Human Molecular Genetics Advance Access published online on January 8, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddl479
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© The Author 2007. Published by Oxford University Press. All rights reserved
The effect of genetic background on the function of Saccharomyces cerevisiae mlh1 alleles that correspond to HNPCC missense mutations.
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853
* Corresponding Author: Dr. Eric Alani Department of Molecular Biology and Genetics, Cornell University, 459 Biotechnology Building, Ithaca, NY 14853-2703, Telephone: 607-254-4811 FAX: 607-255-6249 E-mail: eea3{at}cornell.edu
Received September 1, 2006; Revised December 28, 2006; Accepted December 28, 2006
Germline mutations in the DNA mismatch repair (MMR) gene MLH1 are associated with a large percentage of hereditary non-polyposis colorectal cancers (HNPCC). There are approximately 250 known human mutations in MLH1. Of these, one-third are missense variants which are often difficult to characterize with regards to pathogenicity. We analyzed 28 alleles of baker's yeast MLH1 that correspond to non-truncating human mutant alleles listed in online HNPCC databases, thirteen of which had not been previously studied in functional assays. Using the highly sensitive lys2::InsE-A14 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 fifteen 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.
# These authors contributed equally to this work.
Grant Sponsor: National Institutes of Health GM53085
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