Epistasis - The essential role of gene interactions in the structure and evolution of genetic systems

Nature Reviews Genetics

Volumn 9, Issue 11, 2008, Pages 855-867

  Phillips, Patrick C ^a,b  

^a UNIVERSITY OF OREGON   (United States)

^b INSTITUTO GULBENKIAN DE CIÊNCIA   (Portugal)

Author keywords

[No Author keywords available]

Indexed keywords

AMYOTROPHIC LATERAL SCLEROSIS; COMPOSITIONAL EPISTASIS; GENE EXPRESSION; GENE INTERACTION; GENE LOCUS; GENE MUTATION; GENE SEGREGATION; GENE SYNTHESIS; GENETIC EPISTASIS; GENETIC TRAIT; GENETIC VARIABILITY; GENOME ANALYSIS; GENOTYPE; HIGH THROUGHPUT SCREENING; HUMAN; INSECT GENETICS; MOLECULAR EVOLUTION; MOUSE STRAIN; NATURAL POPULATION; NATURAL SELECTION; NONHUMAN; PHENOTYPE; PLANT GENETICS; PRIORITY JOURNAL; QUANTITATIVE TRAIT LOCUS; REVIEW; STATISTICAL EPISTASIS; SYSTEMS BIOLOGY;

EPISTASIS, GENETIC; EVOLUTION, MOLECULAR; GENE REGULATORY NETWORKS; GENOMICS; MODELS, GENETIC; SYSTEMS BIOLOGY;

EID: 54149088214     PISSN: 14710056     EISSN: 14710064     Source Type: Journal    
DOI: 10.1038/nrg2452     Document Type: Review

References (106)

