期刊
RNA BIOLOGY
卷 16, 期 11, 页码 1574-1585出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15476286.2019.1646079
关键词
tRNA biology; human tRNA variation; tRNA-encoding genes; tRNA capture panel; translation
资金
- University of Western Ontario Collaborative SEED Grant
- Natural Sciences and Engineering Research Council of Canada [RGPIN-04394-2015, RGPIN 04282-2014, RGPIN 03878-2015]
- Canada Research Chairs [950-232341]
- Canadian Institutes of Health Research (Doctoral Research Award)
- Schulich School of Medicine & Dentistry (Cobban Student Award in Heart and Stroke Research)
- Schulich School of Medicine & Dentistry (Nellie L. Farthing Memorial Fellowship in the Medical Sciences)
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 similar to 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 tRNA(Ser) 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.
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