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

所有生命系统的基因组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，但总体上损害适应性的突变更难表征。一类基因最近受到关注，因为它可能通过突变负荷对健康产生影响：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。这个关键的和无处不在的过程也是诱变的；转移RNA基因降解迅速，可能会给生物体和整个物种带来适应性成本。利用先进的基因组测序技术，转移RNA基因的快速进化为实验比较具有不同互补的转移RNA基因集的基因组提供了机会。该项目将估算模式生物秀丽隐杆线虫（一种微观蠕虫）的突变成本，从而得出关于生命系统中一般突变成本的结论。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展活动培养下一代专业人员的生物技术专业知识：为生物学研究生开设交流科学课程，以及在乔治亚州立法学院的生物技术法律专业学生和乔治亚理工学院的基因组学学员之间进行信息交流。这两项活动都强调了在更广泛的知识、社会和合作背景下解释技术学术进步的重要性。转移rna （tRNAs）是在整个生命树中高度保守的重要基因，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，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trna的突变负荷可能是真核生物基因组的普遍特征。最近的研究发现了秀丽隐杆线虫（C. elegans）内核编码trna的种内增益、损失和改变，以及暴露于极高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可追溯性，在实验室的实验进化环境中测试变异的后果。通过测试秀丽隐杆线虫核编码tRNA突变变异的影响，本研究旨在深入了解真核生物基因组中tRNA突变的成本。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值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.