RNA virus evolution and the predictability of next year's flu


Richard Neher
Biozentrum, University of Basel


slides at neherlab.org/201903_APS.html

Human seasonal influenza viruses

slide by Trevor Bedford

Sequences record the spread of pathogens

images by Trevor Bedford


  • Influenza virus evolves to avoid human immunity
  • Vaccines need frequent updates

Vaccine strain selection schedule

Klingen and McHardy, Trends in Microbiology

nextflu.org

joint work with Trevor Bedford & his lab

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

Validate on simulation data

  • simulate evolution
  • sample sequences
  • reconstruct trees
  • infer fitness
  • predict ancestor of future
  • compare to truth
RN, Russell, Shraiman, eLife, 2014

Validation on simulated data

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

There are many ways to escape immunity -- why doesn't influenza speciate?

Le Yan, RN, Shraiman, bioRxiv, 2018

There are many ways to escape immunity -- why doesn't influenza speciate?

Le Yan, RN, Shraiman, bioRxiv, 2018

Combining SIR-models and rapid molecular adaptation

  • Infections with strain $a$: $\frac{d I_a}{dt} = \beta S_a I_a - (\nu+\gamma)I_a$
  • Susceptibility to strain $a$: $S_a =e^{-\sum_b K_{ab} R_b }$
  • Recovered from stain $a$: $\frac{d R_a}{dt} = \nu I_a - \gamma R_a$
  • Cross-immunity: $K_{ab} = e^{-\frac{|a-b|}{d}}$
  • Mutations from $a\to b$ reduce cross-immunity and increase susceptibility
  • Antigenic evolution is essential to establish seasonal patterns
Le Yan, RN, Shraiman, bioRxiv, 2018

Transition from pandemic to seasonal patterns

Le Yan, RN, Shraiman, bioRxiv, 2018

Speciation into antigenically distinct lineages

Le Yan, RN, Shraiman, bioRxiv, 2018

Summary

  • RNA virus evolution can be observed directly
  • Rapidly adapting population require new population genetic models
  • Those model can be used to infer fit clades
  • Future influenza population can be anticipated
  • Automated real-time analysis can help fight the spread of disease
  • Combining epidemiological and population genetic models can explain flu phylogenies

Influenza and Theory acknowledgments

  • Le Yan
  • Boris Shraiman
  • Colin Russell
  • Trevor Bedford
  • Oskar Hallatschek

Acknowledgments -- nextstrain

  • Trevor Bedford
  • Colin Megill
  • Pavel Sagulenko
  • Sidney Bell
  • James Hadfield
  • Wei Ding
  • Emma Hodcroft
  • Sanda Dejanic
  • John Huddleston
  • Barney Potter