Epistasis and quantitative traits: using model organisms to study gene–gene interactions

The role of epistasis in the genetic architecture of quantitative traits is controversial, despite the biological plausibility that nonlinear molecular interactions underpin the genotype–phenotype map. This controversy arises because most genetic variation for quantitative traits is additive. However, additive variance is consistent with pervasive epistasis. In this Review, I discuss experimental designs to detect the contribution of epistasis to quantitative trait phenotypes in model organisms. These studies indicate that epistasis is common, and that additivity can be an emergent property of underlying genetic interaction networks. Epistasis causes hidden quantitative genetic variation in natural populations and could be responsible for the small additive effects, missing heritability and the lack of replication that are typically observed for human complex traits.

[1]  R. Punnett,et al.  The Genetical Theory of Natural Selection , 1930, Nature.

[2]  S. Wright,et al.  Evolution in Mendelian Populations. , 1931, Genetics.

[3]  T. Cockerell,et al.  Genetics and the Origin of Species , 1937 .

[4]  Julian Huxley,et al.  The new systematics , 1941 .

[5]  C. Waddington.  Canalization of Development and the Inheritance of Acquired Characters , 1942, Nature.

[6]  S. Counce.  The Strategy of the Genes , 1958, The Yale Journal of Biology and Medicine.

[7]  C. Pigott.  Genetics and the Origin of Species , 1959, Nature.

[8]  J. Rendel,et al.  CANALIZATION OF THE SCUTE PHENOTYPE OF DROSOPHILA , 1959 .

[9]  D. Falconer,et al.  Introduction to Quantitative Genetics. , 1962 .

[10]  H. Lipkin.  Where is the ?c? , 1978 .

[11]  M. Bulmer.  The Mathematical Theory of Quantitative Genetics , 1981 .

[12]  R. Elston.  The mathematical theory of quantitative genetics , 1982 .

[13]  A. Templeton,et al.  Genetic Revolutions in Relation to Speciation Phenomena: The Founding of New Populations , 1984 .

[14]  C. Goodnight.  ON THE EFFECT OF FOUNDER EVENTS ON EPISTATIC GENETIC VARIANCE , 1987, Evolution; international journal of organic evolution.

[15]  C. Cockerham,et al.  A building block model for quantitative genetics. , 1989, Genetics.

[16]  N. Barton,et al.  Evolutionary quantitative genetics: how little do we know? , 1989, Annual review of genetics.

[17]  J. Cheverud,et al.  Epistasis and its contribution to genetic variance components. , 1995, Genetics.

[18]  J. Doebley,et al.  teosinte branched1 and the origin of maize: evidence for epistasis and the evolution of dominance. , 1995, Genetics.

[19]  D. Zamir,et al.  Less-than-additive epistatic interactions of quantitative trait loci in tomato. , 1996, Genetics.

[20]  C. Laurie,et al.  Molecular dissection of a major gene effect on a quantitative trait: the level of alcohol dehydrogenase expression in Drosophila melanogaster. , 1996, Genetics.

[21]  M. Lynch,et al.  Comparing mutational variabilities. , 1996, Genetics.

[22]  A. Clark,et al.  Epistasis in measured genotypes: Drosophila P-element insertions. , 1997, Genetics.

[23]  R. Lenski,et al.  Test of synergistic interactions among deleterious mutations in bacteria , 1997, Nature.

[24]  G. Gibson,et al.  Is function of the Drosophila homeotic gene Ultrabithorax canalized? , 1997, Genetics.

[25]  G. Gibson,et al.  Naturally occurring genetic variation affects Drosophila photoreceptor determination , 1998, Development Genes and Evolution.

[26]  S. Lindquist,et al.  Hsp90 as a capacitor for morphological evolution , 1998, Nature.

[27]  W. Ewens.  Genetics and analysis of quantitative traits , 1999 .

[28]  G. Gibson,et al.  Potential variance affecting homeotic Ultrabithorax and Antennapedia phenotypes in Drosophila melanogaster. , 1999, Genetics.

