PRJNA575066
Ancient balancing selection maintains incompatible versions of a conserved metabolic pathway in yeast
Accumulation of genetic incompatibilities can lead to speciation, but there are few detailed examples of this process in action. We discovered that the classical galactose pathway of the yeast Saccharomyces cerevisiae exists in two incompatible states maintained by ancient balancing selection. In a mapping study of growth on galactose, we identified a genetic interaction among three unlinked loci in crosses involving the strain CBS2888. All three loci contained components of the galactose pathway (GAL2, GAL1/10/7, and PGM1). We noted that the CBS2888 galactose alleles were highly diverged from the reference strain. We engineered strains carrying all eight allelic combinations at these loci and showed that the reference version of PGM1 is incompatible with the diverged alleles of the other genes. The diverged alleles appear to have split from those of most other S. cerevisiae strains before the birth of the Saccharomyces sensu stricto species cluster ~10-20 MYA. Globally, the diverged alleles are found in isolates from galactose-rich environments, such as cheese, kefir, and milk. Population genetics analysis of linked neutral sites revealed a strong signature of ancient balancing selection. Strains with the diverged alleles grew faster in galactose, but slower in glucose, revealing a tradeoff on which this balancing selection may act. Our work shows that balancing selection on alternative versions of a metabolic process can maintain incompatible but functional unlinked alleles for millions of years.