Tracking and predicting the spread of pathogens and resistance

Richard Neher
Biozentrum, University of Basel

slides at neherlab.org/201903_HMS.html

Human seasonal influenza viruses

slide by Trevor Bedford

Sequences record the spread of pathogens

images by Trevor Bedford

Influenza viruses evolve to avoid human immunity
Vaccines need frequent updates

nextflu.org

joint work with Trevor Bedford & his lab

Beyond tracking: can we predict?

Fitness variation in rapidly adapting populations

Speed of adaptation is logarithmic in population size
Environment (fitness landscape), not mutation supply, determines adaptation
Different models have universal emerging properties

RN, Annual Reviews, 2013; Desai & Fisher; Brunet & Derride; Kessler & Levine

Neutral/Kingman coalescent

strong selection

Bolthausen-Sznitman Coalescent

RN, Hallatschek, PNAS, 2013; see also Brunet and Derrida, PRE, 2007; Desai, Walczak, Fisher, Genetics, 2013

Bursts in a tree ↔ high fitness genotypes

Can we read fitness of a tree?

Predicting evolution

Given the branching pattern:

can we predict fitness?
pick the closest relative of the future?

RN, Russell, Shraiman, eLife, 2014

Fitness inference from trees

$$P(\mathbf{x}|T) = \frac{1}{Z(T)} p_0(x_0) \prod_{i=0}^{n_{int}} g(x_{i_1}, t_{i_1}| x_i, t_i)g(x_{i_2}, t_{i_2}| x_i, t_i)$$

RN, Russell, Shraiman, eLife, 2014

Prediction of the dominating H3N2 influenza strain

no influenza specific input
how can the model be improved? (see model by Luksza & Laessig)
what other context might this apply?

RN, Russell, Shraiman, eLife, 2014

nextstrain.org

joint project with Trevor Bedford & his lab

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

Carbapenemase producing bacteria

Reserve antibiotics used to treat MDR bacteria
Introduced in the 1980ies
Resistance spread rapidly
Resistance is mediated by several distinct beta-lactamases
→ pressing public health problem
→ fascinating instance of genes sweeping the globe by horizontal transfer

Resistance is horizontally acquired
→ tracking the core genome doesn't do it
Need to track genes on there mobilizing genetic background

Tracking bacteria by sequencing

Illumina → millions of short reads (<500bp)
Too short to bridge repetitive elements
→ assemblies are fragmented into 100s of "contigs"
Problem: all the important bits are flanked by repetitive/mobile elements

(really terrible example)

Images: illumina.com, github.com/rrwick

Long-read sequencing

Long-read sequencing of Carbapenemase producing bacteria

Contigs with drug resistance genes ~1-6 genes
→ no phylogenetic resolution
long-read assemblies give full length plasmids
tracking via synteny and structural diversity, not SNPs
→ we need to reconstruct spread from genome structure evolution

Noll et al, biorxiv, 2018

Synteny alignments of Carbapenemase containing loci

Structural changes can resolve evolutionary relationships
Different KPC alleles are found on the same background
Identical KPC alleles are found on different backgrounds
Similar plasmids are spread across MLSTs and species boundaries

Noll et al, biorxiv, 2018

Synteny alignments of Carbapenemase containing loci

Noll et al, biorxiv, 2018

Summary

Timely data sharing + automated analysis allows near real-time tracking of influenza
Such analyses provide important input for vaccine strain selection
Sequencing, analysis, and dissemination can be rapidly set-up for emerging pathogens
Bacterial pathogens come with a special set of challenges
Fascinating evolutionary process beyond mutations in homologous sequence