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Epistasis in a Model of Molecular Signal Transduction Alain Pumir1

Summary: Epistasis in a Model of Molecular Signal Transduction
Alain Pumir1
, Boris Shraiman2
1 Laboratoire de Physique, Ecole Normale Supe´rieure de Lyon, Lyon, France, 2 Kavli Institute for Theoretical Physics and Department of Physics, University of California,
Santa Barbara, California, United States of America
Biological functions typically involve complex interacting molecular networks, with numerous feedback and regulation
loops. How the properties of the system are affected when one, or several of its parts are modified is a question of
fundamental interest, with numerous implications for the way we study and understand biological processes and treat
diseases. This question can be rephrased in terms of relating genotypes to phenotypes: to what extent does the effect of a
genetic variation at one locus depend on genetic variation at all other loci? Systematic quantitative measurements of
epistasis ­ the deviation from additivity in the effect of alleles at different loci ­ on a given quantitative trait remain a major
challenge. Here, we take a complementary approach of studying theoretically the effect of varying multiple parameters in a
validated model of molecular signal transduction. To connect with the genotype/phenotype mapping we interpret
parameters of the model as different loci with discrete choices of these parameters as alleles, which allows us to
systematically examine the dependence of the signaling output ­ a quantitative trait ­ on the set of possible allelic
combinations. We show quite generally that quantitative traits behave approximately additively (weak epistasis) when
alleles correspond to small changes of parameters; epistasis appears as a result of large differences between alleles. When
epistasis is relatively strong, it is concentrated in a sparse subset of loci and in low order (e.g. pair-wise) interactions. We find


Source: Ahlers, Guenter - Department of Physics, University of California at Santa Barbara


Collections: Physics