Conservation of gene linkage in dispersed vertebrate NK homeobox clusters
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Nk homeobox genes are important regulators of many different developmental processes including muscle, heart, central nervous system and sensory organ development. They are thought to have arisen as part of the ANTP megacluster, which also gave rise to Hox and ParaHox genes, and at least some NK genes remain tightly linked in all animals examined so far. The protostome–deuterostome ancestor probably contained a cluster of nine Nk genes: (Msx)–(Nk4/tinman)–(Nk3/bagpipe)–(Lbx/ladybird)–(Tlx/c15)–(Nk7)–(Nk6/hgtx)–(Nk1/slouch)–(Nk5/Hmx). Of these genes, only NKX2.6–NKX3.1, LBX1–TLX1 and LBX2–TLX2 remain tightly linked in humans. However, it is currently unclear whether this is unique to the human genome as we do not know which of these Nk genes are clustered in other vertebrates. This makes it difficult to assess whether the remaining linkages are due to selective pressures or because chance rearrangements have “missed” certain genes. In this paper, we identify all of the paralogs of these ancestrally clustered NK genes in several distinct vertebrates. We demonstrate that tight linkages of Lbx1–Tlx1, Lbx2–Tlx2 and Nkx3.1–Nkx2.6 have been widely maintained in both the ray-finned and lobe-finned fish lineages. Moreover, the recently duplicated Hmx2–Hmx3 genes are also tightly linked. Finally, we show that Lbx1–Tlx1 and Hmx2–Hmx3 are flanked by highly conserved noncoding elements, suggesting that shared regulatory regions may have resulted in evolutionary pressure to maintain these linkages. Consistent with this, these pairs of genes have overlapping expression domains. In contrast, Lbx2–Tlx2 and Nkx3.1–Nkx2.6, which do not seem to be coexpressed, are also not associated with conserved noncoding sequences, suggesting that an alternative mechanism may be responsible for the continued clustering of these genes.
KeywordsNkx Msx Lbx Tlx Hmx CNE
This work was supported in part by a Royal Society University Research Fellowship to KEL and by a EU grant # LSH-CT-2004-511978 Myores to SD.
- Catchen J (2009) Automated methods to infer ancient homology and synteny. Ph.D. Dissertation, Department of Computer and Information Science, University of OregonGoogle Scholar
- Cheng L, Arata A, Mizuguchi R, Qian Y, Karunaratne A, Gray PA, Arata S, Shirasawa S, Bouchard M, Luo P, Chen CL, Busslinger M, Goulding M, Onimaru H, Ma Q (2004) Tlx3 and Tlx1 are post-mitotic selector genes determining glutamatergic over GABAergic cell fates. Nat Neurosci 7(5):510–517CrossRefPubMedGoogle Scholar
- de la Calle-Mustienes E, Feijoo CG, Manzanares M, Tena JJ, Rodriguez-Seguel E, Letizia A, Allende ML, Gomez-Skarmeta JL (2005) A functional survey of the enhancer activity of conserved non-coding sequences from vertebrate Iroquois cluster gene deserts. Genome Res 15(8):1061–1072CrossRefPubMedGoogle Scholar
- Evans SM, Yan W, Murillo MP, Ponce J, Papalopulu N (1995) tinman, a Drosophila homeobox gene required for heart and visceral mesoderm specification, may be represented by a family of genes in vertebrates: XNkx-2.3, a second vertebrate homologue of tinman. Development 121(11):3889–3899PubMedGoogle Scholar
- Holland PW, Garcia-Fernandez J, Williams NA, Sidow A (1994) Gene duplications and the origins of vertebrate development. Dev Suppl 1994:125–133Google Scholar
- Jovelin R, Yan YL, He X, Catchen J, Amores A, Canestro C, Yokoi H, Postlethwait JH (2009) Evolution of developmental regulation in the vertebrate FgfD subfamily. J Exp Zoolog B Mol Dev Evol (in press)Google Scholar
- Kimura-Yoshida C, Kitajima K, Oda-Ishii I, Tian E, Suzuki M, Yamamoto M, Suzuki T, Kobayashi M, Aizawa S, Matsuo I (2004) Characterization of the pufferfish Otx2 cis-regulators reveals evolutionarily conserved genetic mechanisms for vertebrate head specification. Development 131(1):57–71CrossRefPubMedGoogle Scholar
- Pennacchio LA, Ahituv N, Moses AM, Prabhakar S, Nobrega MA, Shoukry M, Minovitsky S, Dubchak I, Holt A, Lewis KD, Plajzer-Frick I, Akiyama J, De Val S, Afzal V, Black BL, Couronne O, Eisen MB, Visel A, Rubin EM (2006) In vivo enhancer analysis of human conserved non-coding sequences. Nature 444(7118):499–502CrossRefPubMedGoogle Scholar