No abstract

BackgroundAlthough most genes in mammalian genomes have multiple isoforms, an ongoing debate is whether these isoforms are all functional as well as the extent to which they increase the functional repertoire of the genome. To ground this debate in data, it would be helpful to have a corpus of experimentally-verified cases of genes which have functionally distinct splice isoforms (FDSIs).ResultsWe established a curation framework for evaluating experimental evidence of FDSIs, and analyzed over 700 human and mouse genes, strongly biased towards genes that are prominent in the alternative splicing literature. Despite this bias, we found experimental evidence meeting the classical definition for functionally distinct isoforms for ~ 5% of the curated genes. If we relax our criteria for inclusion to include weaker forms of evidence, the fraction of genes with evidence of FDSIs remains low (~ 13%). We provide evidence that this picture will not change substantially with further curation and conclude there is a large gap between the presumed impact of splicing on gene function and the experimental evidence. Furthermore, many functionally distinct isoforms were not traceable to a specific isoform in Ensembl, a database that forms the basis for much computational research.ConclusionsWe conclude that the claim that alternative splicing vastly increases the functional repertoire of the genome is an extrapolation from a limited number of empirically supported cases. We also conclude that more work is needed to integrate experimental evidence and genome annotation databases. Our work should help shape research around the role of splicing on gene function from presuming large general effects to acknowledging the need for stronger experimental evidence.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-5013-2) contains supplementary material, which is available to authorized users.

Retrograde BMP signaling and canonical pMad/Medea-mediated transcription regulates diverse target genes across subsets of Drosophila efferent neurons, to differentiate neuropeptidergic neurons and promote motor neuron terminal maturation. How a common BMP signal regulates diverse target genes across neuronal subsets remains largely unresolved, although available evidence implicates subset-specific transcription factor codes rather than differences in BMP signaling. Here, we examine the cis-regulatory mechanisms restricting BMP-induced FMRFa neuropeptide expression to Tv4 neurons. We find that pMad/Medea bind at an atypical, low affinity motif in the FMRFa enhancer. Converting this motif to high affinity caused ectopic enhancer activity and eliminated Tv4 neuron expression. In silico searches identified additional motif instances functional in other efferent neurons, implicating broader functions for this motif in BMP-dependent enhancer activity. Thus, differential interpretation of a common BMP signal, conferred by low affinity pMad/Medea binding motifs, can contribute to the specification of BMP target genes in efferent neuron subsets.