Modeling gene sequences over time in 2009 H1N1 influenza A virus populations

Abstract

Background: A sudden emergence of Influenza A Virus (IAV) infections with a new pandemic H1N1 IAV is taking place since April of 2009. In order to gain insight into the mode of evolution of these new H1N1 strains, we performed a Bayesian coalescent Markov chain Monte Carlo (MCMC) analysis of full-length neuraminidase (NA) gene sequences of 62 H1N1 IAV strains (isolated from March 30th to by July 28th, 2009).

Results: The results of these studies revealed that the expansion population growth model was the best to fit the sequence data. A mean of evolutionary change of 7.84 x 10(-3) nucleotide substitutions per site per year (s/s/y) was obtained for the NA gene. A significant contribution of first codon position to this mean rate was observed. Maximum clade credibility trees revealed a rapid diversification of NA genes in different genetic lineages, all of them containing Oseltamivir-resistant viruses of very recent emergence. Mapping of naturally occurring amino acid substitutions in the NA protein from 2009 H1N1 IAV circulating in 62 different patients revealed that substitutions are distributed all around the surface of the molecule, leaving the hydrophobic core and the catalytic site essentially untouched.

Conclusion: High evolutionary rates and fast population growth have contributed to the initial transmission dynamics of 2009 H1N1 IAV. Naturally occurring substitutions are preferentially located at the protein surface and do not interfere with the NA active site. Antigenic regions relevant for vaccine development can differ from previous vaccine strains and vary among patients.

Figure 1

Bayesian MCMC phylogenetic tree analysis of 62 NA genes from 2009 H1N1 IAV strains. A maximum credibility clade obtained using the GTR model, the expansion population growth model and a relaxed clock (uncorrelated exponential) is shown. Strains in the tree are shown by name. Main genetic sub-branches are indicated by capital letters (A through D). Node ages are shown in days at the nodes of the tree. The tree is rooted to theirMRCA. Bar at the bottom of the tree show time in days. Strains carrying the H275Y, that confers resistance to Oseltamivir, are shown in red.

Figure 2

Mapping of naturally occurring amino acid substitutions in a NA protein 3D structure. The 3D structure model of the NA protein from 2009 H1N1 IAV shown in the figure was obtained by Mauer-Stroh et al. [27] (Bioinformatic Institute, A*STAR's Biomedical Sciences Institutes, Singapore). Oseltamivir atoms are shown in red. Antibodies binding sites are shown in green. Position 275, where substitution H275Y confers resistance to Oseltamivir, is shown in pink. The substitutions found among strains isolated during 30, 60, 90 (where viruses with H275Y substitution also arise) and 119 days (from March 30^th, 2009) are shown in yellow, blue, orange and white in A through D, respectively. Dotted white lines show distances in Å.