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Genomic and protein structural maps of adaptive evolution of human influenza a virus to increased virulence in the mouse

Ping, J and Keleta, L and Forbes, NE and Dankar, S and Stecho, W and Tyler, S and Zhou, Y and Babiuk, L and Weingartl, H and Halpin, RA and Boyne, A and Bera, J and Hostetler, J and Fedorova, NB and Proudfoot, K and Katzel, DA and Stockwell, TB and Ghedin, E and Spiro, DJ and Brown, EG (2011) Genomic and protein structural maps of adaptive evolution of human influenza a virus to increased virulence in the mouse. PLoS ONE, 6 (6).

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Adaptive evolution is characterized by positive and parallel, or repeated selection of mutations. Mouse adaptation of influenza A virus (IAV) produces virulent mutants that demonstrate positive and parallel evolution of mutations in the hemagglutinin (HA) receptor and non-structural protein 1 (NS1) interferon antagonist genes. We now present a genomic analysis of all 11 genes of 39 mouse adapted IAV variants from 10 replicate adaptation experiments. Mutations were mapped on the primary and structural maps of each protein and specific mutations were validated with respect to virulence, replication, and RNA polymerase activity. Mouse adapted (MA) variants obtained after 12 or 20-21 serial infections acquired on average 5.8 and 7.9 nonsynonymous mutations per genome of 11 genes, respectively. Among a total of 115 nonsynonymous mutations, 51 demonstrated properties of natural selection including 27 parallel mutations. The greatest degree of parallel evolution occurred in the HA receptor and ribonucleocapsid components, polymerase subunits (PB1, PB2, PA) and NP. Mutations occurred in host nuclear trafficking factor binding sites as well as sites of virus-virus protein subunit interaction for NP, NS1, HA and NA proteins. Adaptive regions included cap binding and endonuclease domains in the PB2 and PA polymerase subunits. Four mutations in NS1 resulted in loss of binding to the host cleavage and polyadenylation specificity factor (CPSF30) suggesting that a reduction in inhibition of host gene expression was being selected. The most prevalent mutations in PB2 and NP were shown to increase virulence but differed in their ability to enhance replication and demonstrated epistatic effects. Several positively selected RNA polymerase mutations demonstrated increased virulence associated with >300% enhanced polymerase activity. Adaptive mutations that control host range and virulence were identified by their repeated selection to comprise a defined model for studying IAV evolution to increased virulence in the mouse.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Ping, J
Keleta, L
Forbes, NE
Dankar, S
Stecho, W
Tyler, S
Zhou, Y
Babiuk, L
Weingartl, H
Halpin, RA
Boyne, A
Bera, J
Hostetler, J
Fedorova, NB
Proudfoot, K
Katzel, DA
Stockwell, TB
Ghedin, Eelg21@pitt.eduELG21
Spiro, DJ
Brown, EG
ContributionContributors NameEmailPitt UsernameORCID
Centers: Other Centers, Institutes, Offices, or Units > Center for Vaccine Research
Date: 4 July 2011
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 6
Number: 6
DOI or Unique Handle: 10.1371/journal.pone.0021740
Schools and Programs: School of Medicine > Computational and Systems Biology
Refereed: Yes
MeSH Headings: Animals; Cell Line; Dogs; Genome, Viral--genetics; Humans; Influenza A virus--genetics; Influenza A virus--metabolism; Mice; Viral Proteins--genetics; Viral Proteins--metabolism; Virulence--genetics
Other ID: NLM PMC3128085
PubMed Central ID: PMC3128085
PubMed ID: 21738783
Date Deposited: 05 Sep 2012 17:43
Last Modified: 06 Sep 2019 21:55


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