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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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Related in: MedlinePlus

Equivalence between Alternative Splicing and Gene Duplication(A) The alignment shows an example of molecular equivalence between the effects of AS and GD. The human U2AF35 gene has two known splice variants, Hs_U2AF35a and Hs_U2AF35b, that differ along the region marked with a red box. The fugu orthologue Fr_U2AF35-a does not have known splice variants, but instead has a paralogue, Fr_U2AF35-b [9]. All sequences have kindly been provided by T. R. Pacheco and M. Carmo-Fonseca. For some residues (bold, highlighted in light blue), the substitutions amongst the human splice variants are equivalent to those in the fugu GD. The cartoon illustrates the relationship between the human and fugu sequences. The names of genes and their protein products are denoted in small and capital letters, respectively. At the molecular level, AS and GD show equivalent changes to sequence, and therefore are likely to have interchangeable effects on structure and function of the proteins. In this work we study whether such molecular interchangeability holds in general.(B) We compared the characteristics of two types of sequence changes, indels and substitutions, between AS (both shown in dark blue) and GD (shown in dark and light blue). On top, we illustrate an indel event (the deleted stretch is highlighted in red, and two dotted lines denote its location); at the bottom, we illustrate substitution events (red lines represent residue matches between sequences, linked by dotted lines; the continuous lines between alternative splice isoforms represent the boundaries of the interchanged stretches).(C) We used this protocol in all sequence comparisons between AS and GD. Changes between alternative splice isoforms are obtained after comparing the SwissProt [44] reference isoform with the remaining isoforms. Changes between duplicates are obtained by comparing the SwissProt [44] reference isoforms of the genes that are part of one GD family.
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pcbi-0030033-g001: Equivalence between Alternative Splicing and Gene Duplication(A) The alignment shows an example of molecular equivalence between the effects of AS and GD. The human U2AF35 gene has two known splice variants, Hs_U2AF35a and Hs_U2AF35b, that differ along the region marked with a red box. The fugu orthologue Fr_U2AF35-a does not have known splice variants, but instead has a paralogue, Fr_U2AF35-b [9]. All sequences have kindly been provided by T. R. Pacheco and M. Carmo-Fonseca. For some residues (bold, highlighted in light blue), the substitutions amongst the human splice variants are equivalent to those in the fugu GD. The cartoon illustrates the relationship between the human and fugu sequences. The names of genes and their protein products are denoted in small and capital letters, respectively. At the molecular level, AS and GD show equivalent changes to sequence, and therefore are likely to have interchangeable effects on structure and function of the proteins. In this work we study whether such molecular interchangeability holds in general.(B) We compared the characteristics of two types of sequence changes, indels and substitutions, between AS (both shown in dark blue) and GD (shown in dark and light blue). On top, we illustrate an indel event (the deleted stretch is highlighted in red, and two dotted lines denote its location); at the bottom, we illustrate substitution events (red lines represent residue matches between sequences, linked by dotted lines; the continuous lines between alternative splice isoforms represent the boundaries of the interchanged stretches).(C) We used this protocol in all sequence comparisons between AS and GD. Changes between alternative splice isoforms are obtained after comparing the SwissProt [44] reference isoform with the remaining isoforms. Changes between duplicates are obtained by comparing the SwissProt [44] reference isoforms of the genes that are part of one GD family.

Mentions: Alternative splicing (AS) and gene duplication (GD) are two main contributors to the diversity of the protein repertoire with enormous impact on protein sequence, structure, and function [1–5]. Interestingly, several recent studies point to a direct equivalence between AS and GD. There are some cases where alternative splice variants in one organism are similar to gene duplicates in another organism [6–9]. For example, the eukaryotic splicing factor U2AF35 has at least two functional splice variants in human, U2AF35a and U2AF35b, which differ by seven amino acids in the RNA recognition motif (Figure 1A). The fugu orthologue U2AF35-a has no splice variant; instead there is a duplicate gene U2AF35-b with changes identical to those found in the human splice variant U2AF35b [9].


