Moving targets: Genomic epidemiology tools during a pandemic

Richard Neher
Biozentrum & SIB, University of Basel

slides at

From 1'000s to 1'000'000s of samples

From a few labs to hundreds of contributing labs

Our favorite fancy tools and models couldn't handle it

  • Sample size: could only use a tiny fraction of data
  • Slow: Analyses that take weeks are incompatible with actionable insights.
  • Complex: Link between inferences and data signatures too indirect.

Needed tools to make sense of an avalanche of data
  • Fast: immediate results/summaries
  • Robust: data quality varies, sampling is biased. Complex models go wrong in weird ways when assumptions are violated.
  • Simple: anything to complex can't be interpreted reliably.

Many smart people made amazing tools with open data

Sequence analysis and interpretation are challenging

Nextstrain's focus: enable teams to make sense of their data
Workflows to analyze custom data + background
  • Hierarchical sampling: global, country, division.
  • Hosting via Nextstrain groups
  • Aimed at completion within hours
  • Data sharing restriction made this more difficult than it should have been
  • No experience necessary
  • QC: avoid releasing bad data
  • Clades, lineages, mutations
  • Private


Nextclade Web and CLI

  • Aligns, translates, classifies a SARS-CoV-2 genome in 20ms
  • Now used for QC and filtering in many Nextstrain workflows
  • QC and mutations calls used for many downstream analysis
All open sequences annotated and aligned, updated daily:

Nextclade Web and CLI

  • Prevalent QC problems changed over time:
    • Initially: assembly/mapping problems with clustered SNPs
    • Later: Reference calls in uncovered regions
    • Later: Contamination/cross-talk
  • Feature additions:
    • Differentiating between biological (known) frame shifts/stop codons and artefacts
    • Detecting mixed lineages (recombinants, chimeras, contaminants)
    • Added Pango lineage calling
  • Rewrites:
    • Summer 2020: "web-first" JavaScript application (plus node.js CLI)
    • Spring 2021: rewrite in C++ with web-assembly
    • Jun 2022: release of the Rust version

May 2022: Monkeypoxvirus

  • SARS-CoV-2 is a big RNA virus (30kb), the MPXV genome is 200kb long.
  • Repeats, low complexity regions, etc...
  • Can we still align this in the browser?

Take home messages

  • Simple tools often more helpful than sophisticated ones
  • Client side computing in the browser has a lot of potential
  • Upsides: no expensive backends, no data privacy issues
  • Lineage annotations are immensely useful!
    → use sequence information without phylogenetics (done by humans).


Ivan Aksamentov
Cornelius Roemer

Data are contributed by scientists from all over the world and curated by Genbank or GISAID