none

Meiotic Cohesin and Variants Associated With Human Reproductive Aging and Disease.

Successful human reproduction relies on the well-orchestrated development of competent gametes through the process of meiosis. The loading of cohesin, a multi-protein complex, is a key event in the initiation of mammalian meiosis. Establishment of sister chromatid cohesion via cohesin rings is essential for ensuring homologous recombination-mediated DNA repair and future proper chromosome segregation. Cohesin proteins loaded during female fetal life are not replenished over time, and therefore are a potential etiology of age-related aneuploidy in oocytes resulting in decreased fecundity and increased infertility and miscarriage rates with advancing maternal age. Herein, we provide a brief overview of meiotic cohesin and summarize the human genetic studies which have identified genetic variants of cohesin proteins and the associated reproductive phenotypes including primary ovarian insufficiency, trisomy in offspring, and non-obstructive azoospermia. The association of cohesion defects with cancer predisposition and potential impact on aging are also described. Expansion of genetic testing within clinical medicine, with a focus on cohesin protein-related genes, may provide additional insight to previously unknown etiologies of disorders contributing to gamete exhaustion in females, and infertility and reproductive aging in both men and women.

Distinct classes of lagging chromosome underpin age-related oocyte aneuploidy in mouse.

Chromosome segregation errors that cause oocyte aneuploidy increase in frequency with maternal age and are considered a major contributing factor of age-related fertility decline in females. Lagging anaphase chromosomes are a common age-associated phenomenon in oocytes, but whether anaphase laggards actually missegregate and cause aneuploidy is unclear. Here, we show that lagging chromosomes in mouse oocytes comprise two mechanistically distinct classes of chromosome motion that we refer to as "class-I" and "class-II" laggards. We use imaging approaches and mechanistic interventions to dissociate the two classes and find that whereas class-II laggards are largely benign, class-I laggards frequently directly lead to aneuploidy. Most notably, a controlled prolongation of meiosis I specifically lessens class-I lagging to prevent aneuploidy. Our data thus reveal lagging chromosomes to be a cause of age-related aneuploidy in mouse oocytes and suggest that manipulating the cell cycle could increase the yield of useful oocytes in some contexts.

Insufficiency of melatonin in follicular fluid is a reversible cause for advanced maternal age-related aneuploidy in oocytes

Age-related decline in female fertility is a common feature that occurs in the fourth decade of women as a result of a reduction in both oocyte quality and quantity [1]. However, strategies to prevent the deterioration of maternal aged oocytes and relevant mechanisms are still underexplored. Here, we find that the reduced abundance of melatonin in the follicular fluid highly correlates with the advanced maternal age-related aneuploidy. Of note, we show that exposure of oocytes from aged mice both in vitro and in vivo to exogenous melatonin not only eliminates the accumulated reactive oxygen species-induced DNA damage and apoptosis, but also suppresses the occurrence of aneuploidy caused by spindle/chromosome defect that is frequently observed in aged oocytes. Importantly, we reveal that melatonin supplementation reverses the defective phenotypes in aged oocytes through a Sirt1/Sod2-dependent mechanism. Inhibition of Sirt1 activity abolishes the melatonin-mediated improvement of aged oocyte quality. Together our findings provide evidence that supplementation of melatonin is a feasible way to protect oocytes from advanced maternal age-related meiotic defects and aneuploidy, demonstrating the potential for improving the quality of oocytes from aged women and the efficiency of assisted reproductive technology.

Direct Single-Cell Analysis of Human Polar Bodies and Cleavage-Stage Embryos Reveals No Evidence of the Telomere Theory of Reproductive Ageing in Relation to Aneuploidy Generation.

Reproductive ageing in women, particularly after the age of 35, is associated with an exponential increase in the proportion of chromosomally abnormal oocytes produced. Several hypotheses have attempted to explain this observation, including the ‘limited oocyte pool’ hypothesis and the ‘two-hit’ hypothesis, the latter explaining that a depletion in oocyte quality with age results from the multiple opportune stages for errors to occur in meiosis. Recently however, the telomere theory of reproductive ageing in women has been proposed. This suggests that shortened telomeres in oocytes of women of advanced maternal age render oocytes unable to support fertilization and embryogenesis. Despite a credible rationale for the telomere theory of reproductive ageing in women, very few studies have assessed telomere length directly in human oocytes or preimplantation embryos. Therefore, we directly assessed relative telomere length in first polar bodies and blastomeres from cleavage stage (day 3) embryos. In both cell types we tested the hypothesis that (1) older women have shorter telomeres and (2) chromosomally abnormal (aneuploid) gametes/embryos have shorter telomeres. In all cases, we found no evidence of altered telomere length associated with age-related aneuploidy.

