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Literature detail

Adaptive mutation in influenza A virus non-structural gene is linked to host switching and induces a novel protein by alternative splicing.

Mohammed Selman1,2 Samar K Dankar1,2 Nicole E Forbes1,2 Jian-Jun Jia3 Earl G Brown1,2
Affiliations 3 institutions
  1. Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa , Ottawa, Ontario K1H 8M5, Canada
  2. Emerging Pathogens Research Centre, Faculty of Medicine, University of Ottawa , Ottawa, Ontario K1H 8M5, Canada.
  3. Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa , Ottawa, Ontario K1H 8M5, Canada.
PMID 26038410 2012 Emerg Microbes Infect eng ppublish
PubMed DOI Browse context

Article

Publication summary

Little is known about the processes that enable influenza A viruses to jump into new host species. Here we show that the non-structural protein1 nucleotide substitution, A374G, encoding the D125G(GAT→GGT) mutation, which evolved during the adaptation of a human virus within a mouse host, activates a novel donor splice site in the non-structural gene, hence producing a novel influenza A viral protein, NS3. Using synonymous 125G mutations that do not activate the novel donor splice site, NS3 was shown to provide replicative gain-of-function. The protein sequence of NS3 is similar to NS1 protein but with an internal deletion of a motif comprised of three antiparallel β-strands spanning codons 126 to 168 in NS1. The NS1-125G(GGT) codon was also found in 33 natural influenza A viruses that were strongly associated with switching from avian to mammalian hosts, including human, swine and canine populations. In addition to the experimental human to mouse switch, the NS1-125G(GGT) codon was selected on avian to human transmission of the 1997 H5N1 and 1999 H9N2 lineages, as well as the avian to swine jump of 1979 H1N1 Eurasian swine influenza viruses, linking the NS1 125G(GGT) codon with host adaptation and switching among multiple species.

host switch influenza A virus non-structural protein 1 NS gene NS1 NS3 viral splicing

Structured evidence records

Evidence records

5 total
Molecular Adaptation 2 records
Molecular Adaptation Extraction confidence 1.00
Key finding

Influenza A virus acquired an NS1 D125G mutation within a mouse host that activated a new splice donor site in the NS gene, producing a novel NS3 protein linked to host adaptation.

Virus
IAV
Host
Not specified
Location
Not specified
Supporting text

The non-structural protein1 nucleotide substitution, A374G, encoding the D125G(GAT→GGT) mutation, which evolved during the adaptation of a human virus within a mouse host, activates a novel donor splice site in the non-structural gene, hence producing a novel influenza A viral protein, NS3.

Genes or proteins
NS1; NS3; non-structural gene
Mutations
A374G; D125G(GAT→GGT)
Mechanism types
alternative_splicing; replication_efficiency; host_switching
Molecular Adaptation Extraction confidence 1.00
Key finding

The NS1 125G(GGT) codon correlates with avian to mammalian host switching, being present in multiple influenza A virus lineages infecting humans, swine, and canines.

Virus
IAV
Host
Not specified
Location
Not specified
Supporting text

The NS1-125G(GGT) codon was also found in 33 natural influenza A viruses that were strongly associated with switching from avian to mammalian hosts, including human, swine and canine populations.

Genes or proteins
NS1
Mutations
125G(GGT)
Mechanism types
host_switching; molecular_selection
Cross Species Transmission 1 records
Cross Species Transmission Extraction confidence 0.95
Key finding

Influenza A virus carrying the NS1-125G(GGT) codon was linked to an avian-to-swine host jump, indicating cross-species transmission between birds and pigs.

Virus
IAV
Location
Not specified
Supporting text

The NS1-125G(GGT) codon was selected on avian to swine jump of 1979 H1N1 Eurasian swine influenza viruses.

Study design
phylogenetic analysis
Transmission direction
animal-to-animal
Genomic Evolution 1 records
Genomic Evolution Extraction confidence 0.90
Key finding

A D125G mutation in the influenza A virus NS1 gene arose during human-to-mouse adaptation and is also present in multiple avian-to-mammalian host-switching influenza lineages, linking the NS1 125G codon with host adaptation.

Virus
IAV
Location
Not specified
Supporting text

The non-structural protein1 nucleotide substitution, A374G, encoding the D125G(GAT→GGT) mutation, which evolved during the adaptation of a human virus within a mouse host, activates a novel donor splice site in the non-structural gene, producing a novel protein NS3. The NS1-125G(GGT) codon was also found in 33 natural influenza A viruses associated with switching from avian to mammalian hosts.

Genes or proteins
non-structural gene; NS1; NS3
Analysis methods
sequence analysis; comparative genomic analysis
Host Range Experiment 1 records
Host Range Experiment Extraction confidence 0.95
Key finding

Experimental adaptation of a human influenza A virus in mice produced a D125G mutation in the NS1 gene that increased replication via a novel spliced protein NS3.

Virus
IAV
Location
Not specified
Supporting text

The non-structural protein1 nucleotide substitution, A374G, encoding the D125G mutation, which evolved during the adaptation of a human virus within a mouse host, activates a novel donor splice site in the non-structural gene ... NS3 was shown to provide replicative gain-of-function.

Method
experimental adaptation; replication assay
Experimental system
in vivo animal experiment