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Selection against tandem splice sites affecting structured protein regions.

Hiller M, Szafranski K, Huse K, Backofen R, Platzer M - BMC Evol. Biol. (2008)

Bottom Line: 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.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.We estimate that ~2,400 introns are under selection against possessing a tandem site.

View Article: PubMed Central - HTML - PubMed

Affiliation: Bioinformatics Group, Albert-Ludwigs-University Freiburg, Georges-Koehler-Allee 106, 79110 Freiburg, Germany. hiller@informatik.uni-freiburg.de

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.

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Distribution of evolutionary 'young' and 'old' plausible vs. implausible NAGNAG acceptors in ordered and disordered regions. The expected distribution is the overall number of introns in ordered/disordered regions.
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Figure 4: Distribution of evolutionary 'young' and 'old' plausible vs. implausible NAGNAG acceptors in ordered and disordered regions. The expected distribution is the overall number of introns in ordered/disordered regions.

Mentions: Moreover, we analyzed the distribution of evolutionary 'young' and 'old' plausible/implausible NAGNAG acceptors in ordered/disordered regions. As shown in Figure 4, plausible NAGNAG sites that are human specific (not conserved in the orthologous chimpanzee, rhesus, and mouse introns) or human-chimpanzee specific (not conserved in rhesus and mouse) have a significant tendency to avoid ordered regions compared to the respective implausible ones (Fisher's exact test: P = 0.02, P < 0.0001, respectively). A stronger underrepresentation was observed for evolutionary old (conserved between human, mouse, dog, and chicken) plausible NAGNAG acceptors (Fisher's exact test: P < 0.0001). It is noteworthy that implausible NAGNAG acceptors resemble the expected distribution, which is the overall number of introns in ordered/disordered regions (Figure 4). Thus, young and old plausible NAGNAG sites are underrepresented in ordered regions, indicating that selection against such sites is universal and more effective over large evolutionary distances.


Selection against tandem splice sites affecting structured protein regions.

Hiller M, Szafranski K, Huse K, Backofen R, Platzer M - BMC Evol. Biol. (2008)

Distribution of evolutionary 'young' and 'old' plausible vs. implausible NAGNAG acceptors in ordered and disordered regions. The expected distribution is the overall number of introns in ordered/disordered regions.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2279118&req=5

Figure 4: Distribution of evolutionary 'young' and 'old' plausible vs. implausible NAGNAG acceptors in ordered and disordered regions. The expected distribution is the overall number of introns in ordered/disordered regions.
Mentions: Moreover, we analyzed the distribution of evolutionary 'young' and 'old' plausible/implausible NAGNAG acceptors in ordered/disordered regions. As shown in Figure 4, plausible NAGNAG sites that are human specific (not conserved in the orthologous chimpanzee, rhesus, and mouse introns) or human-chimpanzee specific (not conserved in rhesus and mouse) have a significant tendency to avoid ordered regions compared to the respective implausible ones (Fisher's exact test: P = 0.02, P < 0.0001, respectively). A stronger underrepresentation was observed for evolutionary old (conserved between human, mouse, dog, and chicken) plausible NAGNAG acceptors (Fisher's exact test: P < 0.0001). It is noteworthy that implausible NAGNAG acceptors resemble the expected distribution, which is the overall number of introns in ordered/disordered regions (Figure 4). Thus, young and old plausible NAGNAG sites are underrepresented in ordered regions, indicating that selection against such sites is universal and more effective over large evolutionary distances.

Bottom Line: 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.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.We estimate that ~2,400 introns are under selection against possessing a tandem site.

View Article: PubMed Central - HTML - PubMed

Affiliation: Bioinformatics Group, Albert-Ludwigs-University Freiburg, Georges-Koehler-Allee 106, 79110 Freiburg, Germany. hiller@informatik.uni-freiburg.de

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.

Show MeSH
Related in: MedlinePlus