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PubMed2003

Cis-acting intronic elements that regulate cartilage-specific alternative splicing of the type II collagen (Col2) pre-mRNA lie at or near splice site junction sequences flanking exon 2 of the gene.

UNLABELLED: Knowledge of the cis-acting elements is required for identifying trans-acting splicing factors underlying cartilage-specific alternative splicing of Col2 pre-mRNA. By performing desired deletions in the mouse Col2 pre-mRNA, location of the intronic cis-acting elements was narrowed down to be at or near splice-junction sequences flanking exon 2 of the gene. INTRODUCTION: Type II collagen (Col2) pre-mRNA undergoes cartilage-specific alternative splicing involving exon 2 during chondrocyte differentiation. Thus, the trans-acting protein factors that regulate the splicing are associated with the differentiation of chondrocytes. Knowledge of the cognate cis-acting elements is necessary to eventually identify the trans-acting factors. MATERIALS AND METHODS: To localize the cis-acting sequences, we created several deletions within a minigene containing exon 1 to exon 4 of mouse Col 2 gene and evaluated alternative splicing of the resulting pre-mRNAs in ATDC5 cells, a model of insulin-stimulated chondrocyte differentiation. The first deletion reduced intron 1 from 3799 to 259 bp, the second reduced intron 2 from 1108 to 94 bp, the third combined the above two deletions, and the fourth was derived from the third by removing intron 3 and exon 4. ATDC5 cells harboring these constructs were cultured for up to 21 days with or without insulin. Alternative splicing was evaluated by determining the ratio of Col2B (lacks exon 2) to Col2A (has exon 2) RNAs by reverse transcription-polymerase chain reaction. RESULTS: The deletion in intron 1 had no effect on the alternative splicing while other deletions affected splicing (demonstrated by the presence of splicing intermediates) in cells cultured without insulin or with insulin for 1 week. The splicing intermediates were not seen from any construct when cells were cultured longer (14-21 days) with insulin. CONCLUSION: These results show that the 259-bp intron 1, the 94-bp intron 2, and exon 2 sequences retained in the fourth construct provide cis-acting signal sufficient for insulin-induced cartilage-specific alternative splicing of Col2 pre-mRNA.

Alternative Splicing↗

PubMed2006

Unusual intron conservation near tissue-regulated exons found by splicing microarrays.

Alternative splicing contributes to both gene regulation and protein diversity. To discover broad relationships between regulation of alternative splicing and sequence conservation, we applied a systems approach, using oligonucleotide microarrays designed to capture splicing information across the mouse genome. In a set of 22 adult tissues, we observe differential expression of RNA containing at least two alternative splice junctions for about 40% of the 6,216 alternative events we could detect. Statistical comparisons identify 171 cassette exons whose inclusion or skipping is different in brain relative to other tissues and another 28 exons whose splicing is different in muscle. A subset of these exons is associated with unusual blocks of intron sequence whose conservation in vertebrates rivals that of protein-coding exons. By focusing on sets of exons with similar regulatory patterns, we have identified new sequence motifs implicated in brain and muscle splicing regulation. Of note is a motif that is strikingly similar to the branchpoint consensus but is located downstream of the 5' splice site of exons included in muscle. Analysis of three paralogous membrane-associated guanylate kinase genes reveals that each contains a paralogous tissue-regulated exon with a similar tissue inclusion pattern. While the intron sequences flanking these exons remain highly conserved among mammalian orthologs, the paralogous flanking intron sequences have diverged considerably, suggesting unusually complex evolution of the regulation of alternative splicing in multigene families.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Remodeling of the neuromuscular junction in mice with deleted exons 5 and 6 of acetylcholinesterase.

