Shared Gene Structures and Clusters of Mutually Exclusive Spliced Exons within the Metazoan Muscle Myosin Heavy Chain Genes

Abstract

Multicellular animals possess two to three different types of muscle tissues. Striated muscles have considerable ultrastructural similarity and contain a core set of proteins including the muscle myosin heavy chain (Mhc) protein. The ATPase activity of this myosin motor protein largely dictates muscle performance at the molecular level. Two different solutions to adjusting myosin properties to different muscle subtypes have been identified so far: Vertebrates and nematodes contain many independent differentially expressed Mhc genes while arthropods have single Mhc genes with clusters of mutually exclusive spliced exons (MXEs). The availability of hundreds of metazoan genomes now allowed us to study whether the ancient bilateria already contained MXEs, how MXE complexity subsequently evolved, and whether additional scenarios to control contractile properties in different muscles could be proposed, By reconstructing the Mhc genes from 116 metazoans we showed that all intron positions within the motor domain coding regions are conserved in all bilateria analysed. The last common ancestor of the bilateria already contained a cluster of MXEs coding for part of the loop-2 actin-binding sequence. Subsequently the protostomes and later the arthropods gained many further clusters while MXEs got completely lost independently in several branches (vertebrates and nematodes) and species (for example the annelid Helobdella robusta and the salmon louse Lepeophtheirus salmonis). Several bilateria have been found to encode multiple Mhc genes that might all or in part contain clusters of MXEs. Notable examples are a cluster of six tandemly arrayed Mhc genes, of which two contain MXEs, in the owl limpet Lottia gigantea and four Mhc genes with three encoding MXEs in the predatory mite Metaseiulus occidentalis. Our analysis showed that similar solutions to provide different myosin isoforms (multiple genes or clusters of MXEs or both) have independently been developed several times within bilaterian evolution.

The landscape of human mutually exclusive splicing

“…In contrast to cassette exons and micro‐exons, which tend to be located in surface loops and intrinsically disordered regions instead of folded domains (Buljan et al , 2012; Ellis et al , 2012; Irimia et al , 2014), all MXEs, whose protein structures have been analysed, are embedded within folded structural domains as has been shown for, for example, DSCAM (Meijers et al , 2007), H2AFY (Kustatscher et al , 2005), the myosin motor domain (Kollmar & Hatje, 2014) and SLC25A3 (Tress et al , 2017a). As we have shown in the beginning, there is also a subset of 73 MXEs not showing any sequence homology (“annotated no similarity”).…”

“…SCN1A ] with the Drosophila calcium channel cac gene and not the orthologous sodium channel para gene). At least for muscle myosin heavy chain genes it could be demonstrated that Drosophila already lost several MXE clusters compared to, for example, Daphnia pulex (crustacean) and lophotrochozoans (Kollmar & Hatje, 2014) and that the evolutionary history of the MXEs within each cluster is remarkably complex with multiple independent exon duplications and losses (Odronitz & Kollmar, 2008). Thus, detailed studies including more bilaterian and non‐bilaterian taxa would be necessary to finally conclude convergent or divergent evolution for each of the human and Drosophila MXE clusters.…”

Myosin repertoire expansion coincides with eukaryotic diversification in the Mesoproterozoic era

“…duplication of the class-3 and class-7 myosins in the ancestor of arthropods and insects, respectively) and in (according to current sequence data) single species (e.g. duplication of muscle myosin heavy chain genes in the leech Helobdella robusta and the owl limpet Lottia gigantea [ 48 ]; see the myosin inventory table at CyMoBase for more examples). Together, these gene duplications indicate extensive subfunctionalization (Fig.…”

Myosin II sequences for Lethocerus indicus

“…In many species, the myosin gene shows clusters of mutually exclusive exons (MXEs) that are alternatively spliced to give different protein isoforms (Bernstein et al 1986 ; Wassenberg et al 1987 ; George et al 1989 ; Odronitz and Kollmar 2008 ; Kollmar and Hatje 2014 ). Evolutionary analysis shows eleven potential MXE clusters that code for specific regions of the molecule, ten within the S1 myosin head (Fig.…”

“…Evolutionary analysis shows eleven potential MXE clusters that code for specific regions of the molecule, ten within the S1 myosin head (Fig. 1 e) and one within the helical rod domain (Odronitz and Kollmar 2008 ; Kollmar and Hatje 2014 ). The ancestral arthropod gene is predicted to be intron rich, with 42 exons that are typically short (Kollmar and Hatje 2014 ).…”