The Contribution of Exon-Skipping Events on Chromosome 22 to Protein Coding Diversity

Hide, Winston; Babenko, Vladimir N.; Heusden, Peter van; Seoighe, Cathal; Kelso, Janet

doi:10.1101/gr.188001

Cited by 47 publications

(40 citation statements)

References 27 publications

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“…As a reference set of exons, we used a set of 62 alternatively spliced internal exons compiled by Hide et al (2001) from 52 genes on chromosome 22. In their study, Hide et al (2001) used a rigorous in silico method to scan the annotated genomic sequence of chromosome 22 to identify alternatively spliced internal exons that are skipped in some of the transcripts. We took the set of exons from chromosome 22 as a set representing the normal population of alternatively spliced internal exons, and compared it with the set of Alu-containing exons we found.…”

Section: Resultsmentioning

confidence: 99%

“…First, this type is the most frequent type of alternative splicing (Hide et al 2001). Second, many unspliced ESTs found in the ESTs database (dbEST) represent sequenced introns (intron contamination) and contain Alu sequences, and, therefore, we preferred not to use unspliced expressed sequences as evidence for alternative splicing.…”

Section: Discussionmentioning

confidence: 99%

“…Data for 45 Alu-containing exons occurring within the protein-coding region are presented in lighter shaded bars. Data of 48 alternatively spliced internal exons from chromosome 22 (Hide et al 2001), which occur in the protein-coding region, are presented as reference (darker shaded bars). Exons were considered as domain adding if their length was a multiple of three, and there was no in-frame stop codon within them.…”

Section: Discussionmentioning

confidence: 99%

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Alu-Containing Exons are Alternatively Spliced

Sorek¹,

Ast²,

Graur³

2002

Genome Res.

453

452

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Alu repetitive elements are found in ∼1.4 million copies in the human genome, comprising more than one-tenth of it. Numerous studies describe exonizations of Alu elements, that is, splicing-mediated insertions of parts of Alu sequences into mature mRNAs. To study the connection between the exonization of Alu elements and alternative splicing, we used a database of ESTs and cDNAs aligned to the human genome. We compiled two exon sets, one of 1176 alternatively spliced internal exons, and another of 4151 constitutively spliced internal exons. Sixty one alternatively spliced internal exons (5.2%) had a significant BLAST hit to an Alu sequence, but none of the constitutively spliced internal exons had such a hit. The vast majority (84%) of the Alu-containing exons that appeared within the coding region of mRNAs caused a frame-shift or a premature termination codon. Alu-containing exons were included in transcripts at lower frequencies than alternatively spliced exons that do not contain an Alu sequence. These results indicate that internal exons that contain an Alu sequence are predominantly, if not exclusively, alternatively spliced. Presumably, evolutionary events that cause a constitutive insertion of an Alu sequence into an mRNA are deleterious and selected against.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Alu-Containing Exons are Alternatively Spliced

Sorek¹,

Ast²,

Graur³

2002

Genome Res.

453

452

View full text Add to dashboard Cite

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“…Numerous large-scale studies of alternative splicing in humans and other organisms have been carried out using expressed sequence tags (ESTs) and cDNAs [1][2][3][4][5][6] as well as, more recently, microarrays [7]. Estimates from these studies of the proportion of genes that produce alternative transcript isoforms are as high as 74% [7].…”

Section: Introductionmentioning

confidence: 99%

Allele‐specific transcript isoforms in human

Nembaware

Wolfe

Bettoni³

et al. 2004

FEBS Letters

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Estimates of the number of human genes that produce more than one transcript isoform through alternative mRNA splicing depend on the assumption that the observation of multiple transcripts from a gene can be attributed entirely to alternative splicing. It is possible, however, that a substantial proportion of cases where multiple transcripts have been observed for a gene result from differences between alleles. Many examples of genes that are spliced differently from different alleles have been reported but no systematic estimate of the proportion of alternatively spliced genes that are affected by such polymorphisms has been carried out. We find that alternative transcript isoforms are non-randomly associated with closely linked nucleotide polymorphisms, based on an integrated analysis of the dbSNP, dbEST and ASAP databases. From the observed level of association between transcript isoforms and polymorphisms, we estimate that 21% of alternatively spliced genes are affected by polymorphisms that either completely determine which form of the transcript is observed or alter the relative abundances of some of the alternative isoforms. We provide a conservative lower bound of 6% on this estimate and point out that alternative splicing cannot be confirmed absolutely unless more than one transcript is observed from the same allele.

