EDGE CMT: Defining the cost of mutation in nuclear encoded tRNAs

所有生命系统的基因组都存在代价高昂的突变。导致遗传病的个别高影响突变相对容易识别，但损害整体适合性的突变较难表征。有一类基因最近受到了关注，因为它可能通过突变负载对健康产生影响：转移RNA。转移RNA基因对所有生物体都是必不可少的，是生命树上最古老的基因之一。大多数真核生物基因组编码数百个转移RNA基因，这些基因在细胞中高水平表达，在蛋白质合成过程中转移核糖体中的氨基酸。这一关键且无处不在的过程也具有诱变性；转移的RNA基因迅速降解，可能会导致有机体和整个物种的健康成本。转移RNA基因的快速进化为利用先进的基因组测序技术对具有不同互补的转移RNA基因集的基因组进行实验比较提供了机会。这个项目将估计模式生物秀丽线虫的突变成本，以得出关于生命系统中总体突变成本的结论。随着基因组科学越来越多地成为社会的一部分，该项目将通过两项外联活动培养下一代专业人员的生物技术专门知识：为生物学研究生开设的传播科学课程，以及佐治亚州立法学院生物技术法律系学生与佐治亚理工学院基因组学实习生之间的信息交流。这两项活动都强调了在更广泛的智力、社会和协作环境中解释技术学术进展的重要性。转移RNA(TRNAs)是在生命树上高度保守的基本基因，存在于每个活着的有机体的基因组中。然而，tRNA经历了异常高的突变率，并在短时间尺度上表现出快速和动态的进化，可能反映了突变和选择的进化力量之间的紧张关系。因此，核编码的tRNAs上的突变负载可能是真核基因组的普遍特征。最近的工作发现了线虫体内核编码tRNA的种内获得、丢失和改变，以及暴露在极高的转录相关突变率中的证据。该项目建议利用该模型系统的遗传可控性，在实验室的实验进化环境中测试变异的后果。通过测试线虫核编码tRNA突变的影响，这项工作旨在从总体上洞察真核基因组中tRNA突变的成本。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

All living systems harbor costly mutations in their genomes. Individual high-impact mutations that cause genetic disease are relatively easy to identify, but mutations that compromise fitness in aggregate are harder to characterize. One class of genes has recently come under attention for its likely influence on health via mutational load: transfer RNAs. Transfer RNA genes are are essential to all organisms and are among the most ancient genes in the tree of life. Most eukaryotic genomes encode hundreds of transfer RNA genes, which are expressed at high levels in cells to “transfer” amino acids in the ribosome during protein synthesis. This critical and ubiquitous process is also mutagenic; transfer RNA genes degrade rapidly, likely incurring fitness costs to the organism and the species at large. The rapid evolution of transfer RNA genes offers an opportunity to experimentally compare, using advanced genome sequencing technologies, genomes with distinct complements of transfer RNA gene sets. This project will estimate the cost of mutation in the model organism C. elegans, a microscopic worm, to draw conclusions about the cost of mutation in living systems generally. As genomic science increasingly becomes part of society, this project will foster biotechnical expertise in the next generation of professionals via two outreach activities: a communicating science course for biology graduate students, and an information exchange between biotechnology law students at Georgia State College of Law and genomics trainees at Georgia Institute of Technology. Both activities emphasize the importance of interpreting the advances of technical scholarship within a wider intellectual, societal, and collaborative context.Transfer RNAs (tRNAs) are essential genes that are highly conserved across the tree of life and found in the genome of every living organism. Yet, tRNAs experience exceptionally high mutation rates and demonstrate rapid and dynamic evolution over short timescales, likely reflecting tension between the evolutionary forces of mutation and selection. Consequently, mutational load at nuclear encoded tRNAs is likely a universal feature of eukaryotic genomes. Recent work has uncovered intraspecific gains, losses and alterations to nuclear encoded tRNAs within the nematode worm C. elegans, as well as evidence of exposure to extremely high rates of transcription-associated mutagenesis. This project proposes to leverage the genetic tractability of this model system to test the consequences of the variation in an experimental evolution setting in the lab. By testing the effects of mutational variation in nuclear encoded tRNAs in C. elegans, this work aims to provide insight into the cost of tRNA mutation in eukaryotic genomes generally.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.