Biochemistry (Moscow)

, Volume 83, Issue 11, pp 1332–1349 | Cite as

Pseudogenes as Functionally Significant Elements of the Genome

  • T. F. KovalenkoEmail author
  • L. I. Patrushev


Pseudogene is a gene copy that has lost its original function. For a long time, pseudogenes have been considered as “junk DNA” that inevitably arises as a result of ongoing evolutionary process. However, experimental data obtained during recent years indicate this understanding of the nature of pseudogenes is not entirely correct, and many pseudogenes perform important genetic functions. In the review, we have addressed classification of pseudogenes, methods of their detection in the genome, and the problem of their evolutionary conservatism and prevalence among species belonging to different taxonomic groups in the light of modern data. The mechanisms of gene expression regulation by pseudogenes and the role of pseudogenes in pathogenesis of various human diseases are discussed.


pseudogene pseudogene transcription ceRNA lncRNA miRNA 



antisense RNA


competing endogenous RNA


enhancer RNA


genes of high-mobility group A1


long non-coding RNA


mitogen-activated protein kinase




miRNA response elements


mitochondrial DNA


next generation sequencing


nuclear mitochondrial (pseudogenes)


open reading frame


small RNA that interacts with PIWI proteins


RNA of transcribed pseudogenes


RNA interference


small interfering RNA


sense RNA


untranslated region


pseudogene of variable domains of immunoglobulins


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Jacq, C., Miller, J. R., and Brownlee, G. G. (1977) A pseudogene structure in 5S DNA of Xenopus laevis, Cell, 12, 109–120.PubMedCrossRefGoogle Scholar
  2. 2.
    Arnold, G. J., Kahnt, B., Herrenknecht, K., and Gross, H. J. (1987) A variant gene and a pseudogene for human 5S RNA are transcriptionally active in vitro, Gene, 60, 137–144.PubMedCrossRefGoogle Scholar
  3. 3.
    Chiang, J. J., Sparrer, K. M. J., van Gent, M., Lassig, C., Huang, T., Osterrieder, N., Hopfner, K. P., and Gack, M. U. (2018) Viral unmasking of cellular 5S rRNA pseudogene transcripts induces RIG-I-mediated immunity, Nat. Immunol., 19, 53–62.PubMedCrossRefGoogle Scholar
  4. 4.
    Djebali, S., Davis, C. A., Merkel, A., Dobin, A., Lassmann, T., Mortazavi, A., Tanzer, A., Lagarde, J., Lin, W., Schlesinger, F., Xue, C., Marinov, G. K., Khatun, J., Williams, B. A., Zaleski, C., Rozowsky, J., Roder, M., Kokocinski, F., Abdelhamid, R. F., Alioto, T., Antoshechkin, I., Baer, M. T., Bar, N. S., Batut, P., Bell, K., Bell, I., Chakrabortty, S., Chen, X., Chrast, J., Curado, J., et al. (2012) Landscape of transcription in human cells, Nature, 489, 101–108.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Liu, W.-H., Tsai, Z. T.-Y., and Tsai, H.-K. (2017) Comparative genomic analyses highlight the contribution of pseudogenized protein-coding genes to human lincRNAs, BMC Genomics, 18,786.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Hezroni, H., Perry, R. B.-T., Meir, Z., Housman, G., Lubelsky, Y., and Ulitsky, I. (2017) A subset of conserved mammalian long non-coding RNAs are fossils of ancestral protein-coding genes, Genome Biol., 18,162.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Kim, M. S., Pinto, S. M., Getnet, D., Nirujogi, R. S., Manda, S. S., Chaerkady, R., Madugundu, A. K., Kelkar, D. S., Isserlin, R., Jain, S., Thomas, J. K., Muthusamy, B., Leal-Rojas, P., Kumar, P., Sahasrabuddhe, N. A., et al. (2014) A draft map of the human proteome, Nature, 509, 575–581.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Ingolia, N. T., Brar, G. A., Stern-Ginossar, N., Harris, M. S., Talhouarne, G. J., Jackson, S. E., Wills, M. R., and Weissman, J. S. (2014) Ribosome profiling reveals pervasive translation outside of annotated protein-coding genes, Cell Rep., 8, 1365–1379.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Ji, Z., Song, R., Regev, A., and Struhl, K. (2015) Many lncRNAs, 5′UTRs, and pseudogenes are translated, and some are likely to express functional proteins, eLife, 4, e08890.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Poliseno, L. (2012) Pseudogenes: newly discovered players in human cancer, Sci. Signal., 5, 2–13.CrossRefGoogle Scholar
  11. 11.
    Li, W., Yang, W., and Wang, X. (2013) Pseudogenes: pseudo or real functional elements? J. Genet. Genomics, 40, 171–177.PubMedCrossRefGoogle Scholar
  12. 12.
    Zhang, J. (2003) Evolution by gene duplication: an update, Trends Ecol. Evol., 18, 292–298.CrossRefGoogle Scholar
