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Perspectives Copyright 0 1996 by the Genetics Society of America Perspectives Anecdotal, Historical and Critical Commentaries on Genetics Edited by James F. Crow and William F. Dove A Metabolic Basis for Dominance and Recessivity Peter D. Keightley Institute of Cell, Animal and Population Biology, Univmity of Edinburgh, Edinburgh, Scotland HE reasons for the existence of genetic dominance toward understanding the consequences of changes of T have provoked muchdebate in theliterature, enzyme activity on properties of metabolism. starting with FISHER’S (1928) paper on apossible evolu- Evolutionaryand physiological explanationsfor dom- tionary explanation for dominance.Any theory for the inance: FISHER(1928) proposed a general explanation basis of dominance and recessivity, whether evolution- for dominance based on selection ofalleles that in- ary or physiological, should explain three patterns in crease dominance of the wild type. FISHERnoted that dominance relationships of the diploid phenotypes. heterozygotes far outnumber mutant homozygotes, so The first is MENDEL’S observation that the heterozygote the selection pressure acting on heterozygotes to is often indistinguishable in phenotype fromone orthe change thephenotype toward wild type wouldbe much other of the homozygotes, and we now know that in stronger than that acting on homozygotes. He argued the vast majority of casesthe wild type isdominant over that an intermediate phenotype for heterozygotes must the mutant. Second, in the few cases where measure- have been the “original”state for new mutations in the ment of degrees of dominance for mutations of small history of a species and concluded thatan evolutionary phenotypic effect has been carried out, it appears that explanation for dominance of the wild type was neces- the heterozygote phenotype is on average closeto inter- sary. In reaching this conclusion, FISHERseems to have mediate (CROWand SIMMONS1983). Third, there are been particularly impressed by the pattern found for several interesting series of mutations at the same locus series of mutant alleles at the same locus in which het- that produce differentphenotypes, e.g., the albino series erozygotes between the mutants produce intermediate of mutants in rodents. In such cases, heterozygotes be- phenotypes, while dominance of the wild type is typical. tween “lower” mutant alleles of the series are usually WRIGHT(1934) challenged FISHER’S theory of the intermediate in phenotype, whereas the wildtype is evolution of dominance by selection at modifier loci by usually dominant over all of them. showing that the selection coefficients of dominance- In 1981 H. KACSER and J. A. BURNSpublished in GE- modifier alleles would be extremely small, of the order NETICS an explanation for dominancebased on proper- of the mutation rate, and selection would be swamped ties of metabolic systems that can account for each of by the random process of mutation. WRIGHTput for- the above phenomena. They showed that dominance ward an alternative explanation for the general preva- of the wild type over null alleles is an ineuitabb conse- lence of recessivity, but also emphasized thatthere quence of the kinetic properties of metabolic systems, would need to be different explanations in different and their theory has become widely accepted as the cases. He envisaged a“chain of processes” linking explanation of dominance of the wildtype over the genes with phenotypes and placed particular emphasis mutant for themajority of cases. Sadly, HENRIKKACSER on enzymes whoseimportance in intermediary metabo- died on March 13,1995, ending his scientific career lism had become known. WRIGHTconsidered the rela- which for more than40 years was focused on thekinetic tionship between the activity of one enzyme in a meta- properties of living systems. I first met HENRIKin 1981 bolic pathway and the steady-state rate of production as an undergraduate student and can well recall his of the product of the pathway (the pathway flux). The great satisfaction at having published this paper. Al- pathway consisted of a chain of nearly irreversible mo- though some of the basic ideas concerning dominance nomolecular transformations in which the rate of each in metabolic systems appeared much earlier (KACSER step was proportional to the product of enzyme activity 1963), the 1981 paper with BURNSwas the culmination and substrate concentration. Because the product of of years ofexperimental and theoretical effort directed one step was the substrate for the next, the effect of changing one enzyme’s activitydepended on theactivi- Author e-mail: [email protected] ties of all the others. WRIGHTpredicted a hyperbolic Genetics 143 621-625 (June, 1996) 622 P. D. Keightley a background inphysics to take a post in the Epigenetics ."""""