Skip to main content
Article thumbnail
Location of Repository

The Genetic Signatures of Noncoding RNAs

By John S. Mattick

Abstract

The majority of the genome in animals and plants is transcribed in a developmentally regulated manner to produce large numbers of non–protein-coding RNAs (ncRNAs), whose incidence increases with developmental complexity. There is growing evidence that these transcripts are functional, particularly in the regulation of epigenetic processes, leading to the suggestion that they compose a hitherto hidden layer of genomic programming in humans and other complex organisms. However, to date, very few have been identified in genetic screens. Here I show that this is explicable by an historic emphasis, both phenotypically and technically, on mutations in protein-coding sequences, and by presumptions about the nature of regulatory mutations. Most variations in regulatory sequences produce relatively subtle phenotypic changes, in contrast to mutations in protein-coding sequences that frequently cause catastrophic component failure. Until recently, most mapping projects have focused on protein-coding sequences, and the limited number of identified regulatory mutations have been interpreted as affecting conventional cis-acting promoter and enhancer elements, although these regions are often themselves transcribed. Moreover, ncRNA-directed regulatory circuits underpin most, if not all, complex genetic phenomena in eukaryotes, including RNA interference-related processes such as transcriptional and post-transcriptional gene silencing, position effect variegation, hybrid dysgenesis, chromosome dosage compensation, parental imprinting and allelic exclusion, paramutation, and possibly transvection and transinduction. The next frontier is the identification and functional characterization of the myriad sequence variations that influence quantitative traits, disease susceptibility, and other complex characteristics, which are being shown by genome-wide association studies to lie mostly in noncoding, presumably regulatory, regions. There is every possibility that many of these variations will alter the interactions between regulatory RNAs and their targets, a prospect that should be borne in mind in future functional analyses

Topics: Review
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:2667263
Provided by: PubMed Central
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://www.pubmedcentral.nih.g... (external link)
  • Suggested articles

    Citations

    1. (2004). A
    2. (2008). A catalog of published genomewide association studies. Available at:
    3. (2007). A common allele on chromosome 9 associated with coronary heart disease.
    4. (2007). A common variant on chromosome 9p21 affects the risk of myocardial infarction.
    5. (2006). A distant upstream enhancer at the maize domestication gene tb1 has pleiotropic effects on plant and inflorescent architecture.
    6. (2007). A genomewide association study of global gene expression.
    7. (2007). A genomewide association study of type 2 diabetes in Finns detects multiple susceptibility variants.
    8. (2008). A HapMap harvest of insights into the genetics of common disease.
    9. (2003). A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans.
    10. (2006). A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep.
    11. (2009). A myelopoiesis-associated regulatory intergenic non-coding RNA transcript within the human HOXA cluster.
    12. (2008). A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition.
    13. (2005). A new frontier for molecular medicine: noncoding RNAs.
    14. (2007). A new paradigm for developmental biology.
    15. (2006). A noncoding RNA is a potential marker of cell fate during mammary gland development.
    16. (2002). A noncoding RNA regulates human protease-activated receptor-1 gene during embryogenesis.
    17. (2008). A position effect on the heritability of epigenetic silencing.
    18. (2003). A regulatory mutation in IGF2 causes a major QTL effect on muscle growth in the pig.
    19. (2006). A regulatory SNP causes a human genetic disease by creating a new transcriptional promoter.
    20. (2008). A starvation-induced noncoding RNA modulates expression of Dicer-regulated genes.
    21. (2005). A strategy for probing the function of noncoding RNAs finds a repressor of NFAT.
    22. (2009). A susceptibility locus for papillary thyroid carcinoma on chromosome 8q24.
    23. (2006). A translation-independent role of oskar RNA in early Drosophila oogenesis.
    24. (2007). Activation of p53 by MEG3 non-coding RNA.
    25. (1999). aHIF: a natural antisense transcript overexpressed in human renal cancer and during hypoxia.
    26. (2007). Akoulitchev A
    27. (2007). Alternately spliced WT1 antisense transcripts interact with WT1 sense RNA and show epigenetic and splicing defects in cancer.
    28. (2004). An abundance of bidirectional promoters in the human genome.
    29. (2004). An antisense RNA regulates the bidirectional silencing property of the Kcnq1 imprinting control region.
