The allelic heterogeneity of BRCA1, BRCA2, ATM, MLH1, MSH2, and MSH6 mutations creates a challenge for developing an inexpensive and efficient diagnostic test to identify all possible sequence changes in these genes. In collaboration with Affymetrix, oligonucleotide microarrays (DNA chips) consisting of over 200,000 oligonucleotides were designed to screen for mutations in these hereditary breast and colon cancer genes. Blinded mutaional analysis yielded over 90% sensitivity for the BRCA1 and ATM genes, with the false negatives all involving repetitive sequence changes. A systematic survey of over 20 such changes in the BRCA1 gene was undertaken to more fully define the sensitivity of the DNA chips assays. We also applied DNA chip analysis to determine the distant history of human single nucleotide polymorphisms (SNPs). Orthologs from 397 human SNPs were analyzed from great ape DNA samples and 214 proposed ancestral alleles were determined. SNP alleles with higher frequencies were more likely to be ancestral than less frequently occurring alleles, but there were exceptions. Such information could increase the utility of SNPs in linkage disequilibrium studies. In addition, five shared human/great ape polymorphisms were found. The frequency of such occurrences may provide information on relative rates of mutation, recombination, gene conversion, and positive selection. - genetics, cancer research, breast cancer, ovarian cancer, BRCA1/2, human genome research, colo-rectal cancer