  13. 13.
    Esnault, C., Maestre, J., and Heidmann, T. (2000) Human LINE retrotransposons generate processed pseudogenes, Nat. Genet., 24, 363–367.PubMedCrossRefGoogle Scholar
  14. 14.
    Kaessmann, H., Vinckenbosch, N., and Long, M. (2009) RNA-based gene duplication: mechanistic and evolutionary insights, Nat. Rev. Genet., 10, 19–31.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Kubiak, M. R., and Makalowska, I. (2017) Protein-coding genes’ retrocopies and their functions, Viruses, 9, E80.PubMedCrossRefGoogle Scholar
  16. 16.
    Van den Hurk, J. A., Meij, I. C., Seleme, M. C., Kano, H., Nikopoulos, K., Hoefsloot, L. H., Sistermans, E. A., de Wijs, I. J., Mukhopadhyay, A., Plomp, A. S., de Jong, P. T., Kazazian, H. H., and Cremers, F. P. (2007) L1 retrotransposition can occur early in human embryonic development, Hum. Mol. Genet., 16, 1587–1592.PubMedCrossRefGoogle Scholar
  17. 17.
    Cooke, S. L., Shlien, A., Marshall, J., Pipinikas, C. P., Martincorena, I., Tubio, J. M., Li, Y., Menzies, A., Mudie, L., Ramakrishna, M., Yates, L., Davies, H., Bolli, N., Bignell, G. R., Tarpey, P. S., Behjati, S., Nik-Zainal, S., Papaemmanuil, E., Teixeira, V. H., Raine, K., O’Meara, S., Dodoran, M. S., Teague, J. W., Butler, A. P., Iacobuzio-Donahue, C., Santarius, T., Grundy, R. G., Malkin, D., Greaves, M., Munshi, N., Flanagan, A. M., Bowtell, D., Martin, S., Larsimont, D., Reis-Filho, J. S., Boussioutas, A., Taylor, J. A., Hayes, N. D., Janes, S. M., Futreal, P. A., Stratton, M. R., McDermott, U., Campbell, P. J., and ICGC Breast Cancer Group (2014) Processed pseudogenes acquired somatically during cancer development, Nat. Commun., 5, 3644.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Anwar, S. L., Wulaningsih, W., and Lehmann, U. (2017) Transposable elements in human cancer: causes and consequences of deregulation, Int. J. Mol. Sci., 18, E974.PubMedCrossRefGoogle Scholar
  19. 19.
    Ewing, A. D., Ballinger, T. J., Earl, D., Broad Institute Genome Sequencing and Analysis Program and Platform, Harris, C. C., Ding, L., Wilson, R. K., and Haussler, D. (2013) Retrotransposition of gene transcripts leads to structural variation in mammalian genomes, Genome Biol., 14, R22.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Kazazian, H. H., Jr. (2014) Processed pseudogene insertions in somatic cells, Mob. DNA, 5,20.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Dong, P., Zhang, X., Zhang, Y., Ma, X., Chen, L., and Yang, L. (2016) CircRNA-derived pseudogenes, Cell Res., 26, 747–750.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Pei, B., Sisu, C., Frankish, A., Howald, C., Habegger, L., Mu, X. J., Harte, R., Balasubramanian, S., Tanzer, A., Diekhans, M., Reymond, A., Hubbard, T. J., Harrow, J., and Gerstein, M. B. (2012) The GENCODE pseudogene resource, Genome Biol., 13, R51.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Tourmen, Y., Baris, O., Dessen, P., Jacques, C., Malthiery, Y., and Reynier, P. (2002) Structure and chromosomal distribution of human mitochondrial pseudogenes, Genomics, 80, 71–77.PubMedCrossRefGoogle Scholar
  24. 24.
    Calabrese, F. M., Balacco, D. L., Preste, R., Diroma, M. A., Forino, R., Ventura, M., and Attimonelli, M. (2017) NumtS colonization in mammalian genomes, Sci. Rep., 7, 16357.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Hazkani-Covo, E., and Covo, S. (2008) Numt-mediated double-strand break repair mitigates deletions during primate genome evolution, PLoS Genet., 4, e1000237.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Gaziev, A. I., and Shaikhaev, G. O. (2010) Nuclear mitochondrial pseudogenes, Mol. Biol. (Moscow), 44, 405–417.CrossRefGoogle Scholar
  27. 27.
    Turner, C., Killoran, C., Thomas, N. S., Rosenberg, M., Chuzhanova, N. A., Johnston, J., Kemel, Y., Cooper, D. N., and Biesecker, L. G. (2003) Human genetic disease caused by de novo mitochondrial-nuclear DNA transfer, Hum. Genet., 112, 303–309.PubMedGoogle Scholar
  28. 28.
    Singh, K. K., Choudhuryg, A. R., and Tiwarih, H. K. (2017) Numtogenesis as a mechanism for development of cancer, Semin. Cancer Biol., 47, 101–109.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Lang, M., Sazzini, M., Calabrese, F. M., Simone, D., and Boattini, A. (2012) Polymorphic NumtS trace human population relationships, Hum. Genet., 131, 757–771.PubMedCrossRefGoogle Scholar
  30. 30.