    30. (2009). An architectural role for a nuclear noncoding RNA: NEAT1 RNA Is essential for the structure of paraspeckles. Mol Cell, epub ahead of print;
    31. (2008). An epigenetic role for maternally inherited piRNAs in transposon silencing.
    32. (2006). An RNA gene expressed during cortical development evolved rapidly in humans.
    33. (2006). Analysis of a new homozygous deletion in the tumor suppressor region at 3p12.3 reveals two novel intronic noncoding RNA genes.
    34. (2004). Antisense intronic non-coding RNA levels correlate to the degree of tumor differentiation in prostate cancer.
    35. (2007). Antisense RNA stabilization induces transcriptional gene silencing via histone deacetylation in S.
    36. (2005). Antisense transcription in the mammalian transcriptome.
    37. (2001). Antisense transcription through the Xist locus mediates Tsix function in embryonic stem cells.
    38. (2007). Appearances can be deceiving: phenotypes of knockout mice.
    39. (2003). bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila.
    40. (1999). Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests.
    41. (2008). Biogenesis and germline functions of piRNAs.
    42. (2006). Calbindin D(9k) knockout mice are indistinguishable from wild-type mice in phenotype and serum calcium level.
    43. (2003). Challenging the dogma: the hidden layer of non-proteincoding RNAs in complex organisms.
    44. (2007). Characterization of a germ-line deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding RNA whose expression coclusters with ARF.
    45. (2009). Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals.
    46. (1999). Cis and trans effects of the myotonic dystrophy (DM) mutation in a cell culture model.
    47. (1995). Cis and trans interactions between the iab regulatory regions and abdominal-A and abdominal-B in Drosophila melanogaster.
    48. (2008). Comparative genomics beyond sequence-based alignments: RNA structures in the ENCODE regions.
    49. (2006). Complex loci in human and mouse genomes.
    50. (2006). Conservation of RET regulatory function from human to zebrafish without sequence similarity.
    51. (2000). Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA.
    52. (2008). Conserved tissue expression signatures of intronic noncoding RNAs transcribed from human and mouse loci.
    53. (2007). Control of stress-dependent cardiac growth and gene expression by a microRNA.
    54. (2005). Deletion at chromosome band 20p12.1 in colorectal cancer revealed by high resolution array comparative genomic hybridization.
    55. (2007). Deletion of ultraconserved elements yields viable mice.
    56. (2004). Developmental regulation of EVF-1, a novel noncoding RNA transcribed upstream of the mouse Dlx6 gene.
    57. (2008). Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II.
    58. (2008). Differentiating proteincoding and noncoding RNA: challenges and ambiguities.
    59. (2000). Disruption of two novel genes by a translocation co-segregating with schizophrenia.
    60. (2004). DLEU2 encodes an antisense RNA for the putative bicistronic RFP2/ LEU5 gene in humans and mouse.
    61. (2007). Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2.
    62. (2007). EGO, a novel, non-coding RNA gene, regulates eosinophil granule protein transcript expression.
    63. (2001). Endogenous Msx1 antisense transcript: in vivo and in vitro evidences, structure, and potential involvement in skeleton development in mammals.
    64. (2008). Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes.
    65. (2008). Epigenetic events in mammalian germ-cell development: reprogramming and beyond.
    66. (2008). Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA.
    67. (2007). Eukaryotic regulatory RNAs: an answer to the ‘genome complexity’ conundrum.
    68. (2004). Evidence for turnover of functional noncoding DNA in mammalian genome evolution.
    69. (2008). Evo-devo and an expanding evolutionary synthesis: a genetic theory of morphological evolution.
    70. (2003). Evolutionary discrimination of mammalian conserved non-genic sequences (CNGs).
    71. (2006). Evolutionary turnover of mammalian transcription start sites.
    72. (2005). Examples of the complex architecture of the human transcriptome revealed by RACE and highdensity tiling arrays.
    73. (2006). Experimental validation of the regulated expression of large numbers of noncoding RNAs from the mouse genome.
    74. (2008). Expression of a noncoding RNA is elevated in Alzheimer’s disease and drives rapid feed-forward regulation of beta-secretase.
    75. (2006). Forces shaping the fastest evolving regions in the human genome.
    76. (2007). Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs.
    77. (2008). Functional genomics of cancer.
    78. (2007). Functionality or transcriptional noise? Evidence for selection within long noncoding RNAs.
