@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},
  volume =	 {14},
  issn =         {1469-9001},
  issn =         {1355-8382},
  pages =	 {616-29},
  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.},
  user =	 {hiller}
}