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László Patthy - One of the best experts on this subject based on the ideXlab platform.
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Exon skipping-rich transcriptomes of animals reflect the significance of Exon-Shuffling in metazoan proteome evolution
Biology Direct, 2019Co-Authors: László PatthyAbstract:ᅟ Animals are known to have higher rates of Exon skipping than other eukaryotes. In a recent study, Grau-Bové et al. (Genome Biology 19:135, 2018) have used RNA-seq data across 65 eukaryotic species to investigate when and how this high prevalence of Exon skipping evolved. They have found that bilaterian Metazoa have significantly increased Exon skipping frequencies compared to all other eukaryotic groups and that Exon skipping in nearly all animals, including non-bilaterians, is strongly enriched for frame-preserving events. The authors have hypothesized that “ the increase of Exon skipping rates in animals followed a two-step process. First, Exon skipping in early animals became enriched for frame-preserving events. Second, bilaterian ancestors dramatically increased their Exon skipping frequencies, likely driven by the interplay between a shift in their genome architectures towards more Exon definition and recruitment of frame-preserving Exon skipping events to functionally diversify their cell-specific proteomes .” Here we offer a different explanation for the higher frequency of frame-preserving Exon skipping in Metzoa than in all other eukaryotes. In our view these observations reflect the fact that the majority of multidomain proteins unique to metazoa and indispensable for metazoan type multicellularity were assembled by Exon-Shuffling from ‘symmetrical’ modules (i.e. modules flanked by introns of the same phase), whereas this type of protein evolution played a minor role in other groups of eukaryotes, including plants. The higher frequency of ‘symmetrical’ Exons in Metazoan genomes provides an explanation for the enrichment for frame-preserving events since skipping or inclusion of ‘symmetrical’ modules during alternative splicing does not result in a reading-frame shift. Reviewers This article was reviewed by Manuel Irimia, Ashish Lal and Erez Levanon. The reviewers were nominated by the Editorial Board.
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Exon skipping-rich transcriptomes of animals reflect the significance of Exon-Shuffling in metazoan proteome evolution
Biology Direct, 2019Co-Authors: László PatthyAbstract:ᅟ Animals are known to have higher rates of Exon skipping than other eukaryotes. In a recent study, Grau-Bové et al. (Genome Biology 19:135, 2018) have used RNA-seq data across 65 eukaryotic species to investigate when and how this high prevalence of Exon skipping evolved. They have found that bilaterian Metazoa have significantly increased Exon skipping frequencies compared to all other eukaryotic groups and that Exon skipping in nearly all animals, including non-bilaterians, is strongly enriched for frame-preserving events. The authors have hypothesized that “ the increase of Exon skipping rates in animals followed a two-step process. First, Exon skipping in early animals became enriched for frame-preserving events. Second, bilaterian ancestors dramatically increased their Exon skipping frequencies, likely driven by the interplay between a shift in their genome architectures towards more Exon definition and recruitment of frame-preserving Exon skipping events to functionally diversify their cell-specific proteomes .” Here we offer a different explanation for the higher frequency of frame-preserving Exon skipping in Metzoa than in all other eukaryotes. In our view these observations reflect the fact that the majority of multidomain proteins unique to metazoa and indispensable for metazoan type multicellularity were assembled by Exon-Shuffling from ‘symmetrical’ modules (i.e. modules flanked by introns of the same phase), whereas this type of protein evolution played a minor role in other groups of eukaryotes, including plants. The higher frequency of ‘symmetrical’ Exons in Metazoan genomes provides an explanation for the enrichment for frame-preserving events since skipping or inclusion of ‘symmetrical’ modules during alternative splicing does not result in a reading-frame shift. Reviewers This article was reviewed by Manuel Irimia, Ashish Lal and Erez Levanon. The reviewers were nominated by the Editorial Board.
