Ultra-conserved element

An ultra-conserved element (UCE) is a region of DNA that is identical in at least two different species.[1] One of the first studies of UCEs showed that certain human DNA sequences of length 200 nucleotides or greater were entirely conserved (identical nucleic acid sequence) in human, rats, and mice.[2] Despite often being noncoding DNA,[3] some ultra-conserved elements have been found to be transcriptionally active, giving non-coding RNA molecules.[4]

Evolution

Perfect conservation of these long stretches of DNA is thought to imply evolutionary importance as these regions appear to have experienced strong negative (purifying) selection for 300-400 million years.[2][3][5] The probability of finding ultra-conserved elements by chance (under neutral evolution) has been estimated at less than 10−22 in 2.9 billion bases.[2]

Functions

481 ultra-conserved elements have been identified in the human genome.[1][2] A database collecting genomic information about ultra-conserved elements (UCbase) that share 100% identity among human, mouse and rat is available at http://ucbase.unimore.it.[6] A small number of those which are transcribed have been connected with human carcinomas and leukemias.[4] For example, TUC338 is strongly upregulated in human hepatocellular carcinoma cells.[7] Indeed, UCEs are often affected by copy number variation in cancer cells,[8] much more than in healthy contexts,[8][9][10] suggesting that altering the copy number of ultraconserved elements may be deleterious and associated with cancer. A study comparing ultra-conserved elements between humans and the Japanese puffer fish Takifugu rubripes proposed an importance in vertebrate development.[11] Several ultra-conserved elements are located near transcriptional regulators or developmental genes.[2][12] Other functions include enhancing and splicing regulation.[1] Double-knockouts of UCEs near the ARX gene in mice caused a shrunken hippocampus in the brain.[13] The knockout effects are not lethal in laboratory mice, but could be in the wild.

See also

References
  1. Reneker J, Lyons E, Conant GC, Pires JC, Freeling M, Shyu CR, Korkin D (2012). "Long identical multispecies elements in plant and animal genomes". Proceedings of the National Academy of Sciences. 109 (19): E1183–E1191. doi:10.1073/pnas.1121356109. ISSN 0027-8424. PMC 3358895. PMID 22496592.
  2. Bejerano, G; Pheasant, M; Makunin, I; Stephen, S; Kent, WJ; Mattick, JS; Haussler, D (2004-05-28). "Ultraconserved elements in the human genome". Science. 304 (5675): 1321–5. CiteSeerX 10.1.1.380.9305. doi:10.1126/science.1098119. PMID 15131266.
  3. Katzman, S; Kern, AD; Bejerano, G; Fewell, G; Fulton, L; Wilson, RK; Salama, SR; Haussler, D (2007-08-17). "Human genome ultraconserved elements are ultraselected". Science. 317 (5840): 915. doi:10.1126/science.1142430. PMID 17702936.
  4. Calin GA, Liu CG, Ferracin M, Hyslop T, Spizzo R, Sevignani C, Fabbri M, Cimmino A, Lee EJ, Wojcik SE, Shimizu M, Tili E, Rossi S, Taccioli C, Pichiorri F, Liu X, Zupo S, Herlea V, Gramantieri L, Lanza G, Alder H, Rassenti L, Volinia S, Schmittgen TD, Kipps TJ, Negrini M, Croce CM (Sep 2007). "Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas". Cancer Cell. 12 (3): 215–29. doi:10.1016/j.ccr.2007.07.027. PMID 17785203.
  5. Sathirapongsasuti JF, Sathira N, Suzuki Y, Huttenhower C, Sugano S (2011). "Ultraconserved cDNA segments in the human transcriptome exhibit resistance to folding and implicate function in translation and alternative splicing". Nucleic Acids Res. 39 (6): 1967–79. doi:10.1093/nar/gkq949. PMC 3064809. PMID 21062826.
  6. Taccioli C, Fabbri E, Visone R, Volinia S, Calin GA, Fong LY, Gambari R, Bottoni A, Acunzo M, Hagan J, Iorio MV, Piovan C, Romano G, Croce CM (Jan 2009). "UCbase & miRfunc: a database of ultraconserved sequences and microRNA function". Nucleic Acids Res. 37 (Database issue): D41–8. doi:10.1093/nar/gkn702. PMC 2686429. PMID 18945703.
  7. Braconi C, Valeri N, Kogure T, Gasparini P, Huang N, Nuovo GJ, Terracciano L, Croce CM, Patel T (2011-01-11). "Expression and functional role of a transcribed noncoding RNA with an ultraconserved element in hepatocellular carcinoma". Proceedings of the National Academy of Sciences of the United States of America. 108 (2): 786–91. doi:10.1073/pnas.1011098108. PMC 3021052. PMID 21187392.
  8. McCole, Ruth B.; Fonseka, Chamith Y.; Koren, Amnon; Wu, C.-ting (2014-10-23). "Abnormal Dosage of Ultraconserved Elements Is Highly Disfavored in Healthy Cells but Not Cancer Cells". PLOS Genetics. 10 (10): e1004646. doi:10.1371/journal.pgen.1004646. ISSN 1553-7404. PMC 4207606. PMID 25340765.
  9. Derti, Adnan; Roth, Frederick P; Church, George M; Wu, C-ting (2006). "Mammalian ultraconserved elements are strongly depleted among segmental duplications and copy number variants". Nature Genetics. 38 (10): 1216–1220. doi:10.1038/ng1888. PMID 16998490.
  10. Chiang, Charleston W. K.; Derti, Adnan; Schwartz, Daniel; Chou, Michael F.; Hirschhorn, Joel N.; Wu, C.-ting (2008-12-01). "Ultraconserved Elements: Analyses of Dosage Sensitivity, Motifs and Boundaries". Genetics. 180 (4): 2277–2293. doi:10.1534/genetics.108.096537. ISSN 0016-6731. PMC 2600958. PMID 18957701.
  11. Woolfe A, Goodson M, Goode DK, Snell P, McEwen GK, Vavouri T, Smith SF, North P, Callaway H, Kelly K, Walter K, Abnizova I, Gilks W, Edwards YJ, Cooke JE, Elgar G (Jan 2005). "Highly conserved non-coding sequences are associated with vertebrate development". PLoS Biology. 3 (1): e7. doi:10.1371/journal.pbio.0030007. PMC 526512. PMID 15630479.
  12. "Unexpressed but Indispensable—The DNA Sequences That Control Development". PLoS Biology. 3 (1): e19. Jan 2005. doi:10.1371/journal.pbio.0030019. PMC 544543.
  13. Elizabeth Pennisi (2017) Mysterious unchanging DNA finds a purpose in life, Science 02 Jun 2017]

Ryu et al. BMC Evolutionary Biology 2012 http://www.biomedcentral.com/1471-2148/12/236

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