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History of genetic disease

Down syndrome and genetics — a case of linked histories

Nature Reviews Genetics volume 6, pages 137–147 (2005)Cite this article

Abstract

Down syndrome, the most common genetic cause of intellectual disabilities, was first described in 1866, during an era of great change in our understanding of genetics and evolution. Because of its importance, the history of research on Down syndrome parallels the history of human genetics. In many instances, research on Down syndrome has inspired progress in human genetics. In this article, we describe the interplay between advances in the understanding of genetics and the understanding of Down syndrome from its initial description to the present, and on the basis of this historical perspective, speculate briefly about the future of research on Down syndrome.

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Figure 1: Systems biology or the study of “complex webs of biochemical processes”.

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References

  1. Roizen, N. J. & Patterson, D. Down's syndrome. Lancet 361, 1281–1289 (2003).

    Article  PubMed  Google Scholar 

  2. Lejeune, J. Le mongolism: premier exemple d'aberration autosomique humaine. Ann. Genet. 1, 41–49 (1959) (in French).

    Google Scholar 

  3. Friedman, J. M. Racial disparities in median age at death of persons with Down syndrome — United States, 1968–1997. MMWR Morb. Mortal Weekly Rep. 50, 463–465 (2001).

    Google Scholar 

  4. Bittles, A. H. & Glasson, E. J. Clinical, Social, and ethical implications of changing life expectancy in Down syndrome. Dev. Med. Child Neurol. 46, 282–285 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Cohen, W. I. in Down Syndrome: a Promising Future Together (eds Hassold, T. J. & Patterson, D.) 15–36 (Wiley-Liss, New York, 1999).

    Google Scholar 

  6. Tolmie, J. L. in Emery and Rimoin's Principles and Practices of Medical Genetics (eds Rimoin, D. L. et al.) 1129–1183 (Churchill Livingstone, London; New York, 2002).

    Google Scholar 

  7. Darwin, C. The Origin of Species (John Murray, London, 1859).

    Google Scholar 

  8. Darwin, C. The Descent of Man and Selection in Relation to Sex (John Murray, London, 1871).

    Book  Google Scholar 

  9. Mendel, G. Versuche über Pflanzen-Hybriden. Verhand. naturfors. Vereines in Brunn 4, 3–47 (1865) (in German); English translation available online at <http://www.mendelweb.org/Mendel.html>.

    Google Scholar 

  10. Down, J. L. H. Observations on an ethnic classification of idiots. Lond. Hosp. Rep. 3, 259–262 (1866); reprinted in Ment. Retard. 33, 54–56 (1995).

    Google Scholar 

  11. Ward, O. C. John Langdon Down, 1828–1896: a Caring Pioneer (Eponymists in Medicine) (R. Soc. Med. Press, London, 1998).

    Google Scholar 

  12. Shuttleworth, G. E. Mongolian imbecility. BMJ 2, 661–665 (1909).

    Google Scholar 

  13. Fraser, M. & Mitchell, A. Kalmyc idiocy. J. Ment. Sci. 22, 169–179 (1876).

    Article  Google Scholar 

  14. Alzheimer, A., Stelzmann, R. A., Schnitzlein, H. N. & Murtagh, F. R. An English translation of Alzheimer's 1907 paper, “Über eine eigenartige Erkankung der Hirnrinde”. Clin Anat. 8, 429–431 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Jervis, G. A. Early senile dementia in mongoloid idiocy. Am. J. Psychiatry 105, 102–106 (1948).

    Article  CAS  PubMed  Google Scholar 

  16. Allen, G. et al. “Mongolism”. Lancet 1, 775 (1961).

    Article  Google Scholar 

  17. Howard-Jones, N. On the diagnostic term “Down's disease”. Med. Hist. 23, 102–104 (1979).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Flemming, W. Beitrage zur kenntnis der zelle undihrer Lebenserscheinungen, Thiel II. Archiv. Mikroskopische Anatomie 18, 151–259 (1880) (in German); English translation available in J. Cell Biol. 25, 3–69 (1965).

    Article  Google Scholar 

  19. Sutton, W. S. The chromosomes in heredity. Biol. Bull. 4, 231–251 (1903).

    Article  Google Scholar 

  20. Morgan, T. H., Sturtevant, A. H., Muller, H. J. & Bridges, C. B. The Mechanism of Mendelian Heredity (Constable Press, London, 1915).