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Domain architecture evolution of Metazoan proteins
Evolutionary Biology: Exobiology and Evolutionary Mechanisms, 2013Co-Authors: László PatthyAbstract:Appearance of novel multidomain proteins with novel domain architectures (DAs) is closely associated with biological innovations therefore there is a growing interest in genome-scale analysis of the evolutionary history of multidomain proteins. A prerequisite of these studies, however, is that the protein sequences compared are correct and that their evolutionary relationship is correctly defined. We have shown that in the case of most Metazoan proteomes the contribution of mispredicted sequences to apparent DA differences of orthologous and paralogous proteins is greater than the contribution of true gene rearrangements and that analyses of DA evolution frequently suffer from confusing paralogous multidomain proteins (that evolved via gene duplication) with epaktologous multidomain proteins (that are related only through the independent acquisition of the same domain types). Since these methodological errors preferentially increase apparent terminal DA change they may lead to the erroneous conclusion that gene fusion played a dominant role in DA evolution of Metazoan proteins, whereas the contribution of Exon Shuffling was negligible. In contrast with such conclusions, our studies on high quality datasets of orthologous and paralogous proteins have confirmed that Exon Shuffling played a major role in the evolution of multidomain proteins of Metazoa.
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Evidence that human genes of modular proteins have retained significantly more ancestral introns than their fly or worm orthologues.
FEBS letters, 2004Co-Authors: László Bányai, László PatthyAbstract:Comparison of the Exon-intron structures of human, fly and worm orthologues of mosaic genes assembled from class 1-1 modules by Exon-Shuffling has revealed that human genes retained significantly more of the original inter-module introns than their protostome orthologues. It is suggested that the much higher rate of intron loss in the worm- and insect lineages than in the chordate lineage reflects their greater tendency for genome compaction.
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Modular assembly of genes and the evolution of new functions.
Genetica, 2003Co-Authors: László PatthyAbstract:Modular assembly of novel genes from existing genes has long been thought to be an important source of evolutionary novelty. Thanks to major advances in genomic studies it has now become clear that this mechanism contributed significantly to the evolution of novel biological functions in different evolutionary lineages. Analyses of completely sequenced bacterial, archaeal and eukaryotic genomes has revealed that modular assembly of novel constituents of various eukaryotic intracellular signalling pathways played a major role in the evolution of eukaryotes. Comparison of the genomes of single-celled eukaryotes, multicellular plants and animals has also shown that the evolution of multicellularity was accompanied by the assembly of numerous novel extracellular matrix proteins and extracellular signalling proteins that are absolutely essential for multicellularity. There is now strong evidence that Exon-Shuffling played a general role in the assembly of the modular proteins involved in extracellular communications of metazoa. Although some of these proteins seem to be shared by all major groups of metazoa, others are restricted to certain evolutionary lineages. The genomic features of the chordates appear to have favoured intronic recombination as evidenced by the fact that Exon-Shuffling continued to be a major source of evolutionary novelty during vertebrate evolution.
Reimer Stick - One of the best experts on this subject based on the ideXlab platform.
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The gene structure ofXenopus nuclear lamin A: A model for the evolution of A-type from B-type lamins by Exon Shuffling
Chromosoma, 1992Co-Authors: Reimer StickAbstract:Nuclear lamins are intermediate filament (IF) type proteins that form a fibrillar network underlying the inner nuclear membrane. The existence of multiple subtypes of lamins in vertebrates has been interpreted in terms of functional specialization during cell division and differentiation. The structure of a gene encoding an A-type lamin of Xenopus laevis was analysed. Comparison with that of a B-type lamin of the same species shows remarkable conservation of the Exon/intron pattern. In both genes the last Exon, only 9–12 amino acids in length, encodes the complete information necessary for membrane targeting of lamins, i.e. a ras -related CaaX motif. The lamin A specific extension of the tail domain is encoded by a single additional Exon. The 5′ boundary of this Exon coincides with the sequence divergence between human lamins A and C, for which an alternative splice mechanism had previously been suggested. Arguments are presented suggesting that B-type lamins represent the ancestral type of lamins and that A-type lamins derived there from by Exon Shuffling. The acquisition of the new Exon might explain the different fates of A- and B-types lamins during cell division.
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The gene structure of Xenopus nuclear lamin A: a model for the evolution of A-type from B-type lamins by Exon Shuffling.