    Prieto-Godino, L. L., Rytz, R., Bargeton, B., Abuin, L., Arguello, J. R., dal Peraro, M., and Benton, R. (2016) Olfactory receptor pseudo-pseudogenes, Nature, 539, 93–97.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Ciomborowska, J., Rosikiewicz, W., Szklarczykz, D., Makalowski, W., and Makalowska, I. (2012) “Orphan” retrogenes in the human genome, Mol. Biol. Evol., 30, 384–396.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Tang, J., Ning, R., Zeng, B., and Li, Y. (2016) Molecular evolution of PTEN pseudogenes in mammals, PLoS One, 11, e0167851.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Zhang, Z., Harrison, P., and Gerstein, M. (2002) Identification and analysis of over 2000 ribosomal protein pseudogenes in the human genome, Genome Res., 12, 1466–1482.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Nei, M., and Rooney, A. P. (2005) Concerted and birth-and-death evolution of multigene families, Annu. Rev. Genet., 39, 121–152.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Shiina, T., Blancher, A., Inoko, H., and Kulski, J. K. (2016) Comparative genomics of the human, macaque and mouse major histocompatibility complex, Immunology, 150, 127–138.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Niimura, Y. (2012) Olfactory receptor multigene family in vertebrates: from the viewpoint of evolutionary genomics, Curr. Genomics, 13, 103–114.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Thibaud-Nissen, F., Souvorov, A., Murphy, T., DiCuccio, M., and Kitts, P. (2013) Eukaryotic genome annotation pipeline, in The NCBI Handbook [Internet], 2nd Edn., National Center for Biotechnology Information, Bethesda (US).Google Scholar
  38. 38.
    Patrushev, L. I., and Kovalenko, T. F. (2014) Functions of noncoding sequences in mammalian genomes, Biochemistry (Moscow), 79, 1442–1469.CrossRefGoogle Scholar
  39. 39.
    Ohshima, K., Hattori, M., Yada, T., Gojobori, T., Sakaki, Y., and Okada, N. (2003) Whole-genome screening indicates a possible burst of formation of processed pseudo-genes and Alu repeats by particular L1 subfamilies in ancestral primates, Genome Biol., 4, R74.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Rouchka, E. C., and Cha, I. E. (2009) Current trends in pseudogene detection and characterization, Curr. Bioinformatics, 4, 112–119.CrossRefGoogle Scholar
  41. 41.
    Harrison, P. M. (2014) Computational methods for pseudogene annotation based on sequence homology, in Pseudogenes: Functions and Protocols, Methods in Molecular Biology (Poliseno, L., ed.) Vol. 1167, Springer Science + Business Media, N. Y., pp. 27–39.CrossRefGoogle Scholar
  42. 42.
    Andrieux, O. L., and Arenales, D. T. (2014) Whole-genome identification of neutrally evolving pseudogenes using the evolutionary measure dN/dS, in Pseudogenes: Functions and Protocols, Methods in Molecular Biology (Poliseno, L., ed.) Vol. 1167, Springer Science + Business Media, N. Y., pp. 75–85.CrossRefGoogle Scholar
  43. 43.
    Kalyana-Sundaram, S., Kumar-Sinha, C., Shankar, S., Robinson, D. R., Wu, Y. M., Cao, X., Asangani, I. A., Kothari, V., Presner, J. R., Lonigro, R. J., Iyer, M. K., Barrette, T., Shanmugam, A., Dhanasekaran, S. M., Palanisamy, N., and Chinnaiyan A. M. (2012) Expressed pseudogenes in the transcriptional landscape of human cancers, Cell, 149, 1622–1634.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Bensimon, A., Heck, A. J., and Aebersold, R. (2012) Mass spectrometry-based proteomics and network biology, Annu. Rev. Biochem., 81, 379–405.PubMedCrossRefGoogle Scholar
  45. 45.
    Moreau-Aubry, A., Le Guiner, S., Labarriere, N., Gesnel, M., Jotereau, F., and Breathnach, R. (2000) A processed pseudogene codes for a new antigen recognized by a CD8+ T cell clone on melanoma, J. Exp. Med., 191, 1617–1624.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Hendrickson, R. C., Cicinnati, V. R., Albers, A., Dworacki, G., Gambotto, A., Pagliano, O., Tuting, T., Mayordomo, J. I., Visus, C., Appella, E., Shabanowitz, J., Hunt, D. F., and DeLeo, A. B. (2010) Identification of a 17beta-hydroxysteroid dehydrogenase type 12 pseudogene as the source of a highly restricted BALB/c Meth A tumor rejection peptide, Cancer Immunol. Immunother., 59, 113–124.PubMedCrossRefGoogle Scholar
  47. 47.
    Visus, C., Ito, D., Dhir, R., Szczepanski, M. J., Chang, Y. J., Latimer, J. J., Grant, S. G., and DeLeo, A. B. (2011) Identification of hydroxysteroid (17β) dehydrogenase type 12 (HSD17B12) as a CD8+ T-cell-defined human tumor antigen of human carcinomas, Cancer Immunol. Immunother., 60, 919–929.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Reynaud, C. A., Anquez, V., Grimal, H., and Weill, J. C. (1987) A hyperconversion mechanism generates the chicken light chain preimmune repertoire, Cell, 48, 379–388.PubMedCrossRefGoogle Scholar
