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Implications of the systemic approach of Kacser and Burns
- A rational treatment of Mendelian genetics

4. Implications of the systemic approach of Kacser and Burns [3]

Figure 2 shows the response of the phenotype to changes in enzyme activity at a metabolic locus or to changes in gene dose at the corresponding gene locus. It follows, if the response plot takes this form, that increasing the dose of this particular gene in a wild-type haploid cell (or the dose of the normal homozygous alleles in a wild-type diploid or polyploid cell) is unlikely to produce a detectable change in the phenotype (e.g. an increase in the concentration of the trait component produced by a metabolic pathway; or a change in cell function associated with that pathway). It was demonstrated that it was necessary, under these circumstances, to increase concurrently the gene dose at each of no fewer than five loci if significant increases in the flux (and in the concentration of metabolic product) was to be achieved [5]. The systemic approach to a rational explanation of the origins of dominant and recessive traits [3] has obvious implications for biotechnologists.

Figure 2 (representing several plots in Reference [3]) also suggests that somatic recessive conditions (in contrast to so-called dominant conditions) could be ameliorated by partial gene replacement therapy. Experiments in the cystic fibrosis mouse model support this suggestion [7]; they show that the systemic approach to the origins of dominant and recessive traits has implications for medical genetics.

It was pointed out (section 2.6) that substantial decreases in the dose of normal alleles at any one locus (or in the enzyme activity at the corresponding metabolic locus) may not elicit detectable changes in the trait(s) of the cell. In other words, given a response plot approximating to that shown in Figure 2, traits – including associated cell functions – are inherently buffered against substantial increases or decreases in the dose of any one gene, or against substantial changes in enzyme activity at the corresponding metabolic locus. This appears to be the probable origin of the so-called "robustness" or buffering of chemotaxis against changes in enzyme kinetic constants [12-15].

This proposed explanation for metabolic buffering is quite general; it does not depend on the particular kinetic mechanisms that have been suggested to account for this buffering [12]; it also suggests that there is no need to postulate the presence of diagnostic "biological circuits" as the source of this buffering of the phenotype against mutations at a single locus.

Attempts to improve the concentration of metabolic products by increasing the gene dose at one locus above that available in the wild-type or normal cell could be successful, at least to some self-limiting extent, if a response plot like Figure 3 applies. Induced synthesis of one membrane-located enzyme activity to between 20% and 600% of wild-type activity illustrates the possibility [8]. In this instance, plots like Figure 3 applied only to changes in the uptake and phosphorylation of α-methyl glucoside; changes in growth rates and glucose oxidation gave response plots like Figure 2. The explanation for the difference may lie in the suggestion [3] that shorter pathways will yield response plots like Figure 3, while the longer the pathway, the more likely is it that markedly asymmetric plots like Figure 2 will be observed.

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