HUMAN, CANINE AND MURINE BRCA1 GENES - SEQUENCE COMPARISON AMONG SPECIES

Five to ten percent of breast cancer in the western world may be attri buted to the inheritance of highly penetrant mutations in the breast a nd ovarian cancer susceptibility gene, BRCA1. The biological function of BRCA1 and factors affecting expressivity, such as gene-environment and gene-gene interactions, may be more effectively studied in appropr iate animal models. We report the cloning and sequencing of the canine and murine BRCA1 genes and contrast the sequences with human BRCA1. T he amino terminal 120 residues of the gene are >80% identical among th e three species. The C-terminus is also highly conserved, containing a n 80 amino acid stretch that is over 80% identical. Motifs of likely f unctional significance are maintained, including the amino terminal RI NG finger motif (amino acids 24-64) and the granin consensus sequence (1214-1223). The distribution of missense mutations and neutral polymo rphisms identified in BRCA1-linked breast cancer suggests that disease associated missense mutations occur at highly conserved residues wher eas polymorphisms are in regions of lower conservation. Among eighteen missense mutations with unknown consequences, seven occur in amino ac ids that are identical across species. Four of these seven (E1219D, A1 708E, P1749R and M1775R) are also within conserved domains. Taken toge ther, these data predict regions of the gene which may be critical for normal function.