Comparison of avian and human influenza A viruses reveals a mutational bias on the viral genomes

Abstract

In the last few years, the genomic sequence data for thousands of influenza A virus strains, including the 1918 pandemic strain, and hundreds of isolates of the avian influenza virus H5N1, which is causing an increasing number of human fatalities, have become publicly available. This large quantity of sequence data allows us to do comparative genomics with the human and avian versions of the virus. We find that the nucleotide compositions of influenza A viruses infecting the two hosts are sufficiently different that we can determine the host at almost 100% accuracy. This assignment works at the segment level, which allows us to construct the reassortment history of individual segments within each strain. We suggest that the different nucleotide compositions can be explained by a host-dependent mutation bias. To support this idea, we estimate the fixation rates for the different polymerase segments and the ratios of synonymous to nonsynonymous changes. Additionally, we provide evidence supporting the hypothesis that the H1N1 influenza virus entered the human population just prior to the 1918 outbreak, with an earliest bound of 1910.

FIG. 1.

Log-odds scores of human and avian influenza A virus nucleotide composition from the coding sequences of the polymerase genes versus year. Blue asterisks represent human H1N1 strains, purple squares represent H5N1 found in humans, and red pluses represent the remaining human strains available from the NCBI database. Green crosses represent all the avian strains available in the NCBI database at the time of analysis.

FIG. 2.

Same analysis as in Fig. 1, presented in segment-by-segment fashion for all eight influenza virus segments. Blue asterisks represent human H1N1 strains, purple squares represent H5N1 found in humans, and red pluses represent the remaining human strains available from the NCBI database. Green crosses represent all the avian strains available in the NCBI database at the time of analysis. HA, hemagglutinin gene; NA, neuraminidase gene. PB1, PB2, and PA, the three viral polymerase subunits; NP, nucleoprotein; MP, matrix protein; NS, nonstructural.

FIG. 3.

U content evolution of the PB2 gene on segment 1. Blue asterisks are human H1N1 strains, purple squares are H5N1 found in humans, and red pluses are the remaining human strains available from the NCBI database. Green crosses are all the avian strains available in the NCBI database at the time of analysis. The blue dashed line is the predicted evolutionary curve for U content change computed using the U-C block diagonal component of the substitution matrices. This matrix was derived from the nucleotide content of the 1918 H1N1 and 1933 H1N1 Wilson-Smith strains.