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Traversing the conceptual divide between biological and statistical epistasis: systems biology and a more modern synthesis
Abstract
Epistasis plays an important role in the genetic architecture of common human diseases and can be viewed from two perspectives, biological and statistical, each derived from and leading to different assumptions and research strategies. Biological epistasis is the result of physical interactions among biomolecules within gene regulatory networks and biochemical pathways in an individual such that the effect of a gene on a phenotype is dependent on one or more other genes. In contrast, statistical epistasis is defined as deviation from additivity in a mathematical model summarizing the relationship between multilocus genotypes and phenotypic variation in a population. The goal of this essay is to review definitions and examples of biological and statistical epistasis and to explore the relationship between the two. Specifically, we present and discuss the following two questions in the context of human health and disease. First, when does statistical evidence of epistasis in human populations imply underlying biomolecular interactions in the etiology of disease? Second, when do biomolecular interactions produce patterns of statistical epistasis in human populations?Answers to these two reciprocal questions will provide an important framework for using genetic information to improve our ability to diagnose, prevent and treat common human diseases. We propose that systems biology will provide the necessary information for addressing these questions and that model systems such as bacteria, yeast and digital organisms will be a useful place to start. BioEssays 27:637–646, 2005. © 2005 Wiley Periodicals, Inc.
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Citations
Cites
Lecture Notes in Computer Science 1205
(1999) · Industrial Robot: An International Journal · doi:10.1108/ir.1999.04926fae.001 · Cited by 38,662
A novel genetic system to detect protein–protein interactions
Fields, S., & Song, O.-K. (1989) · Nature · doi:10.1038/340245a0 · Cited by 6,114
Principles of Population Genetics.
Cormack, R. M., Hartl, D. L., & Clark, A. G. (1990) · Biometrics · doi:10.2307/2531471 · Cited by 5,242
XV.—The Correlation between Relatives on the Supposition of Mendelian Inheritance.
Fisher, R. A. (1919) · Transactions of the Royal Society of Edinburgh · doi:10.1017/s0080456800012163 · Cited by 4,387
Ritchie, M. D., Hahn, L. W., Roodi, N., Bailey, L. R., Dupont, W. D., Parl, F. F., & Moore, J. H. (2001) · The American Journal of Human Genetics · doi:10.1086/321276 · Cited by 1,898
Self-citationEvolution the Modern Synthesis
Schmidt, K. P., & Huxley, J. (1943) · Copeia · doi:10.2307/1438156 · Cited by 1,790
A comprehensive review of genetic association studies
Hirschhorn, J. N., Lohmueller, K., Byrne, E., & Hirschhorn, K. (2002) · Genetics in Medicine · doi:10.1097/00125817-200203000-00002 · Cited by 1,674
A N EW A PPROACH TO D ECODING L IFE : Systems Biology
Ideker, T., Galitski, T., & Hood, L. (2001) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.2.1.343 · Cited by 1,664
Evolution. The Modern Synthesis.
