Contribution of type W human endogenous retroviruses to the human genome: characterization of HERV-W proviral insertions and processed pseudogenes

ABSTRACT The human genome harbors many distinct families of human endogenous retroviruses (HERVs) that stem from exogenous retroviruses that infected the germ line millions of years ago. Many HERV families remain to be investigated. We report in the present study the detailed characterization of the HERV-K14I and HERV-K14CI families as they are represented in the human genome. Most of the 68 HERV-K14I and 23 HERV-K14CI proviruses are severely mutated, frequently displaying uniform deletions of retroviral genes and long terminal repeats (LTRs). Both HERV families entered the germ line ∼39 million years ago, as evidenced by homologous sequences in hominoids and Old World primates and calculation of evolutionary ages based on a molecular clock. Proviruses of both families were formed during a brief period. A majority of HERV-K14CI proviruses on the Y chromosome mimic a higher evolutionary age, showing that LTR-LTR divergence data can indicate false ages. Fully translatable consensus sequences encoding major retroviral proteins were generated. Most HERV-K14I loci lack an env gene and are structurally reminiscent of LTR retrotransposons. A minority of HERV-K14I variants display an env gene. HERV-K14I proviruses are associated with three distinct LTR families, while HERV-K14CI is associated with a single LTR family. Hybrid proviruses consisting of HERV-K14I and HERV-W sequences that appear to have produced provirus progeny in the genome were detected. Several HERV-K14I proviruses harbor TRPC6 mRNA portions, exemplifying mobilization of cellular transcripts by HERVs. Our analysis contributes essential information on two more HERV families and on the biology of HERV sequences in general.

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Human Endogenous Retrovirus Family HERV-K(HML-5): Status, Evolution, and Reconstruction of an Ancient Betaretrovirus in the Human Genome

Journal of Virology ◽

10.1128/jvi.78.16.8788-8798.2004 ◽

2004 ◽

Vol 78 (16) ◽

pp. 8788-8798 ◽

Cited By ~ 32

Author(s):

Laurence Lavie ◽

Patrik Medstrand ◽

Werner Schempp ◽

Eckart Meese ◽

Jens Mayer

Keyword(s):

Human Genome ◽

Germ Line ◽

Consensus Sequence ◽

Endogenous Retrovirus ◽

Endogenous Retroviruses ◽

Open Reading Frames ◽

Primer Binding Site ◽

Human Endogenous Retrovirus ◽

New World Primates ◽

Human Endogenous Retroviruses

ABSTRACT The human genome harbors numerous distinct families of so-called human endogenous retroviruses (HERV) which are remnants of exogenous retroviruses that entered the germ line millions of years ago. We describe here the hitherto little-characterized betaretrovirus HERV-K(HML-5) family (named HERVK22 in Repbase) in greater detail. Out of 139 proviruses, only a few loci represent full-length proviruses, and many lack gag protease and/or env gene regions. We generated a consensus sequence from multiple alignment of 62 HML-5 loci that displays open reading frames for the four major retroviral proteins. Four HML-5 long terminal repeat (LTR) subfamilies were identified that are associated with monophyletic proviral bodies, implying different evolution of HML-5 LTRs and genes. Sequence analysis indicated that the proviruses formed approximately 55 million years ago. Accordingly, HML-5 proviral sequences were detected in Old World and New World primates but not in prosimians. No recent activity is associated with this HERV family. We also conclude that the HML-5 consensus sequence primer binding site is identical to methionine tRNA. Therefore, the family should be designated HERV-M. Our study provides important insights into the structure and evolution of the oldest betaretrovirus in the primate genome known to date.

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‘There and back again’: revisiting the pathophysiological roles of human endogenous retroviruses in the post-genomic era

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2012.0504 ◽

2013 ◽

Vol 368 (1626) ◽

pp. 20120504 ◽

Cited By ~ 45

Author(s):

Gkikas Magiorkinis ◽

Robert Belshaw ◽

Aris Katzourakis

Keyword(s):

Human Genome ◽

High Throughput Sequencing ◽

Immune Escape ◽

Genomic Sequence ◽

Sequence Data ◽

Endogenous Retroviruses ◽

Human Endogenous Retroviruses ◽

The Past ◽

Sequencing Technologies ◽

Research Questions

Almost 8% of the human genome comprises endogenous retroviruses (ERVs). While they have been shown to cause specific pathologies in animals, such as cancer, their association with disease in humans remains controversial. The limited evidence is partly due to the physical and bioethical restrictions surrounding the study of transposons in humans, coupled with the major experimental and bioinformatics challenges surrounding the association of ERVs with disease in general. Two biotechnological landmarks of the past decade provide us with unprecedented research artillery: (i) the ultra-fine sequencing of the human genome and (ii) the emergence of high-throughput sequencing technologies. Here, we critically assemble research about potential pathologies of ERVs in humans. We argue that the time is right to revisit the long-standing questions of human ERV pathogenesis within a robust and carefully structured framework that makes full use of genomic sequence data. We also pose two thought-provoking research questions on potential pathophysiological roles of ERVs with respect to immune escape and regulation.