1. Phillips, P. C. The language of gene interaction. Genetics 149, 1167-1171 (1998).
2. Phillips, P. C., Otto, S. P. & Whitlock, M. C. in Epistasis and the Evolutionary Process (eds Wolf, J. D., Brodie, E. D., III & Wade, M. J.) 20-38 (Oxford Univ. Press, Oxford, 2000).
3. Malmberg, R. L. & Mauricio, R. QTL-based evidence for the role of epistasis in evolution. Genet. Res. 86, 89-95 (2005).
4. Otto, S. P. & Gerstein, A. C. Why have sex? The population genetics of sex and recombination. Biochem. Soc. Trans. 34, 519-522 (2006).
5. Weinreich, D. M., Watson, R. A. & Chao, L. Perspective: sign epistasis and genetic constraint on evolutionary trajectories. Evolution 59, 1165-1174 (2005).
6. Carlborg, O. & Haley, C. S. Epistasis: too often neglected in complex trait studies? Nature Rev. Genet. 5, 618-625 (2004).
7. Holland, J. B. Genetic architecture of complex traits in plants. Curr. Opin. Plant Biol. 10, 156-161 (2007).
8. Wade, M. J. Epistasis, complex traits, and mapping genes. Genetica 112-113, 59-69 (2001).
9. Azevedo, L., Suriano, G., van Asch, B., Harding, R. M. & Amorim, A. Epistatic interactions: how strong in disease and evolution? Trends Genet. 22, 581-585 (2006).
10. Nadeau, J. H. Modifier genes in mice and humans. Nature Rev. Genet. 2, 165-174 (2001).
11. Moore, J. H. The ubiquitous nature of epistasis in determining susceptibility to common human diseases. Hum. Hered. 56, 73-82 (2003).
12. Cordell, H. J. Epistasis: what it means, what it doesn't mean, and statistical methods to detect it in humans. Hum. Mol. Genet. 11, 2463-2468 (2002). A clear review of the limitations in moving from statistical estimates of epistatic effects to understanding genetic causation.
13. Demuth, J. P. & Wade, M. J. Experimental methods for measuring gene interactions. Ann. Rev. Ecol. Evol. Systematics 37, 289-316 (2006).
14. Musani, S. K. et al. Detection of gene x gene interactions in genome-wide association studies of human population data. Hum. Hered. 63, 67-84 (2007).
15. McKinney, B. A., Reif, D. M., Ritchie, M. D. & Moore, J. H. Machine learning for detecting gene-gene interactions: a review. Appl. Bioinformatics 5, 77-88 (2006).
16. Marchini, J., Donnelly, P. & Cardon, L. R. Genomewide strategies for detecting multiple loci that influence complex diseases. Nature Genet. 37, 413-417 (2005).
17. Alvarez-Castro, J. M., Le Rouzic, A. & Carlborg, O. How to perform meaningful estimates of genetic effects. PLoS Genet. 4, e1000062 (2008).
18. Boone, C., Bussey, H. & Andrews, B. J. Exploring genetic interactions and networks with yeast. Nature Rev. Genet. 8, 437-449 (2007). A comprehensive review of existing work on using high-throughput approaches in yeast to dissect complex gene interaction networks. Includes a good discussion of the overall conceptual framework.
19. Costanzo, M., Giaever, G., Nislow, C. & Andrews, B. Experimental approaches to identify genetic networks. Curr. Opin. Biotechnol. 17, 472-480 (2006).
20. Hansen, T. F. & Wagner, G. P. Modeling genetic architecture: a multilinear theory of gene interaction. Theoretical Popul. Biol. 59, 61-86 (2001).
21. Elena, S. F. & Lenski, R. E. Test of synergistic interactions among deleterious mutations in bacteria. Nature 390, 395-398 (1997). Uses randomly generated mutations in Escherichia coli to demonstrate that epistatic effects between loci can be highly variable and frequently cancel one another out.
22. Routman, E. J. & Cheverud, J. M. Gene effects on a quantitative trait: two-locus epistatic effects measured at microsatellite markers and at estimated QTL. Evolution 51, 1654-1662 (1995).
23. Bateson, W., Saunders, E. R., Punnett, R. C. & Hurst, C. C. Reports to the Evolution Committee of the Royal Society, Report II (Harrison and Sons, London, 1905).
24. Beadle, G. W. Genetics and metabolism in Neurospora. Physiol. Rev. 25, 643-663 (1945).
25. Avery, L. & Wasserman, S. Ordering gene function: the interpretation of epistasis in regulatory hierarchies. Trends Genet. 8, 312-316 (1992).
26. Huang, L. S. & Sternberg, P. W. Genetic dissection of developmental pathways. (doi:10.1895/wormbook.1.88.2) WormBook [online], 〈http://www.wormbook.org/chapters/www_epistasis.2/epistasis.html〉 (2005). A comprehensive treatment of how to use classical epistasis analysis to reconstruct genetic pathways.