  49. 49.
    Reynaud, C. A., Dahan, A., Anquez, V., and Weill, J. C. (1989) Somatic hyperconversion diversifies the single Vh gene of the chicken with a high incidence in the D region, Cell, 59, 171–183.PubMedCrossRefGoogle Scholar
  50. 50.
    Bastianello, G., and Arakawa, H. (2017) A double-strand break can trigger immunoglobulin gene conversion, Nucleic Acids Res., 45, 231–243.PubMedCrossRefGoogle Scholar
  51. 51.
    Kurosawa, K., and Ohta, K. (2011) Genetic diversification by somatic gene conversion, Genes, 2, 48–58.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Rygiel, A. M., Beer, S., Simon, P., Wertheim-Tysarowska, K., Oracz, G., Kucharzik, T., Tysarowski, A., Niepokoj, K., Kierkus, J., Jurek, M., Gawlinski, P., Poznanski, J., Bal, J., Lerch, M. M., Sahin-Toth, M., and Weiss, F. U. (2015) Gene conversion between cationic trypsinogen (PRSS1) and the pseudogene trypsinogen 6 (PRSS3P2) in patients with chronic pancreatitis, Hum. Mutat., 36, 350–356.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Concolino, P., and Costella, A. (2018) Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency: a comprehensive focus on 233 pathogenic variants of CYP21A2 gene, Mol. Diagn. Ther., 22, 261–280.PubMedCrossRefGoogle Scholar
  54. 54.
    Wang, J., Pitarque, M., and Ingelman-Sundberg, M. (2006) 3′-UTR polymorphism in the human CYP2A6 gene affects mRNA stability and enzyme expression, Biochem. Biopys. Res. Commun., 340, 491–497.CrossRefGoogle Scholar
  55. 55.
    Nakano, M., Fukushima, Y., Yokota, S., Fukami, T., Takamiya, M., Aoki, Y., Yokoi, T., and Nakajima, M. (2015) CYP2A7 pseudogene transcript affects CYP2A6 expression in human liver by acting as a decoy for miR-126, Drug Metab. Dispos., 43, 703–712.PubMedCrossRefGoogle Scholar
  56. 56.
    Bartel, D. P. (2009) MicroRNAs: target recognition and regulatory functions, Cell, 136, 215–233.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Liu, H., Lei, C., He, Q., Pan, Z., Xiao, D., and Tao, Y. (2018) Nuclear functions of mammalian microRNAs in gene regulation, immunity and cancer, Mol. Cancer, 17,64.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Poliseno, L., Salmena, L., Zhang, J., Carver, B., Haveman, W. J., and Pandolfi, P. P. (2010) A coding-independent function of gene and pseudogene mRNAs regulates tumour biology, Nature, 465, 1033–1038.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Salmena, L., Poliseno, L., Tay, Y., Kats, L., and Pandolfi, P. P. (2011) A ceRNA hypothesis: the Rosetta stone of a hidden RNA language? Cell, 146, 353–358.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Tay, Y., Rinn, J., and Pandolfi, P. P. (2014) The multilayered complexity of ceRNA crosstalk and competition, Nature, 505, 344–352.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    An, Y., Furber, K. L., and Ji, S. (2017) Pseudogenes regulate parental gene expression via ceRNA network, J. Cell. Mol. Med., 21, 185–192.PubMedCrossRefGoogle Scholar
  62. 62.
    Johnson, T. S., Li, S., Kho, J. R., Huang, K., and Zhang, Y. (2018) Network analysis of pseudogene-gene relationships: from pseudogene evolution to their functional potentials, Pac. Symp. Biocomput., 23, 536–547.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Barbash, S., Simchovitz, A., Buchman, A. S., Bennett, D. A., Shifman, S., and Soreq, H. (2017) Neuronal-expressed microRNA-targeted pseudogenes compete with coding genes in the human brain, Transl. Psychiatry, 7, e1199.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Straniero, L., Rimoldi, V., Samarani, M., Goldwurm, S., Di Fonzo, A., Kruger, R., Deleidi, M., Aureli, M., Solda, G., Duga, S., and Asselta, R. (2017) The GBAP1 pseudo-gene acts as a ceRNA for the glucocerebrosidase gene GBA by sponging miR-22-3p, Sci. Rep., 7, 12702.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Ergun, S., and Oztuzcu, S. (2017) Oncocers: ceRNA-mediated cross-talk by sponging miRNAs in oncogenic pathways, Tumour Biol., 36, 3129–3136.CrossRefGoogle Scholar
  66. 66.
    Li, X., Zheng, L., Zhang, F., Hu, J., Chou, J., Liu, Y., Xing, Y., and Xi, T. (2016) STARD13-correlated ceRNA network inhibits EMT and metastasis of breast cancer, Oncotarget, 7, 23197–23211.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Yang, C., Wu, D., Gao, L., Liu, X., Jin, Y., Wang, D., Wang, T., and Li, X. (2016) Competing endogenous RNA networks in human cancer: hypothesis, validation, and perspectives, Oncotarget, 7, 13479–13490.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Li, C., Zheng, L., Xin, Y., Tan, Z., Zhang, Y., Meng, X., Wang, Z., and Xi, T. (2017) The competing endogenous RNA network of CYP4Z1 and pseudogene CYP4Z2P exerts an anti-apoptotic function in breast cancer, FEBS Lett., 591, 991–1000.PubMedCrossRefGoogle Scholar
