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  • Print publication year: 2013
  • Online publication date: October 2013

29 - Alterations in the gene expression of aneuploid oocytes and associated cumulus cells

from Section 5 - Pathology


The importance of aneuploidy in human reproductive failure

Human reproduction is a remarkably inefficient process. On average, fertile couples attempting to conceive only succeed in achieving a clinical pregnancy one month out of every five. For infertile patients undergoing in vitro fertilization (IVF) pregnancy rates are similarly low. More than 80% of the embryos transferred to the uterus during IVF treatment fail to implant and two-thirds of cycles do not produce a child [1]. As a result, most IVF patients require two or more rounds of treatment to achieve a pregnancy. There are many potential reasons why an embryo might not establish a pregnancy; however, it is clear that one of the most important is chromosome abnormality. This is particularly true for embryos derived from women of advanced reproductive age. While it is not unusual for half of the blastocyst stage embryos produced by women in their early thirties to be chromosomally abnormal, this figure increases dramatically with age, such that an aneuploidy rate exceeding 75% is typical for blastocysts from women over the age of 40 [2]. The high prevalence of aneuploidy, coupled with its detrimental impact on development, explains the majority of embryo implantation failures and miscarriages. Evidence for the lethality of aneuploidy comes from the detection of chromosome imbalances in the majority of miscarriages [3, 4] and from blinded studies where embryos, later revealed to be chromosomally abnormal, had been transferred to patients [5].