27. Goodwin, E. B. & Ellis, R. E. Turning clustering loops: sex determination in Caenorhabditis elegans. Curr. Biol. 12, R111-R120 (2002).
28. Sternberg, P. W. & Horvitz, H. R. The combined action of two intercellular signaling pathways specifies three cell fates during vulval induction in C. elegans. Cell 58, 679-693 (1989).
29. Thomas, J. H., Birnby, D. A. & Vowels, J. J. Evidence for parallel processing of sensory information controlling dauer formation in Caenorhabditis elegans. Genetics 134, 1105-1117 (1993).
30. Tong, A. H. et al. Systematic genetic analysis with ordered arrays of yeast deletion mutants. Science 294, 2364-2368 (2001). A landmark paper that established the high-throughput double-deletion approach to detecting epistatic interactions.
31. Tong, A. H. et al. Global mapping of the yeast genetic interaction network. Science 303, 808-813 (2004).
32. Hartman, J. L., Garvik, B. & Hartwell, L. Principles for the buffering of genetic variation. Science 291, 1001-1004 (2001).
33. Segrè, D., Deluna, A., Church, G. M. & Kishony, R. Modular epistasis in yeast metabolism. Nature Genet. 37, 77-83 (2005).
34. St. Onge, R. P. et al. Systematic pathway analysis using high-resolution fitness profiling of combinatorial gene deletions. Nature Genet. 39, 199-206 (2007). References 33 and 34 show how quantitative information can be incorporated into high-throughput interaction studies to yield deeper insights into the nature of genetic networks.
35. Kroll, E. S., Hyland, K. M., Hieter, P. & Li, J. J. Establishing genetic interactions by a synthetic dosage lethality phenotype. Genetics 143, 95-102 (1996).
36. Sopko, R. et al. Mapping pathways and phenotypes by systematic gene overexpression. Mol. Cell 21, 319-330 (2006).
37. Greenspan, R. J. The flexible genome. Nature Rev. Genet. 2, 383-387 (2001).
38. Lehner, B., Crombie, C., Tischler, J., Fortunato, A. & Fraser, A. G. Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling pathways. Nature Genet. 38, 896-903 (2006).
39. Davierwala, A. P. et al. The synthetic genetic interaction spectrum of essential genes. Nature Genet. 37, 1147-1152 (2005).
40. Tischler, J., Lehner, B. & Fraser, A. G. Evolutionary plasticity of genetic interaction networks. Nature Genet. 40, 390-391 (2008).
41. Wong, S. L. et al. Combining biological networks to predict genetic interactions. Proc. Natl Acad. Sci. USA 101, 15682-15687 (2004).
42. Beyer, A., Bandyopadhyay, S. & Ideker, T. Integrating physical and genetic maps: from genomes to interaction networks. Nature Rev. Genet. 8, 699-710 (2007).
43. Pattin, K. A. & Moore, J. H. Exploiting the proteome to improve the genome-wide genetic analysis of epistasis in common human diseases. Hum. Genet. 124, 19-29 (2008).
44. Zhu, J. et al. Integrating large-scale functional genomic data to dissect the complexity of yeast regulatory networks. Nature Genet. 40, 854-861 (2008). Shows how interaction information from many sources can be combined to provide a more comprehensive picture of interaction networks.
45. Collins, S. R. et al. Functional dissection of protein complexes involved in yeast chromosome biology using a genetic interaction map. Nature 446, 806-810 (2007).
46. Carlborg, O., Jacobsson, L., Ahgren, P., Siegel, P. & Andersson, L. Epistasis and the release of genetic variation during long-term selection. Nature Genet. 38, 418-420 (2006).
47. Stylianou, I. M. et al. Quantitative trait locus analysis for obesity reveals multiple networks of interacting loci. Mamm. Genome 17, 22-36 (2006).
48. Ehrenreich, I. M., Stafford, P. A. & Purugganan, M. D. The genetic architecture of shoot branching in Arabidopsis thaliana: a comparative assessment of candidate gene associations vs. quantitative trait locus mapping. Genetics 176, 1223-1236 (2007).
49. Alvarez-Castro, J. M. & Carlborg, O. A unified model for functional and statistical epistasis and its application in quantitative trait loci analysis. Genetics 176, 1151-1167 (2007).
50. Cheverud, J. M. in Epistasis and the Evolutionary Process (eds Wolf, J., Brodie, E. D., III & Wade, M. J.) 58-81 (Oxford Univ. Press, Oxford, 2000).
51. Sambandan, D., Yamamoto, A., Fanara, J. J., Mackay, T. F. & Anholt, R. R. Dynamic genetic interactions determine odor-guided behavior in Drosophila melanogaster. Genetics 174, 1349-1363 (2006).
