The mechanisms of molecular adaptation to rapidly evolving genes and systems

描述（由申请人提供）：最近，对严格意义酵母菌属的全面测序工作和随后的进化分析表明，大约123个基因正在整个属中快速进化。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与宿主防御和免疫有关。虽然对人类的进化和遗传研究有逻辑上的限制，但对萌发酵母属的成员进行同样的研究要容易得多。本文提出的实验将利用物理和遗传相互作用作图来阐明酿酒酵母菌和bayanus酵母菌的基因组和蛋白质组如何适应快速进化的基因。在第一个目标中，将确定酿酒葡萄球菌和bayanus葡萄球菌中含有快速进化亚基的三种蛋白质复合物的物理相互作用图。在第二个目标中，将使用上位微阵列分析（E-MAP）技术构建遗传相互作用图谱，以识别合成的遗传相互作用

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. PUBLIC HEALTH RELEVANCE: On an evolutionary time-scale, many genes in the human genome are changing rapidly, including genes involved in sensory perception, immunity and host defense. This work strives to better understand how rapidly changing genes evolve, and how organisms adapt to accommodate these genes. Results from these studies will help us understand how hosts and pathogens change their genomes in response to one another, and will eventually enable the identification of therapeutic targets to deter or prevent the adaptation of pathogens to antibiotic and antiviral drugs.