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Epochal evolution shapes the phylodynamics of interpandemic influenza (H3N2). Katia Koelle Sarah Cobey Bryan Grenfell Mercedes Pascual. ?. SI87. VI75. ?. BK79. EN72. TX77. HK68. DIMACS, 9-10 October 2006. Pathogen diversity and cross-immunity. s.

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Katia Koelle Sarah Cobey Bryan Grenfell Mercedes Pascual

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Epochal evolution shapes the phylodynamics of interpandemic influenza (H3N2)

Katia Koelle Sarah Cobey Bryan Grenfell Mercedes Pascual

?

SI87

VI75

?

BK79

EN72

TX77

HK68

DIMACS, 9-10 October 2006


Pathogen diversity and cross immunity l.jpg

Pathogen diversity and cross-immunity

s


Modeling cross immunity l.jpg

e.g. Gog & Grenfell, PNAS (2002)

Modeling Cross-Immunity

  • Strains with high sequence similarity must have high cross-immunity

  • Strains with low sequence similarity must have low cross-immunity


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Explaining limited diversity of hemagglutinin

Strain-specific cross-immunity

Actual HA1

phylogeny

Simulated

phylogeny

Explosive diversity

Ferguson, Galvani, Bush, Nature (2003)


Explaining limited diversity l.jpg

Immunity

Years since infection

Explaining limited diversity

Strain-specific cross-immunity + generalized immunity

Limited diversity

Ferguson, Galvani, Bush, Nature (2003)


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Modeling cross-immunity between flu strains

  • Can sequence evolution be used as a proxy for antigenic evolution when modeling influenza’s hemagglutinin?

  • (i.e. does genotype approximate phenotype?)

  • Propose alternative to this genotype-phenotype map for influenza’s hemagglutinin evolution

  • Consider the effect of this new mapping on the phylogenetics and dynamics (i.e. phylodynamics) of influenza H3N2


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s= >90%

s= >90%

s= 60-80%

Unrooted ML trees of sequences in the HK68 and EN72 clusters

Influenza clusters

Cluster designations as in Smith et al. 2004


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Topology of influenza clusters

  • Strains with high sequence similarity can have low cross-immunity

  • Strains with low sequence similarity can have almost complete cross-immunity

Genotype cannot serve as a proxy for antigenic phenotype


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Sequence (genotype)

Sequence (genotype)

…ATGATGTGCCGGAT…

…ATGATCTGCCGGAT…

…FLIMFYNKSR…

…FLIDFYNKSR…

Tertiary HA structure

(phenotype)

Tertiary HA structure

(phenotype)

Cross-immunity

STRAIN 1

STRAIN 2

Genotype-phenotype

mapping?


Genotype phenotype mapping for rna 2 o structures l.jpg

phenotype

(shape)

genotype

(sequence)

More genotypes than phenotypes

Genotype-phenotype mapping for RNA 2o structures

Fontana & Schuster, JTB (1998)


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Neutral networks

Fontana & Schuster, JTB (1998)


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Average structure distance to target

Evolutionary dynamics on neutral networks

Fontana &

Schuster,

JTB (1998)

  • “A neutral mutation does not change the phenotype but it does change the potential for change… What appears to be a sudden and abrupt change at the phenotypic level has been the result of neutral genetic drift.” -Fontana


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Neutral network mapping for proteins

Lau and Dill

  • Single sequence changes can result in large changes in protein conformation.

  • Changing a sequence by a large number of mutations may have no appreciable effect on protein conformation.


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Traditional

cross-immunity models

…FLIMFYNKSR…

Neutral network topology

Implications for modeling cross-immunity

Bornberg-Bauer & Chan, PNAS (1999)

Bornberg-Bauer


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Modeling influenza’s hemagglutinin

15 a.a.

(45 nucs.)

5 epitopes


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Changing the shape of an epitope

  • Adaptation of Kauffman’s NK model that generates neutral networks in genotype space (Newman and Engelhardt)

3

  • Framework assumes epistatic or context-dependent interaction between amino acids located in the same epitope

15 a.a.

5 epitopes


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Neutrality and sequence evolution:subbasins, portals, and epochal evolution

?

SI87

VI75

?

BK79

EN72

TX77

HK68

Adapted (for flu  ) from Crutchfield, 2002


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Susceptible

Recovered

Coupling to an epidemiological model

Infected

Clusters

Adapted for clusters, from Gog & Grenfell, PNAS (2002)


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Dynamic Consequences of Neutral Network Model

Years

  • Cluster transitions

  • Peaks in incidence during

  • cluster transition years

  • Refractory year


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Comparison with observed influenza dynamics

Greene et al. (2006)


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Phylogenetic Consequences

Simulated tree

Observed HA tree

(from Smith et al.

sequences)

  • Explosion of diversity within clusters

  • Cluster transitions cause selective sweeps

  • No need for generalized immunity to limit HA diversity


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Expected pattern in genetic diversity arising from epochal evolution


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Supporting empirical evidence


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Notions of neutrality

Influential sites model

Only changes at very few sites can precipitate a cluster jump, and their ability to do so does not depend on the genetic background in which they occur.

Genetic diversification within clusters does not facilitate adaptive change, and can be safely ignored.

Context-dependent model

Changes at most sites can precipitate a cluster jump if those changes occur in the right genetic background.

Cluster innovations are guided by the process of neutral diffusion, via changing the genetic background of sequences.

See also Wagner, 2005 for a discussion on types of neutrality in non-flu systems


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Importance of genetic background, i.e.

context-

dependency

Influential sites


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Pairwise nucleotide

differences in HA1

Observed pattern in genetic diversity

Boom-and-bust of genetic diversity empirically supported


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Observations of tree balance

Diversification within clusters cannot be rejected

under the null, neutral model of random speciation.


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Conclusions

  • An alternative, empirically-supported model of influenza’s hemagglutinin evolution can account for both H3N2’s dynamic and the phylogenetic patterns of its HA1.

  • Incorporating appropriate genotype-phenotype maps for the effect of mutations at the phenotypic level may be important for understanding pathogen evolution.


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Acknowledgments

David Alonso, Stefano Allesina,

Luis Chaves, Diego Moreno, Aaron King

Center for the Study of Complex Systems

NSF graduate student fellowship (S.C.)

McDonnell Foundation (Centennial Fellowship to M.P.)

Jamie Lloyd-Smith, Igor Volkov, Mary Poss

CIDD postdoctoral fellowship (K.K.)

Derek Smith, Ron Fouchier, Sharon Greene, Cecile Viboud, Maciej Boni


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Patterns of influenza phylodynamics (H3N2)

1. Annual outbreaks

Greene et al. (2006)

Antigenic change

3. Genetic change

2. Genetic drift

Fitch et al. (1997)

Smith et al. (2004)


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Patterns of genetic diversity


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Antigenic clusters

Characteristics of Influenza Evolution

Sequential replacement of clusters

Cluster #

Season

Smith et al., Science (2004)


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Punctuated antigenic change

Gradual genetic change

Characteristics of Influenza Evolution

Genetic distance from 1968 strain

Antigenic distance from 1968 strain

Smith et al., Science (2004)


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