Alternative splicing of mutually exclusive exons—A review

Pöhl, Martin; Bortfeldt, Ralf; Grützmann, Konrad; Schuster, Stefan

doi:10.1016/j.biosystems.2013.07.003

Cited by 66 publications

(60 citation statements)

References 115 publications

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“…Many other studies have also revealed that specific subsets of exonic splicing silencers exert distinct effects on a multifunctional intron retention reporter, and that one of these subsets is the most likely to be involved in the regulation of endogenous intron retention events. Intron retention could, therefore, affect alternative NA not available a p-Values were calculated from the two-sided χ 2 test; genotype frequency in the lower concentration group vs. in the normal concentration group b p-Values were calculated from the two-sided χ 2 test; genotype frequency in the higher concentration group vs. in the normal concentration group c Considering heterozygotes and homozygotes together splicing of pre-mRNA by influencing the exonic splicing silencers, thus producing different mature mRNAs and then translating proteins with different functions [36][37][38]. Therefore, in the present study, we selected SNPs associated with the voriconazole concentration from the statistical perspective; these SNPs may also have an impact on protein function.…”

Section: Discussionmentioning

confidence: 99%

Effects of CYP3A4 polymorphisms on the plasma concentration of voriconazole

Sun

Ren

et al. 2014

Eur J Clin Microbiol Infect Dis

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Voriconazole is frequently utilized for the prevention and treatment of invasive fungal infections (IFIs), and is extensively metabolized by the cytochrome P450 (CYP) system. The impact of activity of the genes encoding CYP3A4, CYP3A5, and CYP2C9 on the pharmacokinetics of voriconazole cannot be ignored because, second to CYP2C19, they are the most important enzymes involved in voriconazole metabolism. The influence of genetic polymorphisms in CYP3A4, CYP3A5, and CYP2C9 on the plasma concentrations of voriconazole was evaluated in the present study. The study cohort comprised 158 patients with IFIs in whom 22 single-nucleotide polymorphisms (SNPs) in CYP3A4, CYP3A5, and CYP2C9 were genotyped using the Sequenom MassARRAY RS1000 system, and voriconazole plasma concentrations were measured by high-performance liquid chromatography (HPLC). 40, 91, and 27 patients presented with low (<1 mg/L), normal (1-4 mg/L), and high (>4 mg/L) plasma voriconazole concentrations, respectively. Correlation analysis between polymorphisms and the plasma voriconazole concentration revealed an association between the presence of the rs4646437 T allele and a higher plasma voriconazole concentration [p = 0.033, odds ratio (OR) = 2.832, 95% confidence interval (CI) = 1.086-7.384]. This study has identified a new SNP related to the metabolism of voriconazole, potentially providing novel insight into the influence of CYP3A4 on the pharmacokinetics of this antifungal agent.

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Section: Discussionmentioning

confidence: 99%

Effects of CYP3A4 polymorphisms on the plasma concentration of voriconazole

Sun

Ren

et al. 2014

Eur J Clin Microbiol Infect Dis

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“…However, this pattern indicates that the ancestral state (before duplication and subfunctionalization) included mutually exclusive exons or alternative 3 ′ or 5 ′ splice sites. We chose not to study these other types of alternative splicing because cassette exons represent the most common form of alternative splicing (Sorek et al 2004;Pohl et al 2013) and because detecting subfunctionalization of alternative 3 ′ and 5 ′ splice sites, as well as mutually exclusive exons, is computationally very difficult. By omitting other types of alternative splicing events, our estimates of the effects of subfunctionalization are likely conservative, meaning that gene duplication may reduce alternative splicing levels even more than reported here.…”

Section: Discussionmentioning

confidence: 99%

Evidence for widespread subfunctionalization of splice forms in vertebrate genomes

et al. 2015

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Gene duplication and alternative splicing are important sources of proteomic diversity. Despite research indicating that gene duplication and alternative splicing are negatively correlated, the evolutionary relationship between the two remains unclear. One manner in which alternative splicing and gene duplication may be related is through the process of subfunctionalization, in which an alternatively spliced gene upon duplication divides distinct splice isoforms among the newly generated daughter genes, in this way reducing the number of alternatively spliced transcripts duplicate genes produce. Previously, it has been shown that splice form subfunctionalization will result in duplicate pairs with divergent exon structure when distinct isoforms become fixed in each paralog. However, the effects of exon structure divergence between paralogs have never before been studied on a genome-wide scale. Here, using genomic data from human, mouse, and zebrafish, we demonstrate that gene duplication followed by exon structure divergence between paralogs results in a significant reduction in levels of alternative splicing. In addition, by comparing the exon structure of zebrafish duplicates to the co-orthologous human gene, we have demonstrated that a considerable fraction of exon divergent duplicates maintain the structural signature of splice form subfunctionalization. Furthermore, we find that paralogs with divergent exon structure demonstrate reduced breadth of expression in a variety of tissues when compared to paralogs with identical exon structures and singletons. Taken together, our results are consistent with subfunctionalization partitioning alternatively spliced isoforms among duplicate genes and as such highlight the relationship between gene duplication and alternative splicing.

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“…Five types of alternative splicing have been identified to contribute to most mRNA isoforms, which are differential exon inclusion (exon skipping), intron retention, alternative 5′ and 3′ exon splicing, and mutually exclusive splicing (Blencowe, 2006; Pan et al , 2008; Wang et al , 2008; Nilsen & Graveley, 2010). Mutually exclusive splicing generates alternative isoforms by retaining only one exon of a cluster of neighbouring internal exons in the mature transcript and is a sophisticated way to modulate protein function (Letunic et al , 2002; Meijers et al , 2007; Pohl et al , 2013; Tress et al , 2017a). The most extreme cases known so far are the arthropod DSCAM genes, for which up to 99 mutually exclusive exons (MXEs) spread into four clusters were identified (Schmucker et al , 2000; Lee et al , 2010; Pillmann et al , 2011).…”

Section: Introductionmentioning

confidence: 99%

The landscape of human mutually exclusive splicing

Hatje

Rahman

Vidal

et al. 2017

Molecular Systems Biology

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Mutually exclusive splicing of exons is a mechanism of functional gene and protein diversification with pivotal roles in organismal development and diseases such as Timothy syndrome, cardiomyopathy and cancer in humans. In order to obtain a first genomewide estimate of the extent and biological role of mutually exclusive splicing in humans, we predicted and subsequently validated mutually exclusive exons (MXEs) using 515 publically available RNA‐Seq datasets. Here, we provide evidence for the expression of over 855 MXEs, 42% of which represent novel exons, increasing the annotated human mutually exclusive exome more than fivefold. The data provide strong evidence for the existence of large and multi‐cluster MXEs in higher vertebrates and offer new insights into MXE evolution. More than 82% of the MXE clusters are conserved in mammals, and five clusters have homologous clusters in Drosophila. Finally, MXEs are significantly enriched in pathogenic mutations and their spatio‐temporal expression might predict human disease pathology.

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Alternative splicing of mutually exclusive exons—A review

Cited by 66 publications

References 115 publications

Effects of CYP3A4 polymorphisms on the plasma concentration of voriconazole

Effects of CYP3A4 polymorphisms on the plasma concentration of voriconazole

Evidence for widespread subfunctionalization of splice forms in vertebrate genomes

The landscape of human mutually exclusive splicing

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