389. Muscular Dystrophy Genes and the Early Metazoan Transition from Dynein- to Myosin-Powered Locomotion

Abstract

During early animal evolution, the primary source of locomotive mechanical power shifted from axonemal (flagellar) dynein to densely arrayed class II myosin. Although the emergence of muscle conferred the advantage of three-dimensional scalability, the transition brought with it the evolutionarily unprecedented problem of safely transmitting huge forces across rapidly deforming cell membranes. This task in vertebrates is accomplished in part through the dystrophin-dystroglycan-sarcoglycan complex (DGC), which is implicated in most forms of muscular dystrophy. We present the inferred earliest steps in the molecular evolution of these cell surface and cortical cytoskeletal proteins, using genome sequence data from all early branching metazoan phyla and a broad sampling of unicellular taxa. Results: Surprisingly, the phylogeny suggests that a DGC emerged before the “sarcomeric” clade of myosins, implying conserved function(s) among unicellular lineages closely related to the Metazoa. Furthermore, linkage of the DGC to the cytoskeleton occurred before the massive tandem-repeat expansions (>200) seen in sarcomeric scaffolding proteins of the titin superfamily. The rod-like domains of dystrophin and utrophin were coopted at their full length from a rapidly lengthening cytoskeletal protein with an unrelated function, that of connecting actin filaments to microtubules at large physical distances. Finally, intron positions in the inferred dystrophin gene in a common ancestor to all Bilateria provide clues to the molecular basis of Duchenne muscular dystrophy and to emerging therapies. Conclusions: Our reconstruction suggests that evolution of membrane-spanning “muscular dystrophy protein complexes” was an essential process as one geometric constraint on power transduction was traded for another. 80% of the length of dystrophin is attributable to tandem DNA duplications that pre-dated the evolutionary emergence of sarcomeres. This chronology implies that escalating power output from striated muscle played no role in providing selective pressure for the serial expansion of “spectrin-like” repeats. This finding has therapeutic implications, as it suggests that minimal length dystophins or utrophins may fully complement the physiological role of full length dystrophin in vertebrates as long as the deletional juxtaposition of triple helical repeats does not disrupt force transmission. This interpretation is consistent with the clinical findings of Becker Muscular Dystrophy in selected patients with in-frame exon duplications. In this view, the evolutionary stability of the length of the dystrophin rod is driven by the incompatibility, when placed in close physical proximity by deletion, of divergent triple helical repeats. The evolutionary translocation of the protein to the cytoskeletal cortex as part of the DGC may have greatly reduced the metabolic load associated with synthesis of the strong but scarce protein, also facilitating evolutionary drift to the enormous size of the gene in a common mammalian ancestor.