Exploring the role of aneuploidy in phenotypic variability

Abstract

Phenotypic variability is a noted feature of human trisomies. This is exemplified by the presentation of trisomy 21 (Down syndrome). The incidence of and severity of clinical features are highly variable in individuals with Down syndrome. These differences have long been attributed to genetic differences within the population altering the likelihood that particular phenotypes will develop. However, work in yeast and mouse models of aneuploidy suggest that phenotypic variability can be a consequence of aneuploidy itself in the absence of genetic heterogeneity.

By studying variability in induction of the GAL1-10 promoter in aneuploid strains of budding yeast, S. cerevisiae, we show that altering gene dosage can lead to variability. The endocytosis defect caused by a specific aneuploidy (Disome IX) is sufficient to increase variability in the GAL signaling pathway. The addition of a second copy of chromosome IX in haploid yeast increases the dosage of multiple genes involved in endocytosis. This leads to an endocytic defect that impacts the cell surface localization of hexose transporters, which ultimately leads to variability in uptake of hexose sugars and thus variability in induction of the GAL1-10 promoter.