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Retrospective studies of natural zoonoses and passaging in the lab have identified a modest number of host-adaptive mutations. However, it is unclear if these mutations represent all ways that influenza can adapt to a new host. Here we take a prospective approach to this question by completely mapping amino-acid mutations to the avian influenza virus polymerase protein PB2 that enhance growth in human cells. We identify numerous previously uncharacterized human-adaptive mutations. These mutations cluster on PB2\u2019s surface, highlighting potential interfaces with host factors. Some previously uncharacterized adaptive mutations occur in avian-to-human transmission of H7N9 influenza, showing their importance for natural virus evolution. But other adaptive mutations do not occur in nature because they are inaccessible via single-nucleotide mutations. Overall, our work shows how selection at key molecular surfaces combines with evolutionary accessibility to shape viral host adaptation.<\/jats:p>","DOI":"10.7554\/elife.45079","type":"journal-article","created":{"date-parts":[[2019,4,29]],"date-time":"2019-04-29T20:14:03Z","timestamp":1556568843000},"source":"Crossref","is-referenced-by-count":64,"title":["Comprehensive mapping of adaptation of the avian influenza polymerase protein PB2 to humans"],"prefix":"10.7554","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7422-7414","authenticated-orcid":true,"given":"YQ Shirleen","family":"Soh","sequence":"first","affiliation":[{"name":"Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States"},{"name":"Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise H","family":"Moncla","sequence":"additional","affiliation":[{"name":"Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, United States"},{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Eguia","sequence":"additional","affiliation":[{"name":"Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4039-5794","authenticated-orcid":true,"given":"Trevor","family":"Bedford","sequence":"additional","affiliation":[{"name":"Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, United States"},{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1267-3408","authenticated-orcid":true,"given":"Jesse D","family":"Bloom","sequence":"additional","affiliation":[{"name":"Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States"},{"name":"Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, United States"},{"name":"Howard Hughes Medical Institute, Seattle, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2019,4,30]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006288","article-title":"Deep mutational scanning identifies sites in influenza nucleoprotein that affect viral inhibition by MxA","volume":"13","author":"Ashenberg","year":"2017","journal-title":"PLOS Pathogens"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"12241","DOI":"10.1128\/JVI.01563-08","article-title":"Immunomic analysis of the repertoire of T-cell specificities for influenza A virus in humans","volume":"82","author":"Assarsson","year":"2008","journal-title":"Journal of Virology"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"5913","DOI":"10.1073\/pnas.1001755107","article-title":"Association of RIG-I with innate immunity of ducks to influenza","volume":"107","author":"Barber","year":"2010","journal-title":"PNAS"},{"key":"bib4","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":"bib5","doi-asserted-by":"publisher","first-page":"1956","DOI":"10.1093\/molbev\/msu173","article-title":"An experimentally determined evolutionary model dramatically improves phylogenetic fit","volume":"31","author":"Bloom","year":"2014","journal-title":"Molecular Biology and Evolution"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12859-015-0590-4","article-title":"Software for the analysis and visualization of deep mutational scanning data","volume":"16","author":"Bloom","year":"2015","journal-title":"BMC Bioinformatics"},{"key":"bib7","doi-asserted-by":"publisher","DOI":"10.1186\/s13062-016-0172-z","article-title":"Identification of positive selection in genes is greatly improved by using experimentally informed site-specific models","volume":"12","author":"Bloom","year":"2017","journal-title":"Biology Direct"},{"key":"bib8","article-title":"SangerMutantLibraryAnalysis","author":"Bloom","year":"2019","unstructured":"Bloom JD, Doud M, Greaney AJ, Haddox H. 2019. 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