Origin of the 1918 pandemic H1N1 influenza A virus as studied by codon usage patterns and phylogenetic analysis

Abstract

The pandemic of 1918 was caused by an H1N1 influenza A virus, which is a negative strand RNA virus; however, little is known about the nature of its direct ancestral strains. Here we applied a broad genetic and phylogenetic analysis of a wide range of influenza virus genes, in particular the PB1 gene, to gain information about the phylogenetic relatedness of the 1918 H1N1 virus. We compared the RNA genome of the 1918 strain to many other influenza strains of different origin by several means, including relative synonymous codon usage (RSCU), effective number of codons (ENC), and phylogenetic relationship. We found that the PB1 gene of the 1918 pandemic virus had ENC values similar to the H1N1 classical swine and human viruses, but different ENC values from avian as well as H2N2 and H3N2 human viruses. Also, according to the RSCU of the PB1 gene, the 1918 virus grouped with all human isolates and ''classical'' swine H1N1 viruses. The phylogenetic studies of all eight RNA gene segments of influenza A viruses may indicate that the 1918 pandemic strain originated from a H1N1 swine virus, which itself might be derived from a H1N1 avian precursor, which was separated from the bulk of other avian viruses in toto a long time ago. The high stability of the RSCU pattern of the PB1 gene indicated that the integrity of RNA structure is more important for influenza virus evolution than previously thought.

RNA structural constraints in the evolution of the influenza A virus genome NP segment

“…14,40,41 Furthermore, a relatively large number of codons with (nearly) absolute conservation of wobble positions suggests the actual number of base-pairing interactions to be larger than described in this work, which considers only the structures reliably supported by covariation analysis. On the other hand, the locations of structures (Fig.…”

“…41). Unfortunately, the low number of covariation events detected in influenza virus RNA excludes an application of statistics based on counting of covariations occurring in multiple branches of an evolutionary tree in order to filter out spurious coincidences upon speciation.…”

Adaptation of Avian Influenza A Virus Polymerase in Mammals To Overcome the Host Species Barrier

“…A switch in receptor specificity from avian (␣-2,3-linked) to human (␣-2,6-linked) sialic acids as well as stabilization of the stalk region to allow endosomal membrane fusion at the optimal pH is crucial for efficient transmission between mammals (67, 68) and host adaptation (102). Other important factors include appropriate HA glycosylation, the length of the stalk region in the neuraminidase (NA), and specific differences in codon usage (103)(104)(105)(106).…”

Seasonal Trivalent Inactivated Influenza Vaccine Protects against 1918 Spanish Influenza Virus Infection in Ferrets

“…During that year in the United States, outbreaks of respiratory disease occurred simultaneously in humans and swine; whether the H1N1 virus jumped species from humans to pigs or vice versa remains unclear. Recently, it has been suggested that the 1918 pandemic virus was derived from an influenza virus of swine origin and that the precursor of this virus was a descendant of a distinct avian H1N1 virus (1). The H1N1 virus became established in domestic pigs after 1918, forming the classical swine H1N1 lineage, and continued to circulate as the dominant influenza virus in North American swine populations until 1998 (7,29).…”