Triplication of whole autosomes or large autosomal segments is detrimental to the development of a mammalian embryo. The trisomy of human chromosome (Chr) 21, known as Down's syndrome, is regularly associated with mental retardation and a variable set of other developmental anomalies. Several mouse models of Down's syndrome, triplicating 33-104 genes of Chr16, were designed in an attempt to analyze the contribution of specific orthologous genes to particular developmental features. However, a recent study challenged the concept of dosage-sensitive genes as a primary cause of an abnormal phenotype. To distinguish between the specific effects of dosage-sensitive genes and nonspecific effects of a large number of arbitrary genes, we revisited the mouse Ts43H/Ph segmental trisomy. It encompasses >310 known genes triplicated within the proximal 30 megabases (Mb) of Chr17. We refined the distal border of the trisomic segment to the interval bounded by bacterial artificial chromosomes RP23-277B13 (location 29.0 Mb) and Cbs gene (location 30.2 Mb). The Ts43H mice, viable on a mixed genetic background, exhibited spatial learning deficits analogous to those observed in Ts65Dn mice with unrelated trisomy. Quantitative analysis of the brain expression of 20 genes inside the trisomic interval and 12 genes lying outside on Chr17 revealed 1.2-fold average increase of mRNA steady-state levels of triplicated genes and 0.9-fold average down-regulation of genes beyond the border of trisomy. We propose that systemic comparisons of unrelated segmental trisomies, such as Ts65Dn and Ts43H, will elucidate the pathways leading from the triplicated sequences to the complex developmental traits.

Institutes of Molecular Genetics and Physiology Academy of Sciences of the Czech Republic 14220 Prague Czech Republic

Zobrazit více v PubMed

Bailey, J. A., Gu, Z., Clark, R. A., Reinert, K., Samonte, R. V., Schwartz, S., Adams, M. D., Myers, E. W., Li, P. W. & Eichler, E. E. (2002) Science 297, 1003–1007. PubMed

Bailey, J. A., Church, D. M., Ventura, M., Rocchi, M. & Eichler, E. E. (2004) Genome Res. 14, 789–801. PubMed PMC

Tuzun, E., Bailey, J. A. & Eichler, E. E. (2004) Genome Res. 14, 493–506. PubMed PMC

Ohno, S. (1970) Evolution by Gene Duplication (Springer, New York).

Lynch, M. (2002) Science 297, 945–947. PubMed

Emanuel, B. S. & Shaikh, T. H. (2001) Nat. Rev. Genet. 2, 791–800. PubMed

Pearson, P. L. (2001) in Encyclopedia of Genetics, eds. Brenner, S. & Miller, J. H. (Academic, London), Vol. 4, pp. 2056–2058.

Delabar, J. M., Theophile, D., Rahmani, Z., Chettouh, Z., Blouin, J. L., Prieur, M., Noel, B. & Sinet, P. M. (1993) Eur. J. Hum. Genet. 1, 114–124. PubMed

Korenberg, J. R., Chen, X. N., Schipper, R., Sun, Z., Gonsky, R., Gerwehr, S., Carpenter, N., Daumer, C., Dignan, P., Disteche, C., et al. (1994) Proc. Natl. Acad. Sci. USA 91, 4997–5001. PubMed PMC

Reeves, R. H., Baxter, L. L. & Richtsmeier, J. T. (2001) Trends Genet. 17, 83–88. PubMed

Olson, L. E., Richtsmeier, J. T., Leszl, J. & Reeves, R. H. (2004) Science 306, 687–690. PubMed PMC

Reeves, R. H., Irving, N. G., Moran, T. H., Wohn, A., Kitt, C., Sisodia, S. S., Schmidt, C., Bronson, R. T. & Davisson, M. T. (1995) Nat. Genet. 11, 177–184. PubMed

Sago, H., Carlson, E. J., Smith, D. J., Kilbridge, J., Rubin, E. M., Mobley, W. C., Epstein, C. J. & Huang, T. T. (1998) Proc. Natl. Acad. Sci. USA 95, 6256–6261. PubMed PMC

Dierssen, M., Fillat, C., Crnic, L., Arbones, M., Florez, J. & Estivill, X. (2001) Physiol. Behav. 73, 859–871. PubMed

Lyon, M. & Meredith, R. (1966) Cytogenetics 5, 335–354. PubMed

Searle, A. G., Ford, C. E., Evans, E. P., Beechey, C. V., Burtenshaw, M. D., Clegg, H. M. & Papworth, D. G. (1974) Mutat. Res. 22, 157–174. PubMed

Beechey, C. & Evans, E. (1996) in Genetic Variants and Strains of the Laboratory Mouse, eds. Lyon, M., Rastan, S. & Brown, S. (Oxford Univ. Press, Oxford), Vol. 2, pp. 1469–1470.

