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Structural implication of splicing stochastics.

Melamud E, Moult J - Nucleic Acids Res. (2009)

Bottom Line: We find that the vast majority of all alternative isoforms result in unstable protein conformations.Alternative splicing in disease-associated genes produces unstable structures just as frequently as all other genes, indicating that selection to reduce the effects of alternative splicing on this set is not especially pronounced.Overall, the properties of alternative spliced proteins are consistent with the outcome of noisy selection of splice sites by splicing machinery.

View Article: PubMed Central - PubMed

Affiliation: Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, MD 20850, USA. melamud@umbi.umd.edu

ABSTRACT
Even though nearly every human gene has at least one alternative splice form, very little is so far known about the structure and function of resulting protein products. It is becoming increasingly clear that a significant fraction of all isoforms are products of noisy selection of splice sites and thus contribute little to actual functional diversity, and may potentially be deleterious. In this study, we examine the impact of alternative splicing on protein sequence and structure in three datasets: alternative splicing events conserved across multiple species, alternative splicing events in genes that are strongly linked to disease and all observed alternative splicing events. We find that the vast majority of all alternative isoforms result in unstable protein conformations. In contrast to that, the small subset of isoforms conserved across species tends to maintain protein structural integrity to a greater extent. Alternative splicing in disease-associated genes produces unstable structures just as frequently as all other genes, indicating that selection to reduce the effects of alternative splicing on this set is not especially pronounced. Overall, the properties of alternative spliced proteins are consistent with the outcome of noisy selection of splice sites by splicing machinery.

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Identification of PSFs. Protein sequences corresponding to the major and a minor isoform of a gene are aligned, and regions in the alignment that differ identified. Deletions are defined as missing fragments in minor isoforms. Replacement is defined as a substitution of identical size. Truncations and elongations are substitutions that change the length of a fragment. Numbers above each intron bridge are conservation scores, the number of species in which this or a homologous bridge is found. Here, the alternative intron has a score of 2, indicating it was detected in human and one other species (the maximum possible conservation score is 11).
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Figure 1: Identification of PSFs. Protein sequences corresponding to the major and a minor isoform of a gene are aligned, and regions in the alignment that differ identified. Deletions are defined as missing fragments in minor isoforms. Replacement is defined as a substitution of identical size. Truncations and elongations are substitutions that change the length of a fragment. Numbers above each intron bridge are conservation scores, the number of species in which this or a homologous bridge is found. Here, the alternative intron has a score of 2, indicating it was detected in human and one other species (the maximum possible conservation score is 11).

Mentions: Protein translations of isoforms were aligned using the genomic coordinates of the underlying exons. This is done by first generating an mRNA alignment between major and minor isoforms pairs to genomic sequence, and then using the mRNA alignment to generate protein alignment. Protein splicing fragments (PSFs) are defined as regions within the protein alignment that differ. The alternative splicing event(s) that are responsible for producing differences in protein sequence are identified by looking for alternative introns in the region underlying each PSF (Figure 1).Figure 1.


Structural implication of splicing stochastics.

Melamud E, Moult J - Nucleic Acids Res. (2009)

Identification of PSFs. Protein sequences corresponding to the major and a minor isoform of a gene are aligned, and regions in the alignment that differ identified. Deletions are defined as missing fragments in minor isoforms. Replacement is defined as a substitution of identical size. Truncations and elongations are substitutions that change the length of a fragment. Numbers above each intron bridge are conservation scores, the number of species in which this or a homologous bridge is found. Here, the alternative intron has a score of 2, indicating it was detected in human and one other species (the maximum possible conservation score is 11).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2724273&req=5

Figure 1: Identification of PSFs. Protein sequences corresponding to the major and a minor isoform of a gene are aligned, and regions in the alignment that differ identified. Deletions are defined as missing fragments in minor isoforms. Replacement is defined as a substitution of identical size. Truncations and elongations are substitutions that change the length of a fragment. Numbers above each intron bridge are conservation scores, the number of species in which this or a homologous bridge is found. Here, the alternative intron has a score of 2, indicating it was detected in human and one other species (the maximum possible conservation score is 11).
Mentions: Protein translations of isoforms were aligned using the genomic coordinates of the underlying exons. This is done by first generating an mRNA alignment between major and minor isoforms pairs to genomic sequence, and then using the mRNA alignment to generate protein alignment. Protein splicing fragments (PSFs) are defined as regions within the protein alignment that differ. The alternative splicing event(s) that are responsible for producing differences in protein sequence are identified by looking for alternative introns in the region underlying each PSF (Figure 1).Figure 1.

Bottom Line: We find that the vast majority of all alternative isoforms result in unstable protein conformations.Alternative splicing in disease-associated genes produces unstable structures just as frequently as all other genes, indicating that selection to reduce the effects of alternative splicing on this set is not especially pronounced.Overall, the properties of alternative spliced proteins are consistent with the outcome of noisy selection of splice sites by splicing machinery.

View Article: PubMed Central - PubMed

Affiliation: Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, MD 20850, USA. melamud@umbi.umd.edu

ABSTRACT
Even though nearly every human gene has at least one alternative splice form, very little is so far known about the structure and function of resulting protein products. It is becoming increasingly clear that a significant fraction of all isoforms are products of noisy selection of splice sites and thus contribute little to actual functional diversity, and may potentially be deleterious. In this study, we examine the impact of alternative splicing on protein sequence and structure in three datasets: alternative splicing events conserved across multiple species, alternative splicing events in genes that are strongly linked to disease and all observed alternative splicing events. We find that the vast majority of all alternative isoforms result in unstable protein conformations. In contrast to that, the small subset of isoforms conserved across species tends to maintain protein structural integrity to a greater extent. Alternative splicing in disease-associated genes produces unstable structures just as frequently as all other genes, indicating that selection to reduce the effects of alternative splicing on this set is not especially pronounced. Overall, the properties of alternative spliced proteins are consistent with the outcome of noisy selection of splice sites by splicing machinery.

Show MeSH
Related in: MedlinePlus