Huxley, J. S. (1942) · DigitalGeorgetown (Georgetown University Library) · Cited by 1,421
Genetic Dissection of Transcriptional Regulation in Budding Yeast
Brem, R. B., Yvert, G., Clinton, R., & Kruglyak, L. (2002) · Science · doi:10.1126/science.1069516 · Cited by 1,390
The protein–protein interaction map of Helicobacter pylori
Rain, J.-C., Selig, L., De Reuse, H., Battaglia, V., Reverdy, C., Simon, S., Lenzen, G., Petel, F., Wojcik, J., Schächter, V., et al. (2001) · Nature · doi:10.1038/35051615 · Cited by 1,146
Hahn, L. W., Ritchie, M. D., & Moore, J. H. (2003) · Bioinformatics · doi:10.1093/bioinformatics/btf869 · Cited by 1,133
Self-citationIntroduction to Genetic Analysis
Suzuki, D. T., & Griffiths, A. (1976) · Cited by 1,115
Epistasis: what it means, what it doesn't mean, and statistical methods to detect it in humans
Cordell, H. J. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.20.2463 · Cited by 1,084
An Introduction to Genetic Analysis
Teplitz, R. R. (1987) · JAMA: The Journal of the American Medical Association · doi:10.1001/jama.1987.03390160109041 · Cited by 1,070
The evolutionary origin of complex features
Lenski, R. E., Ofria, C., Pennock, R. T., & Adami, C. (2003) · Nature · doi:10.1038/nature01568 · Cited by 751
Principles of Population Genetics
Cazes, M.-H., Hartl, D., & Clark, A. (1999) · Population (French Edition) · doi:10.2307/1534724 · Cited by 749
The Ubiquitous Nature of Epistasis in Determining Susceptibility to Common Human Diseases
Moore, J. H. (2003) · Human Heredity · doi:10.1159/000073735 · Cited by 717
Self-citationPhenotype-genotype relationships in monogenic disease: lessons from the thalassaemias
Weatherall, D. J. (2001) · Nature Reviews Genetics · doi:10.1038/35066048 · Cited by 692
Hanis, C. L., Boerwinkle, E., Chakraborty, R., Ellsworth, D. L., Concannon, P., Stirling, B., Morrison, V. A., Wapelhorst, B., Spielman, R. S., Gogolin-Ewens, K. J., et al. (1996) · Nature Genetics · doi:10.1038/ng0696-161 · Cited by 590
Self-citationModular epistasis in yeast metabolism
Segrè, D., DeLuna, A., Church, G. M., & Kishony, R. (2005) · Nature Genetics · doi:10.1038/ng1489 · Cited by 575
Epistasis and the Evolutionary Process
Hurst, L. D. (2000) · Heredity · doi:10.1046/j.1365-2540.2000.0846b.x · Cited by 563
Ritchie, M. D., Hahn, L. W., & Moore, J. H. (2003) · Genetic Epidemiology · doi:10.1002/gepi.10218 · Cited by 549
Self-citationProceedings of the Genetic and Evolutionary Computation Conference
(2022) · doi:10.1145/3512290 · Cited by 546
Mendel's Principles of Heredity
(1913) · Nature · doi:10.1038/091009b0 · Cited by 521
Epistasis and its contribution to genetic variance components.
Cheverud, J. M., & Routman, E. J. (1995) · Genetics · doi:10.1093/genetics/139.3.1455 · Cited by 518
Genetic Markers in Human Blood.
(1970) · Annals of Internal Medicine · doi:10.7326/0003-4819-73-1-149_1 · Cited by 490
Mendel's principles of heredity / by W. Bateson.
Bateson, W., & Mendel, G. (1909) · University Press eBooks · doi:10.5962/bhl.title.44575 · Cited by 434
Test of synergistic interactions among deleterious mutations in bacteria
Elena, S. F., & Lenski, R. E. (1997) · Nature · doi:10.1038/37108 · Cited by 404
New strategies for identifying gene-gene interactions in hypertension
Moore, J. H., & Williams, S. M. (2002) · Annals of Medicine · doi:10.1080/07853890252953473 · Cited by 393
Self-citationCox, N. J., Frigge, M., Nicolae, D. L., Concannon, P., Hanis, C. L., Bell, G. I., & Kong, A. (1999) · Nature Genetics · doi:10.1038/6002 · Cited by 379
