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: https://doi.org/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


1. Ablashi D, Agut H, Alvarez-Lafuente R, Clark DA, Dewhurst S, DiLuca D, et al. Classification of HHV-6A and HHV-6B as distinct viruses. Arch Virol. 2013 Nov 6;159(5):863–870. doi: 10.1007/s00705-013-1902-5 24193951

2. Epstein LG, Shinnar S, Hesdorffer DC, Nordli DR, Hamidullah A, Benn EK, et al. Human herpesvirus 6 and 7 in febrile status epilepticus: the FEBSTAT study. Epilepsia. 2012 Sep;53(9):1481–8. doi: 10.1111/j.1528-1167.2012.03542.x 22954016

3. Ongradi J, Ablashi DV, Yoshikawa T, Stercz B, Ogata M. Roseolovirus-associated encephalitis in immunocompetent and immunocompromised individuals. J Neurovirol. 2017 Feb;23(1):1–19. doi: 10.1007/s13365-016-0473-0 27538995

4. Leibovitch EC, Jacobson S. Evidence linking HHV-6 with multiple sclerosis: an update. Curr Opin Virol. 2014 Dec;9:127–33. doi: 10.1016/j.coviro.2014.09.016 25462444

5. Readhead B, Haure-Mirande JV, Funk CC, Richards MA, Shannon P, Haroutunian V, et al. Multiscale analysis of independent Alzheimer's cohorts finds disruption of molecular, genetic, and clinical networks by human Herpesvirus. Neuron. 2018 Jul 11;99(1):64–82.e7. doi: 10.1016/j.neuron.2018.05.023 29937276

6. Arbuckle JH, Medveczky MM, Luka J, Hadley SH, Luegmayr A, Ablashi D, et al. The latent human herpesvirus-6A genome specifically integrates in telomeres of human chromosomes in vivo and in vitro. Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5563–8. doi: 10.1073/pnas.0913586107 20212114

7. Daibata M, Taguchi T, Sawada T, Taguchi H, Miyoshi I. Chromosomal transmission of human herpesvirus 6 DNA in acute lymphoblastic leukaemia. Lancet. 1998 Aug 15;352(9127):543–4. doi: 10.1016/S0140-6736(05)79251-5 9716063

8. Daibata M, Taguchi T, Nemoto Y, Taguchi H, Miyoshi I. Inheritance of chromosomally integrated human herpesvirus 6 DNA. Blood. 1999 Sep 1;94(5):1545–9. 10477678.

9. Luppi M, Barozzi P, Morris CM, Merelli E, Torelli G. Integration of human herpesvirus 6 genome in human chromosomes. Lancet. 1998 Nov 21;352(9141): 1707–8. doi: 10.1016/S0140-6736(05)61483-3 9853465

10. Torelli G, Barozzi P, Marasca R, Cocconcelli P, Merelli E, Ceccherini-Nelli L, et al. Targeted integration of human herpesvirus 6 in the p arm of chromosome 17 of human peripheral blood mononuclear cells in vivo. J Med Virol. 1995 Jul;46(3):178–88. doi: 10.1002/jmv.1890460303 7561787

11. Arbuckle JH, Pantry SN, Medveczky MM, Prichett J, Loomis KS, Ablashi D, et al. Mapping the telomere integrated genome of human herpesvirus 6A and 6B. Virology. 2013;442(1):3–11. doi: 10.1016/j.virol.2013.03.030 23648233

12. Wallaschek N, Sanyal A, Pirzer F, Gravel A, Mori Y, Flamand L, et al. The telomeric repeats of human Herpesvirus 6A (HHV-6A) are required for efficient virus integration. PLoS Pathog. 2016 May 31;12(5):e1005666. doi: 10.1371/journal.ppat.1005666 27244446

13. Wallaschek N, Sanyal A, Pirzer F, Gravel A, Mori Y, Flamand L, et al. The telomeric repeats of human Herpesvirus 6A (HHV-6A) are required for efficient virus integration. PLoS Pathog. 2016 May 31;12(5):e1005666. doi: 10.1371/journal.ppat.1005666 27244446

14. Wight DJ, Wallaschek N, Sanyal A, Weller SK, Flamand L, Kaufer BB. Viral proteins U41 and U70 of human Herpesvirus 6A are dispensable for telomere integration. Viruses. 2018 Nov 21;10(11):656. doi: 10.3390/v10110656 30469324

15. Borenstein R, Frenkel N. Cloning human herpes virus 6A genome into bacterial artificial chromosomes and study of DNA replication intermediates. Proc Natl Acad Sci U S A. 2009 Nov 10;106(45):19138–43. doi: 10.1073/pnas.0908504106 19858479