[29]  T. Mackay,et al.  Quantitative trait loci for life span in Drosophila melanogaster: interactions with genetic background and larval density. , 2000, Genetics.

[30]  M. Goddard,et al.  Prediction of total genetic value using genome-wide dense marker maps. , 2001, Genetics.

[31]  J. Cheverud,et al.  Genetic architecture of adiposity in the cross of LG/J and SM/J inbred mice , 2001, Mammalian Genome.

[32]  Ronald W. Davis,et al.  Functional profiling of the Saccharomyces cerevisiae genome , 2002, Nature.

[33]  Daniel E L Promislow,et al.  Testing an ‘aging gene’ in long‐lived Drosophila strains: increased longevity depends on sex and genetic background , 2003, Aging cell.

[34]  T. Mackay,et al.  The genetic architecture of odor-guided behavior in Drosophila: epistasis and the transcriptome , 2003, Nature Genetics.

[35]  G. Gibson,et al.  Evidence that Egfr Contributes to Cryptic Genetic Variation for Photoreceptor Determination in Natural Populations of Drosophila melanogaster , 2003, Current Biology.

[36]  Greg Gibson,et al.  Uncovering cryptic genetic variation , 2004, Nature Reviews Genetics.

[37]  Gary D Bader,et al.  Global Mapping of the Yeast Genetic Interaction Network , 2004, Science.

[38]  J. Cheverud,et al.  Epistasis affecting litter size in mice , 2004, Journal of evolutionary biology.

[39]  Chris S. Haley,et al.  Epistasis: too often neglected in complex trait studies? , 2004, Nature Reviews Genetics.

[40]  Thomas Mitchell-Olds,et al.  Epistasis and balanced polymorphism influencing complex trait variation , 2005, Nature.

[41]  T. Mackay,et al.  Genetics and genomics of Drosophila mating behavior , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Toby Johnson,et al.  Theoretical models of selection and mutation on quantitative traits , 2005, Philosophical Transactions of the Royal Society B: Biological Sciences.

[43]  Ezgi O. Booth,et al.  Epistasis analysis with global transcriptional phenotypes , 2005, Nature Genetics.

[44]  W. G. Hill,et al.  Genetic variability under mutation selection balance. , 2005, Trends in ecology & evolution.

[45]  G. Churchill,et al.  Quantitative trait locus analysis for obesity reveals multiple networks of interacting loci , 2006, Mammalian Genome.

[46]  Ronald W. Davis,et al.  Quantitative trait loci mapped to single-nucleotide resolution in yeast , 2005, Nature Genetics.

[47]  Sean R. Collins,et al.  A strategy for extracting and analyzing large-scale quantitative epistatic interaction data , 2006, Genome Biology.

[48]  John D. Storey,et al.  Genetic interactions between polymorphisms that affect gene expression in yeast , 2005, Nature.

[49]  L. Andersson,et al.  Epistasis and the release of genetic variation during long-term selection , 2006, Nature Genetics.

[50]  A. Fraser,et al.  Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling pathways , 2006, Nature Genetics.

[51]  T. Mackay,et al.  Quantitative Genomics of Aggressive Behavior in Drosophila melanogaster , 2006, PLoS genetics.

[52]  Andrzej T Galecki,et al.  Three-locus and four-locus QTL interactions influence mouse insulin-like growth factor-I. , 2006, Physiological genomics.

[53]  Martin S. Taylor,et al.  Genome-wide genetic association of complex traits in heterogeneous stock mice , 2006, Nature Genetics.

[54]  T. Mackay,et al.  Quantitative genomics of locomotor behavior in Drosophila melanogaster , 2007, Genome Biology.

[55]  M. Causse,et al.  Both additivity and epistasis control the genetic variation for fruit quality traits in tomato , 2007, Theoretical and Applied Genetics.

[56]  H. Bussey,et al.  Exploring genetic interactions and networks with yeast , 2007, Nature Reviews Genetics.

[57]  B. Dickson,et al.  A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila , 2007, Nature.

