PMID- 32776928
OWN - NLM
STAT- MEDLINE
DCOM- 20200923
LR  - 20221207
IS  - 1553-7404 (Electronic)
IS  - 1553-7390 (Print)
IS  - 1553-7390 (Linking)
VI  - 16
IP  - 8
DP  - 2020 Aug
TI  - Endogenization and excision of human herpesvirus 6 in human genomes.
PG  - e1008915
LID - 10.1371/journal.pgen.1008915 [doi]
LID - e1008915
AB  - Sequences homologous to human herpesvirus 6 (HHV-6) are integrated within the 
      nuclear genome of about 1% of humans, but it is not clear how this came about. It 
      is also uncertain whether integrated HHV-6 can reactivate into an infectious 
      virus. HHV-6 integrates into telomeres, and this has recently been associated 
      with polymorphisms affecting MOV10L1. MOV10L1 is located on the subtelomere of 
      chromosome 22q (chr22q) and is required to make PIWI-interacting RNAs (piRNAs). 
      As piRNAs block germline integration of transposons, piRNA-mediated repression of 
      HHV-6 integration has been proposed to explain this association. In vitro, 
      recombination of the HHV-6 genome along its terminal direct repeats (DRs) leads 
      to excision from the telomere and viral reactivation, but the expected "solo-DR 
      scar" has not been described in vivo. Here we screened for integrated HHV-6 in 
      7,485 Japanese subjects using whole-genome sequencing (WGS). Integrated HHV-6 was 
      associated with polymorphisms on chr22q. However, in contrast to prior work, we 
      find that the reported MOV10L1 polymorphism is physically linked to an ancient 
      endogenous HHV-6A variant integrated into the telomere of chr22q in East Asians. 
      Unexpectedly, an HHV-6B variant has also endogenized in chr22q; two endogenous 
      HHV-6 variants at this locus thus account for 72% of all integrated HHV-6 in 
      Japan. We also report human genomes carrying only one portion of the HHV-6B 
      genome, a solo-DR, supporting in vivo excision and possible viral reactivation. 
      Together these results explain the recently-reported association between 
      integrated HHV-6 and MOV10L1/piRNAs, suggest potential exaptation of HHV-6 in its 
      coevolution with human chr22q, and clarify the evolution and risk of reactivation 
      of the only intact (non-retro)viral genome known to be present in human 
      germlines.
FAU - Liu, Xiaoxi
AU  - Liu X
AUID- ORCID: 0000-0002-1933-8613
AD  - Genome Immunobiology RIKEN Hakubi Research Team, RIKEN Cluster for Pioneering 
      Research and RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
FAU - Kosugi, Shunichi
AU  - Kosugi S
AD  - Laboratory for Statistical and Translational Genetics, RIKEN Center for 
      Integrative Medical Sciences, Yokohama, Japan.
FAU - Koide, Rie
AU  - Koide R
AD  - Genome Immunobiology RIKEN Hakubi Research Team, RIKEN Cluster for Pioneering 
      Research and RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
FAU - Kawamura, Yoshiki
AU  - Kawamura Y
AUID- ORCID: 0000-0003-3942-7098
AD  - Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, 
      Japan.
FAU - Ito, Jumpei
AU  - Ito J
AUID- ORCID: 0000-0003-0440-8321
AD  - Division of Systems Virology, Department of Infectious Disease Control, 
      International Research Center for Infectious Diseases, Institute of Medical 
      Science, The University of Tokyo, Tokyo, Japan.
FAU - Miura, Hiroki
AU  - Miura H
AUID- ORCID: 0000-0002-2847-3374
AD  - Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, 
      Japan.
FAU - Matoba, Nana
AU  - Matoba N
AUID- ORCID: 0000-0001-5329-0134
AD  - Laboratory for Statistical and Translational Genetics, RIKEN Center for 
      Integrative Medical Sciences, Yokohama, Japan.
FAU - Matsuzaki, Motomichi
AU  - Matsuzaki M
AUID- ORCID: 0000-0001-5811-798X
AD  - Statistical Genetics Team, RIKEN Center for Advanced Intelligence Project, Tokyo, 
      Japan.
FAU - Fujita, Masashi
AU  - Fujita M
AD  - Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, 
      Yokohama, Japan.
FAU - Kamada, Anselmo Jiro
AU  - Kamada AJ
AUID- ORCID: 0000-0002-0437-0151
AD  - Genome Immunobiology RIKEN Hakubi Research Team, RIKEN Cluster for Pioneering 
      Research and RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
FAU - Nakagawa, Hidewaki
AU  - Nakagawa H
AD  - Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, 
      Yokohama, Japan.
