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.
The short-read sequencing data reported in this study have been deposited to the NCBI BioProject database, accession number PRJNA784975.
Experimentally-evolved Saccharomyces cerevisiae clonesNCBI BioProject, PRJNA784975.
The sequencing of Saccharomyces cerevisiae strainsNCBI BioProject PRJNA205542.
Evolved Autodiploid ClonesNCBI BioProject PRJNA422100.
Evolved S. cerevisiae population sequencingNCBI BioProject PRJNA668346.
- Gregory I Lang
- Richard Steet
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Wenying Shou, University College London, United Kingdom
© 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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