{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T19:03:29Z","timestamp":1791227009109,"version":"4.1.0"},"reference-count":110,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T00:00:00Z","timestamp":1763942400000},"content-version":"vor","delay-in-days":327,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"MLK Visiting Scholars and Professors Program at the Massachusetts Institute of Technology"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI168166"],"award-info":[{"award-number":["R01AI168166"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Science Foundation\u2019s Division of Environmental Biology","award":["2142720"],"award-info":[{"award-number":["2142720"]}]},{"name":"A*STAR National Science Scholarship, Singapore"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Understanding the genetic and genomic underpinnings of infectious disease outbreaks has emerged as a frontier of epidemiology. Here, we argue that epistasis\u2014where the phenotypic effects of mutations or gene variants are dictated by the presence of other mutations or genes\u2014should become a focus of genomic epidemiology. To demonstrate this, we present the results of a systematic review of the literature on epistasis in viruses, focusing on three major human viral systems: (i) influenza, (ii) SARS-CoV-2, and (iii) human immunodeficiency virus, as well as two other bodies of the literature mainly focusing on nonhuman viruses: (iv) tobacco etch virus and (v) experimental evolution of viruses. Our systematic review of these five bodies of the literature highlights that epistasis is prevalent in host\u2013virus systems of various kinds, manifesting within and between different loci, with effects of different magnitudes and directions, and shaping various phenotypic traits of epidemiological interest. At the same time, our systematic review demonstrates that our ability to draw general conclusions about the direction and magnitude of epistasis in viral evolution is constrained by several factors: the idiosyncrasies of virus\u2013host systems, biases in the underlying data collection exercises, and the limitations of existing methods. Moving forward, we encourage collaborations between genomic epidemiologists and evolutionary biologists to identify and measure epistasis in studying the evolution of viral pathogens.<\/jats:p>","DOI":"10.1093\/ve\/veaf091","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T12:48:23Z","timestamp":1763470103000},"source":"Crossref","is-referenced-by-count":6,"title":["The importance of epistasis in the evolution of viral pathogens"],"prefix":"10.1093","volume":"11","author":[{"given":"Swathi Nachiar","family":"Manivannan","sequence":"first","affiliation":[{"name":"Department of Ecology and Evolutionary Biology, Yale University , 165 Prospect Street, New Haven, CT 06511 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Diaz Arenas","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolutionary Biology, Yale University , 165 Prospect Street, New Haven, CT 06511 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan D","family":"Grubaugh","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolutionary Biology, Yale University , 165 Prospect Street, New Haven, CT 06511 ,","place":["United States"]},{"name":"Yale School of Public Health , 60 College Street, New Haven, CT 06510 ,","place":["United States"]},{"name":"Public Health Modeling Unit, Yale School of Public Health , 60 College Street, New Haven, CT 06510 ,","place":["United States"]},{"name":"Department of Microbiology, Immunology and Transplantation, Rega Institute , KU Leuven, Herestraat 49, Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1581-8345","authenticated-orcid":false,"given":"C Brandon","family":"Ogbunugafor","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolutionary Biology, Yale University , 165 Prospect Street, New Haven, CT 06511 ,","place":["United States"]},{"name":"Public Health Modeling Unit, Yale School of Public Health , 60 College Street, New Haven, CT 06510 ,","place":["United States"]},{"name":"Santa Fe Institute , 1399 Hyde Park Road, Santa Fe, NM 87501 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,11,24]]},"reference":[{"key":"2025121205113459300_ref1","doi-asserted-by":"crossref","first-page":"e1002431","DOI":"10.1371\/journal.ppat.1002431","article-title":"Role of permissive neuraminidase mutations in influenza A\/Brisbane\/59\/2007-like (H1N1) viruses","volume":"7","author":"Abed","year":"2011","journal-title":"PLoS