Academic journal article Genetics

DNA Replication Error-Induced Extinction of Diploid Yeast

Academic journal article Genetics

DNA Replication Error-Induced Extinction of Diploid Yeast

Article excerpt

(ProQuest: ... denotes formulae omitted.)

EVOLUTIONARY selection for long-term fi tness acts on the genes for DNA replication and repair, driving spontane- ous mutation rates to a low level (Lynch 2010). Yet at times, selection favors cells with mutator phenotypes that increase the adaptive mutation rate (Chao and Cox 1983; Mao et al. 1997; Sniegowski et al. 1997; Giraud et al. 2001; Notley- Mcrobb et al. 2002; Nilsson et al. 2004; Loh et al. 2010). Many of the general principles governing mutators in repli- cating populations have been established using microbes. Mutators are common in microbial populations because they continually arise and hitchhike on the fitness effects of rare adaptive mutations (Mao et al. 1997; Drake et al. 1998). The relative fitness of mutators is maximal when selection con- ditions require multiple adaptive mutations (Mao et al. 1997; De Visser 2002). But most mutations are deleterious (Sturtevant 1937; Funchain et al. 2000; Giraud et al. 2001), and for haploids, the short-term benefits of being a mutator rapidly erode as mutation burden increases.

To avoid extinction following adaptation, cells must either replace the mutator allele with a wild-type copy (Herr et al. 2011; L. N. Williams et al. 2013) or acquire antimutator mutations that suppress the mutator phenotype (Tröbner and Piechocki 1984; Schaaper and Cornacchio 1992; Fijalkowska and Schaaper 1995; Giraud et al. 2001; Herr et al. 2011; L. N. Williams et al. 2013). Error-induced extinction occurs within a few cell divisions in bacterial and haploid yeast cells lacking both DNA polymerase proofreading and mismatch repair (MMR), because mutation rates exceed an error threshold of one inactivating mutation per essential gene per cell division (Morrison et al. 1993; Fijalkowska and Schaaper 1996; Herr et al. 2011; L. N. Williams et al. 2013). When cells replicate near the haploid error thresh- old, antimutators readily emerge, indicating that strong mutator phenotypes may be inherently transient (Fijalkowska and Schaaper 1996; Herr et al. 2011; L. N. Williams et al. 2013). Thus, while the need for genetic diversity selects for the emergence of mutators during adaptation, the accumu- lation of deleterious mutations limits the persistence of mutators.

Mammalian mutator phenotypes are theorized to play a role in the somatic evolution of tumor cells (Loeb et al. 1974; Loeb 2011). Ample support exists for this hypothesis. Families predisposed to colon and endometrial cancer en- code defects in MMR components or polymerase proofread- ing that increase mutation rate (Lynch et al. 2009; Cancer Genome Atlas Network 2012a; Palles et al. 2012; Church et al. 2013; Kandoth et al. 2013). Mice with engineered defects in MMR (Baker et al. 1995, 1996; De Wind et al. 1995; Edelmann et al. 1996, 1997; Reitmair et al. 1996), poly- merase proofreading (Goldsby et al. 2001, 2002; Albertson et al. 2009), or polymerase accuracy (Venkatesan et al. 2007) also display elevated mutation rates and cancer pre- disposition. Finally, deep sequencing of cancer genomes from human patients reveals thousands of clonal mutations, the hallmark of a mutator phenotype (Loeb 2011; Cancer Ge- nome Atlas Network 2012a,b; Imielinski et al. 2012; Nik-Zainal et al. 2012; Palles et al. 2012; Pugh et al. 2012; Kandoth et al. 2013). Some hypermutated intestinal and endometrial tumors carry defects in both MMR and DNA polymerase proofreading, consistent with synergy between these two pathways in human disease (Cancer Genome Atlas Network 2012a; Palles et al. 2012; Church et al. 2013; Kandoth et al. 2013).

Unlike haploid mutators, diploid mutators are buffered from the effects of recessive deleterious mutations (Morrison et al. 1993). Diploid yeast tolerate mutation loads that are lethal to their haploid offspring (Wloch et al. 2001). This tolerance for recessive mutations has the important benefit of allowing diploid mutators to remain competitive after the acquisition of adaptive mutations (Thompson et al. …

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