At the vertebrate skeletal neuromuscular junction (NMJ), two closely related enzymes can hydrolyze acetylcholine (ACh): acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Advances in mouse genomics offer new approaches to assess the role of specific cholinesterases involved in neuromuscular transmission (Minic et al., 2003). AChE knockout mice provide a valuable tool for examining the effects of long-term complete and selective abolition of AChE activity (Xie et al., 2000). AChE and BChE genes encode two functional domains--the catalytic domain (exons 2, 3, and 4 of AChE, or exon 2 of BChE) and a C-terminal domain (exon 5 or 6 of AChE, or exon 3 of BChE)--that dictate the targeting of the enzymes (Massoulié, 2002). In mammals, the AChE gene produces three types of coding regions by deleting 5'- splice acceptor sites, which generate proteins; these proteins possess the same catalytic domain associated with distinct C-terminal peptides. AChE subunits of type R (readthrough) produce soluble monomers; they are expressed during development and are thought to be induced in the mouse brain by stress (Kaufer et al., 1998). AChE subunits of type H (hydrophobic) produce GPI-anchored dimers, mainly in blood cells. Subunits of type T (tailed) exist for both AChE and BChE. They represent the predominant AChE variant expressed in cholinergically innervated tissues (muscle and nerve). These subunits generate a variety of quaternary structures, including homomeric oligomers (monomers, dimers, tetramers), as well as hetero-oligomeric assemblies with anchoring proteins ColQ (Krejci et al., 1997) and PRiMA (Perrier et al., 2002). At the NMJ, AChE is clustered by the interaction of the coding sequence of exon 6 with ColQ (Feng et al., 1999). The deletion of exons 5 and 6 in the AChE gene transforms anchored AChE into a soluble enzyme (Camp et al., 2004). The present study was designed to evaluate neuromuscular transmission and nicotinic ACh receptor (nAChR) distribution in muscles from mutant mice with deletions of these two spliced exons (AChE-del-exons-5+6-/-).

Acetylcholinesterase↗

PubMed1999

Selective amplification of exons 3 and 8 of the human growth hormone receptor (hGHR) gene based on newly identified intron sequences.

The gene for human growth hormone receptor (hGHR) consists of at least 10 exons, and the corresponding protein is encoded in exons 2-10 which span at least 87 kbp of chromosome 5. Failure to amplify exons 3 and 8 of the hGHR gene from Japanese subjects with the previously reported primers prompted us to determine intron sequences flanking exon 3 and those flanking exon 8 of the hGHR gene, and novel intron sequences flanking exons 3 and 8 of the hGHR gene were identified. We designed new oligonucleotide primers based on these sequences, and successfully amplified DNA fragments encompassing exon 3 and those encompassing exon 8 of the hGHR gene. Since all of the 50 Japanese and the two Caucasians had the very same intron sequences which were different from the previously reported ones, it is more likely that the previously reported sequences were simply wrong than that there exist polymorphic differences in the intron sequences among different ethnic populations.

Asian People↗

PubMed1999

Quantitative differences between aberrant transcripts which occur as common isoforms and due to mutation-based exon skipping of the mismatch repair gene hMLH1.

About one-third of hereditary non-polyposis colorectal cancer-related mutations in the mismatch repair gene hMLH1 result in the loss of entire exons from the wild type transcripts. Here we describe quantitative differences of hMLH1 transcripts without exon 15, exon 16 or exon 17 in several members of a family with hereditary non-polyposis colorectal cancer. The transcript lacking exon 15 is caused by a G to A transition affecting the last nucleotide of the respective exon and results in a truncated protein. The transcripts lacking exon 16 or exon 17, which are in-frame deletions, were also found in all tested samples of a normal population and represent common isoforms. Reverse transcription-polymerase chain reaction-based relative quantification revealed about 50 % signal intensity for the mutation-based transcript, but less than 10% for the common isoforms, if compared to the wild type. All aberrant transcripts were detected from blood-derived cDNAs but not from samples of normal colon epithelium. Although the biological significance of the common isoforms is unknown, they might lead to false risk assessment in hereditary non-polyposis colorectal cancer cases.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Association between the GH receptor/exon 3 genotype and the level of exon 3-positive GH-binding protein in human serum.

