1. Rates and kinds of spontaneous mutations were measured in the eubacterial thermophile Thermus thermophilus. The mutation rate and fraction of base-pair substitutions were indistinguishable from those observed previously in the archaeon Sulfolobus acidocaldarius and were markedly lower than in other DNA microbes. This result strongly supports the hypothesis that the average missense mutation is more deleterious at higher temperatures, which in turn drives the evolution of lower rates of base substitution. These combined results also allow us to reinterpret a classical study to conclude that all three domains of life exhibit the same rate of molecular evolution, but that among the prokaryotes, the thermophiles evolve more slowly.? 2. We reported previously that most mutational spectra contain more mutants with multiple mutations than expected from a random distribution of the mutations. The nonrandom distribution of mutations in tobacco mosaic virus has been modeled as the sum of two sub-populations, a majority with a low mutation frequency and a minority with a high mutation frequency. If this result is general, it will help to model the average mutation rate of riboviruses in combination with their rapid evolution within the host but relative genomic stability over time. Now we are attempting to establish a phage system in which such questions can be more efficiently addressed. We also reported that DNA polymerase molecules copying a template in vitro can produce nonrandom bursts of mutations, suggesting that a substantial minority of the polymerase molecules have a mutator phenotype. Now we are establishing systems to determine the molecular basis of such events. To date, we find evidence suggesting that at least some polymerase molecules have both greater processivity and reduced fidelity.

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Kissling, Grace E; Grogan, Dennis W; Drake, John W (2013) Confounders of mutation-rate estimators: selection and phenotypic lag in Thermus thermophilus. Mutat Res 749:16-20
García-Villada, Libertad; Drake, John W (2013) Experimental selection reveals a trade-off between fecundity and lifespan in the coliphage Qß. Open Biol 3:130043
García-Villada, Libertad; Drake, John W (2012) The three faces of riboviral spontaneous mutation: spectrum, mode of genome replication, and mutation rate. PLoS Genet 8:e1002832
Drake, John W (2012) Contrasting mutation rates from specific-locus and long-term mutation-accumulation procedures. G3 (Bethesda) 2:483-5
Burch, Lauranell H; Zhang, Leilei; Chao, Frank G et al. (2011) The bacteriophage T4 rapid-lysis genes and their mutational proclivities. J Bacteriol 193:3537-45
Drake, John W (2009) Avoiding dangerous missense: thermophiles display especially low mutation rates. PLoS Genet 5:e1000520
Drake, John W (2007) Mutations in clusters and showers. Proc Natl Acad Sci U S A 104:8203-4
Mackwan, Reena R; Carver, Geraldine T; Drake, John W et al. (2007) An unusual pattern of spontaneous mutations recovered in the halophilic archaeon Haloferax volcanii. Genetics 176:697-702
Drake, John W (2007) Too many mutants with multiple mutations. Crit Rev Biochem Mol Biol 42:247-58
Drake, John W (2006) Chaos and order in spontaneous mutation. Genetics 173:1-8

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