{"doi":"10.1016/j.cell.2018.10.021","title":"Scalable, Continuous Evolution of Genes at Mutation Rates above Genomic Error Thresholds","abstract":null,"journal":"Cell","year":2018,"id":595791,"datarank":0.8643077074170267,"base_score":5.762051382780177,"endowment":5.762051382780177,"self_citation_contribution":0.8643077074170267,"citation_network_contribution":0.0,"self_endowment_contribution":0.8643077074170267,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":317,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"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":570434,"name":"Garri A. Arzumanyan","orcid":null,"position":1,"is_corresponding":false},{"id":1525819,"name":"Muaeen K.A. Obadi","orcid":null,"position":2,"is_corresponding":false},{"id":827389,"name":"Alex A. Javanpour","orcid":null,"position":3,"is_corresponding":false},{"id":272468,"name":"Chang C. Liu","orcid":"0000-0002-3290-2880","position":4,"is_corresponding":false},{"id":570433,"name":"Arjun Ravikumar","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Scalable, Continuous Evolution of Genes at Mutation Rates above Genomic Error Thresholds","abstract":"Directed evolution is a powerful approach for engineering biomolecules and understanding adaptation. However, experimental strategies for directed evolution are notoriously labor intensive and low throughput, limiting access to demanding functions, multiple functions in parallel, and the study of molecular evolution in replicate. We report OrthoRep, an orthogonal DNA polymerase-plasmid pair in yeast that stably mutates ∼100,000-fold faster than the host genome in vivo, exceeding the error threshold of genomic replication that causes single-generation extinction. User-defined genes in OrthoRep continuously and rapidly evolve through serial passaging, a highly straightforward and scalable process. Using OrthoRep, we evolved drug-resistant malarial dihydrofolate reductases (DHFRs) in 90 independent replicates. We uncovered a more complex fitness landscape than previously realized, including common adaptive trajectories constrained by epistasis, rare outcomes that avoid a frequent early adaptive mutation, and a suboptimal fitness peak that occasionally traps evolving populations. OrthoRep enables a new paradigm of routine, high-throughput evolution of biomolecular and cellular function.","is_dataset_classified":null,"base_score":5.762051382780177,"endowment":5.762051382780177,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"30415839","pmcid":"PMC6343851","openalex_id":"https://openalex.org/W2952856897","authors":[],"funders":[{"funder_name":"NIH","grant_id":"1DP2GM119163-01","title":"A High-Throughput Continuous Evolution System for in vivo Biosensor Engineering"},{"funder_name":"Defense Advanced Research Projects Agency","grant_id":"HR0011-15-2-0031","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"DP2 GM119163","title":null},{"funder_name":"National Science Foundation","grant_id":"1545158","title":"ERA SynBio: Orthogonal Replication as the Platform for an Episome"},{"funder_name":"Beckman Young Investigator Award","grant_id":"","title":null},{"funder_name":"Dupont Young Professor Award","grant_id":"","title":null},{"funder_name":"Sloan Research Fellowship","grant_id":"","title":null},{"funder_name":"UC Irvine","grant_id":"","title":null}],"total_grants":8,"fwci":14.2725,"citation_percentile":0.99313907,"influential_citations":0,"citation_trend":[{"year":2018,"count":3},{"year":2019,"count":14},{"year":2020,"count":30},{"year":2021,"count":42},{"year":2022,"count":25},{"year":2023,"count":45},{"year":2024,"count":76},{"year":2025,"count":56},{"year":2026,"count":26}],"oa_status":"bronze","license":"Elsevier Non-Commercial","oa_locations":[{"url":"http://www.cell.com/article/S0092867418313308/pdf","host_type":"journal"},{"url":"http://www.cell.com/article/S0092867418313308/pdf","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0092867418313308?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0092867418313308?httpAccept=text/plain","host_type":"publisher"},{"url":"https://doi.org/10.1016/j.cell.2018.10.021","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/30415839","host_type":"repository"},{"url":"https://escholarship.org/uc/item/0ww85211","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/6343851","host_type":"repository"},{"url":"https://doi.org/10.1101/313338","host_type":""},{"url":"https://dx.doi.org/10.1101/313338","host_type":""},{"url":"https://dx.doi.org/10.1016/j.cell.2018.10.021","host_type":""},{"url":"http://dx.doi.org/10.1101/313338","host_type":""},{"url":"https://doi.org/https://doi.org/10.1016/j.cell.2018.10.021","host_type":""}],"fields_of_study":["Evolution and Genetic Dynamics","CRISPR and Genetic Engineering","Genomics and Phylogenetic Studies","0301 basic medicine","03 medical and health sciences","Adaptation, Physiological","DNA-Directed DNA Polymerase","Genome, Fungal","Models, Genetic","Mutation Rate","Saccharomyces cerevisiae","Saccharomyces cerevisiae Proteins"],"mesh_terms":["Adaptation, Physiological","DNA-Directed DNA Polymerase","Models, Genetic","Saccharomyces cerevisiae","Genome, Fungal","Saccharomyces cerevisiae Proteins","Mutation Rate"],"keywords":["Biology","Experimental evolution","Directed evolution","Genetic Fitness","Adaptation (eye)","Epistasis","Directed Molecular Evolution","Genetics","Gene","Computational biology","Mutation","Genome","Mutant","Drug resistance","Error Threshold","Biomolecular Evolution","Continuous Evolution","Orthogonal Replication","Biomedical and clinical sciences","Saccharomyces cerevisiae Proteins","Physiological","DNA-Directed DNA Polymerase","Saccharomyces cerevisiae","Medical and Health Sciences","Rare Diseases","Genetic","Mutation Rate","Models","Adaptation","Models, Genetic","Human Genome","Biological Sciences","Adaptation, Physiological","Fungal","Generic health relevance","Genome, Fungal","Biotechnology","Developmental Biology"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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