COMPLETE GENOMIC SEQUENCE AND ANALYSIS OF 117 KB OF HUMAN DNA CONTAINING THE GENE BRCA1

Over 100 distinct disease-associated mutations have been identified in the breast-ovarian cancer susceptibility gene BRCA1. Loss of the wild -type allele in >90% of tumors from patients with inherited BRCA1 muta tions indicates tumor suppressive function. The low incidence of somat ic mutations suggests that BRCA1 inactivation in sporadic tumors occur s by alternative mechanisms, such as interstitial chromosomal deletion or reduced transcription. To identify possible features of the BRCA1 genomic region that may contribute to chromosomal instability as well as potential transcriptional regulatory elements, a 117,143-bp DNA seq uence encompassing BRCA1 was obtained by random sequencing of four cos mids identified from a human chromosome 17 specific library. The 24 ex ons of BRCA1 span an 81-kb region that has an unusually high density o f Alo repetitive DNA (41.5%), but relatively low density (4.8%) of oth er repetitive sequences, BRCA1 intron lengths range in size from 403 b p to 9.2 kb and contain the intragenic microsatellite markers D17S1323 , D17S1322, and D17S855, which localize to introns 12, 19, and 20, res pectively. In addition to BRCA1 the contig contains two complete genes : Rho7, a member of the rho family of GTP binding proteins, and VAT1, an abundant membrane protein of cholinergic synaptic vesicles. Partial sequences of the 1A1-3B B-box protein pseudogene and IFP 35, an inter feron induced leucine zipper protein, reside within the contig. An L21 ribosomal protein pseudogene is embedded in BRCA1 intron 13. The orde r of genes on the chromosome is: centromere-IFP 35-VAT1-Rho7-BRCA1-1A1 -3B- telomere.