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A distal enhancer and an ultraconserved exon are derived from a novel retroposon

Abstract

Hundreds of highly conserved distal cis-regulatory elements have been characterized so far in vertebrate genomes1. Many thousands more are predicted on the basis of comparative genomics2,3. However, in stark contrast to the genes that they regulate, in invertebrates virtually none of these regions can be traced by using sequence similarity, leaving their evolutionary origins obscure. Here we show that a class of conserved, primarily non-coding regions in tetrapods originated from a previously unknown short interspersed repetitive element (SINE) retroposon family that was active in the Sarcopterygii (lobe-finned fishes and terrestrial vertebrates) in the Silurian period at least 410 million years ago (ref. 4), and seems to be recently active in the ‘living fossil’ Indonesian coelacanth, Latimeria menadoensis. Using a mouse enhancer assay we show that one copy, 0.5 million bases from the neuro-developmental gene ISL1, is an enhancer that recapitulates multiple aspects of Isl1 expression patterns. Several other copies represent new, possibly regulatory, alternatively spliced exons in the middle of pre-existing Sarcopterygian genes. One of these, a more than 200-base-pair ultraconserved region5, 100% identical in mammals, and 80% identical to the coelacanth SINE, contains a 31-amino-acid-residue alternatively spliced exon of the messenger RNA processing gene PCBP2 (ref. 6). These add to a growing list of examples7 in which relics of transposable elements have acquired a function that serves their host, a process termed ‘exaptation’8, and provide an origin for at least some of the many highly conserved vertebrate-specific genomic sequences.

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Figure 1: Coelacanth SINE, human ultraconserved PCBP2 exon and ISL1 proximal enhancer share a common origin.
Figure 2: Phylogeny of chordate genomes searched for instances of the LF-SINE.
Figure 3: A SINE-derived distal enhancer near ISL1.
Figure 4: Neural-specific expression driven by ISL1 -proximal-LF-SINE recapitulates Isl1 expression.

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References

  1. Woolfe, A. et al. Highly conserved non-coding sequences are associated with vertebrate development. PLoS Biol. 3, e7 (2005)

    Article  Google Scholar 

  2. Siepel, A. et al. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 15, 1034–1050 (2005)

    Article  CAS  Google Scholar 

  3. International Mouse Genome Sequencing Consortium. Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002)

    Article  Google Scholar 

  4. Graur, D. & Li, W.-H. Fundamentals of Molecular Evolution 2nd edn, Appendix I (Sinauer, Sunderland, Massachusetts, 2000)

    Google Scholar 

  5. Bejerano, G. et al. Ultraconserved elements in the human genome. Science 304, 1321–1325 (2004)

    Article  ADS  CAS  Google Scholar 

  6. Makeyev, A. V. & Liebhaber, S. A. The poly(C)-binding proteins: A multiplicity of functions and a search for mechanisms. RNA 8, 265–278 (2002)

    Article  CAS  Google Scholar 

  7. Brosius, J. The contribution of RNAs and retroposition to evolutionary novelties. Genetica 118, 99–116 (2003)

    Article  CAS  Google Scholar 

  8. Gould, S. & Vrba, E. Exaptation—a missing term in the science of form. Paleobiology 8, 4–15 (1982)

    Article  Google Scholar 

  9. Bejerano, G., Haussler, D. & Blanchette, M. Into the heart of darkness: Large-scale clustering of human non-coding DNA. Bioinformatics 20, i40–i48 (2004)

    Article  CAS  Google Scholar 

  10. Weiner, A. M. SINEs and LINEs: The art of biting the hand that feeds you. Curr. Opin. Cell Biol. 14, 343–350 (2002)

    Article  CAS  Google Scholar 

  11. Deininger, P. L. & Batzer, M. A. Mammalian retroelements. Genome Res. 12, 1455–1465 (2002)

    Article  CAS  Google Scholar 

  12. Pfaff, S. L., Mendelsohn, M., Stewart, C. L., Edlund, T. & Jessell, T. M. Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation. Cell 84, 309–320 (1996)

    Article  CAS  Google Scholar 

  13. Uemura, O. et al. Comparative functional genomics revealed conservation and diversification of three enhancers of the isl1 gene for motor and sensory neuron-specific expression. Dev. Biol. 278, 587–606 (2005)

    Article  CAS  Google Scholar 

  14. Caton, A. et al. The branchial arches and HGF are growth-promoting and chemoattractant for cranial motor axons. Development 127, 1751–1766 (2000)

