Abstract
The fluxes through metabolic pathways can be considered as model quantitative traits, whose QTL are the polymorphic loci controlling the activity or quantity of the enzymes. Relying on metabolic control theory, we investigated the relationships between the variations of enzyme activity along metabolic pathways and the variations of the flux in a population with biallelic QTL. Two kinds of variations were taken into account, the variation of the average enzyme activity across the loci, and the variation of the activity of each enzyme of the pathway among the individuals of the population. We proposed analytical approximations for the flux mean and variance in the population as well as for the additive and dominance variances of the individual QTL. Monte Carlo simulations based on these approximations showed that an L-shaped distribution of the contributions of individual QTL to the flux variance (R(2)) is consistently expected in an F(2) progeny. This result could partly account for the classically observed L-shaped distribution of QTL effects for quantitative traits. The high correlation we found between R(2) value and flux control coefficients variance suggests that such a distribution is an intrinsic property of metabolic pathways due to the summation property of control coefficients.
Full Text
The Full Text of this article is available as a PDF (221.6 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Albe K. R., Wright B. E. Systems analysis of the tricarboxylic acid cycle in Dictyostelium discoideum. II. Control analysis. J Biol Chem. 1992 Feb 15;267(5):3106–3114. [PubMed] [Google Scholar]
- Beaumont M. A. Stabilizing selection and metabolism. Heredity (Edinb) 1988 Dec;61(Pt 3):433–438. doi: 10.1038/hdy.1988.135. [DOI] [PubMed] [Google Scholar]
- Byrne P. F., McMullen M. D., Snook M. E., Musket T. A., Theuri J. M., Widstrom N. W., Wiseman B. R., Coe E. H. Quantitative trait loci and metabolic pathways: genetic control of the concentration of maysin, a corn earworm resistance factor, in maize silks. Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):8820–8825. doi: 10.1073/pnas.93.17.8820. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cascante M., Canela E. I., Franco R. Control analysis of systems having two steps catalyzed by the same protein molecule in unbranched chains. Eur J Biochem. 1990 Sep 11;192(2):369–371. doi: 10.1111/j.1432-1033.1990.tb19236.x. [DOI] [PubMed] [Google Scholar]
- Clark A. G., Keith L. E. Variation among extracted lines of Drosophila melanogaster in triacylglycerol and carbohydrate storage. Genetics. 1988 Jul;119(3):595–607. doi: 10.1093/genetics/119.3.595. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Clark A. G. Mutation-selection balance and metabolic control theory. Genetics. 1991 Nov;129(3):909–923. doi: 10.1093/genetics/129.3.909. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Clark A. G., Wang L. Epistasis in measured genotypes: Drosophila P-element insertions. Genetics. 1997 Sep;147(1):157–163. doi: 10.1093/genetics/147.1.157. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Corder E. H., Saunders A. M., Strittmatter W. J., Schmechel D. E., Gaskell P. C., Small G. W., Roses A. D., Haines J. L., Pericak-Vance M. A. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993 Aug 13;261(5123):921–923. doi: 10.1126/science.8346443. [DOI] [PubMed] [Google Scholar]
- Damerval C., Maurice A., Josse J. M., de Vienne D. Quantitative trait loci underlying gene product variation: a novel perspective for analyzing regulation of genome expression. Genetics. 1994 May;137(1):289–301. doi: 10.1093/genetics/137.1.289. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Deng A. Y., Rapp J. P. Locus for the inducible, but not a constitutive, nitric oxide synthase cosegregates with blood pressure in the Dahl salt-sensitive rat. J Clin Invest. 1995 May;95(5):2170–2177. doi: 10.1172/JCI117906. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Doebley J., Stec A. Inheritance of the morphological differences between maize and teosinte: comparison of results for two F2 populations. Genetics. 1993 Jun;134(2):559–570. doi: 10.1093/genetics/134.2.559. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dykhuizen D. E., Dean A. M., Hartl D. L. Metabolic flux and fitness. Genetics. 1987 Jan;115(1):25–31. doi: 10.1093/genetics/115.1.25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Edwards M. D., Stuber C. W., Wendel J. F. Molecular-marker-facilitated investigations of quantitative-trait loci in maize. I. Numbers, genomic distribution and types of gene action. Genetics. 