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Most <jats:styled-content style=\"fixed-case\">LCMV<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">LASV<\/jats:styled-content> infections are caused by rodent\u2010to\u2010human transmissions. Thus, viral evolution is largely determined by events that occur in the wildlife reservoirs. We used a set of human\u2010 and rodent\u2010derived viral sequences to investigate the evolutionary history underlying <jats:styled-content style=\"fixed-case\">OW<\/jats:styled-content> arenavirus speciation, as well as the more recent selective events that accompanied <jats:styled-content style=\"fixed-case\">LASV<\/jats:styled-content> spread in West Africa. We show that the viral <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> polymerase (L protein) was a major positive selection target in <jats:styled-content style=\"fixed-case\">OW<\/jats:styled-content> arenaviruses and during <jats:styled-content style=\"fixed-case\">LASV<\/jats:styled-content> out\u2010of\u2010Nigeria migration. No evidence of selection was observed for the glycoprotein, whereas positive selection acted on the nucleoprotein (<jats:styled-content style=\"fixed-case\">NP<\/jats:styled-content>) during <jats:styled-content style=\"fixed-case\">LCMV<\/jats:styled-content> speciation. Positively selected sites in L and <jats:styled-content style=\"fixed-case\">NP<\/jats:styled-content> are surrounded by highly conserved residues, and the bulk of the viral genome evolves under purifying selection. Several positively selected sites are likely to modulate viral replication\/transcription. In both L and <jats:styled-content style=\"fixed-case\">NP<\/jats:styled-content>, structural features (solvent exposed surface area) are important determinants of site\u2010wise evolutionary rate variation. By incorporating several rodent\u2010derived sequences, we also performed an analysis of <jats:styled-content style=\"fixed-case\">OW<\/jats:styled-content> arenavirus codon adaptation to the human host. Results do not support a previously hypothesized role of codon adaptation in disease severity for non\u2010Nigerian strains. In conclusion, L and <jats:styled-content style=\"fixed-case\">NP<\/jats:styled-content> represent the major selection targets and possible determinants of disease presentation; these results suggest that field surveys and experimental studies should primarily focus on these proteins.<\/jats:p>","DOI":"10.1111\/mec.14282","type":"journal-article","created":{"date-parts":[[2017,8,5]],"date-time":"2017-08-05T12:16:37Z","timestamp":1501935397000},"page":"5173-5188","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Evolutionary analysis of Old World arenaviruses reveals a major adaptive contribution of the viral polymerase"],"prefix":"10.1111","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3022-502X","authenticated-orcid":false,"given":"Chiara","family":"Pontremoli","sequence":"first","affiliation":[{"name":"Bioinformatics Scientific Institute IRCCS E. 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