The mechanisms of molecular adaptation to rapidly evolving genes and systems

描述（由申请人提供）：最近对严格意义上的酵母菌属进行的全面测序工作和随后的进化分析表明，该属中约有123个基因正在快速进化。对快速进化基因的研究与人类健康特别相关，因为人类基因组中许多快速进化的基因参与宿主防御和免疫。虽然对人类的进化和遗传研究有逻辑上的限制，但对芽殖酵母属成员的这些研究要容易得多。这里提出的实验将使用物理和遗传相互作用映射来阐明基因组和蛋白质组如何适应酿酒酵母和贝酵母中快速进化的基因。在第一个目标中，一组靶向的三个蛋白质复合物的物理相互作用图，都包含一个快速进化的亚基，将在两个S。cerevisiae和S. bayanus在第二个目标中，将利用上位性微阵列分析（E-MAP）技术构建遗传互作图谱，以鉴定合成的遗传互作 在两组相同的~400个敲除菌株之间，导致在S. bayanus这些结果将与S.酿酒酵母E-MAP数据，以确定在快速进化的基因在S. bayanus和S.酿酒。总之，这些数据将大大扩展我们对密切相关物种中快速进化基因的分子适应性的理解，并可能为未来关于如何靶向微生物中快速进化基因的研究提供信息，以减缓或消除耐药病原体的发展。

DESCRIPTION (provided by applicant): A recent, comprehensive sequencing effort and subsequent evolutionary analysis of the Saccharomyces sensu stricto genus demonstrated that approximately 123 genes are rapidly evolving across the genus. The study of rapidly evolving genes is particularly relevant to human health as many of the rapidly evolving genes in the human genome are involved in host defense and immunity. And although evolutionary and genetic studies on humans have logistical limits, these same studies on members of the budding yeast Saccharomyces genus are much more tractable. The experiments proposed here will use physical and genetic interaction mapping to elucidate how the genome and proteome adapt to accommodate rapidly evolving genes in Saccharomyces cerevisiae and Saccharomyces bayanus. In the first aim, the physical interaction maps of a targeted set of three protein complexes, all containing a rapidly evolving subunit, will be determined in both S. cerevisiae and S. bayanus. In the second aim, a genetic interaction map will be constructed using epistatic mini-array profiling (E-MAP) technology, to identify synthetic genetic interactions between two identical sets of ~400 knockout strains, leading to the analysis of ~160,000 pair wise combinations of double knockouts in S. bayanus. These results will be compared to the extensive set of S. cerevisiae E-MAP data to identify differences in the genetic network connectivity of rapidly evolving genes in S. bayanus and S. cerevisiae. Taken together, these data will substantially expand our understanding of molecular adaptation to rapidly evolving genes among closely related species, and may inform future studies on how to target rapidly evolving genes in microbes so as to slow or eliminate the development of drug-resistant pathogens.