52. Causse, M., Chaïb, J., Lecomte, L., Buret, M. & Hospital, F. Both additivity and epistasis control the genetic variation for fruit quality traits in tomato. Theor. Appl. Genet. 115, 429-442 (2007).
53. Rowe, H. C., Hansen, B. G., Halkier, B. A. & Kliebenstein, D. J. Biochemical networks and epistasis shape the Arabidopsis thaliana metabolome. Plant Cell 20, 1199-1216 (2008).
54. Wolf, J. B., Leamy, L. J., Routman, E. J. & Cheverud, J. M. Epistatic pleiotropy and the genetic architecture of covariation within early and late-developing skull trait complexes in mice. Genetics 171, 683-694 (2005).
55. Sinha, H., Nicholson, B. P., Steinmetz, L. M. & McCusker, J. H. Complex genetic interactions in a quantitative trait locus. PLoS Genet. 2, e13 (2006).
56. Nogami, S., Ohya, Y. & Yvert, G. Genetic complexity and quantitative trait loci mapping of yeast morphological traits. PLoS Genet. 3, e31 (2007).
57. Storey, J. D., Akey, J. M. & Kruglyak, L. Multiple locus linkage analysis of genomewide expression in yeast. PLoS Biol. 3, e267 (2005).
58. Brem, R. B., Storey, J. D., Whittle, J. & Kruglyak, L. Genetic interactions between polymorphisms that affect gene expression in yeast. Nature 436, 701-703 (2005). Shows how genetical genomics can be used to infer patterns of gene interaction.
59. Hill, W. G., Goddard, M. E. & Visscher, P. M. Data and theory point to mainly additive genetic variance for complex traits. PLoS Genet. 4, e1000008 (2008).
60. Cheverud, J. M. & Routman, E. J. Epistasis and its contribution to genetic variance components. Genetics 139, 1455-1461 (1995).
61. Phillips, P. C. & Johnson, N. A. The population genetics of synthetic lethals. Genetics 150, 449-458 (1998).
62. Wellcome Trust Case Control Consortium. Genomewide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661-678 (2007).
63. Tsai, C. T. et al. Renin-angiotensin system gene polymorphisms and coronary artery disease in a large angiographic cohort: detection of high order gene-gene interaction. Atherosclerosis 195, 172-180 (2007).
64. Wiltshire, S. et al. Epistasis between type 2 diabetes susceptibility loci on chromosomes 1q21-25 and 10q23-26 in northern Europeans. Ann. Hum. Genet. 70, 726-737 (2006).
65. Abou Jamra, R. et al. The first genomewide interaction and locus-heterogeneity linkage scan in bipolar affective disorder: strong evidence of epistatic effects between loci on chromosomes 2q and 6q. Am. J. Hum. Genet. 81, 974-986 (2007).
66. Coutinho, A. M. et al. Evidence for epistasis between SLC6A4 and ITGB3 in autism etiology and in the determination of platelet serotonin levels. Hum. Genet. 121, 243-256 (2007).
67. Gregersen, J. W. et al. Functional epistasis on a common MHC haplotype associated with multiple sclerosis. Nature 443, 574-577 (2006). Illustrates how functional hypotheses regarding gene interaction within human populations can be tested using model systems.
68. Trowsdale, J. Multiple sclerosis: putting two and two together. Nature Med. 12, 1119-1121 (2006).
69. Svejgaard, A. The immunogenetics of multiple sclerosis. Immunogenetics 60, 275-286 (2008).
70. Gauderman, W. J. Sample size requirements for association studies of gene-gene interaction. Am. J. Epidemiol. 155, 478-484 (2002).
71. Carlson, C. S., Eberle, M. A., Kruglyak, L. & Nickerson, D. A. Mapping complex disease loci in whole-genome association studies. Nature 429, 446-452 (2004).
72. Xu, S. & Jia, Z. Genomewide analysis of epistatic effects for quantitative traits in barley. Genetics 175, 1955-1963 (2007).
73. Demant, P. Cancer susceptibility in the mouse: genetics, biology and implications for human cancer. Nature Rev. Genet. 4, 721-734 (2003).
74. Jacob, F. Evolution and tinkering. Science 196, 1161-1166 (1977).
75. Lynch, M. The frailty of adaptive hypotheses for the origins of organismal complexity. Proc. Natl Acad. Sci. USA 104 (Suppl. 1), 8597-8604 (2007).
76. Crow, J. F. How important is detecting interaction? Behav. Brain. Sci. 13, 126-127 (1990).
77. Fisher, R. A. The Genetical Theory of Natural Selection (Clarendon, Oxford, 1930).
78. Kauffman, S. A. The Origins of Order: Self-Organisation and Selection in Evolution (Oxford Univ. Press, New York, 1993).
79. Wu, C.-I. & Palopoli, M. F. Genetics of postmating reproductive isolation in animals. Annu. Rev. Genet. 27, 283-208 (1994).
