Evolution of GABA(A) receptor diversity in the human genome

Nowhere is the record of receptor evolution more accessible than in the org anization of the 19 vertebrate genes coding for subunits of the major inhib itory neurotransmitter receptor in the central nervous system, the gamma-am inobutyric acid receptor (GABA(A)R). Co-expression of alpha, beta, and gamm a subunit genes is necessary for the formation of a GABA(A)R that is potent iated by widely used anxiolytics, anticonvulsants, and hypnotics. The ident ification of alpha, beta, and gamma genes on chromosomes 4, 5, and 15 sugge sts that co-localization of a gamma gene with an alpha and beta may be impo rtant for brain function. We have now directly examined the organization of GABA(A)R subunit genes on human chromosomes. Estimates of physical distanc e using in situ hybridization to cells in interphase, and gene localization using hybridization to cells in metaphase demonstrate the existence of bet a-alpha-alpha-gamma gene clusters in cytogenetic bands on chromosomes 4(p12 ) and 5(q34). Sequencing of PAC clones establishes intercluster conservatio n of a unique head-to-head configuration for alpha and beta genes on chromo somes 4, 5, and 15. Remarkably, phylogenetic tree analysis predicts the exi stence of a beta-alpha-gamma ancestral gene cluster in which internal dupli cation of an ancestral alpha was followed by cluster duplication, resulting in the relative chromosomal positions of modern GABA(A)R subunit genes in the human genome. (C) 1999 Elsevier Science B.V. All rights reserved.