Extensive sex differences at the initiation of genetic recombination.

Meiotic recombination differs between males and females; however, when and how these differences are established is unknown. Here we identify extensive sex differences at recombination initiation by mapping hotspots of meiotic DNA double-strand breaks in male and female mice. Contrary to past findings in humans, few hotspots are used uniquely in either sex. Instead, grossly different recombination landscapes result from up to 15-fold differences in hotspot usage between males and females. Indeed, most recombination occurs at sex-biased hotspots. Sex-biased hotspots appear to be partly determined by chromosome structure, and DNA methylation, absent in females at the onset of meiosis, plays a substantial role. Sex differences are also evident later in meiosis as the repair frequency of distal meiotic breaks as crossovers diverges in males and females. Suppression of distal crossovers may help to minimize age-related aneuploidy that arises due to cohesion loss during dictyate arrest in females.

Role of Maternal Serum Human Placental Lactogen in First Trimester Screening.

The most preferred antenatal screening test is first trimester dual test which has a detection rate of 95% for foetal chromosomal anomaly. Maternal serum free β human chorionic gonadotropin (free β hCG) and pregnancy associated plasma protein A are used in first trimester dual test along with maternal demographic and foetal sonographic indices to calculate risk for foetal aneuploidy. Human placental lactogen is a placental hormone that is present in maternal serum only during pregnancy and its level rises in relation to the growth of the foetus and placenta. The objectives of this study was to measure and correlate maternal serum hPL with free β hCG, maternal age, maternal age related risk ratio and calculated risk ratio of first trimester screening. After obtaining permission from the Institutional Ethics Committee, hPL and free β hCG were measured from the serum of 84 pregnant women aged 20-40years in 11-13th weeks + 6days of gestation who underwent dual test during their antenatal check-up. Independent t test, Pearson's correlation, Spearman's correlation, Mann-Whitney U test, ANOVA were used wherever appropriate. A significant positive correlation between maternal serum hPL, maternal age related aneuploidy risk ratio (p value < 0.001) and aneuploidy risk ratio at the time of delivery (p value < 0.001) was observed. Also maternal age was negatively correlated with maternal serum hPL (p value < 0.001) and positively correlated with maternal serum free β hCG (p value 0.023). A significant negative correlation between maternal serum hPL and free β hCG (p value < 0.001) was found. To conclude low level of maternal serum hPL in advanced maternal age may reflect decreased functional syncytiotrophoblast mass which may predispose to adverse pregnancy outcome. As chance of baby born with chromosomal anomaly is known to increase with advancing maternal age, hPL may have role in first trimester screening.

Age-Related Loss of Cohesion: Causes and Effects.

Aneuploidy is a leading genetic cause of birth defects and lower implantation rates in humans. Most errors in chromosome number originate from oocytes. Aneuploidy in oocytes increases with advanced maternal age. Recent studies support the hypothesis that cohesion deterioration with advanced maternal age represents a leading cause of age-related aneuploidy. Cohesin generates cohesion, and is established only during the premeiotic S phase of fetal development without any replenishment throughout a female’s period of fertility. Cohesion holds sister chromatids together until meiosis resumes at puberty, and then chromosome segregation requires the release of sister chromatid cohesion from chromosome arms and centromeres at anaphase I and anaphase II, respectively. The time of cohesion cleavage plays an important role in correct chromosome segregation. This review focuses specifically on the causes and effects of age-related cohesion deterioration in female meiosis.

The effect of DHEA on apoptosis and cohesin levels in oocytes in aged mice.

