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The (in)dependence of alternative splicing and gene duplication.

Talavera D, Vogel C, Orozco M, Teichmann SA, de la Cruz X - PLoS Comput. Biol. (2007)

Bottom Line: All together, these data strongly suggest that both phenomena result in interchangeability between their effects.Further, we conducted a detailed comparison of the effect of sequence changes in both alternative splice variants and gene duplicates on protein structure, in particular the size, location, and types of sequence substitutions and insertions/deletions.Our results reveal an interesting paradox between the anticorrelation of AS and GD at the genomic level, and their impact at the protein level, which shows little or no equivalence in terms of effects on protein sequence, structure, and function.

View Article: PubMed Central - PubMed

Affiliation: Molecular Modeling and Bioinformatics Unit, Parc Científic de Barcelona, Barcelona, Spain.

ABSTRACT
Alternative splicing (AS) and gene duplication (GD) both are processes that diversify the protein repertoire. Recent examples have shown that sequence changes introduced by AS may be comparable to those introduced by GD. In addition, the two processes are inversely correlated at the genomic scale: large gene families are depleted in splice variants and vice versa. All together, these data strongly suggest that both phenomena result in interchangeability between their effects. Here, we tested the extent to which this applies with respect to various protein characteristics. The amounts of AS and GD per gene are anticorrelated even when accounting for different gene functions or degrees of sequence divergence. In contrast, the two processes appear to be independent in their influence on variation in mRNA expression. Further, we conducted a detailed comparison of the effect of sequence changes in both alternative splice variants and gene duplicates on protein structure, in particular the size, location, and types of sequence substitutions and insertions/deletions. We find that, in general, alternative splicing affects protein sequence and structure in a more drastic way than gene duplication and subsequent divergence. Our results reveal an interesting paradox between the anticorrelation of AS and GD at the genomic level, and their impact at the protein level, which shows little or no equivalence in terms of effects on protein sequence, structure, and function. We discuss possible explanations that relate to the order of appearance of AS and GD in a gene family, and to the selection pressure imposed by the environment.

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The 3-D Distribution of Physico–Chemical Changes in the Affected Residues of AS and GDThe example of mitogen-activated protein kinase 9 (MAPK9). The example of human MAPK9 illustrates how differences between AS and GD in the distribution of sequence changes result in different distributions of physico–chemical properties across the 3-D structure. The original structure of MAPK9 was homology-modelled after MAPK10 and is shown in blue; the residue changes are indicated following a colour scale related to the associated difference in hydrophobicity (we use the absolute value of the difference in order to avoid too many colours; the colour scale goes from blue to red, where the latter corresponds to the largest change). For comparison purposes, the location of the AS changes in the three structures is indicated by a yellow box. As a hydrophobicity measure, we used the free energy of water to octanol transfer [77].(A) Alternative splice isoforms of MAPK9.(B) Gene duplicates of high seq.id. (MAPK10; isoform alpha2, 84% seq.id. to MAPK9).(C) Gene duplicates of medium seq.id. (MAPK13; 46% seq.id. to MAPK9).We observe, in accordance with the results from the sequence analysis, that while AS changes are located at a very specific location, GD changes are spread all over the protein surface. As expected, the number of changes between MAPK9 and MAPK13 is the largest. Neither one of MAPK9′s paralogues (MAPK10 and MAPK13) shows a set of residue changes identical to that in the alternative splice variant.
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pcbi-0030033-g005: The 3-D Distribution of Physico–Chemical Changes in the Affected Residues of AS and GDThe example of mitogen-activated protein kinase 9 (MAPK9). The example of human MAPK9 illustrates how differences between AS and GD in the distribution of sequence changes result in different distributions of physico–chemical properties across the 3-D structure. The original structure of MAPK9 was homology-modelled after MAPK10 and is shown in blue; the residue changes are indicated following a colour scale related to the associated difference in hydrophobicity (we use the absolute value of the difference in order to avoid too many colours; the colour scale goes from blue to red, where the latter corresponds to the largest change). For comparison purposes, the location of the AS changes in the three structures is indicated by a yellow box. As a hydrophobicity measure, we used the free energy of water to octanol transfer [77].(A) Alternative splice isoforms of MAPK9.(B) Gene duplicates of high seq.id. (MAPK10; isoform alpha2, 84% seq.id. to MAPK9).(C) Gene duplicates of medium seq.id. (MAPK13; 46% seq.id. to MAPK9).We observe, in accordance with the results from the sequence analysis, that while AS changes are located at a very specific location, GD changes are spread all over the protein surface. As expected, the number of changes between MAPK9 and MAPK13 is the largest. Neither one of MAPK9′s paralogues (MAPK10 and MAPK13) shows a set of residue changes identical to that in the alternative splice variant.

Mentions: Further, we use the maximal distance between replacements as a measure of the distribution of nonconservative changes along the sequence. We find clear differences between AS and GD (Figure 4), in accordance with the previous results. In particular, we observe that, for GD families at both the 40% and 80% levels, replacements are significantly more spread along the sequence than those for AS substitutions. This concentration of AS changes in the sequence in turn may result in a highly localized change in the 3-D distribution of physico–chemical properties, contrary to what happens with GD. Figure 5 illustrates this point using the example of MAPK9.


