Evolution at high mutation rates is expected to reduce population fi tness deterministically by the accumulation of deleterious mutations. A high enough rate should even cause extinction (lethal mutagenesis), a principle motivating the clinical use of mutagenic drugs to treat viral infections. The impact of a high mutation rate on long-term viral fi tness was tested here. A large population of the DNA bacteriophage T7 was grown with a mutagen, producing a genomic rate of 4 non-lethal mutations per generation, 2-3 orders of magnitude above the baseline rate. Fitness - viral growth rate in the mutagenic environment - was predicted to decline substantially; after 200 generations, fi tness had increased, rejecting the model. A high mutation load was nonetheless evident from (i) many low- to moderate-frequency mutations in the population (averaging 245 per genome), and (ii) an 80% drop in average burst size. Twenty eight mutations reached high frequency and were thus presumably adaptive, clustered mostly in DNA metabolism genes, chie fl y DNA polymerase. Yet blocking DNA polymerase evolution failed to yield a fi tness decrease after 100 generations. Although mutagenic drugs have caused viral extinction in vitro under some conditions, this study is the fi rst to match theory and fi tness evolution at a high mutation rate. Failure of the theory challenges the quantitative basis of lethal mutagenesis and highlights the potential for adaptive evolution at high mutation rates.
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