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... exons are adopted into exonic, coding sequences. In 1994, Makalowski and coworkers described 17 events in which intronic transposed elements were inserted within the coding regions of human genes (Makalowski et al. 1994). A further analysis revealed that these elements were incorporated via splicing, i.e., their sequences contained splice sites leading to their recognition as exons (Makalowski et al. 1994; Makalowski 2000). Following the sequencing of the human genome as well as millions of expressed sequence tags (ESTs), hundreds of additional such events were found (Nekrutenko and Li 2001; Sorek et al. 2002). With the accumulation of many recently sequenced vertebrate genomes, reports on exonizations become more abundant and now include thousands of new exons in rodents (Wang et al. 2005), dogs (Wang and Kirkness 2005), and multiple other vertebrate genomes such as cow and fish (Alekseyenko et al. 2007; Krull et al. 2007). MOLECULAR MECHANISMS LEADING TO EXONIZATION The molecular mechanisms leading to exonization of intronic sequences were studied in detail for Alu elements. These elements are primate-specific retrotransposons that appear in the human genome over one million times and constitute ...

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...n the samegene, and becomes alternatively spliced (Fig. 3A).(64,65) About 10% of all genes contain tandemly duplicated exons and about 10% of mutually exclusive alternatively spliced exons originated from tandemly duplicated exons.(2,66) The second mechanism for the origin of alternatively spliced exons involves the emergence of alternatively spliced exons following exonization of intronic sequences (Fig. 3B). For example, the primate-specific Alu retroelement, which is highly abundant in intronic sequences,(67) contains multiple sites that are similar, but not identical, to real splice sites.(68,69) Severalmutations that change pseudo splice sites to real ones can result in the recognition of a part of the Alu element as a bona-fide exon.(53,70,71) About 4% of human genes contain transposable element motifs in their coding regions, indicating that exonsmight have originated from the exonization of these elements.(68,69,72–75) A recent analysis indicated that up to 3.6 times more exons originated from transposable elements in the human genome than in themouse (1824 and 506 exons, respectively), and this difference is primarily attributable to exonization events of the primate-specific Alu...

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...orms agrees well with a number of other recent observations. It has been demonstrated that all human internal exons containing Alu sequences are alternatively spliced using sites within Alu sequences =-=(57)-=-. As this family of repeats is specific to primates, all these cassette exons are necessarily specific to this taxonomic group. Cassette exons demonstrate lower rate of synonymous substitutions and ma...

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...plice sites (4±6). Indeed, more than 5% of the alternatively spliced exons in the human genome are Alu derived. All Alu-containing internal exons studied so far were found to be alternatively spliced =-=(6)-=-. It was, thus, concluded that mutations resulting in constitutively spliced exonic Alus would result, in the vast majority of cases, in the creation of defective genes causing deleterious effects on ...

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...not have a designed probe on the chip (31%) or might be expressed in tissues that were not examined (40%). Consisting with our previous publications, most of TE exonizations are alternatively spliced =-=(7,9,10,39)-=-. We calculated the inclusion level of the exon from the number of deposited transcripts supporting exonD50 Nucleic Acids Research, 2008, Vol. 36, Database issue Table 1. TranspoGene and microTranspo...

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...orted that exons containing Alu sequences are mostly alternatively spliced, suggesting that constitutive (or high level) Alu exon inclusion might be deleterious and, consequently, be selected against =-=(31)-=-. The same possibly holds true for novel exons that do not contain repetitive elements whose origin is, consequently, more dif®cult to establish. In this regard, the availability of a great number of ...

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...lm.nih.gov/dbEST). The genomic sequences were taken from the human genome build 34 (www.ncbi.nlm.nih.gov/genome/guide/human). Details of our multiple alignment (MA) model can be found in Sorek et al. =-=(24)-=-. Details and parameters of the algorithm In order to identify conserved editing sites, we first produced exhaustive lists of potential editing sites for mouse and human. Such potential sites are foun...

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...es and Deininger, 2007; Kreahling and Graveley, 2004). Diseases like congenital cataracts facial dysmorphism neuropathy syndrome are caused by the inclusion of intronic Alu elements that severely disrupt the transcript structure, thereby affecting the function of the resulting protein (Varon et al., 2003). Indeed, a recent study estimated that 11 of 78 documented genetic diseases involving cryptic exons are associated with mutations in Alu elements (Vorechovsky, 2010). Although some studies have previously suggested the involvement of trans-acting factors (Lin et al., 2009; Shen et al., 2011; Sorek et al., 2002), the mechanisms by which cells protect against spurious exonization of Alu elements has remained unknown until now. Our study establishes that one of hnRNP C’s principal functions is to protect the human transcriptome from aberrant Alu exonization. It is important to note that our current analysis of 2,000 Alu exons most likely underestimates the full scale of aberrant exonization in the absence of hnRNP C; this is because Alu elements are notoriously difficult to detect by current RNA-seq methods (Treangen and Salzberg, 2012). Furthermore, although the present study focuses on Alu elements b...

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...Mi et al., 2000). Recently, these retroelements have gained the evolutionary potential role to enhance the coding capacity and regulatory versatility of the genome without compromising its integrity (=-=Sorek et al., 2002-=-). Database for HERV elements was used for searches of individual HERV families (Paces et al., 2002). Over the past decade, a considerable number of studies have been conducted on the capacity to modi...