Chromosoma, 1992Co-Authors: Reimer StickAbstract:Nuclear lamins are intermediate filament (IF) type proteins that form a fibrillar network underlying the inner nuclear membrane. The existence of multiple subtypes of lamins in vertebrates has been interpreted in terms of functional specialization during cell division and differentiation. The structure of a gene encoding an A-type lamin ofXenopus laevis was analysed. Comparison with that of a B-type lamin of the same species shows remarkable conservation of the Exon/intron pattern. In both genes the last Exon, only 9–12 amino acids in length, encodes the complete information necessary for membrane targeting of lamins, i.e. aras-related CaaX motif. The lamin A specific extension of the tail domain is encoded by a single additional Exon. The 5′ boundary of this Exon coincides with the sequence divergence between human lamins A and C, for which an alternative splice mechanism had previously been suggested. Arguments are presented suggesting that B-type lamins represent the ancestral type of lamins and that A-type lamins derived there from by Exon Shuffling. The acquisition of the new Exon might explain the different fates of A- and B-types lamins during cell division.
Sandro J. De Souza - One of the best experts on this subject based on the ideXlab platform.
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Evolutionary history of Exon Shuffling
Genetica, 2012Co-Authors: Gustavo S. França, Douglas V. Cancherini, Sandro J. De SouzaAbstract:Exon Shuffling has been characterized as one of the major evolutionary forces shaping both the genome and the proteome of eukaryotes. This mechanism was particularly important in the creation of multidomain proteins during animal evolution, bringing a number of functional genetic novelties. Here, genome information from a variety of eukaryotic species was used to address several issues related to the evolutionary history of Exon Shuffling. By comparing all protein sequences within each species, we were able to characterize Exon Shuffling signatures throughout metazoans. Intron phase (the position of the intron regarding the codon) and Exon symmetry (the pattern of flanking introns for a given Exon or block of adjacent Exons) were features used to evaluate Exon Shuffling. We confirmed previous observations that Exon Shuffling mediated by phase 1 introns (1-1 Exon Shuffling) is the predominant kind in multicellular animals. Evidence is provided that such pattern was achieved since the early steps of animal evolution, supported by a detectable presence of 1-1 Shuffling units in Trichoplax adhaerens and a considerable prevalence of them in Nematostella vectensis. In contrast, Monosiga brevicollis, one of the closest relatives of metazoans, and Arabidopsis thaliana, showed no evidence of 1-1 Exon or domain Shuffling above what it would be expected by chance. Instead, Exon Shuffling events are less abundant and predominantly mediated by phase 0 introns (0-0 Exon Shuffling) in those non-metazoan species. Moreover, an intermediate pattern of 1-1 and 0-0 Exon Shuffling was observed for the placozoan T. adhaerens, a primitive animal. Finally, characterization of flanking intron phases around domain borders allowed us to identify a common set of symmetric 1-1 domains that have been shuffled throughout the metazoan lineage.
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The role of Exon Shuffling in shaping protein-protein interaction networks.
BMC genomics, 2010Co-Authors: Douglas V. Cancherini, Gustavo S. França, Sandro J. De SouzaAbstract:Physical protein-protein interaction (PPI) is a critical phenomenon for the function of most proteins in living organisms and a significant fraction of PPIs are the result of domain-domain interactions. Exon Shuffling, intron-mediated recombination of Exons from existing genes, is known to have been a major mechanism of domain Shuffling in metazoans. Thus, we hypothesized that Exon Shuffling could have a significant influence in shaping the topology of PPI networks. We tested our hypothesis by compiling Exon Shuffling and PPI data from six eukaryotic species: Homo sapiens, Mus musculus, Drosophila melanogaster, Caenorhabditis elegans, Cryptococcus neoformans and Arabidopsis thaliana. For all four metazoan species, genes enriched in Exon Shuffling events presented on average higher vertex degree (number of interacting partners) in PPI networks. Furthermore, we verified that a set of protein domains that are simultaneously promiscuous (known to interact to multiple types of other domains), self-interacting (able to interact with another copy of themselves) and abundant in the genomes presents a stronger signal for Exon Shuffling. Exon Shuffling appears to have been a recurrent mechanism for the emergence of new PPIs along metazoan evolution. In metazoan genomes, Exon Shuffling also promoted the expansion of some protein domains. We speculate that their promiscuous and self-interacting properties may have been decisive for that expansion.
