Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, MI.
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI.
Mol Biol Evol. 2017 Oct 1;34(10):2486-2502. doi: 10.1093/molbev/msx151.
The budding yeast Saccharomyces cerevisiae is the best studied eukaryote in molecular and cell biology, but its utility for understanding the genetic basis of phenotypic variation in natural populations is limited by inefficient association mapping due to strong and complex population structure. To overcome this challenge, we generated genome sequences for 85 strains and performed a comprehensive population genomic survey of a total of 190 diverse strains. We identified considerable variation in population structure among chromosomes and identified 181 genes that are absent from the reference genome. Many of these nonreference genes are expressed and we functionally confirmed that two of these genes confer increased resistance to antifungals. Next, we simultaneously measured the growth rates of over 4,500 laboratory strains, each of which lacks a nonessential gene, and 81 natural strains across multiple environments using unique DNA barcode present in each strain. By combining the genome-wide reverse genetic information gained from the gene deletion strains with a genome-wide association analysis from the natural strains, we identified genomic regions associated with fitness variation in natural populations. To experimentally validate a subset of these associations, we used reciprocal hemizygosity tests, finding that while the combined forward and reverse genetic approaches can identify a single causal gene, the phenotypic consequences of natural genetic variation often follow a complicated pattern. The resources and approach provided outline an efficient and reliable route to association mapping in yeast and significantly enhance its value as a model for understanding the genetic mechanisms underlying phenotypic variation and evolution in natural populations.
budding 酵母酿酒酵母是分子和细胞生物学中研究得最好的真核生物，但由于种群结构强烈且复杂，其在理解自然种群表型变异的遗传基础方面的应用受到限制，关联作图效率低下。为了克服这一挑战，我们生成了 85 株的基因组序列，并对总共 190 株多样化的菌株进行了全面的种群基因组调查。我们发现染色体之间的种群结构存在很大差异，并鉴定出 181 个不在参考基因组中的基因。这些非参考基因中有许多是表达的，我们功能验证了其中两个基因赋予了抗真菌药物的抗性。接下来，我们同时测量了超过 4500 株实验室菌株的生长速度，这些菌株都缺失一个非必需基因，并且在多个环境中使用每个菌株中独特的 DNA 条码测量了 81 株自然菌株的生长速度。通过将缺失基因的全基因组反向遗传信息与自然菌株的全基因组关联分析相结合，我们鉴定了与自然种群中适应性变异相关的基因组区域。为了实验验证这些关联的一部分，我们使用了相互半合子测试，发现虽然正向和反向遗传方法的组合可以鉴定出一个单一的因果基因，但自然遗传变异的表型后果通常遵循复杂的模式。提供的资源和方法为酵母中的关联作图勾勒出了一条有效且可靠的途径，并大大提高了其作为理解自然种群中表型变异和进化的遗传机制的模型的价值。
