Meiosis errors in over 20,000 oocytes studied in the practice of preimplantation aneuploidy testing.
ABSTRACT This study presents the world’s largest series of over 20,000 oocytes tested for aneuploidies, involving chromosomes 13,16, 18, 21 and 22, providing the data on the rates and types of aneuploidies and their origin. Almost every second oocyte (46.8%) is abnormal, with predominance of extra chromatid errors predicting predominance of trisomies (53%) over monosomies (26%) in the resulting embryos (2:1), which is opposite to monosomy predominance observed in embryo testing. Of the detected anomalies in oocytes, 40% are complex, so testing for a few most prevalent chromosome errors may allow detection of the majority of abnormal embryos. Chromosome 21 and 22 errors are more prevalent, while two different patterns of error origin were observed for different chromosomes: chromosome 16 and 22 errors originate predominantly from meiosis II, compared with chromosome 13, 18 and 21 errors originating from meiosis I. This provides the first evidence for the differences in the aneuploid embryo survival depending on the meiotic origin. Considering the problem of mosaicism, which is the major limitation of the cleavage-stage testing, the direct oocyte aneuploidy testing by polar body analysis may be of obvious practical value in improving accuracy and reliability of avoiding aneuploid embryos for transfer.
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ABSTRACT: As women get older their oocytes become susceptible to chromosome mis-segregation. This generates aneuploid embryos, leading to increased infertility and birth defects 1 . Current models suggest that maternal age related aneuploidy is caused by a lowering of the cohesive forces holding chromosomes together, which results in prematurely separated bivalents, termed univalents, that segregate equationally in meiosis I. This idea is supported by several approaches that increase univalent number allowing direct observation of their fate 2, 3 . However here, using high temporal resolution 4D-CLSM, a different etiology of age-related aneuploidy was found that we define as Premature Separation of Dyads (PSD). Bivalent movement was tracked in maturing oocytes microinjected at the Germinal Vesicle (GV) stage with histone 2B and Cenp-C constructs to label chromosomes and kinetochores respectively. This imaging approach was validated on oocytes with a known segregation defect: non-disjunction in young mice harbouring a deletion of the cell cycle regulator FZR1. These oocytes became aneuploid as a result of persistently non-aligned bivalents which co-segregated, so confirming previous in-vitro knockdown strategies 4 . In contrast, for aged >12 –month old wild-type mice, where FZR1 levels were not appreciably lower, the most common segregation defect led to single chromatids in metaphase II eggs, a finding consistentThe Society for Reproductive Biology, Gold Coast, Australia; 08/2012
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ABSTRACT: OBJECTIVE: To investigate the meiotic segregation patterns of cleavage-stage embryos from robertsonian translocation carriers and aneuploidy of chromosome 18 according to meiotic segregation patterns. DESIGN: Retrospective study. SETTING: Infertility center and laboratory of reproductive biology and infertility. PATIENT(S): Sixty-two couples with robertsonian translocation carriers. INTERVENTION(S): One blastomere was biopsied from embryos and diagnosed with the use of fluorescence in situ hybridization (FISH). Translocation chromosomes were analyzed with the use of locus-specific and subtelomeric FISH probes. Aneuploidy of chromosome 18 was assessed simultaneously with translocation chromosomes. MAIN OUTCOME MEASURE(S): Preimplantation genetic diagnosis (PGD) outcomes, meiotic segregation patterns of robertsonian translocation, and aneuploidy of chromosome 18 depending on meiotic segregation patterns. RESULT(S): Two hundred seventy embryos of 332 transferrable embryos were transferred in 113 cycles, and 27 healthy babies were born. The alternate segregation was significantly higher in male carriers than in female carriers (43.9% vs. 29.9%, respectively), and adjacent segregation was higher in female carriers than in male carriers (44.7% vs. 38.7%, respectively). Aneuploidy of chromosome 18 was significantly increased in 3:0-segregated or chaotic embryos. Forty-seven alternate embryos were excluded from embryo replacement owing to aneuploidy of chromosome 18. CONCLUSION(S): In carriers of robertsonian translocation, meiotic segregation showed differences between men and women. Frequent meiotic errors caused by premature predivision or nondisjunction and less stringent checkpoint in women might cause such differences between sexes. Aneuploidy of chromosome 18 might be influenced by meiotic segregation of translocation chromosomes. Factors that cause malsegregation, such as 3:0 or chaotic segregation, seem to play a role in aneuploidy of chromosome 18.Fertility and sterility 01/2013; · 3.97 Impact Factor
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ABSTRACT: Currently, maternal aging in women, based on mouse models, is thought to raise oocyte aneuploidy rates, because chromosome cohesion deteriorates during prophase arrest, and Sgo2, a protector of centromeric cohesion, is lost. Here we show that the most common mouse strain, C57Bl6/J, is resistant to maternal aging, showing little increase in aneuploidy or Sgo2 loss. Instead it demonstrates significant kinetochore-associated loss in the spindle assembly checkpoint protein Mad2 and phosphorylated Aurora C, which is involved in microtubule-kinetochore error correction. Their loss affects the fidelity of bivalent segregation but only when spindle organization is impaired during oocyte maturation. These findings have an impact clinically regarding the handling of human oocytes ex vivo during assisted reproductive techniques and suggest there is a genetic basis to aneuploidy susceptibility.Cell cycle (Georgetown, Tex.) 04/2014; 13(12). · 5.24 Impact Factor