Variation in human herpesvirus 6B telomeric integration, excision and transmission between tissues and individuals
- University of Leicester, United Kingdom
- MRC-University of Glasgow Centre for Virus Research, United Kingdom
- University of Groningen, Netherlands
- University of Manchester, United Kingdom
- Centre hospitalier de l'Université Laval, Canada
Abstract
Human herpesviruses 6A and 6B (HHV-6A/6B) are ubiquitous pathogens that persist lifelong in latent form and can cause severe conditions upon reactivation. They are spread by community-acquired infection of free virus (acqHHV6A/6B) and by germline transmission of inherited chromosomally-integrated HHV-6A/6B (iciHHV-6A/6B) in telomeres. We exploited a hypervariable region of the HHV-6B genome to investigate the relationship between acquired and inherited virus and revealed predominantly maternal transmission of acqHHV-6B in families. Remarkably, we demonstrate that some copies of acqHHV-6B in saliva from healthy adults gained a telomere, indicative of integration and latency, and that the frequency of viral genome excision from telomeres in iciHHV-6B carriers is surprisingly high and varies between tissues. In addition, newly formed short telomeres generated by partial viral genome release are frequently lengthened, particularly in telomerase-expressing pluripotent cells. Consequently, iciHHV-6B carriers are mosaic for different iciHHV-6B structures, including circular extra-chromosomal forms that have the potential to reactivate. Finally, we show transmission of an HHV-6B strain from an iciHHV-6B mother to her non-iciHHV-6B son. Altogether we demonstrate that iciHHV-6B can readily transition between telomere-integrated and free virus forms.
Data availability
Sequencing data have been deposited in GenBank under accession numbers: MW049313-MW049327.The HHV6 explorer is freely available at https://www.hhv6explorer.org/ and so The source code for the HHV6 explorer and HHV6 counter are available at https://github.com/colinveal/HHV6-Explorer.Other data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
Biotechnology and Biological Sciences Research Council (MIBTP 1645656)
- Michael L Wood
Medical Research Council (G0901657)
- Nicola J Royle
HHV-6 Foundation (Pilot grant)
- Nicola J Royle
Canadian Institutes of Health Research (MOP 123214)
- Louis Flamand
European Commission (FP7-242209- BIOSTAT-CHF)
- Adriaan A Voors
Medical Research Council (MC_UU_12014/3)
- Andrew J Davison
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The study was conducted in accordance with the Declaration of Helsinki and with approval by the relevant ethics committees as follows:The University of Leicester's Research Ethics Committee (refs: 10553-njr-genetics; njr-61d3).The BIOSTAT-CHF study was approved by the relevant ethics committee in each centre, all participants gave their written, informed consent to participate (Voors et al, 2016).
Reviewing Editor
- Melanie M Brinkmann, Technische Universität Braunschweig, Germany
Publication history
- Received: May 17, 2021
- Preprint posted: June 8, 2021 (view preprint)
- Accepted: September 20, 2021
- Accepted Manuscript published: September 21, 2021 (version 1)
- Version of Record published: October 5, 2021 (version 2)
Copyright
© 2021, Wood et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Variation in human herpesvirus 6B telomeric integration, excision and transmission between tissues and individuals
eLife 10:e70452.
https://doi.org/10.7554/eLife.70452
Further reading
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The replication checkpoint is essential for accurate DNA replication and repair, and maintenance of genomic integrity when a cell is challenged with genotoxic stress. Several studies have defined the complement of proteins that change subcellular location in the budding yeast Saccharomyces cerevisiae following chemically induced DNA replication stress using methyl methanesulfonate (MMS) or hydroxyurea (HU). How these protein movements are regulated remains largely unexplored. We find that the essential checkpoint kinases Mec1 and Rad53 are responsible for regulating the subcellular localization of 159 proteins during MMS-induced replication stress. Unexpectedly, Rad53 regulation of the localization of 52 proteins is independent of its known kinase activator Mec1, and in some scenarios independent of Tel1 or the mediator proteins Rad9 and Mrc1. We demonstrate that Rad53 is phosphorylated and active following MMS exposure in cells lacking Mec1 and Tel1. This noncanonical mode of Rad53 activation depends partly on the retrograde signaling transcription factor Rtg3, which also facilitates proper DNA replication dynamics. We conclude that there are biologically important modes of Rad53 protein kinase activation that respond to replication stress and operate in parallel to Mec1 and Tel1.
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Unlike single-gene mutations leading to Mendelian conditions, common human diseases are likely to be emergent phenomena arising from multilayer, multiscale and highly interconnected interactions. Atrial and ventricular septal defects are the most common forms of cardiac congenital anomalies in humans. Atrial septal defects (ASD) show an open communication between left and right atria postnatally, potentially resulting in serious hemodynamic consequences if untreated. A milder form of atrial septal defect, patent foramen ovale (PFO), exists in about one quarter of the human population, strongly associated with ischaemic stroke and migraine. The anatomic liabilities and genetic and molecular basis of atrial septal defects remain unclear. Here, we advance our previous analysis of atrial septal variation through quantitative trait locus (QTL) mapping of an advanced intercross line (AIL) established between the inbred QSi5 and 129T2/SvEms mouse strains, that show extremes of septal phenotypes. Analysis resolved 37 unique septal QTL with high overlap between QTL for distinct septal traits and PFO as a binary trait. Whole genome sequencing of parental strains and filtering identified predicted functional variants, including in known human congenital heart disease genes. Transcriptome analysis of developing septa revealed downregulation of networks involving ribosome, nucleosome, mitochondrial and extracellular matrix biosynthesis in the 129T2/SvEms strain, potentially reflecting an essential role for growth and cellular maturation in septal development. Analysis of variant architecture across different gene features, including enhancers and promoters, provided evidence for involvement of non-coding as well as protein coding variants. Our study provides the first high resolution picture of genetic complexity and network liability underlying common congenital heart disease, with relevance to human ASD and PFO.
