title: Survival of the Curviest: Noise-Driven Selection for Synergistic Epistasis.
abstract: A major goal of human genetics is to elucidate the genetic architecture of human disease, with the goal of fueling improvements in diagnosis and the understanding of disease pathogenesis. The degree to which epistasis, or non-additive effects of risk alleles at different loci, accounts for common disease traits is hotly debated, in part because the conditions under which epistasis evolves are not well understood. Using both theory and evolutionary simulation, we show that the occurrence of common diseases (i.e. unfit phenotypes with frequencies on the order of 1%) can, under the right circumstances, be expected to be driven primarily by synergistic epistatic interactions. Conditions that are necessary, collectively, for this outcome include a strongly non-linear phenotypic landscape, strong (but not too strong) selection against the disease phenotype, and "noise" in the genotype-phenotype map that is both environmental (extrinsic, time-correlated) and developmental (intrinsic, uncorrelated) and, in both cases, neither too little nor too great. These results suggest ways in which geneticists might identify, a priori, those disease traits for which an "epistatic explanation" should be sought, and in the process better focus ongoing searches for risk alleles.
authors.affiliation: Ronin Institute, Montclair, New Jersey, United States of America.
authors.forename: Jon F
authors.identifier: http://orcid.org/0000-0001-6405-6538
authors.initials: JF
authors.lastname: Wilkins
authors.affiliation: Center for Complex Biological Systems & Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California, United States of America.
authors.forename: Peter T
authors.initials: PT
authors.lastname: McHale
authors.affiliation: Center for Complex Biological Systems & Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California, United States of America.
authors.forename: Joshua
authors.initials: J
authors.lastname: Gervin
authors.affiliation: Center for Complex Biological Systems & Department of Developmental and Cell Biology, University of California, Irvine, Irvine, California, United States of America.
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Lander
mesh_terms: D000465:Algorithms; D004843:Epistasis, Genetic / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics; D005828:Genetics, Population; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D010641:Phenotype; D040641:Quantitative Trait Loci