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MBE Advance Access published online on November 29, 2006
Molecular Biology and Evolution, doi:10.1093/molbev/msl188
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© The Author 2006. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
Accepted November 27, 2006

Research Article

The Evolution of GABAA-Receptor-Like Genes

Shui-Ying Tsang 1, Siu-Kin Ng 2, Zhiwen Xu 1, and Hong Xue 1 *

1 Department of Biochemistry and Applied Genomics Laboratory, Clear Water Bay, Kowloon, Hong Kong
2 Department of Biochemistry and Applied Genomics Laboratory, Clear Water Bay, Kowloon, Hong Kong; Graduate Program of Bioengineering, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong

* To whom correspondence should be addressed.
Hong Xue, E-mail: hxue{at}ust.hk


  Abstract

The inhibitory ligand-gated ion-channel family of receptors, including the GABAA and glycine receptors, mediates inhibitory neurotransmissions in the central nervous system. In this study, GABAA receptor evolution was explored through comparative genomics using genomes that span divergent lineages. GABAA/Gly receptor-like (GRL) gene sequences were retrieved from the genomes of various species ranging from mammal to fish to worm, and subjected to cross-species comparison. All vertebrate GRL gene sets in the study but no invertebrate ones exhibit the extensive and conserved pattern of gene clustering that is characteristic of human GABAA receptor genes, indicating that the gene clusters were established early in vertebrate evolution, after divergence from the invertebrates. Moreover, the vertebrate gene structure is highly conserved with a basic 9-coding-exon structure, whereas, as well as being diverse in copy numbers and chromosomal loci, the invertebrate GRL genes display a variety of gene structures. Remarkably, the invertebrates each possess a unique GRL gene pair that lie in neighboring loci within their respective genomes: zc482.5 and zc482.1 in roundworm; CG8916 and CG17336 in fruitfly; Ci4249 and Ci4254 in Ciona, and these were revealed by phylogenetic analysis to be homologous to human GABAA receptor {alpha} and {beta} subunits, respectively. The phylogenetic classification of these genes is also corroborated by experimental ligand binding measurements using recombinant gene products. Furthermore, the three invertebrate gene pairs harbor characteristic key residues, and exhibit similarities in intron positions to their vertebrate counterparts. The results strongly indicate that such a gene pair originally existed in the bilaterian ancestor from which all three phyla evolved, and suggests that the extant GABAA receptor clusters arose from an ancestral {alpha}-{beta} subunit gene pair.

Keywords: Comparative genomics; GABAA receptors; evolution; gene structure; bilaterian ancestral genes.
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