Abstract
The genes of the ionotropic gamma-aminobutyric acid receptor (GABR) subunits have shown an unusual chromosomal clustering, but only now can this be fully specified by analyses of the human genome. We have characterized the genes encoding the 18 known human GABR subunits, plus one now located here, for their precise locations, sizes, and exon/intron structures. Clusters of 17 of the 19, distributed between five chromosomes, are specified in detail, and their possible significance is considered. By applying search algorithms designed to recognize sequences of all known GABR-type subunits in species from man down to nematodes, we found no new GABR subunit is detectable in the human genome. However, the sequence of the human orthologue of the rat GABR rho3 receptor subunit was uncovered by these algorithms, and its gene could be analyzed. Consistent with those search results, orthologues of the beta4 and gamma4 subunits from the chicken, not cloned from mammals, were not detectable in the human genome by specific searches for them. The relationships are consistent with the mammalian subunit being derived from the beta line and epsilon from the gamma line, with mammalian loss of beta4 and gamma4. In their structures the human GABR genes show a basic pattern of nine coding exons, with six different genomic mechanisms for the alternative splicing found in various subunits. Additional noncoding exons occur for certain subunits, which can be regulatory. A dicysteine loop and its exon show remarkable constancy between all GABR subunits and species, of deduced functional significance.
Highlights
The GABAA1 receptors are GABA-gated ion channels that are well known to mediate most of the inhibitory signaling in the vertebrate central nervous system
By applying search algorithms designed to recognize sequences of all known GABRtype subunits in species from man down to nematodes, we found no new GABAA receptor (GABR) subunit is detectable in the human genome
The GABAA receptors are formed as combinations of homologous subunits [6]; these are from 420 to 632 amino acids in length, of which 19 (Fig. 1) have been cloned from mammals but not all from man, each clearly being attributed to a different gene
Summary
Consensus Sequence Searches—The amino acid sequences in and immediately neighboring the Cys loop (as defined under “Results”) were aligned for each receptor family as specified. Taking positions conserved in all of the GABR sequences, a GABR Cys loop consensus was written in nucleotide form, including all codon redundancies and with bidirectionality This consensus was used as a position-specific profile to write an algorithm for a search program (available on request), as described under “Results,” designed to be run against the human or any other genome data base. In all of the GABR sequences, vertebrate and invertebrate, this agreed completely with a second minimal form of the consensus (form E, as defined under “Results”); form E was applied to the human genome search This type of search program registers as hits only cases where all of the specified positions match and does not require probability judgements. Probe a (2.8 kbp) was the sequence of an Image EST clone (H86104, purchased from Genome Systems Inc); this was identified from the overlap of its 5Ј-end with the 3Ј-end of clone 404, which Glatt et al [17] had found maps in this region
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