L1 As A Mutagen

The fact that Li retrotransposition is ongoing in the human genome was realized in i988, when it was discovered that two unrelated patients afflicted with Hemophilia A acquired independent Li retrotransposition events into exon i4 of the Factor VIIIgene (89). Extensive characterization of one of these mutations showed that it was not present in either parent and arose by a de novo retrotransposition event either in the maternal germline or soon after fertilization. Since that time, deleterious Li insertions in the germ lines of both human and mouse have resulted in a variety of genetic disorders (12). In humans, the majority of Li insertions characterized have led to X-linked recessive diseases (Table 2). Although subject to ascertainment biases, it is estimated that deleterious Li insertions are responsible for approx i in i000 disease-producing mutations in man (90), and that approx i/i0 to i/i00 male germ cells may harbor de novo retrotransposition events (91,92).

Somatic Li retrotransposition events also have the potential to cause disease (Table 2). In one instance, an Li insertion into the adenomatous polyposis coli (APC) tumor suppressor gene was implicated in colon cancer because the mutagenic insertion was present only in the tumor and not the surrounding constitutional tissue (93). Moreover, hypomethylation of the Li promoter, an increase in the level of Li transcription and elevated levels of ORFip have been detected in a variety of tumor types, suggesting that retrotransposition may play a role in tumorigenesis and/or tumor progression (94-98).

Li insertions can alter gene expression by disrupting exons, by inducing mis-splicing or premature polyadenylation of primary transcripts, and by altering the transcriptional profile of a gene because of the potent anti-sense promoter located within the Li 5' UTR (see Fig. 4) (12,56,57,99). In addition, it is proposed that Li insertions in the same transcriptional orientation as genes may act as RNA polymerase II transcriptional pause sites that can attenuate gene expression by serving as "molecular rheostats" (100). However, although intriguing, the "molecular rheostat" hypothesis awaits rigorous experimental proof.

Table 2

Disease-Producing L1 Insertions in the Human Genome

Disrupted Insertion L1-mediated

Disease gene size Ta subset transduction

Table 2

Disease-Producing L1 Insertions in the Human Genome

Disrupted Insertion L1-mediated

Disease gene size Ta subset transduction

Hemopilia A

Factor VIII

3.8 kb

Yes

No

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