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Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):10434-10439. doi: 10.1073/pnas.1811940115. Epub 2018 Sep 24.

Human Endogenous Retrovirus-K HML-2 integration within RASGRF2 is associated with intravenous drug abuse and modulates transcription in a cell-line model.

Author information

1
Department of Zoology, University of Oxford, Oxford OX1 3PS, United Kingdom.
2
Public Health Laboratories, Department of Microbiology, Hellenic Pasteur Institute, 11527 Athens, Greece.
3
Division of Virology, National Institute for Biological Standards and Control, Potters Bar EN6 3QG, United Kingdom.
4
Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, United Kingdom.
5
Molecular Virology Laboratory, Department of Microbiology, Hellenic Pasteur Institute, 11527 Athens, Greece.
6
Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.
7
Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
8
Medical Research Council-University of Glasgow Centre for Virus Research, Glasgow G61 1QH, United Kingdom.
9
Department of Zoology, University of Oxford, Oxford OX1 3PS, United Kingdom; aris.katzourakis@zoo.ox.ac.uk gmagi@med.uoa.gr.

Abstract

HERV-K HML-2 (HK2) has been proliferating in the germ line of humans at least as recently as 250,000 years ago, with some integrations that remain polymorphic in the modern human population. One of the solitary HK2 LTR polymorphic integrations lies between exons 17 and 18 of RASGRF2, a gene that affects dopaminergic activity and is thus related to addiction. Here we show that this antisense HK2 integration (namely RASGRF2-int) is found more frequently in persons who inject drugs compared with the general population. In a Greek HIV-1-positive population (n = 202), we found RASGRF2-int 2.5 times (14 versus 6%) more frequently in patients infected through i.v. drug use compared with other transmission route controls (P = 0.03). Independently, in a United Kingdom-based hepatitis C virus-positive population (n = 184), we found RASGRF2-int 3.6 times (34 versus 9.5%) more frequently in patients infected during chronic drug abuse compared with controls (P < 0.001). We then tested whether RASGRF2-int could be mechanistically responsible for this association by modulating transcription of RASGRF2 We show that the CRISPR/Cas9-mediated insertion of HK2 in HEK293 cells in the exact RASGRF2 intronic position found in the population resulted in significant transcriptional and phenotypic changes. We also explored mechanistic features of other intronic HK2 integrations and show that HK2 LTRs can be responsible for generation of cis-natural antisense transcripts, which could interfere with the transcription of nearby genes. Our findings suggest that RASGRF2-int is a strong candidate for dopaminergic manipulation, and emphasize the importance of accurate mapping of neglected HERV polymorphisms in human genomic studies.

KEYWORDS:

HERV-K HML-2; RASGRF2; addiction; endogenous retrovirus; persons who inject drugs

PMID:
30249655
PMCID:
PMC6187174
[Available on 2019-04-09]
DOI:
10.1073/pnas.1811940115
[Indexed for MEDLINE]

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