Nelson, M. R., Kardia, S. L. R., Ferrell, R. E., & Sing, C. F. (2001) · Genome Research · doi:10.1101/gr.172901 · Cited by 375
(2010) · Choice Reviews Online · doi:10.5860/choice.48-2058 · Cited by 374
A Perspective on Epistasis: Limits of Models Displaying No Main Effect
Culverhouse, R., Suarez, B. K., Lin, J., & Reich, T. (2002) · The American Journal of Human Genetics · doi:10.1086/338759 · Cited by 351
Renin-Angiotensin System Gene Polymorphisms and Atrial Fibrillation
Tsai, C.-T., Lai, L.-P., Lin, J.-L., Chiang, F.-T., Hwang, J.-J., Ritchie, M. D., Moore, J. H., Hsu, K.-L., Tseng, C.-D., Liau, C.-S., et al. (2004) · Circulation · doi:10.1161/01.cir.0000124487.36586.26 · Cited by 345
Self-citationProtein interaction networks from yeast to human
Bork, P., Jensen, L. J., von Mering, C., Ramani, A. K., Lee, I., & Marcotte, E. M. (2004) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2004.05.003 · Cited by 333
Trimming, Weighting, and Grouping SNPs in Human Case-Control Association Studies
Hoh, J., Wille, A., & Ott, J. (2001) · Genome Research · doi:10.1101/gr.204001 · Cited by 317
Genome complexity, robustness and genetic interactions in digital organisms
Lenski, R. E., Ofria, C., Collier, T. C., & Adami, C. (1999) · Nature · doi:10.1038/23245 · Cited by 306
Mathematical multi-locus approaches to localizing complex human trait genes
Hoh, J., & Ott, J. (2003) · Nature Reviews Genetics · doi:10.1038/nrg1155 · Cited by 275
The Language of Gene Interaction
Phillips, P. C. (1998) · Genetics · doi:10.1093/genetics/149.3.1167 · Cited by 273
Machine Learning for Detecting Gene-Gene Interactions: A Review
McKinney, B. A., Reif, D. M., Ritchie, M. D., & Moore, J. H. (2006) · Applied Bioinformatics · doi:10.2165/00822942-200605020-00002 · Cited by 254
Self-citationGenetics, statistics and human disease: analytical retooling for complexity
Thornton-Wells, T. A., Moore, J. H., & Haines, J. L. (2004) · Trends in Genetics · doi:10.1016/j.tig.2004.09.007 · Cited by 246
Self-citationComputational analysis of gene-gene interactions using multifactor dimensionality reduction
Moore, J. H. (2004) · Expert Review of Molecular Diagnostics · doi:10.1586/14737159.4.6.795 · Cited by 245
Self-citationGenes, Environment, and Cardiovascular Disease
Sing, C. F., Stengård, J. H., & Kardia, S. L. R. (2003) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000075081.51227.86 · Cited by 239
Moore, J. H. (2005) · Nature Genetics · doi:10.1038/ng0105-13 · Cited by 231
Self-citationRitchie, M. D., White, B. C., Parker, J. S., Hahn, L. W., & Moore, J. H. (2003) · BMC Bioinformatics · doi:10.1186/1471-2105-4-28 · Cited by 224
Self-citationSimulation Models as Opaque Thought Experiments
Di Paolo, E. A., Noble, J., & Bullock, S. (2000) · Artificial Life VII · doi:10.7551/mitpress/1432.003.0068 · Cited by 223
OSTROWSKI, M., DAVID, J., SANTONI, S., MCKHANN, H., REBOUD, X., LE CORRE, V., CAMILLERI, C., BRUNEL, D., BOUCHEZ, D., FAURE, B., et al. (2006) · Molecular Ecology · doi:10.1111/j.1365-294x.2006.02865.x · Cited by 197
Page, G. P., George, V., Go, R. C., Page, P. Z., & Allison, D. B. (2003) · The American Journal of Human Genetics · doi:10.1086/378900 · Cited by 192
A Complete Enumeration and Classification of Two-Locus Disease Models
Li, W., & Reich, J. (2000) · Human Heredity · doi:10.1159/000022939 · Cited by 188
Studying complex biological systems using multifactorial perturbation
