Exploring the molecular etiology of dominant-negative mutations.

Herskowitz (1987) provided the classical definition of dominantnegative (DN) mutations as those leading to mutant polypeptides that disrupt the activity of the wild-type gene when overexpressed. Although Herskowitz’ definition referred basically to intralocus interactions, it is now recognized that interlocus (e.g., trans-acting) interactions can also lead to dominance (Omholt et al., 2000) and to DN effects (DNEs; Veitia 2002). DNEs are thought to have an impact on plant genome evolution. Indeed, Gibson and Spring (1998) have suggested that paralogous genes encoding multidomain proteins might be overretained in polyploids because mutations in such genes could produce DN phenotypes. From a practical viewpoint, DN mutations have been widely used to study gene function in plants, for example, in situations where null mutations of functionally redundant genes result in no phenotype. Here, I explore the mechanistic foundations for DNEs and some of their quantitative aspects to describe the general features of their effects at the molecular level, improved understanding of which should help in the design of DN proteins. Students are accustomed to simplified concepts of dominance and recessivity. These extreme terms stem from the analysis of qualitative characters for which only a few states are scored. More quantitative studies of the phenotypic effects of a mutation have led to proposals for a more exhaustive classification (Müller, 1932). The terms amorph, hypomorph, and hypermorph have been applied to alleles (and gene products) displaying no activity, lower, or higher activity than the wildtype allele, respectively. As noted above, an important source of dominant phenotypes is the production of a mutant protein that interferes with the action of the wild-type one, and alleles producing these DNEs are called antimorphs. The effects of strong antimorphs, such as those reviewed by Herskowitz (1987), can be easily understood. However, the quantitative dimensions of more complex DNEs require further examination in the era of high-throughput genetics and genomics.