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Compensatory relationship between splice sites and exonic splicing signals depending on the length of vertebrate introns.

Dewey CN, Rogozin IB, Koonin EV - BMC Genomics (2006)

Bottom Line: In contrast, for longer introns, this effect was not detectable, and instead, an increase in the strength of the donor and acceptor splice sites was observed.Several weak but statistically significant correlations were observed between vertebrate intron length, splice site strength, and potential exonic splicing signals.Taken together, these findings attest to a compensatory relationship between splice sites and exonic splicing signals, depending on intron length.

View Article: PubMed Central - HTML - PubMed

Affiliation: National Center for Biotechnology Information NLM, National Institutes of Health, Bethesda, MD 20894, USA. cdewey@biostat.wisc.edu <cdewey@biostat.wisc.edu>

ABSTRACT

Background: The signals that determine the specificity and efficiency of splicing are multiple and complex, and are not fully understood. Among other factors, the relative contributions of different mechanisms appear to depend on intron size inasmuch as long introns might hinder the activity of the spliceosome through interference with the proper positioning of the intron-exon junctions. Indeed, it has been shown that the information content of splice sites positively correlates with intron length in the nematode, Drosophila, and fungi. We explored the connections between the length of vertebrate introns, the strength of splice sites, exonic splicing signals, and evolution of flanking exons.

Results: A compensatory relationship is shown to exist between different types of signals, namely, the splice sites and the exonic splicing enhancers (ESEs). In the range of relatively short introns (approximately, < 1.5 kilobases in length), the enhancement of the splicing signals for longer introns was manifest in the increased concentration of ESEs. In contrast, for longer introns, this effect was not detectable, and instead, an increase in the strength of the donor and acceptor splice sites was observed. Conceivably, accumulation of A-rich ESE motifs beyond a certain limit is incompatible with functional constraints operating at the level of protein sequence evolution, which leads to compensation in the form of evolution of the splice sites themselves toward greater strength. In addition, however, a correlation between sequence conservation in the exon ends and intron length, particularly, in synonymous positions, was observed throughout the entire length range of introns. Thus, splicing signals other than the currently defined ESEs, i.e., potential new classes of ESEs, might exist in exon sequences, particularly, those that flank long introns.

Conclusion: Several weak but statistically significant correlations were observed between vertebrate intron length, splice site strength, and potential exonic splicing signals. Taken together, these findings attest to a compensatory relationship between splice sites and exonic splicing signals, depending on intron length.

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Donor, acceptor, and total splice site strength (in bits) increases with increasing intron length in human. Median standard error bars are given for different splice site scores over each range of intron lengths. Values for constitutive and alternative introns are shown with solid and dashed lines, respectively.
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Figure 1: Donor, acceptor, and total splice site strength (in bits) increases with increasing intron length in human. Median standard error bars are given for different splice site scores over each range of intron lengths. Values for constitutive and alternative introns are shown with solid and dashed lines, respectively.

Mentions: We found that, for human introns greater than 1.5 kb in length [the median length of human introns; (Figures S1, S2; see Additional File 1)], total splice site strength is positively correlated with intron length for both constitutive and alternative introns; the correlation coefficients were relatively small (constitutive R = 0.124, alternative R = 0.145) but highly statistically significant (P ≈ 0) (Figure 1). Both the donor sites and, somewhat more prominently, the acceptor sites become stronger as the intron length increases. For introns shorter than 1.5 kb, constitutive and alternative introns displayed opposite, slight (constitutive R = -0.053, alternative R = 0.026) but statistically significant (constitutive P = 3.34e-34, alternative P = 6.27e-5) correlations between intron length and splice site strength (Figure 1). For almost all lengths, constitutive introns had significantly stronger splice sites than alternative introns (Mann-Whitney test). Mouse introns exhibited the same correlations as human introns (Figure S3; See Additional File 1).


Compensatory relationship between splice sites and exonic splicing signals depending on the length of vertebrate introns.

Dewey CN, Rogozin IB, Koonin EV - BMC Genomics (2006)

Donor, acceptor, and total splice site strength (in bits) increases with increasing intron length in human. Median standard error bars are given for different splice site scores over each range of intron lengths. Values for constitutive and alternative introns are shown with solid and dashed lines, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1713244&req=5

Figure 1: Donor, acceptor, and total splice site strength (in bits) increases with increasing intron length in human. Median standard error bars are given for different splice site scores over each range of intron lengths. Values for constitutive and alternative introns are shown with solid and dashed lines, respectively.
Mentions: We found that, for human introns greater than 1.5 kb in length [the median length of human introns; (Figures S1, S2; see Additional File 1)], total splice site strength is positively correlated with intron length for both constitutive and alternative introns; the correlation coefficients were relatively small (constitutive R = 0.124, alternative R = 0.145) but highly statistically significant (P ≈ 0) (Figure 1). Both the donor sites and, somewhat more prominently, the acceptor sites become stronger as the intron length increases. For introns shorter than 1.5 kb, constitutive and alternative introns displayed opposite, slight (constitutive R = -0.053, alternative R = 0.026) but statistically significant (constitutive P = 3.34e-34, alternative P = 6.27e-5) correlations between intron length and splice site strength (Figure 1). For almost all lengths, constitutive introns had significantly stronger splice sites than alternative introns (Mann-Whitney test). Mouse introns exhibited the same correlations as human introns (Figure S3; See Additional File 1).

Bottom Line: In contrast, for longer introns, this effect was not detectable, and instead, an increase in the strength of the donor and acceptor splice sites was observed.Several weak but statistically significant correlations were observed between vertebrate intron length, splice site strength, and potential exonic splicing signals.Taken together, these findings attest to a compensatory relationship between splice sites and exonic splicing signals, depending on intron length.

View Article: PubMed Central - HTML - PubMed

Affiliation: National Center for Biotechnology Information NLM, National Institutes of Health, Bethesda, MD 20894, USA. cdewey@biostat.wisc.edu <cdewey@biostat.wisc.edu>

ABSTRACT

Background: The signals that determine the specificity and efficiency of splicing are multiple and complex, and are not fully understood. Among other factors, the relative contributions of different mechanisms appear to depend on intron size inasmuch as long introns might hinder the activity of the spliceosome through interference with the proper positioning of the intron-exon junctions. Indeed, it has been shown that the information content of splice sites positively correlates with intron length in the nematode, Drosophila, and fungi. We explored the connections between the length of vertebrate introns, the strength of splice sites, exonic splicing signals, and evolution of flanking exons.

Results: A compensatory relationship is shown to exist between different types of signals, namely, the splice sites and the exonic splicing enhancers (ESEs). In the range of relatively short introns (approximately, < 1.5 kilobases in length), the enhancement of the splicing signals for longer introns was manifest in the increased concentration of ESEs. In contrast, for longer introns, this effect was not detectable, and instead, an increase in the strength of the donor and acceptor splice sites was observed. Conceivably, accumulation of A-rich ESE motifs beyond a certain limit is incompatible with functional constraints operating at the level of protein sequence evolution, which leads to compensation in the form of evolution of the splice sites themselves toward greater strength. In addition, however, a correlation between sequence conservation in the exon ends and intron length, particularly, in synonymous positions, was observed throughout the entire length range of introns. Thus, splicing signals other than the currently defined ESEs, i.e., potential new classes of ESEs, might exist in exon sequences, particularly, those that flank long introns.

Conclusion: Several weak but statistically significant correlations were observed between vertebrate intron length, splice site strength, and potential exonic splicing signals. Taken together, these findings attest to a compensatory relationship between splice sites and exonic splicing signals, depending on intron length.

Show MeSH