Identification of Three Novel Ca2+ Channel γ Subunit Genes Reveals Molecular Diversification by Tandem and Chromosome Duplication

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Abstract
Gene duplication is believed to be an important evolutionary mechanism for generating functional diversity within genomes. The accumulated products of ancient duplication events can be readily observed among the genes encoding voltage-dependent Ca2+ ion channels. Ten paralogous genes have been identified that encode isoforms of the α1 subunit, four that encode β subunits, and three that encode α2δ subunits. Until recently, only a single gene encoding a muscle-specific isoform of the Ca2+ channel γ subunit (CACNG1) was known. Expression of a distantly related gene in the brain was subsequently demonstrated upon isolation of the Cacng2 gene, which is mutated in the mouse neurological mutant stargazer (stg). In this study, we sought to identify additional genes that encoded γ subunits. Because gene duplication often generates paralogs that remain in close syntenic proximity (tandem duplication) or are copied onto related daughter chromosomes (chromosome or whole-genome duplication), we hypothesized that the known positions of CACNG1 andCACNG2 could be used to predict the likely locations of additional γ subunit genes. Low-stringency genomic sequence analysis of targeted regions led to the identification of three novel Ca2+ channel γ subunit genes, CACNG3,CACNG4, and CACNG5, on chromosomes 16 and 17. These results demonstrate the value of genome evolution models for the identification of distantly related members of gene families.[The sequence data described in this paper have been submitted to the GenBank data library under accession numbersAF142618–AF142625 and AF148220.]