Opposite Evolutionary Effects between Different Alternative Splicing Patterns

Chen, Feng‐Chi; Chaw, Shu‐Miaw; Tzeng, Yun-Huei; Wang, Sheng‐Shun; Chuang, Trees‐Juen

doi:10.1093/molbev/msm072

Cited by 14 publications

(15 citation statements)

References 13 publications

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“…When ASEs are classified as conserved or non-conserved in exon structure, low synonymous rates are characteristic of conserved ASEs but not of those with non-conserved exonic structure [26]. Moreover, when they are classified as boundary-shifting (complex) ASEs or non-boundary shifting (simple) ASEs (those of the former type change the exon/intron boundaries of the flanking exons whereas those of the latter type do not), complex ASEs are under stronger selection pressure at the amino acid level but less pressure at the RNA level than CSEs, while reverse trends were observed in simple ASEs [27,28]. These opposite evolutionary effects between different AS patterns have been discussed as a key role of AS in the 'switch-like' regulation of gene expression [29].…”

Section: Introductionmentioning

confidence: 99%

A comprehensive survey of human polymorphisms at conserved splice dinucleotides and its evolutionary relationship with alternative splicing

et al. 2010

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BackgroundAlternative splicing (AS) is a key molecular process that endows biological functions with diversity and complexity. Generally, functional redundancy leads to the generation of new functions through relaxation of selective pressure in evolution, as exemplified by duplicated genes. It is also known that alternatively spliced exons (ASEs) are subject to relaxed selective pressure. Within consensus sequences at the splice junctions, the most conserved sites are dinucleotides at both ends of introns (splice dinucleotides). However, a small number of single nucleotide polymorphisms (SNPs) occur at splice dinucleotides. An intriguing question relating to the evolution of AS diversity is whether mutations at splice dinucleotides are maintained as polymorphisms and produce diversity in splice patterns within the human population. We therefore surveyed validated SNPs in the database dbSNP located at splice dinucleotides of all human genes that are defined by the H-Invitational Database.ResultsWe found 212 validated SNPs at splice dinucleotides (sdSNPs); these were confirmed to be consistent with the GT-AG rule at either allele. Moreover, 53 of them were observed to neighbor ASEs (AE dinucleotides). No significant differences were observed between sdSNPs at AE dinucleotides and those at constitutive exons (CE dinucleotides) in SNP properties including average heterozygosity, SNP density, ratio of predicted alleles consistent with the GT-AG rule, and scores of splice sites formed with the predicted allele. We also found that the proportion of non-conserved exons was higher for exons with sdSNPs than for other exons.ConclusionssdSNPs are found at CE dinucleotides in addition to those at AE dinucleotides, suggesting two possibilities. First, sdSNPs at CE dinucleotides may be robust against sdSNPs because of unknown mechanisms. Second, similar to sdSNPs at AE dinucleotides, those at CE dinucleotides cause differences in AS patterns because of the arbitrariness in the classification of exons into alternative and constitutive type that varies according to the dataset. Taking into account the absence of differences in sdSNP properties between those at AE and CE dinucleotides, the increased proportion of non-conserved exons found in exons flanked by sdSNPs suggests the hypothesis that sdSNPs are maintained at the splice dinucleotides of newly generated exons at which negative selection pressure is relaxed.

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Section: Introductionmentioning

confidence: 99%

A comprehensive survey of human polymorphisms at conserved splice dinucleotides and its evolutionary relationship with alternative splicing

et al. 2010

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“…For example, ASEs are known to have increased d N and the d N / d S ratios as compared with CSEs [8,10,18,19]. Therefore, the increase in d N and the d N / d S ratio in longer exons might have resulted from an increase in the proportion of ASEs.…”

