THE MOLECULAR BASIS OF DOMINANCE

Henrik Kacser ¹ and James A. Burns ¹

¹ Department of Genetics, University of Edinburgh, Edinburgh

The best known genes of microbes, mice and men are those that specify enzymes. Wild type, mutant and heterozygote for variants of such genes differ in the catalytic activity at the step in the enzyme network specified by the gene in question. The effect on the respective phenotypes of such changes in catalytic activity, however, is not defined by the enzyme change as estimated by in vitro determination of the activities obtained from the extracts of the three types. In vivo enzymes do not act in isolation, but are kinetically linked to other enzymes via their substrates and products. These interactions modify the effect of enzyme variation on the phenotype, depending on the nature and quantity of the other enzymes present. An output of such a system, say a flux, is therefore a systemic property, and its response to variation at one locus must be measured in the whole system. This response is best described by the sensitivity coefficient, Z, which is defined by the fractional change in flux over the fractional change in enzyme activity.

(see PDF)

Its magnitude determines the extent to which a particular enzyme "controls" a particular flux or phenotype and, implicitly, determines the values that the three phenotypes will have. There are as many sensitivity coefficients for a given flux as there are enzymes in the system. It can be shown that the sum of all such coefficients equals unity.

(see PDF)

Since n, the number of enzymes, is large, this summation property results in the individual coefficients being small. The effect of making a large change in enzyme activity therefore usually results in only a negligible change in flux. A reduction to 50% activity in the heterozygote, a common feature for many mutants, is therefore not expected to be detectable in the phenotype. The mutant would therefore be described as "recessive". The widespread occurrence of recessive mutants is thus seen to be the inevitable consequence of the kinetic structure of enzyme networks. The ad hoc hypothesis of "modifiers" selected to maximize the fitness of the heterozygote, as proposed by Fisher, is therefore unnecessary. It is based on the false general expectation of an intermediate phenotype in the heterozygote. Wright's analysis, substantially sound in its approach, proposed selection of a "safety factor" in enzyme activity. The derivation of the summation property explains why such safety factors are automatically present in almost all enzymes without selection.

This article has been cited by other articles:

				E. M. Torres, B. R. Williams, and A. Amon Aneuploidy: Cells Losing Their Balance Genetics, June 1, 2008; 179(2): 737 - 746. [Abstract] [Full Text] [PDF]

				J. Stout, E. Romero-Severson, M. O. Ruegger, and C. Chapple Semidominant Mutations in Reduced Epidermal Fluorescence 4 Reduce Phenylpropanoid Content in Arabidopsis Genetics, April 1, 2008; 178(4): 2237 - 2251. [Abstract] [Full Text] [PDF]

				W. J. Dickinson Synergistic Fitness Interactions and a High Frequency of Beneficial Changes Among Mutations Accumulated Under Relaxed Selection in Saccharomyces cerevisiae Genetics, March 1, 2008; 178(3): 1571 - 1578. [Abstract] [Full Text] [PDF]

				B. J. Evans Ancestry Influences the Fate of Duplicated Genes Millions of Years After Polyploidization of Clawed Frogs (Xenopus) Genetics, June 1, 2007; 176(2): 1119 - 1130. [Abstract] [Full Text] [PDF]

				J. Flowers, E Sezgin, S Kumagai, D. Duvernell, L. Matzkin, P. Schmidt, and W. Eanes Adaptive Evolution of Metabolic Pathways in Drosophila Mol. Biol. Evol., June 1, 2007; 24(6): 1347 - 1354. [Abstract] [Full Text] [PDF]

				K. L. Montooth, K. T. Siebenthall, and A. G. Clark Membrane lipid physiology and toxin catabolism underlie ethanol and acetic acid tolerance in Drosophila melanogaster J. Exp. Biol., October 1, 2006; 209(19): 3837 - 3850. [Abstract] [Full Text] [PDF]

				T. N. Kristensen, P. Sorensen, K. S. Pedersen, M. Kruhoffer, and V. Loeschcke Inbreeding by Environmental Interactions Affect Gene Expression in Drosophila melanogaster Genetics, July 1, 2006; 173(3): 1329 - 1336. [Abstract] [Full Text] [PDF]

