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Learning Monotonic Genotype-Phenotype Maps

Author

Listed:
  • Beerenwinkel Niko

    (ETH Zürich)

  • Knupfer Patrick

    (ETH Zürich)

  • Tresch Achim

    (Ludwig-Maximilians-Universität München)

Abstract

Evolutionary escape of pathogens from the selective pressure of immune responses and from medical interventions is driven by the accumulation of mutations. We introduce a statistical model for jointly estimating the dynamics and dependencies among genetic alterations and the associated phenotypic changes. The model integrates conjunctive Bayesian networks, which define a partial order on the occurrences of genetic events, with isotonic regression. The resulting genotype-phenotype map is non-decreasing in the lattice of genotypes. It describes evolutionary escape as a directed process following a phenotypic gradient, such as a monotonic fitness landscape. We present efficient algorithms for parameter estimation and model selection. The model is validated using simulated data and applied to HIV drug resistance data. We find that the effect of many resistance mutations is non-linear and depends on the genetic background in which they occur.

Suggested Citation

  • Beerenwinkel Niko & Knupfer Patrick & Tresch Achim, 2011. "Learning Monotonic Genotype-Phenotype Maps," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 10(1), pages 1-27, January.
    • Handle: RePEc:bpj:sagmbi:v:10:y:2011:i:1:n:3
    DOI: 10.2202/1544-6115.1603
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    References listed on IDEAS

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    1. Segal Mark R & Barbour Jason D & Grant Robert M, 2004. "Relating HIV-1 Sequence Variation to Replication Capacity via Trees and Forests," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 3(1), pages 1-20, February.
    2. N. Beerenwinkel & S. Sullivant, 2009. "Markov models for accumulating mutations," Biometrika, Biometrika Trust, vol. 96(3), pages 645-661.
    3. Frank J. Poelwijk & Daniel J. Kiviet & Daniel M. Weinreich & Sander J. Tans, 2007. "Empirical fitness landscapes reveal accessible evolutionary paths," Nature, Nature, vol. 445(7126), pages 383-386, January.
    Full references (including those not matched with items on IDEAS)

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