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. 2016 Aug 3:16:156.
doi: 10.1186/s12862-016-0727-8.

Population genetic processes affecting the mode of selective sweeps and effective population size in influenza virus H3N2

Kangchon Kim  1 , Yuseob Kim  2   3
Affiliations

Population genetic processes affecting the mode of selective sweeps and effective population size in influenza virus H3N2

Kangchon Kim et al. BMC Evol Biol. .

Abstract

Background: Human influenza virus A/H3N2 undergoes rapid adaptive evolution in response to host immunity. Positively selected amino acid substitutions have been detected mainly in the hemagglutinin (HA) segment. The genealogical tree of HA sequences sampled over several decades comprises a long trunk and short side branches, which indicates small effective population size. Various studies have reproduced this unique genealogical structure by modeling recurrent positive selection. However, it has not been clearly demonstrated whether recurrent selective sweeps alone can explain the limited level of genetic diversity observed in the HA of H3N2. In addition, the variation-reducing impacts of other evolutionary processes - background selection and complex demography - relative to that of positive selection have never been explicitly evaluated.

Results: In this paper, using computer simulation of a viral population evolving under recurrent selective sweeps we demonstrate that positive selection alone, if it occurs at a rate estimated by previous studies, cannot lead to such a small effective population size. Genetic hitchhiking fails to completely wipe out pre-existing variation because soft, rather than hard, selective sweeps prevail under realistic parameters of mutation rate and population size. We find that antigenic-cluster-transition substitutions in HA occur as hard sweeps. This indicates that the effective population size under which those mutations arise must be much smaller than the actual population size due to other evolutionary forces before selective sweeps further reduce it. We thus examine the effects of background selection and metapopulation dynamics in reducing the effective population size, using parameter values that reproduce other aspects of molecular evolution in H3N2. When either process is incorporated in recurrent selective sweep simulation, selective sweeps are mostly hard and the observed level of synonymous diversity is obtained with large census population size.

Conclusions: Background selection and metapopulation dynamics have greater variation reducing power than recurrent positive selection under realistic parameters in H3N2. Therefore, these evolutionary processes are likely to play crucial roles in reducing the effective population size of H3N2 viruses and thus explaining the characteristic shape of H3N2 genealogy.

Keywords: Background selection; Influenza virus; Metapopulation; Positive selection; Soft sweep.

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Figures

Fig. 1
Fig. 1
Simulation of recurrent positive selection (model A) under various population sizes and selection coefficients. A sequence of length L = 1,000 contains 230 synonymous sites over which the level of polymorphism is calculated, which models the HA1 segment of H3N2 virus. As we reduced L b (the number of beneficial nonsynonymous sites) with increasing s and N, the numbers of adaptive substitutions per year are similar (k ≈ 1.3) in all cases. a. Per-segment synonymous diversity (πs) as a function of population size with different assumptions on selection coefficient s for beneficial mutations. πs obtained from HA1 is indicated by a dashed line. b. The rate of soft sweeps (f soft) in the same simulation replicates
Fig. 2
Fig. 2
Distinguishing the mode of selective sweep on genealogy. A maximum likelihood tree is reconstructed for simulated (or actual HA segment) sequences sampled over a period that starts before the first mutational origin and ends after the fixation of a (putatively) beneficial allele. The copies of the beneficial allele at the branch tips are shown as pink or red dots. Red dots indicate copies observed when they reached fixation in the population. a. An example of hard selective sweep. All copies of the beneficial allele at the time of fixation (red dots) originate from a single mutation (indicated by blue triangle). b. An example of soft selective sweep. There are two clones originating from two different mutation events (two blue triangles) at the same site at the time of fixation. Examples A and B, from two different sites on the same genealogy, were obtained from the simulation of model B1 with L = 1,000 and N = 10,000. c. A hard selective sweep of the 156 K allele during antigenic cluster change from SI87 to BE92. Identical 156 K mutations arose independently (pink) and co-existed separately in BE89 and BE92 clusters. However, when allele frequency became 1.0 (red), only 156 K mutants in BE92 existed
Fig. 3
Fig. 3
The joint effect of recurrent positive and negative selection with increasing population size. While the rate of adaptive substitutions and selection coefficient (s) are fixed at k ≈ 1.3 and s = 0.1, synonymous diversity is largest in Model A (L = 1,000) and decreases in Model B1 (incorporating background selection) with increasing number of sites under negative selection (L d ≈ L – 230) with s d = 0.1, for a given population size N. Simulations with N = 2,000 in Model A and (N, L) = (5,000, 1,000), (10,000, 2,000), or (100,000, 4,000) in Model B1 generate soft selective sweeps at comparable rates (f soft) (larger markers linked by dashed lines), and they also yield similar levels of synonymous diversity (πs) (larger markers linked by solid lines)
Fig. 4
Fig. 4
Model of complex demography (metapopulation dynamics) under which recurrent positive selection occurs. a. Population is subdivided into six demes in the northern hemisphere (green) and two demes in the southern hemisphere (blue). Viruses migrate between demes in all directions (red arrows). b. Seasonal changes in the carrying capacities (K) of demes. c. Synonymous diversity (πs) and soft sweep rate (f soft) according to population size (N) in metapopulation models. C1: rates of migrations in all directions are equal. C2: immigration and emigration rate of a single northern deme is 10 times larger than the other demes. One of the six northern demes does not undergo the extinction-recolonization cycle but maintains K = 0.2K max (C3a) or 500 (C3b)
Fig. 5
Fig. 5
Summary of evolutionary models and the two-step reduction of effective population size. The degrees of reduction in effective population size due to recurrent selective sweeps are shown by red arrows. Reductions due to background selection and metapopulation dynamics, when parameters are chosen to maximize the variation-reducing effect (and, at the same time, to satisfy the constraints) of the models, are indicated by blue and green arrows, respectively. Black dashed line represents the census (N < 104 in Model A) or effective population size (N e1 in Model B and C) under which positive selection results in small probability of soft selective sweeps (f soft ≈ 0.1). Red dashed line marks the effective population size (N e in Model A with N < 104 and N e2 in Model B and C) that generate the observed sequence diversity (πs ≈ 6.2). Background selection can generate the observed patterns of soft sweeps and sequence diversity in a population with the largest census size
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