Www.fludb.org Comparative Genomics in the Influenza Research Database 17 June 2011 Richard H. Scheuermann, Ph.D. Department of Pathology U.T. Southwestern.

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Comparative Genomics in theInfluenza Research Database17 June 2011

Richard H. Scheuermann, Ph.D.Department of PathologyU.T. Southwestern Medical Center

www.fludb.orgNIAID-sponsoredBioinformatics Resource Centers

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www.fludb.orgQuery Results

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www.fludb.orgWorkbench

www.fludb.orgNovel Data Features in IRDCEIRS Surveillance Data3D Structures and Data IntegrationSequence Feature Variant Typeswww.fludb.orgCEIRS

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www.fludb.org3D Structures & IntegrationVisualize protein structure in 3DDisplay sequence conservation heat map on the structureHighlight sequence features (epitopes, etc.)Download highlighted protein structure imagewww.fludb.org

www.fludb.orgSFVT 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)an alpha-helical region, the binding site for another protein, an enzyme active site, an 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 independentlyInfluenza A_NS1_alpha-helix_171(17)www.fludb.orgInfluenza 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 relationships19Influenza A Sequence Features as of 10JUN2011>4000 SFs total

www.fludb.orgVT for SF8 (nuclear export signal)

www.fludb.orgVT-1 strains

www.fludb.orgAdaptive genetic drivers of species jump events www.fludb.orgFlu pandemics of the 20th and 21st centuries initiated by species jump events1918 flu pandemic (Spanish flu)subtype H1N1 (avian origin)estimated to have claimed between 2.5% to 5.0% of the worlds population (20 > 100 million deaths) Asian flu (1957 1958)subtype H2N2 (avian origin)1 - 1.5 million deathsHong Kong flu (1968 1969)subtype H3N2 (avian origin)between 750,000 and 1 million deaths2009 H1N1subtype H1N1 (swine origin)~ 16,000 deaths as of March 2010www.fludb.org24Each of the known pandemics of the last 100 years was associated with a species jump event.Slide Source: http://en.wikipedia.org/wiki/Influenza

Seasonal flu epidemics occur yearly during the fall/ winter months and result in 3-5 million cases of severe illness worldwide.More than 200,000 people are hospitalized each year with seasonal flu-related complications in the U.S.Approximately 36,000 deaths occur due to seasonal flu each year in the U.S. Source: World Health Organization - http://www.who.int/mediacentre/factsheets/fs211/en/index.html

Pandemic stages

Adaptive driverswww.fludb.orgLarge population of genetically diverse viruses in animal reservoirOccassionally spills over into humanEcological drivers population overlap + risk behaviorAdaptive drivers pathogen genotypeStuttering transmission occasional spillover but never get establishedSustained transmission results in pandemicDifference in the basic reproductive number (R0)25Basic reproductive number (R0)Total number of secondary cases per caseReasonable surrogate of fitnessCharacteristics of pandemic viruses:R0H >1, andIn genetic neighborhood of viruses with R0R>1 and R0H1)Stuttering viruses(R0R>1 and R0H1 and R0H

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