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

Georgia Tech Research Corporation, Atlanta GA

Investigators

Abstract

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.