An ancient genomic regulatory block conserved across bilaterians and its dismantling in tetrapods by retrogene replacement

Developmental genes are regulated by complex, distantly located cis-regulatory modules (CRMs), often forming genomic regulatory blocks (GRBs) that are conserved among vertebrates and among insects. We have investigated GRBs associated with Iroquois homeobox genes in 39 metazoans. Despite 600 million years of independent evolution, Iroquois genes are linked to ankyrin-repeat-containing Sowah genes in nearly all studied bilaterians. We show that Iroquois-specific CRMs populate the Sowah locus, suggesting that regulatory constraints underlie the maintenance of the Iroquois-Sowah syntenic block. Surprisingly, tetrapod Sowah orthologs are intronless and not associated with Iroquois; however, teleost and elephant shark data demonstrate that this is a derived feature, and that many Iroquois-CRMs were ancestrally located within Sowah introns. Retroposition, gene, and genome duplication have allowed selective elimination of Sowah exons from the Iroquois regulatory landscape while keeping associated CRMs, resulting in large associated gene deserts. These results highlight the importance of CRMs in imposing constraints to genome architecture, even across large phylogenetic distances, and of gene duplication-mediated genetic redundancy to disentangle these constraints, increasing genomic plasticity. © 2012 by Cold Spring Harbor Laboratory Press.
M.I., I.M., and J.G.-F. were funded by Grants BFU2005-00252 and BMC2008-03776 and BMC2011-23291 from the Spanish Ministry of Science and Innovation, and J.G.F. by the ICREA Academia Prize. M.I. and I.M. held FPI and FPU grants, respectively. J.-L.G.-S. and J.J.T. were supported by Grants BFU2010-14839, CSD2007-00008 (MEC), and CVI 3488 (Junta de Andalucía). S.C. and E.G.-P. were supported by grants BFU2008-03762/BMC (MICIIN), CDS2007-00008 (MEC), and an institutional grant from Fundación Ramón Areces to the CBMSO. D.T., V.R., and B.V. were supported by the Biomedical Research Council of A*STAR, Singapore.