PMID- 28835501 OWN - NLM STAT- MEDLINE DCOM- 20171102 LR - 20220518 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 91 IP - 22 DP - 2017 Nov 15 TI - Inherited Chromosomally Integrated Human Herpesvirus 6 Genomes Are Ancient, Intact, and Potentially Able To Reactivate from Telomeres. LID - 10.1128/JVI.01137-17 [doi] LID - e01137-17 AB - The genomes of human herpesvirus 6A (HHV-6A) and HHV-6B have the capacity to integrate into telomeres, the essential capping structures of chromosomes that play roles in cancer and ageing. About 1% of people worldwide are carriers of chromosomally integrated HHV-6 (ciHHV-6), which is inherited as a genetic trait. Understanding the consequences of integration for the evolution of the viral genome, for the telomere, and for the risk of disease associated with carrier status is hampered by a lack of knowledge about ciHHV-6 genomes. Here, we report an analysis of 28 ciHHV-6 genomes and show that they are significantly divergent from the few modern nonintegrated HHV-6 strains for which complete sequences are currently available. In addition, ciHHV-6B genomes in Europeans are more closely related to each other than to ciHHV-6B genomes from China and Pakistan, suggesting regional variation of the trait. Remarkably, at least one group of European ciHHV-6B carriers has inherited the same ciHHV-6B genome, integrated in the same telomere allele, from a common ancestor estimated to have existed 24,500 +/- 10,600 years ago. Despite the antiquity of some, and possibly most, germ line HHV-6 integrations, the majority of ciHHV-6B (95%) and ciHHV-6A (72%) genomes contain a full set of intact viral genes and therefore appear to have the capacity for viral gene expression and full reactivation.IMPORTANCE Inheritance of HHV-6A or HHV-6B integrated into a telomere occurs at a low frequency in most populations studied to date, but its characteristics are poorly understood. However, stratification of ciHHV-6 carriers in modern populations due to common ancestry is an important consideration for genome-wide association studies that aim to identify disease risks for these people. Here, we present full sequence analysis of 28 ciHHV-6 genomes and show that ciHHV-6B in many carriers with European ancestry most likely originated from ancient integration events in a small number of ancestors. We propose that ancient ancestral origins for ciHHV-6A and ciHHV-6B are also likely in other populations. Moreover, despite their antiquity, all of the ciHHV-6 genomes appear to retain the capacity to express viral genes, and most are predicted to be capable of full viral reactivation. These discoveries represent potentially important considerations in immunocompromised patients, in particular in organ transplantation and in stem cell therapy. CI - Copyright (c) 2017 Zhang et al. FAU - Zhang, Enjie AU - Zhang E AD - Department of Genetics, University of Leicester, Leicester, United Kingdom. FAU - Bell, Adam J AU - Bell AJ AD - MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom. FAU - Wilkie, Gavin S AU - Wilkie GS AD - MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom. FAU - Suarez, Nicolas M AU - Suarez NM AD - MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom. FAU - Batini, Chiara AU - Batini C AD - Department of Health Sciences, University of Leicester, Leicester, United Kingdom. FAU - Veal, Colin D AU - Veal CD AD - Department of Genetics, University of Leicester, Leicester, United Kingdom. FAU - Armendariz-Castillo, Isaac AU - Armendariz-Castillo I AD - Department of Genetics, University of Leicester, Leicester, United Kingdom. FAU - Neumann, Rita AU - Neumann R AD - Department of Genetics, University of Leicester, Leicester, United Kingdom. FAU - Cotton, Victoria E AU - Cotton VE AD - Department of Genetics, University of Leicester, Leicester, United Kingdom. FAU - Huang, Yan AU - Huang Y AD - Department of Genetics, University of Leicester, Leicester, United Kingdom. FAU - Porteous, David J AU - Porteous DJ AD - Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom. FAU - Jarrett, Ruth F AU - Jarrett RF AD - MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom. FAU - Davison, Andrew J AU - Davison AJ AD - MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom. FAU - Royle, Nicola J AU - Royle NJ AD - Department of Genetics, University of Leicester, Leicester, United Kingdom njr@le.ac.uk. LA - eng GR - CZD/16/6/CSO_/Chief Scientist Office/United Kingdom GR - WT097828MF/WT_/Wellcome Trust/United Kingdom GR - CGA/16/31/CSO_/Chief Scientist Office/United Kingdom GR - WT_/Wellcome Trust/United Kingdom GR - MC_UU_12014/3/MRC_/Medical Research Council/United Kingdom GR - G0901657/MRC_/Medical Research Council/United Kingdom GR - MC_UU_12014/12/MRC_/Medical Research Council/United Kingdom PT - Clinical Trial PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20171027 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 SB - IM MH - *Chromosomes, Human/genetics/virology MH - Female MH - *Genome, Human MH - Genome-Wide Association Study MH - Herpesvirus 6, Human/*genetics MH - Humans MH - Male MH - *Quantitative Trait, Heritable MH - *Telomere/genetics/virology MH - Virus Integration/*genetics PMC - PMC5660504 OTO - NOTNLM OT - Generation Scotland OT - ciHHV-6 OT - human herpesvirus 6 OT - integration OT - molecular dating OT - telomere EDAT- 2017/08/25 06:00 MHDA- 2017/11/03 06:00 PMCR- 2017/10/27 CRDT- 2017/08/25 06:00 PHST- 2017/07/10 00:00 [received] PHST- 2017/08/15 00:00 [accepted] PHST- 2017/08/25 06:00 [pubmed] PHST- 2017/11/03 06:00 [medline] PHST- 2017/08/25 06:00 [entrez] PHST- 2017/10/27 00:00 [pmc-release] AID - JVI.01137-17 [pii] AID - 01137-17 [pii] AID - 10.1128/JVI.01137-17 [doi] PST - epublish SO - J Virol. 2017 Oct 27;91(22):e01137-17. doi: 10.1128/JVI.01137-17. Print 2017 Nov 15.