OBJECTIVE: The human GH-binding protein (GHBP) is derived from the GH receptor (GHR) through proteolytic cleavage of its extracellular domain. Two isoforms of the GHBP exist, differing in the retention or exclusion of exon 3: E3(+)GHBP and E3(-)GHBP. Our study aimed to answer the questions whether the level of E3(+)GHBP in the serum correlates with the GHR exon 3 expression and whether or not the E3 genotype matches the mRNA expression pattern. METHODS: Since exon 3 retention/deletion can be detected at the protein level using epitope-specific antibodies, we were able to quantify the two isoforms by means of specific immunoassays in a total of 37 individuals. Additionally, these persons were also genotyped for exon 3 by genomic PCR and tested for GHR exon 3 mRNA expression by RT-PCR. RESULTS: We found a significant correlation between GHR exon 3 genotype and the ratio of E3(+)GHBP and E3(-)GHBP in the serum. Moreover, the genotype matched exactly the mRNA expression in fibroblasts and/or blood leukocytes in all samples investigated. The levels of E3(+)GHBP are more strongly correlated with body mass index, proinsulin and C-peptide than the levels of the E3(-) isoform. CONCLUSIONS: Our results show that the GHR exon 3 genotype is in accord with the type of GHBP isoforms found in the serum. Our data thus support the idea that the presence of exon 3-retaining and -excluding GHR/GHBP isoforms results from a genomic deletion rather than from alternative splicing.

Adolescent↗

PubMed2001

Simulation of exon deletion mutations induced by low-LET radiation at the HPRT locus.

Friedland, W., Li, W. B., Jacob, P. and Paretzke, H. G. Simulation of Exon Deletion Mutations Induced by Low-LET Radiation at the HPRT Locus. Radiat. Res. 155, 703-715 (2001). The induction of HPRT mutants with exon deletions after irradiation with photons was simulated using the biophysical radiation track structure model PARTRAC. The exon-intron structure of the human HPRT gene was incorporated into the chromatin fiber model in PARTRAC. After gamma and X irradiation, simulated double-stranded DNA fragments that overlapped with exons were assumed to result in exon deletion mutations with a probability that depended on the genomic or the geometric distance between the breakpoints. The consequences of different assumptions about this probability of deletion formation were evaluated on the basis of the resulting fractions of total, terminal and intragenic deletions. Agreement with corresponding measurements was obtained assuming a constant probability of deletion formation for fragments smaller than about 0.1 Mbp, and a probability of deletion formation decreasing with increasing geometric or genomic distance between the end points for larger fragments. For these two assumptions, yields of mutants with exon deletions, size distributions of deletions, patterns of deleted exons, and patterns of deleted STS marker sites surrounding the gene were calculated and compared with experimental data. The yields, size distributions and exon deletion patterns were grossly consistent, whereas larger deviations were found for the STS marker deletion patterns in this comparison.

Chromosome Mapping↗

PubMed2002

Exon concatenation to increase the efficiency of mutation screening by DGGE.

For genes that have a substantial number of exons and long intronic sequences, mutation screening by denaturing gradient gel electrophoresis (DGGE) requires the amplification of each exon from genomic DNA by PCR. This results in a high number of fragments to be analyzed by DGGE so that the analysis of large sample sets becomes labor intensive and time consuming. To address this problem, we have developed a new strategy for mutation analysis, lexon-DGGE, which combines the joining of different exons by PCR (also known as lexons) with a highly sensitive technique such as DGGE to screen for mutations. The lexon technique is based on the concatenation of several exons, adjacent or not, from genomic DNA into a single DNA fragment so that this approach could simultaneously be used to check the mutational status of several small genes. To show the feasibility of the approach, we have used the lexon-DGGE technique to analyze all coding exons, intron-exon junctions, noncoding exon 1, and part of the noncoding region of exon 11 of the TP53 gene. The validity and performance of the technique were confirmed by using negative and positive controls for each of the DNAfragments analyzed.

DNA Mutational Analysis↗

PubMedDate not supplied

Exon 14-skipping of the adenomatous polyposis coli gene in purified epithelial cells of colonic mucosa and tumors.

Adenomatous polyposis coli (APC) exon 14-skipped transcripts encode putative APC proteins of low molecular weight. To prove that exon 14-skipped mRNA variants do not simply represent tissue culture artifacts, expression of these APC transcript variants was demonstrated in native colorectal epithelium. Fresh surgical specimens of human colon were processed and epithelial cells were affinity-purified with the dynabead-immobilized monoclonal antibody Ber-EP4. Epithelium derived cDNA was PCR-amplified in the range of linear accumulation. RT-PCR products with and without APC exon 14 were evaluated by densitometry. Analyses of normal mucosa (n = 8) and matching mucosa--tumor samples (n = 4) revealed a consistent 4 to 1 ratio of APC exon 14-positive to exon 14-negative mRNA levels. We conclude, a) that APC exon 14-skipped transcripts are physiologically expressed in native human colon mucosa, and b) that ratios of exon 14-negative to exon 14-positive isoforms were not altered when colorectal tumor cells were compared with matching normal mucosa (p = 0.80).

