Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Susceptible chiasmate configurations of chromosome 21 predispose to non–disjunction in both maternal meiosis I and meiosis II

Nature Genetics volume 14, pages 400–405 (1996)Cite this article

Abstract

The cause of non–disjunction of chromosome 21 remains largely unknown. Advanced maternal age is associated with both maternal meiosis I (MI) and meiosis II (MII) non–disjunction events. While reduced genetic recombination has been demonstrated in maternal MI errors, the basis for MII errors remains uncertain. We studied 133 trisomy 21 cases with maternal MII errors to test the hypothesis that segregation at MII may also be influenced by genetic recombination. Our data support a highly significant association: MII non–disjunction involves increased recombination that is largely restricted to proximal 21 q. Thus, while absence of a proximal recombination appears to predispose to non–disjunction in MI, the presence of a proximal exchange predisposes to non–disjunction in MII. These findings profoundly affect our understanding of trisomy 21 as they suggest that virtually all maternal non–disjunction results from events occurring in meioisis I.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Sherman, S.L. et al. Trisomy 21: Association between reduced recombination and nondisjunction. Am. J. Hum. Genet. 49, 608–620 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Sherman, S.L. et al. Non-disjunction of chromosome 21 in maternal meiosis I: evidence for a maternal age-dependent mechanism involving reduced recombination. Hum. Mol. Genet. 3, 1529–1535 (1994).

    Article  CAS  Google Scholar 

  3. Yoon, P.W. et al. Advanced maternal age and the risk of Down syndrome characterized by the meiotic stage of the chromosomal error: a population-based study. Am. J. Hum. Genet. 58, 628–633 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Warren, A.C. et al. Evidence for reduced recombination on the nondisjoined chromsome 21 in Down syndrome. Science 237, 652–654 (1987).

    Article  CAS  Google Scholar 

  5. Antonarakis, S.E. et al. The meiotic stage of nondisjunction in trisomy 21: determination by using DNA polymorphisms. Am. J. Hum. Genet. 50, 544–550 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Antonarakis, S.E., Avramopoulos, D., Blouin, J., Talbot, C.C. & Schinzel, A.A. Mitotic errors in somatic cells cause trisomy 21 in about 4.5% of cases and are not associated with advanced maternal age. Nature Genet. 3, 146–150 (1993).

    Article  CAS  Google Scholar 

  7. Antonarakis, S.E. & Down Syndrome Colabrative Group. Parental origin of the extra chromosome in trisomy 21 as indicated by analysis of DNA polymorphisms. New Engl. J. Med. 324, 872–876 (1991).

    Article  CAS  Google Scholar 

  8. Mikkelsen, M. et al. Epidemiology study of Down's syndrome in Denmark, including family studies of chromosomes and DNA markers. Dev. Brain Dysfunct. 8, 4–12 (1995).

    Google Scholar 

  9. Farnet, C., Padmore, R., Cao, L., Raymond, W., Alani, E., Klecher, N., Mechanisms and Consequences of DNA Damage Processing (eds Freidberg, E. & Hanawatt, P. ) (Alan R. Liss, New York, 1989).

    Google Scholar 

  10. Malone, R.E. & Esposito, R.E. Recombinationless meiosis in Saccharomyces cerevisiae Mol. Cell. Biol. 1, 891–901 (1981).

    Article  CAS  Google Scholar 

  11. Roeder, G., Rockmill, B., Engebrecht, J., Thompson, E. & Menees, T. Molecular and Cytogenetic Studies of Non-Disjunction (eds Hassold, T. J. & Epstein, C. J. ) 303–326 (Alan R. Liss, New York, (1989).

    Google Scholar 

  12. Sym, M., Engebrecht, J. & Roeder, G. ZIP1 is a synaptonemal complex protein required for meiotic chromosomal synapsis. Cell 72, 365–378 (1993).

    Article  CAS  Google Scholar 

  13. Hawley, R.S., McKim, K.S. & Arbel, T. Meiotic segregation in DrosophilaMelanogaster females: molecules, mechanisms and myths. Annu. Rev. Genet. 27, 281–317 (1993).

    Article  CAS  Google Scholar 

  14. Hawley, R.S., Frazier, J. & Rasooly, R. Separation anxiety: the biology of non-disjunction in flies and people. Hum. Mol. Genet. 3, 1521–1528 (1994).

    Article  CAS  Google Scholar 

  15. Hassold, T.J., Sherman, S.L., Pettay, D., Page, D.C. & Jacobs, P.A. XY chromosome nondisjunction in man is associated with diminished recombination in the pseudoautosomal region. Am. J. Hum. Genet. 49, 253–260 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. MacDonald, M. et al. The origin of 47,XXY and 47,XXX aneuploidy: heterogeneous mechanisms and role of aberrant recombination. Hum. Mol. Genet. 3, 1365–1371 (1994).

    Article  CAS  Google Scholar 

  17. Robinson, W.P. et al. Nondisjunction of choromsome 15: origin and recombination. Am. J. Hum. Genet. 53, 740–751 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Mascari, M.J. et al. Perturbed recombination of chromosome 15 in PraderWilli patients with maternal disomy. Am. J. Hum. Genet. 53, A260 (1993).