				R. Bernardo and A. Charcosset Usefulness of Gene Information in Marker-Assisted Recurrent Selection: A Simulation Appraisal Crop Sci., February 1, 2006; 46(2): 614 - 621. [Abstract] [Full Text] [PDF]

				B. Fernandez, A. Garcia-Dorado, and A. Caballero The Effect of Antagonistic Pleiotropy on the Estimation of the Average Coefficient of Dominance of Deleterious Mutations Genetics, December 1, 2005; 171(4): 2097 - 2112. [Abstract] [Full Text] [PDF]

				T. J. S. Merritt, D. Duvernell, and W. F. Eanes Natural and Synthetic Alleles Provide Complementary Insights Into the Nature of Selection Acting on the Men Polymorphism of Drosophila melanogaster Genetics, December 1, 2005; 171(4): 1707 - 1718. [Abstract] [Full Text] [PDF]

				F. Roux, C. Camilleri, S. Giancola, D. Brunel, and X. Reboud Epistatic Interactions Among Herbicide Resistances in Arabidopsis thaliana: The Fitness Cost of Multiresistance Genetics, November 1, 2005; 171(3): 1277 - 1288. [Abstract] [Full Text] [PDF]

				M. Lunzer, S. P. Miller, R. Felsheim, and A. M. Dean The Biochemical Architecture of an Ancient Adaptive Landscape Science, October 21, 2005; 310(5747): 499 - 501. [Abstract] [Full Text] [PDF]

				N. Phadnis and J. D. Fry Widespread Correlations Between Dominance and Homozygous Effects of Mutations: Implications for Theories of Dominance Genetics, September 1, 2005; 171(1): 385 - 392. [Abstract] [Full Text] [PDF]

				A. M. Deutschbauer, D. F. Jaramillo, M. Proctor, J. Kumm, M. E. Hillenmeyer, R. W. Davis, C. Nislow, and G. Giaever Mechanisms of Haploinsufficiency Revealed by Genome-Wide Profiling in Yeast Genetics, April 1, 2005; 169(4): 1915 - 1925. [Abstract] [Full Text] [PDF]

				A. Aggarwal, S. H. Leong, C. Lee, O. L. Kon, and P. Tan Wavelet Transformations of Tumor Expression Profiles Reveals a Pervasive Genome-Wide Imprinting of Aneuploidy on the Cancer Transcriptome Cancer Res., January 1, 2005; 65(1): 186 - 194. [Abstract] [Full Text] [PDF]

				H. C. Bagheri and G. P. Wagner Evolution of Dominance in Metabolic Pathways Genetics, November 1, 2004; 168(3): 1713 - 1735. [Abstract] [Full Text] [PDF]

				B. Fernandez, A. Garcia-Dorado, and A. Caballero Analysis of the Estimators of the Average Coefficient of Dominance of Deleterious Mutations Genetics, October 1, 2004; 168(2): 1053 - 1069. [Abstract] [Full Text] [PDF]

				S. Williamson, A. Fledel-Alon, and C. D. Bustamante Population Genetics of Polymorphism and Divergence for Diploid Selection Models With Arbitrary Dominance Genetics, September 1, 2004; 168(1): 463 - 475. [Abstract] [Full Text] [PDF]

				R. A. Veitia Gene Dosage Balance in Cellular Pathways: Implications for Dominance and Gene Duplicability Genetics, September 1, 2004; 168(1): 569 - 574. [Full Text] [PDF]

				D. Gianola and D. Sorensen Quantitative Genetic Models for Describing Simultaneous and Recursive Relationships Between Phenotypes Genetics, July 1, 2004; 167(3): 1407 - 1424. [Abstract] [Full Text] [PDF]

				F. Roux, J. Gasquez, and X. Reboud The Dominance of the Herbicide Resistance Cost in Several Arabidopsis thaliana Mutant Lines Genetics, January 1, 2004; 166(1): 449 - 460. [Abstract] [Full Text] [PDF]

