Endogenization and excision of human herpesvirus 6 in human genomes

Xiaoxi Liu, Shunichi Kosugi, Rie Koide, Yoshiki Kawamura, Jumpei Ito, Hiroki Miura, Nana Matoba, Motomichi Matsuzaki, Masashi Fujita, Anselmo Jiro Kamada, Hidewaki Nakagawa, Gen Tamiya, Koichi Matsuda, Yoshinori Murakami, Michiaki Kubo, Amr Aswad, Kei Sato, Yukihide Momozawa, Jun Ohashi, Chikashi TeraoTetsushi Yoshikawa, Nicholas F. Parrish, Yoichiro Kamatani

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


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.

Original languageEnglish
Article numbere1008915
JournalPLoS Genetics
Issue number8
Publication statusPublished - 2020 Aug 10
Externally publishedYes

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research


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