    Google Scholar 

  19. Hassold, T., Merrill, M., Adkins, K., Freeman, S. & Sherman, S. Recombination and maternal age-dependent non-disjunction: molecular studies of trisomy 16. Am. J. Hum. Genet. 57, 867–874 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Fisher, J.M., Harvey, J.F., Morton, N.E. & Jacobs, P.A. Trisomy 18: studies of the parent and cell division of origin and the effect of aberrant recombination on nondisjunction. Am. J. Hum. Genet. 56, 669–675 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Lorber, B.J., Grantham, M., Peters, J., Willard, H.F. & Hassold, T.J. Nondisjunction of chromosome 21: comparisons of cytogenetic and molecular studies of the meiotic stage and parent of origin. Am. J. Hum. Genet. 51, 1265–1276 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Petersen, M.B. et al. Comparative study of microsatellite and cytogenetic markers for detecting the origin of the nondisjoined chromosome 21 in Down syndrome. Am. J. Hum. Genet. 51, 516–525 (1992).

    PubMed Central  Google Scholar 

  23. Bridges, C.B. Nondisjunction as proof of the chromosome theory of heredity. Genetics 1, 1–52 (1916).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Hassold, T., Pettay, E., May, K. & Robinson, A. Analysis of non-disjunction in sex chromosome tetrasomy and pentasomy. Hum. Genet. 85, 648–650 (1990).

    Article  CAS  Google Scholar 

  25. Miyazaki, W.Y. & Orr-Weaver, T.L. Sister-chromatid cohesion in mitosis and meiosis. Annu. Rev. Genet. 28, 167–187 (1994).

    Article  CAS  Google Scholar 

  26. Abruzzo, M. & Hassold, T.J. Etiology of nondisjunction in humans. Envir. Mol. Mut. 25, 38–47 (1995).

    Article  CAS  Google Scholar 

  27. Henderson, S.A. & Edwards, R.G. Chiasma frequency and maternal age in mammals. Nature 217, 22–28 (1968).

    Article  Google Scholar 

  28. Hassold, T.E., Kumlin, E., Takaesu, N. & Leppert, M. Determination of the parental origin of sex-chromosome monosomy using restriction fragment length polymorphisms. Am. J. Hum. Genet. 37, 965–972 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Van Hul, W. et al. A contiguous physical map of the pericentromeric region of chromosome 21q between D21Z1 and D21S13E . Genomics 15, 626–630 (1993).

    Article  CAS  Google Scholar 

  30. Jabs, E.W. et al. Alphoid DNA polymorphisms for chromosome 21 can be distinguished from those of chromosome 13 using probes homologous to both. Genomics 9, 141–146 (1991).

    Article  CAS  Google Scholar 

  31. Chakravarti, A. & Slaugenhaupt, S.A. Methods for studying recombination on chromosomes that undergo nondisjunction. Genomics 1, 35–42 (1987).

    Article  CAS  Google Scholar 

  32. Morton, N.E. et al. A centromere map of the X chromosome from trisomies of maternal origin. Ann. Hum. Genet. 54, 39–47 (1990).

    Article  CAS  Google Scholar 

  33. Morton, N.E. & Maclean, C.J. Multilocus recombination frequencies. Genet. Res. 44, 99–108 (1984).

    Article  CAS  Google Scholar 

  34. Dausset, J. et al. Centre d'Etude du Polymorphisme Humain (CEPH): Collaborative genetic mapping of the human genome. Genomics 6, 575–577 (1990).

    Article  CAS  Google Scholar 

  35. Lander, E.S. & Green, P. Construction of multilocus genetic linkage maps in humans. Proc. Natl. Acad. Sci. USA 84, 2363–2367 (1987).

    Article  CAS  Google Scholar 

  36. Morton, N.E. & Andrews, V. MAP, an expert system for multiple pairwise linkage analysis. Ann. Hum. Genet. 53, 263–269 (1989).

    Article  CAS  Google Scholar 

  37. Rao, D.C., Morton, N.E., Lindsten, J., Hulten, M. & Yee, S. A mapping function in man. Hum. Hered. 27, 99–104 (1977).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Genetics and Molecular Medicine, Emory University School of Medicine, 1462 Clifton Rd.,, Atlanta, Georgia, 30322, USA

    Neil E. Lamb, Sallie B. Freeman, Amanda Savage-Austin, Dorothy Pettay, Lisa Taft, Jane Hersey, Yuanchao Gu & Stephanie L. Sherman

  2. Department of Genetics and The Center for Human Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

    Joe Shen, Denise Saker, Terry J. Hassold & Stephanie L. Sherman

  3. Division of Medical Genetics, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA

    Kristen M. May

  4. Department of Genetics, Institute of Child Health, Athens, Greece

    Dimitris Avramopoulos & Michael B. Petersen

  5. Danish Center for Human Genome Research, J.F. Kennedy Institute, Glostrup, Denmark

    Michael B. Petersen, Anni Hallberg & Margareta Mikkelsen

Authors
  1. Neil E. Lamb
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sallie B. Freeman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amanda Savage-Austin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dorothy Pettay
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lisa Taft
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jane Hersey
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuanchao Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Joe Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Denise Saker
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kristen M. May
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Dimitris Avramopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Michael B. Petersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Anni Hallberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Margareta Mikkelsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Terry J. Hassold
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Stephanie L. Sherman
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lamb, N., Freeman, S., Savage-Austin, A. et al. Susceptible chiasmate configurations of chromosome 21 predispose to non–disjunction in both maternal meiosis I and meiosis II. Nat Genet 14, 400–405 (1996). https://doi.org/10.1038/ng1296-400

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1296-400

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing