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Many of the newly identified ncRNAs have not been validated for their function.<ref name="pmid15851066">{{cite journal | vauthors = Hüttenhofer A, Schattner P, Polacek N | title = Non-coding RNAs: hope or hype? | journal = Trends in Genetics | volume = 21 | issue = 5 | pages = 289–97 | date = May 2005 | pmid = 15851066 | doi = 10.1016/j.tig.2005.03.007 }}</ref>
There is no consensus in the literature on how much of non-coding transcription is functional. Some researchers have argued that many ncRNAs are non-functional (sometimes referred to as "junk RNA"), spurious transcriptions.<ref name="waste">{{cite journal | vauthors = Brosius J | title = Waste not, want not--transcript excess in multicellular eukaryotes | journal = Trends in Genetics | volume = 21 | issue = 5 | pages = 287–8 | date = May 2005 | pmid = 15851065 | doi = 10.1016/j.tig.2005.02.014 }}</ref><ref name="PalazzoLee2015">{{cite journal | vauthors = Palazzo AF, Lee ES | title = Non-coding RNA: what is functional and what is junk? | journal = Frontiers in Genetics | volume = 6 | pages = 2 | year = 2015 | pmid = 25674102 | pmc = 4306305 | doi = 10.3389/fgene.2015.00002 | doi-access = free }}</ref>
Others, however, disagree, arguing instead that many non-coding transcripts do have functions and that those functions are being and will continue to be discovered.<ref>{{cite book |last1=Mattick |first1=John |last2=Amaral |first2=Paulo |title=RNA, The Epicenter of Genetic Information : A New Understanding of Molecular Biology |date=2022 |publisher=CRC Press |isbn= 9780367623920}}</ref><ref>{{cite journal |last1=Lee |first1=Hyunmin |last2=Zhang |first2=Zhaolei |last3=Krause |first3=Henry M. |title=Long Noncoding RNAs and Repetitive Elements: Junk or Intimate Evolutionary Partners? |journal=Trends in Genetics |date=December 2019 |volume=35 |issue=12 |pages=892–902 |doi=10.1016/j.tig.2019.09.006|pmid=31662190 |s2cid=204975291 |doi-access=free }}</ref>
==History and discovery==
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Another group of introns can catalyse their own removal from host transcripts; these are called self-splicing RNAs. There are two main groups of self-splicing RNAs: [[group I catalytic intron]] and [[group II catalytic intron]]. These ncRNAs catalyze their own excision from mRNA, tRNA and rRNA precursors in a wide range of organisms.{{citation needed|date=June 2017}}
In mammals it has been found that snoRNAs can also regulate the [[alternative splicing]] of mRNA, for example snoRNA [[Small nucleolar RNA SNORD115|HBII-52]] regulates the splicing of [[5-HT2C receptor|serotonin receptor 2C]].<ref name=Kishore>{{cite journal | vauthors = Kishore S, Stamm S | title = The snoRNA HBII-52 regulates alternative splicing of the serotonin receptor 2C | journal = Science | volume = 311 | issue = 5758 | pages = 230–2 | date = January 2006 | pmid = 16357227 | doi = 10.1126/science.1118265 | bibcode = 2006Sci...311..230K | s2cid = 44527461 | doi-access = free }}</ref>
In nematodes, the [[SmY]] ncRNA appears to be involved in mRNA [[trans-splicing]].{{citation needed|date=June 2017}}
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[[File:YRNA-Ro60.png|thumb|250px|The [[TRIM21|Ro autoantigen]] protein (white) binds the end of a double-stranded Y RNA (red) and a single stranded RNA (blue). (PDB: 1YVP [http://www.rcsb.org/pdb/explore.do?structureId=1yvp]).<ref name="pmid15907467">{{cite journal | vauthors = Stein AJ, Fuchs G, Fu C, Wolin SL, Reinisch KM | title = Structural insights into RNA quality control: the Ro autoantigen binds misfolded RNAs via its central cavity | journal = Cell | volume = 121 | issue = 4 | pages = 529–39 | date = May 2005 | pmid = 15907467 | pmc = 1769319 | doi = 10.1016/j.cell.2005.03.009 }}</ref>]]
[[Y RNA]]s are stem loops, necessary for [[DNA replication]] through interactions with [[chromatin]] and initiation proteins (including the [[origin recognition complex]]).<ref name="pmid16943439">{{cite journal | vauthors = Christov CP, Gardiner TJ, Szüts D, Krude T | title = Functional requirement of noncoding Y RNAs for human chromosomal DNA replication | journal = Molecular and Cellular Biology | volume = 26 | issue = 18 | pages = 6993–7004 | date = September 2006 | pmid = 16943439 | pmc = 1592862 | doi = 10.1128/MCB.01060-06 }}</ref><ref>{{cite journal | vauthors = Zhang AT, Langley AR, Christov CP, Kheir E, Shafee T, Gardiner TJ, Krude T | title = Dynamic interaction of Y RNAs with chromatin and initiation proteins during human DNA replication | journal = Journal of Cell Science | volume = 124 | issue = Pt 12 | pages = 2058–69 | date = June 2011 | pmid = 21610089 | pmc = 3104036 | doi = 10.1242/jcs.086561 }}</ref> They are also components of the [[TRIM21|Ro60 ribonucleoprotein particle]]<ref>{{cite journal | vauthors = Hall AE, Turnbull C, Dalmay T | title = Y RNAs: recent developments | journal = Biomolecular Concepts | volume = 4 | issue = 2 | pages = 103–10 | date = April 2013 | pmid = 25436569 | doi = 10.1515/bmc-2012-0050 | s2cid = 12575326 | doi-access = free }}</ref> which is a target of autoimmune antibodies in patients with [[systemic lupus erythematosus]].<ref>{{cite journal | vauthors = Lerner MR, Boyle JA, Hardin JA, Steitz JA | title = Two novel classes of small ribonucleoproteins detected by antibodies associated with lupus erythematosus | journal = Science | volume = 211 | issue = 4480 | pages = 400–2 | date = January 1981 | pmid = 6164096 | doi = 10.1126/science.6164096 | bibcode = 1981Sci...211..400L }}</ref>
===In gene regulation===
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===Bifunctional RNA===
''Bifunctional RNAs'', or ''dual-function RNAs'', are RNAs that have two distinct functions.<ref name="pmid18042713">{{cite journal | vauthors = Wadler CS, Vanderpool CK | title = A dual function for a bacterial small RNA: SgrS performs base pairing-dependent regulation and encodes a functional polypeptide | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 51 | pages = 20454–9 | date = December 2007 | pmid = 18042713 | pmc = 2154452 | doi = 10.1073/pnas.0708102104 | bibcode = 2007PNAS..10420454W | doi-access = free }}</ref><ref name="pmid19043537">{{cite journal | vauthors = Dinger ME, Pang KC, Mercer TR, Mattick JS | title = Differentiating protein-coding and noncoding RNA: challenges and ambiguities | journal = PLOS Computational Biology | volume = 4 | issue = 11 | pages = e1000176 | date = November 2008 | pmid = 19043537 | pmc = 2518207 | doi = 10.1371/journal.pcbi.1000176 | editor1-last = McEntyre | bibcode = 2008PLSCB...4E0176D | editor1-first = Johanna | doi-access = free }}</ref> The majority of the known bifunctional RNAs are mRNAs that encode both a protein and ncRNAs. However, a growing number of ncRNAs fall into two different ncRNA categories; e.g., [[snoRNA|H/ACA box snoRNA]] and [[miRNA]].<ref name="pmid19043559">{{cite journal | vauthors = Saraiya AA, Wang CC | title = snoRNA, a novel precursor of microRNA in Giardia lamblia | journal = PLOS Pathogens | volume = 4 | issue = 11 | pages = e1000224 | date = November 2008 | pmid = 19043559 | pmc = 2583053 | doi = 10.1371/journal.ppat.1000224 | editor1-last = Goldberg | editor1-first = Daniel Eliot | doi-access = free }}</ref><ref name="pmid19026782">{{cite journal | vauthors = Ender C, Krek A, Friedländer MR, Beitzinger M, Weinmann L, Chen W, Pfeffer S, Rajewsky N, Meister G | title = A human snoRNA with microRNA-like functions | journal = Molecular Cell | volume = 32 | issue = 4 | pages = 519–28 | date = November 2008 | pmid = 19026782 | doi = 10.1016/j.molcel.2008.10.017 | doi-access = free }}</ref>
