{"doi":"10.1371/journal.pgen.1004149","title":"Mapping the Fitness Landscape of Gene Expression Uncovers the Cause of Antagonism and Sign Epistasis between Adaptive Mutations","abstract":null,"journal":"PLoS Genetics","year":2014,"id":640944,"datarank":0.687745121800586,"base_score":4.584967478670572,"endowment":4.584967478670572,"self_citation_contribution":0.687745121800586,"citation_network_contribution":0.0,"self_endowment_contribution":0.687745121800586,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":97,"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":1460489,"name":"Nigel F. Delaney","orcid":"0000-0001-9524-2691","position":1,"is_corresponding":false},{"id":570941,"name":"Jeremy A. Draghi","orcid":"0000-0002-7609-7836","position":2,"is_corresponding":false},{"id":561889,"name":"Christopher J. Marx","orcid":"0000-0002-5189-4580","position":3,"is_corresponding":false},{"id":1666107,"name":"Hsin-Hung Chou","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Mapping the Fitness Landscape of Gene Expression Uncovers the Cause of Antagonism and Sign Epistasis between Adaptive Mutations","abstract":"How do adapting populations navigate the tensions between the costs of gene expression and the benefits of gene products to optimize the levels of many genes at once? Here we combined independently-arising beneficial mutations that altered enzyme levels in the central metabolism of Methylobacterium extorquens to uncover the fitness landscape defined by gene expression levels. We found strong antagonism and sign epistasis between these beneficial mutations. Mutations with the largest individual benefit interacted the most antagonistically with other mutations, a trend we also uncovered through analyses of datasets from other model systems. However, these beneficial mutations interacted multiplicatively (i.e., no epistasis) at the level of enzyme expression. By generating a model that predicts fitness from enzyme levels we could explain the observed sign epistasis as a result of overshooting the optimum defined by a balance between enzyme catalysis benefits and fitness costs. Knowledge of the phenotypic landscape also illuminated that, although the fitness peak was phenotypically far from the ancestral state, it was not genetically distant. Single beneficial mutations jumped straight toward the global optimum rather than being constrained to change the expression phenotypes in the correlated fashion expected by the genetic architecture. Given that adaptation in nature often results from optimizing gene expression, these conclusions can be widely applicable to other organisms and selective conditions. Poor interactions between individually beneficial alleles affecting gene expression may thus compromise the benefit of sex during adaptation and promote genetic differentiation.","is_dataset_classified":null,"base_score":4.584967478670572,"endowment":4.584967478670572,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"24586190","pmcid":"PMC3937219","openalex_id":"https://openalex.org/W2098920163","authors":[],"funders":[{"funder_name":"NIGMS NIH HHS","grant_id":"R01 GM078209","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"GM078209","title":null},{"funder_name":"National Institutes of Health","grant_id":"5R01GM078209-05","title":"Systems-level physiological basis of selection and epistasis in adaptation"}],"total_grants":3,"fwci":6.8213,"citation_percentile":0.973097,"influential_citations":0,"citation_trend":[{"year":2014,"count":10},{"year":2015,"count":7},{"year":2016,"count":9},{"year":2017,"count":6},{"year":2018,"count":7},{"year":2019,"count":10},{"year":2020,"count":7},{"year":2021,"count":10},{"year":2022,"count":7},{"year":2023,"count":1},{"year":2024,"count":9},{"year":2025,"count":8},{"year":2026,"count":6}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1004149&type=printable","host_type":"journal"},{"url":"https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1004149&type=printable","host_type":"publisher"},{"url":"http://dx.plos.org/10.1371/journal.pgen.1004149","host_type":"publisher"},{"url":"https://doi.org/10.1371/journal.pgen.1004149","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/24586190","host_type":"repository"},{"url":"http://nrs.harvard.edu/urn-3:HUL.InstRepos:12064360","host_type":"repository"},{"url":"http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.791.4929","host_type":""},{"url":"http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.901.1020","host_type":""},{"url":"https://doaj.org/article/64edf8059db24ec484ccd1ee523bf073","host_type":"repository"},{"url":"http://europepmc.org/articles/PMC3937219","host_type":"repository"},{"url":"https://figshare.com/articles/dataset/_Mapping_the_Fitness_Landscape_of_Gene_Expression_Uncovers_the_Cause_of_Antagonism_and_Sign_Epistasis_between_Adaptive_Mutations_/947175","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/3937219","host_type":"repository"},{"url":"http://hdl.handle.net/20.500.11850/83920","host_type":"repository"},{"url":"https://doi.org/10.3929/ethz-b-000083920","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC3937219","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC3937219?pdf=render","host_type":"Europe_PMC"},{"url":"https://dx.doi.org/10.3929/ethz-b-000083920","host_type":""},{"url":"http://dx.doi.org/10.1371/journal.pgen.1004149","host_type":""},{"url":"https://dx.doi.org/10.1371/journal.pgen.1004149","host_type":""},{"url":"https://sonar.ch/global/documents/253785","host_type":""},{"url":"https://doi.org/https://doi.org/10.1371/journal.pgen.1004149","host_type":""}],"fields_of_study":["Evolution and Genetic Dynamics","CRISPR and Genetic Engineering","Gene Regulatory Network Analysis","0301 basic medicine","03 medical and health sciences","0303 health sciences","Adaptation, Physiological","Epistasis, Genetic","Evolution, Molecular","Gene Expression Regulation, Enzymologic","Genetic Fitness","Methylobacterium extorquens","Mutation","Phenotype","Selection, Genetic"],"mesh_terms":["Adaptation, Physiological","Epistasis, Genetic","Mutation","Phenotype","Selection, Genetic","Gene Expression Regulation, Enzymologic","Evolution, Molecular","Methylobacterium extorquens","Genetic Fitness"],"keywords":["Epistasis","Biology","Fitness landscape","Genetics","Genetic Fitness","Gene","Phenotype","Adaptation (eye)","Genetic architecture","Allele","Gene expression","Mutation","Regulation of gene expression","Evolutionary biology","Computational biology","Population","570","Population genetics","Natural selection","Metabolic networks","QH426-470","Biochemistry","Microbiology","Microbial metabolism","Gene Expression Regulation, Enzymologic","576","Bacterial evolution","Evolution, Molecular","Methylobacterium extorquens","Microevolution","Molecular genetics","Selection, Genetic","Forms of evolution","Microbial mutation","Microbial physiology","Microbial evolution","Bacteriology","Epistasis, Genetic","Adaptation, Physiological","Metabolism","Metabolic pathways","Bacterial biochemistry","Systems biology","Research Article"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"No 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