Title: The effects of a deleterious mutation load on patterns of influenza

34 Recent phylogenetic analyses indicate that RNA virus populations carry a significant deleterious 35 mutation load. This mutation load has the potential to shape patterns of adaptive evolution via 36 genetic linkage to beneficial mutations. Here, we examine the effect of deleterious mutations on 37 patterns of influenza A subtype H3N2’s antigenic evolution in humans. By first analyzing simple 38 models of influenza that incorporate a mutation load, we show that deleterious mutations, as 39 expected, act to slow the virus’s rate of antigenic evolution, while making it more punctuated in 40 nature. These models further predict three distinct molecular pathways by which antigenic 41 cluster transitions occur, and we find phylogenetic patterns consistent with each of these 42 pathways in influenza virus sequences. Simulations of a more complex phylodynamic model 43 further indicate that antigenic mutations act in concert with deleterious mutations to reproduce 44 influenza’s spindly hemagglutinin phylogeny, co-circulation of antigenic variants, and high 45 annual attack rates. 46