Mutator phenotype due to loss of heterozygosity in diploid yeast strains with mutations in MSH2 and MLH1

Mutations in mismatch repair (MMR) genes predispose humans to cancer. Parti cularly prevalent are frameshift and point mutations in MSH2 and MLH1, two genes whose products are required for the early steps in MMR. In normal tis sues of persons predisposed to hereditary non-polyposis colon cancer (HNPCC ), these mutations are usually present in only one allele. In tumor cells o f these patients, the second, wild type allele is typically found to be del eted or inactivated by point mutation. This suggests that loss of heterozyg osity (LOH) results in a strong mutator phenotype that could eventually lea d to the onset of disease. Here we demonstrate that diploid yeast strains t hat are heterozygous for MSH2 and MLH1 alleles have an elevated mutation ra te. We further show that this effect results not from saturation of the MMR capacity of all cells in the population, but rather from loss of the wild type allele in a subpopulation of heterozygous cells. These results have im plications for understanding the mechanisms of carcinogenesis in humans. (C ) 2000 Published by Elsevier Science Ireland Ltd. All rights reserved.