Evolutionary History of Endogenous Human Herpesvirus 6 Reflects Human Migration out of Africa

Author:

Aswad Amr1,Aimola Giulia1,Wight Darren1,Roychoudhury Pavitra23,Zimmermann Cosima1,Hill Joshua234,Lassner Dirk56,Xie Hong23,Huang Meei-Li23,Parrish Nicholas F7,Schultheiss Heinz-Peter6,Venturini Cristina8,Lager Susanne910,Smith Gordon C S10,Charnock-Jones D Stephen10,Breuer Judith8,Greninger Alexander L23,Kaufer Benedikt B1

Affiliation:

1. Institut für Virologie, Freie Universität Berlin, Berlin, Germany

2. Department of Laboratory Medicine, University of Washington, Seattle, WA

3. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Centre, Seattle, WA

4. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA

5. HighTech Center, Vinmec Hospital, Hanoi, Vietnam

6. Institut Kardiale Diagnostik und Therapie, Berlin, Germany

7. Genome Immunobiology RIKEN Hakubi Research Team, RIKEN Cluster for Pioneering Research, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

8. Division of Infection and Immunity, UCL Research Department of Infection, UCL, London, United Kingdom

9. Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden

10. Department of Obstetrics and Gynaecology, Cambridge University, United Kingdom

Abstract

Abstract Human herpesvirus 6A and 6B (HHV-6) can integrate into the germline, and as a result, ∼70 million people harbor the genome of one of these viruses in every cell of their body. Until now, it has been largely unknown if 1) these integrations are ancient, 2) if they still occur, and 3) whether circulating virus strains differ from integrated ones. Here, we used next-generation sequencing and mining of public human genome data sets to generate the largest and most diverse collection of circulating and integrated HHV-6 genomes studied to date. In genomes of geographically dispersed, only distantly related people, we identified clades of integrated viruses that originated from a single ancestral event, confirming this with fluorescent in situ hybridization to directly observe the integration locus. In contrast to HHV-6B, circulating and integrated HHV-6A sequences form distinct clades, arguing against ongoing integration of circulating HHV-6A or “reactivation” of integrated HHV-6A. Taken together, our study provides the first comprehensive picture of the evolution of HHV-6, and reveals that integration of heritable HHV-6 has occurred since the time of, if not before, human migrations out of Africa.

Funder

Einstein International Postdoctoral Award EIPF-Aswad

NIHR UCL/UCLH BRC

Women’s Health theme of the NIHR Cambridge Biomedical Research Centre and the Medical Research Council

HHV-6 foundation

Publisher

Oxford University Press (OUP)

Subject

Genetics,Molecular Biology,Ecology, Evolution, Behavior and Systematics

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