    79. (1993). Genetic complementation reveals a novel regulatory role for 39 untranslated regions in growth and differentiation.
    80. (2007). Genetic screens for Caenorhabditis elegans mutants defective in left/right asymmetric neuronal fate specification.
    81. (2006). Genome-wide analysis of mammalian promoter architecture and evolution.
    82. (2007). Genome-wide transcription and the implications for genomic organization.
    83. (2008). genomic contraction and imprinted repression in early mouse embryos.
    84. (2008). Growth arrest in human T-cells is controlled by the non-coding RNA growth-arrest-specific transcript 5 (GAS5).
    85. (2006). Hearing silence: non-neutral evolution at synonymous sites in mammals.
    86. (2004). Heterochromatic silencing and HP1 localization in Drosophila are dependent on the RNAi machinery.
    87. (2006). Heterotachy in mammalian promoter evolution.
    88. (2008). How does noncoding transcription regulate Hox genes?
    89. (2000). HoxC cluster genes are dispensable for overall body plan of mouse embryonic development.
    90. (2007). Human genome ultraconserved elements are ultraselected.
    91. (2005). Identification and characterization of a novel gene Saf transcribed from the opposite strand of Fas.
    92. (2005). Identification and characterization of a novel, psoriasis susceptibilityrelated noncoding RNA gene,
    93. (2005). Identification and expression analysis of putative mRNA-like non-coding RNA
    94. (1998). Identification of a novel bone morphogenetic protein-responsive gene that may function as a noncoding RNA.
    95. (2006). Identification of a novel non-coding RNA, MIAT, that confers risk of myocardial infarction.
    96. (2009). Identification of a shared genetic susceptibility locus for coronary heart disease and periodontitis.
    97. (2005). Identification of hundreds of conserved and nonconserved human microRNAs.
    98. (2005). Identification of putative noncoding polyadenylated transcripts in Drosophila melanogaster.
    99. (2005). In vivo characterization of a vertebrate ultraconserved enhancer.
    100. (2006). In vivo enhancer analysis of human conserved non-coding sequences.
    101. (2008). Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription.
    102. (2007). Induction of drug resistance and transformation in human cancer cells by the noncoding RNA CUDR.
    103. (2008). Inherited variation at the epigenetic level: paramutation from the plant to the mouse.
    104. (1997). Intergenic transcription and transinduction of the human beta-globin locus.
    105. (2006). Intergenic transcripts regulate the epigenetic state of rRNA genes.
    106. (2008). Intersection of the RNA interference and Xinactivation pathways.
    107. (2007). Intronic microRNA precursors that bypass Drosha processing.
    108. (2000). Intronic U50 small-nucleolar-RNA (snoRNA) host gene of no protein-coding potential is mapped at the chromosome breakpoint t(3;6)(q27;q15) of human B-cell lymphoma.
    109. (2008). Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation.
    110. (2005). Lack of Pwcr1/MBII-85 snoRNA is critical for neonatal lethality in PraderWilli syndrome mouse models.
    111. (2008). Large-scale appearance of ultraconserved elements in tetrapod genomes and slowdown of the molecular clock.
    112. (2005). Large-scale transcriptome analyses reveal new genetic marker candidates of head, neck, and thyroid cancer.
    113. (2007). let-7 regulates self renewal and tumorigenicity of breast cancer cells.
    114. (2009). Long intronic noncoding RNA transcription: expression noise or expression choice?
    115. (2009). Long non-coding RNAs: insights into functions.
    116. (2008). Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation.
    117. (2008). Long, abundantly expressed non-coding transcripts are altered in cancer.
    118. (2003). MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer.
    119. (2001). Male sterility associated with overexpression of the noncoding hsromega gene in cyst cells of testis of Drosophila melanogaster.
    120. (2007). Mammalian mirtron genes.
    121. (2006). Many novel mammalian microRNA candidates identified by extensive cloning and RAKE analysis.
    122. (2005). Mapping of conserved RNA secondary structures predicts thousands of functional noncoding RNAs in the human genome.
    123. (1985). Martinez-Arias A
    124. (2009). MEN e/b nuclear-retained non-coding RNAs are up-regulated upon muscle differentiation and are essential components of paraspeckles.
