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 ; www.viprbrc.org )

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

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Richard h scheuermann ph d department of pathology ut southwestern march 30 2011

Virus Bioinformatics Resource Centers – ViPR & IRD

Richard H. Scheuermann, Ph.D.

Department of Pathology, UT Southwestern

March 30, 2011


Take home messages

Take home messages

  • NIAID Bioinformatics Resource Centers

    • Virus Pathogen Resource (ViPR; www.viprbrc.org )

    • Influenza Research Database (IRD; www.fludb.org )

  • Free and open access virus database and analysis resources

  • Comprehensive data collection

    • Sequence, structure, function, phenotype, surveillance, clinical, immune response

  • Integrated

    • Surveillance metadata with sequence

    • Sequence features and sequence conservation with protein structures

  • Development and adoption of data standards

  • Data sharing infrastructure and policies

  • Novel approach to identification of genetic determinants of important virus characteristics

    • Influenza NS1 nuclear export signal and host range


Niaid research resources

NIAID Research Resources


D mid resources

DMID Resources


D mid resources list

DMID Resources List


Richard h scheuermann ph d department of pathology ut southwestern march 30 2011

BRCs


C ategory a pathogens

Category A Pathogens


C ategory b pathogens

Category B Pathogens


C ategory c pathogens

Category C Pathogens


Pathogen portal

Pathogen Portal

pathogenportal.net


Vipr resource

ViPR Resource


Home page

Home page

www.viprbrc.org


13 virus families

13 virus families


Taxonomy browser

Taxonomy browser


Taxonomy browser expanded

Taxonomy browser expanded


Genome statistics

Genome statistics


Search analyze and save

Search, analyze and save


Search

Search


Analysis

Analysis


Workbench

Workbench


Data integration

Data Integration


Richard h scheuermann ph d department of pathology ut southwestern march 30 2011

IRD

www.fludb.org


Data standards

Data Standards


Ceirs network

CEIRS Network


Other data standards

Other Data Standards

  • Non-human mammalian surveillance

  • Virus isolate characteristics

  • Immuno-assays

  • Virus passage

  • Virus nomenclature

  • Clinical data


Surveillance

Surveillance


Data sharing

Data Sharing


Policies

Policies

  • Sequences – 30 days

  • Initial Surveillance Record – 90 days

  • Completed Virus Isolated Record – 1 year


Submission i nfrastructure

Submission Infrastructure


Do variations in ns1 sequence features influence influenza virus host range

Do variations in NS1 sequence featureS influence influenza virus host range?


Sfvt approach

SFVT approach

Influenza A_NS1_nuclear-export-signal_137(10)

Influenza A_NS1_alpha-helix_171(17)

VT-1I F D R L E T L I L

VT-2I F N R L E T L I L

VT-3I F D R L E T IV L

VT-4L F D Q L E T L VS

VT-5I F D R L E N L T L

VT-6I F N R L E A L I L

VT-7I Y D R L E T L I L

VT-8I F D R L E T L V L

VT-9I F D R L E NIVL

VT-10I F E R L E T L I L

VT-11 L F D QM E T L VS

  • 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 epitope

  • Determine 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 independently

  • Genotype-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 sequence features as of january 2011

Influenza A Sequence Features as of January 2011


Vipr sfvts

ViPRSFVTs

  • Starting with 3 species

    • DENV = 192 SF’s

    • HCV = 335 SF’s

    • Pox = 14 genes, 295 total SF’s

    • HSV coming soon w/ DBP

  • Beginning automatic definition for other virus families

    • Most SF’s pulled from

      • UniProtKB protein annotations

      • IEDB immune epitopes (future)


Ns1 sequence features

NS1 Sequence Features


Vt for sf8 nuclear export signal

VT for SF8 (nuclear export signal)


Vt 1 strains

VT-1 strains


Vt for sf8 nuclear export signal1

VT for SF8 (nuclear export signal)


Causes of apparent ns1 vt associated host range restriction

Causes of apparent NS1 VT-associated host range restriction

  • Virus spread = capability + opportunity

    • Phenotypic property of the virus – limited capacity

    • Founder effect – limited opportunity

      • Restricted spatial-temporal distribution

  • Sampling bias – assumption of random sampling

    • Oversampling – avian H5N1 in Asia; 2009 H1N1

    • Undersampling – large and domestic cats

  • Linkage to causative variant


Vt 10 strains

VT-10 strains


Vt for sf8 nuclear export signal2

VT for SF8 (nuclear export signal)


Vt lineages

VT lineages


Vt 10 lineage

VT-10 lineage


Vt 4 lineage

VT-4 lineage


Vt 4 strains

VT-4 strains


Vt 4 lineage b allele group

VT-4 lineage = B allele/group


Vt 15 vt 8 lineages

VT-15 & VT-8 lineages


Vt 5 strains

VT-5 strains


Summary

Compiling list of all known influenza protein sequence features (SFs) in IRD

Observed dramatic skewing in NS1 SFVT host distributions

In some cases, attributable to sampling biases

VT-1 and Avian H5N1 due to Asian sampling in mid-2000's

VT-2 and human due to 2009 pandemic H1N1

VT-11 and Other (Environment) in Delaware Bay

Performing multivariate statistical analysis to control for confounding variables

In other cases, attributable to founder effects

VT-13 and -14 and Viet Nam 2003

However, in other cases these explanations do not appears to be consistent with the data, suggesting that these may indeed be NS1-mediated host range restrictions

Equine VT-10 lineage

Avian VT-4 lineage (B allele/group)

Human VT-8 lineage

Human VT-15 lineage

Nuclear export vs linkage disequilibrium?

Summary


Influenza sfvt acknowledgments

U.T. Southwestern

Richard Scheuermann

Burke Squires

Jyothi Noronha

Mengya Liu

Victoria Hunt

Shubhada Godbole

Brett Pickett

Ayman Al-Rawashdeh

MSSM

Adolfo Garcia-Sastre

Eric Bortz

Gina Conenello

Peter Palese

Vecna

Chris Larsen

Al Ramsey

LANL

Catherine Macken

Mira Dimitrijevic

U.C. Davis

Nicole Baumgarth

Northrop Grumman

Ed Klem

Mike Atassi

Kevin Biersack

Jon Dietrich

WenjieHua

Wei Jen

Sanjeev Kumar

Xiaomei Li

Zaigang Liu

Jason Lucas

Michelle Lu

Bruce Quesenberry

Barbara Rotchford

Hongbo Su

Bryan Walters

Jianjun Wang

Sam Zaremba

Liwei Zhou

Influenza SFVT Acknowledgments

  • IRD SWG

    • Gillian Air, OMRF

    • Carol Cardona, Univ. Minnesota

    • Adolfo Garcia-Sastre, Mt Sinai

    • ElodieGhedin, Univ. Pittsburgh

    • Martha Nelson, Fogarty

    • Daniel Perez, Univ. Maryland

    • Gavin Smith, Duke Singapore

    • David Spiro, JCVI

    • Dave Stallknecht, Univ. Georgia

    • David Topham, Rochester

    • Richard Webby, St Jude

  • SFVT experts

    • Gillian Air, OMRF

    • Toru Takimoto, Rochester

    • Summer Galloway, Emory

    • Robert Lamb, Northwestern

    • Benjamin Hale, Mt. Sinai

  • USDA

    • David Suarez

  • Sage Analytica

    • Robert Taylor

    • Lone Simonsen

  • CEIRS Centers


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