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)

Equivalence between Alternative Splicing and Gene Duplication(A) The alignment shows an example of molecular equivalence between the effects of AS and GD. The human U2AF35 gene has two known splice variants, Hs_U2AF35a and Hs_U2AF35b, that differ along the region marked with a red box. The fugu orthologue Fr_U2AF35-a does not have known splice variants, but instead has a paralogue, Fr_U2AF35-b [9]. All sequences have kindly been provided by T. R. Pacheco and M. Carmo-Fonseca. For some residues (bold, highlighted in light blue), the substitutions amongst the human splice variants are equivalent to those in the fugu GD. The cartoon illustrates the relationship between the human and fugu sequences. The names of genes and their protein products are denoted in small and capital letters, respectively. At the molecular level, AS and GD show equivalent changes to sequence, and therefore are likely to have interchangeable effects on structure and function of the proteins. In this work we study whether such molecular interchangeability holds in general.(B) We compared the characteristics of two types of sequence changes, indels and substitutions, between AS (both shown in dark blue) and GD (shown in dark and light blue). On top, we illustrate an indel event (the deleted stretch is highlighted in red, and two dotted lines denote its location); at the bottom, we illustrate substitution events (red lines represent residue matches between sequences, linked by dotted lines; the continuous lines between alternative splice isoforms represent the boundaries of the interchanged stretches).(C) We used this protocol in all sequence comparisons between AS and GD. Changes between alternative splice isoforms are obtained after comparing the SwissProt [44] reference isoform with the remaining isoforms. Changes between duplicates are obtained by comparing the SwissProt [44] reference isoforms of the genes that are part of one GD family.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1808492&req=5

pcbi-0030033-g001: Equivalence between Alternative Splicing and Gene Duplication(A) The alignment shows an example of molecular equivalence between the effects of AS and GD. The human U2AF35 gene has two known splice variants, Hs_U2AF35a and Hs_U2AF35b, that differ along the region marked with a red box. The fugu orthologue Fr_U2AF35-a does not have known splice variants, but instead has a paralogue, Fr_U2AF35-b [9]. All sequences have kindly been provided by T. R. Pacheco and M. Carmo-Fonseca. For some residues (bold, highlighted in light blue), the substitutions amongst the human splice variants are equivalent to those in the fugu GD. The cartoon illustrates the relationship between the human and fugu sequences. The names of genes and their protein products are denoted in small and capital letters, respectively. At the molecular level, AS and GD show equivalent changes to sequence, and therefore are likely to have interchangeable effects on structure and function of the proteins. In this work we study whether such molecular interchangeability holds in general.(B) We compared the characteristics of two types of sequence changes, indels and substitutions, between AS (both shown in dark blue) and GD (shown in dark and light blue). On top, we illustrate an indel event (the deleted stretch is highlighted in red, and two dotted lines denote its location); at the bottom, we illustrate substitution events (red lines represent residue matches between sequences, linked by dotted lines; the continuous lines between alternative splice isoforms represent the boundaries of the interchanged stretches).(C) We used this protocol in all sequence comparisons between AS and GD. Changes between alternative splice isoforms are obtained after comparing the SwissProt [44] reference isoform with the remaining isoforms. Changes between duplicates are obtained by comparing the SwissProt [44] reference isoforms of the genes that are part of one GD family.
Mentions: Alternative splicing (AS) and gene duplication (GD) are two main contributors to the diversity of the protein repertoire with enormous impact on protein sequence, structure, and function [1–5]. Interestingly, several recent studies point to a direct equivalence between AS and GD. There are some cases where alternative splice variants in one organism are similar to gene duplicates in another organism [6–9]. For example, the eukaryotic splicing factor U2AF35 has at least two functional splice variants in human, U2AF35a and U2AF35b, which differ by seven amino acids in the RNA recognition motif (Figure 1A). The fugu orthologue U2AF35-a has no splice variant; instead there is a duplicate gene U2AF35-b with changes identical to those found in the human splice variant U2AF35b [9].

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
Related in: MedlinePlus