Abstract
We are interested in identifying and characterizing loci of the human genome that harbor sequences resembling known mitochondrial and nuclear tRNAs. To this end, we used the known nuclear and mitochondrial tRNA genes (the “tRNA-Reference” set) to search for “tRNA-lookalikes” and found many such loci at different levels of sequence conservation. We find that the large majority of these tRNA-lookalikes resemble mitochondrial tRNAs and exhibit a skewed over-representation in favor of some mitochondrial anticodons. Our analysis shows that the tRNA-lookalikes have infiltrated specific chromosomes and are preferentially located in close proximity to known nuclear tRNAs (z-score ≤ −2.54, P-value ≤ 0.00394). Examination of the transcriptional potential of these tRNA-lookalike loci using public transcript annotations revealed that more than 20% of the lookalikes are transcribed as part of either known protein-coding pre-mRNAs, known lncRNAs, or known non-protein-coding RNAs, while public RNA-seq data perfectly agreed with the endpoints of tRNA-lookalikes. Interestingly, we found that tRNA-lookalikes are significantly depleted in known genetic variations associated with human health and disease whereas the known tRNAs are enriched in such variations. Lastly, a manual comparative analysis of the cloverleaf structure of several of the transcribed tRNA-lookalikes revealed no disruptive mutations suggesting the possibility that these loci give rise to functioning tRNA molecules.
Highlights
The non-coding RNAs known as transfer RNAs play critical roles in the translation of messenger RNAs to amino acid sequences
We found eight genomic loci that were identical to a mitochondrial transfer RNAs (tRNAs) from the tRNA-Reference set
We found 497 tRNA-lookalikes with ≤25 mismatches: 454 of these corresponded to the 530 true tRNAs and 43 corresponded to the 102 pseudo-tRNAs contained in the tRNA-Reference set
Summary
The non-coding RNAs (ncRNAs) known as transfer RNAs (tRNAs) play critical roles in the translation of messenger RNAs (mRNAs) to amino acid sequences. Speaking, tRNAs are ancient molecules present in all three kingdoms of life (archaea, bacteria, eukaryota). Beyond their roles in protein synthesis, tRNAs have been found to possess additional regulatory functions (Mei et al, 2010; Phizicky and Hopper, 2010; Durdevic and Schaefer, 2013; Raina and Ibba, 2014). Even though mutations in nuclear tRNA genes have not been associated with any diseases (Abbott et al, 2014), human nuclear tRNAs have been shown to exhibit significant sequence diversity at the population level with functional consequences (Parisien et al, 2013)
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