Convergent evolution of twintron-like configurations: One is never enough

Hafez, M. B.; Hausner, Georg

doi:10.1080/15476286.2015.1103427

Cited by 26 publications

(30 citation statements)

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“…We also observed several occurrences of U12/U2 splice site switching. Alternative splicing of U12-type introns using U2 cryptic donor and acceptor sites, originally described in insects (for review, see Hafez and Hausner 2015), had already been reported in human cells as the result of U6atac snRNA inactivation (Younis et al 2013), knockdown of the 48K protein (Turunen et al 2008), and in the context of isolated familial growth hormone deficiency (Argente et al 2014), and myelodysplastic syndrome (Madan et al 2015). However, this is the first time that such alternative splicing events are found to occur physiologically in humans.…”

Section: Discussionmentioning

confidence: 88%

“…Most interestingly, we also found U12-type introns for which nearby U2 splice site(s) were sometimes favored over U12 splice site(s), probably in the context, in most cases, of a switch from the minor to the major spliceosome for splicing the intron. This phenomenon was first described for the D. melanogaster prospero gene (Scamborova et al 2004); lately, the existence of these introns called U2/U12-type twintrons was extended to several other U12 genes in different species, including humans (for review, see Hafez and Hausner 2015). We identified 21 of such alternative events comprising or not the skipping of an exon in 16 U12 genes.…”

Section: U12/u2 Splice Site Switchingmentioning

confidence: 81%

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New insights into minor splicing—a transcriptomic analysis of cells derived from TALS patients

Cologne

Benoit‐Pilven

Besson

et al. 2019

RNA

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et al.. New insights into minor splicing-a transcriptomic analysis of cells derived from TALS patients. RNA, Cold Spring Harbor Laboratory Press, 2019, pp.ABSTRACT Minor intron splicing plays a central role in human embryonic development and survival. Indeed, biallelic mutations in RNU4ATAC, transcribed into the minor spliceosomal U4atac snRNA, are responsible for three rare autosomal recessive multimalformation disorders named Taybi-Linder (TALS/MOPD1), Roifman (RFMN), and Lowry-Wood (LWS) syndromes, which associate numerous overlapping signs of varying severity. Although RNA-seq experiments have been conducted on a few RFMN patient cells, none have been performed in TALS, and more generally no in-depth transcriptomic analysis of the ∼700 human genes containing a minor (U12-type) intron had been published as yet. We thus sequenced RNA from cells derived from five skin, three amniotic fluid, and one blood biosamples obtained from seven unrelated TALS cases and from age-and sex-matched controls. This allowed us to describe for the first time the mRNA expression and splicing profile of genes containing U12-type introns, in the context of a functional minor spliceosome. Concerning RNU4ATAC-mutated patients, we show that as expected, they display distinct U12-type intron splicing profiles compared to controls, but that rather unexpectedly mRNA expression levels are mostly unchanged. Furthermore, although U12-type intron missplicing concerns most of the expressed U12 genes, the level of U12-type intron retention is surprisingly low in fibroblasts and amniocytes, and much more pronounced in blood cells. Interestingly, we found several occurrences of introns that can be spliced using either U2, U12, or a combination of both types of splice site consensus sequences, with a shift towards splicing using preferentially U2 sites in TALS patients' cells compared to controls. Global mRNA expression levels of U12 genes in control cell typesTo date, despite the large number of transcriptomic studies performed in human tissues and cell types, the spatial Cologne et al.

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Section: Discussionmentioning

confidence: 88%

Section: U12/u2 Splice Site Switchingmentioning

confidence: 81%

New insights into minor splicing—a transcriptomic analysis of cells derived from TALS patients

Cologne

Benoit‐Pilven

Besson

et al. 2019

RNA

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“…Control PPCs also show a small percentage (2.9%) of mRNAs containing PE1 or PE1-PE2. Interestingly, the SDS of PE1 also can be employed as a SAS which, in theory could render this intronic SAS/SDS a target for recursive splicing (Hafez and Hausner 2015). Together, these findings suggest that there is a 'natural sensitivity' for PE1 to be recognized as a PE even if the splice defect is located far downstream.…”

