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We studied the emergence of Venezuelan equine encephalitis virus (VEEV), an alphavirus pathogen of people and equines that has had severe health and economic effects in the Americas since the early 20th century. Between epidemics, VEE disappears for periods up to decades, and the viral source of outbreaks has remained enigmatic. Combined with phylogenetic analyses to predict mutations associated with a 1992\u20131993 epidemic, we used reverse genetic studies to identify an envelope glycoprotein gene mutation that mediated emergence. This mutation allowed an enzootic, equine-avirulent VEEV strain, which circulates among rodents in nearby forests to adapt for equine amplification. RNA viruses including alphaviruses exhibit high mutation frequencies. Therefore, ecological and epidemiological factors probably constrain the frequency of VEE epidemics more than the generation, via mutation, of amplification-competent (high equine viremia) virus strains. These results underscore the ability of RNA viruses to alter their host range, virulence, and epidemic potential via minor genetic changes. VEE also demonstrates the unpredictable risks to human health of anthropogenic changes such as the introduction of equines and humans into habitats that harbor zoonotic RNA viruses.<\/jats:p>","DOI":"10.1073\/pnas.0509961103","type":"journal-article","created":{"date-parts":[[2006,3,20]],"date-time":"2006-03-20T20:44:26Z","timestamp":1142887466000},"page":"4994-4999","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":128,"title":["Venezuelan encephalitis emergence mediated by a phylogenetically predicted viral mutation"],"prefix":"10.1073","volume":"103","author":[{"given":"Michael","family":"Anishchenko","sequence":"first","affiliation":[{"name":"*Center for Biodefense and Emerging Infectious Diseases and Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-0609; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Bowen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Slobodan","family":"Paessler","sequence":"additional","affiliation":[{"name":"*Center for Biodefense and Emerging Infectious Diseases and Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-0609; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Austgen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivorlyne P.","family":"Greene","sequence":"additional","affiliation":[{"name":"*Center for Biodefense and Emerging Infectious Diseases and Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-0609; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott C.","family":"Weaver","sequence":"additional","affiliation":[{"name":"*Center for Biodefense and Emerging Infectious Diseases and Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-0609; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2006,3,20]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1087139"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1085952"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8235615"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2004.08.009"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/17130"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.20506\/rst.23.2.1493"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.74.7.3227-3234.2000"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1567-1348(03)00004-2"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1006\/viro.2000.0320"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1007989407305"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1006"},{"key":"e_1_3_3_12_2","first-page":"203","volume-title":"The Arboviruses: Epidemiology and Ecology","author":"Walton T. 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