57 research outputs found
Large introns in relation to alternative splicing and gene evolution: a case study of Drosophila bruno-3
Background:
Alternative splicing (AS) of maturing mRNA can generate structurally and functionally distinct transcripts from the same gene. Recent bioinformatic analyses of available genome databases inferred a positive correlation between intron length and AS. To study the interplay between intron length and AS empirically and in more detail, we analyzed the diversity of alternatively spliced transcripts (ASTs) in the Drosophila RNA-binding Bruno-3 (Bru-3) gene. This gene was known to encode thirteen exons separated by introns of diverse sizes, ranging from 71 to 41,973 nucleotides in D. melanogaster. Although Bru-3's structure is expected to be conducive to AS, only two ASTs of this gene were previously described.
Results:
Cloning of RT-PCR products of the entire ORF from four species representing three diverged Drosophila lineages provided an evolutionary perspective, high sensitivity, and long-range contiguity of splice choices currently unattainable by high-throughput methods. Consequently, we identified three new exons, a new exon fragment and thirty-three previously unknown ASTs of Bru-3. All exon-skipping events in the gene were mapped to the exons surrounded by introns of at least 800 nucleotides, whereas exons split by introns of less than 250 nucleotides were always spliced contiguously in mRNA. Cases of exon loss and creation during Bru-3 evolution in Drosophila were also localized within large introns. Notably, we identified a true de novo exon gain: exon 8 was created along the lineage of the obscura group from intronic sequence between cryptic splice sites conserved among all Drosophila species surveyed. Exon 8 was included in mature mRNA by the species representing all the major branches of the obscura group. To our knowledge, the origin of exon 8 is the first documented case of exonization of intronic sequence outside vertebrates.
Conclusion:
We found that large introns can promote AS via exon-skipping and exon turnover during evolution likely due to frequent errors in their removal from maturing mRNA. Large introns could be a reservoir of genetic diversity, because they have a greater number of mutable sites than short introns. Taken together, gene structure can constrain and/or promote gene evolution
Evaluation of personalised, one-to-one interaction using Montessori-type activities as a treatment of challenging behaviours in people with dementia: the study protocol of a crossover trial
Tropomyosin 1: multiple roles in the developing heart and in the formation of congenital heart defects
Tropomyosin 1 (TPM1) is an essential sarcomeric component, stabilising the thin filament and facilitating actin's interaction with myosin. A number of sarcomeric proteins, such as alpha myosin heavy chain, play crucial roles in cardiac development. Mutations in these genes have been linked to congenital heart defects (CHDs), occurring in approximately 1 in 145 live births. To date, TPM1 has not been associated with isolated CHDs. Analysis of 380 CHD cases revealed three novel mutations in the TPM1 gene; IVS1 + 2T > C, I130V, S229F and a polyadenylation signal site variant GATAAA/AATAAA. Analysis of IVS1 + 2T > C revealed aberrant pre-mRNA splicing. In addition, abnormal structural properties were found in hearts transfected with TPM1 carrying I130V and S229F mutations. Phenotypic analysis of TPM1 morpholino-treated embryos revealed roles for TPM1 in cardiac looping, atrial septation and ventricular trabeculae formation and increased apoptosis was seen within the heart. In addition, sarcomere assembly was affected and altered action potentials were exhibited. This study demonstrated that sarcomeric TPM1 plays vital roles in cardiogenesis and is a suitable candidate gene for screening individuals with isolated CHDs
Alleviating staff stress in care homes for people with dementia: protocol for stepped-wedge cluster randomised trial to evaluate a web-based Mindfulness- Stress Reduction course
Phylogenetic Distribution of Intron Positions in Alpha-Amylase Genes of Bilateria Suggests Numerous Gains and Losses
Most eukaryotes have at least some genes interrupted by introns. While it is well
accepted that introns were already present at moderate density in the last
eukaryote common ancestor, the conspicuous diversity of intron density among
genomes suggests a complex evolutionary history, with marked differences between
phyla. The question of the rates of intron gains and loss in the course of
evolution and factors influencing them remains controversial. We have
investigated a single gene family, alpha-amylase, in 55 species covering a
variety of animal phyla. Comparison of intron positions across phyla suggests a
complex history, with a likely ancestral intronless gene undergoing frequent
intron loss and gain, leading to extant intron/exon structures that are highly
variable, even among species from the same phylum. Because introns are known to
play no regulatory role in this gene and there is no alternative splicing, the
structural differences may be interpreted more easily: intron positions, sizes,
losses or gains may be more likely related to factors linked to splicing
mechanisms and requirements, and to recognition of introns and exons, or to more
extrinsic factors, such as life cycle and population size. We have shown that
intron losses outnumbered gains in recent periods, but that “resets”
of intron positions occurred at the origin of several phyla, including
vertebrates. Rates of gain and loss appear to be positively correlated. No phase
preference was found. We also found evidence for parallel gains and for intron
sliding. Presence of introns at given positions was correlated to a strong
protosplice consensus sequence AG/G, which was much weaker in the absence of
intron. In contrast, recent intron insertions were not associated with a
specific sequence. In animal Amy genes, population size and
generation time seem to have played only minor roles in shaping gene
structures
The management of acute venous thromboembolism in clinical practice. Results from the European PREFER in VTE Registry
Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in Europe. Data from real-world registries are necessary, as clinical trials do not represent the full spectrum of VTE patients seen in clinical practice. We aimed to document the epidemiology, management and outcomes of VTE using data from a large, observational database. PREFER in VTE was an international, non-interventional disease registry conducted between January 2013 and July 2015 in primary and secondary care across seven European countries. Consecutive patients with acute VTE were documented and followed up over 12 months. PREFER in VTE included 3,455 patients with a mean age of 60.8 ± 17.0 years. Overall, 53.0 % were male. The majority of patients were assessed in the hospital setting as inpatients or outpatients (78.5 %). The diagnosis was deep-vein thrombosis (DVT) in 59.5 % and pulmonary embolism (PE) in 40.5 %. The most common comorbidities were the various types of cardiovascular disease (excluding hypertension; 45.5 %), hypertension (42.3 %) and dyslipidaemia (21.1 %). Following the index VTE, a large proportion of patients received initial therapy with heparin (73.2 %), almost half received a vitamin K antagonist (48.7 %) and nearly a quarter received a DOAC (24.5 %). Almost a quarter of all presentations were for recurrent VTE, with >80 % of previous episodes having occurred more than 12 months prior to baseline. In conclusion, PREFER in VTE has provided contemporary insights into VTE patients and their real-world management, including their baseline characteristics, risk factors, disease history, symptoms and signs, initial therapy and outcomes
Correction to: Cluster identification, selection, and description in Cluster randomized crossover trials: the PREP-IT trials
An amendment to this paper has been published and can be accessed via the original article
- …