Human Molecular Genetics Advance Access originally published online on May 24, 2006
Human Molecular Genetics 2006 15(13):2146-2156; doi:10.1093/hmg/ddl138
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Effects of L1 retrotransposon insertion on transcript processing, localization and accumulation: lessons from the retinal degeneration 7 mouse and implications for the genomic ecology of L1 elements
1 Department of Molecular Biology and Genetics, 2 Department of Neuroscience, 3 Department of Ophthalmology and 4 Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, 805 PCTB, 725 North Wolfe Street, Baltimore, MD 21205, USA
* To whom correspondence should be addressed. Tel: +1 4109554679; fax: +1 4106140827; Email: jnathans{at}jhmi.edu
Received April 19, 2006; Accepted May 21, 2006
The retinal degeneration 7 (rd7) mouse is a naturally occurring model of enhanced S-cone syndrome, Goldman-Favre syndrome and clumped pigmentary retinopathy in humans, allelic disorders caused by inactivation of a photoreceptor-specific nuclear hormone receptor, NR2E3. We show here that the rd7 mutation arose from the antisense insertion of a long interspersed nuclear element (LINE-1) (or L1) into exon 5 of the mouse Nr2e3 gene. L1 insertion blocks splicing of Nr2e3 intron 5 by separating an inefficient splice donor from essential splicing enhancers within exon 5, with the result that incompletely spliced transcripts accumulate to high levels at the mutant Nr2e3 locus in photoreceptor nuclei. The high efficiency of transcription through the 7 kb L1 was unexpected and led us to compare the effect on transcript abundance of sense or antisense L1 insertions in transfected cells. In a variety of sequence contexts antisense L1 insertions had little or no effect on transcript levels or the production of full-length transcripts, whereas sense L1 insertions reduced transcript levels from several-fold to more than 10-fold. A bioinformatic analysis of all mouse L1s shows a 
2-fold under-representation of L1s in introns when compared with bulk genomic DNA, and, within introns, a further 2-fold under-representation of sense when compared with antisense L1s. Interestingly, there is no evidence for orientation-specific positive or negative selection within any subregions of the L1 element. These data suggest that L1s have evolved to present the host transcriptional machinery with a minimally disruptive profile in the antisense orientation such that antisense intronic L1s often escape purifying negative selection.
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