Nuclear and mitochondrial tRNA-lookalikes in the human genome

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.

[1]  T. Pan,et al.  Diversity of human tRNA genes from the 1000-genomes project , 2013, RNA biology.

[2]  Daniel R. Zerbino,et al.  Ensembl 2014 , 2013, Nucleic Acids Res..

[3]  Nazim Madhavji,et al.  Organization , 2020, WER.

[4]  R. Belostotsky,et al.  Human mitochondrial tRNA quality control in health and disease , 2012, RNA biology.

[5]  J. Harrow,et al.  GENCODE: producing a reference annotation for ENCODE , 2006, Genome Biology.

[6]  Peter Schattner,et al.  The tRNAscan-SE, snoscan and snoGPS web servers for the detection of tRNAs and snoRNAs , 2005, Nucleic Acids Res..

[7]  M. Frith,et al.  Mammalian NUMT insertion is non-random , 2012, Nucleic acids research.

[8]  Andrea Califano,et al.  tRNA-derived microRNA modulates proliferation and the DNA damage response and is down-regulated in B cell lymphoma , 2013, Proceedings of the National Academy of Sciences.

[9]  V. Corces,et al.  tDNA insulators and the emerging role of TFIIIC in genome organization , 2012, Transcription.

[10]  A Salas,et al.  Pseudomitochondrial genome haunts disease studies , 2008, Journal of Medical Genetics.

[11]  M. Gartenberg,et al.  Coordination of tRNA transcription with export at nuclear pore complexes in budding yeast , 2014, Genes & development.

[12]  Patricia P. Chan,et al.  GtRNAdb: a database of transfer RNA genes detected in genomic sequence , 2008, Nucleic Acids Res..

[13]  I. Dunham,et al.  DNA sequence and analysis of human chromosome 9 , 2003, Nature.

[14]  M. Ibba,et al.  tRNAs as regulators of biological processes , 2014, Front. Genet..

[15]  R. Pirtle,et al.  A human tRNA gene cluster encoding the major and minor valine tRNAs and a lysine tRNA. , 1989, DNA.

[16]  I. Dunham,et al.  The DNA sequence and analysis of human chromosome 6 , 2003, Nature.

[17]  A. Hopper,et al.  tRNA biology charges to the front. , 2010, Genes & development.

[18]  ENCODEConsortium,et al.  An Integrated Encyclopedia of DNA Elements in the Human Genome , 2012, Nature.

[19]  M. Feldman,et al.  Rates of DNA Duplication and Mitochondrial DNA Insertion in the Human Genome , 2004, Journal of Molecular Evolution.

[20]  R. Pink,et al.  Pseudogenes as regulators of biological function. , 2013, Essays in biochemistry.

[21]  Deanna M. Church,et al.  ClinVar: public archive of relationships among sequence variation and human phenotype , 2013, Nucleic Acids Res..

[22]  Tsutomu Suzuki,et al.  Specific correlation between the wobble modification deficiency in mutant tRNAs and the clinical features of a human mitochondrial disease. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[23]  M. Schaefer,et al.  tRNA modifications: Necessary for correct tRNA‐derived fragments during the recovery from stress? , 2013, BioEssays : news and reviews in molecular, cellular and developmental biology.

[24]  J. Alfonzo,et al.  Transfer RNA modifications: nature's combinatorial chemistry playground , 2013, Wiley interdisciplinary reviews. RNA.

[25]  M. Ibba,et al.  A Pseudo-tRNA Modulates Antibiotic Resistance in Bacillus cereus , 2012, PloS one.

[26]  G. Dakubo,et al.  The pseudo-mitochondrial genome influences mistakes in heteroplasmy interpretation , 2006, BMC Genomics.

[27]  A. Hopper,et al.  Cellular dynamics of tRNAs and their genes , 2010, FEBS letters.

[28]  A. Hopper,et al.  Transfer RNA travels from the cytoplasm to organelles , 2011, Wiley interdisciplinary reviews. RNA.

[29]  Elizabeth M. Smigielski,et al.  dbSNP: the NCBI database of genetic variation , 2001, Nucleic Acids Res..

[30]  E. Myers,et al.  Basic local alignment search tool. , 1990, Journal of molecular biology.

[31]  S. Eddy,et al.  tRNAscan-SE: a program for improved detection of transfer RNA genes in genomic sequence. , 1997, Nucleic acids research.

[32]  R. Montiel,et al.  Nuclear insertions of mitochondrial origin: Database updating and usefulness in cancer studies. , 2011, Mitochondrion.

[33]  J. Yong,et al.  tRNA and cytochrome c in cell death and beyond , 2010, Cell cycle.

[34]  C. Francklyn,et al.  Transfer RNA and human disease , 2014, Front. Genet..

[35]  Data production leads,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[36]  A. Schneider.  Mitochondrial tRNA import and its consequences for mitochondrial translation. , 2011, Annual review of biochemistry.

[37]  N. Polacek,et al.  Slicing tRNAs to boost functional ncRNA diversity , 2013, RNA biology.