Limits...
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.

Show MeSH

Related in: MedlinePlus

Frequency of tandem splice sites in the CDS and UTR. Each bar is the percentage of human introns having a tandem donor (A) or acceptor (B). Introns are divided into a location in the CDS (blue) and the UTR (green). CDS introns are further divided into a location in ordered and disordered protein regions (light blue). Absolute numbers are given above the bars.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2279118&req=5

Figure 1: Frequency of tandem splice sites in the CDS and UTR. Each bar is the percentage of human introns having a tandem donor (A) or acceptor (B). Introns are divided into a location in the CDS (blue) and the UTR (green). CDS introns are further divided into a location in ordered and disordered protein regions (light blue). Absolute numbers are given above the bars.

Mentions: We found that 0.26% of the CDS introns have a tandem donor (100, 142, 127 for Δ3, Δ6, Δ9, respectively) and 1.25% a tandem acceptor (1,396, 238, 132). In contrast, UTR introns, where such subtle events are expected to be neutral or only slightly deleterious, have a more than 2-fold higher fraction of tandem donors and acceptors (0.64% and 2.54%, respectively, Fisher's exact test: P < 0.0001, Figure 1). This suggests a general underrepresentation of tandem splice events in coding regions and is consistent with a report for NAGNAG sites [7].


Selection against tandem splice sites affecting structured protein regions.

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

Frequency of tandem splice sites in the CDS and UTR. Each bar is the percentage of human introns having a tandem donor (A) or acceptor (B). Introns are divided into a location in the CDS (blue) and the UTR (green). CDS introns are further divided into a location in ordered and disordered protein regions (light blue). Absolute numbers are given above the bars.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Frequency of tandem splice sites in the CDS and UTR. Each bar is the percentage of human introns having a tandem donor (A) or acceptor (B). Introns are divided into a location in the CDS (blue) and the UTR (green). CDS introns are further divided into a location in ordered and disordered protein regions (light blue). Absolute numbers are given above the bars.
Mentions: We found that 0.26% of the CDS introns have a tandem donor (100, 142, 127 for Δ3, Δ6, Δ9, respectively) and 1.25% a tandem acceptor (1,396, 238, 132). In contrast, UTR introns, where such subtle events are expected to be neutral or only slightly deleterious, have a more than 2-fold higher fraction of tandem donors and acceptors (0.64% and 2.54%, respectively, Fisher's exact test: P < 0.0001, Figure 1). This suggests a general underrepresentation of tandem splice events in coding regions and is consistent with a report for NAGNAG sites [7].

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