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Aneuploidy: a destroyer of human reproduction health

  • Hefei National Laboratory for Physical Sciences at Microscale, and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China

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  • Corresponding author: SHI Qing-hua, E-mail: qshi@ustc.edu.cn
  • Received Date: 28 June 2008
  • Rev Recd Date: 01 August 2008
  • Publish Date: 31 August 2008
    Abstract

  • Abstract

    Aneuploidy, a numerically chromosomal abnormality, is a major cause of infertility, spontaneous abortion or birth with defects. It occurs at the rate of approximately 5%~7%, 22%~90% and more than 50% in spermatozoa, eggs and early spontaneously aborted fetuses，respectively. The vast majority of frequently observed aneuploidy in humans results from eggs (mothers), and nondisjunction of homologous chromosomes in maternal meiosis I is accused of aneuploid eggs for most chromosomes, except chromosome 13 and 18. Maternal age is the only factor identified epidemically so far for the generation of aneuploid germ cells. Alterations in recombination frequency and location, establishment and maintenance of cohesion between sister chromatids are thought to be responsible for homologous chromosome nondisjunction during meiosis I. Sister chromatids cohesion is established during the last DNA replication before meiosis and homologous chromosomes recombination occurs during meiotic prophase I, both of which happen in fetal ovaries. However, most homologous chromosome nondisjunction takes place in women over the age of 35. This implies that mechanisms incorporating chromosome segregation with recombination and cohesion exist during meiosis, which could be abraded with women aging. Future studies should be focused on what the mechanisms are, and how they work to prevent chromosome missegregation during meiosis.

