The Gnas and Gnal loci, which encode the alpha subunits of stimulatory G-proteins, are among the most complex eukaryotic genes. They combine elaborate patterns of imprinting, alternative splicing, and antisense transcription with tissue- and developmental stage-specific expression. Different regions of these genes evolve at drastically different rates such that some show complete conservation, whereas others are virtually unalignable. Yet, the most unusual feature of the Gnas/Gnal complex is the presence of the longest known overlap between coding regions resulting in the production of two unrelated proteins: XL alpha s and its putative regulator ALEX. Here we elucidate the evolutionary history of both loci and uncover new complexities. First, alternatively spliced regions of both loci evolve under varying selective regimes echoing their distinct biological roles. Second, an enigmatic alternative transcript of the Gnas locus, known as Nesp, is likely bicistronic. Third, rodent XL alpha s and ALEX follow an evolutionary trajectory distinct from that of other mammals and show extensive sequence variation in the internal repeat region, a fact that might be explained by variation in the robustness of imprinting. Fourth, we show that the overlap between the XL alpha s and ALEX frames is restricted to eutherian mammals. Finally, we reconcile our findings with extensive physiological data derived from animal models.
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