    Google Scholar 

  21. Painter, T. The Y-chromosome in mammals. Science 53, 503–504 (1921).

    Article  CAS  PubMed  Google Scholar 

  22. Painter, T. Studies in mammalian spermatogenesis. II. The spermatogenesis of man. J. Exp. Zool. 37, 291–336 (1923).

    Article  Google Scholar 

  23. Davenport, C. B. in Sixth International Congress of Genetics Vol. 1. (ed. Jones, D. F.) 135–140 (Brooklyn Botanic Garden, New York, 1932).

    Google Scholar 

  24. Waardenburg, P. J. Das Menschliche Auge und seine Erbanlagen (Martinus Nijhoff, The Hague, 1932) (in German).

    Google Scholar 

  25. Tjio, J. H. & Levan, A. The chromosome number of man. Hereditas 42, 1–6 (1956).

    Article  Google Scholar 

  26. Kodani, M. Three chromosome numbers in whites and Japanese. Science 127, 1339–1340 (1958).

    Article  CAS  PubMed  Google Scholar 

  27. Tjio, J. H. & Puck, T. T. Genetics of somatic mammalian cells. II. Chromosomal constitution of cells in tissue culture. J. Exp. Med. 108, 259–268 (1958).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Jacobs, P. A., Baikie, A. G, Court–Brown, W. M. & Strong, J. A. The somatic chromosomes in mongolism. Lancet 1, 710 (1959).

    Article  CAS  PubMed  Google Scholar 

  29. Polani, P. E. et al. A mongol girl with 46 chromosomes. Lancet 1, 313–324 (1960).

    Google Scholar 

  30. Carter, C. O., Hamerton, J. L., Polani, P. E., Gunalp, E. & Weller, S. D. Chromosome translocation as a cause of familial mongolism. Lancet 2, 678–680 (1960).

    Article  CAS  PubMed  Google Scholar 

  31. Clarke, C. M., Edwards, J. H. & Smallpiece, V. 21-trisomy/normal mosaicism in an intelligent child with some Mongoloid characters. Lancet 18, 1028–1030 (1961).

    Article  Google Scholar 

  32. Caspersson, T., Zech, L., Johansson, C. & Modest, E. J. Identification of human chromosomes by DNA-binding fluorescent agents. Chromosoma 30, 215–227 (1970).

    Article  CAS  PubMed  Google Scholar 

  33. Caspersson, T., Hultén, M., Lindsten, J. & Zech, L. Distinction between extra G-like chromosomes by quinacrine mustard fluorescence analysis. Exp. Cell Res. 63, 240–243 (1970).

    Article  CAS  PubMed  Google Scholar 

  34. Aula, P., Leisti, J. & von Koskull, H. Partial trisomy 21. Clin. Genet. 4, 241–251 (1973).

    Article  CAS  PubMed  Google Scholar 

  35. Niebuhr, E. Down's syndrome: the possibility of a pathogenetic segment on chromosome no. 21. Humangenetik 21, 99–101 (1974).

    CAS  PubMed  Google Scholar 

  36. Korenberg, J. R. et al. Molecular definition of a region of chromosome 21 that causes features of the Down syndrome phenotype. Am. J. Hum. Genet. 47, 236–246 (1990).

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Delabar, J. -M. et al. Molecular mapping of twenty-four features of Down syndrome on chromosome 21. Eur. J. Hum. Genet. 1, 114–124 (1993).

    Article  CAS  PubMed  Google Scholar 

  38. Korenberg, J. R. et al. Down syndrome phenotypes: the consequences of chromosomal imbalance. Proc. Natl Acad. Sci. USA 91, 4997–5001 (1994).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Barlow, G. M. et al. Down syndrome congenital heart disease: a narrowed region and a candidate gene. Genet. Med. 3, 91–101 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Shapiro, B. L. Down syndrome — a disruption of homeostasis. Am. J. Med. Genet. 14, 241–269 (1983).

    Article  CAS  PubMed  Google Scholar 

  41. Pritchard, M. A. & Kola, I. The 'gene dosage effect' hypothesis versus the 'amplified developmental instability' hypothesis in Down syndrome. J. Neural Transm. 57, 293–303 (1999).

    CAS  Google Scholar 

  42. St George-Hyslop, P. H. et al. The genetic defect causing familial Alzheimer's disease maps on chromosome 21. Science 235, 885–890 (1997).

    Article  Google Scholar 

  43. Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704–706 (1991).

    Article  CAS  PubMed  Google Scholar 

  44. Hasle, H. Pattern of malignant disorders in individuals with Down's syndrome. Lancet Oncol. 2, 429–436 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Bacino, C. A. et al. Clinical and molecular studies in full trisomy 22: further delineation of the phenotype and review of the literature. Am. J. Med. Genet. 56, 359–365 (1995).