Pathog"},{"key":"2025121205113459300_ref2","doi-asserted-by":"crossref","first-page":"e2397","DOI":"10.1371\/journal.pone.0002397","article-title":"Virus adaptation by manipulation of host\u2019s gene expression","volume":"3","author":"Agudelo-Romero","year":"2008","journal-title":"PLoS One"},{"key":"2025121205113459300_ref3","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1007\/s00239-022-10073-1","article-title":"Epistasis-driven evolution of the SARS-CoV-2 secondary structure","volume":"90","author":"Alemrajabi","year":"2022","journal-title":"J Mol Evol"},{"key":"2025121205113459300_ref4","doi-asserted-by":"publisher","first-page":"2595","DOI":"10.1016\/j.cell.2021.03.061","article-title":"Early introductions and transmission of SARS-CoV-2 variant b.1.1.7 in the United States","volume":"184","author":"Alpert","year":"2021","journal-title":"Cell"},{"key":"2025121205113459300_ref5","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1007\/s12551-022-01005-w","article-title":"Intragenic compensation through the lens of deep mutational scanning","volume":"14","author":"Azbukina","year":"2022","journal-title":"Biophys Rev"},{"key":"2025121205113459300_ref6","doi-asserted-by":"crossref","DOI":"10.1016\/j.tim.2022.02.003","article-title":"Molecular mechanisms and drivers of pathogen emergence","volume":"30","author":"Balasubramanian","year":"2022","journal-title":"Trends Microbiol"},{"key":"2025121205113459300_ref7","author":"Ball","year":"2023"},{"key":"2025121205113459300_ref8","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1146\/annurev-ecolsys-102320-112153","article-title":"Epistasis and adaptation on fitness landscapes","volume":"53","author":"Bank","year":"2022","journal-title":"Annu Rev Ecol Evol Syst"},{"key":"2025121205113459300_ref9","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1093\/molbev\/msu301","article-title":"A systematic survey of an intragenic epistatic landscape","volume":"32","author":"Bank","year":"2015","journal-title":"Mol Biol Evol"},{"key":"2025121205113459300_ref10","doi-asserted-by":"crossref","first-page":"18819","DOI":"10.1038\/s41598-022-23482-5","article-title":"The effect of mutations on binding interactions between the SARS-CoV-2 receptor binding domain and neutralizing antibodies B38 and CB6","volume":"12","author":"Barnes","year":"2022","journal-title":"Sci Rep"},{"key":"2025121205113459300_ref11","doi-asserted-by":"publisher","first-page":"50524","DOI":"10.7554\/eLife.50524","article-title":"Epistasis and entrenchment of drug resistance in HIV-1 subtype B","volume":"8","author":"Biswas","year":"2019","journal-title":"eLife"},{"key":"2025121205113459300_ref12","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1534\/genetics.115.182691","article-title":"Epistasis and the structure of fitness landscapes: are experimental fitness landscapes compatible with Fisher\u2019s geometric model?","volume":"203","author":"Blanquart","year":"2016","journal-title":"Genetics"},{"key":"2025121205113459300_ref13","doi-asserted-by":"publisher","first-page":"3537","DOI":"10.1111\/evo.12545","article-title":"Properties of selected mutations and genotypic landscapes under Fisher\u2019s geometric model","volume":"68","author":"Blanquart","year":"2014","journal-title":"Evolution"},{"key":"2025121205113459300_ref14","doi-asserted-by":"publisher","first-page":"1272","DOI":"10.1126\/science.1187816","article-title":"Permissive secondary mutations enable the evolution of influenza oseltamivir resistance","volume":"328","author":"Bloom","year":"2010","journal-title":"Science"},{"key":"2025121205113459300_ref15","doi-asserted-by":"crossref","DOI":"10.1093\/ve\/vex007","article-title":"Adaptation of avian influenza virus to a swine host","volume":"3","author":"Bourret","year":"2017","journal-title":"Virus Evol"},{"key":"2025121205113459300_ref16","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1016\/j.cell.2017.05.038","article-title":"An expanded view of complex traits: from polygenic to omnigenic","volume":"169","author":"Boyle","year":"2017","journal-title":"Cell"},{"key":"2025121205113459300_ref17","doi-asserted-by":"crossref","first-page":"e116301","DOI":"10.1371\/journal.pone.0116301","article-title":"Epistasis as a determinant of the HIV-1 protease\u2019s robustness to mutation","volume":"9","author":"Capel","year":"2014","journal-title":"PLoS One"},{"key":"2025121205113459300_ref18","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1038\/s41579-022-00841-7","article-title":"Sars-cov-2 variant biology: Immune escape, transmission