[58]  Vesteinn Thorsson,et al.  Prediction of phenotype and gene expression for combinations of mutations. , 2007, Molecular systems biology.

[59]  Daniel J. Kliebenstein,et al.  Linking Metabolic QTLs with Network and cis-eQTLs Controlling Biosynthetic Pathways , 2007, PLoS genetics.

[60]  O. Carlborg,et al.  A Unified Model for Functional and Statistical Epistasis and Its Application in Quantitative Trait Loci Analysis , 2007, Genetics.

[61]  Joshua M. Stuart,et al.  A global analysis of genetic interactions in Caenorhabditis elegans , 2007, Journal of biology.

[62]  R. O’Malley,et al.  An adapter ligation-mediated PCR method for high-throughput mapping of T-DNA inserts in the Arabidopsis genome , 2007, Nature Protocols.

[63]  Ronald W. Davis,et al.  Systematic pathway analysis using high-resolution fitness profiling of combinatorial gene deletions , 2007, Nature Genetics.

[64]  T. Mackay,et al.  Phenotypic and transcriptional response to selection for alcohol sensitivity in Drosophila melanogaster , 2007, Genome Biology.

[65]  W. G. Hill,et al.  Data and Theory Point to Mainly Additive Genetic Variance for Complex Traits , 2008, PLoS genetics.

[66]  Bjarne Gram Hansen,et al.  Biochemical Networks and Epistasis Shape the Arabidopsis thaliana Metabolome[W] , 2008, The Plant Cell Online.

[67]  Annie E. Hill,et al.  Genetic architecture of complex traits: Large phenotypic effects and pervasive epistasis , 2008, Proceedings of the National Academy of Sciences.

[68]  P. Phillips.  Epistasis — the essential role of gene interactions in the structure and evolution of genetic systems , 2008, Nature Reviews Genetics.

[69]  David L. Aylor,et al.  From Classical Genetics to Quantitative Genetics to Systems Biology: Modeling Epistasis , 2008, PLoS genetics.

[70]  S. Lindquist,et al.  HSP90-buffered genetic variation is common in Arabidopsis thaliana , 2008, Proceedings of the National Academy of Sciences.

[71]  Judy H. Cho,et al.  Finding the missing heritability of complex diseases , 2009, Nature.

[72]  T. Mackay,et al.  Epistatic interactions attenuate mutations affecting startle behaviour in Drosophila melanogaster. , 2009, Genetics research.

[73]  Greg D. Gale,et al.  A genome-wide panel of congenic mice reveals widespread epistasis of behavior quantitative trait loci , 2009, Molecular Psychiatry.

[74]  E. Stone,et al.  Systems Genetics of Complex Traits in Drosophila melanogaster , 2009, Nature Genetics.

[75]  H. Cordell.  Detecting gene–gene interactions that underlie human diseases , 2009, Nature Reviews Genetics.

[76]  B. Cohen,et al.  Genetic Interactions Between Transcription Factors Cause Natural Variation in Yeast , 2009, Science.

[77]  Peter J. Bradbury,et al.  The Genetic Architecture of Maize Flowering Time , 2009, Science.

[78]  Annie L. Conery,et al.  Whole-animal high-throughput screens: the C. elegans model. , 2009, Methods in molecular biology.

[79]  Jonathan Flint,et al.  Genetic architecture of quantitative traits in mice, flies, and humans. , 2009, Genome research.

[80]  T. Mackay,et al.  Principles of Behavioral Genetics , 2009 .

[81]  Casey S. Greene,et al.  Failure to Replicate a Genetic Association May Provide Important Clues About Genetic Architecture , 2009, PloS one.

[82]  G. Gibson,et al.  Genomic Consequences of Background Effects on scalloped Mutant Expressivity in the Wing of Drosophila melanogaster , 2009, Genetics.

[83]  E. Stone,et al.  The genetics of quantitative traits: challenges and prospects , 2009, Nature Reviews Genetics.

[84]  T. Mackay,et al.  Quantitative Trait Loci for Aggressive Behavior in Drosophila melanogaster , 2009, Genetics.