80. de Visser, J. A. et al. Perspective: evolution and detection of genetic robustness. Evolution 57, 1959-1972 (2003).
81. Bridgham, J. T., Carroll, S. M. & Thornton, J. W. Evolution of hormone-receptor complexity by molecular exploitation. Science 312, 97-101 (2006).
82. Ortlund, E. A., Bridgham, J. T., Redinbo, M. R. & Thornton, J. W. Crystal structure of an ancient protein: evolution by conformational epistasis. Science 317, 1544-1548 (2007). A good example of moving between detailed functional analysis and long-term evolutionary inference.
83. Miller, S. P., Lunzer, M. & Dean, A. M. Direct demonstration of an adaptive constraint. Science 314, 458-461 (2006).
84. Weinreich, D. M., Delaney, N. F., Depristo, M. A. & Hartl, D. L. Darwinian evolution can follow only very few mutational paths to fitter proteins. Science 312, 111-114 (2006).
85. Poelwijk, F. J., Kiviet, D. J., Weinreich, D. M. & Tans, S. J. Empirical fitness landscapes reveal accessible evolutionary paths. Nature 445, 383-386 (2007).
86. Karlin, S. General two locus selection models: some objectives, results and interpretations. Theoret. Popul. Biol. 7, 364-398 (1975).
87. Encode Project Consortium. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447, 799-816 (2007).
88. Moore, J. H. & Williams, S. M. Traversing the conceptual divide between biological and statistical epistasis: systems biology and a more modern synthesis. Bioessays 27, 637-646 (2005).
89. Wagner, G. P., Pavlicev, M. & Cheverud, J. M. The road to modularity. Nature Rev. Genet. 8, 921-931 (2007).
90. Gjuvsland, A. B., Hayes, B. J., Omholt, S. W. & Carlborg, O. Statistical epistasis is a generic feature of gene regulatory networks. Genetics 175, 411-420 (2007).
91. Deutscher, D., Meilijson, I., Kupiec, M. & Ruppin, E. Multiple knockout analysis of genetic robustness in the yeast metabolic network. Nature Genet. 38, 993-998 (2006).
92. Jansen, R. C. Studying complex biological systems using multifactorial perturbation. Nature Rev. Genet. 4, 145-151 (2003). A perspective on how complex genetic systems can be best interrogated using multiple, rather than single, perturbations.
93. Carter, G. W. et al. Prediction of phenotype and gene expression for combinations of mutations. Mol. Syst. Biol. 3, 96 (2007).
94. Bateson, W. Mendel's Principles of Heredity (Cambridge Univ. Press, Cambridge, 1909).
95. Fisher, R. A. The correlations between relatives on the supposition of Mendelian inheritance. Trans. R. Soc. Edinb. 52, 399-433 (1918).
96. Tachida, H. & Cockerham, C. C. A building block model for quantitative genetics. Genetics 121, 839-844 (1989). A greatly underappreciated paper that provides a quantitative framework for moving between different perspectives for how phenotypes are built and how genetic effects can be estimated.
97. Karlin, S. & Feldman, M. W. Simultaneous stability of D=0 and D≠0 for multiplicative viabilities at two loci. Genetics 90, 813-825 (1978).
98. Mani, R., St. Onge, R. P., Hartman, J. L. IV, Giaever, G. & Roth, F. P. Defining genetic interaction. Proc. Natl Acad. Sci. USA 105, 3461-3466 (2008). Shows how dependent the inference of epistasis is upon the scale of measurement.
99. Aylor, D. L. & Zeng, Z. B. From classical genetics to quantitative genetics to systems biology: modeling epistasis. PLoS Genet. 4, e1000029 (2008).
100. Feldman, M. W., Otto, S. P. & Christiansen, F. B. Population genetic perspectives on the evolution of recombination. Annu. Rev. Genet. 30, 261-295 (1997).
101. Bennett, D. C. & Lamoreux, M. L. The color loci of mice - a genetic century. Pigment Cell Res. 16, 333-344 (2003).
102. Steiner, C. C., Weber, J. N. & Hoekstra, H. E. Adaptive variation in beach mice produced by two interacting pigmentation genes. PLoS Biol. 5, e219 (2007).
103. Silvers, W. The Coat Colors of Mice: A model for mammalian gene action and interaction (Springer, Berlin, 1979).
104. Hoekstra, H. E. Genetics, development and evolution of adaptive pigmentation in vertebrates. Heredity 97, 222-234 (2006).
105. Wright, S. The roles of mutation, inbreeding, crossbreeding and selection in evolution. Proc. 6th Int. Cong. Genet. 1, 356-366 (1932).
106. Gavrilets, S. Fitness landscapes and the Origin of Species (Princeton Univ. Press, Princeton, 2004).