    Article  CAS  PubMed  Google Scholar 

  46. Tan, Y. H., Tischfield, J. & Ruddle, F. H. The linkage of genes for the human interferon-induced antiviral protein and indophenol oxidase-B traits to chromosome G-21. J. Exp. Med. 137, 317–330 (1973).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Moore, E. M., Jones, C., Kao, F. -T. & Oates, D. C. Synteny between glycinamide ribonucleotide synthetase and superoxide dismutase (soluble). Am. J. Hum. Genet. 29, 389–396 (1977).

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Cox, D. R. & Shimizu, N. Report of the committee on the genetic constitution of chromosome 21. Cytogenet. Cell Genet. 55, 235–244 (1990).

    Article  CAS  PubMed  Google Scholar 

  49. Graw, S. L. et al. Molecular analysis and breakpoint definition of a set of human chromosome 21 somatic cell hybrids. Somat. Cell Mol. Genet. 21, 415–428 (1995).

    Article  CAS  PubMed  Google Scholar 

  50. Gardiner, K. et al. YAC analysis and minimal tiling path construction for chromosome 21q. Somat. Cell Mol. Genet. 21, 399–414 (1995).

    Article  CAS  PubMed  Google Scholar 

  51. Goss, S. J. & Harris H. New method for mapping genes in human chromosomes. Nature 255, 680–684 (1975).

    Article  CAS  PubMed  Google Scholar 

  52. Cox, D. R., Burmeister, M., Price, E. R., Kim, S. & Myers, R. M. Radiation hybrid mapping: a somatic cell genetic method for constructing high-resolution maps of mammalian chromosomes. Science 259, 245–250 (1990).

    Article  Google Scholar 

  53. Lynn, A. et al. Patterns of meiotic recombination on the long arm of human chromosome 21. Genome Res. 10, 1319–1332 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Hassold, T. & Sherman, S. Down syndrome: genetic recombination and the origin of the extra chromosome 21. Clin. Genet. 57, 95–100 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Cheung, V. G. et al. Integration of cytogenetic landmarks into the draft sequence of the human genome. Nature 409, 953–958 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Schwartz, D. C. & Cantor, C. R. Separation of yeast chromosome-sized DNA's by pulsed field gradient gel electrophoresis. Cell 37, 67–75 (1984).

    Article  CAS  PubMed  Google Scholar 

  57. Gardiner, K., Laas, W. & Patterson, D. Fractionation of large mammalian DNA restriction fragments using vertical pulsed-field gradient gel electrophoresis. Somat. Cell Mol. Genet. 12, 185–195 (1986).

    Article  CAS  PubMed  Google Scholar 

  58. Burke, D. T., Carle, G. F. & Olson, M. V. Cloning of large segments of exogenous DNA into yeast by mean artificial chromosome vector. Science 236, 806–812 (1987).

    Article  CAS  PubMed  Google Scholar 

  59. Gardiner, K. et al. Analysis of human chromosome 21: correlation of physical and cytogenetic maps; gene and CpG island distributions. EMBO J. 9, 25–34 (1990).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Chumakov, I. et al. Continuum of overlapping clones spanning the entire human chromosome 21q. Nature 359, 380–386 (1992).

    Article  CAS  PubMed  Google Scholar 

  61. Ichikawa, H. et al. Long-distance restriction mapping of the proximal long arm of human chromosome 21 with Not I linking clones. Proc. Natl Acad. Sci. USA 89, 23–27 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Shizuya, H. et al. Cloning and stable maintenance of 300-kilobase-pair fragments of human DNA in Escherichia coli using an F-factor-based vector. Proc. Natl Acad. Sci. USA 89, 8794–8797 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wang, D., Fang, H., Cantor, C. R. & Smith, C. L. A contiguous Not I restriction map of band q22.3 of human chromosome 21. Proc. Natl Acad. Sci. USA 89, 3222–3226 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Shepherd, N. S. et al. Preparation and screening of an arrayed human genomic library generated with the P1 cloning system. Proc. Natl Acad. Sci. USA 91, 2629–2633 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Korenberg, J. R. et al. A high-fidelity physical map of human chromosome 21q in yeast artificial chromosomes. Genome Res. 5, 427–443 (1995).

    Article  CAS  PubMed  Google Scholar 

  66. Patterson, D. & Sakaki, Y. The international consortium to sequence human chromosome 21. Genome Digest 4, 9–10 (1997).