Female fertility declines with age as the number of ovarian follicles decreases and aneuploidy increases. Degradation of the cohesin complex might be responsible for age-related aneuploidy. Dehydroepiandrosterone (DHEA) can improve the ovarian reserve and reduce the rate of aneuploidy, but the relationship between DHEA and cohesin levels in oocytes is still unknown. The aim of the current study was to evaluate the effect of the supplement DHEA on ovarian function, including the number of follicles and cohesin levels in oocytes. C57BL/6J mice at 3 weeks, 6 weeks, 12 weeks, 6 months, and 10 months of age were used to obtain a systematic view into follicle apoptosis and cohesin levels in oocytes. Nine-month-old C57BL/6J mice were administered saline (n = 5), 17β-estradiol (100 µg/kg per day, n = 5), or DHEA (5mg/Kg per day, n = 5). After 4 weeks, aged mice were weighed and sacrificed, and ovarian tissue samples were prepared. Anti-VASA staining and HE staining were used to count the number of follicles. Anti-γH2AX staining and TUNEL were used to measure follicle apoptosis and immunofluorescent staining was used to detect the levels of three oocyte cohesin subunits: REC8, SMC1β, and SMC3. Administration of the supplements 17β-estradiol and DHEA to aged mice increased the number of primordial and primary follicles and decreased the age-related apoptosis of follicles. Levels of the cohesin subunits REC8 and SMC1β declined with age, but DHEA and 17β-estradiol tended to delay that decline. The supplement DHEA increased the number of primordial and primary follicles in aged mice by inhibiting follicle apoptosis and tended to delay the decrease in cohesin levels in oocytes.

Chromosome Cohesion Established by Rec8-Cohesin in Fetal Oocytes Is Maintained without Detectable Turnover in Oocytes Arrested for Months in Mice

SummarySister chromatid cohesion mediated by the cohesin complex is essential for chromosome segregation in mitosis and meiosis [1]. Rec8-containing cohesin, bound to Smc3/Smc1α or Smc3/Smc1β, maintains bivalent cohesion in mammalian meiosis [2, 3, 4, 5, 6]. In females, meiotic DNA replication and recombination occur in fetal oocytes. After birth, oocytes arrest at the prolonged dictyate stage until recruited to grow into mature oocytes that divide at ovulation. How cohesion is maintained in arrested oocytes remains a pivotal question relevant to maternal age-related aneuploidy. Hypothetically, cohesin turnover regenerates cohesion in oocytes. Evidence for post-replicative cohesion establishment mechanism exists, in yeast and invertebrates [7, 8]. In mouse fetal oocytes, cohesin loading factor Nipbl/Scc2 localizes to chromosome axes during recombination [9, 10]. Alternatively, cohesion is maintained without turnover. Consistent with this, cohesion maintenance does not require Smc1β transcription, but unlike Rec8, Smc1β is not required for establishing bivalent cohesion [11, 12]. Rec8 maintains cohesion without turnover during weeks of oocyte growth [3]. Whether the same applies to months or decades of arrest is unknown. Here, we test whether Rec8 activated in arrested mouse oocytes builds cohesion revealed by TEV cleavage and live-cell imaging. Rec8 establishes cohesion when activated during DNA replication in fetal oocytes using tamoxifen-inducible Cre. In contrast, no new cohesion is detected when Rec8 is activated in arrested oocytes by tamoxifen despite cohesin synthesis. We conclude that cohesion established in fetal oocytes is maintained for months without detectable turnover in dictyate-arrested oocytes. This implies that women’s fertility depends on the longevity of cohesin proteins that established cohesion in utero.

Bivalent separation into univalents precedes age-related meiosis I errors in oocytes.

The frequency of chromosome segregation errors during meiosis I (MI) in oocytes increases with age. The two-hit model suggests that errors are caused by the combination of a first hit that creates susceptible crossover configurations and a second hit comprising an age-related reduction in chromosome cohesion. This model predicts an age-related increase in univalents, but direct evidence of this phenomenon as a major cause of segregation errors has been lacking. Here, we provide the first live analysis of single chromosomes undergoing segregation errors during MI in the oocytes of naturally aged mice. Chromosome tracking reveals that 80% of the errors are preceded by bivalent separation into univalents. The set of the univalents is biased towards balanced and unbalanced predivision of sister chromatids during MI. Moreover, we find univalents predisposed to predivision in human oocytes. This study defines premature bivalent separation into univalents as the primary defect responsible for age-related aneuploidy.

Age-related increase in aneuploidy and alteration of gene expression in mouse first polar bodies

To confirm that aneuploidy candidate genes are detectable in the first polar body (PB(1)) of MII oocytes and to investigate the age-dependent molecular changes in PB(1). Aged (12-to 15-mo-old) and young (2-mo-old) mice were administered pregnant mare's serum gonadotropin (PMSG) and human chorionic gonadotrophin (hCG). MII oocytes were obtained and the first PB was removed. mRNA from each PB and its sibling oocyte was reverse transcribed. Real-time PCR was performed to quantify the expression of six genes (BUB1, CDC20, Filia, MCAK, SGOL1, SMC1A) in single PB. We first demonstrated that detection and quantification of transcripts associated with aneuploidy in single mouse oocyte and sibling PB(1) is possible and the relative abundance of mRNA transcripts in a single PB faithfully reflects the relative abundance of that transcript in its sibling oocyte. We further found that transcript levels were significantly lower in aged PBs compared with young PBs (P<0.05). Our results suggest that the detection and analysis of polar body mRNA may provide insight in age-related aneuploidy in oocyte. This analysis is a novel concept to investigate the genesis of chromosome abnormality and could potentially assist in the characterization of mechanisms underlying key molecular origin of female meiotic aneuploidy, which would be of great scientific and clinical value.