and fitness","volume":"21","author":"Carabelli","year":"2023","journal-title":"Nat Rev Microbiol"},{"key":"2025121205113459300_ref19","article-title":"Mutation allows coronavirus to infect more cells, study finds. Scientists urge caution","author":"Carey","year":"2020","journal-title":"The New York Times"},{"key":"2025121205113459300_ref20","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1534\/genetics.113.158154","article-title":"Environment determines epistatic patterns for a ssDNA virus","volume":"196","author":"Caudle","year":"2014","journal-title":"Genetics"},{"key":"2025121205113459300_ref21","doi-asserted-by":"crossref","first-page":"20160984","DOI":"10.1098\/rspb.2016.0984","article-title":"Efficient escape from local optima in a highly rugged fitness landscape by evolving RNA virus populations","volume":"283","author":"Cervera","year":"2016","journal-title":"Proc R Soc B Biol Sci"},{"key":"2025121205113459300_ref22","doi-asserted-by":"publisher","first-page":"10160","DOI":"10.1128\/jvi.01243-16","article-title":"Effect of host species on topography of the fitness landscape for a plant RNA virus","volume":"90","author":"Cervera","year":"2016","journal-title":"J Virol"},{"key":"2025121205113459300_ref23","article-title":"Scientists fear the \u2018escape mutant\u2019 in coronavirus variant from South Africa","author":"Cohen","year":"2021","journal-title":"CNN"},{"key":"2025121205113459300_ref24","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1016\/S1473-3099(10)70312-1","article-title":"Towards a conceptual framework to support one-health research for policy on emerging zoonoses","volume":"11","author":"Coker","year":"2011","journal-title":"Lancet Infect Dis"},{"key":"2025121205113459300_ref25","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1057\/biosoc.2010.37","article-title":"Viral cartographies: mapping the molecular politics of global HIV","volume":"6","author":"Crane","year":"2011","journal-title":"BioSocieties"},{"key":"2025121205113459300_ref26","doi-asserted-by":"crossref","first-page":"e1006869","DOI":"10.1371\/journal.pgen.1006869","article-title":"Detecting epistasis with the marginal epistasis test in genetic mapping studies of quantitative traits","volume":"13","author":"Crawford","year":"2017","journal-title":"PLoS Genet"},{"key":"2025121205113459300_ref27","doi-asserted-by":"crossref","first-page":"e28629","DOI":"10.7554\/eLife.28629","article-title":"Inferring genetic interactions from comparative fitness data","volume":"6","author":"Crona","year":"2017","journal-title":"Elife"},{"key":"2025121205113459300_ref28","doi-asserted-by":"crossref","DOI":"10.2174\/1874404400903010009","article-title":"Experimental evolution and population genetics of rna viruses","volume":"3","author":"Cuevas","year":"2009","journal-title":"Open Evol J"},{"key":"2025121205113459300_ref29","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1093\/molbev\/msv028","article-title":"Temporal dynamics of intrahost molecular evolution for a plant RNA virus","volume":"32","author":"Cuevas","year":"2015","journal-title":"Mol Biol Evol"},{"key":"2025121205113459300_ref30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1743-422X-10-243","article-title":"Influenza A\/Hong Kong\/156\/1997 (H5N1) virus NS1 gene mutations F103L and M106I both increase IFN antagonism, virulence and cytoplasmic localization but differ in binding to RIG-I and CPSF30","volume":"10","author":"Dankar","year":"2013","journal-title":"Virol J"},{"key":"2025121205113459300_ref31","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1146\/annurev-genom-083118-014857","article-title":"The causes and consequences of genetic interactions (epistasis)","volume":"20","author":"Domingo","year":"2019","journal-title":"Annu Rev Genomics Hum Genet"},{"key":"2025121205113459300_ref32","doi-asserted-by":"publisher","DOI":"10.1101\/2024.07.09.602773","article-title":"Relaxed selection can speed the evolution of complex adaptations","author":"Draghi","year":"2024"},{"key":"2025121205113459300_ref33","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1146\/annurev.ecolsys.38.091206.095637","article-title":"Virus evolution: Insights from an experimental approach","volume":"38","author":"Elena","year":"2007","journal-title":"Annu Rev Ecol Evol Syst"},{"key":"2025121205113459300_ref34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/1874357900903010001","article-title":"The evolution of viruses in multi-host fitness landscapes","volume":"3","author":"Elena","year":"2009","journal-title":"Open