@article {Zhang166041, author = {Enjie Zhang and Adam J Bell and Gavin S Wilkie and Nicol{\'a}s M Su{\'a}rez and Chiara Batini and Colin D Veal and Isaac Armend{\'a}riz-Castillo and Rita Neumann and Victoria E Cotton and Yan Huang and David J Porteous and Ruth F Jarrett and Andrew J Davison and Nicola J Royle}, title = {Inherited chromosomally integrated human herpesvirus 6 genomes are ancient, intact and potentially able to reactivate from telomeres}, elocation-id = {166041}, year = {2017}, doi = {10.1101/166041}, publisher = {Cold Spring Harbor Laboratory}, 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 {\textpm}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.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 immune-compromised patients, in particular in organ transplantation and in stem cell therapy.}, URL = {https://www.biorxiv.org/content/early/2017/07/20/166041}, eprint = {https://www.biorxiv.org/content/early/2017/07/20/166041.full.pdf}, journal = {bioRxiv} }