Increase of functional diversity by alternative splicing

Kriventseva, Evgenia V.; Koch, Ina; Apweiler, Rolf; Vingron, Martin; Bork, Peer; Gelfand, Mikhail S.; Sunyaev, Shamil

doi:10.1016/s0168-9525(03)00023-4

Cited by 209 publications

(162 citation statements)

References 24 publications

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“…If the same number of splicing events in each alternative isoform were to happen randomly at any of the exon boundaries, they would be expected to fall inside Pfam-A domains in 59.8% of isoforms (84.8% in all Pfam-defined domains). As shown (25), this effect is not due to any correlation between domain and exon boundaries. We found no such correlation.…”

Section: Resultsmentioning

confidence: 68%

The implications of alternative splicing in the ENCODE protein complement

Tress

Martelli

Frankish

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

201

187

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Alternative premessenger RNA splicing enables genes to generate more than one gene product. Splicing events that occur within protein coding regions have the potential to alter the biological function of the expressed protein and even to create new protein functions. Alternative splicing has been suggested as one explanation for the discrepancy between the number of human genes and functional complexity. Here, we carry out a detailed study of the alternatively spliced gene products annotated in the ENCODE pilot project. We find that alternative splicing in human genes is more frequent than has commonly been suggested, and we demonstrate that many of the potential alternative gene products will have markedly different structure and function from their constitutively spliced counterparts. For the vast majority of these alternative isoforms, little evidence exists to suggest they have a role as functional proteins, and it seems unlikely that the spectrum of conventional enzymatic or structural functions can be substantially extended through alternative splicing.function ͉ human ͉ isoforms ͉ splice ͉ structure A lternative mRNA splicing, the generation of a diverse range of mature RNAs, has considerable potential to expand the cellular protein repertoire (1-3), and recent studies have estimated that 40-80% of multiexon human genes can produce differently spliced mRNAs (4, 5). The importance of alternative splicing in processes such as development (6) has long been recognized, and proteins coded by alternatively spliced transcripts have been implicated in a number of cellular pathways (7-9). The extent of alternative splicing in eukaryotic genomes has lead to suggestions that alternative splicing is key to understanding how human complexity can be encoded by so few genes (10).The pilot project of the Encyclopedia of DNA Elements (ENCODE) (11), which aims to identify all the functional elements in the human genome, has undertaken a comprehensive analysis of 44 selected regions that make up 1% of the human genome. One valuable element of the project has been the detailing of a reference set of manually annotated splice variants by the GENCODE consortium (12). The annotation by the GENCODE consortium is an extension of the manually curated annotation by the Havana team at The Sanger Institute.Although a full understanding of the functional implications of alternative splicing is still a long way off, the GENCODE set has provided us with the material to make an in-depth assessment of a systematically collected reference set of splice variants. ResultsAlternative Splicing Frequency. The GENCODE set is made up of 2,608 annotated transcripts for 487 distinct loci. A total of 1,097 transcripts from 434 loci are predicted to be protein coding. There are on average 2.53 protein coding variants per locus; 182 loci have only one variant, whereas one locus, RP1-309K20.2 (CPNE1) has 17 coding variants.A total of 57.8% of the loci are annotated with alternatively spliced transcripts, although there are differences between target re...

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Section: Resultsmentioning

confidence: 68%

The implications of alternative splicing in the ENCODE protein complement

Tress

Martelli

Frankish

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

201

187

View full text Add to dashboard Cite

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“…Can the current results be extrapolated to eukaryotic proteins in general? One study of alternative splicing and protein structure found that, of 1,780 proteins with isoforms produced by alternative splicing, only 48, or 2.7% have a known 3D structure (27). The study used 4,804 known isoforms from higher organisms with fully sequenced genomes (Homo sapiens, Mus musculus, Drosophila melanogaster, and Caenorhabditis elegans) extracted from the SwissProt database (27).…”