				X.-S. Zhang, J. Wang, and W. G. Hill Influence of Dominance, Leptokurtosis and Pleiotropy of Deleterious Mutations on Quantitative Genetic Variation at Mutation-Selection Balance Genetics, January 1, 2004; 166(1): 597 - 610. [Abstract] [Full Text] [PDF]

				B. Walsh and D. Henderson Microarrays and beyond: What potential do current and future genomics tools have for breeders? J Anim Sci, January 1, 2004; 82(13_suppl): E292 - 299. [Abstract] [Full Text] [PDF]

				K. L. Montooth, J. H. Marden, and A. G. Clark Mapping Determinants of Variation in Energy Metabolism, Respiration and Flight in Drosophila Genetics, October 1, 2003; 165(2): 623 - 635. [Abstract] [Full Text] [PDF]

				H.-W. Deng, G. Gao, and J.-L. Li Estimation of Deleterious Genomic Mutation Parameters in Natural Populations by Accounting for Variable Mutation Effects Across Loci Genetics, November 1, 2002; 162(3): 1487 - 1500. [Abstract] [Full Text] [PDF]

				V. Ramensky, P. Bork, and S. Sunyaev Human non-synonymous SNPs: server and survey Nucleic Acids Res., September 1, 2002; 30(17): 3894 - 3900. [Abstract] [Full Text] [PDF]

				M. Lunzer, A. Natarajan, D. E. Dykhuizen, and A. M. Dean Enzyme Kinetics, Substitutable Resources and Competition: From Biochemistry to Frequency-Dependent Selection in lac Genetics, September 1, 2002; 162(1): 485 - 499. [Abstract] [Full Text] [PDF]

				M. L. Siegal and A. Bergman Waddington's canalization revisited: Developmental stability and evolution PNAS, August 6, 2002; 99(16): 10528 - 10532. [Abstract] [Full Text] [PDF]

				B. C. Verrelli and W. F. Eanes The Functional Impact of Pgm Amino Acid Polymorphism on Glycogen Content in Drosophila melanogaster Genetics, September 1, 2001; 159(1): 201 - 210. [Abstract] [Full Text] [PDF]

				M. A. Gilchrist and H. F. Nijhout Nonlinear Developmental Processes as Sources of Dominance Genetics, September 1, 2001; 159(1): 423 - 432. [Abstract] [Full Text] [PDF]

				B. Bost, D. de Vienne, F. Hospital, L. Moreau, and C. Dillmann Genetic and Nongenetic Bases for the L-Shaped Distribution of Quantitative Trait Loci Effects Genetics, April 1, 2001; 157(4): 1773 - 1787. [Abstract] [Full Text]

				J. L. Hartman IV, B. Garvik, and L. Hartwell Principles for the Buffering of Genetic Variation Science, February 9, 2001; 291(5506): 1001 - 1004. [Abstract] [Full Text] [PDF]

				J. R. Chasnov Mutation-Selection Balance, Dominance and the Maintenance of Sex Genetics, November 1, 2000; 156(3): 1419 - 1425. [Abstract] [Full Text]

				E. Zimmerman, A. Palsson, and G. Gibson Quantitative Trait Loci Affecting Components of Wing Shape in Drosophila melanogaster Genetics, June 1, 2000; 155(2): 671 - 683. [Abstract] [Full Text]

				S. W. Omholt, E. Plahte, L. Øyehaug, and K. Xiang Gene Regulatory Networks Generating the Phenomena of Additivity, Dominance and Epistasis Genetics, June 1, 2000; 155(2): 969 - 980. [Abstract] [Full Text]

				N. de la Iglesia, M. Mukhtar, J. Seoane, J. J. Guinovart, and L. Agius The Role of the Regulatory Protein of Glucokinase in the Glucose Sensory Mechanism of the Hepatocyte J. Biol. Chem., March 31, 2000; 275(14): 10597 - 10603. [Abstract] [Full Text] [PDF]

				M. P. Reynolds, M. van Ginkel, and J.-M. Ribaut Avenues for genetic modification of radiation use efficiency in wheat J. Exp. Bot., February 1, 2000; 51(90001): 459 - 473. [Abstract] [Full Text]