    Google Scholar 

  67. Hattori, M. et al. The DNA sequence of human chromosome 21. Nature 405, 311–319 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Yamada, Y. et al. A comprehensive analysis of allelic methylation status of CpG islands on human chromosome 21q. Genome Res. 14, 247–266 (2004).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Kampa, D. et al. Novel RNAs identified from an in-depth analysis of the transcriptome of human chromosomes 21 and 22. Genome Res. 14, 331–342 (2004).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Waterston, R. H. et al. Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. Gardiner, K., Fortna, A., Bechtel, L. & Davisson, M. T. Mouse models of Down syndrome: how useful can they be: comparison of the gene content of human chromosome 21 with orthologous mouse genomic regions. Gene 318, 137–147 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Patil, N. et al. Blocks of limited haplotype diversity revealed by high-resolution scanning of human chromosome 21. Science 294, 1719–1723 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Mao, R., Zielke, C. L., Zielke, H. R. & Pevsner, J. Global up-regulation of chromosome 21 gene expression in the developing Down syndrome brain. Genomics 81, 457–467 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. FitzPatrick, D. R. et al. Transcriptome analysis of human autosomal trisomy. Hum. Mol. Genet. 11, 3249–3256 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Reymond, A. et al. Human chromosome 21 gene expression atlas in the mouse. Nature 420, 582–586 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Gitton, Y. et al. A gene expression map of human chromosome 21 orthologues in the mouse. Nature 429, 586–590 (2002).

    Google Scholar 

  77. Kapranov, P. et al. Large-scale transcriptional activity in chromosomes 21 and 22. Science 296, 916–919 (2002).

    Article  CAS  PubMed  Google Scholar 

  78. O'Farrell, P. H. High resolution two-dimensional electrophoresis of proteins. J. Biol. Chem. 250, 4007–4021 (1975).

    Article  CAS  PubMed  Google Scholar 

  79. Weil, J. & Epstein, C. J. The effect of trisomy 21 on the patterns of polypeptide synthesis in human fibroblasts. Am. J. Hum. Genet. 31, 478–488 (1979).

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Brown, W. T., Dutkowski, R. & Darlington, G. J. Localization and quantitation of human superoxide dismutase using computerized 2-D gel electrophoresis. Biochem. Biophys. Res. Comm. 102, 675–681 (1981).

    Article  CAS  PubMed  Google Scholar 

  81. Klose, J., Zeindl, E. & Sperling, K. Analysis of protein patterns in two-dimensional gels of cultured human cells with trisomy 21. Clin. Chem. 28, 987–992 (1982).

    Article  CAS  PubMed  Google Scholar 

  82. Patterson, D., Jones, C., Scoggin, C., Miller, Y. E. & Graw, S. Somatic cell approaches to Down's syndrome. Ann. NY Acad. Sci. 396, 69–81 (1982).

    Article  CAS  PubMed  Google Scholar 

  83. Van Keuren, M. L., Goldman, D. & Merril, C. R. Protein variations associated with Down's syndrome, chromosome 21, and Alzheimer's disease. Ann. N.Y. Acad. Sci. 396, 55–67 (1982).

    Article  CAS  PubMed  Google Scholar 

  84. Durr, E. et al. Direct proteomic mapping of the lung microvascular endothelial cell surface in vivo and in cell culture. Nature Biotechnol. 22, 985–992 (1994).

    Article  CAS  Google Scholar 

  85. Unlu, M., Morgan, M. E. & Minden, J. S. Difference gel electrophoresis: a single gel method for detecting changes in protein extracts. Electrophoresis 18, 2071–2077 (1997).

    Article  CAS  PubMed  Google Scholar 

  86. Davisson, M. T. & Costa, A. C. S. in Advances in Neurochemistry Vol. 9 (ed. Popko, B.) 297–327 (Kluwer Academic/Plenum, New York, 1999).

    Google Scholar 

  87. McClure, H. M., Belden, K. H., Pieper, W. A. & Jacobson, C. B. Autosomal trisomy in a chimpanzee: resemblance to Down's syndrome. Science 165, 1010–1012 (1969).

    Article  CAS  PubMed  Google Scholar 

  88. Watanabe, H. et al. DNA sequence and comparative analysis of chimpanzee chromosome 22. Nature 429, 382–388 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Shi, J. et al. Divergence of the genes on human chromosome 21 between human and other hominoids and variation of substitution rates among transcription units. Proc. Natl Acad. Sci. USA 100, 8331–8336 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Gropp, A., Giers, D. & Kolbus, U. Trisomy in the fetal backcross progeny of male and female metacentric heterozygotes of the mouse. I. Cytogenet. Cell Genet. 13, 511–535 (1974).

