title: Influenza virus drug resistance: a time-sampled population genetics perspective.
abstract: The challenge of distinguishing genetic drift from selection remains a central focus of population genetics. Time-sampled data may provide a powerful tool for distinguishing these processes, and we here propose approximate Bayesian, maximum likelihood, and analytical methods for the inference of demography and selection from time course data. Utilizing these novel statistical and computational tools, we evaluate whole-genome datasets of an influenza A H1N1 strain in the presence and absence of oseltamivir (an inhibitor of neuraminidase) collected at thirteen time points. Results reveal a striking consistency amongst the three estimation procedures developed, showing strongly increased selection pressure in the presence of drug treatment. Importantly, these approaches re-identify the known oseltamivir resistance site, successfully validating the approaches used. Enticingly, a number of previously unknown variants have also been identified as being positively selected. Results are interpreted in the light of Fisher's Geometric Model, allowing for a quantification of the increased distance to optimum exerted by the presence of drug, and theoretical predictions regarding the distribution of beneficial fitness effects of contending mutations are empirically tested. Further, given the fit to expectations of the Geometric Model, results suggest the ability to predict certain aspects of viral evolution in response to changing host environments and novel selective pressures.
authors.affiliation: School of Life Sciences, 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: Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland ; Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Poh
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Renzette
authors.affiliation: School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland ; Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland ; Department of Biology and Biochemistry, University of Fribourg, Fribourg, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Ferrer-Admetlla
authors.affiliation: School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland ; Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bank
authors.affiliation: School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland ; Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
authors.forename: Hyunjin
authors.initials: H
authors.lastname: Shim
authors.affiliation: Center for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anna-Sapfo
authors.initials: AS
authors.lastname: Malaspinas
authors.affiliation: School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland ; Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
authors.forename: Gregory
authors.initials: G
authors.lastname: Ewing
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.affiliation: Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland ; Department of Biology and Biochemistry, University of Fribourg, Fribourg, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Wegmann
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Caffrey
authors.affiliation: Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Konstantin B
authors.initials: KB
authors.lastname: Zeldovich
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Bolon
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Kowalik
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Celia A
authors.initials: CA
authors.lastname: Schiffer
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Finberg
authors.affiliation: School of Life Sciences, 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
mesh_terms: D001499:Bayes Theorem; D024882:Drug Resistance, Viral / Q000235:genetics*; D040961:Genetic Drift; D005828:Genetics, Population; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000235:genetics*; D007251:Influenza, Human / Q000235:genetics / Q000821:virology; D009154:Mutation; D053139:Oseltamivir / Q000494:pharmacology; D012641:Selection, Genetic
chemical_list: D053139:Oseltamivir