Virol J"},{"key":"2025121205113459300_ref35","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1038\/nmeth.3027","article-title":"Deep mutational scanning: a new style of protein science","volume":"11","author":"Fowler","year":"2014","journal-title":"Nat Methods"},{"key":"2025121205113459300_ref36","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1098\/rsob.170189","article-title":"Predicting virus emergence amid evolutionary noise","volume":"7","author":"Geoghegan","year":"2017","journal-title":"Open Biol"},{"key":"2025121205113459300_ref37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cell.2017.03.018","article-title":"Experimental evolution to study virus emergence","volume":"169","author":"Grubaugh","year":"2017","journal-title":"Cell"},{"key":"2025121205113459300_ref38","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1038\/s41564-018-0296-2","article-title":"Tracking virus outbreaks in the twenty-first century","volume":"4","author":"Grubaugh","year":"2019","journal-title":"Nat Microbiol"},{"key":"2025121205113459300_ref39","doi-asserted-by":"publisher","first-page":"4121","DOI":"10.1093\/bioinformatics\/bty407","article-title":"Nextstrain: real-time tracking of pathogen evolution","volume":"34","author":"Hadfield","year":"2018","journal-title":"Bioinformatics"},{"key":"2025121205113459300_ref40","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1038\/s41559-021-01454-8","article-title":"Towards an ecosystem model of infectious disease","volume":"5","author":"Hassell","year":"2021","journal-title":"Nat Ecol Evol"},{"key":"2025121205113459300_ref41","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1097\/QAD.0b013e328342ff93","article-title":"Global trends in molecular epidemiology of HIV-1 during 2000-2007","volume":"25","author":"Hemelaar","year":"2011","journal-title":"AIDS"},{"key":"2025121205113459300_ref42","doi-asserted-by":"crossref","first-page":"20140292","DOI":"10.1098\/rstb.2014.0292","article-title":"Evaluating the within-host fitness effects of mutations fixed during virus adaptation to different ecotypes of a new host","volume":"370","author":"Hillung","year":"2015","journal-title":"Philos Trans R Soc B: Biol Sci"},{"key":"2025121205113459300_ref43","first-page":"33","article-title":"Revealing the history of infectious disease epidemics through phylogenetic trees","volume":"349","author":"Holmes","year":"1995","journal-title":"Philos Trans R Soc Lond Ser B Biol Sci"},{"key":"2025121205113459300_ref44","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1038\/nature19790","article-title":"The evolution of Ebola virus: insights from the 2013\u20132016 epidemic","volume":"538","author":"Holmes","year":"2016","journal-title":"Nature"},{"key":"2025121205113459300_ref45","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1104\/pp.109.147983","article-title":"A host RNA helicase-like protein, AtRH8, interacts with the potyviral genome-linked protein, VPg, associates with the virus accumulation complex, and is essential for infection","volume":"152","author":"Huang","year":"2010","journal-title":"Plant Physiol"},{"key":"2025121205113459300_ref46","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.1038\/s41401-020-0485-4","article-title":"Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19","volume":"41","author":"Huang","year":"2020","journal-title":"Acta Pharmacol Sin"},{"key":"2025121205113459300_ref47","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1186\/s13059-024-03355-y","article-title":"Real-time identification of epistatic interactions in SARS-CoV-2 from large genome collections","volume":"25","author":"Innocenti","year":"2024","journal-title":"Genome Biol"},{"key":"2025121205113459300_ref48","doi-asserted-by":"publisher","first-page":"e1010540","DOI":"10.1371\/journal.pgen.1010540","article-title":"Inferring selection effects in SARS-CoV-2 with Bayesian viral allele selection","volume":"18","author":"Jankowiak","year":"2022","journal-title":"PLoS Genet"},{"key":"2025121205113459300_ref49","doi-asserted-by":"crossref","first-page":"e01982","DOI":"10.1128\/jvi.01982-21","article-title":"Identification of a permissive secondary mutation that restores the enzymatic activity of oseltamivir resistance mutation H275Y","volume":"96","author":"Jiang","year":"2022","journal-title":"J Virol"},{"key":"2025121205113459300_ref50","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1186\/s12915-023-01585-3","article-title":"Epistasis and evolution: recent advances and an outlook for