    Article  CAS  PubMed  Google Scholar 

  91. Epstein, C. J. in Trisomy 21 (Down Syndrome) Research Perspectives (eds de la Cruz, F. F. & Gerald, P. S.) 263–271 (Univ. Park Press, Baltimore, 1981).

    Google Scholar 

  92. Francke, U. & Taggart, R. T. Assignment of the gene for cytoplasmic superoxide dismutase (SOD1) to a region of chromosome 16 and of Hprt to a region of the X chromosome in the mouse. Proc. Natl Acad. Sci. USA 76, 5230–5233 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Polani, P., E. & Adinolfi, M. Chromosome 21 of man, 22 of the great apes and 16 of the mouse. Dev. Med. Child Neurol. 22, 223–233 (1980).

    Article  CAS  PubMed  Google Scholar 

  94. Miyabara, S., Gropp, A. & Winking, H. Trisomy 16 in the mouse fetus associated with generalized edema and cardiovascular and urinary tract anomalies. Teratology 25, 369–380 (1982).

    Article  CAS  PubMed  Google Scholar 

  95. Gearhart, J. M., Davisson, M. & Oster-Granite, M. L. Autosomal aneuploidy in mice: generation and developmental consequences. Brain Res. Bull. 16, 789–801 (1986).

    Article  CAS  PubMed  Google Scholar 

  96. Davisson, M. T., Schmidt, C. & Akeson E. C. in Molecular Genetics of Chromosome 21 and Down Syndrome (eds Patterson, D. & Epstein, C. J.) 263–280 (Wiley-Liss, New York, 1990).

    Google Scholar 

  97. Davisson, M. T. et al. in The Phenotypic Mapping of Down Syndrome and Other Aneuploid Conditions (ed. Epstein, C. J.) 117–133 (Wiley-Liss, New York, 1993).

    Google Scholar 

  98. Reeves, R. H. et al. A mouse model for Down syndrome exhibits learning and behaviour deficits. Nature Genet. 11, 177–183 (1995).

    Article  CAS  PubMed  Google Scholar 

  99. Holtzman, D. M. et al. Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome. Proc. Natl Acad. Sci. USA 93, 13333–13338 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Hyde, L. A. & Crnic, L. S. Age-related deficits in context discrimination learning in Ts65Dn mice that model Down syndrome and Alzheimer's disease. Behav. Neurosci. 115, 1239–1246 (2001).

    Article  CAS  PubMed  Google Scholar 

  101. Richtsmeier, J. T., Zumwalt, A., Carlson, E. J., Epstein, C. J. & Reeves, R. H. Craniofacial phenotypes in segmentally trisomic mouse models for Down syndrome. Am. J. Med. Genet. 107, 317–324 (2002).

    Article  PubMed  Google Scholar 

  102. Cataldo, A. M. et al. App gene dosage modulates endosomal abnormalities of Alzheimer's disease in a segmental trisomy 16 mouse model of Down syndrome. J. Neurosci. 23, 6788–6792 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Hampton, T. G., Stasko, M. R., Kale, A., Amende, I. & Costa, A. C. Gait dynamics in trisomic mice: quantitative neurological traits of Down syndrome. Physiol. Behav. 82, 381–389 (2004).

    Article  CAS  PubMed  Google Scholar 

  104. Olson, L. E. et al. Down syndrome mouse models Ts65Dn, Ts1Cje, and Ms1Cje/Ts65SDn exhibit variable severity of cerebellar phenotypes. Dev. Dyn. 230, 581–589 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Stasko, M. R. & Costa, A. C. S. Experimental parameters affecting the morris water maze performance of a mouse model of Down syndrome. Behav. Brain Res. 154, 1–17 (2004).

    Article  PubMed  Google Scholar 

  106. Kahlem, P. et al. Transcript level alterations reflect gene dosage effects across multiple tissues in a mouse model of Down syndrome. Genome Res. 14, 1258–1267 (2004).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  107. Sago, H. et al. Ts1Cje, a partial trisomy 16 mouse model for Down syndrome, exhibits learning and behavioral abnormalities. Proc. Natl Acad. Sci. USA 95, 6256–6261 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Sago, H. et al. Genetic dissection of region associated with behavioral abnormalities in mouse models for Down syndrome. Pediatr. Res. 48, 606–613 (2000).

    Article  CAS  PubMed  Google Scholar 

  109. Saran, N. G., Pletcher, M. T., Natale, J. E., Cheng, Y. & Reeves, R. H. Global disruption of the cerebellar transcriptome in a Down syndrome mouse model. Hum. Mol. Genet. 12, 2013–2019 (2003).

