ATAXIA-TELANGIECTASIA LOCUS - SEQUENCE-ANALYSIS OF 184 KB OF HUMAN GENOMIC DNA CONTAINING THE ENTIRE ATM GENE

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involvi ng cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity, and cancer predisposition. The genomic organization of the A-T gene, designated ATM, was established recently. To date, m ore than 100 A-T-associated mutations have been reported in the ATM ge ne that do not support the existence of one or several mutational hots pots. To allow genotype/phenotype correlations it will be important to find additional ARI mutations. The nature and location of the mutatio ns will also provide insights into the molecular processes that underl y the disease. To facilitate the search for ATM mutations and to estab lish the basis for the identification of transcriptional regulatory el ements, we have sequenced and report here 184,490 bp of genomic sequen ce from the human 11q22-23 chromosomal region containing the entire AR I gene, spanning 146 kb, and 10 kb of the S'-region of an adjacent gen e named E14/NPAT. The latter shares a bidirectional promoter with ATM and is transcribed in the opposite direction. The entire region is tra nscribed to similar to 85% and translated to 5%. Genome-wide repeats w ere found to constitute 37.2%, with LINE (17.1%) and Alu (14.6%) being the main repetitive elements. The high representation of LINE repeats is attributable to the presence of three full-length LINE-is, inserte d in the same orientation in introns 18 and 63 as well as downstream o f the AR I gene. Homology searches suggest that ATM exon 2 could have derived from a mammalian interspersed repeat (MIR). Promoter recogniti on algorithms identified divergent promoter elements within the CpG is land, which lies between the ARI and E14/NPAT genes, and provide evide nce for a putative second ATM promoter located within intron 3, immedi ately upstream of the First coding exon. The low G+C level (38.1%) of the ARI locus is reflected in a strongly biased codon and amino acid u sage of the gene.