The (in)dependence of alternative splicing and gene duplication.

Talavera D, Vogel C, Orozco M, Teichmann SA, de la Cruz X - PLoS Comput. Biol. (2007)

The 3-D Distribution of Physico–Chemical Changes in the Affected Residues of AS and GDThe example of mitogen-activated protein kinase 9 (MAPK9). The example of human MAPK9 illustrates how differences between AS and GD in the distribution of sequence changes result in different distributions of physico–chemical properties across the 3-D structure. The original structure of MAPK9 was homology-modelled after MAPK10 and is shown in blue; the residue changes are indicated following a colour scale related to the associated difference in hydrophobicity (we use the absolute value of the difference in order to avoid too many colours; the colour scale goes from blue to red, where the latter corresponds to the largest change). For comparison purposes, the location of the AS changes in the three structures is indicated by a yellow box. As a hydrophobicity measure, we used the free energy of water to octanol transfer [77].(A) Alternative splice isoforms of MAPK9.(B) Gene duplicates of high seq.id. (MAPK10; isoform alpha2, 84% seq.id. to MAPK9).(C) Gene duplicates of medium seq.id. (MAPK13; 46% seq.id. to MAPK9).We observe, in accordance with the results from the sequence analysis, that while AS changes are located at a very specific location, GD changes are spread all over the protein surface. As expected, the number of changes between MAPK9 and MAPK13 is the largest. Neither one of MAPK9′s paralogues (MAPK10 and MAPK13) shows a set of residue changes identical to that in the alternative splice variant.
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Related In: Results  -  Collection

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pcbi-0030033-g005: The 3-D Distribution of Physico–Chemical Changes in the Affected Residues of AS and GDThe example of mitogen-activated protein kinase 9 (MAPK9). The example of human MAPK9 illustrates how differences between AS and GD in the distribution of sequence changes result in different distributions of physico–chemical properties across the 3-D structure. The original structure of MAPK9 was homology-modelled after MAPK10 and is shown in blue; the residue changes are indicated following a colour scale related to the associated difference in hydrophobicity (we use the absolute value of the difference in order to avoid too many colours; the colour scale goes from blue to red, where the latter corresponds to the largest change). For comparison purposes, the location of the AS changes in the three structures is indicated by a yellow box. As a hydrophobicity measure, we used the free energy of water to octanol transfer [77].(A) Alternative splice isoforms of MAPK9.(B) Gene duplicates of high seq.id. (MAPK10; isoform alpha2, 84% seq.id. to MAPK9).(C) Gene duplicates of medium seq.id. (MAPK13; 46% seq.id. to MAPK9).We observe, in accordance with the results from the sequence analysis, that while AS changes are located at a very specific location, GD changes are spread all over the protein surface. As expected, the number of changes between MAPK9 and MAPK13 is the largest. Neither one of MAPK9′s paralogues (MAPK10 and MAPK13) shows a set of residue changes identical to that in the alternative splice variant.
Mentions: Further, we use the maximal distance between replacements as a measure of the distribution of nonconservative changes along the sequence. We find clear differences between AS and GD (Figure 4), in accordance with the previous results. In particular, we observe that, for GD families at both the 40% and 80% levels, replacements are significantly more spread along the sequence than those for AS substitutions. This concentration of AS changes in the sequence in turn may result in a highly localized change in the 3-D distribution of physico–chemical properties, contrary to what happens with GD. Figure 5 illustrates this point using the example of MAPK9.

Bottom Line: All together, these data strongly suggest that both phenomena result in interchangeability between their effects.Further, we conducted a detailed comparison of the effect of sequence changes in both alternative splice variants and gene duplicates on protein structure, in particular the size, location, and types of sequence substitutions and insertions/deletions.Our results reveal an interesting paradox between the anticorrelation of AS and GD at the genomic level, and their impact at the protein level, which shows little or no equivalence in terms of effects on protein sequence, structure, and function.

View Article: PubMed Central - PubMed

Affiliation: Molecular Modeling and Bioinformatics Unit, Parc Científic de Barcelona, Barcelona, Spain.

ABSTRACT
Alternative splicing (AS) and gene duplication (GD) both are processes that diversify the protein repertoire. Recent examples have shown that sequence changes introduced by AS may be comparable to those introduced by GD. In addition, the two processes are inversely correlated at the genomic scale: large gene families are depleted in splice variants and vice versa. All together, these data strongly suggest that both phenomena result in interchangeability between their effects. Here, we tested the extent to which this applies with respect to various protein characteristics. The amounts of AS and GD per gene are anticorrelated even when accounting for different gene functions or degrees of sequence divergence. In contrast, the two processes appear to be independent in their influence on variation in mRNA expression. Further, we conducted a detailed comparison of the effect of sequence changes in both alternative splice variants and gene duplicates on protein structure, in particular the size, location, and types of sequence substitutions and insertions/deletions. We find that, in general, alternative splicing affects protein sequence and structure in a more drastic way than gene duplication and subsequent divergence. Our results reveal an interesting paradox between the anticorrelation of AS and GD at the genomic level, and their impact at the protein level, which shows little or no equivalence in terms of effects on protein sequence, structure, and function. We discuss possible explanations that relate to the order of appearance of AS and GD in a gene family, and to the selection pressure imposed by the environment.

Show MeSH