Intergenic splicing between a HERV-H endogenous retrovirus and two adjacent human genes

We previously reported that a long terminal repeat (LTR) of a human endogen ous retrovirus of the HERV-H family promotes expression of a cellular fusio n transcript in teratocarcinoma cell lines. This transcript was termed PLA2 L due to two regions of similarity to the secreted form of phospholipase A, . In this study, evidence is presented indicating that this transcript appe ars 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 conservati on 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 isola tion of LTR-driven HHLA1 transcripts, unspliced to otoconin-90 exons, with variable sites of polyadenylation; (2) the cloning of both the putative hum an intergenic genomic region and the novel 5' terminus of the mouse otoconi n-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 transc ript; and (4) the lack of detectable chromosomal rearrangements involving t his region in teratocarcinoma cells. The PLA2L transcript therefore represe nts a rare example of intergenic splicing of two closely linked genes. We h ypothesize that human HHLA1 and OC90 are normally expressed independently f rom different promoters but are expressed from the LTR promoter and spliced together in teratocarcinoma cells. It is tempting to speculate that the hi gh activity of the LTR promoter in this cell type may induce transcriptiona l fusion between these two genes. (C) 1999 Academic Press.