@article{Hiller2008Selection,
author = {Hiller, Michael and Szafranski, Karol and Huse, Klaus and
          Backofen, Rolf and Platzer, Matthias},
title = {Selection against tandem splice sites affecting structured
         protein regions},
journal = {BMC Evolutionary Biology},
year = {2008},
doi = {10.1186/1471-2148-8-89},
volume = {8},
user = {hiller},
publists = {All and Michael Hiller and Rolf Backofen},
pages = {89},
issn = {1471-2148},
abstract = {BACKGROUND: Alternative selection of splice sites in tandem
            donors and acceptors is a major mode of alternative
            splicing. Here, we analyzed whether in-frame tandem sites
            leading to subtle mRNA insertions/deletions of 3, 6, or 9
            nucleotides are under natural selection. RESULTS: We found
            multiple lines of evidence that the human protein coding
            sequences are under selection against such in-frame tandem
            splice events, indicating that these events are often
            deleterious. The strength of selection is not homogeneous
            within the coding sequence as protein regions that fold into
            a fixed 3D structure (intrinsically ordered) are under
            stronger selection, especially against sites with a strong
            minor splice site. Investigating structures of functional
            protein domains, we found that tandem acceptors are
            preferentially located at the domain surface and outside
            structural elements such as helices and sheets. Using
            three-species comparisons, we estimate that more than half
            of all mutations that create NAGNAG acceptors in the coding
            region have been eliminated by selection. CONCLUSION: We
            estimate that ~2,400 introns are under selection against
            possessing a tandem site.}
}