Evolution at a High Imposed Mutation Rate: Adaptation Obscures the Load in Phage T7

A Publication of The Genetics Society of America

Rachael Springman 1, Thomas Keller 1, Ian Molineux 1 and James J. Bull 1*

1 University of Texas at Austin

Manuscript received August 20, 2009
Manuscript accepted October 20, 2009


Evolution at high mutation rates is expected to reduce population fitness 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 fitness 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, fitness 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, chiefly DNA polymerase. Yet blocking DNA polymerase evolution failed to yield a fitness decrease after 100 generations. Although mutagenic drugs have caused viral extinction in vitro under some conditions, this study is the first to match theory and fitness 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.

Key Words: adaptation, evolution, lethal mutagenesis, mutation accumulation, virus

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