Evolution at a high imposed mutation rate: adaptation obscures the load in phage T7.
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 nonlethal mutations per generation, two to three 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.
Springman
R
R
Institute for Cellular and Molecular Biology, Center for Computational Biology and Bioinformatics, Section of Integrative Biology, Section of Molecular Genetics and Microbiology, University of Texas, Austin, Texas 78712, USA.
Keller
T
T
Molineux
I J
IJ
Bull
J J
JJ
D000220:Adaptation, Biological / Q000187:drug effects / Q000235:genetics*; D017123:Bacteriophage T7 / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development / Q000502:physiology; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D019143:Evolution, Molecular; D016679:Genome, Viral / Q000235:genetics; D016296:Mutagenesis / Q000187:drug effects / Q000235:genetics*; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D017422:Sequence Analysis, DNA
D009153:Mutagens; D004259:DNA-Directed DNA Polymerase