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Novel genetic effects of a human endogenous retrovirus insertion Kowalski, Paul Edward
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.
Item Metadata
Title |
Novel genetic effects of a human endogenous retrovirus insertion
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
1998
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Description |
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.
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Extent |
9297310 bytes
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Genre | |
Type | |
File Format |
application/pdf
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Language |
eng
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Date Available |
2009-06-22
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Provider |
Vancouver : University of British Columbia Library
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Rights |
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.
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DOI |
10.14288/1.0099344
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
1998-11
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Campus | |
Scholarly Level |
Graduate
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Aggregated Source Repository |
DSpace
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Item Media
Item Citations and Data
Rights
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.