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Genomewide screening reveals high levels of insertional polymorphism in the human endogenous retrovirus family HERV-K(HML2): implications for present-day activity.

ABSTRACT: The published human genome sequence contains many thousands of endogenous retroviruses (HERVs) but all are defective, containing nonsense mutations or major deletions. Only the HERV-K(HML2) family has been active since the divergence of humans and chimpanzees; it contains many members that are human specific, as well as several that are insertionally polymorphic (an inserted element present only in some human individuals). Here we perform a genomewide survey of insertional polymorphism levels in this family by using the published human genome sequence and a diverse sample of 19 humans. We find that there are 113 human-specific HERV-K(HML2) elements in the human genome sequence, 8 of which are insertionally polymorphic (11 if we extrapolate to those within regions of the genome that were not suitable for amplification). The average rate of accumulation since the divergence with chimpanzees is thus approximately 3.8 x 10(-4) per haploid genome per generation. Furthermore, we find that the number of polymorphic elements is not significantly different from that predicted by a standard population genetic model that assumes constant activity of the family until the present. This suggests to us that the HERV-K(HML2) family may be active in present-day humans. Active (replication-competent) elements are likely to have inserted very recently and to be present at low allele frequencies, and they may be causing disease in the individuals carrying them. This view of the family from a population perspective rather than a genome perspective will inform the current debate about a possible role of HERV-K(HML2) in human disease.

SUBMITTER: Belshaw R

PROVIDER: S-EPMC1211540 | biostudies-literature | 2005 Oct

REPOSITORIES: biostudies-literature

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Genomewide screening reveals high levels of insertional polymorphism in the human endogenous retrovirus family HERV-K(HML2): implications for present-day activity.

Belshaw Robert R Dawson Anna L A AL Woolven-Allen John J Redding Joanna J Burt Austin A Tristem Michael M

Journal of virology 20051001 19

The published human genome sequence contains many thousands of endogenous retroviruses (HERVs) but all are defective, containing nonsense mutations or major deletions. Only the HERV-K(HML2) family has been active since the divergence of humans and chimpanzees; it contains many members that are human specific, as well as several that are insertionally polymorphic (an inserted element present only in some human individuals). Here we perform a genomewide survey of insertional polymorphism levels in ...[more]

PMID: 16160178

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Project description:UnlabelledHuman endogenous retroviruses (HERV) make up 8% of the human genome. While the youngest of these retroviruses, HERV-K(HML-2), termed HK2, is able to code for all viral proteins and produce virus-like particles, it is not known if these virus particles package and transmit HK2-related sequences. Here, we analyzed the capacity of HK2 for packaging and transmitting HK2 sequences. We created an HK2 probe, termed Bogota, which can be packaged into HK2 viruses, and transfected it into cells that make HK2 particles. Supernatants of the transfected cells, which contained HK2 viral particles, then were added to target cells, and the transmissibility of the HK2 Bogota reporter was tracked by G418 resistance. Our studies revealed that contemporary HK2 virions produced by some teratocarcinoma and breast cancer cell lines, as well as by peripheral blood lymphocytes from lymphoma patients, can package HK2 Bogota probes, and these viruses transmitted these probes to other cells. After transmission, HK2 Bogota transcripts undergo reverse transcription, a step impaired by antiretroviral agents or by introduction of mutations into the probe sequences required for reverse transcription. HK2 viruses were more efficiently transmitted in the presence of HK2 Rec or HIV-1 Tat and Vif. Transmitted Bogota probes formed episomes but did not integrate into the cellular genome. Resistance to integration might explain the relatively low number of HK2 insertions that were acquired during the last 25 million years of evolution. Whether transient transmission of modern HK2 sequences, which encode two putative oncoproteins, can lead to disease remains to be studied.ImportanceRetroviruses invaded the genome of human ancestors over the course of millions of years, yet these viruses generally have been inactivated during evolution, with only remnants of these infectious sequences remaining in the human genome. One of these viruses, termed HK2, still is capable of producing virus particles, although these particles have been regarded as being noninfectious. Using a genetic probe derived from HK2, we have discovered that HK2 viruses produced in modern humans can package HK2 sequences and transmit them to various other cells. Furthermore, the genetic sequences packaged in HK2 undergo reverse transcription. The transmitted probe circularized in the cell and failed to integrate into the cellular genome. These findings suggest that modern HK2 viruses can package viral RNA and transmit it to other cells. Contrary to previous views, we provide evidence of an extracellular viral phase of modern HK2 viruses. We have no evidence of sustained, spreading infection.

Project description:Endogenous retroviruses are the remnants of past retroviral infections that are scattered within mammalian genomes. In humans, most of these elements are old degenerate sequences that have lost their coding properties. The HERV-K(HML2) family is an exception: it recently amplified in the human genome and corresponds to the most active proviruses, with some intact open reading frames and the potential to encode viral particles. Here, using a reconstructed consensus element, we show that HERV-K(HML2) proviruses are able to inhibit Tetherin, a cellular restriction factor that is active against most enveloped viruses and acts by keeping the viral particles attached to the cell surface. More precisely, we identify the Envelope protein (Env) as the viral effector active against Tetherin. Through immunoprecipitation experiments, we show that the recognition of Tetherin is mediated by the surface subunit of Env. Similar to Ebola glycoprotein, HERV-K(HML2) Env does not mediate Tetherin degradation or cell surface removal; therefore, it uses a yet-undescribed mechanism to inactivate Tetherin. We also assessed all natural complete alleles of endogenous HERV-K(HML2) Env described to date for their ability to inhibit Tetherin and found that two of them (out of six) can block Tetherin restriction. However, due to their recent amplification, HERV-K(HML2) elements are extremely polymorphic in the human population, and it is likely that individuals will not all possess the same anti-Tetherin potential. Because of Tetherin's role as a restriction factor capable of inducing innate immune responses, this could have functional consequences for individual responses to infection.Tetherin, a cellular protein initially characterized for its role against HIV-1, has been proven to counteract numerous enveloped viruses. It blocks the release of viral particles from producer cells, keeping them tethered to the cell surface. Several viruses have developed strategies to inhibit Tetherin activity, allowing them to efficiently infect and replicate in their host. Here, we show that human HERV-K(HML2) elements, the remnants of an ancient retroviral infection, possess an anti-Tetherin activity which is mediated by the envelope protein. It is likely that this activity was an important factor that contributed to the recent, human-specific amplification of this family of elements. Also, due to their recent amplification, HERV-K(HML2) elements are highly polymorphic in the human population. Since Tetherin is a mediator of innate immunity, interindividual variations among HERV-K(HML2) Env genes may result in differences in immune responses to infection.

Dataset Information

Genomewide screening reveals high levels of insertional polymorphism in the human endogenous retrovirus family HERV-K(HML2): implications for present-day activity.

Publications

Genomewide screening reveals high levels of insertional polymorphism in the human endogenous retrovirus family HERV-K(HML2): implications for present-day activity.

Similar Datasets

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