COMPARATIVE MAPPING OF THE DIGEORGE-SYNDROME REGION IN MOUSE SHOWS INCONSISTENT GENE ORDER AND DIFFERENTIAL DEGREE OF GENE CONSERVATION

We have constructed a comparative map in mouse of the critical region of human 22q11 deleted in DiGeoree (DGS) and Velocardiofacial (VCFS) s yndromes. The map includes 11 genes potentially haploinsufficient in t hese deletion syndromes. We have localized all the conserved genes to mouse Chromosome (Chr) 16, bands B1-B3. The determination of gene orde r shows the presence of two regions (distal and proximal), containing two groups of conserved genes. The gene order in the two regions is no t completely conserved; only in the proximal group is the gene order i dentical to human. In the distal group the gene order is inverted. The se two regions are separated by a DNA segment containing at least one gene which, in the human DCS region, is the most proximal of the known deleted genes. In addition, the gene order within the distal group of genes is inverted relative to the human gene order. Furthermore, a cl athrin heavy chain-like gene was not found in the mouse genome by DNA hybridization, indicating that there is an inconsistent level of gene conservation in the region. These and other independent data obtained in our laboratory clearly show a complex evolutionary history of the D GS-VCFS region. Our data provide a framework for the development of a mouse model for the 22q11 deletion with chromosome engineering technol ogies.