About

Dr. C. Joel McManus completed a B.A. in Chemistry at Hiram College and earned a Ph.D. in Biomolecular Chemistry from the University of Wisconsin-Madison, working with Dr. David A. Brow on pre-mRNA splicing mechanisms. Following post-doctoral training with Dr. Brenton Graveley at the University of Connecticut Health Center, he started an independent research group. His lab employs a combination of experimental and computational approaches to study the roles of mRNA sequences and structures in regulating protein synthesis in human genes and fungal pathogens. His research focuses on understanding translation regulation, upstream open reading frames (uORFs), and the molecular mechanisms underlying gene expression, with particular interest in fungal pathogens and human genetic diseases such as Prader-Willi syndrome.

Research topics

• Genetics
• Biology
• Computational biology
• Microbiology
• Cell biology

Selected publications

• Unraveling the influences of sequence and position on yeast uORF activity using massively parallel reporter systems and machine learning

  eLife · 2023 · 39 citations

  Senior authorCorresponding
  • Biology
  • Genetics
  • Computational biology

  yeast. While nearly all AUG uORFs were robust repressors, most non-AUG uORFs had relatively weak impacts on expression. Machine learning regression modeling revealed that both uORF sequences and locations within transcript leaders predict their effect on gene expression. Indeed, alternative transcription start sites highly influenced uORF activity. These results define the scope of natural uORF activity, identify features associated with translational repression and NMD, and suggest that the locations of uORFs in transcript leaders are nearly as predictive as uORF sequences.

  PublisherDOI

• False-positive IRESes from <i>Hoxa9</i> and other genes resulting from errors in mammalian 5′ UTR annotations

  Proceedings of the National Academy of Sciences · 2022 · 35 citations

  Senior authorCorresponding
  • Biology
  • Genetics
  • Computational biology

  gene IRESes. Moreover, we provide evidence that the vast majority of hTLs with putative IRES activity overlap transcriptional promoters, enhancers, and 3' splice sites that are most likely responsible for their reported IRES activities. These results argue strongly against recently reported widespread IRES-like activities from hTLs and contradict proposed interactions between ribosomal expansion segment ES9S and putative IRESes. Furthermore, our work underscores the importance of accurate transcript annotations, controls in bicistronic reporter assays, and the power of synthesizing publicly available data from multiple sources.

  DOI

• Collaboration between Antagonistic Cell Type Regulators Governs Natural Variation in the Candida albicans Biofilm and Hyphal Gene Expression Network

  mBio · 2022 · 30 citations

  • Biology
  • Microbiology
  • Genetics

  Clinical isolates of all pathogens vary in the strength of traits linked to disease. In this study, we focused on variation in a pathogenicity trait of the fungal pathogen Candida albicans, biofilm formation. This trait is under the control of the cell type regulator Efg1. Expression of Efg1 is known from previous studies to be repressed by a second cell type regulator, Wor1. However, we found that natural variation in biofilm formation and biofilm-related gene expression was driven by collaboration between Efg1 and Wor1. Our findings show that analysis of natural isolates can reveal unexpected features of gene function, even for well-studied genes.

  DOI

• Roles of Candida albicans Mig1 and Mig2 in glucose repression, pathogenicity traits, and SNF1 essentiality

  PLoS Genetics · 2020 · 50 citations

  • Biology
  • Genetics
  • Microbiology

  Metabolic adaptation is linked to the ability of the opportunistic pathogen Candida albicans to colonize and cause infection in diverse host tissues. One way that C. albicans controls its metabolism is through the glucose repression pathway, where expression of alternative carbon source utilization genes is repressed in the presence of its preferred carbon source, glucose. Here we carry out genetic and gene expression studies that identify transcription factors Mig1 and Mig2 as mediators of glucose repression in C. albicans. The well-studied Mig1/2 orthologs ScMig1/2 mediate glucose repression in the yeast Saccharomyces cerevisiae; our data argue that C. albicans Mig1/2 function similarly as repressors of alternative carbon source utilization genes. However, Mig1/2 functions have several distinctive features in C. albicans. First, Mig1 and Mig2 have more co-equal roles in gene regulation than their S. cerevisiae orthologs. Second, Mig1 is regulated at the level of protein accumulation, more akin to ScMig2 than ScMig1. Third, Mig1 and Mig2 are together required for a unique aspect of C. albicans biology, the expression of several pathogenicity traits. Such Mig1/2-dependent traits include the abilities to form hyphae and biofilm, tolerance of cell wall inhibitors, and ability to damage macrophage-like cells and human endothelial cells. Finally, Mig1 is required for a puzzling feature of C. albicans biology that is not shared with S. cerevisiae: the essentiality of the Snf1 protein kinase, a central eukaryotic carbon metabolism regulator. Our results integrate Mig1 and Mig2 into the C. albicans glucose repression pathway and illuminate connections among carbon control, pathogenicity, and Snf1 essentiality.

  DOI

Recent grants

• Global analysis of uORF evolution and function

  NIH · $1.3M · 2017–2023

• Global analysis of uORF evolution and function

  NIH · $327k · 2017–2022

Frequent coauthors

• Gemma E. May

  Corteva (United States)

  22 shared

• Brenton R. Graveley

  UConn Health

  17 shared

• Joseph D. Coolon

  Wesleyan University

  11 shared

• Patricia J. Wittkopp

  University of Michigan–Ann Arbor

  11 shared

• Pieter Spealman

  New York University

  8 shared

• Kraig R. Stevenson

  University of Michigan–Ann Arbor

  7 shared

• Christina Akirtava

  University of Colorado Anschutz Medical Campus

  6 shared

• Carl Kingsford

  Carnegie Mellon University

  6 shared

Labs

• McManus LabPI

Education

• Ph.D., Biomolecular Chemistry

  University of Wisconsin Madison

  2007

• B.A., Chemistry

  Hiram College

  2001

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• Christos Nick Faloutsosh-137
• Rongchao Jinh-128
• Ignacio Grossmannh-117
• Neil Donahueh-116