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A standardized ontology for naming tRNA-derived RNAs based on molecular origin

Nature Methods volume 20, pages 627–628 (2023)Cite this article

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The tDR naming system (Fig. 1a) consists of three required components, plus up to two supplemental notations in special cases. First, each name starts with the general prefix “tDR,” which is neutral to any functional role. If the tDR is derived from mitochondrial or plastid tRNAs, “mtDR” or “ptDR” is used. Second, the tDR’s precise start and end positions, relative to its source tRNA, are specified using the standardized Sprinzl tRNA position numbering10 (for example, “tDR-4:33”). This system gives stems and loops consistent base numbers across all tRNAs (for example, the anticodon in every tRNA is at positions 34–36). Third, the identifier of the most similar source tRNA found in the Genomic tRNA Database (GtRNAdb)9 is appended to the tDR name (for example, “Val-AAC-1”). Because some portions of different tRNAs may be identical, tDRs can often be derived from multiple indistinguishable parent tRNAs. In this case, a fourth component is added to the tDR name to indicate the number of potential source tRNAs (for example, “M7”). Finally, nucleotide differences may exist between tDRs and the reference tRNA set as a result of natural genetic variation, or may also be caused by misincorporation by reverse transcriptase at certain RNA modifications. To describe these tDRs succinctly, a name component can be added consisting of the original and substituted bases with their relative positions (for example, “U10A”).

To demonstrate the application of this new naming system with tDRnamer, we created systematic names for existing entries in tRFdb3 (Supplementary Data 1), immediately yielding useful observations. One notable case involves a group of seven tDRs potentially derived from multiple unique transcripts of tRNAPro (Fig. 1b). For tDR-1:31-Pro-AGG-1-M5 (tRFdb ID: 5013c), one can see five possible synonyms corresponding to five matching source tRNAs (Fig. 1c,d and Supplementary Table 2). In previous nomenclatures3,8, this information is necessarily absent. The graphic (Fig. 1b) and alignment (Fig. 1d) show most of these tDRs being anchored to the 5′ end of source tRNAs (for example, “1:15”, “1:18”) while the remaining two align to the 3′ end (“59:76”, “55:76”). The alignment further shows that the longest tDR (5013c) exactly matches five potential source tRNAs, precisely enumerated by numbers in brackets following tDR sequences. Additional examples of complex tDR relationships showcase the unique functionality of the tDRnamer web analysis interface (Supplementary Figs. 2 and 3). For instance, three different regions of human tRNA-Gly-GCC-1 are processed into distinct tDRs of multiple lengths (Supplementary Fig. 2), whereas a tDR derived from the 3′ trailer sequence of tRNA-Arg-ACG-1-3 includes multiple single-nucleotide variants (Supplementary Fig. 3). These examples demonstrate the breadth and descriptive capabilities of the proposed tDR naming system. As such, tDRnamer should become a valuable analytic tool for recognizing the biological relatedness among tDRs, enabling more focused study of their biogenesis from source tRNAs. The new system will also provide a ready means for detailed comparisons of tDR sequencing results between studies, both retrospectively and prospectively, facilitating advances in this blossoming field of noncoding RNA research.

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Fig. 1: Standardized naming for tRNA-derived RNAs (tDRs) illustrated by seven tDRs potentially derived from up to eight human tRNAPro transcripts.

Data availability

The tDRnamer web server is available at http://trna.ucsc.edu/tDRnamer/. Standalone software can be obtained from GitHub at https://github.com/UCSC-LoweLab/tDRnamer and a Docker image at https://hub.docker.com/r/ucsclowelab/tdrnamer. Example data can be downloaded from http://trna.ucsc.edu/tDRnamer/data/examples/. Prebuilt reference databases for model organisms are available at http://trna.ucsc.edu/tDRnamer/docs/refdb/. The complete set of tRFdb3 data reannotations by tDRnamer is available at http://trna.ucsc.edu/tDRnamer/data/tRFdb_reannotations/.

Code availability

The source code of tDRnamer and the source code of its web server are available at https://github.com/UCSC-LoweLab/tDRnamer and https://github.com/UCSC-LoweLab/tDRnamer-web, respectively, both under the GNU General Public License v3.0.

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Acknowledgements

This work was supported by the National Human Genome Research Institute, National Institutes of Health (R01HG006753 to T.L.).

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Author notes

  1. These authors contributed equally: Andrew D. Holmes, Patricia P. Chan.

Authors and Affiliations

  1. Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA

    Andrew D. Holmes, Patricia P. Chan & Todd M. Lowe

  2. Division of Urology, Department of Surgery, School of Medicine, University of Utah, Salt Lake City, UT, USA

    Qi Chen

  3. Department of Medicine, Harvard Medical School, Boston, MA, USA

    Pavel Ivanov

  4. Institut de biologie moléculaire des plantes-CNRS, Université de Strasbourg, Strasbourg, France

    Laurence Drouard

  5. Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Bern, Switzerland

    Norbert Polacek

  6. Departments of Pediatrics and Genetics, Stanford University, Stanford, CA, USA

    Mark A. Kay

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  8. Todd M. Lowe
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Contributions

A.H. and P.C. designed and developed tDRnamer standalone software. P.C. designed and developed the tDRnamer web server. P.C. and T.L. wrote the manuscript. All authors contributed to the design of tDR naming convention and the feature requirements of tDRnamer.

Corresponding author

Correspondence to Todd M. Lowe.

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The authors declare no competing interests.

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Peer review information

Nature Methods thanks Hani Goodarzi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Supplementary information

Supplementary Information

Supplementary Figs. 1–3, Tables 1–4 and Methods

Supplementary Data 1

Reannotation of human tRNA-derived RNAs in tRFdb using tDRnamer

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Holmes, A.D., Chan, P.P., Chen, Q. et al. A standardized ontology for naming tRNA-derived RNAs based on molecular origin. Nat Methods 20, 627–628 (2023). https://doi.org/10.1038/s41592-023-01813-2

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