Intergenic Splicing between a HERV-H Endogenous Retrovirus and Two Adjacent Human Genes

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We previously reported that a long terminal repeat (LTR) of a human endogenous retrovirus of the HERV-H family promotes expression of a cellular fusion transcript in teratocarcinoma cell lines. This transcript was termed PLA2L due to two regions of similarity to the secreted form of phospholipase A2. In this study, evidence is presented indicating that this transcript appears to be the result of intergenic splicing between the HERV-H element and two independent downstream genes. The 5′ gene has been named HHLA1 (HERV-H LTR-associating 1) and is of unknown function but shows sequence conservation in other mammals. The 3′ gene is now known to encode human otoconin-90 (OC90) which, in mice, is a major protein expressed in the fetal inner ear. Evidence for intergenic splicing of these two genes includes: (1) the isolation of LTR-driven HHLA1 transcripts, unspliced to otoconin-90 exons, with variable sites of polyadenylation; (2) the cloning of both the putative human intergenic genomic region and the novel 5′ terminus of the mouse otoconin-90 gene; (3) the identification of homologous potential signal sequences in the 5′ region of mouse otoconin-90 and in the middle of the PLA2L transcript; and (4) the lack of detectable chromosomal rearrangements involving this region in teratocarcinoma cells. The PLA2L transcript therefore represents a rare example of intergenic splicing of two closely linked genes. We hypothesize that human HHLA1 and OC90 are normally expressed independently from different promoters but are expressed from the LTR promoter and spliced together in teratocarcinoma cells. It is tempting to speculate that the high activity of the LTR promoter in this cell type may induce transcriptional fusion between these two genes.