Colon↗

PubMed2001

PTEN mutation located only outside exons 5, 6, and 7 is an independent predictor of favorable survival in endometrial carcinomas.

Although the prognostic impact of PTEN mutation in endometrial carcinoma is beginning to be analyzed, the prognostic significance of mutated PTEN exons has not ever been described. Sixty-seven endometrial carcinomas were analyzed for PTEN mutations using single-strand conformation polymorphism analysis and DNA sequencing. First, survival rates were compared according to PTEN status and mutated PTEN exons. Subsequently, univariate and multivariate analyses of various favorable prognostic factors for survival were conducted. The associations between PTEN mutation and clinicopathological features were also statistically evaluated. PTEN mutations were detected in 37 of 67 (55%) specimens. Among 47 mutations, frameshifts (57%) and mutations in exon 8 (38%) were most frequent. In univariate analysis, a factor of PTEN mutation only outside exons 5-7 was associated with significantly better survival (P = 0.02), although mutation in any exon of PTEN was not (P = 0.33). Subsequent multivariate analysis revealed that factors of mutation only outside exons 5-7 of PTEN, stage I/II, and G1 were significant and independent prognostic indicators for favorable survival (P = 0.004, 0.004, and 0.0006, respectively). In the subset of advanced-stage disease, mutation only outside exons 5-7 was associated with a trend toward better survival (P = 0.13). No significant correlation was observed between PTEN mutation and estrogen-related clinicopathological features. In conclusion, we find that PTEN mutation located only outside exons 5-7 is a significant and independent positive prognostic indicator for survival. The current observation has prognostic and therapeutic implications for the management of patients with endometrial carcinoma.

Adult↗

PubMed2003

The universe of exons revisited.

We study the distribution of exons in eukaryotic genes to determine whether one can detect the reuse of exon sequences and to use the frequency of such reuse to estimate how many ancestral exon sequences there might have been. We use two databases of exons. One contained 56,276 internal exons from putatively unrelated genes (less than 20% sequence identity) and the second contained 8917 internal exons from regions of these genes that are homologous and colinear with prokaryotic genes; these are ancient conserved regions (ACRs). At the 95% significance level we find 3500 exon-sequence matches in the large database and 500 matches in the ACR database. These matches correspond to groups of similar sequences. The size-rank relationship for these groups follows a power law, the size falling off as the inverse square root of the rank. This form of the power law distribution leads us to make an estimate for the size of a possible universe of ancestral exons. Using the data corresponding to the ACR regions, that universe is estimated to be about 15,000-30,000 in size.

Amino Acid Sequence↗

PubMed2005

Mutational risk in highly repetitive exon ORF15 of the RPGR multidisease gene is not associated with haplotype background.

Exon ORF15 is an alternative exon in the retinitis pigmentosa GTPase regulator (RPGR) gene containing a highly repetitive, purine-rich internal region. It constitutes a mutational hot spot giving rise to a group of heterogeneous X-linked retinal disorders. We sought to determine whether non-pathogenic substitutions and sequence length variations in the repetitive sequence have an influence on the risk of pathogenic exon ORF15 mutations. The type and distribution of exon ORF15 polymorphisms were assessed by genotyping 107 healthy German males using standard procedures. Polymorphisms were grouped into haplotypes and their frequencies determined in normal controls and previously analyzed patients with X-linked retinitis pigmentosa (XLRP). In the control group we identified 6 complex variants of the most common, ancestral exon ORF15 allele corresponding to the GenBank reference sequence (accession no. AF286472). Exon ORF15 mutations in XLRP patients were associated with the ancestral allele in 75% of affected cases. Four of the most recent founder haplotypes termed H3, H4, H6 and H7 were not identified in the patient samples. Our analysis and review of polymorphism data from the published literature suggests the presence of common exon ORF15 haplotypes in the European population. While the mutational risk in the RPGR gene appears not to be altered by the haplotype background, exon ORF15 haplotype analysis may be useful for tracing the evolutionary history of RP3-associated diseases.

