Abstract
Recent phylogenetic analyses indicate that RNA virus populations carry a significant deleterious mutation load. This mutation load has the potential to shape patterns of adaptive evolution via genetic linkage to beneficial mutations. Here, we examine the effect of deleterious mutations on patterns of influenza A subtype H3N2's antigenic evolution in humans. By first analyzing simple models of influenza that incorporate a mutation load, we show that deleterious mutations, as expected, act to slow the virus's rate of antigenic evolution, while making it more punctuated in nature. These models further predict three distinct molecular pathways by which antigenic cluster transitions occur, and we find phylogenetic patterns consistent with each of these pathways in influenza virus sequences. Simulations of a more complex phylodynamic model further indicate that antigenic mutations act in concert with deleterious mutations to reproduce influenza's spindly hemagglutinin phylogeny, co-circulation of antigenic variants, and high annual attack rates.
Highlights
Seasonal influenza viruses infect up to 15% of the world’s human population annually, with the majority of flu cases attributable to influenza type A subtype H3N2 (A/H3N2) (World Health Organization, 2014)
We have shown that population genetic and population dynamic models incorporating sublethal deleterious mutations can reproduce the characteristic features of influenza A/H3N2’s evolutionary dynamics in humans
Influenza’s epochal evolution model (Koelle et al, 2006) assumes that neutral or nearly neutral mutations accumulate at HA epitopes and that these changes enable a previously neutral mutation to exact a large antigenic effect and thereby to precipitate an antigenic cluster transition
Summary
Seasonal influenza viruses infect up to 15% of the world’s human population annually, with the majority of flu cases attributable to influenza type A subtype H3N2 (A/H3N2) (World Health Organization, 2014). A large body of research has focused on understanding the process by which influenza evolves antigenically, how point mutations in the virus’s hemagglutinin (HA) protein allow for immune escape (Wiley et al, 1981; Wilson and Cox, 1990; Koel et al, 2013) and how virus strains interact immunologically to shape this subtype’s evolutionary patterns in the long term (Ferguson et al, 2003; Tria et al, 2005; Koelle et al, 2006; Recker et al, 2007; Bedford et al, 2012; Zinder et al, 2013) Distinct from these efforts, several phylogenetic analyses have indicated that influenza A/H3N2 in humans carries a deleterious mutation load (Fitch et al, 1997; Pybus et al, 2007; Strelkowa and Lassig, 2012). This finding again points towards transiently circulating deleterious mutations in influenza and, more
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