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bioRxiv · 10.1101/166041

Inherited chromosomally integrated human herpesvirus 6 genomes are ancient, intact and potentially able to reactivate from telomeres

Zhang, E. J.·Bell, A. J.·Wilkie, G. S.·Suarez, N. M.·Batini, C.·Veal, C. D.·Armendariz-Castillo, I.·Neumann, R.·Cotton, V. E.·Huang, Y.·Porteous, D. J.·Jarrett, R. F.·Davison, A. J.·Royle, N. J.
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Abstract

Human herpesviruses 6A and 6B (HHV6-A and HHV-6B; species Human herpesvirus 6A and Human herpesvirus 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 non-integrated 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, germline 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.\n\nIMPORTANCEInheritance 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 immune-compromised patients, in particular in organ transplantation and in stem cell therapy.

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Zhang, E. J., Bell, A. J., Wilkie, G. S., Suarez, N. M., Batini, C., Veal, C. D., Armendariz-Castillo, I., Neumann, R., Cotton, V. E., Huang, Y., Porteous, D. J., Jarrett, R. F., Davison, A. J., Royle, N. J.. 2017-07-20. Inherited chromosomally integrated human herpesvirus 6 genomes are ancient, intact and potentially able to reactivate from telomeres. https://doi.org/10.1101/166041

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