    125. (2009). MENepsilon/beta noncoding RNAs are essential for structural integrity of nuclear paraspeckles.
    126. (2003). Mosaicism of Solid Gold supports the causality of a noncoding A-to-G transition in the determinism of the callipyge phenotype.
    127. (2008). Nkx2.2 antisense RNA overexpression enhanced oligodendrocytic differentiation.
    128. (2006). Non-coding RNA.
    129. (2008). Non-coding RNAs take centre stage in epithelial-tomesenchymal transition.
    130. (2008). Non-coding RNAs, epigenetics and complexity.
    131. (2008). Noncoding human Y RNAs are overexpressed in tumours and required for cell proliferation.
    132. (2008). Noncoding RNA in development.
    133. (2007). Noncoding RNAs and intranuclear positioning in monoallelic gene expression.
    134. (2006). Noncoding RNAs of trithorax response elements recruit Drosophila Ash1 to Ultrabithorax.
    135. (2007). Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS
    136. (2009). Novel long non-protein coding RNAs involved in Arabidopsis differentiation and stress responses.
    137. (2006). Novel transcription factor zfh-5 is negatively regulated by its own antisense RNA in mouse brain.
    138. (1987). Novel transcripts from the Ultrabithorax domain of the bithorax complex.
    139. (2002). Numerous potentially functional but non-genic conserved sequences on human chromosome 21.
    140. (2006). Oncomirs - microRNAs with a role in cancer.
    141. (2008). p53 mRNA controls p53 activity by managing Mdm2 functions.
    142. (2007). Paramutation: from maize to mice.
    143. (2008). Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome.
    144. (2006). Post-transcriptional small RNA pathways in plants: mechanisms and regulations.
    145. (1993). Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C.
    146. (2008). Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster.
    147. (2008). Prediction of individual genetic risk of complex disease.
    148. (2008). Preferential reciprocal transfer of paternal/maternal DLK1 alleles to obese children: first evidence of polar overdominance in humans.
    149. (1996). Prohibitin in breast cancer cell lines: loss of antiproliferative activity is linked to 39 untranslated region mutations.
    150. (2008). Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes.
    151. (2007). Raising the estimate of functional human sequences.
    152. (2006). Rapid evolution of noncoding RNAs: lack of conservation does not mean lack of function.
    153. (2005). RAS is regulated by the let-7 microRNA family.
    154. (2006). Regulation of apoptosis by a prostate-specific and prostate cancer-associated noncoding gene, PCGEM1.
    155. (2007). Regulation of the germinal center response by microRNA-155.
    156. (2007). Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.
    157. (2007). Requirement of bic/microRNA-155 for normal immune function.
    158. (2009). RNA regulation of epigenetic processes.
    159. (2006). RNA-dominant diseases.
    160. (2007). RNAdb 2.0–an expanded database of mammalian non-coding RNAs.
    161. (2005). RNAi-mediated allelic trans-interaction at the imprinted Rtl1/Peg11 locus.
    162. (2006). RNAmediated response to heat shock in mammalian cells.
    163. (2004). Role of a neuronal small non-messenger RNA: behavioural alterations in BC1 RNA-deleted mice.
    164. (2008). Small non-coding RNAs in animal development.
    165. (2007). Small noncoding RNAs controlling pathogenesis.
    166. (2004). SNPs in the promoter of a B cell-specific antisense transcript, SAS-ZFAT, determine susceptibility to autoimmune thyroid disease.
    167. (1989). Spatially ordered transcription of regulatory DNA in the bithorax complex of Drosophila.
    168. (2008). Specific expression of long noncoding RNAs in the mouse brain.
    169. (2005). Structural and functional characterization of noncoding repetitive RNAs transcribed in stressed human cells.
    170. (1996). Suppression of malignancy by the 39 untranslated regions of ribonucleotide reductase R1 and R2 messenger RNAs.
    171. (2008). Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p.
    172. (2007). Targets of RNA-directed DNA methylation.
    173. (2007). Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends.
    174. (2000). The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans.
    175. (1996). The 39 untranslated region of prohibitin and cellular immortalization.
    176. (2008). The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin.
    177. (2002). The bantam gene regulates Drosophila growth.
    178. (1987). The bithorax complex.
    179. (1993). The C. elegans heterochronic gene lin4 encodes small RNAs with antisense complementarity to lin-14.
