title: Evolution of Nova-dependent splicing regulation in the brain.
abstract: A large number of alternative exons are spliced with tissue-specific patterns, but little is known about how such patterns have evolved. Here, we study the conservation of the neuron-specific splicing factors Nova1 and Nova2 and of the alternatively spliced exons they regulate in mouse brain. Whereas Nova RNA binding domains are 94% identical across vertebrate species, Nova-dependent splicing silencer and enhancer elements (YCAY clusters) show much greater divergence, as less than 50% of mouse YCAY clusters are conserved at orthologous positions in the zebrafish genome. To study the relation between the evolution of tissue-specific splicing and YCAY clusters, we compared the brain-specific splicing of Nova-regulated exons in zebrafish, chicken, and mouse. The presence of YCAY clusters in lower vertebrates invariably predicted conservation of brain-specific splicing across species, whereas their absence in lower vertebrates correlated with a loss of alternative splicing. We hypothesize that evolution of Nova-regulated splicing in higher vertebrates proceeds mainly through changes in cis-acting elements, that tissue-specific splicing might in some cases evolve in a single step corresponding to evolution of a YCAY cluster, and that the conservation level of YCAY clusters relates to the functions encoded by the regulated RNAs.
authors.affiliation: Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York, USA.
authors.forename: Nejc
authors.initials: N
authors.lastname: Jelen
authors.forename: Jernej
authors.initials: J
authors.lastname: Ule
authors.forename: Marko
authors.initials: M
authors.lastname: Zivin
authors.forename: Robert B
authors.initials: RB
authors.lastname: Darnell
mesh_terms: D017398:Alternative Splicing; D058227:Amyloidogenic Proteins / Q000235:genetics*; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics*; D001921:Brain / Q000378:metabolism*; D002645:Chickens; D019143:Evolution, Molecular; D006801:Humans; D051379:Mice; D008954:Models, Biological; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000235:genetics*; D000090682:Neuro-Oncological Ventral Antigen; D009893:Opossums; D016601:RNA-Binding Proteins / Q000235:genetics*; D013045:Species Specificity; D014981:Xenopus; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: D058227:Amyloidogenic Proteins; D000951:Antigens, Neoplasm; C573648:Aplp2 protein, zebrafish; D009419:Nerve Tissue Proteins; D000090682:Neuro-Oncological Ventral Antigen; C515624:Nova2 protein, mouse; D016601:RNA-Binding Proteins; D029961:Zebrafish Proteins