Questioning the Evidence for Genetic Recombination in the 1918 "Spanish Flu" Virus

Influenza viral sequences have been obtained from preserved tissues of victims of the “Spanish flu” pandemic that killed over 20 million people from 1918 to 1919 (1, 2). Phylogenetic analysis of hemagglutinin (HA) gene sequences has indicated that the 1918 Spanish flu virus was more closely related to the human lineage than to the swine or avian influenza lineages of the H1N1 subtype (2). In a recent reanalysis of the 1918 HA gene, however, Gibbs et al. (3) proposed that recombination had occurred such that the majority of the globular domain (HA1) in the Spanish flu virus was acquired from the swine lineage, but its stalk region (HA2) was derived from the human lineage. Gibbs et al. also speculated that this intragenic recombination resulted in the increased virulence associated with the Spanish flu pandemic. We find no evidence for recombination in the 1918 HA gene, however. Rather, the apparent recombination described in (3) results from a difference in the rate of evolution between HA1 and HA2—a difference present only in human influenza A viruses.