Abstract
The non-structural protein 1 (NS1) of influenza A virus (IAV), coded by its third most diverse gene, interacts with multiple molecules within infected cells. NS1 is involved in host immune response regulation and is a potential contributor to the virus host range. Early phylogenetic analyses using 50 sequences led to the classification of NS1 gene variants into groups (alleles) A and B. We reanalyzed NS1 diversity using 14,716 complete NS IAV sequences, downloaded from public databases, without host bias. Removal of sequence redundancy and further structured clustering at 96.8% amino acid similarity produced 415 clusters that enhanced our capability to detect distinct subgroups and lineages, which were assigned a numerical nomenclature. Maximum likelihood phylogenetic reconstruction using RNA sequences indicated the previously identified deep branching separating group A from group B, with five distinct subgroups within A as well as two and five lineages within the A4 and A5 subgroups, respectively. Our classification model proposes that sequence patterns in thirteen amino acid positions are sufficient to fit >99.9% of all currently available NS1 sequences into the A subgroups/lineages or the B group. This classification reduces host and virus bias through the prioritization of NS1 RNA phylogenetics over host or virus phenetics. We found significant sequence conservation within the subgroups and lineages with characteristic patterns of functional motifs, such as the differential binding of CPSF30 and crk/crkL or the availability of a C-terminal PDZ-binding motif. To understand selection pressures and evolution acting on NS1, it is necessary to organize the available data. This updated classification may help to clarify and organize the study of NS1 interactions and pathogenic differences and allow the drawing of further functional inferences on sequences in each group, subgroup and lineage rather than on a strain-by-strain basis.
Highlights
Influenza A virus (IAV) can infect multiple animal species, including birds and mammals, but it is recognized that the avian species are possibly the natural host
non-structural protein 1 (NS1) Phylogenetic Reconstruction A simple clustering approach was applied to reduce sequence data to a manageable level while ensuring that it still represented the diversity of NS1
NS1 in human H2N2 virus sequences appear as common ancestors of NS1 from H3N2 (A4.2), rather than as predecessors of H1N1 (A4.1)
Summary
Influenza A virus (IAV) can infect multiple animal species, including birds and mammals, but it is recognized that the avian species are possibly the natural host. IAV is an enveloped (2) single-strand RNA virus with a genome composed of eight segments that can be exchanged to form novel genomic ‘‘constellations’’ or reassortants [1]. The large diversity observed in IAV [2,3] is caused by reassortment and by genetic drift, selective pressures, host adaptation, phylogeography, and transient gene hitchhiking [4], as well as other factors. The most diverse IAV genes, HA and NA, have been divided into 17 and 10 subtypes, respectively [5,6]. Hostspecific lineages (Equine 1 and 2, Gull, classic and Eurasian swine, Human and various avian lineages) were early identified in HA, NA and other segments, there is limited phylogenetic congruence between each segment [1]
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