16. Prusty BK, Krohne G, Rudel T. Reactivation of chromosomally integrated human herpesvirus-6 by telomeric circle formation. PLoS Genet. 2013 Dec;9(12):e1004033. doi: 10.1371/journal.pgen.1004033 24367281

17. Huang Y, Hidalgo-Bravo A, Zhang E, Cotton VE, Mendez-Bermudez A, Wig G, et al. Human telomeres that carry an integrated copy of human herpesvirus 6 are often short and unstable, facilitating release of the viral genome from the chromosome. Nucleic Acids Res. 2014 Jan;42(1):315–27. doi: 10.1093/nar/gkt840 24057213

18. Endo A, Watanabe K, Ohye T, Suzuki K, Matsubara T, Shimizu N, et al. Molecular and virological evidence of viral activation from chromosomally integrated human herpesvirus 6A in a patient with X-linked severe combined immunodeficiency. Clin Infect Dis. 2014 Aug 15;59(4):545–8. doi: 10.1093/cid/ciu323 24803376

19. Gravel A, Hall CB, Flamand L. Sequence analysis of transplacentally acquired human herpesvirus 6 DNA is consistent with transmission of a chromosomally integrated reactivated virus. J Infect Dis. 2013 May 15;207(10):1585–89. doi: 10.1093/infdis/jit060 23408849

20. Gulve N, Frank C, Klepsch M, Prusty BK. Chromosomal integration of HHV-6A during non-productive viral infection. Sci Rep. 2017 Mar 30;7(1):512. doi: 10.1038/s41598-017-00658-y 28360414

21. Gravel A, Dubuc I, Morissette G, Sedlak RH, Jerome KR, Flamand L. Inherited chromosomally integrated human herpesvirus 6 as a predisposing risk factor for the development of angina pectoris. Proc Natl Acad Sci U S A. 2015 Jun 30;112(26):8058–63. doi: 10.1073/pnas.1502741112 26080419

22. Moustafa A, Xie C, Kirkness E, Biggs W, Wong E, Turpaz Y, et al. The blood DNA virome in 8,000 humans. PLoS Pathog. 2017 Mar 22;13(3):e1006292. doi: 10.1371/journal.ppat.1006292 28328962

23. Telford M, Navarro A, Santpere G. Whole genome diversity of inherited chromosomally integrated HHV-6 derived from healthy individuals of diverse geographic origin. Sci Rep. 2018 Feb 22;8:3472. doi: 10.1038/s41598-018-21645-x 29472617

24. Liu S, Huang S, Chen F, Zhao L, Yuan Y, Francis SS, et al. Genomic analyses from non-invasive prenatal testing reveal genetic associations, patterns of viral infections, and Chinese population history. Cell. 2018 Oct 4;175(2):347–59.e14. doi: 10.1016/j.cell.2018.08.016 30290141

25. Saito K, Nishida KM, Mori T, Kawamura Y, Miyoshi K, Nagami T, et al. Specific association of Piwi with rasiRNAs derived from retrotransposon and heterochromatic regions in the Drosophila genome. Genes Dev. 2006 Aug 15;20(16):2214–22. doi: 10.1101/gad.1454806 16882972

26. Tatsuke T, Sakashita K, Masaki Y, Lee JM, Kawaguchi Y, Kusakabe T. The telomere-specific non-LTR retrotransposons SART1 and TRAS1 are suppressed by Piwi subfamily proteins in the silkworm, Bombyx mori. Cell Mol Biol Lett. 2010;15(1):118–33. doi: 10.2478/s11658-009-0038-9 19943120

27. Parrish NF, Fujino K, Shiromoto Y, Iwasaki YW, Ha H, Xing J, et al. PiRNAs derived from ancient viral processed pseudogenes as transgenerational sequence-specific immune memory in mammals. RNA. 2015 Oct;21(10):1691–703. doi: 10.1261/rna.052092.115 26283688

28. Whitfield ZJ, Dolan PT, Kunitomi M, Tassetto M, Seetin MG, Oh S, et al. The diversity, structure, and function of heritable adaptive immunity sequences in the Aedes aegypti genome. Curr Biol. 2017 Nov 20;27(22):3511–3511-19.e7. doi: 10.1016/j.cub.2017.09.067 29129531

29. Linardopoulou EV, Williams EM, Fan Y, Friedman C, Young JM, Trask BJ. Human subtelomeres are hot spots of interchromosomal recombination and segmental duplication. Nature. 2005 Sep 1;437(7055):94–100. doi: 10.1038/nature04029 16136133