				R. J. E. Anderson and H. G. Spencer Population Models of Genomic Imprinting. I. Differential Viability in the Sexes and the Analogy With Genetic Dominance Genetics, December 1, 1999; 153(4): 1949 - 1958. [Abstract] [Full Text]

				B. Bost, C. Dillmann, and D. de Vienne Fluxes and Metabolic Pools as Model Traits for Quantitative Genetics. I. The L-Shaped Distribution of Gene Effects Genetics, December 1, 1999; 153(4): 2001 - 2012. [Abstract] [Full Text]

				W. Xu, A. Orr-Urtreger, F. Nigro, S. Gelber, C. B. Sutcliffe, D. Armstrong, J. W. Patrick, L. W. Role, A. L. Beaudet, and M. De Biasi Multiorgan Autonomic Dysfunction in Mice Lacking the beta 2 and the beta 4 Subunits of Neuronal Nicotinic Acetylcholine Receptors J. Neurosci., November 1, 1999; 19(21): 9298 - 9305. [Abstract] [Full Text] [PDF]

				L. Ye, A. L. Kruckeberg, J. A. Berden, and K. van Dam Growth and Glucose Repression Are Controlled by Glucose Transport in Saccharomyces cerevisiae Cells Containing Only One Glucose Transporter J. Bacteriol., August 1, 1999; 181(15): 4673 - 4675. [Abstract] [Full Text]

				J.-L. Li, J. Li, and H.-W. Deng The Effect of Overdominance on Characterizing Deleterious Mutations in Large Natural Populations Genetics, February 1, 1999; 151(2): 895 - 913. [Abstract] [Full Text]

				R. Korona Unpredictable Fitness Transitions Between Haploid and Diploid Strains of the Genetically Loaded Yeast Saccharomyces cerevisiae Genetics, January 1, 1999; 151(1): 77 - 85. [Abstract] [Full Text]

				P. Duesberg, C. Rausch, D. Rasnick, and R. Hehlmann Genetic instability of cancer cells is proportional to their degree of aneuploidy PNAS, November 10, 1998; 95(23): 13692 - 13697. [Abstract] [Full Text] [PDF]

				H.-W. Deng Characterization of Deleterious Mutations in Outcrossing Populations Genetics, October 1, 1998; 150(2): 945 - 956. [Abstract] [Full Text]

				J. Wang, A. Caballero, P. D. Keightley, and W. G. Hill Bottleneck Effect on Genetic Variance: A Theoretical Investigation of the Role of Dominance Genetics, September 1, 1998; 150(1): 435 - 447. [Abstract] [Full Text]

				T. Mitchell-Olds and D. Pedersen The Molecular Basis of Quantitative Genetic Variation in Central and Secondary Metabolism in Arabidopsis Genetics, June 1, 1998; 149(2): 739 - 747. [Abstract] [Full Text] [PDF]

				E. Grotewold, M. Chamberlin, M. Snook, B. Siame, L. Butler, J. Swenson, S. Maddock, G. St. Clair, and B. Bowen Engineering Secondar y Metabolism in Maize Cells by Ectopic Expression of Transcription Factors PLANT CELL, May 1, 1998; 10(5): 721 - 740. [Abstract] [Full Text] [PDF]

				H.-W. Deng Estimating Within-Locus Nonadditive Coefficient and Discriminating Dominance Versus Overdominance as the Genetic Cause of Heterosis Genetics, April 1, 1998; 148(4): 2003 - 2014. [Abstract] [Full Text] [PDF]

				L DiMichele, K. Paynter, and D. Powers Evidence of lactate dehydrogenase-B allozyme effects in the teleost, Fundulus heteroclitus Science, August 23, 1991; 253(5022): 898 - 900. [Abstract] [PDF]

				R. Li, A. Sonik, R. Stindl, D. Rasnick, and P. Duesberg Aneuploidy vs. gene mutation hypothesis of cancer: Recent study claims mutation but is found to support aneuploidy PNAS, March 28, 2000; 97(7): 3236 - 3241. [Abstract] [Full Text] [PDF]