Abstract
The influenza virus is an important human pathogen, with a rapid rate of evolution in the human population. The rate of homologous recombination within genes of influenza is essentially zero. As such, where two alleles within the same gene are in linkage disequilibrium, interference between alleles will occur, whereby selection acting upon one allele has an influence upon the frequency of the other. We here measured the relative importance of selection and interference effects upon the evolution of influenza. We considered time-resolved allele frequency data from the global evolutionary history of the haemagglutinin gene of human influenza A/H3N2, conducting an in-depth analysis of sequences collected since 1996. Using a model that accounts for selection-caused interference between alleles in linkage disequilibrium, we estimated the inherent selective benefit of individual polymorphisms in the viral population. These inherent selection coefficients were in turn used to calculate the total selective effect of interference acting upon each polymorphism, considering the effect of the initial background upon which a mutation arose, and the subsequent effect of interference from other alleles that were under selection. Viewing events in retrospect, we estimated the influence of each of these components in determining whether a mutant allele eventually fixed or died in the global viral population. Our inherent selection coefficients, when combined across different regions of the protein, were consistent with previous measurements of dN/dS for the same system. Alleles going on to fix in the global population tended to be under more positive selection, to arise on more beneficial backgrounds, and to avoid strong negative interference from other alleles under selection. However, on average, the fate of a polymorphism was determined more by the combined influence of interference effects than by its inherent selection coefficient.
Highlights
The influenza A virus is an important human pathogen, infecting between 5 and 15% of the global population each year [1]
We examine the factors underlying success for mutations in the HA gene of human influenza virus A/H3N2, defining success as the attainment of a high frequency in the global population
Our results suggest that background effects, subsequent interference, and inherent selection are of similar importance for determining the fate of polymorphisms in the HA gene of human influenza A/H3N2
Summary
The influenza A virus is an important human pathogen, infecting between 5 and 15% of the global population each year [1]. Infection by influenza leads to strain-specific immunity in the human population, driving a rapid process of adaptation in the virus [2], in the viral surface proteins haemagglutinin (HA) and neuraminidase (NA) [3]. For HA and NA, the host immune system is a key driver behind selection [5,6,7,8], but selection can arise from interactions with other viral genes [9], stability of the protein structure [10], adaptation to new species [11], drug resistance [12], and, in HA, glycosylation [13]. Known as reassortment, genes from viruses co-infecting a host combine to produce novel viral strains [14]
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