Phylogeny of teleost connexins reveals highly inconsistent intra- and interspecies use of nomenclature and misassemblies in recent teleost chromosome assemblies

Abstract

Background: Based on an initial collecting of database sequences from the gap junction protein gene family (also called connexin genes) in a few teleosts, the naming of these sequences appeared variable. The reasons could be (i) that the structure in this family is variable across teleosts, or (ii) unfortunate naming. Rather clear rules for the naming of genes in fish and mammals have been outlined by nomenclature committees, including the naming of orthologous and ohnologous genes. We therefore analyzed the connexin gene family in teleosts in more detail. We covered the range of divergence times in teleosts (eel, Atlantic herring, zebrafish, Atlantic cod, three-spined stickleback, Japanese pufferfish and spotted pufferfish; listed from early divergence to late divergence). Results: The gene family pattern of connexin genes is similar across the analyzed teleosts. However, (i) several nomenclature systems are used, (ii) specific orthologous groups contain genes that are named differently in different species, (iii) several distinct genes have the same name in a species, and (iv) some genes have incorrect names. The latter includes a human connexin pseudogene, claimed as GJA4P, but which in reality is Cx39.2P (a delta subfamily gene often called GJD2like). We point out the ohnologous pairs of genes in teleosts, and we suggest a more consistent nomenclature following the outlined rules from the nomenclature committees. We further show that connexin sequences can indicate some errors in two high-quality chromosome assemblies that became available very recently. Conclusions: Minimal consistency exists in the present practice of naming teleost connexin genes. A consistent and unified nomenclature would be an advantage for future automatic annotations and would make various types of subsequent genetic analyses easier. Additionally, roughly 5% of the connexin sequences point out misassemblies in the new high-quality chromosome assemblies from herring and cod.

Connexinplexity: The spatial and temporal expression of connexin genes during vertebrate organogenesis

“…1, 2). Across the family of connexin genes there are seven human connexins for which zebrafish only has a single homolog, eight human connexins for which zebrafish has two homologs, two zebrafish connexins that have no direct homolog but share sequence similarity to human connexins, and sixteen zebrafish connexins that are not present in humans but are conserved in other teleost and mammalian lineages 30 . We summarize these relationships in Table 1, listing zebrafish connexin genes and their closest relationship with their human counterparts, providing known human and zebrafish expression patterns and phenotypes for comparison.…”

“…There are a limited number of rows where the zebrafish connexin gene resembles its human counterpart(s), but the genes are not direct homologs. For example, the human GJB2/GJB6 genes are duplicated in the human lineage while having only a single similar gene in zebrafish called gjb8 30 . Despite not being direct homologs, expression and mutant analyses have found that zebrafish gjb8 and human GJB2/GJB6 genes are all involved in inner-ear support cell function and loss of these genes in their respective systems causes deafness 20,52,53 .…”

“…A major challenge in characterizing connexin expression is the complexity of the gene family. In humans, there are 20 distinct connexin genes, and in other vertebrate lineages the number of Connexin-encoding genes is similarly large and varies widely [28][29][30] . Cell culture and in vitro work suggests that connexin complexity provides functional diversity governed by four general principles: first, hemichannels are created by hexamers of individual Connexin proteins 31 ; second, single or multiple Connexin proteins can contribute to hemichannel formation (homo-or heteromeric hemichannels, respectively) [32][33][34] ; third, gap junctions form intercellular channels via hemichannel docking at cell-cell junctions; fourth, each contributed hemichannel can contain the same or different Connexin proteins (homo-or heterotypic channels, respectively) [32][33][34] .…”