  69. 69.
    Thomson, D. W., and Dinger, M. E. (2016) Endogenous microRNA sponges: evidence and controversy, Nat. Rev. Genet., 17, 272–283.PubMedCrossRefGoogle Scholar
  70. 70.
    Chiefari, E., Iiritano, S., Paonessa, F., Le Pera, I., Arcidiacono, B., Filocamo, M., Foti, D., Liebhaber, S. A., and Brunetti, A. (2010) Pseudogene-mediated posttranscriptional silencing of HMGA1 can result in insulin resistance and type 2 diabetes, Nat. Commun., 1,40.PubMedCrossRefGoogle Scholar
  71. 71.
    Bier, A., Oviedo-Landaverde, I., Zhao, J., Mamane, Y., Kandouz, M., and Batist, G. (2009) Connexin43 pseudogene in breast cancer cells offers a novel therapeutic target, Mol. Cancer Ther., 8, 786–793.PubMedCrossRefGoogle Scholar
  72. 72.
    Rapicavoli, N. A., Qu, K., Zhang, J., Mikhail, M., Laberge, R.-M., and Chang, H. Y. (2013) A mammalian pseudogene lncRNA at the interface of inflammation and anti-inflammatory therapeutics, eLife, 2, e00762.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Katayama, S., Tomaru, Y., Kasukawa, T., Waki, K., Nakanishi, M., Nakamura, M., Nishida, H., Yap, C. C., Suzuki, M., Kawai, J., Suzuki, H., Carninci, P., Hayashizaki, Y., Wells, C., Frith, M., Ravasi, T., Pang, K. C., Hallinan, J., Mattick, J., Hume, D. A., Lipovich, L., Batalov, S., Engstrom, P. G., Mizuno, Y., Faghihi, M. A., Sandelin, A., Chalk, A. M., Mottagui-Tabar, S., Liang, Z., Lenhard, B., Wahlestedt, C., and RIKEN Genome Exploration Research Group, Genome Science Group (Genome Network Project Core Group) and FANTOM Consortium (2005) Antisense transcription in the mammalian transcriptome, Science, 309, 1564–1566.PubMedCrossRefGoogle Scholar
  74. 74.
    Engstrom, P. G., Suzuki, H., Ninomiya, N., Akalin, A., Sessa, L., Lavorgna, G., Brozzi, A., Luzi, L., Tan, S. L., Yang, L., Kunarso, G., Ng, E. L., Batalov, S., Wahlestedt, C., Kai, C., Kawai, J., Carninci, P., Hayashizaki, Y., Wells, C., Bajic, V. B., Orlando, V., Reid, J. F., Lenhard, B., and Lipovich, L. (2006) Complex loci in human and mouse genomes, PLoS Genet., 2, e47.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Faghihi, M. A., Kocerha, J., Modarresi, F., Engstrom, P. G., Chalk, A. M., Brothers, S. P., Koesema, E., Laurent, G. S., and Wahlestedt, C. (2010) RNAi screen indicates widespread biological function for human natural antisense transcripts, PLoS One, 5, e13177.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Pelechano, V., and Steinmetz, L. M. (2013) Gene regulation by antisense transcription, Nat. Rev. Genet., 14, 880–893.PubMedCrossRefGoogle Scholar
  77. 77.
    Wanowska, E., Kubiak, M. R., Rosikiewicz, W., Makaіowska, I., and Szczesniak, M. W. (2018) Natural antisense transcripts in diseases: from modes of action to targeted therapies, Wiley Interdiscip. Rev. RNA, 9, doi: 10.1002/wrna.1461.Google Scholar
  78. 78.
    Korneev, S. A., Park, J. H., and O’Shea, M. (1999) Neuronal expression of neural nitric oxide synthase (nNOS) protein is suppressed by an antisense RNA transcribed from an NOS pseudogene, J. Neurosci., 19, 7711–7720.PubMedCrossRefGoogle Scholar
  79. 79.
    Ye, X., Fan, F., Bhattacharya, R., Bellister, S., Boulbes, D. R., Wang, R., Xia, L., Ivan, C., Zheng, X., Calin, G. A., Wang, J., Lu, X., and Ellis, L. M. (2015) VEGFR-1 pseudogene expression and regulatory function in human colorectal cancer cells, Mol. Cancer Res., 13, 1274–1282.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Carthew, R. W., and Sontheimer, E. J. (2009) Origins and mechanisms of miRNAs and siRNAs, Cell, 136, 642–655.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Lam, J. K. W., Chow, M. Y. T., Zhang, Y., and Leung, S. W. S. (2015) siRNA versus miRNA as therapeutics for gene silencing, Mol. Ther. Nucleic Acids, 4, e252.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Ipsaro, J. J., and Joshua-Tor, L. (2015) From guide to target: molecular insights into eukaryotic RNA-interference machinery, Nature Struct. Mol. Biol., 22, 20–28.CrossRefGoogle Scholar
  83. 83.
    Chan, W. L., and Chang, J. G. (2014) Pseudogene-derived endogenous siRNAs and their function, in Pseudogenes: Functions and Protocols, Methods in Molecular Biology (Poliseno, L., ed.) Vol. 1167, pp. 227–239.CrossRefGoogle Scholar
