FUNCTIONAL SCREENING OF 2 MB OF HUMAN-CHROMOSOME-21Q22.2 IN TRANSGENIC MICE IMPLICATES MINIBRAIN IN LEARNING DEFECTS ASSOCIATED WITH DOWNS-SYNDROME

Using Down syndrome as a model for complex trait analysis, we sought t o identify loci from chromosome 21q22.2 which, when present in an extr a dose, contribute to learning abnormalities. We generated low-copy-nu mber transgenic mice, containing four different yeast artificial chrom osomes (YACs) that together cover approximately 2 megabases (Mb) of co ntiguous 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 mo st severe defects were caused by a 570-kb YAC; the interval responsibl e for these defects was narrowed to a 180-kb critical region as a cons equence of YAC fragmentation, This region contains the human homologue of a Drosophila gene, minibrain, and strongly implicates it in learni ng defects associated with Down syndrome.