Human aneuploidy: mechanisms and new insights into an age-old problem

Nagaoka, So I.; Hassold, Terry; Hunt, Patricia A.

doi:10.1038/nrg3245

Cited by 877 publications

(856 citation statements)

References 126 publications

(133 reference statements)

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“…Aneuploidy, defined as a number of chromosomes different from an integer multiple of the haploid complement, is another phenomenon that correlates with an organism's age: The prevalence of aneuploidy increases in both somatic and germline tissues as organisms age (Lushnikova et al ., 2011; Nagaoka et al ., 2012; Baker et al ., 2013). While it is often proposed that the correlation between age and aneuploidy is due to increased rates of chromosomal missegregation in older cells, it is possible that the relationship is more complex and that aneuploidy itself contributes to aging phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Aneuploidy shortens replicative lifespan in Saccharomyces cerevisiae

et al. 2016

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SummaryAneuploidy and aging are correlated; however, a causal link between these two phenomena has remained elusive. Here, we show that yeast disomic for a single native yeast chromosome generally have a decreased replicative lifespan. In addition, the extent of this lifespan deficit correlates with the size of the extra chromosome. We identified a mutation in BUL1 that rescues both the lifespan deficit and a protein trafficking defect in yeast disomic for chromosome 5. Bul1 is an E4 ubiquitin ligase adaptor involved in a protein quality control pathway that targets membrane proteins for endocytosis and destruction in the lysosomal vacuole, thereby maintaining protein homeostasis. Concurrent suppression of the aging and trafficking phenotypes suggests that disrupted membrane protein homeostasis in aneuploid yeast may contribute to their accelerated aging. The data reported here demonstrate that aneuploidy can impair protein homeostasis, shorten lifespan, and may contribute to age‐associated phenotypes.

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Section: Introductionmentioning

confidence: 99%

Aneuploidy shortens replicative lifespan in Saccharomyces cerevisiae

et al. 2016

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“…Why the human conceptus exhibits such a striking disposition towards genetic instability has puzzled physicians and scientists alike since it was first recognized over 60 years ago [15,16]. But with advances in ART technology, and the adoption of molecular genetics for high resolution characterization of chromosomal disorders, the purview of this problem has shifted from one of documentation to the question of "why"?…”

Section: Chromosomal Disorders and Dna Repair Mechanisms In Human Eggsmentioning

confidence: 99%

“…But with advances in ART technology, and the adoption of molecular genetics for high resolution characterization of chromosomal disorders, the purview of this problem has shifted from one of documentation to the question of "why"? Since the production of aneuploid gametes or embryos as a result of numerical or structural alterations in chromosomes is generally viewed as a source of spontaneous abortion or potential birth defects, the negative connotation of failed reproduction is an apt and widely appreciated example of poor outcomes, just as it has been in the field of cancer biology [16]. But in reproductive medicine, as in other disciplines, the definition of genetic instability has been broadened to account for the discovery of other forms of genomic modifications that are equally important, if not more so, in the generation of congenital diseases or disorders that emerge at later stages of life.…”

Section: Chromosomal Disorders and Dna Repair Mechanisms In Human Eggsmentioning

confidence: 99%

“…By executing checkpoint control at specific stages of the cell cycle, normal tissues avoid accumulating genetic errors that predispose cells or tissues to diseases such as cancer [17]. Robust checkpoints operate during mammalian spermatogenesis to eliminate most chromosomally imbalanced sperm [16]. Surprisingly, human oocytes and embryos, especially those derived from older individuals, fail to implement discriminating cell cycle checkpoints [18] and as a result allow for the propagation of aneuploid cells with both potential beneficial and deleterious effects to the somatic organism [19].…”

Section: Chromosomal Disorders and Dna Repair Mechanisms In Human Eggsmentioning

confidence: 99%

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Birth defects and congenital health risks in children conceived through assisted reproduction technology (ART): a meeting report

Albertini

Evers²,

Geraedts³

et al. 2014

J Assist Reprod Genet

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Purpose Assisted Reproduction Treatment (ART) is here to stay. This review addresses the parental background of birth defects, before, during and after conception and focuses both on the underlying subfertility and on the question whether ART as a treatment is an additional contributing factor. Methods Searches were performed in Medline and other databases. Summaries were discussed in a Delphi panel set-up by the European Society of Human Reproduction and Embryology (ESHRE). Results Several birth defects and adult diseases arise during the earliest stages of ovarian development and oocyte differentiation: this is the case of cleft palate disorders in offspring from female rat exposed to Dioxin during fetal life or the polycystic ovary diseases in female offspring (primates) exposed to elevated androgen concentration during fetal life. Human oocytes and embryos often fail to stop the propagation of aneuploid cells but maintain their ability to repair DNA damages including those introduced by the fertilizing sperm. There is a 29 % increased risk of birth defects in the newborns spontaneously conceived by subfertile couples and the risk is further increased (34 %) when conception is achieved by treating infertlity with ART (Danish IVF Registry). Periconceptional conditions are critical for ART babies: their birth weight is in general smaller (Norvegian Registry) but a more prolonged culture time doubled the number of large babies (Finnish Registry). Conclusion The long-term developmental effects of ART on child and subsequent health as an adult remains a subject worthy of futher monitoring and investigation. Capsule Remaining mindful of the growing body of evidence showing that during gamete production, genetic and epigenetic changes influence offspring health, serves to reinforce the need to continue to monitor ART children.

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“…Chromosome aneuploidy is the major cause of infertility, fetal loss, or birth defects and increases exponentially with maternal age in the decade preceding the menopause [1]. More recently, investigations of gametes and preimplantation embryos conceived using assisted reproductive technology (ART) have identified aneuploidy as the leading impediment to successful pregnancies in this setting [2].…”

mentioning

confidence: 99%

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

Jiao

Woodruff

2014

J Assist Reprod Genet

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Purpose 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 . Methods 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. Results 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). Conclusions 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.

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Human aneuploidy: mechanisms and new insights into an age-old problem

Cited by 877 publications

References 126 publications

Aneuploidy shortens replicative lifespan in Saccharomyces cerevisiae

Aneuploidy shortens replicative lifespan in Saccharomyces cerevisiae

Birth defects and congenital health risks in children conceived through assisted reproduction technology (ART): a meeting report

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

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