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Conservation of gene linkage in dispersed vertebrate NK homeobox clusters

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Abstract

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.

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Acknowledgements

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.

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Author notes

  1. Karl R. Wotton

    Present address: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), UFP, Barcelona, Spain

  2. Lúcia E. Alvares

    Present address: Department of Histology and Embryology, Institute of Biology, State University of Campinas (UNICAMP), São Paulo, Brazil

  3. Susanne Dietrich

    Present address: School of Biomedical and Health Sciences, King’s College London, Hodgkin Building G43S/44S, Guy’s Campus, London, SE1 1UL, UK

Authors and Affiliations

  1. Department of Craniofacial Development, King’s College London, Floor 27 Guy’s Tower, Guy’s Hospital, London Bridge, London, SE1 9RT, UK

    Karl R. Wotton, Lúcia E. Alvares & Susanne Dietrich

  2. Department of Physiology, Development and Neuroscience, Cambridge University, Anatomy Building, Downing Street, Cambridge, CB2 3DY, UK

    Frida K. Weierud, José L. Juárez-Morales & Katharine E. Lewis

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Correspondence to Katharine E. Lewis.

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Communicated by M. Hammerschmidt

Karl Wotton and Frida Weierud contributed equally to this paper.

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Wotton, K.R., Weierud, F.K., Juárez-Morales, J.L. et al. Conservation of gene linkage in dispersed vertebrate NK homeobox clusters. Dev Genes Evol 219, 481–496 (2009). https://doi.org/10.1007/s00427-009-0311-y

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  • DOI: https://doi.org/10.1007/s00427-009-0311-y

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