A generalized model of gene dosage and dominant negative effects in macromolecular complexes

Most genes and their corresponding products are supposed to be involved in genetic or biochemical interactions. A typical example is provided by macromolecular complexes, which may contain tens of proteins in defined stoichiometric proportions. Stoichiometric imbalances in such complexes can be a source of abnormal phenotypes. Comparable effects can also arise from negative dominance/transdominance, even though the underlying mechanisms are different. Here I propose a general yet simple biochemical model accounting for the effects of dosage changes and weak dominant/transdominant negative mutations in macromolecular complexes. The molecular alterations studied are predicted to lead to synergistic effects that can drive total multimer concentration and/or activity in a multiple heterozygote below a critical threshold required to ensure a normal phenotype, thus providing an explanation for the phenomenon of unlinked noncomplementation or nonallelic noncomplementation. The model also helps in understanding the basis of heterosis and the long-term consequences of gene dosage alterations and weak dominant/transdominant negative effects. Indeed, it can explain the observed extensive retention of paralogs in polyploids. Finally, because the effects of weak single-gene alterations can escape selection, they may accumulate in the population. This situation has important evolutionary consequences and may eventually lead to reproductive isolation and speciation.-Veitia, R. A. A generalized model of gene dosage and dominant negative effects in macromolecular complexes.