G93 The Outcome Of Prenatal Identification Of A Sex Chromosome Abnormality

IntroductionPrenatal diagnosis (PND) via amniocentesis or chorionic villus sampling may result in the identification of a sex chromosome abnormality, often as an incidental finding.AimsTo ascertain the incidence of sex chromosome...

Fine-scale mapping of meiotic recombination in Asians

BackgroundMeiotic recombination causes a shuffling of homologous chromosomes as they are passed from parents to children. Finding the genomic locations where these crossovers occur is important for genetic association studies, understanding population genetic variation, and predicting disease-causing structural rearrangements. There have been several reports that recombination hotspot usage differs between human populations. But while fine-scale genetic maps exist for European and African populations, none have been constructed for Asians.ResultsHere we present the first Asian genetic map with resolution high enough to reveal hotspot usage. We constructed this map by applying a hidden Markov model to genotype data for over 500,000 single nucleotide polymorphism markers from Korean and Mongolian pedigrees which include 980 meioses. We identified 32,922 crossovers with a precision rate of 99%, 97% sensitivity, and a median resolution of 105,949 bp. For direct comparison of genetic maps between ethnic groups, we also constructed a map for CEPH families using identical methods. We found high levels of concordance with known hotspots, with approximately 72% of recombination occurring in these regions. We investigated the hypothesized contribution of recombination problems to age-related aneuploidy. Our large sample size allowed us to detect a weak but significant negative effect of maternal age on recombination rate.ConclusionsWe have constructed the first fine-scale Asian genetic map. This fills an important gap in the understanding of recombination pattern variation and will be a valuable resource for future research in population genetics. Our map will improve the accuracy of linkage studies and inform the design of genome-wide association studies in the Asian population.

Causes and consequences of maternal age-related aneuploidy in oocytes: a review

Although a positive correlation between aneuploidy and maternal age was first reported almost a century ago, the underlying mechanisms remain mostly unknown. Different hypotheses regarding age-related aneuploidy rise have been presented, but so far none of them can explain its full mechanism. Age-related aneuploidy is more likely to result from complex events taking place during the entire period of germ cell development, than from the failure of one particular mechanism. Recent findings confirm that the spindle assembly checkpoint (SAC) does not control and correct kinetochore-microtubule attachments in oocytes, enabling further propagation of aneuploidy, which has occurred in the earlier phases of oogenesis. In this review we will discuss the following hypotheses: the &amp;ldquo;limited oocyte pool&amp;rdquo; hypothesis, the &amp;ldquo;two hits&amp;rdquo; hypothesis, weakened centromeric cohesion and cohesin loss, different functions of the spindle assembly checkpoint and finally, changes in global gene expression. &amp;nbsp; &amp;nbsp;

Reduced Chromosome Cohesion Measured by Interkinetochore Distance Is Associated with Aneuploidy Even in Oocytes from Young Mice1

It is becoming clear that reduced chromosome cohesion is an important factor in the rise of maternal age-related aneuploidy. This reduction in cohesion has been observed both in human and mouse oocytes, and it can be measured directly by an increase with respect to maternal age in interkinetochore (iKT) distance between a sister chromatid pair. We have observed variations in iKT distance even in oocytes from young mice and wondered if such differences may predispose those oocytes displaying the greatest iKT distances to be becoming aneuploid. Therefore, we used two methods, one pharmacological (Aurora kinase inhibitor) and one genetic (Fzr1 knockout), to raise aneuploidy rates in oocytes from young mice (age, 1-3 mo) and to examine if those oocytes that were aneuploid had greater iKT distances. We observed that for both Aurora kinase inhibition and Fzr1 knockout, iKT distances were significantly greater in those oocytes that became aneuploid compared to those that remained euploid. Based on these results, we propose that individual oocytes undergo loss in chromosomal cohesion at different rates and that the greater this loss, the greater the risk for becoming aneuploid.

Learning from your mistakes: is aneuploidy so bad, after all?

Learning from your mistakes: is aneuploidy so bad, after all?