MOUSE BRCA1 - LOCALIZATION, SEQUENCE-ANALYSIS AND IDENTIFICATION OF EVOLUTIONARILY CONSERVED DOMAINS

The human gene BRCA1, conferring susceptibility to early-onset breast and ovarian cancer, has recently been isolated. Here we describe isola tion of cDNAs, sequence analysis, and genomic localization of the muri ne homolog, Brca1. The mouse cDNA sequence predicts a protein of 1812 amino acids; a number of small gaps account for the 51 fewer residues in the mouse protein relative to human BRCA1, While the predicted mous e and human proteins display on the whole a high level of homology (58 % identity, 73% similarity), the regions of greatest homology are at t he respective amino and carboxyl termini. Most reported disease-associ ated missense mutations in human BRCA1 occurred within these more high ly conserved terminal regions. A predicted zinc-binding RING finger do main near the amino terminus lies within a 50 amino acid stretch that is perfectly conserved in both species. The strong conservation during mammalian evolution argues for the importance of this domain, perhaps mediating a role for BRCA1 in DNA and/or protein binding. We have als o identified a conserved highly acidic domain in the carboxyl terminal half of the BRCA1 protein resembling acidic transactivation domains o f certain transcription factors, Using an interspecific backcross pane l, Brca1 was mapped to a region of mouse chromosome 11 that exhibits c onserved linkage with human 17q21, The sequence and isolated cDNAs wil l provide useful reagents for studying the expression of Brca1 in the mouse, and for testing the importance of the evolutionarily conserved domains.