title: Positive Selection Drives Preferred Segment Combinations during Influenza Virus Reassortment.
abstract: Influenza A virus (IAV) has a segmented genome that allows for the exchange of genome segments between different strains. This reassortment accelerates evolution by breaking linkage, helping IAV cross species barriers to potentially create highly virulent strains. Challenges associated with monitoring the process of reassortment in molecular detail have limited our understanding of its evolutionary implications. We applied a novel deep sequencing approach with quantitative analysis to assess the in vitro temporal evolution of genomic reassortment in IAV. The combination of H1N1 and H3N2 strains reproducibly generated a new H1N2 strain with the hemagglutinin and nucleoprotein segments originating from H1N1 and the remaining six segments from H3N2. By deep sequencing the entire viral genome, we monitored the evolution of reassortment, quantifying the relative abundance of all IAV genome segments from the two parent strains over time and measuring the selection coefficients of the reassorting segments. Additionally, we observed several mutations coemerging with reassortment that were not found during passaging of pure parental IAV strains. Our results demonstrate how reassortment of the segmented genome can accelerate viral evolution in IAV, potentially enabled by the emergence of a small number of individual mutations.
authors.affiliation: Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester.
authors.forename: Konstantin B
authors.initials: KB
authors.lastname: Zeldovich
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Renzette
authors.affiliation: École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Foll
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester.
authors.forename: Serena T
authors.initials: ST
authors.lastname: Pham
authors.affiliation: Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Venev
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester.
authors.forename: Glen R
authors.initials: GR
authors.lastname: Gallagher
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester.
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Bolon
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester.
authors.forename: Evelyn A
authors.initials: EA
authors.lastname: Kurt-Jones
authors.affiliation: École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Jensen
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Caffrey
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester.
authors.forename: Celia A
authors.initials: CA
authors.lastname: Schiffer
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Kowalik
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester jennifer.wang@umassmed.edu.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Finberg
mesh_terms: D000818:Animals; D019295:Computational Biology; D004285:Dogs; D019143:Evolution, Molecular; D005787:Gene Frequency; D016679:Genome, Viral; D005838:Genotype; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics; D057221:Influenza A Virus, H1N2 Subtype / Q000235:genetics; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics; D029521:Alphainfluenzavirus / Q000235:genetics*; D057230:Limit of Detection; D061985:Madin Darby Canine Kidney Cells; D009698:Nucleoproteins / Q000235:genetics; D016865:Reassortant Viruses / Q000235:genetics*; D012641:Selection, Genetic; D017423:Sequence Analysis, RNA
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D009698:Nucleoproteins
keywords: deep sequencing; evolution; influenza; mutations; reassortment