[85]  Leonid Kruglyak,et al.  Dissection of genetically complex traits with extremely large pools of yeast segregants , 2010, Nature.

[86]  Shizhong Xu,et al.  Genomic value prediction for quantitative traits under the epistatic model , 2011, BMC Genetics.

[87]  P. Visscher,et al.  Common SNPs explain a large proportion of heritability for human height , 2011 .

[88]  Gary D Bader,et al.  The Genetic Landscape of a Cell , 2010, Science.

[89]  T. Mackay,et al.  Quantitative and Molecular Genetic Analyses of Mutations Increasing Drosophila Life Span , 2010, PLoS genetics.

[90]  Wolfgang Huber,et al.  Mapping of signaling networks through synthetic genetic interaction analysis by RNAi , 2011, Nature Methods.

[91]  J. Reecy,et al.  Mapping genetic loci that interact with myostatin to affect growth traits , 2011, Heredity.

[92]  T. Mackay,et al.  Complex genetic architecture of Drosophila aggressive behavior , 2011, Proceedings of the National Academy of Sciences.

[93]  D. Allison,et al.  Beyond Missing Heritability: Prediction of Complex Traits , 2011, PLoS genetics.

[94]  J. Nadeau,et al.  Genetic divergence and the genetic architecture of complex traits in chromosome substitution strains of mice , 2012, BMC Genetics.

[95]  Daniel Gianola,et al.  Marker-assisted prediction of non-additive genetic values , 2011, Genetica.

[96]  Jiabing Ji,et al.  Use of mutant-assisted gene identification and characterization (MAGIC) to identify novel genetic loci that modify the maize hypersensitive response , 2011, Theoretical and Applied Genetics.

[97]  A. Spradling,et al.  The Drosophila Gene Disruption Project: Progress Using Transposons With Distinctive Site Specificities , 2011, Genetics.

[98]  Mats E. Pettersson,et al.  Replication and Explorations of High-Order Epistasis Using a Large Advanced Intercross Line Pedigree , 2011, PLoS genetics.

[99]  J. Cheverud,et al.  Mapping the Epistatic Network Underlying Murine Reproductive Fatpad Variation , 2011, Genetics.

[100]  S. Oliver,et al.  An integrated approach to characterize genetic interaction networks in yeast metabolism , 2011, Nature Genetics.

[101]  D. Pomp,et al.  Sex-, Diet-, and Cancer-Dependent Epistatic Effects on Complex Traits in Mice , 2011, Front. Gene..

[102]  H. Fuchs,et al.  Erratum to: New mouse models for metabolic bone diseases generated by genome-wide ENU mutagenesis , 2014, Mammalian Genome.

[103]  Faculty Opinions recommendation of More than the sum of its parts: a complex epistatic network underlies natural variation in thermal preference behavior in Caenorhabditis elegans. , 2012 .

[104]  R. Gibbs,et al.  INAUGURAL ARTICLE by a Recently Elected Academy Member:Epistasis dominates the genetic architecture of Drosophila quantitative traits , 2012 .

[105]  Leonid Kruglyak,et al.  More Than the Sum of Its Parts: A Complex Epistatic Network Underlies Natural Variation in Thermal Preference Behavior in Caenorhabditis elegans , 2012, Genetics.

[106]  T. Mackay,et al.  Extensive epistasis for olfactory behaviour, sleep and waking activity in Drosophila melanogaster , 2012, Genetics research.

[107]  Kevin R. Thornton,et al.  The Drosophila melanogaster Genetic Reference Panel , 2012, Nature.

[108]  Michael E Goddard,et al.  The future of livestock breeding: genomic selection for efficiency, reduced emissions intensity, and adaptation. , 2013, Trends in genetics : TIG.

[109]  P. Visscher,et al.  Childhood intelligence is heritable, highly polygenic and associated with FNBP1L , 2014, Molecular Psychiatry.

[110]  Hugh Willmott,et al.  Challenges and prospects , 2015 .

[111]  Stuart A. Kauffman,et al.  ORIGINS OF ORDER , 2019, Origins of Order.