171 research outputs found
The importance of being divisible by three in alternative splicing
Alternative splicing events that are conserved in orthologous genes in different species are commonly viewed as reliable evidence of authentic, functionally significant alternative splicing events. Several recent bioinformatic analyses have shown that conserved alternative exons possess several features that distinguish them from alternative exons that are species-specific. One of the most striking differences between conserved and species-specific alternative exons is the high percentage of exons that preserve the reading frame (exons whose length is an exact multiple of 3, termed symmetrical exons) among the conserved alternative exons. Here, we examined conserved alternative exons and found several features that differentiate between symmetrical and non-symmetrical alternative exons. We show that symmetrical alternative exons have a strong tendency not to disrupt protein domain structures, whereas the tendency of non-symmetrical alternative exons to overlap with different fractions of protein domains is similar to that of constitutive exons. Additionally, skipping isoforms of non-symmetrical alternative exons are strongly underrepresented, compared with their including isoforms, suggesting that skipping of a large fraction of non-symmetrical alternative exons produces transcripts that are degraded by the nonsense-mediated mRNA decay mechanism. Non-symmetrical alternative exons also show a tendency to reside in the 5′ half of the CDS. These findings suggest that alternative splicing of symmetrical and non-symmetrical exons is governed by different selective pressures and serves different purposes
Transduplication resulted in the incorporation of two protein-coding sequences into the Turmoil-1 transposable element of C. elegans
Transposable elements may acquire unrelated gene fragments into their
sequences in a process called transduplication. Transduplication of
protein-coding genes is common in plants, but is unknown of in animals. Here,
we report that the Turmoil-1 transposable element in C. elegans has
incorporated two protein-coding sequences into its inverted terminal repeat
(ITR) sequences. The ITRs of Turmoil-1 contain a conserved RNA recognition
motif (RRM) that originated from the rsp- 2 gene and a fragment from the
protein-coding region of the cpg-3 gene. We further report that an open reading
frame specific to C. elegans may have been created as a result of a Turmoil-1
insertion. Mutations at the 5' splice site of this open reading frame may have
reactivated the transduplicated RRM moti
SERpredict: Detection of tissue- or tumor-specific isoforms generated through exonization of transposable elements
Background: Transposed elements (TEs) are known to affect transcriptomes,
because either new exons are generated from intronic transposed elements (this
is called exonization), or the element inserts into the exon, leading to a new
transcript. Several examples in the literature show that isoforms generated by
an exonization are specific to a certain tissue (for example the heart muscle)
or inflict a disease. Thus, exonizations can have negative effects for the
transcriptome of an organism. Results: As we aimed at detecting other tissue-
or tumor-specific isoforms in human and mouse genomes which were generated
through exonization of a transposed element, we designed the automated analysis
pipeline SERpredict (SER = Specific Exonized Retroelement) making use of
Bayesian Statistics. With this pipeline, we found several genes in which a
transposed element formed a tissue- or tumor-specific isoform. Conclusion: Our
results show that SERpredict produces relevant results, demonstrating the
importance of transposed elements in shaping both the human and the mouse
transcriptomes. The effect of transposed elements on the human transcriptome is
several times higher than the effect on the mouse transcriptome, due to the
contribution of the primate-specific Alu element
TEs or not TEs? That is the evolutionary question
Transposable elements (TEs) have contributed a wide range of functional sequences to their host genomes. A recent paper in BMC Molecular Biology discusses the creation of new transcripts by transposable element insertion upstream of retrocopies and the involvement of such insertions in tissue-specific post-transcriptional regulation
The role of transposable elements in the evolution of non-mammalian vertebrates and invertebrates
Background: Transposable elements (TEs) have played an important role in the diversification and enrichment of mammalian transcriptomes through various mechanisms such as exonization and intronization (the birth of new exons/introns from previously intronic/exonic sequences, respectively), and insertion into first and last exons. However, no extensive analysis has compared the effects of TEs on the transcriptomes of mammals, non-mammalian vertebrates and invertebrates. Results: We analyzed the influence of TEs on the transcriptomes of five species, three invertebrates and two non-mammalian vertebrates. Compared to previously analyzed mammals, there were lower levels of TE introduction into introns, significantly lower numbers of exonizations originating from TEs and a lower percentage of TE insertion within the first and last exons. Although the transcriptomes of vertebrates exhibit significant levels of exonization of TEs, only anecdotal cases were found in invertebrates. In vertebrates, as in mammals, the exonized TEs are mostly alternatively spliced, indicating that selective pressure maintains the original mRNA product generated from such genes. Conclusions: Exonization of TEs is widespread in mammals, less so in non-mammalian vertebrates, and very low in invertebrates. We assume that the exonization process depends on the length of introns. Vertebrates, unlike invertebrates, are characterized by long introns and short internal exons. Our results suggest that there is a direct link between the length of introns and exonization of TEs and that this process became more prevalent following the appearance of mammals