  84. 84.
    Tam, O. H., Aravin, A. A., Stein, P., Girard, A., Murchison, E. P., Cheloufi, S., Hodges, E., Anger, M., Sachidanandam, R., Schultz, R. M., and Hannon, G. J. (2008) Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes, Nature, 453, 534–538.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Watanabe, T., Totoki, Y., Toyoda, A., Kaneda, M., Kuramochi-Miyagawa, S., Obata, Y., Chiba, H., Kohara, Y., Kono, T., Nakano, T., Surani, M. A., Sakaki, Y., and Sasaki, H. (2008) Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes, Nature, 453, 539–543.PubMedCrossRefGoogle Scholar
  86. 86.
    Pantano, L., Jodar, M., Bak, M., Ballesca, J. L., Tommerup, N., Oliva, R., and Vavouri, T. (2015) The small RNA content of human sperm reveals pseudogene-derived piRNAs complementary to protein-coding genes, RNA, 21, 1085-1095.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Watanabe, T., Cheng, E., Zhong, M., and Lin, H. (2015) Retrotransposons and pseudogenes regulate mRNAs and lncRNAs via the piRNA pathway in the germline, Genome Res., 25, 368–380.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Iwasaki, Y. W., Siomi, M. C., and Siomi, H. (2015) PIWI-interacting RNA: its biogenesis and functions, Annu. Rev. Biochem., 84, 405–433.PubMedCrossRefGoogle Scholar
  89. 89.
    Watanabe, T., and Lin, H. (2014) Posttranscriptional regulation of gene expression by Piwi proteins and piRNAs, Mol. Cell, 56, 18–27.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Czech, B., and Hannon, G. J. (2016) One loop to rule them all: the ping-pong cycle and piRNA-guided silencing, Trends Biochem. Sci., 41, 324–337.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Weim, J.-W., Huang, K., Yang, C., and Kang, C.-S. (2017) Non-coding RNAs as regulators in epigenetics (review), Oncol. Rep., 37, 3–9.CrossRefGoogle Scholar
  92. 92.
    Wang, C., Wang, L., Ding, Y., Lu, X., Zhang, G., Yang, J., Zheng, H., Wang, H., Jiang, Y., and Xu, L. (2017) LncRNA structural characteristics in epigenetic regulation, Int. J. Mol. Sci., 18, E2659.PubMedCrossRefGoogle Scholar
  93. 93.
    Zeineddine, D., Hammoud, A. A., Mortada, M., and Boeuf, H. (2014) The Oct4 protein: more than a magic stemness marker, Am. J. Stem Cells, 5, 74–82.Google Scholar
  94. 94.
    Hawkins, P. G., and Morris, K. V. (2010) Transcriptional regulation of Oct4 by a long non-coding RNA antisense to Oct4-pseudogene 5, Transcription, 1, 165–175.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Zhao, S., Yuan, Q., Hao, H., Guo, Y., Liu, S., Zhang, Y., Wang, J., Liu, H., Wang, F., Liu, K., Ling, E. A., and Hao, A. (2011) Expression of OCT4 pseudogenes in human tumours: lessons from glioma and breast carcinoma, J. Pathol., 223, 672–682.PubMedCrossRefGoogle Scholar
  96. 96.
    Wang, L., Guo, Z. Y., Zhang, R., Xin, B., Chen, R., Zhao, J., Wang, T., Wen, W. H., Jia, L. T., Yao, L. B., and Yang, A. G. (2013) Pseudogene OCT4-pg4 functions as a natural micro RNA sponge to regulate OCT4 expression by competing for miR-145 in hepatocellular carcinoma, Carcinogenesis, 34, 1773–1781.PubMedCrossRefGoogle Scholar
  97. 97.
    Johnsson, P., Ackley, A., Vidarsdottir, L., Lui, W., Corcoran, M., Grander, D., and Morris, K. V. (2013) A pseudogene long-noncoding-RNA network regulates PTEN transcription and translation in human cells, Nat. Struct. Mol. Biol., 20, 440–446.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Lister, N., Shevchenko, G., Walshe, J. L., Groen, J., Johnsson, P., Vidarsdottir, L., Grander, D., Ataide, S. F., and Morris, K. V. (2017) The molecular dynamics of long noncoding RNA control of transcription in PTEN and its pseudogene, PNAS, 114, 9942–9947.PubMedCrossRefGoogle Scholar
  99. 99.
    Liu, J. L., Zhang, W. Q., and Huang, M. Y. (2017) Transcription start site-associated small RNAs in the PTEN gene, Proc. Natl. Acad. Sci. USA, 114, E10510-E10511.PubMedCrossRefGoogle Scholar
  100. 100.
    Iyer, M. K., Niknafs, Y. S., Malik, R., Singhal, U., Sahu, A., Hosono, Y., Barrette, T. R., Prensner, J. R., Evans, J. R., Zhao, S., Poliakov, A., Cao, X., Dhanasekaran, S. M., Wu, Y. M., Robinson, D. R., Beer, D. G., Feng, F. Y., Iyer, H. K., and Chinnaiyan, A. M. (2015) The landscape of long noncoding RNAs in the human transcriptome, Nat. Genet., 47, 199–208.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Kopp, F., and Mendell, J. T. (2018) Functional classification and experimental dissection of long noncoding RNAs, Cell, 172, 393–407.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Anderson, K. M., Anderson, D. M., McAnally, J. R., Shelton, J. M., Bassel-Duby, R., and Olson, E. N. (2016) Transcription of the non-coding RNA upperhand controls Hand2 expression and heart development, Nature, 539, 433–436.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Bunch, H. (2018) Gene regulation of mammalian long noncoding RNA, Mol. Genet. Genomics, 293, 1–15.PubMedCrossRefGoogle Scholar
