PT - JOURNAL ARTICLE AU - Y.Q. Shirleen Soh AU - Louise H. Moncla AU - Rachel Eguia AU - Trevor Bedford AU - Jesse D. Bloom TI - Comprehensive mapping of avian influenza polymerase adaptation to the human host AID - 10.1101/512525 DP - 2019 Jan 01 TA - bioRxiv PG - 512525 4099 - http://biorxiv.org/content/early/2019/01/04/512525.short 4100 - http://biorxiv.org/content/early/2019/01/04/512525.full AB - Viruses like influenza are infamous for their ability to adapt to new hosts. 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’s 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.