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

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.

Keywords: genomics; human herpesvirus 6; paleovirology; phylogenetics; telomere biology.

Fig. 1.

(A) HHV-6A subtree consisting of 13 circulating HHV-6A and 38 iciHHV-6A sequences. Gray numbers at each node represent posterior probabilities, showing only those with >0.80. Green labels represent endogenous iciHHV-6, whereas blue labels represent circulating infectious viruses. Where available, confirmation of the chromosomal location of iciHHV-6 is indicated with red labels. Gray text at each tip describes the geographical source of the sequence as well as the ethnicity of the patient where this information was available. Black labels indicate known reference strains of HHV-6A. Note that the long branch of KT895199.1 means that we cannot be confident about its placement due to evidence of long-branch attraction from the ML tree (supplementary fig. S2, Supplementary Material online). (B) HHV-6 Bayesian phylogenetic tree reconstructed using 261 HHV-6 and iciHHV-6 sequences.

Fig. 2.

(A) HHV-6B subtree consisting of 72 circulating HHV-6B and 137 iciHHV-6B sequences. Gray numbers at each node represent posterior probabilities, showing only those with >0.80. Green labels represent endogenous iciHHV-6, whereas blue labels represent circulating infectious viruses. Collapsed nodes are represented as triangles for clarity (expanded in fig. 3). Collapsed nodes are labeled either green, blue, or both depending on whether the clade consists entirely of iciHHV-6B, HHV-6B, or a mixture of both. Where available, confirmation of the chromosomal location of iciHHV-6 is indicated with red labels. Gray text at each tip describes the geographical source of the sequence as well as the ethnicity of the patient where this information was available. Black labels indicate known reference strains of HHV-6B. (B) HHV-6 Bayesian phylogenetic tree reconstructed using 261 HHV-6 and iciHHV-6 sequences.

Fig. 3.

HHV-6B subtrees of clades B1–8 collapsed in figure 2. Gray numbers at each node represent posterior probabilities, showing only those with >0.80. Green labels represent endogenous iciHHV-6, blue labels represent circulating infectious viruses. Where available, confirmation of the chromosomal location of iciHHV-6 is indicated with red labels. Gray text at each tip describes the geographical source of the sequence as well as the ethnicity of the patient where this information was available.

Fig. 4.

(A) The Ancient integration of HHV6B. Part of the HHV-6B tree containing the triplet of sequences derived from a Pakistani, Native American, and Maasai Kenyan. (B) A cartoon cladogram indicating the relationships between modern human populations that diverged as humans migrated out of Africa. The model illustrates that the last common ancestor of the three people carrying a near-identical copy of iciHHV-6B must have been before humans left Africa. The cartoon is a simplified interpretation of the model presented in Nielsen et al. (2017).

Fig. 5.

Integration dating analysis. Chart depicting integration date estimates for iciHHV-6 clades A2–4, B3–6, B8, and the “Out of Africa” (OoA) clade consisting of iciHHV-6B sequences from a Maasai Kenyan, Native American, and Pakistani. Each of the colored bars (yellow, blue, and green) represent estimates calculated using different mutation rates as indicated by the key. The error bars shown represent the age estimates based on the upper and lower limits of the 95% confidence interval of the mean pairwise distances in each clade.