  104. 104.
    Sun, Q., Hao, Q., and Prasanth, K. V. (2018) Nuclear long noncoding RNAs: key regulators of gene expression, Trends Genet., 34, 142–157.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Xu, J., and Zhang, J. (2016) Are human translated pseudogenes functional? Mol. Biol. Evol., 33, 755–760.PubMedCrossRefGoogle Scholar
  106. 106.
    Gawlik-Rzemieniewska, N., and Bednarek, I. (2016) The role of NANOG transcriptional factor in the development of malignant phenotype of cancer cells, Cancer Biol. Ther., 17, 1–10.PubMedCrossRefGoogle Scholar
  107. 107.
    Wang, T. H., Lin, Y. S., Chen, Y., Yeh, C. T., Huang, Y. L., Hsieh, T. H., Shieh, T. M., Hsueh, C., and Chen, T. C. (2015) Long non-coding RNA AOC4P suppresses hepato-cellular carcinoma metastasis by enhancing vimentin degradation and inhibiting epithelial-mesenchymal transition, Oncotarget, 6, 23342–23357.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Zhai, L. L., Zhou, J., Zhang, J., Tang, X., Zhou, L. Y., Yin, J. Y., Vanessa, M. D., Peng, W., Lin, J., and Deng, Z. Q. (2017) Down-regulation of pseudogene Vimentin 2p is associated with poor outcome in de novo acute myeloid leukemia, Cancer Biomark., 18, 305–312.PubMedCrossRefGoogle Scholar
  109. 109.
    Siddique, H. R., and Saleem, M. (2012) Role of BMI1, a stem cell factor, in cancer recurrence and chemoresistance: preclinical and clinical evidences, Stem Cells, 30, 372–378.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Zhou, L. Y., Zhai, L. L., Yin, J. Y., Vanessa, M. E., Zhou, J., Zhang, J., Tang, X., Lin, J., Qian, J., and Deng, Z. Q. (2016) Pseudogene BMI1P1 expression as a novel predictor for acute myeloid leukemia development and prognosis, Oncotarget, 7, 47376–47386.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Dankner, M., Rose, A. A. N., Rajkumar, S., Siegel, P. M., and Watson, I. R. (2018) Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations, Oncogene, 37, 3183–3199.PubMedCrossRefGoogle Scholar
  112. 112.
    Karreth, F. A., Reschke, M., Ruocco, A., Ng, C., Chapuy, B., Leopold, V., Sjoberg, M., Keane, T. M., Verma, A., Ala, U., Tay, Y., Wu, D., Seitzer, N., Velasco-Herrera Mdel, C., Bothmer, A., Fung, J., Langellotto, F., Rodig, S. J., Elemento, O., Shipp, M. A., Adams, D. J., Chiarle, R., and Pandolfi, P. P. (2015) The BRAF pseudogene functions as a competitive endogenous RNA and induces lymphoma in vivo, Cell, 161, 319–332.PubMedCrossRefGoogle Scholar
  113. 113.
    Huang, C., Yang, Y., and Liu, L. (2015) Interaction of long noncoding RNAs and microRNAs in the pathogenesis of idiopathic pulmonary fibrosis, Physiol. Genomics, 47, 463–469.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Liu, T. X., Becker, M. W., Jelinek, J., Wu, W. S., Deng, M., Mikhalkevich, N., Hsu, K., Bloomfield, C. D., Stone, R. M., DeAngelo, D. J., Galinsky, I. A., Issa, J. P., Clarke, M. F., and Look, A. T. (2007) Chromosome 5q deletion and epigenetic suppression of the gene encoding alpha-catenin (CTNNA1) in myeloid cell transformation, Nat. Med., 13, 78–83.PubMedCrossRefGoogle Scholar
  115. 115.
    Chen, X., Zhu, H., Wu, X., Xie, X., Huang, G., Xu, X., Li, S., and Xing, C. (2016) Downregulated pseudogene CTNNAP1 promote tumor growth in human cancer by downregulating its cognate gene CTNNA1 expression, Oncotarget, 23, 55518–55528.Google Scholar
  116. 116.
    Yu, W., Chai, H., Li, Y., Zhao, H., Xie, X., Zheng, H., Wang, C., Wang, X., Yang, G., Cai, X., Falck, J. R., and Yang, J. (2012) Increased expression of CYP4Z1 promotes tumor angiogenesis and growth in human breast cancer, Toxicol. Appl. Pharmacol., 1, 73–83.CrossRefGoogle Scholar
  117. 117.
    Zheng, L., Li, X., Gu, Y., Lv, X., and Xi, T. (2015) The 3′UTR of the pseudogene CYP4Z2P promotes tumor angiogenesis in breast cancer by acting as a ceRNA for CYP4Z1, Breast Cancer Res. Treat., 150, 105–118.PubMedCrossRefGoogle Scholar
  118. 118.
    Zheng, L., Li, X., Meng, X., Chou, J., Hu, J., Zhang, F., Zhang, Z., Xing, Y., Liu, Y., and Xi, T. (2016) Competing endogenous RNA networks of CYP4Z1 and pseudogene CYP4Z2P confer tamoxifen resistance in breast cancer, Mol. Cell Endocrinol., 15, 133–142.CrossRefGoogle Scholar
