Apc

538 bp

Yes

Yes

Human diseases resulting from L1 insertion into genes are noted. The size of the insertion and the subfamily that gave rise to the insertion are given (12,121,129,130). Ta, transcribed active L1 (98).

Human diseases resulting from L1 insertion into genes are noted. The size of the insertion and the subfamily that gave rise to the insertion are given (12,121,129,130). Ta, transcribed active L1 (98).

Fig. 4. L1 is an insertional mutagen. L1s can insert into many regions in ene A with exon (white boxes) and intron (bold lines) structure. When L1 inserts into exons it disrupts Gene A protein. Insertion into introns can lead to missplicing of Gene A mRNA. The L1 antisense promoter can facilitate transcription of partial Gene A transcripts when L1 inserts into an intron. The A-richness of L1 can lead to premature polyadenylation of Gene A mRNA when L1 inserts into an intron and may cause an arrest of transcrip-tional elongation as proposed by the molecular rheostat hypothesis. Text in bold represents processes that have been characterized in the human genome, and text in italics refers to proposed effects of L1 on gene expression.

Fig. 4. L1 is an insertional mutagen. L1s can insert into many regions in ene A with exon (white boxes) and intron (bold lines) structure. When L1 inserts into exons it disrupts Gene A protein. Insertion into introns can lead to missplicing of Gene A mRNA. The L1 antisense promoter can facilitate transcription of partial Gene A transcripts when L1 inserts into an intron. The A-richness of L1 can lead to premature polyadenylation of Gene A mRNA when L1 inserts into an intron and may cause an arrest of transcrip-tional elongation as proposed by the molecular rheostat hypothesis. Text in bold represents processes that have been characterized in the human genome, and text in italics refers to proposed effects of L1 on gene expression.

Fig. 5. L1-mediated recombination. Recombination can cause human disease when it occurs at L1 sequences located in introns. Nonhomologous recombination occurs between L1 sequence and sequence within the gene, where the L1 is located, resulting in a deletion of the intervening DNA. This process occurred to cause cases of Alport syndrome and chronic granulamatous disease (101,131). Unequal homologous recombination occurs when there are at least two L1s within a gene. Recombination between different L1s results in deletion and/or duplication gene products. This type of recombination resulted in deletions in sporadic cases of Alport syndrome and phosphorylase kinase deficiency (131,132).

Fig. 5. L1-mediated recombination. Recombination can cause human disease when it occurs at L1 sequences located in introns. Nonhomologous recombination occurs between L1 sequence and sequence within the gene, where the L1 is located, resulting in a deletion of the intervening DNA. This process occurred to cause cases of Alport syndrome and chronic granulamatous disease (101,131). Unequal homologous recombination occurs when there are at least two L1s within a gene. Recombination between different L1s results in deletion and/or duplication gene products. This type of recombination resulted in deletions in sporadic cases of Alport syndrome and phosphorylase kinase deficiency (131,132).

Because L1 and Alu elements are widely distributed across the genome, they also can serve as substrates for unequal homologous or nonhomologous DNA recombination either during or long after their insertion (Fig. 5) (11). Unequal recombination events between Alu elements have resulted in a variety of genetic diseases (see Chapter 1). Although less common, recombination events between homeologous L1 sequences have resulted in sporadic cases of Alport syndrome and chronic granulomatous disease (101,102). Similarly, molecular biological and DNA sequence analyses indicate that both L1 and Alu elements can act as substrates for gene conversion and/or recombinational repair (103,104). Thus, it is tempting to speculate that similar events can lead to the genome instability that frequently is observed in many tumors.

Fig. 6. Ll-mediated movement of other sequences. Lis can move other sequences in cis and in trans. 3' transduction occurs when transcription reads through the Ll poly (A) signal in favor of a stronger downstream poly (A) signal, resulting in insertion of 3' flanking DNA (bold slashed rectangle) with Ll at a new genomic location. Similarly, 5' transduction occurs when transcription is initiated upstream of Ll, resulting insertion of 5' flanking material (bold slashed rectangle) with Ll at a new genomic location. Chimeric pseudogenes are formed when the Ll RT switches templates to small non-coding RNAs, like the U6 snRNA, during TPRT. The Ll proteins also may be used to move non-autonomous retrotransposons, like Alu (black lines denote A and B boxes, speckled box represents A rich region), and cellular mRNAs to form pseudogenes. In all of these cases, Ll-mediated insertions end in a poly (A) tail and are flanked by variable length target site duplications (arrows), which are hallmarks of TPRT.

Fig. 6. Ll-mediated movement of other sequences. Lis can move other sequences in cis and in trans. 3' transduction occurs when transcription reads through the Ll poly (A) signal in favor of a stronger downstream poly (A) signal, resulting in insertion of 3' flanking DNA (bold slashed rectangle) with Ll at a new genomic location. Similarly, 5' transduction occurs when transcription is initiated upstream of Ll, resulting insertion of 5' flanking material (bold slashed rectangle) with Ll at a new genomic location. Chimeric pseudogenes are formed when the Ll RT switches templates to small non-coding RNAs, like the U6 snRNA, during TPRT. The Ll proteins also may be used to move non-autonomous retrotransposons, like Alu (black lines denote A and B boxes, speckled box represents A rich region), and cellular mRNAs to form pseudogenes. In all of these cases, Ll-mediated insertions end in a poly (A) tail and are flanked by variable length target site duplications (arrows), which are hallmarks of TPRT.

Was this article helpful?

0 0

Post a comment