Gregorova, S. & Forejt, J. (2000) Folia Biol. (Prague) 46, 31–41. PubMed

Forejt, J. & Gregorova, S. (1992) Cell 70, 443–450. PubMed

Szabo, P. & Mann, J. (1995) Genes Dev. 9, 3097–3108. PubMed

Vacik, T. & Forejt, J. (2003) Genomics 82, 261–268. PubMed

Chung, Y. J., Jonkers, J., Kitson, H., Fiegler, H., Humphray, S., Scott, C., Hunt, S., Yu, Y., Nishijima, I., Velds, A., et al. (2004) Genome Res. 14, 188–196. PubMed PMC

Kaminsky, Y. & Krekule, I. (1997) Physiol. Res. 46, 223–231. PubMed

Forejt, J., Capkova, J. & Gregorova, S. (1980) Genet. Res. 35, 165–177. PubMed

Fiegler, H., Carr, P., Douglas, E. J., Burford, D. C., Hunt, S., Scott, C. E., Smith, J., Vetrie, D., Gorman, P., Tomlinson, I. P. & Carter, N. P. (2003) Genes Chromosomes Cancer 36, 361–374. PubMed

Hattori, M., Fujiyama, A., Taylor, T. D., Watanabe, H., Yada, T., Park, H. S., Toyoda, A., Ishii, K., Totoki, Y., Choi, D. K., et al. (2000) Nature 405, 311–319. PubMed

Antonarakis, S. E., Lyle, R., Dermitzakis, E. T., Reymond, A. & Deutsch, S. (2004) Nat. Rev. Genet. 5, 725–738. PubMed

Rahmani, Z., Blouin, J. L., Creau-Goldberg, N., Watkins, P. C., Mattei, J. F., Poissonnier, M., Prieur, M., Chettouh, Z., Nicole, A., Aurias, A., et al. (1989) Proc. Natl. Acad. Sci. USA 86, 5958–5962. PubMed PMC

Shapiro, B. L. (1997) Hum. Genet. 99, 421–423. PubMed

Shapiro, B. L. (1983) Am. J. Med. Genet. 14, 241–269. PubMed

Pritchard, M. A. & Kola, I. (1999) J. Neural Transm. 57, Suppl., 293–303. PubMed

Forejt, J., Vacik, T. & Gregorova, S. (2003) Comp. Funct. Genomics 4, 647–652. PubMed PMC

Davisson, M. & Costa, A. (1999) in Mouse Models in the Study of Genetic Neurological Disorders, ed. Popko, K. (Kluwer Academic/Plenum, New York), pp. 297–327.

Holtzman, D. M., Santucci, D., Kilbridge, J., Chua-Couzens, J., Fontana, D. J., Daniels, S. E., Johnson, R. M., Chen, K., Sun, Y., Carlson, E., et al. (1996) Proc. Natl. Acad. Sci. USA 93, 13333–13338. PubMed PMC

Escorihuela, R. M., Vallina, I. F., Martinez-Cue, C., Baamonde, C., Dierssen, M., Tobena, A., Florez, J. & Fernandez-Teruel, A. (1998) Neurosci. Lett. 247, 171–174. PubMed

Escorihuela, R. M., Fernandez-Teruel, A., Vallina, I. F., Baamonde, C., Lumbreras, M. A., Dierssen, M., Tobena, A. & Florez, J. (1995) Neurosci. Lett. 199, 143–146. PubMed

Coussons-Read, M. E. & Crnic, L. S. (1996) Behav. Genet. 26, 7–13. PubMed

Epstein, C. J., Cox, D. R. & Epstein, L. B. (1985) Ann. N.Y. Acad. Sci. 450, 157–168. PubMed

Gregorova, S., Baranov, V. & Forejt, J. (1981) Folia Biol. (Prague) 27, 171–177. PubMed

Amano, K., Sago, H., Uchikawa, C., Suzuki, T., Kotliarova, S. E., Nukina, N., Epstein, C. J. & Yamakawa, K. (2004) Hum. Mol. Genet. 13, 1333–1340. PubMed

Lyle, R., Gehrig, C., Neergaard-Henrichsen, C., Deutsch, S. & Antonarakis, S. E. (2004) Genome Res. 14, 1268–1274. PubMed PMC

FitzPatrick, D. R., Ramsay, J., McGill, N. I., Shade, M., Carothers, A. D. & Hastie, N. D. (2002) Hum. Mol. Genet. 11, 3249–3256. PubMed

Mao, R., Zielke, C. L., Zielke, H. R. & Pevsner, J. (2003) Genomics 81, 457–467. PubMed

Saran, N. G., Pletcher, M. T., Natale, J. E., Cheng, Y. & Reeves, R. H. (2003) Hum. Mol. Genet. 12, 2013–2019. PubMed

Kahlem, P., Sultan, M., Herwig, R., Steinfath, M., Balzereit, D., Eppens, B., Saran, N. G., Pletcher, M. T., South, S. T., Stetten, G., et al. (2004) Genome Res. 14, 1258–1267. PubMed PMC

Genetically enhanced asynapsis of autosomal chromatin promotes transcriptional dysregulation and meiotic failure

Chromosomal rearrangement interferes with meiotic X chromosome inactivation