Nature Genetics
16, 28 - 36 (1997)
doi:10.1038/ng0597-28
Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndromeDesmond J. Smith1, Mary E. Stevens1, Sharmila P. Sudanagunta1, Roderick T. Bronson2, Michael Makhinson3, Ayako M. Watabe3, Thomas J. O'Dell3, Jingly Fung1, Heinz-Ulrich G. Weier1, Jan-Fang Cheng1
& Edward M. Rubin1, 4
1Human Genome Center, Lawrence Berkeley National Laboratory, Berkeley, California, USA 94720.
2USDA Human Nutrition Research Center on Aging, Tufts University Schools of Medicine and Veterinary Medicine, Boston, Massachusetts 02111, USA; and The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
3Department of Physiology, and the Brain Research Institute, UCLA School of Medicine, Los Angeles, California 90024, USA.
4email: EMRubin@lbl.gov. Using Down syndrome as a model for complex trait analysis, we sought to identify loci from chromosome 21q22.2 which, when present in an extra dose, contribute to learning abnormalities. We generated low-copy-number transgenic mice, containing four different yeast artificial chromosomes (YACs) that together cover approximately 2 megabases (Mb) of contiguous DNA from 21q22,2. We subjected independent lines derived from each of these YAC transgenes to a series of behavioural and learning assays. Two of the four YACs caused defects in learning and memory in the transgenic animals, while the other two YACs had no effect. The most severe defects were caused by a 570-kb YAC; the interval responsible for these defects was narrowed to a 180-kb critical region as a consequence of YAC fragmentation. This region contains the human homologue of a Drosophila gene, minibrain, and strongly implicates it in learning defects associated with Down syndrome.
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