    Article  CAS  PubMed  Google Scholar 

  110. Lyle, R., Gehrig, C., Neergaard-Henrichsen, C., Deutsch, S. & Antonarakis, S. E. Gene expression from the aneuploid chromosome in a trisomy mouse model of Down syndrome. Genome Res. 14, 1268–1274 (2004).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  111. Amano, K. et al. Dosage-dependent over-expression of genes in the trisomic region of Ts1Cje mouse model for Down syndrome. Hum. Mol. Genet. 13, 1333–1340 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. Epstein, C. J. et al. Transgenic mice with increased Cu/Zn-superoxide dismutase activity: animal model of dosage effects in Down syndrome. Proc. Natl Acad. Sci. 84, 8044–8088 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Avraham, K. B., Sugarman, H., Rotshenker, S. & Groner, Y. Down's syndrome: morphological remodeling and increased complexity in the neuromuscular junction of transgenic CuZn-superoxide dismutase mice. J. Neurocytol. 20, 208–215 (1991).

    Article  CAS  PubMed  Google Scholar 

  114. Gahtan, E., Auerbach, J. M., Groner, Y. & Segal, M. Reversible impairment of long-term potentiation in transgenic Cu/Zn-SOD mice. Eur. J. Neurosci. 10, 538–544 (1998).

    Article  CAS  PubMed  Google Scholar 

  115. Harris-Cerruti, C. et al. Functional and morphological alterations in compound transgenic mice overexpreszing Cu/Zn superoxide dismutaze and amyloid precursor protein. Eur. J. Neurosci. 19, 1174–1190 (2004).

    Article  PubMed  Google Scholar 

  116. Busciglio, J. et al. Altered metabolism of the amyloid β precursor protein is associated with mitochondrial dysfunction in Down's syndrome. Neuron 33, 677–688 (2002).

    Article  CAS  PubMed  Google Scholar 

  117. Peled-Kamar, M., Degani, H., Bendel, P., Margalit, R. & Groner, Y. Altered brain glucose metabolism in transgenic-PFKL mice with elevated L-phosphofructokinase: in vivo NMR studies. Brain Res. 810, 138–145 (1998).

    Article  CAS  PubMed  Google Scholar 

  118. Martinez de Lagrán, M. et al. Motor phenotypic alterations in TgDyrk1a transgenic mice implicate DYRK1A in Down syndrome motor dysfunction. Neurobiol. Dis. 15, 132–142 (2004).

    Article  CAS  PubMed  Google Scholar 

  119. Chrast, R. et al. Mice trisomic for a bacterial artificial chromosome with the single-minded 2 gene (Sim2) show phenotypes similar to some of those present in the partial trisomy 16 mouse models of Down syndrome. Hum. Mol. Genet. 9, 1853–1864 (2000).

    Article  CAS  PubMed  Google Scholar 

  120. Bell, K., Shokrian, D., Potenzieri, C. & Whitaker-Azmitia, P. M. Harm avoidance, anxiety, and response to novelty in the adolescent S-100β transgenic mouse: role of serotonin and relevance to Down syndrome. Neuropsychopharmacology 28, 1810–1816 (2003).

    Article  CAS  PubMed  Google Scholar 

  121. Wolvetang, E. J. et al. Overexpression of the chromosome 21 transcription factor Ets2 induces neuronal apoptosis. Neurobiol. Dis. 14, 349–356 (2003).

    Article  CAS  PubMed  Google Scholar 

  122. Horton, J. C. in Critical Thinking About Critical Periods (eds Bailey, D. B., Bruer, J. T., Symons, F. J. & Lichtman, J. W.) (Paul H. Brooks, Baltimore, 2001).

    Google Scholar 

  123. Pennington, B. F., Moon, J., Edgin, J., Stedron, J. & Nadel, L. The neuropsychology of Down syndrome: evidence for hippocampal dysfunction. Child. Dev. 74, 75–93 (2003).

    Article  PubMed  Google Scholar 

  124. Aylward, E. H. et al. MRI volumes of the hippocampus and amygdala in adults with Down's syndrome with and without dementia. Am. J. Psychiatry 156, 564–568 (1999).

    CAS  PubMed  Google Scholar 

  125. Pinter, J. D. et al. Amygdala and hippocampal volumes in children with Down syndrome: a high-resolution MRI study. Neurology 56, 972–974 (2001).

