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Genomic regulatory blocks encompass multiple neighboring genes and maintain conserved synteny in vertebrates

¹ Sars Centre for Marine Molecular Biology, University of Bergen, 5008 Bergen, Norway; ² Computational Biology Unit, University of Bergen, 5008 Bergen, Norway; ³ Programme for Genomics and Bioinformatics, Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden; ⁴ Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, United Kingdom; ⁵ Biologie Moléculaire du Développement, INSERM U368, Ecole Normale Supérieure, Paris, 75230 Paris, Cedex 05 France; ⁶ Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany; ⁷ IGBMC, CNRS/INSERM/ULP, BP10142, 67404 Illkirch, Cedex, France; ⁸ Unité de Génétique des Déficits Sensoriels, Institut Pasteur, F-75724 Paris Cedex 15, France; ⁹ Institute of Developmental Genetics, GSF Research Center, 85764 Neuherberg, Germany

We report evidence for a mechanism for the maintenance of long-range conserved synteny across vertebrate genomes. We found the largest mammal-teleost conserved chromosomal segments to be spanned by highly conserved noncoding elements (HCNEs), their developmental regulatory target genes, and phylogenetically and functionally unrelated "bystander" genes. Bystander genes are not specifically under the control of the regulatory elements that drive the target genes and are expressed in patterns that are different from those of the target genes. Reporter insertions distal to zebrafish developmental regulatory genes pax6.1/2, rx3, id1, and fgf8 and miRNA genes mir9-1 and mir9-5 recapitulate the expression patterns of these genes even if located inside or beyond bystander genes, suggesting that the regulatory domain of a developmental regulatory gene can extend into and beyond adjacent transcriptional units. We termed these chromosomal segments genomic regulatory blocks (GRBs). After whole genome duplication in teleosts, GRBs, including HCNEs and target genes, were often maintained in both copies, while bystander genes were typically lost from one GRB, strongly suggesting that evolutionary pressure acts to keep the single-copy GRBs of higher vertebrates intact. We show that loss of bystander genes and other mutational events suffered by duplicated GRBs in teleost genomes permits target gene identification and HCNE/target gene assignment. These findings explain the absence of evolutionary breakpoints from large vertebrate chromosomal segments and will aid in the recognition of position effect mutations within human GRBs.

¹¹ Mischterlich and Partners, 80066 Munich, Germany.

¹² For information on bioinformatic methods, e-mail boris.lenhard@ bccs.uib.no.

¹³ Corresponding author.

E-mail tom.becker{at}sars.no; fax 47-55584305.

[Supplemental material is available online at www.genome.org.]

Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.6086307

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