@article{Hiller2008Assessing,
author = {Hiller, Michael and Szafranski, Karol and Sinha, Rileen and
          Huse, Klaus and Nikolajewa, Swetlana and Rosenstiel, Philip
          and Schreiber, Stefan and Backofen, Rolf and Platzer,
          Matthias},
title = {Assessing the fraction of short-distance tandem splice sites
         under purifying selection},
journal = {RNA},
year = {2008},
doi = {10.1261/rna.883908},
volume = {14},
user = {hiller},
pages = {616-29},
issn = {1469-9001},
abstract = {Many alternative splice events result in subtle mRNA
            changes, and most of them occur at short-distance tandem
            donor and acceptor sites. The splicing mechanism of such
            tandem sites likely involves the stochastic selection of
            either splice site. While tandem splice events are frequent,
            it is unknown how many are functionally important. Here, we
            use phylogenetic conservation to address this question,
            focusing on tandems with a distance of 3-9 nucleotides. We
            show that previous contradicting results on whether
            alternative or constitutive tandem motifs are more conserved
            between species can be explained by a statistical paradox
            (Simpson's paradox). Applying methods that take biases into
            account, we found higher conservation of alternative tandems
            in mouse, dog, and even chicken, zebrafish, and Fugu
            genomes. We estimated a lower bound for the number of
            alternative sites that are under purifying (negative)
            selection. While the absolute number of conserved tandem
            motifs decreases with the evolutionary distance, the
            fraction under selection increases. Interestingly, a number
            of frameshifting tandems are under selection, suggesting a
            role in regulating mRNA and protein levels via
            nonsense-mediated decay (NMD). An analysis of the intronic
            flanks shows that purifying selection also acts on the
            intronic sequence. We propose that stochastic splice site
            selection can be an advantageous mechanism that allows
            constant splice variant ratios in situations where a
            deviation in this ratio is deleterious.}
}