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

所有生命系统的基因组中都有代价高昂的突变。导致遗传疾病的个体高影响突变相对容易识别，但损害整体适应性的突变则更难描述。最近，一类基因因其可能通过突变负荷对健康产生影响而受到关注：转移RNA。转移RNA基因对所有生物体都是必不可少的，是生命之树中最古老的基因之一。大多数真核生物基因组编码数百个转移RNA基因，这些基因在细胞中以高水平表达，以在蛋白质合成期间“转移”核糖体中的氨基酸。这一关键和普遍存在的过程也是诱变性的;转移RNA基因迅速降解，可能导致生物体和整个物种的适应性成本。转移RNA基因的快速进化提供了一个机会，实验比较，使用先进的基因组测序技术，基因组与不同的互补转移RNA基因集。本计画将评估模式生物C的变异成本。elegans，一种显微镜下的蠕虫，得出关于生命系统中突变代价的结论。随着基因组科学日益成为社会的一部分，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交流科学课程，以及格鲁吉亚州立法学院生物技术法学生与格鲁吉亚理工学院基因组学学员之间的信息交流。这两项活动都强调在更广泛的知识，社会和合作背景下解释技术学术进步的重要性。转移RNA（tRNA）是生命之树中高度保守的必需基因，存在于每个生物体的基因组中。然而，tRNA经历了异常高的突变率，并在短时间内表现出快速和动态的进化，这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tRNA的突变负荷可能是真核生物基因组的普遍特征。最近的工作揭示了线虫C.以及暴露于极高的转录相关诱变率的证据。该项目建议利用该模型系统的遗传易处理性来测试实验室中实验进化设置中的变化的后果。通过检测C.这项工作的目的是提供深入了解tRNA突变的成本在真核生物基因组一般。这个奖项反映了NSF的法定使命，并已被认为是值得的支持，通过评估使用基金会的智力价值和更广泛的影响审查标准。

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.