The gene balance hypothesis: implications for gene regulation, quantitative traits and evolution

Abstract

The gene balance hypothesis states that the stoichiometry of members of multisubunit complexes affects the function of the whole because of the kinetics and mode of assembly. Gene regulatory mechanisms also would be governed by these principles. Here, we review the impact of this concept with regard to the effects on the genetics of quantitative traits, the fate of duplication of genes following polyploidization events or segmental duplication, the basis of aneuploid syndromes, the constraints on cis and trans variation in gene regulation and the potential involvement in hybrid incompatibilities.

Fig. 1

Effects of over-expression of a dosage sensitive subunit involved in a macromolecular complex. (a) Irreversible assembly of trimer A-B-C allowing intermediate dimers AB and BC. Although not represented in the figure the reactions involved are A+B=AB, B+C=BC, AB+C=ABC and BC+A=ABC. (b) An excess of the molecular bridge B (1.5 X) leads to a decrease in yield of ABC due to the production of intermediates that cannot be completed because of the lack of enough A and C monomers (notice how incomplete dimeric complexes outnumber the normal expected trimers).

Fig. 2

Heuristic example for the explanation of inverse dosage effects produced by a regulatory trimer ABC with variation of subunit B. Consider that trimer assembly is random and irreversible (the reactions are represented within the frame of the graph and are the same as in Fig. 1). The reaction conditions that can lead to the observed inverse dosage effects mentioned in the text are considered. For each mole of monomer of A and C, the trimerization reaction involves three moles of monomer B and that all kinetic constants are the same (unitary for simplicity). This scenario will yield 0.33 moles of ABC (and incomplete subcomplexes). This reaction will produce 100% of ABC. For the same (unitary) amounts of A and C, halving the amount of B (1.5 moles of B) leads to 200% of trimer yield and increasing the relative amount of B (to 4.5 mole) leads to 67% of trimer. Thus, if the trimer acts positively on target genes and B is varied in an aneuploid series, the inverse effect on target loci would result. This simplified view considers that the reacting amounts of A, B and C in steady state. Notice that A, B and C can also be multi-subunit subcomplexes. Such an example does not exclude the possibility that an inverse dosage effect is produced by negatively acting regulators.

Fig. 3

Idealized informational pathway showing how many genes can have an impact on a transcriptional (and phenotypic output). The membrane receptor and its ligand must respect some balance to prevent outright receptor saturation or insufficient stimulation. The receptor, upon binding its ligand, is able to activate the trimeric kinase (which can undergo the very same dosage effects outlined in Figs 1 and 2). This kinase is counteracted by a phosphatase and they must respect some stoichiometric balance as proposed (Veitia, 2004). Their action leads to some degree of phosphorylation of kinase K which in turns activates a transcription factor that will promote transcription of gene X, which is under the combined control of other transcription factors, responding to the same or different transduction cascades.