Section: Resultsmentioning

confidence: 99%

The evolution of the coding exome of the Arabidopsis species - the influences of DNA methylation, relative exon position, and exon length

et al. 2014

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BackgroundThe evolution of the coding exome is a major driving force of functional divergence both between species and between protein isoforms. Exons at different positions in the transcript or in different transcript isoforms may (1) mutate at different rates due to variations in DNA methylation level; and (2) serve distinct biological roles, and thus be differentially targeted by natural selection. Furthermore, intrinsic exonic features, such as exon length, may also affect the evolution of individual exons. Importantly, the evolutionary effects of these intrinsic/extrinsic features may differ significantly between animals and plants. Such inter-lineage differences, however, have not been systematically examined.ResultsHere we examine how DNA methylation at CpG dinucleotides (CpG methylation), in the context of intrinsic exonic features (exon length and relative exon position in the transcript), influences the evolution of coding exons of Arabidopsis thaliana. We observed fairly different evolutionary patterns in A. thaliana as compared with those reported for animals. Firstly, the mutagenic effect of CpG methylation is the strongest for internal exons and the weakest for first exons despite the stringent selective constraints on the former group. Secondly, the mutagenic effect of CpG methylation increases significantly with length in first exons but not in the other two exon groups. Thirdly, CpG methylation level is correlated with evolutionary rates (dS, dN, and the dN/dS ratio) with markedly different patterns among the three exon groups. The correlations are generally positive, negative, and mixed for first, last, and internal exons, respectively. Fourthly, exon length is a CpG methylation-independent indicator of evolutionary rates, particularly for dN and the dN/dS ratio in last and internal exons. Finally, the evolutionary patterns of coding exons with regard to CpG methylation differ significantly between Arabidopsis species and mammals.ConclusionsOur results suggest that intrinsic features, including relative exonic position in the transcript and exon length, play an important role in the evolution of A. thaliana coding exons. Furthermore, CpG methylation is correlated with exonic evolutionary rates differentially between A. thaliana and animals, and may have served different biological roles in the two lineages.

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“…The splicing sites that enabled the identified transcript to pass the CENTP exon-checking rules stated above and generate the longest transcript were then chosen. Note that, in the CENTP process, if a meta-CENTP exon had been identified as a simple cassette-on exon, it was not further examined for consideration of a complex exon, for simple exons constitute the majority of cassette exons (>80%) (Chen and Chuang 2007;Chen et al 2007a). For accuracy, we only identified complex cassette-on exons that were located in CDSs.…”

Section: Methodsmentioning

confidence: 99%

Identification and analysis of ancestral hominoid transcriptome inferred from cross-species transcript and processed pseudogene comparisons

Huang

Chen²,

Chen³

et al. 2008

Genome Res.

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Comparative transcriptomics studies in hominoids are difficult because of lack of EST information in the great apes. Nevertheless, processed pseudogenes (PPGs), which are reverse-transcribed ancient transcripts present in the current genome, can be regarded as a virtual transcript resource that may compensate for the paucity of ESTs in non-human hominoids. Here we show that chimpanzee PPGs can be applied to identification of novel human exons/alternatively spliced variants (ASVs) and inference of the ancestral hominoid transcriptome and chimpanzee exon loss events. We develop a method for comparatively extracting novel transcripts from PPGs (designated "CENTP") and identify 643 novel human exons/ASVs. RT-PCR-sequencing experiments confirmed >50% of the tested exons/ASVs, supporting the effectiveness of the CENTP pipeline. With reference to the ancestral transcriptome inferred by CENTP, 47 chimpanzee exon loss events are identified. Furthermore, by combining out-group and PPG information, we identify 20 chimpanzee-specific exon loss and 10 human-specific exon gain events. We also demonstrate that the ancestral transcriptome and exon loss/gain events inferred based on comparisons of current transcripts may be incomplete (or occasionally inappropriate) because ancestral transcripts may not be represented in the ESTs of existing species. Finally, functional analysis reveals that the novel exons identified based on chimpanzee transcripts are significantly enriched in genes related to translation regulatory activity and viral life cycle, suggesting different expression levels of the associated transcripts, and thus divergent splicing isoform composition between human and chimpanzee in these functional categories.

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Opposite Evolutionary Effects between Different Alternative Splicing Patterns

Cited by 14 publications

References 13 publications

A comprehensive survey of human polymorphisms at conserved splice dinucleotides and its evolutionary relationship with alternative splicing

A comprehensive survey of human polymorphisms at conserved splice dinucleotides and its evolutionary relationship with alternative splicing

The evolution of the coding exome of the Arabidopsis species - the influences of DNA methylation, relative exon position, and exon length

Identification and analysis of ancestral hominoid transcriptome inferred from cross-species transcript and processed pseudogene comparisons

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