    CAS  PubMed  Google Scholar 

  15. Lev-Maor, G., Sorek, R., Shomron, N. & Ast, G. The birth of an alternatively spliced exon: 3′ splice-site selection in Alu exons. Science 300, 1288–1291 (2003)

    Article  ADS  CAS  Google Scholar 

  16. Makalowski, W. Genomics. Not junk after all. Science 300, 1246–1247 (2003)

    Article  CAS  Google Scholar 

  17. Lewis, B. P., Green, R. E. & Brenner, S. E. Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans. Proc. Natl Acad. Sci. USA 100, 189–192 (2003)

    Article  ADS  CAS  Google Scholar 

  18. Chkheidze, A. N. & Liebhaber, S. A. A novel set of nuclear localization signals determine distributions of the alphaCP RNA-binding proteins. Mol. Cell. Biol. 23, 8405–8415 (2003)

    Article  CAS  Google Scholar 

  19. Kim, J. H., Hahm, B., Kim, Y. K., Choi, M. & Jang, S. K. Protein–protein interaction among hnRNPs shuttling between nucleus and cytoplasm. J. Mol. Biol. 298, 395–405 (2000)

    Article  CAS  Google Scholar 

  20. Waggoner, S. A. & Liebhaber, S. A. Identification of mRNAs associated with αCP2-containing RNP complexes. Mol. Cell. Biol. 23, 7055–7067 (2003)

    Article  CAS  Google Scholar 

  21. Gunduz, E. et al. Genetic and epigenetic alterations of BRG1 promote oral cancer development. Int. J. Oncol. 26, 201–210 (2005)

    CAS  PubMed  Google Scholar 

  22. Li, Y., Lu, W. & Bu, G. Striking differences of LDL receptor-related protein 1B expression in mouse and human. Biochem. Biophys. Res. Commun. 333, 868–873 (2005)

    Article  CAS  Google Scholar 

  23. McClintock, B. The origin and behavior of mutable loci in maize. Proc. Natl Acad. Sci. USA 36, 344–355 (1950)

    Article  ADS  CAS  Google Scholar 

  24. Britten, R. J. & Davidson, E. H. Repetitive and non-repetitive DNA sequences and a speculation on the origins of evolutionary novelty. Q. Rev. Biol. 46, 111–138 (1971)

    Article  CAS  Google Scholar 

  25. Kazazian, H. H. Jr . Mobile elements: Drivers of genome evolution. Science 303, 1626–1632 (2004)

    Article  ADS  CAS  Google Scholar 

  26. McEwen, G. K. et al. Ancient duplicated conserved noncoding elements in vertebrates: A genomic and functional analysis. Genome Res. doi:10.1101/gr.4143406 (2006)

  27. Danke, J. et al. Genome resource for the Indonesian coelacanth, Latimeria menadoensis. J. Exp. Zoolog. A 301, 228–234 (2004)

    Article  Google Scholar 

  28. Kothary, R. et al. A transgene containing lacZ inserted into the dystonia locus is expressed in neural tube. Nature 335, 435–437 (1988)

    Article  ADS  CAS  Google Scholar 

  29. Poulin, F. et al. In vivo characterization of a vertebrate ultraconserved enhancer. Genomics 85, 774–781 (2005)

    Article  CAS  Google Scholar 

  30. Feldheim, D. A. et al. Topographic guidance labels in a sensory projection to the forebrain. Neuron 21, 1303–1313 (1998)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the various sequencing consortia and research groups for the numerous genomic regions used in this study; A. Hinrichs, M. Diekhans, R. Harte, G. Barber and the UCSC browser team, M. Shoukry, I. Plajzer-Frick, S. Chanan and V. Afzal for technical help; R. Baertsch, T. Furey, E. Margulies and J. S. Pedersen for sharing unpublished data; and W. Miller, M. Blanchette, D. Feldheim, M. Nobrega, M. Ares, C. Sugnet, M. Dermitzakis and J. Brosius for discussions. Research conducted at University of California Santa Cruz was supported by the National Human Genome Research Institute and the Howard Hughes Medical Institute; Research conducted at the E.O. Lawrence Berkeley National Laboratory was supported by grants from the Programs for Genomic Application, the NHLBI and performed under a Department of Energy Contract, University of California.

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Correspondence to Gill Bejerano.

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This file contains Supplementary Methods, Supplementary Discussion, Supplementary Figures 1–15 and Supplementary Tables 1–9. (PDF 1641 kb)

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Bejerano, G., Lowe, C., Ahituv, N. et al. A distal enhancer and an ultraconserved exon are derived from a novel retroposon. Nature 441, 87–90 (2006). https://doi.org/10.1038/nature04696

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