FAU - Tamiya, Gen
AU  - Tamiya G
AUID- ORCID: 0000-0002-0597-415X
AD  - Statistical Genetics Team, RIKEN Center for Advanced Intelligence Project, Tokyo, 
      Japan.
FAU - Matsuda, Koichi
AU  - Matsuda K
AD  - Laboratory of Molecular Medicine, Institute of Medical Science, The University of 
      Tokyo, Tokyo, Japan.
AD  - Laboratory for Clinical Genome Sequencing, Graduate School of Frontier Sciences, 
      The University of Tokyo, Tokyo, Japan.
FAU - Murakami, Yoshinori
AU  - Murakami Y
AD  - Division of Molecular Pathology, Institute of Medical Science, The University of 
      Tokyo, Tokyo, Japan.
FAU - Kubo, Michiaki
AU  - Kubo M
AUID- ORCID: 0000-0002-0095-2322
AD  - RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
FAU - Aswad, Amr
AU  - Aswad A
AUID- ORCID: 0000-0002-5776-0057
AD  - Institut fur Virologie, Freie Universitat Berlin, Berlin, Germany.
FAU - Sato, Kei
AU  - Sato K
AUID- ORCID: 0000-0003-4431-1380
AD  - Division of Systems Virology, Department of Infectious Disease Control, 
      International Research Center for Infectious Diseases, Institute of Medical 
      Science, The University of Tokyo, Tokyo, Japan.
FAU - Momozawa, Yukihide
AU  - Momozawa Y
AD  - Laboratory for Genotyping Development, RIKEN Center for Integrative Medical 
      Sciences, Yokohama, Japan.
FAU - Ohashi, Jun
AU  - Ohashi J
AD  - Department of Biological Sciences, Graduate School of Science, The University of 
      Tokyo, Tokyo, Japan.
FAU - Terao, Chikashi
AU  - Terao C
AUID- ORCID: 0000-0002-6452-4095
AD  - Laboratory for Statistical and Translational Genetics, RIKEN Center for 
      Integrative Medical Sciences, Yokohama, Japan.
FAU - Yoshikawa, Tetsushi
AU  - Yoshikawa T
AD  - Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, 
      Japan.
FAU - Parrish, Nicholas F
AU  - Parrish NF
AD  - Genome Immunobiology RIKEN Hakubi Research Team, RIKEN Cluster for Pioneering 
      Research and RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
FAU - Kamatani, Yoichiro
AU  - Kamatani Y
AUID- ORCID: 0000-0001-8748-5597
AD  - Laboratory for Statistical and Translational Genetics, RIKEN Center for 
      Integrative Medical Sciences, Yokohama, Japan.
AD  - Laboratory of Complex Trait Genomics, Graduate School of Frontier Sciences, The 
      University of Tokyo, Japan.
LA  - eng
PT  - Journal Article
DEP - 20200810
PL  - United States
TA  - PLoS Genet
JT  - PLoS genetics
JID - 101239074
RN  - 0 (RNA, Small Interfering)
SB  - IM
MH  - Asian People/genetics
MH  - Chromosomes, Human, Pair 22/genetics
MH  - Evolution, Molecular
MH  - *Genome, Human
MH  - Germ-Line Mutation
MH  - Herpesvirus 6, Human/*genetics
MH  - Humans
MH  - Polymorphism, Single Nucleotide
MH  - RNA, Small Interfering/genetics
MH  - *Virus Integration
PMC - PMC7444522
COIS- The authors have declared that no competing interests exist.
EDAT- 2020/08/11 06:00
MHDA- 2020/09/24 06:00
PMCR- 2020/08/10
CRDT- 2020/08/11 06:00
PHST- 2020/04/13 00:00 [received]
PHST- 2020/06/07 00:00 [accepted]
PHST- 2020/08/20 00:00 [revised]
PHST- 2020/08/11 06:00 [pubmed]
PHST- 2020/09/24 06:00 [medline]
PHST- 2020/08/11 06:00 [entrez]
PHST- 2020/08/10 00:00 [pmc-release]
AID - PGENETICS-D-20-00558 [pii]
AID - 10.1371/journal.pgen.1008915 [doi]
PST - epublish
SO  - PLoS Genet. 2020 Aug 10;16(8):e1008915. doi: 10.1371/journal.pgen.1008915. 
      eCollection 2020 Aug.