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The role of Exon Shuffling in shaping protein-protein interaction networks
BMC Genomics, 2010Co-Authors: Douglas V. Cancherini, Gustavo S. França, Sandro J. De SouzaAbstract:Abstract Background Physical protein-protein interaction (PPI) is a critical phenomenon for the function of most proteins in living organisms and a significant fraction of PPIs are the result of domain-domain interactions. Exon Shuffling, intron-mediated recombination of Exons from existing genes, is known to have been a major mechanism of domain Shuffling in metazoans. Thus, we hypothesized that Exon Shuffling could have a significant influence in shaping the topology of PPI networks. Results We tested our hypothesis by compiling Exon Shuffling and PPI data from six eukaryotic species: Homo sapiens, Mus musculus, Drosophila melanogaster, Caenorhabditis elegans, Cryptococcus neoformans and Arabidopsis thaliana. For all four metazoan species, genes enriched in Exon Shuffling events presented on average higher vertex degree (number of interacting partners) in PPI networks. Furthermore, we verified that a set of protein domains that are simultaneously promiscuous (known to interact to multiple types of other domains), self-interacting (able to interact with another copy of themselves) and abundant in the genomes presents a stronger signal for Exon Shuffling. Conclusions Exon Shuffling appears to have been a recurrent mechanism for the emergence of new PPIs along metazoan evolution. In metazoan genomes, Exon Shuffling also promoted the expansion of some protein domains. We speculate that their promiscuous and self-interacting properties may have been decisive for that expansion.
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a possible role of Exon Shuffling in the evolution of signal peptides of human proteins
FEBS Letters, 2006Co-Authors: Noboru Jo Sakabe, Maria D. Vibranovski, Sandro J. De SouzaAbstract:Abstract It was recently shown that there is a predominance of phase 1 introns near the cleavage site of signal peptides encoded by human genes [Tordai, H. and Patthy, L. (2004) Insertion of spliceosomal introns in proto-splice sites: the case of secretory signal peptides. FEBS Lett. 575, 109–111]. It was suggested that this biased distribution was due to intron insertion at AG∣G proto-splice sites. However, we found that there is no disproportional excess of AG∣G that would support insertion at proto-splice sites. In fact, all nG∣G sites are enriched in the vicinity of the cleavage site. Additional analyses support an alternative scenario in which Exon-Shuffling is largely responsible for such excess of phase 1 introns.
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A possible role of Exon‐Shuffling in the evolution of signal peptides of human proteins
FEBS letters, 2006Co-Authors: Maria D. Vibranovski, Noboru Jo Sakabe, Sandro J. De SouzaAbstract:Abstract It was recently shown that there is a predominance of phase 1 introns near the cleavage site of signal peptides encoded by human genes [Tordai, H. and Patthy, L. (2004) Insertion of spliceosomal introns in proto-splice sites: the case of secretory signal peptides. FEBS Lett. 575, 109–111]. It was suggested that this biased distribution was due to intron insertion at AG∣G proto-splice sites. However, we found that there is no disproportional excess of AG∣G that would support insertion at proto-splice sites. In fact, all nG∣G sites are enriched in the vicinity of the cleavage site. Additional analyses support an alternative scenario in which Exon-Shuffling is largely responsible for such excess of phase 1 introns.
Manyuan Long - One of the best experts on this subject based on the ideXlab platform.
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© 2003 Kluwer Academic Publishers. Printed in the Netherlands. 171 Origin of new genes: evidence from experimental and computational analyses
2014Co-Authors: Manyuan Long, Michael Deutsch, Wen Wang, Frédéric G Brunet, Jianming ZhangAbstract:genes Exon Shuffling is an essential molecular mechanism for the formation of new genes. Many cases of Exon Shuffling have been reported in vertebrate genes. These discoveries revealed the importance of Exon Shuffling in the origin of new genes. However, only a few cases of Exon Shuffling were reported from plants and invertebrates, which gave rise to the assertion that the intron-mediated recombination mechanism originated very recently. We focused on the origin of new genes by Exon Shuffling and retroposition. We will first summarize our experimental work, which revealed four new genes in Drosophila, plants, and humans. These genes are 106 to 108 million years old. The recency of these genes allows us to directly examine the origin and evolution of genes in detail. These observations show firstly the importance of Exon Shuffling and retroposition in the rapid creation of new gene structures. They also show that the resultant chimerical structures appearing as mosaic proteins or as retroposed coding structures with novel regulatory systems, often confer novel functions. Furthermore, these newly created genes appear to have been governed by positive Darwinian selection throughout their history, with rapid changes of amino acid sequence and gene structure in very short periods of evolution. We further analyzed the distribution of intron phases in three non-vertebrate species, Drosophila melanogaster, Caenorhabditis elegans, and Arabidosi
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Origin of new genes: evidence from experimental and computational analyses.
