Negative epistasis between natural variants of the Saccharomyces cerevisiae MLH1 and PMS1 genes results in a defect in mismatch repair
Negative epistasis between natural variants of the Saccharomyces cerevisiae MLH1 and PMS1 genes results in a defect in mismatch repair
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DOI：
10.1073/pnas.0510998103
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发表时间：
2006-02-28
影响因子：
11.1
通讯作者：
Alani, E
中科院分区：
文献类型：
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作者：
Heck, JA;Argueso, JL;Alani, E
在芽殖酵母中，MLH 1-PMS 1异二聚体是主要的MutL同源复合物，其作用是修复DNA复制过程中出现的错配。使用一个高度敏感的诱变剂测定，我们观察到，酿酒酵母菌株轴承S288 c菌株衍生MLH 1基因和SK 1菌株衍生PMS 1基因显示突变率升高，赋予了长期的健身成本。使用S288 c-SK 1嵌合体对这种负上位相互作用进行解剖，发现每个基因中的单个氨基酸多态性导致了这种错配修复缺陷。如果这些菌株在自然种群中杂交，等位基因的分离将产生一种增变基因表型，尽管这种表型可能是短暂适应性的，但由于有害突变的积累，最终将被选择。这种适应性“不相容性”可能有助于地理上分散的酵母之间的生殖隔离。同样的分离突变表型表明了一种机制，可以解释一些被称为遗传性非息肉病性结直肠癌的人类癌症易感性综合征病例，以及一些散发性癌症。
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.