This ' tour de force' dataset allowed Bradley et al. present the first genome-wide study analyzing the potential regulation of NAGNAG alternative splicing using RNA-Seq data from 16 human tissues as well as 8 mouse tissues. In a recent issue of PLoS Biology, Bradley et al. Thus, the jury was still out to characterize NAGNAG alternative splicing. While several experimental attempts have been made to identify examples of regulated NAGNAG alternative splicing, most datasets analyzed were so limited in number that no convincing general conclusions could be drawn. However, even with all these interesting puzzle pieces provided over the last years, it was still not clear if alternative NAGNAG splicing is the result of yet another form of regulated mRNA diversification, or whether it is simply a reflection of splicing inaccuracies that appear to be particularly abundant when splice junctions are presented in such close proximity. The notion of functionally important alternative NAGNAG splicing was further promoted by the demonstration that such events are selected against within parts of an ordered three-dimensional protein structure. Such regulation would imply a biological function to alternative NAGNAG splicing rather then just an imprecision of the spliceosome. Analyzing splicing events covered by a large number of EST entries suggested that some alternative NAGNAG splicing may be tissue specific, a proposal supported by high evolutionary conservation and an overabundance of cis-regulatory elements in proximity of alternatively spliced NAGNAGs. Other approaches supplied indications of regulation. Similarly, machine learning approaches based on such sequence features proved very reliable in predicting whether a NAGNAG configuration at a 3' splice site would elicit alternative splicing. For example, it was argued that constitutive or alternative usage of tandem acceptors strictly depends on the immediate sequence context around NAGNAG sites, thus proposing a simple physical model that implies a stochastic selection process. Several lines of work focused on delineating whether alternative acceptor site selection is actively regulated or stochastically selected during the splicing process. Since the discovery of NAGNAG alternative splicing almost a decade ago, debates about its functional implications and regulatory mechanisms have been controversial. presents the first genome-wide study analyzing the potential regulation of NAGNAG alternative splicing using massive parallel sequencing. The upstream NAG is referred to as the proximal acceptor and the downstream NAG is referred to as the distal acceptor. The two alternative mRNA isoforms differ in length by three nucleotides, altering one or two amino acids in the resulting protein depending on the phase of the intron. Among all reading-frame-preserving alternative splicing events, NAGNAG splicing is the second most frequent form (approximately 20%) after exon skipping (approximately 60%). Their alternative usage alters the transcript by the length of exactly one codon and, thus, is reading frame preserving. Alternative acceptor motifs 3 bp apart from each other, also referred to as NAGNAG or tandem acceptor sites, can be found in 30% of human genes and appear to be functional in at least 5% (Figure 1, upper panel). Often these alternative splice sites can be found in very close proximity to each other. The inclusion or exclusion of an exon, also referred to as exon skipping, is the most prevalent form of alternative splicing, followed by the usage of alternative 3' (acceptor) or 5' (donor) splice sites. Different protein isoforms are produced from a single gene through alternative splicing.
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