Meiotic Interactors of a Mitotic Gene TAO3 Revealed by Functional Analysis of its Rare Variant.
Studying the molecular consequences of rare genetic variants has the potential to identify novel and hitherto uncharacterized pathways causally contributing to phenotypic variation. Here, we characterize the functional consequences of a rare coding variant of TAO3, previously reported to contribute significantly to sporulation efficiency variation in Saccharomyces cerevisiae During mitosis, the common TAO3 allele interacts with CBK1-a conserved NDR kinase. Both TAO3 and CBK1 are components of the RAM signaling network that regulates cell separation and polarization during mitosis. We demonstrate that the role of the rare allele TAO3(4477C) in meiosis is distinct from its role in mitosis by being independent of ACE2-a RAM network target gene. By quantitatively measuring cell morphological dynamics, and expressing the TAO3(4477C) allele conditionally during sporulation, we show that TAO3 has an early role in meiosis. This early role of TAO3 coincides with entry of cells into meiotic division. Time-resolved transcriptome analyses during early sporulation identified regulators of carbon and lipid metabolic pathways as candidate mediators. We show experimentally that, during sporulation, the TAO3(4477C) allele interacts genetically with ERT1 and PIP2, regulators of the tricarboxylic acid cycle and gluconeogenesis metabolic pathways, respectively. We thus uncover a meiotic functional role for TAO3, and identify ERT1 and PIP2 as novel regulators of sporulation efficiency. Our results demonstrate that studying the causal effects of genetic variation on the underlying molecular network has the potential to provide a more extensive understanding of the pathways driving a complex trait.
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
Saumya
0000-0001-7703-918X
S
Gupta
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
Aparna
A
Radhakrishnan
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
Rachana
R
Nitin
Gene Center, Ludwig-Maximilians-Universität, 81377 Munich, Germany.
Pandu
P
Raharja-Liu
Genome Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
Gen
G
Lin
Genome Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany Department of Genetics, School of Medicine, Stanford University, California 94305 Stanford Genome Technology Center, Stanford University, Palo Alto, California 94304.
Lars M
0000-0002-3962-2865
LM
Steinmetz
Gene Center, Ludwig-Maximilians-Universität, 81377 Munich, Germany Department of Informatics, Technische Universität München, 85748 Garching, Germany.
Julien
0000-0002-8924-8365
J
Gagneur
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India Initiative for Biological Systems Engineering, Indian Institute of Technology Madras, Chennai 600036, India sinha@iitm.ac.in.
Himanshu
0000-0001-7031-0491
H
Sinha
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000483:Alleles; D016764:Cell Polarity / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D015966:Gene Expression Regulation, Fungal; D014644:Genetic Variation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008540:Meiosis / Q000235:genetics*; D008938:Mitosis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D015398:Signal Transduction; D013172:Spores, Fungal / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
C066778:ACE2 protein, S cerevisiae; D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C000598641:Ert1 protein, S cerevisiae; D047908:Intracellular Signaling Peptides and Proteins; C100530:PIP2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C456842:TAO3 protein, S cerevisiae; D014157:Transcription Factors; C423362:CBK1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases
TAO3; allelic variant; meiosis; rare variant; transcriptome profiling