title: Epistasis in a model of molecular signal transduction.
abstract: 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 that focusing on interaction between loci that exhibit strong additive effects is an efficient way of identifying most of the epistasis. Our model study defines a theoretical framework for interpretation of experimental data and provides statistical predictions for the structure of genetic interaction expected for moderately complex biological circuits.
authors: Laboratoire de Physique, Ecole Normale Supérieure de Lyon, Lyon, France.
authors: Alain
authors: A
authors: Pumir
authors: Boris
authors: B
authors: Shraiman
references: Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6866-71
references: 19366665
references: Theor Popul Biol. 2001 Feb;59(1):61-86
references: 11243929
references: Front Cell Neurosci. 2009 Jun 11;3:2
references: 19623243
references: PLoS Genet. 2008 Feb;4(2):e33
references: 18454206
references: Nat Rev Genet. 2004 Aug;5(8):618-25
references: 15266344
references: Neuron. 2002 Nov 14;36(4):689-701
references: 12441057
references: J Theor Biol. 2006 Feb 7;238(3):616-35
references: 16111710
references: Methods. 2006 Dec;40(4):344-52
references: 17101447
references: Science. 2007 Jan 12;315(5809):233-7
references: 17218526
references: Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10354-9
references: 18653755
references: J Physiol. 2000 Apr 1;524 Pt 1:179-94
references: 10747191
references: Nature. 2005 Aug 4;436(7051):701-3
references: 16079846
references: J R Soc Interface. 2008 Aug 6;5 Suppl 1:S59-69
references: 18482906
references: PLoS Comput Biol. 2007 Oct;3(10):1871-78
references: 17922568
references: Genetics. 1996 Jun;143(2):621-5
references: 8725213
references: Genetics. 1995 Mar;139(3):1455-61
references: 7768453
references: Nat Rev Genet. 2008 Jun;9(6):477-85
references: 18427557
references: Nature. 1971 Feb 19;229(5286):542-4
references: 4925348
references: Genetics. 1981 Mar-Apr;97(3-4):639-66
references: 7297851
references: Nat Rev Genet. 2005 Feb;6(2):95-108
references: 15716906
references: Genetics. 1965 Nov;52(5):875-90
references: 17248281
references: Nature. 2001 Sep 13;413(6852):186-93
references: 11557987