Endogenization and excision of human herpesvirus 6 in human genomes

Autoři: Xiaoxi Liu aff001;  Shunichi Kosugi aff002;  Rie Koide aff001;  Yoshiki Kawamura aff003;  Jumpei Ito aff004;  Hiroki Miura aff003;  Nana Matoba aff002;  Motomichi Matsuzaki aff005;  Masashi Fujita aff006;  Anselmo Jiro Kamada aff001;  Hidewaki Nakagawa aff006;  Gen Tamiya aff005;  Koichi Matsuda aff007;  Yoshinori Murakami aff009;  Michiaki Kubo aff010;  Amr Aswad aff011;  Kei Sato aff004;  Yukihide Momozawa aff012;  Jun Ohashi aff013;  Chikashi Terao aff002;  Tetsushi Yoshikawa aff003;  Nicholas F. Parrish aff001;  Yoichiro Kamatani aff002
Působiště autorů: Genome Immunobiology RIKEN Hakubi Research Team, RIKEN Cluster for Pioneering Research and RIKEN Center for Integrative Medical Sciences, Yokohama, Japan aff001;  Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan aff002;  Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Japan aff003;  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 aff004;  Statistical Genetics Team, RIKEN Center for Advanced Intelligence Project, Tokyo, Japan aff005;  Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan aff006;  Laboratory of Molecular Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan aff007;  Laboratory for Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan aff008;  Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan aff009;  RIKEN Center for Integrative Medical Sciences, Yokohama, Japan aff010;  Institut für Virologie, Freie Universität Berlin, Berlin, Germany aff011;  Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan aff012;  Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan aff013;  Laboratory of Complex Trait Genomics, Graduate School of Frontier Sciences, The University of Tokyo, Japan aff014
Vyšlo v časopise: Endogenization and excision of human herpesvirus 6 in human genomes. PLoS Genet 16(8): e32767. doi:10.1371/journal.pgen.1008915
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008915


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.

Klíčová slova:

Genome-wide association studies – Genomics – Haplotypes – Human genomics – Chromosomes – Phylogenetic analysis – Telomeres – Viral genomics


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