UC Merced

tRNA genes play a vital role in protein synthesis and are essential components of the translational machinery in all living organisms. Bioinformatic predictions of tRNA functional signatures (features determining tRNA gene function), their evolutionary divergence, and the contributing factors to their evolution is crucial for understanding the accuracy of recognition and interaction-determining features of tRNA molecules with other translational system components. This knowledge has implications for therapeutic interventions and understanding disease mechanisms. However, the species-specific mechanisms of tRNA gene family evolution remain poorly understood, likely due to the small size and high similarity of tRNA genes within the same family. Traditional orthology assignment methods are ineffective, and accurate results require high-quality complete genome assemblies. In addition, the coevolution of tRNA genes is often neglected, and there has been no systematic study of this coevolution that takes into account their spatial organization within the genome. This dissertation provides an analytical tool called tRNA Structure Function Mapper (tSFM) that predicts functional signatures of tRNA genes, calculates their evolutionary divergence with improved efficiency and accuracy of their estimation of statistical significance. The dissertation describes the application of tSFM to bioinformatically prioritize and target specific tRNA-protein interactions as divergent between humans and parasitic Trypanosomes for drug discovery. The custom tRNA gene annotation pipeline undertaken for this work led to more complete and accurate tRNA gene annotations in Trypanosome genomes and the first description of widely conserved tRNA gene arrays in those parasitic genomes. Subsequent work expands our custom annotation and analysis pipelines to tRNA gene arrays in recently published long-read genome assemblies in Drosophila. Furthermore, this research presents a systematic approach to the assignment of orthology of tRNA gene arrays among 89 drosophilid species, reveals the impact of tRNA array composition on the evolution of tRNA genes, and describes the common evolutionary mechanisms acting on multi-copy tRNA gene families.