Kovalevsky, G, Patrizio, P.High rates of embryo wastage with the use of assisted reproductive technology: trends between 1995 and 2001 in the United States. Fertil Steril 2005; 84: 325–30.
Fragouli, E, Wells, D.Aneuploidy in the human blastocyst. Cytogenet Genome Res 2011; 133(2–4): 149–59.
Menasha, J, Levy, B, Hirschhorn, K, et al. Incidence and spectrum of chromosome abnormalities in spontaneous abortions: new insights from a 12-year study. Genet Med 2005; 7: 251–63.
Hassold, T, Chen, N, Funkhouser, J, et al A cytogenetic study of 1000 spontaneous abortions. Ann Hum Genet 1980; 44(Pt 2): 151–78.
Scott, RT Jr, Ferry, K, Su, J, et al. Comprehensive chromosome screening is highly predictive of the reproductive potential of human embryos: a prospective, blinded, nonselection study. Fertil Steril 2012; 97: 870–5.
Fragouli, E, Wells, D, Delhanty, JD.Chromosome abnormalities in the human oocyte. Cytogenet Genome Res 2011; 133(2–4): 107–18.
Fragouli, E, Alfarawati, S, Goodall, NN, et al. The cytogenetics of polar bodies: insights into female meiosis and the diagnosis of aneuploidy. Mol Hum Reprod. 2011; 17(5): 286–95.
Handyside, AH, Montag, M, Magli, MC, et al. Multiple meiotic errors caused by predivision of chromatids in women of advanced maternal age undergoing in vitro fertilisation. Eur J Hum Genet 2012; 20: 742–7.
Fishel, S, Gordon, A, Lynch, C, et al. Live birth after polar body array comparative genomic hybridization prediction of embryo ploidy-the future of IVF?Fertil Steril 2010; 93: 1006.e7–10.
Gabriel, AS, Thornhill, AR, Ottolini, CS, et al. Array comparative genomic hybridisation on first polar bodies suggests that non-disjunction is not the predominant mechanism leading to aneuploidy in humans. J Med Genet 2011; 48: 433–7.
Fragouli, E, Katz-Jaffe, M, Alfarawati, S, et al. Comprehensive chromosome screening of polar bodies and blastocysts from couples experiencing repeated implantation failure. Fertil Steril 2010; 94: 875–87.
Geraedts, J, Montag, M, Magli, MC, et al. Polar body array CGH for prediction of the status of the corresponding oocyte. Part I: clinical results. Hum Reprod 2011; 26: 3173–80.
Jones, GM, Cram, DS, Song, B, et al. Gene expression profiling of human oocytes following in vivo or in vitro maturation. Hum Reprod 2008; 23: 1138–44.
Fragouli, E, Bianchi, V, Patrizio, P, et al. Transcriptomic profiling of human oocytes: association of meiotic aneuploidy and altered oocyte gene expression. Mol Hum Reprod 2010; 16: 570–82.
Grøndahl, ML, Yding, Andersen C, Bogstad, J, et al. Gene expression profiles of single human mature oocytes in relation to age. Hum Reprod 2010; 25: 957–68.
Wood, JR, Dumesic, DA, Abbott, DH, et al. Molecular abnormalities in oocytes from women with polycystic ovary syndrome revealed by microarray analysis. J Clin Endocrinol Metab 2007; 92: 705–13.
Voet, M, Berends, CWH, Perreault, A, et al. NuMA-related LIN-5, ASPM-1, calmodulin and dynein promote meiotic spindle rotation independently of cortical LIN-5/GPR/Ga. Nat Cell Biol 2009; 11: 269–77.
Manning, AL, Ganem, N, Bakhoum, SF, et al. The kinesin-13 proteins Kif2a, Kif2b, and Kif2c/MCAK have distinct roles during mitosis in human cells. Mol Biol Cell 2007; 18: 2970–9.
Bakhoum, SF, Thompson, SL, Manning, AL, et al. Genome stability is ensured by temporal control of kinetochore-microtubule dynamics. Nat Cell Biol 2009; 11: 27–35.
Glessner Bradfield, JP, Wang, K, et al. A genome-wide study reveals copy number variants exclusive to childhood obesity cases. Am J Hum Genet 2010; 87(5): 661–6.
Johnson, F, Kaplitt, MG. Novel mitochondrial substrates of OMI indicate a new regulatory role in neurodegenerative disorders. PLoS One 2009; 18: e7100.
Johnson, MT, Freeman, EA, Gardner, DK, et al. Oxidative metabolism of pyruvate is required for meiotic maturation of murine oocytes in vivo. Biol Reprod 2007; 77: 2–8.
Gohil, VM, Greenberg, ML. Mitochondrial membrane biogenesis: phospholipids and proteins go hand in hand. J Cell Biol 2009; 184: 469–72.
Mathew, R, Kongara, S, Beaudoin, B, et al. Autophagy suppresses tumour progression by limiting chromosomal instability. Genes Dev 2007; 21: 1367–81.
Geng, J, Klionsky, DJ.The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy. EMBO Rep 2008; 9: 859–64.
Steuerwald, N, Cohen, J, Herrera, RJ, et al. Association between spindle assembly checkpoint expression and maternal age in human oocytes. Mol Hum Reprod 2001; 7: 49–55.
Patrizio, P, Fragouli, E, Bianchi, V, et al. Molecular methods for selection of the ideal oocyte. Reprod Biomed Online 2007; 15: 346–53.
Eppig, JJ, Chesnel, F, Hirao, Y, et al. Oocyte control of granulosa cell development: how and why. Hum Reprod 1997; 12: 127–32.
Eppig, JJ,Wigglesworth, K, Pendola, FL. The mammalian oocyte orchestrates the rate of ovarian follicular development. Proc Natl Acad Sci USA 2002; 99: 2890–4.
Assou, S, Anahory, T, Pantesco, V, et al. The human cumulus–oocyte complex gene-expression profile. Hum Reprod 2006; 21: 1705–19.
Feuerstein, P, Cadoret, V, Dalbies-Tran, R, et al. Gene expression in human cumulus cells: one approach to oocyte competence. Hum Reprod 2007; 22: 3069–77.
Sutton-McDowall, ML, Gilchrist, RB, Thompson, JG.The pivotal role of glucose metabolism in determining oocyte developmental competence. Reproduction 2010; 139: 685–95.
Huang, Z, Wells, D.The human oocyte and cumulus cells relationship: new insights from the cumulus cell transcriptome. Mol Hum Reprod 2010; 16: 715–25.
Gilchrist, RB, Lane, M, Thompson, JG.Oocyte-secreted factors: regulators of cumulus cell function and oocyte quality. Hum Reprod Update 2008; 14: 159–77.
Su, YQ, Sugiura, K, Wigglesworth, K, et al. Oocyte regulation of metabolic cooperativity between mouse cumulus cells and oocytes: BMP15 and GDF9 control cholesterol biosynthesis in cumulus cells. Development 2008; 135: 111–21.
Assou, S, Haouzi, D, Mahmoud, K, et al. A non-invasive test for assessing embryo potential by gene expression profiles of human cumulus cells: a proof of concept study. Mol Hum Reprod 2008; 14(12): 711–19.
Assou, S, Haouzi, D, De, Vos J, et al. Human cumulus cells as biomarkers for embryo and pregnancy outcomes. Mol Hum Reprod 2010; 16(8): 531–8.
Gebhardt, KM, Feil, DK, Dunning, KR, et al. Human cumulus cell gene expression as a biomarker of pregnancy outcome after single embryo transfer. Fertil Steril 2011; 96: 47–52.e2.
Ouandaogo, ZG, Haouzi, D, Assou, S, et al. Human cumulus cells molecular signature in relation to oocyte nuclear maturity stage. PLoS One 2011; 6: e27179.
Fragouli, E, Wells, D, Iager, AE, et al. Alteration of gene expression in human cumulus cells as a potential indicator of oocyte aneuploidy. Hum Reprod 2012; 27: 2559–68.
Kuang, Z, Lewis, RS, Curtis, JM, et al. The SPRY domain-containing SOCS box protein SPSB2 targets iNOS for proteasomal degradation. J Cell Biol 2010; 190: 129–41.
Lee, JH, Kang, Y, Khare, V, et al. The p53-inducible gene 3 (PIG3) contributes to early cellular response to DNA damage. Oncogene 2010; 29: 1431–50.
Høst, E, Gabrielsen, A, Lindenberg, S, et al. Apoptosis in human cumulus cells in relation to zona pellucida thickness variation, maturation stage, and cleavage of the corresponding oocyte after intracytoplasmic sperm injection. Fertil Steril 2002; 77: 511–15.