  119. 119.
    Zhou, L. Y., Yin, J. Y., Tang, Q., Zhai, L. L., Zhang, T. J., Wang, Y. X., Yang, D. Q., Qian, J., Lin, J., and Deng, Z. Q. (2015) High expression of dual-specificity phosphatase 5 pseudogene 1 (DUSP5P1) is associated with poor prognosis in acute myeloid leukemia, Int. J. Clin. Exp. Pathol., 8, 16073–16080.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Booth, H. A., and Holland, P. W. (2007) Annotation, nomenclature and evolution of four novel homeobox genes expressed in the human germ line, Gene, 387, 7–14.PubMedCrossRefGoogle Scholar
  121. 121.
    Ma, H. W., Xie, M., Sun, M., Chen, T. Y., Jin, R. R., Ma, T. S., Chen, Q. N., Zhang, E. B., He, X. Z., De, W., and Zhang, Z. H. (2016) The pseudogene derived long non-coding RNA DUXAP8 promotes gastric cancer cell proliferation and migration via epigenetically silencing PLEKHO1 expression, Oncotarget, 8, 52211–52224.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Sun, M., Nie, F. Q., Zang, C., Wang, Y., Hou, J., Wei, C., Li, W., He, X., and Lu, K. H. (2017) The pseudogene DUXAP8 promotes non-small-cell lung cancer cell proliferation and invasion by epigenetically silencing EGR1 and RHOB, Mol. Ther., 1, 739–751.CrossRefGoogle Scholar
  123. 123.
    Wei, C. C., Nie, F. Q., Jiang, L. L., Chen, Q. N., Chen, Z. Y., Chen, X., Pan, X., Liu, Z. L., Lu, B. B., and Wang, Z. X. (2017) The pseudogene DUXAP10 promotes an aggressive phenotype through binding with LSD1 and repressing LATS2 and RRAD in non-small cell lung cancer, Oncotarget, 8, 5233–5246.PubMedGoogle Scholar
  124. 124.
    Huang, W., Li, N., Hu, J., and Wang, L. (2016) Inhibitory effect of RNA-mediated knockdown of zinc finger protein 91 pseudogene on pancreatic cancer cell growth and invasion, Oncol. Lett., 12, 1343–1348.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Cleynen, I., and Van De Ven, W. J. (2008) The HMGA proteins: a myriad of functions, Int. J. Oncol., 32, 289–305.PubMedGoogle Scholar
  126. 126.
    De Martino, M., Forzati, F., Arra, C., Fusco, A., and Esposito, F. (2016) HMGA1-pseudogenes and cancer, Oncotarget, 7, 28724–28735.PubMedPubMedCentralGoogle Scholar
  127. 127.
    Gupta, A., Brown, C. T., Zheng, Y. H., and Christoph, A. (2015) Differentially-expressed pseudogenes in HIV-1 infection, Viruses, 7, 5191–5205.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Han, L., Yuan, Y., Zheng, S., Yang, Y., Li, J., Edgerton, M. E., Diao, L., Xu, Y., Verhaak, R. G. W., and Liang, H. (2014) The Pan-Cancer analysis of pseudogene expression reveals biologically and clinically relevant tumour sub-types, Nat. Commun., 5, 3963.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Welch, J. D., Baran-Gale, J., Perou, C. M., Sethupathy, P., and Prins, J. F. (2015) Pseudogenes transcribed in breast invasive carcinoma show subtype-specific expression and ceRNA potential, BMC Genomics, 16,113.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Shi, X., Nie, F., Wang, Z., and Sun, M. (2016) Pseudogene-expressed RNAs: a new frontier in cancers, Tumour Biol., 37, 1471–1478.PubMedCrossRefGoogle Scholar
  131. 131.
    Poliseno, L., Haimovic, A., Christos, P. J., Vega y Saenz de Miera, E. C., Shapiro, R., Pavlick, A., Berman, R. S., Darvishian, F., and Osman, I. (2011) Deletion of PTENP1 pseudogene in human melanoma, J. Invest. Dermatol., 131, 2497–2500.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Liu, J., Xing, Y., Xu, L., Chen, W., Cao, W., and Zhang, C. (2017) Decreased expression of pseudogene PTENP1 promotes malignant behaviours and is associated with the poor survival of patients with HNSCC, Sci. Rep., 7, 41179.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Dong, L., Qi, P., Xu, M. D., Ni, S. J., Huang, D., Xu, Q. H., Weng, W. W., Tan, C., Sheng, W. Q., Zhou, X. Y., and Du, X. (2015) Circulating CUDR, LSINCT-5 and PTENP1 long noncoding RNAs in sera distinguish patients with gastric cancer from healthy controls, Int. J. Cancer, 137, 1128–1135.PubMedCrossRefGoogle Scholar
  134. 134.
    Uchino, K., Hirano, G., Hirahashi, M., Isobe, T., Shirakawa, T., Kusaba, H., Baba, E., Tsuneyoshi, M., and Akashi, K. (2012) Human Nanog pseudogene8 promotes the proliferation of gastrointestinal cancer cells, Exp. Cell Res., 318, 1799–1807.PubMedCrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2018

Authors and Affiliations

  1. 1.Shemyakin−Ovchinnikov Institute of Bioorganic ChemistryRussian Academy of SciencesMoscowRussia

Personalised recommendations