Genetica, 2003Co-Authors: Manyuan Long, Michael Deutsch, Wen Wang, Esther Betrán, Frédéric G Brunet, Jianming ZhangAbstract:Exon Shuffling is an essential molecular mechanism for the formation of new genes. Many cases of Exon Shuffling have been reported in vertebrate genes. These discoveries revealed the importance of Exon Shuffling in the origin of new genes. However, only a few cases of Exon Shuffling were reported from plants and invertebrates, which gave rise to the assertion that the intron-mediated recombination mechanism originated very recently. We focused on the origin of new genes by Exon Shuffling and retroposition. We will first summarize our experimental work, which revealed four new genes in Drosophila, plants, and humans. These genes are 10(6) to 10(8) million years old. The recency of these genes allows us to directly examine the origin and evolution of genes in detail. These observations show firstly the importance of Exon Shuffling and retroposition in the rapid creation of new gene structures. They also show that the resultant chimerical structures appearing as mosaic proteins or as retroposed coding structures with novel regulatory systems, often confer novel functions. Furthermore, these newly created genes appear to have been governed by positive Darwinian selection throughout their history, with rapid changes of amino acid sequence and gene structure in very short periods of evolution. We further analyzed the distribution of intron phases in three non-vertebrate species, Drosophila melanogaster, Caenorhabditis elegans, and Arabidosis thaliana, as inferred from their genome sequences. As in the case of vertebrate genes, we found that intron phases in these species are unevenly distributed with an excess of phase zero introns and a significant excess of symmetric Exons. Both findings are consistent with the requirements for the molecular process of Exon Shuffling. Thus, these non-vertebrate genomes may have also been strongly impacted by Exon Shuffling in general.
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Exon Shuffling and the origin of the mitochondrial targeting function in plant cytochrome c1 precursor.
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Manyuan Long, S. J. De Souza, Carl Rosenberg, Walter GilbertAbstract:Since most of the examples of "Exon Shuffling" are between vertebrate genes, the view is often expressed that Exon Shuffling is limited to the evolutionarily recent lineage of vertebrates. Although Exon Shuffling in plants has been inferred from the analysis of intron phases of plant genes [Long, M., Rosenberg, C. & Gilbert, W. (1995) Proc. Natl. Acad. Sci. USA 92, 12495-12499] and from the comparison of two functionally unknown sunflower genes [Domon, C. & Steinmetz, A. (1994) Mol. Gen. Genet. 244, 312-317], clear cases of Exon Shuffling in plant genes remain to be uncovered. Here, we report an example of Exon Shuffling in two important nucleus-encoded plant genes: cytosolic glyceraldehyde-3-phosphate dehydrogenase (cytosolic GAPDH or GapC) and cytochrome c1 precursor. The intron-Exon structures of the shuffled region indicate that the Shuffling event took place at the DNA sequence level. In this case, we can establish a donor-recipient relationship for the Exon Shuffling. Three amino terminal Exons of GapC have been donated to cytochrome c1, where, in a new protein environment, they serve as a source of the mitochondrial targeting function. This finding throws light upon an old important but unsolved question in gene evolution: the origin of presequences or transit peptides that generally exist in nucleus-encoded organelle genes.
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Introns and gene evolution
Genes to Cells, 1996Co-Authors: Sandro J. De Souza, Manyuan Long, Walter GilbertAbstract:: In one scenario of gene evolution, Exon Shuffling has a fundamental role in increasing gene diversity. As DNA sequences accumulate in the databases, the picture of the intron/Exon structures of genes becomes more and more clear. We discuss in this review some features of this picture that suggest that introns have been present since the early stages of evolution, and that Exon Shuffling was a fundamental process in the construction of ancient as well as modern genes.