    180. (2003). The callipyge locus: evidence for the trans interaction of reciprocally imprinted genes.
    181. (2008). The Drosophila hairpin RNA pathway generates endogenous short interfering RNAs.
    182. (2001). The evolution of controlled multitasked gene networks: the role of introns and other noncoding RNAs in the development of complex organisms.
    183. (2006). The H19 gene: regulation and function of a non-coding RNA.
    184. (2008). The H19 locus acts in vivo as a tumor suppressor.
    185. (2007). The H19 non-coding RNA is essential for human tumor growth.
    186. (2005). The HS2 enhancer of the beta-globin locus control region initiates synthesis of non-coding, polyadenylated RNAs independent of a cis-linked globin promoter.
    187. (2008). The impact of p53 and p73 on aneuploidy and cancer.
    188. (2006). The imprinted Air ncRNA is an atypical RNAPII transcript that evades splicing and escapes nuclear export.
    189. (2008). The let-7 family of microRNAs.
    190. (2009). The long noncoding RNA Kcnq1ot1 organises a lineage-specific nuclear domain for epigenetic gene silencing.
    191. (2008). The LPSinduced transcriptional upregulation of the chicken lysozyme locus involves CTCF eviction and noncoding RNA transcription.
    192. (1999). The mcp element from the Drosophila melanogaster bithorax complex mediates long-distance regulatory interactions.
    193. (2006). The Mcp element mediates stable long-range chromosome-chromosome interactions in Drosophila.
    194. (2007). The mirtron pathway generates microRNA-class regulatory RNAs in Drosophila.
    195. (2007). The mRNAlike noncoding RNA Gomafu constitutes a novel nuclear domain in a subset of neurons.
    196. (2002). The non-coding Air RNA is required for silencing autosomal imprinted genes.
    197. (2009). The non-coding RNA gadd7 is a regulator of lipid-induced oxidative and ER stress.
    198. (2005). The noncoding RNA taurine upregulated gene 1 is required for differentiation of the murine retina.
    199. (2007). The Piwi-piRNA pathway provides an adaptive defense in the transposon arms race.
    200. (2007). The relationship between non-proteincoding DNA and eukaryotic complexity.
    201. (2004). The spinocerebellar ataxia 8 noncoding RNA causes neurodegeneration and associates with staufen in Drosophila.
    202. (2009). The subcellular distribution of an RNA quality control protein, the ro autoantigen, is regulated by noncoding y RNA binding.
    203. (2005). The transcriptional landscape of the mammalian genome.
    204. (2006). Thousands of corresponding human and mouse genomic regions unalignable in primary sequence contain common RNA structure.
    205. (2007). Transcription and RNAi in heterochromatic gene silencing.
    206. (2003). Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease.
    207. (2006). Transcription of bxd noncoding RNAs promoted by trithorax represses Ubx in cis by transcriptional interference.
    208. (2000). Transcriptional silencing and promoter methylation triggered by doublestranded RNA.
    209. (2008). Translational control by a small RNA: dendritic BC1 RNA targets the eukaryotic initiation factor 4A helicase mechanism.
    210. (2002). Transvection effects in Drosophila.
    211. (1998). Transvection in the Drosophila Abd-B domain: extensive upstream sequences are involved in anchoring distant cis-regulatory regions to the promoter.
    212. (1995). Transvection in the iab-5,6,7 region of the bithorax complex of Drosophila: homology independent interactions in trans.
    213. (2005). Tsix silences Xist through modification of chromatin structure.
    214. (1999). Tsix, a gene antisense to Xist at the X-inactivation centre.
    215. (1993). Tumor suppression by RNA from the 39 untranslated region of alpha-tropomyosin.
    216. (2006). Two or four bristles: functional evolution of an enhancer of scute in Drosophilidae.
    217. (2008). UCA1, a non-protein-coding RNA up-regulated in bladder carcinoma and embryo, influencing cell growth and promoting invasion.
    218. (2008). Ultraconservation identifies a small subset of extremely constrained developmental enhancers.
    219. (2004). Ultraconserved elements in the human genome.
    220. (2007). Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas.
    221. (2004). Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of noncoding RNAs.
    222. (2007). Wutz A
    223. (2008). Zm401, a short-open readingframe mRNA or noncoding RNA, is essential for tapetum and microspore development and can regulate the floret formation in maize.

    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.