prediction","volume":"21","author":"Johnson","year":"2023","journal-title":"BMC Biol"},{"key":"2025121205113459300_ref51","doi-asserted-by":"publisher","first-page":"8399","DOI":"10.1073\/pnas.1208059110","article-title":"Zoonosis emergence linked to agricultural intensification and environmental change","volume":"110","author":"Jones","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025121205113459300_ref52","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1016\/j.tree.2012.06.001","article-title":"Experimental evolution","volume":"27","author":"Kawecki","year":"2012","journal-title":"Trends Ecol Evol"},{"key":"2025121205113459300_ref53","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33554-9","article-title":"Energy landscape reshaped by strain-specific mutations underlies epistasis in NS1 evolution of influenza A virus","volume":"13","author":"Kim","year":"2022","journal-title":"Nat Commun"},{"key":"2025121205113459300_ref54","doi-asserted-by":"publisher","first-page":"2489","DOI":"10.1056\/NEJMc2102507","article-title":"Viral dynamics of SARS-CoV-2 variants in vaccinated and unvaccinated persons","volume":"385","author":"Kissler","year":"2021","journal-title":"N Engl J Med"},{"key":"2025121205113459300_ref55","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1126\/science.1132745","article-title":"Epochal evolution shapes the phylodynamics of interpandemic influenza a (H3N2) in humans","volume":"314","author":"Koelle","year":"2006","journal-title":"Science"},{"key":"2025121205113459300_ref56","doi-asserted-by":"crossref","first-page":"e1001301","DOI":"10.1371\/journal.pgen.1001301","article-title":"Prevalence of epistasis in the evolution of influenza a surface proteins","volume":"7","author":"Kryazhimskiy","year":"2011","journal-title":"PLoS Genet"},{"key":"2025121205113459300_ref57","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/hdy.2012.15","article-title":"Magnitude and sign epistasis among deleterious mutations in a positive-sense plant RNA virus","volume":"109","author":"Lal\u00edc","year":"2012","journal-title":"Heredity"},{"key":"2025121205113459300_ref58","doi-asserted-by":"crossref","first-page":"20120396","DOI":"10.1098\/rsbl.2012.0396","article-title":"Epistasis between mutations is host-dependent for an RNA virus","volume":"9","author":"Lal\u00edc","year":"2013","journal-title":"Biol Lett"},{"key":"2025121205113459300_ref59","doi-asserted-by":"publisher","first-page":"2236","DOI":"10.1111\/jeb.12748","article-title":"The impact of high-order epistasis in the within-host fitness of a positive-sense plant RNA virus","volume":"28","author":"Lal\u00edc","year":"2015","journal-title":"J Evol Biol"},{"key":"2025121205113459300_ref60","doi-asserted-by":"publisher","first-page":"3780","DOI":"10.1128\/JVI.02217-10","article-title":"Exploring the fitness landscape of an RNA virus by using a universal barcode microarray","volume":"85","author":"Lauring","year":"2011","journal-title":"J Virol"},{"key":"2025121205113459300_ref61","doi-asserted-by":"publisher","first-page":"e2208718120","DOI":"10.1073\/pnas.2208718120","article-title":"Epistasis reduces fitness costs of influenza a virus escape from stem-binding antibodies","volume":"120","author":"Lee","year":"2023","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025121205113459300_ref62","doi-asserted-by":"publisher","first-page":"7730","DOI":"10.1128\/jvi.74.17.7730-7737.2000","article-title":"Complex formation between potyvirus VPg and translation eukaryotic initiation factor 4E correlates with virus infectivity","volume":"74","author":"L\u00e9onard","year":"2000","journal-title":"J Virol"},{"key":"2025121205113459300_ref63","doi-asserted-by":"publisher","volume-title":"PLoS Comput Biol","author":"","DOI":"10.1371\/journal.pcbi.1012469"},{"key":"2025121205113459300_ref64","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/nature11879","article-title":"Evolutionary rescue from extinction is contingent on a lower rate of environmental change","volume":"494","author":"Lindsey","year":"2013","journal-title":"Nature"},{"key":"2025121205113459300_ref65","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1016\/j.chom.2022.09.003","article-title":"The evolutionary potential of influenza a virus hemagglutinin is highly constrained by epistatic interactions with neuraminidase","volume":"30","author":"Liu","year":"2022","journal-title":"Cell Host Microbe"},{"key":"2025121205113459300_ref66","doi-asserted-by":"publisher","first-page":"407","DOI":"10.3390\/v10080407","article-title":"Mutation and