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Studies of recent outbreaks of Zika virus in the Pacific, South America, Mexico and the Caribbean have associated the virus with severe neuropathology. Viral evolution may be one factor contributing to an apparent change in Zika disease as it spread from Southeast Asia across the Pacific to the Americas. To address this possibility, we have employed computational tools to compare the phylogeny, geography, immunology and <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> structure of Zika virus isolates from Africa, Asia, the Pacific and the Americas. In doing so, we compare and contrast methods and results for tree search and rooting of Zika virus phylogenies. In some phylogenetic analyses we find support for the hypothesis that there is a deep common ancestor between African and Asian clades (the \u201cAsia\/Africa\u201d hypothesis). In other phylogenetic analyses, we find that Asian lineages are descendent from African lineages (the \u201cout of Africa\u201d hypothesis). In addition, we identify and evaluate key mutations in viral envelope protein coding and untranslated terminal <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> regions. We find stepwise mutations that have altered both immunological motif sets and regulatory sequence elements. Both of these sets of changes distinguish viruses found in Africa from those in the emergent Asia\u2013Pacific\u2013Americas lineage. These findings support the working hypothesis that mutations acquired by Zika virus in the Pacific and Americas contribute to changes in pathology. These results can inform experiments required to elucidate the role of viral genetic evolution in changes in neuropathology, including microcephaly and other neurological and skeletomuscular issues in infants, and Guillain\u2010Barr\u00e9 syndrome in adults.<\/jats:p>","DOI":"10.1111\/cla.12178","type":"journal-article","created":{"date-parts":[[2016,12,12]],"date-time":"2016-12-12T05:08:30Z","timestamp":1481519310000},"page":"1-20","source":"Crossref","is-referenced-by-count":12,"title":["Molecular evolution of Zika virus as it crossed the Pacific to the Americas"],"prefix":"10.1111","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7487-266X","authenticated-orcid":false,"given":"Adriano","family":"de Bernardi Schneider","sequence":"first","affiliation":[{"name":"Department of Bioinformatics and Genomics University of North Carolina at Charlotte 9201 University City Blvd Charlotte 28223\u20100001 NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert W.","family":"Malone","sequence":"additional","affiliation":[{"name":"Atheric Pharmaceutical 2981 Zion Road Troy VA 22974 USA"},{"name":"Class of 2016 Harvard Medical School Global Clinical Scholars Research Training Program Boston MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun\u2010Tao","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Genomics University of North Carolina at Charlotte 9201 University City Blvd Charlotte 28223\u20100001 NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jane","family":"Homan","sequence":"additional","affiliation":[{"name":"ioGenetics LLC 3591 Anderson Street, Suite 218 Madison WI 53704 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregorio","family":"Linchangco","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Genomics University of North Carolina at Charlotte 9201 University City Blvd Charlotte 28223\u20100001 NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zachary L.","family":"Witter","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Genomics University of North Carolina at Charlotte 9201 University City Blvd Charlotte 28223\u20100001 NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dylan","family":"Vinesett","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Genomics University of North Carolina at Charlotte 9201 University City Blvd Charlotte 28223\u20100001 NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lambodhar","family":"Damodaran","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Genomics University of North Carolina at Charlotte 9201 University City Blvd Charlotte 28223\u20100001 NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel A.","family":"Janies","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Genomics University of North Carolina at Charlotte 9201 University City Blvd Charlotte 28223\u20100001 NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,12,12]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(16)00095-5"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.3201\/eid2011.141380"},{"key":"e_1_2_7_4_1","unstructured":"CDC 2016a.Zika Virus in Southeast Asia.https:\/\/wwwnc.cdc.gov\/travel\/page\/zika-virus-southeast-asia(accessed October 20 2016)."},{"key":"e_1_2_7_5_1","unstructured":"CDC 2016b.Zika Virus in Singapore.http:\/\/wwwnc.cdc.gov\/travel\/notices\/alert\/zika-virus-singapore(accessed October 20 2016)."},{"key":"e_1_2_7_6_1","unstructured":"CDC.2016c.Florida investigation links four recent Zika cases to local mosquito\u2010borne virus transmission.http:\/\/www.cdc.gov\/media\/releases\/2016\/p0729-florida-zika-cases.html(accessed October 20 2016)."},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10735-009-9224-3"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.2471\/BLT.16.176990"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0109442"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0035-9203(52)90042-4"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1604449"},{"key":"e_1_2_7_12_1","doi-asserted-by":"crossref","unstructured":"ECDC Stockholm 2016.European Centre for Disease Prevention and Control. 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