Two well known examples of bifunctional RNAs are [[SgrS RNA]] and [[RNAIII]]. However, a handful of other bifunctional RNAs are known to exist (e.g., steroid receptor activator/SRA,<ref name="pmid17710122">{{cite journal | vauthors = Leygue E | title = Steroid receptor RNA activator (SRA1): unusual bifaceted gene products with suspected relevance to breast cancer | journal = Nuclear Receptor Signaling | volume = 5 | pages = e006 | date = August 2007 | pmid = 17710122 | pmc = 1948073 | doi = 10.1621/nrs.05006 }}</ref> VegT RNA,<ref name="pmid9012531">{{cite journal | vauthors = Zhang J, King ML | title = Xenopus VegT RNA is localized to the vegetal cortex during oogenesis and encodes a novel T-box transcription factor involved in mesodermal patterning | journal = Development | volume = 122 | issue = 12 | pages = 4119–29 | date = December 1996 | doi = 10.1242/dev.122.12.4119 | pmid = 9012531 | s2cid = 28462527 }}</ref><ref name="pmid16000384">{{cite journal | vauthors = Kloc M, Wilk K, Vargas D, Shirato Y, Bilinski S, Etkin LD | title = Potential structural role of non-coding and coding RNAs in the organization of the cytoskeleton at the vegetal cortex of Xenopus oocytes | journal = Development | volume = 132 | issue = 15 | pages = 3445–57 | date = August 2005 | pmid = 16000384 | doi = 10.1242/dev.01919 | doi-access = free }}</ref>
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=== As a hormone ===
There is an important link between certain non-coding RNAs and the control of hormone-regulated pathways. In ''[[Drosophila]]'', hormones such as [[ecdysone]] and [[juvenile hormone]] can promote the expression of certain miRNAs. Furthermore, this regulation occurs at distinct temporal points within ''Caenorhabditis elegans'' development.<ref>{{cite journal | vauthors = Sempere LF, Sokol NS, Dubrovsky EB, Berger EM, Ambros V | title = Temporal regulation of microRNA expression in Drosophila melanogaster mediated by hormonal signals and broad-Complex gene activity | journal = Developmental Biology | volume = 259 | issue = 1 | pages = 9–18 | date = July 2003 | pmid = 12812784 | doi = 10.1016/S0012-1606(03)00208-2 | s2cid = 17249847 | doi-access = free }}</ref> In mammals, [[Mir-206|miR-206]] is a crucial regulator of [[estrogen]]-receptor-alpha.<ref>{{cite journal | vauthors = Adams BD, Furneaux H, White BA | title = The micro-ribonucleic acid (miRNA) miR-206 targets the human estrogen receptor-alpha (ERalpha) and represses ERalpha messenger RNA and protein expression in breast cancer cell lines | journal = Molecular Endocrinology | volume = 21 | issue = 5 | pages = 1132–47 | date = May 2007 | pmid = 17312270 | doi = 10.1210/me.2007-0022 | doi-access = free }}</ref>
Non-coding RNAs are crucial in the development of several endocrine organs, as well as in endocrine diseases such as [[diabetes mellitus]].<ref>{{cite journal | vauthors = Knoll M, Lodish HF, Sun L | title = Long non-coding RNAs as regulators of the endocrine system | journal = Nature Reviews. Endocrinology | volume = 11 | issue = 3 | pages = 151–60 | date = March 2015 | pmid = 25560704 | pmc = 4376378 | doi = 10.1038/nrendo.2014.229 | hdl = 1721.1/116703 }}</ref> Specifically in the MCF-7 cell line, addition of 17β-[[estradiol]] increased global transcription of the noncoding RNAs called lncRNAs near estrogen-activated coding genes.<ref>{{cite journal | vauthors = Li W, Notani D, Ma Q, Tanasa B, Nunez E, Chen AY, Merkurjev D, Zhang J, Ohgi K, Song X, Oh S, Kim HS, Glass CK, Rosenfeld MG | title = Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation | journal = Nature | volume = 498 | issue = 7455 | pages = 516–20 | date = June 2013 | pmid = 23728302 | pmc = 3718886 | doi = 10.1038/nature12210 | bibcode = 2013Natur.498..516L }}</ref>
