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

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.

出芽酵母酿酒酵母（Saccharomyces cerevisiae）是分子生物学与细胞生物学中研究最透彻的真核生物，但其用于解析自然表型变异遗传基础的应用价值，却因群体结构强且复杂导致关联作图效率低下而受到限制。为克服这一难题，本研究对190株不同菌株的高质量基因组进行分析（其中85株为新测序菌株），以解析其在不同基因组区域间存在显著差异的群体结构。本研究鉴定出参考基因组中缺失的酿酒酵母基因，并验证了这些基因的表达情况及耐药性等重要功能。采用高通量表型分析方法，本研究在多种环境下同时测定了近5000株敲除非必需基因的实验室菌株，以及81株携带独特条形码的自然菌株的生长速率。基于上述数据，本研究预测了参与环境适应性的关键基因，并通过互补半合子测验对其中一部分基因进行了实验验证。本研究由此为酵母自然表型变异的高效、可靠关联作图提供了数据资源，并显著提升了其作为解析表型多态性与进化遗传机制模型的研究价值。