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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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The percentage of plausible NAGNAG creating mutations eliminated by selection. (A) exonic and synonymous mutations, (B) intronic mutations. The relative risk (RR) indicating how much more likely the creation of an implausible NAGNAG is compared to the creation of a plausible NAGNAG is given above the columns. P-values of the CMH test are indicated as ***: P < 0.0001, **: P < 0.001, *: P < 0.01.
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Figure 5: The percentage of plausible NAGNAG creating mutations eliminated by selection. (A) exonic and synonymous mutations, (B) intronic mutations. The relative risk (RR) indicating how much more likely the creation of an implausible NAGNAG is compared to the creation of a plausible NAGNAG is given above the columns. P-values of the CMH test are indicated as ***: P < 0.0001, **: P < 0.001, *: P < 0.01.

Mentions: We have previously shown that a single nucleotide mutation can create an alternatively spliced NAGNAG acceptor [29]. We asked whether selection acts against single nucleotide substitutions creating plausible NAGNAG acceptors by comparing CDS with UTR as well as ordered with disordered regions. We considered only base exchanges that create a second AG dinucleotide in the context of a non-NAGNAG acceptor. To dissect selection against NAGNAG creations from other evolutionary pressures, we focused only on cases where the required mutation has to occur (i) within the exon and is synonymous (Figure 5A) or (ii) within the intron (Figure 5B). Controlling for different distributions in the required mutations and using implausible NAGNAG creations as a control (see Methods), we estimated the relative risk (RR) for the creation of an implausible vs. plausible NAGNAG acceptors using the Cochran-Mantel-Haenszel (CMH) test. An RR of 1 indicates that the creation of plausible and implausible NAGNAG sites is equally likely, which is consistent with the absence of selection, while an RR > 1 indicates how much more likely the creation of an implausible site is. Using the RR, we can estimate how many mutations that create plausible NAGNAG sites have been eliminated by selection.


Selection against tandem splice sites affecting structured protein regions.

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

The percentage of plausible NAGNAG creating mutations eliminated by selection. (A) exonic and synonymous mutations, (B) intronic mutations. The relative risk (RR) indicating how much more likely the creation of an implausible NAGNAG is compared to the creation of a plausible NAGNAG is given above the columns. P-values of the CMH test are indicated as ***: P < 0.0001, **: P < 0.001, *: P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: The percentage of plausible NAGNAG creating mutations eliminated by selection. (A) exonic and synonymous mutations, (B) intronic mutations. The relative risk (RR) indicating how much more likely the creation of an implausible NAGNAG is compared to the creation of a plausible NAGNAG is given above the columns. P-values of the CMH test are indicated as ***: P < 0.0001, **: P < 0.001, *: P < 0.01.
Mentions: We have previously shown that a single nucleotide mutation can create an alternatively spliced NAGNAG acceptor [29]. We asked whether selection acts against single nucleotide substitutions creating plausible NAGNAG acceptors by comparing CDS with UTR as well as ordered with disordered regions. We considered only base exchanges that create a second AG dinucleotide in the context of a non-NAGNAG acceptor. To dissect selection against NAGNAG creations from other evolutionary pressures, we focused only on cases where the required mutation has to occur (i) within the exon and is synonymous (Figure 5A) or (ii) within the intron (Figure 5B). Controlling for different distributions in the required mutations and using implausible NAGNAG creations as a control (see Methods), we estimated the relative risk (RR) for the creation of an implausible vs. plausible NAGNAG acceptors using the Cochran-Mantel-Haenszel (CMH) test. An RR of 1 indicates that the creation of plausible and implausible NAGNAG sites is equally likely, which is consistent with the absence of selection, while an RR > 1 indicates how much more likely the creation of an implausible site is. Using the RR, we can estimate how many mutations that create plausible NAGNAG sites have been eliminated by selection.

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