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J Theor Biol. 2003 Jan 7;220(1):19-25.

Nonlinear effects in macromolecular assembly and dosage sensitivity.

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UFR de Biologie et Sciences de la Nature, Université Denis DIDEROT/Paris VII, Paris, France.


Haploinsufficiency refers to dominant abnormal phenotypes resulting from the absence of substantial activity from one allele at a normally diploid locus. Haploinsufficiency may also result from an altered stoichiometry in a macromolecular complex. Higher-than-diploid levels of a gene product can also induce abnormalities that may even resemble the haploinsufficient phenotype. Here, I explore possible non-linearities in the assembly of multimeric molecules from the perspective of dose effects. I propose that for any oligomer assembly reaction, there may be a set of conditions (initial subunit concentrations and equilibrium constants) such that changing the input concentration of one component (0.5 x or 1.5x) will lead to a minimum and non-proportional change of the final oligomer concentration. This buffer effect is a general property of multimeric systems in equilibrium and can be, in principle, exploited by selection to diminish dosage sensitivity. Other effects involving cooperativity or sequential assembly may also play a role in palliating the effect of changes in input amounts of monomers.

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