At the BRCA1 tumor suppressor gene, large genomic deletions frequently occur as somatic loss of heterozygosity in breast tumors and as inherited mutations in families. These genomic deletions appear to be the result of aberrant homologous recombination between Alu repetitive elements, which are densely packed at the BRCA1 locus. My hypothesis is that loss of function of a still unknown mutator gene(s) leads to increased frequency of homologous recombination and thereby increased frequency of large genomic deletions at susceptible loci such as BRCA1. The purpose of my project is to identify such mutator gene(s) using BRCA1 as a model. I will create a construct incorporating BRCA1 exons and their flanking Alu sequences to assay for genomic deletions in the Saccharomyces Genome Project collection of yeast strains comprised of all viable individual gene knockouts. After isolating candidate yeast mutator genes, I will identify their human homologs, and screen for mutations in them in breast tumors and in high-risk breast cancer families who are wildtype for all known breast cancer genes.