epistasis in influenza virus evolution","volume":"10","author":"Lyons","year":"2018","journal-title":"Viruses"},{"key":"2025121205113459300_ref67","doi-asserted-by":"crossref","first-page":"msac061","DOI":"10.1093\/molbev\/msac061","article-title":"Selection analysis identifies clusters of unusual mutational changes in omicron lineage ba. 1 that likely impact spike function","volume":"39","author":"Martin","year":"2022","journal-title":"Mol Biol Evol"},{"key":"2025121205113459300_ref68","doi-asserted-by":"crossref","first-page":"e18375","DOI":"10.1371\/journal.pone.0018375","article-title":"Fitness ranking of individual mutants drives patterns of epistatic interactions in hiv-1","volume":"6","author":"Mart\u00ednez","year":"2011","journal-title":"PLoS One"},{"key":"2025121205113459300_ref69","doi-asserted-by":"publisher","first-page":"e2204717119","DOI":"10.1073\/pnas.2204717119","article-title":"Sars-cov-2 variant spike and accessory gene mutations alter pathogenesis","volume":"119","author":"McGrath","year":"2022","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025121205113459300_ref70","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1038\/s41559-022-01709-y","article-title":"Effects of epistasis and recombination between vaccine-escape and virulence alleles on the dynamics of pathogen adaptation","volume":"6","author":"McLeod","year":"2022","journal-title":"Nat Ecol Evol"},{"key":"2025121205113459300_ref71","doi-asserted-by":"crossref","first-page":"e1674","DOI":"10.7717\/peerj.1674","article-title":"Initiating a watch list for Ebola virus antibody escape mutations","volume":"4","author":"Miller","year":"2016","journal-title":"PeerJ"},{"key":"2025121205113459300_ref72","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1002\/bies.20236","article-title":"Traversing the conceptual divide between biological and statistical epistasis: systems biology and a more modern synthesis","volume":"27","author":"Moore","year":"2005","journal-title":"Bioessays"},{"key":"2025121205113459300_ref73","first-page":"195","volume-title":"Emerging Infections: condemned to Repeat. In Microbial Evolution and co-Adaptation: a Tribute to the Life and Scientific Legacies of Joshua Lederberg: workshop Summary","author":"Morse","year":"2009"},{"key":"2025121205113459300_ref74","doi-asserted-by":"publisher","first-page":"e82516","DOI":"10.7554\/eLife.82516","article-title":"Coordinated evolution at amino acid sites of SARS-CoV-2 spike","volume":"12","author":"Neverov","year":"2023","journal-title":"eLife"},{"key":"2025121205113459300_ref75","doi-asserted-by":"crossref","first-page":"e1010896","DOI":"10.1371\/journal.pcbi.1010896","article-title":"Host heterogeneity andepistasis explain punctuated evolution of SARS-CoV-2","volume":"19","author":"Nielsen","year":"2023","journal-title":"PLoS Comput Biol"},{"key":"2025121205113459300_ref76","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1111\/evo.14428","article-title":"The mutation effect reaction norm (mu-rn) highlights environmentally dependent mutation effects and epistaticinteractions","volume":"76","author":"Ogbunugafor","year":"2022","journal-title":"Evolution"},{"key":"2025121205113459300_ref77","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1007\/978-3-030-91374-8_18","volume-title":"Higher-Order Systems. Understanding Complex Systems","author":"Ogbunugafor","year":"2022"},{"key":"2025121205113459300_ref78","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n71","article-title":"The Prisma 2020 statement: an updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"2025121205113459300_ref79","doi-asserted-by":"crossref","first-page":"7385","DOI":"10.1038\/ncomms8385","article-title":"Delayed commitment to evolutionary fate in antibiotic resistance fitness landscapes","volume":"6","author":"Palmer","year":"2015","journal-title":"Nat Commun"},{"key":"2025121205113459300_ref80","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1126\/science.abn6895","article-title":"Epistatic drift causes gradual decay of predictability in protein evolution","volume":"376","author":"Park","year":"2022","journal-title":"Science"},{"key":"2025121205113459300_ref81","doi-asserted-by":"crossref","first-page":"e38795","DOI":"10.7554\/eLife.38795","article-title":"Enhanced ER proteostasis and temperature differentially impact the mutational tolerance of influenza hemagglutinin","volume":"7","author":"Phillips","year":"2018","journal-title":"Elife"},{"key":"2025121205113459300_ref82","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1534\/genetics.104.039438","article-title":"The