Evolution at a high imposed mutation rate: adaptation obscures the load in phage T7

Area of Science:

• Evolutionary Biology
• Microbiology
• Genetics

Background:

• High mutation rates are theoretically expected to decrease population fitness due to deleterious mutations, a principle known as lethal mutagenesis.
• This concept underpins the use of mutagenic drugs for treating viral infections.

Purpose of the Study:

• To investigate the long-term impact of a high mutation rate on viral fitness.
• To test the validity of the lethal mutagenesis theory in a DNA bacteriophage model system.

Main Methods:

• A large population of DNA bacteriophage T7 was cultured with a mutagen, achieving a genomic mutation rate 2-3 orders of magnitude above baseline.
• Fitness was assessed by viral growth rate, and genomic mutations were analyzed over 200 generations.

Main Results:

• Contrary to predictions, viral fitness increased after 200 generations.
• A high mutation load was observed, with an average of 245 mutations per genome and an 80% decrease in burst size.
• Twenty-eight mutations, primarily in DNA metabolism genes like DNA polymerase, reached high frequency, suggesting adaptation.

Conclusions:

• The study refutes the deterministic decline in fitness predicted by lethal mutagenesis theory at high mutation rates.
• Adaptive evolution can occur even under substantial mutation pressure, highlighting the plasticity of viral genomes.
• The findings challenge the quantitative basis of lethal mutagenesis and suggest potential for viral adaptation rather than extinction.