title: The effect of genetic background on the function of Saccharomyces cerevisiae mlh1 alleles that correspond to HNPCC missense mutations.
abstract: Germline mutations in the DNA mismatch repair (MMR) gene MLH1 are associated with a large percentage of hereditary non-polyposis colorectal cancers. There are approximately 250 known human mutations in MLH1. Of these, one-third are missense variants that are often difficult to characterize with regards to pathogenicity. We analysed 28 alleles of baker's yeast MLH1 that correspond to non-truncating human mutant alleles listed in online HNPCC databases, 13 of which had not been previously studied in functional assays. Using the highly sensitive lys2::InsE-A(14) reversion rate assay, we determined the MMR proficiency conferred by each allele in the S288c strain of Saccharomyces cerevisiae. Seven alleles conferred a null phenotype for MMR and eight others showed significant MMR defects, suggesting that all 15 are likely to be pathogenic in humans. In addition, we observed a strong correlation between these results, limited results from previous functional assays and clinical data. To test whether the potential pathogenicity of certain alleles depends on the genetic background of the host, we examined the mutation rates conferred by the mlh1 alleles in a second yeast strain, SK1, which is approximately 0.7% divergent from S288c. Many alleles displayed a difference in MMR efficiency between strain backgrounds with decreasing differences as the severity of the MMR defect increased. These findings suggest that genetic background can play an important role in determining the pathogenicity of MMR alleles and may explain cases of atypical colorectal cancer inheritance.
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Wanat
authors.forename: Nikhil
authors.initials: N
authors.lastname: Singh
authors.forename: Eric
authors.initials: E
authors.lastname: Alani
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D005656:Fungal Proteins / Q000235:genetics* / Q000502:physiology*; D005787:Gene Frequency; D006801:Humans; D000070957:MutL Protein Homolog 1; D020125:Mutation, Missense; D030781:Organisms, Genetically Modified; D010641:Phenotype; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D005656:Fungal Proteins; C088859:MLH1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D000070957:MutL Protein Homolog 1