Whole genome diversity of inherited chromosomally integrated HHV-6 derived from healthy individuals of diverse geographic origin

Abstract

Human herpesviruses 6-A and -B (HHV-6A, HHV-6B) are ubiquitous in human populations worldwide. These viruses have been associated with several diseases such as multiple sclerosis, Hodgkin’s lymphoma or encephalitis. Despite of the need to understand the genetic diversity and geographic stratification of these viruses, the availability of complete viral sequences from different populations is still limited. Here, we present nine new inherited chromosomally integrated HHV-6 sequences from diverse geographical origin which were generated through target DNA enrichment on lymphoblastoid cell lines derived from healthy individuals. Integration with available HHV-6 sequences allowed the assessment of HHV-6A and -6B phylogeny, patterns of recombination and signatures of natural selection. Analysis of the intra-species variability showed differences between A and B diversity levels and revealed that the HHV-6B reference (Z29) is an uncommon sequence, suggesting the need for an alternative reference sequence. Signs of geographical variation are present and more defined in HHV-6A, while they appear partly masked by recombination in HHV-6B. Finally, we conducted a scan for signatures of selection in protein coding genes that yielded at least 6 genes (4 and 2 respectively for the A and B species) showing significant evidence for accelerated evolution, and 1 gene showing evidence of positive selection in HHV-6A.

Endogenization and excision of human herpesvirus 6 in human genomes

“…In fact, across the 143,199 bp of non-repetitive viral genome sequence called from WGS data for all four subjects with integrated HHV-6A, there were only two unique nucleotide substitutions. Notably, U27/U43/U83 sequences from HHV-6A sequences from our study are also identical to those from integrated HHV-6A in the genome of a previously-sequenced Chinese subject (HG00657) {Telford, 2018}, and distinct from circulating or integrated HHV-6 sequences derived from subjects in other locations (Figure 3A). Some, but not all, of the HHV-6B sequences were also identical across the three genes concatenated for this tree (Figure 3A).…”

“…Consistent with chromosomal integration, chimeric reads spanning the integration site or hybrid paired-end reads, with one end matching the virus and one end matching the human chromosome, could be found in about half of these subjects. From the globally diverse 1000 Genome Project (1kGP), WGS data from 2,535 subjects was screened and HHV-6 chromosomal integration in 0.44% on the basis of HHV-6-mapping read depth {Telford, 2018}. In the largest study addressing this topic to date, over 140,000 subjects from China were sequenced genome-wide at low depth (0.3x) using cell-free DNA collected for non-invasive prenatal testing {Liu, 2018} (hereafter, Liu et al .).…”

Evaluation of liver failure in a pediatric transplant recipient of a liver allograft with inherited chromosomally integrated HHV‐6B

“…US strains, with one to 10 differences among the 16 single nucleotide polymorphisms highlighted for HHV-6B ( Figure 1A,B). 7,14,18,19 This led us to suggest that the DNA detected in the blood corresponded to iciHHV-6B originated from the liver and unlikely from an endogenous community strain.…”

“…The part of U39 sequenced in the transplanted liver and the plasma of the recipient was compared to published sequences of different HHV-6B and iciHHV-6B strains from different countries. 7,14,18,19 Only the different sequences represented by a reference strain were used to build a phylogenetic tree using the Maximum Likelihood Table 1). These results were compatible with the presence of iciHHV-6B in the donor (≥1 copy per cell).…”

Endogenization and excision of human herpesvirus 6 in human genomes

“…In about half of these subjects, reads spanning the integration site (one end mapping to virus and the other mapping to a human chromosome) were found, consistent with chromosomal integration. From the globally diverse 1000 Genomes Project (1kGP), HHV-6 chromosomal integration was identified in 0.44% of 2,535 subjects on the basis of viral read depth [23]. In the largest study addressing this topic to date, over 140,000 subjects from China were sequenced genome-wide at low depth (0.3x) using cell-free DNA collected for non-invasive prenatal testing [24] (hereafter, Liu et al).…”