Real-time tracking of pathogen evolution and spread


Richard Neher
Biozentrum & SIB, University of Basel


slides at neherlab.org/201907_ECDC.html

Sequences record the spread of pathogens

Mutations accumulate at a rate of $10^{-5}$ per site and day!
images by Trevor Bedford

Influenza virus genome - 8 segments

Zika virus genome $\sim 10000$ bases

Ebola virus genome $\sim 20000$ bases

Many RNA viruses pick up one mutation every 2-4 weeks!

Frequent mutations imply...

  • most viruses in an outbreak differ from each other
  • transmission chains are can be inferred
  • transmission can be ruled out!
  • geographic spread can be reconstructed
  • phenotypic changes can be inferred (for some pathogens)

GISRS -- Influenza virus surveillance

  • comprehensive coverage of the world
  • timely sharing of data -- often within 2-3 weeks of sampling
  • hundreds of sequences per week (in peak months)
→ requires continuous analysis and easy dissemination
→ interpretable and intuitive visualization

nextflu.org

joint project with Trevor Bedford & his lab

Visualization features of nextstrain

  • Regular and time scaled phylogenies
  • Mutations are mapped to the tree
  • Filtering to time interval, region, country, authors, ...
  • Zoom into clades
  • Information on specific viruses
  • Color by amino acid or nucleotide
  • Frequency trajectories of clades and mutations
  • Color by antigenic advance, predictive scores, etc
Hadfield et al, 2018

Phylodynamic analysis with nextstrain

  • input: metadata (csv table) + sequences
  • composable snakemake pipeline
    • filtering (select relevant strains)
    • alignment
    • tree building (optionally time scaled trees)
    • ancestral state reconstruction and phylogeography
    • additional pathogen specific steps
  • export to visualization
  • runs in minutes to 1h
Hadfield et al, 2018

Web visualization with nextstrain

  • fairly easy to set-up
  • can be run locally (localhost)
  • or be deployed on your own servers
  • work in progress:
    • flexible branding
    • drag and drop features
    • (better docs...)
Hadfield et al, 2018

Enterovirus D68 -- with Robert Dyrdak, Emma Hodcroft & Jan Albert

  • Non-polio enterovirus
  • Almost everybody has antibodies against EV-D68
  • Large outbreak in 2014 with severe neurological symptoms in
    young children (acute flaccid myelitis)
  • Another outbreak in 2016
  • Outbreaks tend to start in late summer/fall
  • Several reports of EV-D68 outbreaks last fall
    (201 AFM cases in the US in 2018)

EV-D68 whole genome deep sequencing project across Europe

Infections with multiple variants

  • A set of iSNVs at very similar frequencies in full linkage
  • Suggest infection with two related variants
  • 3 out of 50 samples: Implies high prevalence
Dyrdak et al, biorxiv

Acknowledgments

  • Trevor Bedford
  • Colin Megill
  • Pavel Sagulenko
  • Sidney Bell
  • James Hadfield
  • Emma Hodcroft
  • and others

Acknowledgments -- Enterovirus

  • Robert Dyrdak
  • Jan Albert
  • Lina Thebo
  • Emma Hodcroft
  • Bert Niesters (Groningen)
  • Randy Poelman (Groningen)
  • Elke Wollants (Leuven)
  • Adrian Egli (Basel)
  • Andrés Antón Pagarolas (Barcelona)