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In addition, to explore how sQTLs overlap motifs of RNA-binding proteins, we retrieved a set of motifs bound, in vitro, by 81 human splicing factors and RNA-binding proteins We then kept a single motif per protein, giving priority to the motif with the highest information content, and used Homer 79 to scan the reference genome sequence for these motifs. Namely, we used findMotifsGenome. To identify shared genetic control of splicing and gene expression, we considered for each sQTL, the levels of LD r 2 , computed across both populations, between the sQTLs and eQTLs detected for the same gene and condition, as a measure of the colocalization between the genetic determinants of splicing and gene expression.
Causal relationships between splicing and expression changes observed at sQTLs were assessed using a two-step approach and a modified version of the Likelihood-based Causal Model Selection Framework described in 44 Supplementary Note 3 ; Supplementary Fig. Using this criterion, we estimate that 5. After excluding nonspecific EFO categories i. For genes that are differentially spliced between populations and harbour a sQTL, we evaluated the fraction of population differences in splicing that are attributable to the sQTL, using the mediate function from the mediation R package To detect signatures of population-specific natural selection, we used two metrics, F ST and iHS, which detect signals of local adaptation.
F ST quantifies the variance of allele frequencies within and between populations to detect outlier values of population differentiation 58 , which may result from the action of positive selection in one specific population. The iHS 59 compares the degree of extended haplotype homozygosity of the derived and ancestral alleles, allowing to identify differences in haplotype length between alleles that can result from the rapid increase in frequency of the putatively selected allele.
Indeed, it has been shown that searching for the occurrence of local enrichments in outliers increases the rate of true selected loci among genome-wide outliers Enrichment p -values were calculated by counting the frequency at which the number of tag-aSNPs in our resampled sets of SNPs exceeded the number of tag-aSNPs observed in our data.
To assess the robustness of our enrichment analyses to changes in the definition of Neanderthal haplotypes, we repeated the resampling with more stringent definitions of archaic haplotypes i. Further information on experimental design is available in the Nature Research Reporting Summary linked to this article.
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Montgomery, S. Transcriptome genetics using second generation sequencing in a Caucasian population. Battle, A. Characterizing the genetic basis of transcriptome diversity through RNA-sequencing of individuals. Gutierrez-Arcelus, M. Tissue-specific effects of genetic and epigenetic variation on gene regulation and splicing. Cheung, R. A multiplexed assay for exon recognition reveals that an unappreciated fraction of rare genetic variants cause large-effect splicing disruptions.
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Immunol Rev 1 — Originally published December 28, Reviewed and updated by Zandile Nare August Has this helped you?
Then please share with your network. Alternative splicing occurs only in eukaryotes. Facebook Twitter LinkedIn More. Written by Yevgeniy Grigoryev. Dr Amanda Welch on May 2, at pm. Taken together, functional coupling appears to maintain an important role in alternative splicing in driving determinative physiological changes, and fine-tune gene expression in mathematical modeling approaches Two models have been suggested to explain the co-transcription process of how transcription coupled repair influences alternative splicing.
The mechanism of the recruitment model may mainly depend on specific features of CTD as mentioned above , whereas the kinetic model is based on the different elongation rates of Pol II, which in turn determine the timing of the presentation of splices sites 47 , Fundamentally, the aforementioned mechanism influences patterns of alternative splicing via the variations in Pol II elongation and recruitment of splicing factors by specific histone marks Thus, alternative splicing is highly influenced not only by transcription, but also by the chromatin structure, which underscores chromatin as another layer in the regulation of alternative splicing.
The resultant mature mRNA is thus a reflection of numerous DNA modifications, such as patterns of histone methylation at exons, modulation of histone modifications and increased DNA methylation at exons 50 , Conversely, a previous study indicated that splicing may mediate chromatin remodeling via deposition of histone marks on DNA or numerous associations between splicing factors and elongation proteins Adding additional complexity to the regulation network is alternative transcription initiation ATI and alternative transcription termination ATT sites.
ATI and ATT significantly contribute to the diversity of the human and mouse transcriptomes to a degree that may exceed alternative splicing, when considering the number of possibilities available through alternative nucleotides, isoforms and introns 52 , By contrast, alternative splicing associated alterations mostly lie within the protein sequence, potentially affecting almost all areas of protein function 14 , NMD is an extensive and complicated mechanism, ranging from yeast to human, exploited to achieve another level of robustness in post-transcriptional gene expression control.
