Journal
PLOS GENETICS
Volume 3, Issue 10, Pages 1838-1847Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.0030173
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Funding
- Howard Hughes Medical Institute Funding Source: Medline
- Medical Research Council [MC_U105185858] Funding Source: Medline
- NCRR NIH HHS [M01 RR000102, M01-RR00102] Funding Source: Medline
- NINDS NIH HHS [R01 NS034389, R01 NS040955, NS40955, R01 NS34389] Funding Source: Medline
- Medical Research Council [MC_U105185858] Funding Source: researchfish
- MRC [MC_U105185858] Funding Source: UKRI
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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.
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