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Targeted sequencing reveals expanded genetic diversity of human transfer RNAs

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posted on 2019-08-13, 15:02 authored by Matthew D. Berg, Daniel J. Giguere, Jacqueline S. Dron, Jeremy T. Lant, Julie Genereaux, Calwing Liao, Jian Wang, John F. Robinson, Gregory B. Gloor, Robert A. Hegele, Patrick O’Donoghue, Christopher J. Brandl

Transfer RNAs are required to translate genetic information into proteins as well as regulate other cellular processes. Nucleotide changes in tRNAs can result in loss or gain of function that impact the composition and fidelity of the proteome. Despite links between tRNA variation and disease, the importance of cytoplasmic tRNA variation has been overlooked. Using a custom capture panel, we sequenced 605 human tRNA-encoding genes from 84 individuals. We developed a bioinformatic pipeline that allows more accurate tRNA read mapping and identifies multiple polymorphisms occurring within the same variant. Our analysis identified 522 unique tRNA-encoding sequences that differed from the reference genome from 84 individuals. Each individual had ~66 tRNA variants including nine variants found in less than 5% of our sample group. Variants were identified throughout the tRNA structure with 17% predicted to enhance function. Eighteen anticodon mutants were identified including potentially mistranslating tRNAs; e.g., a tRNASer that decodes Phe codons. Similar engineered tRNA variants were previously shown to inhibit cell growth, increase apoptosis and induce the unfolded protein response in mammalian cell cultures and chick embryos. Our analysis shows that human tRNA variation has been underestimated. We conclude that the large number of tRNA genes provides a buffer enabling the emergence of variants, some of which could contribute to disease.

Funding

This work was supported by a University of Western Ontario Collaborative SEED Grant to C.J.B., P.O., and R.A.H.; the Natural Sciences and Engineering Research Council of Canada [RGPIN-04394-2015 to C.J.B.; RGPIN 04282-2014 to P.O.; RGPIN 03878-2015 to G.B.G.]; and Canada Research Chairs [950-232341 to P.O.]. M.D.B (CGS-D) and J.T.L. (PGS-D) hold Natural Sciences and Engineering Research Council of Canada Alexander Graham Bell scholarships. M.D.B. is supported by generous donations from Graham Wright and James Robertson. J.S.D. is supported by the Canadian Institutes of Health Research (Doctoral Research Award) and the Schulich School of Medicine & Dentistry (Cobban Student Award in Heart and Stroke Research and Nellie L. Farthing Memorial Fellowship in the Medical Sciences).

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