Section: Current State Of Knowledge On Deep-intronic Variants In Abca4mentioning

confidence: 92%

Resolving the dark matter of ABCA4 for 1,054 Stargardt disease probands through integrated genomics and transcriptomics

Khan¹,

Cornelis²,

Pozo‐Valero³

et al. 2019

Preprint

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Missing heritability in human diseases represents a major challenge. Although whole-genome sequencing enables the analysis of coding and non-coding sequences, substantial costs and data storage requirements hamper its large-scale use to (re)sequence genes in genetically unsolved cases.The ABCA4 gene implicated in Stargardt disease (STGD1) has been studied extensively for 22 years, but thousands of cases remained unsolved. Therefore, single molecule molecular inversion probes were designed that enabled an automated and cost-effective sequence analysis of the complete 128-kb ABCA4 gene. Analysis of 1,054 unsolved STGD and STGD-like probands resulted in bi-allelic variations in 448 probands. Twenty-seven different causal deep-intronic variants were identified in 117 alleles. Based on in vitro splice assays, the 13 novel causal deep-intronic variants were found to result in pseudo-exon (PE) insertions (n=10) or exon elongations (n=3). Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions that were accompanied by flanking exon deletions. Structural variant analysis revealed 11 distinct deletions, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband. Integrated complete gene sequencing combined with transcript analysis, identified pathogenic deep-intronic and structural variants in 26% of bi-allelic cases not solved previously by sequencing of coding regions. This strategy serves as a model study that can be applied to other inherited diseases in which only one or a few genes are involved in the majority of cases.

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“…The strict definition of a twintron, as defined for example by Hafez and Hausner (2015), is an embedded arrangement where the inner intron must be removed first to allow formation of the correct structure that catalyzes removal of the outer intron. In many of the Euglena twintron arrangements the insertion site of the inner intron is in domain V or VI of a group II intron, insertion positions that would be predicted to disrupt the tertiary structure required for outer intron removal in other well-studied group II introns.…”

Section: Chloroplast Intronsmentioning

confidence: 99%

Euglena Transcript Processing

McWatters

Russell

2017

Advances in Experimental Medicine and Biology

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RNA transcript processing is an important stage in the gene expression pathway of all organisms and is subject to various mechanisms of control that influence the final levels of gene products. RNA processing involves events such as nuclease-mediated cleavage, removal of intervening sequences referred to as introns and modifications to RNA structure (nucleoside modification and editing). In Euglena, RNA transcript processing was initially examined in chloroplasts because of historical interest in the secondary endosymbiotic origin of this organelle in this organism. More recent efforts to examine mitochondrial genome structure and RNA maturation have been stimulated by the discovery of unusual processing pathways in other Euglenozoans such as kinetoplastids and diplonemids. Eukaryotes containing large genomes are now known to typically contain large collections of introns and regulatory RNAs involved in RNA processing events, and Euglena gracilis in particular has a relatively large genome for a protist. Studies examining the structure of nuclear genes and the mechanisms involved in nuclear RNA processing have revealed that indeed Euglena contains large numbers of introns in the limited set of genes so far examined and also possesses large numbers of specific classes of regulatory and processing RNAs, such as small nucleolar RNAs (snoRNAs). Most interestingly, these studies have also revealed that Euglena possesses novel processing pathways generating highly fragmented cytosolic ribosomal RNAs and subunits and non-conventional intron classes removed by unknown splicing mechanisms. This unexpected diversity in RNA processing pathways emphasizes the importance of identifying the components involved in these processing mechanisms and their evolutionary emergence in Euglena species.

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Convergent evolution of twintron-like configurations: One is never enough

Cited by 26 publications

References 123 publications

New insights into minor splicing—a transcriptomic analysis of cells derived from TALS patients

New insights into minor splicing—a transcriptomic analysis of cells derived from TALS patients

Resolving the dark matter of ABCA4 for 1,054 Stargardt disease probands through integrated genomics and transcriptomics

Euglena Transcript Processing

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