rate of compensatory mutation in the DNAbacteriophage \u03c6x174","volume":"170","author":"Poon","year":"2005","journal-title":"Genetics"},{"key":"2025121205113459300_ref83","first-page":"2032","article-title":"Functional origins of fitness effect-sizes of compensatory mutations in the DNAbacteriophage \u00f8x174","volume":"60","author":"Poon","year":"2006","journal-title":"Evolution"},{"key":"2025121205113459300_ref84","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1093\/molbev\/msp289","article-title":"Phylogenetic analysis of population-based and deep sequencing data to identify coevolving sites in the nef gene of HIV-1","volume":"27","author":"Poon","year":"2009","journal-title":"Mol Biol Evol"},{"key":"2025121205113459300_ref85","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/ng1324","article-title":"Pervasive joint influence of epistasis and plasticity on mutational effects in Escherichia coli","volume":"36","author":"Remold","year":"2004","journal-title":"Nat Genet"},{"key":"2025121205113459300_ref86","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1093\/molbev\/msn059","article-title":"Evolutionary genomics of host adaptation in vesicular stomatitis virus","volume":"25","author":"Remold","year":"2008","journal-title":"Mol Biol Evol"},{"key":"2025121205113459300_ref87","first-page":"101","volume-title":"Advances in Virus Research","author":"Revers","year":"2015"},{"key":"2025121205113459300_ref88","doi-asserted-by":"publisher","first-page":"e2104241118","DOI":"10.1073\/pnas.2104241118","article-title":"Ongoing global and regional adaptive evolution of SARS-CoV-2","volume":"118","author":"Rochman","year":"2021","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025121205113459300_ref89","article-title":"More covid-19 variants emerge closer to home: What to know about the ones discovered in Brazil, New York, California","author":"Rodriguez","year":"2021","journal-title":"USA Today"},{"key":"2025121205113459300_ref90","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/j.cell.2016.06.047","article-title":"Genotypic context and epistasis in individuals and populations","volume":"166","author":"Sackton","year":"2016","journal-title":"Cell"},{"key":"2025121205113459300_ref91","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1146\/annurev.phyto.42.040803.140322","article-title":"Tobacco mosaic virus: A model system for plant biology","volume":"42","author":"Scholthof","year":"2004","journal-title":"Annu Rev Phytopathol"},{"key":"2025121205113459300_ref92","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-96125-w","article-title":"Molecular epidemiology and HIV-1 variant evolution in Poland between 2015 and 2019","volume":"11","author":"Serwin","year":"2021","journal-title":"Sci Rep"},{"key":"2025121205113459300_ref93","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1155\/2013\/230380","article-title":"Increasing HIV subtype diversity and its clinical implications in a sentinel North American population","volume":"24","author":"Siemieniuk","year":"2013","journal-title":"Can J Infect Dis Med Microbiol"},{"key":"2025121205113459300_ref94","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1534\/genetics.109.112458","article-title":"Fitness epistasis and constraints on adaptation in a human immunodeficiency virus type 1 protein region","volume":"185","author":"Silva","year":"2010","journal-title":"Genetics"},{"key":"2025121205113459300_ref95","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1126\/science.abo7896","article-title":"Shifting mutational constraints in the SARS-CoV-2 receptor-binding domain during viral evolution","volume":"377","author":"Starr","year":"2022","journal-title":"Science"},{"key":"2025121205113459300_ref96","article-title":"Drug-resistant \u201cdual mutant\u201d flu strains now being tracked in U.S., CDC says","author":"Tin","year":"2024","journal-title":"CBS News"},{"key":"2025121205113459300_ref97","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1093\/molbev\/msp272","article-title":"Compensatory molecular evolution of HC-Pro, an RNA-silencing suppressor from a plant RNA virus","volume":"27","author":"Torres-Barcel\u00f3","year":"2009","journal-title":"Mol Biol Evol"},{"key":"2025121205113459300_ref98","doi-asserted-by":"publisher","first-page":"1079","DOI":"10.1016\/j.cell.2016.10.013","article-title":"Human adaptation of Ebola virus during the West African