Exons↗

PubMedDate not supplied

Exonic deletions of mismatch repair genes MLH1 and MSH2 correlate with prognosis and protein expression levels in malignant melanomas.

The mutations of MLH1 and MSH2 have been reported to be responsible for malignant transformation and tumour progression in several sporadic tumours. Eighty-six primary malignant melanomas with known follow-up were investigated. Point mutations of DNA mismatch repair MLH1 and MSH2 in malignant melanomas were not found. Exon 12 (MSH2) was not present in 26 out of the 86 melanomas and exon 13 (MSH2) was lost in 25 of the tumours. The loss of exon 15 (MLH1) was observed in 22 out of the 86 tumours and the loss of exon 16 (MLH1) in 24 melanomas. The loss of exons correlated strongly with the loss of MLH1 and MSH2 protein expression. In multivariate analysis, including all 4 exons and expressions of MLH1 and MSH2, prognostic significance was found only for loss of exon 12 (MSH2) and loss of exon 15 (MLH1).

Adaptor Proteins, Signal Transducing↗

PubMed1991

Mapping of breakpoints, and relationship to BCR-ABL RNA expression, in Philadelphia-chromosome-positive chronic myeloid leukaemia patients with a breakpoint around exon 14 (b3) of the BCR gene.

The BCR gene, on chromosome 22, is involved in the Philadelphia (Ph1) chromosome which is a characteristic cytogenetic marker of chronic myeloid leukaemia (CML). Breakpoints in CML occur within the M-bcr region (5.8 kb) which encompasses exons 12-15 (b1-b4), and the M-bcr can be conveniently divided into five zones by restriction mapping. One of these zones (3) contains exon b3 which can be either present or absent from the hybrid mRNA, even if it is present in the chimaeric gene. We have mapped the breakpoints around BCR exon b3 and related this to the type of RNA splice site expressed, in CML patients at diagnosis. Breakpoints within zone 3 were restriction mapped to one of six sub-zones and the site related to the type of RNA splice site. Two clusters of breakpoints within zone 3 were observed. One cluster was located around exon b3 and often resulted in deletion of exon b3 from the chimaeric gene. The majority of this cluster expressed b2-a2 spliced RNA, usually as a consequence of a deletion removing exon b3. The second cluster occurred within two sub-zones that spanned an Alu sequence, and 90% of this cluster exhibited b3-a2 spliced RNA. Furthermore, a greater number of patients had entered blast crisis if the RNA contained BCR exon b3 (8 of 10 patients), compared to those with b2-a2 spliced RNA (3 of 12 patients). The high degree of heterogeneity in the site of the breakpoint within zone 3 of the M-bcr, combined with the type of BCR-ABL hybrid mRNA expressed, further implicates BCR exon b3 in the pathogenesis of CML.

Base Sequence↗

PubMed1991

Human alpha 3(VI) collagen gene. Characterization of exons coding for the amino-terminal globular domain and alternative splicing in normal and tumor cells.

We recently reported the isolation and sequencing of human cDNA clones corresponding to the alpha 3 chain of type VI collagen (Chu, M.-L., Zhang, R.-Z., Pan, T.-c., Stokes, D., Conway, D., Kuo, H.-J., Glanville, R., Mayer, U., Mann, K., Deutzmann, R., and Timpl, R. (1990) EMBO J. 9, 385-393). The study indicates that the amino-terminal globular domain of the alpha 3(VI) chain consists of nine repetitive subdomains of approximately 200 amino acid residues (N1-N9) and the gene appeared to undergo alternative splicing since some clones lacked regions encoding the N9 and part of the N3 subdomains. In the present study, we report the exon structure for the region encoding the amino-terminal globular domain of the human alpha 3(VI) chain. The nine repetitive subdomains are encoded by 10 exons spanning 26 kilobase pairs of genomic DNA. Eight of the repetitive subdomains (N2-N9) were found to be encoded by separate exons of approximately 600 base pairs each. The only exception is the N1 subdomain which is encoded by two exons of 417 and 146 base pairs. Characterization of the exon/intron structure showed that the cDNA variants were the result of splicing out of exon 9 (encoding the N9 subdomain) and part of exon 3 (encoding the N3 subdomain). Nuclease S1 analysis and the polymerase chain reaction demonstrated that exon 7 (N7 subdomain) was also subject to alternative splicing in normal skin fibroblasts. Examination of these splicing events by nuclease S1 analysis in normal fibroblasts, three different human tumor cell lines, and several human tissues showed that splicing out of exon 9 is much more efficient in normal as compared to tumor cells.

