Insertional polymorphisms of full-length endogenous retroviruses in humans

Abstract

Human endogenous retrovirus K (HERV-K) is distinctive among the retroviruses in the human genome in that many HERV-K proviruses were inserted into the human germline after the human and chimpanzee lineages evolutionarily diverged [1, 2]. However, all full-length endogenous retroviruses described to date in humans are sufficiently old that all humans examined were homozygous for their presence [1]. Moreover, none are intact; all have lethal mutations [1, 3, 4]. Here, we describe the first endogenous retroviruses in humans for which both the full-length provirus and the preintegration site alleles are shown to be present in the human population today. One provirus, called HERV-K113, was present in about 30% of tested individuals, while a second, called HERV-K115, was found in about 15%. HERV-K113 has full-length open reading frames (ORFs) for all viral proteins and lacks any nonsynonymous substitutions in amino acid motifs that are well conserved among retroviruses. This is the first such endogenous retrovirus identified in humans. These findings indicate that HERV-K remained capable of reinfecting humans through very recent evolutionary times and that HERV-K113 is an excellent candidate for an endogenous retrovirus that is capable of reinfecting humans today.

Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

“…A major trigger of the Aza-induced viral defense response appears to be bidirectional transcription of ERVs that are known to fold into dsRNA secondary structures. ERVs, representing more than 8% of the human genome (Bannert and Kurth, 2004;Tristem, 2000), integrated into the genome of mammals between 0.1 and 40 million years ago via exogenous retroviral infections of germ cells (Egan et al, 2004;Turner et al, 2001). Most ERV genes are non-functional due to DNA recombination, mutations and deletions, but some produce functional proteins including group-specific antigen (gag), polymerase (pol) with reverse transcriptase (RT) and the envelope (env) surface unit (SU) with a transmembrane immunosuppressive-like peptide (Mi et al, 2000) (Blaise et al, 2005;de Parseval et al, 2003;Villesen et al, 2004).…”

Large-scale DNA editing of retrotransposons accelerates mammalian genome evolution

“…We thus expected to find that editing has had a significant role also in primate genome evolution. We applied our method to several human endogenous retro virus (HERV) elements, including HERV-K, a retrotransposon family that was shown to be recently active [27][28][29][30] , and found editing in hundreds of elements in both human and chimpanzee (mostly in HERV-K and HERV-9; Table 1; Supplementary Table S2 and Supplementary Fig. S7).…”

Regulation of the Human Endogenous Retrovirus K (HML-2) Transcriptome by the HIV-1 Tat Protein

“…K109 and K113, also likely candidates for replication competence (76,77,79,80), had RPKM values below our limit of detection or were not able to be analyzed in this study, respectively. K113 is the most recent germ line integration known (10,76), with an allele frequency of ϳ16% in the population (10,76); thus, it is not yet fixed in the human population. As such, it is possible that K113 is not present in the genome of the PBL donor.…”

“…Interestingly, a limited number are still active at both the transcriptional and translational levels, with HERV-K (HML-2) being the prime example [HERV-K (HML-2) is a subgroup of HERV-K] (4,(7)(8)(9). This group of retroviruses is one of the most recent entrants into the human genome, with some proviruses having integrated either by reinfection or by intracellular transposition within the last 200,000 years, and they are the only HERVs with conserved and potentially functional open reading frames (ORFs) for all viral proteins (6,(9)(10)(11)(12). Thousands of HERV-K (HML-2) solo LTRs are found in the human genome, along with approximately 91 proviruses (4,9), some of which may encode the basic retroviral proteins and the accessory, putative oncogenes np9 and rec (4,(13)(14)(15)(16).…”

“…It appears that expression depends upon individual host factors, like ethnicity (10,21,22,24), cell populations (18,25,26), and tissue types (27)(28)(29). Additionally, external stimuli, such as infections, viral transactivators, chemical exposures, cytokines, hormones, and inflammation, can induce expression of these proviruses (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46).…”