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Many ncRNAs show abnormal expression patterns in [[cancer]]ous tissues.<ref name="Shahrouki P 2012"/> These include [[microRNA|miRNAs]], [[Long noncoding RNA#Long non-coding RNAs in disease|long mRNA-like ncRNAs]],<ref name="pmid11890990">{{cite journal | vauthors = Pibouin L, Villaudy J, Ferbus D, Muleris M, Prospéri MT, Remvikos Y, Goubin G | title = Cloning of the mRNA of overexpression in colon carcinoma-1: a sequence overexpressed in a subset of colon carcinomas | journal = Cancer Genetics and Cytogenetics | volume = 133 | issue = 1 | pages = 55–60 | date = February 2002 | pmid = 11890990 | doi = 10.1016/S0165-4608(01)00634-3 }}</ref><ref name="pmid16569192">{{cite journal | vauthors = Fu X, Ravindranath L, Tran N, Petrovics G, Srivastava S | title = Regulation of apoptosis by a prostate-specific and prostate cancer-associated noncoding gene, PCGEM1 | journal = DNA and Cell Biology | volume = 25 | issue = 3 | pages = 135–41 | date = March 2006 | pmid = 16569192 | doi = 10.1089/dna.2006.25.135 }}</ref> [[GAS5]],<ref name="pmid18836484">{{cite journal | vauthors = Mourtada-Maarabouni M, Pickard MR, Hedge VL, Farzaneh F, Williams GT | title = GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer | journal = Oncogene | volume = 28 | issue = 2 | pages = 195–208 | date = January 2009 | pmid = 18836484 | doi = 10.1038/onc.2008.373 | doi-access = free }}</ref> [[Small nucleolar RNA SNORD50|SNORD50]],<ref name="pmid19683667">{{cite journal | vauthors = Dong XY, Guo P, Boyd J, Sun X, Li Q, Zhou W, Dong JT | title = Implication of snoRNA U50 in human breast cancer | journal = Journal of Genetics and Genomics = Yi Chuan Xue Bao | volume = 36 | issue = 8 | pages = 447–54 | date = August 2009 | pmid = 19683667 | pmc = 2854654 | doi = 10.1016/S1673-8527(08)60134-4 }}</ref> [[telomerase RNA]] and [[Y RNA]]s.<ref name="pmid18283318">{{cite journal | vauthors = Christov CP, Trivier E, Krude T | title = Noncoding human Y RNAs are overexpressed in tumours and required for cell proliferation | journal = British Journal of Cancer | volume = 98 | issue = 5 | pages = 981–8 | date = March 2008 | pmid = 18283318 | pmc = 2266855 | doi = 10.1038/sj.bjc.6604254 }}</ref> The miRNAs are involved in the large scale regulation of many protein coding genes,<ref name="pmid16308420">{{cite journal | vauthors = Farh KK, Grimson A, Jan C, Lewis BP, Johnston WK, Lim LP, Burge CB, Bartel DP | title = The widespread impact of mammalian MicroRNAs on mRNA repression and evolution | journal = Science | volume = 310 | issue = 5755 | pages = 1817–21 | date = December 2005 | pmid = 16308420 | doi = 10.1126/science.1121158 | bibcode = 2005Sci...310.1817F | s2cid = 1849875 }}</ref><ref name="pmid15685193">{{cite journal | vauthors = Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP, Linsley PS, Johnson JM | title = Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs | journal = Nature | volume = 433 | issue = 7027 | pages = 769–73 | date = February 2005 | pmid = 15685193 | doi = 10.1038/nature03315 | bibcode = 2005Natur.433..769L | s2cid = 4430576 }}</ref> the Y RNAs are important for the initiation of DNA replication,<ref name="pmid16943439"/> telomerase RNA that serves as a primer for telomerase, an RNP that extends [[Telomere|telomeric regions]] at chromosome ends (see [[Telomere#Human telomeres.2C cancer.2C and ALT.|telomeres and disease]] for more information). The direct function of the long mRNA-like ncRNAs is less clear.
