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Mouse annexin V genomic organization includes an endogenous retrovirus.

ABSTRACT: Mouse annexin V genomic clones were characterized by restriction analysis, Southern blotting and DNA sequencing. The entire gene spans close to 50 kb of the mouse genome and contains 14 exons ranging in size from 31 bp for exon 2 to 482 bp for exon 13 up to the polyadenylation site. Intron sizes range from 111 bp for intron 1b to more than 17 kb for intron 2. Non-coding exon 1 is present in two alternative forms separated by approx. 7.4 kb, and the two promoters associated with exons 1a and 1b are quite distinct. The upstream promoter has a TATA box and may direct the limited, tissue-specific expression of mRNA transcripts containing exon 1a. The downstream, TATA-less promoter has high G+C content, and exon 1b predominates among abundantly expressed mRNA species. The conservation of certain cis-elements, including Sp1, AP2, gamma-IRE and NF-IL6, in orthologous species of annexin V genes points to their possible role in trans-acting protein factor binding and gene regulation. Primer-extension analysis revealed multiple origins for transcription, with principal start sites 100-150 bp upstream of the ATG start codon in exon 2. Intron 4 was longer than that previously identified in the orthologous rat gene due to the integration of an apparently complete copy of the murine endogenous retrovirus element, MuERV-L. Phylogenetic analysis of annexin V from 12 species and the presence of neighbouring loci with paralogous counterparts linked to annexin VI pointed to the common ancestry of these genes via chromosomal duplication more than 600 million years ago.

SUBMITTER: Rodriguez-Garcia MI

PROVIDER: S-EPMC1219945 | biostudies-other | 1999 Jan

REPOSITORIES: biostudies-other

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Project description:UnlabelledHuman endogenous retrovirus type K (HERV-K) proviruses are scattered throughout the human genome, but as no infectious HERV-K virus has been detected to date, the mechanism by which these viruses replicated and populated the genome remains unresolved. Here, we provide evidence that, in addition to the RNA genomes that canonical retroviruses package, modern HERV-K viruses can contain reverse-transcribed DNA (RT-DNA) genomes. Indeed, reverse transcription of genomic HERV-K RNA into the DNA form is able to occur in three distinct times and locations: (i) in the virus-producing cell prior to viral release, yielding a DNA-containing extracellular virus particle similar to the spumaviruses; (ii) within the extracellular virus particle itself, transitioning from an RNA-containing particle to a DNA-containing particle; and (iii) after entry of the RNA-containing virus into the target cell, similar to canonical retroviruses, such as murine leukemia virus and HIV. Moreover, using a resuscitated HERV-K virus construct, we show that both viruses with RNA genomes and viruses with DNA genomes are capable of infecting target cells. This high level of genomic flexibility historically could have permitted these viruses to replicate in various host cell environments, potentially assisting in their many integration events and resulting in their high prevalence in the human genome. Moreover, the ability of modern HERV-K viruses to proceed through reverse transcription and package RT-DNA genomes suggests a higher level of replication competency than was previously understood, and it may be relevant in HERV-K-associated human diseases.ImportanceRetroviral elements comprise at least 8% of the human genome. Of all the endogenous retroviruses, HERV-K viruses are the most intact and biologically active. While a modern infectious HERV-K has yet to be found, HERV-K activation has been associated with cancers, autoimmune diseases, and HIV-1 infection. Thus, determining how this virus family became such a prevalent member of our genome and what it is capable of in its current form are of the utmost importance. Here, we provide evidence that HERV-K viruses currently found in the human genome are able to proceed through reverse transcription and historically utilized a life cycle with a surprising degree of genomic flexibility in which both RNA- and DNA-containing viruses were capable of mediating infection.

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Mouse annexin V genomic organization includes an endogenous retrovirus.

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