outbreak","volume":"167","author":"Urbanowicz","year":"2016","journal-title":"Cell"},{"key":"2025121205113459300_ref99","doi-asserted-by":"crossref","first-page":"3617","DOI":"10.1098\/rspb.2011.1537","article-title":"The causes of epistasis","volume":"278","author":"Visser","year":"2011","journal-title":"Proc R Soc B Biol Sci"},{"key":"2025121205113459300_ref100","doi-asserted-by":"crossref","first-page":"e1002947","DOI":"10.1371\/journal.pcbi.1002947","article-title":"Viral phylodynamics","volume":"9","author":"Volz","year":"2013","journal-title":"PLoS Comput Biol"},{"key":"2025121205113459300_ref101","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1007\/978-1-4939-2155-3_8","article-title":"Two rules for the detection and quantification of epistasis and other interaction effects","volume":"1253","author":"Wagner","year":"2015","journal-title":"Methods Mol Biol"},{"key":"2025121205113459300_ref102","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1126\/science.1123539","article-title":"Darwinian evolution can follow only very few mutational paths to fitter proteins","volume":"312","author":"Weinreich","year":"2006","journal-title":"Science"},{"key":"2025121205113459300_ref103","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1016\/j.gde.2013.10.007","article-title":"Should evolutionary geneticists worry about higher-order epistasis?","volume":"23","author":"Weinreich","year":"2013","journal-title":"Curr Opin Genet Dev"},{"key":"2025121205113459300_ref104","doi-asserted-by":"crossref","first-page":"P01001","DOI":"10.1088\/1742-5468\/2013\/01\/P01001","article-title":"Finding the boundary between evolutionary basins of attraction, and implications for Wright\u2019s fitness landscape analogy","volume":"2013","author":"Weinreich","year":"2013","journal-title":"J Stat Mech Theory Exp"},{"key":"2025121205113459300_ref105","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1038\/s41467-018-03663-5","article-title":"A complex epistatic network limits the mutational reversibility in the influenza hemagglutinin receptor-binding site","volume":"9","author":"Wu","year":"2018","journal-title":"Nat Commun"},{"key":"2025121205113459300_ref106","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1038\/s41467-020-15102-5","article-title":"Major antigenic site B of human influenza H3N2 viruses has an evolving local fitness landscape","volume":"11","author":"Wu","year":"2020","journal-title":"Nat Commun"},{"key":"2025121205113459300_ref107","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.1093\/genetics\/160.4.1273","article-title":"Dependence of epistasis on environment and mutation severity as revealed by in silico mutagenesis of phage t7","volume":"160","author":"You","year":"2002","journal-title":"Genetics"},{"key":"2025121205113459300_ref108","doi-asserted-by":"publisher","first-page":"31519","DOI":"10.1073\/pnas.2012331117","article-title":"Global analysis of more than 50,000 SARS-CoV-2 genomes reveals epistasis between eight viral genes","volume":"117","author":"Zeng","year":"2020","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025121205113459300_ref109","doi-asserted-by":"publisher","first-page":"044409","DOI":"10.1103\/PhysRevE.106.044409","article-title":"Temporal epistasis inference from more than 3 500 000 SARS-CoV-2 genomic sequences","volume":"106","author":"Zeng","year":"2022","journal-title":"Phys Rev E"},{"key":"2025121205113459300_ref110","doi-asserted-by":"crossref","first-page":"e2204233119","DOI":"10.1073\/pnas.2204233119","article-title":"Higher-order epistasis and phenotypic prediction","volume":"119","author":"Zhou","year":"2022","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["Virus Evolution"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ve\/advance-article-pdf\/doi\/10.1093\/ve\/veaf091\/65491784\/veaf091.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ve\/article-pdf\/11\/1\/veaf091\/65491784\/veaf091.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ve\/article-pdf\/11\/1\/veaf091\/65491784\/veaf091.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T10:11:50Z","timestamp":1765534310000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ve\/article\/doi\/10.1093\/ve\/veaf091\/8341478"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025]]},"references-count":110,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1,9]]}},"URL":"https:\/\/doi.org\/10.1093\/ve\/veaf091","relation":{},"ISSN":["2057-1577"],"issn-type":[{"value":"2057-1577","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025]]},"published":{"date-parts":[[2025]]},"article-number":"veaf091"}}