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
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
BolthausenSznitman 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
Combining SIRmodels 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 $a$: $\frac{d R_a}{dt} = \nu I_a  \gamma R_a$
 Crossimmunity: $K_{ab} = e^{\frac{ab}{d}}$
 Mutations from $a\to b$ reduce crossimmunity and increase susceptibility
 Antigenic evolution is essential to establish seasonal patterns
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 realtime 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