    Abstract

    Aneuploidy, a numerically chromosomal abnormality, is a major cause of infertility, spontaneous abortion or birth with defects. It occurs at the rate of approximately 5%~7%, 22%~90% and more than 50% in spermatozoa, eggs and early spontaneously aborted fetuses，respectively. The vast majority of frequently observed aneuploidy in humans results from eggs (mothers), and nondisjunction of homologous chromosomes in maternal meiosis I is accused of aneuploid eggs for most chromosomes, except chromosome 13 and 18. Maternal age is the only factor identified epidemically so far for the generation of aneuploid germ cells. Alterations in recombination frequency and location, establishment and maintenance of cohesion between sister chromatids are thought to be responsible for homologous chromosome nondisjunction during meiosis I. Sister chromatids cohesion is established during the last DNA replication before meiosis and homologous chromosomes recombination occurs during meiotic prophase I, both of which happen in fetal ovaries. However, most homologous chromosome nondisjunction takes place in women over the age of 35. This implies that mechanisms incorporating chromosome segregation with recombination and cohesion exist during meiosis, which could be abraded with women aging. Future studies should be focused on what the mechanisms are, and how they work to prevent chromosome missegregation during meiosis.
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    • References(32)
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    [2]
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    Templado C, Bosch M, Benet J. Frequency and distribution of chromosome abnormalities in human spermatozoa[J]. Cytogenet Genome Res, 2005, 111(3-4):199-205.
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    Shi Q, Ko E, Barclay L, et al. Cigarette smoking and aneuploidy in human sperm[J]. Mol Reprod Dev, 2001a, 59(4):417-421.
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    Gutiérrez-Mateo C, Benet J, Starke H, et al. Karyotyping of human oocytes by cenM-FISH, a new 24-colour centromere-specific technique[J]. Hum Reprod, 2005, 20(12):3 395-3 401.
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    Simpson J L. Causes of fetal wastage[J]. Clin Obstet Gynecol, 2007, 50(1):10-30.
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    Turner J M, Mahadevaiah S K, Ellis P J, et al. Pachytene asynapsis drives meiotic sex chromosome inactivation and leads to substantial postmeiotic repression in spermatids[J]. Dev Cell, 2006, 10(4):521-529.
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    [21]
    史庆华，张坚宣，潘淑娟,等.用短串连重复序列多态性诊断21三体患者中超数21号染色体的双亲起源[J].中华医学遗传学杂志,1998a, 15(4): 206-209.
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    史庆华, 张坚宣, 潘淑娟,等.用GT重复多态性诊断21三体患者中超数21号染色体减数分裂起源的研究[J].遗传学报,1998b, 25(6): 478-484.
    [23]
    Lamb N E, Sherman S L, Hassold T J. Effect of meiotic recombination on the production of aneuploid gametes in humans[J]. Cytogenet Genome Res, 2005, 111(3-4):250-255.
    [24]
    Bugge M, Collins A, Hertz J M, et al.Non-disjunction of chromosome 13[J]. Hum Mol Genet, 2007, 16(16):2 004-2 010.
    [25]
    Steuerwald N, Cohen J, Herrera R J, et al. Association between spindle assembly checkpoint expression and maternal age in human oocytes[J]. Mol Hum Reprod, 2001, 7(1):49-55.
    [26]
    Homer H A. Mad2 and spindle assembly checkpoint function during meiosis I in mammalian oocytes[J]. Histol Histopathol, 2006, 21(8):873-886.
    [27]
    Shi Q, Martin R, Ko E, et al. Single sperm typing demonstrates that reduced recombination is associated with the production of aneuploid 24,XY sperm[J]. Am J Med Genet, 2001b, 99(1): 34-38.
    [28]
    Lenzi M L, Smith J, Snowden T, et al. Extreme heterogeneity in the molecular events leading to the establishment of chiasmata during meiosis i in human oocytes[J]. Am J Hum Genet, 2005, 76(1):112-127.
    [29]
    Sun F, Trpkov K, Rademaker A, et al. Variation in meiotic recombination frequencies among human males[J]. Hum Genet, 2005, 116(3):172-178.
    [30]
    Shi Q, Spriggs E, Field L L, et al. Absence of age effect on meiotic recombination between human X and Y chromosomes[J]. Am J Hum Genet, 2002, 71(2):254-261.
    [31]
    Kong A, Barnard J, Gudbjartsson D F, et al. Recombination rate and reproductive success in humans[J]. Nat Genet, 2004, 36(11):1 203-1 206.
    [32]
    Hodges C A, Revenkova E, Jessberger R, et al. SMC1beta-deficient female mice provide evidence that cohesins are a missing link in age-related nondisjunction[J]. Nat Genet, 2005, 37(12):1 351-1 355.
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    [1]
    Heffner L J. Advanced Maternal Age: How Old Is Too Old?[J]. N Engl J Med, 2004, 351(19):1 927-1 929.
    [2]
    Jacobs P A. The chromosome complement of human gametes[J]. Oxf Rev Reprod Biol, 1992, 14:47-72.
    [3]
    Shi Q, Martin R H. Aneuploidy in human sperm: a review of the frequency and distribution of aneuploidy, effects of donor age and lifestyle factors[J]. Cytogenet Cell Genet, 2000a, 90(3-4):219-226.
