Reassortment, positive selection, and the inter-segmental patterns of divergence and polymorphism in influenza virus H3N2

Abstract

Reassortment in viruses with segmented genome is a major evolutionary process for their genetic diversity and adaptation. It is also crucial in generating different levels of sequence polymorphism among segments when positive selection occurs at different rates on them. Previous studies have detected intra-subtype reassortment events in human influenza H3N2 by between-segment incongruity in phylogenetic tree topology. Here, we quantitatively estimate the reassortment rate, probability that a pair of segments in a viral lineage become separated in a unit time, between hemmaglutinin (HA) and four non-antigenic segments (PB2, PB1, PA and NP) in human influenza virus H3N2. Using statistics that measure incongruity in tree topology or linkage disequilibrium between segments and performing simulations that are constrained to reproduce the various patterns of H3N2 molecular evolution, we infer that reassortment rate ranges between 0.001 and 0.01 assuming one generation to be 1/80 year. However, we find that a higher rate of reassortment is required to generate the observed pattern of ~40% less synonymous sequence polymorphism on HA relative to other non-HA segments, which results from recurrent selective sweeps by antigenic variants on the HA segment. Here, synonymous diversity was compared after correcting for difference in inferred mutation rates among segments, which we found significant. We also explored analytic approximations for inter-segmental difference in sequence diversity for a given reassortment rate to understand the underlying dynamics of recurrent positive selection. It is suggested that the effects of clonal interference and potentially demography-dependent rate of reassortment in the process of recurrent selective sweeps must be considered to fully explain the genomic pattern of diversity in H3N2 viruses.