Following transposition downstream of a SET gene (encoding a SET protein domain, characteristic of histone lysine methyltransferases and originally identified in Drosophila), the transposase gene from the mariner mobile element (MAR) was thought to have been captured and fused with the sequences encoding the SET domain leading to exonization and creation of a new intron. The result was the birth of a new chimeric gene in primates some 40-58 million years ago called SETMAR (Cordaux et al. 2006). In humans a copy is found on 3p26. In terms of function of the human SETMAR protein, this remains unclear but the SET domain has histone methyl transferase activity and the MAR domain is capable of binding to the many copies of the Hsmar1 transposon found throughout the human genome which may serve to direct his-tone methylase activity (Liu et al. 2007).
self-replicating genomic parasite of the human genome' (Witherspoon et al. 2006). L1 elements encode their own replication machinery: full length active Lis have an RNA polymerase II promoter region, and two ORFs encoding an RNA binding protein, and a protein with endo-nuclease and reverse transcriptase activity - the former important for creating a nick at the point of genomic insertion (Mathias et al. 1991). This enables Li elements to transpose through target-primed reverse transcription (Luan et al. 1993). There is a catch as completion of this process results in severe truncation of many Li elements such that they lose the ability to catalyse their own replication. This means that there are only a small number of full length retrotransposon competent Li copies in the human genome, so-called 'master' mobile elements approximately 6 kb long (Sassaman et al. 1997; Brouha et al. 2003). Over 500 000 copies of L1s are found in the human genome but more than 99.8% are inactive because of 5' truncations, as well as internal rearrangements and mutations.
An average human is estimated to have between 80 and 100 retrotransposon competent L1s (Brouha et al. 2003). These competent L1s continue to replicate, which means within human populations the presence/absence of insertions remains polymorphic. An estimated 44% of competent L1s are reported to be polymorphic (Brouha et al. 2003). Human-specific L1s (L1Hs) are found, notably Ta (Transcribed, subset a). The preTa subfamily, for example, has an average age of 2.3 million years, with expansion after the divergence of humans and African apes (Boissinot et al. 2000; Myers et al. 2002; Badge et al. 2003; Salem et al. 2003b).
The consequences of L1 insertion events can be severe. Chen and colleagues reviewed L1 mediated retrotrans-position events associated with human disease and identified 48 events (Chen et al. 2005). Overall, L1 mediated retrotransposition events are thought to account for 0.1% of known mutations leading to human genetic diseases (Chen et al. 2006). When 240 male patients with haemophilia A were screened for underlying mutations in the factor VIII gene, two unrelated cases were found to be due to large insertions in exon 14 of the gene (3.8 and 2.3 kb, respectively) (Kazazian et al. 1988). The sequences were consistent with L1 insertions, notably the 3' portion of the L1 element including a poly(A) tract and target site duplications. In an analysis of cases of colon cancer, an L1 insertion event was found into the last exon of the tumour suppressor adenomatous polyposis coli (APC) gene (Miki et al. 1992).
Other examples include an L1 insertion in the dys-trophin (DMD) gene as a rare cause of Duchene muscular dystrophy (Box 3.7). Two Japanese brothers have been reported in whom a 5' truncated consensus L1 element was found inserted within exon 44 of the DMD gene which disrupts the process of splicing such that this exon is lost in the mRNA precursor (Narita et al. 1993). An L1 insertion in the retinitis pigmentosa 2 (RP2) gene at Xp11.4 has also been reported, leading to X-linked retinitis pigmentosa (OMIM 312600) (Schwahn et al. 1998). X-linked retinitis pigmentosa is a progressive disorder affecting the retina and is characterized by the constriction of visual fields and night blindness; there is significant loss of vision by the fourth decade of life and a range of mutations in the RP and neighbouring RPGR
(retinitis pigmentosa GTPase regulator) genes have been identified (Pelletier et al. 2007). Deletions may also result from L1 insertions; 50 deletion events were identified in the human and chimpanzee genomes associated with L1 insertions, and during the primate radiation an estimated 7.5 Mb of sequence was deleted through such events (Han et al. 2005).
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