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  • Review Article
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The evolution of epidemic influenza

Nature Reviews Genetics volume 8, pages 196–205 (2007)Cite this article

Key Points

  • Phylogenetic analysis of newly available complete genome sequences of human influenza A virus reveals that multiple viral lineages frequently co-circulate within single geographical localities. This is in contrast to previous studies of the HA1 (haemagglutinin) domain in isolation, which depicted a single dominant and selectively favoured lineage.

  • Genome sequence data has also shown that reassortment, involving all segments of the influenza virus genome, is a frequent process and might also facilitate major antigenic changes. However, the role (if any) of homologous RNA recombination in generating genetic diversity is still unclear.

  • Natural selection on the HA protein seems to operate in a punctuated manner, causing distinct but irregular episodes of phenotypic change that are manifested as antigenic 'cluster jumps'. However, the fitness effects of the other viral proteins, and how they interact epistatically, is currently unclear.

  • Overall rates of evolutionary change (nucleotide substitution) in influenza A virus are similar in all species that have been studied, from mammals to birds. Furthermore, although rates of non-synonymous (amino-acid) substitution vary more extensively among species, there is little evidence that influenza viruses in wild aquatic birds, which are the main reservoir, have reached an 'evolutionary stasis'.

  • The factors that determine the strong winter seasonality of influenza virus are still unclear. However, it is likely that tropical regions constitute an important reservoir for year-long viral transmission, and that human movement (including workflow) among areas of high population density has a key role in determining epidemic patterns.

  • In the future, it will be necessary to take a synergistic approach to the study of influenza virus epidemiology and evolution, combining genomic, phenotypic (antigenic) and epidemiological data. Major gaps in current genome sequence data include virus samples from tropical regions, from transmission chains, and from within individual hosts.

Abstract

Recent developments in complete-genome sequencing, antigenic mapping and epidemiological modelling are greatly improving our knowledge of the evolution of human influenza virus at the epidemiological scale. In particular, recent studies have revealed a more complex relationship between antigenic evolution, natural selection and reassortment than previously realized. Despite these advances, there is much that remains to be understood about the epidemiology of influenza virus, particularly the processes that determine the virus's strong seasonality. We argue that a complete understanding of the evolutionary biology of this important human pathogen will require a genomic view of genetic diversity, including the acquisition of polymorphism data from within individual hosts and from geographical regions, particularly the tropics, which have been poorly surveyed to date.

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Figure 1: The periodicity of pneumonia and influenza mortality and excess mortality rates.
Figure 2: The structure of influenza A virus.
Figure 3: Phylogenetic relationships of concatenated internal proteins.
Figure 4: A model for the genome-wide evolution of human influenza A/H3N2 virus.
Figure 5: The seasonality of influenza virus.

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Authors and Affiliations

  1. Department of Biology, Center for Infectious Disease Dynamics, The Pennsylvania State University, University Park, Pennsylvania, 16802, USA

    Martha I. Nelson & Edward C. Holmes

  2. Fogarty International Center, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Edward C. Holmes

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Glossary

Pandemic

An epidemic that occurs over a large geographical area, including multiple countries.

Epidemic

The occurrence of more cases than expected of an infectious disease, in a defined geographical area over a defined time period.

Reassortment

A form of recombination in which two (or more) influenza viruses, of the same or different subtypes, co-infect a single cell and exchange RNA segments to form genetically novel viruses.

Haemagglutinin

An influenza virus surface glycoprotein, denoted HA, which is responsible for viral binding and entry into host epithelial cells. Sixteen HA serotypes are present in animal species.

Neuraminidase

An influenza virus surface glycoprotein, denoted NA, which is involved in the budding (release) of new virions from infected cells. Nine NA serotypes are present in animal species.

Antigenic drift

The continual evasion of host immunity by the gradual accumulation of mutations in the haemagglutinin and neuraminidase surface glycoproteins of influenza A virus, changing its antigenic structure.

Epitope

A small sequence of a viral protein that is recognized by either the cellular or humoral arms of the immune system, and therefore frequently undergoes the strongest adaptive selection to rapidly evolve immune-escape mutants.

Population bottleneck

A marked reduction in population size followed by the survival and expansion of a small sample of the original population.

Antigenic shift

The formation of a new influenza virus subtype with a novel combination of haemagglutinin and neuraminidase segments, which are derived from two different parental influenza strains, that combined through genomic reassortment.

Maximum likelihood

A statistical method that selects the phylogenetic tree with the highest probability of explaining the sequence data, under a specific model of substitution (changes in the nucleotide or amino-acid sequence).

Bayesian Markov chain Monte Carlo

(MCMC); Bayesian statistical inference allows the use of prior knowledge in assessing the probability of model parameters in the presence of new data. The prior distribution can strongly affect the posterior (the results). MCMC is a stochastic algorithm for drawing samples from a posterior distribution, therein providing an estimate of the distribution.

Gravity model

A methodology that extends Newtonian gravitational laws to models of behavioural patterns that mimic gravitational interaction, in that the effect of one population (mass) on another is inversely related to the spatial distance between them.

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Nelson, M., Holmes, E. The evolution of epidemic influenza. Nat Rev Genet 8, 196–205 (2007). https://doi.org/10.1038/nrg2053

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