Deciphering the genic basis of environmental adaptations of diverse Saccharomyces cerevisiae strains by simultaneous forward and reverse genetics. Saccharomyces cerevisiae

The budding yeast Saccharomyces cerevisiae is the best studied eukaryote in molecular and cell biology, but its utility for understanding the genetic basis of natural phenotypic variations is limited by the inefficiency of association mapping owing to its strong and complex population structure. To overcome this hurdle, we analyzed 190 high-quality genomes of diverse strains, including 85 newly sequenced ones, to uncover its population structure that varies substantially among genomic regions. We identified S. cerevisiae genes that are absent from the reference genome and demonstrated their expression and important functions such as drug resistance. Using a high-throughput phenotyping method, we measured simultaneously the growth rates of nearly 5000 lab strains each deficient of a nonessential gene and 81 natural strains each carrying a unique barcode, in multiple environments. These data allowed predicting genes underlying environmental adaptations, a subset of which was experimentally validated by a reciprocal hemizygosity test. We thus provided a resource for efficient and reliable association mapping of natural phenotypic variations in yeast and significantly enhanced its value as a model for understanding the genetic mechanisms of phenotypic polymorphism and evolution.