{"doi":"10.1534/genetics.109.108803","title":"Evolution at a High Imposed Mutation Rate: Adaptation Obscures the Load in Phage T7","abstract":"<jats:title>Abstract</jats:title><jats:p>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.</jats:p>","journal":"Genetics","year":2010,"id":46160,"datarank":1.9360926776468763,"base_score":3.9318256327243257,"endowment":3.9318256327243257,"self_citation_contribution":0.5897738449086489,"citation_network_contribution":1.3463188327382274,"self_endowment_contribution":0.5897738449086489,"citer_contribution":1.3463188327382274,"corpus_percentile":null,"corpus_rank":null,"citation_count":50,"citer_count":44,"citers_with_citation_signal":35,"citers_with_endowment":35,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":214497,"name":"T Keller","orcid":null,"position":1,"is_corresponding":false},{"id":214498,"name":"I J Molineux","orcid":null,"position":2,"is_corresponding":false},{"id":214499,"name":"J J Bull","orcid":null,"position":3,"is_corresponding":false},{"id":214496,"name":"R Springman","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":3.9318256327243257,"endowment":3.9318256327243257,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19858285","pmcid":"PMC2815918","openalex_id":"https://openalex.org/W2155896989","authors":[],"funders":[{"funder_name":"NIGMS NIH HHS","grant_id":"R01 GM032095","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"R01 GM057756","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"GM 57756","title":null}],"total_grants":3,"fwci":4.2395,"citation_percentile":0.94650687,"influential_citations":3,"citation_trend":[{"year":2012,"count":7},{"year":2013,"count":5},{"year":2014,"count":1},{"year":2015,"count":1},{"year":2016,"count":4},{"year":2017,"count":3},{"year":2018,"count":1},{"year":2019,"count":4},{"year":2020,"count":2},{"year":2021,"count":1},{"year":2024,"count":3},{"year":2025,"count":3},{"year":2026,"count":1}],"oa_status":"bronze","license":"https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model","oa_locations":[{"url":"https://academic.oup.com/genetics/article-pdf/184/1/221/49429446/genetics0221.pdf","host_type":"journal"},{"url":"https://academic.oup.com/genetics/article-pdf/184/1/221/49429446/genetics0221.pdf","host_type":"BRONZE"},{"url":"https://academic.oup.com/genetics/article-pdf/184/1/221/49429446/genetics0221.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1534/genetics.109.108803","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/19858285","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/2815918","host_type":"repository"}],"fields_of_study":["Evolution and Genetic Dynamics","CRISPR and Genetic Engineering","Bacteriophages and microbial interactions","Biology","Medicine","Environmental Science","Adaptation, Biological","Bacteriophage T7","DNA-Directed DNA Polymerase","Evolution, Molecular","Genome, Viral","Mutagenesis","Mutagens","Mutation","Sequence Analysis, DNA"],"mesh_terms":["Adaptation, Biological","DNA-Directed DNA Polymerase","Mutagens","Mutation","Mutagenesis","Genome, Viral","Bacteriophage T7","Sequence Analysis, DNA","Evolution, Molecular"],"keywords":["Biology","Mutation rate","Genetics","Experimental evolution","Mutation","Mutation Accumulation","Population","Genetic load","Mutagenesis","Genetic Fitness","Mutagen","Viral evolution","Effective population size","DNA polymerase","DNA","Genome","Gene","Genetic variation"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"gen"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-07T03:10:37.219010Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}