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“…The reason for the predominance of unspliced cPLA 2 ␤ cDNA is not known, but it raised the possibility that multiple splice variants exist. Increasing evidence indicates that alternate splicing and exon skipping are major contributors to protein diversity in humans; therefore, it is important to identify the endogenously expressed protein variants in cells and tissues (37)(38)(39)(40)(41)(42)(43). In this study, we describe the identification and characterization of endogenous cPLA 2 ␤ protein, which is derived from a novel splice variant of the cPLA 2 ␤ gene.…”

Section: Discussionmentioning

confidence: 99%

Identification of the Expressed Form of Human Cytosolic Phospholipase A2β (cPLA2β)

Ghosh

Loper

Gelb

et al. 2006

Journal of Biological Chemistry

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In this study, we identify the principal splice variant of human cytosolic phospholipase A 2 ␤ (cPLA 2 ␤) (also known as Group IVB cPLA 2 ) present in cells. In human lung, spleen, and ovary and in a lung epithelial cell line (BEAS-2B), cPLA 2 ␤ is expressed as a 100-kDa protein, not the 114-kDa form originally predicted. Using RNA interference, the 100-kDa protein in BEAS-2B cells was confirmed to be cPLA 2 ␤. BEAS-2B cells contain three different RNA splice variants of cPLA 2 ␤ (␤1, ␤2, and ␤3). cPLA 2 ␤1 is identical to the previously cloned cPLA 2 ␤, predicted to encode a 114-kDa protein. However, cPLA 2 ␤2 and cPLA 2 ␤3 splice variants are smaller and contain internal deletions in the catalytic domain. The 100-kDa cPLA 2 ␤ in BEAS-2B cells is the translated product of cPLA 2 ␤3. cPLA 2 ␤3 exhibits calcium-dependent PLA 2 activity against palmitoyl-arachidonyl-phosphatidylethanolamine and low level lysophospholipase activity but no activity against phosphatidylcholine. Unlike Group IVA cPLA 2 ␣, cPLA 2 ␤3 is constitutively bound to membrane in unstimulated cells, localizing to mitochondria and early endosomes. cPLA 2 ␤3 is widely expressed in tissues, suggesting that it has a generalized function at these unique sites.Phospholipase A 2 (PLA 2 ) 2 enzymes catalyze hydrolysis of sn-2 acyl chains from membrane phospholipids. They execute diverse functions, such as digestion of dietary phospholipids, microbial degradation, membrane remodeling, and production of lipid mediators. Traditionally, PLA 2 s are grouped depending on their active site residues, requirements for calcium, and localization in the cell. Three main classes of PLA 2 s are Group VI intracellular calcium-independent PLA 2 s, low molecular weight secreted PLA 2 s, and Group IV cytosolic PLA 2 s (1, 2). Group IVA cytosolic PLA 2 ␣ has received special attention, because it is the only PLA 2 that selectively hydrolyzes arachidonic acid from the sn-2 position of membrane phospholipids (1). Arachidonic acid is the precursor of prostaglandins and leukotrienes (1, 3). Mice genetically deficient in cPLA 2 ␣ have provided evidence for its critical role in regulating physiological processes and various diseases (4 -11). cPLA 2 ␣ contains an N-terminal calcium binding domain (C2 domain) and a C-terminal catalytic domain (12). Calcium binds to the C2 domain and facilitates the translocation of the enzyme from cytosol to the Golgi, endoplasmic reticulum, and nuclear envelope (13-16). Five other members of the Group IV cPLA 2 family, cPLA 2 ␤ (Group IVB), cPLA 2 ␥ (Group IVC), cPLA 2 ␦ (Group IVD), cPLA 2 (Group IVE), and cPLA 2 (Group IVF), have been identified (17-21). cPLA 2 ␦, -, and -are clustered near cPLA 2 ␤ on mouse chromosome 2 and have more homology to cPLA 2 ␤ than to cPLA 2 ␣ or cPLA 2 ␥ (21). From analysis of the human genome, cPLA 2 ␤ is similarly positioned near cPLA 2 ␦, -, and -on chromosome 15. All members of the Group IV family have a conserved Ser/Asp dyad necessary for catalysis (12).Human cPLA 2 ␤ was originally cloned from human brain ...

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The Contribution of Exon-Skipping Events on Chromosome 22 to Protein Coding Diversity

Cited by 47 publications

References 27 publications

Alu-Containing Exons are Alternatively Spliced

Alu-Containing Exons are Alternatively Spliced

Allele‐specific transcript isoforms in human

Identification of the Expressed Form of Human Cytosolic Phospholipase A2β (cPLA2β)

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