30. Stephens M, Scheet P. Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation. Am J Hum Genet. 2005 Mar;76(3):449–62. doi: 10.1086/428594 15700229

31. Genomes Project C, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, et al. A global reference for human genetic variation. Nature. 2015 Oct 1;526(7571):68–74. doi: 10.1038/nature15393 26432245

32. Miura H, Kawamura Y, Hattori F, Kozawa K, Ihira M, Ohye T, et al. Chromosomally integrated human herpesvirus 6 in the Japanese population. J Med Virol. 2018 Oct;90(10):1636–42. doi: 10.1002/jmv.25244 29905966

33. Nielsen R, Slatkin M. An introduction to population genetics: theory and applications. Sunderland, Mass: Sinauer Associates; 2013.

34. Wood ML, Royle NJ. Chromosomally integrated human Herpesvirus 6: models of viral genome release from the telomere and impacts on human health. Viruses. 2017 Jul 12;9(7):184. doi: 10.3390/v9070184 28704957

35. Pellett PE, Ablashi DV, Ambros PF, Agut H, Caserta MT, Descamps V, et al. Chromosomally integrated human herpesvirus 6: questions and answers. Rev Med Virol. 2012 May;22(3):144–55. doi: 10.1002/rmv.715 22052666

36. Tuddenham L, Jung JS, Chane-Woon-Ming B, Dolken L, Pfeffer S. Small RNA deep sequencing identifies microRNAs and other small noncoding RNAs from human herpesvirus 6B. J Virol. 2012 Feb;86(3):1638–49. doi: 10.1128/JVI.05911-11 22114334

37. Kawamura Y, Ohye T, Miura H, Ihira M, Kato Y, Kurahashi H, et al. Analysis of the origin of inherited chromosomally integrated human herpesvirus 6 in the Japanese population. J Gen Virol. 2017 Jul 1;98(7):1823–30. doi: 10.1099/jgv.0.000834 28699856

38. Zhang E, Bell AJ, Wilkie GS, Suarez NM, Batini C, Veal CD, et al. Inherited chromosomally integrated human Herpesvirus 6 genomes are ancient, intact, and potentially able to reactivate from telomeres. J Virol. 2017 Oct;91(22):e01137–17. doi: 10.1128/JVI.01137-17 28835501

39. Dowd JB, Bosch JA, Steptoe A, Jayabalasingham B, Lin J, Yolken R, et al. Persistent Herpesvirus Infections and Telomere Attrition Over 3 Years in the Whitehall II Cohort. J Infect Dis. 2017 Sep 1;216(5):565–72. doi: 10.1093/infdis/jix255 28931225

40. Duc C, Yoth M, Jensen S, Mouniee N, Bergman CM, Vaury C, et al. Trapping a somatic endogenous retrovirus into a germline piRNA cluster immunizes the germline against further invasion. Genome Biol. 2019 Jun 21;20(1):127. doi: 10.1186/s13059-019-1736-x 31227013

41. Arkhipova IR, Yushenova IA, Rodriguez F. Giant reverse transcriptase-encoding transposable elements at telomeres. Mol Biol Evol. 2017 Sep 1;34(9):2245–2257. doi: 10.1093/molbev/msx159 28575409

42. Cao F, Li X, Hiew S, Brady H, Liu Y, Dou Y. Dicer independent small RNAs associate with telomeric heterochromatin. RNA. 2009 Jul;15(7):1274–81. doi: 10.1261/rna.1423309 19460867

43. Martens UM, Zijlmans JM, Poon SS, Dragowska W, Yui J, Chavez EA, et al. Short telomeres on human chromosome 17p. Nat Genet. 1998 Jan;18(1):76–80. doi: 10.1038/ng0198-018 9425906

44. Bonaglia MC, Giorda R, Beri S, De Agostini C, Novara F, Fichera M, et al. Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with Phelan/McDermid syndrome. PLoS Genet. 2011 Jul;7(7):e1002173. doi: 10.1371/journal.pgen.1002173 21779178

45. Stratton RF, Dobyns WB, Airhart SD, Ledbetter DH. New chromosomal syndrome: Miller-Dieker syndrome and monosomy 17p13. Hum Genet. 1984;67(2):193–200. doi: 10.1007/BF00273000 6745939

46. Kordyukova M, Olovnikov I, Kalmykova A. Transposon control mechanisms in telomere biology. Curr Opin Genet Dev. 2018 Apr;49:56–62. doi: 10.1016/j.gde.2018.03.002 29571043