The Emergence of Alternative 3′ and 5′ Splice Site Exons from Constitutive Exons
Alternative 3′ and 5′ splice site (ss) events constitute a significant part of all alternative splicing events. These events were also found to be related to several aberrant splicing diseases. However, only few of the characteristics that distinguish these events from alternative cassette exons are known currently. In this study, we compared the characteristics of constitutive exons, alternative cassette exons, and alternative 3′ss and 5′ss exons. The results revealed that alternative 3′ss and 5′ss exons are an intermediate state between constitutive and alternative cassette exons, where the constitutive side resembles constitutive exons, and the alternative side resembles alternative cassette exons. The results also show that alternative 3′ss and 5′ss exons exhibit low levels of symmetry (frame-preserving), similar to constitutive exons, whereas the sequence between the two alternative splice sites shows high symmetry levels, similar to alternative cassette exons. In addition, flanking intronic conservation analysis revealed that exons whose alternative splice sites are at least nine nucleotides apart show a high conservation level, indicating intronic participation in the regulation of their splicing, whereas exons whose alternative splice sites are fewer than nine nucleotides apart show a low conservation level. Further examination of these exons, spanning seven vertebrate species, suggests an evolutionary model in which the alternative state is a derivative of an ancestral constitutive exon, where a mutation inside the exon or along the flanking intron resulted in the creation of a new splice site that competes with the original one, leading to alternative splice site selection. This model was validated experimentally on four exons, showing that they indeed originated from constitutive exons that acquired a new competing splice site during evolution
Comparative analysis of transposed element insertion within human and mouse genomes reveals Alu's unique role in shaping the human transcriptome
Background: Transposed elements (TEs) have a substantial impact on mammalian
evolution and are involved in numerous genetic diseases. We compared the impact
of TEs on the human transcriptome and the mouse transcriptome. Results: We
compiled a dataset of all TEs in the human and mouse genomes, identifying
3,932,058 and 3,122,416 TEs, respectively. We than extracted TEs located within
human and mouse genes and, surprisingly, we found that 60% of TEs in both human
and mouse are located in intronic sequences, even though introns comprise only
24% of the human genome. All TE families in both human and mouse can exonize.
TE families that are shared between human and mouse exhibit the same percentage
of TE exonization in the two species, but the exonization level of Alu, a
primatespecific retroelement, is significantly greater than that of other TEs
within the human genome, leading to a higher level of TE exonization in human
than in mouse (1,824 exons compared with 506 exons, respectively). We detected
a primate-specific mechanism for intron gain, in which Alu insertion into an
exon creates a new intron located in the 3' untranslated region (termed
'intronization'). Finally, the insertion of TEs into the first and last exons
of a gene is more frequent in human than in mouse, leading to longer exons in
human. Conclusion: Our findings reveal many effects of TEs on these two
transcriptomes. These effects are substantially greater in human than in mouse,
which is due to the presence of Alu elements in human
Evolution of Nova-dependent splicing regulation in the brain
A large number of alternative exons are spliced with tissue-specific patterns, but little is known about how such patterns have evolved. Here, we study the conservation of the neuron-specific splicing factors Nova1 and Nova2 and of the alternatively spliced exons they regulate in mouse brain. Whereas Nova RNA binding domains are 94% identical across vertebrate species, Nova-dependent splicing silencer and enhancer elements (YCAY clusters) show much greater divergence, as less than 50% of mouse YCAY clusters are conserved at orthologous positions in the zebrafish genome. To study the relation between the evolution of tissue-specific splicing and YCAY clusters, we compared the brain-specific splicing of Nova-regulated exons in zebrafish, chicken, and mouse. The presence of YCAY clusters in lower vertebrates invariably predicted conservation of brain-specific splicing across species, whereas their absence in lower vertebrates correlated with a loss of alternative splicing. We hypothesize that evolution of Nova-regulated splicing in higher vertebrates proceeds mainly through changes in cis-acting elements, that tissue-specific splicing might in some cases evolve in a single step corresponding to evolution of a YCAY cluster, and that the conservation level of YCAY clusters relates to the functions encoded by the regulated RNAs
A network-based method for associating genes with autism spectrum disorder
Autism spectrum disorder (ASD) is a highly heritable complex disease that affects 1% of the population, yet its underlying molecular mechanisms are largely unknown. Here we study the problem of predicting causal genes for ASD by combining genome-scale data with a network propagation approach. We construct a predictor that integrates multiple omic data sets that assess genomic, transcriptomic, proteomic, and phosphoproteomic associations with ASD. In cross validation our predictor yields mean area under the ROC curve of 0.87 and area under the precision-recall curve of 0.89. We further show that it outperforms previous gene-level predictors of autism association. Finally, we show that we can use the model to predict genes associated with Schizophrenia which is known to share genetic components with ASD
- …