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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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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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