HIGH-RESOLUTION MAPPING OF MOUSE-CHROMOSOME-8 IDENTIFIES AN EVOLUTIONARY CHROMOSOMAL BREAKPOINT

The central region of mouse Chromosome (Chr) 8, containing the myodyst rophy (myd) locus, is syntenic with human Chr 4q28-qter. The human neu romuscular disorder facioscapulohumeral muscular dystrophy (FSHD) maps to Chr 4q35, and myd has been proposed as a mouse homolog of FSHD. We have employed a comparative mapping approach to investigate this rela tionship further by extending the mouse genetic map of this region. We have ordered 12 genes in a single cross, 8 of which have human homolo gs on 4q28-qter. The results confirm a general relationship between th e most distal genes on human 4q and the most proximal genes in the mou se 8 syntenic region. Despite chromosomal rearrangements of syntenic g roups in this region, conservation of gene order is maintained between the group of genes in the human telomeric region of 4q35 and MMU8. Fu rthermore, this conserved telomeric HSA4q35 syntenic group maps proxim al to the myd mutation and is flanked by genes with homologs on HSA8p2 2. At the proximal boundary of the MMU8 linkage group we have identifi ed a single 300-kb YAC containing the genes Frgl and Pcml, which have human homologs on 4q35 and 8p22, respectively. Thus, this YAC spans an evolutionary chromosomal breakpoint. As well as providing clues about chromosomal evolution, this map of the FSHD syntenic mouse region sho uld prove invaluable in the isolation of candidate genes for this dise ase.