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Intron phase correlations and the evolution of the intron/Exon structure of genes
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Manyuan Long, Carl Rosenberg, Walter GilbertAbstract:Abstract Two issues in the evolution of the intron/Exon structure of genes are the role of Exon Shuffling and the origin of introns. Using a large data base of eukaryotic intron-containing genes, we have found that there are correlations between intron phases leading to an excess of symmetric Exons and symmetric Exon sets. We interpret these excesses as manifestations of Exon Shuffling and make a conservative estimate that at least 19% of the Exons in the data base were involved in Exon Shuffling, suggesting an important role for Exon Shuffling in evolution. Furthermore, these excesses of symmetric Exons appear also in those regions of eukaryotic genes that are homologous to prokaryotic genes: the ancient conserved regions. This last fact cannot be explained in terms of the insertional theory of introns but rather supports the concept that some of the introns were ancient, the Exon theory of genes.
Hans Bloemendal - One of the best experts on this subject based on the ideXlab platform.
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Molecular mechanisms of Exon Shuffling: illegitimate recombination.
Genetica, 2003Co-Authors: Anke Van Rijk, Hans BloemendalAbstract:Illegitimate recombination (IR) is a process that takes place far more often than homologous recombination and is characterized by the recombination between non-homologous or short homologous sequences. The consequences of IR frequently emerge after the introduction of DNA in cell lines because it more frequently integrates in non-homologous than in homologous regions of the host genome. As a result, unexpected truncated or elongated products may be found. By not discarding those products as transfection artifacts, but by studying how they are generated, it might elucidate a possible molecular mechanism of IR. Here we review the current literature describing different mechanisms by which non-homologous DNA recombination can be induced.
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Characteristics of super αA-crystallin, a product of in vitro Exon Shuffling
FEBS Letters, 2000Co-Authors: Anke Van Rijk, Wilfried W. De Jong, Maarten J.j. Van Den Hurk, Wouter Renkema, Wilbert C. Boelens, Hans BloemendalAbstract:αA-Crystallin, a small heat shock protein with chaperone-like activity, forms dynamic multimeric complexes. Recently we described the spontaneous generation of a mutant protein (super αA-crystallin) by Exon duplication arisen via Exon Shuffling confirming a classic hypothesis by Gilbert [Nature 271 (1978) 501]. Comparison of super αA-crystallin, which is viable in a mouse skeletal muscle cell line, with normal αA-crystallin shows that it has diminished thermostability, increased exposure of hydrophobic patches, a larger complex size and lost its chaperone activity. However, super αA-crystallin subunits exchange as readily between complexes as does normal αA-crystallin. These data indicate that chaperone-like activity may vanish independent of subunit hydrophobicity and exchangeability.
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Exon Shuffling mimicked in cell culture
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Anke Van Rijk, Wilfried W. De Jong, Hans BloemendalAbstract:Undesired side products of DNA transfections are usually discarded. However, here, we show that such products may provide insight into mutational events that are also a major driving force in protein evolution. While studying the small heat-shock protein alphaA-crystallin, we transfected the hamster alphaA-crystallin gene into a mouse muscle cell line. One of the stable transfected cell lines expressed, in addition to the expected normal alphaA- and alternatively spliced alphaAins-crystallins, two slightly larger, immunologically cross-reacting proteins. These proteins were found to be encoded by a mutant alphaA-crystallin gene with a large intragenic duplication, arisen by illegitimate recombination at two CCCAT homologies, approximately 1.8 kilobases apart in the normal hamster alphaA-crystallin gene. As a consequence, a tandem-duplicated Exon 3 sequence is present in the mature mRNA of this gene, resulting in a 41-residue repeat in the translated proteins. Cells expressing the elongated alphaA-crystallins have normal growth characteristics and the usual diffuse cytoplasmic distribution of immunoreactive alphaA-crystallin. Size-exclusion chromatography of cell extracts indicated that the mutant proteins are readily incorporated into the normal large water-soluble alphaA-crystallin complexes, showing that the insert does not disturb the integrity of these complexes. This viable alphaA-crystallin mutant thus mimics the origins and effects of Exon duplication, which is a common consequence of Exon Shuffling in mammalian genome evolution.