Jansen, R. C. (2003) · Nature Reviews Genetics · doi:10.1038/nrg996 · Cited by 187
Cho, Y. M., Ritchie, M. D., Moore, J. H., Park, J. Y., Lee, K.-U., Shin, H. D., Lee, H. K., & Park, K. S. (2004) · Diabetologia · doi:10.1007/s00125-003-1321-3 · Cited by 183
Self-citationDetecting epistatic interactions contributing to quantitative traits
Culverhouse, R., Klein, T., & Shannon, W. (2004) · Genetic Epidemiology · doi:10.1002/gepi.20006 · Cited by 171
Hodgkin, J. (1998) · The International Journal of Developmental Biology · doi:10.1387/ijdb.9654038 · Cited by 164
Multilocus Analysis of Hypertension: A Hierarchical Approach
Williams, S. M., Ritchie, M. D., Phillips, J. A., III, Dawson, E. P., Prince, M., Dzhura, E., Willis, A. S., Semenya, A., Summar, M. L., White, B. C., et al. (2004) · Human Heredity · doi:10.1159/000077387 · Cited by 156
Self-citationRyR2 and Calpain-10 Delineate a Novel Apoptosis Pathway in Pancreatic Islets
Johnson, J. D., Han, Z., Otani, K., Ye, H., Zhang, Y., Wu, H., Horikawa, Y., Misler, S., Bell, G. I., & Polonsky, K. S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m401216200 · Cited by 145
Cordell, H. J., Todd, J. A., Bennett, S. T., Kawaguchi, Y., & Farrall, M. (1995) · PubMed · Cited by 143
Duplicate Genes for Capsule-Form in Bursa Bursa-Pastoris
Shull, G. H. (2018) · Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) · Cited by 143
The genetic architecture of odor-guided behavior in Drosophila: epistasis and the transcriptome
Anholt, R. R. H., Dilda, C. L., Chang, S. H., Fanara, J. J., Kulkarni, N. H., Ganguly, I., Rollmann, S. M., Kamdar, K. P., & Mackay, T. F. C. (2003) · Nature Genetics · doi:10.1038/ng1240 · Cited by 136
Pervasive joint influence of epistasis and plasticity on mutational effects in Escherichia coli
Remold, S. K., & Lenski, R. E. (2004) · Nature Genetics · doi:10.1038/ng1324 · Cited by 116
Multifactorial inheritance in type 1 diabetes
Cordell, H. J., & Todd, J. A. (1995) · Trends in Genetics · doi:10.1016/s0168-9525(00)89160-x · Cited by 97
Williams, S. M., Haines, J. L., & Moore, J. H. (2004) · BioEssays · doi:10.1002/bies.10401 · Cited by 95
Self-citationCordell, H. J., Todd, J. A., Hill, N. J., Lord, C. J., Lyons, P., Peterson, L. B., Wicker, L. S., & Clayton, D. G. (2001) · Genetics · doi:10.1093/genetics/158.1.357 · Cited by 82
Epistatic Interactions Between smell-impaired Loci in Drosophila melanogaster
Fedorowicz, G. M., Fry, J. D., Anholt, R. R. H., & Mackay, T. F. C. (1998) · Genetics · doi:10.1093/genetics/148.4.1885 · Cited by 78
Linkage of Calpain 10 to Type 2 Diabetes
Cox, N. J., Hayes, M. G., Roe, C. A., Tsuchiya, T., & Bell, G. I. (2004) · Diabetes · doi:10.2337/diabetes.53.2007.s19 · Cited by 77
Epistasis, complex traits, and mapping genes
Wade, M. J. (2001) · Contemporary issues in genetics and evolution · doi:10.1007/978-94-010-0585-2_5 · Cited by 75
Ideal Discrimination of Discrete Clinical Endpoints Using Multilocus Genotypes
Hahn, L. W., & Moore, J. H. (2004) · In Silico Biology · doi:10.3233/isb-00126 · Cited by 73
Self-citationReilly, S. L., Ferrell, R. E., & Sing, C. F. (1994) · PubMed · Cited by 72
Epistasis, complex traits, and mapping genes
Wade, M. J. (2001) · Genetica · doi:10.1023/a:1013316611768 · Cited by 69
Human genetics, animal models and computer simulations for studying hypertension☆
Takahashi, N., & Smithies, O. (2004) · Trends in Genetics · doi:10.1016/j.tig.2004.01.004 · Cited by 67
