Ancient balancing selection maintains incompatible versions of the galactose pathway in yeast (Figure creation)

Metabolic pathways differ between species, but are expected to be similar within a species. We discovered two functional, incompatible versions of the galactose pathway in S. cerevisiae. We identified a 3-locus genetic interaction for growth in galactose, and used precisely engineered alleles to show that is arises from variation in the metabolic genes GAL2, GAL1/10/7, and PGM1, and that the reference allele of PGM1 is incompatible with the alternative alleles of the other genes. Multi-locus balancing selection has maintained the two incompatible versions of the pathway for millions of years. Strains with alternative alleles are found primarily in galactose-rich dairy environments, and they grow faster in galactose, but slower in glucose, revealing a tradeoff on which balancing selection may have acted.