[[Germ-line]] mutations in [[Mir-16 microRNA precursor family|miR-16-1]] and [[Mir-15 microRNA precursor family|miR-15]] primary precursors have been shown to be much more frequent in patients with [[chronic lymphocytic leukemia]] compared to control populations.<ref name="pmid16251535">{{cite journal | vauthors = Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, Iorio MV, Visone R, Sever NI, Fabbri M, Iuliano R, Palumbo T, Pichiorri F, Roldo C, Garzon R, Sevignani C, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM | title = A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia | journal = The New England Journal of Medicine | volume = 353 | issue = 17 | pages = 1793–801 | date = October 2005 | pmid = 16251535 | doi = 10.1056/NEJMoa050995 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, Aldler H, Rattan S, Keating M, Rai K, Rassenti L, Kipps T, Negrini M, Bullrich F, Croce CM | title = Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 24 | pages = 15524–9 | date = November 2002 | pmid = 12434020 | pmc = 137750 | doi = 10.1073/pnas.242606799 | bibcode = 2002PNAS...9915524C | doi-access = free }}</ref>
It has been suggested that a rare [[Single-nucleotide polymorphism|SNP]] ([[rs11614913]]) that overlaps [[Mir-196 microRNA precursor family|hsa-mir-196a-2]] has been found to be associated with [[non-small cell lung carcinoma]].<ref name="pmid18521189">{{cite journal | vauthors = Hu Z, Chen J, Tian T, Zhou X, Gu H, Xu L, Zeng Y, Miao R, Jin G, Ma H, Chen Y, Shen H | title = Genetic variants of miRNA sequences and non-small cell lung cancer survival | journal = The Journal of Clinical Investigation | volume = 118 | issue = 7 | pages = 2600–8 | date = July 2008 | pmid = 18521189 | pmc = 2402113 | doi = 10.1172/JCI34934 }}</ref> Likewise, a screen of 17 miRNAs that have been predicted to regulate a number of breast cancer associated genes found variations in the microRNAs [[Mir-17 microRNA precursor family|miR-17]] and [[Mir-30 microRNA precursor|miR-30c-1]]of patients; these patients were noncarriers of [[BRCA1]] or [[BRCA2]] mutations, lending the possibility that familial breast cancer may be caused by variation in these miRNAs.<ref name="pmid19048628">{{cite journal | vauthors = Shen J, Ambrosone CB, Zhao H | title = Novel genetic variants in microRNA genes and familial breast cancer | journal = International Journal of Cancer | volume = 124 | issue = 5 | pages = 1178–82 | date = March 2009 | pmid = 19048628 | doi = 10.1002/ijc.24008 | s2cid = 20960029 | doi-access = free }}</ref>
The [[p53]] tumor suppressor is arguably the most important agent in preventing tumor formation and progression. The p53 protein functions as a transcription factor with a crucial role in orchestrating the cellular stress response. In addition to its crucial role in cancer, p53 has been implicated in other diseases including diabetes, cell death after ischemia, and various neurodegenerative diseases such as Huntington, Parkinson, and Alzheimer. Studies have suggested that p53 expression is subject to regulation by non-coding RNA.<ref name="MorrisKV"/>
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===Cartilage–hair hypoplasia===
