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Figure 1 A segment of a model metabolic pathway. This diagram shows those features, discussed in the text, that permit a systemic analysis of the response of any variable of a metabolic system (e.g. a flux J or the concentration of any intracellular metabolite S) to changes in any one parameter of the system (e.g. an enzyme activity). Each S is an intracellular metabolite; each X is an extracellular metabolite. In a diploid cell, every E stands for a pair of enzymes (allozymes), each specified by one of the two alleles at a gene locus. Each E is then a locus of catalytic activity within a system of enzymes; each v stands for the individual reaction rates catalysed jointly by a pair of allozymes in a diploid cell. Either or both allozymes at such a locus may be mutated.
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Figure 2 Accounting for Mendel's observation of a 3(dominant):1(recessive) trait ratio in his F2 populations of plants. Mendel's notations for a dominant trait, a hybrid and a recessive trait were (A), (Aa) and (a) respectively. For reasons given in the preceding paper [1], a hybrid trait is represented in Figure 2 by (H). The molecular components of all traits are synthesised by a metabolic pathway. When the activity of any one enzyme in a metabolic pathway is changed in discrete steps, the flux to a trait component responds in non-linear (non-additive) fashion [3]. If the flux response is quasi-hyperbolic, as shown here, the hybrid trait (H) will be indistinguishable from the trait (A) expressed in the wild-type cell or organism, even when the enzyme activity in the hybrid (H) has been reduced to 50% of the wild-type activity. Trait (a), will be distinguishable from both traits (A) and (H) only if the enzyme activity is further reduced to a sufficient extent. Under these circumstances the trait series (A + 2H + a) becomes (3A + a); Mendel's 3(dominant):1(recessive) trait ratio is accounted for without introducing arbitrary and inconsistent arguments [1].
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Figure 3 Mendel's 3(dominant):1(recessive) trait ratio does not always occur. Mendel's notation for a dominant trait, a hybrid and a recessive trait were (B), (Bb) and (b) respectively. For reasons given in the preceding paper [1], the hybrid is represented in Figure 3 by (H). When graded changes are made in any one enzyme in a metabolic pathway the response of the flux through that pathway is always non-linear (non-additive) but not always quasi-hyperbolic (Figure 2). Consequently when the enzyme activity at one metabolic locus is decreased in the heterozygote to (say) 50% of wild-type, the trait displayed by the hybrid (H) is now distinguishable from the trait (B) displayed by the wild type cell or organism and from the trait (b) displayed by the homozygously mutant cell or organism. Mendel's 3(dominant):1(recessive trait ratio will not be observed. The explanation is consistent with the explanation for the observation of the 3:1 trait ratio in Figure 2 and achieves what the currently favoured explanation of Mendel's observations cannot achieve [1].
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Figure 4 Accounting for the occurrence of pleiotropy. One unbranched pathway is coupled to another by a conserved metabolite pair p and q. Such coupling is not uncommon in cellular systems and is one source of pleiotropy. Mutation of any one enzyme in one pathway will affect both fluxes (Ja and Jb) to a trait component and the concentrations of those trait components. See also Figure 5. Figure 4, like Figure 1, illustrates the need to adopt a systemic approach in attempts to understand the responses of a metabolising system to changes in any enzyme activity brought about by mutation.
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Figure 5 Accounting for the occurrence of pleiotropy and epistasis. Mutation of any one of enzymes E2, E3, E4 would affect both fluxes Ja and Jb to separate trait components. Mutation of any one of enzymes E5a, E6a, etc would decrease flux Ja to a trait component but increase Jb to another trait component; the concentrations of trait components in pathway Ja would decrease, those in pathway Jb would increase. Epistasis would occur if a subsequent mutation occurred in any one of enzymes E5b, E6b etc. A branched metabolic pathway is thus a potential source of pleiotropy and epistasis; see the text for further discussion. This diagram, like that in Figure 4, emphasises the importance of adopting a systemic approach in understanding the potential effect, on a trait or traits, of a mutation in any one enzyme in enzyme-catalysed systems.
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Figure 6 Biochemistry and genetics merged thirty years ago. The symbol 
indicates the catalysed translocation of an extracellular substrate or substrates (X3) and the subsequent intracellular catalysed transformations, including scavenging pathways, that form nucleoside triphosphate (NTP) precursors for the transcription process. Similarly, 
indicates the catalysed translocation of the extracellular substrates (X2) and the subsequent synthesis from (X2), and other intracellular substrates, of the amino acid (AA) precursors for the translation process. The enzymes subsumed as ETs and ETl are involved in the final stages of the expression (transcription and translation) of genes g1, g2, g3, g4 - - etc as polypeptides (P1, P2, P3, P4 - - etc). In diploid cells a pair of proteins will be synthesised from each pair of alleles at a gene locus. Those pairs of polypeptides (proteins) that are catalytically active in a diploid cell are represented by the single symbols E1, E2, E3, E4 - - - etc in this Figure 6. Further details are given in Section 5.5.
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