Our analysis clearly shows that the WGD event that took place in Actinopterygii involved also DAG1. During evolution, WGD events are expected to have had a high impact on speciation. To fully understand this impact means to unravel all the genetic and molecular details underlying the speciation process, and the knowledge of which genes were retained in duplicate and how the duplication modified their evolutionary fitness is crucial to that aim. Generally, the functional consequences of WGD in fish have been mitigated both by partial gene loss and acquisition of new useful functions [37]. Indeed, in some cases the presence of two functional copies of an important gene like DG, could have represented an improvement of their fitness. The morpholino oligos-driven disruption of DG in zebrafish results in the emergence of a severe dystrophic phenotype in adults that could not be alleviated or compensated by a paralogue isoform of DG [5].
The importance of fish model systems for the study of Duchenne muscular dystrophy and other human muscular diseases is clearly emerging, as highlighted by the work carried out in Kunkel's lab [38]. Due to the important role played by DG in human congenital muscular disorders, comparative genetic and biochemical analyses could be particularly relevant in the race for fully elucidating its function or misfunction in severe diseases, eventually leading to innovative therapeutical strategies related to DG. For example, the DG's high affinity towards the proteoglycan agrin has been one of the factors leading to the design of miniaturized agrin, rescuing the dy/dy dystrophic phenotype in mice [39,40].
A comprehensive understanding of the biological implications of DAG1 duplication in some teleost fish species may have unexpected repercussions on the view of "secondary dystroglycanopathies", since recently paralogue isoforms of glycosyltransferases thought to act specifically on DG (LARGE and POMT among others) were also identified and characterized [41,42]. It is intriguing to hypothesize that in the future "evolution-inspired" gene therapy approaches, implying the introduction (or reintroduction) of a second DAG1 copy or isoform, will be used to alleviate the symptoms of dystrophy in human skeletal muscle.
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