The “Alternative” Choice of Constitutive Exons throughout Evolution

Lev-Maor, Galit; Goren, Amir; Sela, Noa; Kim, Eddo; Keren, Hadas; Doron‐Faigenboim, Adi; Leibman-Barak, Shelly; Pupko, Tal; Ast, Gil

doi:10.1371/journal.pgen.0030203

Cited by 57 publications

(69 citation statements)

References 60 publications

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“…This may be explained by a different origin of these exons. While alternatively spliced exons (cassette exons) originate mostly through exonization of intronic sequences, exon duplication, or exon shuffling (Ast 2004;Blencowe 2006;Lev-Maor et al 2007), exons spliced through the use of 59 and/or 39 splice sites have been suggested to evolve from existing constitutively spliced exons (Zhang and Chasin 2006). Therefore, the observed differences in the length and composition of homopolymer sequences between cassette exons and complex exons may be the consequence of different evolutionary histories among exons.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide evidence for selection acting on single amino acid repeats

Haerty¹,

Golding²

2010

Genome Res.

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Low complexity and homopolymer sequences within coding regions are known to evolve rapidly. While their expansion may be deleterious, there is increasing evidence for a functional role associated with these amino acid sequences. Homopolymer sequences are thought to evolve mostly through replication slippage and, therefore, they may be expected to be longer in regions with relaxed selective constraint. Within the coding sequences of eukaryotes, alternatively spliced exons are known to evolve under relaxed constraints in comparison to those exons that are constitutively spliced because they are not included in all of the mature mRNA of a gene. This relaxed exposure to selection leads to faster rates of evolution for alternatively spliced exons in comparison to constitutively spliced exons. Here, we have tested the effect of splicing on the structure (composition, length) of homopolymer sequences in relation to the splicing pattern in which they are found. We observed a significant relationship between alternative splicing and homopolymer sequences with alternatively spliced genes being enriched in number and length of homopolymer sequences. We also observed lower codon diversity and longer homocodons, suggesting a balance between slippage and point mutations linked to the constraints imposed by selection.

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Section: Discussionmentioning

confidence: 99%

Genome-wide evidence for selection acting on single amino acid repeats

Haerty¹,

Golding²

2010

Genome Res.

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“…suggesting that minor-form exons are shorter on average than major-form exons (Sorek et al 2004;Baek and Green 2005;Lev-Maor et al 2007). The restraints on exon length may reflect size limitations to facilitate bridging across the exon.…”

Section: Discussionmentioning

confidence: 99%

“…These data are consistent with previous evidence that indicates a difference in splicing regulation between minor-and major-form exons. Minor-form exons show evidence of increased purifying selection on RNA sequence (Kaufmann et al 2004;Baek and Green 2005;Xing and Lee 2005;Plass and Eyras 2006;Lev-Maor et al 2007). This effect is especially pronounced at the exon flanks, where splicing regulatory sites are located (Plass and Eyras 2006;).…”

Section: Discussionmentioning

confidence: 99%

The effect of intron length on exon creation ratios during the evolution of mammalian genomes

Roy

Kim²,

Xing³

et al. 2008

RNA

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Recent studies report that alternatively spliced exons tend to occur in longer introns, which is attributed to the length constraints for splice site pairing for the two major splicing mechanisms, intron definition versus exon definition. Using genomewide studies of EST and microarray data from human and mouse, we have analyzed the distribution of various subsets of alternatively spliced exons, based on their inclusion level and evolutionary history, versus increasing intron length. Alternative exons may be included in either a major or minor fraction of all transcripts (known as major-form and minor-form exons, respectively). We find that major-form exons are seven-to eightfold more likely to be contained in short introns (<400 nt) than minor-form exons, which occur preferentially in longer introns. Since minor-form exons are more likely to be novel (;75%), this implied that novel exons arise more frequently in longer introns. To test this hypothesis, we used whole genome alignments to classify exons according to their phylogenetic age. We find that older exons, i.e., exons that are conserved in all mammals, predominate at shorter intron lengths, for both major-and minor-form exons. In contrast, exons that arose recently during primate evolution are more prevalent at longer intron lengths (>1000 nt). This suggests that the observed correlation of longer intron lengths with alternatively spliced exons may be at least partly due to biases in the probability of exon creation, which is higher in long introns.

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“…This involves the recognition of cis-acting sequences, including 59 and 39 splice sites (ss) and other exonic splicing regulators (ESRs) or intronic splicing regulators (ISRs), by trans-acting splicing factors that regulate ss selection. Alternative splicing occurs when more than one mRNA product is formed from the same pre-mRNA and can arise through several mechanisms (Kim et al 2008), including exonization of introns (Sorek 2007), the emergence of alternative 59ss and 39ss via the weakening of 59ss, and changes in the ESR frequency of ancestral constitutive exons (Koren et al 2007;Lev-Maor et al 2007). Therefore, whether an exon is included in the mature mRNA is determined by the frequency and strength of multiple ciselements that recruit trans factors to regulate splicing (Hertel 2008;Wang and Burge 2008).…”

Section: Introductionmentioning

confidence: 99%

Functional implications of the emergence of alternative splicing in hnRNP A/B transcripts

Han

Kassahn²,

Skarshewski³

et al. 2010

RNA

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The heterogeneous nuclear ribonucleoproteins (hnRNPs) A/B are a family of RNA-binding proteins that participate in various aspects of nucleic acid metabolism, including mRNA trafficking, telomere maintenance, and splicing. They are both regulators and targets of alternative splicing, and the patterns of alternative splicing of their transcripts have diverged between paralogs and between orthologs in different species. Surprisingly, the extent of this splicing variation and its implications for posttranscriptional regulation have remained largely unexplored. Here, we conducted a detailed analysis of hnRNP A/B sequences and expression patterns across six vertebrates. Alternative exons emerged via the introduction of new splice sites, changes in the strengths of existing splice sites, and the accumulation of auxiliary splicing regulatory motifs. Observed isoform expression patterns could be attributed to the frequency and strength of cis-elements. We found a trend toward increased splicing variation in mammals and identified novel alternatively spliced isoforms in human and chicken. Pulldown and translational assays demonstrated that the inclusion of alternative exons altered the affinity of hnRNP A/B proteins for their cognate nucleic acids and modified protein expression levels. As the hnRNPs A/B regulate several key steps in mRNA processing, the involvement of diverse hnRNP isoforms in multiple cellular contexts and species implies concomitant differences in the transcriptional output of these systems. We conclude that the emergence of alternative splicing in the hnRNPs A/B has contributed to the diversification of their roles in the regulation of alternative splicing and has thus added an unexpected layer of regulatory complexity to transcription in vertebrates.

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The “Alternative” Choice of Constitutive Exons throughout Evolution

Cited by 57 publications

References 60 publications

Genome-wide evidence for selection acting on single amino acid repeats

Genome-wide evidence for selection acting on single amino acid repeats

The effect of intron length on exon creation ratios during the evolution of mammalian genomes

Functional implications of the emergence of alternative splicing in hnRNP A/B transcripts

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