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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 1000 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.

Evolutionary rescue of phosphomannomutase deficiency in yeast models of human disease