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Abstract

Human endogenous retroviruses (HERVs) are repetitive, noninfectious chromosomal elements degenerated from exogenous retroviruses, and compose as much as 2% of the human genome. The HERV-H family numbers approximately 1000 elements dispersed throughout the human genome. HERV-H elements have been shown to affect the expression of adjacent cellular genes. For example, in teratocarcinoma cell lines, a HERV-H LTR promotes expression of, and splices into a downstream cellular transcript, PLA2L, which contains two phospholipase A₂ (PLA₂)-like domains. PLA2L was determined to be a tripartite fusion transcript, composed of HERV-H sequences, 8-10 exons of an unknown but conserved gene HHAG-1 (HERV-H associated gene 1), and a downstream gene encoding an inner ear structural protein, termed otoconin-90. As no chromosomal rearrangements were found in the teratocarcinoma cell lines expressing the PLA2L fusion, intergenic splicing influenced by the HERV-H promoter is hypothesized to be the cause of gene fusion. Cloning and characterization of both the human genomic locus and the murine otoconin-90 cDNA confirmed that PLA2L is a fusion transcript. The HERV-H insertion into an intron of the HHAG-1 gene was determined to have occurred 15-20 million years ago, with the HERV-H element in this locus being stable and present in all humans and higher primates. The region was localized to human chromosome 8q24.1-8q24.3. Although the tripartite transcript is abundant in teratocarcinoma cell lines, no evidence of protein synthesis was detected in teratocarcinoma cell lysates. Heterologous expression experiments have shown that the full-length HERV-Hcontaining cDNA is transcribed but not translated in COS cells. However, a 5' deletion construct which removes the HERV-H-encoded sequence is efficiently translated, while both constructs were transcribed at comparable levels. These effects are postulated to be caused by the HERV-H sequences acting as a translational inhibitory type of 5' UTR, containing elements known to repress protein synthesis. Both the translation-level effect of a HERV upon an adjacent gene and a HERV-H-associated intergenic fusion have not been previously reported, and suggest more complex types of effects which HERV elements can exert upon nearby human genes.