Analysis of a rare variant of mitotic gene TAO3 reveals its meiotic interactors

Genome-wide association studies have successfully identified thousands of common variants associated with complex traits and diseases. If only common variants are considered, a significant proportion of heritability in common diseases remains unexplained. One of the sources considered to explain this missing heritability are the rare genetic variants. Studying the consequences of rare genetic alterations offers additional opportunity for predicting molecular mediators underlying pathway deregulation. Here, we characterized the functional role of a rare variant having a significant contribution in sporulation efficiency variation. This causal variant is present in the coding sequence of TAO3, encoding a putative scaffolding protein conserved from yeast to humans and component of RAM network in yeast involved in mitosis. We observed that the role of TAO3 allele on meiosis is independent of ACE2, a transcription factor regulated by RAM network during mitosis. By expressing TAO3 causal allele conditionally during sporulation and quantitatively measuring cell cycle progression, we determined its role within the first 6 hours in meiosis, which coincides with cells entering into meiotic cell division. Time-resolved genome-wide gene expression analysis identified genes showing early and increasing expression trend during sporulation to be target genes of UME6, a crucial meiotic regulator. Genes regulating UME6, and other target genes expressed early, specifically, in the presence of causal TAO3, were chosen as candidate genes. Allele-specific functional validations identified ERT1 (regulator of switch from fermentation to respiration) and PIP2, (regulator involved in beta-oxidation of fatty acids) as the mediating genes associated with TAO3 causal allele and responsible for sporulation efficiency variation. Our study uncovered interesting link between TAO3 and regulators of metabolic cues that modulate the switch between multiple developmental phenotypes, viz. mitosis to meiosis. Although a small proportion in a population might contain rare variants, identification of novel regulators of sporulation from our study highlighted the significance of studying rare genetic variants to obtain novel insights into the phenotype and disease biology.