Furthermore, analysis of quantitative alternative splicing microarray profiling has demonstrated that individual knockdown of NMD factors [Up-Frameshift UPF ] strongly affects PTC-introducing alternative splicing events, indicating a role for different UPF factor requirements in alternative splicing regulation In a second example, regulation of intron retention by alternative splicing-NMD in a specific differentiation event has been recently observed Trans-splicing is a common phenomenon in trypanosomes, nematodes, Drosophila and even humans, and refers to the novel and unusual splicing of exons from independent pre-mRNAs 62 , The phenomenon has been explored as a therapeutic option for a variety of genetic diseases, particularly in the treatment of cancer The carcinoembryonic antigen CEA , for example, is associated with a variety of neoplastic processes and was exploited as a target for trans-splicing.
The activity of the ribozyme simultaneously reduced CEA expression and introduced the thymidine kinase gene, which rendered the cells sensitive to ganciclovir treatment.
RNA trans-splicing has also been utilized for the potential treatment of neurodegenerative diseases through a novel technology, spliceosome mediated trans-splicing SMaRT. SMaRT was successfully used in vivo to re-engineer tau mRNA transcripts to include E10, and therefore, offers the opportunity potential to correct tau mis-splicing and treat the underlying disease Non-coding RNAs ncRNAs , including microRNA and small interfering RNA, have recently emerged as novel regulators in alternative splicing, generally through the modulation of the expression of key splicing factors during development and differentiation Stringent regulation of alternative splicing is necessary for the functional requirements of complex tissues under normal conditions, whereas aberrant splicing appears to an underlying cause for an extremely high fraction of dysfunction and disease Aberrant splicing has been suggested to root in alterations of the cellular concentration, composition, localization and activity of regulatory splicing factors, as well as mutations in components of core splicing machinery A changed efficiency of splice site recognition is the immediate consequence, while irregularities in protein isoforms in different systems ultimately establish the disease state.
Any of these alterations affecting alternative splicing can facilitate the appearance of characteristics in cancer cells, including the inappropriate proliferation, migration, methylation changes and resistance to apoptosis and chemotherapy Alternative splicing has been implicated in nearly all aspects of cancer development, and therefore, is a main participant in the disease.
Understanding the basic mechanisms and patterns of splicing in tumor progress will shed light on the biology of cancer and lay the foundation for diagnostic, prognostic and therapeutic tools with minimum treatment toxicity in cancer Extensive research efforts have already committed to developing drugs that target specific cancer protein isoforms.
However, limited success has been achieved by simply activating or inhibiting cancer-associated genes, possibly due to the expression of target genes in normal and cancers cells, such as angiogenic and anti-angiogenic isoforms The lack of specificity of numerous molecular targets for cancer cells favors the development of isoform-specific diagnostic markers as therapeutic targets Therefore, the key task for cancer treatment in the future should be to detect and target the expression of a gene at the gene level.
The combination of an alternative splicing database, tandem mass spectrometry, and even the latest synthetic alternative splicing database may aid with the identification, analysis and characterization of potential alternative splicing isoforms.
Alternative splicing appears to be prevalent in almost all multi-exon genes. All these deficiencies lead to an incomplete understanding of the alternative splicing mechanism and may prevent the correct prediction of splice events in other species, such as the chimpanzee or plant 77 , Distinguishing alternative splicing from other regulatory mechanisms in the gene regulation is also difficult.
Alternative splicing, alternative trans-splicing, NMD, transcriptional efficiency, exon duplication and RNA editing 79 all contribute to an extensive mechanism for generating protein diversity. In addition, the difference between artificial experimental systems and real-life scenarios makes it challenging to transfer functional studies from cells to whole organisms.
Numerous questions remain regarding the global impact of alternative splicing on cellular and organismal homeostasis, as well as its underlying molecular mechanisms. Finally, with regards to cancer-associated alternative splicing, whether a particular splice site selection causes the observed effect or is merely the result of the cancerous transformation is hard to distinguish.
The data collected regarding alternative splicing is likely to represent only the tip of the iceberg, with further information yet to be revealed in future studies.
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