Meiotic interactors of a mitotic geneTAO3revealed by functional analysis of its rare variant

Abstract

ABSTRACTStudying the molecular consequences of rare genetic variants has the potential of identifying novel and hereto uncharacterized pathways causally contributing to phenotypic variation. Here we characterize the functional consequences of a rare coding variant ofTAO3, previously reported to significantly contribute to sporulation efficiency variation inSaccharomyces cerevisiae. During mitosisTAO3interacts withCBK1, a conserved NDR kinase and a component of RAM network. The RAM network genes are involved in regulation cell separation and polarization. We demonstrate that the role of the rare alleleTAO3(4477C)in meiosis is distinct from its role in mitosis by being independent ofACE2, which is a RAM network target gene. By quantitatively measuring cell morphological dynamics and conditionally expressingTAO3(4477C)allele during sporulation, we show thatTAO3has an early role in meiosis. This early role ofTAO3coincides with entry of cells into meiotic division. Time-resolved transcriptome analyses during early sporulation phase identified regulators of carbon and lipid metabolic pathways as candidate mediators. We experimentally show that during sporulation theTAO3allele genetically interacts withERT1andPIP2, the regulators of tricarboxylic acid cycle and gluconeogenic enzymes, respectively. We thus uncover meiotic functions ofTAO3, a mitotic gene and proposeERT1andPIP2as novel regulators of sporulation efficiency. Our results demonstrate that study of causal effects of genetic variation on the underlying molecular network has the potential to provide more extensive comprehension of the pathways driving a complex trait. This can help identify prospective personalized targets for intervention in complex diseases.