Research Article: Components of Selection in the Evolution of the Influenza Virus: Linkage Effects Beat Inherent Selection

Date Published: December 27, 2012

Publisher: Public Library of Science

Author(s): Christopher J. R. Illingworth, Ville Mustonen, Raul Andino.


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.

Partial Text

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], particularly in the viral surface proteins haemagglutinin (HA) and neuraminidase (NA) [3].

The problem of inferring the selection acting at every polymorphism within the history of the human influenza A/H3N2 HA gene represents a significant challenge. Here we have examined the role of interference, as opposed to inherent selection, in determining the eventual fixation or death of polymorphisms. We identified, first, that interference is of great importance in understanding the evolution of influenza. While having no more parameters than the unlinked model, our linked inference model produced trajectories that substantially better fitted observed allele frequencies over time. Next, examining statistics of selection from our linked model, we inferred that, for non-synonymous polymorphisms, the total effect of interference acting on a polymorphism was, in the mean, more significant for its fate than was its inherent selection coefficient. With the inherent selection acting on synonymous polymorphisms expected to be substantially weaker than that acting on non-synonymous polymorphisms (see discussion later), our result is likely to hold for polymorphisms in the HA gene in as a whole.




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