MURINE BRCA1 - SEQUENCE AND SIGNIFICANCE FOR HUMAN MISSENSE MUTATIONS

We have cloned and sequenced a mouse homologue of the human breast and ovarian cancer susceptibility gene, BRCA1. The predicted mouse Brca1 protein is composed of 1812 amino acids, The murine protein is 60% ide ntical and 72% similar to the human BRCA1 protein, Two regions of high homology have been identified between the two proteins. First is the Cys3-His-Cys4 type zinc-finger domain that is identical between the tw o proteins, The second region is defined by 115 amino acids near the c arboxy end of the Brca1 protein that is 83% identical to human BRCA1 s equence. Seven of eight amino acids involved in human missense mutatio ns that are associated with the disease were found to be conserved bet ween the two species, In contrast, most of the amino acids that are in volved in polymorphic variations were not conserved. We therefore prop ose that the interspecies conservation of predicted amino acid sequenc es can be used as an additional criterion to determine the significanc e of human missense mutations.