    Article  CAS  PubMed  Google Scholar 

  126. Kleschevnikov, A. M. et al. Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome. J. Neurosci. 15, 8153–8160 (2004).

    Article  CAS  Google Scholar 

  127. Hernandez, D., Mee, P. J., Martin, J. E., Tybulewicz, V. L. J. & Fisher, E. M. C. Transchromsomal mouse embryonic stem cell lines and chimeric mice that contain freely segregating segments of human chromosome 21. Hum. Mol. Genet. 8, 923–933 (1999).

    Article  CAS  PubMed  Google Scholar 

  128. Shinohara, T. et al. Mice containing a human chromosome 21 model behavioral impairment and cardiac anomalies of Down's syndrome. Hum. Mol. Genet. 10, 1163–1175 (2001).

    Article  CAS  PubMed  Google Scholar 

  129. Olson, L. E., Richtsmeier, J. T., Leszl, J. & Reeves, R. H. A chromosome 21 critical region does not cause specific Down syndrome phenotypes. Science 306, 687–690 (2004).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  130. Gardiner, K., Davisson, M. T. & Crnic, L. S. Building protein interaction maps for Down's syndrome. Brief. Funct. Genomic Proteomic 3, 142–156 (2004).

    Article  CAS  PubMed  Google Scholar 

  131. Reynolds, T. M. Correspondence in J. Clin. Pathol. 54, 573–574 (2001).

    Article  PubMed Central  Google Scholar 

  132. Baker, D., Teklehaimanot, S., Hassan, R. & Guze, C. A look at a Hispanic and African American population in an urban prenatal diagnostic center: referral reasons, amniocentesis acceptance, and abnormalities detected. Genet. Med. 6, 211–218 (2004).

    Article  PubMed  Google Scholar 

  133. Elias, S. et al. Chorionic villus sampling for first-trimester prenatal diagnosis: Northwestern University program. Am. J. Obstet. Gynecol. 152, 204–213 (1985).

    Article  CAS  PubMed  Google Scholar 

  134. Merkatz, I. R., Nitowsky, H. M., Macri, J. N. & Johnson, W. E. An association between low maternal serum α-fetoprotein and fetal chromosomal abnormalities. Am. J. Obstet. Gynecol. 148, 886–894 (1984).

    Article  CAS  PubMed  Google Scholar 

  135. Christiansen, M. et al. Screening for Down's syndrome in early and late first and second trimester using six maternal serum markers. Clin. Genet. 65, 11–16 (2004).

    Article  CAS  PubMed  Google Scholar 

  136. Nicolaides, K. H., Azar, G., Byrne, D., Mansur, C. & Marks, K. Fetal nuchal translucency: ultrasound screening for chromosomal defects in first trimester of pregnancy. BMJ 304, 867–869 (1992).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  137. Bianchi, D. W. et al. Detection of fetal cells with 47,XY,+21 karyotype in maternal peripheral blood. Hum. Genet. 90, 368–370 (1992).

    Article  CAS  PubMed  Google Scholar 

  138. Glover, N. M. & Glover, S. J. Ethical and legal issues regarding selective abortion of fetuses with Down syndrome. Ment. Retard. 34, 207–214 (1996).

    CAS  PubMed  Google Scholar 

  139. James, S. J. et al. Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome. Am. J. Clin. Nutr. 70, 495–501 (1999).

    Article  CAS  PubMed  Google Scholar 

  140. James, S. J. Maternal metabolic phenotype and risk of Down syndrome: beyond genetics. Am. J. Med. Genet. 127 (Part A), 1–4 (2004).

    Article  Google Scholar 

  141. Pogribna, M. et al. Homocysteine metabolism in children with Down syndrome: in vitro modulation. Am. J. Hum. Genet. 69, 88–95 (2001).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  142. Barkai, G., Arbuzova, S., Berkenstadt, M., Heifetz, S. & Cuckle, H. Frequency of Down's syndrome and neural-tube defects in the same family. Lancet 361, 1331–1335 (2003).

    Article  PubMed  Google Scholar 

  143. Hassold, T. & Hunt, P. To err (meiotically) is human: the genesis of human aneuploidy. Nature Rev. Genet. 2, 280–291 (2001).

    Article  CAS  PubMed  Google Scholar 

  144. Aagesen, L., Grinsted, J. & Mikkelsen, M. Advanced grandmaternal age on the mother's side — a risk of giving rise to trisomy 21. Ann. Hum. Genet. 48, 297–302 (1984).

    Article  CAS  PubMed  Google Scholar 

  145. Papp, Z., Varadi, E. & Szabo, Z. Grandmaternal age at birth of parents of children with trisomy. Hum. Genet. 39, 221–224 (1977).

