Evolutionary rescue of phosphomannomutase deficiency in yeast models of human disease

  1. Ryan C Vignogna
  2. Mariateresa Allocca
  3. Maria Monticelli
  4. Joy W Norris
  5. Richard Steet
  6. Ethan O Perlstein
  7. Giuseppina Andreotti  Is a corresponding author
  8. Gregory I Lang  Is a corresponding author
  1. Lehigh University, United States
  2. National Research Council, Italy
  3. Greenwood Genetic Center, United States
  4. Perlara PBC, United States

Abstract

The most common cause of human congenital disorders of glycosylation (CDG) are mutations in the phosphomannomutase gene PMM2, which affect protein N-linked glycosylation. The yeast gene SEC53 encodes a homolog of human PMM2. We evolved 384 populations of yeast harboring one of two human-disease-associated alleles, sec53-V238M and sec53-F126L, or wild-type SEC53. We find that after 1,000 generations, most populations compensate for the slow-growth phenotype associated with the sec53 human-disease-associated alleles. Through whole-genome sequencing we identify compensatory mutations, including known SEC53 genetic interactors. We observe an enrichment of compensatory mutations in other genes whose human homologs are associated with Type 1 CDG, including PGM1, which encodes the minor isoform of phosphoglucomutase in yeast. By genetic reconstruction, we show that evolved pgm1 mutations are dominant and allele-specific genetic interactors that restore both protein glycosylation and growth of yeast harboring the sec53-V238M allele. Finally, we characterize the enzymatic activity of purified Pgm1 mutant proteins. We find that reduction, but not elimination, of Pgm1 activity best compensates for the deleterious phenotypes associated with the sec53-V238M allele. Broadly, our results demonstrate the power of experimental evolution as a tool for identifying genes and pathways that compensate for human-disease associated alleles.

Data availability

The short-read sequencing data reported in this study have been deposited to the NCBI BioProject database, accession number PRJNA784975.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Ryan C Vignogna

    Department of Biological Sciences, Lehigh University, Bethlehem, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5943-6464
  2. Mariateresa Allocca

    Institute of Biomolecular Chemistry, National Research Council, Pozzuoli, Italy
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3693-2515
  3. Maria Monticelli

    Institute of Biomolecular Chemistry, National Research Council, Pozzuoli, Italy
    Competing interests
    No competing interests declared.
  4. Joy W Norris

    Research Division, Greenwood Genetic Center, Greenwood, United States
    Competing interests
    No competing interests declared.
  5. Richard Steet

    Research Division, Greenwood Genetic Center, Greenwood, United States
    Competing interests
    No competing interests declared.
  6. Ethan O Perlstein

    Perlara PBC, Berkeley, United States
    Competing interests
    Ethan O Perlstein, is CEO of Maggie's Pearl, LLC and CEO of Perlara PBC. He holds an ownership stake in both companies..
  7. Giuseppina Andreotti

    Institute of Biomolecular Chemistry, National Research Council, Pozzuoli, Italy
    For correspondence
    gandreotti@icb.cnr.it
    Competing interests
    No competing interests declared.
  8. Gregory I Lang

    Department of Biological Sciences, Lehigh University, Bethlehem, United States
    For correspondence
    glang@lehigh.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7931-0428

Funding

National Institutes of Health (R01GM127420)

  • Gregory I Lang

National Institutes of Health (P20GM139769)

  • Richard Steet

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Wenying Shou, University College London, United Kingdom

Version history

  1. Received: April 7, 2022
  2. Preprint posted: April 8, 2022 (view preprint)
  3. Accepted: October 7, 2022
  4. Accepted Manuscript published: October 10, 2022 (version 1)
  5. Version of Record published: October 18, 2022 (version 2)

Copyright

© 2022, Vignogna et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ryan C Vignogna
  2. Mariateresa Allocca
  3. Maria Monticelli
  4. Joy W Norris
  5. Richard Steet
  6. Ethan O Perlstein
  7. Giuseppina Andreotti
  8. Gregory I Lang
(2022)
Evolutionary rescue of phosphomannomutase deficiency in yeast models of human disease
eLife 11:e79346.
https://doi.org/10.7554/eLife.79346

Share this article

https://doi.org/10.7554/eLife.79346

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