    [4]
    Templado C, Bosch M, Benet J. Frequency and distribution of chromosome abnormalities in human spermatozoa[J]. Cytogenet Genome Res, 2005, 111(3-4):199-205.
    [5]
    Shi Q, Martin R H. Spontaneous frequencies of aneuploid and diploid sperm in 10 normal Chinese men: assessed by multicolor fluorescence in situ hybridization[J]. Cytogenet Cell Genet, 2000b,90(1-2):79-83.
    [6]
    Shi Q, Ko E, Barclay L, et al. Cigarette smoking and aneuploidy in human sperm[J]. Mol Reprod Dev, 2001a, 59(4):417-421.
    [7]
    Pacchierotti F, Adler I D, Eichenlaub-Ritter U, et al. Gender effects on the incidence of aneuploidy in mammalian germ cells[J]. Environ Res, 2007,104(1):46-69.
    [8]
    Kuliev A, Cieslak J, Ilkevitch Y, et al. Chromosomal abnormalities in a series of 6,733 human oocytes in preimplantation diagnosis for age-related aneuploidies[J]. Reprod Biomed Online, 2003, 6(1):54-59.
    [9]
    Verlinsky Y, Cieslak J, Ivakhnenko V, et al. Prepregnancy genetic testing for age-related aneuploidies by polar body analysis[J]. Genet Test, 1997-1998, 1(4):231-235.
    [10]
    Verlinsky Y, Cieslak J, Ivakhnenko V, et al. Prevention of age-related aneuploidies by polar body testing of oocytes[J]. J Assist Reprod Genet, 1999,16(4):165-169.
    [11]
    Kuliev A, Verlinsky Y. Meiotic and mitotic nondisjunction: lessons from preimplantation genetic diagnosis[J]. Hum Reprod Update, 2004, 10(5):401-407.
    [12]
    Wells D, Escudero T, Levy B, et al. First clinical application of comparative genomic hybridization and polar body testing for preimplantation genetic diagnosis of aneuploidy[J]. Fertil Steril, 2002, 78(3):543-549.
    [13]
    Gutiérrez-Mateo C, Benet J, Starke H, et al. Karyotyping of human oocytes by cenM-FISH, a new 24-colour centromere-specific technique[J]. Hum Reprod, 2005, 20(12):3 395-3 401.
    [14]
    Fragouli E, Wells D, Thornhill A, et al. Comparative genomic hybridization analysis of human oocytes and polar bodies[J]. Hum Reprod, 2006, 21(9):2 319-2 328.
    [15]
    Simpson J L. Causes of fetal wastage[J]. Clin Obstet Gynecol, 2007, 50(1):10-30.
    [16]
    Strom C M, Ginsberg N, Applebaum M, et al. Analyses of 95 first-trimester spontaneous abortions by chorionic villus sampling and karyotype[J]. J Assist Reprod Genet, 1992, 9:458-461.
    [17]
    Shimokawa O, Harada N, Miyake N, et al. Array comparative genomic hybridization analysis in first-trimester spontaneous abortions with “normal” karyotypes[J]. Am J Med Genet A, 2006; 140:1 931-1 935.
    [18]
    Hassold T, Abruzzo M, Adkins K, et al. Human aneuploidy: incidence, origin, and etiology[J]. Environ Mol Mutagen, 1996, 28(3):167-175.
    [19]
    Turner J M, Mahadevaiah S K, Ellis P J, et al. Pachytene asynapsis drives meiotic sex chromosome inactivation and leads to substantial postmeiotic repression in spermatids[J]. Dev Cell, 2006, 10(4):521-529.
    [20]
    Hassold T, Hall H, Hunt P. The origin of human aneuploidy: where we have been, where we are going[J]. Hum Mol Genet, 2007,16(Spec 2):R203-208.
    [21]
    史庆华，张坚宣，潘淑娟,等.用短串连重复序列多态性诊断21三体患者中超数21号染色体的双亲起源[J].中华医学遗传学杂志,1998a, 15(4): 206-209.
    [22]
    史庆华, 张坚宣, 潘淑娟,等.用GT重复多态性诊断21三体患者中超数21号染色体减数分裂起源的研究[J].遗传学报,1998b, 25(6): 478-484.
    [23]
    Lamb N E, Sherman S L, Hassold T J. Effect of meiotic recombination on the production of aneuploid gametes in humans[J]. Cytogenet Genome Res, 2005, 111(3-4):250-255.
    [24]
    Bugge M, Collins A, Hertz J M, et al.Non-disjunction of chromosome 13[J]. Hum Mol Genet, 2007, 16(16):2 004-2 010.
    [25]
    Steuerwald N, Cohen J, Herrera R J, et al. Association between spindle assembly checkpoint expression and maternal age in human oocytes[J]. Mol Hum Reprod, 2001, 7(1):49-55.
    [26]
    Homer H A. Mad2 and spindle assembly checkpoint function during meiosis I in mammalian oocytes[J]. Histol Histopathol, 2006, 21(8):873-886.
    [27]
    Shi Q, Martin R, Ko E, et al. Single sperm typing demonstrates that reduced recombination is associated with the production of aneuploid 24,XY sperm[J]. Am J Med Genet, 2001b, 99(1): 34-38.
    [28]
    Lenzi M L, Smith J, Snowden T, et al. Extreme heterogeneity in the molecular events leading to the establishment of chiasmata during meiosis i in human oocytes[J]. Am J Hum Genet, 2005, 76(1):112-127.
    [29]
    Sun F, Trpkov K, Rademaker A, et al. Variation in meiotic recombination frequencies among human males[J]. Hum Genet, 2005, 116(3):172-178.
    [30]
    Shi Q, Spriggs E, Field L L, et al. Absence of age effect on meiotic recombination between human X and Y chromosomes[J]. Am J Hum Genet, 2002, 71(2):254-261.
    [31]
    Kong A, Barnard J, Gudbjartsson D F, et al. Recombination rate and reproductive success in humans[J]. Nat Genet, 2004, 36(11):1 203-1 206.
    [32]
    Hodges C A, Revenkova E, Jessberger R, et al. SMC1beta-deficient female mice provide evidence that cohesins are a missing link in age-related nondisjunction[J]. Nat Genet, 2005, 37(12):1 351-1 355.
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