    Article  CAS  PubMed  Google Scholar 

  146. Muller, H. J. Precision of genetic adaptation. Harvey Lect. 43, 165–229 (1948).

    Google Scholar 

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Acknowledgements

The authors would like to acknowledge the support of the US National Institutes of Health, the Jerome Legeune Foundation, the Bonfils–Stanton Foundation, the Boettcher Foundation, the Denver Foundation and the Alvin Itkin Foundation.

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Authors and Affiliations

  1. Eleanor Roosevelt Institute and the Department of Biological Sciences at the University of Denver and also at the Department of Psychiatry, University of Colorado Health Sciences Center, 1899 Gaylord Street, Denver, 80206, Colorado, USA

    David Patterson & Alberto C. S. Costa

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  1. David Patterson
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Correspondence to David Patterson.

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DATABASES

Entrez

APP

IFNAR1

SOD1

GARS

HPRT

Pfkl

Dyrk1a

Sim2

S100β

Ets2

OMIM

Down syndrome

Alzheimer disease

Acute myeloid leukaemia

Glossary

ACROCENTRIC CHROMOSOME

A chromosome in which the centromere is near to one end, as in human chromosomes 13–15, 21, 22 and Y. All mouse chromosomes are acrocentric.

ACUTE MYELOID LEUKAEMIA

A cancerous overproduction of immature myeloid white blood cells (blast cells).

ANEUPLOID

Having an abnormal number of chromosomes that are not an exact multiple of the haploid number. The antonym is euploid.

CHOLINERGIC MARKERS

These are biochemical or immunological markers for cholinergic neurons (presynaptic neurons that produce acetylcholine). Although it remains controversial, it has been suggested that loss of function of basal forebrain cholinergic neurons might be linked to neurodegenerative changes in the cerebral cortex of individuals with Alzheimer disease and Down syndrome (the so-called cholinergic hypothesis).

CpG ISLAND

A genomic region of about one kilobase that has more than 50% C+G content.

CRANIOFACIAL DYSMORPHOGENESIS

Abnormal development of the bones of the skull, including the facial bones.

DIFFERENCE GEL ELECTROPHORESIS

A technique whereby two or more protein samples are labelled with different fluorescent dyes so that they can be mixed together, co-separated and visualized on a single 2D gel.

DUODENAL ATRESIA

A condition in which the duodenum (the first part of the small bowel) has not developed properly and does not allow the passage of stomach contents.

ENDOSOME

A vesicle formed by invagination of the plasma membrane.

FOETAL NUCHAL TRANSLUCENCY

The appearance on ultrasound examination of a subcutaneous collection of fluid behind the foetal neck.

HAPLOTYPE BLOCKS

The apparent haplotypic structure of the recombining portions of the genome, in which sets of consecutive co-inherited alleles are separated by short boundaries. There is debate about the origins of haplotype blocks and whether the boundaries correspond to recombination hotspots.

HYPERTHYROIDISM

An abnormality of the thyroid gland in which secretion of the thyroid hormone is increased and not regulated properly.

MASS SPECTROMETRY

A technique in which molecules are ionized, the ions are separated in the gaseous state and the ratio of mass to charge is determined to derive structural information. This technique requires only a small amount of sample.

MYELODYSPLASTIC SYNDROME

A condition in which the bone marrow cannot produce blood cells effectively; many of the blood cells that are formed are defective, which results in low blood cell counts.

POSITRON EMISSION TOMOGRAPHY

(PET). Imaging of the emission of positrons from the brain after a small amount of radioactive isotopes have been injected into the blood stream to routinely and quantitatively measure metabolic, biochemical and functional activity in living tissue.

REAL-TIME PCR

A technique designed to detect and quantify sequence-specific PCR products as they accumulate in 'real-time' during the PCR amplification process.

SYNTENIC REGIONS

A genomic region that is collinear in the order of genes (or of other DNA sequences) in a chromosomal region of two species.

TWO-DIMENSIONAL GEL ELECTROPHORESIS

A gel electrophoresis method in which a protein sample is separated by isoelectric point in one dimension and by size in a second, perpendicular dimension.

WHOLE-GENOME ASSOCIATION STUDIES

A set of methods that are used to correlate polymorphisms in genotype to polymorphisms in phenotype in populations on a genome-wide scale.

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Patterson, D., Costa, A. Down syndrome and genetics — a case of linked histories. Nat Rev Genet 6, 137–147 (2005). https://doi.org/10.1038/nrg1525

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