Zee, R. Y. L., Hoh, J., Cheng, S., Reynolds, R., Grow, M. A., Silbergleit, A., Walker, K., Steiner, L. L., Zangenberg, G., Fernández‐Ortíz, A., et al. (2002) · The Pharmacogenomics Journal · doi:10.1038/sj.tpj.6500101 · Cited by 63
Wille, A., Hoh, J. J., & Ott, J. (2003) · Genetic Epidemiology · doi:10.1002/gepi.10263 · Cited by 62
EPISTASIS BETWEEN NEW MUTATIONS AND GENETIC BACKGROUND AND A TEST OF GENETIC CANALIZATION
Elena, S. F., & Lenski, R. E. (2001) · Evolution · doi:10.1111/j.0014-3820.2001.tb00824.x · Cited by 61
Minireview: Computer Simulations of Blood Pressure Regulation by the Renin-Angiotensin System
Takahashi, N., Hagaman, J. R., Kim, H., & Smithies, O. (2003) · Endocrinology · doi:10.1210/en.2002-221045 · Cited by 54
Moore, J. H., Hahn, L. W., Ritchie, M. D., Thornton‐Wells, T. A., & White, B. C. (2002) · PubMed · Cited by 53
Self-citationGenetic dissection of diseases: design and methods
Hoh, J. J., & Ott, J. (2004) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2004.04.006 · Cited by 50
Set Association Analysis of SNP Case-Control and Microarray Data
Ott, J., & Hoh, J. J. (2003) · Journal of Computational Biology · doi:10.1089/10665270360688192 · Cited by 44
Moore, J. H., Boczko, E. M., & Summar, M. L. (2005) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2004.10.006 · Cited by 32
Self-citationPleiotropic and epistatic effects in sickle cell anemia
Nagel, R. L. (2001) · Current Opinion in Hematology · doi:10.1097/00062752-200103000-00008 · Cited by 32
Moore, J. H., Lamb, J., Brown, N., & Vaughan, D. (2002) · Clinical Genetics · doi:10.1034/j.1399-0004.2002.620110.x · Cited by 30
Self-citationMoore, J. H., Smolkin, M., Lamb, J., Brown, N., & Vaughan, D. (2002) · Clinical Genetics · doi:10.1034/j.1399-0004.2002.620107.x · Cited by 28
Self-citationBondos, S. E., Catanese, D. J., Tan, X.-X., Bicknell, A. A., Li, L., & Matthews, K. S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312842200 · Cited by 27
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Cordell, H. J. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2579 · Cited by 1,350
Moore, J. H., Gilbert, J. C., Tsai, C.-T., Chiang, F.-T., Holden, T., Barney, N., & White, B. C. (2006) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2005.11.036 · Cited by 608
Self-citationVelez, D. R., White, B. C., Motsinger, A. A., Bush, W. S., Ritchie, M. D., Williams, S. M., & Moore, J. H. (2007) · Genetic Epidemiology · doi:10.1002/gepi.20211 · Cited by 384
Self-citationNovel Alzheimer risk genes determine the microglia response to amyloid-β but not to TAU pathology
Sierksma, A., Lu, A., Mancuso, R., Fattorelli, N., Thrupp, N., Salta, E., Zoco, J., Blum, D., Buée, L., De Strooper, B., et al. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.201910606 · Cited by 291
Machine Learning for Detecting Gene-Gene Interactions: A Review
McKinney, B. A., Reif, D. M., Ritchie, M. D., & Moore, J. H. (2006) · Applied Bioinformatics · doi:10.2165/00822942-200605020-00002 · Cited by 254
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Metadata
- Authors
- Moore, J. H., & Williams, S. M.
- Venue
- BioEssays
- Publisher
- Wiley
- Published
- 2005-05-12
- Volume
- 27
- Issue
- 6
- Pages
- 637-646
- ISSN
- 0265-9247 (ISSN-L)
- 1521-1878
- OpenAlex
- W2007669896
- Cited by
- 340
- References
- 82
- FWCI
- 1.22
- Type
- journal article
- Language
- en
- Open access
- closed
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