Negative epistasis between natural variants of the Saccharomyces cerevisiae MLH1 and PMS1 genes results in a defect in mismatch repair.
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.
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
Julie Akiko
JA
Heck
Juan Lucas
JL
Argueso
Zekeriyya
Z
Gemici
Richard Guy
RG
Reeves
Ann
A
Bernard
Charles F
CF
Aquadro
Eric
E
Alani
D048868:Adaptor Proteins, Signal Transducing; D020137:Base Pair Mismatch / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D004271:DNA, Fungal / Q000235:genetics / Q000378:metabolism; D004274:DNA, Recombinant / Q000235:genetics; D004843:Epistasis, Genetic; D019143:Evolution, Molecular; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004271:DNA, Fungal; D004274:DNA, Recombinant; D005656:Fungal Proteins; C088859:MLH1 protein, S cerevisiae; C088858:PMS1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins