Rate and effects of spontaneous mutations that affect fitness in mutator<i>Escherichia coli</i>

Trindade, Sandra; Perfeito, Lília; Gordo, Isabel

doi:10.1098/rstb.2009.0287

Cited by 57 publications

(107 citation statements)

References 70 publications

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“…Of the 1.2 × 10 7 possible codon-changing BPSs in the E. coli ge- (7,27), which is, at most, only a fourth of the total mutation rate observed here. The rate of beneficial mutations is even lower, and, in addition, most beneficial and deleterious mutations have only small (<3%) effects on fitness (7,27). Taken together, our results with the wild-type strain are consistent with these findings and support the basic premise that the MA protocol minimizes selection and allows mutations to accumulate in a nearly neutral fashion.…”

Section: Resultsmentioning

confidence: 99%

Rate and molecular spectrum of spontaneous mutations in the bacteriumEscherichia colias determined by whole-genome sequencing

Lee¹,

Popodi

Tang³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

648

131

859

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Knowledge of the rate and nature of spontaneous mutation is fundamental to understanding evolutionary and molecular processes. In this report, we analyze spontaneous mutations accumulated over thousands of generations by wild-type Escherichia coli and a derivative defective in mismatch repair (MMR), the primary pathway for correcting replication errors. The major conclusions are (i) the mutation rate of a wild-type E. coli strain is ∼1 × 10 −3 per genome per generation; (ii) mutations in the wild-type strain have the expected mutational bias for G:C > A:T mutations, but the bias changes to A:T > G:C mutations in the absence of MMR; (iii) during replication, A:T > G:C transitions preferentially occur with A templating the lagging strand and T templating the leading strand, whereas G:C > A:T transitions preferentially occur with C templating the lagging strand and G templating the leading strand; (iv) there is a strong bias for transition mutations to occur at 5′ApC3′/3′TpG5′ sites (where bases 5′A and 3′T are mutated) and, to a lesser extent, at 5′GpC3′/3′CpG5′ sites (where bases 5′G and 3′C are mutated); (v) although the rate of small (≤4 nt) insertions and deletions is high at repeat sequences, these events occur at only 1/10th the genomic rate of base-pair substitutions. MMR activity is genetically regulated, and bacteria isolated from nature often lack MMR capacity, suggesting that modulation of MMR can be adaptive. Thus, comparing results from the wild-type and MMR-defective strains may lead to a deeper understanding of factors that determine mutation rates and spectra, how these factors may differ among organisms, and how they may be shaped by environmental conditions. evolution | mutation accumulation | neutral mutation | mutational hotspots | indels M utations are the source of variation upon which natural selection acts; thus, a complete understanding of evolutionary processes must include an accurate assessment of mutation rates and of the molecular spectrum of mutational events. In addition, we need to know whether, and how, intrinsic and extrinsic factors influence mutational processes. This understanding must be founded on baseline parameters established by analyzing mutations that accumulate in a neutral fashion, unbiased by selective pressures. Much of our knowledge of spontaneous mutation is based on mutations that occur in nonessential reporter genes during short-term laboratory culture of microorganisms (1). An alternative approach is to compare presumably neutral mutations that have accumulated over evolutionary time periods in diverged species (2). Both methods have substantial uncertainties. The experimental approach may use reporter loci that are not representative of the whole genome and necessarily incorporates assumptions about the expression and neutrality of the mutant phenotypes. The historical approach relies on estimated divergence times and the absence of selective pressure on synonymous sequence changes. High-throughput whole-genome sequencing allows some of these limitations to be...

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Section: Resultsmentioning

confidence: 99%

Rate and molecular spectrum of spontaneous mutations in the bacteriumEscherichia colias determined by whole-genome sequencing

Lee¹,

Popodi

Tang³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

648

131

859

View full text Add to dashboard Cite

show abstract

“…Our knowledge of DMEs has come from laboratory experiments like that of Trindade et al (2010) and from population genetics approaches as used by Keightley & Eyre-Walker (2010), both of which are reported in this issue. Experimental approaches for inferring DMEs are based on mutation accumulation experiments pioneered by Mukai in Drosophila (Mukai et al 1972;Keightley & Eyre-Walker 1999;Lynch et al 1999), and one of the most extensive experiments of this type was completed by Charlesworth et al (2004).…”

Section: Mutationsmentioning

confidence: 99%

“…As we discuss below, some can be ordered on a continuum according to the selection coefficients of the most strongly selected mutations that they consider. More work on combining them is needed to deal with the findings of extreme diversity of mutational effects and Trindade et al 2010). Therefore, we start with the theory of background selection (BGS), developed primarily by Charlesworth et al (1993aCharlesworth et al ( , 1995Charlesworth et al ( , 1996a, and reviewed here by Stephan (2010).…”

