Virus evolution and the predictability of next year's flu


Richard Neher
Biozentrum, University of Basel


slides at neherlab.org/201710_EPFL.html

Human seasonal influenza viruses

slide by Trevor Bedford


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

nextflu.org

joint work with Trevor Bedford & his lab

Beyond tracking: can we predict?

Theoretical framework for virus evolution -- population genetics

evolutionary processes ↔ trees ↔ genetic diversity

Clonal interference and traveling waves

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

Typical tree

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

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

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

Hemagglutination Inhibition assays

Slide by Trevor Bedford

Antigenic distance tables

  • Long list of distances between sera and viruses
  • Tables are sparse, only close by pairs
  • Structure of space is not immediately clear
  • MDS in 2 or 3 dimensions
Slide by Trevor Bedford

Integrating antigenic and molecular evolution

  • each branch contributes $d_i$ to antigenic distance
  • sparse solution for $d_i$ through $l_1$ regularization
RN et al, PNAS, 2016

HI distances on the phylogenetic tree

nextstrain.org

joint work with Trevor Bedford & his lab

NextStrain architecture

Using treetime to rapidly compute timetrees

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

Influenza and Theory acknowledgments

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

nextstrain.org

  • Trevor Bedford
  • Colin Megill
  • Pavel Sagulenko
  • Sidney Bell
  • James Hadfield
  • Wei Ding