47. Koonin EV, Krupovic M. The depths of virus exaptation. Curr Opin Virol. 2018 Aug;31:1–8. doi: 10.1016/j.coviro.2018.07.011 30071360

48. Peddu V, Dubuc I, Gravel A, Xie H, Huang ML, Tenenbaum D, et al. Inherited chromosomally integrated HHV-6 demonstrates tissue-specific RNA expression in vivo that correlates with increased antibody immune response. J Virol. 2019 Dec 12;94(1):e01418–19. doi: 10.1128/JVI.01418-19 31597766

49. Hill JA, Magaret AS, Hall-Sedlak R, Mikhaylova A, Huang ML, Sandmaier BM, et al. Outcomes of hematopoietic cell transplantation using donors or recipients with inherited chromosomally integrated HHV-6. Blood. 2017 Aug 24;130(8):1062–9. doi: 10.1182/blood-2017-03-775759 28596425

50. Bonnafous P, Marlet J, Bouvet D, Salame E, Tellier AC, Guyetant S, et al. Fatal outcome after reactivation of inherited chromosomally integrated HHV-6A (iciHHV-6A) transmitted through liver transplantation. Am J Transplant. 2018 Jun;18(6):1548–1551. doi: 10.1111/ajt.14657 29316259

51. Ophinni Y, Palatini U, Hayashi Y, Parrish NF. PiRNA-guided CRISPR-like immunity in eukaryotes. Trends Immunol. 2019 Nov;40(11):998–1010. doi: 10.1016/j.it.2019.09.003 31679813

52. Hirata M, Kamatani Y, Nagai A, Kiyohara Y, Ninomiya T, Tamakoshi A, et al. Cross-sectional analysis of BioBank Japan clinical data: A large cohort of 200,000 patients with 47 common diseases. J Epidemiol. 2017 Mar;27(3S):S9–21. doi: 10.1016/j.je.2016.12.003 28190657

53. Nagai A, Hirata M, Kamatani Y, Muto K, Matsuda K, Kiyohara Y, et al. Overview of the BioBank Japan Project: Study design and profile. J Epidemiol. 2017 Mar;27(3S):S2–8. doi: 10.1016/j.je.2016.12.005 28189464

54. Okada Y, Momozawa Y, Sakaue S, Kanai M, Ishigaki K, Akiyama M, et al. Deep whole-genome sequencing reveals recent selection signatures linked to evolution and disease risk of Japanese. Nat Commun. 2018 Apr 24; 9(1):1631. doi: 10.1038/s41467-018-03274-0 29691385

55. Jun G, Wing MK, Abecasis GR, Kang HM. An efficient and scalable analysis framework for variant extraction and refinement from population-scale DNA sequence data. Genome Res. 2015 Jun;25(6):918–25. doi: 10.1101/gr.176552.114 25883319

56. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009 Jul 15;25(14):1754–60. doi: 10.1093/bioinformatics/btp324 19451168

57. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007 Sep;81(3):559–75. doi: 10.1086/519795 17701901

58. Howie B, Fuchsberger C, Stephens M, Marchini J, Abecasis GR. Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat Genet. 2012 Jul 22;44(8):955–9. doi: 10.1038/ng.2354 22820512

59. Garrison E, Marth G. Haplotype-based variant detection from short-read sequencing. arXiv:1207.3907. 2012 Jul 20. arXiv:1207.3907 [q-bio.GN]. Available from: https://arxiv.org/abs/1207.3907

60. Kumar S, Nei M, Dudley J, Tamura K. MEGA: a biologist-centric software for evolutionary analysis of DNA and protein sequences. Brief Bioinform. 2008 Jul;9(4):299–306. doi: 10.1093/bib/bbn017 18417537

61. Kanai M, Akiyama M, Takahashi A, Matoba N, Momozawa Y, Ikeda M, et al. Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases. Nat Genet. 2018 Mar;50(3):390–400. doi: 10.1038/s41588-018-0047-6 29403010

62. Stephens M, Donnelly P. A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet. 2003 Nov;73(5):1162–9. doi: 10.1086/379378 14574645

63. Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature. 2012 Aug 22;488:471–475. doi: 10.1038/nature11396 22914163

64. Sedlak RH, Cook L, Huang ML, Magaret A, Zerr DM, Boeckh M, et al. Identification of chromosomally integrated human herpesvirus 6 by droplet digital PCR. Clin Chem. 2014 May;60(5):765–72. doi: 10.1373/clinchem.2013.217240 24594780

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