Section: Resultsmentioning

confidence: 99%

Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms

Romero

Zaidi

Fang

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

435

387

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Alternative splicing of pre-mRNA generates two or more protein isoforms from a single gene, thereby contributing to protein diversity. Despite intensive efforts, an understanding of the protein structure-function implications of alternative splicing is still lacking. Intrinsic disorder, which is a lack of equilibrium 3D structure under physiological conditions, may provide this understanding. Intrinsic disorder is a common phenomenon, particularly in multicellular eukaryotes, and is responsible for important protein functions including regulation and signaling. We hypothesize that polypeptide segments affected by alternative splicing are most often intrinsically disordered such that alternative splicing enables functional and regulatory diversity while avoiding structural complications. We analyzed a set of 46 differentially spliced genes encoding experimentally characterized human proteins containing both structured and intrinsically disordered amino acid segments. We show that 81% of 75 alternatively spliced fragments in these proteins were associated with fully (57%) or partially (24%) disordered protein regions. Regions affected by alternative splicing were significantly biased toward encoding disordered residues, with a vanishingly small P value. A larger data set composed of 558 SwissProt proteins with known isoforms produced by 1,266 alternatively spliced fragments was characterized by applying the PONDR VSL1 disorder predictor. Results from prediction data are consistent with those obtained from experimental data, further supporting the proposed hypothesis. Associating alternative splicing with protein disorder enables the time-and tissue-specific modulation of protein function needed for cell differentiation and the evolution of multicellular organisms.evolution ͉ natively unfolded ͉ intrinsically unstructured ͉ protein structure T he splicing of pre-mRNA (1) was first described in 1977. Soon thereafter, Gilbert (2) coined the terms ''intron'' (intragenic region) and ''exon'' (expressed region) for the noncoding and coding regions, respectively. Alternative splicing occurs when different mRNAs are assembled from a single gene by joining exons in different ways. Alternative splicing is proposed to generate complexity in multicellular eukaryotes by increasing protein diversity, and thus proteome size, from a relatively small number of genes (3). Estimates indicate that between 35 and 60% of human genes yield protein isoforms by means of alternatively spliced (AS) mRNA (4). Furthermore, complexity in higher organisms is also brought about by signaling and regulatory networks that enable robustness (5). The importance of alternative splicing as a regulatory process (3, 6) has been highlighted by the high occurrence of such splicing in the pre-mRNAs of regulatory and signaling proteins (7).Alternative splicing can bolster organism complexity, not only by effectively increasing proteome size and regulatory and signaling network complexity, but also by doing so in a time-and tissue-specific manner, supporting ...

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“…The extent to which selection is weakened is comparable to the effect of diploidy. Nevertheless, a detectable level of selection remains: alternative splices tend to insert or delete complete protein domains rather than disrupt structural modules (Kriventseva et al 2003). Also, exons are biased toward exact multiples of three nucleotides, thus preserving the protein reading frame in both exon-inclusion and exon-skip splice forms (Resch et al 2004).…”

Section: Resultsmentioning

confidence: 99%

Cryptic Genetic Variation Is Enriched for Potential Adaptations

2006

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Cryptic genetic variation accumulates under weakened selection and has been proposed as a source of evolutionary innovations. Weakened selection may, however, also lead to the accumulation of strongly deleterious or lethal alleles, swamping the effect of any potentially adaptive alleles when they are revealed. Here I model variation that is partially shielded from selection, assuming that unconditionally deleterious variation is more strongly deleterious than variation that is potentially adaptive in a future environment. I find that cryptic genetic variation can be substantially enriched for potential adaptations under a broad range of realistic parameter values, including those applicable to alternative splices and readthrough products generated by the yeast prion [PSI 1 ]. This enrichment is dramatically stronger when multiple simultaneous changes are required to generate a potentially adaptive phenotype. Cryptic genetic variation is likely to be an effective source of useful adaptations at a time of environmental change, relative to an equivalent source of variation that has not spent time in a hidden state.

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Increase of functional diversity by alternative splicing

Cited by 209 publications

References 24 publications

The implications of alternative splicing in the ENCODE protein complement

The implications of alternative splicing in the ENCODE protein complement

Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms

Cryptic Genetic Variation Is Enriched for Potential Adaptations

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