Adult↗

PubMed1989

Fine mapping of chromosome 22 breakpoints within the breakpoint cluster region (bcr) implies a role for bcr exon 3 in determining disease duration in chronic myeloid leukemia.

The chromosomal translocation that fuses the phl gene with the c-abl proto-oncogene appears to be a pivotal step in the pathogenesis of some leukemias. In chronic myeloid leukemia (CML) the breakage within the phl gene is largely confined to a 5.8-kb segment referred to as the breakpoint cluster region (bcr). To determine whether the presence of specific bcr exons on the Philadelphia chromosome has any clinical significance, we have analyzed the bcr breakpoints in 134 patients with CML. As many as five probes were used in this analysis, including a synthetic oligonucleotide probe homologous to the bcr exon 3 (phl exon 14) region. The distribution of breakpoints indicates that, in fact, breakage is largely confined to a 3.1-kb segment lying between bcr exon 2 and exon 4 (phl exons 13-15). In 61 CML patients analyzed within 1 year of diagnosis, the distribution of breakpoints appeared to be random within the 3.1-kb region. However, a significant excess of 5' breakpoints was observed in the total population studied, consistent with previous data showing that patients with 3' breakpoints have shorter disease durations. Analysis using the bcr exon 3 sequence probe indicated it was probably the presence or absence of bcr exon 3 on the Philadelphia chromosome that accounts for some of the variability in disease duration seen in CML. The data suggest that the phl/abl protein product may influence the timing of the onset of blast crisis and imply a continuing role for this protein during the evolution of the disease.

Blotting, Southern↗

PubMed1987

The human c-myc exon 1 product: preparation of antisera and analysis of its expression.

We investigated the coding capacity of the previously reported open reading frame (ORF) of the human c-myc exon 1. By in vitro translation assay, we found that exon 1 ORF was translated into a 20-kd protein (p20 protein). In order to obtain antisera raised against the p20 protein, we constructed a plasmid vector which expressed most of the exon 1 ORF as a 25-kd (P25) protein in Escherichia coli. Polyclonal antisera raised against this P25 protein specifically precipitated a chimeric protein which contained exon 1-related amino acid sequences. We used these antisera to test for the existence of an exon 1 product in human cells. In the human cell lines tested, these antisera have failed so far to detect any exon 1-related proteins. However, exon 1-related proteins were detected with the anti-p20 antisera in quail embryonic cells (QEC) transfected by human c-myc recombinants constructed to express such proteins, but were expressed at low levels compared with the human c-myc protein also expressed in the transfected QEC. Our results suggest that secondary structure of the mRNA could be responsible for the low expression of the exon 1 product in QEC.

Animals↗

PubMed1987

Minimal exon sequence requirements for efficient in vitro splicing of mono-intronic nuclear pre-mRNA.

Measurements of the in vitro splicing efficiency of deletion mutant RNA precursors containing the small intron of the rabbit beta-globin gene, which are truncated in the first or in the second exon, revealed that no more than approximately 20 nucleotides of either exon are necessary for efficient splicing. At least for the second exon, this minimal length requirement is globin sequence-independent. Reduction of the exon-2 length to 14 nucleotides resulted in very inefficient splicing, whereas further reduction to 5 nucleotides apparently abolished the second splicing step (3' cutting and ligation), whereas the first step (5' cutting and branching) still occurred. The splicing efficiency of a double-mutant substrate retaining approximately 20 nucleotides of each exon was reduced to 50%. A kinetic study indicated that in the reaction of this double-mutant substrate the second, but not the first, splicing step was delayed, in contrast to the reaction of the wild-type precursor. Duplication or triplication of the entire sequence of exon-1 did not affect the splicing efficiency, whereas elongation of this exon with approximately 100 nucleotides of 5'-flanking (nontranscribed) beta-globin sequence diminished the level of correct splicing with the simultaneous appearance of aberrant lariat forms. We conclude that for mono-intronic precursors in which there is only one choice of splice sites, most of the exon sequences are not mechanistically involved in the splicing process.

Animals↗