."""" Research Group in 1962, and went on to do a Ph.D. with KACSER. He studied the relationship between phe- 0.8 I"' / notype and genotype in multienzyme systems, and be- gan by setting up model metabolic systems on an analog computer. BURNSsoon noted that increases of one en- zyme's activity often producedlittle effect on a pathway flux, and this led naturally to the ideaof "control coef- ficients" (earlier called sensitivity coefficients), which have analogies in engineering and economics, and were also studied in the contextof control of metabolism by 0.0 HIGGINS (1965).The control coefficient, C, is defined 0.0 0.2 0.4 0.6 0.8 1.0 as the fractional response of a systemic property of a Enzyme activity metabolic system such as a flux (J, to a fractional FIGURE1.-Flux (arbitrary units)as a function of the activ- change in the activity of one enzyme (Et) ity of one enzyme in a pathway of monomolecular reactions with 10 steps catalyzed by unsaturated enzymes with equiva- lent activities. A reduction in the activity of one enzyme by 50% leads to only a 9% reduction in flux. In their landmark 1973 paper, KACSER and BURNSlaid down a logically consistent framework for measuring relationship between enzyme activity and flux. Thus, if the extent to which elements of a metabolic system the wild-type enzyme activityis usually at the plateau of exert control over systemic properties such as fluxes the fluxenzyme curve and the enzyme activity of the or metabolite concentrations. This metabolic control heterozygote is intermediate, null mutants tend to be analysis is having an increasingly important influence recessive (Figure 1). Although WRIGHTdid not agree in biochemistry (reviewed by FELL1992). Terms such with FISHER'Sargument about the evolution of domi- as "rate limiting step," "key enzyme," or "pacemaker nance modifier alleles, he still invoked an evolutionary enzyme" have dogged the logical analysis ofthe control mechanism by arguing that the wild-type activity would of metabolism, and KACSER was energetically against the tend to lie on theplateau of the curve owingto selection use of such terms, as many of his students will remem- for a "safety factor," an argument also used by HAL ber with amusement. KACSER and BURNS'S(1973) analy- DANE (1930). sis of rate control of biological processes was published Development of theory of the control of metabolic almost at thesame time as an analysis of the same prob- processes: KACSER and BURNS' explanation of the un- lem by HEINRICHand RAPOPORT (1974), working in derlying basis for dominance andrecessivity rests upon Berlin. For any metabolic system of any complexity at global properties of complex metabolic systems, which steady state in which the rates of reaction are propor- result in the control of flux being shared among many tional to enzyme concentration and enzymes are param- enzymes, and upon analysis of the behavior of some eters rather thanvariables of the system, the Edinburgh simple model metabolic pathways. KACSER'S ideas for and Berlin groups independently showed that the sum the control of metabolic processes and his kinetic ap- over all enzymes of control coefficients for a flux is proach to biological phenomena came directly from his unity: background in physical chemistry, which he studied at Queen's University, Belfast. He came to the University Cc{=1 of Edinburgh in 1951 to take a Diploma course at the Institute of Animal Genetics. This course was set up The summation property was observed by BURNS,who specifically to attract students into genetics from other was conducting empirical investigations of the kinetic fields. C. H. WADDINGTON,the Professor of Animal Ge- properties of model metabolic systems by solving the netics at the Institute,was particularly keen on aninter- nonlinear equations for thefluxes with an analog com- disciplinary approach to problems in genetics (WAD- puter. It is valid for complex systems involving nonlin- DINGTON 1969) and appointed KACSER to the staff of earities such as saturation and feedback inhibition. The the Institute in 1955. KACSER was very amused to tell summation property constrains the extent to which dif- the story of howhe was appointed to theacademic staff: ferent enzymes control flux. Experiments involving the during a chanceconversation, WADDINGTONasked him individual modulation of the enzymes controlling aflux what he would be doing next, to which KACSER replied have since provided evidence for the validityof the he didn't know. WADDINGTONasked him if he would summation theorem (GROEN et al. 1982; SALTERet al. like a tenured position at the Institute and that, appar- 1986). ently, was that! A metabolic explanationfor dominance andrecessiv- BURNScame to the Institute of Animal Genetics with
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