| Summary: | <p>Abstract</p> <p>Background</p> <p>First identified in fruit flies with temperature-sensitive paralysis phenotypes, the <it>Drosophila melanogaster TipE </it>locus encodes four voltage-gated sodium (Na<sub>V</sub>) channel auxiliary subunits. This cluster of <it>TipE</it>-like genes on chromosome 3L, and a fifth family member on chromosome 3R, are important for the optional expression and functionality of the Para Na<sub>V </sub>channel but appear quite distinct from auxiliary subunits in vertebrates. Here, we exploited available arthropod genomic resources to trace the origin of <it>TipE</it>-like genes by mapping their evolutionary histories and examining their genomic architectures.</p> <p>Results</p> <p>We identified a remarkably conserved synteny block of <it>TipE</it>-like orthologues with well-maintained local gene arrangements from 21 insect species. Homologues in the water flea, <it>Daphnia pulex</it>, suggest an ancestral pancrustacean repertoire of four <it>TipE</it>-like genes; a subsequent gene duplication may have generated functional redundancy allowing gene losses in the silk moth and mosquitoes. Intronic nesting of the insect <it>TipE </it>gene cluster probably occurred following the divergence from crustaceans, but in the flour beetle and silk moth genomes the clusters apparently escaped from nesting. Across Pancrustacea, <it>TipE </it>gene family members have experienced intronic nesting, escape from nesting, retrotransposition, translocation, and gene loss events while generally maintaining their local gene neighbourhoods. <it>D. melanogaster TipE</it>-like genes exhibit coordinated spatial and temporal regulation of expression distinct from their host gene but well-correlated with their regulatory target, the Para Na<sub>V </sub>channel, suggesting that functional constraints may preserve the <it>TipE </it>gene cluster. We identified homology between TipE-like Na<sub>V </sub>channel regulators and vertebrate Slo-beta auxiliary subunits of big-conductance calcium-activated potassium (BK<sub>Ca</sub>) channels, which suggests that ion channel regulatory partners have evolved distinct lineage-specific characteristics.</p> <p>Conclusions</p> <p><it>TipE</it>-like genes form a remarkably conserved genomic cluster across all examined insect genomes. This study reveals likely structural and functional constraints on the genomic evolution of insect <it>TipE </it>gene family members maintained in synteny over hundreds of millions of years of evolution. The likely common origin of these Na<sub>V </sub>channel regulators with BK<sub>Ca </sub>auxiliary subunits highlights the evolutionary plasticity of ion channel regulatory mechanisms.</p>
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