Richard H. Scheuermann, Ph.D. Department of Pathology, UT Southwestern March 30, 2011

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Virus Bioinformatics Resource Centers ViPR & IRD. Richard H. Scheuermann, Ph.D. Department of Pathology, UT Southwestern March 30, 2011. Take home messages. NIAID Bioinformatics Resource Centers Virus Pathogen Resource ( ViPR ; ) - PowerPoint PPT Presentation


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Richard H. Scheuermann, Ph.D.Department of Pathology, UT SouthwesternMarch 30, 2011

Virus Bioinformatics Resource Centers ViPR & IRDTake home messagesNIAID Bioinformatics Resource CentersVirus Pathogen Resource (ViPR; )Influenza Research Database (IRD; )Free and open access virus database and analysis resourcesComprehensive data collectionSequence, structure, function, phenotype, surveillance, clinical, immune responseIntegratedSurveillance metadata with sequenceSequence features and sequence conservation with protein structuresDevelopment and adoption of data standardsData sharing infrastructure and policiesNovel approach to identification of genetic determinants of important virus characteristicsInfluenza NS1 nuclear export signal and host rangeNIAID Research ResourcesDMID Resources

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Category A Pathogens

Category B Pathogens

Category C Pathogens

pathogenportal.netPathogen PortalViPR ResourceHome page

www.viprbrc.org13 virus families

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Data IntegrationIRD

Data StandardsCEIRS Network

Other Data StandardsNon-human mammalian surveillanceVirus isolate characteristicsImmuno-assaysVirus passageVirus nomenclatureClinical dataSurveillance

Data SharingPoliciesSequences 30 daysInitial Surveillance Record 90 daysCompleted Virus Isolated Record 1 yearSubmission Infrastructure

Do variations in NS1 sequence featureS influence influenza virus host range?SFVT approachVT-1I F D R L E T L I LVT-2I F N R L E T L I LVT-3I F D R L E T I V LVT-4L F D Q L E T L V SVT-5I F D R L E N L T LVT-6I F N R L E A L I LVT-7I Y D R L E T L I LVT-8I F D R L E T L V LVT-9I F D R L E N I V LVT-10I F E R L E T L I LVT-11 L F D Q M E T L V SInfluenza A_NS1_nuclear-export-signal_137(10)

Identify regions of protein/gene with known structural or functional properties Sequence Features (SF)alpha-helical region, host protein binding site, enzyme active site, immune epitopeDetermine the extent of sequence variation for each SF by defining each unique sequence as a Variant Type (VT)High-level, comprehensive grouping of all virus strains by VT membership for each SF independentlyGenotype-phenotype association statistical analysis (virulence, pathogenesis, host range, immune evasion, drug resistance)While phylogenetics reflect evolutionary history of the virus, it is the focused regions in the viral genes/proteins that effect protein expression, structure and/or protein function that are responsible for important virus characteristics

Influenza A_NS1_alpha-helix_171(17)Influenza A NS1 protein (PDB 2GX9) crystal structure showingNuclear Export Signal Sequence Feature (SF) highlighted in RedAlpha-helix SF highlighted in greenAmino acid alignment with colors showing variation within nuclear export signal regionEach sequence with 1+ substitutions comprises a unique fingerprint or Variant Type (VT)A set of unique sequence substitutions existing within any defined region is a sequence feature variant type (SFVT) Statistical analyses on SFVTs can identify genotype-phenotype relationships44ProteinSubtypeFunctionalStructuralImmune EpitopesTotal CountPB2-710564585PB1-F2-22-6PB1-65733744PA-129534565NS2-237883NS1-2115458494NP-1025472512NAN11026113153NAN2959106180M2-41096116M1-1214286312HAH1437335376HAH24102034HAH3259390481HAH53144065HAH7-123Total9731942274709Influenza A Sequence Features as of January 2011ViPR SFVTsStarting with 3 speciesDENV = 192 SFsHCV = 335 SFsPox = 14 genes, 295 total SFsHSV coming soon w/ DBPBeginning automatic definition for other virus familiesMost SFs pulled fromUniProtKB protein annotationsIEDB immune epitopes (future)

NS1 Sequence FeaturesVT for SF8 (nuclear export signal)

VT-1 strains

VT for SF8 (nuclear export signal)

Causes of apparent NS1 VT-associated host range restrictionVirus spread = capability + opportunityPhenotypic property of the virus limited capacityFounder effect limited opportunityRestricted spatial-temporal distributionSampling bias assumption of random samplingOversampling avian H5N1 in Asia; 2009 H1N1Undersampling large and domestic catsLinkage to causative variantVT-10 strains

VT for SF8 (nuclear export signal)

VT lineages

VT-10 lineage

VT-4 lineage

VT-4 strains

VT-4 lineage = B allele/group

VT-15 & VT-8 lineages

VT-5 strains

SummaryCompiling list of all known influenza protein sequence features (SFs) in IRDObserved dramatic skewing in NS1 SFVT host distributionsIn some cases, attributable to sampling biasesVT-1 and Avian H5N1 due to Asian sampling in mid-2000'sVT-2 and human due to 2009 pandemic H1N1VT-11 and Other (Environment) in Delaware Bay Performing multivariate statistical analysis to control for confounding variablesIn other cases, attributable to founder effectsVT-13 and -14 and Viet Nam 2003However, in other cases these explanations do not appears to be consistent with the data, suggesting that these may indeed be NS1-mediated host range restrictionsEquine VT-10 lineageAvian VT-4 lineage (B allele/group)Human VT-8 lineageHuman VT-15 lineageNuclear export vs linkage disequilibrium?63U.T. SouthwesternRichard ScheuermannBurke SquiresJyothi NoronhaMengya LiuVictoria HuntShubhada GodboleBrett PickettAyman Al-RawashdehMSSMAdolfo Garcia-SastreEric BortzGina ConenelloPeter PaleseVecnaChris LarsenAl RamseyLANLCatherine MackenMira DimitrijevicU.C. DavisNicole BaumgarthNorthrop GrummanEd KlemMike AtassiKevin BiersackJon DietrichWenjie HuaWei JenSanjeev KumarXiaomei LiZaigang LiuJason LucasMichelle LuBruce QuesenberryBarbara RotchfordHongbo SuBryan WaltersJianjun WangSam ZarembaLiwei ZhouIRD SWGGillian Air, OMRFCarol Cardona, Univ. MinnesotaAdolfo Garcia-Sastre, Mt SinaiElodie Ghedin, Univ. PittsburghMartha Nelson, FogartyDaniel Perez, Univ. MarylandGavin Smith, Duke SingaporeDavid Spiro, JCVIDave Stallknecht, Univ. GeorgiaDavid Topham, RochesterRichard Webby, St JudeSFVT expertsGillian Air, OMRFToru Takimoto, RochesterSummer Galloway, EmoryRobert Lamb, NorthwesternBenjamin Hale, Mt. SinaiUSDADavid Suarez Sage AnalyticaRobert TaylorLone SimonsenCEIRS Centers

Influenza SFVT Acknowledgments63


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