Mutations within [[RNase MRP]] have been shown to cause [[cartilage–hair hypoplasia]], a disease associated with an array of symptoms such as short stature, sparse hair, skeletal abnormalities and a suppressed immune system that is frequent among [[Amish]] and [[Finland|Finnish]].<ref name="pmid11207361">{{cite journal | vauthors = Ridanpää M, van Eenennaam H, Pelin K, Chadwick R, Johnson C, Yuan B, vanVenrooij W, Pruijn G, Salmela R, Rockas S, Mäkitie O, Kaitila I, de la Chapelle A | title = Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia | journal = Cell | volume = 104 | issue = 2 | pages = 195–203 | date = January 2001 | pmid = 11207361 | doi = 10.1016/S0092-8674(01)00205-7 | s2cid = 13977736 | doi-access = free }}</ref><ref name="pmid17189938">{{cite journal | vauthors = Martin AN, Li Y | title = RNase MRP RNA and human genetic diseases | journal = Cell Research | volume = 17 | issue = 3 | pages = 219–26 | date = March 2007 | pmid = 17189938 | doi = 10.1038/sj.cr.7310120 | doi-access = free }}</ref><ref name="pmid18804272">{{cite journal | vauthors = Kavadas FD, Giliani S, Gu Y, Mazzolari E, Bates A, Pegoiani E, Roifman CM, Notarangelo LD | title = Variability of clinical and laboratory features among patients with ribonuclease mitochondrial RNA processing endoribonuclease gene mutations | journal = The Journal of Allergy and Clinical Immunology | volume = 122 | issue = 6 | pages = 1178–84 | date = December 2008 | pmid = 18804272 | doi = 10.1016/j.jaci.2008.07.036 | doi-access = free }}</ref> The best characterised variant is an A-to-G [[Transition (genetics)|transition]] at nucleotide 70 that is in a loop region two bases 5' of a [[Conserved sequence|conserved]] [[pseudoknot]]. However, many other mutations within RNase MRP also cause CHH.
===Alzheimer's disease===
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===Mitochondrial transfer RNAs===
A number of mutations within mitochondrial tRNAs have been linked to diseases such as [[MELAS syndrome]], [[MERRF syndrome]], and [[chronic progressive external ophthalmoplegia]].<ref>{{cite journal |last1=Taylor |first1=RW |last2=Turnbull |first2=DM |title=Mitochondrial DNA mutations in human disease. |journal=Nature Reviews. Genetics |date=May 2005 |volume=6 |issue=5 |pages=389–402 |doi=10.1038/nrg1606 |pmid=15861210|pmc=1762815 }}</ref><ref>{{cite journal |last1=Yarham |first1=JW |last2=Elson |first2=JL |last3=Blakely |first3=EL |last4=McFarland |first4=R |last5=Taylor |first5=RW |title=Mitochondrial tRNA mutations and disease. |journal=Wiley Interdisciplinary Reviews: RNA |date=September 2010 |volume=1 |issue=2 |pages=304–24 |doi=10.1002/wrna.27 |pmid=21935892|s2cid=43123827 }}</ref><ref>{{cite journal |last1=Zifa |first1=E |last2=Giannouli |first2=S |last3=Theotokis |first3=P |last4=Stamatis |first4=C |last5=Mamuris |first5=Z |last6=Stathopoulos |first6=C |title=Mitochondrial tRNA mutations: clinical and functional perturbations. |journal=RNA Biology |date=January 2007 |volume=4 |issue=1 |pages=38–66 |doi=10.4161/rna.4.1.4548 |pmid=17617745|s2cid=11965790 |doi-access=free }}</ref><ref>{{cite journal |last1=Abbott |first1=JA |last2=Francklyn |first2=CS |last3=Robey-Bond |first3=SM |title=Transfer RNA and human disease. |journal=Frontiers in Genetics |date=2014 |volume=5 |pages=158 |doi=10.3389/fgene.2014.00158 |pmid=24917879|pmc=4042891 |doi-access=free }}</ref>
==Distinction between functional RNA (fRNA) and ncRNA==
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