Section: Theories On the Population Genetics Of Mutationsmentioning

confidence: 99%

“…This is a controversial subject on which Charlesworth (2000) has made significant contributions. Models of the evolution of pathogenic microbes (Sniegowski & Gerrish 2010) and their mutations (Trindade et al 2010) are important for medical applications, such as optimizing the use of antibiotics to minimize resistance evolution and developing vaccines that might anticipate and neutralize simple evolutionary changes a pathogen is expected to produce. The wealth of data that can be obtained for these systems makes them attractive subjects for basic research on evolution.…”

Section: General Questions and Applicationsmentioning

confidence: 99%

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The population genetics of mutations: good, bad and indifferent

Loewe

Hill

2010

Phil. Trans. R. Soc. B

202

129

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Population genetics is fundamental to our understanding of evolution, and mutations are essential raw materials for evolution. In this introduction to more detailed papers that follow, we aim to provide an oversight of the field. We review current knowledge on mutation rates and their harmful and beneficial effects on fitness and then consider theories that predict the fate of individual mutations or the consequences of mutation accumulation for quantitative traits. Many advances in the past built on models that treat the evolution of mutations at each DNA site independently, neglecting linkage of sites on chromosomes and interactions of effects between sites (epistasis). We review work that addresses these limitations, to predict how mutations interfere with each other. An understanding of the population genetics of mutations of individual loci and of traits affected by many loci helps in addressing many fundamental and applied questions: for example, how do organisms adapt to changing environments, how did sex evolve, which DNA sequences are medically important, why do we age, which genetic processes can generate new species or drive endangered species to extinction, and how should policy on levels of potentially harmful mutagens introduced into the environment by humans be determined?

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“…Combining related progress [23][24][25][26][27][28][29][30][31][32][33] in microbiology and molecular biology in recent years and the studies conducted in our laboratory [34][35][36][37][38][39][40][41][42][43], this paper first analyzes microbi-ological evidences for the Luria-Delbrück hypothesis, and discusses limitations and errors in applying the hypothesis to observed data and statistical analysis. It proceeds with a statistical re-analysis of the Luria-Delbrück data, from which new inferences are made.…”

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confidence: 99%

Discussion on research methods of bacterial resistant mutation mechanisms under selective culture—uncertainty analysis of data from the Luria-Delbrück fluctuation experiment

Jin

Wei

Yang

et al. 2012

Sci. China Life Sci.

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Whether bacterial drug-resistance is drug-induced or results from rapid propagation of random spontaneous mutations in the flora prior to exposure, remains a long-term key issue concerned and debated in both genetics and medicinal fields. In a pioneering study, Luria and Delbrück exposed E. coli to T1 phage, to investigate whether the number of resistant colonies followed the Poisson distribution. They deduced that the development of resistant colonies is independent of phage presence. Similar results have since been obtained on solid medium containing antibacterial agents. Luria and Delbrück's conclusions were long considered a gold standard for analyzing drug resistance mutations. More recently, the concept of adaptive mutation has triggered controversy over this approach. Microbiological observation shows that, following exposure to drugs of various concentrations, drug-resistant cells emerge and multiply depending on the time course, and show a process function, inconsistent with the definition of Poisson distribution (which assumes not only that resistance is independent of drug quantity but follows no specific time course). At the same time, since cells tend to aggregate after division rather than separating, colonies growing on drug plates arise from the multiplication of resistant bacteria cells of various initial population sizes. Thus, statistical analysis based on equivalence of initial populations will yield erroneous results. In this paper, 310 data from the Luria-Delbrück fluctuation experiment were reanalyzed from this perspective. In most cases, a high-end abnormal value, resulting from the non-synchronous variation of the two above-mentioned time variables, was observed. Therefore, the mean value cannot be regarded as an unbiased expectation estimate. The ratio between mean value and variance was similarly incomparable, because two different sampling methods were used. In fact, the Luria-Delbrück data appear to follow an aggregated, rather than Poisson distribution. In summary, the statistical analysis of Luria and Delbrück is insufficient to describe rules of resistant mutant development and multiplication. Correction of this historical misunderstanding will enable new insight into bacterial resistance mechanisms.

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Rate and effects of spontaneous mutations that affect fitness in mutatorEscherichia coli

Cited by 57 publications

References 70 publications

Rate and molecular spectrum of spontaneous mutations in the bacteriumEscherichia colias determined by whole-genome sequencing

Rate and molecular spectrum of spontaneous mutations in the bacteriumEscherichia colias determined by whole-genome sequencing

The population genetics of mutations: good, bad and indifferent

Discussion on research methods of bacterial resistant mutation mechanisms under selective culture—uncertainty analysis of data from the Luria-Delbrück fluctuation experiment

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