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Role of Human Endogenous Retroviruses in Lymphoma Pathogenesis and a Possible Biomarker of Disease

Blood ◽

10.1182/blood.v112.11.3751.3751 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3751-3751 ◽

Cited By ~ 2

Author(s):

Scott D. Gitlin ◽

Rafael Contreras- Galindo ◽

Mark H. Kaplan ◽

David M. Markovitz

Keyword(s):

Human Genome ◽

Cell Lines ◽

Endogenous Retroviruses ◽

Human Endogenous Retrovirus ◽

Hiv Positive ◽

Human Endogenous Retroviruses ◽

Viral Expression ◽

Very High

Abstract Actively replicating retroviruses entered hominid species millions of years ago and through mutations preventing replication now exist as 8% of the human genome. Active retroviral particles and antigens from the supposedly dormant human endogenous retrovirus, HERV-K (HML2), have been identified in several cancer cell lines. We have recently demonstrated very high RNA titers of HERV-K (HML2) in the plasma of HIV positive individuals by nucleic acid sequence-based amplification (NASBA) and RT-PCR. We now demonstrate very high HERV-K (HML2) RNA titers in the plasma of patients with HIV positive and HIV negative non-Hodgkin lymphoma (NHL) and in Hodgkin Disease (HD), but not in normal individuals. Different copies of HERV-K (HML-2) present throughout the human genome exist as Type 1 viruses which encode a new oncoprotein, NP9, or as Type 2 viruses which encode a functional envelope (env) and express the Rec oncoprotein. Both Types 1 and 2 viruses appear in NHLs but only Type 1 appears in the plasma of those with HD. HERV-K (HML2) Env and Gag proteins, Env and Gag RNA, and Reverse Transcriptase (RT) activity are isolated from patients with a variety of NHLs, but not in normal controls or in patients with non-malignant diseases. Viral titers dramatically decrease, up to an approximately 7.5 log drop, when patients with NHL or HD go into remission following treatment. To further establish the presence of functional viruses in NHL and HD, immuno-gold electron microscopy allowed demonstration of HERV-K (HML2) particles in the plasma of lymphoma patients. Preliminary analysis of the effect of antiretroviral agents on cell lines infected with HERV-K (HML2) demonstrate a drug class-specific reduction in viral expression at drug concentration levels that range from 0.125 – 1 mcg/mL. In conclusion, we have demonstrated evidence that human endogenous retroviruses are found in the plasma of patients with NHL and HD, suggesting that these viruses, previously presumed to be inactive, may play a role in lymphoma pathogenesis. The observation that viral expression parallels declines in disease activity with treatment of disease may allow use of HERV-K (HML2) expression as a biomarker of lymphoma activity. The role of the HERV-K (HML2)-encoded oncoproteins in disease pathogenesis is under study, as is the potential role of antiretroviral therapy for these malignancies.

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Characterization of Seven Processed Pseudogenes of Nucleophosmin/B23 in the Human Genome

DNA and Cell Biology ◽

10.1089/dna.1993.12.149 ◽

1993 ◽

Vol 12 (2) ◽

pp. 149-156 ◽

Cited By ~ 13

Author(s):

QING-RONG LIU ◽

PUI K. CHAN

Keyword(s):

Human Genome ◽

Processed Pseudogenes

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Genome-Wide Characterization of Zebrafish Endogenous Retroviruses Reveals Unexpected Diversity in Genetic Organizations and Functional Potentials

Microbiology Spectrum ◽

10.1128/spectrum.02254-21 ◽

2021 ◽

Author(s):

Jun Bai ◽

Zuo-zhen Yang ◽

Hao Li ◽

Yun Hong ◽

Dong-dong Fan ◽

...

Keyword(s):

Human Genome ◽

Endogenous Retroviruses ◽

Genetic Evolution ◽

Past Infection ◽

Genome Wide ◽

New Frontier

Endogenous retroviruses (ERVs) are relics of past infection that constitute up to 8% of the human genome. Understanding the genetic evolution of the ERV family and the interplay of ERVs and encoded RNAs and proteins with host function has become a new frontier in biology.

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