PHYSICAL AND GENETIC-MAPPING AT THE ATA ATC LOCUS ON CHROMOSOME 11Q22-23/

Genetic heterogeneity in ataxia-telangiectasia (A-T) points to four di fferent genes responsible for this disease. The two major A-T genes, A TA and ATC, were localized by genetic analysis close to each other on chromosome 11q22-23, prompting efforts of positional cloning. Essentia l steps in positional cloning are long-range cloning of the genomic re gion of interest, and derivation of highly polymorphic markers that wo uld allow further reduction of the interval carrying the A-T gene. We constructed genomic contigs across the D11S611-D1S424 region harbourin g the ATA and ATC genes in yeast artificial chromosome (YAC) vectors. These contigs were used as a fine mapping tool and enabled us to local ize along the A-T region, eight microsatellite markers generated rando mly by genome mapping centres. In addition, we used specific YAC clone s to generate five new microsatellite markers based on polymorphic CA repeats. Recombination mapping based on Israeli A-T families indicates that the ATC gene is distal to the locus D11S1817. Further linkage an alysis using these markers is expected to reduce the major A-T locus c onsiderably to a size appropriate for cosmid cloning and identificatio n of transcribed sequences.