1987 May;116(1):113–125. doi: 10.1093/genetics/116.1.113. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fatokun C. A., Menancio-Hautea D. I., Danesh D., Young N. D. Evidence for orthologous seed weight genes in cowpea and mung bean based on RFLP mapping. Genetics. 1992 Nov;132(3):841–846. doi: 10.1093/genetics/132.3.841. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Groen A. K., van Roermund C. W., Vervoorn R. C., Tager J. M. Control of gluconeogenesis in rat liver cells. Flux control coefficients of the enzymes in the gluconeogenic pathway in the absence and presence of glucagon. Biochem J. 1986 Jul 15;237(2):379–389. doi: 10.1042/bj2370379. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hartl D. L., Dykhuizen D. E., Dean A. M. Limits of adaptation: the evolution of selective neutrality. Genetics. 1985 Nov;111(3):655–674. doi: 10.1093/genetics/111.3.655. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hofmeyr J. H., Kacser H., van der Merwe K. J. Metabolic control analysis of moiety-conserved cycles. Eur J Biochem. 1986 Mar 17;155(3):631–641. doi: 10.1111/j.1432-1033.1986.tb09534.x. [DOI] [PubMed] [Google Scholar]
- Jeunemaitre X., Soubrier F., Kotelevtsev Y. V., Lifton R. P., Williams C. S., Charru A., Hunt S. C., Hopkins P. N., Williams R. R., Lalouel J. M. Molecular basis of human hypertension: role of angiotensinogen. Cell. 1992 Oct 2;71(1):169–180. doi: 10.1016/0092-8674(92)90275-h. [DOI] [PubMed] [Google Scholar]
- Kacser H., Burns J. A. The molecular basis of dominance. Genetics. 1981 Mar-Apr;97(3-4):639–666. doi: 10.1093/genetics/97.3-4.639. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Keightley P. D. Metabolic models of selection response. J Theor Biol. 1996 Oct 7;182(3):311–316. doi: 10.1006/jtbi.1996.0169. [DOI] [PubMed] [Google Scholar]
- Keightley P. D. Models of quantitative variation of flux in metabolic pathways. Genetics. 1989 Apr;121(4):869–876. doi: 10.1093/genetics/121.4.869. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kojima K. ROLE OF EPISTASIS AND OVERDOMINANCE IN STABILITY OF EQUILIBRIA WITH SELECTION. Proc Natl Acad Sci U S A. 1959 Jul;45(7):984–989. doi: 10.1073/pnas.45.7.984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Laurie-Ahlberg C. C., Wilton A. N., Curtsinger J. W., Emigh T. H. Naturally occurring enzyme activity variation in Drosophila melanogaster. I. Sources of variation for 23 enzymes. Genetics. 1982 Oct;102(2):191–206. doi: 10.1093/genetics/102.2.191. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mackay T. F. The nature of quantitative genetic variation revisited: lessons from Drosophila bristles. Bioessays. 1996 Feb;18(2):113–121. doi: 10.1002/bies.950180207. [DOI] [PubMed] [Google Scholar]
- Mitchell-Olds T., Pedersen D. The molecular basis of quantitative genetic variation in central and secondary metabolism in Arabidopsis. Genetics. 1998 Jun;149(2):739–747. doi: 10.1093/genetics/149.2.739. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Paterson A. H., Damon S., Hewitt J. D., Zamir D., Rabinowitch H. D., Lincoln S. E., Lander E. S., Tanksley S. D. Mendelian factors underlying quantitative traits in tomato: comparison across species, generations, and environments. Genetics. 1991 Jan;127(1):181–197. doi: 10.1093/genetics/127.1.181. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schächter F., Faure-Delanef L., Guénot F., Rouger H., Froguel P., Lesueur-Ginot L., Cohen D. Genetic associations with human longevity at the APOE and ACE loci. Nat Genet. 1994 Jan;6(1):29–32. doi: 10.1038/ng0194-29. [DOI] [PubMed] [Google Scholar]
- Szathmáry E. Do deleterious mutations act synergistically? Metabolic control theory provides a partial answer. Genetics. 1993 Jan;133(1):127–132. doi: 10.1093/genetics/133.1.127. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thomson G. HLA disease associations: models for insulin dependent diabetes mellitus and the study of complex human genetic disorders. Annu Rev Genet. 1988;22:31–50. doi: 10.1146/annurev.ge.22.120188.000335. [DOI] [PubMed] [Google Scholar]
- Ward P. J. The inheritance of metabolic flux: expressions for the within-sibship mean and variance given the parental genotypes. Genetics. 1990 Jul;125(3):655–667. doi: 10.1093/genetics/125.3.655. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wright S. Postnatal Changes in the Intensity of Coat Color in Diverse Genotypes of the Guinea Pig. Genetics. 1960 Nov;45(11):1503–1529. doi: 10.1093/genetics/45.11.1503. [DOI] [PMC free article] [PubMed] [Google Scholar]