Negative epistasis between natural variants of the Saccharomyces cerevisiae MLH1 and PMS1 genes results in a defect in mismatch repair

doi:10.1073/pnas.0510998103

Negative epistasis between natural variants of the Saccharomyces cerevisiae MLH1 and PMS1 genes results in a defect in mismatch repair

Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853

Communicated by Thomas D. Petes, University of North Carolina, Chapel Hill, NC, December 20, 2005 (received for review June 22, 2005)

Abstract

In budding yeast, the MLH1-PMS1 heterodimer is the major MutL homolog complex that acts to repair mismatches arising during DNA replication. Using a highly sensitive mutator assay, we observed that Saccharomyces cerevisiae strains bearing the S288c-strain-derived MLH1 gene and the SK1-strain-derived PMS1 gene displayed elevated mutation rates that conferred a long-term fitness cost. Dissection of this negative epistatic interaction using S288c-SK1 chimeras revealed that a single amino acid polymorphism in each gene accounts for this mismatch repair defect. Were these strains to cross in natural populations, segregation of alleles would generate a mutator phenotype that, although potentially transiently adaptive, would ultimately be selected against because of the accumulation of deleterious mutations. Such fitness “incompatibilities” could potentially contribute to reproductive isolation among geographically dispersed yeast. This same segregational mutator phenotype suggests a mechanism to explain some cases of a human cancer susceptibility syndrome known as hereditary nonpolyposis colorectal cancer, as well as some sporadic cancers.

Footnotes

^†To whom correspondence should be addressed at:
Department of Molecular Biology and Genetics, Cornell University, 459 Biotechnology Building, Ithaca, NY 14853-2703.
E-mail: eea3{at}cornell.edu
↵*Present address: Dipartimento di Medicina Sperimentale e Science Biochimiche, Facoltá di Medicina, Sezione Microbiologia, Universita’ di Perugia, Via del Giochetto, 06100 Perugia, Italy.
Author contributions: J.A.H., J.L.A., Z.G., A.B., C.F.A., and E.A. designed research; J.A.H., J.L.A., Z.G., and A.B. performed research; J.A.H., J.L.A., Z.G., R.G.R., and C.F.A. contributed new reagents/analytic tools; J.A.H., J.L.A., Z.G., R.G.R., C.F.A., and E.A. analyzed data; and J.A.H., C.F.A., and E.A. wrote the paper.
Conflict of interest statement: No conflicts declared.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database [accession nos. DQ356633–DQ356646 (MLH1) and DQ356628–DQ356632 (PMS1)].
Abbreviations:

Abbreviations:

MMR,

mismatch repair;

HNPCC,

hereditary nonpolyposis colorectal cancer;

MSH,

MutS homolog;

MLH,

MutL homolog