Dataset Information

Genomic impact, chromosomal distribution and transcriptional regulation of HERV elements.

ABSTRACT: Human endogenous retroviruses (HERVs) mediate structural variation and genomic instability based on their multiple copy number, inherent ability to mobilize via reverse transcriptase, and high sequence similarity. Moreover, they undergo multiple amplification and retrotransposition events, resulting in the widespread distribution of complete or partial retroviral sequences throughout the primate genome. As such, HERV elements have played important biological roles in genome evolution, and their long terminal repeat (LTR) elements contain numerous regulatory sequences, including effective promoters, enhancers, polyadenylation signals, and transcription factorbinding sites. Lastly, HERV elements are capable of influencing the expression of neighboring genes, a process that also contributed to primate evolution.

SUBMITTER: Kim HS

PROVIDER: S-EPMC3887755 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Genomic impact, chromosomal distribution and transcriptional regulation of HERV elements.

Kim Heui-Soo HS

Molecules and cells 20120504 6

Human endogenous retroviruses (HERVs) mediate structural variation and genomic instability based on their multiple copy number, inherent ability to mobilize via reverse transcriptase, and high sequence similarity. Moreover, they undergo multiple amplification and retrotransposition events, resulting in the widespread distribution of complete or partial retroviral sequences throughout the primate genome. As such, HERV elements have played important biological roles in genome evolution, and their ...[more]

PMID: 22562360

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Project description:All genes in the TRIM6/TRIM34/TRIM5/TRIM22 locus are type I interferon inducible, with TRIM5 and TRIM22 possessing antiviral properties. Evolutionary studies involving the TRIM6/34/5/22 locus have predominantly focused on the coding sequence of the genes, finding that TRIM5 and TRIM22 have undergone high rates of both non-synonymous nucleotide replacements and in-frame insertions and deletions. We sought to understand if divergent evolutionary pressures on TRIM6/34/5/22 coding regions have selected for modifications in the non-coding regions of these genes and explore whether such non-coding changes may influence the biological function of these genes. The transcribed genomic regions, including the introns, of TRIM6, TRIM34, TRIM5, and TRIM22 from ten Haplorhini primates and one prosimian species were analyzed for transposable element content. In Haplorhini species, TRIM5 displayed an exaggerated interspecies variability, predominantly resulting from changes in the composition of transposable elements in the large first and fourth introns. Multiple lineage-specific endogenous retroviral long terminal repeats (LTRs) were identified in the first intron of TRIM5 and TRIM22. In the prosimian genome, we identified a duplication of TRIM5 with a concomitant loss of TRIM22. The transposable element content of the prosimian TRIM5 genes appears to largely represent the shared Haplorhini/prosimian ancestral state for this gene. Furthermore, we demonstrated that one such differentially fixed LTR provides for species-specific transcriptional regulation of TRIM22 in response to p53 activation. Our results identify a previously unrecognized source of species-specific variation in the antiviral TRIM genes, which can lead to alterations in their transcriptional regulation. These observations suggest that there has existed long-term pressure for exaptation of retroviral LTRs in the non-coding regions of these genes. This likely resulted from serial viral challenges and provided a mechanism for rapid alteration of transcriptional regulation. To our knowledge, this represents the first report of persistent evolutionary pressure for the capture of retroviral LTR insertions.

Project description:One member of the W family of human endogenous retroviruses (HERV) appears to have been functionally adopted by the human host. Nevertheless, a highly diversified and regulated transcription from a range of HERV-W elements has been observed in human tissues and cells. Aberrant expression of members of this family has also been associated with human disease such as multiple sclerosis (MS) and schizophrenia. It is not known whether this broad expression of HERV-W elements represents transcriptional leakage or specific transcription initiated from the retroviral promoter in the long terminal repeat (LTR) region. Therefore, potential influences of genomic context, structure and orientation on the expression levels of individual HERV-W elements in normal human tissues were systematically investigated.Whereas intronic HERV-W elements with a pseudogene structure exhibited a strong anti-sense orientation bias, intronic elements with a proviral structure and solo LTRs did not. Although a highly variable expression across tissues and elements was observed, systematic effects of context, structure and orientation were also observed. Elements located in intronic regions appeared to be expressed at higher levels than elements located in intergenic regions. Intronic elements with proviral structures were expressed at higher levels than those elements bearing hallmarks of processed pseudogenes or solo LTRs. Relative to their corresponding genes, intronic elements integrated on the sense strand appeared to be transcribed at higher levels than those integrated on the anti-sense strand. Moreover, the expression of proviral elements appeared to be independent from that of their corresponding genes.Intronic HERV-W provirus integrations on the sense strand appear to have elicited a weaker negative selection than pseudogene integrations of transcripts from such elements. Our current findings suggest that the previously observed diversified and tissue-specific expression of elements in the HERV-W family is the result of both directed transcription (involving both the LTR and internal sequence) and leaky transcription of HERV-W elements in normal human tissues.

Dataset Information

Genomic impact, chromosomal distribution and transcriptional regulation of HERV elements.

Publications

Genomic impact, chromosomal distribution and transcriptional regulation of HERV elements.

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